Assisted reproductive technology and the risk of birth defects mediated by multifetal pregnancy: evidence from the China Birth Cohort Study.

Background: Both assisted reproductive technology (ART) and multifetal pregnancy have been reported to be associated with an increased risk of birth defects (BDs). However, it is unclear whether multifetal pregnancy is a mediator that increases the risk of BDs in ART-conceived pregnancies.

Objectives: To investigate the risk of BDs associated with ART, and to quantify the mediating effect of multifetal pregnancy between ART and BDs.

Study design: From November 2017 to August 2021, 132,386 pregnant women from 50 study sites in 17 provinces of China were monitored from their first trimester until delivery (or miscarriage/termination). BDs were detected in both live births and stillbirths. Directed acyclic graph was drawn to understand the causal relationship between ART and BDs, and inverse probability of treatment weighting was used to adjust for confounders. Then, log-binomial generalized estimating equation was established in the inverse probability weighted cohort to estimate the adjusted relative risk (RR) of BDs associated with ART compared to natural conception, while addressing the cluster effect of study sites. Mediation analysis was performed to assess the mediating effect of multifetal pregnancy between ART and BDs. Number needed to harm was calculated for multifetal pregnancy versus singleton pregnancy among ART-conceived pregnancies.

Results: A total of 126,035 naturally conceived and 5124 ART-conceived pregnancies were included in the analysis. The incidence of BDs in the ART conception group (4.2%) was significantly higher than that in the natural conception group (2.5%), with an adjusted RR of 1.48 (95% CI, 1.24 to 1.78). Multifetal pregnancies were also more common in the ART conception group (21.4%) than the natural conception group (1.1%). Mediation through multifetal pregnancy accounted for 25% of the risk of BDs associated with ART. Notably, if ART-conceived pregnant women could have singleton pregnancy rather than multifetal pregnancy, one case of BDs could be potentially avoided for every 52 (95% CI, 29 to 233) pregnancies.

Conclusions: Multifetal pregnancy mediated the effect of ART on BDs. Therefore, when ART treatment is needed, single embryo transfer should be considered under clinically feasible conditions for the prevention of BDs.