Co-exposure to phthalates and their alternatives in early pregnancy and the subsequent risk of pregnancy complications: A nested case-control study

Pregnancy complications pose a major hazard to maternal and fetal health and increase the global burden of disease. Phthalates are extensively encountered by pregnant women. To estimate associations of individual phthalate or mixture exposure in early pregnancy with pregnancy complications, a nested case-control study was conducted, in which cases with gestational diabetes mellitus (GDM), gestational hypertension (PIH), premature rupture of membranes (PROM), placental abnormality (PA), intrauterine distress (IUD), insufficient amniotic fluid (IAF), anemia and preterm birth (PB) were matched with controls by fetal sex, maternal age, sampling year and season, and measured urinary phthalate metabolites in the first trimester. Conditional logistic regression and quantile g-computation models were employed to assess associations of individual phthalate and mixture exposure with pregnancy complications. The conditional logistic regression revealed that certain phthalate exposure in early pregnancy was notably associated with higher risks of pregnancy complications, especially GDM, PIH, and IAF. For example, compared with the 1st tertile, the 2nd and 3rd tertiles of exposure were significantly associated with elevated odds of GDM, PIH, and IAF, with ORs of 1.40–1.76 and 1.38–2.98, 1.41–1.67 and 1.36–2.05, and 2.17–3.17 and 1.97–2.54, respectively. Moreover, these associations varied by fetal sex. Additionally, quantile g-computation models showed that phthalate mixture exposure was significantly associated with elevated ORs of GDM (OR = 1.32; 95% CI: 1.09, 1.74), PIH (OR = 1.49; 95% CI: 1.04, 1.78), and IAF (OR = 1.73; 1.06, 2.47). MBP and DEHP metabolites were likely the major contributors to the joint effects. Prenatal phthalate exposure during early pregnancy may serve as a potential risk factor for pregnancy complications. Further studies are essential to validate these findings.