Cer 217 Infertility Final Report PDF
Cer 217 Infertility Final Report PDF
Cer 217 Infertility Final Report PDF
Number 217
R
Management of Infertility
Comparative Effectiveness Review
Number 217
Management of Infertility
Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
5600 Fishers Lane
Rockville, MD 20857
www.ahrq.gov
Prepared by:
Duke Evidence-based Practice Center
Durham, NC
Investigators:
Evan R. Myers, M.D., M.P.H.
Jennifer L. Eaton, M.D., M.S.C.I.
Kara A. McElligott, M.D., M.P.H.
Patricia G. Moorman, Ph.D., M.S.P.H.
Ranee Chatterjee, M.D., M.P.H.
Arthurine K. Zakama, M.D.
Karen Goldstein, M.D., M.S.P.H.
Jennifer Strauss, Ph.D.
Remy R. Coeytaux, M.D., Ph.D.
Adam Goode, D.P.T., Ph.D.
Ethan Borre, B.A.
Geeta K. Swamy, M.D.
Amanda J. McBroom, Ph.D.
Kathryn Lallinger, M.S.L.S.
Robyn Schmidt, B.A.
J. Kelly Davis, B.A.
Victor Hasselblad, Ph.D.
Gillian D. Sanders, Ph.D.
Key Messages
• The ability to compare the effectiveness of treatments would be enhanced by greater
consistency in reporting of outcomes, particularly live birth rates, as well as reporting of
diagnosis-specific outcomes for treatments, such as assisted reproductive technology, that
are used for multiple diagnoses.
• Letrozole most likely results in more live births with lower multiple births than
clomiphene alone in women with polycystic ovary syndrome.
• For women with unexplained infertility, there is most likely shorter time to pregnancy for
women with immediate in vitro fertilization (IVF) than for those who undergo other
treatments prior to IVF. For the outcomes of live birth, multiple births, ectopic
pregnancy, miscarriage, low birthweight, and ovarian hyperstimulation syndrome
however, there may be no difference between the two groups.
• Across all diagnoses, elective single-embryo transfer results in slightly lower live birth
rates but substantially lower reductions in multiple birth rates than multiple-embryo
transfer.
ii
This report is based on research conducted by the Duke Evidence-based Practice Center (EPC)
under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD
(Contract No. 290-2015-00004-I. The findings and conclusions in this document are those of the
authors, who are responsible for its contents; the findings and conclusions do not necessarily
represent the views of AHRQ. Therefore, no statement in this report should be construed as an
official position of AHRQ or of the U.S. Department of Health and Human Services.
None of the investigators have any affiliations or financial involvement that conflicts with
the material presented in this report.
The information in this report is intended to help healthcare decision makers—patients and
clinicians, health system leaders, and policymakers, among others—make well-informed
decisions and thereby improve the quality of healthcare services. This report is not intended to be
a substitute for the application of clinical judgment. Anyone who makes decisions concerning the
provision of clinical care should consider this report in the same way as any medical reference
and in conjunction with all other pertinent information, i.e., in the context of available resources
and circumstances presented by individual patients.
This report is made available to the public under the terms of a licensing agreement between the
author and the Agency for Healthcare Research and Quality. This report may be used and
reprinted without permission except those copyrighted materials that are clearly noted in the
report. Further reproduction of those copyrighted materials is prohibited without the express
permission of copyright holders.
AHRQ or U.S. Department of Health and Human Services endorsement of any derivative
products that may be developed from this report, such as clinical practice guidelines, other
quality enhancement tools, or reimbursement or coverage policies, may not be stated or implied.
This report may periodically be assessed for the currency of conclusions. If an assessment is
done, the resulting surveillance report describing the methodology and findings will be found on
the Effective Health Care Program website at www.effectivehealthcare.ahrq.gov. Search on the
title of the report.
Persons using assistive technology may not be able to fully access information in this report. For
assistance contact epc@ahrq.hhs.gov.
Suggested citation: Myers ER, Eaton JL, McElligott KA, Moorman PG, Chatterjee R, Zakama
AK, Goldstein K, Strauss J, Coeytaux RR, Goode A, Borre E, Swamy GK, McBroom AJ,
Lallinger K, Schmidt R, Davis JK, Hasselblad V, Sanders GD. Management of Infertility.
Comparative Effectiveness Review No. 217. (Prepared by the Duke Evidence-based Practice
Center under Contract No. 290-2015-00004-I.) AHRQ Publication No. 19-EHC014-EF.
Rockville, MD: Agency for Healthcare Research and Quality; May 2019. Posted final reports
are located on the Effective Health Care Program search page.
DOI: https://doi.org/10.23970/AHRQEPCCER217.
iii
Preface
The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based
Practice Centers (EPCs), sponsors the development of systematic reviews to assist public- and
private-sector organizations in their efforts to improve the quality of healthcare in the United
States. These reviews provide comprehensive, science-based information on common, costly
medical conditions, and new healthcare technologies and strategies.
Systematic reviews are the building blocks underlying evidence-based practice; they focus
attention on the strength and limits of evidence from research studies about the effectiveness and
safety of a clinical intervention. In the context of developing recommendations for practice,
systematic reviews can help clarify whether assertions about the value of the intervention are
based on strong evidence from clinical studies. For more information about AHRQ EPC
systematic reviews, see www.effectivehealthcare.ahrq.gov/reference/purpose.cfm.
AHRQ expects that these systematic reviews will be helpful to health plans, providers,
purchasers, government programs, and the healthcare system as a whole. Transparency and
stakeholder input are essential to the Effective Health Care Program. Please visit the website
(www.effectivehealthcare.ahrq.gov) to see draft research questions and reports or to join an
email list to learn about new program products and opportunities for input.
If you have comments on this systematic review, they may be sent by mail to the Task Order
Officer named below at: Agency for Healthcare Research and Quality, 5600 Fishers Lane,
Rockville, MD 20857, or by email to epc@ahrq.hhs.gov.
iv
Acknowledgments
The authors thank Megan von Isenburg, M.S.L.S., for help with the literature search and
retrieval; Samantha Bowen, Ph.D., for project leadership; Megan Chobot, M.S.L.S., for
assistance with project coordination; and Liz Wing, M.A., and Rebecca Gray, Ph.D., for editorial
assistance.
Key Informants
In designing the study questions, the EPC consulted several Key Informants who represent the
end-users of research. The EPC sought the Key Informant input on the priority areas for research
and synthesis. Key Informants are not involved in the analysis of the evidence or the writing of
the report. Therefore, in the end, study questions, design, methodological approaches, and/or
conclusions do not necessarily represent the views of individual Key Informants.
Key Informants must disclose any financial conflicts of interest greater than $5,000 and any
other relevant business or professional conflicts of interest. Because of their role as end-users,
individuals with potential conflicts may be retained. The TOO and the EPC work to balance,
manage, or mitigate any conflicts of interest.
The list of Key Informants who provided input to this report follows:
v
Technical Expert Panel
In designing the study questions and methodology at the outset of this report, the EPC consulted
several technical and content experts. Broad expertise and perspectives were sought. Divergent
and conflicting opinions are common and perceived as healthy scientific discourse that results in
a thoughtful, relevant systematic review. Therefore, in the end, study questions, design,
methodologic approaches, and/or conclusions do not necessarily represent the views of
individual technical and content experts.
Technical Experts must disclose any financial conflicts of interest greater than $5,000 and any
other relevant business or professional conflicts of interest. Because of their unique clinical or
content expertise, individuals with potential conflicts may be retained. The TOO and the EPC
work to balance, manage, or mitigate any potential conflicts of interest identified.
The list of Technical Experts who provided input to this report follows:
vi
Peer Reviewers
Prior to publication of the final evidence report, EPCs sought input from independent Peer
Reviewers without financial conflicts of interest. However, the conclusions and synthesis of the
scientific literature presented in this report do not necessarily represent the views of individual
reviewers.
Peer Reviewers must disclose any financial conflicts of interest greater than $5,000 and any
other relevant business or professional conflicts of interest. Because of their unique clinical or
content expertise, individuals with potential nonfinancial conflicts may be retained. The TOO
and the EPC work to balance, manage, or mitigate any potential nonfinancial conflicts of interest
identified.
vii
Management of Infertility
Structured Abstract
Objective. Previous studies have demonstrated varying success for treatment of infertility. Much
of this literature, however, does not focus on treatment of women with specific diagnoses. This
systematic review evaluated the comparative effectiveness and safety of fertility treatment
strategies for (a) women of reproductive age (18–44) who are infertile due to polycystic ovary
syndrome (PCOS), endometriosis, unknown reasons, or tubal or peritoneal factors or (b) couples
with male factor infertility, and evaluated short- and long-term health outcomes of gamete
donors in infertility.
Data sources. We searched PubMed®, Embase®, and the Cochrane Database of Systematic
Reviews for English-language studies published from January 1, 2007, to October 3, 2018, that
reported live birth rates, pregnancy and neonatal outcomes, time to pregnancy, and short-term
and long-term adverse outcomes for mothers and children born after infertility treatment. For
male and female donors, we searched for studies reporting short- and long-term adverse effects
and quality-of-life outcomes.
Review methods. Two investigators screened each abstract and full-text article for inclusion;
abstracted data; and performed quality ratings, applicability ratings, and evidence grading.
Where appropriate, random-effects models were used to compute summary estimates of effects.
Results. We identified a total of 151 studies/primary articles that met our inclusion criteria: 56
for PCOS, 7 for endometriosis, 50 for infertility secondary to unknown causes, 8 for
tubal/peritoneal factor infertility, 23 for male factor infertility, and 5 for outcomes in male and
female gamete donors. There were also 21 studies that adjusted for cause of infertility but whose
findings were relevant across all infertility diagnoses. For women with infertility associated with
PCOS, there was moderate strength of evidence (SOE) that letrozole results in higher live birth
rates than clomiphene while reducing multiple births and with no difference in ectopic
pregnancies (moderate SOE). No differences were seen in low birthweight or time to pregnancy
(low SOE). There was moderate SOE that there is no difference between clomiphene and
metformin as primary therapy. Comparing laparoscopic ovarian drilling with oral agents, live
birth rates were not different (moderate SOE). For couples with unexplained infertility, there is
no difference between the oral agents of letrozole and anastrozole for the outcome of ectopic
pregnancy (low SOE), but evidence is insufficient for other outcomes of interest. There was also
no difference between differing adjunct treatments used in combination with oral agents and
intrauterine insemination (IUI) for the outcomes of live birth, miscarriage, and ovarian
hyperstimulation syndrome (OHSS) (low SOE for all outcomes). Time to pregnancy was shorter
with immediate in vitro fertilization (IVF) compared with strategies that started with clomiphene
and IUI or gonadotropins and IUI, followed by IVF if necessary (moderate SOE). For couples
with male factor infertility, live birth rate (moderate SOE) and miscarriage (low SOE) did not
differ between intracytoplasmic sperm injection (ICSI) and intracytoplasmic morphological
sperm injection. (The latter is not used in the United States.) For oocyte donors, studies
suggested a lower incidence of OHSS with gonadotropin-releasing hormone (GnRH) agonist
trigger than with human chorionic gonadotropin (hCG) trigger (low SOE). However, there was a
lack of evidence on any long-term outcomes. Evidence concerning specific comparisons was
viii
insufficient for couples with tubal factor or endometriosis infertility. Findings applicable across
all indications for infertility for couples undergoing assisted reproductive technology (ART)
included lower live birth rates for African-Americans compared with other racial/ethnic groups
(low SOE); lower live birth rates but significant reductions in multiple birth rates with elective
single-embryo transfer compared with multiple embryo transfer (low SOE); no increase in most
maternal cancers after ART treatment after adjustment for infertility in general or specific causes
(low SOE); and, for children born after ART, a possible increased risk of neurodevelopmental
disorders after ICSI compared with IVF (low SOE).
Conclusions. Although there is evidence supporting some strategies for treatment of infertility,
both for specific diagnoses and for couples with any diagnosis, consensus on which outcomes to
collect and report, and which areas of uncertainty are most important to resolve, is needed in
order to design future studies that will improve the ability of patients and clinicians to make
optimal decisions.
ix
Contents
Evidence Summary ................................................................................................................. ES-1
Introduction ................................................................................................................................... 1
Background ................................................................................................................................. 1
Condition................................................................................................................................. 1
Treatment Strategies ............................................................................................................... 1
Complexity of Decision Making for Treatments of Infertility ............................................... 3
Limitations of the Evidence Base ........................................................................................... 3
Scope and Key Questions ........................................................................................................... 4
Scope of the Review ............................................................................................................... 4
Key Questions ......................................................................................................................... 4
Organization of This Report ....................................................................................................... 7
Methods .......................................................................................................................................... 8
Topic Refinement and Review Protocol ..................................................................................... 8
Literature Search Strategy........................................................................................................... 8
Search Strategy ....................................................................................................................... 8
Inclusion and Exclusion Criteria............................................................................................. 9
Study Selection ..................................................................................................................... 12
Data Extraction ..................................................................................................................... 13
Quality (Risk of Bias) Assessment of Individual Studies ......................................................... 13
Data Synthesis ........................................................................................................................... 14
Strength of the Body of Evidence ............................................................................................. 15
Applicability ............................................................................................................................. 16
Peer Review and Public Commentary ...................................................................................... 16
Results .......................................................................................................................................... 17
Results of Literature Searches .................................................................................................. 17
Description of Included Studies ................................................................................................ 19
Key Question 1. PCOS ............................................................................................................. 19
Description of Studies Included for KQ 1 (PCOS)............................................................... 19
Key Points for PCOS ............................................................................................................ 20
Detailed Synthesis by Treatment for PCOS.......................................................................... 21
Subgroups of Interest for PCOS ........................................................................................... 46
Strength of Evidence for PCOS ............................................................................................ 46
Key Question 2. Endometriosis ................................................................................................ 52
Description of Included Studies for KQ 2 (Endometriosis).................................................. 53
Key Points for Endometriosis ............................................................................................... 53
Detailed Synthesis by Treatment for Endometriosis ............................................................ 53
Subpopulations of Interest for Endometriosis....................................................................... 55
Strength of Evidence for Endometriosis ............................................................................... 55
Key Question 3. Unexplained Infertility................................................................................... 57
Description of Included Studies for KQ 3 (Unexplained Infertility) .................................... 57
Key Points for Unexplained Infertility ................................................................................. 57
Detailed Synthesis by Treatment for Unexplained Infertility ............................................... 58
Strength of Evidence for Unexplained Infertility ................................................................. 74
x
Key Question 4. Tubal and Peritoneal Factor Infertility........................................................... 77
Description of Included Studies for KQ 4 (Tubal and Peritoneal Factor Infertility) ............ 78
Key Points for Tubal or Peritoneal Factor Infertility ............................................................ 78
Detailed Synthesis by Treatment for Tubal or Peritoneal Factor Infertility ......................... 78
Strength of Evidence for Tubal and Peritoneal Factor Infertility ......................................... 80
Key Question 5. Male Factor Infertility.................................................................................... 81
Description of Included Studies for KQ 5 (Male Factor) ..................................................... 82
Key Points for Male Factor Infertility .................................................................................. 82
Detailed Synthesis by Treatment for Male Factor Infertility ................................................ 83
Strength of Evidence for Male Factor Infertility .................................................................. 90
Key Question 6. Donors in Infertility ....................................................................................... 93
Description of Included Studies for KQ 6 (Donors) ............................................................. 93
Key Points for Donors .......................................................................................................... 93
Detailed Synthesis for Oocyte Donors .................................................................................. 93
Strength of Evidence for Donors .......................................................................................... 95
Key Findings Across All Infertility Diagnoses ......................................................................... 95
Description of Included Studies Across All KQs ................................................................. 95
Key Points for Any Infertility Diagnosis .............................................................................. 96
Subgroups of Interest (With Any Infertility Diagnosis) ....................................................... 99
Strength of Evidence (With Any Infertility Diagnosis) ...................................................... 102
Publication Bias ...................................................................................................................... 104
Discussion................................................................................................................................... 105
Key Findings and Strength of Evidence ................................................................................. 105
Findings in Relation to What Is Already Known.................................................................... 106
Applicability ........................................................................................................................... 119
Implications for Clinical and Policy Decision Making............................................................ 121
Limitations of the Systematic Review Process ....................................................................... 122
Research Recommendations ................................................................................................... 123
Conclusion .............................................................................................................................. 125
References .................................................................................................................................. 126
Acronyms and Abbreviations .................................................................................................. 149
Tables
Table A. Summary of strength of evidence for major outcomes—KQ 1 (PCOS) ................... ES-9
Table B. Summary of strength of evidence for major outcomes—KQ 2 (endometriosis) ..... ES-12
Table C. Summary of strength of evidence for major outcomes—KQ 3 (unexplained
infertility) ................................................................................................................................ ES-13
Table D. Summary of strength of evidence for major outcomes—KQ 4 (tubal and
peritoneal factor infertility). .................................................................................................... ES-15
Table E. Summary of strength of evidence for major outcomes—KQ 5 (male factor
infertility) ................................................................................................................................ ES-16
Table F. Summary of strength of evidence for major outcomes—KQ 6 (donors in
infertility) ................................................................................................................................ ES-18
Table G. Summary of strength of evidence for major outcomes—all infertility diagnoses ... ES-19
Table 1. Inclusion and exclusion criteria ........................................................................................ 9
xi
Table 2. Definitions of overall quality ratings .............................................................................. 14
Table 3. Key to primary and companion articles .......................................................................... 17
Table 4. Outcomes for comparisons of oral agents alone in women with PCOS ......................... 24
Table 5. Outcomes for comparisons of oral agents alone versus acupuncture in women with
PCOS............................................................................................................................................. 28
Table 6. Outcomes for oral agents alone versus oral agents with IUI in women with PCOS ...... 29
Table 7. Outcomes for oral agents alone versus surgical management in women with PCOS .... 31
Table 8. Outcomes for oral agents versus gonadotropins in women with PCOS ......................... 34
Table 9. Outcomes for lifestyle intervention versus oral contraceptive pills or no intervention in
women with PCOS........................................................................................................................ 36
Table 10. Outcomes for surgical management versus gonadotropins in women with PCOS ...... 37
Table 11. Outcomes for gonadotropins with IUI in women with PCOS ...................................... 38
Table 12. Outcomes for comparisons of IVF treatments in women with PCOS .......................... 41
Table 13. Outcomes for adjuncts to IVF in women with PCOS................................................... 43
Table 14. Outcomes for fresh versus frozen embryo transfer in IVF in women with PCOS ....... 44
Table 15. Outcomes for comparisons of ICSI treatment in women with PCOS .......................... 45
Table 16. Strength of evidence for major outcomes—KQ 1 (PCOS)........................................... 47
Table 17. Strength of evidence for major outcomes—KQ 2 (endometriosis) .............................. 56
Table 18. Outcomes for comparisons of oral agents without IUI in women with unexplained
infertility ....................................................................................................................................... 59
Table 19. Outcomes for comparisons of oral agents versus unstimulated IUI versus expectant
management in women with unexplained infertility .................................................................... 60
Table 20. Outcomes for comparisons of oral agents with IUI in women with unexplained
infertility ....................................................................................................................................... 62
Table 21. Outcomes for comparisons of oral agents with IUI versus gonadotropins with IUI for
unexplained infertility ................................................................................................................... 64
Table 22. Outcomes for comparisons of different treatment strategies for controlled ovarian
hyperstimulation with gonadotropins and IUI in women with unexplained infertility ................ 66
Table 23. Outcomes for comparisons of immediate IVF versus other treatments prior to IVF in
women with unexplained infertility .............................................................................................. 67
Table 24. Strength of evidence for major outcomes—KQ 3 (unexplained infertility) ................. 74
Table 25. Strength of evidence for major outcomes—KQ 4 (tubal and peritoneal factor
infertility) ...................................................................................................................................... 80
Table 26. Outcomes for comparisons of IVF in couples with male infertility ............................. 84
Table 27. Strength of evidence for major outcomes—KQ 5 (male factor infertility) .................. 90
Table 28. Strength of evidence for major outcomes—KQ 6 (donor) ........................................... 95
Table 29. Cancer risk (95% CI) for ever use of clomiphene citrate by infertility diagnosis ........ 97
Table 30. Cancer risk (95% CI) for ever use of gonadotropins by infertility diagnosis ............... 97
Table 31. Cancer risk (SIR 95% CI) among women who underwent assisted reproduction by
infertility diagnosis ....................................................................................................................... 98
Table 32. Birth rates by number of embryos transferred ............................................................ 100
Table 33. Outcomes with fresh and frozen IVF cycles ............................................................... 100
Table 34. Strength of evidence for major outcomes—across all infertility diagnoses ............... 102
Table 35. Report findings and major guidelines/recommendations—KQ 1. PCOS................... 108
Table 36. Report findings and major guidelines/recommendations—KQ 2, endometriosis ...... 110
xii
Table 37. Report findings and major guidelines/recommendations—KQ 3, unexplained infertility
..................................................................................................................................................... 111
Table 38. Report findings and major guidelines/recommendations—KQ 4, tubal and peritoneal
factor infertility ........................................................................................................................... 112
Table 39. Report findings and major guidelines/recommendations—KQ 5, male factor infertility
..................................................................................................................................................... 114
Table 40. Report findings and major guidelines/recommendations—KQ 6, donors .................. 115
Table 41. Report findings and major guidelines/recommendations—all KQs: long-term outcomes
of treatments................................................................................................................................ 117
Table 42. Potential issues with applicability of included studies ............................................... 119
Figures
Figure A. Analytic framework .................................................................................................. ES-5
Figure 1. Analytic framework ......................................................................................................... 6
Figure 2. Literature flow diagram ................................................................................................. 18
Figure 3. Effect of ICSI versus IMSI on live birth ....................................................................... 86
Appendixes
Appendix A. Exact Search Strings
Appendix B. Data Abstraction Elements
Appendix C. List of Included Studies
Appendix D. List of Excluded Studies
Appendix E. Characteristics of Included Studies
Appendix F. AMSTAR Quality Assessment for Systematic Reviews
Appendix G. Risk of Bias Assessment for Included Studies
Appendix H. Supplemental Project To Assess the Transparency of Reporting for Trials
Evaluating Treatment for Infertility
xiii
Evidence Summary
Background
Condition and Therapeutic Strategies
“Infertility” has traditionally been defined as failure to achieve pregnancy after 12 months of
regular unprotected intercourse with the same partner (or after 6 months for women greater than
35 years of age). However, as many as half of such couples will conceive without intervention
over the next 12-24 months. Because of this, the term “subfertility” is preferred by many.1 From
a population perspective, couples who meet the dichotomous criteria for “infertility” include
couples who are “normal” but who are in the upper end of the population distribution for “time
to pregnancy,” and couples who have a physiological or anatomical cause for a prolonged time to
pregnancy. However, to be concise, we will use the term “infertility” throughout this report.
Self-reported infertility in the United States, using the 12-month definition, affected
approximately 6 percent of married women aged 15-44 in the 2006-2010 National Survey of
Family Growth (the most recent available data).2 In one population-based study, approximately
10 percent of pregnant women reported receiving infertility treatment, with 29 percent of these
women using fertility-enhancing medications; 21 percent using assisted reproductive technology
(ART), including in vitro fertilization (IVF); 15 percent using artificial insemination with
fertility-enhancing drugs; and 23 percent using other treatments, including surgery.3 Other
estimates of the prevalence of infertility treatment are similar.4-8 Particularly in the United States,
where availability of infertility services is variable depending on a number of factors, particularly
insurance coverage, utilization of infertility treatments may underestimate the overall burden of
infertility.
The most common demographic factor associated with female infertility is “advanced
reproductive age,” although the probability of pregnancy begins to decline by the mid-20’s, the
slope of decline sharply increases by age 35.9 Other common causes of female infertility include
polycystic ovary syndrome (PCOS), endometriosis, occlusion of the fallopian tubes from prior
infectious disease,6 and infertility secondary to cancer treatment.10-12 Isolated male factor
infertility affects approximately 17 percent of couples seeking treatment, with 34.6 percent of
couples having both male and female diagnoses.13
Treatment options are usually dependent on the underlying etiology of infertility. For female
causes, options include surgical management of tubal occlusion, surgical treatment of
endometriosis, ovarian “drilling” for treatment of PCOS, use of ovulation-induction agents
including oral (clomiphene citrate or letrozole) and injected drugs (gonadotropins), artificial
insemination with either partner or donor sperm (depending on partner fertility status), and ART,
which includes both traditional IVF (fertilization of the egg by the sperm occurs without direct
manipulation) and IVF with intra-cytoplasmic sperm injection (ICSI) (fertilization occurs via
direct injection of sperm into the egg).14,15 Treatment options for male factor infertility include
medical treatment of a diagnosed endocrinopathy or other conditions affecting sperm production,
empiric treatments with hormonal or other agents, surgical management of varicocele,
intrauterine insemination, IVF, ICSI, or use of donor sperm.16 Options appropriate for some
diagnoses (e.g., ovulation induction in PCOS or unexplained infertility) may not be appropriate
for others (e.g., women with documented tubal occlusion). In other cases, the appropriate
ES-1
comparisons may involve sequencing or combinations of treatment options—for example, one
strategy might consist of several cycles of ovulation induction, followed by ART only if
pregnancy does not occur, compared to proceeding directly to ART. Note that throughout this
report, we use the term “adjunct treatments” to refer to interventions performed within a major
treatment category (for example, comparison of metformin to placebo as pretreatment in women
with PCOS undergoing IVF).
Although there has been ongoing debate about the most appropriate outcome for evaluation
of infertility treatments, there is a growing consensus that live birth is the most important patient-
centered outcome.17,18 Trade-offs between outcomes (particularly multiple gestations), time to
pregnancy, and out-of-pocket costs might be different between the various treatment strategies
even if cumulative live birth rates were identical.
Different treatments also carry different safety risks. There are known short-term risks such
as ovarian hyperstimulation syndrome (OHSS) or acute risks associated with any surgery.
Surgery may have additional longer-term risks which may affect subsequent fertility (such as
scarring or decreased ovarian reserve with procedures such as laparoscopic ovarian drilling
(LOD). The literature suggests that observed associations between infertility treatment and
female reproductive cancers, particularly ovarian cancer, are likely the result of the underlying
infertility rather than treatment itself. There is, however, some uncertainty surrounding some
cancer outcomes in subgroups of patients.19-21
Some adverse pregnancy outcomes, such as preterm birth, are associated with infertility
treatment; however, many of the conditions associated with infertility are also associated with
these adverse outcomes, complicating assessment of comparative effectiveness.22-25 There may
also be direct effects of some treatments that have unclear implications for long-term health in
children born after these treatments.26,27 Finally, infertility clearly has an emotional impact,12,28,29
and the comparative effects of infertility treatments on quality of life are an important
consideration for both women and men.
There may be significant variation in outcomes of different treatments in specific
subpopulations. For example, age affects the likelihood of conception, and the risk of many
pregnancy complications associated with infertility treatments, such as preterm birth or low
birthweight, are also increased with higher maternal age. Obesity is common in women with
PCOS, and, like older maternal age, is also associated with adverse pregnancy outcomes
independent of its association with infertility. The utilization and outcomes of infertility
treatment differ among different racial and ethnic groups, even after adjusting for insurance
coverage.30-33
Finally, a unique subpopulation is women who donate oocytes for use by other couples in
ART. There are almost no data on the long-term safety of multiple courses of ovulation induction
for the purposes of oocyte donation.34 In addition, there are complex ethical and legal
considerations, including the balance between fair compensation and inducement,35 and sharing
information about donors with recipients.36
ES-2
The specific Key Questions (KQs) addressed in this review are listed below, and Figure A
displays the analytic framework that guided our work.
• KQ 1. What are the comparative safety and effectiveness of available
treatment strategies for women with polycystic ovary syndrome
who are infertile and who wish to become pregnant?
o KQ 1a. Does the optimal treatment strategy vary by patient
characteristics such as age, ovarian reserve, race, body mass
index (BMI), presence of other potential causes of female
infertility, or presence of male factor infertility?
• KQ 2. What are the comparative safety and effectiveness of available
treatment strategies for women with endometriosis who are infertile
and who wish to become pregnant?
o KQ 2a. Does the optimal treatment strategy vary by patient
characteristics such as age, ovarian reserve, race, BMI, stage
of endometriosis, presence of other potential causes of female
infertility, or presence of male factor infertility?
• KQ 3. What are the comparative safety and effectiveness of available
treatment strategies for women who are infertile for unknown
reasons and who wish to become pregnant?
o KQ 3a. Does the optimal treatment strategy vary by patient
characteristics such as age, ovarian reserve, race, BMI,
presence of other potential causes of female infertility, or
presence of male factor infertility?
• KQ 4. What are the comparative safety and effectiveness of available
treatment strategies for women with tubal or peritoneal factors
(e.g., pelvic adhesions) who are infertile and who wish to become
pregnant?
o KQ 4a. Does the optimal treatment strategy vary by patient
characteristics such as age, ovarian reserve, race, BMI,
presence of other potential causes of female infertility, or
presence of male factor infertility?
• KQ 5. What are the comparative safety and effectiveness of available
treatment strategies for couples with male factor infertility and no
evidence of an underlying diagnosis associated with infertility in the
female partner?
o KQ 5a. Does the optimal treatment strategy vary by
characteristics in either partner such as age, ovarian reserve,
race, or BMI?
• KQ 6. What are the short- and long-term health outcomes of donors
in infertility?
ES-3
o KQ 6a. For female oocyte donors:
1. Do specific aspects of the pre-donation evaluation identify
potential donors at greater risk for short- or long-term
adverse outcomes (e.g., OHSS, quality-of-life issues)?
2. Do short- and long-term outcomes differ among different
stimulation/retrieval protocols?
o KQ 6b. For male semen donors:
Are there long-term health, quality-of-life, or other adverse
outcomes associated with donation?
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Figure A. Analytic framework
Potential Modifiers
• Age • Concomitant diagnoses
• Ovarian reserve o Male factor + female
• Race/ethnicity factor
• Obesity/BMI o Multiple female
• Prior treatments factors
• Primary vs. secondary • Comorbidities
infertility • Setting/provider
• Maternal parity • Insurance status
Treatments
KQ 1
• Watchful waiting
PCOS • Weight loss
• Timed intercourse
KQ 2 • Surgery
Subfertile/ Endometriosis • Clomiphene
infertile • Letrozole
couples • Metformin Final Outcomes
who wish to KQ 3 • Gonadotropins Intermediate • Live birth
Unexplained Infertility • GnRH agonists/ Outcomes o Single
become
antagonists • Time to o Multiple
pregnant • Costs (of treatment
• Intrauterine pregnancy
KQ 4 insemination and outcomes)
Tubal or Peritoneal Factor o Patient
o Donor
KQ 5 • ART
Male Factor o Patient
o Donor
KQs 1-5
KQ 6
Adverse Effects-Child
Adverse Effects-Donor
Adverse Effects-Patient • Short-term (congenital
• Short-term (OHSS,
• Short-term (OHSS, anomalies, death,
surgical complications,
surgical complications) birthweight)
side effects)
• Long-term (cancer, • Long-term (cancer,
• Long-term (cancer, future
subsequent neurodevelopmental,
fertility, age at
pregnancies) specific issues related to
menopause, quality of life)
treatment)
Abbreviations: ART=assisted reproductive technology; BMI=body mass index; GnRH=gonadotropin-releasing hormone; KQ=Key Question; OHSS=ovarian hyperstimulation
syndrome; PCOS=polycystic ovary syndrome
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Methods
Detailed methods are available in the full report and the posted protocol
(http://effectivehealthcare.ahrq.gov/index.cfm ).
ES-6
potential confounding), as detailed in AHRQ’s Methods Guide for Effectiveness and
Comparative Effectiveness Reviews.38 Briefly, we rated each study as being of good, fair, or poor
quality based on its adherence to well-accepted standard methodologies. For each study, one
investigator assigned a summary quality rating, which was then reviewed by a second
investigator; disagreements were resolved by consensus or by a third investigator if agreement
could not be reached.
We also rated quality for identified systematic reviews to provide additional context for the
findings of the included studies. Rating was performed using AMSTAR (A Measurement Tool to
Assess the Methodological Quality of Systematic Reviews).39 For each study, one investigator
assigned a summary quality rating, which was then reviewed by a second investigator;
disagreements were resolved by consensus or by a third investigator if agreement could not be
reached. Reviews were then assigned overall quality scores of good (low risk of bias), fair
(moderate risk of bias), or poor (high risk of bias). The consistency of the findings from these
systematic reviews were incorporated in to our strength of evidence ratings as described below.
Data Synthesis
We began by summarizing key features of the included studies for each KQ. To the degree
that data are available, we abstracted information on study design; patient characteristics; clinical
settings; interventions; and intermediate, final, and adverse event outcomes. If not reported, 95-
percent confidence intervals for dichotomous outcomes (e.g., live birth rates) were calculated
from the numbers provided in the study.
We then determined the feasibility of completing a quantitative synthesis (i.e., meta-analysis,
decision analysis, or simulation model). For a meta-analysis, feasibility depends on the volume
of relevant literature (requiring at least three relevant studies), conceptual homogeneity of the
studies (similar intervention comparisons and outcome definitions), completeness of the
reporting of results, and the adequacy and completeness of any existing meta-analyses.
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deficiencies (or both). We believe that additional evidence is needed before concluding
either that the findings are stable or that the estimate of effect is close to the true effect.
• Insufficient Strength of Evidence—We have no evidence, we are unable to estimate an
effect, or we have no confidence in the estimate of effect for this outcome.
Results
We briefly summarize the results of our literature searches, description of included studies,
key points, and strength of evidence for each KQ. Note we only list here comparisons and
outcomes with strength of evidence rated as low, moderate, or high. Full findings are available in
the full report.
Summary of Studies
The literature search yielded 17,391 citations. In total, 1,909 studies were screened in full
text, in which 1,748 were excluded for reasons listed in Figure 2 and Appendix D in the full
report. We identified 161 articles describing 151 unique studies. The relationship of studies to
the review questions is as follows: 56 studies relevant to KQ 1, 7 studies relevant to KQ 2, 50
studies relevant to KQ 3, 8 studies relevant to KQ 4, 23 studies relevant to KQ 5, and 5 studies
relevant to KQ 6 (some studies were relevant to more than one KQ). There were also 21 studies
relevant to findings across all KQs.
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• There was no difference between type 1 diabetes mellitus diagnoses in children
conceived with ART compare to children conceived with no fertility treatment
(moderate SOE)
• As with other indications for IVF, use of single-embryo transfer is associated with
slightly lower live birth rates but significantly reduced multiple gestation rates (low
SOE)
In general, SOE was judged insufficient or low for most outcomes, with the a few exceptions
including live births with the use of letrozole versus clomiphene or oral agents versus surgical
management, and miscarriage between clomiphene and metformin or oral agents and surgical
management which were rated moderate SOE. A common limitation across all comparisons was
lack of precision for estimates of rare but important harms such as OHSS or surgical
complications (Table A).
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Strength of
Study Design
Comparison Outcome Conclusion Evidence
(Sample Size)
(Rationale)a
Time to 1 RCT44 No difference: No significant difference Low
pregnancy (750) in time to pregnancy between (1 study)
clomiphene vs. letrozole
Oral agents Live birth 3 RCTs53,72,79 No difference: No statistical difference Moderate
alone: (any/patient) (842) between clomiphene and metformin or (Suspected
Clomiphene vs. between clomiphene and combination reporting bias)
Metformin vs. 2 SRs therapy of metformin and clomiphene
Metformin + (3 studies, 912
Clomiphene patients104); (9
studies, 1079
patients105)
Pregnancy 3 RCTs63,70,72 No difference: No differences in Low
complications: (921) multiple birth rates between clomiphene (Imprecise,
Multiple births alone, metformin alone, and suspected
1 SR105 clomiphene plus metformin reporting bias)
(9 studies, 1079
patients)
Pregnancy 3 RCTs70,72,79 No difference: No difference between Low
complications: (1,005) studied oral agents. Very few ectopic (Imprecise
Ectopic pregnancies overall. findings with
pregnancy moderate study
limitations)
Pregnancy 3 RCTs63,70,72,79 Increase: Higher rate of miscarriage in Low
complications: (817) the combined therapy group (Suspected
Miscarriage (clomiphene and metformin) compared reporting bias,
1 SR105 to clomiphene alone imprecise)
(9 studies, 1079
patients)
Time to 1 RCT53 No difference: No significant difference Low
Pregnancy (343) in time to pregnancy between (1 study)
clomiphene vs. metformin
Oral agents Live birth 1 RCT99 No difference: No significant difference Low
alone: (any/patient) (88) in live birth rates between tamoxifen (Imprecise)
Clomiphene vs. and clomiphene
Tamoxifen 1 SR106
(2 studies, 195
women)
Pregnancy 1 RCT99 No difference: No significant difference Low
complications: (88) in miscarriage rates between tamoxifen (Iimprecise)
Miscarriage and clomiphene
1 SR106
(2 studies, 195
women)
Active Live birth 1 RCT96 Improvement: Live birth rates Low
Acupuncture + (1000) significantly higher for clomiphene vs. (1 study with
Clomiphene vs. placebo; not significantly different for potential risk of
Control active vs. control bias)
Acupuncture + Acupuncture
Clomiphene vs. Pregnancy 1 RCT96 No difference: no significant difference Low
Active complications: (1000) in ectopic pregnancy rates between oral (1 study with
Acupuncture + Ectopic agents and acupuncture strategies. potential risk of
Placebo vs. pregnancy bias)
Control Pregnancy 1 RCT96 No difference: no significant difference Low
Acupuncture + complications: (1000) in miscarriage rates between oral (1 study with
Placebo Miscarriage agents and acupuncture strategies. potential risk of
bias)
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Strength of
Study Design
Comparison Outcome Conclusion Evidence
(Sample Size)
(Rationale)a
Neonatal 1 RCT96 No difference: no significant difference Low
outcomes: (1000) in congenital abnormality rates between (1 study with
Congenital oral agents and acupuncture strategies. potential risk of
Abnormalities bias)
Neonatal 1 RCT96 No difference: no significant difference Low
Death (1000) in neonatal death rates between oral (1 study with
agents and acupuncture strategies. potential risk of
bias)
Oral agents Live birth 1 SR107 No difference: No statistically Moderate
alone vs. LOD (any/patient) (8 studies, 1,034 significant differences between LOD (Suspected
women) and oral agents reporting bias)
Pregnancy 1 SR107 Reduction: There was a reduction in Moderate
complications: (15 studies, 1,129 multiple births given LOD as compared (Suspected
Multiple births women) to oral agents reporting bias)
Pregnancy 1 RCT97 No difference: No significant Low
complications: (80) differences in miscarriage between (Imprecise,
Miscarriage LOD and oral agents suspected
1 SR107 reporting bias)
(15 studies, 1,592
women)
Clomiphene Pregnancy 3 RCTs54,82,95 No difference: Ectopic pregnancy rate Low
citrate vs. low- complications: (1072) did not differ between FSH and (Imprecise)
dose FSH Ectopic clomiphene strategies.
pregnancy
Lifestyle Live birth 3 RCTs75,78,87 No difference: No difference in live Moderate
modifications + (1688) birth rates for women who underwent (Heterogeneity
IVF vs. IVF lifestyle modification in combination in interventions)
alone with IVF compared with IVF alone
ART IVF: GnRH Live birth 4 RCTs48,52,68,71 No difference: No significant difference Low
agonist +/- IVF (cycle) (408) in included studies but varying (Imprecise
vs. GnRH interventions and comparators with low findings with
antagonist +/- numbers of live birth moderate study
IVF limitations)
Pregnancy 3 RCTs68,71,77 No difference: No differences in Moderate
complications: (279) miscarriage rates for GnRH agonist vs. (Imprecise
Miscarriage antagonist, or hCG medium, hCG-free findings with
medium with transfer, and hCG-free moderate study
medium without transfer. limitations)
ART IVF: Fresh Live birth 1 RCT80 Improvement: Live birth rates were Low
vs. Frozen (any/cycle) (1508) significantly higher with frozen embryo (1 study)
Embryos in IVF transfer compared to fresh embryos
for PCOS Pregnancy 1 RCT80 No difference: No difference in multiple Low
complications: (1508) births with fresh versus frozen embryo (1 study)
Multiple births transfer
Pregnancy 1 RCT80 Reduction: Ectopic pregnancies were Low
complications: (1508) reduced with frozen embryo transfer (1 study)
Ectopic
pregnancy
Pregnancy 1 RCT80 Reduction: Miscarriages were reduced Low
complications: (1508) with frozen embryo transfer (1 study)
Miscarriage
Neonatal 1 RCT80 No difference: No difference Low
Outcomes: (1508) congenital abnormalities with fresh (1 study)
Congenital versus frozen embryo transfer
abnormalities
Neonatal 1 RCT80 No difference: No difference neonatal Low
Death (1508) deaths with fresh versus frozen embryo (1 study)
transfer
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Strength of
Study Design
Comparison Outcome Conclusion Evidence
(Sample Size)
(Rationale)a
ART vs. no Long-term 1 Obs90 No difference: No significant difference Moderate
infertility outcomes: (565,116 found between type 1 diabetes mellitus (Imprecise)
treatment Child (type 1 pregnancies) diagnoses in children born to patients
diabetes with PCOS infertility conceived with
mellitus) ART compared to children conceived
with no fertility treatment
aCriteria for downgrading strength of evidence is described as Rationale; when these criteria are insufficient for understanding the
In general, the SOE across all outcomes was judged to be insufficient or low, primarily due
to imprecision and small numbers of studies, especially for both short-term harms (such as
OHSS) (Table B).
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Key Question 3. Unexplained Infertility
We identified 50 individual studies that met inclusion criteria for KQ 3 and had unexplained
infertility (infertility with no other documented female or male diagnosis).75,91,92,111,113-158
Key findings for couples with unexplained infertility included:
• There is no difference between the oral agents of letrozole and anastrozole for the
outcome of ectopic pregnancy (low SOE) but evidence is insufficient for other
outcomes of interest.
• There is no difference between letrozole and clomiphene for outcomes of multiple
births or miscarriage (moderate SOE).
• There is no difference between differing adjunct treatments used in combination with
oral agents and IUI for the outcomes of live birth, miscarriage, and OHSS (low SOE
for all outcomes).
• There are no differences between immediate IVF versus other treatments prior to IVF
for the outcomes of live birth, multiple births, ectopic pregnancy, miscarriage, low
birthweight, and OHSS (low SOE for all outcomes). There is however shorter time to
pregnancy with immediate IVF (moderate SOE).
• As with other indications for IVF, use of single-embryo transfer is associated with
slightly lower live birth rates but significantly reduced multiple gestation rates (low
SOE)
SOE for most outcomes was judged to be insufficient or low, primarily because of
imprecision or small numbers of studies of fair quality. Two exceptions were multiple births and
miscarriages for oral agents without IUI where an existing systematic review existed, and time to
pregnancy between different strategies for sequencing treatment, where precision was
reasonable. In both cases SOE for these outcomes was judged to be moderate (Table C).
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Strength of
Study Design
Comparison Outcome Conclusion Evidence
(Sample Size)
(Rationale)a
Oral Agents vs. Live birth 1 SR160 Improvement: A significant increase Low
Unstimulated (3 studies, 370) in live births was found for women (Inconsistent)
IUI vs. treated with IUI and ovarian
Expectant hyperstimulation compared to women
Management treated with IUI only
Adjunct Live birth 5 No difference: No difference Low
Treatments with RCTs124,130,140,153,156 between adjunct treatments with oral (Moderate
Oral Agents (1859) agents and IUI study
and IUI limitations)
Pregnancy 5 No difference: No difference Low
complications: RCTs130,138,142,143,156 between adjunct treatments with oral (Moderate
Miscarriage (1859) agents and IUI study
limitations)
Short term 3 RCTs124,138,156 No difference: No difference Low
adverse effects (1189) between adjunct treatments with oral (Moderate
of treatment: agents and IUI study
OHSS limitations)
Oral Agents Pregnancy 3 RCTs144,152,155 No difference: No difference Low
With IUI vs. complications: (1,654) between oral agents with IUI versus (Imprecise)
Gonadotropins Miscarriage gonadotropins with IUI
With IUI Pregnancy 1 RCT144 Increased risk: Greater multiple Low
complications: (742) gestations with gonadotropins (one study)
Multiple births compared to either clomiphene or
letrozole
Immediate IVF Live birth 3 RCTs118,120,131,151 No difference: Live birth does not Low
vs. Other (812) differ between differing strategies of (Imprecise)
Treatments other treatments prior to IVF
Prior to IVF Pregnancy 2 RCTs118,131 No difference: No significant Low
complications: (657) difference between other treatments (Imprecise)
Multiple births prior to IVF and immediate IVF.
Pregnancy 3 RCTs118,120,131,151 No difference: No significant Low
complications: (812) difference between other treatments (Imprecise)
Ectopic prior to IVF and immediate IVF.
pregnancy
Pregnancy 3 RCTs118,120,131,151 No difference: No significant Low
complications: (812) difference between other treatments (Imprecise)
Miscarriage prior to IVF and immediate IVF.
Neonatal 2 RCTs118,131 No difference: No significant Low
outcomes: (657) difference between other treatments (Imprecise)
Birthweight prior to IVF and immediate IVF.
Time to 2 RCTs118,131 Reduction: Shorter time to Moderate
pregnancy (657) pregnancy with immediate IVF
compared with other treatments prior
to IVF
Short term 2 RCTs118,131 No difference: No significant Low
adverse effects (657) difference between other treatments (Imprecise)
of treatment: prior to IVF and immediate IVF.
OHSS
ART: IVF vs. Neonatal 1 Obs91 No difference: No significant Low
ICSI outcomes: Birth (90,401 cycles) differences in rates of r low birth (1 study with
weight weight between ICSI versus moderate
conventional-IVF cycles study
limitations)
ART: Long-term 1 Obs121 No difference: The overall cancer Low
Unspecified outcomes: Child (33,840) incidence was not elevated in (Moderate
(cancer) children born after assisted study
conception for unexplained infertility. limitations)
ES-14
aCriteria for downgrading strength of evidence is described as Rationale; when these criteria are insufficient for understanding the
final strength of evidence, additional explanation is provided.
The SOE was judged to be insufficient for most outcomes primarily due to imprecision based
on few studies meeting our inclusion criteria (Table D).
Table D. Summary of strength of evidence for major outcomes—KQ 4 (tubal and peritoneal factor
infertility)
Strength of
Study Design
Comparison Outcome Conclusion Evidence
and Sample Size
(Rationale)a
ART: 2-embryo Live birth (patient) 1 Obs111 Improvement. The live birth Low
transfer vs. 1- (69,028 cycles) rate per cycle was higher in (Imprecise)
embryo transfer couples who underwent 2
embryo transfer as compared
with single embryo transfer
ART: IVF+ICSI Neonatal 1 Obs91 No difference: No significant Low
vs. IVF outcomes: Birth (90,401 cycles) differences in rates of r low (1 study with
weight birth weight between ICSI moderate study
versus conventional-IVF limitations)
cycles
ART vs. no Long-term 1 Obs90 No difference: No significant Moderate
fertility treatment outcomes: Child (565,116 difference found between (Imprecise)
(type 1 diabetes pregnancies) type 1 diabetes mellitus
mellitus) diagnoses in children born to
patients with tubal factor
infertility conceived with ART
compared to children
conceived with no fertility
treatment
aCriteria for downgrading strength of evidence is described as Rationale; when these criteria are insufficient for understanding the
Abbreviations: ART=assisted reproductive technology; ICSI=intra-cytoplasmic sperm injection; IVF=in vitro fertilization;
KQ=Key Question; Obs=observational study
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Key Question 5. Male Factor Infertility
We identified 23 individual studies75,90-92,111,115,121,130,147,153,166-179 that addressed the
comparative effectiveness or safety of interventions applied to patients with male factor
infertility.
Key findings for patients with male factor infertility included:
• Live birth rate (moderate SOE) and miscarriage (low SOE) did not differ between
intracytoplasmic sperm injection (ICSI) and intracytoplasmic morphological sperm
injection (IMSI). Of note, IMSI is not used in the United States.
• There was no difference in live birth rates or any adverse pregnancy events between
couples using frozen embryo versus fresh embryo transfer (low SOE)
• The overall cancer incidence was not elevated in children born after assisted conception
for male factor infertility (low SOE).
• There was no difference between type 1 diabetes mellitus diagnoses in children born to
patients with male factor infertility conceived with ART compared to children conceived
with no fertility treatment (moderate SOE)
• Live birth rate (low SOE) improved with vitamin E or zinc supplementation relative to
placebo or no supplementation.
• As with other indications for IVF, use of single-embryo transfer is associated with
slightly lower live birth rates but significantly reduced multiple gestation rates (low SOE)
The SOE was judged to be insufficient or low for all outcomes except for the comparison of IVF
versus ICSI for live birth and long term outcomes related to diabetes (Table E).
Table E. Summary of strength of evidence for major outcomes—KQ 5 (male factor infertility)
Strength of
Study Design
Comparison Outcome Conclusion Evidence
and Sample Size
(Rationale)a
ART IVF: ICSI or Live birth 2 Obs111,171 Improvement. Greater live births Low
assisted hatching (272,717 cycles) with multiple embryos transferred (Imprecise)
(1 embryo compared to 1 embryo transferred
transferred) vs.
ICSI or assisted
hatching (multiple
embryos
transferred)
TESE vs.
ejaculated OAT
ART IVF: Frozen Live birth 1 RCT177 No difference: no difference in live Low
vs. fresh embryo (2,157 patients) birth rates between couples using (1 study,
transfer frozen embryo versus fresh embryo heterogeneous
transfer infertility
indication)
Pregnancy 1 RCT177 No difference: no difference in Low
complications: (2,157 patients) ectopic pregnancy rates between (1 study,
Ectopic couples using frozen embryo heterogeneous
pregnancy versus fresh embryo transfer infertility
indication)
ES-16
Strength of
Study Design
Comparison Outcome Conclusion Evidence
and Sample Size
(Rationale)a
Pregnancy 1 RCT177 No difference: no difference in Low
complications: (2,157 patients) multiple birth rates between (1 study,
Multiple births couples using frozen embryo heterogeneous
versus fresh embryo transfer infertility
indication)
Pregnancy 1 RCT177 No difference: no difference in Low
complications: (2,157 patients) miscarriage rates between couples (1 study,
Miscarriage using frozen embryo versus fresh heterogeneous
embryo transfer infertility
indication)
Neonatal 1 RCT177 No difference: no difference in low Low
outcomes: (2,157 patients) birthweight rates between couples (1 study,
Birthweight using frozen embryo versus fresh heterogeneous
embryo transfer infertility
indication)
Neonatal 1 RCT177 No difference: no difference in Low
outcomes: (2,157 patients) congenital anomalies rates (1 study,
Congenital between couples using frozen heterogeneous
anomalies embryo versus fresh embryo infertility
transfer indication)
IVF vs. ICSI Live birth 3 RCTs166,170,173 No difference. Meta-analysis of 3 Moderate
(497 patients) RCTs does not demonstrate a (Moderate study
difference between ICSI and IMSI. limitations)
2 Obs168,172
(771,661 cycles)
Pregnancy 1 RCT166 No difference. Both included Low
complications: (121 patients) studies and an existing systematic (High study
Miscarriage review supported no difference in limitations,
1 Obs168 miscarriage. SOE was reduced imprecise)
(499,135 cycles) because of quality of included
studies and imprecision of findings.
1 SR180
(6 studies, 552
women)
Neonatal 1 RCT166 No difference: No significant Low
outcomes: (121 patients) differences in rates of low birth (Moderate study
Birthweight weight between ICSI versus limitations)
3 Obs91,168,172 conventional-IVF cycles
(862,062 cycles)
ART: Unspecified Long-term 1 Obs121 No difference: The overall cancer Low
outcomes: (924,427 patients) incidence was not elevated in (Moderate study
Child (cancer) children born after assisted limitations)
conception for male factor infertility.
Long-term 1 Obs90 No difference: No significant Moderate
outcomes: (565,116 difference found between type 1 (Imprecise)
Child (type 1 pregnancies) diabetes mellitus diagnoses in
diabetes children born to patients with male
mellitus) factor infertility conceived with ART
compared to children conceived
with no fertility treatment
Other strategies: Live birth 1 SR181 Improvement: Increase in live birth Low
Antioxidant use (4 studies of 277 rate associated with vitamin E or (Imprecise,
for Male Infertility couples) zinc supplementation relative to small studies)
placebo or no supplementation
aCriteria for downgrading strength of evidence is described as Rationale; when these criteria are insufficient for understanding the
ES-17
Abbreviations: ART=assisted reproductive technology; ICSI=intra-cytoplasmic sperm injection; IVF=in vitro fertilization;
KQ=Key Question; OAT=oligo-astheno-teratozoospermia; Obs=observational study; RCT=randomized controlled trial;
TESE=extracted testicular sperm
Table F summarizes the SOE for KQ 6 and specifically for the incidence of OHSS with
GnRH agonist trigger versus hCG trigger. All other short- and long-term outcomes had
insufficient SOE or were not evaluated in the limited set of included studies.
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• Elective single-embryo transfer is associated with lower live birth rates but a significant
reduction in multiple birth rates compared to multiple-embryo transfer (low SOE for both
outcomes).
• There was no difference in the odds of low birth weight between ICSI versus
conventional IVF cycles (low SOE). However, among couples undergoing ART with a
singleton pregnancy, frozen embryo transfers result in a higher average birthweight, with
a subsequent reduction in the incidence of low birthweight and an increase in the
incidence of macrosomia (low SOE).
Table G summarizes the SOE for findings that are applicable across all infertility diagnoses.
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Strength of
Study Design
Comparison Outcome Conclusion Evidence
(Sample Size)
(Rationale)a
Long-term 2 Obs167,209 Greater risk. IVF was Low
outcomes: (280,950) associated with a statistically (Imprecise, older
Maternal (cancer) significant increased risk of all study)
ovarian neoplasms and
borderline ovarian tumors,
and colorectal cancer
Discussion
In this Comparative Effectiveness Review, we reviewed 151 studies described in 161
publications that directly compared infertility management strategies in couples with infertility
due to PCOS (KQ 1) or endometriosis (KQ 2); unexplained infertility (KQ 3); tubal and
peritoneal factor infertility (KQ 4); and male factor infertility (KQ 5). We also explored the
comparative safety and effectiveness of management strategies for donors in infertility (KQ 6).
Although the ultimate goal with any infertility management strategy is to improve live birth rates
of healthy infants to a healthy couple, many studies initially identified in our review only
reported on pregnancy rates or focused on other short-term outcomes and did not differentiate by
the underlying causes of infertility. Our findings are based on those 151 studies which evaluated
the comparative effectiveness of infertility management strategies in couples with a known cause
of infertility (including unexplained infertility) and which evaluated the outcome of live birth or
another long-term outcome.
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primary outcome, the majority of the literature, particularly randomized trials, is still based on
pregnancy or ongoing pregnancy. Lack of precision for comparative estimates of rates for less
common but important outcomes, such as complications, continues to be a major limitation.
We compared our findings to evidence-based guidelines from the National Institute for
Health and Care Excellence (NICE) in the United Kingdom (UK), and the American Society for
Reproductive Medicine (ASRM). In general, findings of our review were concordant with the
guidelines, with differences primarily attributable to differences in inclusion/exclusion criteria.
For women with PCOS, both NICE and ASRM support use of clomiphene citrate alone as
first-line therapy, with the NICE guidance recommending ultrasound monitoring for dose
adjustment to minimize risk of multiple pregnancy, followed by combination therapy with
metformin or gonadotropins for women who do not conceive after a 3-6 month course of
clomiphene alone. Both our review and NICE suggest letrozole may be superior to clomiphene
as first line therapy, and that pretreatment with metformin may improve outcomes in women
with PCOS being treated with gonadotropins.
For women with endometriosis, ASRM concluded that evidence for surgical treatment of
women with mild to moderate endometriosis was insufficient to recommend treatment, while the
NICE guidance suggests some benefit, and our review was inconclusive. For those patients going
directly to ART, surgical treatment of endometriosis, including endometrioma, prior to ART
does not improve outcomes.
For women with unexplained infertility, NICE recommends against use of oral agents
entirely, while ASRM suggests clomiphene plus IUI may improve cycle fecundity compared to
expectant management; our review found insufficient evidence. Based on our review, immediate
IVF results in higher live birth rates and shorter time to pregnancy in women aged 38-42
compared with a trial of clomiphene and IUI or gonadotropins and IUI, with most live births
ultimately resulting from IVF.
For women with suspected tubal factor infertility, both NICE and ASRM recommend
imaging for diagnosis (which is outside the scope of our review), although, when ART is readily
available and affordable, proceeding directly to ART without a definitive diagnosis of tubal
disease may be more efficient.
For male factor infertility, our review found no relevant findings compared to the
recommendations, primarily because of limited data on live birth outcomes.
For both male and female donors, both NICE and ASRM recommend psychological
evaluation and counseling, including, for females, the short term risks of ovarian stimulation and
oocyte collection; our review found evidence on outcomes was limited only to the known short-
term risks of these procedures, with no evidence on potential longer term risks.
For long-term outcomes in women and children after infertility treatment, our review found
limited or inconsistent evidence. Risks of adverse longer term maternal cancer outcomes were
generally not increased after adjustment for the risk associated with infertility itself. ICSI
however may be associated with an increased risk of neurodevelopmental disorders in children
compared to those conceived through IVF. The NICE guidance was generally consistent with
this assessment, and recommended that patients should be informed that any absolute risk was
low, while there was still uncertainty about longer-term outcomes.
In general, our current review’s findings are consistent with the NICE and ASRM
guidelines—there is a general consensus that the overall body of evidence for many aspects of
infertility treatment across all patient groups is limited. One consistent limitation is the relative
paucity of studies utilizing live birth per couple as the primary outcome.
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Applicability
Two broad issues relate to the overall applicability of the available evidence to clinical
practice in the United States—one geographic and one temporal. Many of the RCTs meeting our
criteria were performed outside of the United States. Leaving aside any issues related to
differences in study oversight or reporting, the populations of these studies may differ from U.S.
infertility patients in two potentially important ways.
The first issue is that there may be clinically relevant differences between populations in
terms of non-clinical factors affecting outcomes. For example, live birth rates for African-
American women undergoing ART in the US are lower than for white women 211, which may
reflect issues related to socioeconomic status, insurance coverage, or other factors (such as well-
established racial differences in the risk of many adverse pregnancy outcomes). Differences in
access to infertility services between countries may lead to differences in the likelihood of
treatment success. Although the estimate of any relative difference between two interventions
derived from an unbiased RCT should in theory be independent of the probability of specific
outcomes, the more clinically relevant absolute difference may be substantially different (e.g.,
the risk of preterm birth in African-American compared to white women is consistently
elevated). To the extent that the probability of specific outcomes of interest may differ between
populations because of differences in genetic risk, exposures to other factors affecting risk, or
non-biological factors such as access to care, there may be substantial differences in estimates of
absolute risk differences. For relatively uncommon but important outcomes, these differences
might also affect precision of estimates—confidence intervals for any treatment effect will be
wider in populations where the outcome is less common.
In addition to the potential impact of race/ethnicity, there may be important differences in the
distribution of socioeconomic status between populations. Access to infertility diagnosis and
treatment varies across countries, and certainly within the United States.212 Differences in
socioeconomic status could affect applicability in several ways. Differences in access to care
may lead to differences in the spectrum of severity of “disease” for U.S. patients who given the
financial burden of treatment options they may wait longer to undergo evaluations. Although
summary statistics of baseline characteristics may allow some judgment of comparability, there
may be potentially important differences in the distribution that are obscured by the typical
reporting of means and standard deviations (particularly if the underlying characteristic is not
normally distributed), or by differences within a given stage. Socioeconomic status may also
potentially affect some important outcomes independently of any specific treatment—for
example, neurodevelopmental outcomes such as specific learning skills may be strongly
correlated with parental socioeconomic status.
The second issue is that changes in practice over time have a major impact on applicability,
particularly for long-term outcomes. The long lag time between exposure to infertility treatment
and the potential development of longer term outcomes such as cancer means that data available
today necessarily reflect women exposed to treatments at least 10 years in the past; even if the
specific exposure is similar, there may be differences between past and current practice in
potentially important attributes such as dosage, timing, patient selection criteria, use of
adjunctive treatments, etc. For example, evidence that immediate use of IVF leads to shorter time
to pregnancy than strategies where IVF is used only after a trial of agents such as clomiphene or
gonadotropins has led to a change in guidelines.213 which now suggest that the cumulative
exposure to gonadotropins during the course of treatment is likely to decrease compared to
earlier cohorts of women, reducing any long-term risks.
ES-22
In addition, there may be cohort effects in terms of other exposures that may affect the
absolute risk of some outcomes (e.g., changes in the use of postmenopausal hormone
replacement therapy or ages of mammography screening affecting breast cancer risk), which in
turn would impact any additional absolute risk due to exposure to infertility treatments. Because
of this phenomenon, there is likely to always be some unresolvable uncertainty about long-term
outcomes for both parents undergoing current infertility treatments and their children..
Research Recommendations
In an era of constrained resources, future clinical research, especially comparative
effectiveness research—which helps resolve current uncertainties regarding clinical or policy
decisions—should receive priority. For most of the KQs, there are multiple areas of remaining
uncertainty based on the existing evidence. In part because of the diversity of causes and
treatment options, it is difficult to make specific recommendations for specific topics.
Before setting a specific agenda for future research in infertility, we believe a more general
approach to identifying priorities would be helpful. Achieving consensus on the relative priority
of specific outcomes, incorporating the perspective of multiple stakeholders (similar to the
approach used for developing a research agenda for comparative effectiveness research for
uterine fibroids.214,215 Ideally, these outcome priorities would be used for subsequent evidence
syntheses and guideline development.
As part of this consensus process, additional areas of discussion include:
• Formal consideration of the limits of acceptability for specific quantitative harms (e.g.,
preterm birth) and clinically meaningful differences in benefits (e.g., live birth).
• Formal discussion of the potential role of cost-effectiveness in decision making,
including issues of willingness-to-pay and appropriate choice of outcome. This is
particularly important because there are significant methodological challenges to the use
of “standard” measures such as quality-adjusted life expectancy in the setting of
infertility treatment.
• Issues related to study design, particularly from the patient stakeholder perspective. For
example, in settings where patients and/or clinicians may have strong preferences for
specific treatments, recruitment into RCTs may be difficult.216 In the uterine fibroid
consensus process, patient stakeholders strongly preferred observational designs to
randomized treatment assignment.214 Discussion of potential trade-offs between risk of
bias, efficiency, ability to measure all relevant potential confounders and effect modifiers,
appropriateness of alternative approaches such as Zelen randomization (where subjects
are randomized prior to consent, then allowed to either receive the assigned treatment or
choose the alternative217), and the likelihood that a specific study design would resolve a
specific area of uncertainty should all be included.
• Issues related to data reporting. Particularly for ART and other treatments which are used
for multiple indications, reporting of results separately by indication in both randomized
trials and large observational studies would be extremely useful. Although these
subgroup results may have insufficient power to detect clinically relevant differences
within the context of individual studies (particularly RCTs), their routine publication
would eventually allow synthesis of results using methods such as meta-analysis
(including individual-level meta-analysis.)
ES-23
The Society for Assisted Reproductive Technology Clinic Outcome Reporting System
(SART CORS) and the National ART Surveillance System (NASS), which includes data
submitted through SART CORS (the majority of clinics providing ART as well as a smaller
number of non-SART participating clinics who report directly to the Centers for Disease Control
and Prevention (CDC), are outstanding examples of what a large-scale, population-based registry
can achieve in terms of providing data on treatment outcomes. However, the major limitation of
the database in the past has been that data are only published on a per-cycle, rather than per-
couple, basis. Recently the database methods have changed and now they are publicly reporting
the cumulative success rate per patient. Results, however, are still reported at the clinic level, so
patients who receive care at more than one clinic do not have the full range of outcomes
captured, and there is no mechanism for prospectively collecting long-term outcomes of patients
or children. Facilitating reporting of results so that outcomes are reported on a per-couple basis
will substantially improve the ability to generate estimates of the likely outcome of specific
ART-related decisions.
Based on input from key informants and our technical expert panel (TEP), we structured the
review based on infertility diagnosis, and required studies to report outcomes specifically by
diagnosis, or to adjust for diagnosis in multivariable analyses. As noted above, this led to
exclusion of a number of papers, particularly those related to ART methods. There is clear
evidence that the probability of some outcomes of interest, both short-term (e.g., OHSS) and
long-term (certain cancers) differs based on underlying diagnosis. Although this may not be the
case for all outcomes, we believe it would be helpful for future studies of interventions
performed in patients with different underlying diagnoses to report results separately by
diagnosis. Within an individual study powered on the basis of the total patients, estimates of
diagnosis-specific outcomes may be too imprecise to confidently rule out clinically relevant
differences—consistency of reporting would allow formal synthesis of estimates across studies.
We found very limited evidence on outcomes among sperm or oocyte donors. Oocyte donors,
who undergo controlled ovarian hyperstimulation and oocyte retrieval in the same manner as
patients undergoing IVF using their own eggs, have, in theory, at least the same risk of short-
term adverse events as patients. The frequency with which oocyte donors are used is increasing,
and evidence from the SART CORS database suggests that the risk of certain pregnancy
complications is lower when donor oocytes are used.34,218 If demand for donor oocytes continues
to increase, much more evidence on the specific short- and long-term outcomes of donation
(especially if a donor undergoes multiple cycles) is needed.
Conclusions
There is evidence supporting some strategies for treatment of infertility, both for specific
diagnoses and for couples with any diagnosis, in part because of recent adaptation of more
rigorous methods for evaluating treatments for infertility, particularly regarding treatments for
PCOS and approaches to timing of interventions in patients undergoing ART. In addition,
ongoing refinements to the SART CORS database continue to make it a valuable resource,
particularly for data on short-term outcomes. However, given the diversity of infertility causes
and treatments, there is considerable residual uncertainty about the optimal treatment options for
specific patients. Consensus on which outcomes to report (such as encouraging reporting of live
birth rates on a per couple basis as well as per cycle, and, for studies of treatment such as ART,
reporting of both overall and diagnosis-specific outcomes) and which areas of uncertainty are
ES-24
most important to resolve (in order to prioritize research) is needed to improve the ability of
patients and clinicians to make decisions about the most appropriate treatment.
ES-25
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Introduction
Background
Condition
“Infertility” has traditionally been defined as failure to achieve pregnancy after 12 months of
regular unprotected intercourse with the same partner (or after 6 months for women greater than
35 years of age). However, as many as half of such couples will conceive without intervention
over the next 12–24 months. Because of this, the term “subfertility” is preferred by many.1 From
a population perspective, couples who meet the dichotomous criteria for “infertility” include
couples who are “normal” but who are in the upper end of the population distribution for “time
to pregnancy”, and couples who have a physiological or anatomical cause for a prolonged time to
pregnancy. However, to be concise, we use the term “infertility” throughout this report.
Self-reported infertility in the United States, using the 12-month definition, affected
approximately 6 percent of married women aged 15–44 in the 2006-2010 National Survey of
Family Growth (the most recent available data).2 In one population-based study, approximately
10 percent of pregnant women reported receiving infertility treatment, with 29 percent of these
women using fertility-enhancing medications; 21 percent using assisted reproductive technology
(ART), including in vitro fertilization (IVF); 15 percent using artificial insemination with
fertility-enhancing drugs; and 23 percent using other treatments, including surgery.3 Other
estimates of the prevalence of infertility treatment are similar.4-8 Particularly in the US, where
availability of infertility services is variable depending on a number of factors, particularly
insurance coverage, utilization of infertility treatments may underestimate the overall burden of
infertility.
The most common demographic factor associated with female infertility is “advanced
reproductive age”; although the probability of pregnancy begins to decline by the mid-20’s, the
slope of decline sharply increases by age 35.9 For example, the prevalence of “unexplained
infertility” (infertility with no other documented female or male diagnosis) is substantially higher
in older women,10 and “diminished ovarian reserve,” which is most commonly associated with
increased age, is the single most common diagnosis among women undergoing ART, accounting
for 27.5 percent of cycles.11 Other common causes of female infertility include polycystic ovary
syndrome (PCOS), endometriosis, and occlusion of the fallopian tubes from prior infectious
disease.6 A growing number of women also experience infertility secondary to cancer
treatment.12-14. Although there are other potentially treatable causes of infertility (conditions
other than PCOS which affect ovulatory function, congenital uterine anomalies, uterine fibroids),
this review is based on the most common conditions, based on input from our Technical Expert
Panel.
Based on estimates of patients attending ART clinics, isolated male factor infertility affects
approximately 17 percent of couples seeking treatment, with 34.6 percent of couples having both
male and female diagnoses.15
Treatment Strategies
Treatment options are usually dependent on the underlying etiology of infertility. For female
causes, options include surgical management of tubal occlusion, surgical treatment of
endometriosis, ovarian “drilling” for treatment of PCOS, use of ovulation-induction agents
1
including oral (clomiphene citrate or letrozole) and injected drugs (gonadotropins), artificial
insemination with either partner or donor sperm (depending on partner fertility status), and ART,
which includes both traditional IVF (fertilization of the egg by the sperm occurs without direct
manipulation) and IVF with intra-cytoplasmic sperm injection (ICSI) (fertilization occurs via
direct injection of sperm into the egg).16,17 Treatment options for male factor infertility include
medical treatment of a diagnosed endocrinopathy or other conditions affecting sperm production,
empiric treatments with hormonal or other agents, surgical management of varicocele,
intrauterine insemination, IVF, ICSI, or use of donor sperm.18 Options appropriate for some
diagnoses (e.g., ovulation induction in PCOS or unexplained infertility) may not be appropriate
for others (e.g., women with documented tubal occlusion). In other cases, the appropriate
comparisons may involve sequencing or combinations of treatment options—for example, one
strategy might consist of several cycles of ovulation induction, followed by ART only if
pregnancy does not occur, compared to proceeding directly to ART. Note that throughout this
report, we use the term “adjunct treatments” to refer to interventions performed within a major
treatment category (for example, comparison of metformin to placebo as pretreatment in women
with PCOS undergoing IVF).
Benefits
There has been ongoing debate about the most appropriate outcome for evaluation of
infertility treatments—ovulation (in anovulatory women such as PCOS patients), pregnancy, live
birth, or term live birth.19-23 However, there is a growing consensus that live birth is the most
important patient-centered outcome.22,23 Trade-offs in outcomes (particularly multiple
gestations), time to pregnancy, and out-of-pocket costs might be different among the various
treatment strategies even if cumulative live birth rates are identical.
Harms
Different treatments also carry different safety risks. There are known short-term risks such
as ovarian hyperstimulation syndrome (OHSS) or acute risks associated with any surgery.
Surgery may have additional longer-term risks which may affect subsequent fertility (such as
scarring or decreased ovarian reserve with procedures such as laparoscopic ovarian drilling
(LOD). The literature suggests that observed associations between infertility treatment and
female reproductive cancers, particularly ovarian cancer, are likely the result of the underlying
infertility rather than treatment itself. There is, however, some uncertainty surrounding some
cancer outcomes in subgroups of patients.24-26
Some adverse pregnancy outcomes, such as preterm birth, are associated with infertility
treatment; however, many of the conditions associated with infertility are also associated with
these adverse outcomes, complicating assessment of comparative effectiveness.19,21,27,28 There
may also be treatments that have unclear effects on the long-term health in children born
following these treatments For example, there is the possibility that epigenetic changes from
treatments such as IVF/ICSI may lead to increased risk of some disorders (e.g., Beckwith-
Wiedemann syndrome) later in life—or that an increase in multiple births or other causes of
prematurity or fetal growth restriction/low birthweight from treatments may result in poor
neurodevelopmental outcomes.29,30 Finally, infertility clearly has an emotional impact,14,31,32 and
the comparative effects of infertility treatments on quality of life are an important consideration
for both women and men.
2
There may be significant variation in outcomes of different treatments in specific
subpopulations. For example, age affects the likelihood of conception, and the risk of many
pregnancy complications associated with infertility treatments, such as preterm birth or low
birthweight, are also increased with higher maternal age. Obesity is common in women with
PCOS, and, like older maternal age, is also associated with adverse pregnancy outcomes
independent of its association with infertility. The utilization and outcomes of infertility
treatment differ among different racial and ethnic groups, even after adjusting for insurance
coverage.33-36
Finally, a unique subpopulation is women who donate oocytes for use by other couples in
ART. An increasing number of women undergoing ART are receiving donor oocytes,37 and there
are almost no data on the long-term safety of multiple courses of ovulation induction for the
purposes of oocyte donation.38 In addition, there are complex ethical and legal considerations,
including the balance between fair compensation and inducement,39 and sharing information
about donors with recipients.40
3
cycle (rather than the individual patient) as the unit of analysis; (b) lack of long-term follow-up
data for individual patients38; and (c) some concern about underreporting of some adverse
outcomes.54 NASS 2.0, introduced at the end of 2016, now includes both unique patient and
cycle identifiers, meaning that cumulative success rates per patient should be available in future
years.55 In addition, mechanisms for capturing outcomes from patients who receive care at
multiple clinics have been put into place. On the other hand, randomized controlled trials (RCTs)
may not provide data on important long-term outcomes, or may be underpowered to detect
clinically relevant differences in complications of treatment.
Key Questions
The specific Key Questions (KQs) addressed in this review are listed below, and Figure 1
displays the analytic framework that guided our work.
• KQ 1. What are the comparative safety and effectiveness of available
treatment strategies for women with polycystic ovary syndrome
(PCOS) who are infertile and who wish to become pregnant?
o KQ 1a. Does the optimal treatment strategy vary by patient
characteristics such as age, ovarian reserve, race, body mass
index (BMI), presence of other potential causes of female
infertility, or presence of male factor infertility?
• KQ 2. What are the comparative safety and effectiveness of available
treatment strategies for women with endometriosis who are infertile
and who wish to become pregnant?
o KQ 2a. Does the optimal treatment strategy vary by patient
characteristics such as age, ovarian reserve, race, BMI, stage
of endometriosis, presence of other potential causes of female
infertility, or presence of male factor infertility?
• KQ 3. What are the comparative safety and effectiveness of available
treatment strategies for women who are infertile for unknown
reasons and who wish to become pregnant?
o KQ 3a. Does the optimal treatment strategy vary by patient
characteristics such as age, ovarian reserve, race, BMI,
4
presence of other potential causes of female infertility, or
presence of male factor infertility?
• KQ 4. What are the comparative safety and effectiveness of available
treatment strategies for women with tubal or peritoneal factors
(e.g., pelvic adhesions) who are infertile and who wish to become
pregnant?
o KQ 4a. Does the optimal treatment strategy vary by patient
characteristics such as age, ovarian reserve, race, BMI,
presence of other potential causes of female infertility, or
presence of male factor infertility?
• KQ 5. What are the comparative safety and effectiveness of available
treatment strategies for couples with male factor infertility and no
evidence of an underlying diagnosis associated with infertility in the
female partner?
o KQ 5a. Does the optimal treatment strategy vary by
characteristics in either partner such as age, ovarian reserve,
race, or BMI?
• KQ 6. What are the short- and long-term health outcomes of donors
in infertility?
o KQ 6a. For female oocyte donors:
3. Do specific aspects of the pre-donation evaluation identify
potential donors at greater risk for short- or long-term
adverse outcomes (e.g., OHSS, quality-of-life issues)?
4. Do short- and long-term outcomes differ among different
stimulation/retrieval protocols?
o KQ 6b. For male semen donors:
1. Are there long-term health, quality-of-life, or other adverse
outcomes associated with donation?
5
Figure 1. Analytic framework
Potential Modifiers
• Age • Concomitant diagnoses
• Ovarian reserve o Male factor + female
• Race/ethnicity factor
• Obesity/BMI o Multiple female
• Prior treatments factors
• Primary vs. secondary • Comorbidities
infertility • Setting/provider
• Maternal parity • Insurance status
Treatments
KQ 1
• Watchful waiting
PCOS • Weight loss
• Timed intercourse
KQ 2 • Surgery
Subfertile/ Endometriosis • Clomiphene
infertile • Letrozole
couples • Metformin Final Outcomes
who wish to KQ 3 • Gonadotropins Intermediate • Live birth
Unexplained Infertility • GnRH agonists/ Outcomes o Single
become
antagonists • Time to o Multiple
pregnant • Costs (of treatment
• Intrauterine pregnancy
KQ 4 insemination and outcomes)
Tubal or Peritoneal Factor o Patient
o Donor
KQ 5 • ART
Male Factor o Patient
o Donor
KQs 1-5
KQ 6
Adverse Effects-Child
Adverse Effects-Donor
Adverse Effects-Patient • Short-term (congenital
• Short-term (OHSS,
• Short-term (OHSS, anomalies, death,
surgical complications,
surgical complications) birthweight)
side effects)
• Long-term (cancer, • Long-term (cancer,
• Long-term (cancer, future
subsequent neurodevelopmental,
fertility, age at
pregnancies) specific issues related to
menopause, quality of life)
treatment)
Abbreviations: ART=assisted reproductive technology; BMI=body mass index; GnRH=gonadotropin-releasing hormone; KQ=Key Question; OHSS=ovarian hyperstimulation
syndrome; PCOS=polycystic ovary syndrome
6
Figure 1 depicts the KQs within the context of the populations, interventions, comparators,
outcomes, timings, and settings (PICOTS) considered in this review. The figure illustrates how a
wide range of treatments for infertility may result in intermediate outcomes such as time to
pregnancy and/or final outcomes such as live birth (single or multiple) or costs in couples with
different underlying causes of infertility. A separate KQ focuses on outcomes in female and male
donors in infertility. Short- and long-term adverse effects may occur at any point during
treatment and may affect donors, patients, and/or children. Optimal treatment strategies may vary
by important patient characteristics and/or by setting/provider.
7
Methods
Methods for this systematic review follow the Agency for Healthcare Research and Quality
(AHRQ) Methods Guide for Effectiveness and Comparative Effectiveness Reviews56 and the
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.57
See the review protocol (http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-
reviews-and-reports/?productid=2131&pageaction=displayproduct) for full details.
8
published in the peer-reviewed literature and therefore are not able to reflect studies which found
no difference or negative results but did not reach one of these outlets.
Approaches to identifying relevant gray literature included notification to stakeholders of the
opportunity to submit scientific information packets of material relevant to the KQs. This
notification was coordinated by the SRC. We also searched the ClinicalTrials.gov study registry
and the World Health Organization (WHO) International Clinical Trials Registry Platform
(ICTRP) search portal to identify potentially relevant study records, and subsequently searched
for relevant articles from completed studies.
9
PICOTS Exclusion
Inclusion Criteria
Element Criteria
(male and female), race/ethnicity, obesity/BMI, history of prior
treatments, primary vs. secondary infertility, diagnostic criteria used
for male infertility, insurance status, and presence or absence of
common comorbidities such as hypertension and diabetes.
KQ 6:
• Women of reproductive age (18-44) who are potential donors of
oocytes for ART, and males donating semen for intrauterine
insemination or ART
Interventions KQ 1: Clomiphene citrate, letrozole, diet/exercise/other weight loss
strategies, timed intercourse using various technologies in conjunction with
oral ovulation induction, metformin, combination oral medications, ovulation
induction with gonadotropins with or without intrauterine insemination (IUI),
surgery (ovarian drilling), ART (IVF and ICSI) with patient and donor oocytes
KQ 4: Surgical repair, ART (IVF and ICSI) with patient and donor oocytes
10
PICOTS Exclusion
Inclusion Criteria
Element Criteria
o Ectopic pregnancies
o Miscarriage
• Neonatal outcomes
o Death
o Birthweight (categorized as low birthweight/normal
birthweight)
o Congenital anomalies
• Time to pregnancy
o Calendar time (months)
o Number of cycles
• Costs
o Patient
o Health system
o Societal
• Short-term adverse effects of treatments
o OHSS
o Surgical complications
• Long-term outcomes (child)
o Neurodevelopmental/other issues related to prematurity
o Specific issues related to infertility treatment (epigenetic
changes, sex chromosomal abnormalities, etc.)
o Cancer (all types)
• Long-term outcomes (maternal)
o Cancer
o Subsequent fertility
KQ 6:
• Women:
o Short-term adverse effects of treatments
OHSS
Surgical complications
Adverse effects of treatments
o Long-term outcomes (donor)
Downstream fertility
Cancer
Age at menopause
o Quality-of-life outcomes
• Men:
o Quality-of-life outcomes
o Short- and long-term health outcomes
Timing KQs 1-5:
• Short-term
o From beginning of treatment through first 12 months of life
if live birth occurs
• Long-term
o 12 months or more from completion of treatment (no live
birth) or from date of live birth
KQ 6:
• Short-term:
o From time of beginning donation process to 12 months
after donation
• Long-term:
o 12 months or more from time of first donation
Settings • Subspecialty practice (infertility specialist) (KQs 1-6)
• General gynecology practice (KQs 1-5)
• Family practice/general internist/nurse practitioner/other non-
gynecologist primary care provider (KQs 1-6)
• Male reproductive medicine specialist/urologist (KQ 5)
11
PICOTS Exclusion
Inclusion Criteria
Element Criteria
Study design • Original data Editorials,
• RCTs, prospective and retrospective observational studies with nonsystematic
comparator; for test characteristics, cross-sectional studies were reviews,
acceptable if they included patients with diagnostic uncertainty and direct abstracts only,
comparison of test results with an appropriate reference standard letters, case
series, case
• Study design limitations by outcome type:
reports, articles
o KQs 1-5:
that have been
Short-term outcomes: RCTs of any sample size; retracted or
observational studies of ≥100 subjects presenting data
withdrawn
from the National ART Surveillance System
Long-term outcomes: RCTs of any sample size;
observational studies of ≥100 subjects
o KQ 6 (all outcomes):
RCTs of any sample size; observational studies of ≥100
subjects
Publications • English-language only Non-English
• Published January 1, 2007, to present language
articlesb
• Relevant systematic reviews, meta-analyses, or methods articles
aStudies which included patients outside this age range were included if findings were reported separately for this age group of
interest or if at least 80% of women were within this age range. bNon-English articles were excluded due to: (1) the high volume
of literature available in English-language publications (including the majority of known important studies); and (2) concerns
about the applicability of non-English publication studies to populations in the United States.
Study Selection
For citations retrieved from PubMed, Embase, and the Cochrane Database of Systematic
Reviews, two reviewers independently screened each title and abstract for potential relevance to
the research questions using prespecified inclusion/exclusion criteria described in Table 1.
Articles included by either reviewer underwent full-text screening.
At the full-text screening stage, two reviewers independently reviewed the full text of each
article and indicated a decision to include or exclude the article for data abstraction. When paired
reviewers arrived at different decisions about whether to include or exclude an article, or about
the reason for exclusion, we reconciled the difference through review and discussion among
investigators. Articles meeting eligibility criteria were included for data abstraction. All
screening results were tracked using the DistillerSR data synthesis software program (Evidence
Partners Inc., Manotick, ON, Canada).
Appendix C provides a list of all articles included for data abstraction. Appendix D provides
a list of articles excluded at the full-text screening stage, with reasons for exclusion.
While systematic reviews and meta-analyses were not study designs qualifying for inclusion
and abstraction under our screening criteria, we did flag relevant articles of these types as part of
the screening process. Component references from these systematic reviews were reviewed and
when studies met our inclusion criteria, they were included in our report. For systematic reviews
which were identified as relevant to the individual KQs but included mostly studies prior to
2007, we summarize the findings from these existing reviews and the consistency of their
findings with those from our included studies in the appropriate results sections.
12
Data Extraction
The investigative team created data abstraction forms that were programmed in the
DistillerSR software for collection of data from included studies. The abstraction forms were
pilot-tested with a sample of included articles to ensure that all relevant data elements were
captured and that there was consistency and reproducibility between abstractors. Based on their
clinical and methodological expertise, a pair of researchers were assigned to abstract data from
each of the eligible articles. One researcher abstracted the data, and the second over-read the
article and the accompanying abstraction to check for accuracy and completeness. Disagreements
were resolved by consensus or by obtaining a third reviewer’s opinion if consensus could not be
reached.
We designed the data abstraction forms to collect the data required to evaluate the specified
eligibility criteria for inclusion in this review, as well as demographic and other data needed for
determining outcomes (intermediate, final, and adverse events outcomes). We paid particular
attention to describing the details of the treatment (e.g., for comparisons of in vitro fertilization
[IVF] to other therapies, the specific IVF protocol used), patient characteristics (e.g., age of
female partners, presence or absence of male factor infertility), setting (e.g., U.S.- vs. non-U.S.-
based studies), and study design (e.g., RCT vs. observational) that may be related to outcomes.
In addition, we described comparators carefully, as treatment standards may have changed
during the period covered by the review. The safety outcomes were framed to help identify
adverse events, including those from medical therapies (e.g., ovarian hyperstimulation
syndrome) and those resulting from procedural complications. Data necessary for assessing
quality and applicability, as described in AHRQ’s Methods Guide for Effectiveness and
Comparative Effectiveness Reviews,56 were also abstracted. A complete list of data abstraction
elements is provided in Appendix B.
13
Table 2. Definitions of overall quality ratings
Quality Rating Description
Good (low risk of bias) These studies had the least bias, and the results were considered valid.
These studies adhered to the commonly held concepts of high quality,
including the following: a clear description of the population, setting,
approaches, and comparison groups; appropriate measurement of
outcomes; appropriate statistical and analytical methods and reporting; no
reporting errors; a low dropout rate; and clear reporting of dropouts.
Fair (moderate risk of These studies were susceptible to some bias, but not enough to invalidate
bias) the results. They did not meet all the criteria required for a rating of good
quality because they had some deficiencies, but no flaw was likely to
cause major bias. The study may have been missing information, making it
difficult to assess limitations and potential problems.
Poor (high risk of bias) These studies had significant flaws that might have invalidated the results.
They had serious errors in design, analysis, or reporting; large amounts of
missing information; or discrepancies in reporting.
The grading was outcome-specific such that a given study that analyzed its primary outcome
well but did an incomplete analysis of a secondary outcome could be assigned a different quality
grade for each of the two outcomes. Studies of different designs were graded within the context
of their respective designs as good, fair, or poor (Appendix G).
We also rated the quality of systematic reviews that were identified and discussed in the
report using AMSTAR (A Measurement Tool to Assess the Methodological Quality of
Systematic Reviews).113 For each study, one investigator assigned a summary quality rating, a
second investigator reviewed the rating; disagreements were resolved by consensus or by a third
investigator. Reviews were then assigned overall quality scores according to the following
categories114:
The AMSTAR quality assessment components for the individual systematic reviews are
detailed in Appendix F.
Data Synthesis
We began by summarizing key features of the included studies for each KQ. To the degree
that data are available, we abstracted information on study design; patient characteristics; clinical
settings; interventions; and intermediate, final, and adverse event outcomes. If not reported, 95-
percent confidence intervals for dichotomous outcomes (e.g., live birth rates) were calculated
from the numbers provided in the study, in order to characterize the degree of precision of a
particular estimate. This helped inform grading of the strength of evidence, as well as provided
insight about the degree to which lack of statistical power may have affected study conclusions
about lack of a treatment effect.
14
We then determined the feasibility of completing a quantitative synthesis (i.e., meta-analysis,
decision analysis, or simulation model). For a meta-analysis, feasibility depends on the volume
of relevant literature (requiring at least three relevant studies), conceptual homogeneity of the
studies (similar intervention comparisons and outcome definitions), completeness of the
reporting of results, and the adequacy and completeness of any existing meta-analyses.
When the above criteria were met and a meta-analysis was considered appropriate, we used
random-effects models within the Comprehensive Meta-Analysis software to synthesize the
available evidence quantitatively. We tested for heterogeneity using graphical displays and test
statistics (Q and I2 statistics), while recognizing that the ability of statistical methods to detect
heterogeneity may be limited. For comparison, we also performed fixed-effect meta-analyses.
We present summary estimates, standard errors, and confidence intervals. We anticipated that
intervention effects may be heterogeneous. We hypothesized that the methodological quality of
individual studies, study type, the characteristics of the comparator, and patients’ underlying
clinical presentation would be associated with the intervention effects. If there were sufficient
studies, we performed subgroup analyses and/or meta-regression analyses to examine these
hypotheses. We performed quantitative and qualitative syntheses separately by study type and
discuss their consistency qualitatively.
Applicability
We assessed applicability across our KQs using the method described in AHRQ’s EPC
Methods Guide for Effectiveness and Comparative Effectiveness Reviews56,118 In brief, this
method uses the PICOTS format as a way to organize information relevant to applicability. The
most important issue with respect to applicability is whether the outcomes were different across
studies that recruit different populations (e.g., age groups, U.S. vs. non-U.S. settings) or used
different methods to implement the interventions of interest; that is, important characteristics are
those that affect baseline (control group) rates of events, intervention group rates of events, or
both. We used a checklist applied to each abstracted study to guide the assessment of
applicability (Appendix B). For each study, one investigator assigned a summary quality rating,
which was then reviewed by a second investigator; disagreements were resolved by consensus or
by a third investigator if agreement could not be reached. We summarize issues of applicability
qualitatively.
16
Results
We begin by describing the results of our literature searches. We then provide an overall
description of the included studies. The remainder of the chapter is organized by Key Question
(KQ). Under each of the six KQs, we begin with a brief description of the included studies,
followed by a bulleted list of the key points of the findings and a detailed synthesis of the
evidence. Within each KQ the detailed syntheses are organized first by treatment comparison and
then by outcome. The outcomes of interest are ordered in approximate relative importance to
patients, based on input from topical experts and Key Informants, rather than temporal
occurrence in the clinical pathway: live birth, pregnancy complications, neonatal outcomes, time
to pregnancy, costs, short term adverse effects of treatment, and long term outcomes. We
conducted quantitative syntheses where possible, as described in the Methods chapter. Although
not considered as formal included articles, we discuss findings from relevant systematic reviews
– and whether these findings are consistent or not with the evidence from our included articles.
We end each treatment section by highlighting any evidence for specific subgroups of interest.
Each KQ results section concludes with a summary of the strength of evidence for the main
findings. For findings applicable across all KQs, please refer to “Key Findings Across All
Infertility Diagnoses,” which is presented at the end of the results section. For a list of
abbreviations, please refer to the end of the report.
17
Study Designation Primary Abstracted Article Companion Articles
None Brinton, 2015136 Brinton, 2014137
Brinton, 2013138
Trabert, 201326
None Custers, 2012139 Steures, 2006140a
None Nahuis, 2011141 Nahuis, 2012142
aUsed for background information only.
Figure 2 depicts the flow of articles through the literature search and screening process.
18
Description of Included Studies
Overall, we included 151 studies described in 161 publications: 56 studies were relevant to
KQ 1, 7 studies to KQ 2, 50 studies to KQ 3, 8 studies to KQ 4, 23 studies to KQ 5, and 5 studies
to KQ 6 (some studies were relevant to more than one KQ). Of the 151 included studies, 21
studies had adjusted their results for cause of infertility, but did not report their findings for
specific causes of infertility and are discussed at the end of the results section. Globally the
evidence supporting findings varying by patient characteristics such as age, ovarian reserve, race,
BMI, and presence of other potential causes was minimal. We highlight in the report those cases
where findings in these specific subgroups was possible.
Studies were conducted wholly or partly in continental Europe or the United Kingdom (52
studies, 34%), the United States or Canada (34 studies, 23%), the Middle East (32 studies, 21%),
Asia (19 studies, 12%), Africa (10 studies, 7%), and other locations (Latin America [1 study; this
study also had sites in the UK/Europe] and Australia/New Zealand [3 studies], total 2%).
Appendix C provides a detailed listing of included articles. Appendix D provides a complete list
of articles excluded at the full-text screening stage, with reasons for exclusion. Further details on
the studies included for each KQ are provided in the relevant results sections, below, and in
Appendix E. Detailed risk of bias information for each included study is reported in Appendix G.
19
Middle East,143,145,148,157,158,161,170,176,178,182,183,189-194 5 studies in the United States,128,131,159,172,185
16 studies in the United Kingdom or continental Europe,119,141,144,151,153,155,163-165,177,179-181,184,186,187
and 1 study in the UK/Europe and Latin America.152 Settings included 2 studies conducted in
general gynecology practices,173,182 3 studies conducted in a hospital,180,183,191 2 studies
conducted in a combination of gynecological or subspecialty practices,153,193 6 studies where the
setting was unclear or not reported,131,141,144,147,177,184 while the remaining 42 studies were
conducted in subspecialty practices. Last, 8 studies reported government
funding,119,131,141,149,164,171,172,187 3 studies reported industry funding,152,159,186 7 studies reported
non-government, non-industry funding,148,157,165,178,181,183,184 6 studies reported a combination of
funding from a variety of sources,128,146,160,174,179,188 while the remaining 33 studies did not report
a funding source or it was unclear.
Further details on the characteristics of studies included for this KQ are provided in the
following sections and Appendix E.
In addition to the above studies, seven systematic reviews; six good quality,66,81,90,195-197 one
fair quality,78 addressed the comparative effectiveness of various treatments for infertility in
women with PCOS are also discussed below and the consistency of their findings with our
included studies are incorporated in to our strength of evidence ratings. In general, the
randomized trials used standardized diagnostic criteria for PCOS, while the nonrandomized
observational studies may have included other ovulatory disorders.
21
The meta-analysis did not report on ectopic pregnancies. The three individual RCTs reported
no significant difference in ectopic pregnancy between the clomiphene and letrozole arms and a
meta analysis of these three studies representing 886 women showed no difference (OR = 0.72,
95% CI 0.24 to 2.17) (SOE moderate).131,170,179
Miscarriage was reported in all 3 studies and in the meta-analysis by Franik and colleagues,
with several definitions of miscarriage utilized. From the meta analysis, 2385 patients from 12
trials demonstrated no difference between letrozole and clomiphene in miscarriage rates (pooled
OR 1.32, 95% CI 0.92 to 1.88) (moderate SOE).66 The two additional individual RCTs not
included in the meta analysis comprised an additional 136 women and also reported no
significant differences in miscarriage between the treatment arms.170,179
Neonatal death was reported in one good-quality RCT,131 which compared clomiphene to
letrozole. There was not a significant difference between clomiphene and letrozole for cases of
neonatal death although given the rarity of the outcome, much larger data sets are needed
(insufficient SOE).
Finally, one good-quality RCT reported time to pregnancy for clomiphene versus
letrozole.131 It did not show a significant difference in mean days to pregnancy between study
arms (low SOE).
22
with 1096 women.199 None of the individual studies reported a statistically significant difference
between the groups, although in each of the studies the miscarriage rate was higher in the
clomiphene plus metformin group than the clomiphene group.128,160,166,173 Together these studies
supported a low SOE of a higher rate of miscarriage in the combined therapy group.
The 2017 meta-analysis199 and our included studies did not support a difference in multiple
births between clomiphene and metformin. Given the imprecision in these findings and
suspected reporting bias of the included studies the strength of evidence was rated as low. Our
included studies also did not support a difference in ectopic pregnancy (low SOE for both
outcomes).
For the outcomes of congenital anomalies, the anomalies reported in these studies varied in
severity and type and given the rarity of outcomes and imprecise evidence the SOE was rated as
insufficient. None of the studies however found significant differences between intervention
groups.
One good-quality RCT reported time to pregnancy for clomiphene versus metformin or
placebo in combination with clomiphene.151 It did not show a significant difference in mean days
to pregnancy between study arms (low SOE).
23
Table 4. Outcomes for comparisons of oral agents alone in women with PCOS
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Live birth: Legro, CC Letrozole 72/376 103/374 0.007 Greater live
Any/patient 2014131 (19.1) (27.5) births with
(15.3 to 23.3) (23.1 to 32.2) letrozole
RCT compared to
(750) clomiphene
Amer, CC Letrozole 28/79 39/80 0.089 No
2017179 (35.4) (48.8) difference
RCT
(159)
Morin- CC Metformin+ 46/160 66/160 0.03 Greater live
Papunen, CC (28.9) (41.1) births with
2012151 (22.0 to 36.0) (33.8 to 38.9) combination
of metformin
RCT and
(320) clomiphene
compared to
clomiphene
alone
Legro, CC Metformin 47/209 15/208 <0.001 Greater live
2007128 (22.5) (7.2) births with
(17.1 to 28.4) (4.1 to 11.1) clomiphene
RCT compared to
(626) metformin
Metformin+ 47/209 56/209 0.31 No
CC (22.5) (26.8) difference
(17.1 to 28.4) (21.0 to 33.0)
Kar, CC Metformin 9/32 9/24 0.46 No
2015173 (28.1) (37.5) difference
Metformin+ 9/32 10/24 0.29 No
RCT CC (28.1) (41.6) difference
(105)
Topçu, CC Tamoxifen 6/46 8/42 0.617 No
2017191 (13.0) (19.0) difference
RCT
(88)
Wu, Letrozole Berberine 78/215 47/214 0.001 Greater live
2016175 (36.3) (22.0) births for
Berberine + 78/215 74/215 0.687 letrozole or
RCT Letrozole (36.3) (34.4) letrozole +
(644) berberine
compared
with
berberine
alone. No
difference
between
letrozole
and
letrozole +
berberine
24
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Pregnancy Legro, CC Letrozole 5/376 4/374 0.175 No
complications: 2014131 (1.3) (1.1) difference
Multiple births (0.4 to 2.7) (0.3 to 2.3)
RCT
(750)
Ghahiri, CC Letrozole 0/24 0/24 NS No
2016 170 (0) (0) difference
RCT
(100)
Amer, CC Letrozole 0/34 3/49 0.201 No
2017179 (0.0) (6.1) difference
RCT
(159)
Johnson, CC Metformin 1/36 1/35 0.98 No
2010160 (2.8) (2.9) difference
(0.1 to 10.0) (0.1 to 10.3)
RCT Metformin+ 1/36 1/35 0.98 No
(171) CC (2.8) (2.9) difference
(0.1 to 10.0) (0.1 to 10.3)
Zain, CC Metformin 0/39 0/38 NS No
2009166 (0) (0) difference
Metformin+ 0/39 0/38 NS No
RCT CC (0) (0) difference
(124)
Legro, CC Metformin 3/50 0/18 0.29 No
2007128 (6.0) (0) difference
(1.3 to 14.0)
RCT Metformin+ 3/50 3/65 0.74 No
(626) CC (6.0) (4.6) difference
(1.3 to 14.0) (1.0 to 10.8)
Zahran, CC CC + 1/8 2/19 0.83 No
2018192 Cabergoline (12.5) (10.5) difference
RCT
(130)
Wu, Letrozole Berberine 1/78 0/47 NS No
2016175 (1.2) (0.0) difference
Berberine + 1/78 3/74 0.357
RCT Letrozole (1.2) (4.1)
(644)
Pregnancy Legro, CC Letrozole 3/376 4/374 0.67 No
complications: 2014131 (0.8) (1.1) difference
Ectopic (0.2 to 1.9 (0.3 to 2.3)
pregnancy RCT
(750)
25
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Amer, CC Letrozole 0/34 1/49 NS No
2017179 (0.0) (2.0) difference
RCT
(159)
Zain, CC Metformin 0/39 0/38 NS No
2009166 (0) (0) difference
Metformin+ 0/39 0/38 NS No
RCT CC (0) (0) difference
(124)
Legro, CC Metformin 2/209 0/208 0.16 No
2007128 (1.0) (0) difference
(0.1 to 2.6)
RCT Metformin+ 2/209 2/209 NS No
(626) CC (1.0) (1.0) difference
(0.1 to 2.6) (0.1 to 2.6)
Kar, 2015 CC Metformin 1/10 0/13 NS No
173
(10) (0.0) difference
Metformin+ 1/10 0/12 NS No
RCT CC (10) (0.0) difference
(105)
Pregnancy Legro, CC Letrozole 30/103 49/154 0.65 No
complications: 2014131 (29.1) (31.8) difference
Miscarriage (20.8 to 38.2) (24.7 to 39.4)
RCT
(750)
Ghahiri, CC Letrozole 6/24 5/29 0.38 No
2016 170 (25.0) (17.2) difference
RCT
(100)
Amer, CC Letrozole 6/34 9/49 0.93 No
2017179 (17.6) (18.4) difference
RCT
(159)
26
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Kar, 2015 CC Metformin 0/10 4/13 NS No
173
(0.0) (30.7) difference
Metformin+ 0/10 2/12 NS No
RCT CC (0.0) (16.6) difference
(105)
Topçu, CC Tamoxifen 3/9 2/10 NS No
2017 191 (33.3) (20.0) difference
RCT
(88)
Zahran, CC CC + 2/8 3/19 0.74 No
2018192 Cabergoline (25.0) (15.8) difference
RCT
(130)
Wu, Letrozole Berberine 17/98 14/61 0.386 No
2016175 (17.4) (23.0) difference
Berberine + 17/98 27/105 0.148
RCT Letrozole (17.4) (25.7)
(644)
Neonatal Legro, CC Letrozole Mean = 3.23 Mean = 3.23 0.83 No
outcomes: 2014131 (+/- 0.7153) (+/- 0.6574) difference
Birthweight
(kg) RCT
(750)
Wu, Letrozole Berberine Mean = 3.463 Mean = 3.542 0.216 No
2016175 (+/-0.575 SD) (+/- 0.399 difference
SD)
RCT Berberine + Mean = 3.463 Mean = 3.484 0.246
(644) Letrozole (+/- 0.575 (+/- 0.504
SD) SD)
Neonatal Legro, CC Letrozole 1/66 4/102 0.37 No
outcomes: 2014131 (1.5) (3.9) difference
Congenital (0.0 to 5.5) (1.1 to 8.4)
anomalies RCT
(750)
Amer, CC Letrozole 0 0 NS No
2017179 difference
RCT
(159)
27
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Morin- CC Metformin+ 172 171 0.9 No
Papunen, CC difference
2012151
RCT
(320)
Abbreviations: CC=clomiphene citrate; CI=confidence interval; N=number of patients; NS= not statistically significant;
PCOS=polycystic ovary syndrome; RCT=randomized control trial; SD=standard deviation.
Table 5. Outcomes for comparisons of oral agents alone versus acupuncture in women with PCOS
Study Results Results
Outcome Design Intervention Comparator Summary of
Intervention Comparator P Value
(N N N Study Findings
Patients) (%) (%)
Live birth: Wu, Active Control 69/235 66/236 0.73 Live birth rates
Any/patient 2017188 Acupuncture Acupuncture (29.4) (28.0) significantly
+ CC + CC higher for
RCT Active 69/235 31/223 0.0001 clomiphene vs.
(1000) Acupuncture (29.4) (13.9) placebo; not
+ Placebo significantly
Control 69/235 39/232 0.0013 different for
Acupuncture (29.4) (16.8) active vs.
+ Placebo control
acupuncture
Pregnancy Wu, Active Control 1/108 2/106 0.54 No difference
complications: 2017188 Acupuncture Acupuncture (0.9) (1.9)
Ectopic + CC + CC
Pregnancy RCT Active 1/51 0.56
(1000) Acupuncture (2.0)
+ Placebo
Control 0/55 NS
Acupuncture (0.0)
+ Placebo
Pregnancy Wu, Active Control 38/108 37/106 0.96 No difference
complications: 2017188 Acupuncture Acupuncture (35.2) (34.9)
Miscarriage + CC + CC
RCT Active 19/51 0.80
(1000) Acupuncture (37.3)
+ Placebo
Control 16/55 0.43
Acupuncture (29.1)
+ Placebo
Neonatal Wu, Active Control 1/69 0/66 NS No difference
outcomes: 2017188 Acupuncture Acupuncture (1.4) (0.0)
+ CC + CC
28
Study Results Results
Outcome Design Intervention Comparator Summary of
Intervention Comparator P Value
(N N N Study Findings
Patients) (%) (%)
Congenital Active 0/31 NS
Abnormalities RCT Acupuncture (0.0)
(1000) + Placebo
Control 0/39 NS
Acupuncture (0.0)
+ Placebo
Neonatal Wu, Active Control 0/69 0/66 NS No difference
outcomes: 2017188 Acupuncture Acupuncture (0.0) (0.0)
Neonatal + CC + CC
Death RCT Active 0/31 NS
(1000) Acupuncture (0.0)
+ Placebo
Control 2/39 NS
Acupuncture (5.1)
+ Placebo
Abbreviations: CC=clomiphene citrate; CI=confidence interval; N=number of patients; NS= not statistically significant;
PCOS=polycystic ovary syndrome; RCT=randomized control trial; SD=standard deviation.
3. Oral Agents Alone Versus Oral Agents With IUI for PCOS
One good-quality RCT157 compared clomiphene citrate without IUI to clomiphene citrate
with IUI in women with PCOS. The results for live birth (reported as any live birth per patient),
pregnancy complications (multiple births, ectopic, miscarriage) were reported. Results for live
births and pregnancy complications are summarized in Table 6 (insufficient SOE). There was no
evidence for this treatment regarding neonatal outcomes, time to pregnancy, costs, short-term
adverse effects, and long-term child or maternal outcomes.
A second good-quality RCT182 compared Myo-inositol before and during ovulation induction
followed by IUI compared to ovulation induction and IUI alone in women with PCOS.
Frequency of OHSS and multiple births were reported and are summarized in Table 6
(insufficient SOE).
Table 6. Outcomes for oral agents alone versus oral agents with IUI in women with PCOS
Results Results
Study
Intervention Comparator Summary
Outcome Design
Intervention Comparator N N P Value of Study
(N
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Live birth: Abu CC + IUI CC + timed 18/93 17/95 0.33 No
Any/patient Hashim, Intercourse (19.4%) (17.9%) difference
2011157 (12.0% to (10.9% to
27.9%) 26.2%)
RCT
(188)
Pregnancy Abu CC + IUI CC + timed 2/22 2/21 0.46 No
complications: Hashim, Intercourse (9.1%) (9.5%) difference
Multiple births 2011157 (1.2% to (1.2% to
23.8%) 24.9%)
RCT
(188)
29
Results Results
Study
Intervention Comparator Summary
Outcome Design
Intervention Comparator N N P Value of Study
(N
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Emekci MYO COH/IUI 2/16 1/11 0.78 No
Ozay +COH/IUI (12.5%) (9.1%) difference
2017182
RCT
(196)
Pregnancy Abu CC + IUI CC + timed 0/93 0/95 NS No
complications: Hashim, Intercourse (0%) (0%) difference
Ectopic 2011157
pregnancy
RCT
(188)
Pregnancy Abu CC + IUI CC + timed 4/22 4/21 0.31 No
complications: Hashim, Intercourse (18.2%) (19.0%) difference
Miscarriage 2011157 (5.4% to (5.7% to
36.3%) 37.9%)
RCT
(188)
Short-term Emekci MYO +IUI IUI alone 1/86 3/90 0.35 No
adverse Ozay (1.2%) (3.3%) difference
effects: OHSS 2017182
RCT
(196)
Abbreviations: CC=clomiphene citrate; CI=confidence interval; COH=controlled ovarian hyperstimulation; IUI=intrauterine
insemination; MYO=Myo-inositol; N=number of patients; NR=not reported; NS= not statistically significant; OHSS=ovarian
hyperstimulation syndrome; PCOS=polycystic ovary syndrome; RCT=randomized control trial; SD=standard deviation
30
other treatments (OR 1.1, 95% CI 0.74 to 1.61) (low SOE). The evidence was downgraded since
there were inadequate explanations of randomization (in 3 trials), allocation concealment (8
trials) and inadequate or no blinding reported in 8 trials. The one study not included in the
systematic review189 also showed no significant difference in miscarriage (18% vs. 7%, p=0.41).
The multiple pregnancy rate was evaluated in 12 studies (1129 women) and found to be
lower in women undergoing LOD (OR 0.21, 95% CI 0.08 to 0.58) (moderate SOE).81
The evidence did not show any differences between treatments for the outcomes of OHSS,
and surgical complications but was considered insufficient SOE given the small numbers of
events and the imprecision in the included studies.
There was no evidence for this treatment regarding neonatal outcomes, time to pregnancy,
costs, and long-term child or maternal outcomes.
Table 7. Outcomes for oral agents alone versus surgical management in women with PCOS
Results Results
Study
Intervention Comparator Summary of
Outcome Design P
Intervention Comparator N N Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Live birth: Abu CC LOD 25/89 28/87 0.55 No difference
Any/patient Hashim, (28.1) (32.2)
2011154 (19.3 to 37.8) (22.8 to 42.3)
RCT
(176)
Palomba, CC LOD 12/23 13/24 1 No difference
2010163 (52.2) (54.2)
(32.2 to 71.8) (34.5 to 73.2)
RCT
(47)
Amer, CC LOD 18/32 15/33 0.27 No difference
2009165 (56.3) (45.5)
(39.1 to 72.7) (29.1 to 62.3)
RCT
(65)
Abu Letrozole LOD 32/128 33/132 1 No difference
Hashim, (25.0) (25.0)
2010168 (17.9 to 32.8) (18.0 to 32.7)
RCT
(260)
Zakherah CC + LOD 37/75 33/75 0.35 No difference
, 2010169 tamoxifen (49.3) (44.0)
(38.1 to 60.6) (33.0 to 55.3)
RCT
(150)
Pregnancy Abdellah, Letrozole LOD 0/23 0/16 NS No difference
complications: 2011156 (0) (0)
Multiple births
RCT
(140)
31
Results Results
Study
Intervention Comparator Summary of
Outcome Design P
Intervention Comparator N N Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Abu Letrozole LOD 0/128 0/132 NS No difference
Hashim, (0) (0)
2010168
RCT
(260)
Amer, CC LOD 0/20 0/17 NS No difference
2009165 (0) (0)
RCT
(65)
Pregnancy Abu CC LOD 5/30 6/34 0.92 No difference
complications: Hashim, (16.7) (17.6)
Miscarriage 2011154 (5.8 to 31.7) (7.0 to 31.6)
RCT
(176)
Abdellah, Letrozole LOD 2/25 4/20 0.231 No difference
2011156 (8.0) (20.0)
(1.0 to 2.1) (6.1 to 39.6)
RCT
(140)
Amer, CC LOD 2/20 2/17 0.62 No difference
2009165 (10.0) (11.8)
(1.3 to 26.0) (1.6 to 30.2)
RCT
(65)
Abu Letrozole LOD 4/128 4/132 0.92 No difference
Hashim, (3.1) (3.0)
2010168 (0.9 to 6.7) (0.8 to 6.5)
RCT
(260)
Zakherah CC + LOD 3/40 5/38 0.06 No difference
, 2010169 tamoxifen (7.5) (13.2)
(1.6 to 17.3) (4.5 to 25.4)
RCT
(150)
Ibrahim, Letrozole LOD 1/14 2/11 0.41 No difference
2017189 (7) (18)
RCT
(80)
Short-term Amer, CC LOD 1/32 0/33 0.31 No difference
adverse 2009165 (3.1) (0)
effects: OHSS (0.1 to 11.2)
RCT
(65)
32
Results Results
Study
Intervention Comparator Summary of
Outcome Design P
Intervention Comparator N N Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Abu Letrozole LOD 0/128 0/132 NS No difference
Hashim, (0) (0)
2010168
RCT
(260)
Surgical Palomba, CC LOD NA 0/24 NR No difference
complications 2010163 (0)
RCT
(47)
Amer, CC LOD NA 1/33 NR No difference
2009165 (3.0)
(0.1 to 10.9)
RCT
(65)
Abbreviations: CC=clomiphene citrate; CI=confidence interval; LOD=laparoscopic ovarian drilling; N=number of patients;
NA=not applicable; NR=not reported; NS=not statistically significant; OHSS=ovarian hyperstimulation syndrome;
PCOS=polycystic ovary syndrome; RCT=randomized control trial
33
different, based on three studies including 84 women (OR 0.62, 95% CI 0.19 to 2.01). OHSS
also was not significantly different based on two studies including180 women (OR 0.32, 95% CI
0.01 to 8.23). The authors of the meta-analysis judged the overall SOE to be low.
Table 8. Outcomes for oral agents versus gonadotropins in women with PCOS
Results Results
Study
Intervention Comparator Summary
Outcome Design
Intervention Comparator N N P Value of Study
(N
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Live birth: Homburg, CC FSH 53/143 72/159 0.12 No
Any/patient 2012152 (37.1) (45.3) difference
(29.4 to 45.1) (37.6 to 53.0)
RCT
(302)
Hossein- CC FSH 5/52 5/44 0.78 No
Rashidi, (9.6) (11.4) difference
2016176
RCT
(104)
Weiss, CC CC+IUI 66/171 72/163 FSH vs. Greater
2018 187 (38.6) (44.2) CC: live births
FSH 78/163 0.0124 for FSH
RCT (47.9) than CC;
(666) IUI vs. no
FSH+IUI 89/164 inter- significant
(54.3) course: difference
0.12 between
IUI and
intercours
e.
Ghanem, CC + FSH FSH 22/87 19/87 0.85 No
2013145 (25.3) (21.8) difference
(16.8 to 34.9) (13.9 to 31.0)
RCT
(159)
Pregnancy Homburg, CC FSH 0/143 2/159 0.17 No
complications: 2012152 (0) (1.3) difference
Multiple births (0.2 to 3.5)
RCT
(302)
Pregnancy Homburg, CC FSH 1/143 1/159 0.91 No
complications: 2012152 (0.7) (0.6) difference
Ectopic (0.0 to 2.6) (0.0 to 2.3)
pregnancy RCT
(302)
Weiss, CC CC+IUI 1/171 3/163 0.31 No
2018187 (0.6) (1.8) difference
FSH 1/163 NS
RCT (0.6)
(666)
FSH+IUI 1/164 NS
(0.6)
Pregnancy Homburg, CC FSH 5/143 7/159 0.68 No
complications: 2012152 (3.5) (4.4) difference
Miscarriage (1.2 to 7.1) (1.8 to 8.1)
RCT
(302)
34
Results Results
Study
Intervention Comparator Summary
Outcome Design
Intervention Comparator N N P Value of Study
(N
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Hossein- CC FSH 0/52 1/44 0.27 No
Rashidi, (0.0) (2.3) difference
2016176
RCT
(104)
Weiss, CC CC+IUI 3/171 8/163 FSH vs. Higher
2018187 (1.8) (4.9) CC: 0.02; miscarriag
FSH 9/163 IUI vs. e rate with
RCT inter- FSH and
(5.5)
(666) course with IUI
FSH+IUI 15/164 0.05
(9.1)
Hassan Letrozole FSH 2/21 3/24 0.999 No
2017 183 difference
Badawy Extended FSH 5/160 4/158 NS No
2008 193 CC difference
Neonatal Weiss, CC CC+IUI 3.408 3.178 FSH vs. No
outcomes: 2018187 (0.491 SD) (0.714 SD) CC: 0.96; difference
Birthweight FSH 3.302 IUI vs.
(kg) RCT (0.769 SD) inter-
(666) FSH+IUI 3.279 course
0.14
(0.695 SD)
Abbreviations: CC=clomiphene citrate; CI=confidence interval; FSH=follicle-stimulating hormone; IUI=intrauterine
insemination; N=number of patients; NR=not reported; NS=not statistically significant; PCOS=polycystic ovary syndrome;
RCT=randomized control trial; SD=standard deviation
35
6. Lifestyle Interventions for PCOS
Three studies looked at methods of lifestyle modifications for women with PCOS and their
impact on outcomes of interest. One good-quality 3-arm study172compared preconception
continuous oral contraceptives (OCPs) to lifestyle modification with carloric restriction, weight
loss medication and increased physical activity to a combined treatment of OCPs and lifestyle
modifications. After the preconception intervention, all women started standard ovulation
induction for four cycles with clomiphene citrate. The primary outcome was live birth rate, and
relevant secondary outcomes included fecundity per ovulated patient, and adverse outcomes
(ectopic pregnancy). Results are summarized in Table 9. There was no evidence for difference in
live birth rate between arms, though fecundity per patient who ovulated was higher in women
randomized to lifestyle intervention compared to OCP alone.
One good-quality multicenter RCT (LIFEstyle study)119 conducted a predetermined
subgroup analyses based on ovulatory status (anovulatory vs. ovulatory). The intervention
consisted of a 6-month program aimed at loss of 5-10% of original body weight. Of those
women who were anovulatory, 76% of women in the intervention group (pre-treatment lifestyle)
and 74% in the control group (prompt treatment) met criteria for PCOS. Outcomes reported
include overall and healthy live birth <24 months. There were no significant differences between
lifestyle intervention and control on healthy live birth rate or overall live birth rate between
ovulatory and anovulatory women. In addition, the effect of lifestyle intervention on overall and
healthy birth rate was not altered by ovulatory status.
Finally, a third good-quality multi-center RCT 181 compared a pre-IVF treatment 12 week
strict low calorie liquid formula diet (LCD) to IVF treatment alone. 23% of intervention
participants and 18.3% of IVF only participants had PCOS, and a subgroup analysis was
conducted for this group of 81 women (Table 9). No difference was seen between arms in the
live birth rates. Combined, these three studies supported a moderate SOE for no difference in
live birth rates from lifestyle modification interventions
Table 9. Outcomes for lifestyle intervention versus oral contraceptive pills or no intervention in
women with PCOS
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Live birth: Legro Lifestyle + OCP + CC 13/50 5/49 0.06 No
Any/patient 2015172 CC (26.0) (10.2) difference
RCT
(564)
Einarsson, LCD +IVF IVF alone 11/40 9/41 0.75 No
2017181 (27.5) (22.0) difference
RCT
(317)
36
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Live birth: Per- Legro Lifestyle + OCP + CC 13/36 5/36 0.04 Increased
ovulated 2015172 CC (36.1) (13.9) live birth
patient rate for
RCT Lifestyle
(132) intervention
than OCPs
alone.
OCP 12/39 0.10 No
+Lifestyle + (30.8) difference
CC
Pregnancy Legro Lifestyle + OCP + CC 1/16 0/8 NS No
complications: 2015172 CC (6.3) (0) difference
Ectopic OCP+ 0/14
pregnancy RCT Lifestyle + (0)
(132) CC
Abbreviations: CC = clomiphene citrate; CI=confidence interval; hMG=human menopausal gonadotropin; LCD=low calorie
liquid formula diet; N=number of patients; NR=not reported; NS=not statistically significant; OCP=oral contraceptives;
OHSS=ovarian hyperstimulation syndrome; PCOS=polycystic ovary syndrome; RCT=randomized control trial;
rFSH=recombinant follicle-stimulating hormone
Table 10. Outcomes for surgical management versus gonadotropins in women with PCOS
Results Results
Study Intervention Comparator Summary of
Outcome P
Design Intervention Comparator N N Study
Value
(N Patients) (%) (%) Findings
(95% CI) (95% CI)
Live birth: Nahuis, LEC rFSH 71/83 69/85 0.63 No
Any/patient 2011141 (85.5) (81.2) difference
(77.3 to 92.2) (72.3 to
RCT 88.7)
(168)
Pregnancy Nahuis, LEC rFSH 7/134 10/124 0.35 No
complications: 2011141 (5.2) (8.1) difference
Multiple births (2.1 to 9.6) (4.0 to 13.4)
RCT
(168)
37
Results Results
Study Intervention Comparator Summary of
Outcome P
Design Intervention Comparator N N Study
Value
(N Patients) (%) (%) Findings
(95% CI) (95% CI)
Mean direct Nahuis, LEC rFSH 9,560 euros 11,708 NS No
medical costs 2011142 (8,212 to euros difference
in euros 10,907) (9,845 to
RCT 13,561)
(168)
Short-term Mehrabian, LEC hMG 0/52 2/52 0.16 No
adverse 2012148 (0) (3.8) difference
effects: OHSS (0.5 to 10.4)
RCT
(104)
Abbreviations: CI=confidence interval; LEC=laparoscopic electrocauterization; hMG=human menopausal gonadotropin;
N=number of patients; NR=not reported; NS=not statistically significant; OHSS=ovarian hyperstimulation syndrome;
PCOS=polycystic ovary syndrome; RCT=randomized control trial; rFSH=recombinant follicle-stimulating hormone
Table 11. Outcomes for gonadotropins with IUI in women with PCOS
Results Results
Study Intervention Comparator
Outcome P Summary of
Design Intervention Comparator N N
Value Study Findings
(N Patients) (%) (%)
(95% CI) (95% CI)
Live birth: Stadtmauer, rFSH rFSH + 10/53 18/54 0.09 No difference
Any/cycle 2011159 GnRH (18.9) (33.3)
antagonist
RCT (flexible)
(98) rFSH + 10/53 7/47 0.37 No difference
GnRH (18.9) (12.3)
antagonist
(start day)
Live birth: Rashidi, rFSH hMG 21/132 14/144 0.14 No difference
Single/cycle 2015143 (15.9) (9.7)
RCT
(276)
38
Results Results
Study Intervention Comparator
Outcome P Summary of
Design Intervention Comparator N N
Value Study Findings
(N Patients) (%) (%)
(95% CI) (95% CI)
Pregnancy Rashidi, rFSH hMG 1/132 2/144 0.62 No difference
complications: 2015143 (0.8%) (1.4)
Multiple births (0.0 to 2.8) (0.2 to 3.8)
RCT
(276)
Stadtmauer, rFSH rFSH + 0/10 2/18 0.27 No difference
2011159 GnRH (0) (11.1)
antagonist (1.5 to 28.7
RCT (flexible)
(98) rFSH + 0/10 1/7 0.22 No difference
GnRH (0) (14.3)
antagonist (0.4 to 45.9)
(start day)
Pregnancy Rashidi, rFSH hMG 3/25 3/18 0.63 No difference
complications: 2015143 (12.0) (16.7)
Miscarriage (2.7 to 27.0) (3.8 to 36.4)
RCT
(276)
Stadtmauer, rFSH rFSH + 2/12 1/19 0.30 No difference
2011159 GnRH (16.7) (5.3)
antagonist (2.3 to 41.3) (0.1 to 18.5)
RCT (flexible)
(98) rFSH + 2/12 2/9 0.75 No difference
GnRH (16.7) (22.2)
antagonist (2.3 to 41.3) (3.2 to 52.7)
(start day)
Short-term Rashidi, rFSH hMG 1/132 2/144 0.61 No difference
adverse 2015143 (0.8) (1.4)
effects: OHSS (0.0 to 2.8) (0.2 to 3.8)
RCT
(276)
Abbreviations: CI=confidence interval; GnRH=gonadotropin-releasing hormone; hMG=human menopausal gonadotropin;
N=number of patients; NR=not reported; NS=not statistically significant; OHSS=ovarian hyperstimulation syndrome;
PCOS=polycystic ovary syndrome; RCT=randomized control trial; rFSH=recombinant follicle-stimulating hormone
39
placebo; metformin resulted in significantly more live births than placebo.146 This evidence
however was rated as insufficient strength of evidence given findings form one fair quality trial.
Of the four studies that reported live birth according to any live birth per cycle, three
incorporated gonadotropin use as adjunct therapy. The results of any live birth per cycle were not
significant across intervention groups (low SOE).
Three studies examined pregnancy complications,164,167,171 with all three reporting on
miscarriage, one164 reporting on multiple births, and one171 reporting on ectopic pregnancies.
None of the studies reported significant differences between intervention groups for miscarriages
(moderate SOE) but given the heterogeneity in intervention protocols we did not perform a meta-
analysis of these findings synthesis. Multiple births were reported in one study164 without
significant differences measured but the strength of evidence was rated as insufficient given
findings from one fair-quality trial. Ectopic pregnancies were not significantly different in the
one fair-quality study that reported this outcome (insufficient SOE).171
Five studies examined short-term adverse effects of ART153,161,162,164,178 with all 6 reporting
on OHSS. One study153 compared metformin with placebo as oral ovulation induction in addition
to IVF. Two studies161,178 reported outcomes by severity of OHSS. Heterogeneity in comparisons
and findings as well as the studies being underpowered to detect differences in OHSS led to an
insufficient strength of evidence rating.
Three observational studies explored the comparative effectiveness of ART with other
infertility treatments in women with PCOS.180,184,186
One nationwide birth cohort study184 identified all pregnancies with a live-single born child
over an 8 year period in Denmark and compared the incidence of type I diabetes among those
conceived with fertility treatment to those conceived naturally. There was no association
between PCOS infertility as an indicator for fertility treatment and the subsequent development
of Type I diabetes in offspring (adjusted HR 0.98, 95% CI 0.32 to 3.05) (moderate SOE).
A second Danish national cohort study from registry data examined success rates across
complete fertility treatment courses including insemination, ART, and natural conception among
couples treated using homologous gametes and no previous live births due to fertility
treatment.186 13.7% (95% CI 13.1 to 14.4) of women with first treatment by IUI and 4.2%
(95%CI 3.7 to 4.6) of women with first treatment with ART were diagnosed with anovulation as
the specified cause of female infertility. Across all women, anovulatory infertility was predictor
of high live birthrate. The adjusted OR for live birth within 2 years from first IUI treatment was
1.31 (95% CI 1.15 to 1.50; p<0.0001) and 1.57 for ART (95% CI 1.18 to 2.11; p =0.002). Live
birthrate differed by maternal age for women with anovulatory infertility less than 35 years 45.3
(95% CI 42.8 to 47.9) with IUI and 14.8 (95% CI 13.1 to 16.7) for ART. This compares to 31.7
(95% CI 25.2 to 38.9) for IUI among women over 35 years and 6.9 (95% CI 3.7 to 11.5) for
ART.
Finally, a prospective cohort study180 of women with PCOS compared maternal and neonatal
outcomes with a reference population. Of the 188 included women with PCOS, 14 percent had
conceived spontaneously, 68 percent had undergone ovulation induction, and 16 percent
underwent IVF/ICSI. A subgroup analysis found no differences in maternal or neonatal
(including small for gestational age and neonatal death) complications across presence/absence
and type of fertility treatment.
40
Table 12. Outcomes for comparisons of IVF treatments in women with PCOS
Results Results
Study Intervention Comparator Summary
Outcome
Design Intervention Comparator N N P Value of Study
(N Patients) (%) (%) Findings
(95% CI) (95% CI)
Live birth: An, 2014146 Berberine Metformin 18/37 14/38 0.30 No
Any/patient +IVF +IVF (48.6) (36.8) difference
RCT (32.9 to 64.5) (22.5 to
(109) 52.5)
Placebo 18/37 7/34 0.013 Greater live
+IVF (48.6) (20.6) birth with
(32.9 to 64.5) (9.0 to 35.5) berberine
compared
to placebo
Live birth: Choi, IVM + hCG GnRH 5/14 5/14 NS No
Any/cycle 2012147 agonist (35.7) (35.7) difference
(13.9 to 61.4) (13.9 to
RCT 61.4)
(61) GnRH 10/39 0.47 No
antagonist (25.6) difference
(13.4 to
40.2)
Kim, 2012150 GnRH GnRH 36/103 36/105 No
agonist antagonist (35.0) (34.3) difference
RCT 0.92
(26.1 to 44.4) (25.6 to
(208) 43.6)
Kurzawa, GnRH GnRH 18/37 14/33 No
2008164 agonist antagonist (48.6) (42.4) difference
(32.9 to 64.5) (26.4 to 0.481
RCT 59.4)
(70)
Ge 2008167 hCG hCG free 9/29 10/30 No
medium medium + (31.0) (33.3) difference
RCT 0.85
transfer (15.9 to 48.7) (17.9 to
(62) 50.8)
hCG free 10/30 No
medium (33.3) difference
0.85
(17.9 to
50.8)
Pregnancy Kurzawa, GnRH GnRH 5/37 3/33 0.5 No
complications: 2008164 agonist antagonist (13.5) (9.1) difference
Multiple births +IVF +IVF (4.7 to 26.1) (2.0 to 20.8)
RCT
(70)
Pregnancy Kurzawa, GnRH GnRH 2/37 6/33 0.154 No
complications: 2008164 agonist antagonist (5.4) (18.2) difference
Miscarriage +IVF (0.7 to 14.5) (7.2 to 32.8)
RCT
(70)
Ge 2008167 hCG hCG-free 3/29 3/30 0.97 No
medium medium + (10.3) (10.0) difference
RCT transfer (2.3 to 23.5) (17.9 to
(62) 50.8)
hCG-free 3/29 2/30 0.62 No
medium (10.3) (6.7) difference
(2.3 to 23.5) (0.8 to 17.8)
41
Results Results
Study Intervention Comparator Summary
Outcome
Design Intervention Comparator N N P Value of Study
(N Patients) (%) (%) Findings
(95% CI) (95% CI)
Wang, MPA + Short 4/75 7/84 0.457 No
2016171 hMG+IVF protocol (5.33) (8.33) difference
(Decapeptyl,
RCT hMG, hCG)
(120)
Pregnancy Wang, MPA + Short 1/49 1/45 0.952 No
complications: 2016171 hMG+IVF protocol (2.04) (2.22) difference
Ectopic (Decapeptyl,
pregnancy RCT hMG, hCG)
(120)
Short-term Palomba, Metformin+ Placebo+IVF 5/60 18/60 0.003 Reduced
adverse 2011153 IVF (8.3) (30.0) OHSS with
effects: OHSS, (2.8 to 16.5) (19.2 to metformin
any RCT 42.1) compared
(120) to placebo
Aboulghar, rFSH uFSH 0/42 1/42 0.31 No
2010162 (0) (2.4) difference
(0.1 to 8.6)
RCT
(84)
Short-term Tehranineja GnRH GnRH 10/45 0/45 0.001 Reduced
adverse d, 2010161 agonist antagonist (22.2) (0) OHSS with
effects: OHSS, (11.5 to 35.3) GnRH
moderate RCT antagonist
(90) compared
to GnRH
agonist
Short-term Tehranineja GnRH GnRH 5/45 0/45 0.02 Reduced
adverse d, 2010161 agonist antagonist (11.1) (0) OHSS with
effects: OHSS, (3.8 to 21.7) GnRH
severe antagonist
compared
to GnRH
agonist
Aghahossein Low-dose Low-dose 13/40 5/40 0.03 Reduced
i, 2017 178 hCG at time hCG 35 hrs (32.5) (12.5) OHSS with
of GnRH after GnRH hCG given
RCT agonist agonist 35 hours
(100) after GnRH
agonist
aP values for berberine vs. placebo, metformin vs. placebo, and berberine vs. metformin were each <0.05.
42
stimulation), and those women randomized to the study who started ovarian stimulation (ART
population). Note that we judge only the intention-to-treat results as fair quality, with the others
poor (due to increased risk of bias). The other study of pretreatment with metformin reported
significantly lower birth rates in the metformin group. The live birth results are presented in
Table 13 (insufficient SOE). There was no difference in OHSS in one study177 (Table 13) and no
evidence regarding pregnancy complications, neonatal outcomes, time to pregnancy, costs, other
short-term adverse effects, and long-term child or maternal outcomes. The third study190 reported
on OHSS in women treated with methylprednisolone as an adjunct to IVF. No differences
overall or by severity of OHSS were reported. (Table 13). SOE was rated as insufficient for all
outcomes given the small studies with varying adjuncts.
Results Results
Study
Intervention Comparator Intervention Comparator P Summary of
Outcome Design
(population) (population) N N Value Study
(N Patients)
(%) (%) Findings
Live birth: Kjotrod, Metformin Placebo 36/74 24/75 0.038 Greater live
Any/patient 2011155 (Intention to (Intention to (48.6) (32.0) births with
treat) treat) metformin
RCT compared to
(149) placebo
within the
intention to
treat
analysis
Metformin Placebo 21/56 16/56 0.32 No
(ART) (ART) (37.5) (28.6) difference
Live birth: Jacob, Metformin Placebo 16/58 33/64 0.01 Lower birth
Any/embryo 2016177 (27.6) (51.6) rates in
transfer metformin
RCT group.
(153)
Short-term Jacob, Metformin Placebo 21/75 16/74 0.726 No
adverse 2016177 (28.0) (21.6) difference
effects:
OHSS, any RCT
(153)
Yeganeh, Methy- Placebo 18/93 15/91 0.61 No
2018190 prednisolone (19.4) (16.5) difference
RCT
(219)
Short-term Yeganeh, Methy- Placebo 10/93 5/91 NS No
adverse 2018190 prednisolone (10.8) (5.5) difference
effects:
OHSS, mild RCT
(219)
Short-term Jacob, Metformin Placebo 12/75 9/74 0.66 No
adverse 2016177 (16) (12.2) difference
effects:
OHSS, RCT
moderate/ (153)
severe
43
Results Results
Study
Intervention Comparator Intervention Comparator P Summary of
Outcome Design
(population) (population) N N Value Study
(N Patients)
(%) (%) Findings
RCT
(219)
OHSS, Yeganeh, Methy- Placebo 4/93 5/91 NS No
severe 2018190 prednisolone (4.3) (5.5) difference
RCT
(219)
Abbreviations: ART=assisted reproductive technology; CI=confidence interval, N=number of patients; NS=not statistically
significant; OHSS=ovarian hyperstimulation Syndrome; PCOS=polycystic ovary syndrome; RCT=randomized control trial
Table 14. Outcomes for fresh versus frozen embryo transfer in IVF in women with PCOS
Results Results
Study Intervention Comparator Summary of
Outcome P
Design Intervention Comparator N N Study
Value
(N Patients) (%) (%) Findings
(95% CI) (95% CI)
Live birth: Chen, Frozen Fresh 368/746 320/762 0.004 Greater live
Any/patient 2016174 Embryo Embryo (49.3) (42.0) births with
Transfer in Transfer in frozen
RCT IVF IVF embryo
(1508) transfer
Pregnancy Chen, Frozen Fresh 118/746 108/762 0.41 No
complications: 2016174 Embryo Embryo (15.8) (14.2) difference
Multiple births Transfer in Transfer in
RCT IVF IVF
(1508)
Pregnancy Chen, Frozen Fresh 108/492 161/492 <0.00 Lower
complications: 2016174 Embryo Embryo (22.0) (32.7) 1 miscarriages
Miscarriage Transfer in Transfer in with frozen
RCT IVF IVF embryo
(1508) transfer
Pregnancy Chen, Frozen Fresh 10/492 54/762 <0.00 Lower
complications: 2016174 Embryo Embryo (2.0) (7.1) 1 ectopic
Ectopic Transfer in Transfer in pregnancies
pregnancy RCT IVF IVF with frozen
(1508) embryo
transfer
44
Results Results
Study Intervention Comparator Summary of
Outcome P
Design Intervention Comparator N N Study
Value
(N Patients) (%) (%) Findings
(95% CI) (95% CI)
Neonatal Chen, Frozen Fresh 2/370 0 0.50 No
outcomes: 2016174 Embryo Embryo (0.5) (0) difference
Stillbirth Transfer in Transfer in
RCT IVF IVF
(1508)
Neonatal Chen, Frozen Fresh 24/491 17/432 0.52 No
outcomes: 2016174 Embryo Embryo (4.9) (3.9) difference
Congenital Transfer in Transfer in
abnormalities RCT IVF IVF
(1508)
Abbreviations: CI=confidence interval, IVF=in vitro fertilization; N=number of patients; PCOS=polycystic ovary syndrome;
RCT=randomized control trial
Table 15. Outcomes for comparisons of ICSI treatment in women with PCOS
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Live birth: Zheng, hCG Priming No hCG 9/40 13/42 0.39 No
Any/patient 2012149 Priming (22.5) (31.0) difference
(11.1 to (18.1 to 45.5)
RCT 36.5)
(82)
Pregnancy Hosseini, GnRH GnRH 4/55 8/57 0.219 No
complications: 2010158 agonist antagonist (7.3) (17.6) difference
Miscarriage (2.1 to 15.4) (6.9 to 25.8)
RCT
(112)
45
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Short-term Hosseini, GnRH GnRH 35/55 25/57 0.036 Reduced
adverse 2010158 agonist antagonist (63.6) (43.9) OHSS with
effects: OHSS (50.6 to (34.0 to 60.5) GnRH
RCT 75.7) antagonist
(112) compared
to GnRH
agonist
Short-term Hosseini, GnRH GnRH 18/55 16/57 0.78 No
adverse 2010158 agonist antagonist (32.7) (29) difference
effects: OHSS, (21.1 to (18.7 to 43.1)
mild RCT 45.6)
(112)
Short-term Hosseini, GnRH GnRH 17/55 9/57 0.09 No
adverse 2010158 agonist antagonist (30.9) (15.7) difference
effects: OHSS, (19.5 to (8.2 to 28.1)
moderate/ RCT 43.6)
severe (112)
47
Study Design SOE
Comparison Outcome Conclusion
(Sample Size) (Rationale)a
Oral agents Live birth 3 RCTs128,151,173 No difference: No statistical difference Moderate
alone: (any/patient) (842) between clomiphene and metformin or (Suspected
Clomiphene vs. between clomiphene and combination reporting bias)
Metformin vs. 2 SRs therapy of metformin and clomiphene
Metformin + (3 studies, 912 (OR 1.21, 95% CI 0.92 to 1.59)
Clomiphene patients78); (9
studies, 1079
patients199)
Pregnancy 3 RCTs128,160,166 No difference: No differences in Low
complications: (921) multiple birth rates between clomiphene (Imprecise,
Multiple births alone, metformin alone, and suspected
1 SR199 clomiphene plus metformin reporting bias)
(9 studies, 1079
patients)
Pregnancy 3 RCTs128,166,173 No difference: No difference between Low
complications: (1,005) studied oral agents. Very few ectopic (Imprecise
Ectopic pregnancies overall. findings with
pregnancy moderate study
limitations)
Pregnancy 3 RCTs128,160,166,173 Increase: Higher rate of miscarriage in Low
complications: (817) the combined therapy group (Suspected
Miscarriage (clomiphene and metformin) compared reporting bias,
1 SR199 (9 studies, to clomiphene alone (OR 1.59, 95% CI, imprecise)
1079 patients) 1.03 to 2.46)
Neonatal 3 RCTs128,166,173 Inconclusive: SOE was insufficient Insufficient
outcomes: (1,005) given the imprecise evidence from (Imprecise,
Congenital identified studies. Given the rarity of the suspected
anomalies outcomes, much larger data sets are reporting bias)
needed.
Time to 1 RCT151 No difference: No significant difference Low (Findings
Pregnancy (343) in time to pregnancy between from 1 study)
clomiphene vs. metformin
Oral agents Pregnancy 1 RCT192 Inconclusive: SOE was insufficient Insufficient
alone: complications: (130) given the findings from 1 small study (1 study,
Clomiphene vs. Multiple births with potential limitations moderate
Clomiphene + limitations)
Cabergoline Pregnancy 1 RCT192 Inconclusive: SOE was insufficient Insufficient
complications: (130) given the findings from 1 small study (1 study,
Miscarriage with potential limitations moderate
limitations)
Oral agents Live birth 1 RCT191 No difference: No significant difference Low
alone: (any/patient) (88) in live birth rates between tamoxifen (Imprecise)
Clomiphene vs. and clomiphene (OR 1.24, 95% CI
Tamoxifen 1 SR198 0.59-2.62)
(2 studies, 195
women)
Pregnancy 1 RCT191 No difference: No significant difference Low
complications: (88) in miscarriage rates between tamoxifen (Imprecise)
Miscarriage and clomiphene (OR 1.81, 95% CI
1 SR198 0.80-4.12)
(2 studies, 195
women)
Oral agents Live birth 1 RCT188 Improvement: Live birth rates Low
alone vs. (1000) significantly higher for clomiphene vs. (1 study with
acupuncture: placebo; not significantly different for potential risk of
Active active vs. control acupuncture bias)
48
Study Design SOE
Comparison Outcome Conclusion
(Sample Size) (Rationale)a
Acupuncture + Pregnancy 1 RCT188 No difference: no significant difference Low
Clomiphene vs. complications: (1000) in ectopic pregnancy rates between oral (1 study with
Control Ectopic agents and acupuncture strategies. potential risk of
Acupuncture + pregnancy bias)
Clomiphene vs. Pregnancy 1 RCT188 No difference: no significant difference Low
Active complications: (1000) in miscarriage rates between oral (1 study with
Acupuncture + Miscarriage agents and acupuncture strategies. potential risk of
Placebo vs. bias)
Control Neonatal 1 RCT188 No difference: no significant difference Low
Acupuncture + outcomes: (1000) in congenital abnormality rates between (1 study with
Placebo Congenital oral agents and acupuncture strategies. potential risk of
Abnormalities bias)
Neonatal 1 RCT188 No difference: no significant difference Low (1 study
Death (1000) in neonatal death rates between oral with potential
agents and acupuncture strategies. risk of bias)
Oral agents Live birth 1 RCT157 Inconclusive: SOE was insufficient Insufficient
alone vs. oral (188) given evidence from 1 small trial. (Imprecise, 1
agents with IUI: small trial)
Clomiphene Pregnancy 1 RCT157 Inconclusive: SOE was insufficient Insufficient
without IUI vs. complications: (188) given evidence from 1 small trial. (Imprecise, 1
Clomiphene Multiple births small trial)
with IUI Pregnancy 1 RCT157 Inconclusive: SOE was insufficient Insufficient
complications: (188) given evidence from 1 small trial. (Imprecise, 1
Ectopic small trial)
pregnancy
Pregnancy 1 RCT157 Inconclusive: SOE was insufficient Insufficient
complications: (188) given evidence from 1 small trial. (Imprecise, 1
Miscarriage small trial)
Oral agents Pregnancy 1 RCT182 Inconclusive: SOE was insufficient Insufficient
alone vs. oral complications: (196) given evidence from 1 small trial. (Imprecise, 1
agents with IUI: Multiple births small trial)
Myo-inositol + Adverse 1 RCT182 Inconclusive: SOE was insufficient Insufficient
Ovulation events: (196) given evidence from 1 small trial. (Imprecise, 1
induction + IUI OHSS small trial)
vs. Ovulation
induction and
IUI alone
Oral agents vs. Live birth 1 SR81 No difference: No statistically Moderate
LOD (any/patient) (8 studies, 1,034 significant differences between LOD (Suspected
women) and oral agents (OR = 0.77, 95% CI reporting bias)
0.59 to 1.01)
Pregnancy 1 SR81 Reduction: There was a reduction in Moderate
complications: (15 studies, 1,129 multiple births given LOD as compared (Suspected
Multiple births women) to oral agents (OR 0.21, 95% CI 0.08 to reporting bias)
0.58)
Pregnancy 1 RCT189 No difference: No significant Low
complications: (80) differences in miscarriage between (Imprecise,
Miscarriage LOD and oral agents (OR 1.1, 95% CI suspected
1 SR81 0.74 to 1.61) reporting bias)
(15 studies, 1,592
women)
Short term 2 RCTs165,168 Inconclusive: SOE was insufficient Insufficient
adverse (325) given the imprecision and small (Imprecise,
effects of numbers of events in the identified suspected
treatment: studies. reporting bias, 1
OHSS small study)
49
Study Design SOE
Comparison Outcome Conclusion
(Sample Size) (Rationale)a
Short term 2 RCTs163,165 Inconclusive: SOE was insufficient Insufficient
adverse (89) given the imprecision and small (Imprecise,
effects of numbers of events in the identified suspected
treatment: studies. reporting bias,
Surgical small sample
complications size)
Oral agents Live birth 3 RCTs152,176,187 Inconclusive: SOE was insufficient Insufficient
alone vs. (1072) given the inconsistent evidence from (Imprecise,
gonadotropins: included studies inconsistent)
Clomiphene
citrate vs. low- Pregnancy 1 RCT152 Inconclusive: SOE was insufficient Insufficient
dose FSH complications: (302) given only 1 identified trial. (Imprecise, 1
Multiple births study)
Oral agents Live birth 1 RCT145 Inconclusive SOE was insufficient Insufficient
alone vs. (174) given only 1 identified trial (Imprecise, 1
gonadotropins small study)
Clomiphene
plus urinary
FSH vs. FSH
alone
Lifestyle Live birth 3 RCTs119,172,181 No difference: No difference in live Moderate
modifications + (1688) birth rates for women who underwent (Heterogeneity
IVF vs. IVF lifestyle modification in combination in interventions)
alone with IVF compared with IVF alone
LEC vs. rFSH Live birth 1 RCT141 Inconclusive: SOE was insufficient Insufficient
(168) given only 1 study with moderate risk of (Imprecise, 1
LEC vs. hMG bias. study with
limitations)
Pregnancy 1 RCT141 Inconclusive: SOE was insufficient Insufficient
complications: (168) given only 1 study with moderate risk of (Imprecise, 1
Multiple births bias. study with
limitations)
Costs 1 RCT141 Inconclusive: SOE was insufficient Insufficient
(168) given only 1 study with moderate risk of (Imprecise, 1
bias. study with
limitations)
Short term 1 RCT148 Inconclusive: SOE was insufficient Insufficient
adverse (104) given only 1 study with moderate risk of (Imprecise, 1
effects of bias. study with
treatment: limitations)
OHSS
rFSH vs. rFSH Live birth 2 RCTs143,159 Inconclusive: SOE was insufficient Insufficient
+ GnRH (any/cycle) (374) given studies with moderate risk of bias (Moderate
antagonist or and varying definitions of live birth study
hMG limitations)
Pregnancy 2 RCTs143,159 Inconclusive: SOE was insufficient Insufficient
complications: (374) given imprecise findings from studies of (Imprecise
Multiple births moderate risk of bias. findings with
moderate study
limitations)
50
Study Design SOE
Comparison Outcome Conclusion
(Sample Size) (Rationale)a
Pregnancy 2 RCTs143,159 Inconclusive: SOE was insufficient Insufficient
complications: (374) given imprecise findings from studies of (Imprecise
Miscarriage moderate risk of bias. findings with
moderate study
limitations)
Short term 1 RCT143 Inconclusive: SOE was insufficient Insufficient
adverse (276) given only 1 study with moderate risk of (Imprecise
effects of bias. findings with
treatment: moderate study
OHSS limitations)
ART IVF: GnRH Live birth 1 RCT146 Inconclusive: SOE was insufficient Insufficient
agonist +/- IVF (patient) (109) given only 1 study with moderate risk of (Imprecise
vs. GnRH bias and with imprecise findings findings with
antagonist +/- moderate study
IVF limitations)
Live birth 4 RCTs147,150,164,167 No difference: No significant difference Low
(cycle) (408) in included studies but varying (Imprecise
interventions and comparators with low findings with
numbers of live birth moderate study
limitations)
Pregnancy 1 RCT164 Inconclusive: SOE was insufficient Insufficient
complications: (70) given only 1 small study with moderate (Moderate
Multiple births risk of bias. study
limitations)
Pregnancy 1 RCT171 Inconclusive: SOE was insufficient Insufficient
complications: (120) given only 1 small study with moderate (Moderate
Ectopic risk of bias. study
pregnancy limitations)
Pregnancy 3 RCTs164,167,171 No difference: No differences in Moderate
complications: (279) miscarriage rates for GnRH agonist vs. (Imprecise
Miscarriage antagonist, or hCG medium, hCG-free findings with
medium with transfer, and hCG-free moderate study
medium without transfer. limitations)
Short term 5 Inconclusive: SOE was insufficient Insufficient
adverse RCTs153,161,162,164,178 given that all identified studies were (Imprecise,
effects of (468) underpowered to detect differences in underpowered
treatment: OHSS. studies)
OHSS
Adjunct to IVF Live birth 1 RCT155 Inconclusive: SOE was insufficient Insufficient
(patient) (149) given only 1 small study with moderate (Moderate
risk of bias. study
limitations)
Short term 2 RCTs177,190 Inconclusive: SOE was insufficient Insufficient
adverse (372) given only small studies with moderate (Moderate
effects of risk of bias and varying adjuncts. study
treatment: limitations)
OHSS
Fresh vs. Live birth 1 RCT174 Improvement: Live birth rates were Low
Frozen (any/cycle) (1508) significantly higher with frozen embryo (1 study)
Embryos in IVF transfer compared to fresh embryos
for PCOS Pregnancy 1 RCT174 No difference: No difference in multiple Low
complications: (1508) births with fresh versus frozen embryo (1 study)
Multiple births transfer
Pregnancy 1 RCT174 Reduction: Ectopic pregnancies were Low
complications: (1508) reduced with frozen embryo transfer (1 study)
Ectopic
pregnancy
51
Study Design SOE
Comparison Outcome Conclusion
(Sample Size) (Rationale)a
Pregnancy 1 RCT174 Reduction: Miscarriages were reduced Low
complications: (1508) with frozen embryo transfer (1 study)
Miscarriage
Neonatal 1 RCT174 No difference: No difference Low
Outcomes: (1508) congenital abnormalities with fresh (1 study)
Congenital versus frozen embryo transfer
abnormalities
Neonatal 1 RCT174 No difference: No difference neonatal Low
Death (1508) deaths with fresh versus frozen embryo (1 study)
transfer
ART vs. no Long-term 1 Obs184 No difference: No significant difference Moderate
infertility outcomes: (565,116 found between type 1 diabetes mellitus (Imprecise)
treatment Child (type 1 pregnancies) diagnoses in children born to patients
diabetes with PCOS infertility conceived with
mellitus) ART compared to children conceived
with no fertility treatment
ART ICSI: Live birth 1 RCT149 Inconclusive: SOE was insufficient Insufficient
GnRH agonist (82) given only 1 small study with moderate (Imprecise
vs. GnRH risk of bias. findings with
antagonist moderate study
limitations, 1
small study)
Pregnancy 1 RCT158 Inconclusive: SOE was insufficient Insufficient
complications: (112) given only 1 small study with moderate (Imprecise
Miscarriage risk of bias. findings with
moderate study
limitations, 1
small study)
Short term 1 RCT158 Inconclusive: SOE was insufficient Insufficient
adverse (112) given only 1 small study with moderate (Imprecise
effects of risk of bias. findings with
treatment: moderate study
OHSS limitations, 1
small study)
aCriteria for downgrading strength of evidence is described as Rationale; when these criteria are insufficient for understanding the
Abbreviations: ART=assisted reproductive technology; BMI=body mass index; CI=confidence interval; FSH=follicle-stimulating
hormone; GnRH=gonadotropin-releasing hormone; hCG=human chorionic gonadotropin; hMG=human menopausal
gonadotropin; IUI=intrauterine insemination; IVF=in vitro fertilization; IVM=in vitro maturation; KQ=Key Question;
LEC=laparoscopic electrocauterization; LOD=laparoscopic ovarian drilling/diathermy; N=number of patients/participants;
NA=not applicable; NR=not reported; Obs=observational study; OHSS=ovarian hyperstimulation syndrome; OR=odds ratio;
PCOS=polycystic ovary syndrome; RCT=randomized controlled trial; rFSH=recombinant follicle-stimulating hormone;
SR=systematic review; uFSH=urinary follicle-stimulating hormone
52
Endometriosis is a condition defined by the presence of endometrial tissue outside the uterus,
most commonly on the ovary and peritoneum. It is observed in approximately 6–10 percent of
women of fertile age, and in up to 35–50 percent of women with infertility, pelvic pain, or
both.200 Endometriosis severity is defined in a system of stages that are based on a weighted
point system. The severity of the disease is classified as minimal (Stage I), mild (Stage II),
moderate (Stage III), or severe (Stage IV) based on surgical findings.201
53
1. Oral Agents With IUI After Laparoscopic Treatment for
Endometriosis
One good-quality RCT examined pregnancy outcomes after ovulation induction with IUI in
136 infertile women with minimal/mild endometriosis who sought infertility treatment 6 to 12
months after laparoscopic treatment.204 Women were randomized to treatment with clomiphene
or letrozole for 5 days starting on day 3 of the menstrual cycle. Human chorionic gonadotropin
(hCG; 10,000 IU) was given intramuscularly when one follicle measuring at least 18 mm was
identified. IUI was performed 32–36 hours after HCG injection. There was no significant
difference in live birth rate among women treated with letrozole and IUI (44.9%) as compared
with clomiphene citrate and IUI (40.3%; RR 0.89; 95% CI, 0.43 to 1.58) (low SOE). There was
also no significant difference in miscarriage rate among women treated with letrozole and IUI
(12.4%) as compared with clomiphene citrate and IUI (12.9%; RR 1.13; 95% CI, 0.76 to 1.68).
Both outcomes were rated as insufficient SOE given findings from one small study. Other
pregnancy complication outcomes, neonatal outcomes, time to pregnancy, costs, short term
adverse effects of treatments, or long term effects were not evaluated.
54
A good-quality cohort study of the national Danish ART registry and Medical Birth registry
compared live birth rates after treatment with ART versus IUI for women with endometriosis,
stratified by age.186 Compared to IUI and natural conception, live birth rates were higher among
women who received ART. For women ≥ 35 years of age live birthrate (95% CI) for women
undergoing ART was 39.0 (24.2, 55.5); undergoing IUI 0 (0.0 to 8.6); and natural conception 4.9
(0.6 to 16.5).186 For women <35 years of age, live birthrate (95% CI) for women undergoing
ART was 51.3 (44.1 to 58.4); undergoing IUI 0.5 (0.0 to 2.8); and natural conception 9.6 (5.9 to
14.7) (low SOE).
One fair-quality observational study123 examined the effectiveness of ART using data from
the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART
CORS) database, a collective cohort of 305,774 pregnancies in the United States. The good-
quality retrospective analysis examined live birth rates, maternal complications, and neonatal
complications based on the number of embryos transferred in 69,028 ART cycles.123 In this
study, 7,104 cycles of IVF or ICSI were performed in couples with the diagnosis of
endometriosis. In this endometriosis subgroup, the live birth rate per cycle after treatment with
either IVF or ICSI was 48.7%. For women with endometriosis, the live birth rate per cycle was
higher in couples who underwent two embryo transfer (n=3808 cycles, live birth rate=51.5%) as
compared with single-embryo transfer (n=319 cycles, live birth rate=46.6%) (p<0.0001) (low
SOE).
55
Table 17. Strength of evidence for major outcomes—KQ 2 (endometriosis)
Comparison Outcome Study Design Conclusion Strength of
(Sample Size) Evidence
(Rationale)a
Letrozole vs. Live birth 1 RCT204 Inconclusive: SOE was insufficient Insufficient
Clomiphene (any/patient) (136) given imprecise evidence from 1 (Imprecise
with IUI study with moderate risk of bias findings from one
small study with
limitations)
Pregnancy 1 RCT204 Inconclusive: SOE was insufficient Insufficient
complications: (136) given imprecise evidence from 1 (Imprecise
Miscarriage study with moderate risk of bias findings from one
small study with
limitations)
Hormonal Live birth 2 RCTs202,205 Inconclusive: SOE was insufficient Insufficient
Therapy After (300) given imprecise evidence from 2 (Imprecise
Surgical studies from non-US settings with findings with
Treatment vs. moderate risk of bias moderate study
no treatment limitations)
Pregnancy 1 RCT202 Inconclusive: SOE was insufficient Insufficient
complications: (156) given imprecise evidence from 1 (Imprecise
Miscarriage study with moderate risk of bias findings with
moderate study
limitations)
Pregnancy 1 RCT202 Inconclusive: SOE was insufficient Insufficient
complications: (156) given imprecise evidence from 1 (Imprecise
Ectopic study with moderate risk of bias findings with
pregnancy moderate study
limitations)
Neonatal 1 RCT202 Inconclusive: SOE was insufficient Insufficient
outcomes: (156) given imprecise evidence from 1 (Imprecise
Death study with moderate risk of bias findings with
moderate study
limitations)
ART: IVF/ICSI Live birth 1 Obs123 Improvement: For women with Low
vs. no (69,028 cycles) endometriosis, the live birth rate per (Imprecise)
treatment cycle was higher in couples who
underwent 2 embryo transfer
(51.5%) as compared with single-
embryo transfer (46.6%)
(p<0.0001).
IUI vs. ART Live birth 1 Obs186 Improvement: For women with Low (one study)
(19,884) endometriosis, the live birth rate per
cycle was higher in couples who
underwent ART than those who
used IUI
aCriteria for downgrading strength of evidence is described as Rationale; when these criteria are insufficient for understanding the
Abbreviations: ART=assisted reproductive technology; CI=confidence interval; HR=hazard ratio; ICSI=intra-cytoplasmic sperm
injection; IUI=intrauterine insemination; IVF=in vitro fertilization; KQ=Key Question; N=number of patients/participants;
NA=not applicable; Obs=observational study; RCT=randomized controlled trial; RR=relative risk
56
Key Question 3. Unexplained Infertility
KQ 3. What are the comparative safety and effectiveness of available
treatment strategies for women who are infertile for unknown reasons and
who wish to become pregnant?
KQ 3a. Does the optimal treatment strategy vary by patient
characteristics such as age, ovarian reserve, race, BMI, presence of
other potential causes of female infertility, or presence of male factor
infertility?
Unexplained infertility is defined as infertility with no other documented female or male
diagnosis.
57
• There are no differences between immediate IVF versus other treatments prior to IVF
for the outcomes of live birth, multiple births, ectopic pregnancy, miscarriage, low
birthweight, and OHSS (low SOE for all outcomes). There is however shorter time to
pregnancy with immediate IVF (moderate SOE).
• As with other indications for IVF, use of single-embryo transfer is associated with
slightly lower live birth rates but significantly reduced multiple gestation rates (low
SOE)
58
Table 18. Outcomes for comparisons of oral agents without IUI in women with unexplained
infertility
Results Results
Study
Intervention Comparator Summary of
Outcome Design P
Intervention Comparator N N Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Live birth: Yapca, CC CC + 2/40 8/40 0.043 Greater live
Any/patient 2015206 hydrotubation (5) (20) births with
(0.6 to 13.5) (9.3 to 33.5) clomiphene
RCT and
(80) hydrotubatio
n compared
to
clomiphene
alone
Pregnancy Badawy, CC Letrozole 1/420 0/269 0.43 No
complications: 2009222 (0.2) (0) difference
Ectopic (0.06 to 0.9) (0 to 0.9)
pregnancy RCT Anastrozole 0/107 0.62 No
(996) (0) difference
(0 to 2.3)
Harira CC+ Letrozole 0/86 0/86 NS No
2018246 estradiol (0) (0) difference
RCT
(172)
Pregnancy Yapca, CC CC + 1/40 0/40 0.31 No
complications: 2015206 hydrotubation (2.5) (0) difference
Miscarriage (0.06 to 9.0) (0 to 6.1)
RCT
(80)
Badawy, CC Letrozole 8/77 4/36 0.91 No
2009222 (10.4) (11.1) difference
(4.7 to 18.1) (3.2 to 23.1)
RCT Anastrozole 2/15 0.74 No
(996) (13.3) difference
(1.8 to 33.9)
Harira CC Letrozole 4/86 (4.6) 3/86 (3.4) 0.67 No
2018246 +estradiol difference
RCT
(172)
Short-term Harira CC Letrozole 0/86 0/86 NS No
adverse effects: 2018246 +estradiol difference
OHSS
RCT
(172)
Neonatal Badawy, CC Letrozole 3/65 2/30 0.68 No
outcomes: 2009222 (4.6) (6.7) difference
Birthweight (1.0 to 10.8) (0.8 to 17.8)
(small for RCT Anastrozole 1/11 0.54 No
gestational age) (996) (9.1) difference
(95 0.3 to
30.8)
Neonatal death Badawy, CC Letrozole 0/65 1/30 0.14 No
2009222 (0) (3.3) difference
(0 to 3.8) (0.09 to
11.9)
59
Results Results
Study
Intervention Comparator Summary of
Outcome Design P
Intervention Comparator N N Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
RCT Anastrozole 0/11 NS No
(996) (0) difference
(0 to 20.8)
Abbreviations: CC=clomiphene citrate; CI=confidence interval; N=number of patients; NR=not reported; NS= not statistically
significant; OHSS=ovarian hyperstimulation syndrome; RCT=randomized control trial
Table 19. Outcomes for comparisons of oral agents versus unstimulated IUI versus expectant
management in women with unexplained infertility
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Live birth: Bhattachar CC IUI 26/192 43/191 0.022 Greater live
Any/patient ya, 2008135 (13.5) (22.5) births with
(9.1 to 18.7) (16.9 to IUI
RCT 28.7) compared
(576) to
clomiphene
Expectant 32/193 0.40 No
management (16.5) difference
(11.7 to
22.1)
Farquhar, IUI Expectant 31/101 9/100 0.000 Greater live
2018238 CC or management (31) (9) 1 births with
letrozole IUI and oral
RCT agents than
(201) with
expectant
manageme
nt
Pregnancy Bhattachar CC IUI 0/192 2/191 0.24 No
complications: ya, 2008135 (0) (1.0) difference
Ectopic (0 to 1.3) (0.1 to 2.9)
pregnancy RCT
(576) Expectant 1/193 0.68 No
management (0.5) difference
(0.01 to 1.9)
Farquhar, IUI Expectant 4/101 0/100 0.097 No
2018238 CC or management (3.9) (0) 4 difference
letrozole
RCT
(201)
60
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Pregnancy Bhattachar CC IUI 10/38 9/55 0.24 No
complications: ya, 2008135 (26.3) (16.3) difference
Miscarriage (13.8 to (7.9 to 27.1)
RCT 41.2)
(576) Expectant 14/46 0.68 No
management (30.4) difference
(18.2 to
44.3)
Farquhar, IUI Expectant 6/37 1/11 0.153 No
2018238 CC or management (16.2) (9.1) difference
letrozole
RCT
(201)
Time to Bhattachar CC Expectant HR of CC HR of IUI NS No
pregnancy ya, 2008135 IUI management compared to compared to difference
expectant expectant
RCT managemen managemen
(576) t 0.83 t 1.40
(0.42 to (0.77 to
1.63) 2.56)
Abbreviations: CC=clomiphene citrate; CI=confidence interval; HR=hazard ratio; IUI=intrauterine insemination; N=number of
patients; NS=not statistically significant; RCT=randomized control trial
This comparison was also evaluated in two good-quality systematic reviews.87,92 Both of
these systematic reviews included our included study by Bhattacharya and colleagues.135
One systematic review examined outcomes with clomiphene citrate for unexplained
infertility as compared to expectant management.92 Seven RCTs were included (1,159 patients),
of which only the one study by Bhattacharya135 reported on outcomes of interest. In this study,
there was no benefit of clomiphene citrate over placebo for live birth (OR 0.79; 95% CI, 0.44 to
1.38, p=0.41) or miscarriage (OR = 0.71, 95% CI 0.31 to 1.61). The SOE was rated as
insufficient given imprecise findings from one study.
Another good-quality systematic review of 14 studies examined outcomes following ovarian
stimulation, IUI, or both in 2,033 patients with unexplained infertility.87 Comparisons were made
between IUI and timed intercourse (TI) with and without ovarian hyperstimulation. Clomiphene
citrate, gonadotropins, or a combination of clomiphene citrate and gonadotropins were utilized
for ovarian hyperstimulation. Fourteen RCTs were included, of which one135 was included in our
systematic review. Overall for the 14 included studies, they noted that the risk of bias was
“substantial” due to failure to report allocation concealment and details of randomization.
When comparing IUI versus expectant management, only one good-quality, low risk of bias
study was included, also included in the present systematic review.135 Live birth rates were not
significantly differently between groups (23% with IUI, 16% with expectant management; OR
1.60; 95% CI, 0.92 to 2.78). Miscarriage rates were similar between groups (OR 0.77; 95% CI,
0.28 to 2.11). There were 2 ectopic pregnancies in the IUI group (OR 5.06; 95% CI, 0.24 to
106.21) (insufficient SOE).
For the comparison of IUI versus TI with ovarian hyperstimulation, only 2 studies examined
live birth rates. Live birth rates were similar between groups (OR 1.59; 95% CI, 0.88 to 2.88).
For the comparison of IUI in a natural cycle versus IUI in a stimulated cycle, 3 studies
examined live birth rates, all excluded from the present review due to publication prior to 2007.
61
Live birth rates were significantly higher with ovarian hyperstimulation/IUI compared to IUI
alone (OR 2.07; 95% CI, 1.22 to 3.50) (low SOE).
Finally, only one study was included for in the meta analysis which compared IUI in a
natural cycle versus TI in a stimulated cycle (also included in the present study).135 Odds of live
birth were higher with IUI than with ovarian hyperstimulation/TI (OR 1.95; 95% CI, 1.10 to
3.44) (insufficient SOE).
Overall this systematic review suggested that there is evidence that IUI with ovarian
hyperstimulation increases the live birth rate compared to IUI alone. Other comparisons had
insufficient SOE.
Table 20. Outcomes for comparisons of oral agents with IUI in women with unexplained infertility
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Live birth: Ebrahimi, CC/hMG + CC/hmG+No 19/98 15/102 0.38 No
Any/patient 2010229 Progesteron support (19.4) (14.7) difference
e (12.2 to 27.7) (85.6 to
RCT 22.2)
(200)
Bagis, CC+Double CC+Single 1/19 2/17 0.48 No
2010221 insemination insemination (5.3) (11.7) difference
(0.1 to 18.5) (1.5 to 30.2)
RCT
(228)
Rashidi, CC+rFSH CC+hMG 19/132 16/127 0.12 No
2013216 (14.5) (12.6) difference
( 9.0 to 21.0) (7.4 to 18.9)
RCT
(259)
van Supine Immediate 73/226 92/245 0.13 No
Rijswijk, immobilizatio mobilization + (32) (37) difference
2017242 n + IUI IUI
RCT
(481)
62
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Maher, Cervical No mucus 97/361 66/353 0.009 Greater
2018245 mucus removal (26.9) (18.7) live birth
removal rate in the
RCT cervical
(714) mucus
removal
group
Pregnancy Morad, Lidocaine Saline 1/109 1/107 0.99 No
complications: 2012227 hydrotubatio hydrotubation (0.9) (0.9) difference
Ectopic n prior to CC prior to CC + (0.02 to 3.4) (0.02 to 3.4)
pregnancy RCT + IUI IUI
(216)
63
4. Oral Agents With IUI Versus Gonadotropins With IUI for
Unexplained Infertility
Six RCTs (4 good,208,226,233,234 one fair,244 and one poor quality241) compared outcomes
between oral agents/IUI and gonadotropins/IUI. Table 21 summarizes the findings from these
studies. Evidence supported no difference in miscarriage rates between strategies (low SOE). All
other outcomes had inconsistent and imprecise findings resulting in insufficient SOE.
Table 21. Outcomes for comparisons of oral agents with IUI versus gonadotropins with IUI for
unexplained infertility
Study Results Results
Summary
Outcome Design Intervention Comparator P
Intervention Comparator of Study
(N N N Value
Findings
Patients) (%) (%)
Live birth: Erdem, CC rFSH with IUI 42/94 25/87 0.026 Greater
Any/patient 2015208 (44.7) (28.7) live births
with CC
RCT
(174)
Gregoriou, Letrozole rFSH with IUI 7/25 5/25 0.51 No
2008226 (28) (20) difference
RCT
(50)
Diamond, CC with IUI Subcutaneous 70/300 97/301 0.02 Greater
2015233 gonadotropin (23.3) (32.2) live birth
with IUI with
RCT gonadotro
(900) pins
compared
to CC
Letrozole 56/299 0.000 Greater
with IUI (18.7) 1 live birth
with
gonadotro
pins
compared
to
letrozole
Danhof, CC with IUI FSH with IUI 92/369 105/369 0.36 No
2018244 (25) (28) significant
difference
RCT
(738)
Pregnancy Pourali, CC + HMG + Letrozole + hMG 5/87 4/83 0.80 No
complications: 2017241 IUI + IUI (5.7) (4.8) difference
Miscarriage
RCT
(180)
Diamond, CC with IUI Subcutaneous 31/106 51/140 0.24 No
2015233 gonadotropin (29.3) (36.4) difference
Letrozole with IUI 26/85 0.37 No
RCT with IUI (30.6) difference
(900)
Danhof, CC with IUI FSH with IUI 31/369 32/369 0.63 No
2018244 (8) (9) difference
RCT
(738)
64
Study Results Results
Summary
Outcome Design Intervention Comparator P
Intervention Comparator of Study
(N N N Value
Findings
Patients) (%) (%)
Pregnancy Diamond, CC with IUI Subcutaneous 4/70 31/97 <0.00 Greater
complications: 2015233 gonadotropin (5.7) (32.0) 01 multiple
Multiple births with IUI gestations
RCT with
(900) gonadotro
pins
compared
to CC
Letrozole 8/56 0.015 Greater
with IUI (14.3) multiple
gestations
with
gonadotro
pins
compared
to
letrozole
Short-term Nada, CC with IUI GnRH antagonist 6/297 30/298 <0.00 Higher
adverse 2016234 with IUI (2) (10) 01 rate of
effects: OHSS mild
RCT OHSS
(595) among
those in
GnRH
antagonist
group
Pourali, CC + HMG + Letrozole + hMG 5/87 0/83 0.027 Rate of
2017241 IUI + IUI (5.7) (0) cancelled
cycles for
RCT OHSS
(170) higher in
CC group
Ectopic Danhof, CC with IUI FSH with IUI 3/369 2/369 1 No
pregnancy 2018244 (1) (1) difference
RCT
(738)
Abbreviations: CC=clomiphene citrate; CI=confidence interval; FSH=follicle-stimulating hormone; hMG=human menopausal
gonadotropin; IUI=intrauterine insemination; N=number of patients; NS=not statistically significant; OHSS=ovarian
hyperstimulation syndrome; RCT=randomized control trial; rFSH=recombinant follicle-stimulating hormone; uFSH=urinary
follicle-stimulating hormone
65
(insufficient SOE). The imprecise findings from heterogeneous interventions for miscarriage
resulted in an insufficient strength of evidence rating. Finally, evidence from one study with no
events provided insufficient evidence to support statements about the impact on OHSS. No other
outcomes of interest were reported.
Table 22. Outcomes for comparisons of different treatment strategies for controlled ovarian
hyperstimulation with gonadotropins and IUI in women with unexplained infertility
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Live birth: Seckin, Progesterone No support 14/71 11/78 0.36 No
Any/patient 2014209 (19.7) (14.1) difference
RCT
(149)
Erdem, Progesterone No support 39/223 (per 19/204 (per 0.016 Greater
2009225 cycle) cycle) live births
(17.5) (9.3) with
RCT progestero
(214) ne
compared
to no
support
Yildiz, Uterine No 10/79 20/101 0.20 No
2014211 perturbation intervention (12.7) (19.8) difference
(6.3 to 20.8) (12.6 to 28.1)
RCT
(180)
Pregnancy Bagis, Double Single 6/20 4/16 0.74 No
complications: 2010221 insemination insemination (30) (25) difference
Miscarriage (12.6 to 51) (7.8 to 48.1)
RCT
(228)
Yildiz, Uterine No 1/79 3/101 0.44 No
2014211 perturbation intervention (1.3) (3.0) difference
(0.03 to 4.5) (0.6 to 7.0)
RCT
(180)
Demirol, rFSH hMG 2/81 hMG: 0.99 No
2007230 (2.5) 2/80 difference
(0.3 to 6.8) (2.5)
RCT (0.3 to 6.9)
(241)
uFSH uFHS: 0.57 No
1/80 difference
(1.2)
(0.03 to 4.5)
Short-term Demirol, rFSH hMG 0/81 hMG: NS No
adverse 2007230 (0) 0/80 difference
effects: OHSS (0 to 3.1) (0)
(0 to 3.1)
uFSH uFSH: NS No
0/80 difference
(0)
(0 to 3.1)
Abbreviations: CI=confidence interval; FSH=follicle-stimulating hormone; hMG=human menopausal gonadotropin;
IUI=intrauterine insemination; N=number of patients; NS=not statistically significant; OHSS=ovarian hyperstimulation
66
syndrome; RCT=randomized control trial; rFSH=recombinant follicle-stimulating hormone; uFSH=urinary follicle-stimulating
hormone
67
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Goldman, IVF CC/IUIIVF 0/51 CC/IUIIVF: 0.32 No
2014210 (0) 1/51 difference
(95 CI 0 to (2.0)
RCT 4.8) (0.04 to 7.1)
(154) Gonadotropins Gonadotropins 0.08 No
/ IUIIVF / IUIIVF: difference
3/52
(5.8)
(1.2 to 13.5)
Nandi, 3 cycles IUI + IVF 2/101 0/106 NS No
2017240 ovarian (1.98) (0) difference
hyperstimulati
RCT on with
(207) gonadotropin
s
Pregnancy Reindollar, CCIVF (fast CC 38/256 32/247 0.54 No
complications: 201052 track) gonadotropins (14.8) (13.0) difference
Miscarriage IVF (10.8 to (9.1 to 17.4)
RCT (conventional) 19.4)
(503)
Goldman, IVF CC/IUIIVF 11/51 CC/IUIIVF: 0.45 No
2014210 (21.6) 8/51 difference
(11.5 to (15.7)
RCT 33.7) (7.2 to 26.7)
(154) Gonadotropins Gonadotropins 0.77 No
/ IUIIVF / IUIIVF: difference
10/52
(19.2)
(9.8 to 30.9)
Nandi, 3 cycles IUI + IVF 3/34 13/49 0.11 No
2017240 ovarian (12) (26.5) difference
hyper-
RCT stimulation
(207) with
gonadotropin
s
Pregnancy Reindollar, CCIVF (fast CC 34/171 30/150 (twins) 0.98 No
complications: 201052 track) gonadotropins (twins) (20) difference
Multiple births IVF (19.9) (14.0 to 26.7)
RCT (conventional) (14.3 to
(503) 26.2)
Goldman, IVF CC/IUIIVF 3/24 (twins) CC/IUIIVF: 0.30 No
2014210 (12.5) 6/25 (twins) difference
(2.8 to 28.0) (25)
RCT (9.8 to 42.2)
(154) Gonadotropins Gonadotropins 0.59 No
/ IUIIVF / IUIIVF: difference
4/22 (3 twins, 1
triplet)
(18.2)
(5.4 to 36.3)
Neonatal Reindollar, CCIVF (fast CC 30/171 23/150 0.59 No
outcomes: Low 201052 track) gonadotropins (17.5) (15.3) difference
birthweight IVF (95 CI (10.0 to 21.5)
RCT (conventional) 12.2 to 23.6)
(503)
68
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
Goldman, IVF CC/IUIIVF 2/24 CC/IUIIVF: 0.97 No
2014210 (8.3) 2/25 difference
(1.1 to 21.9) (2.8)
RCT (1.0 to 21.1)
(154) Gonadotropins Gonadotropins 0.93 No
/ IUIIVF / IUIIVF: difference
2/22
(9.1)
(1.2 to 23.8)
Neonatal Reindollar, CCIVF (fast CC 0/171 0/150 NS No
outcomes: 201052 track) gonadotropins (0) (0) difference
Neonatal IVF (0 to 1.5) (0 to 1.7)
deaths RCT (conventional)
(503)
Goldman, IVF CC/IUIIVF 0/24 CC/IUIIVF: NS No
2014210 (0) 0/25 difference
(0 to 10.0) (0)
RCT (0 to 9.6)
(154) Gonadotropins Gonadotropins NS No
/ IUIIVF / IUIIVF: difference
0/22
(0)
(0 to 10.9)
Time to Reindollar, CCIVF (fast CC 8 months 11 months 0.045 Shorter
pregnancy 201052 track) gonadotropins time to
IVF pregnancy
RCT (conventional) with
(503) immediate
IVF
compared
to
gonadotro
pins prior
to IVF
Goldman, IVF CC/IUIIVF 8.7 ± 0.5 CC/IUIIVF: <0.05 Shorter
2014210 months 9.1 ± 0.6 time to
pregnancy
RCT with
(154) immediate
IVF
compared
to IUI prior
to IVF
Gonadotropins Gonadotropins <0.05 Shorter
/ IUIIVF / IUIIVF: time to
12.2 ± 0.7 pregnancy
with
immediate
IVF
compared
to IUI and
gonadotro
pins prior
to IVF
69
Results Results
Study
Intervention Comparator Summary
Outcome Design P
Intervention Comparator N N of Study
(N Value
(%) (%) Findings
Patients)
(95% CI) (95% CI)
OHSS Reindollar, CCIVF (fast CC 18/256 18/247 0.93 No
201052 track) gonadotropins (7.0) (7.3) difference
IVF (4.2 to 10.5) (4.4 to 10.8)
RCT (conventional)
(503)
Goldman, IVF CC/IUIIVF 3/51 CC/IUIIVF: 0.65 No
2014210 (5.9) 2/51 difference
(1.3 to 13.7) (3.9)
RCT (0.5 to 10.6)
(154) Gonadotropins Gonadotropins 0.98 No
/ IUIIVF / IUIIVF: difference
3/52
(5.8)
(1.2 to 13.5)
aUse of an arrow in the table indicates a second treatment that followed the first treatment.
Abbreviations: CC=clomiphene citrate; CI=confidence interval; eSET=elective single-embryo transfer; HR=hazard ratio;
IUI=intrauterine insemination; IVF=in vitro fertilization; N=number of patients; NS=not statistically significant; OHSS=ovarian
hyperstimulation syndrome; RCT=randomized control trial
A cost-effectiveness analysis of the U.S.-based FASTT trial52 reported charges per delivery
were $9,846 lower (95% CI, $25,099 lower to $3,869 higher; p=0.084) for the fast track arm
than the conventional arm. The difference in the infertility treatment-related charges per delivery
was $5,802 (95% CI, -$14,388 to $2,299; p=0.08) (insufficient SOE). Note that multiple birth
rates did not differ significantly between the two arms.
70
guidelines.119 Of the 161 women with unexplained infertility, 86 were assigned to the
intervention and 77 to the control groups. Within this group, there were no significant differences
in the outcomes of vaginal birth of healthy singleton at term or of live births. Compared to the
control group, the RR (95% CI) of vaginal birth of health singleton at term for the intervention
group was 0.73 (0.47 to 1.1); compared to the control group, the RR (95% CI) of live births for
the intervention group was 0.85 (0.64 to 1.1).119
Finally, a good-quality systematic review84 examined outcomes following IVF for
unexplained infertility. Within this analysis, the live birth rate was higher with IVF than
expectant management (45.8% vs. 3.7%, OR 22.00; 95% CI, 2.56 to 189.37) based on 1 RCT
with 51 women. Given the inconsistent findings we rated the SOE as insufficient.
71
utilized PGS technologies that are no longer current. Therefore, the review is not applicable to
today’s clinical practice and strength of evidence for all outcomes was rated as insufficient.
72
Subgroups of Interest for Unexplained Infertility
Five total studies, one fair-quality observational study,122 two fair-quality RCTs,217,243 and
two good-quality RCTs,235,237 reported data on outcomes with IVF in subgroups of interest for
women with infertility of unknown etiology.
73
Miscarriage rates and multiple birth rates were similar. In the advanced maternal age
population, the miscarriage rate was 16.7% in the PGS group versus 22.2% in the no-PGS group
(p>0.05). The twin birth rate was 25% in the PGS group versus 21.4% in the no-PGS group
(p>0.05) (insufficient SOE for all outcomes).
74
Strength of
Study Design
Comparison Outcome Conclusion Evidence
(Sample Size)
(Rationale)a
Oral Agents vs. Live birth 1 SR87 (3 studies, Improvement: A significant Low (Inconsistent)
Unstimulated 370) increase in live births was found
IUI vs. for women treated with IUI and
Expectant ovarian hyperstimulation
Management compared to women treated with
IUI only
Pregnancy 1 RCT135 Inconclusive: SOE was Insufficient
complications: (580) insufficient given imprecise (Imprecise, one
Ectopic evidence from 1 trial. study)
pregnancy
Pregnancy 1 RCT135 Inconclusive: SOE was Insufficient
complications: (580) insufficient given imprecise (Imprecise, one
Miscarriage evidence from 1 trial. study)
Time to 1 RCT135 Inconclusive: SOE was Insufficient
pregnancy (580) insufficient given imprecise (Imprecise, one
evidence from 1 trial. study)
Adjunct Live birth 5 No difference: No difference Low
Treatments with RCTs216,221,229,242,245 between adjunct treatments with (Moderate study
Oral Agents (1859) oral agents and IUI limitations)
and IUI Pregnancy 1 RCT227 Inconclusive: SOE was Insufficient
complications: (216) insufficient given imprecise (Imprecise, one
Ectopic evidence from 1 trial. study)
pregnancy
Pregnancy 5 No difference: No difference Low
complications: RCTs221,227,231,232,245 between adjunct treatments with (Moderate study
Miscarriage oral agents and IUI limitations)
(1859)
Short term 3 RCTs216,227,245 No difference: No difference Low
adverse effects (1189) between adjunct treatments with (Moderate study
of treatment: oral agents and IUI limitations)
OHSS
Oral Agents Live birth 4 RCTs208,226,233,244 Inconclusive: Conflicting Insufficient
With IUI vs. (1708) findings from RCTs resulted in (Imprecise,
Gonadotropins insufficient SOE inconsistent)
With IUI Pregnancy 1 RCT244 Inconclusive: SOE was Insufficient
complications: (738) insufficient given evidence from (one study,
Ectopic 1 trial with moderate study moderate study
pregnancy limitations. limitations)
Pregnancy 3 RCTs233,241,244 No difference: No difference Low
complications: (1,654) between oral agents with IUI (Imprecise)
Miscarriage versus gonadotropins with IUI
Pregnancy 1 RCT233 Increased risk: Greater multiple Low
complications: (742) gestations with gonadotropins (one study)
Multiple births compared to either clomiphene
or letrozole
Short term 2 RCTs234,241 Inconclusive: SOE was Insufficient
adverse effects (765) insufficient given inconsistent (Inconsistent and
of treatment: and imprecise findings. Imprecise findings
OHSS with moderate
study limitations)
Different Live birth 3 RCTs209,211,225 Inconclusive: SOE was Insufficient
Treatment (837) insufficient given inconsistent (Inconsistent and
Strategies for and imprecise findings. Imprecise findings
Controlled with moderate
Ovarian Hyper study limitations)
75
Strength of
Study Design
Comparison Outcome Conclusion Evidence
(Sample Size)
(Rationale)a
stimulation with Pregnancy 3 RCTs211,221,230 Inconclusive: SOE was Insufficient
Gonadotropins complications: (929) insufficient given imprecise (Imprecise findings
& IUI Miscarriage evidence about the outcome with moderate
from 3 studies targeting each an study limitations))
individual intervention.
Short term 1 RCT230 Inconclusive: SOE was Insufficient
adverse effects (161) insufficient given imprecise (Imprecise, one
of treatment: evidence from 1 trial with no small study)
OHSS events.
Immediate IVF Live birth 3 RCTs52,210,212,240 No difference: Live birth does Low
vs. Other (812) not differ between differing (Imprecise)
Treatments strategies of other treatments
Prior to IVF prior to IVF
Pregnancy 2 RCTs52,210 No difference: No significant Low
complications: (657) difference between other (Imprecise)
Multiple births treatments prior to IVF and
immediate IVF.
Pregnancy 3 RCTs52,210,212,240 No difference: No significant Low
complications: (812) difference between other (Imprecise)
Ectopic treatments prior to IVF and
pregnancy immediate IVF.
Pregnancy 3 RCTs52,210,212,240 No difference: No significant Low
complications: (812) difference between other (Imprecise)
Miscarriage treatments prior to IVF and
immediate IVF.
Neonatal 2 RCTs52,210 Inconclusive: SOE was Insufficient
outcomes: (657) insufficient given imprecise (Imprecise, rare
Death evidence for a rare event which events)
requires a larger data set to draw
inferences
Neonatal 2 RCTs52,210 No difference: No significant Low
outcomes: (657) difference between other (Imprecise)
Birthweight treatments prior to IVF and
immediate IVF.
Time to 2 RCTs52,210 Reduction: Shorter time to Moderate
pregnancy (657) pregnancy with immediate IVF
compared with other treatments
prior to IVF
Costs 1 RCT52 Inconclusive: Insufficient SOE Insufficient
(619) given one study with imprecise (Imprecise, one
and overlapping findings study)
Short term 2 RCTs52,210 No difference: No significant Low
adverse effects (657) difference between other (Imprecise)
of treatment: treatments prior to IVF and
OHSS immediate IVF.
Expectancy Live birth 119 Inconclusive: Insufficient SOE Insufficient
1 RCT
Management (161) given inconsistent findings from (Inconsistent; small
vs. Other small studies studies)
Interventions SR84 (1 study, 51
patients)
Pregnancy 1 RCT228 (105) Inconclusive: Insufficient SOE Insufficient
complications: given imprecise findings from (Imprecise findings
Multiple births one small study from small study)
Pregnancy 1 RCT228 (105) Inconclusive: Insufficient SOE Insufficient
complications: given imprecise findings from (Imprecise findings
Miscarriage one small study from small study)
76
Strength of
Study Design
Comparison Outcome Conclusion Evidence
(Sample Size)
(Rationale)a
Costs 1 RCT139 (253) Inconclusive: Insufficient SOE Insufficient
given imprecise findings from (Imprecise findings
one small study published from small study)
outside US
ART: Live birth 1 RCT214 Inconclusive: Insufficient SOE Insufficient
ICSI (156) given imprecise findings from (Imprecise findings
one study with moderate risk of with moderate
bias study limitations)
Pregnancy 1 RCT214 Inconclusive: Insufficient SOE Insufficient
complications: (156) given imprecise findings from (Imprecise findings
Miscarriage one study with moderate risk of with moderate
bias study limitations)
ART: Costs 1 Obs215 Inconclusive: SOE was Insufficient
IVF vs. ICSI (154) insufficient given imprecise (Imprecise, one
evidence from 1 small small study)
observational trial.
Neonatal 1 Obs185 No difference: No significant Low (one study
outcomes: Birth (90,401 cycles) differences in rates of r low birth with moderate
weight weight (OR 1.03, 95% CI 0.73 to study limitations)
1.47) between ICSI versus
conventional-IVF cycles
ART: Long-term 1 Obs213 No difference: The overall Low
Unspecified outcomes: Child (33,840) cancer incidence was not (Moderate study
(cancer) elevated in children born after limitations)
assisted conception for
unexplained infertility. The SIR
for all cancers in children
conceived with assisted
conception for unexplained
infertility compared to the
general population of the same
age was 0.84 (95% CI, 0.57 to
1.18).
aCriteria for downgrading strength of evidence is described as Rationale; when these criteria are insufficient for understanding the
Abbreviations: AH=assisted hatching; AMA=advanced maternal age; ART=assisted reproductive technology; CC=clomiphene
citrate; CI=confidence interval; DHEA=dehydroepiandrosterone; FASTT=Fast Track and Standard Treatment; FSH=follicle-
stimulating hormone; hMG=human menopausal gonadotropin; HR=hazard ratio; ICER=incremental cost-effectiveness ratio;
ICSI=intra-cytoplasmic sperm injection; IUI=intrauterine insemination; IVF=in vitro fertilization; KQ=Key Question; N=number
of patients/participants; NA=not applicable; Obs=observational study; OHSS=ovarian hyperstimulation syndrome; OR=odds
ratio; PGS=preimplantation genetic screening; RCT=randomized controlled trial; rFSH=recombinant follicle-stimulating
hormone; RIF=recurrent implantation failure; SIR=standardized incidence ratio; uFSH=urinary follicle-stimulating hormone
77
Description of Included Studies for KQ 4 (Tubal and Peritoneal
Factor Infertility)
We identified eight individual studies123,184,185,248-252 that addressed outcomes after treatment
for tubal or peritoneal factor infertility.
Among the eight studies that addressed outcomes after treatment for tubal or peritoneal factor
infertility, three were RCTs. One was rated as good quality,250 one was rated as fair quality,252
and one was rated as poor quality.248 The remaining five studies were observational; three were
good quality,184,249,251 and two were fair quality.123,185 Geographically, three studies were
conducted in the U.K. or continental Europe184,249,250, three were conducted in the U.S.123,185,251,
and two were conducted in Asia.248,252 Four studies were conducted in, or used data from,
fertility subspecialty clinics,185,250-252 whereas setting was not specified for the remaining
four.123,184,248,249 With regard to funding source, one study was government funded,252, one was
industry funded,250 two reported non-government, non-industry funding,123,184 and, for the
remaining four, funding source was not specified or was unclear.185,248,249,251
Outcomes and complications of pregnancy were described in three RCTs248,250,252 and five
observational studies.27,123,124,185,251 One observational study reported on long-term outcomes in
the child.184 One observational study reported on treatment costs.249
The main classes of treatment investigated were oral ovulation induction with or without IUI,
gonadotropins with or without IUI, surgical treatment and surgery with hormonal adjunctive
therapy, and ART (IVF or ICSI) alone or with adjunctive acupressure treatment. We did not
perform meta-analysis because of the lack of studies reporting results for similar outcomes and
treatment comparisons.
In addition to the above studies, one good-quality systematic review that addressed the
comparative effectiveness of various treatments for infertility in women with tubal factor
infertility (5 studies, 646 patients) is discussed below and the consistency of its findings with our
included studies is incorporated in to our strength of evidence ratings.93
78
1. Surgical Management for Tubal or Peritoneal Factor Infertility
Three studies and one systematic review explored the use of surgical management strategies
in women with tubal or peritoneal factor infertility.
We identified one RCT of a surgical intervention that examined live birth outcomes. A good-
quality RCT250 compared hysteroscopic proximal tubal occlusion via Essure® to laparoscopic
salpingectomy prior to IVF/ICSI in 85 women. They found that there was no difference in
pregnancy complications of miscarriage or ectopic pregnancy between groups, but that women
who underwent laparoscopic salpingectomy had a significantly higher live birth rate than women
who underwent Essure® prior to IVF/ICSI in the ITT analysis (21.4% vs. 46.5%, respectively).
However, this difference was no longer significant in the per protocol analyses (p = 0.143).
Given imprecise findings from just one small study the SOE was rated as insufficient.
The risk of ectopic pregnancy was examined in one poor-quality RCT of women who
underwent transcervical falloposcopy tubal dilatation as an adjunctive therapy during surgical
treatment of tubal fertility.248 The study examined 468 infertile women with evidence of
fallopian tube disease who underwent laparoscopic salpingolysis and/or salpingostomy. Patients
were included if they had tubal factor infertility on hysterosalpingography, and were excluded if
they had evidence of uterine fibroids, endometriosis, male factor infertility, genital
malformations, unilateral salpingectomy, or endocrine pathology. A total of 256 patients were
randomized to the intervention, transcervical falloposcopy tubal dilatation, and 212 patients did
not receive the additional procedure (control group). The ectopic pregnancy rate in women who
underwent transcervical falloposcopy tubal dilatation was 2% compared with 5.4% in the control
group (p=0.647) (insufficient SOE).
One good-quality study evaluated costs of different diagnostic and treatment scenarios for
women with tubal infertility.249 Six different scenarios involving different diagnostic approaches
(no diagnostics, hysterosalpingogram, laparoscopy) and delayed or immediate IVF treatment
were examined using a computer-generated Markov model. Costs were based on those in the
Netherlands. Costs per live birth of the various diagnostic and treatment scenarios differed by
more than 3000 euros. The costliest intervention was no diagnostics with immediate IVF
treatment (8927 euros), and the least expensive was no diagnostics with 12 cycles of expectant
management followed by 3 cycles of IVF (6459 euros) (insufficient SOE).
Finally, one good-quality Cochrane systematic review involving 5 RCTs with a total of 646
women explored surgical treatment for tubal disease in women undergoing IVF. None of the
included trials reported on the primary outcome of live birth, and therefore they were excluded
from our systematic review. They did, however, report an increase in ongoing pregnancy and
clinical pregnancy with laparoscopic salpingectomy for hydrosalpinges prior to IVF versus non-
surgical management. No significant differences were seen in any of the adverse effects of
surgical treatments.93
79
alternating low and high frequencies (2/100 Hz). The women receiving TEAS at alternating low
and high frequencies 2/100Hz had a higher live birth rate (55/144, 48.25%) when compared to
each of the other study arms (p<0.05).
Live birth rates was also evaluated in one observational study. The good-quality study251
used the Society for Assisted Reproductive Technology Clinic Outcome Reporting System
(SART CORS) database to compare outcomes for conventional IVF and use of ICSI in women
with tubal ligation. In adjusted analyses, use of ICSI was associated with lower odds of live birth
(AOR 0.77, 0.69-0.85) (low SOE). There were no significant differences in plurality, mean
length of gestation, or birth weight.251
An analysis of the SART CORS database compared success and complications associated
with treatment patterns for women undergoing IVF/ICSI: live birth rates and maternal and
neonatal complications based on the number of embryos transferred in 69,028 ART cycles.123
Among women with tubal infertility, the live birth rate after treatment with IVF or ICSI was 44.4
percent. In women with tubal fertility, the live birth rate was higher in couples who underwent
two embryo transfer (47.5%) as compared with single-embryo transfer (41.1%) (p=0.05) (low
SOE).123
Other outcomes of interest were evaluated in three observational studies. One fair-quality
study185 used the SART CORS database to examine prevalence of preterm delivery and low birth
weight among singletons conceived with ICSI compared to conventional IVF. In secondary
analyses conducted on the subset of patients who used autologous sperm, had a favorable fertility
prognosis based on female age <35, and > three oocytes retrieved, no significant differences in
rates of preterm delivery or low birth weight was observed among those with tubal factor only
infertility (preterm delivery OR 1.14, 95% CI -.79 to 1.65, p = .49; low birth weight OR 0.88,
95% CI 0.56 to 1.37, p = .56) (low SOE).185
One nationwide birth cohort study identified all pregnancies with a live-single born child
over an 8-year period in Denmark and compared the incidence of type I diabetes among those
conceived with fertility treatment to those conceived naturally.184 There was no association
between tubal factor infertility as an indicator for fertility treatment and the subsequent
development of Type I diabetes in offspring (HR 1.08, 95% to 0.61 to 1.91) (moderate SOE).
Table 25. Strength of evidence for major outcomes—KQ 4 (tubal and peritoneal factor infertility)
Strength of
Study Design
Comparison Outcome Conclusion Evidence
(Sample Size)
(Rationale)a
Hysteroscopic Live birth (patient) 1 RCTs250 Inconclusive. SOE was Insufficient
proximal (85) insufficient given imprecise (Imprecise, 1
occlusion vs. findings from 1 small study small study)
laparoscopic
salpingectomy
Transcervical Pregnancy 1 RCT248 Inconclusive. SOE was Insufficient
falloposcopy complications: (468) insufficient given imprecise (Imprecise
tubal dilatation Ectopic pregnancy evidence from 1 trial with high findings with
vs. no potential limitations high study
intervention limitations, 1
study)
80
Strength of
Study Design
Comparison Outcome Conclusion Evidence
(Sample Size)
(Rationale)a
Hysterosal- Costs 1 Obs249 Inconclusive. SOE was Insufficient
pingogram, (NA) insufficient given imprecise (Imprecise;
laparoscopy, no evidence from 1 modeling indirect findings,
intervention vs. study 1 study)
IVF
ART: 2-embryo Live birth (patient) 1 Obs123 Improvement. The live birth Low
transfer vs. 1- (69,028 cycles) rate per cycle was higher in (Imprecise)
embryo transfer couples who underwent 2
embryo transfer as compared
with single-embryo transfer
ART: Live birth (patient) 1 RCT252 (481) Inconclusive. SOE was Insufficient
Frequencies of insufficient given imprecise (Imprecise, 1
transcutaneous findings from 1 fair-quality fair-quality
electrical study study)
acupoint
stimulation prior
to IVF
ART: IVF vs. Live birth (patient) 1 Obs 251 Reduction: Lower odds of Low
ICSI (7145) live birth with ICSI (1 study)
ART: IVF+ICSI Neonatal 1 Obs185 No difference: No significant Low
vs. IVF outcomes: Birth (90,401 cycles) differences in rates of low (1 study with
weight birth weight (OR 0.88, 95% CI moderate study
0.56 to 1.37) between ICSI limitations)
versus conventional-IVF
cycles
ART vs. no Long-term 1 Obs184 No difference: No significant Moderate
fertility treatment outcomes: Child (565,116 difference found between (Imprecise)
(type 1 diabetes pregnancies) type 1 diabetes mellitus
mellitus) diagnoses in children born to
patients with tubal factor
infertility conceived with ART
compared to children
conceived with no fertility
treatment
aCriteria for downgrading strength of evidence is described as Rationale; when these criteria are insufficient for understanding the
Abbreviations: ART=assisted reproductive technology; CI=confidence interval; HR=hazard ratio; ICSI=intra-cytoplasmic sperm
injection; IUI=intrauterine insemination; IVF=in vitro fertilization; KQ=Key Question; N=number of patients/participants;
NA=not applicable; Obs=observational study; RCT=randomized controlled trial; RR=relative risk; SIR=standardized incidence
ratio
81
Description of Included Studies for KQ 5 (Male Factor)
We identified 23 individual studies119,123-125,184-186,208,213,221,236,242,253-264 that addressed the
comparative effectiveness or safety of interventions applied to patients with male factor
infertility.
Eleven studies were RCTs119,208,221,242,253,255,256,258,261,262,264 and 12 were observational
studies.123,124,184-186,213,236,254,257,259,260,263 Of the 11 RCTs, four studies were rated good
quality,119,208,261,262 five were rated fair quality,221,242,256,258,264 and two were rated poor
quality.253,255 Of the 12 observational studies, three were rated good quality,184,186,236 seven were
rated fair quality,123,124,185,213,254,260,263 and two were rated poor quality.257,259
Of the 23 studies, six were conducted in the United States,123,124,185,236,254,263 10 in the UK or
continental Europe,119,184,186,213,221,242,253,256,259,264 five in the Middle East,208,255,258,260,261 and two
in Asia.257,262 All but three studies were conducted in subspecialty practices; the remaining three
did not report the setting or the setting was unclear.123,184,213 Finally, six studies reported
government funding,119,213,254,256,259,262 one reported industry funding,186 three studies reported
non-government, non-industry funding,123,184,257 two studies reported a combination of funding
sources,124,236 and the remaining eleven studies did not report funding source or the funding
source was unclear.185,208,221,242,253,255,258,260,261,263,264 The interventions and comparisons evaluated
in the included studies are summarized in Appendix E.
In addition to the above studies, four good-quality systematic reviews72,79,265,266 that
addressed the comparative effectiveness of various treatments in men with male factor infertility
are discussed below and the consistency of their findings with our included studies are
incorporated in to our strength of evidence ratings.
82
Detailed Synthesis by Treatment for Male Factor Infertility
Included studies and their findings for the following treatments for unexplained infertility are
detailed in this section:
1. IUI With Adjunct Treatment for Female Partners
2. ART
a. IVF
b. ICSI
c. IVF Versus ICSI
d. ART Unspecified
3. Other Strategies
1. IUI With Adjunct Treatments for Female Partners With Male Factor
Infertility
A single fair-quality RCT221 that compared single versus double IUI in multifollicular
ovarian hyperstimulation cycles reported live birth rates and pregnancy complications.
Clomiphene citrate or recombinant FSH or both were used for ovarian hyperstimulation in both
study arms. Of the 228 women in the trial, male factor was the cause of infertility for 67 couples
in the single IUI arm and 65 couples in the double IUI arm. Among the couples with male factor
infertility, double IUI was associated with a crude OR of 0.71 (95% CI, 0.21 to 2.37; p=0.764)
relative to single IUI for live birth rate. This trial was conducted in a single subspecialty clinic in
Turkey and given the imprecise findings was rated as insufficient strength of evidence.
A single good-quality RCT208 compared rFSH with clomiphene citrate in IUI cycles in
couples with infertility. Of the 219 couples in the trial, male factor was the cause of infertility for
15 couples in rFSH group and 22 couples in the clomiphene citrate group. Among the couples
with male factor infertility, the live birth rate per patient was 20 percent in the rFSH group and
13.6 percent in the clomiphene citrate group (p value reported as “not significant”). This trial
was conducted in a single subspecialty clinic in Turkey (insufficient SOE).
Related to these included studies, two good-quality systematic reviews published in 2007265
and 2017266 evaluated outcomes associated with IUI for male-factor infertility. The study by
Bensdorp, 2007 compared ovarian hyperstimulation with IUI with IUI alone among couples with
male factor infertility did not demonstrate a significant difference in live birth rates (OR 0.87;
95% CI, 0.28 to 2.70). The more recent systematic review by Cissen, 2016 also compared
ovarian hyperstimulation with IUI with IUI alone among couples with male factor infertility
summarizing 3 RCTs of a total of 346 couples (OR 1.34, 95% CI 0.77, 2.33; I2=0%) findings no
evidence of a difference with live births. They noted very low quality of evidence for this
outcome given potential high risk of bias in the included studies, inconsistencies in the data, and
imprecise findings. This review also identified two RCTs (1 low quality and 1 very low quality)
examining IVF versus IUI in natural cycles or cycles with ovarian hyperstimulation. This review
found no evidence of a difference in live birth rates between IVF versus IUI in natural cycles (1
RCT, 53 couples; OR 0.77, 95% CI 0.25, 2.53) or IVF versus IUI in cycles with ovarian
hyperstimulation (2 RCTs, 86 couples; OR 1.03 95% CI 0.43, 2.45; I2=0%) and again with very
low quality evidence.
83
2. ART for Male Factor Infertility
Table 26. Outcomes for comparisons of IVF in couples with male infertility
Results Results
Study Intervention Comparator Summary
P
Outcome Design Intervention Comparator N N of Study
value
(N Patients) (%) (%) Findings
(95% CI) (95% CI)
Live birth: Tsai, 2011257 TESE Ejaculated 40.7% 30.2% 0.197 No
Any/patient OAT difference
RCT
(191 cycles)
Luke, ICSI or ICSI or 44.7% 52.1% (2 <0.00 Greater
2010123 assisted assisted embryos) 1 live births
hatching (1 hatching 46.9% (3 with
RCT embryo (multiple embryos) multiple
(69,028 ART transferred) embryos 40.4% (4 embryos
cycles) transferred) embryos) transferre
(number d
transferred) compared
to 1
embryo
transferre
d
Shi, 2018262 Frozen Fresh embryo 48.7% 50.2% 0.50 No
embryo transfer difference
RCT transfer
(2,157
patients)
Pregnancy Shi, 2018262 Frozen Fresh embryo 2.7% 1.7% 0.23 No
complications: embryo transfer difference
Ectopic RCT transfer
pregnancy (2,157
patients)
Pregnancy Shi, 2018262 Frozen Fresh embryo Among clinical Among 0.22 No
complications: embryo transfer pregnancies clinical difference
Miscarriage RCT transfer 9.4% pregnancies
(2,157 11.5%
patients)
Pregnancy Shi, 2018262 Frozen Fresh embryo Singleton 31.3% Singleton 0.18 No
complications: embryo transfer Twin 17.4% 34.0% 0.40 difference
Multiple births RCT transfer Triplet 0.1% Twin 16.0% 1.00
(2,157 Triplet 0.2%
patients)
84
Results Results
Study Intervention Comparator Summary
P
Outcome Design Intervention Comparator N N of Study
value
(N Patients) (%) (%) Findings
(95% CI) (95% CI)
Neonatal Tsai, 2011257 TESE Ejaculated 38.3% 23.8% 0.292 No
outcomes: extreme difference
Birthweight RCT severe OAT
(191 cycles) sperm
Shi, 2018262 Frozen Fresh embryo 3373g (+/-515) 3380g (+/- 0.85 No
embryo transfer 502) difference
RCT transfer
(2,157
patients)
Neonatal Tsai, 2011257 TESE Ejaculated 1.7% (major) 4.7% (major) 0.454 No
outcomes: extreme 8.3% (minor) 4.8% (minor) 0.591 difference
Congenital RCT sever OAT
anomalies (191 cycles) sperm
Shi, 2018262 Frozen Fresh embryo 2.2% 3.6% 0.12 No
embryo transfer difference
RCT transfer
(2,157
patients)
Abbreviations: CI=confidence interval; HR=hazard ratio; ICSI=intra-cytoplasmic sperm injection; N=number of patients;
NS=not statistically significant; OAT=oligo-astheno-teratozoospermia; RCT=randomized control trial; SOE = strength of
evidence; TESE=extracted testicular sperm
85
effect model (with identical results using a random effects model). The Q-value was 0.2913 with
2 degrees of freedom, with an I2 of 0%, suggesting no significant heterogeneity. This meta-
analysis corroborates the findings of each of the three primary studies, which is that there is no
significant difference in live birth rates per cycle between ICSI and IMSI procedures for male
factor infertility. The systematic review published in 201379 included 9 trials with 2,014 couples
however only the study by Balaban and colleagues258 reported on live birth. We rated the
strength of evidence for no difference in live birth as moderate based on the findings of our
meta-analysis.
We also identified two fair-quality observational studies124,254 that analyzed data from the
SART CORS database to compare ICSI with IVF for male factor infertility. These two studies
may report data from the same patients. One of the studies compared live birth rates of both
couples with male factor infertility who received conventional IVF (N=4973 cycles) or combined
IVF with ICSI (N=72,459 cycles).124 Among couples with male factor infertility, the live birth
rate for the 1989 cycles that resulted in a pregnancy after treatment with conventional IVF was
84.9%, compared with 85.2% live birth rate among the approximately 32,896 cycles that resulted
in a pregnancy after treatment with ICSI. This corresponds to an OR of 0.98 (95% CI, 0.90 to
1.06) for live birth rate given a pregnancy associated with IVF relative to ICSI among couples
with male factor infertility and supports the findings from our meta-analysis. The second study
compared outcomes associated with 10,933 cycles of conventional IVF with 153,968 ICSI cycles
for male factor infertility reported to the SART registry during 1996-2012.254 The adjusted RR
for live birth per cycle among transfers associated with conventional IVF relative to ICSI was
0.98 (95% CI, 0.95 to 1.02; p>0.99). The multivariate analysis was adjusted for maternal age,
number of prior live births, number of prior miscarriages, number of prior assisted reproductive
technology cycles, number of oocytes retrieved, number of embryos cryopreserved, donor
egg/embryo, donor sperm, use of preimplantation genetic testing, and infertility diagnosis (tubal
factor, endometriosis, uterine factor, ovulatory disorder, and diminished ovarian reserve). Again
86
this observational study supports the findings from our meta analysis of no difference between
IVF and ICSI for the outcome of live birth (moderate SOE).
Miscarriage
We identified two studies (one poor-quality RCT253 and one fair-quality observational
study254) that compared ICSI to IMSI for male factor infertility in relation to miscarriage rates.
The RCT253 reported miscarriage rates of 20.5% (15/73) for ICSI and 22.9% (11/48) for IMSI
(p=0.823) while the observational study254 calculated an adjusted RR of 0.97 (95% CI, 0.91 to
1.04) for miscarriage among pregnancies for ICSI relative to IVF among couples with male
factor infertility.
Our findings are consistent with the good-quality systematic review by Teixeira and
colleagues which consisted of 6 RCTs (552 women)79 that concluded that there is no evidence of
effect on miscarriage between ICSI and IMSI. Although all of these studies support there being
no difference in miscarriage rates, the SOE was rated as low given large imprecision in the
findings and the high risk of bias in the included studies.
Multiple Births
In addition to miscarriage rates, the two studies above253,254 reviewed multiple birth events
when comparing ICSI to IMSI for male factor infertility. The poor-quality RCT reported that
22.2% (2/9) and 36.4 % (4/11) of births were twin deliveries in the ICSI and IMSI arms,
respectively (p=0.496).253 The fair-quality observational study by Boulet and associates254
compared outcomes associated with conventional IVF with ICSI calculated an adjusted RR of
0.87 (95% CI, 0.83 to 0.91) for multiple live births among pregnancies for ICSI relative to IVF
among couples with male factor infertility. Given the quality of these two studies and the
imprecision of the findings the SOE was rated as insufficient.
Birthweight
One poor-quality RCT253 and three fair-quality observational studies compared birthweight
for ICSI versus conventional IVF.124,185,254 Boulet’s observational study254 compared birthweight
for ICSI (4230 live births) versus conventional IVF (60,273 live births). Among couples with
male factor infertility, they calculated an adjusted RR of low birthweight of 0.93 (95% CI, 0.88
to 0.98) for ICSI relative to IVF. The second observational study124 evaluated outcomes
associated with conventional IVF versus ICSI among both couples with male factor infertility
reported singleton birth weights of 3270 grams (standard deviation [SD] 580) among
conventional IVF recipients versus 3266 grams (SD 637) among ICSI recipients (p=0.67). The
third fair-quality observational study185 examined neonatal outcomes for fresh ICSI compared
with IVF cycles among patients with male factor infertility. This study used data from the society
for assisted reproductive technologies clinical outcomes reporting system database from 2004 to
2013. Conventional IVF participants were one-to-one propensity score matched with ICSI
participants. Among matched patients with male factor infertility (n=2,184) no significant
association was found with preterm delivery (OR 0.77 95% CI 0.54, 1.12) or low birth weight
(OR 1.06 95% CI 0.70, 1.61).
Finally, one poor-quality RCT found that the mean birthweight was 2535 grams (SD 710)
associated with IMSI versus 2789 grams (SD 575) associated with ICSI (p=0.492), not
demonstrating a difference.253 Given the poor- and fair-quality of the included studies and the
lack of quality RCT evidence, the SOE was rated as low for no difference in birthweight.
87
Congenital Anomalies
Three studies explore congenital anomalies associated with infertility treatments for male
infertility. One poor-quality RCT looked at congenital anomalies when comparing ICSI to IMSI
for male factor infertility. The study reported zero cases of congenital anomalies for ICSI and
18.2% (2/11) for IMSI (p=0.190).253 Additionally, a fair-quality observational study263
investigated rates of birth defects in patients who conceived through IVF and ICSI. This study
found birth defects in 2.4% of infants conceived through IVF for male factor infertility, which
was significantly lower than the 3.2% of infants with birth defects conceived through ICSI.
However, these results should be interpreted with caution. The male infertility factor group in
this study seems to include couples with and without female infertility indication.
Finally a third fair-quality observational study260 was conducted in Israel in a single
outpatient infertility clinic of couples presenting with male factor infertility. The objective of the
study was to determine the birth defect rates among ICSI and IMSI groups. Among 1,981
pregnancies, sixty-three pregnancies involving fetal malformation were reported with 3.9% in
the ICSI group and 2.3% in the IMSI group. However no significant association was found
between the two groups OR 0.71 (95% CI 0.39–1.22). Given the study limitations of these
included studies with imprecise findings, the SOE was rated as insufficient.
Birthweight
One good-quality observational study236 looked at all singleton live births in Florida and
Massachusetts between 2000 and 2010 and Michigan between 2000-2009 and used data from the
States Monitoring Assisted Reproductive Technology (SMART) Collaborative. Both
conventional and discordant-sibling pairs analyses were conducted. For the discordant sibling
pairs the study population was restricted to singleton live births where one sibling was conceived
through ART and the other was conceived naturally. In conventional analysis, when compared to
naturally conceiving, those with male factor only indication for ART had significant associations
with low birth weight (OR 1.15 95% CI 1.04 to 1.27) and preterm birth (OR 1.19 95% CI 1.10 to
1.29).236
3. Other Strategies
Table 27. Strength of evidence for major outcomes—KQ 5 (male factor infertility)
Strength of
Study Design
Comparison Outcome Conclusion Evidence
and Sample Size
(Rationale)a
Single vs. Live birth 2 RCTs208,221 Inconclusive. SOE was Insufficient
double IUI (447 patients) insufficient given imprecise (Imprecise;
evidence studies with varying findings from
rFSH vs. 2 SRs265,266 (4 quality and differing strategies. studies with
clomiphene studies, 1,278 varying quality
citrate couples) and differing
strategies)
IUI vs. IUI with
ovarian
hyperstimulati
on
ART IVF: ICSI Live birth 2 Obs123,257 Improvement. Greater live births Low (Imprecise)
or assisted (272,717 cycles) with multiple embryos transferred
hatching (1 compared to 1 embryo transferred
embryo
transferred)
vs. ICSI or
assisted
hatching
(multiple
embryos
transferred)
TESE vs.
ejaculated
OAT
ART IVF: Neonatal 1 Obs257 Inconclusive. SOE was Insufficient
TESE vs. outcomes: (191 cycles) insufficient given imprecise (Imprecise
ejaculated Birthweight evidence from one observational findings with
OAT study with potential limitations high study
limitations)
Neonatal 1 Obs257 Inconclusive. SOE was Insufficient
outcomes: (191 cycles) insufficient given imprecise (Imprecise
Congenital evidence from one observational findings with
anomalies study with potential limitations high study
limitations)
ART IVF: Live birth 1 RCT262 No difference: no difference in Low (one study,
Frozen vs. (2,157 patients) live birth rates between couples heterogeneous
fresh embryo using frozen embryo versus fresh infertility
transfer embryo transfer indication)
Pregnancy 1 RCT262 No difference: no difference in Low (one study,
complications: (2,157 patients) ectopic pregnancy rates between heterogeneous
Ectopic couples using frozen embryo infertility
pregnancy versus fresh embryo transfer indication)
90
Strength of
Study Design
Comparison Outcome Conclusion Evidence
and Sample Size
(Rationale)a
Pregnancy 1 RCT262 No difference: no difference in Low (one study,
complications: (2,157 patients) multiple birth rates between heterogeneous
Multiple births couples using frozen embryo infertility
versus fresh embryo transfer indication)
Pregnancy 1 RCT262 No difference: no difference in Low (one study,
complications: (2,157 patients) miscarriage rates between couples heterogeneous
Miscarriage using frozen embryo versus fresh infertility
embryo transfer indication)
Neonatal 1 RCT262 No difference: no difference in Low (one study,
outcomes: (2,157 patients) low birthweight rates between heterogeneous
Birthweight couples using frozen embryo infertility
versus fresh embryo transfer indication)
Neonatal 1 RCT262 No difference: no difference in Low (one study,
outcomes: (2,157 patients) congenital anomalies rates heterogeneous
Congenital between couples using frozen infertility
anomalies embryo versus fresh embryo indication)
transfer
ART ICSI: Live birth 1 RCT255 Inconclusive. SOE was Insufficient
ICSI vs. (182 patients) insufficient given imprecise (Imprecise
Laser-assisted evidence from 1 low-quality trial findings with
hatching high study
limitations)
Pregnancy 1 RCT264 Inconclusive. SOE was Insufficient
complications: (62) insufficient given imprecise (Imprecise
Miscarriage evidence from 1 small moderate- findings from
quality trial one small study
with moderate
limitations)
Pregnancy 1 RCT255 Inconclusive. SOE was Insufficient
complications: (182 patients) insufficient given imprecise (Imprecise
Multiple births evidence from 1 low-quality trial. findings with
high study
limitations)
Neonatal 1 RCT255 Inconclusive. SOE was Insufficient
outcomes: (182 patients) insufficient given imprecise (Imprecise
Congenital evidence from 1 low-quality trial. findings with
anomalies high study
limitations and a
suspected
reporting bias)
IVF vs. ICSI Live birth 3 RCTs253,256,258 No difference. Meta-analysis of 3 Moderate
(497 patients) RCTs produced a summary (Moderate study
estimate of the OR for live birth per limitations)
2 Obs124,254 cycle associated with ICSI of 1.218
(771,661 cycles) (95% CI, 0.779 to 1.903) relative to
IMSI and therefore does not
demonstrate a difference between
ICSI and IMSI.
Pregnancy 1 RCT253 No difference. Both included Low
complications: (121 patients) studies and an existing systematic (High study
Miscarriage review supported no difference in limitations,
1 Obs254 (499,135 miscarriage. SOE was reduced imprecise)
cycles) because of quality of included
studies and imprecision of findings.
1 SR79 (6 studies,
552 women)
91
Strength of
Study Design
Comparison Outcome Conclusion Evidence
and Sample Size
(Rationale)a
Pregnancy 1 RCT253 Inconclusive. SOE was Insufficient
complications: (121 patients) insufficient given imprecise (Imprecise with
Multiple births evidence from 1 trial and 1 moderate study
1 Obs254 (499,135 observational study with moderate limitations)
cycles) study limitations
Neonatal 1 RCT253 No difference: No significant Low (moderate
outcomes: (121 patients) differences in rates of low birth study
Birthweight weight between ICSI versus limitations)
3 Obs124,185,254 conventional-IVF cycles
(862,062 cycles)
Neonatal 1 RCT253 Inconclusive. SOE was Insufficient
outcomes: (121 patients) insufficient given imprecise (Imprecise;
Congenital evidence from studies with findings with
anomalies 2 Obs260,263 significant study limitations. high study
(143,436) limitations)
ART Long-term 1 Obs213 No difference: The overall cancer Low
unspecified outcomes: (924,427 patients) incidence was not elevated in (Moderate study
Child (cancer) children born after assisted limitations)
conception for male factor
infertility. The SIR for all cancers in
children conceived with assisted
conception for male factor infertility
compared to the general
population of the same age was
0.92 (95% CI, 0.53 to 1.49).
Long-term 1 Obs184 No difference: No significant Moderate
outcomes: (565,116 difference found between type 1 (Imprecise)
Child (type 1 pregnancies) diabetes mellitus diagnoses in
diabetes children born to patients with male
mellitus) factor infertility conceived with ART
compared to children conceived
with no fertility treatment
Other Live birth 1 RCT261 Inconclusive. SOE was Insufficient
strategies: (386 patients) insufficient given imprecise (Imprecise; one
Exercise for evidence from 1 small trial. study)
Male Infertility
Other Live birth 1 SR72 (4 studies Improvement: Increase in live Low (Imprecise,
strategies: of 277 couples) birth rate associated with vitamin E small studies)
Antioxidant or zinc supplementation relative to
use for Male placebo or no supplementation
Infertility
aCriteria for downgrading strength of evidence is described as Rationale; when these criteria are insufficient for understanding the
Abbreviations: ART=assisted reproductive technology; CI=confidence interval; HR=hazard ratio; ICSI=intra-cytoplasmic sperm
injection; IMSI=intracytoplasmic morphologically selected sperm injection; IUI=intrauterine insemination; IVF=in vitro
fertilization; KQ=Key Question; N=number of patients/participants; NA=not applicable; NR=not reported; OAT=oligo-astheno-
teratozoospermia; Obs=observational study; OR=odds ratio; RCT=randomized controlled trial; rFSH=recombinant follicle-
stimulating hormone; RR=relative risk; SD=standard deviation; SIR=standardized incidence ratio; TESE=extracted testicular
sperm
92
Key Question 6. Donors in Infertility
KQ 6. What are the short- and long-term health outcomes of donors in
infertility?
KQ 6a. For female oocyte donors:
1. Do specific aspects of the pre-donation evaluation identify
potential donors at greater risk for short- or long-term adverse
outcomes (e.g., OHSS, quality-of-life issues)?
2. Do short- and long-term outcomes differ among different
stimulation/retrieval protocols?
KQ 6b. For male semen donors:
1. Are there long-term health, quality-of-life, or other adverse
outcomes associated with donation?
93
of OHSS, 18 (11.6%) reported OHSS-related hospitalization and/or paracentesis. This study was
rated as poor quality because of the high risk of bias due to the relatively low response rate and
the self-selected nature of the study sample (insufficient SOE for all outcomes).
A randomized crossover trial conducted in Cyprus in 2008 compared outcomes associated
with hCG versus GnRH agonist (leuprolide acetate) trigger among 50 oocyte donors.267 Both
study protocols used recombinant FSH or hMG administered beginning on day 3 of each donor’s
menstrual cycle for donor stimulation. Among the 44 donors who received both triggering agents
in 2 consecutive cycles, 3 cases (6.8%) of mild-to-moderate OHSS were reported after
administration of hCG. No cases of OHSS were reported after administration of the GnRH
agonist leuprolide. The between-group difference in rates of OHSS was not statistically
significant, but this trial may have been underpowered to detect a statistically significant effect
for this clinical outcome. This study was rated as fair quality because of the small sample size
and the exclusion from the analysis of patients who did not complete the trial (insufficient SOE).
Two publications reported retrospectively assessed outcomes observed among overlapping
cohorts of oocyte donors treated at a private infertility clinic in Spain between 2001 and
2007.268,269 Among 1907 donors who collectively underwent 4052 stimulation cycles that
reached oocyte retrieval, the stimulation protocol and triggering agents used were as follows:
1238 cycles with a GnRH agonist protocol and hCG trigger; 1295 cycles with a GnRH
antagonist protocol and hCG trigger; and 1519 cycles with a GnRH antagonist protocol and a
GnRH agonist trigger. The incidence of moderate or severe OHSS resulting from these three
protocols were, respectively, 0.65 percent, 1.08 percent, and 0 percent (difference not statistically
significant).268 The other publication from this cohort of patients reported an incidence of 13
cases of moderate or severe OHSS associated with 624 cycles of hCG triggering (2.1%) and no
cases of moderate or severe OHSS associated with 547 cycles of triggering with a GnRH
agonist.269 These two studies were rated as fair quality because of their retrospective design.
Together they suggest a lower incidence of OHSS with GnRH agonist trigger than with hCG
trigger (low SOE).
The fifth study was a retrospective analysis of all attempts at oocyte donations by anonymous
and known directed donors at a medical center in the United States from 1991 to 2007.270 The
charts of 587 donors (481 anonymous and 106 directed) who participated in 973 stimulation
cycles and 886 retrievals were reviewed. The age of the donors ranged from 20 to 42 years. Of
the 886 stimulation cycles, 12 (1.4%) were associated in mild or moderate OHSS that led to 2
outpatient office visits, and 4 (0.5%) were associated with moderate OHSS that led to 3 or 4
office visits. There was a single case (0.1%) of intraabdominal bleeding and 18 cases (2.0%) of
other complications such as cysts, hematomas, urinary tract infections, yeast infections, or
“vague symptoms.” This study was rated as fair quality because of its retrospective design and
because details of the stimulation and retrieval protocols were not reported. In addition, the
applicability of these findings is limited in that clinical practice have evolved since 1991 and
how the protocol during the study period reflected these changes in practice is unclear
(insufficient SOE).
94
donor sibling. Of the 287 women with valid e-mail addresses who were invited via an email
message to participate in the study, 155 (54%) completed the 25-item questionnaire. The mean
age of respondents at the time of the survey was 35.8 years, and the number of years since first
donation was 9.4 years (SD 5.2). Details of the stimulation protocols and oocyte retrieval
methods were not reported. Of the 155 respondents, and 41 (26.4%) reported infertility and/or
menstrual changes since donation. Fifteen of these women (9.6% of the total sample) reported
new infertility problems; of these, only 4 reported having become pregnant. This study was rated
as poor quality because of the high risk of bias due to the relatively low response rate and the
self-selected nature of the study sample (insufficient SOE for all outcomes)
95
funding sources,125,288,289 and the remaining four did not report a funding source or it was
unclear.185,248,249,251,286,291
96
Table 29. Cancer risk (95% CI) for ever use of clomiphene citrate by infertility diagnosis
Tubal or Peritoneal
Cancer Endometriosis (N=2196) Male Factor (N=2218)
Factor (N=3496)
Ovarian 1.01 (0.43 to 2.36) 0.98 (0.46 to 2.07) 1.18 (0.52 to 2.68)
Endometrial 1.79 (0.76 to 4.23) 1.14 (0.59 to 2.21) 1.55 (0.82 to 2.96)
Breast 1.23 (0.92 to 1.65) 1.12 (0.87 to 1.45) 1.25 (0.92 to 1.69)
Colon 0.53 (0.22 to 1.27) 0.66 (0.31 to 1.40) 1.14 (0.42 to 3.06)
Lung 1.68 (0.71 to 3.99) 1.78 (0.90 to 3.54) 1.35 (0.51 to 3.61)
Thyroid 0.87 (0.28 to 2.67) 1.08 (0.40 to 2.88) 2.46 (0.64 to 9.49)
Melanoma 1.10 (0.42 to 2.89) 0.98 (0.36 to 2.73) 1.10 (0.27 to 4.46)
Abbreviations: CI=confidence interval; N=number of patients
Table 30. Cancer risk (95% CI) for ever use of gonadotropins by infertility diagnosis
Tubal or Peritoneal
Cancer Endometriosis (N=2196) Male Factor (N=2218)
Factor (N=3496)
Endometrial 1.15 (0.72 to 1.83) 1.16 (0.77 to 1.74) 1.29 (0.79 to 2.11)
Breast 2.74 (0.96 to 7.85) 0.94 (0.32 to 2.70) 0.74 (0.22 to 2.43)
Abbreviations: CI=confidence interval; N=number of patients
While the findings from this cohort are suggestive that, in couples with infertility due to
endometriosis, tubal factors, or male factors, that women treated with clomiphene citrate or
gonadotropins are not at markedly increased risk for any common cancer, the size of the cohort
was not adequate to detect modest increases in risk. In addition, the size of the cohort precluded
conducting more detailed analyses in relation to the number of cycles received or age at
treatment (low SOE).
Cancer risk in relation to ART treatment was examined in two good-quality observational
cohort studies, described in four papers.125-127,289 Results from a study conducted in the
Netherland were described in papers examining melanoma risk125 , ovarian neoplasms,126 and
colorectal cancers 127. In this study, the underlying cause of infertility was adjusted for along
with other potential confounders. The cohort was comprised of 19,158 women who received IVF
treatment and 6006 infertile women who did not receive IVF treatment after a median follow-up
of 15 years. IVF was not significantly associated with melanoma risk (standardized incidence
ratio [(SIR] 1.27; 95% CI, 0.75 to 2.15) when controlling for cause of infertility.125 IVF was
associated with a statistically significant increased risk of all ovarian malignancies (HR 2.05;
95% CI, 1.10 to 3.82). This risk was increased most notably for borderline ovarian tumors (HR
6.38; 95% CI, 2.05 to 19.84) as compared to the increase seen in invasive ovarian cancer (HR
1.14; 95% CI, 0.54 to 2.41) (low SOE).126 For colorectal cancers, IVF was not associated with a
significant risk of colorectal cancer compared to the general population (SIR 1.00; 95% CI, 0.80
to 1.23), but was increased compared to infertile patients who did not receive IVF (HR 1.80,
95% CI, 1.10-2.94). Interestingly, this may be due to a significantly lower risk for colorectal
cancers in this group compared to the general population (SIR 0.58, 95% CI, 0.36-0.88), which
the authors speculated may have been due to a “healthy female effect”, but could also have been
a chance finding because of a small number of cases in the non-IVF group.127
The applicability of the findings may be limited since the study was conducted in the
Netherlands and the IVF treatments were received in the period between 1983 and 1995. With
the evolution of IVF treatment over time, findings from this study may not reflect the risk for
women currently undergoing IVF.
The second study, conducted in the UK, examined ovarian, breast and corpus uteri cancers in
a cohort of 255,786 women who underwent ART and were followed for an average of 8.8
years.289 SIRs were calculated comparing the observed incidence rates to expected rates based on
97
national cancer incidence rates in women and are summarized in Table 31. Breast cancer risk
(invasive or in situ) was not significantly increased in any of the female infertility diagnoses
categories, and was significantly lower among those with a male factor diagnosis. Both invasive
and borderline ovarian cancers were significantly increased among women with a diagnosis of
endometriosis or tubal disease. Corpus uteri cancer risk was significantly higher only among
women with a diagnosis of ovulatory problems.
Table 31. Cancer risk (SIR 95% CI) among women who underwent assisted reproduction by
infertility diagnosis
Endometriosis Tubal Disease Ovulatory Problems Male Factor
Cancer (181,279 Person- (710,522 Person- (311,523 Person- (757,063 Person-
Years) Years) Years) Years)
Invasive breast
0.95 (0.82 to 1.10) 0.94 (0.87 to 1.01) 0.91 (0.81 to 1.02) 0.89 (0.83 to 0.96)
cancer
In situ breast
1.25 (0.81 to 1.83) 1.11 (0.89 to 1.36) 1.05 (0.75 to 1.42) 1.18 (0.95 to 1.44)
cancer
Invasive
2.47 (1.75 to 3.39) 1.71 (1.40 to 2.08) 1.16 (0.80 to 1.63) 1.09 (0.84 to 1.39)
ovarian tumors
Borderline
2.03 (1.18 to 3.25) 1.62 (1.21 to 2.12) 1.52 (0.96 to 2.31) 0.96 (0.66 to 1.35)
ovarian tumors
Corpus uteri
0.75 (0.35 to 1.43) 1.23 (0.93 to 1.58) 1.59 (1.13 to 2.17) 0.91 (0.65 to 1.24)
cancer
Abbreviations: CI=confidence interval; N=number of patients; SIR=standardized incidence ratio
Congenital Anomalies
A good-quality observational study277 using the States Monitoring ART (SMART)
Collaborative and linked ART surveillance, birth certificates, and birth defects registry data for
Florida, Massachusetts, and Michigan from 2000 to 2010 (n=64,861). The objective of this study
98
was to examine the prevalence of birth defects among liveborn infants conceived with and
without ART and to evaluate risks associated with certain ART procedures among ART-
conceived infants. Overall, the prevalence ratio was significantly higher for ART versus non-
ART birth (adjusted risk ratio 1.28, 95% CI 1.15 to 1.42, p<0.001) (low SOE).
Neurodevelopmental Outcomes
Risk of autism through age 5 was examined in one good-quality observational study
involving 42,383 children conceived with ART in California between 1997 and 2006.272
Analyses did not examine associations with type of embryo fertilization (ICSI or conventional
IVF) stratified by cause of infertility, but did control for infertility diagnosis in multivariable
analyses. Among ART-conceived infants, use of ICSI was associated with a higher incidence of
autism in both singleton births (HR 1.65; 95% CI, 1.08 to 2.52) and multiple births (HR 1.71;
95% CI, 1.10 to 2.66) in multivariable analyses that controlled for infertility diagnosis (low
SOE). Results of ICSI versus IVF were not described for specific causes of infertility, although
male factor infertility was the most common diagnosis in the cohort.
One fair-quality273 observational study compared outcomes between ART and no
intervention/expectant management. Risk of neurological dysfunction at 2 years was assessed in
a fair-quality observational study examining children conceived with IVF (n=122), conceived
naturally to subfertile parents (n=87), or born to parents without fertility problems (n=101).273
Outcomes reported were simple or complex minor neurological dysfunction. Results were
stratified by underlying cause of infertility. None of the specific causes of infertility were related
to the rates of neurological dysfunction (insufficient SOE).
99
Table 32. Birth rates by number of embryos transferred
# Embryos 1 Embryo 2 Embryos 3 Embryos 4+ Embryos
P Value
Transferred Transferred Transferred Transferred Transferred
Singleton birth 1,302/3,037 13,779/42,396 4,632/17,480 1,424/6,115 p<0.0001
(42.9%) (32.5%) (26.5%) (23.3%)
Multiple birth 15/3,037 8,055/42,396 3,094/17,480 923/6,115 p<0.0001
(0.5%) (19.0%) (17.7%) (15.1%)
Total births 1,318/3,037 21,834/42,396 7,726/17,480 2,348/6,115 p<0.0001
per cycle (43.4%) (51.5%) (44.2%) (38.4%)
A good-quality study from NASS assessed correlation between infertility clinic eSET rates
and pregnancy outcomes—there was a significant linear decrease in multiple birth rates with
increasing eSET rates with no significant differences in clinic-level live birth rates for women
younger than 38 years.283
Another good-quality SART CORS study found no difference in live birth or miscarriage
rate for fresh or frozen oocytes in autologous cycles, but a significantly lower rate of live birth
with frozen oocytes in donor cycles (adjusted Risk Ratio [aRR] 0.87, 95% CI, 0.80 to 0.95), with
no difference in miscarriage rates. 281
A good-quality observational study examined birth outcomes among all live births in
Massachusetts (2004 through 2008) that linked to ART cycles in the Society for Assisted
Reproductive Technology Clinic Online Reporting System (SART CORS) and the Pregnancy to
Early Life Longitudinal (PELL) data system274 and found lower birthweight with thawed
100
embryos compared to fresh (adjusted OR and 95% CI 0.79, 0.65 to 0.96). There was no
difference in low birth weight by assisted hatching, donor/autologous source of oocytes/semen,
number of embryos or ICSI.274
Finally, within frozen cycles, another good-quality SART CORS study compared the live
birth rate in first-cycle frozen embryo transfers with and without assisted hatching using
propensity score matching.282 The propensity score matching, which included infertility
diagnosis as one of the factors used to calculated propensity scores, resulted in 70,738 assisted
hatching cycles and 80,795 cycles without assisted hatching. The live birth rate was significantly
lower in the assisted hatching cohort compared to the no assisted hatching cohort (34.2% versus
35.4%, p<0.001).
101
live birth per transfer was lower for all types of PGD cycles when compared with non-PGD
cycles. Among live-birth deliveries, in models adjusting for cause of infertility, the adjusted OR
(95% CI) for low birth weight among PGD-Genetic cycles was 0.73 (0.54 to 0.98) as compared
to those resulting from non-PGD cycles. In contrast, the adjusted OR (95% CI) for low birth
weight among PGD-Aneuploidy cycles was 1.25 (1.01 to 1.54) compared with non-PGD cycles.
Among live births, the adjusted OR (95% CI) for multiple birth in PGD-Other cycles was 0.76
(0.60 to 0.97) compared with non-PGD cycles. Results for women 35-37 and >37 years of age
for low birth weight among PGD-Genetic cycles as compared to those resulting from non-PGD
cycles or for PGD-Aneuploidy cycles compared with non-PGD cycles were not statistically
significantly different. Results for women 35-37 and >37 years of age for multiple births among
PGD-Genetic cycles as compared to those resulting from non-PGD cycles or for PGD-
Aneuploidy cycles compared with non-PGD cycles were also not statistically significantly
different.276
In another good-quality study from SART CORS, PGD was associated with a lower chance
of live birth with donor oocyte cycles compared to non-PGD cycles (OR 0.65, 95% CI, 0.53 to
0.80).280
Insurance Coverage
A cohort study of the SART CORS database examined pregnancy in States with mandated
insurance of IVF coverage as compared with States without mandated IVF coverage. In models
adjusted for cause of infertility, there was no significant difference in the odds of live birth in
states with mandated insurance IVF coverage as compared with states with non-mandated IVF
coverage (aOR 1.02, 95% CI 0.97 to 1.07). The odds of multiple birth or higher-order multiple
birth were lower in States with mandated insurance IVF coverage as compared with States with
non-mandated IVF coverage. The adjusted odds ratio (95% CI) of multiple birth or higher order
multiple-birth in States with mandated IVF coverage was 0.87 (0.80 to 0.94) and 0.74 (0.53 to
1.03), respectively, as compared with States without mandated IVF coverage. There was no
statistically significant difference in the odds of low birth weight in States with mandated IVF
coverage as compared with States without mandated IVF coverage (aOR 0.95, 95% CI 0.88 to
1.03).279
Table 34. Strength of evidence for major outcomes—across all infertility diagnoses
Strength of
Study Design
Comparison Outcome Conclusion Evidence
(Sample Size)
(Rationale)a
Clomiphene Long-term 1 Obs136 No difference. Ever use of Low
citrate and outcomes: Maternal (9892 patients) clomiphene citrate was not (Size of cohort not
gonadotropin cancer statistically significantly sufficient to detect
associated with maternal modest increases
ovarian, breast, endometrial, in risk)
lung, thyroid, colon, or
melanoma cancer.
Gonadotropin use was not
associated with increased risk
for breast or endometrial
cancer
102
Strength of
Study Design
Comparison Outcome Conclusion Evidence
(Sample Size)
(Rationale)a
ART: IVF Live birth (by race) 1 Obs292 Greater disparity. Lower live Low
(13,473 cycles) birth rate for blacks as (Imprecise, 1
compared to white (p<0.001) study)
Live birth (by 1 Obs123 Improvement. Increased live Low
number of embryos (69,028 cycles) birth rate per cycle with 2 (Imprecise, findings
transferred) embryo transfer as compared with moderate
to single-embryo transfer study limitations)
Pregnancy 1 Obs123 Greater risk. Multiple live birth Low
complications: (69,028 cycles) rates are significantly higher (Imprecise, findings
Multiple births (by with a 2-embryo transfer than with moderate
number of embryos a single-embryo transfer, but study limitations)
transferred) do not increase further with 3-
or 4-embryo transfers
Neonatal 1 Obs274 No difference: No significant Low
outcomes: (8,948) difference in rates of low (Imprecise)
Birthweight birthweight using ART by
assisted hatching, source of
oocytes/semen, number of
embryos or ICSI
Neonatal 1 Obs277 Greater risk. Risk of birth Low
outcomes: (64,861) defects was greater in infants (1 study)
Congenital conceived using ART
Anomalies (adjusted risk ratio 1.28, 95%
CI 1.15 to 1.42)
Long-term 1 Obs272 Greater risk. Risk of autism Low
outcomes: Child (42,383) was greater in children (Imprecise)
(Autism) conceived with ART with ICSI
as compared to ART without
ICSI (HR 1.65, p<0.05)
Long-term 1 Obs273 Inconclusive. SOE was Insufficient
outcomes: Child (310 patients) insufficient given imprecise (imprecise findings
(neurological) evidence from 1 small with moderate
observational study with study limitations,
moderate risk of bias small study)
Long-term 2 Obs125,289 Greater risk. IVF was Low
outcomes: Maternal (280,950) associated with a statistically (Imprecise, older
(cancer) significant increased risk of all study)
ovarian neoplasms (HR 2.05;
95% CI, 1.20 to 3.82) and
borderline ovarian tumors (HR
6.28; 95% CI, 2.05 to 19.84),
and colorectal cancer (HR
1.80, 95% CI 1.10 to 2.94)
103
Abbreviations: ART=assisted reproductive technology; CI=confidence interval; HR=hazards ratio; ICSI=intra-cytoplasmic sperm
injection; IUI=intrauterine insemination; IVF=in vitro fertilization; KQ=Key Question; N=number of patients/participants;
Obs=observational study; RCT=randomized controlled trial; SOE=strength of evidence
Publication Bias
As part of the Evidence-based Practice Center (EPC) Program, AHRQ sought to assess
whether information from ClinicalTrials.gov would impact the conclusions of five ongoing
systematic reviews. This infertility systematic review was part of this methods project
(Augmenting Systematic Reviews with Information from ClinicalTrials.gov to Increase
Transparency and Reduce Bias).
For this purpose, we searched the ClinicalTrials.gov registry of clinical studies to ascertain
publication bias by identifying studies that have been completed but are as yet unpublished. Our
search yielded 354 records of completed trials about treatments for infertility for screening (see
Appendix A for our search strategy and Appendix H for details on our findings). Initial manual
review identified 94 of these records as potentially relevant; subsequent review by a topic expert
reduced this number to 66. Of these 66 records, we were not able to identify publications for 12
studies that had expected completion dates 3 years or more prior to our search. During the search
update period we again looked for publications covering these 12 studies. No new publications
were found.
Of these 12 trials with unpublished results, two were considered potentially relevant to KQ 1,
9 potentially relevant to KQ 3, and 1 potentially relevant to KQ 5. Implications for KQs 1, 2, and
4 are discussed in more detail in Appendix H as part of the augmenting transparency methods
project.
For this current systematic review, the two trials identified as potentially relevant to KQ 1
had a combined sample size of 340 patients and were completed more than 3 years ago. These
two “missing” trials are unlikely to have had a meaningful impact on our review’s results
especially given the presence of two systematic reviews for women with infertility from PCOS.
For KQ 3, there were nine potentially relevant unpublished studies where the underlying
diagnosis of infertility was not listed. It is not clear whether these trials are specifically relevant
to patients with infertility for unknown reasons as is required for inclusion in KQ 3 since the
trials may focus on patients with identified infertility diagnoses. This diagnosis specification
however is not available from the missing trials. The nine studies differed in terms of treatments
evaluated and outcomes assessed. All studies were fairly small studies (planned enrollment
varying between 60 and 242 individuals) and most of them focused on pregnancy rates rather
than live births though could potentially be relevant based on information about miscarriages,
ovarian hyperstimulation syndrome (OHSS), or other adverse events.
For KQ 5, there was one unpublished potentially relevant study which sought to determine
whether couples with male factor infertility, specifically with elevated sperm DNA damage
undergoing in vitro fertilization (IVF)/intra-cytoplasmic sperm injection (ICSI), should use
testicular sperm extraction to improve their reproductive outcomes. Although this study did have
live birth listed as the primary outcome, it had an enrollment of 25 males and so would not likely
change any of our findings.
In summary, because of the relatively low number of unpublished studies identified through
our ClinicalTrials.gov registry analysis as compared to our included set of studies, we do not
believe these findings indicate significant publication bias in the evidence base that would
impact our overall conclusions.
104
Discussion
In this Comparative Effectiveness Review, we reviewed 151 studies described in 161
publications that directly compared infertility management strategies in couples with infertility
due to polycystic ovary syndrome (PCOS; Key Question [KQ] 1) or endometriosis (KQ 2);
unexplained infertility (KQ 3); tubal and peritoneal factor infertility (KQ 4); and male factor
infertility (KQ 5). We also explored the comparative safety and effectiveness of management
strategies for donors in infertility (KQ 6). Although the ultimate goal with any infertility
management strategy is to improve live birth rates of healthy infants to a healthy couple, many
studies initially identified in our review only reported on pregnancy rates or focused on other
short-term outcomes and did not differentiate by the underlying causes of infertility. Our findings
are based on those 151 studies which evaluated the comparative effectiveness of infertility
management strategies in couples with a known cause of infertility (including unexplained
infertility) and which evaluated the outcome of live birth or another long-term outcome.
105
infertility in general or specific causes (low SOE), and, for children born after ART, a possible
increased risk of neurodevelopmental disorders after ICSI compared to IVF (low SOE) but no
evidence of an increased risk of Type I diabetes.
106
those patients going directly to ART, surgical treatment of endometriosis, including
endometrioma, prior to ART does not improve outcomes.
For women with unexplained infertility (Table 37), NICE recommends against use of oral
agents entirely, while ASRM suggests clomiphene plus IUI may improve cycle fecundity
compared to expectant management; our review found insufficient evidence. Based on our
review, immediate IVF results in higher live birth rates and shorter time to pregnancy in women
aged 38-42 compared with a trial of clomiphene and IUI or gonadotropins and IUI, with most
live births ultimately resulting from IVF.
For women with suspected tubal factor infertility (Table 38), both NICE and ASRM
recommend imaging for diagnosis (which is outside the scope of our review), although, when
ART is readily available and affordable, proceeding directly to ART without a definitive
diagnosis of tubal disease may be more efficient.
For male factor infertility (Table 39), our review found no relevant findings compared to the
recommendations, primarily because of limited data on live birth outcomes.
For both male and female donors (Table 40), both NICE and ASRM recommend
psychological evaluation and counseling, including, for females, the short term risks of ovarian
stimulation and oocyte collection; our review found evidence on outcomes was limited only to
the known short-term risks of these procedures, with no evidence on potential longer term risks.
For long-term outcomes in women and children after infertility treatment (Table 41), our
review found limited or inconsistent evidence. Risks of adverse longer term maternal cancer
outcomes were generally not increased after adjustment for the risk associated with infertility
itself. ICSI however may be associated with an increased risk of neurodevelopmental disorders
in children compared to those conceived through IVF. The NICE guidance was generally
consistent with this assessment, and recommended that patients should be informed that any
absolute risk was low, while there was still uncertainty about longer-term outcomes.
107
Table 35. Report findings and major guidelines/recommendations—KQ 1. PCOSa
Intervention Evidence Report Findings NICE ASRM
Selective estrogen Clomiphene citrate does not result in higher For women with WHO Group II ovulation Clomiphene citrate is an effective first-line
receptor live birth rates compared with metformin disorders (PCOS), offer as initial treatment for the majority of women with
modulators (low SOE). Differences are also not found treatment clomiphene, metformin, or a anovulatory infertility.293
in the rates of miscarriage, multiple birth, combination, considering potential
ectopic pregnancy, or time to pregnancy adverse effects, ease and mode of use, Failure to conceive after 3 to 4 successful CC-
(low SOE for all outcomes) the woman's BMI, and monitoring induced ovulation cycles is indication for further
needed evaluation to exclude other contributing causes
of infertility, particularly in women >35 years of
For women who are taking clomiphene age.293
citrate, offer ultrasound monitoring during
at least the first cycle of treatment to
ensure that they are taking a dose that
minimizes the risk of multiple pregnancy.
108
Intervention Evidence Report Findings NICE ASRM
Aromatase Letrozole has a higher live birth rate than In women with polycystic ovary No specific recommendations
inhibitors clomiphene citrate alone and lower multiple syndrome, letrozole appears to be
births (moderate SOE for both outcomes), associated with a higher live birth rate,
with no difference in ectopic pregnancy, lower rates of multiple pregnancy and
miscarriage, low birthweight, or time to lower incidence of ovarian
pregnancy (low SOE for these outcomes) hyperstimulation syndrome (OHSS) than
clomiphene citrate.295
Surgical There was no difference between For women with WHO Group II ovulation No specific recommendations
Management laparoscopic ovarian drilling (LOD) and oral disorders [PCOS] who are known to be
agents for live birth (moderate SOE) or resistant to clomiphene citrate, consider
miscarriage rates (low SOE). Multiple births one of the following second-line
were reduced given LOD (moderate SOE) treatments, depending on clinical
circumstances and the woman's
preference:
• LOD or
• combined treatment with
clomiphene citrate and
metformin if not already offered
as first-line treatment or
• gonadotropins
Gonadotropins Use of gonadotropins as primary therapy Women with polycystic ovary syndrome No specific recommendations
alone does not improve outcomes compared to who are being treated with
oral agents gonadotropins should not be offered
treatment with gonadotropin-releasing
hormone agonist concomitantly because
it does not improve pregnancy rates, and
it is associated with an increased risk of
ovarian hyperstimulation.
Adjuncts to Pretreatment with metformin prior to ART The use of adjuvant growth hormone No specific recommendations
gonadotropins may improve live birth rates and decrease treatment with gonadotropin-releasing
OHSS. hormone agonist and/or human
menopausal gonadotropin during
Use of GnRH antagonists as part of the ovulation induction in women with
controlled ovarian hyperstimulation protocol polycystic ovary syndrome who do not
in IVF/ICSI reduces the incidence of OHSS respond to clomiphene citrate is not
compared to GnRH agonists. recommended because it does not
improve pregnancy rates.
aSections or statements shaded in gray represent outcomes where our review’s findings were different from those of the major guidelines/recommendations.
Abbreviations: ART=assisted reproductive technology; ASRM=American Society for Reproductive Medicine; BMI=body mass index; CC=clomiphene citrate;
GnRH=gonadotropin-releasing hormone; ICSI=intra-cytoplasmic sperm injection; IVF=in vitro fertilization; KQ=Key Question; NICE=National Institute for Health and Care
Excellence (UK); OHSS=ovarian hyperstimulation syndrome; PCOS=polycystic ovary syndrome; SOE=strength of evidence; WHO=World Health Organization
109
Table 36. Report findings and major guidelines/recommendations—KQ 2, endometriosisa
Intervention Evidence Report Findings NICE ASRM296
Medical Strength of evidence was insufficient for all Medical treatment of minimal and mild There is no evidence that medical treatment of
management comparisons. endometriosis diagnosed as the cause of endometriosis improves fertility
infertility in women does not enhance
fertility and should not be offered. In younger women (under age 35 years) with
stage I/II endometriosis-associated infertility,
expectant management or superovulation with
IUI can be considered as first-line therapy. For
women 35 years of age or older, more
aggressive therapy (superovulation with IUI or
IVF) may be considered.
Abbreviations: SRM=American Society for Reproductive Medicine; CC=clomiphene citrate; ET=embryo transfer; IUI=intrauterine insemination; IVF=in vitro fertilization;
KQ=Key Question; NICE=National Institute for Health and Care Excellence (UK)
110
Table 37. Report findings and major guidelines/recommendations—KQ 3, unexplained infertilitya
Oral ovarian There is no difference between the oral Do not offer oral ovarian stimulation The treatment effects with non-ART treatment
stimulation agents of letrozole and anastrozole for the agents (such as clomiphene citrate, for unexplained infertility generally are small.
outcome of ectopic pregnancy (low SOE) anastrozole or letrozole) to women with Empiric treatment may do no more than
but evidence is insufficient for other unexplained infertility. hasten conception in those couples who would
outcomes of interest conceive eventually without treatment.297
There is no difference between differing Level I evidence from randomized clinical trials
adjunct treatments used in combination supports short-term use of IUI, CC,
with oral agents and IUI for the outcomes gonadotropins and IUI, and ART treatment for
of live birth, miscarriage, and OHSS (low unexplained infertility but is insufficient for
SOE for all outcomes) conclusions regarding CC/IUI treatment.
Abbreviations: ART=assisted reproductive technology; ASRM=American Society for Reproductive Medicine; CC=clomiphene citrate; FSH=follicle-stimulating hormone;
ICSI=intra-cytoplasmic sperm injection; IUI=intrauterine insemination; IVF=in vitro fertilization; KQ=Key Question; NICE=National Institute for Health and Care Excellence
(UK); OHSS=ovarian hyperstimulation syndrome; SOE=strength of evidence
111
Table 38. Report findings and major guidelines/recommendations—KQ 4, tubal and peritoneal factor infertility
Intervention Evidence Report Findings NICE ASRM298
Diagnosis Strength of evidence was insufficient for Women who are not known to have There is good evidence to support HSG as the
all comparisons. comorbidities (such as pelvic standard firstline test to assess tubal patency,
inflammatory disease, previous ectopic but it is limited by false positive diagnoses of
pregnancy or endometriosis) should be proximal tubal blockage.
offered HSG to screen for tubal occlusion
because this is a reliable test for ruling • The evidence is fair to recommend
out tubal occlusion, and it is less invasive tubal cannulation for proximal tubal
and makes more efficient use of obstruction in young women with no
resources than laparoscopy. [2004] other significant infertility factors.
• The evidence is fair to recommend
Where appropriate expertise is available, laparoscopic fimbrioplasty or
screening for tubal occlusion using neosalpingostomy for the treatment of
hysterosalpingo-contrast- mild hydrosalpinges in young women
ultrasonography should be considered with no other significant infertility
because it is an effective alternative to factors.
hysterosalpingography for women who
are not known to have comorbidities.
[2004]
112
Intervention Evidence Report Findings NICE ASRM298
Surgery Strength of evidence was insufficient for For women with mild tubal disease, tubal There are no adequate trials comparing
all comparisons. surgery may be more effective than no pregnancy rates with tubal surgery vs. IVF.
treatment. In centres where appropriate However, IVF has a higher per-cycle
expertise is available it may be pregnancy rate.
considered as a treatment option. [2004]
The evidence is fair to recommend tubal
For women with proximal tubal cannulation for proximal tubal obstruction in
obstruction, selective salpingography young women with no other significant
plus tubal catheterisation, or infertility factors.
hysteroscopic tubal cannulation, may be
treatment options because these The evidence is fair to recommend
treatments improve the chance of laparoscopic fimbrioplasty or
pregnancy. [2004] neosalpingostomy for the treatment of mild
hydrosalpinges in young women with no other
significant infertility factors.
113
Table 39. Report findings and major guidelines/recommendations—KQ 5, male factor infertilitya
Intervention Evidence Report Findings NICE ASRM
Gonadotropins No relevant findings Men with hypogonadotrophic No specific recommendations
hypogonadism should be offered
gonadotrophin drugs because these are
effective in improving fertility.
Surgical No relevant findings Where appropriate expertise is available, • Infertility due to obstructive azoospermia
men with obstructive azoospermia may be treated effectively by surgical
should be offered surgical correction of reconstruction or by retrieval of sperm from
epididymal blockage because it is likely the epididymis or testis, followed by
to restore patency of the duct and IVF/ICSI.
improve fertility. Surgical correction • When obstructive azoospermia results
should be considered as an alternative to from a vasectomy performed less than 15
surgical sperm recovery and IVF. years before and there are no coexisting
female infertility factors, microsurgical
Men should not be offered surgery for reconstruction of the reproductive tract
varicoceles as a form of fertility treatment generally is preferred over sperm retrieval
because it does not improve pregnancy and IVF/ICSI.
rates.
ART Live birth rate (moderate SOE) and Couples should be informed that ICSI No specific recommendations
miscarriage (low SOE) did not differ improves fertilisation rates compared to
between intracytoplasmic sperm injection IVF alone, but once fertilisation is
(ICSI) and intracytoplasmic morphological achieved the pregnancy rate is no better
sperm injection (IMSI). than with IVF.
aSections or statements shaded in gray represent outcomes where our review’s findings were different from those of the major guidelines/recommendations.
Abbreviations: ASRM=American Society for Reproductive Medicine; ICSI=intra-cytoplasmic sperm injection; IVF=in vitro fertilization; KQ=Key Question; NICE=National
Institute for Health and Care Excellence (UK)
114
Table 40. Report findings and major guidelines/recommendations—KQ 6, donors
Intervention Evidence Report Findings NICE ASRM
Male donors No evidence on short- or long-term All potential semen donors should be Psychological evaluation and counseling by a
outcomes offered counselling from someone who is qualified mental health professional is strongly
independent of the treatment unit recommended for all sperm donors. The
regarding the implications for themselves assessment should include a clinical interview
and their genetic children, including any and, where appropriate, psychological testing.
potential children resulting from donated Psychological consultation should be required
semen. for individuals in whom there appear to be
factors that warrant further evaluation. In
cases of directed donation, psychological
evaluation and counseling are strongly
recommended for the donor and his partner (if
applicable) as well as for the recipient female
and her partner (if applicable). The potential
impact of the relationship between the donor
and recipient should be explored. The
psychological assessment also should address
the potential psychological risks and evaluate
for evidence of coercion (financial or
emotional). It is important to ascertain whether
the donor is well informed about the extent to
which information about him might be
disclosed and about any plans that may exist
relating to future contact.299
115
Female donors Limited evidence on short-term outcomes, Before donation is undertaken, oocyte Psychological evaluation and counseling by a
no evidence on long-term outcomes donors should be screened for both qualified mental health professional is strongly
infectious and genetic diseases in recommended for the oocyte donor and her
Observational studies suggest a lower accordance with the 'UK guidelines for partner (if applicable). The assessment should
incidence of OHSS with GnRH agonist the medical and laboratory screening of include a clinical interview and, where
trigger than with hCG trigger (low SOE). sperm, egg and embryo donors' (2008). appropriate, psychological testing.
Psychological consultation should be required
Oocyte donors should be offered for individuals in whom there appear to be
information regarding the potential risks factors that warrant further evaluation. In
of ovarian stimulation and oocyte circumstances involving known donors,
collection. psychological evaluation and counseling is
strongly recommended for the donor and her
Oocyte recipients and donors should be partner, if applicable, as well as for the
offered counselling from someone who is recipient and her partner, if applicable. The
independent of the treatment unit potential impact of the relationship between
regarding the physical and psychological the donor and recipient should be explored.
implications of treatment for themselves The psychological assessment also should
and their genetic children, including any address the potential psychological risks and
potential children resulting from donated evaluate for evidence of coercion (financial or
oocytes. emotional). It is important to ascertain whether
the donor is well informed about the extent to
which information about her may be disclosed
and about any plans that may exist relating to
future contact
• All oocyte donors should be advised
explicitly of the risks and adverse effects
of ovarian stimulation and retrieval, with
such counseling documented by informed
consent in the patient's permanent
medical record.299
Oocyte donors are exposed to the risks of
controlled ovarian stimulation, oocyte retrieval,
and anesthesia.
The risk of OHSS is estimated to occur in 1%–
2% of donation cycles and may be further
reduced by the use of GnRH agonists for
triggering final oocyte maturation.
The risk of serious acute complications
associated with these procedures is small
(<0.5%).
As these are independent events, the
cumulative risk of multiple procedures should
be similarly low.
The preponderance of data does not
demonstrate a significant risk of future cancers
116
Intervention Evidence Report Findings NICE ASRM
in women undergoing stimulation and egg
retrieval.
While the data are limited, available evidence
does not suggest that oocyte donation is
associated with changes in the donor's ovarian
reserve.
Currently, there are no clearly documented
long-term risks associated with oocyte
donation and as such no definitive data upon
which to base absolute recommendations.
However, because of the possible health risks
outlined in the preceding discussion, it is
prudent to limit the number of stimulated
cycles for a given oocyte donor to 6.300
Abbreviations: ASRM=American Society for Reproductive Medicine; GnRH=gonadotropin-releasing hormone; hCG=human chorionic gonadotropin; ICSI=intra-cytoplasmic
sperm injection; KQ=Key Question; NICE=National Institute for Health and Care Excellence (UK); OHSS=ovarian hyperstimulation syndrome; SOE=strength of evidence
Table 41. Report findings and major guidelines/recommendations—all KQs: long-term outcomes of treatments
Intervention Evidence Report Findings NICE ASRM
Ovulation • Infertility itself is associated with an Inform women who are offered ovulation No specific recommendations
Induction Agents increased risk of some cancers, and the induction or ovarian stimulation that:
overall risk of cancer in women exposed to • No direct association has been found
oral ovulation agents, gonadotropins, and between these treatments and invasive
IVF/ICSI is not increased after adjustment cancer and
for infertility in general or specific causes, • No association has been found in the
although there are some associations with short- to medium-term between these
less common cancers (low SOE). treatments and adverse outcomes
• For children born after ART, ICSI may be (including cancer) in children born from
associated with an increased risk of ovulation induction and
neurodevelopmental disorders compared to • Information about long-term health
IVF, although evidence is inconsistent (low outcomes in women and children is still
SOE). awaited.
117
Intervention Evidence Report Findings NICE ASRM
IVF/ICSI • Infertility itself is associated with an Inform women that while the absolute risks of No specific recommendations
increased risk of some cancers, and the long-term adverse outcomes of IVF
overall risk of cancer in women exposed to treatment, with or without ICSI, are low, a
oral ovulation agents, gonadotropins, and small increased risk of borderline ovarian
IVF/ICSI is not increased after adjustment tumours cannot be excluded.
for infertility in general or specific causes,
although there are some associations with Inform people who are considering IVF
less common cancers (low SOE).In one treatment that the absolute risks of long-term
large study from the United Kingdom, the adverse outcomes in children born as result
risk of colorectal cancer was not increased of IVF are low.
among women undergoing ART compared
to the general population, but was
increased compared infertile women who
did not undergo ART (low SOE).
• For children born after ART, ICSI may be
associated with an increased risk of
neurodevelopmental disorders compared to
IVF, although evidence is inconsistent (low
SOE).
Abbreviations: ART=assisted reproductive technology; ASRM=American Society for Reproductive Medicine; ICSI=intra-cytoplasmic sperm injection; IVF=in vitro fertilization;
KQs=Key Questions; NICE=National Institute for Health and Care Excellence (UK)
118
In general, this review’s findings are consistent with the guidelines cited above—there is a
general consensus that the overall body of evidence for many aspects of infertility treatment
across all patient groups is limited. One consistent limitation is the relative paucity of studies
utilizing live birth per couple as the primary outcome. Where there are differences between our
findings and these guidelines, or between guidelines, they can be attributed to the following:
• Differences in study inclusion/exclusion criteria, particularly in study dates and outcomes
considered.
• Differences in grading individual study quality, which are then reflected in grading of the
overall strength of evidence.
• Differences in the approach to guideline development—the NICE guidance follows the
Grading of Recommendations Assessment, Development and Evaluation (GRADE)
system similar to our approach, while the ASRM uses a less structured approach.
• Differences in settings, which affect the manner in which cost considerations are weighed
in formulating recommendations. NICE guidance is designed for use within the UK
National Health Service, and cost-effectiveness is considered from a health system
perspective. Conversely, the ASRM guidelines are meant to be applied in the more
diverse U.S. setting, where coverage of infertility services is much more varied, and the
perspective of individual payers and patients, who are likely to bear a much higher
proportion of the cost of care, must be considered.
Applicability
Table 42 summarizes the applicability scores across KQs.
119
Across
KQ 1 KQ 2 KQ 3 KQ 4 KQ 5 KQ 6 Total
All KQs
N=56 N=7 N=50 N=8 N=23 N=5 N=151
Issues N=21
Specialty population 0 0 0 0 0 0 0 0
or level of care
aNumbers in cells represent the number of included studies that were identified as having potential issues related to the specific
item. Columns represent numbers for each Key Question and then for all included studies.
Two broad issues relate to the overall applicability of the available evidence to clinical
practice in the United States—one geographic and one temporal. Many of the randomized
controlled trials (RCTs) meeting our criteria were performed outside of the United States.
Leaving aside any issues related to differences in study oversight or reporting, the populations of
these studies may differ from U.S. infertility patients in two potentially important ways.
The first issue is that there may be clinically relevant differences between populations in
terms of non-clinical factors affecting outcomes. For example, live birth rates for African-
American women undergoing ART in the US are lower than for white women 292, which may
reflect issues related to socioeconomic status, insurance coverage, or other factors (such as well-
established racial differences in the risk of many adverse pregnancy outcomes). Differences in
access to infertility services between countries may lead to differences in the likelihood of
treatment success. Although the estimate of any relative difference between two interventions
derived from an unbiased RCT should in theory be independent of the probability of specific
outcomes, the more clinically relevant absolute difference may be substantially different (e.g.,
the risk of preterm birth in African-American compared to white women is consistently
elevated). To the extent that the probability of specific outcomes of interest may differ between
populations because of differences in genetic risk, exposures to other factors affecting risk, or
non-biological factors such as access to care, there may be substantial differences in estimates of
absolute risk differences. For relatively uncommon but important outcomes, these differences
might also affect precision of estimates—confidence intervals for any treatment effect will be
wider in populations where the outcome is less common.
In addition to the potential impact of race/ethnicity, there may be important differences in the
distribution of socioeconomic status between populations. Access to infertility diagnosis and
treatment varies across countries, and certainly within the United States.301 Differences in
socioeconomic status could affect applicability in several ways. Differences in access to care
may lead to differences in the spectrum of severity of “disease” for U.S. patients who given the
financial burden of treatment options they may wait longer to undergo evaluations. Although
summary statistics of baseline characteristics may allow some judgment of comparability, there
may be potentially important differences in the distribution that are obscured by the typical
reporting of means and standard deviations (particularly if the underlying characteristic is not
normally distributed), or by differences within a given stage. Socioeconomic status may also
potentially affect some important outcomes independently of any specific treatment—for
example, neurodevelopmental outcomes such as specific learning skills may be strongly
correlated with parental socioeconomic status.
The second issue is that changes in practice over time have a major impact on applicability,
particularly for long-term outcomes. The long lag time between exposure to infertility treatment
and the potential development of longer term outcomes such as cancer means that data available
today necessarily reflect women exposed to treatments at least 10 years in the past; even if the
specific exposure is similar, there may be differences between past and current practice in
potentially important attributes such as dosage, timing, patient selection criteria, use of
120
adjunctive treatments, etc. For example, evidence that immediate use of IVF leads to shorter time
to pregnancy than strategies where IVF is used only after a trial of agents such as clomiphene or
gonadotropins has led to a change in guidelines.297 which now suggest that the cumulative
exposure to gonadotropins during the course of treatment is likely to decrease compared to
earlier cohorts of women, reducing any long-term risks.
In addition, there may be cohort effects in terms of other exposures that may affect the
absolute risk of some outcomes (e.g., changes in the use of postmenopausal hormone
replacement therapy or ages of mammography screening affecting breast cancer risk), which in
turn would impact any additional absolute risk due to exposure to infertility treatments. Because
of this phenomenon, there is likely to always be some unresolvable uncertainty about long-term
outcomes for both parents undergoing current infertility treatments and their children.
121
uncertainty about long-term safety for patients making decisions now. To some extent, this is
true of most clinical decision making (for example, estimates of the impact of specific
interventions such as cancer screening on life expectancy are based on assumptions about
treatment effectiveness, competing risks, etc., that do not reflect potential future changes). This is
another area where more insight into relative preferences for both outcomes and timing of
outcomes (e.g., is there a potential increased risk in the risk of cancer in 20 or 30 years that
patients would be willing to trade off for an increased probability of a live birth within the next
year) would be helpful.
A potential first step toward addressing these uncertainties within the U.S. context would be
to create a formal structure for evaluating specific decisions relevant to infertility management,
similar to the GRADE approach used by NICE. Achieving consensus on at least the relative
importance of specific outcomes (potentially including costs), the ideal method for measuring
those outcomes, and acceptable trade-offs between harms and benefits (such as the number of
cases of OHSS per live birth, or number of preterm births attributable to multiple births per live
birth), would be useful for structuring future reviews, guidelines development, and, through
methods such as value-of-information analysis,310 prioritizing future research.
122
evidence through its effect on directness, our overall assessment of strength of evidence would
not likely have substantially changed.
Our review process was structured by KQ and, for each outcome, we required that outcomes
be reported for the specific patient population covered by the KQ, or, in the case of observational
studies, that the underlying diagnosis be included in multivariate analyses so that the reported
overall measure of association accounted for variability based on diagnosis. This approach led to
the exclusion of a number of studies of treatments used across multiple diagnoses, particularly
those involving ART. The extent to which specific outcomes might differ based on underlying
diagnosis is unclear. For long-term outcomes such as cancer in female patients, there is evidence
that certain infertility diagnoses increase risk independently of any treatment effects (for
example, PCOS and endometrial cancer, or endometriosis and ovarian cancer). Risks of some
adverse outcomes (e.g., OHSS or ectopic pregnancy) differ in different populations (e.g., women
with PCOS, tubal factor, or endometriosis infertility). However, there is less evidence that
treatment effectiveness varies by diagnosis, although even when relative differences are similar,
there still may be clinically important differences in the absolute probability of specific benefits
and harms. One alternative approach to structuring the review would be to focus diagnosis-
specific reviews only on treatments used prior to initiation of ART, and report comparative
effectiveness of treatments used in ART under the assumption that outcomes are similar across
patient populations. However, even if this approach expanded the evidence base, there still
would be residual uncertainty surrounding quantitative estimates of outcome likelihood in
specific patient populations.
Last, we did not include studies published in languages other than English, primarily due to
resource limitations. However, given differences in the way infertility evaluation and treatment is
financed in different countries, our judgment (discussed in more detail under Applicability) is
that there may be important differences, both measurable and unmeasurable, between couples
undergoing infertility in the United States compared with other countries. Inclusion of non-
English language studies would only make this problem worse.
Research Recommendations
In an era of constrained resources, future clinical research, especially comparative
effectiveness research—which helps resolve current uncertainties regarding clinical or policy
decisions—should receive priority. For most of the KQs, there are multiple areas of remaining
uncertainty based on the existing evidence. In part because of the diversity of causes and
treatment options, it is difficult to make specific recommendations for specific topics.
Before setting a specific agenda for future research in infertility, we believe a more general
approach to identifying priorities would be helpful. Achieving consensus on the relative priority
of specific outcomes, incorporating the perspective of multiple stakeholders (similar to the
approach used for developing a research agenda for comparative effectiveness research for
uterine fibroids.311,312 Ideally, these outcome priorities would be used for subsequent evidence
syntheses and guideline development.
As part of this consensus process, additional areas of discussion include:
• Formal consideration of the limits of acceptability for specific quantitative harms (e.g.,
preterm birth) and clinically meaningful differences in benefits (e.g., live birth).
• Formal discussion of the potential role of cost-effectiveness in decision making,
including issues of willingness-to-pay and appropriate choice of outcome. This is
particularly important because there are significant methodological challenges to the use
123
of “standard” measures such as quality-adjusted life expectancy in the setting of
infertility treatment.
• Issues related to study design, particularly from the patient stakeholder perspective. For
example, in settings where patients and/or clinicians may have strong preferences for
specific treatments, recruitment into RCTs may be difficult.313 In the uterine fibroid
consensus process, patient stakeholders strongly preferred observational designs to
randomized treatment assignment.311 Discussion of potential trade-offs between risk of
bias, efficiency, ability to measure all relevant potential confounders and effect modifiers,
appropriateness of alternative approaches such as Zelen randomization (where subjects
are randomized prior to consent, then allowed to either receive the assigned treatment or
choose the alternative314), and the likelihood that a specific study design would resolve a
specific area of uncertainty should all be included.
• Issues related to data reporting. Particularly for ART and other treatments which are used
for multiple indications, reporting of results separately by indication in both randomized
trials and large observational studies would be extremely useful. Although these
subgroup results may have insufficient power to detect clinically relevant differences
within the context of individual studies (particularly RCTs), their routine publication
would eventually allow synthesis of results using methods such as meta-analysis
(including individual-level meta-analysis.)
Part of this process could include value-of-information analysis, a formal method for
quantifying the impact of existing uncertainty on the likelihood of making the “wrong”
decision.315-317 Although the approach has classically been used in the framework of cost-
effectiveness, the basic methods for illustrating the impact of uncertainty on the probability of
making an optimal decision can also be applied using specific harms and benefits.
In addition to development of a specific consensus-driven approach to resolving uncertainty,
other specific recommendations apply across all areas of infertility treatment. Empiric
measurement of patient preferences using validated measures would have substantial impact. In
the context of infertility treatment, where approaches such as the standard gamble or time trade-
off (which require trading off risk of immediate death or life expectancy versus specific health
benefits) may be both conceptually difficult and counter-intuitive to patients, approaches such as
discrete choice experiments (DCE) may be preferable (DCE, or conjoint analysis, also has the
advantage of being able to explicitly incorporate costs to measure willingness-to-pay).318,319
The SART CORS and National ART Surveillance System (which includes data submitted
through SART CORS (the majority of clinics providing ART) as well as a smaller number of
non-SART participating clinics who report directly to CDC) databases are outstanding examples
of what a large-scale, population-based registry can achieve in terms of providing data on
treatment outcomes. However, the major limitation of the database in the past has been that data
are only published on a per-cycle, rather than per-couple, basis. Recently the database methods
have changed and now they are publicly reporting the cumulative success rate per patient.
Results, however, are still reported at the clinic level, so patients who receive care at more than
one clinic do not have the full range of outcomes captured, and there is no mechanism for
prospectively collecting long-term outcomes of patients or children. Facilitating reporting of
results so that outcomes are reported on a per-couple basis will substantially improve the ability
to generate estimates of the likely outcome of specific ART-related decisions.
124
Based on input from key informants and our Technical Expert Panel, we structured the
review based on infertility diagnosis, and required studies to report outcomes specifically by
diagnosis, or to adjust for diagnosis in multivariable analyses. As noted above, this led to
exclusion of a number of papers, particularly those related to ART methods. There is clear
evidence that the probability of some outcomes of interest, both short-term (e.g., OHSS) and
long-term (certain cancers) differs based on underlying diagnosis. Although this may not be the
case for all outcomes, we believe it would be helpful for future studies of interventions
performed in patients with different underlying diagnoses to report results separately by
diagnosis. Within an individual study powered on the basis of the total patients, estimates of
diagnosis-specific outcomes may be too imprecise to confidently rule out clinically relevant
differences—consistency of reporting would allow formal synthesis of estimates across studies.
We found very limited evidence on outcomes among sperm or oocyte donors. Oocyte donors,
who undergo controlled ovarian hyperstimulation and oocyte retrieval in the same manner as
patients undergoing IVF using their own eggs, have, in theory, at least the same risk of short-
term adverse events as patients. The frequency with which oocyte donors are used is increasing,
and evidence from the SART CORS database suggests that the risk of certain pregnancy
complications is lower when donor oocytes are used.37,38 If demand for donor oocytes continues
to increase, much more evidence on the specific short- and long-term outcomes of donation
(especially if a donor undergoes multiple cycles) is needed.
Conclusion
Recently there has been growing adaptation of more rigorous methods for evaluating
treatments for infertility, particularly regarding treatments for PCOS and approaches to timing of
interventions in patients undergoing ART. In addition, ongoing refinements to the SART CORS
database continue to make it a valuable resource, particularly for data on short-term outcomes.
However, given the diversity of infertility causes and treatments, there is considerable residual
uncertainty about the optimal treatment options for specific patients. Consensus on which
outcomes to report (such as encouraging reporting of live birth rates on a per couple basis as well
as per cycle, and, for studies of treatment such as ART, reporting of both overall and diagnosis-
specific outcomes) and which areas of uncertainty are most important to resolve (in order to
prioritize research) is needed to improve the ability of patients and clinicians to make decisions
about the most appropriate treatment.
125
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Acronyms and Abbreviations
AHRQ Agency for Healthcare Research and Quality
ART assisted reproductive technology
ASRM American Society for Reproductive Medicine
BMI body mass index
CDC Centers for Disease Control and Prevention
CI confidence interval
DCE discrete choice experiments
DHEA dehydroepiandrosterone
DOR diminished ovarian reserve
EHC Effective Health Care
EPC Evidence-based Practice Center
eSET elective single-embryo transfer
FASTT Fast Track and Standard Treatment
FORT-T Forty and Over Treatment Trial
FSH follicle-stimulating hormone
GnRH gonadotropin-releasing hormone
GRADE Grading of Recommendations Assessment, Development, and Evaluation
hCG human chorionic gonadotropin
hMG human menopausal gonadotropin
HR hazard ratio
ICTRP International Clinical Trials Registry Platform
ICSI intra-cytoplasmic sperm injection
IMSI intra-cytoplasmic morphologically selected sperm injection
IUI intrauterine insemination
IVF in vitro fertilization
IVM in vitro maturation
KIs Key Informants
KQ Key Question
NASS National ART Surveillance System
NICE National Institute for Health and Care Excellence (UK)
NIH National Institutes of Health
NR not reported
NS not statistically significant
OAT oligo-astheno-teratozoospermia
OHSS ovarian hyperstimulation syndrome
OR odds ratio
149
PCOS polycystic ovary syndrome
PGS preimplantation genetic screening
PICOTS populations, interventions, comparators, outcomes, timing, settings
PICSI physiological intra-cytoplasmic sperm injection
PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses
RCT randomized controlled trial
rFSH recombinant follicle-stimulating hormone
RR relative risk
SART Society for Assisted Reproductive Technology
SART CORS Society for Assisted Reproductive Technology Clinic Outcome Reporting
System
SD standard deviation
SIR standardized incidence ratio
SOE strength of evidence
SRC Scientific Resource Center
TEP Technical Expert Panel
TESE extracted testicular sperm
uFSH urinary follicle-stimulating hormone
UK United Kingdom
WHO World Health Organization
150
Appendix A. Exact Search Strings
A-1
Set Terms
#3 (randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR randomised[tiab]
OR randomization[tiab] OR randomisation[tiab] OR randomly[tiab] OR Clinical trial[pt] OR “clinical
trial”[tiab] OR “clinical trials”[tiab] OR "evaluation studies"[Publication Type] OR "evaluation studies as
topic"[MeSH Terms] OR "evaluation study"[tiab] OR evaluation studies[tiab] OR "intervention
studies"[MeSH Terms] OR "intervention study"[tiab] OR "intervention studies"[tiab] OR "case-control
studies"[MeSH Terms] OR "case-control"[tiab] OR "cohort studies"[MeSH Terms] OR cohort[tiab] OR
"longitudinal studies"[MeSH Terms] OR "longitudinal”[tiab] OR longitudinally[tiab] OR "prospective"[tiab]
OR prospectively[tiab] OR "retrospective studies"[MeSH Terms] OR "retrospective"[tiab] OR "follow
up"[tiab] OR "comparative study"[Publication Type] OR "comparative study"[tiab] OR systematic[subset]
OR "meta-analysis"[Publication Type] OR "meta-analysis as topic"[MeSH Terms] OR "meta-
analysis"[tiab] OR "meta-analyses"[tiab]) NOT (Editorial[ptyp] OR Letter[ptyp] OR Case Reports[ptyp] OR
Comment[ptyp]) NOT (animals[mh] NOT humans[mh])
#4 #1 AND #2 AND #3
#5 Dates: 2007/01/01 – present
#6 Limit: English
Set Terms
#1 'infertility'/exp OR 'anovulation'/exp OR “infertility”:ab,ti OR “infertile”:ab,ti OR “subfertility”:ab,ti OR
“subfertile”:ab,ti OR “sub-fertility”:ab,ti OR “sub-fertile”:ab,ti OR “anovulation”:ab,ti OR “aspermia”:ab,ti
OR “asthenozoospermia”:ab,ti OR “azoospermia”:ab,ti OR “oligospermia”:ab,ti OR “sertoli cell-only
syndrome”:ab,ti
A-2
Set Terms
#2 'infertility therapy'/exp OR 'diet therapy'/exp OR 'weight reduction'/exp OR 'exercise'/exp OR
'kinesiotherapy'/exp OR 'fertility promoting agent'/exp OR 'clomifene'/exp OR 'gonadorelin'/exp OR
'metformin'/exp OR 'hormone antagonist'/exp OR 'gonadotropin'/exp OR 'watchful waiting'/exp OR 'family
planning'/exp OR 'ovulation detection'/exp OR 'gynecologic surgery'/exp OR 'arginine'/exp OR 'aspartic
acid'/exp OR 'citrulline'/exp OR 'flavonoid'/exp OR 'corticosteroid'/exp OR 'low level laser therapy'/exp OR
'dexamethasone'/exp OR 'vasovasostomy'/exp OR 'urofollitropin'/exp OR 'electrocoagulation'/exp OR
'prenatal diagnosis'/exp OR 'artificial insemination'/exp OR 'ovulation prediction'/exp OR 'genetic
screening'/exp OR 'letrozole'/exp OR 'cetrorelix'/exp OR 'ganirelix'/exp OR 'recombinant follitropin'/exp
OR 'progesterone'/exp OR 'recombinant chorionic gonadotropin'/exp OR “reproductive techniques”:ab,ti
OR “reproductive technology”:ab,ti OR “reproductive technique”:ab,ti OR “reproductive
technologies”:ab,ti OR “assisted reproductive”:ab,ti OR “ivf”:ab,ti OR “in vitro”:ab,ti OR invitro:ab,ti OR
“sperm injection”:ab,ti OR “ICSI”:ab,ti OR “IUI”:ab,ti OR “intrauterine insemination”:ab,ti OR
“intrauterine implantation”:ab,ti OR “embryo transfer”:ab,ti OR “artificial insemination”:ab,ti OR “assisted
pregnancy”:ab,ti OR “assisted reproduction”:ab,ti OR “ovulation induction”:ab,ti OR “ovarian
stimulation”:ab,ti OR “ovarian hyperstimulation”:ab,ti OR “clomiphene”:ab,ti OR “serophene”:ab,ti OR
“clomiphene citrate”:ab,ti OR “letrozole”:ab,ti OR “metformin”:ab,ti OR “gonadotropins”:ab,ti OR
“gonadotropin releasing hormone”:ab,ti OR “hormone antagonists”:ab,ti OR “menotropins”:ab,ti OR
“menopur”:ab,ti OR “repronex”:ab,ti OR “goserelin”:ab,ti OR “Zoladex”:ab,ti OR “leuprolide”:ab,ti OR
“Lupron”:ab,ti OR “nafarelin”:ab,ti OR “Synarel”:ab,ti OR “cetrorelix”:ab,ti OR “Cetrotide”:ab,ti OR
“degarelix”:ab,ti OR “Firmagon”:ab,ti OR “ganirelix”:ab,ti OR “antagon”:ab,ti OR exercise:ab,ti OR
diet:ab,ti OR “weight loss”:ab,ti OR “natural family planning”:ab,ti OR “timed intercourse”:ab,ti OR
“Billings”:ab,ti OR “Creighton”:ab,ti OR “rhythm method”:ab,ti OR “standard days method”:ab,ti OR
“calendar method”:ab,ti OR “basal body temperature method”:ab,ti OR “hysteroscopy”:ab,ti OR
“hysteroscopic”:ab,ti OR “microhysteroscopy”:ab,ti OR “microhysteroscopic”:ab,ti OR “ovarian
drilling”:ab,ti OR “donor oocytes”:ab,ti OR “oocyte retrieval”:ab,ti OR “sperm donation”:ab,ti OR “sperm
donor”:ab,ti OR “semen donation”:ab,ti OR “semen donor”:ab,ti OR “sperm extraction”:ab,ti OR “sperm
retrieval”:ab,ti OR “sperm aspiration”:ab,ti OR “tesa”:ab,ti OR “micro tese”:ab,ti OR “mesa”:ab,ti OR
“pesa”:ab,ti OR “ejaculatory duct resection”:ab,ti OR “recombinant human follicle stimulating
hormone”:ab,ti OR “rhFSH”:ab,ti OR “rFSH”:ab,ti OR “hormone therapy”:ab,ti OR “laser
vaporization”:ab,ti OR “laser vaporisation”:ab,ti OR “dexamethasone”:ab,ti OR “vasectomy
reversal”:ab,ti OR “sterilization reversal”:ab,ti OR “superovulation”:ab,ti OR “follistim”:ab,ti OR “Gonal
F”:ab,ti OR “Gonal-F”:ab,ti OR “Bravelle”:ab,ti OR “crinone”:ab,ti OR “endometrim”:ab,ti OR
“prometrium”:ab,ti OR “fulguration”:ab,ti OR “endometriosis excision”:ab,ti OR “endometrioma
excision”:ab,ti OR “ovarian cystectomy”:ab,ti OR “tubal ligation reversal”:ab,ti OR “tubal
cannulation”:ab,ti OR “therapeutic donor insemination”:ab,ti OR “ovulation prediction”:ab,ti OR
“ovidrel”:ab,ti OR “assisted hatching”:ab,ti OR “preimplantation diagnosis”:ab,ti OR “preimplantation
genetic diagnosis”:ab,ti OR “preimplantation screening”:ab,ti OR “preimplantation genetic
screening”:ab,ti OR “preimplantation testing”:ab,ti OR “preimplantation genetic testing”:ab,ti
#3 'randomized controlled trial'/exp OR 'crossover procedure'/exp OR 'double blind procedure'/exp OR
'single blind procedure'/exp OR random*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR (cross NEAR/1
over*):ab,ti OR placebo*:ab,ti OR (doubl* NEAR/1 blind*):ab,ti OR (singl* NEAR/1 blind*):ab,ti OR
assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti OR 'clinical study'/exp OR “clinical trial”:ti,ab OR
“clinical trials”:ti,ab OR 'evaluation'/exp OR “evaluation study”:ab,ti OR “evaluation studies”:ab,ti OR
“intervention study”:ab,ti OR “intervention studies”:ab,ti OR “case control”:ab,ti OR 'cohort analysis'/exp
OR cohort:ab,ti OR longitudinal*:ab,ti OR prospective:ab,ti OR prospectively:ab,ti OR retrospective:ab,ti
OR 'follow up'/exp OR “follow up”:ab,ti OR 'comparative effectiveness'/exp OR 'comparative study'/exp
OR “comparative study”:ab,ti OR “comparative studies”:ab,ti OR 'evidence based medicine'/exp OR
“systematic review”:ab,ti OR “meta-analysis”:ab,ti OR “meta-analyses”:ab,ti NOT ('case report'/exp OR
'case study'/exp OR 'editorial'/exp OR 'letter'/exp OR 'note'/exp) AND [humans]/lim AND [embase]/lim
NOT [medline]/lim
#4 #1 AND #2 AND #3
#5 #4 AND [2007-2015]/py
#6 #5 AND [english]/lim
A-3
Cochrane Search Strategy (October 3, 2018)
Platform: Wiley
Database searched: Cochrane Database of Systematic Reviews
Set Terms
#1 MeSH descriptor Infertility expolode all trees OR MeSH descriptor Anovulation explode all trees OR
“infertility”:ab,ti,kw OR “infertile”:ab,ti,kw OR “subfertility”:ab,ti,kw OR “subfertile”:ab,ti,kw OR “sub-
fertility”:ab,ti,kw OR “sub-fertile”:ab,ti,kw OR “anovulation”:ab,ti,kw OR “aspermia”:ab,ti,kw OR
“asthenozoospermia”:ab,ti,kw OR “azoospermia”:ab,ti,kw OR “oligospermia”:ab,ti,kw OR “sertoli cell-only
syndrome”:ab,ti,kw
#2 Dates: 2007/01/01 – present
#3 Limit: Cochrane Reviews
Set Terms
Condition infertility OR infertile OR subfertility OR subfertile OR sub-fertility OR sub-fertile
Limits interventional studies
A-4
ClinicalTrials.gov – Narrow search for the Appendix H. Supplemental Project to Assess the
Transparency of Reporting for Trials Evaluating Treatment for Infertility (February 5,
2016)
Set Terms
Search terms infertility OR infertile OR subfertility OR subfertile OR sub-fertility OR sub-fertile
Condition terms polycystic ovary OR polycystic ovaries OR PCOS OR PCO
endometriosis OR endometrioma
unexplained OR ovarian reserve OR DOR OR ovarian response OR POR or responded OR
maternal age OR AMA OR reproductive age
tubal factor OR peritoneal factor OR pelvic adhesions OR pelvic adhesive OR hydrosalpinx
OR tubal obstruction OR tubal blockage
male factor OR male infertility OR Oligozoospermia OR Oligospermia OR Azoospermia OR
Asthenospermia OR Teratospermia
oocyte donor OR oocyte donation OR egg donation OR egg donor OR sperm donor OR
sperm donation OR donor eggs OR donor oocytes OR donor sperm OR oocyte recipient
Limits interventional studies
WHO: International Clinical Trials Registry Platform Search Portal (January 27, 2016)
KQs 1-6
Condition infertility OR infertile OR subfertility OR subfertile OR sub-fertility OR sub-fertile
Recruiting status All
A-5
Appendix B. Data Abstraction Elements
Study Characteristics
• Study Identifiers
o Study Name or Acronym
o NCT number or other trial registry identifier
o Last name of first author
• Additional Articles Used in This Abstraction
• Study Sites
o Single center, Multicenter, Unclear/Not reported
o Number of sites
• Geographic Location (Select all that apply)
o US, Canada, UK/Europe, Latin America, Middle East (including Israel), Asia,
Africa, Australia/NZ, Unclear/Not reported
• Study Design
o RCT
o Observational
• Funding Source (Select all that apply)
o Government, Industry, Non-government/non-industry, Unclear/Not reported
• Setting (Select all that apply)
o Subspecialty practice (infertility specialist, urologist, etc.); General gynecology
practice; Family practice/general internist/nurse practitioner/other non-
gynecologist primary care provider; Unclear/Not reported
• Study Definition of Infertility
o No pregnancy after 12 months of regular intercourse for women <35 years old or
6 months for women 35 and older; Other (specify); Not applicable; Not reported
• Study Enrollment/Study Completion
o N enrolled/included
o N completed
• Key Question Applicability (Select all that apply)
o KQ1, KQ2, KQ3, KQ4, KQ5, KQ6
• Baseline Characteristics – Record the following elements for Total Population, Women,
Men, Arm 1, Arm 2, Arm 3, and Arm 4 (as applicable)
o Number of Patients (N and %)
o Age in years
Mean
Median
Standard Deviation
Min
Max
25% IQR
75% IQR
Categorical
Other, specify
o Race/Ethnicity (N and %)
B-1
Hispanic or Latino
Black/African American
American Indian or Alaska Native
Asian
Native Hawaiian or Pacific Islander
White
Multiracial
Other (specify)
• Were there significant differences noted between groups in any baseline characteristic?
(Yes/No)
o If yes, please explain the differences
• Comments
Intervention Characteristics
• Is the comparison within a single intervention class or between classes?
• Intervention Descriptors
o Describe the intervention received by each patient group.
• Indicate components of the intervention (For each Arm)
o Oral Ovulation Induction with IUI
o Oral Ovulation Induction without IUI
o Surgical Management
o Gonadotropins with IUI
o Gonadotropins without IUI
o IVF
o ICSI
o No intervention / expectant management
• Indicate all intervention characteristics that are varied in this study
o IUI Details
IUI methods
Adjuvant treatments
o Oral Ovulation Induction Details
Medication type
Timing of medication
Adjuvant treatments
Dose
o Surgical Management Details
Female – Surgical approach (e.g., laparoscopic vs. open)
Female – Surgery vs. alternatives
Male – Surgical repair
o Gonadotropin Details
Ovarian stimulation (non-IVF) – medication type
Ovarian stimulation (non-IVF) – timing
o IVF Details
Pre-stimulation/adjuvant methods
Down regulation methods
Ovarian stimulation – medication type
B-2
Ovarian stimulation – monitoring
Ovarian stimulation – poor responders
Ovarian stimulation – natural cycle IVF
Ovulation triggering methods
Oocyte retrieval methods
Sperm retrieval methods
Laboratory phase methods
Embryo transfer – stage of development
Embryo transfer – # of embryos
Embryo transfer – transfer technique
Luteal phase support
Frozen embryos
Prevention of ovarian hyperstimulation syndrome
o ICSI Details
Sperm retrieval methods
Sperm injection methods
ICSI vs IVF
Other (specify)
• Comments
Outcomes
• Select the outcome reported on this form:
o Live Birth
Singleton (reported per cycle)
Singleton (reported per patient)
Multiple (reported per cycle)
Multiple (reported per patient)
Any (reported per cycle)
Any (reported per patient)
o Pregnancy Complications
Multiple births (and associated complications)
Ectopic pregnancies
Miscarriage
o Neonatal Outcomes
Death
Birthweight
Congenital anomalies
o Time to Pregnancy
Calendar time (months)
Number of cycles
o Costs
Patient
Health system
Societal
o Short-term Adverse Effects of Treatment
OHSS
B-3
Surgical complications
o Long-term Outcomes – Child
Neurodevelopment / other issues related to prematurity
Specific issues related to infertility treatment (epigenetic changes, sex
chromosomal abnormalities, etc.)
Cancer (all types)
o Long-term Outcomes – Maternal
Cancer
Subsequent fertility
o Donor Women Outcomes
Short-term – OHSS
Short-term – Surgical Complications
Short-term – Adverse effects of treatments
Long-term – Downstream fertility
Long-term – Cancer
Long-term – Age at menopause
Quality of Life
o Donor Men Outcomes
Quality of life
Short- and long-term health outcomes
• Any additional description / clarification of the outcome reported on this form
• Is this outcome form for a subgroup of interest? (Yes/No)
o What subpopulation is this outcome reported for on this form?
Age
Race/ethnicity
Obesity/BMI
Ovarian reserve
History of prior treatment
Primary vs. secondary infertility
Maternal parity
Insurance status
Diagnostic criteria / evaluation
Presence or absence of male factor infertility
Other female causes of infertility
Hypertension
Diabetes
Women without male partners (single women or lesbian couples)
Anatomic cause of tubal occlusion (e.g. prior sterilization vs. adhesions)
Cause of male infertility)
o Any additional description / clarification of subgroup reported on this form
• Total N Analyzed for this outcome
• Timepoint reported on this form
o Short-term
o Long-term
• Specify actual timing of the outcome (in months)
• For each arm:
B-4
o N Analyzed (enter UNK if unknown)
o Unadjusted Result
Number of patients with outcome
% of patients with outcome
Events/denominator
Odds ratio
Hazard ratio
Relative risk
Mean
Median
Mean within group change
Mean between group change
Other (specify)
o Unadjusted Result Variability
95% CI
IQR
Standard Error (SE)
Standard Deviation (SD)
Other % CI (specify)
Other (specify)
o Unadjusted Result, p-value between groups
o Unadjusted Result, indicate reference group (for comparison between groups)
o Adjusted Result
Number of patients with outcome
% of patients with outcome
Events/denominator
Odds ratio
Hazard ratio
Relative risk
Mean
Median
Mean within group change
Mean between group change
Other (specify)
o Adjusted Result Variability
95% CI
IQR
Standard Error (SE)
Standard Deviation (SD)
Other % CI (specify)
Other (specify)
o Adjusted Result, p-value between groups
o Adjusted Result, indicate reference group (for comparison between groups)
o If adjusted data is recorded, indicate the adjustments applied
• Comments
B-5
Quality
• Study Type (select one): RCT, Cohort, Case-control, Cross-sectional
• If RCT, select Yes/No/Unclear for each of the following questions:
o Selection Bias
Was the allocation sequence generated adequately (e.g., random number
table, computer-generated randomization)?
Was the allocation of treatment adequately concealed (e.g., pharmacy-
controlled randomization or use of sequentially numbered sealed
envelopes)?
Were participants analyzed within the groups they were originally
assigned to?
Does the design or analysis control account for important confounding and
modifying variables through matching, stratification, multivariable
analysis, or other approaches?
o Performance Bias
Did researchers rule out any impact from a concurrent intervention or an
unintended exposure that might bias results?
Did the study maintain fidelity to the intervention protocol?
o Attrition Bias
If attrition (overall or differential nonresponse, dropout, loss to follow-up,
or exclusion of participants) was a concern, were missing data handled
appropriately (e.g., intention-to-treat analysis and imputation)?
o Detection Bias
In prospective studies, was the length of follow-up different between the
groups, or in case-control studies, was the time period between the
intervention/exposure and outcome the same for cases and controls?
Were the outcome assessors blinded to the intervention or exposure status
of participants?
Were interventions/exposures assessed/defined using valid and reliable
measures, implemented consistently across all study participants?
Were outcomes assessed/defined using valid and reliable measures,
implemented consistently across all study participants?
o Reporting Bias
Were the potential outcomes prespecified by the researchers? Are all
prespecified outcomes reported?
• If Cohort, select Yes/No/Unclear for each of the following questions:
o Selection Bias
Were participants analyzed within the groups they were originally
assigned to?
Did the study apply inclusion/exclusion criteria uniformly to all
comparison groups?
Did the strategy for recruiting participants into the study differ across
study groups?
Does the design or analysis control account for important confounding and
modifying variables through matching, stratification, multivariable
analysis, or other approaches?
B-6
o Performance Bias
Did researchers rule out any impact from a concurrent intervention or an
unintended exposure that might bias results?
Did the study maintain fidelity to the intervention protocol?
o Attrition Bias
If attrition (overall or differential nonresponse, dropout, loss to follow-up,
or exclusion of participants) was a concern, were missing data handled
appropriately (e.g., intention-to-treat analysis and imputation)?
o Detection Bias
In prospective studies, was the length of follow-up different between the
groups, or in case-control studies, was the time period between the
intervention/exposure and outcome the same for cases and controls?
Were the outcome assessors blinded to the intervention or exposure status
of participants?
Were interventions/exposures assessed/defined using valid and reliable
measures, implemented consistently across all study participants?
Were outcomes assessed/defined using valid and reliable measures,
implemented consistently across all study participants?
Were confounding variables assessed using valid and reliable measures,
implemented consistently across all study participants?
o Reporting Bias
Were the potential outcomes prespecified by the researchers? Are all
prespecified outcomes reported?
• If Case-Control, select Yes/No/Unclear for each of the following questions:
o Selection Bias
Were cases and controls selected appropriately (e.g., appropriate
diagnostic criteria or definitions, equal application of exclusion criteria to
case and controls, sampling not influenced by exposure status)
Does the design or analysis control account for important confounding and
modifying variables through matching, stratification, multivariable
analysis, or other approaches?
o Performance Bias
Did researchers rule out any impact from a concurrent intervention or an
unintended exposure that might bias results?
Did the study maintain fidelity to the intervention protocol?
o Attrition Bias
If attrition (overall or differential nonresponse, dropout, loss to follow-up,
or exclusion of participants) was a concern, were missing data handled
appropriately (e.g., intention-to-treat analysis and imputation)?
o Detection Bias
In prospective studies, was the length of follow-up different between the
groups, or in case-control studies, was the time period between the
intervention/exposure and outcome the same for cases and controls?
Were the outcome assessors blinded to the intervention or exposure status
of participants?
B-7
Were interventions/exposures assessed/defined using valid and reliable
measures, implemented consistently across all study participants?
Were outcomes assessed/defined using valid and reliable measures,
implemented consistently across all study participants?
Were confounding variables assessed using valid and reliable measures,
implemented consistently across all study participants?
o Reporting Bias
Were the potential outcomes prespecified by the researchers? Are all
prespecified outcomes reported?
• If Cross-sectional, select Yes/No/Unclear for each of the following questions:
o Selection Bias
Did the study apply inclusion/exclusion criteria uniformly to all
comparison groups?
Does the design or analysis control account for important confounding and
modifying variables through matching, stratification, multivariable
analysis, or other approaches?
o Performance Bias
Did researchers rule out any impact from a concurrent intervention or an
unintended exposure that might bias results?
o Attrition Bias
If attrition (overall or differential nonresponse, dropout, loss to follow-up,
or exclusion of participants) was a concern, were missing data handled
appropriately (e.g., intention-to-treat analysis and imputation)?
o Detection Bias
Were the outcome assessors blinded to the intervention or exposure status
of participants?
Were interventions/exposures assessed/defined using valid and reliable
measures, implemented consistently across all study participants?
Were outcomes assessed/defined using valid and reliable measures,
implemented consistently across all study participants?
Were confounding variables assessed using valid and reliable measures,
implemented consistently across all study participants?
o Reporting Bias
Were the potential outcomes prespecified by the researchers? Are all
prespecified outcomes reported?
• Other Bias
o If applicable, describe any other concerns that may impact risk of bias
• Overall Study Rating (Good/Fair/Poor)
o Good (low risk of bias). These studies have the least bias, and the results are
considered valid. These studies adhere to the commonly held concepts of high
quality, including the following: a clear description of the population, setting,
approaches, and comparison groups; appropriate measurement of outcomes;
appropriate statistical and analytical methods and reporting; no reporting errors; a
low dropout rate; and clear reporting of dropouts.
o Fair. These studies are susceptible to some bias, but not enough to invalidate the
results. They do not meet all the criteria required for a rating of good quality
B-8
because they have some deficiencies, but no flaw is likely to cause major bias.
The study may be missing information, making it difficult to assess limitations
and potential problems.
o Poor (high risk of bias). These studies have significant flaws that may have
invalidated the results. They have serious errors in design, analysis, or reporting;
large amounts of missing information; or discrepancies in reporting.
o If the study is rated as “Fair” or “Poor,” provide rationale.
• Outcome-specific quality rating
o Do you think that any of the outcomes abstracted for this study should be assigned
a quality rating DIFFERENT from the overall study rating? (No/Yes)
If you think any of the abstracted outcomes should have a quality rating
different from the overall study, please provide the outcome(s), rating(s)
and rationale(s).
Applicability – Use the PICOS format to identify specific issues, if any, that may limit the
applicability of the study.
• Population (P)
o Study population demographics not representative of intended population
o Narrow or unrepresentative severity/stage/comorbidity
• Intervention (I)
o Treatment protocol not representative of current practice
o Change in standard of care
• Comparator (C)
o Comparator not representative of current practice
• Outcomes (O)
o Timing of outcome assessment
• Setting (S)
o Standards or access to care vary from US setting
o Specialty population or level of care
• Comments
B-9
Appendix C. List of Included Studies
Abdellah MS. Reproductive outcome after letrozole Amer SA, Smith J, Mahran A, et al. Double-blind
versus laparoscopic ovarian drilling for clomiphene- randomized controlled trial of letrozole versus
resistant polycystic ovary syndrome. Int J Gynaecol clomiphene citrate in subfertile women with
Obstet 2011;113(3):218-21. PMID: 21457973. polycystic ovarian syndrome. Hum Reprod
2017;32(8):1631-1638. PMID: 28854590.
Aboulghar M, Saber W, Amin Y, et al. Prospective,
randomized study comparing highly purified urinary An Y, Sun Z, Zhang Y, et al. The use of berberine for
follicle-stimulating hormone (FSH) and recombinant women with polycystic ovary syndrome undergoing
FSH for in vitro fertilization/intracytoplasmic sperm IVF treatment. Clin Endocrinol (Oxf)
injection in patients with polycystic ovary syndrome. 2014;80(3):425-31. PMID: 23869585.
Fertil Steril 2010;94(6):2332-4. PMID: 20188364.
Badawy A, Allam A and Abulatta M. Extending
Abu Hashim H, El Rakhawy M and Abd Elaal I. clomiphene treatment in clomiphene-resistant women
Randomized comparison of superovulation with with PCOS: a randomized controlled trial. Reprod
letrozole vs. clomiphene citrate in an IUI program for Biomed Online 2008;16(6):825-9. PMID: 18549692.
women with recently surgically treated minimal to
Badawy A, Shokeir T, Allam AF, et al. Pregnancy
mild endometriosis. Acta Obstet Gynecol Scand
outcome after ovulation induction with aromatase
2012;91(3):338-45. PMID: 22181973.
inhibitors or clomiphene citrate in unexplained
Abu Hashim H, Foda O, Ghayaty E, et al. infertility. Acta Obstet Gynecol Scand
Laparoscopic ovarian diathermy after clomiphene 2009;88(2):187-91. PMID: 19089782.
failure in polycystic ovary syndrome: is it
Bagis T, Haydardedeoglu B, Kilicdag EB, et al.
worthwhile? A randomized controlled trial. Arch
Single versus double intrauterine insemination in
Gynecol Obstet 2011;284(5):1303-9. PMID:
multi-follicular ovarian hyperstimulation cycles: a
21755338.
randomized trial. Hum Reprod 2010;25(7):1684-90.
Abu Hashim H, Mashaly AM and Badawy A. PMID: 20457669.
Letrozole versus laparoscopic ovarian diathermy for
Balaban B, Yakin K, Alatas C, et al. Clinical
ovulation induction in clomiphene-resistant women
outcome of intracytoplasmic injection of spermatozoa
with polycystic ovary syndrome: a randomized
morphologically selected under high magnification: a
controlled trial. Arch Gynecol Obstet
prospective randomized study. Reprod Biomed
2010;282(5):567-71. PMID: 20577748.
Online 2011;22(5):472-6. PMID: 21324747.
Abu Hashim H, Ombar O and Abd Elaal I.
Barad DH, Darmon SK, Kushnir VA, et al. Impact of
Intrauterine insemination versus timed intercourse
preimplantation genetic screening on donor oocyte-
with clomiphene citrate in polycystic ovary
recipient cycles in the United States. Am J Obstet
syndrome: a randomized controlled trial. Acta Obstet
Gynecol 2017;217(5):576.e1-576.e8. PMID:
Gynecol Scand 2011;90(4):344-50. PMID:
28735705.
21306326.
Belva F, Bonduelle M, Schiettecatte J, et al. Salivary
Aghahosseini M, Aleyasin A, Chegini V, et al. Low-
testosterone concentrations in pubertal ICSI boys
dose hCG as trigger day and 35 hr later have different
compared with spontaneously conceived boys. Hum
ovarian hyperstimulation syndrome occurrence in
Reprod 2011;26(2):438-41. PMID: 21138905.
females undergoing In vitro fertilization: An RCT.
Int J Reprod Biomed (Yazd) 2017;15(11):735-740. Bhattacharya S, Harrild K, Mollison J, et al.
PMID: 29404536. Clomifene citrate or unstimulated intrauterine
insemination compared with expectant management
Amer SA, Li TC, Metwally M, et al. Randomized
for unexplained infertility: pragmatic randomised
controlled trial comparing laparoscopic ovarian
controlled trial. Bmj 2008;337:a716. PMID:
diathermy with clomiphene citrate as a first-line
18687718.
method of ovulation induction in women with
polycystic ovary syndrome. Hum Reprod
2009;24(1):219-25. PMID: 18794162.
C-1
Bodri D, Guillen JJ, Galindo A, et al. Triggering with Choi MH, Lee SH, Kim HO, et al. Comparison of
human chorionic gonadotropin or a gonadotropin- assisted reproductive technology outcomes in
releasing hormone agonist in gonadotropin-releasing infertile women with polycystic ovary syndrome: In
hormone antagonist-treated oocyte donor cycles: vitro maturation, GnRH agonist, and GnRH
findings of a large retrospective cohort study. Fertil antagonist cycles. Clin Exp Reprod Med
Steril 2009;91(2):365-71. PMID: 18367175. 2012;39(4):166-71. PMID: 23346527.
Bodri D, Guillen JJ, Polo A, et al. Complications Crawford S, Boulet SL, Kawwass JF, et al.
related to ovarian stimulation and oocyte retrieval in Cryopreserved oocyte versus fresh oocyte assisted
4052 oocyte donor cycles. Reprod Biomed Online reproductive technology cycles, United States, 2013.
2008;17(2):237-43. PMID: 18681998. Fertil Steril 2017;107(1):110-118. PMID: 27842997.
Boulet SL, Kirby RS, Reefhuis J, et al. Assisted Custers IM, van Rumste MM, van der Steeg JW, et
reproductive technology and birth defects among al. Long-term outcome in couples with unexplained
liveborn infants in Florida, Massachusetts, and subfertility and an intermediate prognosis initially
Michigan, 2000-2010. JAMA Pediatrics 2016;170(6). randomized between expectant management and
immediate treatment. Hum Reprod 2012;27(2):444-
Boulet SL, Mehta A, Kissin DM, et al. Trends in use
50. PMID: 22114108.
of and reproductive outcomes associated with
intracytoplasmic sperm injection. Jama Danhof NA, van Wely M, Repping S, et al. Follicle
2015;313(3):255-63. PMID: 25602996. stimulating hormone versus clomiphene citrate in
intrauterine insemination for unexplained subfertility:
Brinton LA, Moghissi KS, Scoccia B, et al. Effects of
a randomized controlled trial. Hum Reprod
fertility drugs on cancers other than breast and
2018;33(10):1866-1874. PMID: 30137325.
gynecologic malignancies. Fertil Steril 2015. PMID:
26232746. de Wilde MA, Lamain-de Ruiter M, Veltman-
Verhulst SM, et al. Increased rates of complications
Brinton LA, Scoccia B, Moghissi KS, et al. Long-
in singleton pregnancies of women previously
term relationship of ovulation-stimulating drugs to
diagnosed with polycystic ovary syndrome
breast cancer risk. Cancer Epidemiol Biomarkers
predominantly in the hyperandrogenic phenotype.
Prev 2014;23(4):584-93. PMID: 24700523.
Fertil Steril 2017;108(2):333-340. PMID: 28778282.
Brinton LA, Westhoff CL, Scoccia B, et al. Fertility
Demirol A and Gurgan T. Comparison of different
drugs and endometrial cancer risk: results from an
gonadotrophin preparations in intrauterine
extended follow-up of a large infertility cohort. Hum
insemination cycles for the treatment of unexplained
Reprod 2013;28(10):2813-21. PMID: 23943795.
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intracytoplasmic sperm injection (ICSI) using normogonadotropic anovulation and clomifene
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C-9
Appendix D. List of Excluded Studies
All studies listed below were reviewed in their full-text version and excluded for the reasons
cited. Reasons for exclusion signify only the usefulness of the articles for this study and are not
intended as criticisms of the articles.
Abdalmageed OS, Farghaly TA, Ismail AM, et al. Impact of metformin on in vitro fertilization
outcomes in overweight and obese polycystic ovary syndrome women: A prospective cohort
Study. Fertility and Sterility 2016;106:e262.
Acharya KS, Keyhan S, Acharya CR, et al. Noncompliance with ASRM/SART guidelines
continues to be high in 2013 compared to 2011-2012 in donor oocyte cycles with blastocyst
transfer. Fertility and Sterility 2016;106:e323-e324.
AkçelIk Y, Çögendez E, D.B SI, et al. Comparison of clomiphene citrate and low dose
recombinant fsh for induction of ovulation in infertilewomen with polycystic ovary syndrome.
Turkiye Klinikleri Jinekoloji Obstetrik 2015;25(1):19-26.
Alasmari N. Randomized trial on the effect of prewashing the insemination catheter on the
pregnancy outcome. Fertility and Sterility 2016;106:e346.
Barad DH, Darmon S, Kushnir VA, et al. Prevalence and effect of preimplantation genetic
screening (PGS) on oocyte donation cycles in the United States: 2005 to 2013. Fertility and
Sterility 2016;106:e330.
Beliveau LN, Vilos A, Tekpetey F, et al. Impact of the number of lead follicles at time of trigger
on intrauterine insemination(IUI) pregnancy outcomes. Fertility and Sterility 2016;106:e182.
Çakar E, Taşan HA, Kumru P, et al. Is adding estradiol (E2) to progesterone for luteal phase
support in antagonist protocol stimulated in vitro fertilisation (IVF) cycles beneficial?. Journal of
the Turkish German Gynecology Association 2016;17:S212-S213.
Chan S, Greenstein Y, Dasig D, et al. Perinatal outcomes after fresh versus frozen embryo
transfers. Fertility and Sterility 2016;106:e324-e325.
Chang TA, Jacoby ES, Su YT, et al. Utilization of intracytoplasmic sperm injection (ICSI)
among fertility centers in the United States 2000-2013. Fertility and Sterility 2016;106:e312.
D-1
Chiu Y, Gaskins AJ, Williams P, et al. Fruit and vegetable intake and their pesticide residues in
relation to outcomes of assisted reproductive technology. Fertility and Sterility 2016;106:e27.
Christopoulos G, Vlismas A, Carby A, et al. GnRH agonist trigger with intensive luteal phase
support versus human chorionic gonadotropin trigger in high responders: An observational study
reporting pregnancy outcomes and incidence of ovarian hyperstimulation syndrome. BJOG: An
International Journal of Obstetrics and Gynaecology 2016;123:69.
Collins G, Thakore S and Goldfarb JM. IVF outcomes in young patients with unexplained
infertility: An analysis of 273,779 cycles from the 2011-2013 society for assisted reproductive
technology clinic outcome reporting system registry. Fertility and Sterility 2016;106:e171.
Du T, Chen Q, Lyu Q, et al. Is blastocyst transfer associated with a significantly lower incidence
of ectopic pregnancy? A strictly controlled retrospect cohort study based on more than 30,000
frozen embryo transfer cycles. Fertility and Sterility 2016;106:e105.
Elnashar I, Farghaly TA, Abdalbadie AS, et al. Low cost ovarian stimulation protocolis
associated with lower pregnancy rate in normal responders in comparison to long protocol.
Fertility and Sterility 2016;106:e194-e195.
Hatirnaz S, Hatirnaz ES, Tan SL, et al. Outcomes of single vs double embryo transfer in in-vitro
maturation cycles done in women with polycystic ovary syndrome. Fertility and Sterility
2016;106:e258-e259.
Hebisha SA, Aboelazm BA, Adel HM, et al. Impact of the oxytocin receptor antagonist
(atosiban) administered shortly before embryo transfer on pregnancy outcome after
intracytoplasmic sperm injection (ICSI). Fertility and Sterility 2016;106:e88-e89.
Herrero B, Lusignan M, Son W, et al. Effects of sperm quality on the success of intracytoplasmic
sperm injection (ICSI) with testicular sperm in couples with recurrent ICSI failure with
ejaculated sperm. Fertility and Sterility 2016;106:e226.
Hilton JL, Liu K, Laskin CA, et al. Effect of endometrial biopsy on in vitro fertilization clinical
pregnancy rates-a randomized multicentre study. Fertility and Sterility 2016;106:e344.
Hipp H, Crawford S, Kawwass JF, et al. In-vitro fertilization cycles among women ages 40 and
older. Fertility and Sterility 2016;106:e182-e183.
Humphries LA, Dodge LE, Kennedy EB, et al. Is younger better? donor age less than 25 does
not predict more favorable outcomes after in vitro fertilization. Fertility and Sterility
2016;106:e176.
D-2
Hurley EG and De Franco E. Influence of paternal age on perinatal outcomes in pregnancies
achieved with assisted reproductive technologies. Fertility and Sterility 2016;106:e166.
Hurst BS, Merriam K, Marshburn P, et al. Optimal timing for intrauterine insemination (IUI)
after administering HCG in ovulation induction IUI cycles. Fertility and Sterility 2016;106:e305-
e306.
Irani M, Gunnala V, Goldschlag DE, et al. Does trigger of final oocyte maturation with pure
GNRH-agonist have adverse effects on pregnancy outcomes of donor/recipient cycles?. Fertility
and Sterility 2016;106:e189.
Irani M, Setton R, Gunnala V, et al. Dose of human chorionic gonadotropin to trigger final
oocyte maturation. Fertility and Sterility 2016;106:e262-e263.
Janitz A, Peck JD and Craig LB. Ethnic and racial differences in the utilization of infertility
services: National survey of family growth(NSFG). Fertility and Sterility 2016;106:e112-e113.
Jayakumaran J, Silva C, Gangrade BK, et al. Ethnic differences in ovarian reserve and assisted
reproductive technology outcomes. Fertility and Sterility 2016;106:e368-e369.
Kawwass JF, Crawford S, Hipp H, et al. Embryo donation: National trends and outcomes, 2000-
2013. Fertility and Sterility 2016;106:e320.
Kawwass JF, Kulkarni A, Hipp H, et al. Assisted reproductive technology cycle and obstetric
outcomes among underweight and overweight women. Fertility and Sterility 2016;106:e21.
Keyhan S, Acharya KS, Acharya CR, et al. Are we transferring too many embryos in the most
favorable group of fresh autologous IVF cycles: A 2013 update. Fertility and Sterility
2016;106:e52-e53.
Khudhari A, Hemmings R, Phillips S, et al. How does art singletons differ from naturally
conceived (NC) singletons; comparison of perinatal data of 872 art to 19317 (NC) singleton
babies. Fertility and Sterility 2016;106:e176-e177.
Kjotrod S, Carlsen SM, Rasmussen PE, et al. Metformin treatment before and during IVF or
ICSI in PCOS women with BMI < 28 kg/m?: A prospective, randomized, double-blind,
multicenter study. Human Reproduction 2010;25:i286-i287.
Knudtson J, Failor C, Gelfond J, et al. The effect of assisted hatching on frozen embryo transfer
live birth rate and clinic trends. Fertility and Sterility 2016;106:e141.
D-3
Konar H, Sharma S, Chakraborty P, et al. Endometrial vascularity and increasing endometrial
thickness can predict live birth: A retrospective analysis of 1575 Fet cycles. Fertility and Sterility
2016;106:e215-e216.
Kort J, Riestenberg C, Shah M, et al. Effect of BMI on live birth rates in euploid frozen single
embryo transfers. Fertility and Sterility 2016;106:e265.
Kriplani A, Goel T, Mahey R, et al. Pregnancy rate after endometrial scratching in couples with
unexplained infertility in ovulation induction & IUI cycles-a randomised controlled trial. Fertility
and Sterility 2016;106:e329.
Kushnir VA, Barad DH, Darmon S, et al. Contribution of third party reproduction to the birth
cohort following art in the U.S.A. Fertility and Sterility 2016;106:e108.
Kushnir VA, Shapiro A, Barad DH, et al. Effect of race and ethnicity on fertility rates and
utilization of art in the USA. Fertility and Sterility 2016;106:e367-e368.
Li X, Huang R, Fang C, et al. Live birth rate after fresh or frozen-thawed embryo transfers in
relation to maternal age: A retrospective cochort study of 13426 cycles. Fertility and Sterility
2016;106:e142.
Londra LC and Mumford SL. Birth weight in singletons after autologous fresh transfer according
to the ovarian hyperstimulation protocol used. Fertility and Sterility 2016;106:e170.
Luke B, Brown MB and Spector LG. Risk of maternal morbidity in IVF and non-IVF births: A
US study in five states. Fertility and Sterility 2016;106:e104.
Luke B, Brown MB and Wantman E. Physician prediction model for live birth and multiple
births after assisted reproductive technology. Fertility and Sterility 2016;106:e177-e178.
Mancuso A, Boulet S, Duran EH, et al. Live birth and multiple birth rates in women under age
38 by elective single embryo transfer (ESET) versus double embryo transfer (DET) in United
States IVF clinics. Fertility and Sterility 2016;106:e104.
Marín D and Labarta E. Potential use of kisspeptin in ovarian stimulation treatments. Medicina
Reproductiva y Embriologia Clinica 2015;2(3):115-125.
Maslow BL, Griffin D, Benadiva CA, et al. Prospective double-blind randomized placebo
controlled clinical trial comparing pregnancy rates after co-administration of low dose hcg at the
time of GNRH-agonist trigger or 35 hours later, for the prevention of ohss. Fertility and Sterility
2016;106:e58.
McClennen EL, Richter KS, Moon K, et al. The impact of race and ethnicity on assisted
reproductive technology (ART) outcomes: A retrospective cohort study. Fertility and Sterility
2016;106:e99-e100.
D-4
Mizuta S, Yamaguchi K, Nishiyama R, et al. Intracytoplasmic sperm injection (ICSI) outcome
using immotile spermatozoa even after pentoxifyllin administration in non-obstructive
azoospermic patients. Fertility and Sterility 2016;106:e225.
Orvieto R. Mono-ovulation in women with polycystic ovary syndrome: The role of step-up,
ultra-low-dose gonadotrophin regimen. Reproductive BioMedicine Online 2016.
Pandian Z, Akande VA, Bhattacharya S, et al. Effectiveness of surgical treatment for tubal
infertility. Cochrane Database of Systematic Reviews 2007.
Parneix I, Arvis P, Paillet S, et al. Long term outcome of couples undertaking their first IVF/ICSI
attempt: A french study. Value in Health 2016;19(7):A406.
Plowden TC, Mumford SL, Kim K, et al. Racial disparities in elective single embryo transfer
(ESET) utilization in the United States: A national study. Fertility and Sterility 2016;106:e366.
Puntoni M, Costa M, Paleari L, et al. Ovarian stimulation for infertility treatment and cancer
risk: An Italian cohort study. Journal of Clinical Oncology 2016;34.
Putra DE, Birowo P, Widyahening IS, et al. The role of varicocele repair in nonobstructive
azoospermic men: A systematic review. BJU International 2016;117:5-6.
Salem W, Ho J, Bendikson KA, et al. Modified natural cycle IVF increases value and access to
care over traditional IVF for good prognosis patients: A decision analytic model and cost
effectiveness analysis. Fertility and Sterility 2016;106:e74-e75.
Shapiro A, Barad DH, Darmon S, et al. Effect of race and ethnicity on live birth rates in third-
party art cycles in the U.S. Fertility and Sterility 2016;106:e367.
Shapiro A, Barad DH, Darmon S, et al. Racial and ethnic disparities in the use of third party art
in the U.S. Fertility and Sterility 2016;106:e108-e109.
Singh S, Singh S, Raman AK, et al. Efficacy of cabergoline in the prevention of ovarian
hyperstimulation syndrome: A randomized, double-blind and placebo-controlled trial.
International Journal of Infertility and Fetal Medicine 2017;8(2):54-60.
D-5
Siristatidis CS, Bhattacharya S and Maheshwari A. In vitro maturation in sub fertile patients with
polycystic ovarian syndrome undergoing assisted reproduction. Cochrane Database of
Systematic Reviews 2007.
Smith MB, Hodes-Wertz B, Grifo J, et al. Are the biggest losing? analyzing the effect of body
mass index (BMI) on pregnancy rates in euploid frozen embyro transfer (FET) cycles. Fertility
and Sterility 2016;106:e102.
Souza PV, Simões AC, Zanini FE, et al. Infertility treatment of women over age 35 in Brazil: An
economic evaluation of recombinant Vs. urinary gonadotropins. Value in Health
2016;19(7):A402.
Stevens JM, Schneiderman A, Maruniak K, et al. Euploid blastocyst transfer is aviable clinical
option for male factor infertility with high sperm DNA fragmentation. Fertility and Sterility
2016;106:e233.
Styer AK, Mumford SL, Plowden T, et al. Racial disparities in live birth pregnancy outcomes
following fresh elective single embryo transfer: A sart-cors analysis 2004-2013. Fertility and
Sterility 2016;106:e98.
Vega MG, Zaghi S, Jindal SK, et al. Impact of ovarian aging on perinatal outcomes: Analysis of
135,252 art cycles reported to sart. Fertility and Sterility 2016;106:e167.
Wang AY. Increased rate of adverse neonatal outcomes among twins following assisted
reproductive technology. Fertility and Sterility 2016;106:e174.
D-6
Emergui Zrihen Y, García Escribano PA, Escamilla Galindo EP, et al. Birth defects in women
undergoing assisted reproduction techniques. Clinica e Investigacion en Ginecologia y
Obstetricia 2017;44(4):152-156.
Gabriele V, Benabu JC, Ohl J, et al. Does fertility treatment increase the risk of breast cancer?
Current knowledge and meta-analysis. Gynecologie Obstetrique Fertilite et Senologie
2017;45(5):299-308.
Liu Z, Tang HL and Zhai SD. Aromatase inhibitors in ovulation induction for women with
unexplained infertility: A systematic review. Chinese Journal of Evidence-Based Medicine
2011;11(11):1327-1334.
Zhao J, Gou J, Li DH, et al. Salpingectomy before IVF-ET for hydrosalpinx among Chinese
Women: A systematic review. Chinese Journal of Evidence-Based Medicine 2011;11(9):1039-
1046.
Not original data from an RCT, SR/MA, or observational study with comparator:
Aarts JW, Huppelschoten AG, van Empel IW, et al. How patient-centred care relates to patients'
quality of life and distress: a study in 427 women experiencing infertility. Hum Reprod
2012;27(2):488-95. PMID: 22108249.
Abbott J. Surgical treatment is an excellent option for women with endometriosis and infertility.
Australian and New Zealand Journal of Obstetrics and Gynaecology 2017;57(6):679-681.
Abd El Fattah EA. Uterine Cavity Abnormalities in Patients with Endometriosis in Alexandria:
A Diagnostic Test Accuracy Study. Obstet Gynecol Int 2017;2017:5869028. PMID: 28638413.
Abu Hashim H, Al-Inany H, De Vos M, et al. Three decades after Gjonnaess's laparoscopic
ovarian drilling for treatment of PCOS; what do we know? An evidence-based approach. Arch
Gynecol Obstet 2013;288(2):409-22. PMID: 23543241.
Akanji Tijani H and Bhattacharya S. The role of intrauterine insemination in male infertility.
Hum Fertil (Camb) 2010;13(4):226-32. PMID: 21117932.
Al-Malki AH, Alrabeeah K, Mondou E, et al. Testicular sperm aspiration (TESA) for infertile
couples with severe or complete asthenozoospermia. Andrology 2017;5(2):226-231. PMID:
28187532.
D-7
Almog B, Shalom-Paz E, Dufort D, et al. Promoting implantation by local injury to the
endometrium. Fertil Steril 2010;94(6):2026-9. PMID: 20171615.
Alom M, Ziegelmann M, Savage J, et al. Office-based andrology and male infertility procedures-
a cost-effective alternative. Transl Androl Urol 2017;6(4):761-772. PMID: 28904909.
Al-Ruthia YS, Al-Mandeel H, AlSanawi H, et al. The effect of metformin use on pregnancy rates
among polycystic ovary syndrome patients undergoing in vitro fertilization: A retrospective-
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Al-Shaikh SFMH, Al-Mukhatar EJ, Al-Zubaidy AA, et al. Use of clomiphene or letrozole for
treating women with polycystic ovary syndrome related subfertility in Hilla city. Middle East
Fertility Society Journal 2017;22(2):105-110
Al-Taee H and Edan BJ. Estimation of Day-Specific Probabilities of Conception during Natural
Cycle in Women from Babylon. Int J Fertil Steril 2018;11(4):314-317. PMID: 29043709.
Anderson BJ, Haimovici F, Ginsburg ES, et al. In vitro fertilization and acupuncture: clinical
efficacy and mechanistic basis. Altern Ther Health Med 2007;13(3):38-48. PMID: 17515023.
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endometriosis. Gynecol Endocrinol 2015:1-4. PMID: 26172932.
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maturation of medium-sized follicles in patients undergoing superovulation for IVF/ICSI.
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Banker M, Sorathiya D and Shah S. Vitamin D Deficiency Does Not Influence Reproductive
Outcomes of IVF-ICSI: A Study of Oocyte Donors and Recipients. J Hum Reprod Sci
2017;10(2):79-85. PMID: 28904494.
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D-8
Basatemur E and Sutcliffe A. Follow-up of children born after ART. Placenta 2008;29(Suppl
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of baseline follicle-stimulating hormone and antral follicle count is not associated with
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PMID: 29202975.
Casamonti E, Vinci S, Serra E, et al. Short-term FSH treatment and sperm maturation: a
prospective study in idiopathic infertile men. Andrology 2017;5(3):414-422. PMID: 28296254.
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born after in vitro fertilization. Fertil Steril 2008;90(5):1662-73. PMID: 18163998.
Chambers GM, Paul RC, Harris K, et al. Assisted reproductive technology in Australia and New
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D-9
Checa MA, Teixeira DM, González-Comadran M, et al. Luteal phase support for women trying
to conceive by intrauterine insemination or sexual intercourse. Cochrane Database of Systematic
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Connell MT, Patounakis G, Healy MW, et al. Is the effect of premature elevated progesterone
augmented by human chorionic gonadotropin versus gonadotropin-releasing hormone agonist
trigger?. Fertil Steril 2016;106(3):584-589.e1. PMID: 27178228.
Danhof NA, van Wely M, Koks CAM, et al. The SUPER study: protocol for a randomised
controlled trial comparing follicle-stimulating hormone and clomiphene citrate for ovarian
stimulation in intrauterine insemination. BMJ Open 2017;7(5):e015680. PMID: 28550023.
Davies MJ, Rumbold AR and Moore VM. Assisted reproductive technologies: a hierarchy of
risks for conception, pregnancy outcomes and treatment decisions. J Dev Orig Health Dis
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Diergaarde B and Kurta ML. Use of fertility drugs and risk of ovarian cancer. Curr Opin Obstet
Gynecol 2014;26(3):125-9. PMID: 24752005.
El Hachem H, Antaki R, Sylvestre C, et al. Clomiphene Citrate versus Letrozole for Ovarian
Stimulation in Therapeutic Donor Sperm Insemination. Gynecol Obstet Invest 2016. PMID:
27852078.
Elizur SE and Tulandi T. Drugs in infertility and fetal safety. Fertil Steril 2008;89(6):1595-602.
PMID: 18519067.
Elkhateeb RR, Mahran AE and Kamel HH. Long-term use of clomiphene citrate in induction of
ovulation in PCO patients with clomiphene citrate resistance. Journal of Gynecology Obstetrics
and Human Reproduction 2017;46(7):575-577.
Farhi J and Fisch B. Risk of major congenital malformations associated with infertility and its
treatment by extent of iatrogenic intervention. Pediatr Endocrinol Rev 2007;4(4):352-7. PMID:
17643083.
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23714436.
D-10
G.A R, Cheemakurthi R, Prathigudupu K, et al. Role of Lh polymorphisms and r-hLh
supplementation in GnRh agonist treated ART cycles: A cross sectional study. European Journal
of Obstetrics Gynecology and Reproductive Biology 2018;222:119-125.
Groen H, Tonch N, Simons AH, et al. Modified natural cycle versus controlled ovarian
hyperstimulation IVF: a cost-effectiveness evaluation of three simulated treatment scenarios.
Hum Reprod 2013;28(12):3236-46. PMID: 24166594.
Guo H, Wang Y, Chen Q, et al. Effect of Natural Cycle Endometrial Preparation for Frozen-
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Appendix E. Characteristics of Included Studies
Table E-1 shows the study characteristics for the included studies. For full study citations, please refer to the report’s main
reference list.
E-1
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Aghahosseini, 2017178 RCT 100 Low dose hCG 35 hours after GnRH agonist OHSS Good
Middle East 80 Vs
KQ 1 PCOS Low dose hCG simultaneously with GnRH
agonist
in PCOS patients undergoing IVF
Amer, 2009165 RCT 72 Laparoscopic ovarian diathermy for Live birth Fair
UK/Europe 65 endometriosis, periadnexal adhesions, and Miscarriage
KQ 1 PCOS adhesions Multiple births
vs. OHSS
CC 50 - 150 mg/d on cycle days 2–6 Surgical complications
Amer, 2017179 RCT 159 Clomiphene Live birth Good
UK/Europe 149 vs.
KQ 1 PCOS Letrozole
An, 2014146 RCT 150 Berberine was administered at a dosage of 3 x Live birth Fair
Asia 109 500 mg daily for greater than or equal to 12
KQ 1 PCOS weeks before controlled ovarian stimulation.
vs.
Metformin was administered at a dosage of 3 x
500 mg daily for greater than or equal to 12
weeks before controlled ovarian stimulation.
vs.
Placebo was administered as one tablet three
times daily for greater than or equal to 12 weeks
before controlled ovarian stimulation.
Badawy, 2008193 RCT 318 Clomiphene citrate Miscarriage Fair
Middle East 318 vs.
KQ 1 PCOS Gonadotrophin
Badawy, 2009222 RCT 996 Letrozole 5 mg/d for 5 days Miscarriage Fair
Middle East 996 vs. Ectopic pregnancy
KQ 3 Unknown Anastrozole 1 mg/d for 5 days Birthweight
vs. Neonatal death
CC 100 mg/d for 5 days.
vs.
Spontaneous pregnancy
E-2
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Bagis, 2010221 RCT 228 IUI performed 36 hours after hCG injection Live birth (male) Fair
UK/Europe 226 vs. Miscarriage
KQ 3, 5 Unknown, Male IUI performed 18 hours after hCG injection
followed by second IUI performed 40 hours after
hCG
Balaban, 2011258 RCT 77 cycles ICSI Live birth Fair
Middle East 77 cycles vs.
KQ 5 Male IMSI
Barad, 2017280 Observational 33,756 PGD Live birth Fair
US 21,008 vs. Miscarriage
Across All KQs All Non-PGD in donor oocyte cycles
Belva, 2011259 Observational 120 Male offspring born to parents who underwent Birthweight Poor
UK/Europe 120 ICSI
KQ 5 Male vs.
Male offspring born to parents who conceived
spontaneously
Bhattacharya, 2008135 RCT 580 Expectant Management Live birth (diagnostic Good
UK/Europe 576 vs. criteria)
SUIT Unknown CC 50 mg days 2-6 of cycle Time to pregnancy
vs. Ectopic pregnancy
KQ 3 IUI Miscarriage
Patient costs
Bodri, 2008268 Observational 2,653 Ovarian stimulation with GnRH agonist OHSS Fair
UK/Europe 2,653 vs.
KQ 6 Donor Ovarian stimulation with GnRH antagonist/hCG
vs.
Ovarian stimulation with GnRH antagonist/GnRH
agonist
vs.
A control group was created by taking into
account all IVF cycles reaching oocyte retrieval
performed during the same period
Bodri, 2009269 Observational 1,171 Triggering with recombinant hCG OHSS Fair
UK/Europe 1,171 vs.
KQ 6 Donor Triggering with GnRH
E-3
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Boulet, 2015254 Observational 499,135 cycles Conventional IVF Live birth Fair
US NA vs. Miscarriage
NASS Male ICSI Multiple pregnancies
Birthweight
KQ 5
Boulet, 2016277 Observational 4,618,076 No intervention (spontaneous conception) Congenital anomalies Good
US 4,618,076 vs.
Across All KQs All Conventional IVF
vs.
IVF + ICSI
Brinton, 2015136 Observational 9,892 Control Maternal cancer Good
US 9,892 vs.
Across All KQs All CC
vs.
Companions: Gonadotropins
Brinton, 2013138;
Brinton, 2014137;
Trabert, 201326
Butts, 2014122 Observational 38,926 ICSI Live birth (ovarian reserve) Fair
US 38,926 vs.
NASS Unknown IVF
vs.
KQ 3 Assisted hatching
vs.
No assisted hatching
Chang, 2016276 Observational 106,902 cycles PGD Live birth Good
US 106,902 cycles vs. Multiple births
Across All KQs All PGD done for concern of aneuploidy Miscarriage
vs. Birthweight
PGD done for other concern outside of
genetics/aneuploidy
vs.
No PGD
E-4
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Chen, 2016174 RCT 1,508 Frozen embryo transfer Live birth Good
Asia 1,508 vs. Miscarriage
KQ 1 PCOS Fresh embryo transfer Multiple births
Birthweight
OHSS
Ectopic pregnancy
Neonatal death
Congenital anomalies
Choi, 2012147 RCT 61 IVM/IVF with FSH and hCG priming protocol Live birth Poor
Asia 61 vs.
KQ 1 PCOS GnRH agonist long protocol group
vs.
GnRH antagonist multi-dose flexible protocol
Crawford, 2017281 Observational 105,517 cycles Autologous cycles: Live birth Good
US 105,517 cycles Cryopreserved oocyte Miscarriage
Across All KQs All vs.
Fresh oocyte
Donor cycles:
Cryopreserved oocyte
vs.
Fresh oocyte
Custers, 2012139 RCT 253 Expectant Management for 6 months, followed Miscarriage Good
UK/Europe 253 by six cycles of IUI-COS, followed by 3 cycles of Ectopic pregnancy
KQ 3 Unknown IVF Multiple birth
vs. Health system costs
IUI with controlled ovarian stimulation (IUI-COS)
for 6 months followed by 3 cycles of IVF
Danhof, 2018244 RCT 738 CC with IUI Live birth Fair
UK/Europe 738 vs. Ectopic pregnancy
KQ 3 Unknown FSH with IUI Miscarriage
Multiple births
OHSS
E-5
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
de Wilde, 2017180 Observational 3,077 Natural conception Birthweight Good
UK/Europe 3,077 vs. Neonatal death
KQ 1 PCOS Ovulation Induction
vs.
IVF-ICSI
Demirol, 2007230 RCT 241 IUI following : Miscarriage Good
UK/Europe 241 OHSS
KQ 3 Unknown Group I (Gonal-F, Serono, Turkey), 81 Follitropin
alpha
vs.
Group II (Metrodin-HP, Serono), highly-purified
uFSH
vs.
Group III (Pergonal, Serono), hMG
Dhalwani, 2016236 Observational 3,896,242 births ART Birthweight Good
US 3,896,242 births vs.
KQ 3 and 5 Unknown, Male No intervention (spontaneous conception)
Diamond, 2015233 RCT 900 Gonadotropin Live birth Good
US 746 vs. Multiple births
KQ 3 Unknown Clomiphene Miscarriage
vs. Ectopic pregnancy
Letrozole Birthweight
Neonatal death
Congenital anomalies
Dreyer, 2016250 RCT 85 Hysteroscopic proximal occlusion by intratubal Live birth Good
UK/Europe 85 (for ITT device placement (Essure Device) Miscarriage
KQ 4 analysis) vs. Ectopic pregnancy
Tubal Laparoscopic salpingectomy Time to pregnancy
Ebrahimi, 2010229 RCT 200 CC 50 mg BID on cycle days 3-7 followed by 75 Live birth Good
Middle East 179 IU hMG on cycle days 7-9 and adjusted Multiple births
KQ 3 Unknown thereafter. IUI performed following triggered
ovulation.
E-6
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Einarsson, 2017181 RCT 962 Lifestyle change (weight reduction) +IVF Live birth Good
UK/Europe 317 vs. Multiple births
KQ 1 PCOS IVF only Miscarriage
Ectopic pregnancy
OHSS
Elsedeek, 2014194 RCT 220 cycles Clomiphene citrate 200mg/day over 5 days Live birth Fair
Middle East 220 cycles vs.
KQ 1 PCOS Clomiphene citrate 100mg/day over 10 days
Emekci, 2017182 RCT 196 4g Myo-Inositol (MYO) plus 400 mg folic acid Miscarriage Good
Middle East 196 vs.
KQ 1 PCOS Recombinant FSH and no MYO administration
Erdem, 2009225 RCT 214 Gonadotropin IUI followed by luteal support with Live birth Fair
UK/Europe 214 crinone once a day beginning 2 days after
KQ 3 Unknown insemination until pregnancy testing.
vs.
Gonadotropin IUI without luteal support.
Erdem, 2015208 RCT 219 rFSH followed by triggered ovulation Live birth Good
Middle East 174 vs.
KQ 3, 5 Unknown, Male CC 100 mg/d on days 3-7 of cycle followed by
triggered ovulation
Farquhar, 2018238 RCT 473 IUI Live birth Good
Australia/N.Z. 201 vs. Multiple births
KQ 3 Unknown Expectant Management Miscarriage
Ectopic pregnancy
Ge, 2008167 RCT 62 IVF using oocytes cultured in media containing Live birth Good
Asia 62 hCG, rFSH, and rhCG Miscarriage
KQ 1 PCOS vs.
hCG-free media with rFSH for the first 10 hours,
then were transferred to the same medium the
group above
vs.
hCG-free media only
E-7
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Ghahiri, 2016170 RCT 101 Clomiphene 100 mg Multiple births Fair
Middle East 101 vs. Miscarriage
KQ 1 PCOS Letrozole 5 mg Ectopic pregnancy
OHSS
Time to pregnancy
Ghanem, 2013145 RCT 174 CC 100 mg/d for 5 days plus uFSH 37.5 IU/d. Live birth Good
Middle East 159 vs.
KQ 1 PCOS uFSH 37.5 IU/d only
Gibreel, 2013228 RCT 105 Endometrial scratching using a pipelle biopsy Miscarriage Good
Africa 90 catheter with biopsies obtained Multiple births
KQ 3 Unknown vs.
Sham procedure using uterine sound only
Goldman, 2014210 RCT 154 CC 100 mg/d for 5 days followed by IUI, Live birth Good
US 115 maximum 2 cycles after which patients Time to pregnancy
FORT-T Unknown proceeded to IVF up to 6 cycles Ectopic pregnancy
vs. Miscarriage
KQ 3 rFSH followed by IUI. maximum 2 cycles after Multiple births
which patients proceeded to IVF up to 6 cycles Birthweight
vs. Neonatal death
Immediate IVF up to 6 cycles. OHSS
Gregoriou, 2008226 RCT 50 rFSH beginning on cycle day 3 Live birth (prior treatments) Good
UK/Europe 50 vs.
KQ 3 Unknown Letrozole 5 mg/d on cycle day 3
Grimstad, 2016251 Observational 7,145 IVF Live birth Good
US 7,145 vs. Multiple births
KQ 4 Tubal ICSI Miscarriage
Birthweight
Hajizadeh, 2017261 RCT 419 Structured aerobic exercise for 12 weeks Live birth Good
Middle East 386 vs.
KQ 5 Male No exercise
Harira, 2018246 RCT 172 CC + estradiol Ectopic pregnancy Good
Middle East 172 vs. Miscarriage
KQ 3 Unknown Letrozole OHSS
Hassan, 2017183 RCT 182 Letrozole Miscarriage Good
Middle East 140 vs. Adverse events
KQ 1 PCOS FSH Cost effectiveness
E-8
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Hershko-Klement, Observational 2,406 ICSI Congenital anomalies Fair
2016260 Middle East 1,981 vs.
Male IMSI
KQ 5
Homburg, 2012152 RCT 302 CC 50 – 150 mg/d for 5 days, triggered ovulation Live birth Good
UK/Europe & 255 vs. Ectopic pregnancy
KQ 1 Latin America PCOS rhFSH, triggered ovulation Miscarriage
Multiple births
Hosseini, 2010158 RCT NR Long-term desensitization protocol using GnRH Miscarriage Fair
Middle East 112 agonist buserelin 500 mcg SQ. Gonal F started OHSS
KQ 1 PCOS on day 3, replaced by hMG after 7th day of
stimulation.
vs.
Gonal F for ovarian stimulation. Cetrorelix
(GnRH antagonist) 0.35 mg/d injected SQ for 3
days. hMG prescribed after 7th day of
stimulation. Fertilization via ICSI. 3 good quality
embryos transferred 3 days later.
Hossein-Rashidi, RCT 104 Clomiphene Live birth Fair
2016176 Middle East 96 vs. Miscarriage
PCOS Recombinant human fSH OHSS
KQ 1
Ibrahim, 2017189 RCT 80 Laparoscopic Ovarian Drilling Miscarriage Fair
Middle East 80 vs.
KQ 1 PCOS Letrozole
Jacob, 2016177 RCT 153 Placebo Live birth Good
UK/Europe 153 vs. OHSS
KQ 1 PCOS Metformin
Jahromi, 2017243 RCT 80 Melatonin along with ART Miscarriage Fair
Middle East 66 vs.
KQ 3 Unknown Placebo with ART
E-9
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Johnson, 2010160 RCT 171 Placebo, BMI>32. Standard care. Live birth (obesity/BMI) Good
Australia/NZ 168 vs. Miscarriage (obesity/BMI)
KQ 1 PCOS Metformin, BMI>32. Multiple births (obesity/BMI)
vs.
CC, BMI<=32
vs.
Metformin, BMI<=32
vs.
Both, BMI<=32
Kansal Kalra, 2008223 RCT 18 Follicular arm - rFSH on cycle day 1 or 2 of the Live birth (ovarian reserve) Fair
US 18 oocyte retrieval cycle.
KQ 3 Unknown vs.
Luteal phase arm - rFSH 9 days after
spontaneous LH surge of the menstrual cycle
preceding oocyte retrieval
Kar, 2015173 RCT 105 Clomiphene Live birth Fair
Asia 80 vs. Miscarriage
KQ 1 PCOS Metformin
vs.
Clomiphene + Metformin
Kettner, 2016184 Observational 565,116 No fertility treatment Type 1 diabetes in children Good
UK/Europe pregnancies vs.
KQ 1, 4, 5 565,116 IUI or OI
pregnancies vs.
PCOS, Tubal,
IVF or ICSI
Male
Keyhan, 2018185 Observational 90,401 cycles ICSI Birthweight Fair
US 90,401 cycles vs. (male infertility, age)
KQ 1, 2, 3, 4, 5 PCOS, IVF
Endometriosis,
Unknown, Tubal,
Male
Khosravi, 2015232 RCT 180 Oral dydrogesterone Miscarriage Fair
Middle East 150 vs.
KQ 3 Unknown Vaginal cyclogest
E-10
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Kim, 2011219 RCT 110 IVF/ICSI with testosterone gel pretreatment (12.5 Live birth (ovarian reserve) Fair
Asia 110 mg/d) starting on cycle day 6 of the estrogen- Miscarriage (ovarian
KQ 3 Unknown progesterone pretreatment. reserve)
vs.
21 days pretreatment with estradiol valerate and
norethindrone
Kim, 2012150 RCT 211 Ovarian stimulation using 50 - 150 IU of rhFSH Live birth Fair
Asia 208 after establishing ovarian and uterine quiescence
KQ 1 PCOS using vaginal ultrasound. GnRH antagonist,
cetrorelix (Cetrotide) 0.125 mg/d was
administered in the morning of stimulation day 1
and 2. When the mean diameter of lead follicle
reached 13 mm, cetrorelix at a dose of 0.25 mg/d
was started again and continued daily up to the
day of rhCG (injection).
vs.
GnRH agonist, triptorelin (Decapeptyl) at a dose
of 0.1 mg/d was initiated from day 18 of oral
contraceptive pretreatment cycle. All patients
had withdrawal bleeding after discontinuation of
oral contraceptive. When pituitary desensitization
was achieved, ovarian stimulation was started
and the dose of triptorelin was reduced to 0.05
mg daily and continues up to day of rhCG
administration. Ovarian stimulation was
performed in the same manner.
Kissin, 2015272 Observational 42,383 Singleton ICSI Neurodevelopment-autism Good
US 42,383 vs. diagnosis (male)
Across All KQs All Singleton Conventional IVF (without ICSI)
vs.
Multiples ICSI
vs.
Multiples Conventional IVF (without ICSI)
E-11
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Kjotrod, 2011155 RCT 150 Metformin prior to, and during, AFT Live birth Fair
UK/Europe 149 vs. (ITT
KQ 1 PCOS Placebo prior to, and during, AFT results)
Poor
(non-
ITT
results)
Knudtson, 2017282 Observational 151,533 first- Frozen embryo without assisted hatching Live birth Good
US cycle vs. (race, age, etiology of
Across All KQs 151,533 first- Frozen embryo with assisted hatching infertility)
cycle
All
Kramer, 2009271 Observational 287 All respondents were egg donors Adverse effects of Poor
US 155 vs. treatments
KQ 6 Donor No comparator OHSS
Downstream fertility
Kurzawa, 2008164 RCT 74 All patients received oral contraceptives pills x 1 Live birth Fair
UK/Europe 70 month before starting controlled ovarian Miscarriage
KQ 1 PCOS hyperstimulation. None of the patients used oral Multiple births
antidiabetic medications (biguanides or OHSS
thiazolidinediones).
E-12
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Kuzmin, 2014248 RCT 468 Laparoscopy, salpingolysis, salpingostomy, and Ectopic pregnancy Poor
Asia 468 transcervical falloposcopy tubal dilatation (TFTD)
KQ 4 Tubal Factor vs.
Laparoscopy, salpingolysis, salpingostomy
La Sala, 2015253 RCT 242 IMSI Live birth Poor
UK/Europe 242 vs. Miscarriage
KQ 5 Male ICSI Multiple births
Birthweight
Congenital anomalies
Leandri, 2013256 RCT 255 Conventional ICSI Live birth Fair
UK/Europe 255 vs.
KQ 5 Male IMSI
Legro, 2007128 RCT 626 CC initial dose of 50 mg of CC on days 3–7 of Live birth (obesity/BMI) Good
US 450 each treatment cycle on-study Ectopic pregnancy
PPCOS PCOS vs. Miscarriage
Metformin 500 mg/d, increased to 2000 mg/d Multiple births
KQ 1 Vs. Congenital anomalies
Combination of CC and metformin
Companion:
Rausch, 2009129
Legro, 2014131 RCT 750 CC 50 mg daily starting on cycle day 3 for 5 days Live birth Good
US 750 vs. Time to pregnancy
PPCOS 2 PCOS Letrozole 2.5 mg daily starting on cycle day 3 for Ectopic pregnancy
5 days Miscarriage
KQ 1 Birthweight
Maximum treatment duration up to 5 cycles Congenital anomalies
Companion: Neonatal death
Polotsky, 2015132
Legro, 2015172 RCT 149 Continuous OCP Live birth Good
US 132 vs. Birthweight
KQ 1 PCOS Lifestyle changes (caloric restriction, physical Ectopic pregnancy
activity, weight loss medication) Miscarriage
vs.
Combined OCP and lifestyle changes
E-13
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Levi Dunietz, 2017239 Observational 4,292,779 Non-ART Birthweight Good
US 4,292,779 vs.
KQ 3 Unknown Fresh embryos
vs.
Cryopreserved embryos
Litzky, 2018284 Observational 1,008,393 Fresh embryo transfers Birthweight Fair
US 180,184 vs.
Across All KQs All Frozen/thawed embryo transfers
E-14
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Magnusson, 2018287 Observational 44,369 Number of oocytes retrieved: Birthweight Good
UK/Europe 27,359 <10 Congenital anomalies
Across All KQs All vs. Neonatal death
10-14
vs.
15-19
vs.
>20
Maher, 2018245 RCT 714 Unstimulated IUI: Live birth Fair
Middle East 714 Cervical mucus removal (internal and external) Miscarriage
KQ 3 Unknown vs. Multiple births
No mucus removal
Majumdar, 2013214 RCT 156 ICSI with sperm selection based on visual Live birth Fair
Asia 151 assessment Miscarriage
KQ 3 Unknown vs.
ICSI with sperm selection based on ability to bind
hyaluronic acid
Malchau, 2017186 Observational 19,884 IUI Live birth Good
UK/Europe 19,884 vs. Time to birth
KQ 1, 2, 3, 5 PCOS, ART
Endometriosis, vs.
Unknown, Male
No treatment
Mancuso, 2016283 Observational 914 Elective single embryo transfer (eSET) Live birth Good
US 914 vs. Multiple birth
Across All KQs All Double embryo transfer (DET)
Maxwell, 2008270 Observational 587 Oocyte Donors Adverse effects of Fair
US 587 vs. treatments
KQ 6 Donor No comparison OHSS
Mehrabian, 2012148 RCT 104 hMG followed by triggered ovulation OHSS Fair
Middle East Unclear vs.
KQ 1 PCOS Laparoscopic ovarian drilling
E-15
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Mohammadi, 2018190 RCT 219 Methylprednisolone OHSS Fair
Middle East 184 vs.
KQ 1 PCOS No treatment
Morad, 2012227 RCT 234 Hydrotubation performed one day before IUI Ectopic pregnancy Good
Africa 231 using: Miscarriage
KQ 3 Unknown Multiple births
20 mL of saline OHSS
vs.
20 mL of 0.1 mg Lidocaine/mL saline mixed with
19.9 cc of saline)
Morin-Papunen, RCT 320 Metformin (500 mg) was initiated at a dose of Live birth (obesity/BMI) Good
2012151 UK/Europe 259 one tablet once a day for the first week and Time to pregnancy
PCOS increased thereafter by one tablet daily in weekly
KQ 1 steps up to three tablets (one + two daily) in
nonobese women and to four tablets (two + two
daily) in obese women and was continued up to
a maximum of 9 months.
E-16
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Muller, 2017205 RCT 144 Dienogest Live birth Fair
UK/Europe 144 vs.
KQ 2 Endometriosis a-GnRH
vs.
No treatment
Mutsaerts, 2016119 RCT 577 6-month lifestyle intervention preceding Live birth Good
UK/Europe 564 treatment for infertility Ectopic pregnancy
KQ 1, 3, 5 PCOS, vs. Miscarriage
Unknown, Male Prompt treatment for infertility Time to pregnancy
Companions:
Neonatal death
van Oers, 2016120
van Oers, 2018121 Birthweight
Congenital anomalies
Nada, 2016234 RCT 622 Pts given human menopausal gonadotropins OHSS Good
Africa 595 form Day 2 to reach DF of 18-22 mm. Then Cost
KQ 3 Unknown Ganirelix acetate 0.25 mg SQ started from Day 6
or 7. Then IUI of 0.5 mL.
vs.
Clomiphene citrate 100 mg from Day 2 to 6.
Monitor ovulation., the hCG given at dose of
10,000 IU IM. Then, IUI of 0.5 mL
Nahuis, 2011141 RCT 168 Laparoscopic electrocautery (LEC). LEC Live birth Fair
UK/Europe 168 followed by clomiphene citrate and then rFSH if Patient costs
KQ 1 PCOS still anovulatory.
vs.
Companion: rFSH
Nahuis, 2012142
Nandi, 2017240 RCT 207 Three cycles of IUI+COH Live birth Fair
UK/Europe 207 vs. Multiple birth
KQ 3 Unknown One cycle of IVF Miscarriage
Ectopic pregnancy
OHSS
Nangia, 2011124 Observational 77,432 cycles IVF w/o ICSI, Male only Live birth Fair
US 77,432 cycles vs. Birthweight
NASS Male ICSI, Male only
KQ 5
E-17
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Oyesanya 2009224 RCT 353 Provided that 6 or more oocytes were retrieved Ectopic pregnancy Fair
UK/Europe 351 from the prospective donor, half were given to (diagnostic criteria)
KQ 3 Unknown the recipient and half were given to another
recipient.
vs.
Recipients received all retrieved oocytes from
their altruistic donor.
Palomba, 2010163 RCT 50 Laparoscopic ovarian diathermy. No drugs to Live birth Good
UK/Europe 47 trigger ovulation. Surgical complications
KQ 1 PCOS vs.
CC for up to 6 cycles plus metformin 500 mg
tapered upwards. No drugs to trigger ovulation.
Palombia, 2011153 RCT 120 Metformin 500 mg three times daily Live birth Good
UK/Europe 120 vs. OHSS
KQ 1 PCOS Placebo
E-18
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Pourali, 2017241 RCT 180 5 mg/day letrozole on day 3-7 of menstrual cycle Miscarriage Fair
Middle East 170 vs. OHSS
KQ 3 Unknown 100 mg/day clomiphene on day 3-7 of menstrual Cost
cycle
E-19
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Rahman, 2017264 RCT 66 Recombinant FSH (r-FSH) supplemented by r- Miscarriage Fair
UK/Europe 61 LH in the late follicular phase starting the same
KQ 5 Male day of GnRH-antagonist (GnRH-ant)
administration
vs.
r-FSH alone
E-20
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Rubio, 2013217 RCT 274 IVF with day-5 blastocyst transfer (no PGD) Live birth Fair
UK/Europe 274 vs. Miscarriage
KQ 3 Unknown IVF, embryo biopsy and FISH for 9 Multiple births
chromosomes on day 3, transfer on day 5 (RIF and AMA)
Schendelaar, 2011273 Observational NR Children who were not born to sub-fertile parents Neurodevelopmental issues Fair
UK/Europe 310 vs.
Across All KQs Children born to sub-fertile parents who received
IVF (either COH-IVF or MNC-IVF)
Seckin, 2014209 RCT 149 Luteal phase support with 90 mg/d vaginal 8% Live birth Good
UK/Europe 139 progesterone gel starting on the day of IUI until
KQ 3 Unknown pregnancy testing
vs.
No drug for luteal phase support
Selman, 2016237 RCT 85 Clomiphene citrate and corifollitropin alfa for the Live birth Good
UK/Europe 76 first 7 days of stimulation followed by Miscarriage
KQ 3 Unknown recombinant follicle stimulating hormone (rFSH)
in a gonadotropin-releasing hormone antagonist
protocol
vs.
Clomiphene citrate and a daily injection of rFSH
in a gonadotropin-releasing hormone antagonist
protocol
Shi, 2018262 RCT 2,157 Fresh-embryo transfer Live birth Good
Asia 1,782 vs. Multiple births
KQ 4 and 5 Tubal, Male Embryo cryopreservation followed by frozen- Miscarriage
embryo transfer OHSS
Birthweight
Sismanoglu, 2009267 RCT 50 Donor triggering with hCG OHSS Fair
UK/Europe 44 vs.
KQ 6 Donor Donor triggering with GnRH agonist
E-21
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Spaan, 2015125 Observational 25,108 Received at least one IVF cycle with ovarian Maternal cancer Good
UK/Europe 25,108 stimulation
OMEGA All vs.
Subfertile women with other treatments including
Across All KQs tubal surgery, IUI, or hormonal treatment OR
withdrew from IVF waiting list
Companions:
Spaan, 2016127;
van Leeuwen, 2011126
Stadtmauer, 2011159 RCT 98 rFSH Follistim starting on cycle day 3 until the Live birth Fair
US NR appropriate follicle size was reached. Miscarriage
KQ 1 PCOS vs. Multiple births
Ganirelix 0.25 mg SQ/d added to rFSH in a
flexible protocol when the leading follicle
diameter reached R13 mm.
vs.
rFSH and Ganirelix
Stewart, 2013203 Observational 22,045 Women receiving infertility treatment but not IVF Maternal cancer (parity) Fair
Australia/NZ 21,646 vs.
KQ 2 Endometriosis Women receiving IVF
Tartagni, 2015207 RCT 109 IVF with DHEA 75 mg/d for 8 weeks pre- Live birth Fair
UK/Europe 109 treatment Miscarriage
KQ 3 Unknown vs.
Placebo
Tehraninejad, 2010161 RCT 95 Pretreatment with OCP for 21 days, controlled OHSS Fair
Middle East 90 ovarian stim started on day 2-3. Cetrolix
KQ 1 PCOS (antagonist) 0.25 mg SQ started when follicles
12-14 mm.
vs.
Control group. Pretreatment with OCP for 21
days, along with buserelin (agonist) 500 mcg/d
SQ. Buserelin then reduced to 250 mcg/d.
Controlled ovarian stimulation with hMG.
E-22
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Toftager, 2016275 RCT 1,099 GnRH antagonist protocol: Women with regular Live birth Good
UK/Europe 1,023 cycles (≤35 days) received daily injections with OHSS
Across All KQs All recombinant human FSH. Controlled ovarian
stimulation (COS) was initiated on cycle day 2 or
3 and continued until the day of ovulation
induction. A fixed dose of rFSH was used for the
first 6 days, either 150 or 225 IU according to
age ≤36 years or age >36 years. After 6 days of
stimulation the rFSH doses were adjusted
according to ovarian response evaluated using
transvaginal ultrasonography. A daily GnRH
antagonist (Ganirelix) dose of 0.25 mg was used
starting on stimulation day 6 and was
administered until the day of ovulation induction.
vs.
GnRH agonist protocol: Women with regular
cycles (≤35 days) started daily nasal
administration of 200 mg three times daily of
GnRH agonist (Nafarelin—Synarelaw; Pfizer,
Ballerup, Denmark) on Day 21 of the preceding
cycle to initiate pituitary down-regulation if luteal
phase characteristics were verified by
transvaginal ultrasound. After 14 days of GnRH
agonist administration (cycle day 35)
gonadotrophin stimulation was initiated if ovarian
follicles ≤10 mm diameter and endometrial
thickness ≤6 mm was confirmed by transvaginal
ultrasound. A fixed dose of rFSH (Puregon) was
used for the first 6 days, either 150 or 225 IU
according to age ≤36 or .36 years. After 6 days
of stimulation the rFSH doses were adjusted
according to ovarian response evaluated using
transvaginal ultrasonography. Nasal
administration of 200 mg two times daily of
GnRH agonist was continued during rFSH
stimulation and until ovulation induction.
Toftager, 2017285 RCT 1,050 Short GnRH-antagonist protocol Live birth Good
UK/Europe 1,023 vs. Miscarriage
Across All KQs All Long GnRH-agonist protocol Time to pregnancy
E-23
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Topcu, 2017191 RCT 101 Tamoxifen 20mg/daily for 5 consecutive days Live birth Fair
Middle East 88 vs. Miscarriage
KQ 1 PCOS Clomiphene citrate 50mg/daily for 5 consecutive Multiple births
days OHSS
E-24
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Wang, 2016171 RCT 120 hMG 150-225IU/day and MPA 10mg/day from Multiple births Fair
Asia 108 day 3 of menstruation. Both cotriggered with Miscarriage
KQ 1 PCOS GnRHa and hCG and underwent IVF/ICSI. Ectopic pregnancy
vs. OHSS
Patients received GnRHa (decapeptyl) 0.1mg
beginning of day 2 of menstruation and adding
hMG on day 3 of menstruation. Both cotriggered
with GnRHa and hCG and underwent IVF/ICSI.
Wang, 2017286 Observational 509,938 cycles Fresh blastocyst Live birth Good
US 509,938 cycles vs. Miscarriage
Across All KQs All Fresh non-blastocyst Ectopic pregnancy
vs.
Frozen blastocyst
vs.
Frozen non-blastocyst
Weiss, 2018187 RCT 666 Six cycles with gonadotrophins plus intrauterine Live birth Good
UK/Europe 661 insemination Multiple births
KQ 1 and 3 PCOS, Unknown vs. Miscarriage
Six cycles with gonadotrophins plus intercourse Ectopic pregnancy
vs. Time to pregnancy
Six cycles with clomifene citrate plus intrauterine Birthweight
insemination
vs.
Six cycles with clomifene citrate plus intercourse
E-25
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Wiser, 2010220 RCT 33 Long-stimulation protocol IVF with 75 mg DHEA Live birth (ovarian reserve) Fair
Middle East 33 orally, once a day, at least 6 weeks before
KQ 3 Unknown starting the first cycle of ovulation induction.
Patients who did not conceive and continued to
the second cycle took DHEA for at least 16–18
weeks.
vs.
Standard long-stimulation protocol IVF
Wu, 2016175 RCT 644 Letrozole 2.5 mg plus placebo for Berberine, Live birth Good
Asia 644 in analysis increased to 5.0 mg on days 3-7 of last 3 Multiple births
KQ 1 PCOS treatment cycles Miscarriage
vs. Ectopic pregnancy
Berberine 1.5 mg plus placebo for Letrozole Birthweight
vs. Neonatal death
Combination letrozole and berberine
Wu, 2017188 RCT 1,000 Active acupuncture administered twice a week Live birth Good
Asia 926 plus clomiphene administered for 5 days per Multiple births
KQ 1 PCOS cycle, for up to 4 cycles Miscarriage
vs. Ectopic pregnancy
Active acupuncture administered twice a week Neonatal death
plus placebo for clomiphene administered for 5
days per cycle, for up to 4 cycles
vs.
Control acupuncture administered twice a week
plus clomiphene administered for 5 days per
cycle, for up to 4 cycles
vs.
Control acupuncture administered twice a week
plus placebo for clomiphene administered for 5
days per cycle, for up to 4 cycles
Xiong, 2017263 Observational 141,030 IVF Neonatal death Fair
US 141,030 vs. Preterm birth
KQ 5 Male ICSI Congenital anomaly
E-26
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Yapca, 2015206 RCT 80 CC 100 mg/d on cycle days 3 - 7 followed by Live birth Fair
UK/Europe 80 time-limited hydrotubation performed after Miscarriage
KQ 3 Unknown detection of the dominant follicle and then timed
intercourse
vs.
No hydrotubation
Yazici, 2014144 RCT 110 Ovarian stimulation using rFSH followed by IUI Live birth Poor
UK/Europe 56 and luteal support with vaginal micronized
KQ 1 PCOS progesterone 300 mg/d
vs.
No luteal support
Yildiz, 2014211 RCT 180 Follitropin alpha, follitropin beta, uhMG and Live birth Poor
UK/Europe 180 urofolitropin were used for ovarian stimulation. Miscarriage
KQ 3 Unknown Ovulation induction was started between 2-5
days of menstruation on patients who had no
residual cysts larger than 15 mm as visualized
with basal transvaginal USG (ultrasound). All
patients had 75-150 IU/d drug as an initial dose.
On cycle day 5-6, stimulated follicles were
measured ultrasonographically. Induction doses
were increased or decreased between 37.5-75
IU/d according to follicle size. When 1-2 follicles
reached a mean diameter of 17 mm, 250 mcg of
rhCG was administered to trigger ovulation.
Uterine washing was accomplished by
introducing a silicone catheter through the
internal cervical os, after which 20 cc saline and
1 cc jetocain were slowly injected. The speculum
was removed and the procedure completed after
the injection. At 35-36 hours after the hCG
injection, IUI was performed.
vs.
Same procedures except no uterine washing
performed
E-27
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Youssef, 2016235 RCT 394 Mild ovarian stimulation. Pretreatment with an Miscarriage Good
Africa 394 oral contraceptive pill was followed by ovarian
KQ 3 Unknown stimulation starting with a fixed daily dose of 150
IU/day FSH on Day 5. On stimulation Day 6, 0.25
mg/day s.c. of a GnRH antagonist (Cetrotide®)
was commenced. Ovulation was triggered by
10,000 IU human chorionic gonadotropin
hormone (Pregnyl) when a leading follicle
reached 18 mm, and follicle aspiration was done
by transvaginal ultrasound guided oocyte
retrieval 34–36 h thereafter. Subsequently,
embryo transfers were performed according to
the local policy
vs.
Conventional stimulation protocol. In the women
allocated to the conventional ovarian stimulation
strategy, daily injections were given of 0.1 mg s.c
of a gonadotropin releasing hormone
agonist to prevent premature ovulation
(Decapepetyl®) followed by stimulation with
fixed daily injections of 450 IU HMG (Menopur®
or Merional®). Ovulation was triggered by
10,000 IU human chorionic gonadotropins
hormone (Pregnyl) when a leading follicle
reached 18 mm and follicle aspiration
was done by transvaginal ultrasound guided
oocyte retrieval 34–36 h thereafter. The
remainder of the cycle was identical to the mild
ovarian stimulation strategy
Yu, 2018247 RCT 116 Modified GnRH agonist (triptorelin) Live birth Fair
Asia 116 vs.
KQ 3 Unknown Mild stimulation protocol with letrozole
vs.
Antagonist protocol with triptorelin
Zahran, 2018192 RCT 130 CC + Cabergoline Miscarriage Fair
Middle East 120 vs. OHSS
KQ 1 PCOS CC alone
E-28
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Zain, 2009166 RCT 124 Metformin tablets at the initial dose of 500 mg Live birth Fair
Asia 115 and increased in a step- wise fashion during the Ectopic pregnancy
KQ 1 PCOS first 3 weeks to a total dose of 1,500 mg/d. The Miscarriage
patients were then asked to make a telephone Multiple births
call once they had a menstrual period and a
transvaginal ultrasound (TVS) and follicular
tracking was done to document evidence of
follicular growth and ovulation on days 2, 8, 12,
and 16. A menstrual calendar chart recorded
menses cycles monthly.
vs.
CC at a dose of 50 mg on days 2–6. The TVS
and follicular tracking were done to document
follicular growth and ovulation on days 2, 8, 12,
and 16. If there was absence of ovulation, the
CC dose was increased stepwise on a treatment
cycle basis after a P withdrawal bleed to a
maximum of 200 mg. If there was evidence of
ovulation but the patient did not get pregnant, the
same dosage was continued for a maximum of
six cycles.
vs.
Metformin was given in a similar manner to the
metformin only group. CC was given at a dose of
50 mg on days 2–6. The TVS and follicular
tracking were done to document evidence of
follicular growth and ovulation on days 2, 8, 12,
and 16. If there was absence of ovulation, the
CC dose was increased step-wise on a treatment
cycle basis after a P withdrawal bleed to a
maximum of 200 mg. If there was evidence of
ovulation but patient did not get pregnant, a
similar dosage was continued for a maximum of
six cycles.
E-29
Study N Enrolled
Study Design
ACRONYM N Completed Outcomes
Geographic Interventions Quality
KQs Underlying (Subgroups analyzed)
Location
Companion Studies Diagnosis
Zakherah, 2010169 RCT 150 CC 150 mg + Tamoxifen 40 mg from cycle days Live birth Good
Africa 150 3 to 7, maximum treatment duration 6 cycles. Miscarriage
KQ 1 PCOS vs.
Laparoscopic ovarian drilling (LOD) performed
through triple-puncture laparoscopy followed by
timed intercourse.
Zarei, 2016231 RCT 260 Clomid days 5-9, recombinant FSH days 8+, Miscarriage Fair
Middle East 260 hCG trigger, IUI x up to 3 cycles. Piroxicam days
KQ 3 Unknown 4-6 after IUI.
vs.
Clomid days 5-9, recombinant FSH days 8+,
hCG trigger, IUI x up to 3 cycles.
Zheng, 2012149 RCT 82 Primed with 10,000 IU hCG after progesterone Live birth Fair
Asia 74 induced withdrawal bleeding.
KQ 1 PCOS
Immature oocytes were collected 36-38 hours
after hCG priming. IVM and ICSI were done.
vs.
No priming after progesterone induced
withdrawal bleeding.
E-30
Abbreviations: ART=assisted reproductive technology; BID=two times per day; BMI=body mass index; CARE Consortium=Centres for Assisted Reproduction;
CC=clomiphene citrate; COH=controlled ovarian hyperstimulation; COS=controlled ovarian stimulation; DHEA=dehydroepiandrosterone; FASTT=Fast Track
and Standard Treatment Trial; FISH=fluorescence in situ hybridization; FORT-T=Forty and Over Treatment Trial; FSH=follicle stimulating hormone;
GnRH=gonadotropin-releasing hormone; hCG=human chorionic gonadotropin; hMG=human menopausal gonadotropin; ICSI=intracytoplasmic sperm injection;
IMSI=Intrycytoplasmic morphologically selected sperm injection; ITT=intention-to-treat; IU=international units; IUI=intrauterine insemination; IVF=in vitro
fertilization; IVM=in vitro maturation; KQ=key question; mcg=microgram; MNC=modified natural cycle; MOSART=Massachusetts Outcomes Study of
Assisted Reproductive Technologies; NA=not applicable; NASS=National Artificial Reproductive Technology Surveillance System; NR=Not Reported;
OCP=oral contraceptive pill; OHSS=Ovarian Hyperstimulation Syndrome; PCOS=Polycystic Ovary Syndrome; PGD=preimplantation genetic diagnosis;
PPCOS=Pregnancy in Polycystic Ovary Syndrome; RCT=Randomized Controlled Trial; rFSH=recombinant follicle stimulating hormone; rhFSH=recombinant
human follicle stimulating hormone; SQ=subcutaneous; SUIT=Scottish Unexplained Infertility Trial; TVS=transvaginal ultrasound; uFSH=urinary follicle
stimulating hormone; uhMG=urinary human menopausal gonadotropin
E-31
Appendix F. AMSTAR Quality Assessment for Systematic Reviews
Table F-1 shows the AMSTAR (A Measurement Tool to Assess the Methodological Quality of Systematic Reviews) quality
assessment for the included systematic reviews. For full study citations, please refer to the report’s main reference list.
used appropriately in
used as an inclusion
excluded) provided?
Scientific quality of
(i.e. grey literature)
Conflict of interest
selection and data
Characteristics of
"A Priori" design
Methods used to
included studies
included studies
literature search
publication bias
Comprehensive
Duplicate study
List of studies
documented?
assessed and
(included and
conclusions?
Likelihood of
appropriate?
abstraction?
performed?
formulating
assessed?
provided?
provided?
included?
of studies
criterion?
Study
Al-Inany, 2016320 Y Y Y Y Y Y Y Y Y Y Y
Attia, 201373 Y Y Y Y Y Y Y Y Y Y Y
Barbosa, 201464 Y Y Y Y Y Y Y Y Y Y Y
Bensdorp, 2007265 Y Y Y Y Y Y Y Y Y Y Y
Bhattacharya, 201090 Y C Y N Y Y Y Y Y N Y
Bordewijk, 2017197 Y Y Y Y Y Y Y Y Y Y Y
Brown, 2016198 Y Y Y Y Y Y Y Y Y Y Y
Brown, 2016321 Y Y Y Y Y Y Y Y Y Y Y
Brown, 2016322 Y Y Y Y Y Y Y Y Y Y Y
Chua, 2017323 Y Y Y Y Y Y Y Y Y Y Y
Cissen, 2016266 Y Y Y Y Y Y Y Y Y Y Y
Duffy, 201465 Y Y Y Y Y Y Y Y Y Y Y
Farquhar, 2018324 Y Y Y Y Y Y Y Y Y Y Y
Farquhar, 201281 Y Y Y Y Y Y Y Y Y Y Y
Farquhar, 2017325 Y Y Y Y Y Y Y Y Y Y Y
Franik, 2018326 Y Y Y Y Y Y Y Y Y Y Y
Franik, 2015327 Y Y Y Y Y Y Y Y Y Y Y
Franik, 201466 Y Y Y Y Y Y Y Y Y Y Y
Ghobara, 2017328 Y Y Y Y Y Y Y Y Y Y Y
Hamdan, 201560 Y Y Y Y N Y Y Y Y N Y
Hamdan, 2015329 Y Y Y N N Y Y Y Y N Y
Hu, 2018330 Y Y Y Y Y Y Y Y Y Y Y
Hughes, 201092 Y Y Y Y Y Y Y Y Y Y Y
F-1
used appropriately in
used as an inclusion
excluded) provided?
Scientific quality of
(i.e. grey literature)
Conflict of interest
selection and data
Characteristics of
"A Priori" design
Methods used to
included studies
included studies
literature search
publication bias
Comprehensive
Duplicate study
List of studies
documented?
assessed and
(included and
conclusions?
Likelihood of
appropriate?
abstraction?
performed?
formulating
assessed?
provided?
provided?
included?
of studies
criterion?
Study
Jie, 2018331 Y Y Y Y Y Y Y Y Y Y Y
Johnson, 201093 Y Y Y Y Y Y Y Y Y Y Y
Lensen, 2016332 Y Y Y Y Y Y Y Y Y Y Y
Lim, 2016195 Y Y Y Y Y Y Y Y Y Y Y
Liu, 201470 Y Y Y Y N Y Y Y Y Y Y
Morley, 2017199 Y Y Y Y Y Y Y Y Y Y Y
Mourad, 2017333 Y Y Y Y Y Y Y Y Y Y Y
Nagels, 2015334 Y Y Y Y Y Y Y Y Y Y Y
Noble, 201094 Y Y Y C Y Y N N Y N Y
Osman, 201561 Y Y Y Y N Y N N Y N Y
Pandian, 201284 Y Y Y Y Y Y Y Y Y Y Y
Pandian, 2015335 Y Y Y Y Y Y Y Y Y Y Y
Pandian, 201095 Y Y Y Y Y Y Y Y Y Y Y
Reavey, 2016196 Y Y Y Y Y Y Y Y Y Y Y
Showell, 2011336 Y Y Y Y Y Y Y Y Y Y Y
Siristatidis, 2016337 Y Y Y Y Y Y Y Y Y Y Y
Siristatidis, 2015338 Y Y Y Y Y Y Y Y Y Y Y
Sun, 201378 Y Y Y C N Y N N Y N Y
Tang, 2016339 Y Y Y Y Y Y Y Y Y Y Y
Teixeira, 201379 Y Y Y Y Y Y Y Y Y Y Y
Veltman-Verhulst, 201287 Y Y Y Y Y Y Y Y Y Y Y
Veltman-Verhulst, 2016340 Y Y Y Y Y Y Y Y Y Y Y
Vermey, 2018341 Y Y Y Y Y Y Y Y Y Y Y
Vitaglia, 2018342 Y Y Y Y Y Y Y Y Y Y Y
Youssef, 2016343 Y Y Y Y Y Y Y Y Y Y Y
Youssef, 2015344 Y Y Y Y Y Y Y Y Y Y Y
Yu, 2018345 Y Y Y N Y Y N N Y N Y
Zhou, 2016346 Y Y Y Y Y Y Y Y Y Y Y
Abbreviations: C=Can’t answer; N=No; Y=Yes
F-2
Figure F-1. Summary of AMSTAR quality assessment for systematic reviews
F-3
Luke, 2010123
Butts, 2014122
Bodri, 2009269
Bodri, 2008268
Belva, 2011259
Litzky, 2018290
Litzky, 2018284
Kissin, 2015272
Muller, 2017205
Boulet, 2016277
Boulet, 2015254
Chang, 2016276
Brinton, 2015136
Kettner, 2016184
Keyhan, 2018185
Maxwell, 2008270
Study
Malchau, 2017186
de Wilde, 2017180
Mancuso, 2016283
Crawford, 2017281
Dhalwani, 2016236
Knudtson, 2017282
Magnusson, 2018287
Levi Dunietz, 2017239
Hershko-Klement, 2016260
Were participants analyzed
within the groups they were
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
N
U
N
N
N
originally assigned to?
(selection bias)
report’s main reference list.
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
N
uniformly to all comparison
groups? (selection bias)
N
N
N
N
N
U
N
N
N
N
N
N
U
N
N
N
N
N
N
N
U
U
U
U
participants differ across
study groups? (selection bias)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
N
N
N
N
N
N
matching, stratification,
multivariable analysis, or other
approaches? (selection bias)
Did researchers rule out any
impact from concurrent
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
N
U
U
U
N
U
U
U
U
U
U
N
N
N
Table G-1. Risk of bias assessment for included cohort studies
intervention or unintended
exposure that might bias
results? (performance bias)
G-1
Did the study maintain fidelity
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
N
U
U
N
U
U
N
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
N
U
U
U
U
U
N
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
U
N
U
U
N
N
U
N
U
U
U
U
U
N
N
N
N
U
N
U
N
U
U
U
N
N
Were interventions/exposures
assessed/defined using valid
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
implemented consistently
across all study participants?
(detection bias)
Were outcomes assessed,
implemented consistently
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
U
U
U
(detection bias)
Were confounding variables
implemented consistently
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
N
U
N
U
N
N
(detection bias)
N
U
U
N
Vitek, 2013215
Xiong, 2017263
Wang, 2017286
Spaan, 2015125
Nangia, 2011124
Stewart, 2013203
Study
Williams, 2018289
Williams, 2013213
Verhoeve, 2013249
Oyesanya, 2009224
Schendelaar, 2011273
Were participants analyzed
within the groups they were
Y
Y
Y
Y
Y
Y
Y
Y
U
N
N
U
originally assigned to?
(selection bias)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
N
U
N
N
N
N
U
N
N
N
U
N
U
N
N
N
matching, stratification,
multivariable analysis, or other
approaches? (selection bias)
Did researchers rule out any
impact from concurrent
Y
Y
N
U
U
U
U
N
U
U
N
N
intervention or unintended
exposure that might bias
results? (performance bias)
G-2
Did the study maintain fidelity
Y
Y
Y
Y
Y
Y
Y
U
U
U
U
U
U
U
N
U
U
N
U
N
N
Were interventions/exposures
assessed/defined using valid
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
implemented consistently
across all study participants?
(detection bias)
Were outcomes assessed,
implemented consistently
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
N
N
U
N
U
U
U
U
U
Were participants analyzed within the groups they were originally assigned to?
(selection bias)
Did the study apply inclusion/exclusion criteria uniformly to all comparison
groups? (selection bias)
Did the strategy for recruiting participants into the study differ across study
groups? (selection bias)
Does the design or analysis control account for important confounding and
modifying variables through matching, stratification, multivariable analysis, or…
Did researchers rule out any impact from a concurrent intervention or an
unintended exposure that might bias results? (performance bias)
Did the study maintain fidelity to the intervention protocol? (performance bias)
Yes No Unclear
G-3
Study
Luke, 2016274
Barad, 2017280
Londra, 2016278
Kramer, 2009271
Provost, 2016279
Grimstad, 2016251
Did the study apply
inclusion/exclusion criteria uniformly
Y
Y
Y
Y
Y
Y
to all comparison groups? (selection
bias)
Y
Y
Y
Y
Y
N
matching, stratification, multivariable
analysis, or other approaches?
(selection bias)
Y
Y
Y
Y
N
U
G-4
Table G-2. Risk of bias assessment for included cross-sectional studies
U
U
U
U
U
Were interventions/exposures
assessed/defined using valid and
Y
Y
Y
Y
Y
Yes No Unclear
G-5
An, 2014146
Choi , 2012147
Chen, 2016174
Amer, 2009165
Amer, 2017179
Bagis, 2010221
Dreyer, 2016250
Demirol, 2007230
Custers, 2012139
Danhof,, 2018244
Badawy, 2009222
Badawy, 2008193
Balaban, 2011258
Abdellah, 2011156
Ebrahimi, 2010229
Diamond, 2015233
Einarsson, 2017181
Aboulghar, 2010162
Bhattacharya, 2008135
Aghahosseini, 2017178
main reference list.
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
U
U
N
adequately? (selection bias)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
N
U
U
U
N
U
U
concealed? (selection bias)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
N
groups they were originally assigned to?
(selection bias)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
U
N
N
N
N
N
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
N
U
U
N
N
N
N
N
G-6
(performance bias)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
U
U
N
U
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
U
U
N
U
N
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
U
N
N
N
U
N
N
U
U
N
U
N
U
U
U
U
N
N
Were interventions/exposures
assessed/defined using valid and reliable
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
N
Kar, 2015173
Kim, 2012150
Kim, 2011219
Jacob, 2016177
Harira, 2018246
Erdem, 2015208
Erdem, 2009225
Kjotrod, 2011155
Gibreel, 2013228
Ghahiri, 2016170
Kuzmin, 2014248
Ibrahim, 2017189
Hassan, 2017183
Jahromi, 2017243
Johnson, 2010160
Hosseini, 2010158
Ghanem, 2013145
Kurzawa, 2008164
Goldman, 2014210
Farquhar, 2018238
Homburg, 2012152
Elsedeek, 2014194
Khosravi , 2015232
Hajizadeh, 2017261
Gregoriou, 2008226
Study
Hossein-Rashidi, 2016176
Was the allocation sequence generated
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
N
U
adequately? (selection bias)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
N
U
U
U
U
N
N
concealed? (selection bias)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
U
U
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
N
N
N
N
N
U
N
U
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
N
U
U
N
U
N
N
U
U
U
G-7
(performance bias)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
U
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
U
U
N
U
U
N
U
N
U
U
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
U
U
U
N
N
N
U
N
U
U
U
N
U
N
N
U
U
N
U
N
Were interventions/exposures
assessed/defined using valid and reliable
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
U
N
U
U
U
U
U
N
Razi, 2013255
Nada, 2016234
Legro, 2015172
Legro, 2014131
Legro, 2007128
Rubio, 2013217
Ragni, 2012218
Nandi, 2017240
Morad, 2012227
Maher, 2018245
Seckin, 2014209
Pourali, 2017241
Nahuis, 2011141
Rashidi, 2015143
Rashidi, 2013216
Leandri, 2013256
Selman, 2016237
La Sala, 2015253
Peeraer, 2015288
Rahman, 2017264
Palomba, 2011153
Palomba, 2010163
Reindollar, 201052
Mutsaerts, 2016119
Majumdar, 2013214
Mehrabian, 2012148
Study
Morin-Papunen, 2012151
Mohammadi Yeganeh, 2018190
Was the allocation sequence generated
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
U
U
U
U
U
N
adequately? (selection bias)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
N
N
U
U
U
U
U
U
U
N
concealed? (selection bias)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
N
U
U
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
N
U
N
N
N
N
N
N
N
N
N
N
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
N
U
U
U
U
N
U
N
U
U
U
U
U
N
G-8
(performance bias)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
U
U
U
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
N
N
N
N
U
N
U
N
U
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
U
U
U
U
N
N
U
U
U
U
U
U
N
U
U
N
N
U
U
U
N
Were interventions/exposures
assessed/defined using valid and reliable
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
U
U
U
U
U
U
U
N
Wu, 2017188
Wu, 2016175
Zhu, 2014202
Zain, 2009166
Zarei, 2016231
Yildiz, 2014211
Wiser, 2010220
Wang, 2016171
Yazici, 2014144
Weiss, 2018187
Topçu, 2017191
Zheng, 2012149
Yapca, 2015206
Zahran, 2018192
Youssef, 2016235
Tartagni, 2015207
Toftager, 2017285
Toftager, 2016275
Zakherah, 2010169
Stadtmauer, 2011159
Tehraninejad, 2010161
Was the allocation sequence generated
N
N
N
U
adequately? (selection bias)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
N
U
N
N
U
U
N
U
N
concealed? (selection bias)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
U
N
U
N
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
U
U
N
N
U
N
U
U
N
U
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
U
U
N
N
U
U
U
U
U
U
U
N
U
N
N
N
G-9
(performance bias)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
U
U
U
U
U
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
U
N
N
U
U
U
U
N
U
N
N
U
U
U
U
U
N
U
U
U
N
N
U
U
N
U
U
U
N
U
N
N
U
Were interventions/exposures
assessed/defined using valid and reliable
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
U
U
U
U
U
U
U
U
U
U
N
U
Were participants analyzed within the groups they were originally assigned to? (selection bias)
Does the design or analysis control account for important confounding and modifying variables
through matching, stratification, multivariable analysis, or other approaches? (selection bias)
Did researchers rule out any impact from a concurrent intervention or an unintended exposure that
might bias results? (performance bias)
Did the study maintain fidelity to the intervention protocol? (performance bias)
If attrition was a concern, were missing data handled appropriately? (attrition bias)
In prospective studies, was the length of follow-up the same between the groups, or in case-control
studies, was the time period between the intervention/exposure and outcome the same for cases
and controls? (detection bias)
Were the outcome assessors blinded to the intervention or exposure status of participants?
(detection bias)
Were outcomes assessed/defined using valid and reliable measures, implemented consistently
across all study participants? (detection bias)
Were the potential outcomes prespecified by the researchers? Are all prespecified outcomes
reported? (reporting bias)
0% 25% 50% 75% 100%
Percent of studies with low, high, or unclear risk of bias
Yes No Unclear
G-10
Appendix H. Supplemental Project To Assess the
Transparency of Reporting for Trials Evaluating
Treatment for Infertility
Authors: Williams JW Jr., Eaton JL, Gierisch JM, Masilamani V, von Isenburg M, Chobot MMa
Methods
Scope and General Approach
We adopted a pragmatic approach, using methods that could be readily incorporated into
future systematic reviews. To maintain feasibility while still applying our methods to a range of
interventions, we included KQ 1, KQ 2, and KQ 4 from the Management of Infertility review in
this analysis. The KQs are listed below:
KQ 1: What are the comparative safety and effectiveness of available treatment strategies for
women with polycystic ovary syndrome (PCOS) who are subfertile/infertile and who wish to
become pregnant?
KQ 2: What are the comparative safety and effectiveness of available treatment strategies for
women with endometriosis who are subfertile/infertile and who wish to become pregnant?
KQ 4: What are the comparative safety and effectiveness of available treatments for women with
tubal or peritoneal factors (e.g., pelvic adhesions) who are subfertile/infertile and who wish to
become pregnant?
a
Williams JW Jr., Eaton JL, Gierisch JM, Masilamani V, von Isenburg M, Chobot M. Supplemental Project To Assess the
Transparency of Reporting for Trials Evaluating Treatment for Infertility. Methods Research Report. AHRQ Publication No. 17-
EHC022-EF. Rockville, MD: Agency for Healthcare Research and Quality. June 2017.
H-1
Searching CT.gov
We searched CT.gov for trials potentially applicable to the KQs with the assistance of our
search librarian. Because CT.gov does not use MeSH-based search terms, we adapted the search
strategies developed for the Management of Infertility review to language appropriate for
CT.gov. We conducted two searches, a broad search using the basic interface and a more specific
search using the advanced interface in CT.gov. For the broad search, we searched for synonyms
for infertility (infertility OR infertile OR subfertility OR subfertile OR sub-fertility OR sub-
fertile) in the conditions field and limited our results to interventional studies. For the narrow
search, we searched for the same synonyms for infertility in the broader search terms field and
combined this with multiple, separate searches for each of the conditions of interest. This
narrower search was also limited to interventional studies. Exact search strings used in both
searches are given in Appendix A.
Results of the two searches were imported into Excel.
Matching Studies
We matched randomized controlled trials (RCTs) identified in CT.gov with those identified
for the Management of Infertility review at several levels.
First, we determined whether RCTs reporting a live birth outcome that were included in the
Management of Infertility review had a matching record in CT.gov. Matching was performed
initially using the NCT identifier (NCTID). Our intention was to conduct this matching using a
semi-automated process within EndNote. This approach proved infeasible due to inconsistent
assignment of NCTIDs to EndNote fields. Thus, all matching was accomplished by manual
review. For unmatched studies, we conducted a secondary match using other trial registration
numbers and then trial characteristics, including: condition, intervention, sample size, and
author/investigator. Matching was performed initially for the broad CT.gov search. We then
determined the proportion of matched studies that were not identified by the narrow CT.gov
search.
Second, for matched studies (i.e., studies included in the Management of Infertility review
with a CT.gov record), we abstracted selected variables from the CT.gov record to determine
whether key study design variables and reported outcomes matched information in the published
manuscript. Variables abstracted were:
• Date of completion
• Number of study arms
• Intervention description
• Study design
• Outcomes measures and results prioritized in the Management of Infertility review
• Analysis approach
• Subgroup analyses
Data from CT.gov were compared to published data. For each variable, the result was
classified as: matching, discrepant, or possibly discrepant. Discrepant data were defined as cases
where information was absent in one source but reported in another, or when the information
given in the two sources was contradictory. Discrepancies were summarized narratively.
Third, we screened the unmatched CT.gov citations for potentially eligible completed trials.
Eligibility criteria for each KQ are given in Table 1 of the Methods chapter of the main
H-2
Management of Infertility review. For potentially eligible studies identified from CT.gov, we
used author names and intervention terms to search for a matching publication in PubMed. We
classified studies into two groups: (1) potentially eligible completed study without a published
manuscript; and (2) potentially eligible completed study with a matching published manuscript
that was not identified in the systematic review search.
All matching was limited to studies published since the 2005 International Committee of
Medical Journal Editors (ICMJE) policy requiring trial registration. Matching was performed
initially by a research assistant, and reviewed by a study investigator. Team members involved in
matching piloted the data collection forms and procedures to refine them before full use.
Results
Results are presented in five sections: (1) concordance between RCTs included in the
Management of Infertility review and in CT.gov; (2) studies identified from CT.gov as
potentially eligible but not included in the Management of Infertility review; (3) concordance
between data from CT.gov and published studies for studies present in both sources; (4) effects
of CT.gov results on SOE and review conclusions; and (5) person-hours required to generate
these results.
H-3
All matched studies were confirmed by an investigator. Three preliminary matches based on
“other criteria” were not confirmed by study investigators and are included in the 12 unmatched
studies above.
Only one-third of the included trials were matched to a CT.gov record using the NCTID, the
most reliable and readily applied matching variable. When using all available data, 50% (95%
CI, 30 to 50%) of the eligible studies were matched to a CT.gov record.
Only 5 potentially eligible studies were identified across the 3 KQs. Of these, 2 are recently
completed trials (2015) and no journal publication was expected. Two trials with a combined
sample size of 340 patients were completed more than 3 years ago, indicating potential
publication bias. Both of these trials were applicable to KQ 1. One trial was excluded at the title-
and-abstract screening phase of the review; upon review of the full text, the study was
reclassified as eligible and included in the review.
H-4
• The KQ classification matched for all 8 studies.
• The study design and number of study arms matched for all 8 studies.
• Of 5 studies reporting the enrolled “n,” 4 were exact matches and 1 had a discrepancy in
the estimated enrollment (326) vs. the number enrolled (320). Three studies did not report
the sample size in CT.gov and thus were classified as discrepant.
• Intervention descriptions were substantially concordant for all 8 studies and thus were
classified as matching.
• The analytic approach and any plans for subgroup analyses were not addressed in CT.gov
for any of the studies. However, subgroup analyses were not reported in the published
manuscripts for any of these trials.
• The funding sources was classified as matched for 6 studies. Two studies were classified
as discrepant: 1 of these was classified as non-government/non-industry from CT.gov and
as “not reported” from manuscript, and 1 was classified as non-government/non-industry
from CT.gov and as government from the published manuscript.
Outcomes were compared at 2 levels: the outcomes planned from CT.gov to those reported in
published manuscripts, and the results reported in CT.gov to those reported in published
manuscripts.
• Planned outcomes: 11 outcomes were reported in both sources and classified as matched.
Three outcomes reported as planned in CT.gov were not abstracted from manuscripts:
quality of life,7 miscarriage,8 and live birth.9 In 4 studies, outcomes reported in published
manuscripts were not described in CT.gov: live birth,8,10 miscarriage,11 multiple
births,11,12 and surgical complications.12
• Only 17 of the 8 trials reported results in CT.gov, and these results matched those
reported in the manuscript for the single outcome present in both sources.
H-5
Person-Hours Required for Data Collection and Analysis
Overall, the project team devoted an estimated 74.5 hours to planning and conducting this
study. Data by investigator vs. staff are given in Table H-2.
Discussion
This substudy found that CT.gov has important limitations for identifying selective reporting.
Only one-third of the studies included in the Management of Infertility review were matched to a
CT.gov record based on NCTID, and only 1 of those studies reported results in CT.gov. In
addition, there were few discrepancies between planned outcomes reported in CT.gov and those
reported in published manuscripts. A careful search and inspection of CT.gov for potentially
eligible studies not identified by the review team yielded only 2 studies without a publication and
1 study incorrectly excluded at the title-and-abstract screening stage. These data had no impact
on the SOE ratings or study conclusions, but required substantial person-hours to generate.
It is possible that CT.gov will mature into a more useful resource for the purpose of
identifying selective reporting. Using data from CT.gov for the dates of trial registration
compared to conduct of the study, it is clear that some studies were registered retrospectively.
Prospective registration may yield more complete records and more informative data. However,
it is likely that changes to CT.gov will be required for this database to serve as a useful source
for identifying selective reporting.
At present, these results do not support the routine use of CT.gov to evaluate selective
reporting. However, our study examined a small set of interventions for a single condition
(infertility) and included a relatively small set of trials. Additional studies are needed before
definitive conclusions can be drawn about the utility of CT.gov for detecting selective reporting.
If changes to CT.gov were made to facilitate its use for this purpose, other resources could
improve efficiency, including: a customized EndNote filter for importing CT.gov results, a
standard methodology to guide investigators, and additional data on the activities that can be
reliably completed by study staff versus investigators.
References to Appendix H
1. Borenstein M, Hedges LV, Higgins JPT, et 3. Sterne JA, Sutton AJ, Ioannidis JP, et al.
al. Publication Bias. Introduction to Meta- Recommendations for examining and
Analysis: John Wiley & Sons, Ltd; interpreting funnel plot asymmetry in meta-
2009:277-92. analyses of randomised controlled trials.
BMJ. 2011;343:d4002. PMID: 21784880.
2. Song F, Parekh S, Hooper L, et al.
Dissemination and publication of research
findings: an updated review of related
biases. Health Technology Assessment.
2010;14(8):iii, ix-xi, 1-193. PMID:
20181324.
H-6
4. Dwan K, Altman DG, Clarke M, et al. 9. Palomba S, Falbo A, Carrillo L, et al.
Evidence for the selective reporting of Metformin reduces risk of ovarian
analyses and discrepancies in clinical trials: hyperstimulation syndrome in patients with
a systematic review of cohort studies of polycystic ovary syndrome during
clinical trials. PLoS Med. gonadotropin-stimulated in vitro fertilization
2014;11(6):e1001666. PMID: 24959719. cycles: a randomized, controlled trial. Fertil
Steril. 2011;96(6):1384-90.e4. PMID:
5. Hartung DM, Zarin DA, Guise JM, et al.
21982727.
Reporting discrepancies between the
ClinicalTrials.gov results database and peer- 10. Abu Hashim H, El Rakhawy M, Abd Elaal I.
reviewed publications. Ann Intern Med. Randomized comparison of superovulation
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IUI program for women with recently
6. Agency for Healthcare Research and Quality
surgically treated minimal to mild
(AHRQ). Methods Guide for Effectiveness
endometriosis. Acta Obstet Gynecol Scand.
and Comparative Effectiveness Reviews.
2012;91(3):338-45. PMID: 22181973.
AHRQ Publication No. 10(14)-EHC063-EF.
Rockville, MD: Agency for Healthcare 11. Johnson NP, Stewart AW, Falkiner J, et al.
Research and Quality. February 2015. PCOSMIC: a multi-centre randomized trial
Available at: in women with PolyCystic Ovary Syndrome
https://www.effectivehealthcare.ahrq.gov/to evaluating Metformin for Infertility with
pics/cer-methods-guide/overview. Accessed Clomiphene. Hum Reprod.
April 1, 2016. 2010;25(7):1675-83. PMID: 20435692.
7. Legro RS, Brzyski RG, Diamond MP, et al. 12. Palomba S, Falbo A, Battista L, et al.
Letrozole versus clomiphene for infertility Laparoscopic ovarian diathermy vs
in the polycystic ovary syndrome. N Engl J clomiphene citrate plus metformin as
Med. 2014;371(2):119-29. PMID: second-line strategy for infertile anovulatory
25006718. patients with polycystic ovary syndrome: a
randomized controlled trial. Am J Obstet
8. Morin-Papunen L, Rantala AS, Unkila-
Gynecol. 2010;202(6):577.e1-8. PMID:
Kallio L, et al. Metformin improves
20096821.
pregnancy and live-birth rates in women
with polycystic ovary syndrome (PCOS): a
multicenter, double-blind, placebo-
controlled randomized trial. J Clin
Endocrinol Metab. 2012;97(5):1492-500.
PMID: 22419702.
H-2