Abstract
BACKGROUND: Adverse events during pregnancy are implicated in increasing the risk of congenital malformations in offspring. Current research does not fully encompass the spectrum of adverse events nor the mechanisms by which they affect fetal development. METHODS: A two-sample and two-step Mendelian randomization (MR) study was conducted to assess the association between adverse events during pregnancy and congenital malformations in offspring, and to investigate the mediating role of circulating metabolites in linking these adverse events to congenital malformations. RESULTS: Maternal bleeding during pregnancy was associated with an increased risk of congenital ichthyosis and a decreased risk of congenital hydrocephalus. Anemia during pregnancy showed a significant correlation with an increased risk of atrioventricular septal defects. Placenta previa and placental abruption were associated with a decreased risk of congenital hydrocephalus and an increased risk of congenital malformation of the breast. Premature birth was associated with an increased risk of complex heart defects. Fetal malposition correlated with a decreased risk of cleft lip. Urogenital infection during pregnancy was linked to an increased risk of congenital malformation of cardiac chambers and connection. Glycine may mediate approximately 1.1% of the effect of premature birth on the risk of complex heart defects. CONCLUSION: MR was employed to elucidate the mediating role of circulating metabolites in the impact of these adverse events on congenital malformations, providing new insights into their causal relationships. However, the underlying mechanisms remain unclear, necessitating further research and clinical trials to elucidate these relationships.