Prenatal phthalate exposure in relation to placental corticotropin releasing hormone (pCRH) concentrations in the CANDLE study

Abstract

BACKGROUND AND AIM: Studies suggest that prenatal phthalate exposure may contribute to preterm birth. Placental corticotropin releasing hormone (pCRH) may be a “placental clock” whereby levels rise in late pregnancy, triggering parturition. To explore a possible mechanism linking phthalates to preterm birth, the ECHO-PATHWAYS Consortium examined associations between phthalate exposure and pCRH concentrations in mid-late pregnancy. METHODS: We measured urinary phthalate metabolites and serum pCRH in the 2nd(T2: mean 23.0 weeks) and 3rd(T3: mean 31.8 weeks) trimesters in CANDLE study participants (n=1018). We fit covariate adjusted models associating log(pCRH) (at each timepoint) with 15 log-transformed phthalate metabolites and Σdi(2-ethylhexyl)phthalate(ΣDEHP), in individual regression models and as mixtures using weighted quantile sums (WQS) regression. We evaluated effect modification by gestational diabetes (GDM) and gestational hypertension (GHTN). RESULTS:Median pCRH was 37.6±75.0 and 235.2±429.0 pg/mL in T2 and T3, respectively. In WQS models, phthalate mixtures were not associated with CRH at either timepoint. Monobutyl phthalate was associated with higher T2 pCRH (β=0.07, 95%CI:0.004, 0.13). Monoethyl phthalate was associated with lower pCRH at both visits, while monomethyl phthalate was associated with higher T3 pCRH (β=0.04, 95%CI:0.01, 0.08). In interaction models, positive associations were observed between each phthalate metabolite and T3 pCRH among women with GHTN (n=102), whereas each association was negative for women without GHTN (p0.05 for interaction in 9 of 15 models). By contrast, among women with GDM (n=59), most individual phthalate metabolites were associated with lower pCRH at T3, with associations being strongest for the DEHP metabolites. CONCLUSIONS:In the whole cohort, we observed few associations between phthalate metabolites and CRH. However associations between phthalate exposure and pCRH in late pregnancy may differ among women with or without GDM or GHTN. More research is needed to understand whether women with pregnancy complications may be more vulnerable to reproductive effects of phthalates. KEYWORDS: phthalates, pregnancy, CRH, preterm birth, pregnancy complications, endocrine disruption