Ecological Associations of Orofacial, Neural Tube, and Abdominal Wall Birth Defects with Per- and Polyfluoroalkyl Substances in Public Water Systems in the United States

Abstract Toxicological research indicates that per- and polyfluoroalkyl substances (PFAS) may induce structural birth defects, though epidemiological research has been limited, particularly for specific outcomes. We conducted a ZIP Code Tabulation Area (ZCTA) level ecological study to estimate rate ratios (RRs) for cleft lip and/or palate (CL/P), cleft lip with or without cleft palate, cleft palate alone (CP), grouped neural tube defects, spina bifida, anencephaly, gastroschisis, and omphalocele among live births in relation to PFAS in drinking water across Alabama, California, Delaware, Florida, and Georgia. For the 1,637 study ZCTAs, we merged data on drinking water contaminants from the U.S. Environmental Protection Agency’s Third Unregulated Contaminant Monitoring Rule (UCMR3; 2013–2015) for public water systems; maternal characteristics, birth defects, and total live births from 10,640,156 individual live birth certificates (2000–2016); and sociodemographic data from the 2010 U.S. Census. We estimated RRs for detections of any PFAS and for four individual PFAS types via Poisson regression models with a ZCTA random intercept, controlling for state, year, maternal demographics (age, race, ethnicity), and ZCTA-level poverty and educational attainment. In adjusted models with ZCTA random intercepts, we observed above-null RRs for any PFAS detection with CL/P (RR = 1.08 [95% confidence interval: 0.97, 1.21]) and omphalocele (1.28 [0.92, 1.77]), for any PFOA detection with CL/P (1.19 [1.04, 1.37]), gastroschisis (1.30 [1.04, 1.64]), and omphalocele (1.72 [1.18, 2.52]), for any PFHxS detection with CP (1.41 [1.00, 1.99]) and omphalocele (1.67 [1.06, 2.64]), and for any PFHpA detection with omphalocele (1.58 [1.05, 2.37]). These findings are consistent with some specific exposure-outcome associations observed in toxicological studies but with limited epidemiological evidence, e.g., PFOA and PFHxS with orofacial clefts and abdominal wall defects. These results must be interpreted within the limitations of this ecological study design.