The definition of unexplained infertility: A systematic review

Claudia Raperport; Jessica Desai; Danya Qureshi; Edward Rustin; Aparna Balaji; Elpiniki Chronopoulou; Roy Homburg; Khalid Saeed Khan; Priya Bhide

doi:10.1111/1471-0528.17697

Research Methods Evidence Synthesis

The definition of unexplained infertility: A systematic review

Raperport C, Desai J, Qureshi D, Rustin E, Balaji A, Chronopoulou E, Homburg R, Khan KS, Bhide P

Published June 2024 BJOG : an international journal of obstetrics and gynaecology, 131(7), 880-897

DOI 10.1111/1471-0528.17697 PMID 37957032

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

This review examined how 258 published studies defined unexplained infertility. The differences can skew results when studies are combined. The authors propose shared criteria: semen tests graded by WHO limits, both tubes open, confirmed ovulation, and a normal uterine cavity. The authors note they used only two databases and left out non-English papers. The findings support more research on shared criteria for unexplained infertility.

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.

Topics

Research Methods › Evidence Synthesis › Systematic Reviews · Infertility › Evaluation › Unexplained Infertility · Clinical Guidelines and Standards › Diagnostic Criteria and Classification › Diagnostic Criteria

Claudia Raperport, Jessica Desai, Danya Qureshi, Edward Rustin, Aparna Balaji, Elpiniki Chronopoulou, Roy Homburg, Khalid Saeed Khan, Priya Bhide

C Raperport, Jess Desai, J Desai, D Qureshi, Ed Rustin, Ted Rustin, E Rustin, A Balaji, E Chronopoulou, R Homburg, K Khan, P Bhide

PMID 37957032 37957032 DOI 10.1111/1471-0528.17697 10.1111/1471-0528.17697 Raperport et al. 2024, Raperport 2024

Keywords

definition, heterogeneity, inclusion criteria, unexplained infertility

The definition of unexplained infertility: A systematic review

Studies of unexplained infertility use widely different criteria

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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Keywords