Prenatal exposure to per- and polyfluoroalkyl substances, placental DNA methylation, and small vulnerable newborns: Insights from the Shanghai maternal-child pairs cohort.

Small vulnerable newborns (SVN), a novel conceptual framework proposed in recent Lancet Series, encompassing preterm birth (PTB), small for gestational age (SGA), and low birthweight (LBW), are at increased risk of adverse health outcomes across the life course. While prenatal exposure to per- and polyfluoroalkyl substances (PFAS) has been linked to adverse birth outcomes, existing evidence remains inconsistent, and evidence within the broader SVN framework is limited. This study analyzed data from 1021 mother-child pairs in the Shanghai Maternal-Child Pairs Cohort to explore associations between prenatal PFAS exposure, SVN, and placental DNA methylation. PFAS concentrations were measured in umbilical cord serum using high-performance liquid chromatography-triple quadrupole mass spectrometry. Placental DNA methylation was profiled using the Illumina Infinium HumanMethylationEPIC BeadChip in a subsample of 80 participants. Higher exposure to 6:2 Cl-PFESA and total molar concentration of PFAS (∑PFAS) was significantly associated with increased SVN risk, while perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS), 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), and ∑PFAS were specifically linked to the term SGA subtype. Associations were more pronounced among female infants, with significant positive associations of PFOA, PFHxS, 6:2 Cl-PFESA, and ∑PFAS with SVN. In the methylation analysis, prenatal ∑PFAS exposure was associated with differential methylation at 87 placental CpG sites related to developmental and cell migration-related processes, 18 of which were also associated with SVN. This study suggests that prenatal PFAS exposure may contribute to neonatal developmental vulnerability, potentially in relation to alterations in placental DNA methylation.