Prenatal Exposure to Nonpersistent Chemical Mixtures and Fetal Growth: A Population-Based Study

Background: Prenatal exposure to mixtures of nonpersistent chemicals is universal. Most studies examining these chemicals in association with fetal growth have been restricted to single exposure models, ignoring their potentially cumulative impact. Objective: We aimed to assess the association between prenatal exposure to a mixture of phthalates, bisphenols, and organophosphate (OP) pesticides and fetal measures of head circumference, femur length, and weight. Methods: Within the Generation R Study, a population-based cohort in Netherlands (n=776), urinary concentrations of 11 phthalate metabolites, 3 bisphenols, and 5 dialkylphosphate (DAP) metabolites were measured at 25 weeks of gestation and averaged. Ultrasound measures of head circumference, femur length, and estimated fetal weight (EFW) were taken at 18-25 and > 25 weeks of gestation, and measurements of head circumference, length, and weight were performed at delivery. We estimated the difference in each fetal measurement per quartile increase in all exposures within the mixture with quantile g-computation. Results: The average EFW at 18-25 wk and > 25 wk was 369 and 1,626g, respectively, and the average birth weight was 3,451g. Higher exposure was associated with smaller fetal and newborn growth parameters in a nonlinear fashion. At 18-25 wk, fetuses in the second, third, and fourth quartiles of exposure (Q2-Q4) had 26g [95% confidence intervals (CI): − 38, −13], 35g (95% CI:−55, −15), and 27g (95% CI: −54, 1) lower EFW compared with those in the first quartile (Q1). A similar dose-response pattern was observed at > 25wk, but all effect sizes were smaller, and no association was observed comparing Q4 to Q1. At birth, we observed no differences in weight between Q1-Q2 or Q1-Q3. However, fetuses in Q4 had 91g (95% CI: −258, 76) lower birth weight in comparison with those in Q1. Results observed at 18-25 and > 25wk were similar for femur length; however, no differences were observed at birth. No associations were observed for head circumference. Discussion: Higher exposure to a mixture of phthalates, bisphenols, and OP pesticides was associated with lower EFW in the midpregnancy period. In late pregnancy, these differences were similar but less pronounced. At birth, the only associations observed appeared when comparing individuals from Q1 and Q4. This finding suggests that even low levels of exposure may be sufficient to influence growth in early pregnancy, whereas higher levels may be necessary to affect birth weight. Joint exposure to nonpersistent chemicals may adversely impact fetal growth, and because these exposures are widespread, this impact could be substantial. https://doi.org/10.1289/EHP9178. This research was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) (ZIAES101575). It was additionally supported by grants from the NIH (RO1ES022972 and RO1ES029779) and NIEHS, NIH (HHSN273201500003C). H.T. was supported by the Netherlands Organization for Scientific Research (NWO) VICI grant (NWO-ZonMW: 016. VICI.170.200). M.G. is funded by a Miguel Servet fellowship (MS13/00054, CP18/00018) awarded by the Spanish Institute of Health Carlos III. We acknowledge support from the Spanish Ministry of Science and Innovation and the State Research Agency through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. The research leading to these results received funding from the European Union Horizon 2020 Research and Innovation Programme under Grant Agreement 733206 (LifeCycle), 874583 (ATHLETE) and 824989 (EUCAN-Connect). V.W.V.J. received grant ERC-2014-CoG-648916 from the European Research Council. R.G. received funding from the Dutch Heart Foundation (grant number 2017T013), the Dutch Diabetes Foundation (grant number 2017.81.002) and Netherlands Organization for Health Research and Development (NWO, ZonMW, grant number 543003109).