Raperport, C., Desai, J., Qureshi, D., Rustin, E., Balaji, A., Chronopoulou, E., Homburg, R., Khan, K. S., & Bhide, P. (2024). The definition of unexplained infertility: A systematic review. BJOG : an international journal of obstetrics and gynaecology, 131(7), 880-897. https://doi.org/10.1111/1471-0528.17697
Raperport C, Desai J, Qureshi D, Rustin E, Balaji A, Chronopoulou E, Homburg R, Khan KS, Bhide P. The definition of unexplained infertility: A systematic review. BJOG : an international journal of obstetrics and gynaecology. 2024;131(7):880-897. doi:10.1111/1471-0528.17697
Raperport, C., et al. "The definition of unexplained infertility: A systematic review." BJOG : an international journal of obstetrics and gynaecology, vol. 131, no. 7, 2024, pp. 880-897.
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RRM Academy Synopsis
Studies of unexplained infertility use widely different criteria
Studies of unexplained infertility enroll couples under very different rules, a review of 258 published studies found. About 4 out of 10 studies that required a semen test used WHO limits. Rules for the tubes, ovulation and other tests also differed between studies.
Key Findings
The database search found 751 papers. Of the 375 papers that remained, 117 did not define unexplained infertility, leaving 258 primary studies with stated inclusion criteria.
Semen analysis was required in 220/258 (85.3%) studies. Of these, 87/220 (39.5%) used WHO criteria, 68/220 (30.9%) used other reference ranges and 65/220 (29.5%) did not specify.
Patent fallopian tubes were required in 232/258 (89.9%) studies. Bilateral patency was required in 145/232 (62.5%). 24/232 (10.3%) accepted unilateral patency, and 63/232 (27.2%) did not specify.
Regular ovulation was required in 205/258 (79.5%) studies. Mid-luteal serum progesterone was accepted in 115/205 (56.1%) and patient-reported regular cycles were required in 87/205 (42.4%).
Uterine cavity assessment appeared in 121/258 (46.9%) studies, and a normal hormone profile was required in 114/258 (44.2%).
Interpretation
The review counts how published studies defined their unexplained infertility groups. It reports no treatment results. The authors copied criteria from each methods section and could not reach study authors, so a study that applied criteria without stating them counts as unspecified, though it may have used them. They searched two databases, left out non-English papers and did not rate study quality. They argue the variation biases meta-analyses. They propose interim criteria: semen analysis graded by WHO, both tubes open, confirmed ovulation and a normal uterine cavity.
RRM Context
Unexplained infertility means the tests done so far found no cause. The review links the diagnosis to how deep the testing went. Just 16/258 (6.2%) studies required exclusion of endometriosis or evidence of only minimal disease. The authors cite a review suggesting HSG or HyCoSy may miss 21% to 68% of abnormalities later seen at laparoscopy, usually related to undiagnosed endometriosis. Restorative reproductive medicine treats this label as undiagnosed.
Our editorial summary of this paper, not the article's abstract.
Abstract
Background
There is no consensus on tests required to either diagnose unexplained infertility or use for research inclusion criteria. This leads to heterogeneity and bias affecting meta-analysis and best practice advice.
Objectives
This systematic review analyses the variability of inclusion criteria applied to couples with unexplained infertility. We propose standardised criteria for use both in future research studies and clinical diagnosis.
Search Strategy
CINAHL and MEDLINE online databases were searched up to November 2022 for all published studies recruiting couples with unexplained infertility, available in full text in the English language.
Data Collection and Analysis
Data were collected in an Excel spreadsheet. Results were analysed per category and methodology or reference range.
Main Results
Of 375 relevant studies, only 258 defined their inclusion criteria. The most commonly applied inclusion criteria were semen analysis, tubal patency and assessment of ovulation in 220 (85%), 232 (90%), 205 (79.5%) respectively. Only 87/220 (39.5%) studies reporting semen analysis used the World Health Organization (WHO) limits. Tubal patency was accepted if bilateral in 145/232 (62.5%) and if unilateral in 24/232 (10.3%). Ovulation was assessed using mid-luteal serum progesterone in 115/205 (56.1%) and by a history of regular cycles in 87/205 (42.4%). Other criteria, including uterine cavity assessment and hormone profile, were applied in less than 50% of included studies.
Conclusions
This review highlights the heterogeneity among studied populations with unexplained infertility. Development and application of internationally accepted criteria will improve the quality of research and future clinical care.
Almohammadi A et al., 2025·International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics·Free full text on PubMed Central
[BACKGROUND] Recurrent implantation failure (RIF) has a multifactorial etiology. An umbrella review was undertaken to evaluate the multiple proposed interventions. [OBJECTIVES] To summarize and assess the strength of evidence of interventions for RIF from published systematic reviews (SR) of randomized clinical trials (RCTs). [SEARCH STRATEGY] After prospective registration (PROSPERO CRD42023414255), a systematic search was conducted in the Cochrane Library, Scopus and Medline from inception until March 2024. [SELECTION CRITERIA] SRs of RCTs, with or without meta-analyses (MA), were included if they reported clinical pregnancy rates (CPR) or live birth rates (LBR). [DATA COLLECTION AND ANALYSIS] The methodological quality of the included SRs was appraised independently in duplicate using the AMSTAR 2 tool. For each intervention, the MAs of RCTs with statistically significant improvements were counted as a percentage of the total assessing the strength of evidence using the GRADE system. [MAIN RESULTS] A total of 47 SRs were included: 32 reviews covered immunomodulatory interventions, 10 (68 RCTs) covered uterine and endometrial interventions, one covered antibiotics, and four (69 RCTs) addressed mixed approaches, including laboratory interventions. AMSTAR 2 appraised 41 (88%) SRs as critically low or low, and 6 (12%) as moderate or high in quality. The SRs often had a level of overlap of RCTs (median 33.3%), inconsistent definitions of RIF, and varied comparisons for the interventions. Considering the significant meta-analytic evidence of high-moderate GRADE strength: Granulocyte colony-stimulating factor (G-CSF) showed improvement in CPR in 9/13 (69.2%) MAs and LBR in 1/7 (14%); intralipid infusion showed improvement in CPR in 4/6 (57.14%) MAs and LBR in 3/4 (75%); peripheral blood mononuclear cells (PBMC) showed improvement in CPR in 4/8 (50%) MAs and LBR 3/5 (60%); platelet-rich plasma (PRP) intervention showed improvement in CPR in 6/10 (60%) MAs and LBR in 1/5 (20%); human chorionic gonadotropins showed improvement in CPR in 3/3 (100%) MAs; growth hormone showed improvement in CPR in 1/1 (100%) MA; low molecular weight heparin showed improvement in CPR in 1/1 (100%) MAs and LBR in 1/2 (50%); hysteroscopy showed improvement in CPR in 1/2 (50%) MAs; and, intentional endometrial injury showed improvement in CPR in 3/4 (75%) MAs and LBR in 2/3 (66.66%). [CONCLUSIONS] Evidence syntheses of RCTs evaluating interventions for RIF suggest a consistent direction, with high to moderate strength, indicating that immunomodulatory treatments, including G-CSF, PBMC, PRP, intralipid infusion, and intentional endometrial injury are likely to be effective. However, this conclusion should be interpreted with caution due to the generally low methodological quality of the included studies and the clinical heterogeneity observed in most SRs.
Guidelines by Clinical Area · Fertility and Infertility Guidelines
How do numbers of oocytes retrieved per In vitro fertilisation (IVF) cycle impact on the live birth rate (LBR) and multiple gestation pregnancy (MGP) rates? Retrospective observational longitudinal study. UK IVF clinics. Non-donor IVF patients. LBR per IVF cycle and MGP levels against number of oocytes retrieved into subgroups: 0, 1-5, 6-15, 16-25, 26-49 oocytes and 50+ oocytes. Relative risk (RR) and 95% CIs were calculated for each group against the intermediate responder with '6-15 oocytes collected'. From 172 341 attempted fresh oocyte retrieval cycles, the oocyte retrieved was: 0 in 10 148 (5.9%) cycles from 9439 patients; 1-5 oocytes in 42 574 cycles (24.7%); 6-15 oocytes in 91 797 cycles (53.3%); 16-25 oocytes in 23 794 cycles (13.8%); 26-49 oocytes in 3970 cycles (2.3%); >=50 oocytes in 58 cycles (0.033%). The LBRs for the 1-5, 6-15, 16-25 and 26-49 subgroups of oocytes retrieved were 17.2%, 32.4%, 35.3% and 18.7%, respectively. The RR (95% CI) of live birth in comparison to the intermediate group (6-15) for 1-5, 16-25 and 26-49 groups was 0.53 (0.52 to 0.54), 1.09 (1.07 to 1.11) and 0.58 (0.54 to 0.62), respectively. The corresponding MGP rates and RR were 9.2%, 11.0%, 11.4% and 11.3%, respectively and 0.83 (0.77 to 0.90), 1.04 (0.97 to 1.11) and 1.03 (0.84 to 1.26), respectively. There was only limited benefit in LBR beyond the 6-15 oocyte group going to the 16-25 oocytes group, after which there was significant decline in LBR. The MGP risk was lower in 1-5 group.
Sawant S et al., 2019·Clinical medicine insights. Reproductive health·Free full text on PubMed Central
Polycystic ovary syndrome is the most common endocrinological disorder in women of reproductive age. It is commonly associated with anovulatory subfertility, for which there are a range of treatment options available to help them conceive. These options are given in a step-wise manner with an appropriate selection of patients to maximise success rates with minimal complications. This review discusses the importance and involvement of multidisciplinary care when offering treatment to women with subfertility. Multidisciplinary care gives an excellent opportunity to identify, assess risk, and potentially prevent future morbidities and complications while treating women for fertility issues. We have also summarised the various options available for fertility treatment: pharmacological treatments, nonpharmacological intervention, and assisted reproductive technology.
Gelbaya TA et al., 2014·Obstetrical & gynecological survey
The diagnosis of unexplained infertility can be made only after excluding common causes of infertility using standard fertility investigations,which include semen analysis, assessment of ovulation, and tubal patency test. These tests have been selected as they have definitive correlation with pregnancy. It is estimated that a standard fertility evaluation will fail to identify an abnormality in approximately 15% to 30% of infertile couples. The reported incidence of such unexplained infertility varies according to the age and selection criteria in the study population. We conducted a review of the literature via MEDLINE. Articles were limited to English-language, human studies published between 1950 and 2013. Since first coined more than 50 years ago, the term unexplained infertility has been a subject of debate. Although additional investigations are reported to explain or define other causes of infertility, these have high false-positive results and therefore cannot be recommended for routine clinical practice. Couples with unexplained infertility might be reassured that even after 12 months of unsuccessful attempts, 50% will conceive in the following 12 months and another 12% in the year after.
Guideline Appraisal · Guideline Variation and Disagreement
Grande G et al., 2024·Human reproduction (Oxford, England)
Sir, We read with interest the guideline about unexplained infertility developed by the Guideline Group (GDG) on Unexplained Infertility of ESHRE (Romualdi et al., 2023). We appreciated the efforts to have clear, evidence-based recommendations on this important topic but would like to point out fundamental problems and misunderstandings on the approach to the male factor. Although we can agree on the definition of unexplained infertility made by the GDG as ‘infertility in couples with apparently normal ovarian function, fallopian tubes, uterus, cervix and pelvis, age ≤40 years and with adequate coital frequency; and apparently normal testicular function, genito-urinary anatomy, and a normal ejaculate’, substantial differences in the diagnostic approach for the female and male partner are then proposed to assess these features. In fact, a comprehensive evaluation of the female partner is recommended considering ovulation, ovarian reserve, tubal factor, uterine factor, and even vaginal microbiota, whereas the approach to the male partner is limited only to semen analysis. The entire following line of reasoning assumes that a normal semen analysis is sufficient to rule out male factor infertility and no further examination is needed. There are several problems with this approach. First of all, it is quite clear that a normal testicular function and genito-urinary anatomy cannot be determined by semen analysis only, but instead require a combination of, at least, history, physical examination, endocrine assessment, and ultrasound examination of the testes and seminal tract. For semen analysis, the GDG correctly refers to the World Health Organization (WHO) manual for semen analysis (6th edition) (World Health Organization, 2021) but misinterpreted it because the GDG does not recommend any other diagnostic procedure when ‘semen analysis according to WHO criteria is normal’. Not only did the GDG neglect to consider a broad approach to understand whether the testicular function and genito-urinary anatomy are normal, but also it made substantial misunderstandings on the role and significance of semen analysis and its relation with fertility. A main point is that the WHO manual does not define normal semen analysis (World Health Organization, 2021), simply because the so-called ‘reference values’, and in particular the fifth percentile reference, do not represent cut-off limits for fertility and infertility. These values represent the distribution of results from around 3500 presumed fertile men and they are ‘not sufficient to establish clinically useful decision limits’ (World Health Organization, 2021). WHO is very clear when stating that ‘reference values cannot be used to distinct limits between fertile and subfertile men’, ‘the lower fifth percentile of data from men in the reference population does not represent a limit between fertile and infertile men’, and ‘for an individual patient, a semen analysis is never prognostic of infertility’. Since, it is well known that natural fertility is possible with semen parameters below the fifth percentile and infertility with semen parameters above the fifth percentile, a ‘normal ejaculate’ cannot be defined. Therefore, there is a ‘problem in applying a dichotomous categorization to fertility that must be considered a continuum. It is also well known that there is a substantial overlap of semen examination results between fertile and infertile men’ (World Health Organization, 2021). Hence, the reference limits cannot be used as a specific limit between infertile and fertile men (Björndahl et al., 2023). Results of semen examination below the WHO reference values do not automatically mean that the problem of the couple resides in the male, and results above the limits do not always mean that the male partner of an infertile couple is undoubtedly fertile (Björndahl et al., 2023). Semen analysis is fundamental in the initial investigation of the male partner of an infertile couple, but its [truncated]
Outcomes and Effectiveness · Outcomes by Diagnosis
Wang R et al., 2019·The Cochrane database of systematic reviews·Free full text on PubMed Central
Clinical management for unexplained infertility includes expectant management as well as active treatments, including ovarian stimulation (OS), intrauterine insemination (IUI), OS-IUI, and in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI).Existing systematic reviews have conducted head-to-head comparisons of these interventions using pairwise meta-analyses. As this approach allows only the comparison of two interventions at a time and is contingent on the availability of appropriate primary evaluative studies, it is difficult to identify the best intervention in terms of effectiveness and safety. Network meta-analysis compares multiple treatments simultaneously by using both direct and indirect evidence and provides a hierarchy of these treatments, which can potentially better inform clinical decision-making. To evaluate the effectiveness and safety of different approaches to clinical management (expectant management, OS, IUI, OS-IUI, and IVF/ICSI) in couples with unexplained infertility. We performed a systematic review and network meta-analysis of relevant randomised controlled trials (RCTs). We searched electronic databases including the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, the Cochrane Central Register of Studies Online, MEDLINE, Embase, PsycINFO and CINAHL, up to 6 September 2018, as well as reference lists, to identify eligible studies. We also searched trial registers for ongoing trials. We included RCTs comparing at least two of the following clinical management options in couples with unexplained infertility: expectant management, OS, IUI, OS-IUI, and IVF (or combined with ICSI). Two review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardised forms. The primary effectiveness outcome was a composite of cumulative live birth or ongoing pregnancy, and the primary safety outcome was multiple pregnancy. We performed a network meta-analysis within a random-effects multi-variate meta-analysis model. We presented treatment effects by using odds ratios (ORs) and 95% confidence intervals (CIs). For the network meta-analysis, we used Confidence in Network Meta-analysis (CINeMA) to evaluate the overall certainty of evidence. We included 27 RCTs (4349 couples) in this systematic review and 24 RCTs (3983 couples) in a subsequent network meta-analysis. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity.Ten RCTs including 2725 couples reported on live birth. Evidence of differences between OS, IUI, OS-IUI, or IVF/ICSI versus expectant management was insufficient (OR 1.01, 95% CI 0.51 to 1.98; low-certainty evidence; OR 1.21, 95% CI 0.61 to 2.43; low-certainty evidence; OR 1.61, 95% CI 0.88 to 2.94; low-certainty evidence; OR 1.88, 95 CI 0.81 to 4.38; low-certainty evidence). This suggests that if the chance of live birth following expectant management is assumed to be 17%, the chance following OS, IUI, OS-IUI, and IVF would be 9% to 28%, 11% to 33%, 15% to 37%, and 14% to 47%, respectively. When only including couples with poor prognosis of natural conception (3 trials, 725 couples) we found OS-IUI and IVF/ICSI increased live birth rate compared to expectant management (OR 4.48, 95% CI 2.00 to 10.1; moderate-certainty evidence; OR 4.99, 95 CI 2.07 to 12.04; moderate-certainty evidence), while there was insufficient evidence of a difference between IVF/ICSI and OS-IUI (OR 1.11, 95% CI 0.78 to 1.60; low-certainty evidence).Eleven RCTs including 2564 couples reported on multiple pregnancy. Compared to expectant management/IUI, OS (OR 3.07, 95% CI 1.00 to 9.41; low-certainty evidence) and OS-IUI (OR 3.34 95% CI 1.09 to 10.29; moderate-certainty evidence) increased the odds of multiple pregnancy, and there was insufficient evidence of a difference between IVF/ICSI and expectant management/IUI (OR 2.66, 95% CI 0.68 to 10.43; low-certainty evidence). These findings suggest that if the chance of multiple pregnancy following expectant management or IUI is assumed to be 0.6%, the chance following OS, OS-IUI, and IVF/ICSI would be 0.6% to 5.0%, 0.6% to 5.4%, and 0.4% to 5.5%, respectively.Trial results show insufficient evidence of a difference between IVF/ICSI and OS-IUI for moderate/severe ovarian hyperstimulation syndrome (OHSS) (OR 2.50, 95% CI 0.92 to 6.76; 5 studies; 985 women; moderate-certainty evidence). This suggests that if the chance of moderate/severe OHSS following OS-IUI is assumed to be 1.1%, the chance following IVF/ICSI would be between 1.0% and 7.2%. AUTHORS' There is insufficient evidence of differences in live birth between expectant management and the other four interventions (OS, IUI, OS-IUI, and IVF/ICSI). Compared to expectant management/IUI, OS may increase the odds of multiple pregnancy, and OS-IUI probably increases the odds of multiple pregnancy. Evidence on differences between IVF/ICSI and expectant management for multiple pregnancy is insufficient, as is evidence of a difference for moderate or severe OHSS between IVF/ICSI and OS-IUI.
Quaas A et al., 2008·Rev Obstet Gynecol·Free full text on PubMed Central
Over the past decade, significant advances have occurred in the diagnosis and treatment of reproductive disorders. In this review, we discuss the routine testing performed to diagnose unexplained infertility. We also discuss additional testing, such as assessment of ovarian reserve, and the potential role of laparoscopy in the complete workup of unexplained infertility. Finally, we outline the available therapeutic options and discuss the efficacy and the cost-effectiveness of the existing treatment modalities. The optimal treatment strategy needs to be based on individual patient characteristics such as age, treatment efficacy, side-effect profile, and cost considerations.
Research Methods › Evidence Synthesis › Systematic Reviews · Infertility › Evaluation › Unexplained Infertility · Clinical Guidelines and Standards › Diagnostic Criteria and Classification › Diagnostic Criteria
PMID 37957032 37957032 DOI 10.1111/1471-0528.17697 10.1111/1471-0528.17697 Raperport et al. 2024, Raperport 2024
Cite this article
Raperport, C., Desai, J., Qureshi, D., Rustin, E., Balaji, A., Chronopoulou, E., Homburg, R., Khan, K. S., & Bhide, P. (2024). The definition of unexplained infertility: A systematic review. BJOG : an international journal of obstetrics and gynaecology, 131(7), 880-897. https://doi.org/10.1111/1471-0528.17697
Raperport C, Desai J, Qureshi D, Rustin E, Balaji A, Chronopoulou E, Homburg R, Khan KS, Bhide P. The definition of unexplained infertility: A systematic review. BJOG : an international journal of obstetrics and gynaecology. 2024;131(7):880-897. doi:10.1111/1471-0528.17697
Raperport, C., et al. "The definition of unexplained infertility: A systematic review." BJOG : an international journal of obstetrics and gynaecology, vol. 131, no. 7, 2024, pp. 880-897.