Causal Effects of Common Pregnancy Complications on Neonatal Birth Weight: A Mendelian Randomization Study

This study aimed to investigate, using a two-sample Mendelian randomization approach, the potential causal effects of major pregnancy complications on neonatal birth weight.

Summary statistics from genome-wide association studies (GWAS) for intrahepatic cholestasis of pregnancy (ICP), gestational diabetes mellitus (GDM), preeclampsia/eclampsia, placenta previa, and placental abruption were obtained from the FinnGen R9 consortium. Birth weight data were obtained from the Early Growth Genetics (EGG) consortium. We conducted a two-sample MR analysis to assess the causal effects of these pregnancy complications on neonatal birth weight. Univariate MR (UVMR) analyses were mainly conducted using inverse variance weighting (IVW), supported by complementary methods including MR-Egger and weighted median approaches. Sensitivity analyses employed several tests to evaluate robustness, including Cochran's Q test for heterogeneity, the MR-Egger intercept test for directional pleiotropy, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) for outlier detection, and leave-one-out analysis to assess result stability. Multivariable MR (MVMR) was applied to determine the independent effects of these pregnancy complications on neonatal birth weight.

UVMR showed that ICP was associated with lower neonatal birth weight (β_UVMR = -0.008, 95% CI: -0.013 to -0.002, P = 0.005), and genetically predicted preeclampsia or eclampsia was associated with lower neonatal birth weight (β_UVMR = -0.041, 95% CI: -0.070 to -0.011, P = 0.007). In contrast, genetically predicted GDM was associated with higher neonatal birth weight (β_UVMR = 0.048, 95% CI: 0.024 to 0.073, P < 0.001). No evidence of causal association was observed for placenta previa (β_UVMR = -0.003, 95% CI: -0.010 to 0.004, P = 0.374) or placental abruption (β_UVMR = -0.001, 95% CI: -0.007 to 0.006, P = 0.856) with neonatal birth weight. Sensitivity analysis showed no evidence of substantial heterogeneity or horizontal pleiotropy. Multivariable MR results were directionally consistent with the univariate findings.

This study provides genetic evidence supporting causal associations of ICP and preeclampsia/eclampsia with lower neonatal birth weight, and of GDM with higher neonatal birth weight. These findings enhance understanding of the genetic links between pregnancy complications and neonatal birth weight.