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Modified natural vs. natural cycle for endometrial preparation in frozen embryo transfer: a meta-analysis
Christos Venetis1, Kokkoni Kiose2, Maria Apostolidou2
1Unit for Human Reproduction, 1st Dept of Obstetrics and Gynaecology, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece; Center for Big Data Research in Health, Faculty of Medicine & Health, University of New South Wales, Sydney, Australia.
Importance:
Frozen-thawed embryo transfer cycles have risen substantially. Synchronization between the embryo and endometrium is achieved via natural or artificial hormonal preparation. Emerging data associate artificial regimens with hypertensive disorders, potentially favoring natural cycles. Because of their limited scheduling flexibility, modified natural cycles (mNCs) have been proposed, although equivalence in live birth outcomes remains unconfirmed.
Objective:
To identify whether there is a difference in the probability of live birth between women undergoing frozen embryo transfer (FET) in the mNC and those in the natural cycle (NC).
Data Sources:
A literature search was conducted until October 2024 in MEDLINE, Embase, Cochrane CENTRAL, Scopus, Web of Science and Clinicaltrials.gov to identify eligible randomized controlled trials (RCTs).
Study Selection And Synthesis:
Data were independently extracted by three reviewers. Quality and trustworthiness were assessed using the RoB2 tool and the Trustworthiness in RAndomised Controlled Trials (TRACT) checklist, respectively. Sensitivity analysis was performed by excluding studies with a high risk of bias. Meta-analysis was performed using the random or fixed effects model depending on the presence or absence of significant statistical (I2>50%) or clinical heterogeneity.
Main Outcomes:
The primary outcome was live birth. Secondary outcomes included clinical and ongoing pregnancy, cycle cancellation, and miscarriage.
Results:
Six RCTs (n = 1,708) (published between 2010 and 2024) were identified. Three RCTs were deemed to have a high risk of bias. All studies were considered trustworthy for inclusion in the meta-analysis according to the TRACT checklist. No significant difference was observed in live birth rates (risk ratio [RR]: 0.93, 95% confidence interval [CI]: 0.74-1.17; I2 = 0%, 4 studies, n = 1,280; [sensitivity analysis: RR: 0.90, 95% CI: 0.32-2.52; I2 = 0%, 2 studies, n = 1,060]), ongoing pregnancy rates (RR: 0.74, 95% CI: 0.37-1.51; I2 = 1%, 3 studies, n = 536), and clinical pregnancy rates (RR: 0.86, 95% CI: 0.67-1.10; I2 = 0%, 4 studies, n = 648). Similarly, no significant difference was observed in cycle cancellation rates and miscarriage rates. The sensitivity analysis, performed by excluding the three studies deemed to be at high risk of bias, did not materially alter the results obtained for all the aforementioned outcomes.
Conclusion And Relevance:
Clinicians and patients should be informed that, on the basis of the best available evidence, frozen-thawed embryo transfer in mNC results in comparable live birth rates with NC, making it a pragmatic option for scheduling or convenience.
Trial Registration:
The protocol for the systematic review was registered in The International Prospective Register of Systematic Reviews (PROSPERO; CRD42024609589) before the quantitative analysis.
