Trial characteristics, geographic distribution, and selected methodological issues of 1425 infertility trials published from 2012 to 2023: a systematic review
Authors: Feng Qian , Li Wanlin , Crispin James , Longobardi Salvatore , D’Hooghe Thomas , Mol Ben W , Li Wentao 
Published: January 2025

Abstract

STUDY QUESTION
What are the trial characteristics, geographic distribution, and selected methodological issues of randomized controlled trials (RCTs) in infertility published from 2012 to 2023?

SUMMARY ANSWER
Of the 1425 infertility RCTs, over two-thirds focused on IVF, nearly two-fifths did not use pregnancy or live birth as the primary outcome, a third lacked a primary outcome, a half were unregistered, and just over half were conducted in China (22%), Iran (20%), or Egypt (10%).

WHAT IS KNOWN ALREADY
RCTs are the main source of evidence on the effectiveness of interventions. Knowledge about RCTs in infertility from the recent past will help to pinpoint research gaps and prioritize the future research agenda. Here, we aim to present a descriptive analysis of trial characteristics, geographic distribution, and selected methodological issues in infertility trials published in the last decade.

STUDY DESIGN, SIZE, DURATION
This is a systematic review. We systematically searched Embase, Medline, and Cochrane Central for RCTs in infertility from January 2012 to August 2023. RCTs involving subfertile women and women who reported pregnancy endpoints were eligible, while conference abstracts or secondary analyses were not. We did not limit our search based on the language of the articles.

PARTICIPANTS/MATERIALS, SETTING, METHODS
The full articles were text-mined and manually extracted for the description of trials’ characteristics (e.g. sample size, blinding method, types of intervention), the country where the patients were recruited, and methodological issues (trial registrations and specification of primary outcomes). We extracted funding statements from Dimensions, a literature database chosen for its comprehensive and robust metadata. Gross domestic product (GDP) data were obtained from the United Nations’ official website. The accuracy of extracted data was validated in a random sample of 50 articles, and false positivity and false negativity were all at or below 8%. We used descriptive statistics, including frequencies and percentages to illustrate the overall and temporal trends.

MAIN RESULTS AND THE ROLE OF CHANCE
Among 8757 records, we found 1425 eligible RCTs, with a median sample size of 140, and 33.3% had a sample size &lt;100. Most (69.6%) of the trials focused on IVF, with the rest focusing on ovulation induction (12.4%), intrauterine insemination (10.6%), surgeries (4.8%), or other interventions (2.6%). Regarding the geographic distribution, China (n = 310), Iran (n = 284), and Egypt (n = 138) contributed to 51% of the RCTs, followed by Turkey (n = 82), India (n = 71), and the USA (n = 69); mainland Europe produced 343 trials. Ranked by publications of trials per trillion GDP, Greece had the most papers with 4.6, followed by Iraq at 3.9, and Iran at 2.5. Regarding trial registration, 47.8% of trials were unregistered, the proportion of studies that were unregistered halved from 70.0% in 2012 to 34.6% in 2022. Of all RCTs, 37.6% had primary outcomes unspecified; the proportion of trials specifying primary outcomes increased from 49.5% in 2012 to 61.4% in 2022. The proportion of trials which declared receiving no funding was 76.9%.

LIMITATIONS, REASONS FOR CAUTION
We primarily used text mining for data extraction. Despite optimizing the algorithm to identify all outcome definitions and manually curating the extracted data, there were inaccuracies in data extraction; however, the false positivity and false negativity of data extraction were all at or below 8%. Also, we focused on trials reporting pregnancy outcomes, as these are of primary interest to patients and carry significant implications on clinical practice. However, we acknowledge that early-stage trials with only upstream endpoints also play an important role and should be considered when evaluating the full spectrum of infertility trials. Finally, we only included published RCTs and hence, our results cannot be extrapolated to unpublished RCTs.

WIDER IMPLICATIONS OF THE FINDINGS
The domination of RCTs on IVF calls for a reconsideration of other topics to be studied and a realignment of research priorities. The imbalanced geographic distribution of infertility trials raises questions about the generalizability of study results and equity in the distribution of healthcare resources. The prevalence of trials without registration or primary outcomes specified highlights the imperative to improve trial design and reporting quality. Encouragingly, the improving trial registrations suggest the enforcement of trial registrations from the journals is effective.

STUDY FUNDING/COMPETING INTEREST(S)
B.W.M. is supported by an NHMRC Investigator grant (GNT1176437). W.T.L. is supported by an NHMRC Investigator grant (GTN2016729). W.L.L. reports receiving a PhD scholarship from the China Scholarship Council. Q.F. reports receiving a PhD scholarship from Merck. B.W.M. reports receiving consultancy fees, travel support, and research funding from Merck; consultancy fees from Organon and Norgine; and stock ownership in ObsEva. T.D.H and S.L. are employees of Merck. W.T.L., W.L.L., and J.C. report no conflicts of interest.

REGISTRATION NUMBER
PROSPERO CRD42024498624.