2025 WHO指南：不孕症的预防、诊断和治疗

指南妇产科· 妇科疾病 · 2025

© World Health Organization 2025

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Foreword $\ldots$ vi

Acknowledgements viii

Abbreviations $\ldots$ x

Executive summary. $\ldots$ xi

1. Introduction 1

1. Epidemiology and global burden of infertility 1

1.2 The need to strengthen global efforts to prevent, diagnose and treat infertility 4

2. Rationale and methodology $\ldots$ 12

2.1 Rationale. 12

2.2 Goals and objectives .................................................... 12

2.3 Scope. 13

2.4 Target audience $\ldots$ 14

2.5 Guiding principles $\ldots$ 14

2.6 Methods .................................................. 15

3. Approach to evaluation and management of infertility 21

3.1 Objective 22

3.2 Indication .................................................... 22

3.3 Elements of evaluation and management .................................................... 22

4. Prevention of infertility 30

4.1 Information provision on fertility and infertility for the general population. 31

4.2 Information provision for individuals and couples with infertility $\ldots$ 37

4.3 Risk reduction from the use of tobacco $\ldots$ 41

4.4 Risk reduction from sexually transmitted infections $\ldots$ 47

5. Diagnosis of infertility. 51

5. Diagnosis of infertility due to ovulatory dysfunction 52

5.2 Confirmation of ovulation. 52

5.3 Assessment of reproductive hormones 61

5.4 Assessment of ovarian reserve .................................................. 68

5. Diagnosis of infertility due to tubal disease $\ldots$ 76

5.6 Diagnosis of infertility due to uterine cavity disorder $\ldots$ 82

5.7 Diagnosis of infertility due to male factors $\ldots$ 107

5.8 Diagnosis of unexplained infertility 116

6. Treatment of infertility due to ovulatory dysfunction 52

6.1 Treatment of infertility due to ovulatory dysfunction caused by PCOS 120

7. Treatment of infertility due to tubal disease $\ldots$ 143

7.1 Use of surgery or IVF for treatment of tubal disease $\ldots$ 143

7.2 Treatment of hydrosalpinx before IVF $\ldots$ 148

8. Treatment of infertility due to uterine cavity disorder $\ldots$ 154

8.1 Management of uterine septum in females with infertility $\ldots$ 154

9. Treatment of infertility due to male factors $\ldots$ 159

9.1 Use of antioxidants. .................................................. 159

9.2 Treatment of varicocele. 163

10. Treatment of couples with unexplained infertility. 181

10. First-line management of couples with unexplained infertility. 181

10.2 Second-line management of couples with unexplained infertility. 189

10. Third-line management of couples with unexplained infertility $\ldots$ 196

11. Dissemination, local adaptation, implementation, monitoring and evaluation. 201

11. Dissemination. 201

11.2 Local adaptation .................................................... 201

11.3 Implementation .................................................. 202

11.4 Monitoring and evaluation $\ldots$ 202

12. Research gaps, future scope and updating the guideline .................................................... 204

12.1 Research gaps $\ldots$ 204

12.2 Future scope and updating this guideline .................................................... 205

Annex 1. Distribution of the causes of infertility $\ldots$ 207

Annex 2. Members of the GDG .................................................... 212

Annex 3. Members of the ERG .................................................... 214

Annex 4. Summary of declared interests from members of the GDG. 217

Annex 5. Summary of declared interests from members of the ERG $\ldots$ .220

Annex 6. Components of female medical history and physical examination . . . . 224

Annex 7. Components of male medical history and physical examination .................................................. 231

Web Annex A. Evidence to decision tables for approach to the evaluation and management of infertility. https://doi.org/10.2471/B09575.

Web Annex B. Evidence to decision tables for prevention of infertility. https://doi.org/10.2471/B09576.

Web Annex C. Evidence to decision tables for diagnosis of infertility. https://doi.org/10.2471/B09577.

Web Annex D. Evidence to decision tables for the treatment of infertility due to ovulatory dysfunction, tubal disease and uterine cavity disorder. https://doi.org/10.2471/B09589.

Web Annex E. Evidence to decision tables for treatment of infertility due to male factors. https://doi.org/10.2471/B09578.

Web Annex F. Evidence to decision tables for treatment of couples with unexplained infertility. https://doi.org/10.2471/B09579.

List of tables

Table 1. Summary of recommendations and key guidance .................................................. xiii

Table 2.1. Evidence to decision framework .................................................... 17

Table 5.1. Test performance of a single mid-luteal progesterone test .................................................... 55

Table 5.2. Absolute effects on 100 women when different combinations of mid-luteal progesterone test with or without ultrasound are provided .................................................... 55

Table 5.3. Sensitivity and specificity for AFC, AMH and FSH $\ldots$ 70

Table 5.4. Absolute effects on 100 women when AFC, AMH and FSH are provided $\ldots$ 70

Table 5.5. Results for poor response from a systematic review $\ldots$ 70

Table 5.6. Sensitivity and specificity of HyCoSy and HSG $\ldots$ 77

Table 5.7. Comparison of 3D US, SIS, 2D US and HSG with hysteroscopy for the diagnosis of uterine cavity disorders. 82

Table 5.8. Sensitivity and specificity for 3D US and SIS with 95% CIs from one paired study $\ldots$ 85

Table 5.9. Studies comparing 3D US and SIS, and the conditions identified $\ldots$ 85

Table 5.10. Sensitivity and specificity of 3D US and SIS with 95% CIs from unpaired studies $\ldots$ 86

Table 5.11. Included studies comparing 3D and 2D US, and the conditions identified $\ldots$ 90

Table 5.12. Pooled sensitivity and specificity for 3D and 2D US with 95% CIs. 91

Table 5.13. Included studies comparing SIS and 2D US, and conditions identified $\ldots$ 95

Table 5.14. Pooled sensitivity and specificity for SIS and 2D US with 95% CIs. 95

Table 5.15. Included studies comparing HSG and SIS, and conditions identified. 100

Table 5.16. Pooled sensitivity and specificity for HSG and SIS with 95% CIs $\ldots$ 100

Table 5.17. Included studies comparing 2D US and HSG, and conditions identified $\ldots$ 104

Table 5.18. Pooled sensitivity and specificity for 2D US and HSG, with 95% CIs from paired studies ... 104

Table A1.1. General categories of infertility (percentages of couples). 206

Table A1.2. Specific diagnoses of infertility (percentages of couples) $\ldots$ 208

List of figures

Fig. 1.1. Epidemiology and global burden of infertility $\ldots$ 2

Fig. 1.2. Addressing infertility is central to human rights and global health aspirations $\ldots$ 4

Fig. 2.1. Scope and audience $\ldots$ 13

Fig. 2.2. Methodology for guideline development. 15

Fig. 3.1. Elements of evaluation and management $\ldots$ 22

Fig. 4.1. Information on fertility and infertility. 32

Fig. 4.2. Recommendations for preventing infertility included in the guideline 34

Fig. 5.1. Diagnostic algorithm for female-factor and unexplained factor infertility 53

Fig. 5.2. Diagnostic algorithm for the assessment of the uterine cavity. 83

Fig. 5.3. Diagnostic algorithm for male-factor infertility. 108

Fig. 6.1. Management of anovulatory infertility due to PCOS $\ldots$ 120

Fig. 10.1. Treatment algorithm for unexplained infertility $\ldots$ 182

Fig. 12.1. The need to address critical research gaps $\ldots$ 204

Fig. 12.2. Future guideline scope and updates. 205

Fig. A1.1. Causes of infertility. 208

Fig. A1.2. Specific diagnoses of infertility (male) $\ldots$ 210

Fig. A1.3. Specific diagnoses of infertility (female) $\ldots$ 210

Foreword

This first WHO Guideline for the prevention, diagnosis and treatment of infertility is grounded in the principles of equity, scientific rigour and respect for human rights. This guideline responds to the urgent need for evidence-based, person-centred, and universally accessible services for managing infertility as an integral part of sexual and reproductive health. Fertility care – which includes prevention, diagnosis and treatment of infertility – should be accessible to all who need it without stigma or discrimination.

The recommendations in this guideline are informed by the best available scientific evidence, generated through systematic reviews and robust evaluation of the benefits, harms, values, costs, feasibility and impact on equity. The guideline development process was multidisciplinary and inclusive, drawing on the expertise of clinicians, researchers, policy-makers and – critically – the lived experiences of people impacted by infertility.

Despite progress within sexual and reproductive health care, many countries still do not include the prevention, diagnosis or treatment of infertility in health policies, financing and services. There is also a pressing need for more research to better understand the epidemiology, causes and optimal management of infertility, with a particular focus on underserved and at-risk populations.

This guideline covers multiple topics and provides guidance to facilitate the provision of safe and effective services in clinical settings. Of course, infertility also involves decisions far beyond the clinic, including policy, social and non-clinical aspects, all of which must be addressed through evidence-informed interventions. The guideline calls for ongoing evidence generation to inform future editions so that fertility care continues to advance in line with scientific progress and the evolving needs of all people.

By centring equity, science and the imperative to provide fertility care as part of universal health coverage, this guideline aims to support countries in delivering high-quality, equitable and effective health care for all.

![oflL\n](1/parseimages/figurede1250fa8b224004a30b299a2b346e6c_0_7.png)

Dr Tedros Adhanom Ghebreyesus

Director-General, World Health Organization

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Acknowledgements

The World Health Organization (WHO) and the UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP) acknowledges the contributions of many individuals and organizations that supported the development of this guideline.

Sincere thanks to the members of the Guideline Development Group (GDG): Richard Kennedy (Chair; Birmingham Women's and Children's NHS Foundation Trust, United Kingdom of Great Britain and Northern Ireland), Cynthia Farquhar (Co-Chair; Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand), Adam H. Balen (Leeds Teaching Hospitals, Leeds, United Kingdom), Jacky Boivin (School of Psychology, Cardiff University, Cardiff, United Kingdom), Barbara L. Collura (RESOLVE: The National Infertility Association, McLean, United States of America [USA]), Ben Cohlen (Isala Fertility Centre, Zwolle, the Netherlands), Christopher J. De Jonge (University of Minnesota, Minneapolis, USA), Sandro C. Esteves (ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil), Klaudija Kordic (Fertility Europe [Pan-European organisation representing patients' associations], Evere, Belgium), Linda C. Giudice (UCSF School of Medicine, San Francisco, USA), Luca Gianaroli (Reproductive Medicine Unit, SISMER, Bologna, Italy), Carin Huyser (Steve Biko Academic Hospital, University of Pretoria, South Africa), Dmitry Kissin (Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, USA), Tansu Kucuk (Department of Obstetrics and Gynaecology, Acibadem Maslak Hospital, Istanbul, Türkiye), Nalini Mahajan (Department of Reproductive Medicine, Mother and Child Hospital, New Delhi, India), Ragaa Mansour (The Egyptian IVF Center, Ma'adi, Cairo, Egypt), Alfred Murage (Aga Khan University Hospital, Nairobi, Kenya), Willem Ombelet (Genk Institute for Fertility Technology, Genk, Belgium), Allan Pacey (Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom), Guido Pennings (Department of Philosophy and Moral Sciences, Ghent University, Ghent, Belgium), Robert W. Rebar (Homer Stryker School of Medicine, Western Michigan University, Kalamazoo, USA), Richard Reindollar (Geisel School of Medicine, Dartmouth, USA), Roberta Rizzo (University of Ferrara, Ferrara, Italy), Rita Sembuya (Joyce Fertility Support Centre, Kampala, Uganda), Gamal Serour (Al Azhar University, Cairo, Egypt), Basil Tarlatzis (Aristotle University of Thessaloniki, Thessaloniki, Greece), Carla Tatone (University of L'Aquila, L'Aquila, Italy), Lan N. Vuong (University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Viet Nam), Marie Lena Windt De Beer (Tygerberg Academic Hospital, Stellenbosch University, Cape Town, South Africa) and Cong Yali (Health Science Centre, Peking University, Beijing, China).

Sincere thanks also to the following members of the External Review Group (ERG), who peer-reviewed the following sections of the guideline.

Introduction, methodology and approach to the evaluation and management of infertility: Julia Chain (Human Fertilization and Embryology Authority, London, United Kingdom), Muntaha Gharaibeh (Department of Maternal and Child Health, Jordan University of Science and Technology, Irbid, Jordan), Márcia C. Inhorn (Department of Anthropology, Yale University, New Haven, USA), Karla Torres (Centre for Reproductive Rights, New York, USA) and Sheryl Van der Poel (International Health Consultant, Geneva, Switzerland).

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Prevention of infertility: Ivonne J. Diaz Yamal (Department of Gynecology and Obstetrics, Central Military Hospital, Bogota, Colombia), Joyce Harper (Institute for Women's Health, University College London, London, United Kingdom), Tamar Khomasuridze (eastern Europe and Central Asia Regional Office, United Nations Population Fund [UNFPA], Istanbul, Türkiye, Zozo Nene (Department of Obstetrics and Gynaecology, University of Pretoria, Pretoria, South Africa), Promise E. Sefogah (Department of Obstetrics and Gynaecology, University of Ghana Medical School, Accra, Ghana) and Nathalie Vermeulen (European Society of Human Reproduction and Embryology [ESHRE], Strombeek-Bever, Belgium).

Diagnosis of female infertility: Márcia Mendonça Carneiro (Department of Obstetrics and Gynecology, Federal University of Minas Gerais, Minas Gerais, Brazil), Bart C.J.M. Fauser (Reproductive Medicine, University Medical Center Utrecht, Utrecht, the Netherlands), Grigoris F. Grimbizis (Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Thessaloniki, Greece), Qiao Jie (Peking University Health Science Center, Peking University Third Hospital, Beijing, China), Neena Malhotra (Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India) and Trinh The Son (Military Institute of Clinical Embryology and Histology, Hanoi, Viet Nam).

Treatment of female infertility: Amal Benbella (Reproductive Health Hospital, Ibn Sina University Hospital, Rabat, Morocco), Edgar Mocanu (Department of Obstetrics and Gynecology, RCSI University of Medicine and Health Sciences, Dublin, Ireland), Sasha Ottey (PCOS Challenge: The National Polycystic Ovary Syndrome Association, Atlanta, USA) and Maria P. Velez (Division of Reproductive Endocrinology and Infertility, McGill University, Montreal, Canada).

Diagnosis and treatment of male infertility: Mohan S. Kamath (Department of Reproductive Medicine and Surgery, Christian Medical College, Vellore, Tamil Nadu, India), Ameet Patki (Indian Society for Assisted Reproduction, Mumbai, India), Oleg Tishkevich (Centre of Assisted Reproduction, Minsk, Belarus) and Mónica Vazquez-Levin (Institute of Biology and Experimental Medicine – National Scientific and Technical Research Council [IBYME-CONICET], Buenos Aires, Argentina).

Diagnosis and treatment of unexplained infertility: David Adamson (The International Committee Monitoring Assisted Reproductive Technologies, Saratoga, USA), Ben Willem Mol (Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia), Olarik Musigavong (Chaophya Abhaibhubejhr Hospital, Prachin Buri, Thailand), Robert J. Norman (Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia) and Mohamed Youssef (Department of Obstetrics and Gynecology, Cairo University, Cairo, Egypt).

Special thanks go to the Evidence Synthesis Team, who prepared the Grading of Recommendations Assessment, Development and Evaluation (GRADE) systematic reviews, led by Nancy Santesso (Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Canada).

Sincere thanks also go to the guideline methodologist Romina Brignardello-Petersen (Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Canada).

The following WHO staff were members of the Guideline Steering Group or otherwise reviewed or provided specific inputs: Lianne Gonsalves, Ndema Habib, James Kiarie, Gitau Mburu, Aasa Nihlén and Nandita Thatte (Department of Sexual and Reproductive Health and Research), Anna Coates (Department of Gender Equity and Rights), Daniel McCartney, Remco Peters and Teodora Elvira Wi

(Department of Global HIV, Hepatitis and Sexually Transmitted Infections Programmes), Dongbo Fu and Kerstin Schotte (Health Promotion Department), Elena Fidarova (Department of Management of Noncommunicable Diseases), Lisa Rogers (Department of Nutrition and Food Safety), Lorenzo Moja (Department of Health Products Policy and Standards), Meera Thapa Upadhyay (Department of Maternal, Newborn, Child and Adolescent Health and Ageing) and Oleg Kuzmenko (WHO Regional Office for Europe). During the initial stages of guideline planning, the Guideline Steering Group members also included Ian Askew, Rajat Khosla and Thabo Matsaseng (formerly with the Department of Sexual and Reproductive Health and Research).

The following consultants provided input at various stages during the development of the guideline: Paula Amato (Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, USA), Priya Satsalkar-Götz (formerly Independent Consultant, Ghent, Belgium) and Jaime Onofre (Independent Consultant, Brussels, Belgium).

Special thanks to the WHO Guidelines Review Committee (GRC) Secretariat Marion Blacker and Rebekah Thomas-Bosco (Department of Quality Assurance, Norms and Standards) for their valuable feedback at every stage of the guideline development process.

The overall process of generating this guideline was led by Gitau Mburu with the support of James Kiarie and Pascale Allotey (Department of Sexual and Reproductive Health and Research). Therese Curtin provided administrative support.

This work received funding from HRP, a cosponsored programme executed by the WHO.

Abbreviations

2D US two-dimensional ultrasound

3D US three-dimensional ultrasound

4D US four-dimensional ultrasound

AMH anti-Müllerian Hormone

ART assisted reproductive technologies

BMI body mass index

CI confidence interval

COI conflict of interest

DOI declaration of interest

DTA diagnostic test accuracy

E2 estradiol

ERG External Review Group

EtD evidence to decision

FSH follicle-stimulating hormone

GDG Guideline Development Group

GnRH gonadotrophin-releasing hormone

GRADE Grading of Recommendations Assessment, Development and Evaluation

GRC Guidelines Review Committee

HIC high-income country

HOMP high-order multiple pregnancy

HPO hypothalamic-pituitary-ovarian

HSG hysterosalpingogram

HyCoSy hysterosalpingo contrast sonography

ICSI intracytoplasmic sperm injection

IUI intrauterine insemination

IVF in vitro fertilization

LH luteinizing hormone

LMIC low- and middle-income country

LOD laparoscopic ovarian drilling

OHSS ovarian hyperstimulation syndrome

OR odds ratio

OS ovarian stimulation

PCOS polycystic ovary syndrome

PICO population, intervention, comparator, outcome

PRL proclatin

RCT randomized controlled trial

RD risk difference

RR relative risk

SDGs Sustainable Development Goals

SIS saline infusion sonohysterography

S-IUI stimulated intrauterine insemination

STI sexually transmitted infection

T testosterone

TSH thyroid-stimulating hormone

U-IUI unstimulated intrauterine insemination

US ultrasound

WHO World Health Organization

Executive summary

Infertility is a disease of the male and female reproductive system defined as the failure to achieve a pregnancy after 12 months of regular unprotected sexual intercourse. Globally, approximately one in six people of reproductive age experience infertility at some stage in their lives. Lifetime prevalence of infertility does not differ between high-income and low- and middle-income countries, or according to world regions, indicating that infertility is a global public health issue affecting people from all regions and countries.

Individuals and couples have the right to decide the number, timing and spacing of their children; however, there is a gap between desired and actual fertility in many countries, implying constraints to people's ability to realize their reproductive goals because of a variety of reasons that may include infertility. Therefore, addressing infertility is an important part of enabling individuals and couples to achieve their fertility preferences. The provision of high-quality services for family planning, including services to prevent, diagnose and treat infertility, is one of the core elements of reproductive health. However, access to fertility care remains a challenge in most countries. By acting urgently, countries have an opportunity to respond to the need for services for the prevention, diagnosis and treatment of infertility, and mitigate the many inequities in the availability, accessibility, acceptability and quality of fertility care.

This is the first WHO Guideline for the prevention, diagnosis and treatment of infertility, which aims to improve the implementation of evidence-based interventions related to infertility.

The objectives of this guideline are:

$\bullet$ to provide evidence-based recommendations for the prevention, diagnosis and treatment of infertility;

$\bullet$ to provide explicit explanations of all the relevant factors that guided the development of the recommendations in order to maximize the adaptation and implementation of the guideline in different settings;

$\bullet$ to provide a source for countries to adopt, adapt or update their national guidelines for the prevention, diagnosis and treatment of infertility.

This guideline is primarily intended for use by health care professionals (including physicians, embryologists, nurses, midwives, laboratory specialists and other health care providers) involved in the provision of fertility care. This guideline is of interest to policy-makers responsible for the development of national health (and other) policies, services and financing because its recommendations use a population perspective that considers resource considerations, acceptability, feasibility and impact on equity. This guideline may be used to inform the work of professional patient support, as well as advocacy organizations, funding and philanthropic agencies, civil society, professional societies and other nongovernmental organizations that provide social, financial and technical support to reproductive health programmes. The guideline can also be used as an advocacy tool for evidence-based fertility care for everyone.

xii

This guideline was developed according to the methods outlined in the WHO handbook for guideline development. A Guideline Development Group (GDG) was assembled and included a multidisciplinary and regionally diverse set of clinicians, researchers, policy-makers, implementers and representatives of patient groups. Existing or new systematic reviews of the effects of the interventions related to the prevention, diagnosis and treatment of infertility were used to inform the recommendations. The GDG reviewed the evidence and made recommendations. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the evidence and formulate the recommendations. An External Review Group (ERG) reviewed the guideline.

The recommendations in this guideline cover the prevention of infertility, and the diagnosis and treatment of infertility due to female, male or unexplained factors. However, they do not cover all aspects of infertility and fertility care. It is anticipated that subsequent editions of this guideline will expand the scope of recommendations (see section 12.2).

Summary of recommendations

Table 1 presents all the recommendations included in this guideline, including the strength of the recommendation and certainty of the evidence supporting each recommendation. These recommendations are also presented in the relevant chapters of the guideline, accompanied by explanations for the judgements, appropriate diagnostic flow charts and treatment algorithms.

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Table 1. Summary of recommendations and key guidance

![III0。E4\n](1/parseimages/figure31b52d1af28a4d1886732233886b0195_0_2.png)

General approach and management of infertility

Good practice statements on the general approach and management of infertility $\rightarrow$

For males and females being evaluated and managed for infertility, it is good practice to:

![](1/parseimages/figure2fb9de9747644ed49e4e3153b20b3af0_0_6.png) ``` select diagnostic tests based on the clinical findings from the medical history and physical examination to ensure that evaluation is systematic and cost-effective. (Good practice statement) ```

![](1/parseimages/figure2c1165b82b58491f80707df0664faa4c_0_8.png) > listen to individuals and couples, respect their preferences, discuss if psychological and social or peer support is needed, and if needed, provide it or refer patients for it. (Good practice statement)

![](1/parseimages/figure958b060d193f461995403dcd916d9acf_0_10.png) base treatment decisions on benefits and harms, patient values and preferences, feasibility, costs and availability of resources. (Good practice statement)

![](1/parseimages/figure95f9ecfbb08d49599db723c6d42b2542_0_12.png) consider the cost-effectiveness of treatment (e.g. least expensive but effective treatments should be provided initially). (Good practice statement)

![](1/parseimages/figureb18893fd6a2946d2834f0c2e11d82780_0_14.png) discuss the plan for clinical follow-up and management of potential risks that may occur during infertility treatment. (Good practice statement)

![](1/parseimages/figureb638965462524c8299aff889a02cb982_0_16.png) document the outcomes of pregnancies resulting from infertility treatment. (Good practice statement)

![](1/parseimages/figure313a9877f9d54e439d11592dd068d785_0_18.png)

Recommendations for the prevention of infertility

Recommendations for information provision on fertility and infertility

For the general population of reproductive age, WHO suggests providing information about fertility and infertility using low-cost strategies or whenever there is opportunity. (Conditional recommendation, very low certainty of evidence)

Remarks:

$\bullet$ Low-cost strategies may include information in digital or paper format when opportunities occur in schools, at primary health care centres or at reproductive health (contraceptive, sexual health) clinics.

xiv

Recommendations for information provision on fertility and infertility (cont.)

![](1/parseimages/figuref7b729d5301e4f7db2b15a8ce6b9762d_0_2.png) $\bullet$ Information adapted to local contexts and audiences, including how to reduce risk factors for infertility, lifestyle modification, age-related fertility decline/potential, and timely medical consultation, may increase the likelihood of information uptake and beneficial outcomes.

For individuals and couples with infertility, WHO suggests providing low-cost lifestyle advice before and during infertility treatment. (Conditional recommendation, low certainty of evidence)

Remark:

* Lifestyle advice may include advice to change diet, alcohol intake, smoking, physical activity and/or weight management.

Recommendation for risk reduction from tobacco smoking

WHO recommends that brief advice (between 30 seconds and 3 minutes per encounter) be consistently provided by health care providers as a routine practice to all tobacco users accessing any health care settings. (Strong recommendation, moderate certainty of evidence)

Remarks:

* This is an existing WHO recommendation for the general population that also applies to individuals and couples who are planning a pregnancy, attempting to achieve a pregnancy or with infertility, given the association between infertility and current or previous history of smoking.

$\bullet$ Assessment of lifestyle, including the use of tobacco, is part of medical history when evaluating individuals and couples for infertility.

$\bullet$ Brief advice is advice to stop using tobacco – usually taking only a few minutes – given to all tobacco users, usually during a routine consultation or interaction.

$\bullet$ Brief advice should include informing individuals and couples that (i) use of tobacco, particularly smoking, is associated with a higher risk of infertility; (ii) the risk of infertility due to tobacco smoking is higher among women; and (iii) a range of interventions to assist in cessation of tobacco use exist.

$\bullet$ Brief advice should include the 5As: asking about tobacco use; advising to make a quit attempt; assessing readiness to quit; assisting in making a quit plan; and arranging a follow-up. Advice should be tailored or personalized based on individual circumstances.

$\bullet$ All adults interested in quitting smoking should be offered or referred to interventions to assist in tobacco cessation as recommended by existing WHO guidelines for preventing tobacco use uptake, promoting tobacco cessation or diagnosing and treating tobacco dependence.

Recommendation for risk reduction from sexually transmitted infections

Couples and individuals planning or attempting to achieve pregnancy who are accessing any health care settings should be routinely informed about sexually transmitted infections (STIs), including the risk of infertility when STIs are untreated. Couples and individuals should be encouraged to seek prompt care and treatment if they have symptoms of STIs. (Good practice statement)

Remark:

$\bullet$ If symptoms of an STI are present, or if infection is confirmed, WHO guideline recommendations on the management of STIs are available.

![](1/parseimages/figurec7483d22e0fd43d0a0556a9a291f069e_0_5.png) Recommendations for the diagnosis of female-factor infertility

Recommendations for the diagnosis of infertility due to ovulatory dysfunction

For females with infertility but normal findings on history-taking (including regular menstrual cycles) and physical examination, WHO suggests presumptive confirmation of ovulation by measuring the level of mid- luteal serum progesterone rather than performing an ultrasound scan. For females in whom the initial mid-luteal serum progesterone indicates no ovulation, a repeat measurement is suggested to minimize the risk of an inaccurate diagnosis of anovulation. (Conditional recommendation, very low certainty of evidence)

Remarks:

$\bullet$ Mid-luteal serum progesterone levels are assessed approximately 7 days before the expected onset of the next menses, noting that the specific cycle day can vary based on the length of the menstrual cycle.

$\bullet$ A repeat mid-luteal serum progesterone measurement could be performed in a subsequent menstrual cycle, considering the turnaround time for tests and cycle-to-cycle variations.

For females with infertility and suspected anovulation or oligo-ovulation, it is good practice to assess reproductive hormones related to the hypothalamic-pituitary-ovarian (HPO) axis (such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in some clinical presentations, estradiol (E2) and testosterone [T]). Additional testing (e.g. thyroid-stimulating hormone (TSH), prolactin [PRL]) may also be indicated based on the clinical presentation. The choice of diagnostic tests should be based on clinical findings from a comprehensive medical history and physical examination, to ensure that evaluation is systematic and cost-effective. (Good practice statement)

xvi

Recommendations for the diagnosis of infertility due to ovulatory dysfunction (cont.)

For females with infertility in whom other causes of anovulation and oligo- ovulation have been ruled out, WHO suggests that a diagnosis of low ovarian reserve should be based on age rather than diagnostic tests. If ovarian reserve diagnostic testing is conducted, WHO suggests using antral follicle count (AFC), anti-Müllerian hormone (AMH) or day 2 or 3 follicle-stimulating hormone (FSH). (Conditional recommendation, very low certainty of evidence)

Remarks:

$\bullet$ Age is the most important predictor of ovarian reserve. Therefore, ordering an ovarian reserve test in addition to age assessment may not substantially improve the accuracy of diagnosing low ovarian reserve (as assessed by poor response to stimulation). Note that the ability of age to predict ovarian reserve may be limited in some clinical scenarios, such as cases of premature ovarian insufficiency.

* Selection of the test to assess ovarian reserve should be based on relative acceptability, availability and resources in local contexts.

Recommendation for the diagnosis of infertility due to tubal disease $\rightarrow$

For females with infertility and suspected tubal disease, WHO suggests using either hysterosalpingogram (HSG) or hysterosalpingo contrast sonography (HyCoSy) to assess tubal patency. (Conditional recommendation, low certainty of evidence)

Remark:

$\bullet$ When selecting whether to use HSG or HyCoSy to assess tubal patency, consider feasibility, the availability of trained health care providers and the potential for allergy.

Recommendations for the diagnosis of infertility due to uterine cavity disorder

For females with infertility who are suspected to have a uterine cavity disorder, WHO suggests assessing the uterine cavity with saline infusion sonohysterography (SIS) rather than three-dimensional ultrasound (3D US). (Conditional recommendation, low certainty of evidence)

Remark:

$\bullet$ In settings where 3D US is already available within the existing resources, 3D US may be the preferred option.

For females with infertility who are suspected to have a uterine cavity disorder, WHO suggests assessing the uterine cavity with three-dimensional ultrasound (3D US) rather than two-dimensional ultrasound (2D US) where resources are available. (Conditional recommendation, low certainty of evidence)

For females with infertility who are suspected to have a uterine cavity disorder, WHO suggests assessing the uterine cavity with saline infusion sonohysterography (SIS) rather than two-dimensional ultrasound (2D US). (Conditional recommendation, low certainty of evidence)

xvii

Recommendation for the diagnosis of infertility due to uterine cavity disorder (cont.) $\rightarrow$

For females with infertility due to suspected uterine cavity disorder, WHO suggests assessing the uterine cavity with saline infusion sonohysterography (SIS) rather than hysterosalpingogram (HSG). (Conditional recommendation, very low certainty of evidence)

Remark:

$\bullet$ Health care providers may choose to use 2D US rather than HSG when resources are limited. Follow-up would be required for women who are negative on 2D US but still suspected of uterine cavity disorder because of high rates of false negatives.

![](1/parseimages/figure2b27f9815fd04325a5f047764e21ebc1_0_5.png) Recommendations for the diagnosis of male-factor infertility

Recommendation for semen analysis

For males (in couples with infertility) with one or more semen parameters outside the WHO reference ranges, WHO suggests repeating the semen analysis after a minimum of 11 weeks. (Conditional recommendation, very low certainty of evidence)

For males (in couples with infertility) with all semen parameters within the WHO reference ranges, WHO suggests not repeating the semen analysis. (Conditional recommendation, very low certainty of evidence)

Remark:

$\bullet$ The latest edition of the WHO laboratory manual for the examination and processing of human semen provides WHO reference ranges for semen parameters and details about the standardized procedures for semen collection and analysis.

![](1/parseimages/figure45c897896d85416c90eeffb85f715cb5_0_12.png) Recommendation for the diagnosis of unexplained- factor infertility

WHO suggests making a diagnosis of unexplained infertility in a couple when all the following have occurred:

$\bullet$ failure to achieve pregnancy after 12 months of regular unprotected sexual intercourse;

$\bullet$ normal physical examination and medical history in both the male and female;

$\bullet$ presumptive confirmation of ovulation and patent tubes in the female partner; and

$\bullet$ semen parameters that are within the WHO reference ranges in the male partner.

(Conditional recommendation, very low certainty of evidence)

xviii

Recommendations for the treatment of female-factor infertility

Recommendations for the treatment of infertility due to ovulatory dysfunction

For females with infertility due to ovulatory dysfunction caused by polycystic ovary syndrome (PCOS), WHO suggests using letrozole over clomiphene citrate or metformin. Using letrozole alone rather than with metformin is suggested. (Conditional recommendation, low certainty of evidence for letrozole compared to clomiphene citrate, low certainty evidence for letrozole compared with metformin alone and very low certainty of evidence for letrozole compared to letrozole with metformin)

Where off-label use of letrozole is not permitted, use of clomiphene citrate with metformin rather than clomiphene citrate alone or metformin alone is suggested. (Conditional recommendation, moderate certainty of evidence for clomiphene citrate compared to clomiphene with metformin, very low certainty of evidence for clomiphene citrate compared to metformin)

As part of management of polycystic ovary syndrome (PCOS), it is good practice to advise patients on lifestyle interventions such as a healthy diet, regular physical activity and/or weight management. (Good practice statement)

For females with infertility due to ovulatory dysfunction caused by polycystic ovary syndrome (PCOS) who have been unsuccessful with oral pharmacological therapies such as letrozole or clomiphene citrate with metformin, WHO suggests using gonadotrophins over laparoscopic ovarian drilling (LOD). (Conditional recommendation, low certainty of evidence)

For females with infertility due to ovulatory dysfunction caused by polycystic ovary syndrome (PCOS) who have been unsuccessful with pharmacological therapies such as letrozole, clomiphene citrate with metformin or gonadotrophins, WHO suggests in vitro fertilization (IVF) rather than expectant management. (Conditional recommendation, very low certainty of evidence)

For females with infertility due to ovulatory dysfunction caused by hyperprolactinaemia, WHO suggests using cabergoline over bromocriptine. (Conditional recommendation, low certainty of evidence)

Recommendations for the treatment of infertility due to tubal disease

For females aged < 35 years with mild-to-moderate tubal disease (Hull and Rutherford grades I and II), WHO suggests surgery rather than in vitro fertilization (IVF). (Conditional recommendation, very low certainty of evidence)

Remarks:

$\bullet$ After surgery, a reasonable minimum time to wait to achieve pregnancy before pursuing other interventions, such as IVF, is 1 year.

$\bullet$ This recommendation does not apply to females who have had previous tubal sterilization.

xix

Recommendations for the treatment of infertility due to tubal disease (cont.)

For females aged < 35 years with severe tubal disease (Hull and Rutherford grade III), WHO suggests in vitro fertilization (IVF) rather than surgery. (Conditional recommendation, very low certainty of evidence)

Remark:

$\bullet$ This recommendation does not apply to females who have had previous tubal sterilization.

For females aged ≥ 35 years with any tubal disease, WHO suggests in vitro fertilization (IVF) rather than surgery. (Conditional recommendation, very low certainty of evidence)

For females with tubal factor infertility due to hydrosalpinx, WHO suggests either salpingectomy or tubal occlusion before provision of in vitro fertilization (IVF). (Conditional recommendation, very low certainty evidence)

Remark:

$\bullet$ When selecting whether to use salpingectomy or tubal occlusion, consider feasibility, availability of trained health care providers and presence of adhesions.

For females with tubal factor infertility caused by hydrosalpinx, WHO suggests either salpingectomy or tubal occlusion rather than transvaginal aspiration of hydrosalpingeal fluid before provision of in vitro fertilization (IVF). (Conditional recommendation, very low certainty of evidence)

Remark:

$\bullet$ In settings where salpingectomy and tubal occlusion are not available or feasible, transvaginal aspiration may be offered.

Recommendation for the treatment of infertility due to uterine cavity disorder

For females with infertility and uterine septum who have no history of recurrent pregnancy loss, WHO suggests that hysteroscopic septum resection (septoplasty) not be performed. (Conditional recommendation, low certainty of evidence)

Recommendations for the treatment of male-factor infertility

Recommendation on the use of antioxidants

For males with infertility and one or more semen parameters that are outside the WHO reference ranges who are attempting to achieve pregnancy with or without medically assisted reproduction, the WHO infertility Guideline Development Group (GDG) did not make a recommendation for or against the use of antioxidant supplements.

Remark:

$\bullet$ Optimal nutrition is important during the pre-pregnancy period for the couple; however, the effects of antioxidant supplements for males with specific male-factor pathologies in couples with infertility are currently not known.

Recommendations for the treatment of varicocele

For males with infertility and clinical varicocele, WHO suggests surgical or radiological treatment over expectant management. (Conditional recommendation, low certainty of evidence)

Remarks:

* Males with clinical varicocele and semen parameters that are outside the WHO reference ranges are more likely to benefit from receiving treatment for varicocele, compared to men with semen parameters within the WHO reference ranges.

$\bullet$ This recommendation applies to males with varicocele in couples with infertility who are not undergoing treatment with assisted reproductive technology (ART).

For males with infertility undergoing treatment of varicocele, WHO suggests using either surgical or radiological treatment. (Conditional recommendation, very low certainty of evidence)

Remarks:

$\bullet$ When selecting whether to use surgical or radiological treatment, consider feasibility, the availability of trained health care providers and patient preferences regarding the type of treatment procedure.

$\bullet$ This recommendation applies to males with varicocele in couples with infertility who are not undergoing treatment with assisted reproductive technology (ART).

xxi

Recommendations for the treatment of varicocele (cont.)

For males with infertility undergoing surgical treatment of varicocele, WHO suggests using microscopic surgery rather than other surgical procedures.

(Conditional recommendation, very low certainty of evidence)

![](1/parseimages/figure83856068a809400ba177353df6dd4702_0_4.png)

Remarks:

$\bullet$ Subinguinal microsurgery is a common surgical varicoelectomy procedure, while other surgical procedures include non-microscopic open approaches (such as inguinal and retroperitoneal) and laparoscopic methods.

$\bullet$ In settings where the expertise to perform microscopic surgery is not available, other surgical techniques may be used.

$\bullet$ This recommendation applies to males with varicocele in couples with infertility who are not undergoing treatment with assisted reproductive technology (ART).

For males with infertility undergoing non-microscopic surgical treatment of varicocele, WHO suggests using either inguinal or retroperitoneal surgical procedures. (Conditional recommendation, very low certainty of evidence)

Remarks:

$\bullet$ When selecting whether to use an inguinal or retroperitoneal surgical procedure, consider feasibility and the availability of trained health care providers.

$\bullet$ This recommendation applies to males with varicocele in couples with infertility who are not undergoing treatment with assisted reproductive technology (ART).

![](1/parseimages/figure2205fc3125a24262ab737b424fee3d9a_0_13.png) Recommendations for the treatment of unexplained infertility

Recommendations for first-line management of couples with unexplained infertility

For couples with unexplained infertility, WHO suggests expectant management rather than unstimulated intrauterine insemination (U-IUI). (Conditional recommendation, low certainty of evidence)

Remarks:

* Expectant management refers to monitoring the couple with the expectation that pregnancy will be achieved without medical intervention. It includes providing advice on lifestyle and the most fertile days of the menstrual cycle, and monitoring if pregnancy will occur; however, no medical intervention is provided.

$\bullet$ The duration of expectant management was typically 3-6 months in studies informing this recommendation.

xxii

Recommendations for first-line management of couples with unexplained infertility (cont.)

For couples with unexplained infertility, WHO suggests expectant management rather than ovarian stimulation with timed intercourse. (Conditional recommendation, low certainty of evidence)

Remarks:

$\bullet$ Expectant management refers to monitoring the couple with the expectation that pregnancy will be achieved without medical intervention. It includes providing advice on lifestyle and the most fertile days of the menstrual cycle, and monitoring if pregnancy will occur; however, no medical intervention is provided.

$\bullet$ The duration of expectant management was typically 3-6 months in studies informing this recommendation.

Recommendations for second-line management of couples with unexplained infertility $\rightarrow$

For couples with unexplained infertility, where expectant management has been unsuccessful, WHO suggests stimulated intrauterine insemination (S-IUI) with either clomiphene citrate or letrozole. (Conditional recommendation, low certainty of evidence)

Remarks:

$\bullet$ When selecting whether to use clomiphene citrate or letrozole, consider the applicable national laws and regulations related to off-label use of letrozole.

$\bullet$ The optimal number of S-IUI cycles is unknown; in the studies used to inform this recommendation, different numbers of cycles were provided, ranging from one to six, with more recent studies providing three to six cycles.

For couples with unexplained infertility, where expectant management has been unsuccessful, WHO suggests stimulated intrauterine insemination (S-IUI) with either clomiphene citrate or letrozole rather than with gonadotrophins. (Conditional recommendation, very low certainty of evidence)

Remark:

Recommendations for third-line management of unexplained infertility $\rightarrow$

For couples with unexplained infertility, where stimulated intrauterine insemination (S-IUI) has been unsuccessful, WHO suggests in vitro fertilization (IVF) rather than expectant management. (Conditional recommendation, low certainty of evidence)

For couples with unexplained infertility undergoing in vitro fertilization (IVF) after S-IUI has been unsuccessful, WHO recommends using IVF alone rather than IVF with intracytoplasmic sperm injection (ICSI). (Strong recommendation, low certainty of evidence)

Chapter 1 Introduction

This chapter provides background information on infertility, including its epidemiology and the need to strengthen global efforts to prevent, diagnose and treat it.

1.1 Epidemiology and global burden of infertility

Infertility is a disease of the male and female reproductive system, which is defined as the failure to achieve a pregnancy after 12 months of regular unprotected sexual intercourse (1, 2). Infertility can be primary or secondary. Primary infertility is when a pregnancy has never been achieved, and secondary infertility is when at least one prior pregnancy has been achieved. Individuals and couples have the right to decide the number, timing and spacing of their children (3). Persons of full age, without any limitation due to race, nationality or religion, have the right to marry and found a family (4). However, there is a gap between desired and actual fertility in many settings (5), implying constraints to people's ability to realize their reproductive goals because of several reasons that may include infertility. Therefore, addressing infertility is an important part of enabling individuals and couples to achieve their fertility preferences. Addressing infertility will enable individuals and couples to exercise their sexual and reproductive health and rights and achieve their desired family size.

Globally, approximately one in six people of reproductive age experience infertility at some stage in their lives (6). Lifetime prevalence of infertility is 17.5%, while period prevalence is 12.6%. In addition, infertility prevalence does not differ significantly between high-income and low- and middle-income countries (LMICs), or according to world regions, indicating that infertility is a global public health issue affecting people in all regions

and countries (6). Although the overall period and lifetime prevalence is similar across regions, the distribution of the underlying risks of infertility (such as postpartum infections, unsafe abortions and some sexually transmitted infections [STIs]) can vary across countries and regions and potentially cause differences in the patterns of primary versus secondary infertility (6–8). Using different definitions and methodological approaches, the numbers of people affected by infertility were estimated to be 186 million individuals in 2004 (9) and 48.5 million couples in 2010 (10). (See Fig. 1.1).

Classically, each type of infertility can be attributed to congenital or acquired causes (11). The former stem from abnormalities in the development of the genital tract in either males or females (11). Infertility in both males and females can be associated with impairments affecting any portion of the hypothalamic-pituitary-gonadal axis and reproductive organs (i.e. testes, ducts and penis in males, and ovaries, uterus, fallopian tubes, cervix and vagina in females). In general terms, these reproductive impairments are often associated with congenital or acquired abnormalities, genetic aberrations, urogenital infections, malignancies, endocrine disturbances, gonadotoxic exposures, sexual dysfunction, immunological abnormalities, iatrogenic factors and other physiological factors such as age (12, 13). In general, less is known about male causes of infertility than female causes; of those causes that can be identified in the male, fewer are amenable to corrective treatment.

Guideline for the prevention, diagnosis and treatment of infertility

Fig. 1.1. Epidemiology and global burden of infertility

Approximately one in six people of reproductive age experience infertility at some stage in their lives.$^{a}$

![](1/parseimages/figure55f053699c1742a6b869e7adaa7dcf9e_0_4.png) Infertility can be caused by female, male or unexplained factors; sometimes the cause may not be identified during routine investigations. A large WHO multi-country study involving 8500 couples$^{b}$ in 25 countries found that infertility was due to:

![30.6%26.3%18.7%10.8%?Female factorsMale factorsBoth maleNo causefoundalonealoneand femaleMale factor contributes wholly or inpart to 45.1% of infertility cases.\n](1/parseimages/figuree3df6b0f579048109392f2ec771273a5_0_6.png) ![17.5%Estimated lifetimeprevalence ofinfertility12.6%Estimated periodprevalence ofinfertility\n](1/parseimages/figureef4483c4f9fe42f1a1be2606cc622311_0_7.png) Infertility is a global public health issue affecting people in all regions and countries. This is evidenced by the fact that infertility prevalence does not differ by WHO world regions or between high-income countries (HICs) and low- and middle-income countries (LMICs).

Lifetime infertility prevalence in:

![HICS17.8%LMICS16.5%\n](1/parseimages/figureb0421b75993e440597a29cfcfe3e794c_0_10.png) ª See more details in WHO infertility prevalence estimates 1990–2021 (6).

b 13.3% became pregnant in the course of study investigations. See details in Cates et al., 1985 (14) and WHO, 1992 (15).

A large World Health Organization (WHO) multi-country study involving 8500 couples in 25 countries found that infertility was due to female factors alone in 30.6%, both male and female factors in 26.3%, and male factors alone in 18.7% of cases (14, 15). No cause was found in 10.8% of cases (14, 15). The remaining 13.3% became pregnant during investigations. Based on this study, male factors contributed wholly or in part

to 45.1% of infertility cases. In this study, the most common identifiable causes of female infertility included anovulatory and oligo-ovulatory disorders (26.1%), endometriosis (4.8%), pelvic (including uterine) adhesions (14.8%), bilateral tubal blockage (17.7%), acquired tubal abnormalities (11.6%) and hyperprolactinemia (6.7%). In this study, rates of infertility due to tubal causes were higher in LMICs compared to high-income countries (14–16).

1 Introduction

Among males, identifiable causes of infertility included varicocele (13.1%), primary testicular failure (12.0%) and accessory gland infection (7.1%). Abnormal semen parameters (morphology and motility) were identified in 9.7% of males diagnosed with infertility (14). In this study, male factors contributed wholly or in part to 45.1% of infertility cases (14). However, these multi-country data are relatively old and new patterns may have emerged across high-income, middle-income and low-income settings (see Annex 1. Distribution of the causes of infertility).

In the absence of more recent epidemiological studies, there are knowledge gaps and uncertainty regarding the precise proportions of infertility caused by male, female, both male and female or unexplained factors in the general population of reproductive age. Many studies and systematic reviews quantifying the relative contributions of these factors are based on clinic samples (17) in single countries (18) or on samples with restricted inclusion criteria (6), which together with the varying extents of selection and investigation of each partner, makes it difficult to determine an unbiased prevalence of these causes among global populations of reproductive age.

In terms of risk factors, the most consistent predictive factor of infertility is increasing female/ maternal age (19–22). In both males and females, infertility is also associated with lifestyle risk factors such as smoking (23–26), excessive alcohol intake (27, 28), obesity (29), underweight (30), as well as sexually transmitted, reproductive tract, and other pelvic infections (31, 32), although evidence is not equally strong across these factors (33). Exposure to environmental endocrine-disrupting chemicals can interfere with the reproductive system, resulting in poor quantity or quality of gametes, and potentially contributing to infertility (34–37); however, definitive conclusions cannot be made based on the available data (37). Several causal diagnoses may be present simultaneously and may be coincidental or causal (e.g. an STI-induced pathology in both male and female partners). The temporal or geographical

contribution of specific etiological factors, such as postpartum or post-abortion infections, genital tuberculosis, schistosomiasis, iatrogenic causes and female genital mutilation is uncertain. For many etiologies, there are knowledge gaps in the natural history and sequence of intermediate sequelae that lead to infertility. In summary, the relative prevalence of the causes and risk factors for infertility differ from country to country (16) and there is a lack of comprehensive data in many countries.

The possibility for multiple factors to contribute to infertility in a couple, as well as variations in definition, data collection methods and outcomes reported in existing studies, continue to pose measurement challenges (38, 39). Temporal epidemiological trends in infertility may also be modified by global efforts to address STIs, unsafe abortions and other risk factors, as well as demographic trends. Declining total fertility rates (40, 41), rising maternal and paternal age at first birth (42–44) and possible temporal and geographical declines in reported semen parameters (45, 46), could potentially contribute to a greater need for prevention, diagnosis and treatment of infertility; however, the influence of paternal age on fecundity, compared to maternal age (47), is less certain; declines in semen parameters have not been observed universally among all male populations (48) and semen parameters per se are not a reliable diagnostic indicator of male fertility status (49, 50).

To quantify causes more clearly, it is necessary to distinguish between the inability to achieve pregnancy, the inability to carry a pregnancy to a live birth and the failure of a live birth to survive, all of which contribute to involuntary childlessness. Although infertility is an important cause of involuntary childlessness, other biomedical (e.g. pregnancy loss), biopsychosocial (e.g. sexual dysfunction) or non-biomedical (e.g. legal, regulatory, cultural or social) situations may impede individuals' ability to have children (51, 52). Desire or intentions for parenthood in otherwise

Guideline for the prevention, diagnosis and treatment of infertility

fertile populations can be modified by multiple concerns (53, 54). A wide variety of people may not be infertile, as they have biological reproductive capacity, but could need interventions to have children and fulfil their fertility preferences.$^{1}$

Overall, better epidemiological data relating to the extent and causes of infertility, and the need for fertility care arising because of different reasons, are required to inform health (and other) policies and services.

1.2 The need to strengthen global efforts to prevent, diagnose and treat infertility

Fig. 1.2. Addressing infertility is central to human rights and global health aspirations

![Gender equalityRight to healthWomen are often disproportionatelyEveryone has a right to enjoy theaffected by the consequences ofhighest attainable standard ofinfertility. Addressing infertility isphysical, mental and socialrelevant to gender equalitywell-beingRight to enjoy theUniversal healthbenefits of scientificcoverage (UHC)progress and itsPrevention, diagnosisapplicationsand treatment ofInterventions like assistedinfertility should bereproductive technologiesintegrated into health(ARTs) have a role to play iservices and systemsaddressing infertilityEquitable accessPrimary health care (PHC)+to health careEnsuring that basicInfertility should beinterventions such as fertilityconsistently includededucation are available at thePHC level will contribute toin health policies,services and financingenhanced service coverageFinancial protectionGiven the risk of large out-of-pocket costsfor preventing, diagnosing or treatinginfertility, fertility care should be providedwhile upholding financial protectionhe Universal Declaration of Human Rightsor religion, have the right to marry and found aArticle 16) states that "men and women of fullfamily" (4). A significant proportion of young adulin demographic health surveys express a desirege, without any limitation due to race, nationalityBecause of the need to refer to biological sex characteristics on clinical grounds, this guideline uses terms such as male anfemale (in its recommendations), and men and women (in text synthesizing research) to indicate biological sex assignedat birth, and uses "couples" to refer to heterosexual partnerships. However, a wide variety of people, including individualswho are single or who are in same-sex or gender-diverse relationships, may need services to fulfil their fertility preferencesProviders of fertility care should consider the needs of, and provide equal care to, all individuals\n](1/parseimages/figureb6fbd7fad0da43e29d69aaaf18757a4f_0_6.png) 1 Introduction

for children (55–58) and infertility can prevent the ability of individuals to achieve their preferences regarding the number, timing and spacing of their children. Services for the prevention, diagnosis and treatment of infertility are an essential element of reproductive health care included in the 1994 International Conference on Population and Development call to action, to, among others, achieve universal access to a full range of reproductive health services (59). A wide variety of individuals and couples may require infertility management and fertility care services (60); individual circumstances should not lead to discrimination.

Addressing infertility is central to the achievement of the right to health. Every human being has a right to the enjoyment of the highest attainable standard of physical, mental and social well-being. Infertility has a negative impact on mental well-being, relationships and quality of life (61, 62) and is associated with a high prevalence of intimate partner violence (63). Therefore, improving access to prevention, diagnosis and treatment of infertility is needed to mitigate the negative health and psychosocial consequences of infertility. The right to health is closely linked with the right to enjoy the benefits of scientific progress and its applications (64). Although assisted reproductive technologies (ARTs) and a range of other interventions may have a role in partially compensating for postponement of births (65-67), demographic changes and declines in total fertility rates should not be used as a basis for restricting or coercing access to fertility care and other reproductive services (68); instead, health (and other) policies and services should be aimed at facilitating the achievement of people's fertility goals and preferences through a rights-based approach (69).

Addressing infertility is also relevant to gender equality. Women are often disproportionately affected by the consequences of infertility (62, 70, 71) and tend to bear the blame for infertility in couples (9, 72). Infertility also affects men's mental health and well-being (73), yet its impact is often concealed

because of stigma, masculine norms (74) and low participation of men in infertility studies and services (75-77). Many social norms stigmatize infertility and affect reproductive decision-making in women and men. (See Fig. 1.2).

Addressing infertility is necessary to enhance equitable access to health care. Infertility is not consistently included in health policies, services and financing. Consequently, access to fertility care remains a challenge for many people. Although worldwide provision of in vitro fertilization (IVF) has increased over time (78), there are marked disparities in the availability, accessibility, acceptability and quality of services for preventing, diagnosing and treating infertility between regions, countries and populations (79, 80). Only about half of all couples with infertility seek any form of infertility services (81), but this can vary from country to country (82). Although many reasons prevent access to fertility care, cost is among the most common barriers, particularly in settings that do not have fully funded fertility care (80, 83, 84). It is the responsibility of Member States to put in place legislative frameworks, determine eligibility criteria and facilitate equitable access to fertility care for those in need. Member States have an obligation to facilitate access to health care, including preventing infertility and enabling access to diagnostic and treatment services (85, 86). By acting urgently, countries have an opportunity to respond to the need for services for the prevention, diagnosis and treatment of infertility and mitigate the many inequities in access to safe and effective fertility care.

Efforts to achieve universal health coverage should include measures to address the needs of people with infertility by integrating the prevention, diagnosis and treatment of infertility into sexual and reproductive health services and wider health systems. It is essential to ensure that services for infertility are available, accessible, acceptable and of good quality. This will require having supportive health (and other) policies to ensure that all people have access to services to prevent, diagnose and treat infertility that they need, when and where they

Guideline for the prevention, diagnosis and treatment of infertility

need them. However, in many countries, infertility services and policies are not prioritized or included in health systems, including services or financing (87-89). Achieving universal health coverage will require provision of health financing, trained personnel, medicines, equipment, infrastructure and effective monitoring of services through robust health information systems. Ensuring that fertility care is provided while upholding

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1 Introduction

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19. Chua S, Danhof N, Mochtar M, Van Wely M, McLernon D, Custers I et al. Age-related natural fertility outcomes in women over 35 years: a systematic review and individual participant data meta-analysis. Hum Reprod. 2020;35(8):1808-20 (https://doi.org/10.1093/humrep/deaa129).

20. Steiner AZ, Jukic AMZ. Impact of female age and nulligravidity on fecundity in an older reproductive age cohort. Fertil Steril. 2016;105(6):1584-8. (https://doi.org/10.1016/j.fertnstert.2016.02.028).

21. Wesselink AK, Rothman KJ, Hatch EE, Mikkelsen EM, Sørenns HT, Wise LA. Age and fecundability in a North American preconception cohort study. Am J Obstet Gynecol. 2017;217(6):667.e1-667.e8 (https://doi.org/10.1016/j.ajog.2017.09.002).

22. ESHRE Capri Workshop Group. Fertility and ageing. Hum Reprod Update. 2005;11(3):261-76 (https://doi.org/10.1093/humupd/dmi006).

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24. Laurent SL, Thompson SJ, Addy C, Garrison CZ, Moore EE. An epidemiologic study of smoking and primary infertility in women. Fertil Steril. 1992;57(3):565-72 (https://doi.org/10.1016/S0015-0282(16)54901-2).

25. Waylen AL, Metwally M, Jones GL, Wilkinson AJ, Ledger WL. Effects of cigarette smoking upon clinical outcomes of assisted reproduction: a meta-analysis. Hum Reprod Update. 2008;15(1):31-44 (https://doi.org/10.1093/humupd/dmn046).

26. Bundhun PK, Janoo G, Bhurtu A, Teeluck AR, Soogund MZS, Pursun M et al. Tobacco smoking and semen quality in infertile males: a systematic review and meta-analysis. BMC Public Health. 2019;19(1):36 (https://doi.org/10.1186/s12889-018-6319-3).

27. Ricci E, Al Beitawi S, Cipriani S, Candiani M, Chiaffarino F, Viganò P et al. Semen quality and alcohol intake: a systematic review and meta-analysis. Reprod Biomed Online. 2017;34(1):38-47 (http://dx.doi.org/10.1016/j.rbmo.2016.09.012).

28. Fan D, Liu L, Xia Q, Wang W, Wu S, Tian G et al. Female alcohol consumption and fecundability: a systematic review and dose-response meta-analysis. Sci Rep. 2017;7(1):13815 (https://doi.org/10.1038/s41598-017-14261-8).

29. Sharma R, Biedenharn KR, Fedor JM, Agarwal A. Lifestyle factors and reproductive health: taking control of your fertility. Reprod Biol Endocrinol. 2013;11:66 (https://doi.org/10.1186/1477-7827-11-66).

30. Boutari C, Pappas PD, Mintziori G, Nigdelis MP, Athanasiadis L, Goulis DG et al. The effect of underweight on female and male reproduction. Metabolism. 2020;107:154229 (https://doi.org/10.1016/j.metabol.2020.154229).

31. Bayoumi RR, Fatemi HM, Hurt L, Serour GI, van der Poel S, Venetis C et al. A critical systematic review and meta-analyses of risk factors for fertility problems in a globalized world. Reprod Biomed Online. 2024;48(3):103217 (https://doi.org/10.1016/j.rbmo.2023.04.008).

32. Reekie J, Donovan B, Guy R, Hocking JS, Kaldor JM, Mak D et al. Risk of ectopic pregnancy and tubal infertility following gonorrhea and chlamydia infections. Clin Infect Dis. 2019;69(9):1621-3 (https://doi.org/10.1093/cid/ciz145).

Guideline for the prevention, diagnosis and treatment of infertility

33. de Angelis C, Nardone A, Garifalos F, Pivonello C, Sansone A, Conforti A et al. Smoke, alcohol and drug addiction and female fertility. Reprod Biol Endocrinol. 2020;18(1):21 (https://doi.org/10.1186/s12958-020-0567-7).

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35. Segal TR, Giudice LC. Before the beginning: environmental exposures and reproductive and obstetrical outcomes. Fertil Steril. 2019;112(4):613-21 (https://doi.org/10.1016/j.fernstert.2019.08.001).

36. Gore AC, Chappell VA, Fenton SE, Flaws JA, Nadal A, Prins GS et al. EDC-2: the Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals. Endocr Rev. 2015;36(6):E1-E150 (https://doi.org/10.1210/er.2015-1010).

37. State of the science of endocrine disrupting chemicals 2012: summary for decision-makers. Geneva: World Health Organization; 2012 (https://iris.who.int/handle/10665/78102).

38. Barratt CLR, Björndahl L, De Jonge CJ, Lamb DJ, Osorio Martini F, McLachlan R et al. The diagnosis of male infertility: an analysis of the evidence to support the development of global WHO guidance-challenges and future research opportunities. Hum Reprod Update. 2017;23(6):660-80 (https://doi.org/10.1093/humupd/dmx021).

39. Cox CM, Thoma ME, Tchangalova N, Mburu G, Bornstein MJ, Johnson CL et al. Infertility prevalence and the methods of estimation from 1990 to 2021: a systematic review and meta-analysis. Hum Reprod Open. 2022;2022(4): hoac051 (https://doi.org/10.1093/hropen/hoac051).

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41. Bhattacharjee NV, Schumacher AE, Aali A, Abate YH, Abbasgholizadeh R, Abbasian M et al. Global fertility in 204 countries and territories, 1950-2021, with forecasts to 2100: a comprehensive demographic analysis for the Global Burden of Disease Study 2021. Lancet. 2024;403(10440):2057-99 (https://doi.org/10.1016/s0140-6736(24)00550-6).

42. Mathews TJ, Hamilton BE. Mean age of mothers is on the rise: United States, 2000–2014. Hyattsville: National Center for Health Statistics; 2016 (https://www.cdc.gov/nchs/data/databriefs/db232.pdf).

43. Khandwala YS, Zhang CA, Lu Y, Eisenberg ML. The age of fathers in the USA is rising: an analysis of 168 867 480 births from 1972 to 2015. Hum Reprod. 2017;32(10):2110-6 (https://doi.org/10.1093/humrep/ex267).

44. Birth characteristics in England and Wales: 2021. Fareham: Office for National Statistics; 2023 (https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/livebirths/bulletins/birthcharacteristicsinenglandandwales/2021).

45. Gourinat A, Mazeaud C, Hubert J, Eschwege P, Koscinski I. Impact of paternal age on assisted reproductive technology outcomes and offspring health: a systematic review. Andrology. 2023;11(6):973-86 (https://doi.org/10.1111/andr.13385).

46. Levine H, Jørgensen N, Martino-Andrade A, Mendiola J, Weksler-Derri D, Mindlis I et al. Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update. 2017;23(6):646-59 (https://doi.org/10.1093/humupd/dmx022).

47. Paulson RJ, Milligan RC, Sokol RZ. The lack of influence of age on male fertility. Am J Obstet Gynecol. 2001;184(5):818-22 (https://doi.org/10.1067/mob.2001.113852).

48. Campbell MJ, Lotti F, Baldi E, Schlatt S, Festin MPR, Björndahl L et al. Distribution of semen examination results 2020: a follow up of data collated for the WHO semen analysis manual 2010. Andrology. 2021;9(3):817-22 (https://doi.org/10.1111/andr.12983).

1 Introduction

49. Boeri L, Belladelli F, Capogrosso P, Cazzaniga W, Candela L, Pozzi E et al. Normal sperm parameters per se do not reliably account for fertility: a case-control study in the real-life setting. Andrologia. 2021;53(1):e13861 (https://doi.org/10.1111/and.13861).

50. WHO laboratory manual for the examination and processing of human semen, sixth edition. Geneva: World Health Organization; 2021 (https://iris.who.int/bitstream/handle/10665/343208/9789240030787-eng.pdf).

51. Berger MH, Messore M, Pastuszak AW, Ramasamy R. Association between infertility and sexual dysfunction in men and women. Sex Med Rev. 2016;4(4):353-65 (https://doi.org/10.1016/j.sxmr.2016.05.002).

52. Davis MF, Khosla R. Infertility and human rights: a jurisprudential survey (June 26, 2020). Colum J Gender & L. Paper No. 381-2020 (https://ssrn.com/abstract=3636206).

53. Dillardone H, Brown LJ, Flores EC. Climate change, mental health, and reproductive decision-making: a systematic review. PLOS Climate. 2023;2(11):e0000236 (https://doi.org/10.1371/journal.pclm.0000236).

54. Boivin J, Buntin L, Kalebic N, Harrison C. What makes people ready to conceive? Findings from the International Fertility Decision-Making Study. Reprod Biomed Soc Online. 2018;6:90-101 (https://doi.org/10.1016/j.rbms.2018.10.012).

55. Having children or not: results from a questionnaire survey about women's and men's attitudes towards having children. Örebro: SCB (Statistics Sweden); 2009 (https://www.scb.se/be0701-en).

56. Westoff CF. Desired number of children: 2000-2008. Calverton: USA ICF Macro; 2010 (https://www.dhsprogram.com/pubs/pdf/CR25/CR25.pdf)

57. Cools S, Strøm M. Ønsker om barn-en spørreundersøkelse om fertilitet, arbeidsliv og familiepolitikk. Institutt for samfunnsforskning; 2020 (https://hdl.handle.net/11250/2645776).

58. Li Q, Yang R, Zhou Z, Qian W, Zhang J, Wu Z et al. Fertility history and intentions of married women, China. Bull World Health Organ. 2024;102(4):244-54 (https://doi.org/10.2471/ blt.23.289736).

59. Programme of action adopted at the International Conference on Population and Development, Cairo, 1994. New York: United Nations Population Fund; 1994.

60. Infertility Fact Sheet [Internet web page]. Geneva: World Health Organization; 2024 (https://www.who.int/news-room/fact-sheets/detail/infertility).

61. Luk BH-K, Loke AY. The impact of infertility on the psychological well-being, marital relationships, sexual relationships, and quality of life of couples: a systematic review. J Sex Marital Ther. 2015;41(6):610-25 (https://doi.org/10.1080/0092623X.2014.958789).

62. Chachamovich JR, Chachamovich E, Ezer H, Fleck MP, Knauth D, Passos EP. Investigating quality of life and health-related quality of life in infertility: a systematic review. J Psychosom Obstet Gynaecol. 2010;31(2):101-10 (https://doi.org/10.3109/016748 2X.2010.481337).

63. Wang Y, Fu Y, Ghazi P, Gao Q, Tian T, Kong F et al. Prevalence of intimate partner violence against infertile women in low-income and middle-income countries: a systematic review and meta-analysis. Lancet Glob Health. 2022;10(6):e820-e30 (https://doi.org/10.1016/s2214-109x(22)00098-5).

64. International Covenant on Economic, Social Cultural Rights (CESCR). New York: United Nations General Assembly; 1966.

65. Fauser BCJM, Adamson GD, Boivin J, Chambers GM, de Geyter C, Dyer S et al. Declining global fertility rates and the implications for family planning and family building: an IFFS consensus document based on a narrative review of the literature. Hum Reprod Update. 2024;10:dmad028 (https://doi.org/10.1093/humupd/dmad028).

66. Bergsvik J, Fauske A, Hart RK. Can policies stall the fertility fall? A systematic review of the (quasi-) experimental literature. Popul Dev Rev. 2021;47(4):913-64 (https://doi.org/10.1111/ padr.12431).

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67. Lazzari E, Gray E, Chambers GM. The contribution of assisted reproductive technology to fertility rates and parity transition. Demogr Res. 2021;45:1081-96 (https://doi.org/10.4054/DemRes.2021.45.35).

68. Mburu G, Kamuyango A, Kidula N, Kabra R, Thatte N, Kiarie J et al. Fulfilment of fertility desires for the attainment of Global Sustainable Development Goals. BMJ Glob Health. 2023;8(4):e12322 (https://doi.org/10.1136/bmjgh-2023-012322).

69. Mburu G, Kiarie J, Allotey P. Towards a nuanced view and response to global fertility trends. Lancet. 2024;403(10440):1953-6 (https://doi.org/10.1016/s0140-6736(24)00490-2).

70. Ying LY, Wu LH, Loke AY. Gender differences in experiences with and adjustments to infertility: a literature review. Int J Nurs Stud. 2015;52(10):1640-52 (https://doi.org/10.1016/j.ijnurstu.2015.05.004).

71. Koert E, Takefman J, Boivin J. Fertility quality of life tool: update on research and practice considerations. Hum Fertil. 2021;24(4):236-48 (https://doi.org/10.1080/14647273.2019.1648887).

72. Thoma M, Fledderjohann J, Cox C, Kantum Adageba R. Biological and social aspects of human infertility: a global perspective. Oxford: Oxford University Press; 2021 (https://doi.org/10.1093/acrefore/9780190632366.013.184).

73. Fallara G, Pozzi E, Belladelli F, Boeri L, Capogrosso P, Corona G et al. A systematic review and meta-analysis on the impact of infertility on men's general health. Eur Urol Focus. 2024;10:98-106 (https://doi.org/10.1016/j.euf.2023.07.010).

74. Inhorn MC. Middle Eastern masculinities in the age of new reproductive technologies: male infertility and stigma in Egypt and Lebanon. Med Anthropol Q. 2004;18(2):162-82 (https://doi.org/10.1525/maq.2004.18.2.162).

75. Fisher JR, Hammarberg K. Psychological and social aspects of infertility in men: an overview of the evidence and implications for psychologically informed clinical care and future research. Asian J Androl 2012;14(1):121 (https://doi.org/10.1038/aja.2011.72).

76. Culley L, Hudson N, Lohan M. Where are all the men? The marginalization of men in social scientific research on infertility. Reprod Biomed Online. 2013;27(3):225-35 (https://doi.org/10.1016/j.rbmo.2013.06.009).

77. De Jonge CJ, Gellatly, Vazquez-Levin MH, Barratt CLR, Rautakallio-Hokkanen S. Male attitudes towards infertility: results from a global questionnaire. World J Mens Health. 2023;41(1):204-14 (https://doi.org/10.5534/wjmh.220099).

78. Adamson GD, Creighton P, de Mouzon J, Zegers-Hochschild F, Dyer S, Chambers GM. How many infants have been born with the help of assisted reproductive technology? Fertil Steril. 2025; S0015-0282(25)00085-8 (https://doi.org/10.1016/j.fernstert.2025.02.009).

79. Ombelet W. Global access to infertility care in developing countries: a case of human rights, equity and social justice. Facts Views Vis Obgyn. 2011;3(4):257-66 (https://pubmed.ncbi.nlm.nih.gov/24753875/).

80. Botha B, Shamley D, Dyer S. Availability, effectiveness and safety of ART in sub-Saharan Africa: a systematic review. Hum Reprod Open. 2018;2018(2):hoy003 (https://doi.org/10.1093/hopen/hoy003).

81. Boivin J, Bunting L, Collins JA, Nygren KG. International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod. 2007;22(6):1506-12 (https://doi.org/10.1093/humrep/dem046).

82. Bell SO, Larson E, Bittle D, Moreau C, Omoluabi E, OlaOlorun FM et al. Care-seeking for difficulties conceiving in sub-Saharan Africa: findings from population-based surveys in eight geographies. Hum Reprod. 2024;39(8):1712-23 (https://doi.org/10.1093/humrep/deae084).

83. Njagi P, Groot W, Arsenijevic J, Dyer S, Mburu G, Kiarie J. Financial costs of assisted reproductive technology for patients in low-and middle-income countries: a systematic review. Hum Reprod Open. 2023;hoad007 (https://doi.org/10.1093/hropen/hoad007).

1 Introduction

84. Chambers GM, Hoang VP, Sullivan EA, Chapman MG, Ishihara O, Zegers-Hochschild F et al. The impact of consumer affordability on access to assisted reproductive technologies and embryo transfer practices: an international analysis. Fertil Steril. 2014;101(1):191-8 (https://doi.org/10.1016/j.fertnstert.2013.09.005).

85. Shah PK, Gher JM. Human rights approaches to reducing infertility. Int J Gynaecol Obstet. 2023;162(1):368-74 (https://doi.org/10.1002/ijgo.14878).

86. Human rights and infertility: research paper. Geneva: Office of the High Commissioner for Human Rights; 2023 (https://www.ohchr.org/sites/default/files/documents/issues/women/Research-Paper-HRs-Infertility.pdf).

87. International Federation of Fertility Societies' surveillance, 2022: global trends in reproductive policy and practice, 9th edition. Glob Reprod Health. 2022;7(3):e58 (https://doi.org/10.1097/GRH.0000000000000058).

88. Morshed-Behbahani B, Lamyian M, Joulaei H, Rashidi BH, Montazeri A. Infertility policy analysis: a comparative study of selected lower middle-middle- and high-income countries. Global Health. 2020;16(1):104 (https://doi.org/10.1186/s12992-020-00617-9).

89. Afferri A, Allen H, Booth A, Dierickx S, Pacey A, Balen J. Barriers and facilitators for the inclusion of fertility care in reproductive health policies in Africa: a qualitative evidence synthesis. Hum Reprod Update. 2022;28(2):190-9 (https://doi.org/10.1093/humupd/dmab040).

90. Elliott PA, Hoffman J, Abad-Santos M, Herndon C, Katz PP, Smith JF. Out-of-pocket costs for men undergoing infertility care and associated financial strain. Urol Pract. 2016;3(4):256-61 (https://doi.org/10.1016/j.urpr.2015.07.010).

Chapter 2 Rationale and methodology

This chapter presents information on the rationale, overall goals and methodology used to develop this guideline.

2.1 Rationale

This guideline responds to requests from Member States, organizations, institutions and health care providers for evidence-based norms and standards related to infertility. Despite the high burden of disease, infertility is often neglected (1, 2). Management of infertility is continually evolving. Absence of clear guidelines contributes to inconsistent outcomes and variable practices and can exacerbate existing disparities. Implementation of best practices that emphasize cost-effective interventions is a key strategy to reduce disparities in access to services.

2.2 Goals and objectives

The goal of this guideline is to provide evidence-informed guidance for the prevention, diagnosis and treatment of infertility to improve the standard of fertility care globally, with a focus on public health perspective. The objectives are:

$\bullet$ to provide evidence-based recommendations for the prevention, diagnosis and treatment of infertility;

This guideline underscores the importance of infertility as a global public health issue. The prevention, diagnosis and treatment of infertility is an integral component of comprehensive sexual and reproductive health, and is aligned with Sustainable Development Goal (SDG) 3, which aims to ensure healthy lives and promote well-being for all at all ages, and SDG 5, which aims to achieve gender equality and empower all women and girls. Prevention, diagnosis and treatment of infertility is also needed to ensure universal access to sexual and reproductive health care, and to achieve universal health coverage.

$\bullet$ to provide a source for countries to adopt, adapt or update their national guidelines for the prevention, diagnosis and treatment of infertility.

2 Rationale and methodology

Fig. 2.1. Scope and audience

Intended users of the guideline include:

![Guldeline for theprevention, diagnosisProfessionalHealth careand treatmentof infertilitysocietiesprofessionalsand otherincluding physicians,organizationsembryologists, nursesinvolved in sexuamidwives, laboratoryand reproductivespecialists, and otherhealth programmeshealth care providersFunding andPatient supportand advocacyphilanthropicPreventionTreatmentorganizationsagenciesDiagnosisThe scope of this guideline includes thediagnosis and treatment of:prevention,Policy-makerswho develop national healthrpolicies, services and financingFemale-factorUnexplainedMale-factorinfertilityinfertilityinfertility\n](1/parseimages/figure70c6c96da40e45f0a6bccf1cf73e47be_0_4.png)

2.3 Scope

This guideline provides recommendations related to prevention, as well as diagnosis and treatment of female-factor (tubal, ovulatory dysfunction and uterine causes), male-factor and unexplained infertility.

Given that this is the first WHO guideline on the prevention, diagnosis and treatment of infertility, it does not cover all aspects of infertility and important gaps remain. It is anticipated that subsequent editions of this guideline will have an expanded scope, allowing it to address topics that are not included currently, including management of other risk factors (such as obesity, low body weight, excessive intake of alcohol and other substances (including use of cannabis,

use of vapes and e-cigarettes, or non-smoked/ smokeless tobacco products, among others) and sexual dysfunction, as well as non-individual risk factors (e.g. environmental and workplace factors), fertility preservation in the context of gonadotoxic therapy, third-party reproduction (donor gametes, surrogacy), fertility care for individuals with pre-existing medical conditions that affect fertility (such as endometriosis and fibroids), or with obstructive, congenital, accessory gland, genital or hormonal abnormalities associated with male infertility, as well as psychosocial support for people with infertility. These topics received relatively limited attention in this first version (based on initial scoping) and will be considered in subsequent editions.

Guideline for the prevention, diagnosis and treatment of infertility

2.4 Target audience

This guideline is primarily intended for use by health care professionals, including physicians, embryologists, nurses, midwives, laboratory specialists and other health care providers, involved in the care of individuals or couples with infertility in primary, secondary and tertiary settings in both the private and public sectors. This guideline is of interest to policy-makers responsible for the development of national health (and other) policies, services and financing, as its recommendations use a population perspective that considers resource needs, acceptability, feasibility and impact on equity. The recommendations have been developed through a public health lens. This guideline

2.5 Guiding principles

The following principles have informed the development of this guideline and should guide the implementation of the recommendations:

$\bullet$ Development of the guideline responds to unmet need for guidance for a specified audience.

$\bullet$ Implementation of the guideline should inform and contribute to national goals and relevant global targets, including attainment of SDG 3 (to ensure healthy lives and promote well-being for all at all ages) and SDG 5 (to achieve gender equality and empower all women and girls).

$\bullet$ Implementation of the guideline should ensure that the prevention, diagnosis and treatment of infertility is considered an integral component of sexual and reproductive health and rights and should be aimed at achieving universal health coverage.

$\bullet$ Implementation of the guideline needs to be accompanied by efforts to promote and protect the right to health of people with or at risk of infertility.

can be used to inform the financial and human resources required to deliver adequate, acceptable and equitable fertility care for all populations in need. In addition, this guideline may be used to inform the work of patient support and advocacy organizations, mental health professionals, funding and philanthropic agencies, civil society, professional societies and other nongovernmental organizations that provide social, financial and technical support to sexual and reproductive health programmes. The guideline can also be used as an advocacy tool to ensure adequate, acceptable and equitable fertility care for everyone. (See Fig. 2.1)

$\bullet$ Implementation of the guideline should be based on a public health approach as a key strategy to reduce access disparities, by ensuring all populations in need of such services are reached with interventions to prevent, diagnose and treat infertility, including populations in low-resource settings.

$\bullet$ Implementation of the recommendations in this guideline should be informed by local context, including epidemiology and prevalence of infertility, the values and preferences of local populations or patients and feasibility, as well as the organization and capacity of the health system. Other contextual considerations may be related to demographic resilience, fertility and demographic trends, which require policies geared towards the achievement of universal access to sexual and reproductive health and rights.

2 Rationale and methodology

Fig. 2.2. Methodology for guideline development

![Guideline Development Group(GDG) establishedDetermining the scope of theguidelineIdentifying recommendationquestionsEvidence retrieval and synthesisPresentation of evidence usingGRADE methodologyMethodologyfor guidelinedevelopmentRecommendationsdrafted by the GDGExternal review of guideline byExternal Review Group (ERG)Review and approval of guideline byWHO Guideline Review Committee (GRC)Publication, dissemination andimplementation of the guideline\n](1/parseimages/figure7b689ff341b54d4d82ed43afa23aa7e4_0_3.png)

2.6 Methods

This guideline was developed in accordance with the 2014 WHO handbook for guideline development (3). (See Fig. 2.2).

Guideline Development Group

A WHO steering group was convened to facilitate the scoping of the guideline, including priority

topics related to the prevention, diagnosis and treatment of infertility. The steering group consisted of WHO staff members from different departments in WHO. A systematic review lead and guideline methodologist were appointed by the WHO steering group. The WHO steering group consulted with experts, clinicians,

Guideline for the prevention, diagnosis and treatment of infertility

researchers, patient organizations and other key stakeholders and established the WHO Infertility Guideline Development Group (GDG), which included 30 members from different regions and with expertise in different topics related to the prevention, diagnosis and treatment of infertility. The GDG consisted of clinicians, researchers, implementers and patient advocate groups (see Annex 2. Members of the GDG). A Chair and co-Chair were appointed to lead the GDG meetings. Two leaders were also assigned to each subtopic within the scope of the guideline.

External Review Group

An External Review Group (ERG) that included 30 clinical experts, policy-makers and patient advocates was established. The ERG reviewed the recommendations and provided feedback on critical implementation considerations (see Annex 3. Members of the ERG).

Determining the scope of the guideline and recommendation questions

In 2018, the WHO Infertility GDG met virtually to define the scope of this guideline. The WHO GDG provided input, which was used to brainstorm and prioritize questions. The questions were divided into subtopics: prevention and information provision, and diagnosis and treatment of infertility due to female factors, male factors and unexplained factors. Recommendation questions were developed using the population, intervention, comparator, outcome (PICO) framework, related to diagnostic tests, surgical and medical treatments, and information provision (see Web Annexes A-F for the guideline for the prevention, diagnosis and treatment of infertility). The GDG identified outcomes that included live birth rates, ongoing pregnancy rates, clinical pregnancy rates and quality of life, multiple pregnancy, miscarriage, preterm birth and other relevant adverse events. Based on input from a virtual meeting with the GDG, the WHO Steering Group finalized the prioritized PICO questions, which then formed the basis for systematic reviews.

Retrieval and synthesis of evidence

Systematic reviews were conducted by the Michael G. DeGroote Cochrane Canada Centre at McMaster University. The team took a hierarchical approach and searched for published systematic reviews, and then primary studies when no review was available, or updated a review when out-of-date. The systematic reviews assessed the benefits and harms of the interventions (and diagnostic tests), as well as acceptability, feasibility, equity and resource requirements. Searches for randomized or non-randomized studies were conducted from 1990 up to December 2019 in multiple databases including MEDLINE, Embase, Cochrane Central Register of Controlled Trials and LILACS. Additional searches up to 2023 were conducted for selected questions. Based on feedback from the GDG, targeted monitoring of evidence (and an updated search) was conducted for selected guideline questions in which new studies were likely to be published, allowing results from new studies to potentially be added to evidence summaries. If a study was published after the search and was identified by the GDG to likely have an impact on the recommendation, it was also incorporated into the review. Cochrane methods for conducting systematic reviews (4) were followed: using a comprehensive search strategy; duplicate screening of articles; duplicate assessment of risk of bias using study-design-specific tools; data abstraction by one investigator and verification by another; and synthesis through meta-analysis (using RevMan) when possible, otherwise performing a narrative synthesis. Subgroup analyses were conducted when data were available for key parameters that could affect outcomes such as body mass index (BMI) or semen parameters.

Because of concerns about the number of retracted papers in the field of reproductive medicine, a search was conducted in the Retraction Watch Database version 1.0.8.0 (https://retractiondatabase.org/) for studies included in the systematic reviews. When a study was retracted or under investigation, it was excluded from the pairwise meta-analyses and new calculations were made, or new analyses were sought in the case of network meta-analyses.

2 Rationale and methodology

Presentation of the evidence

Tables to facilitate decision-making for recommendations (evidence to decision [EtD] frameworks) were produced for each recommendation and presented to the GDG using the GRADEpro online software (www.gradepro.org/). These tables include a summary of the problem – test (diagnostic)

accuracy; summary of the evidence for benefits and harms (including for different subgroups); certainty of the evidence; relevant patient values and preferences; and other issues, such as cost, resources, feasibility, equity and acceptability. Table 2.1 illustrates how each of the EtD factors influences a guideline recommendation.

Table 2.1. Evidence to decision framework

|Domain|Favours strong recommendations|Favours conditional recommendations| |---|---|---| |Balance of benefits and harms|Benefits highly outweigh harms or vice versa|Benefits and harms are more closely balanced| |Quality of evidence|Higher certainty|Lower certainty| |Values/preferences regarding outcomes|Benefits to harms assessment not impacted by variability in values or preferences|Variability in values or preferences would impact benefits to harms assessment| |Acceptability|Highly acceptable|Low or variable acceptability| |Costs/resources|Cost-saving/cost-effective|Costly/cost-ineffective| |Feasibility|Feasible in intended settings|Unfeasible or feasibility varies in intended settings| |Equity|Increased equity|Decreased equity or effect on equity is variable|

The certainty of the body of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach (5), based on considerations of risk of bias, inconsistency, indirectness, imprecision, publication bias, effect size, dose-response and opposing confounding. Based on these criteria, the overall certainty of evidence was defined as follows:

$\bullet$ high (we are very confident that the true effect lies close to that of the estimate of the effect);

$\bullet$ moderate (we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different);

$\bullet$ low (we have limited confidence in the effect estimate: the true effect may be substantially different from the estimate of the effect);

$\bullet$ very low (we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect).

The evidence about benefits and harms was summarized in the GRADE summary of findings tables and Evidence Profiles that contained the estimates of the effect (in relative and absolute terms), and the assessments of the certainty of evidence (see Web Annexes A-F for the evidence to decision tables).

Review of evidence and drafting of recommendations

The GDG met virtually to review the evidence. Because of the complexity of developing the

Guideline for the prevention, diagnosis and treatment of infertility

recommendations, several subgroup virtual meetings were held with the topic leaders to further review the evidence before or after GDG meetings and draft judgements (with explanations) for each EtD factor, as well as recommendations (with justifications). The GDG assessed the EtDs, judged on different considerations and voted on their agreement or disagreement with the draft recommendations using GRADEpro Panelvoice (www.gradepro.org/panelvoice). Judgements about benefits and harms were based on the direction and size of the estimated effects and the uncertainty in those effects (GRADE-level evidence), not on whether the effect was statistically significant (i.e. avoiding the misinterpretation that "not statistically significant" means "no effect" [6]).

Making of recommendations

During the GDG meetings, judgements for each of the criteria of the EtD made during voting were discussed and the GDG recommendation drafts were confirmed or revised. A methodologist facilitated the process during the GDG meetings, and the Chair and co-Chair led the discussions. Using the GRADE approach, the strength of each recommendation was rated as either strong or conditional. Strong recommendations are presented using the wording "WHO recommends...", while conditional recommendations are worded as "WHO suggests ...". These were arrived at after consideration of the various domains of the EtD framework. Strong and conditional recommendations have differing implications, as shown in Table 2.2.

Table 2.2. Implications of differing strengths of GRADE recommendations

|Implications|Strong recommendation WHO recommends ...|Conditional recommendation WHO suggests ...| |---|---|---| |For patients|Most individuals in this situation would want the recommended course of action and only a small proportion would not. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences.|The majority of individuals in this situation would want the suggested course of action, but many would not.| |For clinicians|Most individuals should receive the recommended course of action. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator.|Clinicians should recognize that different choices will be appropriate for each individual and that clinicians must help each individual arrive at a management decision consistent with the individual's values and preferences. Decision aids may be useful to help individuals make decisions consistent with their values and preferences.| |For policy-makers|The recommendation can be adopted as policy in most situations.|Policy-making will require substantial debate and the involvement of various stakeholders.|

When addressing patients' values (for which there was no research evidence available), judgements about the most important outcomes and the

likelihood of variability across people were made by the GDG. It was agreed that, across the recommendation questions, the most important

2 Rationale and methodology

outcome for people was live birth. It was also agreed that there was probably no important variability across people on how they trade off outcomes. The value placed on these outcomes were considered for all recommendations.

All decisions on recommendations were reached by discussion and consensus in virtual meetings, informed by the voting about agreement or disagreement using the GRADEPro online software, including the strength of the recommendations, and where appropriate, the remarks for each recommendation. Before the process, the group decided that any recommendation with less than 80% agreement would undergo discussion and revisions, whereas recommendations with more than 80% agreement would be presented to the GDG for confirmation and a plan for addressing minor comments to improve the clarity of the EtD frameworks. In cases where there was disagreement, additional evidence and data were requested and reviewed, additional discussions were held with topic leaders, and recommendations were redrafted and posted for virtual voting, with the goal of reaching a consensus. In all cases, the percentage of panel members in disagreement and their reasons or comments were summarized and shared with the topic leaders. Additional guidance to facilitate the implementation of the guideline recommendations in different settings was also written according to discussions and comments made by the GDG. The full guideline document was circulated to the GDG, reviewed and approved.

Good practice statements

Good practice statements were made in topics where GDG agreed that the guidance was necessary, but a review of the evidence was not warranted because the benefits of the practice were unequivocal and other factors (such as equity) would not have an impact. Good practice statements were rooted in the fact that answers were deemed obvious by the GDG. The methodologist guided the development of good practice statements based on existing GRADE guidance (7).

Implementation considerations and research gaps

Implementation considerations highlighting critical elements that facilitate the appropriate application of recommendations (8) were drafted and presented to the GDG for their input, comments or agreements. Research gaps summarized important questions that needed to be addressed in each topic.

Management of conflicts of interest

Management of conflicts of interest (COIs) was a priority throughout the guideline development process. Before assuming their roles, all external contributors to the guideline, including members of the GDG, completed a WHO declaration of interests (DOI) form in accordance with WHO policy for experts. A brief biography of each GDG member was published on the WHO website for 14 days before the first meeting of the GDG. No public comments or objections were received.

The DOI forms were reviewed by the WHO Secretariat; statements therein were summarized and a management plan was developed and documented. At the beginning of guideline development, three invited members of the GDG were identified as having COIs. The Secretariat consulted with the Department of Compliance and Risk Management and Ethics and jointly determined that one member could participate fully, a second could participate as temporary adviser and a third was excluded from the GDG. During the development of the guideline, DOIs were updated by each GDG member every 2 years. After analysing the updated DOI, the WHO Secretariat concluded that four GDG members had a COI. These GDG members were not excluded from participating but their votes were not counted on specific PICOs where they had a COI. None of the members of the ERG were determined to have COIs that required exclusion from reviewing the guideline; however, consideration of comments from several ERG members was restricted on several topics based on their declared interests (see Annexes 4 and 5 for the summary of declared interests from members of the GDG and ERG, respectively).

Guideline for the prevention, diagnosis and treatment of infertility

References

1. Infertility Fact Sheet [Internet web page]. Geneva: World Health Organization; 2024 (https://www.who.int/news-room/fact-sheets/detail/infertility).

2. Morshed-Behbahani B, Lamyian M, Joulaei H, Rashidi BH, Montazeri A. Infertility policy analysis: a comparative study of selected lower middle-middle- and high-income countries. Global Health. 2020;16(1):104 (https://doi.org/10.1186/s12992-020-00617-9).

3. WHO handbook for guideline development, second edition. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/145714).

4. Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ et al. Cochrane handbook for systematic reviews of interventions, second edition. Chichester: John Wiley & Sons; 2019.

5. Schünemann H, Brożek J, Guyatt G, Oxman A. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach [website]. GRADE Working Group; 2013 (https://gdt.gradepro.org/app/handbook/handbook.html).

6. Amrhein V, Greenland S, McShane B. Scientists rise up against statistical significance. Nature. 2019;567(7748):305-7 (https://doi.org/10.1038/d41586-019-00857-9).

7. Guyatt GH, Alonso-Coello P, Schünemann HJ, Djulbegovic B, Nothacker M, Lange S et al. Guideline panels should seldom make good practice statements: guidance from the GRADE Working Group. J Clin Epidemiol. 2016;80:3-7 (https://doi.org/10.1016/j.jclinepi.2016.07.006).

8. Lotfi T, Hajizadeh A, Moja L, Akl EA, Piggott T, Kredo T et al. A taxonomy and framework for identifying and developing actionable statements in guidelines suggests avoiding informal recommendations. J Clin Epidemiol. 2022;141:161-71 (https://doi.org/10.1016/j.clinepi.2021.09.028).

![Chapter\n](1/parseimages/figured03c90ec84fd4cc18ca15448055b7a26_0_0.png)

Chapter 3 Approach to evaluation and management of infertility

This chapter provides information on the objective and key steps involved in the clinical assessment and management of infertility.

3.1 Objective

3.2 Indication $\rightarrow$

3.3 Elements of evaluation and management $\rightarrow$

Relevant resources

Annex 6. Components of female medical history and physical examination

Annex 7. Components of male medical history and physical examination

Web Annex A. Evidence to decision tables for approach to the evaluation and management of infertility

Guideline for the prevention, diagnosis and treatment of infertility

3.1 Objective

The objective of a comprehensive evaluation is to facilitate prompt diagnosis and treatment of infertility, while mitigating predisposing risk

3.2 Indication

Evaluation of both the female and male partners is initiated simultaneously to provide prompt diagnosis of infertility before commencing treatment. A diagnosis of infertility is arrived at if there is failure to achieve a pregnancy after 12 months of unprotected intercourse (1).

factors in order to enhance the chances of achieving a pregnancy.

![](1/parseimages/figure60699cc172a94fbaa2b3b1367b600ee4_0_7.png) WHO defines infertility as failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse.

3.3 Elements of evaluation and management

Fig. 3.1. Elements of evaluation and management

The basic evaluation and management of infertility includes the following components:

![InitialTaking and recording aConducting a physicalmedical historyconsultationexamination7Provision of informationDiscussion ofConducting a diagnosticdiagnosis, etiologyabout pre-pregnancyevaluation of the maleadvice, counselling or careand treatment optionsand female reproductivefunctionsAgreeing on andProviding a clinicalDocumentingIdentification andproviding treatmentfollow-up andthe outcomeserral of patients withfor infertilitymanaging the risks ofof infertilityexisting conditions toinfertility treatmenttreatmentother services\n](1/parseimages/figure215615acc33544bdab1b74c0279be4c4_0_12.png) 3 Approach to evaluation and management of infertility

![](1/parseimages/figurefbe3104fd5dd4cb6afbf601d9566d41d_0_2.png)

Initial consultation

The first contact with a health provider is often initiated by patients,

especially females, with concerns about a delay or failure to achieve pregnancy. The disproportionate blame for infertility placed on females can result in them seeking care unaccompanied by their male partners. In other cases, infertility may come up in the context of other health issues. Specific complaints and symptoms are identified during the initial consultation. In all cases, it is essential that there is a conducive and private environment to enable individuals and couples to freely discuss their complaints or concerns with the health care provider.

It is important for health care providers to anticipate and manage privacy, which can affect (or cause discomfort with) the disclosure of sensitive information among couples with infertility. Interactions with people with infertility may involve some loss of privacy (2–4). Although it is helpful to interview the couple together for history-taking, creating opportunities for interviewing each partner separately can be more gender-sensitive because it can avail additional or sensitive information; some questions are better asked when either partner is alone, for example, history of previous sexual partners, pregnancies, STIs and intimate partner violence, among others. These questions can be asked conveniently at the same time as the physical examination is performed (5, 6).

![](1/parseimages/figurec643897fe5ec43a38784b0effa81c02c_0_7.png)

Taking and recording medical history

A comprehensive history is important

in establishing the likelihood of infertility and potential risk factors that could be contributing to it. Some readily apparent causes of infertility can be identified through a comprehensive medical history and examination. It is important for health care providers to be non-judgemental in their approach to history-taking.

For females, key aspects of medical history include obstetric history, pregnancy history, duration of attempting to get pregnant, menstrual history, past medical and surgical history, gynaecological history (including previous investigations or treatment for infertility), history of STIs, sexual history (including frequency and timing of sex, and sexual dysfunction), childhood and developmental history, family history, occupational history (including history of potential gonadotoxic exposure) and a review of systems, current health status, lifestyle (including tobacco smoking, alcohol and substance use) and medications (see Annex 6. Components of female medical history and physical examination).

For males, history typically covers past medical history, reproductive history, sexual history (including STIs, erectile dysfunction, ejaculatory dysfunction and injuries to reproductive organs), duration of attempting to achieve pregnancy, past medical and surgical history (including previous investigations or treatment for infertility), childhood and developmental history, family history, occupational history (including history of potential gonadotoxic exposure) and a review of systems, current health status, lifestyle (including tobacco smoking, alcohol and substance use) and medications (see Annex 7. Components of male medical history and physical examination.)

Guideline for the prevention, diagnosis and treatment of infertility

![](1/parseimages/figure536310dddefe43b88964b08220db5be8_0_2.png)

Conducting a physical examination

A focused physical examination is essential. The scope and procedures for the physical examination of couples are outlined in the WHO manual for the standardized investigation and diagnosis of the infertile couple (6). For females, a targeted physical examination may include vital signs, BMI, breast examination, thyroid examination, examination of the external genitalia, speculum/ vaginal examination and a bimanual pelvic examination, which includes an examination of the vaginal, cervical, uterine and pelvic anatomy (see Annex 6. Components of female medical history and physical examination).

For males, a focused physical examination includes assessment of vital signs and BMI, examination of the body characteristics (such as poor virilization, gynaecomastia or obesity), inguinal and genital areas (for scars), external genitalia including the penis (for hypospadias, epispadias, phimosis or curvature), testes (for location, size, texture, consistency, pain, nodules or tenderness), vas deferens and epididymis (if present, absent, inflamed or obstructed), and the spermatic cord and scrotum (for varicocele, hydrocele or cysts) (see Annex 7. Components of male medical history and physical examination).

Health care providers should inform patients what the examination will entail, obtain consent and

conduct the examination in privacy, under hygienic conditions and in the presence of a chaperone if required. If presence of a chaperone is not feasible (e.g. because of staff shortage), health care providers should obtain consent from the patients to be examined without a chaperone. All findings should be recorded.

![一\n](1/parseimages/figure0570603a790e44eba9564fcd9b305ed6_0_8.png)

Conducting a diagnostic evaluation of the male and female reproductive functions

The basic diagnostic evaluation includes the following:

$\bullet$ Semen analysis. The procedures for the evaluation and interpretation of a semen analysis are included in the WHO laboratory manual for the examination and processing of human semen (7), which is updated regularly (see Chapter 5.4 for recommendations on semen analysis);

$\bullet$ Assessment of ovulation and ovulatory function (see Chapter 5.1 for recommendations on confirmation of ovulation, assessment of reproductive hormones and assessment of ovarian reserve);

$\bullet$ Assessment of the fallopian tubes (see Chapter 5.2 for recommendations related to the diagnostic evaluation of fallopian tubes);

$\bullet$ Assessment of the uterus (see Chapter 5.3 for recommendations on diagnostic evaluation of the uterine cavity).

![](1/parseimages/figureb4180b0e8301445aba617b456637ad4d_0_15.png)

Good practice statement

For males and females being evaluated and managed for infertility, it is good practice to select diagnostic tests based on the clinical findings from the medical history and physical examination to ensure that evaluation is systematic and cost-effective.

3 Approach to evaluation and management of infertility

![..oo\n](1/parseimages/figure5e62909c5e46463da59d562ec3a4bd40_0_2.png)

Discussion of diagnosis, etiology and treatment options

The purpose of the initial and any additional diagnostic tests is to identify the cause(s) of infertility, which could be due to female factors, male factors, a combination of these or unexplained factors, which can then be treated to improve fertility outcomes. There may be specific underlying causes of infertility, such as fibroids, endometriosis, ovarian damage caused by prior ovarian surgery, infection, obstruction, varicocele, chemotherapy and radiation therapy, among others. An important consideration is age-related fertility decline, particularly in females. As the number of oocytes in the ovaries decreases progressively through atresia (8, 9), fecundity decreases with increasing age (10). Information about the causes of infertility, including age, comorbidities, previous STIs, reproductive tract and other pelvic infections, lifestyle and behavioural factors (including exercise, BMI, diet and the use of alcohol

and tobacco products), and environmental and occupational factors, will be helpful to patients (see Chapter 4.2 on information provision for couples with infertility and Chapter 4.3 on risk reduction from use of tobacco).

Informing patients about the diagnostic and treatment options is important. When discussing treatment options, it is important to inform patients about the inter-pregnancy interval, the fertility window (as appropriate) and the likelihood of pregnancy and live birth in the context of parental goals and desired family size. Patients seeking fertility care are often anxious or worried about their diagnosis of infertility (11–13) but the ability of health care providers to identify the psychological and emotional support needs of patients is often suboptimal (14). Patients may require supportive psychosocial services on-site or via referrals.

![](1/parseimages/figure5d6fade6e02f4cdb8eb77fa7d68e02b2_0_7.png)

Good practice statement

For males and females being evaluated and managed for infertility, it is good practice to listen to individuals and couples, respect their preferences, discuss if psychological and social or peer support is needed, and if needed, provide it or refer patients for it.

![i\n](1/parseimages/figureadde709130744de6a8a1053c53175de8_0_10.png)

Provision of pre-pregnancy advice, counselling or care

The goal of providing pre-pregnancy advice, counselling or care for individuals with pregnancy intentions is to reduce the risk of adverse reproductive and obstetric outcomes by improving or optimizing health, addressing modifiable risk factors during the pre-pregnancy or peri-conception period. Providing information on factors that can increase the risk of infertility is an important part of pre-pregnancy advice, counselling and care. It provides an opportunity to assess lifestyle, improve health status and modify behaviours and other individual, behavioural and environmental factors that could contribute to poor pregnancy outcomes around the time of

conception (15). It also provides an opportunity to review medications, immunization status, nutritional status and carrier and other genetic conditions, such as neural tube defects (15). Nutrition is important during pre-pregnancy or the peri-conception period for a couple, and a balanced diet provides many vitamins and trace elements that are essential for good health (16).

diet provides many vitamins and trace elements that are essential for good health (16).

![](1/parseimages/figuref88ec2edf2924b89a6325e1c5f938915_0_15.png)

Identification and referral of patients with coexisting conditions to other services

Multiple health conditions may affect the ability to achieve pregnancy and subsequent pregnancy outcomes. Such comorbidities may coexist alongside

Guideline for the prevention, diagnosis and treatment of infertility

infertility or may contribute to infertility itself. Comorbidities may include communicable (such as STIs) or noncommunicable (such as cancer, cardiovascular disease, diabetes, and poor mental health) conditions. Depending on the capacity of the health care system, patients may need to be referred to other specialities or centres for appropriate management of the identified comorbidities. Some patients with coexisting conditions may be identified and managed easily on-site, while others may require referral to a specialist for a thorough workup and management, to ensure that no comorbidities are missed.

![=I\n](1/parseimages/figuree9b79ae8440f44cb9d7dd1e5fc95e082_0_3.png)

Agreeing on and providing treatment for infertility

Based on the identified causes of infertility, it is essential to provide appropriate treatment without unnecessary delay. Treatment is provided after agreeing with patients about the treatment approach and obtaining informed

consent, based on collaborative decision-making and transparent information from health care providers about treatment expectations and what is involved. Treatment should be evidence-based and should adhere to the non-maleficence principle (first do no harm); great care must be taken not to induce any pathology in the mother or the offspring (5). The diagnostic pathway, referral and management plan for either partner ought to be informed by the results of the tests of the other partner, and be progressively adjusted to optimize efficiency. For example, in some couples presenting initially with an isolated pathology in one partner, a relevant complementary pathology may thereafter be identified in the other partner during investigations, which may alter the overall management plan (5). See the following chapters for recommendations related to treatment of infertility because of ovulatory dysfunction (Chapter 6), tubal disease (Chapter 7), uterine cavity disorders (Chapter 8), male factors (Chapter 9) and unexplained factors (Chapter 10).

![](1/parseimages/figurea182701c710041098ef3f1f13d318be6_0_7.png)

Good practice statements

For males and females being evaluated and managed for infertility, it is good practice to base treatment decisions on benefits and harms, patient values and preferences, feasibility, costs and availability of resources.

For males and females being evaluated and managed for infertility, it is good practice to consider the cost-effectiveness of treatment (e.g. least expensive but effective treatments should be provided initially).

3 Approach to evaluation and management of infertility

![](1/parseimages/figure38a91d8fa1fe44429be5681ca194e3a8_0_2.png)

Providing a clinical follow-up and managing the risks of infertility treatment

While IVF and other fertility treatments are generally safe, a variety of risks can be encountered, which may range from minor side-effects to serious complications, such as multiple pregnancy, ovarian hyperstimulation syndrome (OHSS), infections and iatrogenic adverse effects. Infertility patients may also be exposed to a variety of risks due to cross-border reproduction, disease epidemics or natural disasters. Patients with infertility often travel long distances to access fertility care; depending on the health care system context, they may occasionally come under interim care of health care providers

who have less knowledge of infertility treatments, for example, in geographically underserved areas. In some countries, the health system may require transfer of patients to other health care providers for ongoing care after infertility treatment has been provided. Although information about the plan for clinical follow-up and management of potential risks that could occur during treatment of infertility and how to mitigate risks is desired by patients (17, 18), health care providers do not always provide it (19). It is important for health care providers to discuss clinical care plans and how potential risks can be managed with their patients, as part of a wider safety and risk management strategy for fertility care services.

![](1/parseimages/figure98904e016ee44e4d9fadbadb6db8d018_0_6.png)

Good practice statement

For males and females being evaluated and managed for infertility, it is good practice to discuss the plan for clinical follow-up and management of potential risks that may occur during infertility treatment.

![](1/parseimages/figureeb9265fd95ae4a0d81fca630c67e6c73_0_9.png)

Documenting the outcomes of infertility treatment

seeking pregnancy are generally highly motivated; however, treatment dropout rates can be high for several reasons (20–22), and among patients who complete their treatment journey, outcomes may vary. Antenatal guideline recommendations are provided by WHO to facilitate a positive pregnancy experience while enhancing continuity and quality of care throughout pregnancy and ensure good outcomes (23). However, reporting of the outcomes of infertility treatment, including of resulting

pregnancies, by health care providers is often suboptimal. Improved documentation of outcomes is required to verify the effects of infertility treatment and facilitate monitoring, surveillance and quality improvement of fertility care. Depending on the health care system context and capacity, the following may be required: referrals; integrated reporting or better data connectivity in health information systems, which enables linking ART and other medically assisted reproduction registries; birth and neonatal registries; and other electronic health records.

![](1/parseimages/figure65485aea02ed4d0e9f210ddaee7cdcd1_0_13.png)

Good practice statement

For males and females being evaluated and managed for infertility, it is good practice to document the outcomes of pregnancies resulting from infertility treatment.

Guideline for the prevention, diagnosis and treatment of infertility

References

1. International Classification of Diseases, 11th Revision (ICD-11) Geneva: World Health Organization; 2018 (https://www.who.int/classifications/icd/en/).

2. Steuber KR, Solomon DH. Relational uncertainty, partner interference, and privacy boundary turbulence: explaining spousal discrepancies in infertility disclosures. J Soc Pers Relat. 2012;29(1):3-27 (https://doi.org/10.1177/0265407511406896).

3. Bute JJ. "Nobody thinks twice about asking": women with a fertility problem and requests for information. Health Commun. 2009;24(8):752-63 (https://doi.org/10.1080/10410230903265920).

4. Inhorn MC. Sexuality, masculinity, and infertility in Egypt: potent troubles in the marital and medical encounters. J Mens Stud. 2002;10(3):343-59 (https://doi.org/10.3149/jms.1003.343).

5. Rowe PJ, Comhaire FH, Hargreave TB, Mahmoud AM. WHO manual for the standardized investigation and diagnosis of the infertile male. Cambridge: Cambridge University Press; 2000 (https://iris who.int/handle/10665/42437).

6. Rowe PJ, Comhaire FH, Hargreave TB, Mellows HJ, editors. WHO manual for the standardized investigation and diagnosis of the infertile couple. Cambridge: Cambridge University Press; 1993 (https://iris.who.int/handle/10665/36983).

7. WHO laboratory manual for the examination and processing of human semen, sixth edition. Geneva: World Health Organization; 2021 (https://iris.who.int/bitstream/handle/10665/343208/9789240030787-eng.pdf)

8. Wallace WH, Kelsey TW. Human ovarian reserve from conception to the menopause. PLoS One. 2010;5(1):e8772 (https://doi.org/10.1371/journal.pone.0008772).

9. Matsuda F, Inoue N, Manabe N, Ohkura S. Follicular growth and atresia in mammalian ovaries: regulation by survival and death of granulosa cells. J Reprod Dev. 2012;58(1):44-50 (https://doi.org/10.1262/jrd.2011-012).

10. Chua S, Danhof N, Mochtar M, Van Wely M, McLernon D, Custers I et al. Age-related natural fertility outcomes in women over 35 years: a systematic review and individual participant data meta-analysis. Hum Reprod. 2020;35(8):1808-20 (https://doi.org/10.1093/humrep/deaa129).

11. Simionescu G, Doroftei B, Maftei R, Obreja BE, Anton E, Grab D et al. The complex relationship between infertility and psychological distress (review). Exp Ther Med. 2021;21(4):306 (https://doi.org/10.3892/etm.2021.9737).

12. Greil AL. Infertility and psychological distress: a critical review of the literature. Soc Sci Med. 1997;45(11):1679-704 (https://doi.org/10.1016/s0277-9536(97)00102-0).

13. Nik Hazlina NH, Norhayati MN, Shaiful Bahari I, Nik Muhammad Arif NA. Worldwide prevalence, risk factors and psychological impact of infertility among women: a systematic review and meta-analysis. BMJ Open. 2022;12(3):e057132 (https://doi.org/10.1136/bmjopen-2021-057132).

14. Murray S, Awartani KA, Péloquin S. International challenges in patient-centred care in fertility clinics offering assisted reproductive technology: providers' gaps and attitudes towards addressing the patients' psychological needs. J Eur CME. 2015;4(1):27578 (https://doi.org/10.3402/jecme.v4.27578).

15. Preconception care: maximizing the gains for maternal and child health. Geneva: World Health Organization; 2013 (https://iris.who.int/bitstream/handle/10665/340533/WHO-FWC-MCA-13.02-eng.pdf?sequence=1).

16. Vitamin and mineral requirements in human nutrition. Geneva: World Health Organization and Food and Agriculture Organization of the United Nations; 2004 (https://iris.who.int/handle/10665/42716).

17. Dancet EAF, Nelen WLDM, Sermeus W, De Leeuw L, Kremer JAM, D'Hooghe TM. The patients' perspective on fertility care: a systematic review. Hum Reprod Update. 2010;16(5):467-87 (https://doi.org/10.1093/humupd/dmq004).

3 Approach to evaluation and management of infertility

18. von Estorff F, Mochtar MH, Lehmann V, van Wely M. Driving factors in treatment decision-making of patients seeking medical assistance for infertility: a systematic review. Hum Reprod Update. 2024;30(3):341-54 (https://doi.org/10.1093/humupd/dmae001).

19. Stewart DE, Rosen B, Irvine J, Ritvo P, Shapiro H, Murphy J et al. The disconnect: infertility patients' information and the role they wish to play in decision making. Medscape Womens Health. 2001;6(4):1 (http://europepmc.org/abstract/MED/11547268).

20. Gameiro S, Boivin J, Peronace L, Verhaak CM. Why do patients discontinue fertility treatment? A systematic review of reasons and predictors of discontinuation in fertility treatment. Hum Reprod Update. 2012;18(6):652-69 (https://doi.org/10.1093/humupd/dms031).

21. Ghorbani M, Hoseini FS, Yunesian M, Salehin S, Keramat A, Nasiri S. A systematic review and meta-analysis on dropout of infertility treatments and related reasons/factors. J Obstet Gynaecol. 2022;42(6):1642-52 (https://doi.org/10.1080/01443615.2022.2071604).

22. Shen Q, Wang B, He T, Li S, Peng E, Lei J. Factors associated with discontinuation in fertility treatment: a systematic scoping review. J Assist Reprod Genet. 2024;41:409-21 (https://doi.org/10.1007/s10815-023-02982-x).

23. WHO recommendations on antenatal care for a positive pregnancy experience. Geneva: World Health Organization; 2016 (https://www.who.int/publications/i/item/9789241549912).

Chapter 4 Prevention of infertility

This chapter presents several recommendations related to the prevention of infertility.

4.1 Information provision on fertility and infertility for the general population

4.2 Information provision for individuals and couples with infertility

4.3 Risk reduction from the use of tobacco $\rightarrow$

4.4 Risk reduction from sexually transmitted infections $\rightarrow$

Relevant resources

Web Annex B. Evidence to decision tables for prevention of infertility $\rightarrow$

4 Prevention of infertility

4.1 Information provision on fertility and infertility for the general population

![](1/parseimages/figure8f8b3e779d824824b83ff0edf8178ad1_0_3.png)

Recommendation

Remarks:

$\bullet$ Information adapted to local contexts and audiences, including how to reduce risk factors for infertility, lifestyle modification, age-related fertility decline/ potential, and timely medical consultation, may increase the likelihood of information uptake and beneficial outcomes.

Background and rationale

Education about fertility and infertility can be provided at various stages of the reproductive lifespan, for example, to the general population who may consider concelving in the future, individuals who are trying to achieve a pregnancy, people who are at high risk of infertility or those who are already experiencing infertility.

Information on fertility and infertility can be provided at different time points in relation to risk factors that limit fertility: (i) before the risk factor is present; (ii) when the risk factor is present but not yet fertility-limiting (population is at risk); or (iii) when the disease is present (population has infertility). The present recommendation applies to the general population not at risk of infertility.

For the general population, fertility education can include information on fertility potential, risk factors for infertility and how to reduce risk factors or improve healthy lifestyle factors in general. The aim of information provision in this (presumed fertile) population is to improve fertility awareness and future pregnancy planning. Fertility awareness is defined as the “understanding of reproduction, fecundity, fecundability, and related individual risk factors (e.g. advanced age, sexual health factors

such as sexually transmitted infections (STIs), and lifestyle factors such as smoking, obesity) and non-individual risk factors (e.g. environmental and workplace factors); including the awareness of societal and cultural factors affecting options to meet reproductive family planning, as well as family building needs" (1).

Fertility education can be provided through a variety of methods, including information pamphlets, brochures, counselling and online platforms, such as websites, videos or animations, mobile applications or other information tools aimed at increasing public awareness about fertility and infertility. It can be provided individually or in group settings. Other preventive interventions can also be provided to the general population to reduce risk factors that go beyond simply education, such as nutrition and fitness and wellness programmes. Recommendations for these types of interventions are not addressed in this guideline but will be in the future.

For this recommendation, the GDG addressed the question: should information on fertility and infertility be provided to the general population or people who are not at risk or not?

Guideline for the prevention, diagnosis and treatment of infertility

Fig. 4.1. Information on fertility and infertility

![Providing informationSchools / educationa一on fertility andinstitutionsinfertility to peopleIntegrate into healthof reproductive ageeducationhelps reduce riskfactors and promotesWhere toPrimary caretimely care-seeking.During routine healthIt also enablesprovide fertilityvisits and checkupsreproductive planning.information一Sexual healthFamily planning andreproductive clinicsUnderstandingHealthy lifestyleinfertilityRisk factors include:What infertility is, commonKey messages● smoking,causes, when to seek help● excessive alcohol useand available support options· obesityfor individuals and couples● being underweight●others (see Chapters 1 and 4of this quideline).\n](1/parseimages/figurefb85f5515a924e1a81c2c59eeccbcf70_0_3.png)

Age-related fertility decline

Understanding fertility potential changes with age especially among females

Balancing harms and benefits

A systematic review was conducted and identified nine trials (10 publications) that reported on the effects of specific information provision interventions on a group of participants. Two trials recruited women presenting at primary care clinics (2) or to donate oocytes (3). Two trials recruited women visiting midwives for contraceptive counselling (4, 5). Four trials recruited adolescents and young adults (6-10) and one trial involved women of reproductive age (11). One study included men (8). All studies compared an education intervention to a control or no

Sexual health

Untreated sexually transmitted infections can cause infertility

intervention. Specific education interventions addressed in these trials included:

$\bullet$ fertility-related brochures (3, 6, 8, 9, 11);

$\bullet$ fertility-related� brochures (3, 6, 8, 9, 11);

$\bullet$ reproductive life plan counselling (2-5);

$\bullet$ informative fertility awareness videos (7);

$\bullet$ fertility education chatbot (11).

When considering the effects of all information provision interventions compared to a control or no intervention, evidence indicated that there may be small benefits. Knowledge is likely increased with education, but intentions to improve pre-pregnancy behaviours or optimally plan for

4 Prevention of infertility

pregnancy (e.g. advanced intended timing of childbirth or the age of the first or last child) are likely minimally changed or inconsistently affected. The GDG was uncertain about the effects of education on live births (54 more [from 11 fewer to 226 more] per 1000; relative risk [RR]: 2.12; 95% confidence interval [CI]: 0.78-5.71 after 1 year of follow-up; 42 more [from 31 fewer to 146 more] per 1000; RR: 1.22; 95% CI: 0.84-1.76 after 2 years of follow-up) and there were no data on pregnancy. The GDG was also uncertain about whether education may accelerate the timing of childbirth: in one study (8), where the sample mean age was 30-31 years, there was a fivefold increase in new births at 12 months among partnered individuals in the intervention group compared to the control group; however, both groups had similar numbers of new births at 24 months.

In terms of undesirable effects, the GDG judged that information provision probably results in a trivial increase in anxiety levels compared to no information provision (mean difference: 1.94 higher with education; 95% CI: 1.18-2.7 higher on the State subscale of the State-Trait Anxiety Inventory score; score range: 20-80) (12).

Overall, the GDG agreed that there may be greater benefit than harm with fertility information provision, but the certainty of evidence was very low because of few participants or events, high heterogeneity and potential risk of bias because of poor randomization and incomplete data. Given that outcomes such as live births and pregnancy are probably the most important to most individuals trying to achieve pregnancy, the GDG agreed that providing education is probably favoured.

Other considerations

Provision of information requires resources and results in additional costs when applied population-wide. The GDG judged that the resources required for fertility education vary depending on context and the methods used to disseminate information. Some modalities, such as brochures or pamphlets, cost less when compared to other interventions, such as counselling. Therefore, when costs are low, small and uncertain benefits could outweigh the costs but the downsides of high-cost interventions would outweigh potential benefits.

Regarding equity, the GDG agreed that providing education could be applied across different populations and settings and may not have a differential impact on equity because the whole population would be reached with the intervention. However, differences could emerge if the method of providing education was more resource-intensive (e.g. providing in-person counselling for some populations and information leaflets for other populations).

Several studies provided evidence on the acceptability of fertility-related brochures (6, 13), reproductive life plan counselling (2, 4, 5, 14), chatbot education (11) and a culturally adapted fertility status awareness tool (FertiSTAT) (15). Based on data from these studies, the GDG judged that both the general population and health care providers would probably find education interventions acceptable. In addition, the GDG judged that providing information to the general population would be feasible in schools, clinics and primary care settings where other health information is being provided and noted that information and education should be adapted and tailored to local contexts, the audience, risk factors and methods of dissemination.

Guideline for the prevention, diagnosis and treatment of infertility

![](1/parseimages/figured4f541fd219e4d9f8fc4fe378be07360_0_2.png)

Summary justification

Overall, there is very-low-certainty evidence for small benefits, such as increased knowledge and improved behaviours, and for trivial harms, such as anxiety, when providing fertility information. Evidence is very uncertain on the effect of information on live births, and no data are available on pregnancies. Providing information may incur varying costs depending on the format or channel used; therefore, when cheaper dissemination methods, such as pamphlets and posters, are used, benefits may likely outweigh the costs in the general population not at risk (i.e. the presumed fertile general population). However, when costly strategies are used, such as counselling, the benefits are unlikely to outweigh the costs. Provision of information adapted and tailored to local contexts and audiences is probably acceptable and probably feasible.

Fig. 4.2. Recommendations for preventing infertility included in the guideline

General population of reproductive age

Provide fertility information whenever there's an opportunity in schools / educational institutions, primary health care centres, and contraceptive/ sexual health clinics

Risk reduction from Sexually transmitted infections (STIs)

Routinely inform people planning or attempting pregnancy about infertility risk when STIs are untreated; encourage or refer for prompt care for symptoms

Individuals and couples with infertility

Offer lifestyle advice before and during infertility treatment (e.g., diet, alcohol, smoking, physical activity, weight management)

Preventing infertility

Risk reduction from tobacco smoking

Provide brief advice to all tobacco users in any health-care setting, explaining that smoking is associated with higher infertility risk and that cessation support exists

4 Prevention of infertility

Implementation considerations

Education messages need to be adapted and tailored to local contexts, risk factors, the audience (e.g. age and sex among others) and available methods of dissemination. For example, educational resources can be co-designed with the participation of the intended target audience, in their contexts. In all contexts providing specific information on age-related fertility decline/potential, and the long-term impact of lifestyle factors will be important. It is important for individuals and couples to obtain accurate information on fertility and infertility from trusted sources to minimize the risk of misinformation (e.g. via social media [16] or online marketing [17]); health care providers have a role in providing educational information that can inform reproductive planning. In implementing this recommendation, health care providers should note that this guideline contains several

recommendations for preventing infertility for different population groups and risk factors (See Fig. 4.1 and Fig. 4.2).

Research gaps and future guideline update

Given the variability in the evidence on the impact of information provision on fertility outcomes, future evaluation of what information works for whom, in which setting and why, will be needed to ascertain the value of providing information to the public according to the context. Future research is required to ascertain whether subpopulations of people (e.g. partnered individuals, single women of advanced age, among others) may respond differently to fertility information. Fertility education should include men because men also benefit from fertility education; therefore, future studies should include more men as they were underrepresented in the studies evaluated.

References

1. Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, De Mouzon J, Sokol R et al. The international glossary on infertility and fertility care, 2017. Hum Reprod. 2017;32(9):1786-801 (https://doi.org/10.1093/humrep/dex234).

2. Fooladi E, Weller C, Salehi M, Abhari FR, Stern J. Using reproductive life plan-based information in a primary health care center increased Iranian women's knowledge of fertility, but not their future fertility plan: a randomized, controlled trial. Midwifery. 2018;67:77-86 (https://doi.org/10.1016/j.midw.2018.09.011).

3. García D, Vassena R, Prat A, Vernaeve V. Increasing fertility knowledge and awareness by tailored education: a randomized controlled trial. Reprod Biomed Online. 2016;32(1):113-20 (https://doi.org/10.1016/j.rbmo.2015.10.008).

4. Skogsdal Y, Fadl H, Cao Y, Karlsson J, Tydén T. An intervention in contraceptive counseling increased the knowledge about fertility and awareness of preconception health—a randomized controlled trial. Ups J Med Sci. 2019;124(3):203-12 (https://doi.org/10.1080/03009734.2019.1653407).

5. Stern J, Larsson M, Kristiansson P, Tydén T. Introducing reproductive life plan-based information in contraceptive counselling: an RCT. Hum Reprod. 2013;28(9):2450-61 (https://doi.org/10.1093/humrep/det279).

6. Boivin J, Koert E, Harris T, O'Shea L, Perryman A, Parker K et al. An experimental evaluation of the benefits and costs of providing fertility information to adolescents and emerging adults. Hum Reprod. 2018;33(7):1247-53 (https://doi.org/10.1093/humrep/dey107).

7. Conceição C, Pedro J, Martins MV. Effectiveness of a video intervention on fertility knowledge among university students: a randomised pre-test/post-test study. Eur J Contracept Reprod Health Care. 2017;22(2):107-13 (https://doi.org/10.1080/13625187.2017.1288903).

8. Maeda E, Boivin J, Toyokawa S, Murata K, Saito H. Two-year follow-up of a randomized controlled trial: knowledge and reproductive outcome after online fertility education. Hum Reprod. 2018;33(11):2035-42 (https://doi.org/10.1093/humrep/dey293).

Guideline for the prevention, diagnosis and treatment of infertility

9. Maeda E, Nakamura F, Kobayashi Y, Boivin J, Sugimori H, Murata K et al. Effects of fertility education on knowledge, desires and anxiety among the reproductive-aged population: findings from a randomized controlled trial. Hum Reprod. 2016;31(9):2051-60 (https://doi.org/10.1093/humrep/dew133).

10. Williamson LEA, Lawson KL, Downe PJ, Pierson RA. Informed reproductive decision-making: the impact of providing fertility information on fertility knowledge and intentions to delay childbearing. J Obstet Gynaecol Can. 2014;36(5):400-5 (https://doi.org/10.1016/S1701-2163(15)30585-5).

11. Maeda E, Miyata A, Boivin J, Nomura K, Kumazawa Y, Shirasawa H et al. Promoting fertility awareness and preconception health using a chatbot: a randomized controlled trial. Reprod Biomed Online. 2020;41(6):1133-43 (https://doi.org/10.1016/j.rbmo.2020.09.006).

12. Spielberger CD, Gonzalez-Reigosa F, Martinez-Urrutia A, Natalicio LF, Natalicio DS. The state-trait anxiety inventory. Interam J Psychol. 197;5:3-4.

13. Boivin J, Sandhu A, Brian K, Harrison C. Fertility-related knowledge and perceptions of fertility education among adolescents and emerging adults: a qualitative study. Hum Fertil. 2019;22(4):291-9 (https://doi.org/10.1080/14647273.2018.1486514).

14. Bodin M, Tydén T, Käll L, Larsson M. Can reproductive life plan-based counselling increase men's fertility awareness? Ups J Med Sci. 2018;123(4):255-63 (https://doi.org/10.1080/03009734.2018.1541948).

15. Bayoumi RR, van der Poel S, El Samani EZ, Boivin J. An evaluation of comprehensiveness, feasibility and acceptability of a fertility awareness educational tool. Reprod Biomed Soc Online. 2018;6:10-21 (https://doi.org/10.1016/j.rbms.2018.06.003).

16. John JN, Gorman S, Scales D, Gorman J. Online misleading information about women's reproductive health: a narrative review. J Gen Intern Med. 2025;40:1123-31 (https://doi.org/10.1007/s11606-024-09118-6).

17. Copp T, Pickles K, Smith J, Hersch J, Johansson M, Doust J et al. Marketing empowerment: how corporations co-opt feminist narratives to promote non-evidence based health interventions. BMJ. 2024;384:e076710 (https://doi.org/10.1136/bmj-2023-076710).

4 Prevention of infertility

4.2 Information provision for individuals and couples with infertility

![](1/parseimages/figure24d770a7c8cc4af08f25e40e87fc8494_0_3.png)

Recommendation

For individuals and couples with infertility, WHO suggests providing low-cost lifestyle advice before and during infertility treatment. (Conditional recommendation, low certainty of evidence)

Remarks:

* Lifestyle advice may include advice to change diet, alcohol intake, smoking, physical activity and/or weight management.

Background and rationale

Lifestyle advice can be provided at various stages of the reproductive lifespan, for example, to the general population who may consider having a child in the future, individuals who are currently trying to achieve pregnancy, people who are at high risk of infertility or those who are already diagnosed with infertility. The present recommendation refers to individuals with infertility.

Modifiable lifestyle behaviours such as diet, physical activity, alcohol intake and smoking may affect fertility (1). Although the extent of the impact varies (2), these factors may negatively affect the ability of people with infertility to achieve a pregnancy resulting in a live birth. Providing lifestyle advice regarding these factors to people with infertility is intended to optimize the pre-pregnancy health of women and men with infertility and improve their fertility outcomes, such as achieving a pregnancy or live birth. Lifestyle advice includes provision of information, education or counselling about modifiable lifestyle behaviours.

For people with infertility, lifestyle advice could be provided before beginning infertility treatments such as ovulation induction, intrauterine insemination (IUI) or IVF or when receiving these treatments. Lifestyle advice can be provided individually or in group counselling sessions, through web-based or mobile-based applications, telephone calls, pamphlets, booklets or by a combination of these and other delivery channels.

For this recommendation, the GDG addressed the question: should lifestyle advice be provided to people with infertility or not?

Balancing harms and benefits

A published systematic review provided data for this assessment (3). Seven randomized controlled trials (RCTs) published up to January 2021 were included in this review. Most couples and women with infertility in the studies received information before and/or while receiving fertility treatment, specifically: before fertility treatment in the intervention group (4, 5); before ovulation induction (6); while receiving IVF, IUI or none (7); before any type of fertility treatment in the intervention group (8); while undergoing IVF treatment (9); while having investigations or receiving treatment (10); or before or while undergoing IVF with or without intracytoplasmic sperm injection (ICSI) (11). Of these, one study included men and women (11).

The types of lifestyle advice included a smartphone coaching programme, individual and group counselling (motivational interviewing) and workouts, or information and behavioural modification. Lifestyle advice was provided for 6–24 months.

In terms of desirable effects, the GDG agreed that there are likely small effects on important outcomes, such as live births and clinical pregnancies (RR: 0.90; 95% CI: 0.77–1.06 and

Guideline for the prevention, diagnosis and treatment of infertility

RR: 1.17; 95% CI: 0.90–1.53, respectively). There is likely no difference to behavioural changes, although diet-related behaviours (such as fruit intake and lower alcohol intake) may be slightly improved. Evidence suggests no difference to quality of life.

In terms of undesirable effects, evidence suggested trivial increases in miscarriages (RR: 1.49; 95% CI: 0.96–2.32, meaning 46 more [from four fewer to 124 more] per 1000 couples) and hypertension during pregnancy (RR: 1.07; 95% CI: 0.66–1.75, meaning 11 more [from 55 fewer to 121 more] per 1000 couples). The overall certainty of evidence was low because of lack of blinding, unclear randomization in some studies and few participants or events. Notably, most of the control groups in the studies also received some form of lifestyle advice. As such, comparisons were more about the effects of more intensive or detailed forms of providing advice than no advice per se. The GDG agreed that couples value pregnancy and live births and that there is probably no important variability in how people value these outcomes. Overall, the GDG judged that the balance of effects probably favours information provision over no provision of information on lifestyle.

Other considerations

Provision of lifestyle advice involves resources; however, the GDG judged that the costs vary: some lifestyle advice interventions may be costly (such as individual one-to-one counselling), while others may

incur lower costs (e.g. information brochures). The GDG also considered evidence from two studies (12, 13) showing that providing lifestyle advice could be cost-effective. When considering the small increase in pregnancy rates, a low-cost lifestyle advice intervention may be favoured.

In relation to equity, the GDG noted that while not all forms and intensities of information delivery would be available everywhere, individuals with infertility could be reached with lifestyle advice through delivery methods available locally. However, differences in equity could emerge if the method of providing lifestyle advice was more resource-intensive (e.g. providing in-person counselling for some populations and settings, and information leaflets for other populations and settings).

The GDG considered evidence from two studies (6, 11) and agreed that providing lifestyle advice may be acceptable to most couples; however, increased efforts to maintain participation may be needed. The GDG noted that the evidence is from couples before or during treatment, who were also receiving different fertility treatments; therefore, lifestyle advice is likely applicable and acceptable to couples at different treatment stages or receiving a variety of fertility treatments. None of the studies examined the effects in people with infertility who chose not to undergo treatment. Feasibility may be dependent on the intensity and timing of the lifestyle advice; intense or multi-component lifestyle advice may be more challenging to provide and use.

![=0-=\n](1/parseimages/figure638f4b4734174e8ea8a4a8093e72deab_0_9.png)

Summary justification

Overall, there is low-certainty evidence that the small improvements in live births and pregnancy and health behaviours may outweigh the trivial harms. Although costs may be greater for some types of lifestyle advice, the benefits may outweigh costs when low-cost lifestyle advice is provided. Providing lifestyle advice is probably acceptable to most people, and feasible.

4 Prevention of infertility

Implementation considerations

When implementing this guideline, health care providers should try to maintain contact and engagement with patients. Sustained engagement for some populations (e.g. patients who need to manage their weight [14]) and some forms of lifestyle advice (e.g. more intensive forms of lifestyle face-to-face advice) may be difficult to maintain unless specific efforts are put in place. The goal should be to respectfully explain lifestyle-related risk factors and provide advice, while remaining sensitive to patient experiences and avoiding placing blame on them.

Health care providers should monitor and support compliance and should regularly assess prevalent lifestyle risks (e.g. during clinic visits) to continually tailor lifestyle advice. Health care providers should select contextually appropriate lifestyle advice and delivery channels

according to prevalent lifestyle risks and audience preferences in different settings.

Research gaps and future guideline update

Future research and guidance will be needed on the optimal components of lifestyle advice, their timing and intensity. In addition, future studies should include a diverse group of patients, including men, the male and female partners of patients, and men and women of advanced age, among others. Most of the available evidence is about couples who are receiving ART; future studies should include couples with infertility who are not and people not seeking any medical treatment. Future guidance will be required for specific subgroups, such as those with a high BMI and impaired glucose tolerance, among others. Future research is needed on which lifestyle modification techniques are optimal for achieving the desired effects.

References

1. Sharma R, Biedenharn KR, Fedor JM, Agarwal A. Lifestyle factors and reproductive health: taking control of your fertility. Reprod Biol Endocrinol. 2013;11:66 (https://doi.org/10.1186/1477-7827-11-66).

2. Homan GF, Davies M, Norman R. The impact of lifestyle factors on reproductive performance in the general population and those undergoing infertility treatment: a review. Hum Reprod Update. 2007;13(3):209-23 (https://doi.org/10.1093/humupd/dml056).

3. Boedt T, Vanhove AC, Vercoe MA, Matthys C, Dancet E, Lie Fong S. Preconception lifestyle advice for people with infertility. Cochrane Database Syst Rev. 2021;(4):CD008189 (https://doi.org/10.1002/14651858.CD008189.pub3).

4. Belan M, Carranza-Mamane B, AinMelk Y, Pesant M-H, Duval K, Jean-Denis F et al. Lifestyle modifications in male partners of subfertile couples in which the spouse is obese improves the chances of the couple to conceive. Fertil Steril. 2019;112(3):e213 (https://doi.org/10.1016/j.fertnstert.2019.07.670).

5. Belan M, Carranza-Mamane B, AinMelk Y, Pesant M-H, Duval K, Jean-Denis F et al. A lifestyle intervention targeting women with obesity and infertility improves their fertility outcomes, especially in women with PCOS: a randomized controlled trial. Fertil Steril. 2019;112(3):e40 (https://doi.org/10.1016/j.fertnstert.2019.07.234).

6. Mutsaerts MA, Van Oers AM, Groen H, Burggraaff JM, Kuchenbecker WK, Perquin DA et al. Randomized trial of a lifestyle program in obese infertile women. N Engl J Med. 2016;374:1942-53 (https://doi.org/10.1056/NEJMoa1505297).

Guideline for the prevention, diagnosis and treatment of infertility

7. Alibeigi Z, Jafari-Dehkordi E, Kheiri S, Nemati M, Mohammadi-Farsani G, Tansaz M. The impact of traditional medicine-based lifestyle and diet on infertility treatment in women undergoing assisted reproduction: a randomized controlled trial. Complement Med Res. 2020;27(4):230-41 (https://doi.org/10.1159/000505016).

8. Hughes EG, Lamont DA, Becroft ML, Wilson DM, Brennan BG, Rice SC. Randomized trial of a "stage-of-change" oriented smoking cessation intervention in infertile and pregnant women. Fertil Steril. 2000;74(3):498-503 (https://doi.org/10.1016/s0015-0282(00)00687-7).

9. Rossi BV, Chang G, Berry KF, Hornstein MD, Missmer SA. In vitro fertilization outcomes and alcohol consumption in at-risk drinkers: the effects of a randomized intervention. Am J Addict. 2013;22(5):481-5 (https://doi.org/10.1111/j.1521-0391.2013.12019.x).

10. Ng KYB, Wellstead S, Cheong Y, Macklon N. A randomised controlled trial of a personalised lifestyle coaching application in modifying periconceptional behaviours in women suffering from reproductive failures (IPLAN trial). BMC Womens Health. 2018;18(1):196 (https://doi.org/10.1186/s12905-018-0689-7).

11. Oostingh EC, Koster MP, van Dijk MR, Willemsen SP, Broekmans FJ, Hoek A et al. First effective mHealth nutrition and lifestyle coaching program for subfertile couples undergoing in vitro fertilization treatment: a single-blinded multicenter randomized controlled trial. Fertil Steril. 2020;114(5):945-54 (https://doi.org/10.1016/j.fertnstert.2020.04.051).

12. Oostingh EC, Ophuis RH, Koster MP, Polinder S, Lingsma HF, Laven JS et al. Mobile health coaching on nutrition and lifestyle behaviors for subfertile couples using the smarter pregnancy program: model-based cost-effectiveness analysis. JIMR Mhealth Uhealth. 2019;7(10):e13935 (https://doi.org/10.2196/13935).

13. Van Oers AM, Mutsaerts MA, Burggraaff JM, Kuchenbecker WK, Perquin DA, Koks CA et al. Cost-effectiveness analysis of lifestyle intervention in obese infertile women. Hum Reprod. 2017;32(7):1418-26 (https://doi.org/10.1093/humrep/dex092).

14. Burgess E, Hassmén P, Welvaert M, Pumpa KL. Behavioural treatment strategies improve adherence to lifestyle intervention programmes in adults with obesity: a systematic review and meta-analysis. Clin Obes 2017;7(2):105-14 (https://doi.org/10.1111/cob.12180).

4 Prevention of infertility

4.3 Risk reduction from the use of tobacco

![](1/parseimages/figure1fe47b8165784a6fa6e0d5a2110ace04_0_3.png)

Recommendation

Remarks:

$\bullet$ This is an existing WHO recommendation for the general population that also applies to individuals and couples who are planning a pregnancy, attempting to achieve a pregnancy or with infertility, given the association between infertility and a current or previous history of smoking.

$\bullet$ Assessment of lifestyle, including the use of tobacco, is part of medical history-taking when evaluating individuals and couples for infertility.

$\bullet$ Brief advice is advice to stop using tobacco – usually taking only a few minutes – given to all tobacco users, usually during a routine consultation or interaction.

Background and rationale

Tobacco use is highly prevalent among populations of reproductive age (1, 2) and is a leading cause of morbidity and mortality globally (2-5). Nicotine is the pharmacologically active compound that occurs naturally in the tobacco plant and is typically consumed via inhalation or ingestion. It is highly addictive; a significant number of people who use tobacco regularly do so because they are addicted to it (6, 7).

Tobacco has negative effects on health (5). Cigarette smoke contains several chemicals that may act in isolation or cumulatively (8) to negatively affect

cellular apoptosis, autophagy, DNA damage, meiosis and signalling (8, 9). These effects of cigarette smoke may be mediated by individual vulnerability, timing and type of exposure (8). For this recommendation, the GDG addressed the question: should brief advice about tobacco be provided to couples who are planning a pregnancy, attempting to achieve a pregnancy or with infertility when they access health care settings or not?

Balancing harms and benefits

A recommendation concerning brief advice to tobacco users was published in 2024 in the WHO clinical treatment guideline for tobacco cessation

Guideline for the prevention, diagnosis and treatment of infertility

in adults (10). It built on existing WHO guidance, including the actions recommended by the guidelines for implementation of Article 14 of the WHO Framework Convention on Tobacco Control to help tobacco users quit as part of a tobacco control approach (11). The GDG adopted this recommendation by considering the evidence used to make the original recommendation.

Evidence of the harms and benefits used to make the original recommendation

A systematic review of 13 RCTs comparing the provision of brief advice to no advice to tobacco users provided information about the benefits of brief advice (10). The review found that brief advice slightly increases short-term abstinence from smoking and likely increases it over the long term. However, brief advice probably has little to no effect on quitting attempts. No harms were reported in the systematic review. Subgroup analyses found that the effects were similar across multiple populations. The GDG noted that the evidence reviewed for the original recommendation was not specific to populations planning a pregnancy or attempting to achieve a pregnancy.

Applicability of evidence to men and women planning a pregnancy or attempting to achieve a pregnancy

To determine whether the evidence from the original systematic review of brief advice would also be beneficial to people planning a pregnancy, or attempting to achieve a pregnancy, we conducted an overview of reviews published since 2015 and tracked references to other systematic reviews. Four reviews were found that covered smoking and the risk of infertility in men or women.

Several reviews published before 2015 reported a positive association between smoking and infertility in women. A 1998 review reported that the odds of infertility among female smokers was 1.6 times (95% CI: 1.3–1.9) the odds in non-smokers (12). In 2011, a comprehensive review of clinical

and experimental studies evaluated the effects of exposure to cigarette smoke across different stages of reproduction from folliculogenesis to implantation. The review suggested that cigarette smoking impairs, alters, adversely affects or interferes with normal reproductive functions (8). More recently, a review of three non-randomized studies reported that the odds of infertility in female smokers was 1.85 times (95% CI: 1.08–2.14) the odds in non-smokers (13).

Evidence on infertility and smoking in men was reviewed in a 2016 study, which assessed the association between smoking and semen quality using the 2010 WHO laboratory manual for the examination and processing of human semen. Twenty studies with 5865 men contributed to the analyses (14). It reported that smoking may be associated with a reduction in some semen parameters: semen volume; sperm count; sperm motility; and sperm morphology. A subgroup analysis of a smaller set of studies reported that reductions in semen parameters may be greater in moderate and heavy smokers. Although some results were statistically significant, it is not clear whether the magnitude of the reductions in semen parameters is clinically relevant and whether the observed reductions affect fertility, given that semen parameters per se are not a reliable indicator of male fertility status (15, 16).

Other considerations

No research evidence was identified specifically from fertility contexts regarding the feasibility, acceptability, equity, cost or cost-effectiveness of brief advice. In keeping with the recommendation and evidence published in the original recommendation in the WHO clinical treatment guideline for tobacco cessation in adults in 2024 (10), the GDG agreed that brief advice was also supported by its likely feasibility and acceptability, negligible costs, cost-effectiveness and low impact on equity.

4 Prevention of infertility

![=②\n](1/parseimages/figure07da3e8a67b74c9cb086acc74fe31e4c_0_2.png)

Summary justification

The GDG adopted the strong recommendation for brief advice for all tobacco smokers from the WHO clinical treatment guideline for tobacco cessation in adults published in 2024 (10). There was moderate certainty of evidence in the general population for the benefits of providing brief advice. Given that there is likely an association of smoking with infertility in women and there may be an association of smoking with reduced semen parameters in men, the GDG decided that this evidence would apply directly to couples who are planning a pregnancy or attempting to achieve a pregnancy. The GDG also agreed with the judgements in the original recommendation that providing brief advice is probably low-cost, feasible, acceptable and would probably have no impact on equity.

Implementation considerations

$\rightarrow$ Assessment of lifestyle, including the use of tobacco, is part of the medical history-taking (see Chapter 3 and accompanying algorithms in this guideline). This guideline suggests providing information about fertility and infertility using low-cost strategies, or whenever there is an opportunity, including how to reduce risk factors for infertility (see Chapter 4). Despite the need, information on the risks of tobacco smoking, and referral to tobacco cessation services, are not consistently provided by health care providers during the pre-pregnancy period (17) at primary health care centres (18, 19), when referring for fertility care (20), or when providing infertility evaluation and treatment (17, 21).

Development of specific job aids or tools (such as scripts) for brief advice may be necessary to ensure that messages provided by health care providers are consistent. Brief advice should be tailored or personalized based on individual circumstances and may need to be adapted to local contexts and audiences.

Depending on the context, advice may be tailored to the audience to pinpoint the biological functions that are affected by smoking. For more information on the 5As (referred to in the remarks section), see the existing WHO guidance related to disease interventions at the primary health care level (22).

Health care providers should note that not all smokers may be willing to quit; however, those willing to quit may be more receptive to being provided information, and offered or referred to appropriate services aimed at aiding cessation. Providing access to and encouraging the use of effective cessation interventions increases the likelihood of successfully quitting tobacco; however, health care providers should respect individual choice. Repeated brief advice during appointments can allow progressive tailoring of information and dialogue to the specific circumstances and readiness to quit of an individual (20); however, health care providers should note that acceptability of persistent information can differ among smokers because it can evoke guilt, self-blame or frustration (23). The goal should be to respectfully provide brief advice, while remaining sensitive to patient experiences and avoiding putting the blame on patients.

People who are willing to quit may prefer using some or multiple tobacco cessation interventions. To identify the range of interventions that couples can be informed about, provided with or referred to, health care providers should refer to the WHO clinical treatment guideline for tobacco cessation in adults (10) and other existing WHO guidelines for preventing tobacco use uptake, promoting tobacco cessation or diagnosing and treating tobacco dependence (11, 22, 24). Given that tobacco cessation can be influenced by social interactions, including with partners (25, 26), health

Guideline for the prevention, diagnosis and treatment of infertility

care providers should aim to reach both partners in a couple with brief advice, based on individual circumstances.

$\rightarrow$ Tobacco use may adversely affect maternal or neonatal outcomes after pregnancy. The WHO guideline on antenatal care provides recommendations regarding the need for health care providers to ask all pregnant women about their tobacco use (past and present) and exposure to second-hand smoke as early as possible in the pregnancy and at every antenatal care visit (27).

Cigarette smoking can have negative effects on a range of reproductive parameters or functions in women (8, 9, 28, 29) or men (14, 30). However, more research is needed in assessing and quantifying the risk of infertility in men who smoke or use tobacco.

Additionally, the GDG is aware of studies exploring the effects of cessation of tobacco smoking on fecundability in women (31–33) and on sperm parameters in men (34–36), which suggests that smoking cessation could have a role in reversing infertility. More research addressing this question would be beneficial for future guideline updates. Future guidance will be required regarding information that should be provided by health care providers regarding tobacco use during assisted reproduction, which is not within the scope of this PICO question because it relates to a slightly different population (i.e. people already diagnosed with infertility, who are accessing ART). Future guidance will also be required in relation to exposure to secondary smoke, use of vapes and e-cigarettes, non-smoked/smokeless tobacco products, as well as other smoked substances, such as cannabis (see section 12.2).

References

1. Jafari A, Rajabi A, Gholian-Aval M, Peyman N, Mahdizadeh M, Tehrani H. National, regional, and global prevalence of cigarette smoking among women/females in the general population: a systematic review and meta-analysis. Environ Health Prev Med. 2021;26(1:5) (https://doi.org/10.1136/s12199-020-00924-y).

2. Vollset S, Tverdal A, Gjessing H. Smoking and deaths between 40 and 70 years of age in women and men. Ann Intern Med. 2006;144(6):381-9 (https://doi.org/10.7326/0003-4819-144-6-200603210-00004).

3. GBD 2017 Risk Factor Collaborators. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1923-94 (https://doi.org/10.1016/s0140-6736(18)32225-6).

4. Renteria E, Jha P, Forman D, Soerjomataram I. The impact of cigarette smoking on life expectancy between 1980 and 2010: a global perspective. Tob Control. 2016;25(5):551-7 (https://doi.org/10.1136/tobaccococontrol-2015-052265).

5. WHO report on the global tobacco epidemic, 2011: warning about the dangers of tobacco. Geneva: World Health Organization; 2011 (https://iris.who.int/handle/10665/44616).

6. Scragg R, Wellman RJ, Laugesen M, DiFranza JR. Diminished autonomy over tobacco can appear with the first cigarettes. Addict Behav. 2008;33(5):689-98 (https://doi.org/10.1016/j.addbeh.2007.12.002).

7. WHO report on the global tobacco epidemic, 2019: offer help to quit tobacco use. Geneva: World Health Organization; 2019 (https://iris.who.int/handle/10665/326043).

8. Dechanet C, Anahory T, Mathieu Daude JC, Quantin X, Reyftmann L, Hamamah S et al. Effects of cigarette smoking on reproduction. Hum Reprod Update. 2011;17(1):76-95 (https://doi.org/10.1093/humupd/dmq033).

4 Prevention of infertility

9. Budani MC, Tiboni GM. Ovotoxicity of cigarette smoke: a systematic review of the literature. Reprod Toxicol. 2017;72:164-81 (https://doi.org/10.1016/j.reprotox.2017.06.184).

10. WHO clinical treatment guideline for tobacco cessation in adults. Geneva: World Health Organization; 2024 (https://iris.who.int/handle/10665/377825).

11. WHO Framework Convention on Tobacco Control. Guidelines for implementation of Article 14. Geneva: World Health Organization; 2013 (https://fctc.who.int/resources/publications/m/item/guidelines-for-implementation-of-article-14).

12. Augood C, Duckitt K, Templeton AA. Smoking and female infertility: a systematic review and meta-analysis. Hum Reprod. 1998;13(6):1532-9 (https://doi.org/10.1093/humrep/13.6.1532).

13. Nik Hazlina NH, Norhayati MN, Shaiful Bahari I, Nik Muhammad Arif NA. Worldwide prevalence, risk factors and psychological impact of infertility among women: a systematic review and meta-analysis. BMJ Open. 222;12(3):e057132 (https://doi.org/10.1136/bmjopen-2021-057132).

14. Sharma R, Harlev A, Agarwal A, Esteves SC. Cigarette smoking and semen quality: a new meta-analysis examining the effect of the 2010 World Health Organization Laboratory Methods for the Examination of Human Semen. Eur Urol. 2016;70(4):635-45 (https://doi.org/10.1016/j.eururo.2016.04.010).

15. WHO laboratory manual for the examination and processing of human semen, sixth edition. Geneva: World Health Organization; 2021 (https://iris who.int/handle/10665/343208).

16. Boeri L, Belladelli F, Capogrosso P, Cazzaniga W, Candela L, Pozzi E et al. Normal sperm parameters per se do not reliably account for fertility: a case-control study in the real-life setting. Andrologia. 2021;53(1):e13861 (https://doi.org/10.1111/and.13861).

17. Nekuei N, Nasr Esfahani MH, Kazemi A. Preconception counseling in couples undergoing fertility treatment. Int J Fertil Steril. 2012;6(2):79-86.

18. Vogt F, Hall S, Marteau TM. General practitioners' and family physicians' negative beliefs and attitudes towards discussing smoking cessation with patients: a systematic review. Addiction. 2005;100(10):1423-31 (https://doi.org/10.1111/j.1360-0443.2005.01221.x).

19. Heyes T, Long S, Mathers N. Preconception care: practice and beliefs of primary care workers. Fam Pract. 2004;21(1):22-7 (https://doi.org/10.1093/fampra/cmh106).

20. Hughes EG, Lamont DA, Beecroft ML, Wilson DM, Brennan BG, Rice SC. Randomized trial of a "stage-of-change" oriented smoking cessation intervention in infertile and pregnant women. Fertil Steril. 2000;74(3):498-503 (https://doi.org/10.1016/s0015-0282(00)00687-7).

21. Bolumar F, Olsen J, Boldsen J. Smoking reduces fecundity: a European multicenter study on infertility and subfecundity. The European Study Group on Infertility and Subfecundity. Am J Epidemiol. 1996;143(6):578-87 (https://doi.org/10.1093/oxfordjournals.aje.a008788).

22. Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings. Geneva: World Health Organization; 2010 (https://iris.who.int/handle/10665/44260).

23. Butler CC, Pill R, Stott NC. Qualitative study of patients' perceptions of doctors' advice to quit smoking: implications for opportunistic health promotion. BMJ. 1998;316(7148):1878-81 (https://doi.org/10.1136/bmj.316.7148.1878).

24. WHO recommendations for the prevention and management of tobacco use and second-hand smoke exposure in pregnancy. Geneva: World Health Organization; 2013 (https://iris.who.int/handle/10665/94555).

25. Gage JD, Everett KD, Bullock L. A theoretical explanation of male partner participation in smoking cessation during the transition to fatherhood. J Smok Cessat. 2011;6(2):89-96 (https://doi.org/10.1375/jsc.6.2.89).

Guideline for the prevention, diagnosis and treatment of infertility

26. McBride CM, Baucom DH, Peterson BL, Pollak KI, Palmer C, Westman E et al. Prenatal and postpartum smoking abstinence a partner-assisted approach. Am J Prev Med. 2004;27(3):232-8 (https://doi.org/10.1016/j.amepre.2004.06.005).

27. WHO recommendations on antenatal care for a positive pregnancy experience. Geneva: World Health Organization; 2016 (https://iris.who.int/handle/10665/250796).

28. Talbot P, Riveles K. Smoking and reproduction: the oviduct as a target of cigarette smoke. Reprod Biol Endocrinol. 2005;3:52 (https://doi.org/10.1186/1477-7827-3-52).

29. Dhage VD, Nagtode N, Kumar D, Bhagat AK. A narrative review on the impact of smoking on female fertility. Cureus. 2024;16(4):e58389 (https://doi.org/10.7759/cureus.58389).

30. Bundhun PK, Janoo G, Bhurtu A, Teeluck AR, Soogund MZS, Pursun M et al. Tobacco smoking and semen quality in infertile males: a systematic review and meta-analysis. BMC Public Health. 2019;19(1):36 (https://doi.org/10.1186/s12889-018-6319-3).

31. Howe G, Westhoff C, Vessey M, Yeates D. Effects of age, cigarette smoking, and other factors on fertility: findings in a large prospective study. Br Med J (Clin Res Ed). 1985;290(6483):1697-700 (https://doi.org/10.1136/bmj.290.6483.1697).

32. Hernáez Á, Wootton RE, Page CM, Skåra KH, Fraser A, Rogne T et al. Smoking and infertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study. Fertil Steril. 2022;118(1):180-90 (https://doi.org/10.1016/j.fertnstert.2022.04.001).

33. Radin RG, Hatch EE, Rothman KJ, Mikkelsen EM, Sørensen HT, Riis AH et al. Active and passive smoking and fecundability in Danish pregnancy planners. Fertil Steril. 2014;102(1):183-91 (https://doi.org/10.1016/j.fertnstert.2014.03.018).

34. Trummer H, Habermann H, Haas J, Pummer K. The impact of cigarette smoking on human semen parameters and hormones. Hum Reprod. 2002;17(6):1554-9 (https://doi.org/10.1093/humrep/17.6.1554).

35. Prentki Santos E, López-Costa S, Chenlo P, Pugliese MN, Curi S, Ariagno J et al. Impact of spontaneous smoking cessation on sperm quality: case report. Andrologia. 2011;43(6):431-5 (https://doi.org/10.1111/j.1439-0272.2010.01089.x).

36. Kulaksiz D, Toprak T, Tokat E, Yilmaz M, Ramazanoglu MA, Garayev A et al. Sperm concentration and semen volume increase after smoking cessation in infertile men. Int J Impot Res. 2022;34(6):614-9 (https://doi.org/10.1038/s41443-022-00605-0).

4 Prevention of infertility

4.4 Risk reduction from sexually transmitted infections

![](1/parseimages/figure447ac9116d284a05be97e5a827e244f3_0_3.png)

Good practice statement

Remark:

$\bullet$ If symptoms of an STI are present, or if infection is confirmed, WHO guideline recommendations on the management of STIs are available.

Background

Variable proportions of infertility are attributable to untreated infections that ascend along the reproductive tract, capable of causing inflammation, abscess, damage, adhesions or permanent scarring to reproductive organs (see Annex 1. Distribution of the causes of infertility). Several pathogenic mechanisms have been proposed in females (1-3) and males (4, 5) for some organisms. However, the speed and extent to which such infections induce these pathogenic processes and progressively alter the anatomy or physiology of reproductive organs differs between organisms and individuals (6): not all reproductive tract infections have been clearly demonstrated to contribute to the pathogenesis of infertility in females (7) or males (8). Notably, reproductive tract infections that are associated with infertility may be sexually or non-sexually transmitted (e.g. genital schistosomiasis or tuberculosis) with varying virulence.

WHO has quantified the burden of selected curable STIs (9-11) and issued recommendations related to the screening, diagnosis and management of STIs (12). Recommendations for the testing and treatment of people with symptoms, such as vaginal discharge (in females), abdominal pain (in females), urethral discharge (in males) or genital ulcers, including anorectal ulcers (in both males and females), are available from WHO (13).

Necessity of the message

Given some potential uncertainty and variability about the timing, sequence and magnitude of the effects of STIs on the reproductive tract and subsequent infertility (15-18), clinicians may not always communicate with patients about these infections. A lack of information about STIs and the consequences of infertility exists, which is often linked to stigma, embarrassment, privacy, lack of centres for sexual health, or lack of communication and counselling from health care providers on sexual issues (19-21). Although health care providers are an important and often preferred source of information on sexually transmitted infections (21, 22), missed opportunities for communicating about STIs and sexual health have been identified in clinical settings (22).

Consequences

The GDG agreed that there would be net positive consequences of communicating about STIs and the risk of infertility, given the risk of infertility in people with a history of STIs. A systematic review of over 147 studies in populations with infertility found that the prevalence of Neisseria gonorrhoeae was higher in those populations than in the general population globally (2.2% versus 0.8%). Populations with tubal factor infertility, a variety of different types of infertility, unexplained infertility and secondary infertility had the highest prevalence compared to other conditions; prevalence was also

Guideline for the prevention, diagnosis and treatment of infertility

higher in women than in men (14). In addition, a systematic review of studies including women with current or a history of infection with N. gonorrhoeae found a greater but small risk of tubal infertility in women compared to women without an STI infection, and a greater risk in women with overt pelvic inflammatory disease (PID) (15).

A systematic review of case-control studies also found approximately 2.2 greater odds of infertility in males or females with Chlamydia trachomatis (16). Another systematic review found that the prevalence of Trichomonas vaginalis in women attending infertility clinics in the Middle East and North Africa was higher than in a general population of women (17). Untreated N. gonorrhoeae and C. trachomatis infection can lead to PID. A longitudinal follow-up of women in the PEACH trial, which included approximately 800 women, found that the odds of

infertility may be approximately two times greater in women with recurrent PID versus women with no recurrent PID (18).

The GDG agreed that given the higher prevalence of STIs in women and men with infertility, and the likelihood of temporal precedence (rather than infertility leading to greater STI incidence), routinely informing couples about STIs, including the risk of infertility when untreated, or encouraging that they seek care if they have symptoms of STIs, would result in benefits and little to no harm. The GDG noted that the burden of STIs varies across countries, but awareness about STIs can contribute towards prevention. The GDG also agreed that informing couples would be acceptable and feasible to both clinicians and couples, and there would be negligible costs or resources required. In addition, it would probably have limited impact on equity.

![00\n](1/parseimages/figure9ff506a538fb4f6a814029884274f33f_0_6.png)

Rationale

Overall, the GDG agreed that informing people of the risk of infertility caused by STIs would increase awareness and potentially reduce infertility as evidence found greater prevalence of some types of STIs in people with infertility. Informing couples is acceptable, feasible and requires negligible resources and costs, and probably has no impact on equity. The opportunity cost of collecting and summarizing evidence is large.

Implementation considerations

In implementing this good practice statement, health care providers should note that providing information on factors that can increase the risk of infertility is an important part of pre-pregnancy advice, counselling and care (see Chapter 3). In addition, assessment of previous lifestyle history, including history and management of sexually transmitted, non-sexually transmitted and other reproductive tract infections, is important when evaluating couples for infertility (see Chapter 3). Implementation of this good practice complements other avenues for providing information about fertility and infertility, adapted to local contexts and audiences, when opportunities

occur in schools, at primary health care centres or reproductive health (contraceptive, sexual health) clinics (see Chapter 4.1 for the recommendation on information provision on infertility and fertility for the general population).

It is important for health care providers to be aware and to communicate to couples and individuals that some reproductive tract infections are not acquired sexually but could also be associated with infertility; therefore, health care providers should also assess for these in the medical history and physical examination. Health care providers should inform couples and individuals that some STIs may be asymptomatic

4 Prevention of infertility

and that diagnostic screening could be indicated. If the symptoms of an STI are present or infection is confirmed, WHO guidelines for the diagnosis and management of STIs are available (12, 13, 19, 20).

Given that a person with an STI will have contracted it from a sexual partner who also had the infection, health care providers should aim to inform all sexual partners. Awareness and preventive actions can be hindered by a low perception of an STI risk with trusted partners (21), a lack of knowledge of a partner's prior risky sexual behaviours (22), or low awareness or use of STI prevention interventions (12).

Following pregnancy, STIs can have a negative impact on maternal and neonatal outcomes. The WHO antenatal guideline provides

recommendations regarding the identification and management of STIs during pregnancy (23) to reduce the risk of adverse reproductive, obstetric and neonatal outcomes.

Research gaps and future guideline update

Better quantification of the risks of infertility from some sexually transmitted and non-sexually transmitted infections of the reproductive tract is needed. Efforts to improve the quality of the data (e.g. using standardized criteria instead of relying on self-reporting) are also needed. Studies (including modelling) to explore infertility risk reversal after treatment of STIs and other reproductive tract infections are needed. Specific guidance will be required in future regarding screening for STIs as part of pre-pregnancy care, which is not within the scope of this guideline.

References

1. Stephens DS, McGee ZA, Cooper MD. Cytopathic effects of the pathogenic Neisseria. Studies using human fallopian tube organ cultures and human nasopharyngeal organ cultures. Antonie Van Leeuwenhoek. 1987;53(6):575-84 (https://doi.org/10.1007/BF00415519).

2. Linhares IM, Witkin SS. Immunopathogenic consequences of Chlamydia trachomatis 60 kDa heat shock protein expression in the female reproductive tract. Cell Stress Chaperones. 2010;15(5):467-73 (https://doi.org/10.1007/s12192-010-0171-4).

3. Hirano Y, Shibahara H, Koriyama J, Tokunaga M, Shimada K, Suzuki M. Incidence of sperm-immobilizing antibodies in infertile women with past Chlamydia trachomatis infection. Am J Reprod Immunol. 2011;65(2):127-32 (https://doi.org/10.1111/j.1600-0897.2010.00883.x).

4. Munoz MG, Witkin SS. Autoimmunity to spermatozoa, asymptomatic Chlamydia trachomatis genital tract infection and γδ T lymphocytes in seminal fluid from the male partners of couples with unexplained infertility. Hum Reprod. 1995;10(5):1070-4 (https://doi.org/10.1093/oxfordjournals.humrep.a136096).

5. Eley A, Pacey AA, Galdiero M, Galdiero M, Galdiero F. Can Chlamydia trachomatis directly damage your sperm? Lancet Infect Dis. 2005;5(1):53-7 (https://doi.org/10.1016/S1473-3099(04)01254-X).

6. Edwards JL, Apicella MA. The molecular mechanisms used by Neisseria gonorrhoeae to initiate infection differ between men and women. Clin Microbiol Rev. 2004;17(4):965-81 (https://doi.org/10.1128/CMR.17.4.965-981.2004).

7. Tsevat DG, Wiesenfeld HC, Parks C, Peipert JF. Sexually transmitted diseases and infertility. Am J Obstet Gynecol. 2017;216(1):1-9 (https://doi.org/10.1016/j.ajog.2016.08.008).

Guideline for the prevention, diagnosis and treatment of infertility

8. Fode M, Fusco F, Lipshultz L, Weidner W. Sexually transmitted disease and male infertility: a systematic review. Eur Urol Focus. 2016;2(4):383-93 (https://doi.org/10.1016/j.euf.2016.08.002).

9. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10(12):e0143304 (https://doi.org/10.1371/journal.pone.0143304).

10. Rowley J, Vander Hoorn S, Korenromp E, Low N, Unemo M, Abu-Raddad LJ et al. Chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016. Bull World Health Organ. 2019;97(8):548-62P (https://doi.org/10.2471/blt.18.228486).

11. Global prevalence and incidence of selected curable sexually transmitted infections: overview and estimates. Geneva: World Health Organization; 2001 (https://iris.who.int/handle/10665/66818).

12. Guidelines for the management of symptomatic sexually transmitted infections. Geneva: World Health Organization; 2021 (https://iris.who.int/handle/10665/342523).

13. Laboratory and point-of-care diagnostic testing for sexually transmitted infections, including HIV. Geneva: World Health Organization; 2023 (https://iris.who.int/handle/10665/374252).

14. Chemaitelly H, Majed A, Abu-Hijleh F, Blondeel K, Matsaseng TC, Kiarie J et al. Global epidemiology of Neisseria gonorrhoeae in infertile populations: systematic review, meta-analysis and metaregression. Sex Transm Infect. 2021;97(2):157-69 (https://doi.org/10.1136/sextrans-2020-054515).

15. Whelan J, Eeuwijk J, Bunge E, Beck E. Systematic literature review and quantitative analysis of health problems associated with sexually transmitted Neisseria gonorrhoeae infection. Infect Dis Ther. 2021;10:1887-905 (https://doi.org/10.1007/s40121-021-00481-z).

16. Ahmadi MH, Mirsalehian A, Bahador A. Association of Chlamydia trachomatis with infertility and clinical manifestations: a systematic review and meta-analysis of case-control studies. Infect Dis. 2016;48(7):517-23 (https://doi.org/10.3109/23744235.2016.1160421).

17. Harfouche M, Gherbi WS, Alareeki A, Alaama AS, Hermez JG, Smolak A et al. Epidemiology of Trichomonas vaginalis infection in the Middle East and North Africa: systematic review, meta-analyses, and meta-regressions. EBioMedicine. 2024;106 (https://doi.org/10.1016/j.ebiom.2024.105250).

18. Trent M, Bass D, Ness RB, Haggerty C. Recurrent PID, subsequent STI, and reproductive health outcomes: findings from the PID evaluation and clinical health (PEACH) study. Sex Transm Dis. 2011;38(9):879-81 (https://doi.org/10.1097/OLQ.0b013e31821f918c).

19. Recommendations for the treatment of Trichomonas vaginalis, Mycoplasma genitalium, Candida albicans, bacterial vaginosis and human papillomavirus (anogenital warts). Geneva: World Health Organization; 2024 (https://iriswho.int/handle/10665/378215).

20. Updated recommendations for the treatment of Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum (syphilis) and new recommendations on syphilis testing and partner services. Geneva: World Health Organization; 2024 (https://iris.who.int/handle/10665/378213).

21. Witte SS, El-Bassel N, Gilbert L, Wu E, Chang M. Lack of awareness of partner STD risk among heterosexual couples. Perspect Sex Reprod Health. 2010;42(1):49-55 (https://doi.org/10.1363/4204910).

22. Masaro CL, Dahinten VS, Johnson J, Ogilvie G, Patrick DM. Perceptions of sexual partner safety. Sex Transm Dis. 2008;35(6):566-71 (https://doi.org/10.1097/OLQ.0b013e3181660c43).

23. WHO recommendations on antenatal care for a positive pregnancy experience. Geneva: World Health Organization; 2016 (https://iris.who.int/handle/10665/250796).

Chapter 5 Diagnosis of infertility

This chapter provides guidance related to diagnosis of infertility. These are grouped into three main categories:

$\bullet$ Female factors – such as ovulation, fallopian tubes, and the uterus

$\bullet$ Male factors – issues that may affect sperm health and function

$\bullet$ Unexplained factors – when no clear cause is found

![](1/parseimages/figure71515d5e616e47edad76699df5dac5ba_0_5.png) Female-factor diagnosis

5.1 Diagnosis of infertility due to ovulatory dysfunction

5.2 Confirmation of ovulation

5.3 Assessment of reproductive hormones

5.4 Assessment of ovarian reserve

5.5 Diagnosis of infertility due to tubal disease

5.6 Diagnosis of infertility due to uterine cavity disorder

![](1/parseimages/figureb678dc3b395d415e9f1ca36ad767c002_0_13.png) Male-factor diagnosis

5.7 Diagnosis of infertility due to male factors

![?\n](1/parseimages/figured898f6d62e5a401fa8422959f870d907_0_16.png) Unexplained infertility

5.8 Diagnosis of unexplained infertility

Relevant resources

Figures: diagnostic algorithms

5.1 Female-factor infertility and unexplained infertility $\rightarrow$

5.2 Assessment of the uterine cavity $\rightarrow$

5.3 Male-factor infertility $\rightarrow$

Annex 6. Components of female medical history and physical examination $\rightarrow$

Annex 7. Components of male medical history and physical examination $\rightarrow$

Web Annex C. Evidence to decision tables for diagnosis of infertility $\rightarrow$

Guideline for the prevention, diagnosis and treatment of infertility

5.1 Diagnosis of infertility due to ovulatory dysfunction

This and subsequent sections contain recommendations related to the diagnosis of infertility due to female-factor (sections 5.1–5.6), male-factor (section 5.7) and unexplained-factor (section 5.8). Recommendations on infertility due to female factors are related to ovulation (sections 5.2–5.4), tubal disease (section 5.5) or uterine cavity disorder (section 5.6). Figure 5.1 below shows how recommendations on female factors and unexplained factors relate to each other, illustrated in a diagnostic algorithm. A diagnostic algorithm related to male factors is presented later in section 5.7.

5.2 Confirmation of ovulation

![](1/parseimages/figure043e0f2ea3304b28902f44857f39b38c_0_5.png)

Recommendation

For females with infertility but normal findings on history-taking (including regular menstrual cycles) and physical examination, WHO suggests presumptive confirmation of ovulation by measuring the level of mid-luteal serum progesterone rather than performing an ultrasound scan. For women in whom the initial mid-luteal serum progesterone indicates no ovulation, a repeat measurement is suggested to minimize the risk of an inaccurate diagnosis of anovulation. (Conditional recommendation, very low certainty of evidence)

Remarks:

$\bullet$ A repeat mid-luteal serum progesterone measurement could be performed in a subsequent menstrual cycle, considering the turnaround time for tests and cycle-to-cycle variations

Background and rationale

Disorders of ovulation can cause infertility (1, 2). In a multi-country study involving 8500 patients in 25 countries, anovulatory and ovulatory disorders accounted for 26.1% of identifiable causes of female infertility (3); therefore, a key aspect of management of infertility includes the assessment of ovulation.

When a couple presents with a history of failure to achieve a pregnancy, history-taking and a physical examination are conducted in the female.

If these are normal$^{2}$ (including a history of regular menstrual cycles), ovulation is assessed (see Fig. 5.1 Diagnostic algorithm for female-factor infertility and unexplained infertility). Although a history of regular menstrual cycles may be clinically suggestive of ovulation in most cases, further assessment of ovulation with diagnostic tests may be needed given the small potential for anovulatory menstrual cycles in eumenorrheic women, as reported in studies (4–6).

5 Diagnosis of infertility

Fig. 5.1. Diagnostic algorithm for female-factor and unexplained factor infertility

![Couple presents with history of failure to achieve a pregnancyFemale in a couple with infertilityaMale in a couple with infertility↓History+physical examinationSee Section 5.7 for assessment ofthe male in an infertile couplebNormal?YesNo↓Female with normal examinationHistory of abnormal uterine bleeding±History of STI or abdominal/History of absent or irregular periodsfindings and medical historypelvic surgerypelvic mass on exam↓↓Suspected tubal diseaseSuspected uterine cavity disorderSuspected ovulation dysfunction↓↓↓Investigate cause of anovulation/OptionalConfirm ovulationConfirm tubal patencyInvestigate tube patencyInvestigate uterine cavityoligo-ovulationinvestigationsd↓↓↓↓Assess with:Mid-lutealAsses with: Is(orpreferably3D UsifiAssess with: Either HSGAssess with: Either HSGAssess/excluded:HPO axis (E2,T,FSH,is available) OR either HSG OR 2D USCOR HyCoSyOR HyCoSyprogesteroneLH)TSH,PRLAssess ovarian reserve↓Uterine cavityNoeNormal?YesNormal?NoNoabnormalityCauseAssess with:AMH ORNoidentified?identified?AFC OR FSHInvestigateInvestigate cause ofanovulation/oligo-ovulationfother causesgYesYesUnexplained infertility (if semen parameters are within theInfertility due toInfertility due toInfertility dueInfertility due toWHO reference ranges in a male with normal history andtubal blockage oruterine cavityto ovulationreduced ovariandiseaseabnormalitydisordersphysical exam)hreserve↓↓Provide treatment (see relevant sections in this guideline)k\n](1/parseimages/figure4cb62762fc2846c2a1d7e5ac7f5fd2bd_0_3.png) a Infertility is defined as failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse.

b See section 5.7 and Fig. 5.3 for diagnosis of infertility due to male factors.

c See detailed diagnostic algorithm for uterine factors in Fig. 5.2.

d Based on clinical findings; see Good Practice Statements in Chapter 3.

e Repeat if initial test result shows anovulation.

f Follow the pathway for investigating the cause of anovulation. or oligo-ovulation shown on the right side of this chart.

g Such as adenomyosis or endometriosis.

h See recommendation on semen analysis in section 5.7.

Such as polycystic ovarian syndrome (PCOS), functional hypothalamic amenorrhoea, premature ovarian insufficiency (POI), hypothyroidism, hyperthyroidism, hyperprolactinaemia, among others see sections 5.1-5.4.

$\bullet$ For example, due to advanced age, ovarian surgery, POI.

* See Chapters 6-10 for treatment recommendations.

2D US, two-dimensional ultrasound; 3D US, three-dimensional ultrasound; AFC, antral follicle count; AMH, anti-Müllerian hormone; E2, estradiol; FSH, follicle-stimulating hormone; HPO, hypothalamic-pituitary-ovarian; HSG, hysterosalpingogram; HyCoSy, hysterosalpingo contrast sonography; LH, luteinizing hormone; PRL, prolactin; SIS, saline infusion sonohysterography; STI, sexually transmitted infection; T, testosterone; TSH, thyroid-stimulating hormone.

Guideline for the prevention, diagnosis and treatment of infertility

Historically, several tests have been used to either predict or detect ovulation (7–10). Tests that predict impending ovulation (e.g. urine ovulation predictor kits that measure urinary luteinizing hormone [LH] surge levels) could be useful for proper timing of intercourse during the fertile period (11), and are increasingly available over the counter (12, 13). Tests that are intended to confirm ovulation are important for diagnostic purposes in the context of evaluation of the female. The latter application (related to the confirmation of ovulation) was prioritized by the GDG, given the uncertainty regarding anovulatory menstrual cycles in regularly menstruating women (4, 5).

The GDG agreed that a key decision when investigating women with infertility and suspected ovarian pathology is whether to perform ultrasound scan or measure mid-luteal serum progesterone level to presumptively confirm ovulation. The GDG noted that existing tests only provide presumptive or indirect evidence of ovulation. For this recommendation, the GDG addressed the question: should mid-luteal progesterone versus ultrasound be used to confirm ovulation in women with infertility but normal exam findings and history, or not?

Ultrasound imaging (sonography) involves the generation and transmission of ultrasonic (high-frequency sound) waves from a transducer and processing of a returning echo to generate an image. It is based on non-ionizing energy (14). Ovulation is indirectly established using ultrasound follicle tracking through a series of ultrasound scans that are performed between mid-follicular phase (day 8/9) to mid-luteal phase (15). The development, growth and morphological changes of follicles are monitored (15, 16). The collapse of the dominant follicle indicates ovulation (16–18). Although US examination may be conducted using several approaches (19–21), the transvaginal approach is most commonly used for assessing ovulation (22).

Progesterone is a steroidal female sex hormone essential for endometrial receptivity, embryogenesis and the successful establishment of pregnancy. It is produced by ovarian granulosa-theca and corpus luteum cells and, during pregnancy, by placental tissue (23). Assessment of the serum progesterone indirectly establishes ovulation by measuring whether the peak (mid-luteal) levels of progesterone are above a specified threshold (24–26). Progesterone levels are measured several days (typically seven) before the expected menses. Levels greater than certain arbitrary thresholds,$^{3}$ provide presumptive evidence of ovulation (25, 27).

Balancing harms and benefits

Literature searches were conducted to identify diagnostic accuracy studies addressing mid-luteal progesterone and ultrasound follicle tracking from 1990 up to September 2019. The accuracy studies could have compared the tests to a presumed gold standard or compared two or more tests to predict the presence or absence of ovulation. An updated search was later conducted in PubMed up to October 2023.

No studies comparing both tests to endometrial biopsy were identified. One study compared the accuracy of mid-luteal progesterone to the "gold standard" of ultrasound in women with infertility who also had regular menstrual cycles (28). In this study, which involved 101 women (97 menstrual cycles with ovulation), mid-luteal serum progesterone threshold level of at least 6 ng/ml was compared to transvaginal US. The sensitivity and specificity are presented in Table 5.1. These results imply that of 100 women, of whom 96 ovulate, 19 would be incorrectly classified as not ovulating (false negative); in addition, one woman would be incorrectly classified as having ovulated (false positive) if mid-luteal progesterone is used to determine ovulation (see Table 5.1).

5 Diagnosis of infertility

Table 5.1. Test performance of a single mid-luteal progesterone test

||Single mid-luteal progesterone test| |---|---| |Sensitivity (95% CI)|80% (72-88%)| |Specificity (95% CI)|71% (not reported)|

CI, confidence interval.

In assessing benefits, the GDG noted that there were fewer true positives and true negatives with mid-luteal progesterone compared to ultrasound (as ultrasound had higher sensitivity and specificity); however, the number of true positives or true

negatives could be increased if a repeat mid-luteal progesterone test is performed in women whose initial test results indicate anovulation, as illustrated in Table 5.2.

Table 5.2. Absolute effects on 100 women when different combinations of mid-luteal progesterone test with or without ultrasound are provided

||Progesterone only|Progesterone + repeat progesterone for women whose results show that they are anovulatory on the initial progesterone test|Progesterone followed by US for women whose results show that they are anovulatory on the initial progesterone test| |---|---|---|---| |True positives|77|81|81| |True negatives|3|13|18| |False positives|1|6|1| |False negatives|19|1|0| |Sensitivity|80|80 (first test), 80 (repeat test)|80 (progesterone), 100 (US)| |Specificity|71|71 (first test), 71 (repeat test)|80 (progesterone), 100 (US)|

US, ultrasound.

Based on these data, the GDG concluded that the benefits of mid-luteal progesterone compared to ultrasound may be trivial when the mid-luteal progesterone measurement is repeated in women whose initial test results indicate anovulation. In reaching this conclusion, the GDG considered that ultrasound is not a gold standard per se; it provides presumptive evidence of ovulation, and false positives are possible, given that ultrasonic

evidence of luteinization has been documented in unruptured preovulatory follicles (15, 29, 30).

Regarding harms, the GDG agreed that with the use of a single mid-luteal progesterone measurement approach, the harms of one out of 100 false positives may be trivial; however, 19 out of 100 false negatives may mean that these women (who are ovulating) would undergo unnecessary tests.

Guideline for the prevention, diagnosis and treatment of infertility

However, if a mid-luteal progesterone measurement were to be repeated in women who were negative (i.e. 22% of women), the number of women who would be incorrectly classified as anovulatory (i.e. false positives) may increase slightly (from 1 to 6 women out of 100), but the women who would have unnecessary investigations for anovulation or oligo-ovulation may be greatly reduced (from 19 to 1 out of 100). Therefore, the GDG concluded that the difference in harms may be trivial when using this testing approach.

Considering these benefits and harms, the GDG agreed that the balance of effects of repeating mid-luteal progesterone in women with an initial negative mid-luteal progesterone test result may be similar to the balance of effects when performing ultrasound as a single test. The GDG noted that, when mid-luteal progesterone measurement is repeated, 94 out of 100 women will be accurately diagnosed and that 100 women may be accurately diagnosed with ultrasound (assuming that ultrasound has 100% specificity and sensitivity).

Although no studies on patient values were available, the GDG reached a consensus that women would value tests capable of correctly assessing ovulation, and they would also value tests with few harms, such as unnecessary tests, frequent travel (e.g. for serial tests) and costs. The GDG judged that there are probably no important uncertainties or variabilities in how much people value these outcomes.

The overall certainty of evidence was rated as very low because of the limited number of available studies and the absence of a reference standard. The GDG agreed that both ultrasound and mid-luteal progesterone measurement provide indirect and presumptive confirmation of ovulation.

Other considerations

Two studies from the United Kingdom showed that the cost differences between mid-luteal progesterone measurement and ultrasound are negligible (31, 32). However, the GDG agreed that

in LMICs, the cost differences may be greater, with serum progesterone measurements possibly costing moderately less and resulting in savings. In addition, the GDG judged that the cost difference would not change significantly even when the progesterone measurement is repeated in women whose results indicate anovulation on the initial progesterone measurement result.

No data on cost-effectiveness were available. However, the guideline panel agreed that, given that there are similar benefits and harms between ultrasound and a strategy that involves repeat progesterone measurement in women whose results indicate anovulation on the initial progesterone test, and the cost of ultrasound is greater than serum progesterone, then cost-effectiveness probably favours the mid-luteal progesterone measurement. The GDG judged that cost-effectiveness would likely not change significantly when the progesterone test is repeated in women whose initial progesterone measurement results indicate anovulation.

Although there was no direct evidence on the impact of either test on equity, the GDG agreed that a mid-luteal progesterone measurement could probably increase equity because it requires fewer resources and is more widely available than ultrasound. The GDG judged that equity would likely not change significantly even when the progesterone measurement is repeated in women whose initial progesterone measurement results indicate anovulation.

In terms of acceptability, one study reported that serial ultrasound is time-consuming, which may lead to frustration in patients and overcrowded waiting rooms (33). No studies assessing the acceptability of a mid-luteal progesterone measurement were found. In the absence of comparative data, the GDG agreed that although some women would require a repeat measurement, a mid-luteal serum progesterone test is likely more acceptable than transvaginal ultrasound for most patients.

5 Diagnosis of infertility

No comparative studies were identified on the feasibility of mid-luteal progesterone measurement and US. In the absence of direct evidence, the GDG judged that measuring the level of mid-luteal

progesterone is probably feasible to perform; it could also be more feasible than US considering that it requires fewer resources than ultrasound, and ultrasound requires training.

![](1/parseimages/figure298b1fd2f4a94c20a7a8ea04e95bcd73_0_4.png)

Summary justification

There is very low certainty evidence indicating that a small number of women may be incorrectly informed that they have not ovulated when using mid-luteal serum progesterone measurement. For women whose results show no ovulation from the initial mid-luteal serum progesterone level, providing an additional mid-luteal serum progesterone measurement would likely reduce the number of women referred for additional investigations for anovulation or oligo-ovulation. Measuring the level of mid-luteal progesterone costs less, is more feasible and probably more acceptable compared to performing an US scan.

Implementation considerations

$\rightarrow$ While regular menstrual cycles are predictive of ovulation in most women (4–6), it is important to confirm ovulation for the purpose of arriving at a diagnosis that can be communicated to patients, most of whom have expressed a desire to be informed about the cause of their infertility (34).

Health care providers should note that similar to ultrasound, serum progesterone level only provides "indirect" or "presumptive" evidence of ovulation. Measurement of serum progesterone indicates the formation of a corpus luteum, but does not provide definitive proof that a mature, fertilizable oocyte has been released from the ovary (35). Additionally, suboptimal timing of sample collection (vis-à-vis menstrual cycle day), pulsatile secretion, circadian effect, assay error, luteinized unruptured follicles and inherent biological heterogeneity all contribute to variability and potential false negative results (36-40); hence, the need to repeat it if the initial measurement result indicates no ovulation in women with normal findings on history and physical examination.

Considering the normal variation of secreted progesterone in ovulatory menstrual cycles (41, 42), and given that the follicular and luteal phases differ in their contribution to this

variability (37, 41), health care providers should note that obtaining mid-luteal serum progesterone levels approximately 7 days before the expected onset of the next menses is more informative than obtaining it on a specified cycle day. While mid-luteal serum progesterone levels should be assessed approximately 7 days before the expected onset of the next menses, the specific cycle day can vary based on the length of the cycle, for example, day 21 of a 28-day cycle or day 28 of a 35-day cycle.

Research gaps and future guideline update

There were limited data on the acceptability of mid-luteal progesterone measurement or its impact on equity. Implementation research is required to assess the downstream impact of implementing the suggested test for ovulation (mid-luteal progesterone) for women with normal findings on history (including regular menstrual cycles) and physical examination, including regularly menstruating non-hirsute women; such data can inform future considerations. Guidance regarding the role or potential use of LH assessments for the confirmation of ovulation will be required in the future. This recommendation relates to the application of ovulation tests in health care settings and does not relate to direct-to-consumer products, such as fertility tracking wearables and applications, which will require future guidance.

Guideline for the prevention, diagnosis and treatment of infertility

References

1. World Health Organization. Advances in methods of fertility regulation: report of a WHO scientific group. Geneva: World Health Organization; 1973 (https://iris.who.int/handle/10665/38224).

2. Munro MG, Balen AH, Cho S, Critchley HOD, Díaz I, Ferriani R et al. The FIGO Ovulatory Disorders Classification System. Hum Reprod. 2022;37(10):2446-64 (https://doi.org/10.1093/humrep/deac180).

3. Recent advances in medically assisted conception: report of a WHO Scientific Group. Geneva: World Health Organization; 1992 (https://iris.who.int/bitstream/handle/10665/38679/WHOTRS_820_eng.pdf).

4. Lynch KE, Mumford SL, Schliep KC, Whitcomb BW, Zarek SM, Pollack AZ et al. Assessment of anovulation in eumenorrheic women: comparison of ovulation detection algorithms. Fertil Steril. 2014;102(2):511-8 (https://doi.org/10.1016/j.fertnstert.2014.04.035).

5. Malcolm CE, Cumming DC. Does anovulation exist in eumenorrheic women? Obstet Gynecol. 2003;102(2):317-8 (https://doi.org/10.1016/S0029-7844(03)00527-1).

6. Chinta P, Rebekah G, Kunjummen AT, Kamath MS. Revisiting the role of serum progesterone as a test of ovulation in eumenorrheic subfertile women: a prospective diagnostic accuracy study. Fertil Steril. 2020;114(6):1315-21 (https://doi.org/10.1016/j.fertnstert.2020.06.030).

7. Leader A, Wiseman D, Taylor PJ. The prediction of ovulation: a comparison of the basal body temperature graph, cervical mucus score, and real-time pelvic ultrasonography. Fertil Steril. 1985;43(3):385-8 (https://doi.org/10.1016/s0015-0282(16)48436-0).

8. Garcia JE, Jones GS, Wright GL Jr. Prediction of the time of ovulation. Fertil Steril. 1981;36(3):308-15 (https://doi.org/10.1016/S0015-0282(16)45730-4).

9. Robertson RD, Picker RH, Wilson PC, Saunders DM. Assessment of ovulation by ultrasound and plasma estradiol determinations. Obstet Gynecol. 1979;54(6):686-91.

10. Murray MJ, Meyer WR, Zaino RJ, Lessey BA, Novotny DB, Ireland K et al. A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women. Fertil Steril. 2004;81(5):1333-43 (https://doi.org/10.1016/j.fertnstert.2003.11.030).

11. Temporal relationships between ovulation and defined changes in the concentration of plasma estradiol-17β, luteinizing hormone, follicle-stimulating hormone, and progesterone. I. Probit analysis. Health Organization, Task Force on Methods for the Determination of the Fertile Period World Special Programme of Research, Development and Research Training in Human Reproduction. Am J Obstet Gynecol. 1980;138(4):383-90 (https://doi.org/10.1016/0002-9378(80)90133-7).

evidence. Obstet Gynecol. 2002;100(6):1333-41 (https://doi.org/10.1016/S0029-7844(02)02382-7).

13. McGovern PG, Myers ER, Silva S, Coutifaris C, Carson SA, Legro RS et al. Absence of secretory endometrium after false-positive home urine luteinizing hormone testing. Fertil Steril. 2004;82(5):1273-7 (https://doi.org/10.1016/j.fertnstert.2004.03.070).

14. Tole N. Basic physics of ultrasonic imaging. Geneva: World Health Organization; 2005 (https://apps.who.int/iris/handle/10665/43179).

Organization; 2005 (https://apps.who.int/iris/handle/10665/43179).

15. Queenan JT, O'Brien GD, Bains LM, Simpson J, Collins WP, Campbell S. Ultrasound scanning of ovaries to detect ovulation in women. Fertil Steril. 1980;34(2):99-105 (https://doi.org/10.1016/S0015-0282(16)44889-2).

16. Kerin JF, Edmonds DK, Warnes GM, Cox LW, Seamark RF, Matthews CD et al. Morphological and functional relations of Graafian follicle growth to ovulation in women using ultrasonic, laparoscopic and biochemical measurements. Br J Obstet Gynaecol. 1981;88(2):81-90 (https://doi.org/10.1111/j.1471-0528.1981.tb00947.x).

5 Diagnosis of infertility

17. de Crespigny LC, O'Herlihy C, Robinson HP. Ultrasonic observation of the mechanism of human ovulation. Am J Obstet Gynecol. 1981;139(6):636-9 (https://doi.org/10.1016/0002-9378(81)90476-2).

18. Hanna MD, Chizen DR, Pierson RA. Characteristics of follicular evacuation during human ovulation. Ultrasound Obstet Gynecol. 1994;4(6):488-93 (https://doi.org/10.1046/j.1469-0705.1994.04060488.x).

19. Manual of diagnostic ultrasound. Geneva: World Health Organization; 1995 (https://iris.who.int/handle/10665/38652).

20. Manual of diagnostic ultrasound, second edition, vol. 1. Geneva: World Health Organization; 2011 (https://iris.who.int/handle/10665/43881).

21. Wall DJ, Reinhold C, Akin EA, Ascher SM, Brook OR, Dassel M et al. ACR Appropriateness Criteria® female infertility. J Am Coll Radiol. 2020;17(5, Supplement):S113-S24 (https://doi.org/10.1016/j.jacr.2020.01.018).

22. Manual of diagnostic ultrasound, second edition, vol. 2. Geneva: World Health Organization; 2013 (https://iris.who.int/handle/10665/85386).

23. Enna SJ, Bylund DB. Progesterone. In: Enna SJ, Bylund DB, editors. xPharm: The Comprehensive Pharmacology Reference. New York: Elsevier; 2007:1-2 (https://doi.org/10.1016/B978-008055232-3.62470-5).

24. Israel R, Mishell DR, Stone SC, Thorneycroft IH, Meyer DL. Single luteal phase serum progesterone assay as an indicator of ovulation. Am J Obstet Gynecol. 1972;112(8):1043-6 (https://doi.org/10.1016/0002-9378(72)90178-0).

25. Wathen N, Perry L, Lilford R, Chard T. Interpretation of single progesterone measurement in diagnosis of anovulation and defective luteal phase: observations on analysis of the normal range. Br Med J (Clin Res Ed). 1984;288(6410):7-9 (http://doi.org/10.1136/bmj.288.6410.7).

26. Abdulla U, Diver MJ, Hipkin LJ, Davis JC. Plasma progesterone levels as an index of ovulation. Br J Obstet Gynaecol. 1983;90(6):543-8 (https://doi.org/10.1111/j.1471-0528.1983.tb08965.x).

27. Rowe PJ, Comhaire FH, Hargreave TB, Mellows HJ. WHO manual for the standardized investigation and diagnosis of the infertile couple. Cambridge: Cambridge University Press; 1993 (https://iris.who.int/handle/10665/36983).

28. Guermandi E, Vegetti W, Bianchi MM, Uglietti A, Ragni G, Crosignani P. Reliability of ovulation tests in fertile women. Obstet Gynecol. 2001;97(1):92-6 (https://doi.org/10.1016/s0029-7844(00)01083-8).

29. Coulam CB, Hill LM, Breckle R. Ultrasonic evidence for luteinization of unrupted preovulatory follicles. Fertil Steril. 1982;37(4):524-9 (https://doi.org/10.1016/S0015-0282(16)46160-1).

30. Hackelöer BJ, Robinson HP. [Ultrasound examination of the growing ovarian follicle and of the corpus luteum during the normal physiologie menstrual cycle (author's translation)]. Geburtshilfe Frauenheilkd. 1978;38(3):163-8 (in German).

31. Ojha K, Philips Z, Darne FJ. Diagnosing infertility in a district general hospital: a case-note and cost analysis. Hum Fertil. 2003;6(4):169-73 (https://doi.org/10.1080/1046470312331369443).

32. Cooper NA, Barton PM, Breijer M, Caffrey O, Opmeer BC, Timmermans A et al. Cost-effectiveness of diagnostic strategies for the management of abnormal uterine bleeding (heavy menstrual bleeding and post-menopausal bleeding): a decision analysis. Health Technol Assess. 2014;18(24):1-201 (https://doi.org/10.3310/hta18240).

33. Revelli A, Casano S, Salvagno F, Delle Piane L. Milder is better? Advantages and disadvantages of "mild" ovarian stimulation for human in vitro fertilization. Reprod Biol Endocrinol. 2011;9(1):1-9 (https://doi.org/10.1186/1477-7827-9-144).

34. Dancet EAF, Nelen WLDM, Sermeus W, De Leeuw L, Kremer JAM, D'Hooghe TM. The patients' perspective on fertility care: a systematic review. Hum Reprod Update. 2010;16(5):467-87 (https://doi.org/10.1093/humupd/dmq004).

Guideline for the prevention, diagnosis and treatment of infertility

35. ESHRE Capri Workshop Group. Diagnosis and management of the infertile couple: missing information. Hum Reprod Update. 2004;10(4):295-307 (https://doi.org/10.1093/humupd/dmh024).

36. Janssen-Caspers HA, Kruitwagen RF, Wladimiroff JW, de Jong FH, Drogendijk AC. Diagnosis of luteinized unruptured follicle by ultrasound and steroid hormone assays in peritoneal fluid: a comparative study. Fertil Steril. 1986;46(5):823-7 (https://doi.org/10.1016/s0015-0282(16)49819-5).

37. Rahman SA, Grant LK, Gooley JJ, Rajaratnam SMW, Czeisler CA, Lockley SW. Endogenous circadian regulation of female reproductive hormones. J Clin Endocrinol Metab. 2019;104(12):6049-59 (https://doi.org/10.1210/jc.2019-00803).

38. Fujimoto VY, Clifton DK, Cohen NL, Soules MR. Variability of serum prolactin and progesterone levels in normal women: the relevance of single hormone measurements in the clinical setting. Obstet Gynecol. 1990;76(1):71-8.

39. Filicori M, Butler JP, Crowley WF Jr. Neuroendocrine regulation of the corpus luteum in the human. Evidence for pulsatile progesterone secretion. J Clin Invest. 1984;73(6):1638-47 (https://doi.org/10.1172/jci111370).

40. Steele PA, White GH, Judd SJ. Reliability of a single serum progesterone determination as an indicator of ovulation. Clin Reprod Fertil. 1985;3(2):125-30 (http://europepmc.org/abstract/MED/4052919).

41. Fehring RJ, Schneider M, Raviele K. Variability in the phases of the menstrual cycle. J Obstet Gynecol Neonatal Nurs. 2006;35(3):376-84 (https://doi.org/10.1111/j.1552-6090.2006.00051.x).

42. Bull JR, Rowland SP, Scherwitzl EB, Scherwitzl R, Danielsson KG, Harper J. Real-world menstrual cycle characteristics of more than 600,000 menstrual cycles. NPJ Digit Med. 2019;2(1):83 (https://doi.org/10.1038/s41746-019-0152-7).

5 Diagnosis of infertility

5.3 Assessment of reproductive hormones

![](1/parseimages/figuref0d210547279450ca9de592c33407b75_0_3.png)

Good practice statement

For females with infertility and suspected anovulation or oligo-ovulation, it is good practice to assess reproductive hormones related to the hypothalamic-pituitary-ovarian (HPO) axis (such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in some clinical presentations, estradiol (E2), testosterone [T]). Additional testing (e.g. thyroid-stimulating hormone [TSH], prolactin [PRL]) may also be considered based on the clinical presentation. The choice of diagnostic tests should be based on clinical findings from a comprehensive medical history and physical examination to ensure that evaluation is systematic and cost-effective.

Background and rationale

The clinical pattern of ovulation is influenced by several physiological factors (1, 2). When a couple presents with a history of failure to achieve a pregnancy, history-taking and a physical examination are conducted in the female. If these are normal,$^{4}$ including a history of regular menstrual cycles, ovulation is assessed (see section 5.2). Diagnostic assessment of the female and male should take place concurrently (see sections 3, 5.5 and 5.7).

If the history identifies women who do not have a regular menstrual pattern (menstrual bleeding at intervals of 28 ± 7 days) further hormonal evaluation is indicated to identify potential causes of anovulation and oligo-ovulation. These women may include those with primary amenorrhea (patients aged over 18 years$^{5}$ who have never experienced spontaneous vaginal bleeding), secondary amenorrhea (absence of spontaneous vaginal bleeding for 6 months or more in a patient who had previously experienced it) or oligomenorrhea (infrequent or scanty menstruation characterized by spontaneous vaginal bleeding at intervals from 36 days to 6 months) (1). Age of menarche varies (3, 4).

WHO classifies ovulation disorders into three groups (2) as follows:

$\bullet$ Group I: women with amenorrhea and little or no evidence of endogenous estrogen activity, including patients with (i) hypogonadotropic ovarian failure, (ii) complete or partial hypopituitarism or (iii) pituitary-hypothalamic dysfunction. Group I is characterized by low or unmeasurable serum and urinary gonadotrophins, and low estrogen levels. Plasma progesterone levels are typically less than 1.0 ng/ml and plasma hydroxyprogesterone are typically less than 0.2 ng/ml. Patients in WHO Group I may have primary or secondary amenorrhoa.

* Group II: women with a variety of menstrual cycle disturbances (including amenorrhoea) who exhibit distinct endogenous estrogen activity (urinary estrogens usually less than 10 µg/24 h), whose urinary and serum gonadotrophins are in the normal range and fluctuating, and who may have fairly regular spontaneous menstrual bleeding (i.e. less than 35 days apart), but without ovulation. Patients with galactorrhoea associated with amenorrhoea may be classified under WHO Group II or, rarely, WHO Group

Guideline for the prevention, diagnosis and treatment of infertility

I based on laboratory and indirect clinical findings.

$\bullet$ Group III: women with primary ovarian failure associated with low endogenous estrogen activity and pathologically elevated serum and urinary gonadotrophins.

This WHO diagnostic classification aims to inform clinical management of infertility and does not aim to provide a comprehensive classification (1). Other more comprehensive classifications exist (5, 6). For this recommendation, the GDG addressed the question: should reproductive hormones versus none be performed for the initial evaluation of women with infertility and suspected anovulation and oligo-ovulation.

Considering existing guidance on good practice statements (7), the GDG agreed that it is good practice to evaluate reproductive hormones during the initial evaluation of anovulation and oligo-ovulation, specifically those related to the HPO axis (such as FSH and LH, and in some clinical presentations, E2, T). The GDG agreed that additional testing (e.g. TSH, PRL) may also be considered based on the clinical presentation. The GDG agreed that the choice of diagnostic tests should be based on clinical findings from a comprehensive medical history and physical examination, and should ensure that evaluation is systematic and cost-effective.

Necessity of the message

Given the importance of hormonal and endocrine causes of female infertility (1, 8), the GDG agreed that it is important for health care providers to have clear guidance on whether reproductive hormones should be assessed or not in women with infertility and suspected anovulation or oligo-ovulation.

Consequences

The GDG agreed that normal menstrual function involves the coordinated function of several physiological and structural components: the hypothalamus, the anterior pituitary gland, the ovary and the genital outflow tract composed of

the uterus/endometrium, cervix and vagina. The physiological balance between gonadotrophic hormones and ovarian sex steroids is necessary for an orderly ovulatory sequence; failure to ovulate may be the result of a dysfunction at any level of this system. This system involves hormonal functions in higher centres in the brain, the HPO axis and the steroid feedback mechanism. In this context, the GDG agreed that measuring the following hormones will identify dysfunction in the ovulatory sequence and inform diagnosis, prognosis and management of anovulation and oligo-ovulation leading to large net positive consequences.

FSH and LH

The gonadotrophin-releasing hormone (GnRH) stimulates the synthesis and secretion of pituitary gonadotrophin hormones, FSH and LH. FSH and LH stimulate and sustain follicular growth and maturation (differentiation and luteinization) (9, 10). In the absence of the FSH and LH hormones, the development of ovarian follicles is impaired at early antral or preovulatory stages, respectively (9, 10), although follicular proliferation may not be entirely inhibited (10, 11). Gonadotropins also have a part in sustaining follicular steroidogenesis (10) by mediating aromatization of androgens to estrogens (12). Gonadotropin deficiency can result either from a pituitary abnormality (13, 14) or a deficiency of GnRH (14). FSH and LH levels are low or unmeasurable in WHO Group I, normal in WHO Group II and high in WHO Group III.

Estradiol

Estrogens have an important role in the development of ovarian follicles by regulating gonadotrophin secretion for ovulation (15). Ovarian granulosa cells are the key source of serum estrogens in premenopausal women; smaller amounts are produced in peripheral adipose tissue (15, 16). Estrogen regulates FSH secretion through a negative feedback loop on the HPO axis (17): it stimulates the production of GnRH, which in turn stimulates FSH; when FSH levels are high, E2 secretion is inhibited. Estrogens occur

5 Diagnosis of infertility

in various isoforms including estrone (E1), 17β-estradiol (E2), estriol (E3) and estetrol (E4) (18). E2 is the main circulating and most potent naturally occurring estrogen in premenopausal women; it is predominantly produced in the ovaries (17). E2 levels are low in WHO Group I, normal in WHO Group II and low in WHO Group III.

Testosterone

Several androgens, including testosterone, are produced in the ovary and the adrenal glands in women (15, 19). Ovarian androgens are generated in the calcel cells and mediated by gonadotrophins, particularly LH (12, 20, 21). Androgens are also produced in peripheral tissues through local conversion of prohormones (15, 22). Ovarian hyperandrogenism, typically featuring high levels of testosterone, is characterized by oligomenorrhoea, hirsutism or acne (23).

Progesterone

Progesterone is required for the maintenance of pregnancy (24, 25) and is initially produced by the corpus luteum after ovulation (24) and later by the fetoplacental unit after implantation (25). Measurement of progesterone is suggested for the assessment of ovulation in this guideline (see section 5.2 on the use of progesterone for presumptive confirmation of ovulation).

PRL

Hyperprolactinaemia is present in 6.6% of those with infertility (26, 27), while hypoprolactinaemia is rare (28). PRL secretion is regulated by multiple factors, including thyroid-releasing hormone (TRH) (29) and dopamine (30). Clinical features of hyperprolactinaemia include oligomenorrhoea, amenorrhoea, infertility and galactorrhoea (31). Symptoms of pituitary mass effect, such as headaches and visual disturbances, may also be present (31).

TSH

When thyroid antibodies are present, both hypothyroidism and hyperthyroidism are more frequent in women with infertility (32). Both hyperthyroidism and hypothyroidism can lead to menstrual disturbances (32, 33) and may result in changes in sex hormone binding globulin (SHBG) and sex steroids (32). Hyperthyroidism arises when the thyroid gland produces excessive amounts of the thyroid hormones T₄ and/or T₃. Hyperthyroidism may present with either too scanty (hypomenorrhoea) or too frequent (polymenorrhoea) uterine bleeding, alongside other clinical features ranging from subclinical hyperthyroidism, overt hyperthyroidism, Graves' disease, toxic multinodular goitre and toxic adenoma (32). Hypothyroidism results from an underactive thyroid gland (34) and may present with oligomenorrhoea alongside wide-ranging features, from subclinical hypothyroidism, overt hypothyroidism, or with symptoms secondary to pituitary disease (13, 32). Hypothyroidism results in excessive hypothalamic secretion of TRH, which increases TSH (29, 32) and can affect PRL secretion (29, 35, 36).

International reference standards

WHO international reference biological standards for bioassay and immunoassay are available for FSH, LH (37, 38), PRL (38, 39) and TSH (38, 40). In addition, an international reference biological standard for SHBG, which has clinical utility in interpreting the result of E2 and T, is also available (38). In addition, FSH, LH, E2, PRL and TSH are already included in the WHO model list of essential in vitro diagnostics (41). However, future efforts will be needed to include T in the WHO model list of essential in vitro diagnostics.

Guideline for the prevention, diagnosis and treatment of infertility

![一一\n](1/parseimages/figureb6d0caac2f714a1795ac181b9f907ad9_0_2.png)

Rationale

The GDG agreed that measuring these hormones will assist to identify ovulation dysfunction and in selecting appropriate management of infertility. Assessment of these hormones will result in large net positive consequences and the opportunity cost of collecting and summarizing evidence is large. The GDG agreed that the choice of diagnostic tests should be based on clinical findings from a comprehensive medical history and physical examination, and ensure that evaluation is systematic and cost-effective.

Implementation considerations

The GDG agreed that multiple endocrinopathies may coexist in the same patient, which may require concomitant identification; therefore, the utility of each test may depend on the clinical profile. Indiscriminate ordering of tests should be avoided. Interactions between metabolic and reproductive systems may occur in patients (42), including those with anovulation and oligo-ovulation, for example, in polycystic ovary syndrome (PCOS) (43). Anovulation and oligo-ovulation may occur in a small proportion of eumenorrhoeic women (such as those with hirsutism and/or obesity) (44, 45), whose differential diagnosis can be informed by history-taking and a physical examination. Consequently, selection of diagnostic tests based on clinical findings from medical history-taking and a physical examination is needed to ensure that evaluation is systematic and cost-effective (see Chapter 3. Approach to the evaluation and management of infertility).

$\rightarrow$ Laboratory technical parameters can affect test results, and training and rigorous quality safeguards are necessary to minimize errors. Invalid results may result from cross-reactivity, interference, inter-assay or inter-laboratory variability, sample integrity, stability, storage and handling, and lack of standardization, among other factors. Whenever possible, laboratories should be encouraged to use low-cost matched reagents or international standards, engage in regular reagent and kit renewal, and perform internal and external quality assurance. Health care providers should note that hormones have infradian, circadian and

ultradian rhythms (46–48) that may affect the results or optimal timing of blood draws (1). To maintain a high-quality service, laboratories should be accredited to a suitable national or international body, such as the International Organization for Standardization (ISO), with a goal to comply with relevant standards, such as the international standard ISO 15189 (49).

It is good practice to evaluate reproductive hormones during the initial evaluation of anovulation and oligo-ovulation, but these may not always ascertain a final diagnosis from a list of differential diagnoses. Further clinical or diagnostic evaluation may be required to fulfil the specific diagnosis. For example, further assessment of specific hormones is required to fulfil the diagnostic criteria for PCOS (50), while further clinical evaluation is required to ensure that no anatomical or organic cause of amenorrhoea exists before making a diagnosis of functional hypothalamic amenorrhoea. In addition, measurement of E2 is essential in interpreting FSH levels, while measurement of SHBG is required to correctly interpret the serum levels of E2 and T. Similarly, when TSH is elevated, measurement of other thyroid parameters, such as serum free $T_4$ may be needed to make the final diagnosis. Depending on the clinical presentation, other hormonal assessments such as 17-α-hydroxyprogesterone or dehydroepiandrosterone sulfate, among others, may be needed to diagnose a range of endocrine conditions associated with anovulation and oligo-ovulation. Health care providers should carefully consider a potential differential diagnosis

5 Diagnosis of infertility

based on clinical profile while ordering tests (see Fig. 5.1. Diagnostic algorithm for female-factor infertility and unexplained infertility). In all cases of amenorrhoea, health care providers should exclude pregnancy as part of infertility investigation.

Research gaps and future guideline update

Future updating of WHO classification of ovulation disorders is required through the revision procedures of the International Classification of Diseases.

References

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2. Agents stimulating gonadal function in the human. Report of a WHO scientific group. World Health Organ Tech Rep Ser. 1973;514:1-30.

3. World Health Organization multicenter study on menstrual and ovulatory patterns in adolescent girls. I. A multicenter cross-sectional study of menarche. J Adolesc Health Care. 1986;7(4):229-35 (https://doi.org/10.1016/S0197-0070(86)80014-6).

4. Morabia A, Costanza MC. International variability in ages at menarche, first livebirth, and menopause. World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives. Am J Epidemiol. 1998;148(12):1195-205 (https://doi.org/10.1093/oxfordjournals.aje.a009609).

5. Balen AH, Tamblyn J, Skorupskaite K, Munro MG. A comprehensive review of the new FIGO classification of ovulatory disorders. Hum Reprod Update. 2024;30(3):355-82 (https://doi.org/10.1093/humupd/dmae003).

6. Munro MG, Balen AH, Cho S, Critchley HOD, Díaz I, Ferriani R et al. The FIGO Ovulatory Disorders Classification System. Hum Reprod. 2022;37(10):2446-64 (https://doi.org/10.1093/humrep/deac180).

7. Guyatt GH, Alonso-Coello P, Schünemann HJ, Djubegovic B, Nothacker M, Lange S et al. Guideline panels should seldom make good practice statements: guidance from the GRADE Working Group. J Clin Epidemiol. 2016;80:3-7 (https://doi.org/10.1016/j.jclinepi.2016.07.006).

8. Unuane D, Tournaye H, Velkeniers B, Poppe K. Endocrine disorders & female infertility. Best Pract Res Clin Endocrinol Metab. 2011;25(6):861-73 (https://doi.org/10.1016/j.beem.2011.08.001).

9. Markström E, Svensson E, Shao R, Svanberg B, Billig H. Survival factors regulating ovarian apoptosis - dependence on follicle differentiation. Reproduction. 2002;123(1):23-30 (https://doi.org/10.1530/rep.0.1230023).

10. Gougeon A. Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev. 1996;17(2):121-55 (https://doi.org/10.1210/edrv-17-2-121).

11. Barnes RB, Namnoum AB, Rosenfield RL, Layman LC. The role of LH and FSH in ovarian androgen secretion and ovarian follicular development: clinical studies in a patient with isolated FSH deficiency and multicystic ovaries. Hum Reprod. 2002;17(1):88-91 (https://doi.org/10.1093/humrep/171.88).

12. Hillier SG, Whitelaw PF, Smyth CD. Follicular oestrogen synthesis: the 'two-cell, two-gonadotrophin' model revisited. Mol Cell Endocrinol. 1994;100(1-2):51-4 (https://doi.org/10.1016/0303-7207(94)90278-x).

13. Karavitaki N, Wass JAH. Disorders of the anterior pituitary gland. 2020. In: Gurnell M, Firth J, Conlon C, Cox T, editors. Oxford textbook of medicine. Oxford: Oxford University Press; 2020:597-603 (https://doi.org/10.1093/med/9780198746690.003.0244).

14. Ciccone NA, Kaiser UB. The biology of gonadotroph regulation. Curr Opin Endocrinol Diabetes Obes. 2009;16(4):321-7 (https://doi.org/10.1097/MED.0b013e32832d88fb).

Guideline for the prevention, diagnosis and treatment of infertility

15. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32(1):81-151 (https://doi.org/10.1210/ er.2010-0013).

16. Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinshelwood MM, Graham-Lorence S et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev. 1994;15(3):342-55 (https://doi.org/10.1210/edrv-15-3-342).

17. Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Dermatol. 2001;45(3 Suppl):S116-S24 (https://doi.org/10.1067/mjd.2001.117432).

18. Thomas MP, Potter BV. The structural biology of oestrogen metabolism. J Steroid Biochem Mol Biol. 2013;137:27-49 (https://doi.org/10.1016/j.jsmb.2012.12.014).

19. Burger HG. Androgen production in women. Fertil Steril. 2002;77 Suppl 4:S3-S5 (https://doi.org/10.1016/s0015-0282(02)02985-0).

20. Bogovich K, Richards JS. Androgen biosynthesis in developing ovarian follicles: evidence that luteinizing hormone regulates thecal 17a-hydroxylase and C17-20-lyase activities. Endocrinology. 1982;111(4):1201-8 (https://doi.org/10.1210/endo-111-4-1201).

21. Smyth CD, Miró F, Whitelaw PF, Howles CM, Hillier SG. Ovarian thecal/interstitial androgen synthesis is enhanced by a follicle-stimulating hormone-stimulated paracrine mechanism. Endocrinology. 1993;133(4):1532-8 (https://doi.org/10.1210/en.133.4.1532).

22. Judd HL, Judd GE, Lucas WE, Yen SSC. Endocrine function of the postmenopausal ovary: concentration of androgens and estrogens in ovarian and peripheral vein blood. J Clin Endocrinol Metab. 1974;39(6):1020-4 (https://doi.org/10.1210/jcem-39-6-1020).

23. Ehrmann DA, Rosenfield RL, Barnes RB, Brigell DF, Sheikh Z. Detection of functional ovarian hyperandrogenism in women with androgen excess. N Engl J Med. 1992;327(3):157-62 (https://doi.org/10.1056/NEJM199207163270304).

24. Niswender GD, Juengel JL, Silva PJ, Rollyson MK, McIntush EW. Mechanisms controlling the function and life span of the corpus luteum. Physiol Rev. 2000;80(1):1-29 (https://doi.org/10.1152/physrev.2000.80.1.1).

25. Tuckey RC. Progesterone synthesis by the human placenta. Placenta. 2005;26(4):273-81 (https://doi.org/10.1016/j.placenta.2004.06.012).

26. Cates W, Farley TM, Rowe PJ. Worldwide patterns of infertility: is Africa different? Lancet. 1985;2(8455):596-8 (https://doi.org/10.1016/s0140-6736(85)90594-x).

27. Recent advances in medically assisted conception: report of a WHO Scientific Group. Geneva: World Health Organization; 1992 (https://iris.who.int/bitstream/handle/106655/38679/WHO_TRS820_eng.pdf).

28. Toledano Y, Lubetsky A, Shimon I. Acquired prolactin deficiency in patients with disorders of the hypothalamic-pituitary axis. J Endocrinol Invest. 2007;30(4):268-73 (https://doi.org/10.1007/bf03346292).

29. Galas L, Raoult E, Tonon MC, Okada R, Jenks BG, Castaña J Pet al. TRH acts as a multifunctional hypophysiotropic factor in vertebrates. Gen Comp Endocrinol. 2009;164(1):40-50 (https://doi.org/10.1016/j.ygcen.2009.05.003).

30. Ben-Jonathan N, Hnasko R. Dopamine as a prolactin (PRL) inhibitor. Endocr Rev. 2001;22(6):724-63 (https://doi.org/10.1210/edrv.22.6.0451).

31. Mah PM, Webster J. Hyperprolactinemia: etiology, diagnosis, and management. Semin Reprod Med. 2002;20(04):365-74 (https://doi.org/10.1055/s-2002-36709).

32. Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocr Rev. 2010;31(5):702-55 (https://doi.org/10.1210/er.2009-0041).

33. Doufas AG, Mastorakos G. The hypothalamic-pituitary–thyroid axis and the female reproductive system. Ann N Y Acad Sci. 2000;900:65-76 (https://doi.org/10.1111/j.1749-6632.2000.tb06217.x).

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34. Persani L. Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab. 2012;97(9):3068-78 (https://doi.org/10.1210/jc.2012-1616).

35. Kanasaki H, Oride A, Mijiddorj T, Kyo S. Role of thyrotropin-releasing hormone in prolactin-producing cell models. Neuropeptides. 2015;54:73-7 (https://doi.org/10.1016/j.npep.2015.08.001).

36. Fekete C, Lechan RM. Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions. Endocr Rev. 2014;35(2):159-94 (https://doi.org/10.1210/er.2013-1087).

37. WHO Expert Committee on Biological Standardization: seventy-eighth report. Geneva: World Health Organization; 2024 (https://iris.who.int/handle/10665/376596).

38. Health products policy and standards. Catalogue of the WHO international reference standards for biological products. Geneva: World Health Organization; 2024 (www.who.int/teams/health-product-policy-and-standards/standards-and-specifications/norms-and-standards/catalogue).

39. WHO International collaborative study of the proposed 4th International Standard for Prolactin, Human. Geneva: World Health Organization; 2016 (https://iris.who.int/handle/10665/253053).

40. WHO Expert Committee on Biological Standardization. WHO 4th International Standard for TSH (human, pituitary). Geneva: World Health Organization; 2023 (www.who.int/publications/m/item/who-bs-2023-2454).

41. The selection and use of essential in vitro diagnostics: report of the fourth meeting of the WHO Strategic Advisory Group of Experts on In Vitro Diagnostics, 2022 (including the fourth WHO model list of essential in vitro diagnostics). Geneva: World Health Organization; 2023 (https://iris.who.int/handle/10665/373322).

42. Navarro VM, Kaiser UB. Metabolic influences on neuroendocrine regulation of reproduction. Curr Opin Endocrinol Diabetes Obes. 2013;20(4):335-41 (https://doi.org/10.1097/MED.0b013e32836318ce).

43. Teede H, Deeks A, Moran L. Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med. 2010;8:41 (https://doi.org/10.1186/1741-7015-8-41).

44. Azziz R, Carmina E, Sawaya ME. Idiopathic Hirsutism. Endocr Rev. 2000;21(4):347-62 (https://doi.org/10.1210/edrv.21.4.0401).

45. Oldfield AL, Vanden Brink H, Carter FE, Jarrett BY, Lujan ME. Obesity is associated with alterations in antral follicle dynamics in eumenorrheic women. Hum Reprod. 2023;38(3):459-70 (https://doi.org/10.1093/humrep/dead007).

46. Lewy H, Naor Z, Ashkenazi IE. From ultradian to infradian rhythms: LH releases patterns in vitro. Chronobiol Int. 1999;16(4):441-50 (https://doi.org/10.3109/07420529908998719).

47. Bittman EL. Timing in the testis. J Biol Rhythms. 2016;31(1):12-36 (https://doi.org/10.1177/0748730415618297).

48. Cargille C, Ross G, Yoshimi T. Daily variations in plasma follicle stimulating hormone, luteinizing hormone and progesterone in the normal menstrual cycle. J Clin Endocrinol Metab. 1969;29(1):12-9 (https://doi.org/10.1210/jcem-29-1-12).

49. Laboratory quality management system: handbook, version 1.1. Geneva: World Health Organization; 2011 (https://iris.who.int/handle/10665/44665).

50. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19-25 (https://doi.org/10.1016/j.fertnstert.2003.10.004).

Guideline for the prevention, diagnosis and treatment of infertility

5.4 Assessment of ovarian reserve

![](1/parseimages/figure95cf863ff5644e2b8029ca81b95b1406_0_3.png)

Recommendation

For females with infertility in whom other causes of anovulation and oligovulation have been ruled out, WHO suggests that a diagnosis of low ovarian reserve should be based on age rather than diagnostic tests. If ovarian reserve diagnostic testing is conducted, WHO suggests using antral follicle count (AFC), anti-Müllerian hormone (AMH) or day 2 or 3 follicle-stimulating hormone (FSH). (Conditional recommendation, very low certainty of evidence)

Remarks:

$\bullet$ Selection of the test to assess ovarian reserve should be based on relative acceptability, availability and resources in local contexts.

Background

Disorders of ovulation can cause infertility. In a multi-country study involving 8500 patients in 25 countries, anovulation and oligo-ovulatory disorders accounted for 26.1% of identifiable causes of female infertility (1, 2); therefore, a key aspect of management of infertility includes the assessment of ovulation.

Ovarian reserve refers to the quantity of oocytes remaining in a woman's ovaries that have the potential to yield a pregnancy. The need to quantify the amount of remaining oocytes is based on the fact that the number of oocytes in the ovaries decreases progressively through atresia (3, 4), resulting in declining fecundity over time (5). Age is the most important determinant of reproductive potential; however, women of the same chronological age may have varying quantity and quality of oocytes (6, 7), and there is a lack of a reliable metric for assessing oocyte quality.

When a couple presents with history of infertility and ovulatory dysfunction is suspected as a cause,

several investigations may be undertaken to assess the HPO axis and endocrine hormones, as suggested in Section 5.3. In this PICO question, the GDG was interested in evaluating the role of ovarian reserve testing in the evaluation of anovulation or oligo-ovulation as a cause of infertility.

Conceptually, counting the number of oocytes would provide the definitive indicator of ovarian reserve; however, it can only be directly assessed through the histological examination of entire ovaries. Consequently, there are two overlapping interpretations and application of ovarian reserve testing, that is, (i) as an indirect indicator of biological reserve and (ii) as an indication of clinical response to stimulation (8, 9). The first is related to the true number of primordial follicles. The second is a functional assessment of ovarian response to stimulation, that is, the quantity of follicles that are at late stages of development and capable of responding to stimulation (8), that is, the potential number of oocytes that could potentially be available for retrieval during IVF (9). Patients whose biological reserve is low are likely to exhibit a "poor"

5 Diagnosis of infertility

response to ovarian stimulation (OS) (10); however, there is a lack of consensus on the threshold that constitutes a decreased ovarian reserve.

Several tests are used for ovarian reserve testing, including AFC measured sonographically, E2, FSH, and inhibin B, and AMH (11). For this PICO, the GDG was interested in the first application. The GDG agreed that an important decision that health care providers face is whether to use AFC, AMH or FSH.

AFC is an ultrasonographic test of ovarian reserve that quantifies the total number of follicles in both ovaries (typically 2–10 mm in diameter) observed during a transvaginal ultrasound scan (12), typically during the early follicular phase. The number of antral follicles is interpreted as being an indirect indicator of the magnitude of the remaining follicular pool based on demonstrated correlations between AFC with histologically determined primordial follicle numbers (11).

AMH is a glycoprotein produced by the granulosa cells of ovarian follicles (13, 14). AMH declines as the number of ovarian follicles declines with age (15, 16), and its levels correlate with the primordial follicular pool (11).

FSH is a glycoprotein secreted in the anterior pituitary gland in response to the production of inhibin B by preantral follicles via a negative feedback loop that involves a complex interaction of several factors, including sex steroid hormones (mainly estrogens) and GnRH (17, 18). With advancing age, secretion of early follicular phase inhibin B declines, which partly contributes to increased pituitary FSH secretion, and higher late luteal and early follicular FSH concentrations (19-21). Measuring FSH levels (typically around cycle day 3) provides an indirect measure of pool of ovarian follicles (7, 8).

For this recommendation, the GDG addressed the question: should AFC versus FSH or AMH be used for the assessment of ovarian reserve in women with infertility in whom other causes of anovulation or oligo-ovulation have been ruled out?

Balancing harms and benefits

We first searched for systematic reviews published since 2000 and found three reviews published in the early 2000s (22–24). These reviews assessed FSH, AMH and AFC to predict poor response to ovarian stimulation which can provide indirect evidence for ovarian reserve. More recently, a systematic review and meta-analysis of individual patient data was conducted to assess the effect of adding ovarian reserve tests to age to predict poor response to ovarian stimulation (25). This review reported that age was a good predictor of poor response and the addition of tests such as AFC and AMH only marginally improved this prediction.

Searches were also previously conducted from 1990 to July 2019 for test accuracy studies and studies measuring health outcomes that directly compared AFC versus FSH versus AMH in the same women. We found a systematic review published in 2023 by Liu et al. (26) with a search date up to May 2022 (26), comparing AMH and AFC, and one study by Jaiswar et al. (27) comparing all three tests.

The study by Jaiswar et al. (27) was a low risk of bias study that included 100 women with infertility aged < 40 years old in India who received clomiphene citrate stimulation and poor response was defined as < 3 oocytes retrieved. In this study, FSH was measured once per participant, and paired E2 levels were not assessed. Sensitivity and specificity were calculated from this study (with 95% lower and upper confidence intervals [CIs]) as shown in Tables 5.3 and 5.4.

Guideline for the prevention, diagnosis and treatment of infertility

Table 5.3. Sensitivity and specificity for AFC, AMH and FSH

||AFC|AMH|FSH| |---|---|---|---| |Sensitivity (95% CI)|78% (64-88%)|80% (67-90%)|63% (48-76%)| |Specificity (95% CI)|65% (51-76%)|74% (61-84%)|69% (55-79%)|

AFC, antral follicle count; AMH, anti-Müllerian hormone; CI, confidence interval; FSH, follicle-stimulating hormone. Source: Jaiswar et al., 2015 (27).

Table 5.4. Absolute effects on 100 women when AFC, AMH and FSH are provided

||AFC|AMH|FSH| |---|---|---|---| |True positives|36|37|29| |True negatives|35|40|37| |False positives|19|14|17| |False negatives|10|9|17|

AFC, antral follicle count; AMH, anti-Müllerian hormone; CI, confidence interval; FSH, follicle-stimulating hormone. Source: Jaiswar et al., 2015 (27).

The systematic review by Liu et al. (26) included 42 studies and did not conduct a paired analysis of studies; it pooled studies together that assessed the accuracy of one test and then compared those pooled results to the pooled analysis of the studies

that assessed the accuracy of the other test. Studies were conducted in women with infertility to predict poor or high response to IVF treatment. The results for poor response are presented in Table 5.5 (a range of cut-offs were used).

Table 5.5. Results for poor response from a systematic review

||AMH|AFC| |---|---|---| |Sensitivity (95% CI)|80% (74-85%)|73% (62-83%)| |Specificity (95% CI)|81% (75-85%)|85% (78-90%)|

AFC, antral follicle count; AMH, anti-Müllerian hormone; CI, confidence interval.

Source: Liu et al., 2023 (26).

This review (26) showed that per 100 patients tested, and compared to AMH, the use of AFC resulted in two fewer true positives, two more false

negatives, three more true negatives and three fewer false positives.

5 Diagnosis of infertility

In considering desirable effects, the GDG noted that the study comparing all tests and the systematic review comparing AFC to AMH reported differences in false positives and false negatives of about 2-5 women out of 100. The GDG agreed that the benefits of AFC compared to AMH or FSH are trivial. In addition, the GDG considered the systematic reviews of poor response showing that when compared to age, AMH may moderately predict a poor response, AFC could be a good predictor at very low levels and FSH may not be a better predictor, and agreed that the benefits of these tests were trivial. The GDG agreed that when added to age, the benefits of these tests were trivial.

In terms of harms, the GDG noted that the comparative study comparing all tests and the systematic review comparing AFC to AMH found differences in false positives and false negatives of about 2-5 women out of 100. The GDG agreed that the harms of AFC compared to AMH or FSH are trivial.

The certainty of the evidence in the comparative accuracy of the tests was low and was further rated to very low because of indirectness by the GDG. The studies did not quantify the numbers of oocytes remaining in a woman's ovaries; instead, they measured ovarian response to stimulation, which is then taken as an indirect measure of the numbers of oocytes remaining in a woman's ovaries with the potential to yield a pregnancy.

No studies were identified on patient values; however, the GDG agreed that women would value tests that can identify the diagnosis correctly and would seek to minimize the harms of unnecessary tests, frequent travel (e.g. for serial tests) and costs. The GDG agreed that probably no important uncertainty or variability existed in how much people value these outcomes. Based on these data, the GDG agreed that the balance of effects does not favour any of the tests compared to one another.

Other considerations

There was no direct research evidence for resources required; however, the GDG agreed that in LMICs the cost differences vary among AFC, AMH and FSH. There was no direct evidence on cost-effectiveness; however, the GDG agreed that given that there are similar benefits and harms with all tests, and the cost differences vary, then cost-effectiveness would vary. No studies reported on health inequities related to any of the three tests; however, the GDG agreed that in some settings certain tests may be more available. Therefore, the impact on equity varies.

The GDG considered several studies that assessed the acceptability of these tests to patients (8) and providers (28–33) and judged that acceptability varies. The GDG agreed that the feasibility and availability of the different tests varies in different settings and countries.

![=-\n](1/parseimages/figure1107c2b353ce442a850c9828f62b9e24_0_9.png)

Summary justification

Evidence found that there may be little to no difference in the test accuracy of AFC or AMH or day 3 FSH, but this evidence is of very low certainty. The costs, resources, feasibility and acceptability of FSH, AMH and AFC likely vary across different settings and countries; therefore, the preferred test will be dependent on those factors.

Implementation considerations

![](1/parseimages/figureced5869091744c6e9839174de5bf0af9_0_13.png) Health care providers should note that ovarian reserve tests are suggested in this

guideline as an optional test for diagnostic

purposes, during the evaluation of anovulation or oligo-ovulation, where other causes of anovulation or oligo-ovulation have been excluded or have not been identified (e.g. by assessing the HPO axis [E2,

Guideline for the prevention, diagnosis and treatment of infertility

T, FSH, LH], as well as TSH and PRL), and whose explanation of failure to achieve pregnancy could potentially be related to reduced numbers (or quality) of oocytes.

Health care providers should note that the primordial follicles count is the definitive indicator of ovarian reserve; however, it can only be measured directly using histological examination of entire ovaries. For this reason, surrogate markers, such as AFC, AMH and FSH, which may correlate with the primordial follicle count, provide an indirect indication of biological reserve. Health care providers should note that each of these tests have advantages and disadvantages, whose relative importance varies in different settings and countries; therefore, it is important to consult with the patients when selecting the test, through a process of collaborative decision-making. The application of these tests during IVF treatment, including to predict outcomes, is not within the scope of this diagnostic PICO.

Selection of optional test to assess ovarian reserve should be based on relative acceptability, availability and resources in local contexts. In selecting these tests, health care providers should also consider several technical parameters, such as those related to inter-laboratory or inter-observer variability (8, 34), turnaround times for these tests and availability of WHO international assay standards (35–37). Technical parameters can affect test results, and training and rigorous quality safeguards are necessary to minimize errors.

Correct interpretation of the results of hormonal tests, such as FSH, may require

concomitant evaluation of other test results (e.g. E2 [38]) and may be influenced by cycle-to-cycle variations, particularly AMH and AFC (8, 35). In the studies reviewed for this recommendation, AFC was assessed in the first half of the menstrual cycle, AMH was cycle-independent and FSH in combination with E2 was assessed on either cycle days 2–3 or cycle days 2–4.

Health care providers should consider how these tests fit in with other planned investigations. Selection of diagnostic tests should be based on clinical findings from comprehensive medical history and physical examination to ensure that evaluation is systematic and cost-effective (see Chapter 3). For example, the ability of age to predict ovarian reserve may be limited in some clinical scenarios such as cases of premature ovarian insufficiency.

Research gaps and future guideline update

Data were insufficient to determine if there are subgroups of patients that may benefit more from any of the tests, for example, patients with ovarian endometriomas or other ovarian masses. Future comparative studies among different subgroups are needed to respond to this gap. Given the very low certainty of evidence, future comparative studies assessing ovarian reserve should be better designed and implemented. Future guidance will be required on the role of ovarian reserve testing during IVF, including to predict outcomes and the likelihood of success, as this was not within the scope of this diagnostic PICO. This recommendation relates to application of these tests in health care settings and does not relate to direct-to-consumer tests, for example, AMH tests (39), which will require future guidance.

5 Diagnosis of infertility

References

1. Recent advances in medically assisted conception: report of a WHO Scientific Group. Geneva: World Health Organization; 1992 (https://iris who.int/bitstream/handle/10665/38679/WHO_TRS_820_eng.pdf).

2. Cates W, Farley TM, Rowe PJ. Worldwide patterns of infertility: is Africa different? Lancet. 1985;2(8455):596-8 (https://doi.org/10.1016/s0140-6736(85)90594-x).

3. Wallace WH, Kelsey TW. Human ovarian reserve from conception to the menopause. PLoS One. 2010;5(1):e8772 (https://doi.org/10.1371/journal.pone.0008772).

4. Matsuda F, Inoue N, Manabe N, Ohkura S. Follicular growth and atresia in mammalian ovaries: regulation by survival and death of granulosa cells. J Reprod Dev. 2012;58(1):44-50 (https://doi.org/10.1262/jrd.2011-012).

5. Chua S, Danhof N, Mochtar M, Van Wely M, McLernon D, Custers I et al. Age-related natural fertility outcomes in women over 35 years: a systematic review and individual participant data meta-analysis. Hum Reprod. 2020;35(8):1808-20 (https://doi.org/10.1093/humrep/deaa129).

6. Bentzen JG, Forman JL, Johannsen TH, Pinborg A, Larsen EC, Andersen AN. Ovarian antral follicle subclasses and anti-Müllerian hormone during normal reproductive aging. J Clin Endocrinol Metab. 2013;98(4):1602-11 (https://doi.org/10.1210/jc.2012-1829).

7. Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril. 2020;114(6):1151-7 (https://doi.org/10.1016/j.fertnstert.2020.09.134).

8. Iliodromiti S, Anderson RA, Nelson SM. Technical and performance characteristics of anti-Müllerian hormone and antral follicle count as biomarkers of ovarian response. Hum Reprod Update. 2015;21(6):698-710 (https://doi.org/10.1093/humupd/dmu062).

9. Ulrich ND, Marsh EE. Ovarian reserve testing: a review of the options, their applications, and their limitations. Clin Obstet Gynecol. 2019;62(2):228-37 (https://doi.org/10.1097/ grf.0000000000000445).

10. Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011;26(7):1616-24 (https://doi.org/10.1093/humrep/der092).

11. Hansen KR, Hodnett GM, Knowlton N, Craig LB. Correlation of ovarian reserve tests with histologically determined primordial follicle number. Fertil Steril. 2011;95(1):170-5 (https://doi.org/10.1016/j.fertnstert.2010.04.006).

12. Pache TD, Wladimiroff JW, de Jong FH, Hop WC, Fauser BC. Growth patterns of nondominant ovarian follicles during the normal menstrual cycle. Fertil Steril. 1990;54(4):638-42 (https://doi.org/10.1016/s0015-0282(16)53821-7).

13. Rajp:De Myets E, Jørgensen N, Graem N, Müller J, Cate RL, Skakkebaek NE. Expression of anti-Müllerian hormone during normal and pathological gonadal development: association with differentiation of Sertoli and granulosa cells. J Clin Endocrinol Metab. 1999;84(10):3836-44 (https://doi.org/10.1210/jcem.84.10.6047).

14. Rey R, Lukas-Croisier C, Lasala C, Bedecarrás P. AMH/MIS: what we know already about the gene, the protein and its regulation. Mol Cell Endocrinol. 2003;211(1-2):21-31 (https://doi.org/10.1016/j.mce.2003.09.007).

15. Sowers MR, Eyvazzadeh AD, McConnell D, Yosef M, Jannausch ML, Zhang D et al. Anti-Mullerian hormone and inhibin B in the definition of ovarian aging and the menopause transition. J Clin Endocrinol Metab. 2008;93(9):3478-83 (https://doi.org/10.1210/jc.2008-0567).

16. de Vet A, Laven JS, de Jong FH, Themmen AP, Fauser BC. Antimüllerian hormone serum levels: a putative marker for ovarian aging. Fertil Steril. 2002;77(2):357-62 (https://doi.org/10.1016/s0015-0282(01)02993-4).

Guideline for the prevention, diagnosis and treatment of infertility

17. Chappel SC, Ulloa-Aguirre A, Coutifaris C. Biosynthesis and secretion of follicle-stimulating hormone. Endocr Rev. 1983;4(2):179-211 (https://doi.org/10.1210/edrv-4-2-179).

18. Ulloa-Aguirre A, Espinoza R, Damian-Matsumura P, Chappel SC. Immunological and biological potencies of the different molecular species of gonadotrophins. Hum Reprod. 1988;3(4):491-501 (https://doi.org/10.1093/oxfordjournals.humrep.a136734).

19. Klein NA, Illingworth PJ, Groome NP, McNeilly AS, Battaglia DE, Soules MR. Decreased inhibin B secretion is associated with the monotropic FSH rise in older, ovulatory women: a study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles. J Clin Endocrinol Metab. 1996;81(7):2742-5 (https://doi.org/10.1210/jcem.81.7.8675606).

20. Reame NE, Wyman TL, Phillips DJ, de Kretser DM, Padmanabhan V. Net increase in stimulatory input resulting from a decrease in inhibin B and an increase in activin A may contribute in part to the rise in follicular phase follicle-stimulating hormone of aging cycling women. J Clin Endocrinol Metab. 1998;83(9):3302-7 (https://doi.org/10.1210/jcem.83.9.5130).

21. Burger HG, Dudley EC, Hopper JL, Groome N, Guthrie JR, Green A et al. Prospectively measured levels of serum follicle-stimulating hormone, estradiol, and the dimeric inhibins during the menopausal transition in a population-based cohort of women. J Clin Endocrinol Metab. 1999;84(11):4025-30 (https://doi.org/10.1210/jcem.84.11.6158).

22. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update. 2006;12(6):685-718 (https://doi.org/10.1093/humupd/dml034).

23. Hendriks DJ, Mol BW, Bancsi LF, Te Velde ER, Broekmans FJ. Antral follicle count in the prediction of poor ovarian response and pregnancy after in vitro fertilization: a meta-analysis and comparison with basal follicle-stimulating hormone level. Fertil Steril. 2005;83(2):291-301 (https://doi.org/10.1016/j.fertnstert.2004.10.011).

24. Broer SL, Mol BW, Hendriks D, Broekmans FJ. The role of antimullerian hormone in prediction of outcome after IVF: comparison with the antral follicle count. Fertil Steril. 2009;91(3):705-14 (https://doi.org/10.1016/j.fertnstert.2007.12.013).

25. Broer SL, van Disseldorp J, Broeze KA, Dolleman M, Opmeer BC, Bossuyt P et al. Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach. Hum Reprod Update. 2013;19(1):26-36 (https://doi.org/10.1093/humupd/dms041).

26. Liu Y, Pan Z, Wu Y, Song J, Chen J. Comparison of anti-Mullerian hormone and antral follicle count in the prediction of ovarian response: a systematic review and meta-analysis. J Ovarian Res. 2023;16(1):117 (https://doi.org/10.1186/s13048-023-01202-5).

27. Jaiswar SP, Natu SM, Sujata, Sankhwar PL, Manjari G. Prediction of poor ovarian response by biochemical and biophysical markers: a logistic regression model. J Obstet Gynaecol India. 2015;65(6):411-6 (https://doi.org/10.1007/s13224-014-0639-8).

28. La Marca A, Ferraretti AP, Palermo R, Ubaldi FM. The use of ovarian reserve markers in IVF clinical practice: a national consensus. Gynecol Endocrinol. 2016;32(1):1-5 (https://doi.org/10.3109/90513590.2015.1102879).

29. Tobler KJ, Shoham G, Christianson MS, Zhao Y, Leong M, Shoham Z. Use of anti-mullerian hormone for testing ovarian reserve: a survey of 796 infertility clinics worldwide. J Assist Reprod Genet. 2015;32(10):1441-8 (https://doi.org/10.1007/s10815-015-0562-7).

5 Diagnosis of infertility

30. Patrizio P, Vaiarelli A, Levi Setti PE, Tobler KJ, Shoham G, Leong M et al. How to define, diagnose and treat poor responders? Responses from a worldwide survey of IVF clinics. Reprod Biomed Online. 2015;30(6):581-92 (https://doi.org/10.1016/j.rbmo.2015.03.002).

31. Christianson MS, Shoham G, Tobler KJ, Zhao Y, Cordeiro CN, Leong M et al. Measurement of antral follicle count in patients undergoing in vitro fertilization treatment: results of a worldwide web-based survey. J Assist Reprod Genet. 2015;32(10):1435-40 (https://doi.org/10.1007/s10815-015-0555-6).

32. Costa M, Chiaffarino F, De Stefano C, Parazzini F. Timing, characteristics and determinants of infertility diagnostic work up before admission to eleven second-level assisted reproductive techniques (ART) centres in Italy. Eur J Obstet Gynecol Reprod Biol. 2013;167(1):53-8 (https://doi.org/10.1016/j.ejogrb.2012.10.022).

33. Cédrin-Durnerin I, Belaisch-Allart J, Avril C, Pouly JL. Facteurs prédictifs de succès de l'induction d'ovulation par FSH recombinante: résultats de l'étude Indigo [Predictive factors of success in ovulation induction with recombinant FSH: results of Indigo study]. Gynecol Obstet Fertil. 2010;38(2):105-13 (https://doi.org/10.1016/j.gyobfe.2009.12.002) (in French).

34. Manual of diagnostic ultrasound, Vol. 2, second edition. Geneva: World Health Organization; 2013 (https://iris.who.int/handle/10665/85386).

35. Li HWR, Robertson DM, Burns C, Ledger WL. Challenges in measuring AMH in the clinical setting. Front Endocrinol. 2021;12:691432 (https://doi.org/10.3389/fendo.2021.691432).

36. Ferguson J, Hockley J, Rigsby P, Burns C. Establishment of a WHO reference reagent for anti-Mullerian hormone. Reprod Biol Endocrinol. 2020;18(1):86 (https://doi.org/10.1186/s12958-020-00641-9).

37. WHO Expert Committee on Biological Standardization: seventy-eighth report. Geneva: World Health Organization; 2024 (https://iris.who.int/handle/10665/376596).

38. Tal R, Seifer DB. Ovarian reserve testing: a user's guide. Am J Obstet Gynecol. 2017;217(2):129-40 (https://doi.org/10.1016/j.ajog.2017.02.027).

39. Johnson A, Thompson R, Nickel B, Shih P, Hammarberg K, Copp T. Websites selling direct-to-consumer anti-Mullerian hormone tests. JAMA Netw Open. 2023;6(8):e2330192 (https://doi.org/10.1001/jamanetworkopen.2023.30192).

Guideline for the prevention, diagnosis and treatment of infertility

5.5 Diagnosis of infertility due to tubal disease

![](1/parseimages/figuree09ff8059b3b4df2ae8fa3c5b6d70530_0_3.png)

Recommendation

Remark:

$\bullet$ When selecting whether to use HSG or HyCoSy to assess tubal patency, consider feasibility, the availability of trained health care providers and the potential for allergy.

Background and rationale

Evaluation of tubal patency is an essential part of investigating the cause of infertility. In a large WHO multi-country study involving 8500 couples in 25 countries, bilateral tubal blockage contributed to 17.7% of identifiable causes of female infertility (1). The diagnosis of tubal occlusion is generally established by a combination of clinical suspicion based on patient history and confirmatory diagnostic tests. Diagnostic laparoscopy with chromopertubation is considered the reference gold standard for confirming suspected tubal disease because it allows visualization of the fallopian tubes and adjacent pelvic tissue. However, it is invasive and costly, and requires general anaesthesia, making it unsuitable for routine diagnostic assessment of tubal pathology. Alternative options include HSG and HyCoSy. HSG and HyCoSy are typically performed during the follicular phase of the menstrual cycle between cycle days 6 and 10, before the lining gets too thick, which may obscure any pathology, and to avoid interrupting an undiagnosed very early pregnancy.

During HSG, iodinated contrast medium is slowly flushed through the uterine cavity and fallopian tubes using a catheter or cannula, resulting in their distension and visualization under fluoroscopic guidance. Still radiographs are performed.

HSG uses either oil- or water-soluble contrast medium (2). Opacification of the fallopian tubes with subsequent free intraperitoneal spill is considered a sign of tubal patency. Although HSG is less invasive than laparoscopy, it may result in adverse effects, such as pain, infection, allergic reaction to iodine, as well as exposure to ionizing radiation (3).

During HyCoSy, echogenic distending medium is slowly injected distending the uterine cavity, uterus and fallopian tubes using a catheter or cannula, allowing visualization of the fallopian tubes with the aid of transvaginal or rarely, transabdominal ultrasonography. HyCoSy can be performed with either air-saline or microbubble distending medium. High-contrast echoes in the fallopian tube indicate tubal patency. Although HyCoSy circumvents the risk of iodine allergy and radiation, it may also be complicated by adverse effects, such as pain, infection, or allergy to the distending medium used (3). The GDG agreed that a key decision when investigating women with infertility and suspected tubal disease is whether to use HSG or HyCoSy. For this recommendation, the GDG addressed the question: should HyCoSy versus HSG be used to evaluate women with infertility and suspected tubal disease? Assessment of the uterine cavity is presented in section 5.6 and is not included in this recommendation question.

Balancing harms and benefits

Diagnostic test accuracy

We updated a prior systematic review by Maheux-

Adverse effects

To assess whether the use of HyCoSy versus HSG could lead to better management and fewer side-effects, a systematic search was conducted and 11 comparative non-randomized studies were included (8, 12, (14) (15) (16) (17) (18) (19) (20) (21) (22) . per 1000, five studies; RR: 0.72; 95% CI 0.34-1.5), ectopic pregnancies and anxiety. Although there is radiation exposure with HSG, the GDG did not consider the potential harms to be of great concern but noted the need for future evaluation of its effects on maternal and neonatal outcomes.

The certainty of evidence was moderate for differences in the accuracy of the tests and low to very low for the downstream health outcomes.

Thus, the overall certainty of the evidence is low.

There were no studies on patient values; however, the GDG agreed that women would value better

References

Guideline for the prevention, diagnosis and treatment of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

pregnancy and birth outcomes and would seek to

minimize harms. Given that the net desirable and undesirable effects between HyCoSy and HSG are

trivial, neither test is favoured over the other.

Other considerations

No data were identified related to costs or costeffectiveness between HSG and HyCoSy. Although

HSG may require a radiographic unit, the GDG

considered that HyCoSy is highly operatordependent (23), but both HSG and HyCoSy require training of health care providers. Thus, the GDG agreed that both tests likely involve similar costs

and resources, and there is likely no difference in

cost-effectiveness between the two. Given that the

costs are similar between HSG and HyCoSy, the

GDG agreed that providing one test rather than

another would probably have no impact on equity.

A systematic search was conducted of other

factors related to the acceptability of HSG and

HyCoSy. The GDG considered evidence from several studies (21, 24–26) and agreed that both tests are

probably acceptable to patients and providers. The GDG agreed that both tests are similarly feasible

and require resources and expertise to conduct

or interpret, based on the evidence from two

studies (23, 27).

Summary justification

Overall, there was low-certainty evidence for trivial differences in desirable and undesirable effects between the use of HSG or HyCoSy in women who have

infertility and suspected tubal disease. The costs, resources, feasibility and

acceptability are probably similar, and choosing either test would probably have no impact on equity.

Implementation considerations

When selecting a diagnostic method, health care providers should also consider the

potential for allergy and the need to evaluate the uterus, ovaries and myometrium in the context of infertility. Health care providers should monitor

patients for adverse effects and consider analgesics

as appropriate (28). Health care providers should be aware of and monitor patients for potential thyroid dysfunction associated with iodine-based contrast media and should adhere to contraindications of

specific products to prevent such harms, especially

among patients with thyroid disease (29).

To ensure safety, training of health care

providers on how to perform HSG or HyCoSy procedures is required. Given equipoise between

HSG and HyCoSy, health care providers should seek

patients’ preferences in keeping with the principles

of shared decision-making. Future studies

comparing HSG and HyCoSy should report patient

preferences and whether the use of either test improves management and, consequently, the

effects on live births to better inform future

recommendations.

Research gaps and future guideline update

Additional data are required on the costs and

cost-effectiveness of HSG and HyCoSy, given

the lack of evidence on these aspects. Further guidance is required to identify populations that

would benefit from the use of oil-based contrast

compared with water-based contrast during HSG. Further guidance is required on the use of either air-saline or microbubble commercial contrast

media, probe type (vaginal versus abdominal) and Doppler sonography versus conventional twodimensional (2D) or three-dimensional (3D) US

during HyCoSy. Future guidance is required on the

effect of location of tubal pathology (distal versus

proximal) on the test performance of both HSG and HyCoSy. Although radiation exposure with HSG is

Abstract

Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps considered low, there is a need for the evaluation of the potential effects of peri-conceptional radiation exposure on maternal thyroid function and offspring neurodevelopment. Further guidance will be needed on whether prophylactic antibiotics should be used during HyCoSy or HSG.

References

Guideline for the prevention, diagnosis and treatment of infertility 80 Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Authors

References

5 Diagnosis of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

27. Omurtag K, Grindler NM, Roehl KA, Bates GW Jr,

Beltsos AN, Odem RR et al. How members of

the Society for Reproductive Endocrinology and Infertility and Society of Reproductive Surgeons

evaluate, define, and manage hydrosalpinges.

Fertil Steril. 2012;97(5):1095-100 (https://doi.

org/10.1016/j.fertnstert.2012.02.026).

28. Hindocha A, Beere L, O’Flynn H, Watson A,

Ahmad G. Pain relief in hysterosalpingography. Cochrane Database Syst Rev. 2015;(9):CD006106 (https://doi.org/10.1002/14651858.CD006106.

pub3).

29. Bednarczuk T, Brix TH, Schima W, Zettinig G, Kahaly GJ. 2021 European Thyroid Association

guidelines for the management of iodine-based contrast media-induced thyroid dysfunction.

Eur Thyroid J. 2021;10(4):269-84 (https://doi.

org/10.1159/000517175).

Guideline for the prevention, diagnosis and treatment of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

5.6 Diagnosis of infertility due to uterine cavity disorder

This section contains several recommendations related to the diagnostic assessment of

the uterine cavity. Figure 5.2. shows how these recommendations relate to each other,

illustrated in a diagnostic algorithm. Specific recommendations are presented in the

sections that follow, based on head-to-head comparisons of different diagnostics methods.

Hierarchy of uterine investigations

Hysteroscopy (± laparoscopy) is the gold standard in the assessment of the uterine cavity; however, it is an invasive procedure that may require anaesthesia or sedation, making it unsuitable for routine diagnostic assessment of the uterine cavity. As illustrated in Fig. 5.2, this guideline suggests that saline infusion

sonohysterography (SIS) should be ordinarily used because of cost considerations, unless 3D US is readily available within existing resources. Where SIS or 3D US are not available, either HSG or 2D US may be

used. Table 5.7 shows the comparison of test performance between 3D US, SIS, 2D US and HSG with

hysteroscopy for the diagnosis of uterine cavity disorders.

Table 5.7. Comparison of 3D US, SIS, 2D US and HSG with hysteroscopy for the diagnosis of uterine cavity disorders

3D US

SIS

2D US (paired data with 3D US)

HSG (paired data with SIS)

Hysteroscopy

Sensitivity (95% CI)

96% (59–100)

89% (72–95)

68% (59–75)

72% (56–84)

100%

Specificity (95% CI)

94% (77–99)

100% (27–100)

93% (64–99)

93% (66–99)

100%

True positives

False negatives

False positives

True negatives

85 2D, two-dimensional ultrasound; 3D, three-dimensional; CI, confidence interval; HSG, hysterosalpingogram; SIS, saline infusion sonohysterography; US, ultrasound.

5 Diagnosis of infertility

Executive summaryIntroRationale & methodologyApproach & managementPreventionDiagnosisTreatmentDisseminationResearch gaps

5 Diagnosis of infertility

F i g.

D i a g n o s t i c a l g o r i t h m f o r t h e a s s e s s m e n t o f t h e u t e r i n e c a v i t y

F e m a l e s u s p e c t e d o f u t e r i n e c a v i t y d i s o r d e r o n

m e d i c a l h i s t o r y a n d p h y s i c a l e x a m i n a t i o n

I n v e s t i g a t e t h e u t e r i n e c a v i t y

U s e S I S

N o r m a l c a v i t y N o r m a l c a v i t y

U s e 3 D U S

d U

d i s o r d e r c o n fi r m e d

r e a t

T r e a t

Y e s N o

Y e s

S e e

F i g.

f o r t h e o v e r a l l d i a g n o s t i c a l g o r i t h m f o r f e m a l e-f a c t o r i n f e r t i l i t y.

S e e r e c o m m e n d a t i o n s f o r t h e t r e a t m e n t o f u t e r i n e-f a c t o r i n f e r t i l i t y i n

C h a p t e r 8

S e e t h e

T a b l e 5.

D,t w o-d i m e n s i o n a l;3 D,t h r e e-d i m e n s i o n a l;H S G,h y s t e r o s a l p i n g o g r a m;S I S,s a l i n e i n f u s i o n s o n o h y s t e r o g r a p h y;U S,u l t r a s o u n d.

U s e e i t h e r H S G

O R

2 D U S 2 D U S

S G

M a y b e n o r m a l c a v i t y.

F o l l o w-u p

m a y b e n e e d e d b e c a u s e o f h i g h

r a t e s o f f a l s e n e g a t i v e s

P r o b a b l y n o r m a l

c a v i t y

d U

d i s o r d e r c o n fi r m e d

P o s i t i v e r e s u l t P o s i t i v e r e s u l t

N e g a t i v e r e s u l t

e g a t i v e r e s u l t

N e g a t i v e r e s u l t

o s i t i v e r e s u l t P o s i t i v e r e s u l t

N e g a t i v e r e s u l t

S I S o r 3 D U S n o t

a v a i l a b l e?

A r e t h e r e r e s o u r c e

c o n s t r a i n t s?

5 D i a g n o s i s o f i n f e r t i l i t y

8 3

E x e c u t i v e s u m m a r y I n t r o R a t i o n a l e&m e t h o d o l o g y A p p r o a c h&m a n a g e m e n t P r e v e n t i o n D i a g n o s i s T r e a t m e n t D i s s e m i n a t i o n R e s e a r c h g a p s

Guideline for the prevention, diagnosis and treatment of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Recommendation

For females with infertility who are suspected to have a uterine cavity

disorder, WHO suggests assessing the uterine cavity with saline infusion

sonohysterography (SIS) rather than three-dimensional ultrasound (3D US).

(Conditional recommendation, low certainty of evidence)

Remark:

• In settings where 3D US is already available within the existing resources,

3D US may be the preferred option.

Background and rationale

Infertility can be affected by uterine cavity

abnormalities. The incidence of intrauterine

abnormalities, such as polyps, fibroids, adhesions

and congenital malformations, is higher in women with infertility than in the general population (1, 2). Therefore, accurate detection of uterine cavity

abnormalities is important in the identification

of the cause and subsequent management of infertility.

Hysteroscopy is considered the reference

gold standard for the assessment of uterine

abnormalities because it allows direct visualization

of the endometrial cavity, as well as the ability to obtain tissue for histological diagnosis. The

procedure involves inserting a flexible, semi-flexible

or rigid telescope into the endometrial cavity.

To optimize visualization, uterine distension

with carbon dioxide or normal saline is typically

performed. However, it is an invasive procedure

that may require anaesthesia or sedation, making it unsuitable for routine diagnostic assessment of the uterine cavity.

SIS is a diagnostic procedure that involves the

manual installation of saline into the uterine cavity transcervically to act as a negative contrast agent

and facilitate enhanced endometrial visualization

during transvaginal assessment of the endometrial cavity using ultrasound (3, 4). The infusion of sterile

isotonic fluid during transvaginal sonography into

the uterine cavity facilitates uterine distension and enhanced visual contrast during real-time ultrasonographic examination (4, 5).

Ultrasonography (US imaging) involves the

generation and transmission of ultrasonic

(high-frequency sound) waves from a transducer and processing of a returning echo to

generate an image. It is based on non-ionizing

energy (6). Although ultrasound examination

of the myometrium may be performed using

a transabdominal transvaginal or more rarely

transrectal approach (7, 8), the transvaginal

approach is most commonly used for assessing

uterine abnormalities (7–9). 3D US is an

enhancement of ultrasonography, which formats the sound wave data into 3D images and enables their offline examination and manipulation (9, 10).

The GDG agreed that a key decision when

investigating women with infertility and suspected uterine pathology is whether to use SIS or 3D US. For this recommendation, the GDG addressed

the question: should SIS versus 3D US be used

to evaluate women with infertility and suspected uterine cavity abnormality?

Balancing harms and benefits

De novo searches were conducted to identify

diagnostic test accuracy (DTA) studies on SIS and 3D US and to identify studies on health outcomes up to November 2019. We found one study in which women received both SIS and 3D transvaginal ultrasound,

and results were compared to the reference standard of hysteroscopy. It determined the sensitivity and

specificity of each test to identify fibroids, endometrial polyps, intrauterine synechiae and Müllerian

anomalies, as well as arcuate, unicornuate, bicornuate and subseptate uteri (11), as shown in Table 5.8.

References

Guideline for the prevention, diagnosis and treatment of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Test modality Study

Condition identified

Alborzi et al. (22)

Total tubal and uterine pathologies: tubal obstruction.

Intracavitary pathologies: Asherman syndrome, endometrial polyps, myomatous uterus. Structural uterine anomalies:

septate uterus and other structural uterine anomalies

De Felice et al. (23)

Abnormalities of the uterine cavity

Aboulghar et al. (11)

Fibroids; endometrial polyps; intrauterine synechiae; Müllerian

anomalies; arcuate, unicornuate, bicornuate and subseptate

uteri (few)

3D, three-dimensional; SIS, saline infusion sonohysterography; US, ultrasound.

Calculations of sensitivity and specificity were conducted based on unpaired studies, as shown in Table 5.10.

Table 5.10. Sensitivity and specificity of 3D US and SIS with 95% CIs from unpaired studies

3D US

SIS

Sensitivity (95% CI)

96% (59–100%)

88% (72–95%)

Specificity (95% CI)

94 (77–99%)

100 (27–100%)

3D, three-dimensional; CI, confidence interval; SIS, saline infusion sonohysterography; US, ultrasound.

Calculations of absolute effects on true and false

negatives and positives were based 15% prevalence

of uterine cavity disorders in women with infertility. The results showed that there may be one less

true positive per 100 with SIS than with 3D US,

one more false negative per 100 with SIS than

3D US, five more true negatives per 100 with SIS

compared with 3D US and five fewer false positives

per 100 with SIS compared with 3D US. The GDG agreed that in a population where the prevalence

of uterine cavity disorder was 15%, five fewer false positives is a trivial difference in the number of

women correctly identified with SIS compared to

3D US; likewise, one more missed woman with uterine cavity disorder (false negative) with SIS is considered trivial. The GDG noted that the

synthesized evidence combined the analysis of

many uterine abnormalities, and that sensitivity and

specificity may differ between anomalies.

Additional data for health outcomes, such as adverse events, were obtained from

studies (11, 19, 20, 24–28). Based on these data, the

GDG judged that the undesirable effects with SIS

may be trivial compared to 3D US although the

evidence is uncertain. Given the trivial differences in benefits and harms between SIS and 3D US, the GDG judged that the balance of effects probably

does not favour one over the other. There were no studies on patient values; however, the GDG agreed that women would likely value tests that can identify

the diagnosis correctly and would seek to minimize

harms, and that there was probably no important uncertainty or variability in how women value these outcomes. The overall certainty of evidence was low.

Other considerations

Although comparative data about costs were

not available, the GDG agreed that 3D US is likely more expensive than SIS and SIS would probably lead to moderate savings. There were no data on

cost-effectiveness; however, the GDG agreed that given the trivial differences in benefits and harms

but moderate savings with SIS, that SIS is probably

5 Diagnosis of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

favoured. In addition, the GDG judged that SIS

could probably increase equity because it is more widely available than 3D US. Although no data were available, the GDG agreed that SIS and 3D US are likely both acceptable. One study (29) provided an

analysis of feasibility of 3D US and SIS. The GDG

considered that although both require training of

health care providers, SIS is probably more feasible than 3D US because 3D US is not as widely available.

Summary justification

There is low-certainty evidence that there are trivial differences in benefits and harms with SIS compared to 3D US. Although both are acceptable, 3D US likely costs more than SIS and is less available; therefore SIS is suggested. In settings where it is already available within the existing resources, 3D US may be the

preferred option.

Implementation considerations

Training of health care providers is required to ensure the correct assessment,

documentation and reporting of uterine cavity

assessment (9, 30).

Research gaps and future guideline update

Because of the lack of large studies on each uterine

anomaly, the synthesized evidence in this PICO

is based on pooled data related to many uterine abnormalities. Future large studies are required

to provide sufficient discriminatory power. Future

guidance is required to compare the role of colour, power and spectral Doppler, as well as fourdimensional (4D) ultrasonography in evaluating

uterine cavity disorders, including different types of Müllerian anomaly disorders (31).

References

1. Saravelos SH, Cocksedge KA, Li TC. Prevalence

and diagnosis of congenital uterine anomalies in women with reproductive failure: a critical

appraisal. Hum Reprod Update. 2008;14(5):415-29 (https://doi.org/10.1093/humupd/dmn018).

2. Chan Y, Jayaprakasan K, Zamora J, Thornton J,

Raine-Fenning N, Coomarasamy A. The

prevalence of congenital uterine anomalies

in unselected and high-risk populations:

a systematic review. Hum Reprod Update.

2011;17(6):761-71 (https://doi.org/10.1093/

humupd/dmr028).

3. Syrop CH, Sahakian V. Transvaginal sonographic

detection of endometrial polyps with fluid

contrast augmentation. Obstet Gynecol. 1992;79(6):1041-3.

4. Parsons AK, Lense JJ. Sonohysterography for

endometrial abnormalities: preliminary results. J Clin Ultrasound. 1993;21(2):87-95 (https://doi.

org/10.1002/jcu.1870210203).

5. Bonilla‐Musoles F, Simón C, Serra V,

Sampaio M, Pellicer A. An assessment of

hysterosalpingosonography (HSSG) as a

diagnostic tool for uterine cavity defects and

tubal patency. J Clin Ultrasound. 1992;20(3):175-81 (https://doi.org/10.1002/jcu.1870200303).

6. Tole N. Basic physics of ultrasonic imaging.

In Ostensen H, editor. Basic physics of

ultrasonic imaging. Geneva: World Health

Organization; 2005 (https://apps.who.int/iris/

handle/10665/43179).

Keywords

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps 7, Manual of diagnostic ultrasound, Vol, 2, second edition, Geneva: World Health Organization; 2013

References

22. Alborzi S, Dehbashi S, Khodaee R.

Sonohysterosalpingographic screening

for infertile patients. Int J Gynaecol Obstet. 2003; 82(1) :57-62 (https://doi.org/10.1016/s0020-7292(02)00417-4).

References

Guideline for the prevention, diagnosis and treatment of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Recommendation

Background and rationale

Ultrasound imaging (sonography) involves

the generation and transmission of ultrasonic

(high-frequency sound) waves from a transducer

and processing of a returning echo to generate an image. It is based on non-ionizing energy (1). The

image is subsequently displayed on a monitor, from which a hard copy may be captured, for example,

using thermal printing paper (1). Although US

examination of the myometrium may be performed using a transabdominal transvaginal or more rarely transrectal approach (2, 3), a transvaginal approach is more commonly used for assessing uterine

abnormalities (2–4). 3D US is an enhancement of

ultrasonography, which formats the sound wave

data into 3D images and enables their examination offline (4, 5).

The GDG agreed that a key decision when

investigating women with infertility and suspected uterine pathology is whether to use 3D or 2D US.

For this recommendation, the GDG addressed

the question: should 3D versus 2D US be used for women with infertility and suspected uterine cavity

abnormality? Although advancements in technology

have allowed further enhancements of sonography, including colour, power and spectral Doppler, which allow assessments of endometrial vascularity and

blood flow, as well as 4D US, this PICO focuses on

3D US compared to 2D US.

Balancing harms and benefits

A de novo search was conducted to identify DTA

studies on 3D and 2D US up to November 2019.

Studies included women who received 3D or 2D US and compared results to the reference standard

of hysteroscopy. Because of the lack of large

studies on each uterine anomaly, the synthesized

evidence in this recommendation question pooled data related to many uterine abnormalities. The

identified studies assessed the sensitivity and

specificity of uterine cavity disorders as shown in

Table 5.11.

Table 5.11. Included studies comparing 3D and 2D US, and the conditions identified

Study

Condition identified

Abdelmagied et al. (6)

Cavitary lesions (e.g. polyps in 47%)

Aboulghar et al. (7)

Fibroids; endometrial polyps; intrauterine synechiae; Müllerian anomalies;

arcuate, unicornuate, bicornuate and subseptate uteri (few)

Niknejadi et al. (8)

Septate uterus (arcuate, subseptate, septate)

2D, two-dimensional; 3D, three-dimensional; CI, confidence interval; US, ultrasound.

5 Diagnosis of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Pooled sensitivity and specificity were calculated across the studies with paired analysis (with 95% lower

and upper CIs) as shown in Table 5.12.

Table 5.12. Pooled sensitivity and specificity for 3D and 2D US with 95% CIs

3D US

2D US

Sensitivity (95% CI)

96% (59–100%)

68% (59–75%)

Specificity (95% CI)

94% (77–99%)

93% (64–99%)

2D, two-dimensional; 3D, three-dimensional; CI, confidence interval; US, ultrasound.

The GDG noted that 3D US had greater sensitivity

and specificity compared to 2D US, although

there was overlap in CIs. The GDG noted that

the synthesized evidence combined the analysis

of many uterine abnormalities, but sensitivity

and specificity may differ between anomalies;

however, available data are insufficient to provide

discriminatory power.

Calculations for the absolute effects on true and

false negatives and positives were conducted,

assuming a 15% prevalence of uterine cavity

disorders among women with infertility. Based

on this prevalence, results showed that there may be four more true positives with 3D US compared to 2D US, four fewer false negatives with 3D US

compared to 2D US, one more true negative with 3D US compared to 2D US and one fewer false

positive with 3D US compared to 2D US. The GDG judged that in a population where 15 out of 100 people have a uterine cavity disorder, four more true positives and four more true negatives was a

small number of women correctly identified with

and without uterine cavity abnormality, and that

even fewer women were missed (false negatives).

Data for health outcomes such as adverse events and complications were available from Soares

et al. (9) and Aboulghar et al. (7). In terms of harms, data from two RCTs showed that no complications were reported from participants who underwent both procedures. The GDG agreed that adverse

events (pain and complications) may be similar

between 3D and 2D US, but the evidence is

uncertain. There were no data for pregnancy or

quality of life outcomes.

There were no studies on patient values; however, the GDG agreed that women would value tests

that can identify the diagnosis correctly and would

seek to minimize harms, and there was probably

no important uncertainty or variability in these

outcomes. Given the small benefits and trivial

harms, the balance of effects probably favoured

3D over 2D US. The GDG judged that the certainty of evidence was low.

Other considerations

Although comparative data for costs were

not available, the GDG judged that 3D US is

relatively more expensive than 2D US. In regard

to cost-effectiveness, and in the absence of data, the GDG judged that given the small benefits and

moderate costs of 3D US, neither 3D nor 2D US

is favoured. There were no data on acceptability; however, the GDG judged that 3D US and 2D US

are both acceptable. The GDG agreed that 3D

US could probably reduce equity because it is

less widely available than 2D US. One study (10)

reported an analysis of feasibility of 3D and 2D US. The GDG agreed that 3D US is probably feasible, but it requires appropriate probes, software and software maintenance and training of health

care providers.

Implementation considerations

Training is required to ensure that health care providers have the skills to assess safely and correctly document and report findings while evaluating the uterus (2, 4, 11, 12) .

Research gaps and future guideline update

Because of the lack of large studies on each uterine anomaly, the synthesized evidence combined the analysis of many uterine abnormalities. Future large studies are required to provide sufficient discriminatory power. Future guidance is required to compare the role of colour, power and spectral Doppler, as well as 4D ultrasonography.

References

5 Diagnosis of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

10. Grimbizis GF, Di Spiezio Sardo A, Saravelos SH,

Gordts S, Exacoustos C, Van Schoubroeck D et al. The Thessaloniki ESHRE/ESGE consensus

on diagnosis of female genital anomalies. Hum Reprod. 2016;31(1):2-7 (https://doi.org/10.1093/humrep/dev264).

11. Leone FP, Timmerman D, Bourne T, Valentin L, Epstein E, Goldstein SR et al. Terms, definitions

and measurements to describe the sonographic features of the endometrium and intrauterine

lesions: a consensus opinion from the

International Endometrial Tumor Analysis (IETA) group. Ultrasound Obstet Gynecol. 2010;35(1):103-12 (https://doi.org/10.1002/uog.7487).

12. Good clinical diagnostic practice: a guide for

clinicians in developing countries to the clinical

diagnosis of disease and to making proper use of clinical diagnostic services. Geneva: World Health Organization; 2005 (https://apps.who.int/iris/

handle/10665/119735).

General: Tile 1A

Guideline for the prevention, diagnosis and treatment of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Recommendation

For females with infertility who are suspected to have a uterine cavity

disorder, WHO suggests assessing the uterine cavity with saline infusion sonohysterography (SIS) rather than two-dimensional ultrasound (2D US).

(Conditional recommendation, low certainty of evidence)

Background and rationale

SIS is a diagnostic procedure that involves the

manual installation of saline into the uterine cavity transcervically to act as a negative contrast agent

and facilitate enhanced endometrial visualization

during transvaginal assessment of the endometrial cavity using ultrasound (1, 2). The infusion of sterile

isotonic fluid during transvaginal sonography into

the uterine cavity facilitates uterine distension

and enhanced visual contrast during real-time

ultrasonographic examination (2, 3). SIS is also

referred to as SHG.

Ultrasound imaging (sonography) involves the

generation and transmission of ultrasonic (highfrequency sound) waves from a transducer and

processing of a returning echo to generate an

image. It is based on non-ionizing energy (4). The

image is subsequently displayed on a monitor, from which a hard copy may be captured, for example,

using thermal printing paper (4). Although US

examination of the myometrium may be performed using a transabdominal transvaginal or more

rarely transrectal approach (5, 6), the transvaginal

approach is more commonly used for assessing

uterine abnormalities (5–7). 2D US is the use of

ultrasonic data to display the acquired information in two dimensions, B-scan (4).

For this recommendation, the GDG addressed the

question: should SIS (i.e. SHG) versus 3D US be used for women with suspected uterine cavity disorder

infertility? The GDG agreed that a key decision when

investigating women with infertility and suspected uterine pathology is whether to use SIS or 2D US.

Balancing harms and benefits

We conducted de novo searches to identify DTA

studies on SIS and 2D US up to November 2019.

Studies included women who received SIS or 2D

transvaginal ultrasound and compared the results to the reference standard of hysteroscopy. Because of the lack of large studies on each uterine anomaly,

the synthesized evidence in this recommendation

question pooled data related to many uterine

abnormalities. Each identified study assessed

sensitivity and specificity to diagnose the uterine

cavity disorders shown in Table 5.13.

In terms of adverse effects, evidence from three (13, 14, 16) in which participants underwent both tests (n = 734), there were two complications

References

Guideline for the prevention, diagnosis and treatment of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

with SIS and none with 2D US. In another RCT (17)

(n = 77), participants did not report any discomfort or pain after undergoing both procedures. Based on these data, the GDG concluded that adverse events (pain and complications) may be similar between

SIS and 2D US. The overall certainty of evidence was rated low because of risk of bias, and few events

and low total numbers of participants across all the studies. There were no studies on patient values;

however, the GDG agreed that women would value tests that can identify the diagnosis correctly and

would seek to minimize harms.

Given the small benefits and trivial harms of SIS

compared to 2D US, SIS is probably favoured. The

GDG noted that the synthesized evidence combined

the analysis of many uterine abnormalities, but

sensitivity and specificity may differ between

anomalies; however, available data are insufficient

to provide discriminatory power.

Other considerations

No data were available on resource requirements; however, the guideline panel agreed that the

additional resources required for SIS are negligible.

The GDG agreed that given the small benefits, but

negligible additional costs of SIS compared to 2D

US, that SIS is likely more cost-effective. The GDG

agreed that there is probably no impact on equity. Although no data were available on acceptability,

the GDG agreed that SIS is likely acceptable. One

study (18) provided an analysis of feasibility of 2D

US but none was available for SIS. The GDG agreed that SIS is probably feasible and requires training of health care providers.

Summary justification

There is low certainty evidence that there are small benefits and trivial differences in harms with SIS compared to 2D US. The balance of effects favours SIS. In

addition, SIS is acceptable and feasible, and has negligible additional resource

requirements and impact on equity when compared to 2D US.

Implementation considerations

Training is required to ensure that health care providers have the skills to safely and correctly assess, document and report diagnostic findings while evaluating the uterus (5, 7, 19, 20).

Research gaps and future guideline update

Because of the lack of large studies on each uterine

anomaly, synthesized evidence combined the

analysis of many uterine abnormalities. Future

large studies are required to provide sufficient

discriminatory power. Future guidance is required to compare the role of colour, power and spectral Doppler, as well as 4D ultrasonography.

References

1. Syrop CH, Sahakian V. Transvaginal sonographic

detection of endometrial polyps with fluid

contrast augmentation. Obstet Gynecol. 1992;79(6):1041-3.

2. Parsons AK, Lense JJ. Sonohysterography for

endometrial abnormalities: preliminary results. J Clin Ultrasound. 1993;21(2):87-95 (https://doi.

org/10.1002/jcu.1870210203).

References

Guideline for the prevention, diagnosis and treatment of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

18. Grimbizis GF, Di Spiezio Sardo A, Saravelos SH,

Gordts S, Exacoustos C, Van Schoubroeck D et al. The Thessaloniki ESHRE/ESGE consensus

on diagnosis of female genital anomalies. Hum Reprod. 2016;31(1):2-7 (https://doi.org/10.1093/humrep/dev264).

19. Leone FP, Timmerman D, Bourne T, Valentin L, Epstein E, Goldstein SR et al. Terms, definitions

and measurements to describe the sonographic features of the endometrium and intrauterine

lesions: a consensus opinion from the

International Endometrial Tumor Analysis

(IETA) group. Ultrasound Obstet Gynecol.

2010;35(1):103-12 (https://doi.org/10.1002/

uog.7487).

20. Good clinical diagnostic practice: a guide for

clinicians in developing countries to the clinical

diagnosis of disease and to making proper use of clinical diagnostic services. Geneva: World Health Organization; 2005 (https://apps.who.int/iris/

handle/10665/119735).

5 Diagnosis of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Recommendation

For females with infertility due to suspected uterine cavity disorder, WHO

suggests assessing the uterine cavity with saline infusion sonohysterography (SIS) rather than hysterosalpingogram (HSG). (Conditional recommendation, very low certainty of evidence)

Background and rationale

HSG and SIS could be potential alternatives in the investigation of the uterine cavity; the GDG agreed that a key decision when investigating women

with infertility and suspected uterine pathology is whether to use SIS or HSG.

HSG involves the flushing of iodinated contrast

medium through the uterine cavity using a

catheter or cannula, resulting in the distension of

the uterine cavity, and allowing it to be visualized under fluoroscopic guidance using an X-ray. Still

radiographs are performed. HSG uses either oil- or water-soluble contrast medium (1).

SIS is a diagnostic procedure that involves the

manual installation of saline into the uterine cavity transcervically to act as a negative contrast agent

and facilitate enhanced endometrial visualization

during transvaginal assessment of the endometrial cavity using ultrasound (2, 3). The infusion of sterile

isotonic fluid during transvaginal sonography into

the uterine cavity facilitates uterine distension

and enhanced visual contrast during real-time

ultrasonographic examination (3, 4). SIS is also

referred to as SHG.

HSG and SIS are typically performed during the follicular phase of the menstrual cycle before the

lining becomes too thick, which may obscure any pathology, and to avoid an undiagnosed very early pregnancy. For this recommendation, the GDG

addressed the question: should HSG versus SIS

be used for women with infertility and suspected

uterine cavity disorder? Although HSG and SIS could

be used for assessment of the fallopian tubes, this recommendation focuses on their use for assessing the uterine cavity. The assessment of fallopian

tubes is presented in Section 5.5.

Balancing harms and benefits

Evidence from a 2015 systematic review by

Seshadri et al. (5) was used. The search was then updated to search for new studies from 2014

to November 2019 and no further studies were

identified. Studies included at least 80% of women who had infertility; women were not specifically

suspected of uterine cavity disorders. The studies directly compared women who were assessed

with HSG and SIS, and the diagnostic accuracy

of both tests reported. The reference standard

was hysteroscopy with or without laparoscopy (6). Several studies (6–10) assessed sensitivity and

specificity in identifying uterine cavity disorders

as shown in the Table 5.15. Comparative data for health outcomes, such as adverse events (10) and pain (11–14) were also obtained.

Guideline for the prevention, diagnosis and treatment of infertility

100

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Table 5.15. Included studies comparing HSG and SIS, and conditions identified

Study

Sample size, n Conditions identified

Acholonu et al. (7)

149

Polyps, cavitary fibroids, adhesions and septae

Alatas et al. (8)

Endometrial polyp, uterine anomaly, submucous myoma

Alborzi et al. (9)

186

Total tubal and uterine pathologies: tubal obstruction.

Intracavitary pathologies: Asherman syndrome, endometrial polyps, myomatous uterus. Structural uterine anomalies:

septated uterus and other structural uterine anomalies

De Felice et al. (6)

104

Abnormalities of the uterine cavity

Soares et al. (10)

Polypoid lesions, uterine malformations, intrauterine adhesions and endometrial hyperplasia

Pooled sensitivity and specificity estimates with 95% lower and upper CIs were calculated across

the studies from the raw data extracted from the studies. Details of the extracted data are shown in

the relevant EtD tables in the Web Annexes A–F.

Calculations of pooled estimates used a 15%

baseline risk of uterine cavity disorder in women with infertility.

Table 5.16. Pooled sensitivity and specificity for HSG and SIS with 95% CIs

HSG

SIS

Sensitivity (95% CI)

0.717 (0.555–0.837)

0.894 (0.819–0.940)

Specificity (95% CI)

0.931 (0.661–0.989)

1 (0.587–1)

CI, confidence interval; HSG, hysterosalpingogram; SIS, sonohysterography.

In terms of beneficial effects, the results showed

that there are likely two fewer true positives per

100 with HSG than SIS, two more false negatives

per 100 with HSG than SIS, six fewer true negatives per 100 with HSG than SIS and six more false

positives per 100 with HSG than SIS. Based on

these data, the GDG agreed that compared to SIS,

the desirable benefits of HSG compared to SIS are

likely trivial given that the increase in true negatives were trivial with HSG compared to SIS. The GDG

noted that the synthesized evidence combined

the analysis of many uterine abnormalities, but

sensitivity and specificity may differ between

anomalies; however, available data are sufficient to

provide discriminatory power.

In terms of harms, one complication (pelvic pain)

was reported with SIS and none with HSG in an

RCT (10). In another RCT, mean pain scores were

lower with SIS compared with HSG when assessed on a scale of 0–10 (mean scores of 2.7 versus 5.8;

P <0.0001), where higher scores reflected more

pain) (13). Among participants who underwent both procedures, 45 participants reported pain with

SIS and 154 reported pain with HSG (11, 12). The

GDG agreed that compared to SIS, the harms of

HSG may be small because of slightly greater false negatives, more false positives and greater pain.

There were no studies on patient values; however, the GDG agreed that women would value tests

that can identify the diagnosis correctly and would

101

5 Diagnosis of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

seek to minimize harms, and that there is probably

no important uncertainty or variability in how

much people value these outcomes. Overall, the

certainty of evidence was rated very low because

of low evidence from diagnostic accuracy data,

which also included women who were not recruited into studies on the basis of suspected uterine

pathology and very low certainty with harms (such

as pain). The GDG agreed that the balance of effects

probably favours SIS because HSG may have slightly greater harms (greater false negatives and false

positives and pain).

Other considerations

The GDG judged that although HSG is probably

feasible, it involves moderately more resources and

costs compared to SIS (e.g. fluoroscopy equipment,

radiology facility), whereas SIS adds minimal

additional resources and time to conventional

ultrasonography. Given that the equipment

required for SIS is more widely available, the GDG agreed that HSG could probably reduce equity,

although there were no direct data on this factor.

Similarly, no evidence on cost-effectiveness was identified. Nevertheless, the GDG considered that

given the moderate costs of HSG, and slightly

greater harms, HSG is unlikely to be as cost-effective

as SIS. In terms of acceptability, the GDG considered that SIS does not use radiation and does not use

iodine contrast. Based on further evidence from

two studies (14, 15), the panel concluded that SIS is probably more acceptable and better tolerated by

patients compared to HSG.

Summary justification

There was very low certainty evidence that the balance of desirable and

undesirable effects probably favours SIS over HSG in women who have infertility and suspected uterine cavity disorder. Although HSG is probably feasible, it

requires moderate resources related to the need for a radiological unit. SIS is

cheaper and probably more acceptable to patients compared to HSG. Given the cost and resource requirements, HSG may probably reduce equity.

Implementation considerations

Health care providers require training to

ensure they have the skills and experience to safely evaluate the uterine cavity using SIS. Health care providers should monitor patients for pain,

discomfort and other adverse effects and consider

analgesics as appropriate. Health care providers should be aware and observe general

contraindications for this procedure (e.g. women who are pregnant or who could be pregnant).

Research gaps and future guideline updates

Current evidence is insufficient to provide sufficient

data to separately assess diagnostic accuracy for separate subgroups of uterine cavity pathology,

such as polyps, fibroids, adhesions and congenital

uterine malformations. Future larger studies are

required to circumvent the current lack of statistical

power, which limits recommendations to specific

subgroups. Further guidance will be needed on whether prophylactic antibiotics should be used during SIS procedures.

References

103

5 Diagnosis of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Recommendation

For females with infertility who are suspected to have a uterine cavity disorder, WHO suggests assessing the uterine cavity with either two-dimensional

ultrasound (2D US) or hysterosalpingogram (HSG). (Conditional recommendation, very low certainty of evidence)

Remark:

• Health care providers may choose to use 2D US rather than HSG when

resources are limited. Follow-up would be required for women who are negative

on 2D US but still suspected of uterine cavity disorder because of high rates of

false negatives.

Background and rationale

Ultrasound imaging (sonography) involves the

generation and transmission of ultrasonic (highfrequency sound) waves from a transducer and

processing of a returning echo to generate an

image. It is based on non-ionizing energy (1). The

image is subsequently displayed on a monitor,

from which a hard copy may be captured, for

example, using thermal printing paper (1). Although ultrasound examination of the myometrium may be performed using a transabdominal, transvaginal or more rarely transrectal approach, the transvaginal approach (2, 3) is more commonly used for

assessing uterine abnormalities (2–4). 2D US is

the use of ultrasonic data to display the acquired

information in two dimensions, B-scan (1).

HSG involves the flushing of iodinated contrast

medium through the uterine cavity (and fallopian

tubes) using a transcervical catheter or cannula,

resulting in the distension of the uterine cavity,

and allowing it to be visualized under fluoroscopic guidance using an X-ray. Still radiographs are

performed. HSG uses either oil- or water-soluble

contrast medium (5).

The GDG agreed that guidance on whether to use 2D US or HSG is needed, particularly in settings

where 3D US or SIS are not available. Therefore,

in this recommendation, the GDG addressed the

question: should 2D US versus HSG be used for

women with infertility and suspected uterine cavity

abnormality?

Balancing harms and benefits

A de novo search was conducted to identify

DTA studies on 2D US and HSG up to November

2019. Studies included at least 80% of women who had infertility (women were not specifically

suspected to have uterine cavity disorders). Women received both 2D US and HSG and their results

were compared to the reference standard of

hysteroscopy.

We found two comparative studies (6, 7) with useful data that could be pooled, and another study (8)

from which data could not be pooled because

of how the data were reported. The first two of these studies assessed sensitivity and specificity

to diagnose the uterine cavity disorders shown in Table 5.17.

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Table 5.17. Included studies comparing 2D US and HSG, and conditions identified

Study

Condition identified

Alatas et al. (6)

Endometrial polyp, uterine anomaly, submucous myoma

Soares et al. (7)

Polypoid lesions, uterine malformations, intrauterine adhesions and endometrial hyperplasia

We calculated sensitivity and specificity based on paired studies as shown in Table 5.18.

Table 5.18. Pooled sensitivity and specificity for 2D US and HSG, with 95% CIs from paired studies

2D US

HSG

Sensitivity (95% CI)

40% (21–62%)

60% (38–79%)

Specificity (95% CI)

100% (0–100%)

98% (93–100%)

2D, two-dimensional; CI, confidence interval; HSG, hysterosalpingogram; US, ultrasound.

Calculations for the absolute effects on true and

false negatives and positives were based on a

15% prevalence of uterine cavity disorders in women

with infertility. Results showed that there may be

three fewer true positives with 2D US, three more

false negatives with 2D US, two more true negatives with 2D US and two fewer false positives with 2D

US. Based on these data, the GDG agreed that the

benefits of 2D US are trivial in correctly identifying

uterine cavity pathologies; there were two fewer

false positives with 2D US (incorrect diagnosis of

uterine cavity disorder). The GDG agreed that there may be more harm (three more false negatives) with

2D US but that this difference was trivial.

Data on adverse effects were not reported in the

studies included. The GDG noted that the synthesized

evidence combined the analysis of many uterine

abnormalities, but sensitivity and specificity may differ between anomalies; however, available data are insufficient to provide discriminatory power.

There were no studies on patient values; however, the GDG agreed that women would value tests that can identify the diagnosis correctly and would seek

to minimize harms, and that there was probably

no uncertainty or variability on how people value these outcomes. The GDG agreed that the balance

of effects does not favour either 2D US or HSG.

Certainty of evidence was judged as very low because there was a lack of evidence for adverse events.

Other considerations

Although comparative data about costs were not available, the guideline panel agreed that 2D US is less costly than HSG and could lead to moderate savings. There was no direct evidence on costeffectiveness; however, given that HSG has increased costs, the GDG agreed that cost-effectiveness

probably favours 2D US. In addition, the GDG

agreed that 2D US could probably increase equity as it requires fewer resources and is more widely

available compared to HSG. Although no data were available, the GDG judged that 2D US is probably

acceptable. The GDG considered the available

analysis on feasibility from one study (9) and agreed that 2D US is probably feasible to perform. HSG

requires a radiography unit and training, but it is

widely available and it is also feasible.

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Summary justification

There is very low certainty in the evidence that the balance of effects does not

favour either HSG or 2D US. However, there are slightly more false negatives

with 2D US that may necessitate following up. Both 2D US and HSG are probably feasible and acceptable, but 2D US likely requires fewer resources, and may be the preferred option in low-resource settings.

Implementation considerations

Training is required to ensure that health

care providers have the skills to safely and correctly assess, document and report US and

HSG findings while evaluating the uterus (4, 10–12).

Research gaps and future guideline updates

Because of the lack of large studies on each

uterine anomaly, the synthesized evidence

combined the analysis of data related to many uterine abnormalities. Future large studies are

required to provide sufficient discriminatory power.

Future guidance is required to compare the role of colour, power and spectral Doppler, as well as 4D ultrasonography.

References

1. Tole N. Basic physics of ultrasonic imaging.

In: Ostensen H, editor. Basic physics of

ultrasonic imaging. Geneva: World Health

Organization; 2005 (https://apps.who.int/iris/

handle/10665/43179).

2. Manual of diagnostic ultrasound. Vol. 2, second edition. Geneva: World Health Organization; 2013 (https://iris.who.int/handle/10665/85386).

3. Manual of diagnostic ultrasound. Vol. 1, second edition. Geneva: World Health Organization; 2011 (https://iris.who.int/handle/10665/43881).

4. Van den Bosch T, Dueholm M, Leone FP,

Valentin L, Rasmussen CK, Votino A et al. Terms, definitions and measurements to describe

sonographic features of myometrium and

uterine masses: a consensus opinion from the

Morphological Uterus Sonographic Assessment (MUSA) group. Ultrasound Obstet Gynecol.

2015;46(3):284-98 (https://doi.org/10.1002/

uog.14806).

5. Dreyer K, van Rijswijk J, Mijatovic V, Goddijn M,

Verhoeve HR, van Rooij IAJ et al. Oil-based or

water-based contrast for hysterosalpingography in infertile women. N Engl J Med.

2017;376(21):2043-52 (https://doi.org/10.1056/

NEJMoa1612337).

6. Alatas C, Aksoy E, Akarsu C, Yakin K, Aksoy S,

Hayran M. Evaluation of intrauterine

abnormalities in infertile patients by

sonohysterography. Hum Reprod.

1997;12(3):487-90 (https://doi.org/10.1093/

humrep/12.3.487).

7. Soares SR, Barbosa dos Reis MM, Camargos

AF. Diagnostic accuracy of sonohysterography, transvaginal sonography, and

hysterosalpingography in patients with uterine cavity diseases. Fertil Steril. 2000;73(2):406-11

(https://doi.org/10.1016/s0015-0282(99)00532-4).

8. Vahdat M, Sariri E, Kashanian M, Najmi Z,

Mobasseri A, Marashi M et al. Can combination of hysterosalpingography and ultrasound

replace hysteroscopy in diagnosis of uterine

malformations in infertile women? Med J Islam

Repub Iran. 2016;30:352.

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9. Grimbizis GF, Di Spiezio Sardo A, Saravelos SH,

Gordts S, Exacoustos C, Van Schoubroeck D et

al. The Thessaloniki ESHRE/ESGE consensus

on diagnosis of female genital anomalies. Hum

Reprod. 2016;31(1):2-7 (https://doi.org/10.1093/

humrep/dev264).

10. Good clinical diagnostic practice: a guide for

clinicians in developing countries to the clinical

diagnosis of disease and to making proper use of clinical diagnostic services. Geneva: World Health Organization; 2005 (https://apps.who.int/iris/

handle/10665/119735).

11. Leone FP, Timmerman D, Bourne T, Valentin L, Epstein E, Goldstein SR et al. Terms, definitions

and measurements to describe the sonographic features of the endometrium and intrauterine

lesions: a consensus opinion from the

International Endometrial Tumor Analysis

(IETA) group. Ultrasound Obstet Gynecol.

2010;35(1):103-12 (https://doi.org/10.1002/

uog.7487).

12. Barnett S. Safety of diagnostic ultrasound. In:

Buscarini E, Lutz H, Mirk P, editors. Manual of

diagnostic ultrasound, second edition. Geneva: World Health Organization; 2013 (https://iris.who.

int/handle/10665/85386).

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5.7 Diagnosis of infertility due to male factors

This section contains recommendations related to the diagnosis of infertility due to

male factors, and referral pathways for further evaluation. Figure 5.3 illustrates this in a diagnostic algorithm.

Recommendation

For males (in couples with infertility) with one or more semen parameters

outside the WHO reference ranges, WHO suggests repeating the semen analysis after a minimum of 11 weeks. (Conditional recommendation, very low certainty

of evidence)

Remark:

• The latest edition of the WHO laboratory manual for the examination and

processing of human semen provides WHO reference ranges for semen

parameters and details about the standardized procedures for semen collection

and analysis.

Background and rationale

According to the largest multi-country study to

date, involving 8500 couples in 25 countries, male

factors contribute wholly or in part to 45.1% of

infertility cases (1) (see Annex 1. Distribution of

the causes of infertility). Therefore, investigation of the male partner is essential in the diagnosis

and treatment of infertility (see Fig. 5.3 Diagnostic algorithm for male-factor infertility).

A semen analysis, as outlined in the WHO laboratory manual for the examination and processing of human semen is recommended for assessing male fertility (2). Notably, semen parameters per se are not a

reliable diagnostic indicator of fertility status as

shown by several studies (3–5). However, when

combined with a thorough history and physical

examination (6), a basic semen analysis provides

valuable information about the male reproductive function. Semen parameters may fall within or

outside the reference ranges provided in the

WHO laboratory manual for the examination and processing of human semen (2).

Spermatogenesis is a biological process (7),

which displays intraindividual variability of

semen parameters in healthy (8, 9) and infertile men (10). Given this intraindividual variability, the WHO laboratory manual for the examination and processing of human semen (2) indicates that “to

define an exact baseline of an individual, it may

be necessary to examine two or three ejaculates”, citing several studies (9, 11–14).

Concerns with conducting one test or repeating a test are related to one of two risks: (i) unnecessarily referring men who do not need to be referred for

further investigation; or (ii) failing to identify men

with infertility who need to be investigated further, leading to underdiagnosis of male factors and delay in treatment.

References

In this context, the GDG agreed that there was a need to provide guidance regarding whether two consecutive samples are necessary for all males who are being investigated for infertility by the initial evaluating health care provider. For this recommendation, the GDG addressed the question: should the initial semen analysis be repeated in a male in a couple with infertility? The studies reported that in men who had:

Balancing harms and benefits

Within-individual variability of semen analysis

• normozoospermia on the first semen analysis, 27% had pathological results on the second semen analysis (15);

• normozoospermia on the first semen analysis, 60% had pathological results on the second semen analysis (16);

• normozoospermia on the first semen analysis, 51% had pathological results on the second analysis (17);

• pathological results on the first semen analysis, 23% had normozoospermia on the second semen analysis (15);

• pathological results on the first semen analysis, 8.5% had normozoospermia on the second semen analysis (17).

The 2010 WHO laboratory manual for the examination and processing of human semen reported that it may be necessary to test two or three ejaculates based on four studies reporting variability in results (9, 11-14). The sixth edition of the WHO laboratory manual for the examination and processing of human semen, published in 2021 (2), states that it may be necessary to examine two or three ejaculates to establish a true baseline for an individual.

Variation in semen parameters

The sixth edition of the WHO laboratory manual for the examination and processing of human semen also reported that semen analysis results can be affected by ejaculate characteristics that depend on the following: (i) whether a complete sample is collected; (ii) activity of the accessory sex glands;

Timing of semen analysis

Spermatogenesis is a complex process involving distinct phases, such as proliferation, meiosis and spermiogenesis, and each phase has its specific duration (18, 19). Spermatogenesis was initially thought to take 64 days (7). However, further empirical evidence showed that it takes approximately 74 days, which is equivalent to four and a half cycles of the seminiferous epithelium (20), with some likely variability of up to 74 ± 2 days (4.6 cycles) (21). There are still ongoing uncertainties, as suggested by some studies (22, 23).

For instance, in an in vivo study (n = 11) that used stable isotope labelling of sperm DNA followed by gas chromatography and mass spectrometry analyses, Misell et al. (23) reported that the duration of spermatogenesis, that is, the duration it took to detect labelled sperm, was an average ± standard deviation (SD) of 64 ± 8 days (range: 42-76 days).

Other outcomes

Other outcomes, such as quality of life, including fear, worry or other psychosocial and psychological impacts, and accuracy and downstream consequences of diagnosis were not reported in studies.

References

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Based on this summary of evidence, the GDG

agreed that the results of semen analysis may not

always be consistent between a first and second

(repeat) test. The GDG also agreed that semen parameters outside the WHO reference ranges

could be a reflection of the true baseline of an

individual or could be due to transient factors not related to infertility (e.g. incomplete sample taken, a febrile illness or intraindividual biological variability).

In terms of the benefits of repeating a semen

analysis, the GDG agreed that when the first semen

analysis results are outside the WHO reference

ranges, the benefits of a repeat analysis may

be moderate by ruling out a “diagnosis” of male

infertility (in cases where the second test results

are within the reference ranges) as it would avoid

unnecessary fear or the psychological impact

associated with an “abnormal” semen analysis result, and also reduce the risk of an unnecessary referral to infertility specialists. The GDG agreed that when

the results of the first semen analysis are within

the WHO reference range, the benefits of a repeat

analysis may be trivial. This is because diagnosis

is based not only on semen analysis but also on

complete history-taking and a physical examination.

The GDG agreed that the maximum benefit of a

repeat test is after a minimum of 11 weeks, aligning with the duration for spermatogenesis.

In terms of the harms of repeating a semen

analysis, the GDG agreed that when the first

analysis is outside the reference ranges, there are no adverse events that would arise from a repeat semen analysis. The GDG agreed that when the

results of the first semen analysis are within the

WHO reference range, small harms may occur if

the second test is outside the reference ranges,

which may be due to factors not related to infertility and occurs in many individuals, and may result in

unnecessary and high referral rates; it may also

cause unnecessary fear or have a psychological

impact (false positive). Although some cases may be missed by not doing a repeat test (false negative),

the risk of not identifying men with infertility is

likely low as the diagnosis is based not only on the

semen analysis but also on comprehensive medical history and physical examination. Additionally, if

after investigation of the female partner a couple is infertile (e.g. because of unexplained infertility), additional assessment of sperm will most likely be conducted during the course of treatment.

The GDG considered the values of patients; in

the absence of specific studies on these, the

GDG agreed that men would value confirmation

of results that are outside the WHO reference

ranges before referral to an infertility specialist.

The GDG placed a greater weight on reducing false positives in this PICO because of the downstream consequences, including referrals to specialists and associated costs.

Considering all of the judgements, the GDG

concluded that the balance of effects favours a repeat test when the first analysis is outside the

WHO reference ranges, and that the balance

of effects favours NO repeat test when the first

analysis is within the WHO reference ranges. Overall, the certainty of evidence was very low because of a lack of evidence for important

patient outcomes.

Other considerations

The GDG considered resource requirements

and judged that although there are costs with

performing any test, the costs of a semen analysis are negligible. The cost of performing one

additional repeat test is also negligible. The GDG agreed that for men whose semen parameters are outside the WHO reference ranges, repeating the test would result in negligible costs and moderate

benefits because referral rates are reduced,

meaning it is cost-effective; therefore, repeating

the test is favoured. However, for men whose

parameters are within the WHO reference ranges,

even though the costs of testing are negligible,

sending men to an infertility specialist based on an abnormal repeat test may result in moderate harms, meaning that repeating the test in this scenario is

not cost-effective; therefore, not repeating the test

is probably favoured.

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The GDG agreed that although there are no direct data on equity, there is potential for inequity

in men’s access to and use of infertility testing.

However, semen tests are widely available;

therefore, requiring a repeat test may not have an impact on equity.

There was no evidence identified on acceptability

of repeat semen analysis among health providers or patients. However, the GDG agreed that the

initial evaluating health care provider would find

it acceptable to perform a repeat test in men with results outside the WHO reference ranges before

referral, and not to repeat it in men with results

within the WHO reference ranges. Both physicians

and men would likely find it acceptable to avoid

referrals and unnecessary additional testing.

Similarly, there were no identified studies on the

feasibility of repeat semen analysis. However,

the GDG agreed that performing repeat tests

is feasible. The GDG also considered that male

infertility specialists (e.g. urologist or clinical

andrologist) are often not widely available, and agreed that increasing referral to male infertility specialists may not be feasible in many countries.

Summary justification

There was very-low-certainty evidence for the benefits and harms of repeating or not repeating semen analysis. Evidence suggests that when a semen analysis test is conducted twice, the semen parameter results may not always be consistent

between the first and second test.

Evidence also suggests that semen parameters outside the WHO reference

ranges could be a reflection of the true baseline of an individual or could be due to transient factors not related to infertility (e.g. incomplete sample taken, a febrile

illness or intraindividual biological variability).

The GDG agreed that when a first test reports semen parameters outside the

WHO reference ranges and a repeat test is not conducted and the man is sent

for investigation, there is a concern that too many men will be sent for further

investigation who did not need to because the results were likely due to transient factors unrelated to infertility (e.g. incomplete sample taken, a febrile illness or

intraindividual biological variability). A repeat test would minimize the effect of

transient factors unrelated to infertility and confirm that parameters are outside the WHO references ranges and are likely related to infertility; therefore, men

with two tests reporting parameters that are outside the WHO references ranges would be appropriately sent for further investigation by male infertility specialists.

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When the first test (performed in accordance with the standardized procedures

outlined in the WHO laboratory manual for the examination and processing of

human semen) reports semen parameters outside the WHO reference ranges and the repeat test shows parameters within the WHO reference ranges, a possible

explanation is that the first test was likely outside the WHO reference ranges

because of transient factors unrelated to infertility, and the man would not need further investigation or referral to a male infertility specialist. If these men are not investigated or referred to a male infertility specialist, the risk of not identifying

men with infertility due to male factors is likely low because the diagnosis is

based not only on semen analysis but also on comprehensive medical history

and physical examination. If after investigation of the female partner a couple is

infertile (e.g. because of unexplained factors), additional assessment of sperm

will most likely be conducted during treatment; therefore, these men will likely be retested and will not be missed. Therefore, the GDG agreed that a repeat test may be conducted if one or more parameters are outside the WHO reference ranges

because repeating the semen analysis could reduce unnecessary referral rates

and could reduce the negative psychological impact and fear in men and couples associated with a test outside the WHO ranges; the test is low-cost and probably acceptable and feasible. The GDG also agreed that given that the minimum

duration of spermatogenesis is approximately 11 weeks, repeating the test should align with this time period.

If all semen parameters are within the WHO reference ranges and a repeat test is not performed, the risk of not identifying men with infertility is likely low because if after investigation of the female partner a couple is infertile (e.g. because

of unexplained infertility), additional assessment of sperm will most likely be

conducted during treatment. In addition, if a repeat test is conducted and the

parameters are outside the WHO reference ranges, then some men would have

been sent for further testing without need as the parameters could be outside the reference ranges because of transient factors unrelated to infertility. Therefore,

the GDG agreed to not repeating the test when a first test is within the WHO

reference ranges to reduce unnecessary referral and associated costs and burden, and also agreed that not performing a repeat test is probably acceptable.

Implementation considerations

Health care providers should note that

semen analysis provides partial information related to fertility potential, and that reference

range thresholds do not entirely distinguish

between fertile and infertile males. This and other limitations may contribute to the shifting of the

burden of infertility investigation and management to the female partner (24), despite male factors

contributing wholly or in part to 45.1% of infertility

cases (1, 25). In addition, although the odds of a man

being infertile increase when more parameters are outside the WHO reference ranges (5), the

abnormalities themselves (either one or all) are not reliable indicators of fertility status (4, 5). Therefore, semen analysis should be performed in conjunction with comprehensive (medical, reproductive and

sexual) history-taking, and physical examination.

Spermatogenesis is a complex process

involving distinct phases, such as

proliferation, meiosis and spermiogenesis, each

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with its specific duration (18, 19). Repeating a semen analysis after 11 weeks aligns with the estimated

time for spermatogenesis to occur. In addition, time is needed for the effect of any modifiable factors on semen parameters to wane (e.g. febrile illnesses,

medications, among others). To ensure that the

results are valid and provide useful information, the latest edition of the WHO laboratory manual for the examination and processing of human semen

outlines standardized procedures for semen

collection and analysis. It provides guidance on:

(i) semen examination; (ii) sperm preparation and

cryopreservation; and (iii) quality assessment and

quality control.

The evaluation and management of male

infertility is a stepwise process involving

comprehensive assessment and consultation to

determine appropriate treatment options (see

Fig. 5.3 for the diagnostic algorithm for male-factor infertility). Referral of the male to a specialist and

further evaluation may identify comorbidities

requiring management beyond fertility (26, 27).

Health care providers should be aware of this and, whenever possible, mitigate contextual issues that may affect the implementation of this

recommendation related to the health system

(e.g. personnel training and quality control of

laboratories), economics (e.g. cost of tests and

repeat appointment) and social (e.g. stigma,

masculine norms or other cultural) barriers to

male testing.

In addition, female evaluation is essential and it should proceed regardless of the outcome of semen analysis. Evaluation and management

should be conducted in parallel for both male and female partners, and the investigation of a female

partner should not be delayed by repeated semen analyses. At the same time, the diagnostic pathway, referral and management plan for the male partner should be informed by, and be progressively

adjusted, based on the results of the tests of the

female partner to optimize efficiency (see

Chapter 3. Approach to the evaluation and

management of patients with infertility).

Research gaps and future guideline update

Future studies should assess relevant outcomes, including values, preferences, costs and

cost-effectiveness of repeat semen testing. Given

that semen analysis per se does not entirely

rule out the presence of a male-factor cause of

infertility, further research is required to determine the downstream outcomes of males with semen

samples within and outside the WHO reference

ranges, as well as those with borderline semen

parameters, to determine if any subsets of these

populations could benefit from further advanced

tests. Current evidence is of very low certainty.

Better-quality data from more studies evaluating

the results of semen analysis are needed to improve the certainty of evidence.

Current evidence on the estimated time that

spermatogenesis takes is based on data from

limited old studies. Some uncertainty exists based on biological plausibility (22) and observations from vivo studies (23). Impact of sperm maturation and

epididymal transport and storage on the duration

is uncertain (28) and may require consideration in

future studies. Further large studies are required

to strengthen the evidence base regarding the

duration of spermatogenesis.

The diagnostic scope of the guideline

recommendation is limited, addressing only a

subset of male infertility topics within the broader

and evolving field of male infertility investigation.

Specifically, this PICO provides guidance to the initial

health care provider investigating a couple with

infertility; guidance for male infertility specialists

will be developed in the future. This approach

acknowledges the positive momentum in diagnostic interventions for male-factor infertility. Emerging

technologies have the potential to advance adjunct diagnostic tests that could complement semen

analysis and improve the clinical diagnosis of

male infertility; however, these have not been

evaluated in this edition of the guideline and will be considered in future editions.

References

Abstract

Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps 17. Chiu YH, Edifor R, Rosner BA, Nassan FL, Gaskins AJ, Mínguez-Alarcón L et al. What does a single semen sample tell you? Implications for male factor infertility research.

References

Guideline for the prevention, diagnosis and treatment of infertility

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5.8 Diagnosis of unexplained infertility

This section contains recommendations related to the diagnosis of infertility due to

unexplained factors. Figure 5.1, near the start of this chapter, illustrates how a diagnosis of unexplained infertility is made.

Recommendation

WHO suggests making a diagnosis of unexplained infertility in a couple when all the following have occurred:

• failure to achieve pregnancy after 12 months of regular unprotected sexual

intercourse;

• normal physical examination and medical history in both the male and female;

• presumptive confirmation of ovulation and patent tubes in the female partner;

and

• semen parameters that are within the WHO reference ranges in the male

partner. (Conditional recommendation, very low certainty of evidence)

Background and rationale

In a WHO multi-country study conducted in

25 countries and involving 8500 couples, no cause was identified in 10.8% of infertility cases (1). As

unexplained infertility is a diagnosis of exclusion,

reported prevalence ranges vary widely, as

demonstrated in several systematic reviews and

meta-analyses from different global regions (2–4).

While there may be several detectable and

undetectable reproductive defects that could

hinder a couple from achieving pregnancy, different settings may apply different tests for exclusion

based on the available resources.

This WHO guideline contains other conditional

recommendations made based on a review of the

evidence (rated as very-low certainty) about which tests to use to:

i. investigate anovulation and oligo-ovulation or

tubal disease or blockage in females who have a

normal physical examination and medical history;ii. investigate uterine cavity abnormality, ovulation

disorders and reduced ovarian reserve in

females who do not have a normal physical

exam and medical history; and

iii. assess males.

For (ii) and (iii) a diagnosis of infertility is based

on the cause found through the investigations. However, for (i), when pathologies have not been

identified, infertility remains unexplained, provided

semen parameters are within the WHO reference ranges in a male with a normal history and physical examination (see Fig. 5.1).

Using a minimum set of criteria is probably

feasible, acceptable and reduces costs in most

resource settings. Therefore, the GDG agreed

that at a minimum, a diagnosis of unexplained

infertility should be arrived at if a couple has

been unsuccessful in achieving pregnancy

after 12 months of regular unprotected sexual

intercourse; the physical examination and medical history in both the male and female are normal;

ovulation and patent tubes in the female have been

presumptively confirmed; and semen parameters

are within the WHO reference ranges in the male.

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Summary justification

Given that other recommendations for diagnosing infertility in this guideline are

conditional, this recommendation for using a minimum set of tests that can rule

out other causes of infertility is also conditional based on the very low certainty of the evidence. The minimum set of tests apply in couples with infertility who have normal physical examinations and medical histories with presumptively confirmed ovulation, tubal patency and semen parameters that are within the WHO

reference ranges. The minimum set of tests are feasible, acceptable and require

fewer resources to implement in many resource settings.

Implementation considerations

Specific details and recommendations

regarding medical history-taking and

physical examination in a couple, evaluation of

ovarian function, tubal patency and uterine cavity in the female, and semen analysis in the male, are

outlined in the relevant chapters of this guideline.

Procedures for semen analysis are detailed in the

WHO laboratory manual for the examination and

processing of human semen (5). Health care

providers should ensure that physical examination and medical history-taking are conducted

concurrently in both males and females as part of the initial diagnosis of unexplained infertility. If

abnormalities affecting reproduction are found,

diagnosis of unexplained infertility would not apply,

as a cause would have been identified. Health care

providers should be aware of, and mitigate, the

psychological aspects of infertility, including when causes are unexplained (see Chapter 3). Health

care providers should also be aware of, and

whenever possible mitigate, the contextual issues

that may affect the implementation of this

recommendation related to the health system (e.g. personnel training and quality control of laboratories), economics (e.g. cost of tests) and

social (e.g. stigma, masculine norms or other cultural) barriers to male testing.

Research gaps and future guideline update

Future studies are required to establish the

magnitude of unexplained infertility using the

above criteria, as available data are not current,

and to understand the causes of infertility. Given that unexplained infertility is a diagnosis of

exclusion, the fewer the number of diagnostics

tests performed, the more likely infertility might be unexplained, while performing multiple tests could potentially result in an abnormal result,

which may or may not be related to the failure to achieve pregnancy, and in the latter scenario, lead to unnecessary intervention. Future research is

needed to determine whether any additional tests or criteria (such as an upper limit of female age)

should be routine used in the initial evaluation

of couples who would otherwise be classified as

having unexplained infertility based on the above criteria. Implementation research is encouraged

to validate data, document costs and inform

whether the minimum diagnostic criteria should be

resource-stratified.

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References

1. Recent advances in medically assisted

conception: report of a WHO Scientific

Group. Geneva: World Health Organization;

1992 (https://iris.who.int/bitstream/

handle/10665/38679/WHO_TRS_820_eng.pdf).

2. Abangah GH, Rashidian T, Parizad Nasirkandy M, Azami M. A meta-analysis of the prevalence

and etiology of infertility in Iran. Int J Fertil Steril. 2023;17(3):160-73 (https://doi.org/10.22074/

ijfs.2023.541991.1215).

3. Abdulla AA, Ahmed M, Oladokun A. Prevalence of infertility in Sudan: a systematic review and

meta-analysis. Qatar Med J. 2021;2021(3):47

(https://doi.org/10.5339/qmj.2021.47).

4. Abebe MS, Afework M, Abaynew Y. Primary and secondary infertility in Africa: systematic review with meta-analysis. Fertil Res Pract. 2020;6(1):20 (https://doi.org/10.1186/s40738-020-00090-3).

5. WHO laboratory manual for the examination

and processing of human semen, sixth edition.

Geneva: World Health Organization; 2021

(https://iris.who.int/handle/10665/343208).

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6-10 Treatment of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

6-10 Treatment of infertility

These chapters provide guidance on the treatment of infertility. These treatments are divided into three main groups:

Female-factor treatments

6.1 Treatment of infertility due to ovulatory dysfunction caused by PCOS

7.1 Use of surgery or IVF for treatment of

tubal disease

7.2 Treatment of hydrosalpinx before IVF

8.1 Management of uterine septum in females with infertility

Male-factor treatments

9.1 Use of antioxidants

9.2 Treatment of varicocele

Unexplained infertility treatments

10.1 First-line management of couples

with unexplained infertility

10.2 Second-line management of couples with unexplained infertility

10.3 Third-line management of couples with unexplained infertility

Relevant resources:

Figure 6.1 Treatment algorithm for

anovulatory infertility due to PCOS

Figure 10.1 Treatment algorithm for

unexplained infertility

Web Annex D. Evidence to decision

tables for treatment of infertility due to ovulatory dysfunction, tubal disease and uterine cavity disorder

Web Annex E. Evidence to decision tables for treatment of infertility due to male

factors

Web Annex F. Evidence to

decision tables for

treatment of couples

with unexplained

infertility

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6 Treatment of infertility due to ovulatory dysfunction

6.1 Treatment of infertility due to ovulatory dysfunction caused by PCOS

This section contains recommendations related to the management of infertility due to PCOS. Figure 6.1 shows how these recommendations relate to each other. Specific recommendations are presented in the sections that follow.

Fig. 6.1. Management of anovulatory infertility due to PCOS

a Baseline investigations:

1. Diagnosis of PCOS according to the Rotterdam criteria (endocrine profile and pelvic ultrasound scan) see Chapter 6.1.

2. Additional assessment tests may be required, including during the pre-pregnancy period see Chapter 3.

3. Consider assessing tubal patency see Chapter 5.5.

4. Assess the male partner, including semen analysis see Chapter 5.7.

b As part of the management of PCOS, it is good practice to advise patients on lifestyle interventions, such as healthy diet and

regular physical activity. (Good practice statement).

c Use repeated cycles based on shared decision-making considering age and resources.

d Monitor patients regularly (with US as needed) and manage potential risks that may occur during treatment see Chapter 3 and Chapter 6.1.

e If capacity for side-effect management exists.

f Use IVF as third-line medical treatment unless other factors (e.g. male factors or tubal factor infertility) exist, and manage

potential risks (such as OHSS) that may occur during treatment see Chapter 3 and Chapter 6.1.

IVF, in vitro fertilization; LOD, laparoscopic ovarian drilling; PCOS, polycystic ovary syndrome; US, ultrasound.

Provide clinical follow up and document pregnancy outcomes

Ovulation detected and pregnancy achieved?

PCOS

Diagnosis: Rotterdam criteriaa

Lifestyle modificationsb

Letrozole, with monitoring,c,d

adjusting dose as needed

Gonadotrophin with

monitoring,c,d,e adjusting dose as needed

IVFf

Alternative, if letrozole not available:

clomiphene citrate ± metformin

Alternative, depending on

facilities and skills: LOD

Yes

Central pathway preferred

First-line

medical

treatment

Second-line

medical

treatment

Third-line medical treatment

1 2 3

Ovulation detected and pregnancy achieved?

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Recommendation

(Conditional recommendation, low certainty of evidence for letrozole compared to

clomiphene citrate, low certainty evidence for letrozole compared with metformin alone and very low certainty of evidence for letrozole compared to letrozole with metformin)

Where off-label use of letrozole is not permitted, use of clomiphene citrate

with metformin rather than clomiphene citrate alone or metformin alone

is suggested. (Conditional recommendation, moderate certainty of evidence for

clomiphene citrate compared to clomiphene citrate with metformin, very low certainty of evidence for clomiphene citrate compared to metformin)

As part of management of polycystic ovary syndrome (PCOS), it is good practice to advise patients on lifestyle interventions such as healthy diet, regular

physical activity and/or weight management. (Good practice statement).

Background and rationale

PCOS is a common condition affecting 6–13%

of women of reproductive age, although the

reported prevalence varies depending on the

diagnostic criteria (1, 2). Many women in the WHO

Group II anovulation have PCOS. A diagnosis

of PCOS in adults is based on the presence of

two of the following three criteria: anovulation

or oligo-ovulation; clinical or biochemical

hyperandrogenism; or polycystic ovary morphology, and exclusion of related disorders (Rotterdam

criteria) (3).

PCOS has multiple reproductive, metabolic and

psychosocial impacts (4). Clinical features in PCOS

commonly include irregular menstrual cycles,

signs of androgen excess, such as hirsutism, and

infertility (3). PCOS is one of the most common

causes of anovulatory infertility (5). In addition,

the prevalence of other comorbidities, such

as obesity (6), impaired glucose tolerance and

metabolic syndrome (7), is also high among women

with PCOS, which may require identification and

management.

Options for the treatment of infertility in PCOS

include lifestyle interventions, pharmacological

therapies, surgical laparoscopic ovarian diathermy or IVF. Pharmacological therapies include estrogen receptor modulators (such as clomiphene citrate),

aromatase inhibitors (such as letrozole), insulinsensitizing medications (such as metformin) and

direct hormonal stimulation of the ovaries (with

gonadotrophins). The costs and complexities of

these interventions vary significantly (see Fig. 6.1. for the treatment algorithm for anovulatory

infertility due to PCOS).

Pharmacological options include oral ovulation

induction agents such as clomiphene citrate

or letrozole, used alone or in combination with

metformin. Clomiphene citrate is a selective

estrogen receptor modulator (8) that acts

primarily by binding with estrogen receptors at

the hypothalamus (9). It is administered orally,

typically for 5 days from cycle days 3–7 or 5–9 (10) but can have side-effects, including changes to

the endometrium and cervical mucus and hot

flushes (11). Ultrasound monitoring is often used to monitor follicular growth during a stimulation cycle (12, 13).

Letrozole is a newer drug that blocks estrogen synthesis; it is also administered orally. It is an aromatase inhibitor ( 14 Metformin is an antihyperglycaemic biguanide drug, which is widely used for lowering insulin levels (19). Women with PCOS often present with insulin resistance and hyperinsulinaemia (20) (21) (22) .

Insulin resistance and/or poor glycaemic control, is hypothesized to have an important role in the pathogenesis of . Therefore, metformin is an (off-label) option used as an insulin-sensitizing medication in people with PCOS, as an adjunct to ovulation induction medications (19, 26, 27), but it may cause gastrointestinal side-effects, and rarely, lactic acidosis and liver failure (26). It is generally administered daily, and for longer durations, even when used in combination therapy with letrozole or clomiphene citrate (26).

For this recommendation, the GDG addressed the following questions: (i) should letrozole versus

Balancing harms and benefits

Use of monotherapy

Two systematic reviews (18, 28) and an RCT (29) provided relevant data related to the benefits and harms of letrozole compared to clomiphene citrate. There was a moderate increase in live births with letrozole (RR: 1.52; 95% CI: 1.28-1.82) and likely no difference in these effects based on BMI. Mixed results were observed across undesirable effects: miscarriages (small increase with letrozole); multiple birth rates (trivial decrease with letrozole); OHSS (small decrease with letrozole); and congenital malformations (inconsistent effect between RCTs and nonrandomized studies). Given that there is likely no important uncertainty or variability among different populations in how people value benefits (live births) and harms (miscarriages, multiple birth rates and other side-effects), the GDG judged that, overall, the benefits are greater with letrozole and outweigh any harms that may be slightly increased (low-certainty evidence). The GDG emphasized that clomiphene citrate can be used as an alternative if letrozole is not available.

A systematic review and network meta-analysis by Wang et al. (30) , which was updated without retracted articles (31), provided data comparing letrozole to metformin. Letrozole likely results in more live births (OR: 1.85; 95% CI: 1.02-3.45).

The observed increase of 116 more per 1000 was judged by the GDG to be a large desirable effect. The use of letrozole may slightly increase miscarriages (OR: 1.30; 95% CI: 0.54-3.13) and multiple pregnancy (OR: 2.22; 95% CI: 0.47-11.11).

Given the large benefits and small harms, the GDG judged that the balance of effects favours the use of letrozole over metformin (moderate-certainty evidence).

References

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and fewer multiple pregnancy (OR: 0.29; 95%

CI: 0.06–1.43) compared to clomiphene citrate.

In addition, the potential benefit of metformin in

reducing multiple pregnancy and miscarriages

based on a BMI threshold of over or under 30 kg/m2 was inconsistent. The GDG noted that the use

of metformin alone is less effective than either clomiphene citrate or letrozole alone. The GDG

judged that although there may be fewer harms

with metformin alone in some populations, overall,

there may be greater benefits with clomiphene

citrate (very-low-certainty evidence).

Adjunct use of metformin in combination therapy

Two RCTs provided relevant data comparing

letrozole in combination with metformin versus

letrozole alone (33, 34). The addition of metformin to letrozole may result in no difference in effect on live births (RR: 1.00; 95% CI: 0.61–1.65), while clinical pregnancies may increase slightly (by 58 per 1000 [from 58 fewer to 215 more] compared to letrozole alone (RR: 1.15; 95% CI: 0.85–1.56). There are no

data to determine the effects based on insulin

resistance or BMI (mean BMI in the two included studies was < 30 kg/m2). In terms of undesirable

effects, a small increase of miscarriages (60 per

1000 [from 41 fewer to 290 more] may occur when metformin is combined with letrozole compared to letrozole alone (RR 1.50; 95% CI: 0.66 to 3.43).

Gastrointestinal side-effects may occur when

letrozole is combined with metformin, whereas

there may be none with letrozole alone. The

GDG noted that although clinical pregnancies

may increase when metformin is combined with

letrozole, there may be a similar increase in

miscarriages and more gastrointestinal effects.

Therefore, the balance of effects probably favours letrozole alone (very-low-certainty evidence).

A systematic review (32) compared metformin

in combination with clomiphene citrate versus

clomiphene citrate alone. Evidence showed that

there is likely a moderate increase in live births

(47 per 1000 [from 12 fewer to 123 more]; RR: 1.20;

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

95% CI: 0.95–1.52) and clinical pregnancies

(111 more per 1000 [from 42 to 194 more]; RR: 1.40; 95% CI: 1.15–1.70) with metformin combined with

clomiphene citrate compared to clomiphene

citrate alone. Analyses using a BMI threshold

of approximately < or >30 kg/m2 found similar

relative risks for live births and clinical pregnancy,

suggesting that there are little to no differences in desirable effects based on BMI. Women with insulin resistance were identified and included in

three of the 19 RCTs included in the review and

had similar relative risks. In relation to harms, use of clomiphene citrate combined with metformin

may slightly reduce OHSS (11 fewer per 1000 [from 11 to 10 fewer]; risk difference [RD]: -0.002; 95% CI:

-0.033 to -0.027) and multiple pregnancy (8 fewer

per 1000 [from 14 fewer to 13 more]; RR: 0.57; 95%

CI: 0.19–1.72), but likely increases miscarriages

(21 more per 1000 [from 9 fewer to 65 more]; RR:

1.27; 95% CI: 0.88–1.85) and gastrointestinal sideeffects (180 more per 1000 [from 78 more to 343 more]; RR: 3.12; 95% CI: 1.92–5.05) compared to

clomiphene citrate alone. Although miscarriages

and gastrointestinal side-effects are likely greater

when metformin is used with clomiphene citrate, the GDG agreed that they are comparatively

less serious compared to OHSS and multiple

pregnancy, and that there was still an increase

in clinical pregnancies. The GDG judged that the use of clomiphene citrate with metformin may

have moderate benefits and small harms when

compared to clomiphene citrate alone (moderatecertainty evidence).

Other considerations

The GDG judged that it is probably feasible to

provide oral medications for ovulation induction

and noted that the exact cost of these medications may vary from country to country. Given that the

use of letrozole could reduce equity, as it is may be

more expensive than clomiphene citrate (35), the

GDG emphasized that clomiphene citrate can be

used if letrozole is not available.

The GDG noted that either letrozole or clomiphene

citrate may be acceptable for use by physicians

in different settings, based on studies conducted

among physicians in China (36), Estonia, Denmark,

Finland, Iceland, Norway and Sweden (37), as well

as the United States of America (38). In one of

these studies, Piltonen et al. (37) found that 29% of 382 medical and reproductive endocrinologists and obstetrician-gynaecologists in multiple countries

prescribed clomiphene citrate in conjunction with

metformin (37).

The cost of metformin is generally low, but

monitoring of metformin therapy is generally limited once the optimum dose is achieved. Therefore, the GDG judged that the additional resources required to add metformin to clomiphene citrate are probably negligible, and it is probably feasible.

Of note, there were no studies reporting the

acceptability of these agents for ovulation induction among women with PCOS. In addition, the GDG

noted that acceptability of letrozole among

physicians could depend on its off-label use (38),

given that it is not currently approved by several

regulatory authorities such as the U.S. Food and

Drug Administration or European Medicines Agency for ovulation induction (26).

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Summary justification

Use of monotherapy

Overall, there may be greater benefits (live births) with letrozole compared to

clomiphene citrate (low-certainty evidence) or metformin (low-certainty evidence), which outweigh any harms that may be slightly increased. Although the potentially higher cost of letrozole could negatively affect equity, it is feasible and probably

acceptable to provide. However, letrozole may not be available in all settings

for off-label use. Therefore, letrozole is suggested over clomiphene citrate, but

clomiphene citrate with metformin can be used where off-label use of letrozole is not permitted or is unavailable.

Use of metformin in combination therapy

The balance of effects likely favours the use of clomiphene citrate with metformin over clomiphene citrate alone. The addition of metformin may result in moderate benefits and small undesirable effects. The use of clomiphene citrate with

metformin is feasible and probably acceptable where off-label use (of metformin for PCOS) is allowed, and the additional costs of adding metformin to the

stand-alone cost of clomiphene citrate alone is negligible.

There was very low certainty evidence that the benefits probably outweigh the

harms of using letrozole alone compared to letrozole with metformin. The addition of metformin to letrozole may result in a small increase in clinical pregnancy but

a corresponding small increase in miscarriages, resulting in no net effect on live

births compared to letrozole alone. In addition, metformin may also increase

gastrointestinal side-effects.

Implementation considerations

Health care providers should consider

offering lifestyle advice (e.g. on healthy diet

and regular physical activity) as part of the

management of PCOS. In addition, health care

providers need to be aware of the potential risk of

comorbidities, such as impaired glucose tolerance, obesity and metabolic syndrome, among others, in patients with PCOS (6, 7), which may require

additional management.

Health care providers should be aware of and mitigate the overall impact of stimulating

agents such as letrozole or clomiphene citrate by monitoring patients to optimize achieving a

pregnancy, while mitigating undesirable outcomes. Monitoring ovarian stimulation with ultrasound may

be considered to assess ovarian response and to mitigate the risk of multiple pregnancies. Health care providers should counsel patients regarding the potential morbidity that may result from

multiple gestation.

Use of letrozole as an ovulation induction

agent is not approved by several regulatory authorities such as the U.S. Food and Drug

Administration or the European Medicines

Agency (26). The use of metformin in patients with

PCOS is also off-label. Health care providers should familiarize themselves with applicable national

regulations related to off-label use of medicines for ovulation induction. Where off-label use of letrozole

as an ovulation induction agent is not permitted or

is unavailable, health care providers should offer

treatment with other ovulation agents, such as clomiphene citrate.

Health care providers should take patients' values and preferences into account as no studies reporting the acceptability of ovulation induction agents among patients with PCOS were identified in the evidence reviewed for this guideline.

Research gaps and future guideline update

The uncertainty in the evidence related to the

References

Abstract

Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps 9. Kurl RN, Morris ID. Differential depletion of cytoplasmic high affinity oestrogen receptors after the in vivo administration of the antioestrogens, clomiphene, MER-25 and tamoxifen.

References

Abstract

Molecular mechanisms of insulin resistance in polycystic ovary syndrome. Trends Mol Med.

References

Recommendation

Abstract

Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Abstract

Background and rationale

Treatment options for women who have been unsuccessful with oral pharmacological therapy with letrozole or clomiphene citrate with metformin include surgical treatment with LOD or pharmacological treatment with injectable gonadotrophins.

Gonadotropins include naturally occurring LH

and FSH from the pituitary, and human chorionic gonadotrophin (HCG) from the placenta, as well as their recombinant glycoforms, rFSH, rLH and rHCG (1, 2). Human menopausal gonadotrophins (hMGs) contain both FSH and LH (3). In females, gonadotrophins influence follicular recruitment, oocyte maturation, E2 secretion, ovulation and progesterone production (1). Based on these effects, gonadotrophins are an option for ovulation induction in the treatment of infertility (4). However, they can cause adverse effects, such as multiple gestation and OHSS (5), and need to be injected intramuscularly or subcutaneously (6). Recombinant forms differ from urine-derived or serum-derived gonadotrophins in terms of purity and batchto-batch consistency in biological activity (7).

To prevent multiple pregnancies and ovarian hyperstimulation, gonadotrophins are typically administered in individualized, step-up or (rarely) step-down regimens (8, 9). Ultrasound is used to monitor follicular growth during a stimulation cycle.

LOD is a surgical procedure whereby multiple perforations are made in the ovarian surface and stroma (the inner area of the ovary) to stimulate follicle development and ovulation induction (10, 11). LOD uses several cautery techniques to make perforations (12, 13), and the number and depth of perforations, and dose and duration of energy may vary (11). The precise mechanism through which LOD causes therapeutic effects is unknown, but is postulated to include changes in both circulating hormones and a pituitary feedback mechanism (14, 15) . LOD is typically performed as an outpatient procedure. For this recommendation, the GDG addressed the question: should LOD versus gonadotrophins be used for females with infertility due to ovulatory dysfunction caused by PCOS who fail oral pharmacological therapies such as letrozole or clomiphene citrate with metformin?

Balancing harms and benefits

A systematic review of RCTs provided data for the benefits and harms of LOD compared with gonadotrophins (16). There is likely little to no differences in live births (RR: 0.98; 95% CI: 0.79-1.21) and clinical pregnancies (RR: 1.02; 95% CI: 0.87-1.19), quality of life or depression between the two interventions. There may be large reductions in OHSS (RD: -0.02; 95% CI: -0.06 to 0.03) and multiple pregnancies (RR: 0.22; 95% CI: 0.09-0.54) and a small reduction in miscarriages (RR: 0.90; 95% CI: 0.57-1.45) with the use of LOD compared with gonadotrophins. Data on other adverse events were not reported, but the GDG noted that LOD is a surgical procedure requiring general anaesthesia, which could potentially increase the risks of bleeding, infection, thermal damage to adjacent organs and postoperative effects on ovarian reserve and adhesion formation. The GDG agreed that although gonadotrophins may increase the risk of OHSS and multiple pregnancies, these risks could be minimized with appropriate treatment regimens, surveillance and monitoring. Therefore, the GDG judged the benefits of LOD to be trivial and its

References

Guideline for the prevention, diagnosis and treatment of infertility

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

harms small compared to gonadotrophins. The overall certainty of evidence was low.

Other considerations

Although LOD is probably feasible, it requires

training in surgical skills. The review reported costs

from three RCTs and found that LOD was generally

less costly than gonadotrophins (16). However,

a retrospective health-economic evaluation

performed from a societal perspective comparing gonadotrophins with LOD (n = 35), followed by

ovulation induction with clomiphene citrate and/

or hMGs, reported that if spontaneous ovulation

did not occur within 2 months, then the societal

cost per patient was higher after LOD versus

gonadotrophins (17). Most of the cost in this

retrospective study was due to productivity loss

with LOD (17). Two studies reported the comparative cost-effectiveness of LOD versus gonadotrophins

per additional ongoing pregnancy and live birth,

but the results were inconsistent (17, 18). Based on these data, the GDG agreed that although LOD may

cost less and may lead to cost savings because of

a lesser need for monitoring (because of monoovulation), the harms that may occur with an

invasive surgical intervention may lead to additional health care costs. Along with the additional greater

training needs for LOD, this would balance out

the potential cost savings, probably resulting in

little difference in the cost-effectiveness of the

two treatments.

There were no studies assessing equity, but the

GDG judged that LOD probably has no impact on

equity compared to gonadotrophins. One study that assessed patient preferences reported that

couples were willing to accept LOD over ovarian

stimulation if both treatments resulted in similar

chances of pregnancy (19); based on this finding,

the GDG judged that there is probably no variability in how much people value pregnancy, noting that

most people would want to minimize adverse effects and would probably opt for the treatment that most increases their chances of pregnancy and live births.

Summary justification

Gonadotropins may increase live births more than LOD. Although data on

undesirable outcomes indicate that LOD has fewer harms, the GDG agreed that

LOD may cause moderate risks because it is a surgical procedure. Although

gonadotrophins may increase the risk of OHSS and multiple pregnancy, these

risks could be minimized with adequate monitoring. Gonadotropins are probably feasible, do not require training in surgical skills and may have no impact on

equity compared to LOD. Gonadotropins are probably acceptable as they increase the chances of pregnancy and are less invasive compared to LOD, but health care providers should discuss treatment options, particularly in settings where optimal monitoring of gonadotrophin treatment is not possible.

Implementation considerations

Health care providers should be aware of the risks of ovulation induction, including the

occurrence of OHSS and multiple pregnancy on

patients and health systems, and consider

implementing monitoring strategies (e.g. with

ultrasound or hormone measurement) to manage potential harms. Health care providers should

counsel patients on treatment options, particularly in settings where optimal monitoring of

gonadotrophin treatment is not possible. When

gonadotrophins are used, it should be in settings

where capacity for the management of side-effects and specified risk mitigation factors are in place

(e.g. individualized, step-up or step-down

protocols).

Abstract

Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps Research gaps and future guideline update Future studies should report outcomes comprehensively, including cost-effectiveness, time to pregnancy, postoperative effects of LOD on ovarian reserve, thermal damage to adjacent organs, infections, adhesion formation and other longer-term outcomes. Future guidance will be needed on specific dosing regimens for ovulation induction with gonadotrophins.

References

Guideline for the prevention, diagnosis and treatment of infertility

132

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

15. Keckstein G, Rossmanith W, Spatzier K,

Schneider V, Börchers K, Steiner R. The effect

of laparoscopic treatment of polycystic ovarian disease by CO2-laser or Nd:YAG laser. Surg

Endosc. 1990;4(2):103-7 (https://doi.org/10.1007/BF00591271).

16. Bordewijk EM, Ng KYB, Rakic L, Mol BWJ, Brown J, Crawford TJ et al. Laparoscopic ovarian drilling for

ovulation induction in women with anovulatory polycystic ovary syndrome. Cochrane Database Syst Rev. 2020;(2):CD001122 (https://doi.

org/10.1002/14651858.CD001122.pub5).

17. De Frène V, Gerris J, Weyers S, Dhont M,

Vansteelandt S, Annemans L et al. Gonadotropin

therapy versus laparoscopic ovarian drilling in clomiphene citrate-resistant polycystic

ovary syndrome patients: a retrospective

cost-effectiveness analysis. Gynecol Obstet

Invest. 2015;80(3):164-9 (https://doi.

org/10.1159/000373888).

18. Nahuis M, Oude Lohuis E, Kose N, Bayram N,

Hompes P, Oosterhuis G et al. Long-term followup of laparoscopic electrocautery of the ovaries versus ovulation induction with recombinant

FSH in clomiphene citrate-resistant women

with polycystic ovary syndrome: an economic evaluation. Hum Reprod. 2012;27(12):3577-82 (https://doi.org/10.1093/humrep/des336).

19. Bayram N, van Wely M, van der Veen F,

Bossuyt PM. Treatment preferences and

trade-offs for ovulation induction in clomiphene

citrate-resistant patients with polycystic ovary syndrome. Fertil Steril. 2005;84(2):420-5 (https://doi.org/10.1016/j.fertnstert.2005.02.026).

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Recommendation

For females with infertility due to ovulatory dysfunction caused by polycystic

ovary syndrome (PCOS) who have been unsuccessful with pharmacological

therapies such as letrozole, clomiphene citrate with metformin or

gonadotrophins, WHO suggests using in vitro fertilization (IVF) rather than

expectant management. (Conditional recommendation, very low certainty of evidence)

Background and rationale

Women with infertility due to PCOS may fail to achieve pregnancy after treatment with

letrozole, clomiphene citrate with metformin

or gonadotrophins. Therefore, it is important

to explore what approach should be followed

when gonadotrophins have been unsuccessful.

Options for women may include IVF or expectant

management.

IVF is a procedure where oocytes and sperm are

co-incubated outside the human body with the goal

of achieving fertilization, after which the embryo

is transferred to the uterus. IVF was first reported in humans in the late 1960s (1); in 1978, the first

birth resulting from IVF was reported (2). IVF is

traditionally the next line of treatment when most other approaches have been unsuccessful. The

procedure involves several steps: (i) the retrieval of the woman’s oocytes from the ovaries; (ii) exposure of the retrieved oocytes to sperm outside the

body for fertilization; (iii) culture of the resulting

embryo(s) for 3–5 days; and (iv) transfer of the

embryo to the uterus (3).

Globally, a significant number of people have

conceived through IVF (4), but it involves costs (5), and may also have adverse effects, such as

multiple pregnancy (6, 7) and OHSS, which is

a serious and potentially fatal condition (8).

Ultrasound is typically used to monitor ovarian

response and follicular growth during stimulation cycles for IVF (9). IVF allows control over the

number of embryos transferred, while allowing

spare embryos to be cryopreserved for future

use, obviating the need for further ovarian

stimulation (10). For this recommendation, the

GDG addressed the question: should IVF versus expectant management be used for females with infertility due to ovulatory dysfunction caused by PCOS who fail pharmacological therapies such as

letrozole, clomiphene citrate with metformin or gonadotrophins?

Balancing harms and benefits

The review team conducted a broad de novo search and did not identify any published

systematic reviews, RCTs or non-randomized

studies comparing IVF/ICSI versus no IVF/ICSI in women with ovulation dysfunction due to PCOS. Evidence from nine non-comparative, singlearm, non-randomized studies among women

receiving IVF for ovulation dysfunction due to

PCOS were identified (11–19). Of these, only one

study (12) reported that women (n = 1508) had been unsuccessful on other treatments.

Evidence from observational non-comparative

studies indicated that the use of IVF may result

in 550 clinical pregnancies (proportion: 0.55; 95%

CI: 0.43–0.66) and 520 live births per 1000 women (proportion: 0.52; 95% CI: 0.34–0.70). In terms

of undesirable effects, for every 1000 women

receiving IVF, there may be 50 cases of OHSS

(proportion: 0.05; 95% CI: 0–0.10) and 180 cases

of multiple pregnancy (proportion: 0.18; 95%

CI: 0.12–0.25) and a low incidence of miscarriages

(proportion: 0.16; 95% CI: 0.13–0.20). The GDG

noted the difficulty of judging the magnitude of

undesirable effects by looking at proportions, but also noted that OHSS and multiple pregnancy are

inherently associated with IVF. Although IVF may

cause harms such as OHSS and multiple pregnancy, these can be mitigated with appropriate treatment

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regimens, surveillance, monitoring and policies regarding embryo transfer.

Direct evidence is lacking with respect to patients’

values and preferences comparing IVF with no IVF (i.e. expectant management). Indirect evidence

from two discrete experimental studies that

involved 297 Dutch women with infertility (n = 206 and n = 91) eligible for IVF showed that acceptability of IVF was increased by its potential to increase

pregnancies and live births, but was reduced by outof-pocket costs and potential risk of OHSS (20, 21).

The GDG judged that the benefits of IVF probably

outweigh the potential harms for women with

infertility due to PCOS when other initial treatments have been unsuccessful. The overall certainty of

evidence was judged to be very low given the lack of appropriate comparative studies.

Other considerations

IVF is probably feasible but requires investments in health systems because of the costs involved (5, 22).

Safe provision of IVF requires specialized

equipment and training of health care providers.

The GDG judged that resource requirements on

health systems and individuals are moderate to

large, noting that costs to individuals and the

health system may result from the IVF procedure itself or from the management of OHSS, multiple

pregnancy and other complications that may result from IVF. IVF probably reduces equity if it is only

available to select people, for example, in settings where IVF facilities are not available or physically

or financially accessible. To mitigate the impact on

equity, appropriate assisted reproduction policies and services are required to ensure access to those that need it.

In the absence of direct evidence on acceptability, values and preferences from patients with PCOS,

the GDG agreed that women with infertility value

live births over potential harms and considered that ethically, such patients should have options when

other treatments have been unsuccessful. Overall, the GDG judged that IVF is probably acceptable if

the frequency of OHSS and costs are reduced.

Summary justification

The higher number of live births, relatively low undesirable effects, feasibility and acceptability of IVF probably favours the use of IVF over expectant management.

Implementation considerations

Women with PCOS undergoing IVF should be

informed about the potential benefits, costs

and risks of IVF, such as OHSS and multiple

pregnancy. Health care providers should consider

ways of minimizing potential harms, including

through appropriate treatment regimens and

protocols, surveillance and monitoring, and policies on the number of embryos to transfer (7, 23–26).

Given the lack of direct evidence on patients’

values and preferences, health care providers

should seek to understand patients’ acceptability of

IVF when other treatment options have been

unsuccessful, as well as social, cultural, economic and other concerns that patients may have.

Acceptability of IVF may be affected by a range of

individual and sociocultural factors (27, 28). Health care providers should inform patients about

prognostic factors such as female age, duration of subfertility and number of oocytes, among

others (29), and support patients to make informed decisions in keeping with the principles of shared decision-making based on their values and

preferences. Health care providers should also be aware and, whenever possible, mitigate contextual

issues that may affect the implementation of this

recommendation related to the health system

Abstract

Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps (e.g. availability of IVF facilities, personnel training and quality control of laboratories), economics (e.g. costs of IVF) and sociocultural factors (e.g. religious beliefs related to ART). Research gaps and future guideline update Further guidance will be required on the role of the GnRH agonist trigger, in vitro maturation, single embryo transfer, minimal ovarian stimulation and other prognostic factors, protocols and strategies that may increase the efficiency and effectiveness of IVF, while reducing any potential harms. Future research should involve patients and identify their values, preferences and acceptability of IVF interventions. In addition, future research is needed to assess strategies for making IVF more affordable (30, 31) given that IVF is economically out of reach for many individuals (31, 32).

References

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

29. van Loendersloot LL, van Wely M, Limpens J,

Bossuyt PMM, Repping S, van der Veen F.

Predictive factors in in vitro fertilization (IVF):

a systematic review and meta-analysis. Hum Reprod Update. 2010;16(6):577-89 (https://doi.

org/10.1093/humupd/dmq015).

30. Chiware TM, Vermeulen N, Blondeel K,

Farquharson R, Kiarie J, Lundin K et al. IVF

and other ART in low- and middle-income

countries: a systematic landscape analysis. Hum Reprod Update. 2021;27(2):213-28 (https://doi.

org/10.1093/humupd/dmaa047).

31. Njagi P, Groot W, Arsenijevic J, Dyer S,

Mburu G, Kiarie J. Financial costs of assisted

reproductive technology for patients in low-and middle-income countries: a systematic review. Hum Reprod Open. 2023;2023(2):hoad007

(https://doi.org/10.1093/hropen/hoad007).

32. Dyer SJ, Patel M. The economic impact of

infertility on women in developing countries

– a systematic review. Facts Views Vis Obgyn.

2012;4(2):102-9.

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Recommendation

For females with infertility due to ovulatory dysfunction caused by

hyperprolactinaemia, WHO suggests using cabergoline over bromocriptine.

(Conditional recommendation, low certainty of evidence)

Background and rationale

Hyperprolactinaemia is a common endocrine

disorder of the hypothalamic–pituitary axis. Normal

prolactin (PRL) levels in women and men are below 25 µg/L and 20 µg/L, respectively (1). Data on the

global prevalence of hyperprolactinaemia are

sparse; however, an analysis of 1607 medically

treated patients with hyperprolactinaemia reported a prevalence of 10.8 per 100 000 in men and

29.5 per 100 000 in women, with a peak incidence

among women aged 25–34 years (2). Although

hyperprolactinaemia is diagnosed in less than 1% in the unselected general population, it is reported

to occur in 5–17% of women with secondary

amenorrhoea (3–6) and in 6.7% of those with

infertility (7, 8).

There are many possible causes of

hyperprolactinaemia, including physiological,

pharmacological, pathological or idiopathic

etiologies (9). Pituitary adenoma or prolactinoma

is one of the most frequent pathological cause of

hyperprolactinaemia (10). Physiological states such as pregnancy can cause PRL elevation (11), while

pharmacological causes include side-effects from

some antipsychotics, opiates, antihypertensives and antidepressants (12).

PRL exerts many physiological functions; clinical

manifestations of hyperprolactinaemia are exerted through its effects on the hypothalamic–pituitary–

gonadal axis, mammary glands (i.e. breast) and

adenoma mass effects in the region of the sella

turcica (13). In women, hyperprolactinaemia often

leads to oligomenorrhoea, amenorrhoea, infertility and galactorrhoea (14). These symptoms are related to the physiological actions of PRL on lactogenesis and also result in hypogonadotropic hypogonadism,

low estrogen and oligo-ovulation or anovulation.

Other symptoms may include headaches and visual

disturbances because of local mass effects of

pituitary adenomas and prolactinomas (14).

Dopamine agonists are often the first-line

treatment for patients with hyperprolactinaemia

due to a pituitary adenoma (1). Pituitary PRL

secretion is mainly under inhibitory control by

dopamine in the hypothalamic tuberoinfundibular pathway. It is secreted into the hypophyseal portal system and reaches the pituitary lactotrophs

where it activates dopamine D2 receptors to

suppress PRL secretion (15). Because dopamine

inhibits PRL secretion, dopamine agonists, such as bromocriptine and cabergoline, reduce serum PRL levels by directly stimulating dopamine receptors in pituitary lactotrophs, thereby lowering circulating PRL levels. A reduction in PRL levels subsequently leads to the resumption of ovulatory menstrual

cycles, shrinking of pituitary prolactinomas,

resolution of visual field defects and resolution of galactorrhoea (16).

For this recommendation, the GDG addressed the

question: should cabergoline versus bromocriptine be used for the treatment of anovulatory infertility caused by hyperprolactinaemia? Bromocriptine

is the primary dopamine agonist against which

newer ergot derivatives are typically compared (17); it has side-effects common to all ergot derivatives, such as nausea and vomiting (18). Although it is

generally effective, some patients may not tolerate bromocriptine at therapeutic doses (19, 20) and

are resistant to it (21). Cabergoline is a newer ergot derivative with a longer half-life allowing it to be

taken only once or twice weekly, which may improve therapeutic compliance (18, 22). The outcomes of

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6 Treatment of infertility due to ovulatory dysfunction

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

interest for this recommendation were live births,

clinical pregnancy rates and adverse effects of

these medications. Although return of ovulation is an important intermediate step towards live births in women with anovulatory infertility secondary

to hyperprolactinaemia, it was not independently

assessed as an outcome; instead, the GDG prioritized

pregnancies and live births as primary outcomes.

Balancing harms and benefits

A systematic search for randomized and nonrandomized studies was conducted in MEDLINE,

Embase and the Cochrane Central Register of Controlled Trials from 1990 until June 2019. The

search identified five relevant RCTs that compared

cabergoline and bromocriptine (23–27). There is lowquality evidence from these RCTs that cabergoline

may be more effective in terms of both biochemical (RR: 1.65; 95% CI: 0.95–2.86) and clinical (RR: 1.46; 95% CI: 1.19–1.78) pregnancy, assessed at 4 and

6–7 weeks of gestation, respectively. In these RCTs, live birth rates were not assessed.

In terms of undesirable effects, there is moderate

to very-low evidence from RCTs that medication

side-effects are likely less common with cabergoline

compared to bromocriptine, suggesting

that cabergoline is likely more tolerable. Two

studies (24, 25) reported on miscarriages, which

were rare, but these studies were rated as being of very low quality for failing to report results between comparison groups, incomplete outcome data and having very few events. In all studies, the route

of administration was oral for both medications,

although the GDG noted some variations in the

dosages of the two medications administered

across the studies. These studies used lower levels of bromocriptine than what is typical in clinical

practice. The overall certainty of evidence was

rated as low. Data are lacking on patient values

and preferences; however, the GDG judged that

there is no important uncertainty in how people

value the main outcomes. Because patients are

likely to prefer the option that is more effective and

better tolerated, the GDG judged that the balance

of effects probably favours cabergoline compared

to bromocriptine.

Additional considerations

There is a lack of studies assessing the acceptability of dopamine agonists among patients. However,

given the less frequent oral dosing and

better tolerability of cabergoline compared to

bromocriptine, the GDG judged that it is probably acceptable. Although there was limited evidence

regarding feasibility, the GDG judged that provision of cabergoline, including management of sideeffects, is likely feasible. Two studies reported

that cabergoline is slightly more expensive than

bromocriptine when analysed per tablet (28, 29).

However, costs are likely to be comparable,

given the less frequent dosing schedule of

cabergoline (29). Therefore, the GDG concluded that overall, recommending cabergoline would result

in negligible costs compared to bromocriptine,

although costs may differ slightly across countries.

Summary justification

Overall, there is low quality evidence that cabergoline may be more effective in

increasing the rate of both clinical and biochemical pregnancy and is likely more

tolerable. Live birth rates were not reported in the studies. Because patients are

likely to prefer the option that is more effective while having fewer side-effects, the balance of effects probably favours cabergoline. In addition, cabergoline is probably acceptable and is feasible. Although the cost per tablet of cabergoline could be

higher than bromocriptine, the dosing regimen can reduce cabergoline costs.

Therefore, women with ovulatory dysfunction infertility due to hyperprolactinaemia are more likely to benefit more from cabergoline than bromocriptine.

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Implementation considerations

Once hyperprolactinaemia is confirmed, the

primary cause needs to be investigated

before initiating treatment with dopamine

agonists. Evaluation is aimed at excluding

pharmacological or extra-pituitary causes of

hyperprolactinaemia, such as medication use,

renal failure, primary hypothyroidism and

parasellar tumours (9), and may include historytaking, visual and physical examination, and

laboratory and imaging tests. The higher the level

of PRL in general, the greater the likelihood of a

pituitary adenoma and the greater the likelihood it

will be a macroadenoma. Higher levels of PRL are

associated with prolactinomas and

macroadenomas (30, 31).

Macroadenomas of the pituitary can be

associated with visual field defects and may

alter secretion of other pituitary hormones.

Clinically significant tumour growth can occur

during pregnancy.

After commencement of treatment, health care providers should monitor whether

dopamine agonists are working effectively,

including regularly assessing PRL levels, side-effects

and return of ovulation. Further evaluation should be considered if menses do not return, or if new symptoms appear or persist, which may indicate possible pregnancy or persistent

hyperprolactinaemia requiring dose adjustment.

Research gaps and future guideline update

In terms of future research, studies comparing

cabergoline and bromocriptine should assess

live birth outcomes, as well as patient-centred

outcomes, including acceptability and quality of

life. Current studies focus on reporting pregnancy

rates and normalization of PRL levels. Future

research and guidance will be required on whether to discontinue bromocriptine or cabergoline

therapy in women who become pregnant after

normalization of PRL levels. Such guidance will

need to consider the potential risk of continuing

dopamine agonists vis-à-vis the risk of recurrence of hyperprolactinaemia on medication withdrawal.

References

1. Casanueva FF, Molitch ME, Schlechte JA, Abs R, Bonert V, Bronstein MD et al. Guidelines of

the Pituitary Society for the diagnosis and

management of prolactinomas. Clin Endocrinol. 2006;65(2):265-73 (https://doi.org/10.1111/j.1365-2265.2006.02562.x).

2. Kars M, Souverein PC, Herings RMC, Romijn JA,

Vandenbroucke JP, de Boer A et al. Estimated

age- and sex-specific incidence and prevalence

of dopamine agonist-treated hyperprolactinemia. J Clin Endocrinol Metab. 2009;94(8):2729-34

(https://doi.org/10.1210/jc.2009-0177).

3. Lee DY, Oh YK, Yoon BK, Choi DS. Prevalence of

hyperprolactinemia in adolescents and young

women with menstruation-related problems. Am J Obstet Gynecol. 2012;206(3):213.e1-5 (https://

doi.org/10.1016/j.ajog.2011.12.010).

4. Greer ME, Moraczewski T, Rakoff JS. Prevalence

of hyperprolactinemia in anovulatory women. Obstet Gynecol. 1980;56(1):65-9.

5. Biller BM, Luciano A, Crosignani PG, Molitch M,

Olive D, Rebar R et al. Guidelines for the

diagnosis and treatment of hyperprolactinemia. J Reprod Med. 1999;44(12 Suppl):1075-84 (https://pubmed.ncbi.nlm.nih.gov/10649814/).

6. Souter I, Baltagi LM, Toth TL, Petrozza JC.

Prevalence of hyperprolactinemia and abnormal

magnetic resonance imaging findings in

a population with infertility. Fertil Steril.

2010;94(3):1159-62 (https://doi.org/10.1016/j.

fertnstert.2009.12.017).

7. Recent advances in medically assisted

conception: report of a WHO Scientific Group. Geneva: World Health Organization; 1992

(https://iris.who.int/handle/10665/38679).

References

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26. Al-Husaynei AJ, Mahmood IH, Al-Jubori ZS.

Comparison of the effects of cabergoline

and bromocriptine in women with

hyperprolactinemic amenorrhea. Middle East Fertil Soc J. 2008;13(1):33-8.

27. Sabuncu T, Arikan E, Tasan E, Hatemi H.

Comparison of the effects of cabergoline

and bromocriptine on prolactin levels in

hyperprolactinemic patients. Intern Med.

2001;40(9):857-61 (https://doi.org/10.2169/

internalmedicine.40.857).

28. Bahceci M, Sismanoglu A, Ulug U. Comparison

of cabergoline and bromocriptine in

patients with asymptomatic incidental

hyperprolactinemia undergoing ICSI-ET. Gynecol Endocrinol. 2010;26(7):505-8 (https://doi.

org/10.3109/09513591003632233).

29. Molitch ME. Cabergoline versus bromocriptine: a

meta-analysis? Nat Rev Endocrinol. 2011;7(5):254-

5 (https://doi.org/10.1038/nrendo.2011.33).

30. Pinzone JJ, Katznelson L, Danila DC, Pauler DK, Miller CS, Klibanski A. Primary medical therapy

of micro- and macroprolactinomas in men. J Clin Endocrinol Metab. 2000;85(9):3053-7 (https://doi.

org/10.1210/jcem.85.9.6798).

31. Vilar L, Freitas MC, Naves LA, Casulari LA,

Azevedo M, Montenegro R et al. Diagnosis and

management of hyperprolactinemia: results of a

Brazilian multicenter study with 1234 patients. J

Endocrinol Invest. 2008;31(5):436-44 (https://doi.

org/10.1007/BF03346388).

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7 Treatment of infertility due to tubal disease

The following sections 7.1–7.2 present recommendations related to the management of tubal blockage and hydrosalpinx.

7.1 Use of surgery or IVF for treatment of tubal disease

Recommendation

For females aged < 35 years with mild-to-moderate tubal disease (Hull and Rutherford grades I and II), WHO suggests surgery rather than in vitro

fertilization (IVF). (Conditional recommendation, very low certainty of evidence)

Remarks:

• After surgery, a reasonable minimum time to wait to achieve pregnancy

before pursuing other interventions, such as IVF, is 1 year.

• This recommendation does not apply to females who have had previous

tubal sterilization.

For females aged < 35 years with severe tubal disease (Hull and Rutherford grade III), WHO suggests in vitro fertilization (IVF) rather than surgery.

(Conditional recommendation, very low certainty of evidence)

Remark:

• This recommendation does not apply to females who have had previous

tubal sterilization.

For females aged ≥ 35 years with any tubal disease, WHO suggests IVF rather than surgery. (Conditional recommendation, very low certainty of evidence).

Background and rationale

Tubal factor infertility occurs when some pathology proximally at the uterotubal junction or more

distally in the fallopian tube(s), caused by disease, obstruction, damage, scarring, congenital

malformations or other factors, prevents oocyte

pickup by the fimbriated ends of the tube or sperm access to the oocyte for fertilization in the tube,

or impedes the fertilized egg and developing

embryo from descending into the uterus, thereby preventing pregnancy or resulting in ectopic

pregnancy. Of the different causes, the most

prevalent is PID or salpingitis. In a large WHO

multi-country study, bilateral tubal occlusion and

acquired tubal abnormalities accounted for 17.7% and 11.6%, respectively, of all identifiable causes

of female infertility (1, 2), although the distribution can vary between high-income, middle-income and low-income settings (see Annex 1. Distribution

of the causes of infertility). Given the role of the fallopian tube in gamete and embryo transport (3), assessment of tubal disease, particularly tubal

patency is important in the investigation of

female infertility.

The two modalities for managing (or overcoming) tubal factor infertility, such as blockage, are IVF and tubal surgery. IVF is an ART procedure that involves combining eggs and sperm outside the body in a LBR/3 years) (7). For these recommendations, the GDG addressed the question: should surgery versus IVF be used for women with infertility due to tubal disease? For these recommendations, surgical procedures for tubal disease exclude tubal re-anastomosis after sterilization (sterilization reversal). These recommendations assume that no significant male factor exists.

Balancing harms and benefits

A systematic review of the literature for randomized and non-randomized studies from 1990 to July 2019 was conducted. No RCTs comparing pregnancy rates after tubal surgery versus IVF were identified.

Available evidence was identified from comparative non-randomized studies (8-10); the certainty of the evidence was very low because of potential confounding, low number of events and wide CIs, and the heterogeneity of surgical approaches. RR: 0.84; 95% CI: 0.54-1.30). Of note, the benefits from surgery were mainly from microsurgical techniques. The GDG judged these desirable effects to be large.

In terms of harms, the data showed that surgery may result in more ectopic pregnancies (120 more per 1000; risk difference (%): 12; 95% CI: 9-15). Data on multiple gestations and OHSS were not reported in the studies included. The GDG noted the absence of data on important outcomes such as bleeding, infection, injury to internal organs and blood vessels, risks of general anaesthesia, OHSS and high-order multiple pregnancy (HOMP). The GDG considered that there is very little risk, if any, of OHSS and HOMP with surgery but IVF may increase the risk of OHSS and HOMP; however, effective strategies to

References

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

mitigate these risks of IVF, such as elective single

embryo transfer, exist. However, the GDG noted

that the greater risk of ectopic pregnancy, which

may occur with surgery, may be more relevant in

rural settings. However, in most cases these can be well managed by instituting heightened awareness and appropriate surveillance. The GDG considered that the outcomes of surgery are highly operatordependent and may also be dependent on the

extent and site of tubal disease. The GDG judged the

undesirable effects to be small.

Although no evidence was found regarding

values, the GDG agreed that women with infertility value pregnancy and live birth highly as the

main outcomes of the intervention, as well as

minimizing risks.

Based on these data, the GDG judged that the

overall balance of effects probably does not favour

either surgery or IVF. The GDG also noted that IVF outcomes and tubal surgery outcomes may vary

in different settings depending on several factors,

including the quality of the IVF laboratory and surgeon experience and expertise. In addition,

the GDG considered the varying benefits of

surgery for different subgroups, noting that the outcomes appear to be potentially influenced

by several factors, including age and duration of follow-up. Cumulative pregnancy outcomes with surgery accrue over a longer duration of followup that ranges from 1 to 5 years, compared to

IVF. Therefore, it is reasonable to offer surgery

to younger patients (< 35 years) with mild and

moderate disease (Hull and Rutherford grades I

and II) because younger women may have time

to explore other assisted reproduction options

if pregnancy is not achieved after surgery. Given

the resources expended in providing surgery,

and the time required to achieve spontaneous

(i.e. unassisted) pregnancy after surgery, it is

recommended that health providers wait for a

reasonable time (at least 1 year) after surgery

before providing other interventions such as IVF.

Most pregnancies occur within 1–2 years of surgical

treatment of distal tubal disease (7, 11); therefore, waiting a minimum of 1 year may be reasonable. It should be noted that this recommendation does

not apply to women desiring pregnancy after tubal

ligation or sterilization.

For younger women aged < 35 years with severe

disease (Hull and Rutherford grade III) the harms of

surgery probably outweigh its benefits. Although

younger women aged < 35 years may have time

to explore other assisted reproduction options if

pregnancy is not achieved after surgery, severe

disease (Hull and Rutherford grade III) has poor

prognosis; therefore, IVF is recommended over

surgery for these women.

Given concerns related to age-related fertility

decline, IVF is also suggested over surgery in women aged ≥ 35 years regardless of the severity of tubal

disease. For older women (≥ 35 years) the additional time required to undergo surgery and wait for

spontaneous (i.e. unassisted) pregnancy means

that women would be much older before exploring other options such as IVF, should pregnancy not be achieved after surgery; therefore, they would have

a much lower chance of achieving pregnancy. For

older women, the benefits of IVF probably outweigh

the harms compared to surgery. For women who are older, women with severe tubal disease and couples

with male-factor infertility, IVF could be offered. The

overall certainty of evidence was judged to be very low; all studies included were observational.

Other considerations

Performing tubal reconstructive surgery with good results requires a well-equipped health system and a high level of expertise or training. Although it is

probably feasible to train health professionals to

provide surgery (12), the resource requirements are often not available or met in many low-resource

settings. Thus, the GDG judged that large resources are required for surgery and that compared to IVF,

surgery would probably have no or limited effect

on equity as IVF also involves high costs to be set up and operate.

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Tubal surgery is often a one-time procedure

that may be conducted as a minimally invasive

outpatient procedure. It is more invasive than

IVF. Given the impact of both age and severity of disease on pregnancies and live births, surgery is

probably acceptable in younger patients with Hull and Rutherford grade I or II tubal disease, while in severe tubal disease (Hull and Rutherford grade III), IVF would probably be acceptable.

Summary justification

Surgery may increase pregnancies and live births after 5 years of follow-up more

than IVF. Although surgery may increase the risk of ectopic pregnancy, a heightened awareness of its possibility with appropriate surveillance and management may

minimize this risk. Surgery also may have fewer harms, including reduced risk of

OHSS and HOMP. The overall desirable effects of clinical pregnancy and live births

probably outweigh the risk of ectopic pregnancy. In addition, surgery is probably

feasible to provide, is probably acceptable, and it probably has no impact on equity compared to IVF.

Younger women (< 35 years) can pursue other assisted reproduction interventions if pregnancy fails to occur after surgery. However, for older women (≥ 35 years), the additional time required to undergo surgery and then receive IVF if surgery fails,

means they would be much older and have a further reduced chance of pregnancy. Therefore, for older women the benefits of IVF probably outweigh its harms

compared to surgery. Although IVF can increase the risk of OHSS and HOMP, these risks can be mitigated by strategies such as single embryo transfer.

Time to pregnancy in patients with good, intermediate and poor prognosis (3-year rates) justify an age cut-off of 35 years because this age allows up to 3 years of

follow-up at a time when women’s fertility potential is narrowing.

The minimum time to wait after surgery before offering IVF is similar to the duration for the definition of infertility for women < 35 years, that is, failure to conceive

within 1 year. Although the treatment timeline can be different from the diagnostic timeline, data show that most pregnancies occur within 1–2 years after surgery.

Implementation considerations

Health care providers should counsel

patients, communicate the prognosis, clearly discuss the options and costs of surgery and IVF,

and consider patient preferences. In settings where the infrastructure for tubal surgery or IVF does not exist, patient referrals to adequately equipped

centres should be considered. Health care providers should be trained to adequately monitor, mitigate

and manage the undesirable effects of surgery

(such as ectopic pregnancy) and IVF (such as OHSS and HOMP).

In implementing this recommendation,

health care providers should consider

whether patients have hydrosalpinges which may

have a negative effect on pregnancy and IVF

success rates (13). If hydrosalpinx is present in

women planning to undergo IVF, health care

providers should implement recommendations

related to treatment of hydrosalpinx before IVF, as described in the next section. In addition, these

recommendations assume that no significant male

factor exists.

Abstract

Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps Research gaps and future guideline update Ovarian reserve may be an additional factor to consider; however, data were not available on the subgroup of women with decreased ovarian reserve, which should be addressed in future studies. Future studies should also assess important outcomes such as bleeding, infection, injury to internal organs and vessels, risks of general anaesthesia, OHSS and HOMP, and patients' values, including attitudes towards surgery or IVF, and preferences related to time to pregnancy and desired family size.

References

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7.2 Treatment of hydrosalpinx before IVF

Recommendation

For females with tubal factor infertility due to hydrosalpinx, WHO suggests either salpingectomy or tubal occlusion before provision of in vitro fertilization (IVF).

(Conditional recommendation, very low certainty evidence)

Remark:

• When selecting whether to use salpingectomy or tubal occlusion, consider

feasibility, availability of trained health care providers and presence of

adhesions.

Background and rationale

In cases of tubal disease or blockage, women may develop hydrosalpinx, a condition where

fluid accumulates inside the fallopian tubes. The

presence of hydrosalpinx may have a negative

effect on successful embryo implantation and affect

IVF outcomes (1). Therefore, the GDG agreed that guidance is needed regarding the management of hydrosalpinx in patients who are scheduled to undergo IVF.

Treatment of hydrosalpinx is aimed at preventing

the hydrosalpingeal fluid from reaching the uterine

cavity (2). Options for hydrosalpinx treatment include surgically resecting and removing the

affected fallopian tubes (salpingectomy), isolating

the hydrosalpinx from the uterine cavity using laparoscopic or hysteroscopic tubal occlusion,

transvaginal aspiration of hydrosalpingeal fluid

under ultrasound guidance or draining the

hydrosalpingeal fluid by means of salpingostomy (3).

For this recommendation, the GDG addressed the question: should salpingectomy or tubal occlusion versus none be used to treat tubal disease due to hydrosalpinx in women due to undergo IVF?

Balancing harms and benefits

A systematic review published in 2020 was identified,

with a search date from inception of the databases

up to January 2020 (3). From this systematic review, four RCTs published between 1998 and 2006

provided data for the outcomes (4–7).

The results showed that compared to no treatment, conducting salpingectomy or tubal occlusion before IVF may result in slightly greater pregnancies and

no difference in ectopic pregnancy and miscarriage.

There were 151 more pregnancies (from 58 to

287 more) per 1000 (RR: 2.01; 95% CI: 1.39–2.91),

three fewer miscarriages (from 32 fewer to 71

more) per 1000 (RR: 0.94; 95% CI: 0.36–2.41) and

nine fewer ectopic pregnancies (from 14 fewer to

15 more) per 1000 (RR: 0.39; 95% CI: 0.08–1.97). Live births and quality of life outcomes were not

reported. Compared to no treatment before IVF, conducting salpingectomy or tubal occlusion

before IVF may result in 10 more conversions to

laparotomy (RD: 0.01; 95% CI: -0.02 to 0.03) and 10 more pelvic infections per 1000 (RD: 0.01; 95%

CI: -0.02 to 0.03). Although not measured, the GDG noted that the risk of other potential complications, such as visceral injuries, injury to blood vessels and bleeding, may exist with salpingectomy or tubal

occlusion conducted before IVF. The GDG agreed

that there were moderate benefits, but small harms,

based on the very low certainty of the evidence because of few events or participants. Therefore,

the GDG judged that the balance of effects probably

favours surgery over no treatment before IVF.

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Other considerations

No studies documented patient values; however, the GDG agreed that most couples would place

higher value on maximizing pregnancy and birth outcomes and minimizing harms. The GDG agreed

that the resources for surgery (e.g. equipment) and personnel training would result in moderate costs, although some cost variations between countries is expected.

No evidence was found on cost-effectiveness. The

GDG noted that because of the costs, treatment with salpingectomy or tubal occlusion before

IVF would probably reduce equity in settings

with limited public health financing of infertility

treatment. The GDG judged that surgery is probably acceptable, noting that while most couples would

prefer to avoid invasive treatment, someone with

confirmed hydrosalpinx who understands the

impact of the condition on their IVF outcome would probably opt for treatment with salpingectomy

or tubal occlusion to optimize the chance of

success with subsequent IVF. The GDG judged that salpingectomy and tubal occlusion are probably

feasible but require surgical facilities and training.

Summary justification

Compared to no treatment before IVF, salpingectomy or tubal occlusion before IVF may lead to a moderate increase in clinical pregnancies but may have little

to no effect on ectopic pregnancy or miscarriage; there is no information about the effects on live births or quality of life. The evidence was uncertain about

whether salpingectomy or tubal occlusion before IVF increases the risk of

surgical complications. Despite the moderate additional cost of salpingectomy or tubal occlusion before IVF, both interventions may improve the effectiveness of IVF; therefore, the GDG suggests that either salpingectomy or tubal occlusion be used for the treatment of hydrosalpinx before IVF. Salpingectomy and/or tubal

occlusion are probably feasible, and probably acceptable as most patients would likely want to improve IVF outcomes.

Implementation considerations

Caution should be taken during

salpingectomy for hydrosalpinx conducted before IVF to avoid compromising the vascular

supply to the ovaries, which could potentially result in suboptimal ovarian stimulation. Health care

providers may consider several factors to

determine whether to offer salpingectomy or tubal

occlusion before IVF, for example, the presence of dense adhesions and patient preferences. Health care providers should monitor patients for

potential complications after salpingectomy or

tubal occlusion.

Research gaps and future guideline update

Future studies should report outcomes related to live birth rates, complications and quality of life,

and should compare the different techniques of

salpingectomy or tubal occlusion. Future guidance

will be required on subgroups that may benefit

optimally, for example, based on whether the

hydrosalpinx is communicating or not. Future guidance will be required regarding the optimal timing of salpingectomy or tubal occlusion in

relation to ovarian stimulation and egg retrieval.

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References

1. Strandell A, Waldenström U, Nilsson L,

Hamberger L. Hydrosalpinx reduces in-vitro fertilization/embryo transfer pregnancy rates.

Hum Reprod. 1994;9(5):861-3 (https://doi.

org/10.1093/oxfordjournals.humrep.a138606).

2. Palagiano A, Cozzolino M, Ubaldi FM, Palagiano C, Coccia ME. Effects of hydrosalpinx on

endometrial implantation failures: evaluating salpingectomy in women undergoing

in vitro fertilization. Rev Bras Ginecol

Obstet. 2021;43(4):304-10 (https://doi.

org/10.1055/s-0040-1722155).

3. Melo P, Georgiou EX, Johnson N, Voorst SF,

Strandell A, Mol BWJ et al. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database

Syst Rev. 2020;(10):CD002125 (https://doi.

org/10.1002/14651858.CD002125.pub4).

4. Strandell A, Lindhard A, Waldenström U,

Thorburn J, Janson P, Hamberger L. Hydrosalpinx and IVF outcome: a prospective, randomized

multicentre trial in Scandinavia on salpingectomy prior to IVF. Hum Reprod. 1999;14(11):2762-9

(https://doi.org/10.1093/humrep/14.11.2762).

5. Kontoravdis A, Makrakis E, Pantos K, Botsis D,

Deligeoroglou E, Creatsas G. Proximal tubal occlusion and salpingectomy result in similar

improvement in in vitro fertilization outcome

in patients with hydrosalpinx. Fertil Steril. 2006;86(6):1642-9 (https://doi.org/10.1016/j.

fertnstert.2006.05.032).

6. Déchaud H, Daurès JP, Arnal F, Humeau C, Hédon B. Does previous salpingectomy

improve implantation and pregnancy rates in patients with severe tubal factor infertility who

are undergoing in vitro fertilization? A pilot prospective randomized study. Fertil Steril.

1998;69(6):1020-5 (https://doi.org/10.1016/s0015-0282(98)00077-6).

7. Moshin V, Hotineanu A. Reproductive outcome

of the proximal tubal occlusion prior to IVF in

patients with hydrosalpinx. Abstracts of the 22nd Annual Meeting of ESHRE. Hum Reprod. 2006;21 (Suppl 1):i189-i193 (https://doi.org/10.1093/

oxfordjournals.humrep.a002507).

Abstract

Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps Recommendation For females with tubal factor infertility due to hydrosalpinx, WHO suggests either salpingectomy or tubal occlusion rather than transvaginal aspiration of hydrosalpingeal fluid before provision of in vitro fertilization (IVF). (Conditional recommendation, very low certainty of evidence for salpingectomy compared with tubal occlusion, and very low certainty of evidence for transvaginal aspiration compared to no treatment)

Abstract

Remark:

Abstract

• In settings where salpingectomy and tubal occlusion are not available or feasible, transvaginal aspiration may be offered.

Background and rationale

Options for hydrosalpinx treatment include

Balancing harms and benefits

A systematic review published in 2020 was identified, with a search date from inception of the databases up to January 2020 (1). From this systematic review, three RCTs published between 2008 and 2015 provided data for the outcomes (2-4).

The results showed that transvaginal aspiration before IVF may result in a small increase in pregnancies and no differences in ectopic pregnancy or miscarriage compared to no treatment before IVF. There may be 96 more clinical pregnancies (from 12 to 226 more) per 1000 with transvaginal aspiration (RR: 1.64; 95% CI: 1.08-2.51), 12 more miscarriages (from 27 fewer to 118 more) per 1000 (RR: 1.24; 95% CI: 0.46-3.36) and five fewer ectopic pregnancies (from 13 fewer to 54 more) per 1000 (RR: 0.69; 95% CI: 0.10-4.62).

Live births and quality of life outcomes were not reported. In addition, there may be no difference in pelvic infection, but a slight increase in multiple pregnancy, which is likely attributable to IVF treatment: transvaginal aspiration may result in zero fewer pelvic infections per 1000 (RD: 0; 95% CI: -0.03 to 0.03) and 53 more multiple pregnancies (from 19 fewer to 373 more) per 1000 (RR: 2.33; 95% CI: 0.52-10.32). There may also be an important proportion of women with recurrence after transvaginal aspiration; the number of other major or minor complications is low. Overall, recurrence with or without sclerotherapy occurred in 27% (18-39%). More specifically, without sclerotherapy, recurrence was 53% (46-60%); with sclerotherapy, it was 14% (8-22%). Major complications occurred in 10 out of 1297 (0.7%) and minor complications (e.g. pain, extravasation, ruptured cyst, flush reactions and gastrointestinal discomfort) in 80 out of 1297 (6%). Based on these data, the GDG judged that there may be small desirable and undesirable effects of transvaginal aspiration compared to no treatment before IVF.

The certainty of evidence was judged to be very low because of inconsistent blinding of participants and outcome assessors, loss to follow-up and few events or participants; some studies were not comparative.

Although the GDG agreed that most people would place higher value on pregnancy and birth outcomes, while wanting to minimize harms, they judged that the balance of effects probably does not favour either transvaginal aspiration or no treatment.

References

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Other considerations

The GDG agreed that the resources for transvaginal aspiration would result in moderate costs. No

data were found on cost-effectiveness; however,

the GDG considered that transvaginal aspiration

would probably not be cost-effective because of the moderate costs, small benefits and small harms.

No studies of the impact on health equity were

available; however, the GDG judged that in women receiving IVF, the addition of transvaginal aspiration

of hydrosalpingeal fluid before IVF would probably

reduce equity because of additional costs.

No data were identified on acceptability; however,

the GDG judged that transvaginal aspiration

would probably not be acceptable given that most people would like to avoid an invasive procedure

when there may be little benefit compared

to harm. Nevertheless, the GDG judged that

transvaginal aspiration is probably feasible, noting that ultrasound is available in most settings as a basic tool for gynaecological assessment; training of health care providers is required to perform

transvaginal aspiration safely.

Summary justification

Transvaginal aspiration before IVF may lead to a small increase in clinical

pregnancies, but it may have little to no effect on ectopic pregnancy or

miscarriage; there are no data about its effects on live births or quality of

life. There may be a slight increase in multiple pregnancy when transvaginal

aspiration is conducted before IVF, and a clinically important proportion of

women may experience recurrence after aspiration; however, the rates of other complications are low. As the benefits may be small, the GDG agreed that other procedures for the treatment of hydrosalpinx with greater benefits, that is,

salpingectomy or tubal occlusion be used instead of transvaginal aspiration.

However, in settings where salpingectomy and tubal occlusion are not available or feasible, transvaginal aspiration may be considered.

Implementation considerations

Health care providers should monitor

patients for potential complications after

treatment of hydrosalpinx, including post-aspiration

infection, recurrence of fluid accumulation and accumulation of fluid in the endometrial cavity.

Health care providers should note that transvaginal

aspiration may only be offered if salpingectomy and

tubal occlusion are not available or feasible.

Research gaps and future guideline update

Future guidance comparing transvaginal aspiration with salpingectomy or tubal occlusion should report outcomes related to live birth rates and surgical

complications, optimal timing of procedures in

relation to ovarian stimulation and oocyte retrieval or embryo transfer, and quality of life. Further

guidance will be required regarding whether

antibiotic prophylaxis should be used routinely if

transvaginal aspiration is provided before IVF.

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

References

1. Melo P, Georgiou EX, Johnson N, Voorst SF,

Strandell A, Mol BWJ et al. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database

Syst Rev. 2020;(10):CD002125 (https://doi.

org/10.1002/14651858.CD002125.pub4).

2. An J, Ni Y, Liu X, Gao X, Wang Y. Effects of

transvaginal aspiration of hydrosalpinx combined auricular point sticking on IVF-ET outcomes

[article in Chinese]. Zhongguo Zhong Xi Yi Jie He

Za Zhi. 2015;35(6):682-5 (in Chinese).

3. Hammadieh N, Coomarasamy A, Ola B,

Papaioannou S, Afnan M, Sharif K. Ultrasoundguided hydrosalpinx aspiration during oocyte collection improves pregnancy outcome in IVF:

a randomized controlled trial. Hum Reprod.

2008;23(5):1113-7 (https://doi.org/10.1093/humrep/den071).

4. Fouda UM, Sayed AM. Effect of ultrasoundguided aspiration of hydrosalpingeal fluid during

oocyte retrieval on the outcomes of in vitro

fertilisation-embryo transfer: a randomised

controlled trial (NCT01040351). Gynecol

Endocrinol. 2011;27(8):562-7 (https://doi.org/10.3 109/09513590.2010.507290).

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8 Treatment of infertility due to uterine cavity disorder

This section presents recommendations related to the management of uterine cavity

disorders. Abnormalities of the uterine cavity may be congenital and acquired; rarely,

they have an unknown etiology. Congenital abnormalities stem from aberrations in the

development of the genital tract in the female (1). Examples of acquired abnormalities

include intrauterine adhesions, adenomas, fibroids or polyps, among others (see the

WHO manual for the standardized investigation and diagnosis of the infertile couple [2] and

its annexes). This chapter discusses the management of congenital abnormalities of the uterine cavity prioritized by the GDG, specifically uterine septum in women with infertility. Further guidance for other uterine conditions will be provided in a subsequent edition of this guideline.

8.1 Management of uterine septum in females with infertility

Recommendation

For females with infertility and uterine septum who have no history of

recurrent pregnancy loss, WHO suggests that hysteroscopic septum resection (septoplasty) not be performed. (Conditional recommendation, low certainty

of evidence)

Background and rationale

Congenital uterine malformations represent a variety of anomalies of the female reproductive tract, which result from the abnormal

differentiation, formation, migration, fusion,

canalization or resorption of the Müllerian system

during the fetal period (3). The prevalence of congenital uterine malformations has been

estimated at 4.3% in fertile women, 3.5–8.0% in women with infertility and 13–13.3% in women

with recurrent pregnancy losses (4, 5). Discrepancy in the prevalence rates has been reported in

the literature, potentially because of different classifications (4, 6–12) and the use of different

diagnostic methods, with variable ability of identifying and distinguishing these uterine malformations (5). There is a lack of a single

universally accepted evidence-based system for

the definitions and diagnostic criteria of Müllerian

anomalies.

Uterine malformations include:

• Müllerian agenesis, which is characterized by a

failure of the Müllerian ducts to develop.

• Arcuate uterus, which is characterized by a mild

concave indentation at the uterine fundus.

• Unicornuate or bicornuate uteri or uterus

didelphys, which is characterized by varying

abnormalities in fusion or unification defects of

the Müllerian ducts.

• Subseptate or septate uteri characterized by

varying abnormalities in canalization of the

Müllerian ducts.

these malformations, septate, bicornuate and arcuate uteri are the most commonly reported among unselected populations (4, 5); however, a septate uterus is likely more prevalent among populations at the highest risk of poor reproductive outcomes (5, 13). A 2011 systematic review and meta-analysis found that presence of a subseptate or septate uterus is associated with reduced fertility (RR: 0.86; 95% CI: 0.77-0.96), increased first-trimester miscarriage rates (RR: 2.9; 95% CI 2.0 0-4.1) and increased preterm births (RR: 2.1; 95% CI 1.5-3.1) (14).

In the same meta-analysis, arcuate uteri were associated with increased rates of second-trimester miscarriage (RR: 2.39; 95% CI, 1.33-4.27), while unification defects (unicornuate or bicornuate uteri or uterus didelphys) were associated with increased rates of preterm birth (RR: 2.97; 95% CI: 2.08-4.23) (14). Given that a septate uterus is among the most common uterine malformations (4, 5) and has the most data available from studies, the GDG guideline prioritized management of septate uterus over other uterine anomalies.

Options for managing uterine septae include expectant management, or surgery through hysteroscopic septum resection (13). Although hysteroscopic septum resection is widely reported in the literature and is not uncommon in clinical practice, there is uncertainty regarding its benefit.

For this recommendation, the GDG addressed the question: should hysteroscopic metroplasty (resection of uterine septum ["septoplasty"]) versus no treatment (i.e. expectant management) be used for women with infertility and uterine septae? Therefore, the population of interest for this recommendation are women with infertility and without recurrent pregnancy loss. Although the literature often includes women with miscarriage as part of the infertile population (13, 15) , this recommendation considered these as separate groups.

Balancing harms and benefits

Evidence was identified from a recent review (16), a recent RCT (17) and nine non-randomized comparative studies (18-26).

Low-certainty evidence showed that both the benefits and harms of septoplasty are small. In terms of benefits, data showed that providing hysteroscopic septoplasty may increase clinical pregnancies slightly (RR: 1.13; 95% CI: 0.74-1.74; 65 more, [from 130 fewer to 370 more], per 1000), but may have little to no difference on live births compared to expectant management (RR: 0.92; 95% CI: 0.48-1.75; Notably, this study reported higher miscarriage and lower live birth rates with surgery, which potentially changed the overall result to null in the adjusted analyses. The inclusion of data from women with an arcuate uterus, for which septoplasty may not be indicated, did not seem to affect the balance of effects. These results suggested that there is no clear evidence that the benefits of septoplasty outweigh its harms. The GDG judged that the balance of desirable and undesirable effects probably did not favour either septoplasty or expectant management.

References

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Other considerations

Evidence on patient values and acceptability was

limited. However, the GDG noted that some women may prefer to avoid invasive surgery, especially

when the benefit is small. Among health care

providers, acceptability for septoplasty varied. In

a randomized study involving 191 gynaecologists

from 43 countries, the agreement on the need for surgery once a septate uterus had been diagnosed was low (27). Although hysteroscopic septoplasty

is probably feasible, it involves moderate costs.

Equipment and training of health care providers

are required for the safe provision of hysteroscopic

septoplasty, including prevention of fluid overload,

which may not be available in all settings. The GDG

acknowledged that contextual differences may exist

in terms of the costs associated with hysteroscopic

septoplasty and may also depend on differences in

the availability of funding for infertility treatment. No

relevant studies comparing the cost-effectiveness

of hysteroscopic septoplasty versus expectant

management were found. While limited evidence related to the impact of hysteroscopy on costeffectiveness (28) or equity exists, the GDG judged that hysteroscopic septoplasty would likely reduce equity if only select people can afford it, which is likely given the potential costs to both individuals and health care systems.

Summary justification

Low-certainty evidence shows that there may be small undesirable effects

with hysteroscopic uterine septum resection, particularly miscarriage, ectopic

pregnancy and preterm birth, which balance with the small overall increase in

benefits (including clinical pregnancy and live birth) that may result from the

procedure. The balance of desirable and undesirable effects probably does not

favour either hysteroscopic septoplasty or expectant management for treatment of infertility. Although hysteroscopic septoplasty is probably feasible to provide, it involves moderate cost or resources compared to expectant management.

Acceptability of hysteroscopic septoplasty among health providers varies; in the absence of direct evidence from patients, it is possible that some women would likely want to avoid invasive procedures, especially when the benefit is small.

Implementation considerations

Health care providers should be aware that this recommendation also applies to women with an arcuate uterus, which is regarded as a

variant of normal morphology for which

hysteroscopic septum resection is generally not

indicated. This recommendation does not address intrauterine polyps, a bicornuate uterus or uterine

fibroids. Health care providers should take caution regarding different or changing definitions of what

constitutes a uterine septum or an arcuate uterus.

Definitions of septate and arcuate uteri vary widely

(e.g. length, width of septum).

Research gaps and future guideline update

Large randomized controlled studies are required to provide high-quality evidence on the effects of hysteroscopic septoplasty and to identify specific subgroups with infertility that could benefit

from septoplasty. Future studies should be large

enough to measure outcomes stratified according

to types, depth or width of uterine septae, and

other subgroup categories of interest to health

practitioners (including those due to undergo IVF). Careful attention to inclusion and exclusion criteria is warranted to ensure that any future studies are

meaningful. These efforts should be complemented

This recommendation relates to populations of women with infertility but not those with recurrent pregnancy loss. Future guidance will be required on the role of septoplasty in fertile women (with a septate uterus) who have recurrent pregnancy losses after achieving a pregnancy. In addition, this recommendation does not assess the harms or benefits of septoplasty in women (with a septate uterus) who have implantation failure; future guidance will be required to address this question.

References

Abstract

Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps 14. Chan Y, Jayaprakasan K, Tan A, Thornton J, Coomarasamy A, Raine-Fenning N. Reproductive outcomes in women with congenital uterine anomalies: a systematic review. Ultrasound

References

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

9 Treatment of infertility due to male factors

The following sections 9.1–9.2 present recommendations related to the management of male-factor infertility.

9.1 Use of antioxidants

Recommendation

For males with infertility and one or more semen parameters that are outside the WHO reference ranges attempting to achieve pregnancy with or without medically assisted reproduction, the WHO infertility Guideline Development Group (GDG) did not make a recommendation for or against the use of

antioxidant supplements.

Remark:

• Optimal nutrition is important during the pre-pregnancy period for the couple;

however, the effects of antioxidant supplements for males with specific malefactor pathologies in couples with infertility are currently not known.

Background and rationale

Globally, the main cause of infertility reported in a large WHO multi-country study involving

8500 couples in 25 countries was due to female

factors alone in 30.6% of cases, both male and

female factors in 26.3% and male factors alone in

18.7% of cases (1). Based on this study, male factors contributed wholly or in part to 45.1% of infertility

cases (see Annex 1. Distribution of the causes of infertility).

Reactive oxygen species (ROS), such as superoxide (O2•-), nitric oxide (NO•) and hydrogen peroxide

(H2O2), are by-products of oxygen metabolism

under normal physiological conditions (2, 3).

However, an imbalance in reduction–oxidation

reactions is thought to increase intracellular

concentration of ROS and to potentially have a

role in disease processes (4, 5). In the context of

infertility, oxidative stress may increase the levels of ROS in the male tract or seminal secretions, which is

hypothesized to negatively affect male fertility (6, 7). Oxidative stress can result from several sources,

including seminal leukocytes (8, 9).

Although there is still a need for definitive evidence (for a validated or certain test, assay or proof)

linking reduction–oxidation imbalances with fertility outcomes (8), as indicated in some studies (10, 11),

it is accepted that oxidative stress is probably an

important modulator of human sperm function (8). In this context, oral antioxidant therapy has been

increasingly investigated for the possibility that

it could ameliorate oxidative stress, and improve

human sperm function (12), under an overarching

hypothesis that individuals exposed to increased

oxidative stress may have raised antioxidant

requirements.

In general, a dietary antioxidant is a substance

in foods that significantly decreases the adverse

effects of ROS, reactive nitrogen species or both,

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on normal physiological function in humans (13). While fruits and vegetables typically contain safe levels of dietary antioxidants (3, 14, 15), the GDG

agreed that an important question is whether oral

antioxidant supplements are beneficial or harmful

for men with male-factor infertility, and what

types and amounts of antioxidants are useful for

this population. The GDG agreed and noted that

clinicians may be suggesting antioxidants for men with infertility, particularly those who have semen parameters outside the WHO reference ranges,

and also that men may be asking about whether to take antioxidants, yet there have been uncertainties

about the general health effects and potential

harms of supplementation with antioxidants

supplements, as reported in some studies (16).

In the context of male-factor infertility, an

antioxidant is a substance that has the ability to

protect spermatozoa against oxidative damage, for example, through neutralizing actions, or by

functioning as a component of an antioxidant

enzyme (12). These antioxidant properties may

also contain membrane stability effects (3, 17). Oral antioxidant supplements typically include some

types of vitamins, trace elements and other mineral

compounds that are chemically synthesized and

packaged as pills. They are generally dispensed

without prescription, either separately or in any

combination among themselves, or in combination with other vitamins, trace elements or mineral

compounds that do not have antioxidant effects.

For this recommendation, the GDG addressed the question: should oral antioxidant supplements

versus no oral antioxidant supplements be used by men with infertility and semen parameters outside

the WHO reference range? In this recommendation,

the GDG was interested in fertility outcomes rather

than changes in specific semen parameters. Herbal

preparations are not included.

Balancing harms and benefits

Data were obtained from a systematic review (12) and a targeted search for RCTs. Based on

the evidence, the GDG concluded that no

recommendation can be made about the use of antioxidant supplements for men in couples with infertility and semen parameters that are outside the WHO reference range attempting to achieve pregnancy with or without medically assisted

reproduction (see Web Annexes A–F for the

detailed evidence to decision tables).

Summary justification

The available studies from a systematic review (12) and a targeted search for

RCTs up to April 2024 were in men with different pathologies for infertility and

evaluated a variety of antioxidants in combination or as a single supplement and in different doses in men with one or more semen parameters outside the WHO reference ranges. This evidence could not be used to inform a recommendation about the use of antioxidants for this population.

Research gaps and future guideline update

Overall, stronger evidence is still needed to

demonstrate clear reversal of imbalance in

reduction–oxidation equilibrium reactions, which

forms the basis of the use of oral supplemental

antioxidants in men with infertility, while precluding the risk of possible reductive stress (18–20).

In particular, large, good-quality RCTs on oral

supplemental antioxidants are required among

men in couples with infertility, particularly men

with one or more semen parameters that are

outside the WHO reference ranges, noting simple

diagnostic tests that can identify men with oxidative stress may also be needed (21). Such studies should focus on cases where female factors have been

excluded. Such studies should be well‐powered

Future research is required to address this gap.

References

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13. Institute of Medicine (US) Standing Committee

on the Scientific Evaluation of Dietary Reference

Intakes. Dietary reference intakes: proposed

definition and plan for review of dietary

antioxidants and related compounds. Washington, DC: National Academies Press (US); 1998 (https://doi.org/10.17226/6252).

14. Diplock AT, Charleux JL, Crozier-Willi G, Kok FJ,

Rice-Evans C, Roberfroid M et al. Functional food science and defence against reactive oxidative species. Br J Nutr. 1998;80(Suppl 1):S77-S112

(https://doi.org/10.1079/bjn19980106).

15. McKevith B, Kelly C, Stanner S, Hughes J, Buttriss J. The Food Standards Agency’s

antioxidants in food programme – a summary. J Hum Nutr Diet. 2003;16(4):257-63 (https://doi.

org/10.1046/j.1365-277x.2003.00436.x).

16. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials

of antioxidant supplements for primary and

secondary prevention: systematic review and

meta-analysis. JAMA. 2007;297(8):842-57 (https://doi.org/10.1001/jama.297.8.842).

17. Halliwell B. Free radicals, antioxidants, and human disease: curiosity, cause, or

consequence? Lancet. 1994;344(8924):721-4

(https://doi.org/10.1016/s0140-6736(94)92211-x).

18. Henkel R, Sandhu IS, Agarwal A. The excessive use of antioxidant therapy: a possible cause of

male infertility? Andrologia. 2019;51(1):e13162

(https://doi.org/10.1111/and.13162).

19. Moustakli E, Zikopoulos A, Skentou C,

Katopodis P, Domali E, Potiris A et al. Impact of

reductive stress on human infertility: underlying mechanisms and perspectives. Int J Mol Sci.

2024;25(21):11802 (https://doi.org/10.3390/

ijms252111802).

20. Caroppo E, Dattilo M. Sperm redox biology

challenges the role of antioxidants as a treatment for male factor infertility. F&S Rev. 2022;3(1):90-

104 (https://doi.org/10.1016/j.xfnr.2021.12.001).

21. Aitken RJ. Antioxidant trials-the need to test for

stress. Hum Reprod Open. 2021;2021(1):hoab007 (https://doi.org/10.1093/hropen/hoab007).

22. The selection and use of essential medicines

2023: web annex A: World Health Organization

model list of essential medicines: 23rd list

(2023). Geneva: World Health Organization; 2023

(https://iris.who.int/handle/10665/371090).

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9 Treatment of infertility due to male factors

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

9.2 Treatment of varicocele

This section contains several recommendations related to the management of varicocele regarding treatment, treatment modalities or approaches that should be read together.

Recommendation

For males with infertility and clinical varicocele, WHO suggests surgical or radiological treatment over expectant management. (Conditional

recommendation, low certainty of evidence)

Remarks:

• Males with clinical varicocele and semen parameters outside the WHO reference

ranges are more likely to benefit from receiving treatment for varicocele,

compared to men with semen parameters within the WHO reference ranges.

• This recommendation applies to males with clinical varicocele in couples

with infertility who are not undergoing treatment with assisted reproductive technology (ART).

Background and rationale

Varicoceles are vascular lesions resulting from the dilation and distention of the internal spermatic

vein and pampiniform plexus within the spermatic cord in the scrotum. While most varicoceles

are left-sided, they may occur on the right or

bilaterally (1) and they are a common finding among men being evaluated for infertility. In a large WHO multi-country study involving 8500 couples in

25 countries, varicocele constituted 13.1% of male

infertility cases (2). In the same study, varicocele

was found in 25.4% of male partners with abnormal semen parameters, compared with 11.7% of male

partners with normal semen parameters (3). While varicoceles occur more frequently in infertile

compared to fertile men, not all men with a

varicocele have infertility (4).

Common symptoms of varicoceles include pain or

discomfort. Varicoceles may also have negative (5, 6) and possibly progressive effects (7) on semen

parameters and sperm function (8). The exact

mechanisms according to which varicoceles cause negative effect on spermatogenesis are unknown; however, testicular temperature elevation, venous

reflux and oxidative stress are hypothesized to

have important roles (9). Others include reflux of

renal and adrenal products, hormonal dysfunction, autoimmunity, apoptosis, hypoxia, genetics,

defects in acrosome reaction and DNA damage,

among others (9–13). Despite ongoing research,

the pathophysiological mechanisms through

which varicoceles impair testicular function

remain inconclusive; many of these factors may

act in concert.

A varicocele may be clinical or subclinical.

A subclinical varicocele is not palpable (nor visible) on scrotal examination; it requires additional

diagnostic aids to detect. A clinical varicocele is

palpable and is diagnosed by physical examination through palpation before and during a Valsalva

manoeuvre with the patient in a standing position at room temperature. Clinical varicoceles are

further graded as follows:

• grade I: palpable during a Valsalva

manoeuvre only;

• grade II: palpable but not visible;

• grade III: palpable and visible.

Evidence showed that treatment of varicocele may result in a moderate increase in clinical pregnancies among men with semen parameters outside the WHO reference ranges (RR: 1.94; 95% CI: 1.23-3.05).

However, the effect was uncertain among men with subclinical varicocele and semen parameters within the normal range (RR: 1.09; 95% CI: 0.55-2.26).

Live births were not reported in the studies. In absence of data on live births, clinical pregnancies were assessed. The GDG noted that the effect of treatment on live births would be expected to be less than the effect on pregnancies; the certainty of evidence from this review was judged to be low.

In terms of undesirable effects, in the studies in the review by Persad et al. (21) comparing surgical treatments to each other and to radiological treatments (to each other), the incidence of varicocele recurrence was between 3% and 20%.

Pain with surgery was approximately 2-20%, testicular atrophy with surgery 0-4%, hydrocele formation with surgery 5-10%, and wound infection approximately 4%. The GDG judged these to be small harms. The GDG agreed that certainty of evidence is low for men with clinical varicocele with semen parameters outside the WHO reference range and very low for men with clinical varicocele with semen parameters within the WHO reference range; overall, the overall certainty of evidence was judged to be very low.

Limited data were identified related to patient values on treatment or expectant management.

Nevertheless, the GDG judged that patients would likely value pregnancies and live births, and would

References

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9 Treatment of infertility due to male factors

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

seek to minimize adverse events; probably, no

important variability exists in how people value

these outcomes. Given that more value is placed on

the potential for small benefits and less on adverse

events, treatment is probably favoured in men with clinical varicocele with semen parameters outside the normal range. For men with clinical varicocele with semen parameters within the normal range, treatment is probably not favoured.

Other considerations

Limited data exist concerning the acceptability and

feasibility of surgical or radiological treatment of varicocele. However, the GDG judged that surgery

would probably be acceptable to men to improve fertility. In addition, the GDG judged that it is

probably feasible to provide varicocele treatment. However, training and expertise is required to

ensure safety and minimize complications. Based

on data from studies in Kuwait (36), China (37) and

Canada (38), the GDG judged that surgery involves

moderate costs compared to no treatment. However, a variation in costs to individuals and health systems may exist from country to country. Subsequently,

the GDG judged that equity may be reduced with

treatment if some populations are unable to access it, especially in settings without public financing or

insurance cover for infertility treatment.

Summary justification

Treatment of varicocele may have a small desirable effect by increasing clinical pregnancies, and a small undesirable effect resulting from complications of

surgical or radiological procedures (very low certainty of evidence). Given the higher value that people ascribe to pregnancy compared to the undesirable

effects, the balance of effects favours the intervention. Treatment may incur

moderate costs and probably reduce equity if some populations cannot access it; however, it is probably acceptable and probably feasible.

Implementation considerations

This recommendation focuses on treatment of varicocele to improve current fertility

among adult males with infertility and clinical

varicocele who are not undergoing ART. Treatment of varicocele to improve other outcomes (e.g. to

relieve pain or to prevent future reproductive

problems) is beyond the scope of this

recommendation.

For optimal benefit, varicocele treatment is

suggested for men with infertility intending to conceive if they have (i) a clinical varicocele and (ii) semen parameters that are outside the WHO

reference range. In addition, patients should be

clearly informed that the impact on live births is

unknown. In implementing this recommendation, health care providers should note that it is likely to involve moderate costs and potential exposure to

harms associated with surgery or radiological

treatments. Results of semen analysis based on the procedures outlined in the WHO manual for the

examination and processing of human semen (39)

should be used to identify men who are likely to

benefit from the intervention. After treatment,

patients should be monitored for potential

complications, such as hydrocele, recurrence and ultimately improvement in fertility status.

Research gaps and future guideline update

Current evidence is of very low quality. Large, randomized studies are required to provide

high-quality evidence. In addition, future studies should include live births as an outcome. The

overall impact of the grade of a clinical varicocele (i.e. grade I, II or III) on treatment outcome could not be determined from the current evidence.

Future studies should be designed to identify

Abstract

Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps which grades of a clinical varicocele may optimally benefit from treatment, including one-sided versus bilateral varicocele. Further research is needed on the pathophysiological mechanisms and potential new therapies. Future guidance is required in relation to treatment options among infertile men with clinical varicocele who do not respond to surgical or radiological therapy. The evidence reviewed in this recommendation relates to men with clinical varicocele in couples with infertility who are not undergoing ART. Future guidance is required in relation to the role of treatment of varicocele before ART.

References

Abstract

Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps 15. Diegidio P, Jhaveri JK, Ghannam S, Pinkhasov R, Shabsigh R, Fisch H. Review of current varicocelectomy techniques and their outcomes.

References

Guideline for the prevention, diagnosis and treatment of infertility

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

31. Ghanaie MM, Asgari SA, Dadrass N, Allahkhah

A, Iran-Pour E, Safarinejad MR. Effects of

varicocele repair on spontaneous first trimester miscarriage: a randomized clinical trial. Urol J.

2012;9(2):505-13.

32. Yamamoto M, Hibi H, Hirata Y, Miyake K, Ishigaki T. Effect of varicocelectomy on sperm parameters

and pregnancy rate in patients with subclinical

varicocele: a randomized prospective controlled

study. J Urol. 1996;155(5):1636-8.

33. Unal D, Yeni E, Verit A, Karatas OF. Clomiphene

citrate versus varicocelectomy in treatment of

subclinical varicocele: a prospective randomized

study. Int J Urol. 2001;8(5):227-30 (https://doi.

org/10.1046/j.1442-2042.2001.00289.x).

34. Bo J, Wang Y, Qian X, Han Y, Liu D, Len J.

Controlled trial of high spermatic vein ligation for varicocele in infertile men. Chin J Androl. 1996;10:141-5.

35. Breznik R, Vlaisavuevic V, Borko E. Treatment

of varicocele and male fertility. Arch Androl. 1993;30(3):157-60 (https://doi.

org/10.3109/01485019308987750).

36. Alkandari MH, Al-Hunayan A. Varicocelectomy:

modified loupe-assisted versus microscopic

technique – a prospective comparative

study. Arab J Urol. 2017;15(1):74-7 (https://doi.

org/10.1016/j.aju.2016.12.002).

37. Liu S, Hu C, Jiang N, Wang G. Laparoscopic

versus open inguinal spermatic vessel ligation in infertile men with varicocele. Biomed Res. 2018;29(7):1389-93 (https://doi.org/10.4066/biomedicalresearch.29-17-1789).

38. Kovac JR, Fantus J, Lipshultz LI, Fischer MA, Klinghoffer Z. Cost-effectiveness analysis

reveals microsurgical varicocele repair is

superior to percutaneous embolization in the

treatment of male infertility. Can Urol Assoc J.

2014;8(9-10):E619-E265 (https://doi.org/10.5489/cuaj.1873).

39. WHO laboratory manual for the examination

and processing of human semen, sixth edition.

Geneva: World Health Organization; 2021

(https://iris.who.int/handle/10665/343208).

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9 Treatment of infertility due to male factors

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Recommendation

For males with infertility undergoing treatment of varicocele, WHO suggests using either surgical or radiological treatment. (Conditional recommendation, very low certainty of evidence)

Remarks:

• When selecting whether to use surgical or radiological treatment, consider

feasibility, the availability of trained health care providers and patient

preferences regarding the type of treatment procedure.

• This recommendation applies to males with varicocele in couples with infertility

who are not undergoing treatment with assisted reproductive technology (ART).

Background and rationale

This guideline suggests surgical or radiological

treatment over expectant management of clinical varicocele in men with infertility, with certainty

of evidence that is low (see previous sections of this chapter).

Once a decision to treat clinical varicocele has

been arrived at, options for treatment include

surgical repair or radiological treatment. Surgical treatment involves varicocelectomy, conducted

via retroperitoneal or conventional inguinal open techniques, microsurgical inguinal or subinguinal approaches, or laparoscopic repairs (1–3).

Radiological treatment involves varicocele

embolization or sclerotherapy. Embolization

involves blocking one or more blood vessels

or abnormal vascular channels using a coil or a

balloon, while sclerotherapy involves injecting a

sclerosing agent into the spermatic vein, resulting in shrinkage and lumen occlusion (4).

Surgical repair of varicoceles is widely practised

using different techniques; however, it may be

complicated by varicocele persistence, recurrence or injury to surrounding tissue; depending on the procedure, it may also require general anaesthesia or a longer time to operate (2, 5).

Radiological treatments may be complicated

by failure, recurrence, thrombosis, scrotal

subcutaneous emphysema, injury to blood

vessels, haemorrhage, epididymitis, scrotal pain

and allergic reaction to contrast agents (5, 6).

However, radiological treatments are generally

less invasive than most surgical treatments, may

be performed under local anaesthesia (7), and

patients often require a shorter time to recover (8).

As embolization is intravascular, it may minimize the

risks of injury to adjacent vessels and lymphatics.

Given the potential advantages and disadvantages of surgical and radiological treatments (6), the GDG agreed that there is need for guidance on which

treatment modality between the two is preferred. Therefore, for this recommendation, the GDG

addressed the question: should surgical versus

radiological treatment be used for men with clinical

varicocele in couples with infertility? It does not

assess the use of these treatments before or in combination with ART.

Balancing desirable and undesirable effects

Evidence from a recent systematic review of

RCTs was included (9). The search date was up to

April 2020. The review pooled together studies

comparing surgical versus radiological procedures. From that review, only studies in men with

confirmed clinical varicocele were included (10–15). Importantly, all included studies directly comparing surgical versus radiological procedures concern

the use of non-microsurgical techniques (high or

inguinal open methods).

Results showed that compared to radiological

treatments, surgery may result in 54 more live

Guideline for the prevention, diagnosis and treatment of infertility

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

births (from 37 fewer to 261 more,) per 1000

(RR: 1.49; 95% CI: 0.66–3.37), and likely 28 more

pregnancies (from 60 fewer to 155 more) per 1000

(RR: 1.11; 95% CI: 0.76–1.62). The GDG judged these desirable effects of surgical repair to be trivial

compared to radiological treatment.

In terms of undesirable effects, data showed

that surgery may result in 35 more varicocele recurrences or persistence (from 29 fewer to

137 more) per 1000 (RR: 1.25; 95% CI: 0.79–1.98),

and 11 fewer complications, such as extravasation, wound infection and hydrocele formation, (from

56 fewer to 68 more) per 1000 (RR: 0.91; 95%

CI: 0.53–1.57), when compared to radiological treatments. The GDG judged the magnitude of

these differences to be trivial. The GDG agreed

that couples would likely value pregnancies and

live births and would want to minimize adverse

events, and judged that there was probably no

important uncertainty or variability in how much

people valued these outcomes. The GDG concluded

that the balance of effects probably does not

favour either surgery or radiological treatment.

The overall certainty of evidence for the effects was

very low, primarily because the studies compared non-microscopic surgical methods with radiological treatment, which was considered indirect evidence

of the effect of surgery. Studies comparing

microsurgical varicocele repair with radiological

treatment were lacking. In addition, there were few participants and events in the analyses. Despite the

evidence being indirect regarding the overall effects

of all surgical procedures (i.e. both microsurgical

and non-microsurgical methods [retroperitoneal or inguinal vein ligation]), it was still used to inform the

recommendation.

Other considerations

Both surgical and radiological treatments involve costs. A Canadian simulation study (16) showed

that embolization may be less cost-effective than

surgery. However, the GDG considered that given

that there are trivial differences in benefits or harms and negligible cost differences, both may have

similar cost-effectiveness. The GDG also considered

that costs and insurance coverage between surgery and radiological treatment may vary from country to country and that equity may be reduced if

some populations are unable to access treatment, especially in those countries and settings with

limited public financing of insurance for infertility

treatments.

No data were found comparing acceptability

between surgery and embolization. However, in

the absence of data, the GDG judged that both

surgical and radiological treatments are probably acceptable. In terms of feasibility, the GDG agreed that both procedures are feasible in most settings. However, training is required to assure safety and

minimize complications. However, availability of

trained surgeons and interventional radiologists

may vary, especially in LMICs.

Summary justification

Overall, there is very-low-certainty evidence that there are trivial differences between surgical and radiological treatments in terms of benefits, harms and costs. Studies comparing microsurgical varicocele repair with radiological

treatment were scarce, thus contributing to the GDG’s assessment that the

evidence was indirect. Compared to each other, both treatments are probably feasible, acceptable and have little difference in impact on equity.

9 Treatment of infertility due to male factors Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Implementation considerations

This recommendation focuses on the treatment of clinical varicocele to improve fertility in men with infertility who are not undergoing ART. This recommendation does not address the role of varicocele treatment before ART.

References

Guideline for the prevention, diagnosis and treatment of infertility

172

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

10. Fayez A, El Shantaly K, Abbas M, Hauser S, Müller S, Fathy A. Comparison of inguinal

approach, scrotal sclerotherapy and

subinguinal antegrade sclerotherapy in

varicocele treatment: a randomized prospective

study. Urol Int. 2010;85(2):200-3 (https://doi.

org/10.1159/000316338).

11. Nieschlag E, Behre H, Schlingheider A,

Nashan D, Pohl J, Fischedick A. Surgical ligation

vs. angiographic embolization of the vena

spermatica: a prospective randomized study for the treatment of varicocele‐related infertility.

Andrologia. 1993;25(5):233-7 (https://doi.

org/10.1111/j.1439-0272.1993.tb02716.x).

12. Yavetz H, Levy R, Papo J, Yogev L, Paz G, Jaffa A et al. Efficacy of varicocele embolization

versus ligation of the left internal spermatic vein for improvement of sperm quality. Int J Androl. 1992;15(4):338-44 (https://www.doi.

org/10.1111/j.1365-2605.1992.tb01133.x).

13. Sayfan J, Soffer Y, Orda R. Varicocele treatment: prospective randomized trial of 3 methods. J

Urol. 1992;148(5):1447-9 (https://doi.org/10.1016/s0022-5347(17)36934-3).

14. Nieschlag E, Hertle L, Fischedick A, Abshagen K,

Behre H. Update on treatment of varicocele:

counselling as effective as occlusion of the vena

spermatica. Hum Reprod. 1998;13(8):2147-50 (https://doi.org/10.1093/humrep/13.8.2147).

15. Nieschlag E, Hertle L, Fischedick A, Behre H.

Treatment of varicocele: counselling as

effective as occlusion of the vena spermatica.

Hum Reprod. 1995;10(2):347-53 (https://doi.

org/10.1093/oxfordjournals.humrep.a135941).

16. Kovac JR, Fantus J, Lipshultz LI, Fischer MA, Klinghoffer Z. Cost-effectiveness analysis

reveals microsurgical varicocele repair is

superior to percutaneous embolization in the

treatment of male infertility. Can Urol Assoc J.

2014;8(9–10):E619-E625 (https://doi.org/10.5489/cuaj.1873).

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Recommendation

For males with infertility undergoing surgical treatment of varicocele, WHO suggests using microscopic surgery rather than other surgical procedures.

(Conditional recommendation, very low certainty of evidence)

Remarks:

• Subinguinal microsurgery is a common surgical varicocelectomy procedure,

while other surgical procedures include non-microscopic open approaches

(such as inguinal and retroperitoneal) and laparoscopic methods.

• In settings where the expertise to perform microscopic surgery is not available,

other surgical techniques may be used.

• This recommendation applies to males with varicocele in couples with infertility

who are not undergoing treatment with assisted reproductive technology (ART).

Background and rationale

This guideline suggests the use of either surgical

or radiological treatment of varicocele in men with infertility, with certainty of evidence that is low (see previous sections). If surgical methods are selected, further decisions would be needed to choose which surgical methods would be used to treat clinical

varicocele.

Options for surgical varicocelectomy include

retroperitoneal or conventional inguinal open

techniques, microsurgical inguinal or subinguinal

approaches, or laparoscopic repair (1–4). Surgical

repair of varicocele using different techniques

may be complicated by varicocele persistence,

recurrence or injury to surrounding tissue;

depending on the procedure, general anaesthesia or longer time to operate may be required (2, 5).

Postoperative hydrocele formation is a frequent

complication of varicocelectomy resulting from

the disruption of lymphatic vessels. Different

techniques have been developed in an attempt to

minimize such complications, for example, to reduce

recurrence rates, which may be more common with some surgical approaches (6, 7).

Microscopic varicocelectomy is typically performed using a subinguinal approach, which involves

making a 2–3-cm transverse skin incision centred

over the external inguinal ring to approach the

spermatic cord, with the aid of an operating

microscope, after which the spermatic veins are

ligated while preserving the testicular arteries and lymphatics. Microscopic inguinal varicocelectomy is less common and involves making an incision in a way that provides access to the ilioinguinal nerves, applying similar procedural principles of ligating

the spermatic veins while preserving the testicular arteries and lymphatics.

For this recommendation, the GDG addressed

the question: should microscopic varicocelectomy versus other non-microscopic surgical

varicocelectomy techniques be used for men with

clinical varicocele in couples with infertility? This

question was identified by the GDG as a priority and

is provided in the context of the recommendation related to the treatment of clinical varicocele in men with infertility. It does not assess the use of surgical treatment before or in combination with ART.

Balancing desirable and undesirable effects

A systematic review (8) reported the effects of

surgical and radiological treatment of varicoceles in subfertile men. We used the data from studies that included men with clinical varicocele as reported by the authors of the original studies.

Sixteen studies that compared microscopic surgical treatment to other surgery were included (9–24).

Subinguinal microsurgery was the most common

surgical varicocelectomy procedure assessed in the

Guideline for the prevention, diagnosis and treatment of infertility

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studies. Results showed that there is likely a small

increase in pregnancies with microscopic subinguinal

surgery (60 more [from 3 to 126 more] per 1000; RR: 1.20; 95% CI: 1.01–1.42) when compared to

other surgical approaches. Data on live births and quality of life were not reported. In relation to

undesirable effects, microscopic surgery may slightly reduce varicocele recurrence, but the effects on

other adverse events, such as hydrocele formation, testicular atrophy, wound infection and haematoma, are very uncertain and not consistently less. Most

studies did not report on the randomization or

allocation method and had incomplete follow-up; there were few participants or events related to

adverse effects. Because of the uncertainty of the

evidence for adverse events, the overall certainty of evidence is rated very low. Although no data on patient values were available, the GDG agreed that most patients valued pregnancy and live births,

while seeking to minimize harms. Therefore, based

on the likely small increase in pregnancies and

decrease in varicocele recurrence, the GDG agreed

that microscopic treatment is probably favoured over other treatments.

Other considerations

Based on data from studies (25, 26), the GDG agreed that microscopic surgery may cost slightly more

than most non-microscopic surgical approaches (and may vary across countries) and that training may be required; however, these additional costs were considered negligible because most other surgical procedures involve large costs.

Although a modelling study (25) suggested that

microscopic surgery is more cost-effective than

non-microscopic surgery, the pregnancy estimates in the model were much higher than reported in

the systematic review of RCTs by Persad et al. (8).

Given the trivial differences in benefits and harms

from the systematic review, and the negligible

cost differences between microscopic and other

procedures in most countries, the GDG judged that

cost-effectiveness did not favour either microscopic

or other surgical procedures.

The GDG judged that microscopic surgical

procedures are probably feasible to provide but may require expertise, equipment or training to perform safely. As surgical procedures are likely available and involve similar large costs, there is probably no impact on equity. In addition,

although there were no data regarding patient preferences for any of the procedures, the GDG agreed that microscopic surgery is probably

acceptable to patients.

Summary justification

There is likely a small increase in pregnancies and trivial decrease in varicocele

recurrence with microscopic surgery, but there is no or uncertain evidence for other benefits or harms. Performing microscopic surgery is probably feasible; it requires greater expertise and it may incur negligible additional costs. Microscopic surgery is probably acceptable; given the negligible cost differences between microsurgical and other surgical procedures, there would probably be no impact on equity.

Implementation considerations

When implementing these

recommendations, health care providers

should monitor patients for complications to ensure safety. To ensure good-quality outcomes from

microscopic surgery, expertise and training may be required. In low-resource and other settings where the expertise to perform microscopic surgery is not available, other surgical techniques may be

considered, bearing in mind patients’ preferences.

Abstract

Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps Research gaps and future guideline update Future studies should include live births and quality of life as outcomes, and patient preferences, and should also endeavour to report adverse events alongside desirable outcomes. Blinding of outcome assessors in future studies would be important. Future guidance is needed on the effects of microsurgical versus other treatment modalities in subgroups of patients with recurrent clinical varicoceles.

References

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Recommendation

Remarks:

• When selecting whether to use an inguinal or retroperitoneal surgical

procedure, consider feasibility and the availability of trained health

care providers.

• This recommendation applies to males with varicocele in couples with

infertility who are not undergoing treatment with assisted reproductive

technology (ART).

Background and rationale

Once a decision to treat clinical varicocele has

been arrived at, options for treatment include

surgical repair or radiological treatment. Options

for surgical varicocelectomy include retroperitoneal or conventional inguinal open techniques,

microsurgical inguinal or subinguinal approaches, or laparoscopic repair (1–3).

Surgical repair of varicocele using different

techniques may be complicated by varicocele recurrence or injury to surrounding tissue;

depending on the specific procedure, it may require

general anaesthesia, microsurgical expertise

or longer operative time (2, 4). Postoperative

hydrocele formation is a frequent complication of varicocelectomy resulting from the disruption

of lymphatic vessels. Different techniques have been developed in an attempt to minimize such

complications and to reduce recurrence rates,

which may be more common with some surgical

approaches (5, 6).

This guideline suggests surgical or radiological

treatment over expectant management of clinical varicocele in men with infertility, with certainty of

evidence that is low. In addition, this WHO infertility guideline suggests microsurgical subinguinal

varicocele repair over other surgical procedures

to treat clinical varicocele in men in couples with

infertility (see previous sections). In settings where the expertise to perform microsurgical subinguinal

varicocele repair is unavailable, other surgical

techniques may be considered. Such options

include inguinal or retroperitoneal procedures.

Inguinal varicocelectomy involves an incision over the inguinal canal, starting at the external inguinal ring and extending 3–4 cm laterally parallel to the

inguinal ligament, which allows the identification of

the spermatic cord and exposure of the enlarged pampiniform veins for ligation (7). This is an open surgical procedure, typically performed without a

microscope. The conventional non‐magnified open

inguinal varicocelectomy is also referred to as the Ivanissevich technique (8).

Retroperitoneal varicocelectomy, also referred to as suprainguinal, Palomo, high-ligation, highest entry point or abdominal varicocelectomy, is an open varicocelectomy procedure that involves a medial inferior incision to the ipsilateral anterior superior iliac spine through the external and

internal oblique fascia to access and ligate the

internal spermatic vein (9, 10).

For this recommendation, the GDG addressed

the question: should surgical treatment of clinical varicoceles be performed using conventional

non‐magnified open inguinal techniques

(Ivanissevich technique) versus a retroperitoneal

surgical technique? This recommendation does not

assess the use of surgical treatment before or in combination with ART.

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Balancing desirable and undesirable effects

We used the data from a systematic review (9) that

addressed the effects of surgical and radiological

treatment for clinical varicoceles in subfertile

men. We used data from studies that compared

inguinal to retroperitoneal surgery among men

with clinical varicoceles only (11–21). Results showed

that there may be no difference in the number of pregnancies with either procedure. There were five

more pregnancies (46 fewer to 70 more) per 1000

(RR: 1.02; 95% CI: 0.82–1.27) with inguinal surgery

compared to retroperitoneal surgery. There were no data for live births or quality of life. In terms

of undesirable effects, the evidence showed that there may be no difference with the inguinal

approach in varicocele recurrence compared to

the retroperitoneal approach (three more [from 64 fewer to 164 more] per 1000; RR: 1.03; 95%

CI: 0.43–2.46) or hydrocele formation (two more

[from 45 fewer to 161 more] per 1000; RR: 1.03; 95% CI: 0.31–3.47). Evidence is also uncertain for

other adverse events, including testicular atrophy, haematoma and wound infection. In addition,

most studies did not report the randomization or

allocation method and had incomplete follow-up; there were also few participants or events related

to desirable and undesirable effects. Given these

limitations, the overall certainty of evidence was

very low. The GDG agreed that individuals with infertility place greater value on live births and pregnancies and would likely avoid harms. Since

there were trivial differences in desirable effects

and harms, and the evidence is very uncertain for other adverse events, the GDG agreed that one

procedure is probably not favoured over the other.

Other considerations

The GDG agreed that there would likely be a

negligible difference in the costs between the

two techniques. Evidence is uncertain for no

differences in benefits and harms between the two procedures; cost differences are probably

negligible. Therefore, the GDG agreed that

cost-effectiveness does not favour either

procedure. The GDG judged that both inguinal and retroperitoneal approaches are similarly available and are likely to involve similar costs; therefore, there would be no impact on equity if either is recommended over the other. No

evidence on acceptability was identified. However,

the GDG agreed that either procedure is probably

acceptable to patients. No specific evidence was

available on feasibility. However, the GDG judged that both procedures would be probably feasible given that training, equipment and time required for surgery are probably similar.

Summary justification

There may be little difference in pregnancies, varicocele recurrence or hydrocele formation with either procedure, and the evidence is uncertain for other harms. Performing either procedure would likely result in similar costs and likely be

similarly acceptable and feasible, and would probably have no impact on equity.

Implementation considerations

Health care providers should monitor

patients for complications. To ensure the safety of procedures, training of health care

providers may be required.

Research gaps and future guideline update

Future studies should comprehensively report

live births, quality of life, patient preferences and adverse events. Future studies should assess

whether either procedure evaluated separately

improves these outcomes, compared to no

treatment. Blinding of outcome assessors in such future studies would be important.

9 Treatment of infertility due to male factors Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

References

Guideline for the prevention, diagnosis and treatment of infertility

180

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

17. Su H, Li T, Fan Y, Li X, Zhao G, Zhang H. The effect

of four surgical approaches on the semen quality and pregnancy rate in patients with subclinical

varicocele [Bùtóng shǒushù fāngshì duì jīng suǒ jìngmài qūzhāng huànzhě jīngyè zhìliàng hé

pèi'ǒu shòuyùn lǜ yǐngxiǎngvolume_up]. Hebei

Med Univ J. 2017;23(3):380-4.

18. Sun HB, Liu Y, Yan MB, Li ZD, Gui XG. Comparing three different surgical techniques used in

adult bilateral varicocele. Asian J Endosc Surg. 2012;5(1):12-6 (https://doi.org/10.1111/j.1758-5910.2011.00109.x).

19. Telkar S, Goudar BV, Lamani YP, Ambi U, Koppal R. Laparoscopic versus open varicocelectomy

a prospective study. J Clin Diagn Res.

2012;6(2):271‐3.

20. Al-Kandari AM, Shabaan H, Ibrahim HM,

Elshebiny YH, Shokeir AA. Comparison of

outcomes of different varicocelectomy

techniques: open inguinal, laparoscopic, and subinguinal microscopic varicocelectomy: a

randomized clinical trial. Urology. 2007;69(3):417-

20 (https://doi.org/10.1016/j.urology.2007.01.057).

21. Al-Said S, Al-Naimi A, Al-Ansari A, Younis N,

Shamsodini A, A-sadiq K et al. Varicocelectomy

for male infertility: a comparative study of open, laparoscopic and microsurgical approaches.

J Urol. 2008;180(1):266-70 (https://doi.

org/10.1016/j.juro.2008.03.050).

181

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10 Treatment of couples with unexplained infertility

This section contains recommendations related to the management of unexplained

infertility. Figure 10.1 shows how these recommendations relate to each other, illustrated in a diagnostic algorithm. Specific recommendations are presented in the sections that follow.

10.1 First-line management of couples with unexplained infertility

Recommendation

For couples with unexplained infertility, WHO suggests expectant

management rather than unstimulated intrauterine insemination (U-IUI).

(Conditional recommendation, low certainty of evidence)

Remarks:

• Expectant management refers to monitoring the couple with the expectation

that pregnancy will be achieved without medical intervention. It includes

providing advice on lifestyle and the most fertile days of the menstrual cycle, and

monitoring if pregnancy will occur; however, no medical intervention is provided.

• The duration of expectant management was typically 3–6 months in studies

informing this recommendation.

Background and rationale

Unexplained infertility is diagnosed when there

is failure to achieve pregnancy after 12 months

of regular unprotected intercourse, and when

investigations fail to identify a cause in either the

female or male partner (such as tubal disease or

uterine cavity abnormalities, ovulation dysfunction in the female partner, or semen parameters that

are outside the WHO reference ranges in the

male partner) (see section 5.8 for the criteria

for diagnosis of unexplained infertility). For this

recommendation, the GDG addressed the question: should U-IUI versus expectant management be

used for couples with unexplained infertility? This was assessed in the context of first-line

management of unexplained infertility.

Expectant management refers to monitoring the

couple with the expectation that pregnancy will

be achieved without medical intervention. While

the likelihood of spontaneous (i.e. unassisted)

pregnancy without medical intervention among

couples with unexplained infertility varies from

study to study (1–6), it is typically greater than zero

but less than that of fertile couples (5). Therefore,

expectant management could reduce overtreatment

(7) as some couples with infertility may conceive

during expectant management (8–10). Based on

this possibility for spontaneous (i.e. unassisted)

pregnancy, couples with unexplained infertility

are advised on lifestyle, provided information

regarding their most fertile days and monitored if

they will become pregnant, but are not provided any treatment (see Fig. 10.1 for the treatment algorithm for unexplained infertility).

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Fig. 10.1. Treatment algorithm for unexplained infertility

Alternative: gonadotrophinsg

First-line

medical

treatment

Second-line medical

treatment

Third-line medical

treatment

1 2

Unexplained infertility

Expectant

management c,d

S-IUIe

Clomiphene citrate OR

letrozole,f with monitoring. Adjust dose as required.

IVF without ICSI

Provide clinical

follow-up; document pregnancy outcomes

Provide clinical

follow-up; document pregnancy outcomes

Provide clinical

follow-up; document pregnancy outcomes

Further advanced evaluation and managementh

Yes

Yes OR

No No

Pregnancy detected?

See Section 5.8 for diagnosisa,b

a Infertility is defined as failure to achieve pregnancy after 12 months or more of regular unprotected sexual intercourse.

b Criteria for the diagnosis of unexplained infertility:

• failure to achieve pregnancy after 12 months of regular unprotected sexual intercourse;

• normal physical examination and medical history in both the male and female;

• presumptive confirmation of ovulation and patent tubes in the female partner; and

• semen parameters that are within the WHO reference ranges in the male partner.

c Expectant management refers to monitoring the couple with the expectation that pregnancy will be achieved without medical

intervention. It includes providing advice on lifestyle and the most fertile days of the menstrual cycle, and monitoring if pregnancy

will occur; however, no medical intervention is provided.

d The duration of expectant management was typically 3–6 months in studies informing this recommendation.

e The optimal number of S-IUI cycles is unknown; in the studies used to inform this recommendation, different numbers of cycles

were provided, ranging from one to six, with more recent studies providing three to six cycles.

f If off-label use of letrozole is allowed.

g If capacity for side-effect management exists.

h Individualized approach or under research conditions.

ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization; S-IUI, stimulated intrauterine insemination.

IUI is a fertility treatment that places processed sperm directly into the uterus at the time of ovulation. In IUI, the male partner's semen is processed using established standards (10) and the sperm placed into the uterus with a suitable transcervical catheter around the time of ovulation.

Balancing harms and benefits

A systematic review with network meta-analysis by Wang et al. (12) provided evidence for expectant management versus U-IUI. We also extracted results from pairwise meta-analyses and examined the primary studies included in the review for additional outcomes.

The evidence showed that the benefits of U-IUI are likely trivial when compared to expectant management, with only 28 more live births (from 58 fewer to 160 more) per 1000 (OR: 1.21; 95% CI: 0.61-2.43) and 26 more clinical pregnancies (from 55 fewer to 148 more) per 1000 women treated (OR: 1.20; 95% CI: 0.61-2.36). In the studies where desirable outcomes were observed, clinical pregnancies occurred within 3-6 months' duration.

The differences in undesirable effects are also trivial between U-IUI and expectant management. The GDG considered that people with unexplained infertility highly value live births and do not desire negative outcomes, and that these values are unlikely to vary among different groups. Given the trivial benefits and trivial harms, the GDG judged that the balance of effects probably does not favour either U-IUI or expectant management.

Other considerations

The GDG considered evidence from two studies (4, 13) showing that U-IUI requires personnel, laboratory equipment, materials, medication and overhead costs, and judged that the procedure is associated with moderate costs compared to expectant management. The GDG judged that U-IUI is probably feasible and noted that although the U-IUI technique itself is not complex, training is still needed to perform it correctly and ensure optimal timing of the insemination. The GDG considered evidence from one study (14) showing that U-IUI was acceptable to most women if it increases the chances of pregnancy; however, data showed that it has minimal benefits compared to expectant management. Because of the costs involved, U-IUI may result in decreased equity compared to expectant management, especially in settings where fertility treatment is not publicly funded.

Given that U-IUI involves costs and yet it has trivial benefits, the GDG concluded that cost-effectiveness probably favours expectant management.

References

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Summary justification

U-IUI may have trivial benefits on live births and pregnancies compared to

expectant management and trivial differences in adverse events. Although U-IUI is probably acceptable and feasible, it is not cost-effective and may reduce equity compared to expectant management. Therefore, expectant management was

suggested rather than U-IUI.

Implementation considerations

Couples with unexplained infertility should

be informed of the rationale and success rate with expectant management, noting that age and

ovarian reserve may have an impact on the

outcomes of expectant management. Unstimulated IUI is no better than expectant management and is not recommended. Health care providers should

inform couples regarding the duration of expectant management, and counsel them regarding the

possibility of offering second-line treatments if

expectant management is not successful. Adequate counselling and education regarding expectant

management and its duration is essential given that some couples with unexplained infertility may have

low confidence with spontaneous (i.e. unassisted)

pregnancy (15).

Research gaps and future guideline update

Future guidance will require availability of sufficient

data from studies to perform subgroup analyses for prognostic factors, such as age, duration of

unexplained infertility and ovarian reserve, among others, for example, using prognostic models or

other approaches.

References

1. Collins JA, Burrows EA, Willan AR. The prognosis for live birth among untreated infertile couples. Fertil Steril. 1995;64(1):22-8 (https://doi.

org/10.1016/S0015-0282(16)57650-X).

2. Steures P, van der Steeg JW, Hompes PGA,

Habbema JDF, Eijkemans MJC, Broekmans FJ et al. Intrauterine insemination with controlled ovarian hyperstimulation versus expectant management for couples with unexplained subfertility and an intermediate prognosis: a randomised clinical

trial. Lancet. 2006;368(9531):216-21 (https://doi.

org/10.1016/S0140-6736(06)69042-9).

3. Farquhar CM, Liu E, Armstrong S, Arroll N,

Lensen S, Brown J. Intrauterine insemination

with ovarian stimulation versus expectant

management for unexplained infertility (TUI): a pragmatic, open-label, randomised, controlled, two-centre trial. Lancet. 2018;391(10119):441-50 (https://doi.org/10.1016/S0140-6736(17)32406-6).

4. Wordsworth S, Buchanan J, Mollison J, Harrild K, Robertson L, Tay C et al. Clomifene citrate and

intrauterine insemination as first-line treatments for unexplained infertility: are they cost-effective?

Hum Reprod. 2010;26(2):369-75 (https://doi.

org/10.1093/humrep/deq315).

5. Guzick D, Sullivan M, Adamson GD, Cedars M, Falk R, Peterson E et al. Efficacy of treatment

for unexplained infertility. Fertil Steril.

1998;70(2):207-13 (https://doi.org/10.1016/S0015-0282(98)00177-0).

6. McLernon DJ, Lee AJ, Maheshwari A,

van Eekelen R, van Geloven N, Putter H et al. Predicting the chances of having a baby

with or without treatment at different time

points in couples with unexplained subfertility. Hum Reprod. 2019;34(6):1126-38 (https://doi.

org/10.1093/humrep/dez049).

185

10 Treatment of couples with unexplained infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

7. Kersten FA, Hermens RP, Braat DD, Hoek A,

Mol BW, Goddijn M et al. Overtreatment in

couples with unexplained infertility. Hum Reprod. 2015;30(1):71-80 (https://doi.org/10.1093/

humrep/deu262).

8. Evers JL, de Haas HW, Land JA, Dumoulin JC,

Dunselman GA. Treatment-independent

pregnancy rate in patients with severe

reproductive disorders. Hum Reprod.

1998;13(5):1206-9 (https://doi.org/10.1093/

humrep/13.5.1206).

9. Dunson DB, Baird DD, Colombo B. Increased

infertility with age in men and women.

Obstet Gynecol. 2004;103(1):51-6 (https://doi.

org/10.1097/01.AOG.0000100153.24061.45).

10. van der Steeg JW, Steures P, Eijkemans MJ,

Habbema JD, Hompes PG, Broekmans FJ et al. Pregnancy is predictable: a large-scale

prospective external validation of the prediction of spontaneous pregnancy in subfertile couples. Hum Reprod. 2007;22(2):536-42 (https://doi.

org/10.1093/humrep/del378).

11. WHO laboratory manual for the examination

and processing of human semen, sixth edition.

Geneva: World Health Organization; 2021

(https://iris.who.int/handle/10665/343208).

12. Wang R, Danhof NA, Tjon‐Kon‐Fat RI,

Eijkemans MJ, Bossuyt PM, Mochtar MH et al. Interventions for unexplained infertility: a

systematic review and network meta‐analysis.

Cochrane Database Syst Rev. 2019;(9):CD012692 (https://doi.org/10.1002/14651858.CD012692.

pub2).

13. Goverde AJ, McDonnell J, Vermeiden JP,

Schats R, Rutten FF, Schoemaker J. Intrauterine insemination or in-vitro fertilisation in idiopathic subfertility and male subfertility: a randomised

trial and cost-effectiveness analysis. Lancet.

2000;355(9197):13-8 (https://doi.org/10.1016/S0140-6736(99)04002-7).

14. Weiss NS, Schreurs AMF, van der Veen F,

Hompes PGA, Lambalk CB, Mol BW et al.

Women's perspectives on ovulation

induction with or without IUI as treatment for normogonadotrophic anovulation: a discrete choice experiment. Hum Reprod Open.

2017;2017(3):hox021 (https://doi.org/10.1093/hropen/hox021).

15. Dreischor F, Laan ETM, Peeters F, Peeraer K, Lambalk CB, Goddijn M et al. The needs of

subfertile couples continuing to attempt natural conception: in-depth interviews. Hum Reprod

Open. 2022;2022(4):hoac037 (https://doi.

org/10.1093/hropen/hoac037).

Guideline for the prevention, diagnosis and treatment of infertility

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Recommendation

For couples with unexplained infertility, WHO suggests expectant

management rather than ovarian stimulation with timed intercourse.

(Conditional recommendation, low certainty of evidence)

Remarks:

• Expectant management refers to monitoring the couple with the expectation

that pregnancy will be achieved without medical intervention. It includes

providing advice on lifestyle and most fertile days of the menstrual cycle,

and monitoring if pregnancy will occur; however, no medical intervention

is provided.

• The duration of expectant management was typically 3–6 months in studies

informing this recommendation.

Background and rationale

Expectant management refers to monitoring

the couple with the expectation that pregnancy

will be achieved without medical intervention. It

includes providing advice on lifestyle and the most fertile days of the menstrual cycle, and monitoring if pregnancy will occur; however, no medical

intervention is provided (see the previous section

for the rationale for expectant management).

Ovarian Stimulation (OS) refers to the

pharmacological treatment to induce the

development of (typically multiple, and ideally three or fewer) ovarian follicles and hence oocytes available

for fertilization. Commonly used medications for

ovarian stimulation include clomiphene citrate,

letrozole and gonadotrophin modulators (1–4).

Because of their mechanism of action and effects on follicle development, medications used for ovarian stimulation such as clomiphene citrate, letrozole or gonadotrophins may increase the risk of adverse

events, such as multiple pregnancy and OHSS (1, 5) (see Chapter 6.1 for details on the mechanisms of

actions of these medications).

When ovarian stimulation is provided in

combination with timed intercourse, couples with unexplained infertility are prescribed ovarian

stimulation medications and advised to have

sexual intercourse during the fertile period, which is typically a few (≈6) days up to and including the

day of ovulation (6–8). For this recommendation,

the GDG addressed the question: should ovarian

stimulation with timed intercourse versus expectant management be used for couples with unexplained

infertility? It was assessed in the context of first-line

management for unexplained infertility.

Balancing harms and benefits

A systematic review by Wang et al. (9) provided data for this comparison. The review included 13 RCTs

comparing ovarian stimulation using several

medications (e.g. clomiphene citrate, letrozole,

or gonadotrophins) with timed intercourse or

IUI to no treatment. Results comparing ovarian

stimulation with timed intercourse versus expectant management were extracted. Data for additional

relevant outcomes were extracted from the primary studies included in the network meta-analysis.

The analysis reported that although ovarian

stimulation with timed intercourse likely results

in 77 more clinical pregnancies (from 1 fewer to

180 more) per 1000 women treated (OR: 1.64; 95%

CI: 0.99–2.73) and one more live birth (from 74

fewer to 117 more) (OR: 1.01; 95% CI: 0.51–1.98),

when compared to expectant management. In the studies where desirable outcomes were observed,

clinical pregnancies occurred within 3–6 months’

duration. In terms of harms, ovarian stimulation likely results in 12 more multiple pregnancies

(from zero to 48 more) (OR: 3.07; 95% CI: 1.00–9.41),

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10 Treatment of couples with unexplained infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

and may result in 156 more miscarriages (from 190 fewer to 654 more) per 1000 women treated

(OR: 2.08; 95% CI: 0.16–26.37) compared to

expectant management. Slight increases in pain

(205 more [from 75 to 416 more] per 1000; OR:

9.55; 95% CI: 3.66–24.91) and nausea (107 more [from 24 to 287 more] per 1000; OR: 5.92; 95%

CI: 1.99–17.59) may occur, but there may be no

difference in anxiety (OR: 1.09; 95% CI: 0.63–1.87), depression (OR: 0.98; 95% CI: 0.24–3.97) or

hospitalization (OR: 0.95; 95% CI: 0.13–6.84). There

were no data on OHSS. A planned subgroup

analysis according to age was not conducted in the systematic review by Wang et al. (9) because

of lack of sufficient studies reporting outcomes

according to age; only one study reported these

data. The GDG judged that ovarian stimulation with

timed intercourse may result in small benefits and moderate undesirable effects. The GDG also judged

that people with unexplained infertility highly value live births and do not desire negative outcomes,

and that these values are unlikely to vary among

different groups. Therefore, the balance of effects

probably favours expectant management over ovarian stimulation with timed intercourse. The overall certainty of evidence was low.

Other considerations

The GDG judged that although ovarian stimulation with timed intercourse is probably feasible, it

involves moderate resources because of the cost

of medications, ultrasound monitoring or hormone assays (10). The GDG noted that the costs of

stimulating agents vary from country to country,

but are likely higher for gonadotrophins. Although the costs of some medications, such as clomiphene citrate, could be low, overall, ovarian stimulation

would probably reduce equity, especially in settings

where fertility treatments are not publicly financed.

Based on data presented from two studies (11, 12), the GDG judged that the acceptability of ovarian stimulation among patients varies.

Summary justification

Overall, there is low certainty evidence for small desirable effects and moderate

undesirable effects with ovarian stimulation with timed intercourse compared to

expectant management. In addition, ovarian stimulation with timed intercourse

involves moderate costs, which may reduce equity compared to expectant

management, and its acceptability varies. Therefore, the undesirable consequences of ovarian stimulation with timed intercourse probably outweigh the desirable

consequences; therefore, expectant management is suggested.

Implementation considerations

Health care providers implementing

expectant management should counsel

couples on lifestyle and their most fertile days and monitor if they will become pregnant. Health care

providers should inform couples about the duration and potential outcomes of expectant management, and ensure that couples understand the rationale for expectant management. They should also

counsel patients about the possibility of offering

second-line treatments if expectant management is not successful.

Research gaps and future guideline update

Further guidance is needed on whether and how the duration of unexplained infertility, age, ovarian reserve and other prognostic factors can further inform expectant management.

References

Abstract

• When selecting whether to use clomiphene citrate or letrozole, consider the applicable national laws and regulations related to off-label use of letrozole.

Abstract

• The optimal number of S-IUI cycles is unknown; in the studies used to inform this recommendation, different numbers of cycles were provided, ranging from one to six, with more recent studies providing three to six cycles.

Background and rationale

This guideline suggests expectant management as first-line management in couples with unexplained infertility rather than ovarian stimulation with timed intercourse or U-IUI. S-IUI involves the use of ovarian stimulation medications to increase the number of mature oocytes available for fertilization.

Commonly

Balancing harms and benefits

We used evidence from two systematic reviews: Data showed that there are likely greater pregnancies with S-IUI than expectant management (approximately 100-200 more per 1000) but likely little to no difference between the ovarian stimulation drugs. There may also be little to no difference in live births between the drugs.

Compared to clomiphene citrate, stimulation with letrozole may result in similar number of live births per 1000 pregnancies (RR: 1.00; 95% CI: 081-1.22) and likely 80 more biochemical pregnancies [from 43 fewer to 272 more] per 1000 (RR: 1.32; 95% CI: 0.83-2.09). In terms of harms, there may be little to no difference in harms or adverse events between letrozole and clomiphene citrate, but greater harms compared to expectant management (e.g. OHSS may occur in 11 per 1000 with ovarian stimulation but not with expectant management).

References

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

study, the review (2) reported similar rates of

abdominal bloating (16.8% versus 18.6%), breast

pain (6.4% versus 7.2%) and headache (34.9% versus

41.9%) between clomiphene citrate and letrozole.

Hot flushes (30.9% versus 16.8%) and constipation (9.4% versus 2.7%) were higher with clomiphene

citrate, while joint and limb pain were more

common with letrozole (5.8% versus 2.7%). In the RCTs, different numbers of cycles were provided,

ranging from one to six, with more recent studies providing three to six cycles. Overall, the certainty of the evidence was low because the numbers of

events in the analyses were small. Although data

on patient values were not available, the GDG

judged that people highly value live births and seek

to minimize harms, such as multiple pregnancy,

miscarriage or congenital anomalies. Given the

moderate benefits and small increase in harms

compared to expectant management, but trivial

differences in harms and benefits between the

drugs, the GDG judged that the balance of effects

probably favours S-IUI but does not favour either

letrozole or clomiphene citrate.

Other considerations

Stimulation with either clomiphene citrate or letrozole

is feasible; it requires similar access to specialist care and ultrasound monitoring. The GDG judged that

use of clomiphene citrate and letrozole is probably

acceptable (11), but noted that the acceptability of

letrozole may also depend on whether off-label use

is permitted (12). The cost and access to letrozole

may vary substantially between countries; although

it could be more expensive compared to clomiphene citrate in some contexts, the GDG agreed that relative to the overall cost of IUI, choosing letrozole would

have negligible effects on overall costs and equity

in access. No evidence on cost-effectiveness was

found; however, the GDG judged that given the trivial differences in benefits and harms and negligible

differences in costs, cost-effectiveness probably does not favour either medication.

Summary justification

There are likely moderate benefits and small harms with S-IUI compared to

expectant management but there may be little difference in live births and likely

little difference in pregnancies between letrozole and clomiphene citrate. There may also be little difference in adverse effects, such as miscarriage, multiple pregnancy and ectopic pregnancy. Relative to the cost of S-IUI, cost differences between

clomiphene citrate and letrozole would probably have no impact on equity; both are acceptable and feasible to provide.

Implementation considerations

Health care providers should be aware and mitigate the potential risks of stimulating

agents, including clomiphene citrate and letrozole.

Health care providers should consider monitoring

ovarian response with US to minimize the risk of

multifollicular development and multiple pregnancy. Health care providers may consider switching

clomiphene citrate and letrozole based on patient

symptoms and ultrasound monitoring. Relevant

stakeholders should familiarize themselves with

applicable national laws and regulations related to

the off-label use of letrozole.

Research gaps and future guideline update

Future research and guidance will be required on

the timing of IUI in stimulated cycles, and whether

to use single or double IUI in stimulated cycles.

Ongoing research and surveillance of fetal outcomes should be encouraged. Future research is required regarding the impact of age and other prognostic

factors on the outcome of stimulated IUI.

References

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Recommendation

For couples with unexplained infertility, where expectant management has been unsuccessful, WHO suggests S-IUI with either clomiphene citrate or letrozole

rather than with gonadotrophins. (Conditional recommendation, very low certainty

of evidence)

Remark:

• The optimal number of S-IUI cycles is unknown; in the studies used to inform this

recommendation, different numbers of cycles were provided, ranging from one to

six, with more recent studies providing three to six cycles.

Background and rationale

Ovarian Stimulation is a pharmacological treatment used to induce the development of (typically

multiple and ideally three or fewer) ovarian follicles;

hence more oocytes available for fertilization.

Commonly used medications for ovarian

stimulation include anti-estrogens (e.g. clomiphene

citrate), aromatase inhibitors (e.g. letrozole) and

gonadotrophins (e.g. FSH and LH) (1–4).

In the previous section, this WHO guideline

suggests the use of S-IUI with either letrozole

or clomiphene citrate for ovarian stimulation

(conditional recommendation, low certainty of

evidence). While both clomiphene citrate and

letrozole are oral medications, gonadotrophins

are injected. Because of their mechanism of

action and effects on follicle development,

medications used for ovarian stimulation such as

clomiphene citrate, letrozole or gonadotrophins,

may increase the risk of multiple pregnancy to

varying extents; gonadotrophins may also increase the risk of OHSS (1) (further details on these

ovulation-stimulating agents are described in

Section 6.1).

Given the potential differences in benefits, the

GDG considered it a priority to determine whether to preferentially provide the oral medications

(letrozole or clomiphene citrate) or gonadotrophins as stimulation agents for treatment of unexplained infertility. For this recommendation, the GDG

addressed the question: should S-IUI with

gonadotrophins versus S-IUI with clomiphene

citrate or S-IUI with letrozole be used in couples with unexplained infertility? This was assessed

in the context of second-line management of unexplained infertility.

Balancing harms and benefits

To compare clomiphene citrate with

gonadotrophins, evidence was obtained from

a review by Athaullah et al. (5), consisting of

five RCTs (6–10) that compared stimulation with

clomiphene citrate versus gonadotrophins in

patients with unexplained infertility undergoing

IUI. The results showed that compared to

gonadotrophins, clomiphene citrate may

result in 105 fewer live births (from 193 fewer

to 79 more), (OR: 0.51; 95% CI: 0.18–1.47), and

90 fewer pregnancies (from 137 to one fewer)

per 1000 women (OR: 0.44; 95% CI: 0.19–0.99).

The mean pregnancy rate per cycle was 25% with

gonadotrophins and 8% with clomiphene citrate.

However, clomiphene citrate may also result in

97 fewer miscarriages (from 185 fewer to 254

more), (OR: 0.46; 95% CI: 0.06–3.33) and 140 fewer multiple pregnancies (from 230 fewer to 198 more), per 1000 pregnancies (OR: 0.37; 95% CI: 0.06–2.43). None of the RCTs reported cases of OHSS. The GDG noted that the higher pregnancy rate that may

occur with gonadotrophins was at the expense of a higher multiple pregnancy rate and other adverse effects. Based on these data, the GDG concluded

that the balance of effects probably favours

clomiphene citrate over gonadotrophins. The

certainty of the evidence was considered very low because of very few events across the RCTs.

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To compare letrozole with gonadotrophins, a new

search and review of evidence were conducted. Three

eligible RCTs comparing letrozole to gonadotrophins in patients with unexplained infertility were identified (11–13). The evidence showed that letrozole may result

in fewer live births and pregnancies compared to gonadotrophins: 103 fewer live births (from 138 to

57 fewer), (RR: 0.59; 95% CI: 0.45–0.77) and 108 fewer

clinical pregnancies (from 150 to 57 fewer), per 1000

women treated (RR: 0.64; 95% CI: 0.50–0.81). The

GDG judged that the magnitude of these effects

was small. Letrozole may also result in moderate

reductions in undesirable effects. Evidence suggests

140 fewer multiple pregnancies (from 193 to

40 fewer), (RR: 0.44; 95% CI: 0.23–0.84), 32 fewer

miscarriages (from 86 fewer to 48 more), (RR: 0.84;

95% CI: 0.57–1.24), and six fewer cases of OHSS,

(from 11 fewer to 34 more per 1000), (RR: 0.43; 95% CI: 0.05–4.07). In the RCTs, different numbers of

cycles were provided, which ranged from one to six, with more recent studies providing 3–6 cycles. The GDG noted that although pregnancy and live birth rates are higher with gonadotrophins compared

to letrozole, this comes at the expense of higher

multiple pregnancy rates. The GDG judged that most

patients value live births and would want to minimize serious side-effects, and that these values likely do not differ among couples with unexplained infertility. Thus, the GDG concluded that the balance of effects probably favours letrozole over gonadotrophins. The

certainty of the evidence was low because of few events and wide CIs.

Other considerations

Ovarian stimulation involves the cost of

medications, ultrasound monitoring, hormone

assays and skilled personnel. Although the overall cost of S-IUI may vary from country to country,

the GDG agreed that the cost of oral agents is

considerably lower than that of gonadotrophins; moderate savings would be achieved with the

use of either clomiphene citrate or letrozole

compared to gonadotrophins. The GDG considered studies showing the importance of treatment

costs to couples and health systems (11, 14–16)

and judged that use of oral agents would be

expected to increase equity of access to fertility

treatment as they are considerably cheaper than

gonadotrophins.

Based on two studies (17, 18), the GDG judged that ovarian stimulation with IUI is probably feasible.

Variations in gonadotrophin treatment protocols

(e.g. doses) can affect the ability of health systems

to respond to the complications of gonadotrophins, such as OHSS. Health systems capacity to

implement gonadotrophins safely and manage their

potential side-effects varies widely. While using

low-dose gonadotrophins could reduce the risk of HOMP and OHSS, this is applied inconsistently

across different jurisdictions and studies. On the

other hand, the GDG judged that clomiphene citrate

and letrozole have similar feasibility, in contexts where the off-label use of letrozole is permitted.

Although direct evidence from patients was

lacking, the GDG noted that the injectable nature

of gonadotrophins, the need for more frequent

monitoring (because of the higher risk of multiple follicle recruitment and the associated risks of

multiple pregnancy and OHSS) and refrigerated

storage requirements could potentially reduce their acceptability.

Summary justification

Although there may be slightly fewer pregnancies and live births when providing S-IUI with either clomiphene citrate or letrozole, these oral agents may have

fewer adverse effects compared to gonadotrophins. In addition, clomiphene

citrate and letrozole are less expensive compared to gonadotrophins, and their use is likely to result in moderate resource savings and higher equity; they are

probably acceptable and feasible.

Implementation considerations

This guideline suggests that clomiphene

Research gaps and future guideline update

Future guidance is required on how to take into account prognostic factors, such as the age of the female partner and duration of infertility, during S-IUI, for example, using prognostic models. Future research and guidance will be required on the timing of IUI in stimulated cycles, and whether to use single or double IUI in stimulated cycles.

References

Abstract

Tartaryn I. A randomized trial of CC plus IUI versus rFSH plus IUI for the treatment of subfertility. Fertil Steril (Suppl). 1999;72:208.

References

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10.3 Third-line management of couples with unexplained infertility

Recommendation

For couples with unexplained infertility, where stimulated intrauterine

insemination (S-IUI) has been unsuccessful, WHO suggests in vitro fertilization (IVF) rather than expectant management. (Conditional recommendation, low

certainty of evidence)

Background and rationale

For couples with unexplained infertility who

fail to achieve pregnancy with S-IUI, options

for management include IVF or expectant

management. Expectant management refers

to monitoring the couple with the expectation

that pregnancy will be achieved without medical

intervention. It includes providing advice on lifestyle and most fertile days of the menstrual cycle, and

monitoring if pregnancy will occur; however, no

treatment is provided (see section 10.1 for the

rationale for expectant management).

Conventional IVF is an insemination procedure

where oocytes and sperm are co-incubated

outside the human body with the goal of achieving

fertilization, after which the embryo is transferred

to the uterus. IVF allows control over the number of embryos transferred, while allowing spare embryos to be cryopreserved for future use, obviating the

need for further ovarian stimulation (1). However,

IVF involves costs (2, 3) and may have undesirable outcomes (4) warranting its comparison with

expectant management. For this recommendation, the GDG addressed the question: should IVF (with or without ICSI) versus no treatment be used for

couples with unexplained infertility?

Balancing harms and benefits

Evidence was reviewed from a network metaanalysis (5), two RCTs (6, 7) and a non-randomized

study (8). When comparing IVF to expectant

management, IVF may result in 204 more clinical

pregnancies (from 40 to 407 more), (OR: 3.03;

95% CI: 1.32–6.94) and 106 more live births (from

27 fewer to 300 more), (OR: 1.88; 95% CI: 0.81–4.38),

but 10 more multiple pregnancies (from two fewer to 53 more), per 1000 women treated (OR: 2.66;

95% CI: 0.68–10.43). This difference was considered

moderate, and the GDG noted the possibility of further mitigating the risk of multiple pregnancy through the adoption of elective single embryo transfer. In the studies, one to six cycles of

IVF were provided. The GDG concluded that

the balance of effects probably favours IVF over

expectant management and judged the certainty of the evidence to be low.

Other considerations

When comparing IVF to expectant management,

the GDG judged that IVF is feasible because the

infrastructure can be developed and training

provided, making it possible to implement it with

strong collaborations and support. IVF is expensive and may not be readily accessible in some settings because of lack of infrastructure and its high

cost. Thus, IVF likely reduces equity compared

to expectant management. Data on the values

and acceptability of IVF compared to expectant

management; however, the GDG acknowledged

that the trade-offs patients undergoing infertility

treatments are willing to make may vary depending

on different factors, including burden, effectiveness, safety and financial costs (9). Thus, although values

were not directly assessed, the GDG agreed that

patients are likely to value live births highly while

avoiding side-effects, and this is unlikely to vary

among different patient groups. In addition, the GDG judged that for patients who have been unsuccessful with other treatments, IVF is probably acceptable;

ethically, such patients should have options when

other treatments have been unsuccessful.

197

10 Treatment of couples with unexplained infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Summary justification

In couples with unexplained infertility, there may be large benefits in live

births and clinical pregnancies with IVF compared to expectant management.

Although there may be a moderate risk of multiple pregnancy, the balance of

effects probably favours IVF compared to expectant management. Although IVF is expensive, it reduces time to pregnancy, which may be of greater benefit for

couples with unexplained infertility where S-IUI has been unsuccessful. Although IVF may probably reduce equity, it is probably acceptable and probably feasible.

Implementation considerations

In implementing these recommendations,

health care providers should consider and

mitigate the risks associated with IVF, such as OHSS, and the surgical risks associated with oocyte

retrieval. Health care providers should provide

information about benefits, costs and the potential

risks of IVF to couples with unexplained infertility undergoing IVF.

Research gaps and future guideline update

Future research and guidance on how to incorporate possible prognostic factors is needed, including

the age of the female partner and the duration of

infertility (10, 11). Future research and guidance

are needed to determine the optimal or maximum

number of IVF cycles that should be provided.

Further research and guidance on management

options when IVF fails to achieve pregnancy in

couples with unexplained infertility is needed.

References

1. Trounson A, Mohr L. Human pregnancy following

cryopreservation, thawing and transfer of an

eight-cell embryo. Nature. 1983;305(5936):707-9 (https://doi.org/10.1038/305707a0).

2. Collins JA. An international survey of the health

economics of IVF and ICSI. Hum Reprod Update. 2002;8(3):265-77 (https://doi.org/10.1093/

humupd/8.3.265).

3. Chambers GM, Sullivan EA, Ishihara O,

Chapman MG, Adamson GD. The economic

impact of assisted reproductive technology:

a review of selected developed countries.

Fertil Steril. 2009;91(6):2281-94 (https://doi.

org/10.1016/j.fertnstert.2009.04.029).

4. Pandey S, Shetty A, Hamilton M, Bhattacharya S, Maheshwari A. Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Hum

Reprod Update. 2012;18(5):485-503 (https://doi.

org/10.1093/humupd/dms018).

5. Wang R, Danhof NA, Tjon‐Kon‐Fat RI,

Eijkemans MJ, Bossuyt PM, Mochtar MH et al. Interventions for unexplained infertility: a

systematic review and network meta‐analysis.

Cochrane Database Syst Rev. 2019;(9):CD012692 (https://doi.org/10.1002/14651858.CD012692.

pub2).

6. Foong SC, Fleetham JA, O’Keane JA, Scott SG,

Tough SC, Greene CA. A prospective randomized trial of conventional in vitro fertilization versus

intracytoplasmic sperm injection in unexplained infertility. J Assist Reprod Genet. 2006;23(3):137-40 (https://doi.org/10.1007/s10815-005-9008-y).

7. Dang VQ, Vuong LN, Luu TM, Pham TD, Ho TM,

Ha AN et al. Intracytoplasmic sperm injection

versus conventional in-vitro fertilisation in

couples with infertility in whom the male partner has normal total sperm count and motility:

an open-label, randomised controlled trial.

Lancet. 2021;397(10284):1554-63 (https://doi.

org/10.1016/S0140-6736(21)00535-3).

Guideline for the prevention, diagnosis and treatment of infertility

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

8. Boulet SL, Mehta A, Kissin DM, Warner L, Kawwass JF, Jamieson DJ. Trends in use of

and reproductive outcomes associated with intracytoplasmic sperm injection. JAMA.

2015;313(3):255-63 (https://doi.org/10.1001/jama.2014.17985).

9. Dancet EA, D’Hooghe TM, van der Veen F,

Bossuyt P, Sermeus W, Mol B-W et al. “Patientcentered fertility treatment”: what is required?

Fertil Steril. 2014;101(4):924-6 (https://doi.

org/10.1016/j.fertnstert.2013.12.045).

10. Brandes M, Hamilton CJ, van der Steen JO, de

Bruin JP, Bots RS, Nelen WL et al. Unexplained

infertility: overall ongoing pregnancy rate and mode of conception. Hum Reprod.

2011;26(2):360-8 (https://doi.org/10.1093/humrep/deq349).

11. McLernon DJ, Lee AJ, Maheshwari A,

van Eekelen R, van Geloven N, Putter H et al. Predicting the chances of having a baby

with or without treatment at different time

points in couples with unexplained subfertility. Hum Reprod. 2019;34(6):1126-38 (https://doi.

org/10.1093/humrep/dez049).

0 Treatment of couples with unexplained infertility Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps Recommendation For couples with unexplained infertility undergoing in vitro fertilization (IVF) after stimulated intrauterine insemination (S-IUI) has been unsuccessful, WHO recommends using IVF alone rather than IVF with intracytoplasmic sperm injection (ICSI)

Background and rationale

Conventional IVF is an insemination procedure where oocytes and sperm are co-incubated outside the human body with the goal of achieving fertilization. Introduced in 1992, ICSI involves injecting a single sperm into an oocyte with the goal of achieving fertilization (1, 2). It is often performed as an additional procedure to conventional IVF for male-factor infertility. However, the rationale for the use of ICSI for non-male-factor infertility, including unexplained infertility, is unclear (3), and the procedure increases costs (4). The GDG agreed that guidance was needed regarding the addition of ICSI to conventional IVF in the management of unexplained infertility. For this recommendation the GDG addressed the question: should IVF versus ICSI be used for couples with unexplained infertility in whom other treatments have been unsuccessful?

Balancing harms and benefits

Evidence was reviewed from two RCTs (5, 6) and a non-randomized observational study (3). In the studies, the IVF/ICSI cycles provided ranged from one to six. Evidence showed that, when comparing IVF to ICSI for the treatment of unexplained infertility, IVF likely results in up to 28 fewer clinical pregnancies (from 66 fewer to 18 more), (RR: 0.93; 95% CI: 0.82-1.06), and likely up to 28 fewer live births (from 72 fewer to 24 more), per 1000 (RR: 0.91; 95% CI: 0.78-1.06) compared to ICSI. These differences were considered trivial by the GDG. There may also be little or no difference in adverse effects when comparing IVF with ICSI, such as multiple pregnancy (RR: 0.87; 95% CI: 0.62-1.21), although the studies were unclear on whether a similar number of embryos were transferred in all participants; miscarriages (RR: 0.96; 95% CI: 0.58-1.61); ectopic pregnancies (RR: 1.00; 95% CI: 0.42-2.38); and OHSS (RR: 1.17; 95% CI: 0.39-3.45). The GDG judged these differences in both benefits and undesirable effects to be trivial; the evidence was of low quality because of small events contributing to the data, and the risk of confounding for adverse events from the comparative non-randomized study.

Other considerations

When comparing IVF to ICSI, the GDG considered that ICSI requires additional laboratory resources, personnel, time and expertise compared to IVF.

Therefore, the use of IVF is expected to lead to large cost savings compared to ICSI. A 2013 modelling study (7) , which compared all IVF versus a 50:50 split between IVF and ICSI, found a 3% increase in cumulative births from ICSI for an additional cost of US$ 1763. However, the GDG noted that these data did not necessarily show that ICSI was costeffective. Given the trivial differences in live births and clinical pregnancies and the high additional cost of ICSI, the GDG judged that IVF is probably more cost-effective than ICSI for the treatment of unexplained infertility. The GDG judged that if IVF is recommended, it would lead to increased equity and significant cost savings compared to ICSI.

In addition, the GDG judged that IVF is probably feasible, and probably more feasible than ICSI, given the additional training, expertise and resources necessary for ICSI. Based on existing GRADE criteria (8), the GDG made a strong recommendation despite the low certainty of evidence, given that the two interventions being compared may have equivalent benefits (low or very low certainty in benefits), while one option (in this case IVF) is less risky or less costly.

References

Implementation considerations

Research gaps and future guideline update

Abstract

In couples with unexplained infertility, IVF and ICSI likely result in similar clinical pregnancies and live births, and similar harms such as miscarriage, OHSS and ectopic pregnancy. However, the costs and resources needed for ICSI are considerably higher. Compared to ICSI, IVF results in large cost savings and is probably more costeffective. In addition, IVF is probably more feasible compared to ICSI.

Abstract

Health care providers should note that unexplained infertility implies semen parameters that are within the WHO reference ranges as indicated in the WHO laboratory manual for the examination and processing of human semen ( 9 ).

Abstract

Future research and guidance are needed to determine the optimal or maximum number of IVF cycles that should be provided. Further research and guidance is needed on further advanced evaluation and management options that are available when IVF fails to achieve pregnancy in couples with unexplained infertility.

References

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11 Dissemination, local adaptation, implementation, monitoring and evaluation

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11 Dissemination, local adaptation, implementation, monitoring and evaluation

This chapter provides information on how the guideline recommendations could be adapted, implemented and continuously monitored.

11.1 Dissemination

The recommendations in this guideline will

be disseminated through a broad network of international partners, including WHO country

and regional offices, ministries of health,

WHO collaborating centres, other United

Nations agencies, international development agencies, universities, professional societies

and nongovernmental organizations, including

non-state actors in official relations with WHO. The

guideline will be published on the WHO website in English; the executive summary will be available in all six United Nations languages. A summary

of recommendations aimed at policy-makers,

programme managers and health care providers

will be developed and disseminated in the six United

Nations languages. A commentary summarizing

the guideline recommendations will be published

in English in an open access academic journal. The guideline will also be disseminated through a global fertility care community of practice. Infographics,

social media kits and web stories will be developed,

and webinars and scientific sessions organized to

further raise awareness of the guideline.

11.2 Local adaptation

The recommendations in this guideline have been developed for a global audience. It is expected

that countries will adapt the recommendations to suit their national needs, based on local contexts, through inclusive engagement of all local partners, including national and subnational governments,

civil society, patient organizations and professional

societies of various health care providers involved in fertility care. It is anticipated that national

adaptation will be based on the epidemiological

profile related to the burden of infertility and needs

assessments, and will consider the capacity of the health care system, required resources, as well

as the local health, social, cultural and economic contexts. Guideline adaptation may involve

translation into national or local languages. In 2023, WHO published updated estimates on the global

prevalence of infertility (1), which will be useful to

countries adapting these guidelines. In settings

lacking the local data needed for adaptation, the

recommendations in this guideline could be adopted as presented because evidence has been assessed globally. Countries will be encouraged to hold key

stakeholder consultations to inform the decisions

to introduce the guideline recommendations

into national programmes. During adaptation,

policy-makers are expected to consider how the

recommendations in this guideline align and

complement existing WHO guidance on other issues related to sexual and reproductive health.

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11.3 Implementation

Successful implementation of the recommendations in this guideline will require endorsement by

multiple stakeholders at the country level, including ministries of health, local professional societies,

nongovernmental organizations, civil society and patient groups. For effective use of these

recommendations, it is essential that the health

systems at the country level create an enabling

environment for the prevention, diagnosis and

treatment of infertility. This may include, for

example, ensuring that infertility is included in

relevant government departments, health and

other policies (e.g. educational or social), strategic

plans, services and financing, as well as ensuring

that fertility care medicines are included in essential medicines list, training health care providers on

infertility, modifying health information systems

to incorporate data on infertility and developing

national clinical guidelines on infertility. WHO has

updated its model lists of essential medicines (2)

and the WHO model list of essential in vitro

diagnostics (3) to include relevant medications

and reproductive hormone-related infertility

care; countries will be encouraged to consult

these when quantifying, costing and procuring

relevant supplies. Political support is essential, as is the need to embed a reproductive rights-based approach to implementation. Providers of fertility care should consider the needs of, and provide

equal care to, all individuals. Demographic trends such as total fertility rates should not be used to

prioritize or deprioritize guideline implementation; rather, efforts should aim to support individuals

and couples achieve their fertility preferences,

reproductive goals and aspirations (4). Additionally, implementation research should be encouraged to inform guideline adaptation, implementation and

continuous quality improvement. Adaptation of the recommendations into digital and app format is also encouraged, where feasible.

11.4 Monitoring and evaluation

WHO will aim to collect regular feedback from

key stakeholders to understand the usefulness

and impact of this guideline. WHO will monitor

the uptake of the guideline in national policies

and programmes by reviewing the number of

countries that have adapted or endorsed it.

Implementation research related to this guideline,

including to evaluate how practice is aligned

with the recommendations, will be encouraged.

Monitoring and evaluation should be built into

the implementation process to provide important

lessons to continually improve implementation. The implementation of the guideline recommendations should involve national programmes (and relevant

partners) collecting and reporting data on services provided to prevent, diagnose or treat infertility. This may require review of existing health information

systems, including ART and other medically assisted reproduction (MAR) registries, which capture

data related to fertility care, medical electronic

records and other patient electronic reporting

and vital registration systems, to ensure that

service provision data are adequately captured

and reported. WHO plans to develop a core and

expanded set of indicators for the prevention,

diagnosis and treatment of infertility, which will aid monitoring and impact evaluation. Some indicators that can be used to monitor progress may already be available in the existing health management

information systems, national surveillance systems or ART and other MAR registries that capture data related to fertility care; for others, periodic surveys or evaluations may be required.

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

References

1. Infertility prevalence estimates: 1990–2021.

Geneva: World Health Organization; 2023

(https://apps.who.int/iris/handle/10665/366700).

2. The selection and use of essential medicines

2023: web annex A: World Health Organization model list of essential medicines: 23rd list

(2023). Geneva: World Health Organization; 2023 (https://iris.who.int/handle/10665/371090).

3. The selection and use of essential in vitro

diagnostics: report of the fourth meeting of the WHO Strategic Advisory Group of Experts on

In Vitro Diagnostics, 2022 (including the fourth WHO model list of essential in vitro diagnostics).

Geneva: World Health Organization; 2023

(https://iris.who.int/handle/10665/373322).

4. Mburu G, Kiarie J, Allotey P. Towards a nuanced

view and response to global fertility trends. Lancet. 2024;403(10440):1953-56 (https://doi.

org/10.1016/s0140-6736(24)00490-2).

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12 Research gaps, future scope and updating the guideline

This chapter provides a summary of research gaps and future updating of this guideline.

12.1 Research gaps

The recommendations in this guideline are based on the best global evidence available at the time

of compilation. The GDG identified important gaps

in research that need to be addressed through

primary research studies and RCTs of interventions.

Research gaps for specific interventions are

many and are summarized under each relevant

section throughout this guideline. Overall,

relatively few studies from LMICs were identified.

Additionally, there was a dearth of studies on patient values, preferences and acceptability of

different interventions. Data on the costs and

cost-effectiveness of interventions were suboptimal

for most interventions and very few studies

assessed the feasibility of introducing interventions

in different settings. Less emphasis was placed in studies regarding the effect of interventions on live

birth rate (and not just on biochemical or clinical

pregnancy rate). These gaps affected the quality of

evidence underlying the many recommendations. Some of these research gaps are crucial and results from these studies will be needed to update the

guideline in the future. WHO will continue to track relevant results from the research community.

Fig. 12.1. The need to address critical research gaps

These gaps affected the quality of evidence underlying many

recommendations. Some are crucial and results from studies addressing these gaps will be needed to update the guideline in the future.

Key research gaps identified include:

Relatively few studies from low- and

middle-income countries (LMICs)

were identified

Studies on patient values, preferences and acceptability of different

interventions were lacking

Data on costs and cost-effectiveness

were suboptimal for most interventions

Very few studies assessed the

feasibility of introducing interventions in different settings

Limited emphasis in studies regarding

the effect of interventions on live birth rate

(and not just on biochemical or clinical

pregnancy rate)

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12.2 Future scope and updating this guideline

Given that this is the first WHO guideline on the

prevention, diagnosis and treatment of infertility,

it does not cover all aspects of infertility, and

important gaps remain. It is anticipated that

subsequent editions of this guideline will have an

expanded scope, allowing future recommendations to address topics that are not currently included.

These include management of other personal risk factors (such as obesity, low body weight, excessive intake of alcohol and other substances, including

use of cannabis, vapes and e-cigarettes or nonsmoked and smokeless tobacco products, among

others), sexual dysfunction as well as non-personal risk factors (e.g. environmental and workplace

factors), fertility preservation in the context of

gonadotoxic therapy, third-party reproduction

(donor gametes, surrogacy), fertility care for

individuals with pre-existing medical conditions that

affect fertility (such as endometriosis and fibroids),

or with obstructive, congenital, accessory gland, genital or hormonal abnormalities associated with male infertility, as well as psychosocial support

for people with infertility. Future guidance will

be needed for advanced sperm function testing, sperm retrieval techniques for obstructive and

non-obstructive azoospermia, ART modalities,

and non-invasive therapeutic approaches beyond antioxidant supplements. Guidance is also needed on the use of adjunct IVF “add-ons”, and how to

further minimize multiple pregnancies. These

topics received relatively limited attention in this

initial guideline (based on the initial scoping by the GDG) and will need to be considered in subsequent editions. Similarly, subsequent editions of this

guideline will need to consider expansion of critical outcomes, as appropriate, to incorporate outcomes that are increasingly important to patients, such as time to pregnancy.

Non-personal risk factors such as environmental and workplace factors

Expanded guidance on advanced

diagnosis and treatment modalities for male- factor infertility is also needed.

New interventions in infertility are

emerging, including the use of AI,

equipment technology, and medical

treatments. WHO will track such

developments for potential inclusion in subsequent updates of the guideline.

Fertility care for individuals with pre- existing medical conditions that affect fertility (such as endometriosis and fibroids)

Fertility preservation in the context

of gonadotoxic therapy

Male infertility due to obstructive, congenital, accessory gland, genital or hormonal

abnormalities

Third-party reproduction including:

• donor gametes

• surrogacy

Management of other personal risk factors such as: obesity,

low body weight, excessive intake of alcohol and other substances, including the use of cannabis, vapes and e-cigarettes or

non-smoked/smokeless tobacco products

Future guideline editions need to address topics that are not

currently included in this edition.

These could include:

Addressing sexual dysfunction, IVF “add ons” and multiple pregnancies

Psychosocial support for people with infertility

Fig. 12.2. Future guideline scope and updates.

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An expanded guideline is expected to be available

in five years. Feedback from key stakeholders will

help guide the next edition of this guideline. WHO

Secretariat, in consultation with technical experts, will continue to follow research development in infertility, particularly for questions in which the certainty of

evidence was found to be of low or very low certainty. New and experimental interventions in infertility

are emerging, including use of artificial intelligence,

equipment technology, medical treatments (such as uterine transplants), among others.

WHO will track these and other developments for

potential consideration in subsequent updates of

the guideline. If the guideline merits an update in

the interim, or if new evidence emerges or other

important developments arise that may have an

impact on the validity of current recommendations in this version, the Department of Sexual, Reproductive, Maternal, Child and Adolescent Health and Ageing

will coordinate the guideline update, adhering to the formal procedures outlined in the WHO handbook for guideline development (1).

Reference

1. WHO handbook for guideline development, second edition. Geneva: World Health

Organization; 2014 (https://apps.who.int/iris/handle/10665/145714).

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Annex 1. Distribution of the causes of infertility

Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Annex 1. Distribution of the causes of infertility

Table A1.1. General categories of infertility (percentages of couples)a,b,c,d,e

Highincome countries

Regions in LMICs

Average LMICs

Average across all countriesf

Africa

Asia

Latin America

Eastern

Mediterranean

Female cause only

31.00

37.00

34.00 25.00

25.00

30.25

30.62

Male cause only

22.00

8.00

13.00

22.00

19.00

15.5

18.75

Causes found in both 21.00

35.00 24.00 30.00

38.00

31.75

26.37

No cause found in either

14.00

5.00

13.00

10.00

3.00

7.75

10.87

Became pregnant during the course of the study

12.00

15.00

16.00

13.00

15.00

14.75

13.37

Total

100.00 100.00 100.00 100.00

100.00

99.98

a Data adapted from Cates et al., 1985 (1); see also WHO, 1992 (2).

b Study involved 8500 couples in 33 medical centres in 25 countries representing high-, middle- and low-income

countries.

c 8500 couples were enrolled and just over 5800 (≈69%) completed the investigation to the point of a diagnosis being

made for both partners.

d Couples were admitted to the study if they had been infertile for at least 1 year (i.e. inclusion criteria).

e Classifications of income categories of countries as at the time of the original study.

f The average across all countries was derived by summing the prevalence in the “high-income countries” and

“average LMICs” columns and dividing this by 2.

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Fig. A1.1. Causes of infertilitya

a Data adapted from Cates et al., 1985 (1); see also WHO, 1992 (2).

31%

Female cause only

Male cause only

Causes found in both

No cause found in either

Became pregnant during the course of the study

22%

30.25%

30.62%

18.75%

26.37%

10.87%

13.37%

15.5%

21%

31.75%

14%

7.75%

12%

14.75%

Average across all countries

High-income countries

Average low- and

middle-income countries

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Table A1.2. Specific diagnoses of infertility (percentages of couples)a,b,c,d,e,f

Highincome countries

LMICs

Average LMICs

Average across all countriesg

Africa Asia

Latin America

Eastern

Mediterranean

Female diagnosis

No demonstrable cause

40.00 16.00 31.00 35.00

26.00

27.00

33.50

Bilateral tubal occlusion 11.00 49.00 14.00 15.00

20.00

24.50

17.75

Pelvic adhesions

13.00 24.00 13.00 17.00

13.00

16.75

14.87

Acquired tubal abnormality

12.00 12.00 12.00 12.00

9.00

11.25

11.62

Anovulatory regular cyclesh

10.00 14.00 9.00

9.00

15.00

11.75

10.87

Anovulatory

oligomenorrhoeah

9.00

3.00 7.00

9.00

11.00

7.50

8.25

Ovulatory

oligomenorrhoeah

7.00

4.00 11.00

5.00

8.00

7.00

Hyperprolactinaemia

7.00

5.00 7.00

8.00

6.00

6.50

6.75

Endometriosis

6.00

1.00 10.00

3.00

1.00

3.75

4.87

Male diagnosis

No demonstrable cause

49.00 46.00 58.00 41.00

28.00

43.25

46.12

Varicocele

11.00 20.00 10.00 19.00

12.00

15.25

13.12

Primary testicular failure

10.00

7.00 11.00 13.00

25.00

14.00

12.00

Accessory gland infection

7.00

11.00 3.00

12.00

3.00

7.25

7.12

Abnormal sperm morphologyi

8.00

5.00 3.00

4.00

3.00

3.75

5.87

Low sperm motilityi

3.00

1.00 5.00

8.00

5.00

4.75

3.87

a Data adapted from Cates et al., 1985 (1); see also WHO, 1992 (2).

b Study involved 8500 couples in 33 medical centres in 25 countries representing high-, middle- and low-income settings.

c 8500 couples were enrolled and just over 5800 (≈69%) completed the investigation to the point of a diagnosis being made

for both partners.

d Couples were admitted to the study if they had been infertile for at least 1 year (i.e. inclusion criteria).

e Classifications of income categories of countries as at the time of the original study.

f Not all diagnostic categories were listed in the original publication; some patients had more than one diagnosis or cause.

g The average across all countries was derived by summing the prevalence in the “high-income countries” and “average

LMICs” columns and dividing this by 2.

h Categories merged and reported under anovulatory and oligo-ovulatory disorders in this guideline, with a total

prevalence of 26.1% across all countries.

i Categories merged and reported under abnormal semen parameters in this guideline, with a total of 9.7% across all

countries.

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Fig. A1.2. Specific diagnoses of infertility (male)a

Fig. A1.3. Specific diagnoses of infertility (female)a

No demonstrable cause Bilateral tubal occlusion Pelvic adhesions

Acquired tubal abnormality Anovulatory regular cycles Anovulatory oligomenorrhoea

Ovulatory oligomenorrhoea Hyperprolactinaemia Endometriosis

High-income countries

Low- and middle-income countries

27%

7%7%

11%

10%

24.50%

40%

Female diagnosis

3.75%

6%6.50%

7.50%1

No demonstrable cause Varicocele Primary testicular failure Accessory gland infection Abnormal sperm morphology Low sperm motility

High-income countries

Low- and middle-income countries

43.25%7%

49%

Male diagnosis

4.75%

3.75%

7.25%

10%

a Data adapted from Cates et al., 1985 (1); see also WHO, 1992 (2).

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

References

1. Cates W, Farley TM, Rowe PJ. Worldwide

patterns of infertility: is Africa different? Lancet.

1985;2(8455):596-8 (https://doi.org/10.1016/s0140-6736(85)90594-x).

2. Recent advances in medically assisted

conception: report of a WHO Scientific Group. Geneva: World Health Organization; 1992

(https://iris.who.int/handle/10665/38679).

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Executive summary Intro Rationale & methodology Approach & management Prevention Diagnosis Treatment Dissemination Research gaps

Annex 2. Members of the GDG

Adam H. Balen

Leeds Teaching Hospitals, Leeds

United Kingdom of Great Britain and Northern Ireland

Ragaa Mansour

The Egyptian IVF Center, Ma`adi Cairo

Egypt

Jacky Boivin

School of Psychology, Cardiff University Cardiff

United Kingdom

Alfred Murage

Aga Khan University Hospital

Nairobi

Kenya

Barbara Collura

RESOLVE: The National Infertility Association McLean, VI

United States of America (USA)

Willem Ombelet

Genk Institute for Fertility Technology Genk

Belgium

Ben Cohlen

Isala Fertility Centre Zwolle

The Netherlands

Allan Pacey

Faculty of Biology, Medicine and Health, University of Manchester Manchester

United Kingdom

Christopher J. De Jonge

University of Minnesota Minneapolis

USA

Guido Pennings

Department of Philosophy and Moral Sciences, Ghent University Ghent

Belgium

Sandro C. Esteves

ANDROFERT, Andrology and Human Reproduction Clinic Campinas

Brazil

Robert W. Rebar

Homer Stryker School of Medicine,Western Michigan University

Kalamazoo

USA

Cynthia Farquhar

University of Auckland Auckland

New Zealand

Richard Reindollar

Geisel School of Medicine Dartmouth

USA

Richard Kennedy

Birmingham Women’s and

Children’s NHS Foundation Trust Birmingham

United Kingdom

Roberta Rizzo

University of Ferrara Ferrara

Italy

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Klaudija Kordic

Fertility Europe (Pan-European organisation

representing patients’ associations)

Evere

Belgium

Rita Sembuya

Joyce Fertility Support Centre

Kampala

Uganda

Linda Giudice

UCSF School of Medicine San Francisco

USA

Gamal Serour

Al Azhar University

Cairo Egypt

Luca Gianaroli

Reproductive Medicine Unit, S.I.S.Me.R.

Bologna

Italy

Basil Tarlatzis

Aristotle University of Thessaloniki Thessaloniki

Greece

Carin Huyser

Steve Biko Academic Hospital,University of Pretoria

South Africa

Carla Tatone

University of L’Aquila L’Aquila

Italy

Dmitry Kissin

Division of Reproductive Health,

Centers for Disease Control and Prevention Atlanta

USA

Lan N. Vuong

University of Medicine and Pharmacy Ho Chi Minh City

Viet Nam

Tansu Kucuk

Department of Obstetrics and Gynaecology,

Acıbadem Maslak Hospital

Istanbul

Türkiye

Marie Lena Windt De Beer

Tygerberg Academic Hospital,Stellenbosch University

Cape Town

South Africa

Nalini Mahajan

Department of Reproductive Medicine, Mother and Child Hospital

New Delhi

India

Cong Yali

Health Science Centre,Peking University

Beijing

China

The following GDG members contributed to the initial part of the guideline but later stepped down: Anna Krawczack (Fertility Europe [Pan-European organisation representing patients’ associations], Evere, Belgium), Lars Björndahl

(Karolinska Institutet, Stockholm, Sweden), Kersti Lundin (Sahlgrenska University Hospital, Gothenburg, Sweden),

Rebecca Sokol (Keck School of Medicine, University of Southern California, Los Angeles, USA) and Roy Farquharson (Liverpool Women’s NHS Foundation Trust, Liverpool, United Kingdom).

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Annex 3. Members of the ERG

Introduction, methods and approach to the evaluation and management of infertility

Julia Chain

Human Fertilization and Embryology Authority London

United Kingdom of Great Britain and Northern

Ireland

Karla Torres

Centre for Reproductive Rights New York

USA

Muntaha Gharaibeh

Department of Maternal & Child Health, Jordan University of Science and Technology

Irbid

Jordan

Sheryl Van der Poel

International Health Consultant Geneva

Switzerland

Márcia C. Inhorn

Department of Anthropology,Yale University

New Haven

United States of America (USA)

Prevention of infertility

Joyce Harper

Institute for Women’s Health, University College London

London

United Kingdom

Zozo Nene

Department of Obstetrics & Gynaecology University of Pretoria

Pretoria

South Africa

Ivonne J. Diaz Yamal,

Department of Gynecology and

Obstetrics, Central Military Hospital Bogota

Colombia

Nathalie Vermeulen

European Society of Human Reproduction and Embryology Strombeek-Bever

Belgium

Promise E. Sefogah

Department of Obstetrics & Gynaecology, University of Ghana Medical School,

Accra

Ghana

Tamar Khomasuridze

Eastern Europe and Central Asia Regional Office,

United Nations Population Fund (UNFPA)Istanbul

Türkiye

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Diagnosis of female infertility

Grigoris F. Grimbizis

Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki

Thessaloniki

Greece

Bart C.J.M. Fauser

Reproductive Medicine, University Medical Center Utrecht

Utrecht

The Netherlands

Trinh The Son

Military Institute of Clinical Embryology and Histology Hanoi

Viet Nam

Qiao Jie

Peking University Health Science Center, Peking University Third Hospital

Beijing

China

Márcia Mendonça Carneiro

Department of Obstetrics and Gynecology, Federal University of Minas Gerais

Minas Gerais

Brazil

Neena Malhotra

Department of Obstetrics and Gynecology, All India Institute of Medical Sciences

New Delhi

India

Treatment of female infertility

Amal Benbella

Reproductive Health Hospital,IbnSina University Hospital

Rabat

Morocco

Sasha Ottey

PCOS Challenge: The National Polycystic Ovary Syndrome Association

Atlanta, Georgia

USA

Edgar Mocanu

Department of Obstetrics and Gynecology,

RCSI University of Medicine and Health Sciences Dublin

Ireland

Maria P. Velez

Division of Reproductive Endocrinology and Infertility, McGill University,

Montreal

Canada

Male infertility (diagnosis and treatment)

Ameet Patki

Indian Society for Assisted Reproduction Mumbai

India

Mónica Vazquez-Levin

Institute of Biology and Experimental Medicine –

National Scientific and Technical Research Council

(IBYME–CONICET)Buenos Aires

Argentina

Mohan S. Kamath

Department of Reproductive Medicine and Surgery, Christian Medical College, Vellore Tamil Nadu

India

Oleg Tishkevich

Centre of Assisted Reproduction Minsk

Belarus

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Unexplained infertility (diagnosis and treatment)

David Adamson

The International Committee Monitoring Assisted Reproductive Technologies, Saratoga

California

USA

Robert J Norman

Faculty of Health and Medical Sciences,The University of Adelaide

Adelaide

Australia

Ben Willem Mol

Department of Obstetrics and Gynaecology, Monash University

Melbourne

Australia

Mohamed Youssef

Department of Obstetrics and Gynecology,Cairo University

Cairo

Egypt

Olarik Musigavong

Chaophya Abhaibhubejhr Hospital Prachin Buri

Thailand

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Annex 4. Summary of declared

interests from members of the GDG

GDG membera

Affiliation

Nature of declared interestb

Adam H. Balen

Leeds Teaching Hospitals, Leeds, United Kingdom of

Great Britain and Northern Ireland

Shareholding, Consulting or Chair (CARE Fertility,

Leeds, United Kingdom, and UK Innovation and

Research Board); Advisory board membership, (Novo Nordisk Pharmaceuticals). Director and/

or Partner (Balance Reproductive Health Ltd;

Partner Balance Mind Ltd, and Balance Fertility Ltd); Trustee, Chair or Past Chair (British Fertility

Society, NHS England IVF Pricing Development

Expert Advisory Group); Fellows’ Representative,

RCOG Council (until 2023). Guideline member (PCOS Global Guideline Group); Member, FIGO Steering Group on Anovulatory Infertility. No amounts declared for these roles.

Jacky Boivin

School of Psychology, Cardiff University, Cardiff, United

Kingdom

Non-monetary support £250 (ESHRE). Research

support (£100 219, Merck Serono Ltd, paid to

Cardiff University) non-interventional investigator

led study on treatment planning. Consulting (£14

907, Ferring Pharmaceutical UK, United Kingdom,

the Netherlands, Global). Public statements

(total: £1750). Speaker fees (£26 107, Ferring

Pharmaceutical, Merck, Gedeon-Richter, British Fertility Society, IVI-RMA).

Barbara Collura

The National Infertility

Association (RESOLVE),

Washington DC, United States of America (USA)

Employment (Resolve); non-monetary support valued >US$ 1000; public statements.

Ben Cohlen

Isala Fertility Centre, Zwolle, the Netherlands

Research support for clinic projects (grants)

from Merck (US$ 30 000), Ferring (US$ 10 000), Gideon Richter (US$ 10 000).

Christopher J. De Jonge

University of Minnesota, Minneapolis, USA

No interests declared.

Sandro C. Esteves

ANDROFERT, Andrology and Human Reproduction Clinic,

Campinas, Brazil

Research support grant (Merck) US$ 90 000.

Speaker fees (Merck, US$ 20 000; MedE.A./Med.E.A, US$ 9000). Non-monetary support valued at over

US$ 1000 (Merck KGaA). Public statements.

Cynthia Farquhar

University of Auckland, Auckland, New Zealand

No interest declared.

Richard Kennedy

Birmingham Women’s and Children’s NHS Foundation Trust, United Kingdom

No interest declared.

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GDG membera

Affiliation

Nature of declared interestb

Klaudija Kordic

Fertility Europe (PanEuropean organisation

representing patients’

associations), Evere, Belgium

No interest declared.

Linda Giudice

UCSF School of Medicine, San Francisco, USA

Investments in stocks (Merck), US$ 5000, (Pfizer)

US$ 5000. Public statements as President of IFFS. Speaker fees (IBSA Pharma).

Luca Gianaroli

Reproductive Medicine Unit, S.I.S.Me.R., Bologna, Italy

Employment and stakeholder in SISMER (up to

2024); consulting; non-monetary support valued at over US$ 1000; speaker fees; public statements; investments up to 2020 except in SISMER. Nonrecurring fees from Merck, Theramex, InMed,

MedThink. Consultant at Interdisciplinary Institute of Reproductive Medicine (IIRM) and at ART

Fertility Clinic and Next Clinic (since 2025).

Carin Huyser

Steve Biko Academic Hospital, University of Pretoria, South Africa

No interest declared.

Dmitry Kissin

Division of Reproductive

Health, Centers for Disease Control and Prevention,

Atlanta, USA

No interest declared.

Tansu Kucuk

Department of Obstetrics

and Gynaecology, Acıbadem

Maslak Hospital, Istanbul,

Türkiye

No interest declared.

Nalini Mahajan

Department of Reproductive Medicine, Mother and Child Hospital, New Delhi, India

No interest declared.

Ragaa Mansour

The Egyptian IVF Center, Ma`adi, Cairo, Egypt

No interest declared.

Alfred Murage

Aga Khan University

Hospital, Nairobi, Kenya

No interest declared.

Willem Ombelet

Genk Institute for Fertility Technology, Genk, Belgium

No interest declared.

Allan Pacey

Faculty of Biology, Medicine and Health, University of

Manchester, Manchester,

United Kingdom

Monetary support to employer valued at over

US$ 1000 for consultancy/public speaking (Carrot

Fertility [current], Cryos International [current], IBSA

Institut Biochimique SA, Mealis Group). Several unpaid positions: Member of Advisory Board of

Progress Educational Trust; Co-Chair, UKNEQAS

Reproductive Sciences Advisory Committee;

Member, Science Media Centre Advisory Board;

Patron, Fertility Alliance (United Kingdom).

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GDG membera

Affiliation

Nature of declared interestb

Guido Pennings

Department of Philosophy and Moral Sciences, Ghent University, Ghent, Belgium

Non-monetary support valued at over US$ 1000 (Merck). Honorarium of speaker fees (Merck, US$ 2000; Teva Pharma, US$ 2000). Consulting fees (IVIRMA for membership of Ethics Committee,

€20 000; Cryos Int. for membership of External

Scientific Advisory Committee, €8000). Speakers

fees (Gedeon Richter, €2000).

Robert Rebar

Homer Stryker School of

Medicine, Western Michigan

University, Kalamazoo, USA

Employment (Lecturer WMU; editorial honorariums [NEJM Journal Watch Editor]) US$ 2500, honorarium

(Contraception Journal deputy editor), US$ 3000. Honorarium (Associate editor Obs Gyn Clinical Alert), US$ 1600); consulting (BSMB for several clinical trials (Myovant; US$ 6000) up to 2020.

Richard Reindollar Geisel School of Medicine,

Dartmouth, New Hampshire, USA

No interest declared.

Roberta Rizzo

University of Ferrara, Ferrara, Italy

No interest declared.

Rita Sembuya

Joyce Fertility Support

Centre, Kampala, Uganda

No interest declared.

Gamal Serour

Al Azhar University, Cairo,

Egypt

No interest declared.

Basil Tarlatzis

Aristotle University of

Thessaloniki, Thessaloniki, Greece

Consulting; non-monetary support valued at

>US$ 1000; research support for unrestricted research grants (Merk Serono) and Travel grants (MSD),

honorariums (IBSA; Ferring - company sponsored speakers bureau); Advisory board (Ovascience).

Carla Tatone

University of L’Aquila, L’Aquila,

Italy

No interest declared.

Lan N. Vuong

University of Medicine and Pharmacy, Ho Chi Minh City, Viet Nam

Research support/grants (2018–2020), valued

at US$ 49 478 (Ferring). Non-monetary support

valued at over US$ 1000 (Merck, for public

education workshops). Speaker fees from Ferring (two conferences per year valued at US$ 500-1700), MSD (US$ 500–700), Merck (US$ 500–700) and

ARD (US$ 3000). Travel support (including meeting registration fees) from Ferring, MSD and Merck.

Marie Lena Windt De Beer

Tygerberg Academic Hospital, Stellenbosch University, Cape Town, South Africa

No interest declared.

Cong Yali

Health Science Centre, Peking University, Beijing, China

No interests declared.

a The following GDG members contributed to the initial part of the guideline but later stepped down: Lars Björndahl

(Karolinska Institutet, Stockholm, Sweden), Roy Farquharson (Liverpool Women’s NHS Foundation Trust, Liverpool,

United Kingdom), Anna Krawczack (Fertility Europe [Pan-European organisation representing patients’ associations],

Evere, Belgium), Kersti Lundin (Sahlgrenska University Hospital, Gothenburg, Sweden) and Rebecca Sokol (Keck School

of Medicine, University of Southern California, Los Angeles, USA).

b The published interests exclude declared income from employment with public, regulatory, non-profit or

nongovernmental organizations, academic institutions or universities, or public hospitals.

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Annex 5. Summary of declared

interests from members of the ERG

ERG membera

Affiliation

Nature of declared interest

David Adamson

The International Committee Monitoring Assisted

Reproductive Technologies, Saratoga, United States of

America (USA)

Consultant manuscript author fees over US$ 1000 (Organon), 2024. Conference speaker fees (ESHRE) US$ 5000 annually ongoing); Founder and CEO

(ARC Fertility).

Amal Benbella

Reproductive Health

Hospital, IbnSina University Hospital, Rabat, Morocco

No interest declared.

Márcia Mendonça Carneiro

Department of Obstetrics and Gynecology, Federal University of Minas Gerais,

Minas Gerais, Brazil

Travel grants and honorariums for speaker fees and lectures (Ferring, Organon, Johnson and

Johnson, Boehringer), with a total amount of

less than US$ 10 000 in the last 4 years; ongoing lectures, 2024.

Julia Chain

Human Fertilization and

Embryology Authority,

London, United Kingdom of

Great Britain and Northern Ireland

No interests declared.

Ivonne J.

Diaz Yamal

Department of Gynecology and Obstetrics, Central

Military Hospital, Bogota, Colombia

No interests declared.

Bart C.J.M. Fauser

Reproductive Medicine, University Medical

Center Utrecht, Utrecht, the Netherlands

Consultant (Ferring, Celmatix, Univfy ReproNovo Vortex Imaging) amounts not disclosed; all

current. Member of DSMB (Myovant), current;

Co-chair (COGI) amounts not disclosed, current. Author fees (UpToDate) amount not disclosed,

current.

Muntaha Gharaibeh

Department of Maternal & Child Health, Jordan

University of Science and Technology, Irbid, Jordan

No interests declared.

Grigoris F. Grimbizis Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Thessaloniki, Greece

No interests declared.

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ERG membera

Affiliation

Nature of declared interest

Joyce Harper

Institute for Women’s Health, University College London,

London, United Kingdom

Paid talks (Gedeon Richter), £4000, ceased;

conference speaker fees (Cook IVF), £2000,

ceased; manuscript author fees (Ferring) £2000; ceased.

Márcia C. Inhorn

Department of

Anthropology,

Yale University, New Haven,USA

No interests declared.

Mohan S. Kamath

Department of Reproductive Medicine and Surgery,

Christian Medical College,

Vellore, Tamil Nadu,

India

Research grants support via CMC Vellore (ICMR)

(US$ 110 000 for whole project, ongoing 2023–

2026). Journal editorial honorarium (€3000 paid to employer annually; ongoing 2023–2025). Several unpaid honorary editorial positions (ESHRE

journals, ISAR journals and Cochrane Gynaecology and Fertility groups); all ongoing.

Tamar

Khomasuridze

Eastern Europe and Central

Asia Regional Office, United

Nations Population Fund

(UNFPA), Istanbul, Türkiye

No interests declared.

Neena Malhotra

Department of Obstetrics

and Gynecology, All India

Institute of Medical Sciences, New Delhi, India

Research grant support (Ferring Pharmaceuticals)

for a multicentre randomized controlled trial

assessing the efficacy and safety of follitropin

delta versus follitropin alfa (GONAL-F) in controlled

ovarian stimulation for ART; no personal income received, grant provided solely to conduct IVF for individuals.

Edgar Mocanu

Department of Obstetrics and Gynaecology, RCSI

University of Medicine and Health Sciences, Dublin,

Ireland

Scientific/research adviser fees (Cryos) €4000

per year, ceased. Conference travel and

accommodation support (Merck) value not

declared, ceased. President (IFFS) income not declared; current.

Ben W. Mol

Department of Obstetrics and Gynaecology, Monash University, Melbourne,

Australia

Consultant fees (Merck KGaA, Organon and

Norgine); amounts not disclosed, all current.

Research grant (NHMRC); amount not disclosed,

current. Travel grants (Merck KGaA); amount

not disclosed, current. Stock Options (ObsEva); amounts not declared; current.

Olarik Musigavong Chaophya Abhaibhubejhr Hospital, Prachin Buri,

Thailand

No interests declared.

Zozo Nene

Department of Obstetrics & Gynaecology University of Pretoria, Pretoria,

South Africa

ESHRE Conference sponsorship 2024

(Ferring Pharmaceuticals), 2024; travel and accommodation only.

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ERG membera

Affiliation

Nature of declared interest

Robert J. Norman

Faculty of Health and Medical Sciences, The University of

Adelaide, Adelaide,

Australia

Consultancy fees (an IVF unit in Hanoi, Viet Nam, with no ownership of the IVF unit itself, minor

income declared, ongoing).

Sasha Ottey

PCOS Challenge: The

National Polycystic Ovary Syndrome Association,

Atlanta, USA

Non-monetary support (Androgen Excess

and PCOS Society, Jones Foundation Infertility

Counselors Conference [ JFICC], Fertility

Empowerment International Conference [FEI]).

Conference travel costs (AE-PCOS annual meeting) 2023; (FEI), 2024; and (JFICC), 2024.

Ameet Patki

Indian Society for Assisted Reproduction, Mumbai,

India

No interests declared.

Jie Qiao

Peking University Health Science Center, Peking

University Third Hospital, Beijing, China

No interests declared.

Promise E. Sefogah Department of Obstetrics & Gynaecology, University of Ghana Medical School,

Accra, Ghana

Research grant and Research Fellowship Training Grant (Fogarty International Center, Northern

Pacific Global Health), US$ 10 000; 2023.

Trinh The Son

Military Institute of Clinical Embryology and Histology, Hanoi, Viet Nam

No interests declared.

Oleg Tishkevich

Centre of Assisted Reproduction,

Minsk, Belarus

Acting Chairman of the Board (Belarusian Medical Society for Human Reproduction, 2021–2024),

current. No other declared interest.

Karla Torres

Centre for Reproductive Rights, Geneva,

Switzerland

No interests declared.

Sheryl Van der Poel International Health Consultant,

Geneva, Switzerland

Travel reimbursements (Carrot Fertility, USA);

several flights and/or hotel, no current travel.

Stock options (Carrot Fertility, USA), US$ 4500, current; Stock options (Bea Fertility, United

Kingdom), US$ 365, current. Adviser (Fertility

Basics, USA), unpaid, current.

Mónica

Vazquez-Levin

Institute of Biology and Experimental Medicine

–National Scientific and

Technical Research Council, (IBYME–CONICET), Buenos Aires, Argentina

Consultant fees related to Spanish translation of WHO Semen Manual sixth edition (WHO); current.

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ERG membera

Affiliation

Nature of declared interest

Maria P. Velez

Division of Reproductive

Endocrinology and Infertility, McGill University, Montreal, Canada

No interests declared.

Nathalie Vermeulen European Society of

Human Reproduction and Embryology, StrombeekBever, Belgium

No interests declared.

Mohamed Youssef Department of Obstetrics and Gynaecology, Cairo University, Cairo, Egypt

No interests declared.

a Several ERG members declared current income from employment, including those working with public, regulatory,

non-profit and nongovernmental organizations, academic institutions and universities, or public hospitals; these are not

included above.

Annex 5

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Annex 6. Components of female medical history and physical

examination1

1 Form developed for a standardized investigation, diagnosis and management of the infertile female

Personal information

Full name

Date of birth

Age

Address

Contact

information

(phone, email)

Occupation

Marital or

relationship status

Relevant dates for evaluation

Date of history taking

Date

Month

Year

Date of birth of male

partner

Date

Month

Year

Date of birth of female

partner

Date

Month

Year

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Infertility history

Infertility

☐ Primary

☐ Secondary

Duration of infertility infertility/attempting to achieve pregnancy

years

If secondary, months since last pregnancy

months

Previous investigation(s) and/or treatments for infertility

☐ No ☐ Yes

If yes, please specify:

Previous pregnancy

☐ Current partner

☐ Another partner

Previous miscarriage

☐ Current partner

☐ Another partner

Treatments/evaluations of the male partner

Please specify:

1. Sexual history

Sexual activity and practices

Frequency of sexual activity

☐ Regular

☐ Irregular ☐ Rarely

Timing of intercourse

☐ Spontaneous

☐ Around ovulation

Pain during intercourse (dyspareunia)

☐ Yes

☐ No

Presence of sexual anxiety

☐ Yes

☐ No

Stress

☐ Yes

☐ No

Psychological barriers to sexual function

☐ Yes

☐ No

Use of sexual performance enhancers or lubricants

☐ Yes

☐ No

Prolonged abstinence

☐ Yes

☐ No

If yes, please specify duration:

days

months

Perceived quality of sexual activity

☐ Normal

☐ Inadequate

Previous or current sexual dysfunction

☐ Yes

☐ No

2. Menstrual history

Age at menarche

years old

Cycle characteristics

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Length of cycle

days ☐ Regular

☐ Irregular

Duration of bleeding

days

Flow

☐ Light

☐ Moderate ☐ Heavy

Dysmenorrhea (painful periods)

☐ Yes

☐ No

Severity

/10

Intermenstrual spotting

☐ Yes

☐ No

3. Obstetric history

Total number of pregnancies

Number of live births

Number of miscarriages

Number of stillbirths

Number of ectopic pregnancies Termination of pregnancy

☐ Yes

☐ No If yes how many:

History of complications during

pregnancy (e.g. preeclampsia, gestational diabetes)

Specify:

4. Contraceptive history

Previous contraceptive methods used

Specify:

Type

Specify:

Duration of use

Date of cessation: specify:

Use of emergency contraception

☐ Yes

☐ No

5. Childhood and development history

Pubertal development

Age at onset of puberty:

Sexual development

☐ Normal

☐ Delayed

History of ovarian or uterine abnormality ☐ Yes

☐ No

Treatment for ovarian or uterine abnormality

☐ Medical

☐ Surgical

Congenital anomaly

☐ Yes

☐ No If yes, please specify:

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Vaginal anomalies

☐ Yes

☐ No If yes, please specify:

Pathology possibly causing ovarian or uterine damage

Pelvic inflammatory disease (PID)

☐ Yes

☐ No

Endometriosis

☐ Yes

☐ No

Polycystic ovarian syndrome (PCOS)

☐ Yes

☐ No

Ovarian torsion

☐ Yes

☐ No

☐ Left

☐ Right

Surgery on reproductive organs

☐ Yes

☐ No If yes, please specify:

6. Medical history

a. History of disease

☐ None

☐ Diabetes

☐ Hypertension

☐ Thyroid disorders

☐ Autoimmune diseases

☐ Neurologic disease

☐ Fibrocystic of the pancreas ☐ Chronic respiratory tract disease ☐ Tuberculosis (or exposure) ☐ Uterine fibroids

☐ Ovarian cysts

☐ Other, please specify:

b. History of infection

☐ None

High fever in past 6 months

☐ Yes

☐ No

Urinary infection

☐ Yes

☐ No

Sexually transmitted disease (STI) ☐ Yes

☐ No

☐ Syphilis

☐ Gonorrhoea ☐ Chlamydia

☐ HPV (human papillomavirus) ☐ Trichomoniasis ☐ Herpes simplex virus (HSV) ☐ Cervicitis

☐ Other, specify:

c. History of surgery

☐ None

Retroperitoneal and/or pelvic surgery

☐ Hysterectomy

☐ Salpingectomy

☐ Pelvic adhesion surgery

☐ Oophorectomy

☐ Myomectomy (fibroid removal)

Inguinal or perineal surgery

☐ Inguinal hernia repair☐ Endometriosis surgery ☐ Tubal ligation

☐ Tubal ligation reversal

☐ Cyst removal (e.g. ovarian or pelvic cysts)

☐ Laparoscopy (diagnostic or therapeutic)

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Bariatric, bladder, or prostate surgery

☐ Bariatric surgery

☐ Uterine reconstruction

☐ Transvaginal or abdominal bladder surgery

Cranial surgery

☐ Pituitary surgery

Spinal surgery

☐ Spinal cord surgery

Urethral and genital reconstruction ☐ Vaginal reconstruction

☐ Urethral surgery

Sympathetic nervous system surgery

☐ Sympathectomy

☐ Other, please specify:

d. Occupational history

Current occupation

Specify:

Duration

years

months

Work Environment

☐ Indoors

☐ Outdoors

Exposure to

☐ extreme temperatures ☐ poor ventilation

☐ noise

Exposure to chemicals

☐ solvents ☐ heavy metals ☐ toxic substances at work If yes, specify the substances:

Exposure to radiation

☐ Yes

☐ No

If yes, specify the source/type:

If yes, specify if doses were above recommended occupational levels☐ Yes

☐ No

e. History of gonadotoxic medication

☐ ß-blockers ☐ Finasteride ☐ Opioids

☐ Chemotherapy

☐ Calcium blockers

☐ Serotonin reuptake inhibitors☐ Anabolic steroids

Prescription medications

☐ Immunosuppressants

(e.g. glucocorticoids, calcineurin inhibitors)

☐ Anti-epileptic drugs (AEDs)

☐ Serotonin reuptake inhibitors (SSRIs)

☐ Thiazide

☐ Other, specify:

☐ Cimetidine

☐ Allopurinol

☐ Sulfasalazine☐ Colchicine

☐ Nitrofurantoin

f. Lifestyle History

Physical activity

☐ Regular

☐ Irregular ☐ Rarely

Diet

☐ Balanced ☐ High-protein ☐ Vegetarian ☐ Vegan

☐ Keto

☐ Mediterranean ☐ Processed ☐ Please specify:

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Smoking or use of tobacco

products including electronic cigarette?

☐ Yes

☐ No

Number of cigarettes

Per day:

Number of years smoking:

Consumption of alcohol

☐ Yes

☐ No

If yes, how often: ☐ Regular

☐ Irregular ☐ Rarely

How much? (units/week)

Use recreational drugs?

☐ Yes

☐ No

If yes, which ones (specify): Frequency

☐ Regular

☐ Irregular ☐ Rarely

Recent stressors or changes in life ☐ Yes

☐ No If yes, specify:

g. Family history

Infertility in the family

☐ Yes

☐ No

Genetic or hereditary conditions

☐ Cystic fibrosis

☐ Kartagener syndrome

☐ Endometriosis

☐ PCOS

☐ Other, specify: Family history of early menopause ☐ Yes

☐ No

Endocrine diseases

☐ Yes

☐ No If yes, specify:

7. General physical examination

Height (cm)

BMI

Weight (kg)

Blood pressure (mmHG)

General physical examination

☐ Normal

☐ Abnormal If abnormal specify:

Signs of virilization

☐ Yes

☐ No If yes, specify:

Signs of hypoestrogenism

☐ Yes

☐ No If yes, specify:

Signs of hyperandrogenism

☐ Yes

☐ No If yes, specify:

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Skin changes

☐ Yes

☐ No If yes, specify:

Thyroid examination

☐ Normal

☐ Enlarged thyroid (goiter) ☐ Thyroid nodules

8. Gynecological examination

External genitalia (vulva)

☐ Normal

☐ Scars

☐ Lacerations

☐ Other, specify:

Vagina

☐ Normal

☐ Atrophic (dryness, thinning) ☐ Narrowed☐ Abnormal discharge. If present, specify:

Cervix

☐ Normal

☐ Ectropion (cervical eversion) ☐ Cervical scars☐ Other, specify:

Uterus

☐ Normal

☐ Enlarged ☐ Fibroids (size and location) ☐ Retroverted ☐ Anomalies, specify:

Ovaries

☐ Normal

☐ Polycystic (PCO)

☐ Enlarged ☐ Tender☐ Cystic lesions, specify size and type:

Fallopian tubes

☐ Patency (confirmed by

)

☐ Blocked (if known)

☐ Abnormalities, specify:

Pelvic examination

Tenderness:

☐ Yes

☐ No

If yes specify location: Thickened uterus: ☐ Yes

☐ No

Cystic or mass lesions:

☐ Yes

☐ No

If yes specify size: Specify location:

Palpable adnexal masses:

☐ Yes

☐ No

If yes specify location:

Other:

Specify:

Rectal examination

(if performed)

☐ Normal

☐ Tender ☐ Masses ☐ Abnormal ☐ Soft swelling ☐ Hard swelling

☐ Other, specify:

9. Additional information

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Annex 7. Components of male medical history and physical examination1

1 Adapted from the WHO manual for the standardized investigation, diagnosis and management of the infertile male.

Personal information

Full name

Date of birth

Age

Address

Contact

information

(phone, email)

Occupation

Marital or

relationship status

Relevant dates for evaluation

Date of history taking

Date

Month

Year

Date of birth of male

partner

Date

Month

Year

Date of birth of female

partner

Date

Month

Year

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Infertility history

Infertility

☐ Primary

☐ Secondary

Duration of infertility/attempting to achieve pregnancy

years

If secondary, months since last impregnation

months

Previous investigation (s) and/or treatments for infertility

☐ No ☐ Yes

If yes, please specify:

Contraceptive methods used

Please specify:

Duration of contraception use:

Previous pregnancy

☐ Current partner

☐ Another partner

Previous miscarriage

☐ Current partner

☐ Another partner

Treatments/evaluations of the female partner Please specify:

1. Sexual history

Sexual activity and practices

Frequency of sexual activity

☐ Regular

☐ Irregular ☐ Rarely

Timing of intercourse

☐ Spontaneous

☐ Around ovulation

Erectile dysfunction

☐ Yes

☐ No

☐ Normal

☐ Inadequate

Ejaculatory dysfunction

☐ Yes

☐ No

Pain during intercourse

☐ Yes

☐ No

Presence of sexual anxiety

☐ Yes

☐ No

Stress

☐ Yes

☐ No

Psychological barriers to sexual function

☐ Yes

☐ No

Use of sexual performance enhancers or lubricants

☐ Yes

☐ No

Prolonged abstinence

☐ Yes

☐ No

If yes, please specify duration:

days

months

Perceived quality of sexual activity

☐ Normal

☐ Inadequate

Previous or current sexual dysfunction

☐ Yes

☐ No

2. Childhood and development history

Pubertal development

Age at onset of puberty:

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Sexual development

☐ Normal

☐ Delayed

History of undescended testicle

☐ Yes

☐ No

☐ Left

☐ Right

Treatment of undescended testicle

☐ Yes

☐ No

☐ Medical

☐ Surgical

Epispadia

☐ Yes

☐ No

Hypospadia

☐ Yes

☐ No

Pathology possibly causing testicular damage

☐ Yes

☐ No

Injury

☐ Left

☐ Right

Torsion

☐ Left

☐ Right

Orchitis: mumps ☐ Left

☐ Right

Orchitis: other ☐ Left

☐ Right

3. Medical history

a. History of disease

☐ None

☐ Diabetes

☐ Hypertension

☐ Thyroid disorders

☐ Autoimmune diseases

☐ Neurologic disease

☐ Fibrocystic of the pancreas ☐ Chronic respiratory tract disease ☐ Tuberculosis (or exposure) ☐ Other, please specify:

b. History of infection

☐ None

High fever in past 6 months

☐ Yes

☐ No

Urinary infection

☐ Yes

☐ No

Epididymitis

☐ Yes

☐ No If yes, specify:

☐ Left

☐ Right

Orchitis

☐ Yes

☐ No If yes, specify:

☐ Left

☐ Right

Sexually transmitted disease (STI) ☐ Yes

☐ No

☐ Syphilis

☐ Gonorrhoea ☐ Chlamydia ☐ Other, specify:

Treatment for STIs

☐ Yes

☐ No If yes, specify treatment:

Symptoms of current infection

☐ Yes

☐ No

☐ Discharge ☐ Testicular pain

☐ Fever

☐ Other, specify:

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c. History of surgery

☐ None

Retroperitoneal and/or pelvic surgery

☐ Prostate

☐ Bladder neck

Inguinal, scrotal or perineal surgery

☐ Herniorraphy

☐ Inguinal hernia repair ☐ Hydrocele

☐ Vasectomy

☐ Epididymal cyst removal

☐ Orchiectomy

☐ Varicocele repair

☐ Testicular surgery☐ Vasectomy reversal

Sperm retrieval

☐ PESA

☐ MESA

☐ Electroejaculation

☐ TESE

☐ Penile vibratory stimulation

Bariatric, bladder, or prostate surgery

☐ Bariatric surgery

☐ Transurethral resection of the prostate (TURP)

Cranial surgery

☐ Pituitary surgery

Spinal surgery

☐ Spinal cord surgery Urethral and genital reconstruction ☐ Hypospadias repair

☐ Urethral structures surgery

Hernia treatment

☐ Yes

☐ No

Sympathetic nervous system surgery

☐ Sympathectomy

☐ Other, please specify:

d. Occupational history

Current occupation

Specify:

Duration

years

months

Work environment

☐ Indoors

☐ Outdoors

Exposure to

☐ Extreme temperatures ☐ Poor ventilation

☐ Noise

Exposure to chemicals

☐ Solvents ☐ Heavy metals☐ Toxic substances at work

If yes, specify the substances:

Exposure to radiation

☐ Yes

☐ No

If yes, specify the source/type:

If yes, specify if doses were above recommended occupational levels☐ Yes

☐ No

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e. History of gonadotoxic medication

☐ ß-blockers ☐ Finasteride ☐ Opioids

☐ Chemotherapy

☐ Calcium blockers

☐ Serotonin reuptake inhibitors☐ Anabolic steroids

Prescription medications

☐ Immunosuppressants (e.g. glucocorticoids, calcineurin

inhibitors)

☐ Anti-epileptic drugs (AEDs)

☐ Selective serotonin reuptake inhibitors (SSRIs)

☐ Thiazide

☐ Other, specify:

☐ Cimetidine

☐ Allopurinol

☐ Sulfasalazine☐ Colchicine

☐ Nitrofurantoin

f. Lifestyle History

Physical activity

☐ Regular

☐ Irregular ☐ Rarely

Diet

☐ Balanced ☐ High-protein ☐ Vegetarian ☐ Vegan

☐ Keto

☐ Mediterranean ☐ Processed ☐ Please specify:

Smoking or use of tobacco products including electronic cigarette?

☐ Yes

☐ No

Number of cigarettes

Per day:

Number of years smoking:

Consumption of alcohol

☐ Yes

☐ No

If yes, how often: ☐ Regular

☐ Irregular ☐ Rarely

How much? (units/week)

Use recreational drugs?

☐ Yes

☐ No

If yes, which ones (specify): Frequency: ☐ Regular

☐ Irregular ☐ Rarely

Recent stressors or changes in life ☐ Yes

☐ No If yes, specify:

g. Family history

Infertility in the family

☐ Yes

☐ No

Genetic or hereditary conditions

☐ Cystic fibrosis

☐ Kartagener syndrome

☐ Varicocele ☐ Other, specify:

Endocrine diseases

☐ Yes

☐ No If yes, specify:

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4. General physical examination

Height (cm)

BMI

Weight (kg)

Blood pressure (mmHg)

General physical examination

☐ Normal

Abnormal ☐ Hypoandrogenism☐ Hyperandrogenism

Signs of virilization

☐ Normal

Abnormal ☐ Testicular enlargement☐ Other, specify:

5. Uro-genital examination

Penis

☐ Normal

☐ Scars

☐ Hypospadias ☐ Plaques ☐ Epispadias ☐ Curvature ☐ Other, specify:

Testes

Side: Left - Right

Palpable in the scrotum

☐ Both palpable

☐ Abnormal

L ☐ R ☐

Palpable in inguinal region

☐ Both palpable

☐ Abnormal

L ☐ R ☐

☐ Both palpable

☐ Thickened

L ☐ R ☐

☐ Cystic/Nodule

L ☐ R ☐

☐ Tender

L ☐ R ☐

Volume (ml)

Left:

Right:

Device used for measurement

☐ Prader orchidometer ☐ Pachymeter ☐ Other

Epididymis

☐ Both normal

☐ Thickened

L ☐ R ☐

☐ Cystic

L ☐ R ☐

☐ Tender

L ☐ R ☐

Vas deferens

☐ Both normal

☐ Non palpable

L ☐ R ☐

☐ Thickened

L ☐ R ☐

Spermatic cord/Scrotum

☐ Normal

☐ Hydrocele

L ☐ R ☐

☐ Hernia

L ☐ R ☐

Varicocele

☐ Normal

☐ Grade III

L ☐ R ☐

☐ Grade II

L ☐ R ☐

☐ Grade I

L ☐ R ☐

☐ Subclinical

L ☐ R ☐

Inguinal examination

☐ Normal

☐ Lymphadenopaty

L ☐ R ☐

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Scrotal skin

☐ Normal

☐ Infectious scars

L ☐ R ☐

☐ Surgical scars

L ☐ R ☐

Rectal examination

Prostate

☐ Normal

☐ Soft swelling

☐ Tender

☐ Hard swelling

☐ Other

☐ Palpable

☐ Abnormal

Seminal vesicles

☐ Normal

☐ Soft swelling

☐ Tender

☐ Hard swelling

☐ Other

☐ Palpable

☐ Abnormal

6. Additional information

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For further information, please contact:

Department of Sexual, Reproductive, Maternal, Child and Adolescent Health and Ageing: Advancing Life

Course Health and Reproduction (LHR)

Human Reproduction Programme (HRP)

World Health Organization

Avenue Appia 20

CH-1211, Geneva 27

Switzerland

Email: srhcfc@who.int

Website: https://www.who.int/health-topics/infertility www.who.int

表 1
Domain	Favours strong recommendations	Favours conditional recommendations
Balance of benefits and harms	Benefits highly outweigh harms or vice versa	Benefits and harms are more closely balanced
Quality of evidence	Higher certainty	Lower certainty
Values/preferences regarding outcomes	Benefits to harms assessment not impacted by variability in values or preferences	Variability in values or preferences would impact benefits to harms assessment
Acceptability	Highly acceptable	Low or variable acceptability
Costs/resources	Cost-saving/cost-effective	Costly/cost-ineffective
Feasibility	Feasible in intended settings	Unfeasible or feasibility varies in intended settings
Equity	Increased equity	Decreased equity or effect on equity is variable

表 2
Implications	Strong recommendation WHO recommends ...	Conditional recommendation WHO suggests ...
For patients	Most individuals in this situation would want the recommended course of action and only a small proportion would not. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences.	The majority of individuals in this situation would want the suggested course of action, but many would not.
For clinicians	Most individuals should receive the recommended course of action. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator.	Clinicians should recognize that different choices will be appropriate for each individual and that clinicians must help each individual arrive at a management decision consistent with the individual's values and preferences. Decision aids may be useful to help individuals make decisions consistent with their values and preferences.
For policy-makers	The recommendation can be adopted as policy in most situations.	Policy-making will require substantial debate and the involvement of various stakeholders.

表 3
	Single mid-luteal progesterone test
Sensitivity (95% CI)	80% (72-88%)
Specificity (95% CI)	71% (not reported)

表 4
	Progesterone only	Progesterone + repeat progesterone for women whose results show that they are anovulatory on the initial progesterone test	Progesterone followed by US for women whose results show that they are anovulatory on the initial progesterone test
True positives	77	81	81
True negatives	3	13	18
False positives	1	6	1
False negatives	19	1	0
Sensitivity	80	80 (first test), 80 (repeat test)	80 (progesterone), 100 (US)
Specificity	71	71 (first test), 71 (repeat test)	80 (progesterone), 100 (US)

表 5
	AFC	AMH	FSH
Sensitivity (95% CI)	78% (64-88%)	80% (67-90%)	63% (48-76%)
Specificity (95% CI)	65% (51-76%)	74% (61-84%)	69% (55-79%)
True positives	36	37	29
True negatives	35	40	37
False positives	19	14	17
False negatives	10	9	17

表 7
	AMH	AFC
Sensitivity (95% CI)	80% (74-85%)	73% (62-83%)
Specificity (95% CI)	81% (75-85%)	85% (78-90%)

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图示：30.6%26.3%18.7%10.8%?Female factorsMale factorsBoth maleNo causefoundalonealoneand femaleMale factor contributes wholly or inpart to 45.1% of infertility cases.

图示：17.5%Estimated lifetimeprevalence ofinfertility12.6%Estimated periodprevalence ofinfertility

图示：HICS17.8%LMICS16.5%

图示：Gender equalityRight to healthWomen are often disproportionatelyEveryone has a right to enjoy theaffected by the consequences ofhighest attainable standard ofinfertility. Addressing infertility isphysical, mental and socialrelevant to gender equalitywell-beingRight to enjoy theUniversal healthbenefits of scientificcoverage (UHC)progress and itsPrevention, diagnosisapplicationsand treatment ofInterventions like assistedinfertility should bereproductive technologiesintegrated into health(ARTs) have a role to play iservices and systemsaddressing infertilityEquitable accessPrimary health care (PHC)+to health careEnsuring that basicInfertility should beinterventions such as fertilityconsistently includededucation are available at thePHC level will contribute toin health policies,services and financingenhanced service coverageFinancial protectionGiven the risk of large out-of-pocket costsfor preventing, diagnosing or treatinginfertility, fertility care should be providedwhile upholding financial protectionhe Universal Declaration of Human Rightsor religion, have the right to marry and found aArticle 16) states that "men and women of fullfamily" (4). A significant proportion of young adulin demographic health surveys express a desirege, without any limitation due to race, nationalityBecause of the need to refer to biological sex characteristics on clinical grounds, this guideline uses terms such as male anfemale (in its recommendations), and men and women (in text synthesizing research) to indicate biological sex assignedat birth, and uses "couples" to refer to heterosexual partnerships. However, a wide variety of people, including individualswho are single or who are in same-sex or gender-diverse relationships, may need services to fulfil their fertility preferencesProviders of fertility care should consider the needs of, and provide equal care to, all individuals

图示：Guldeline for theprevention, diagnosisProfessionalHealth careand treatmentof infertilitysocietiesprofessionalsand otherincluding physicians,organizationsembryologists, nursesinvolved in sexuamidwives, laboratoryand reproductivespecialists, and otherhealth programmeshealth care providersFunding andPatient supportand advocacyphilanthropicPreventionTreatmentorganizationsagenciesDiagnosisThe scope of this guideline includes thediagnosis and treatment of:prevention,Policy-makerswho develop national healthrpolicies, services and financingFemale-factorUnexplainedMale-factorinfertilityinfertilityinfertility

图示：Guideline Development Group(GDG) establishedDetermining the scope of theguidelineIdentifying recommendationquestionsEvidence retrieval and synthesisPresentation of evidence usingGRADE methodologyMethodologyfor guidelinedevelopmentRecommendationsdrafted by the GDGExternal review of guideline byExternal Review Group (ERG)Review and approval of guideline byWHO Guideline Review Committee (GRC)Publication, dissemination andimplementation of the guideline

图示：Chapter

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图示：InitialTaking and recording aConducting a physicalmedical historyconsultationexamination7Provision of informationDiscussion ofConducting a diagnosticdiagnosis, etiologyabout pre-pregnancyevaluation of the maleadvice, counselling or careand treatment optionsand female reproductivefunctionsAgreeing on andProviding a clinicalDocumentingIdentification andproviding treatmentfollow-up andthe outcomeserral of patients withfor infertilitymanaging the risks ofof infertilityexisting conditions toinfertility treatmenttreatmentother services

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图示：Providing informationSchools / educationa一on fertility andinstitutionsinfertility to peopleIntegrate into healthof reproductive ageeducationhelps reduce riskfactors and promotesWhere toPrimary caretimely care-seeking.During routine healthIt also enablesprovide fertilityvisits and checkupsreproductive planning.information一Sexual healthFamily planning andreproductive clinicsUnderstandingHealthy lifestyleinfertilityRisk factors include:What infertility is, commonKey messages● smoking,causes, when to seek help● excessive alcohol useand available support options· obesityfor individuals and couples● being underweight●others (see Chapters 1 and 4of this quideline).

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图示：Couple presents with history of failure to achieve a pregnancyFemale in a couple with infertilityaMale in a couple with infertility↓History+physical examinationSee Section 5.7 for assessment ofthe male in an infertile couplebNormal?YesNo↓Female with normal examinationHistory of abnormal uterine bleeding±History of STI or abdominal/History of absent or irregular periodsfindings and medical historypelvic surgerypelvic mass on exam↓↓Suspected tubal diseaseSuspected uterine cavity disorderSuspected ovulation dysfunction↓↓↓Investigate cause of anovulation/OptionalConfirm ovulationConfirm tubal patencyInvestigate tube patencyInvestigate uterine cavityoligo-ovulationinvestigationsd↓↓↓↓Assess with:Mid-lutealAsses with: Is(orpreferably3D UsifiAssess with: Either HSGAssess with: Either HSGAssess/excluded:HPO axis (E2,T,FSH,is available) OR either HSG OR 2D USCOR HyCoSyOR HyCoSyprogesteroneLH)TSH,PRLAssess ovarian reserve↓Uterine cavityNoeNormal?YesNormal?NoNoabnormalityCauseAssess with:AMH ORNoidentified?identified?AFC OR FSHInvestigateInvestigate cause ofanovulation/oligo-ovulationfother causesgYesYesUnexplained infertility (if semen parameters are within theInfertility due toInfertility due toInfertility dueInfertility due toWHO reference ranges in a male with normal history andtubal blockage oruterine cavityto ovulationreduced ovariandiseaseabnormalitydisordersphysical exam)hreserve↓↓Provide treatment (see relevant sections in this guideline)k

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引用 / 出处

2025 WHO指南：不孕症的预防、诊断和治疗. 2025.

2025 WHO指南：不孕症的预防、诊断和治疗

© World Health Organization 2025

Contents

List of tables

List of figures

Foreword

Dr Tedros Adhanom Ghebreyesus

Acknowledgements

Abbreviations

Executive summary

The objectives of this guideline are:

Summary of recommendations

General approach and management of infertility

Good practice statements on the general approach and management of infertility $\rightarrow$

Recommendations for the prevention of infertility

Recommendations for information provision on fertility and infertility

Remarks:

Recommendations for information provision on fertility and infertility (cont.)

Recommendation for risk reduction from tobacco smoking

Recommendation for risk reduction from sexually transmitted infections

Recommendations for the diagnosis of infertility due to ovulatory dysfunction

Recommendations for the diagnosis of infertility due to ovulatory dysfunction (cont.)

Remarks:

Recommendation for the diagnosis of infertility due to tubal disease $\rightarrow$

Remark:

Recommendations for the diagnosis of infertility due to uterine cavity disorder

Remark:

Recommendation for the diagnosis of infertility due to uterine cavity disorder (cont.) $\rightarrow$

Recommendation for semen analysis

Recommendations for the treatment of infertility due to ovulatory dysfunction

Recommendations for the treatment of infertility due to tubal disease

Remarks:

Recommendations for the treatment of infertility due to tubal disease (cont.)

Recommendation for the treatment of infertility due to uterine cavity disorder

Recommendation on the use of antioxidants

Remark:

Recommendations for the treatment of varicocele

Remarks:

Remarks:

Recommendations for the treatment of varicocele (cont.)

Remarks:

Remarks:

Recommendations for first-line management of couples with unexplained infertility

Remarks:

Recommendations for first-line management of couples with unexplained infertility (cont.)

Remarks:

Recommendations for second-line management of couples with unexplained infertility $\rightarrow$

Remarks:

Remark:

Recommendations for third-line management of unexplained infertility $\rightarrow$

Chapter 1 Introduction

1.1 Epidemiology and global burden of infertility

Fig. 1.1. Epidemiology and global burden of infertility

1.2 The need to strengthen global efforts to prevent, diagnose and treat infertility

References

Chapter 2 Rationale and methodology

2.1 Rationale

2.2 Goals and objectives

Fig. 2.1. Scope and audience

Intended users of the guideline include:

2.3 Scope

2.4 Target audience

2.5 Guiding principles

Fig. 2.2. Methodology for guideline development

2.6 Methods

Guideline Development Group

External Review Group

Determining the scope of the guideline and recommendation questions

Retrieval and synthesis of evidence

Presentation of the evidence

Table 2.1. Evidence to decision framework

Review of evidence and drafting of recommendations

Making of recommendations

Table 2.2. Implications of differing strengths of GRADE recommendations

Good practice statements

Implementation considerations and research gaps

Management of conflicts of interest

References

Chapter 3 Approach to evaluation and management of infertility

Relevant resources