Assisted reproductive technology and reproductive, perinatal, and maternal outcomes: evidence from an umbrella review of systematic reviews with meta-analyses of randomized controlled trials

Abstract Background The expanding global use of assisted reproductive technology (ART) warrants rigorous evidence synthesis. This umbrella review (UR) evaluated the strength and validity of evidence on ART effects on reproductive, perinatal, and maternal outcomes. Methods We searched five databases and reference lists (Inception to 15 June 2025) to identify systematic reviews with meta-analyses of randomized controlled trials (RCTs). For each extracted association, we performed a reanalysis using random-effects models, calculated the 95% prediction interval, heterogeneity, small-study effect, and evaluated excess significance bias. The quality of systematic reviews was evaluated using A Measurement Tool to Assess Systematic Reviews (AMSTAR). The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system, and the strength of evidence was also evaluated on a grading scale. This study is registered with PROSPERO (CRD42024563290). Results The UR included 23 meta-analyses (200 associations from 109 RCTs), with 69.6% rated high quality. Regarding reproductive outcomes, high credibility of evidence showed that frozen embryo transfer (ET), compared with fresh ET, was associated with a reduced risk of ectopic pregnancy. Sequential ET significantly improved ongoing pregnancy rates relative to single blastocyst or cleavage-stage ET. Single ET, compared with double ET, reduced multiple births, but decreased live birth rate. Regarding perinatal and maternal outcomes, high-credibility evidence indicated that frozen ET, compared with fresh ET, was associated with increased birth weight of singletons, and a higher rate of large for gestational age infants and miscarriage, but a lower rate of small for gestational age infants in cumulative measures and ovarian hyperstimulation syndrome. While frozen ET significantly reduced the risk of preterm delivery, it paradoxically increased the rate of neonatal hospitalization. Conclusions This UR delineates trade-offs between ART and reproductive, perinatal, and maternal outcomes. Clinical decisions should balance effectiveness against potential risks, with future research focusing on personalized treatment strategies.