Intrauterine exposures to legacy and emerging PFAS in the first trimester and their associations with early pregnancy loss

Exposure to per- and polyfluoroalkyl substances (PFAS), including emerging substitutes, is associated with several adverse pregnancy outcomes. However, the evidence on intrauterine exposure to PFAS during human early pregnancy was limited. This study measured the concentrations of 31 (18 legacy and 13 emerging) PFAS chemicals in 402 maternal serum and 221 placental villi tissues collected during the first trimester. The associations of individual and combined PFAS exposures with early pregnancy loss (EPL) were estimated using multivariable generalized additive models, logistic regression models, quantile g-computation, subgroup stratified, and interaction analyses. Six PFAS chemicals detected simultaneously in the serum and villi with detection rates exceeding 80% showed strong correlations between the two matrices, with correlation coefficients ranging from 0.78 to 0.93, and with 9-chlorohexadecafluoro-3-oxanonane-1-sulfonate (9Cl-PF3ONS) exhibiting the highest correlation. Odds ratios (95% confidence intervals) of EPL were 1.72 (1.04, 2.83), 2.18 (1.02, 4.69), 1.99 (1.04, 3.79), 2.66 (1.35, 5.22), and 5.17 (2.30, 11.63) associated with per ten-fold increase in the concentrations of serum 9Cl-PF3ONS, serum perfluorohexane sulfonate (PFHxS), serum perfluorooctane sulfonate (PFOS), villi 9Cl-PF3ONS, and villi perfluorooctanoic acid (PFOA), respectively. However, the associations of serum 9Cl-PF3ONS, PFHxS, and PFOS with EPL were no longer statistically significant after false discovery rate correction. The joint association between PFAS mixture in villi and EPL was positive, with 9Cl-PF3ONS having the largest positive weights. Subgroups with age ≤ 30 years, body mass index ≥ 24 kg/m 2 , or tobacco exposure showed higher odds ratios of EPL associated with specific PFAS chemicals. In conclusion, emerging substitute 9Cl-PF3ONS could arrive at early placenta. Maternal and placental exposure to PFAS including 9Cl-PF3ONS showed positive associations with EPL; however, the findings in serum should be interpreted cautiously.