The risk of congenital malformations and neonatal outcomes among singletons and twins born after in vitro fertilization/intracytoplasmic sperm injection: a systematic review and Bayesian network meta-regression analysis

While in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) have been widely used for infertility treatment, concerns still persist towards the potential risks of congenital malformations and adverse neonatal outcomes. In this work, we estimate the risk of congenital malformations and neonatal outcomes among singletons and twins born after IVF or ICSI.

The PubMed, Cochrane Library, Scopus, Embase, and Google Scholar databases were systematically searched to identify eligible studies. A Bayesian network meta-regression model was used to synthesize direct and indirect evidence. The natural logarithm of the hazard ratio (lnHR) and its standard error (SElnHR) were calculated to obtain pooled hazard ratios (HRs) with 95% confidence intervals (CIs), adjusting for the number of fetuses. The primary outcome was congenital malformations (CM). All analyses were performed using RStudio version 4.3.1.

A total of 24 studies were included in the Bayesian network meta-regression, comprising 105,152 IVF, 254,538 ICSI, and 4,048,050 spontaneous conception (SC) pregnancies. Compared with SC, singletons conceived by IVF and ICSI showed higher risks of CM (HR 1.32, 95% CI 1.19–1.48; HR 1.47, 95% CI 1.35–1.62). For circulatory system malformations, singletons conceived by ICSI had a higher risk than those conceived by SC (HR 1.47, 95% CI 1.19–1.87) and IVF (HR 1.41, 95% CI 1.04–1.93). Among twins, ICSI was associated with increased risks of CM (HR 1.17, 95% CI 1.05–1.32), preterm birth (PTB) (HR 1.39, 95% CI 1.04–1.98), and perinatal death (HR 1.61, 95% CI 1.12–2.45). Singletons conceived by IVF also showed higher risks of PTB (HR 1.54, 95% CI 1.10–2.22) and low birth weight (LBW) (HR 1.59, 95% CI 1.13–2.21).

Both IVF and ICSI were associated with higher risks of congenital malformations in singletons, while only ICSI was associated with elevated risks in twins. IVF was associated with increased risks of preterm birth and low birth weight in singletons, whereas ICSI was associated with greater risks of circulatory malformations in singletons and preterm birth and perinatal death in twins. These findings may assist clinicians in counseling ART patients about potential risks and underscore the importance of vigilant perinatal monitoring, rather than serving as direct clinical recommendations.