The presence, clarity, and consistency of definitions in pregnancy outcomes in infertility trials: a systematic review.

Study Question: How frequently do infertility trials report live birth and pregnancy, and how consistently were their definitions reported?

Summary Answer: One-third of 1425 infertility trials published in the last decade reported live birth, with one in eight reporting clinical pregnancy, ongoing pregnancy, and live birth concurrently; absent, ambiguous, or heterogeneous definitions were common.

What Is Known Already: Absent or inconsistent outcome definitions in randomized controlled trials (RCTs) limit their interpretation and complicate subsequent evidence synthesis. While reporting live birth in infertility trials has been a long-running recommendation, the extent to which this is adhered to, and the temporal trend of adherence, is unclear. Furthermore, it is unknown if outcome reporting in infertility trials is clear and consistent.

Study Design, Size, Duration: We studied all RCTs in infertility published between 2012 and 2023. We aimed to assess (i) whether biochemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth were reported; the temporal trends in reporting these pregnancy outcomes, and compare the characteristics of trials reporting each type of outcome; (ii) whether and how these pregnancy outcomes were defined.

Participants/materials, Setting, Methods: We systematically searched Embase, Medline, and CENTRAL for RCTs in infertility from January 2012 to August 2023. RCTs involving infertile women that reported either biochemical pregnancy, clinical pregnancy, ongoing pregnancy, or live birth were eligible. Secondary analyses, interim analyses, or conference abstracts were not eligible. Two authors independently screened articles. We extracted pregnancy definitions and trial characteristics primarily using text mining in R, a programming environment for data analysis, and supplemented by manual checking. The accuracy of extracted data was validated in a random sample of 50 articles, with sensitivity and specificity all at or above 90%.

Main Results And The Role Of Chance: We included 1425 infertility RCTs. Among these, 419 (29.4%) reported biochemical pregnancy. While 1359 (95.4%) RCTs reported clinical pregnancy, 404 (28.4%) reported ongoing pregnancy, and 484 (34.0%) reported live birth, only 174 (12.2%) reported all three outcomes. The proportion of trials reporting live birth increased from 23.1% in 2012 to 33.7% in 2023. Trials reporting up to biochemical pregnancy or clinical pregnancy were more likely to be unregistered, smaller, single-centered, and published in non-first quarter journals. Definitions for biochemical, clinical, ongoing pregnancy, and live birth were provided in 68.5% (287/419), 64.5% (876/1359), 70.5% (285/404), and 41.1% (199/484) of articles reporting on these outcomes. Among 876 clinical pregnancy definitions, 63.4% (n = 555) specified the pregnancy confirmation timing. Of the 220 definitions that reported gestational weeks (ranging from 4 to 16 weeks), the most common cut-off was 6 weeks, used in 48.2% (n = 106) of cases. For ongoing pregnancy definitions, 96.1% (n = 274) of the 285 definitions included gestational age in weeks (ranging from 6 to 32 weeks), with 12 weeks being the most common cut-off used in 49.1% (n = 140) of definitions. Among 199 live birth definitions, 62.3% (n = 124) used a gestational age threshold (ranging from 20 to 37 weeks), with 24 weeks being the most common cut-off, used in 28.6% (n = 57) of trials.

Limitations, Reasons For Caution: Due to the vast data we needed to extract, we used text-mining supplemented by manual data extraction. While we optimized the text-mining algorithm attempting to identify all types of outcome definitions and manually curated all extracted definitions, definitions were missed in less than 10% of randomly checked studies, which is a limitation of this study. We only described definition patterns in published RCTs, and our results cannot be extrapolated to unpublished RCTs.

Wider Implications Of The Findings: Despite long-standing recommendations to report live birth in infertility trials, in the last decade only a third of RCTs did so. This highlights a disconnection between the advocated outcome and what researchers are reporting. We observed an encouraging trend that there has been a consistent rise in the proportion of trials reporting live birth. Furthermore, the significant lack and variability of pregnancy definitions underscore the imperative to increase the dissemination and uptake of standardized pregnancy outcomes.

Study Funding/competing Interest(s): No funding was received for the study. Q.F. reports receiving a PhD scholarship from Merck. B.W.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.M. reports consultancy, travel support, and research funding from Merck and consultancy for Organon and Norgine. B.W.M. holds stock from ObsEva. W.T.L. is supported by an NHMRC Investigator grant (GTN2016729). W.L.L. reports receiving a PhD scholarship from the China Scholarship Council. T.D.H and S.L. are employees of Merck Healthcare KGaA, Darmstadt, Germany. R.W. is supported by an NHMRC Investigator grant (GTN2009767). The other author has no conflict of interest to declare.

Registration Number: CRD42024498624.