Associations of Serum Perfluoroalkyl Substances and Placental Human Chorionic Gonadotropin in Early Pregnancy, Measured in the UPSIDE Study in Rochester, New York

Abstract

Background: Per- and polyfluoroalkyl substances (PFAS) are widely detected in pregnant women and associated with adverse outcomes related to impaired placental function. Human chorionic gonadotropin (hCG) is a dimeric glycoprotein hormone that can indicate placental toxicity.

Objectives: Our aim was to quantify the association of serum PFAS with placental hCG, measured as an intact molecule (hCG), as free alpha-($\text{hCG}\alpha$) and beta-subunits ($\text{hCG}\beta$), and as a hyperglycosylated form (h-hCG), and evaluate effect measure modification by social determinants and by fetal sex.

Methods: Data were collected from 326 pregnant women enrolled from 2015 to 2019 in the UPSIDE study in Rochester, New York. hCG forms were normalized for gestational age at the time of blood draw in the first trimester [multiple of the median (MoM)]. Seven PFAS were measured in second-trimester maternal serum. Multivariate imputation by chained equations and inverse probability weighting were used to evaluate robustness of linear associations. PFAS mixture effects were estimated by Bayesian kernel machine regression.

Results: Perfluorohexane sulfonic acid (PFHxS) [$\text{hCG}\beta$: 0.29 log MoM units per log PFHxS; 95% confidence interval (CI): 0.08, 0.51] and perfluorodecanoic acid (PFDA) (hCG: $-0.09$; 95% CI: $-0.16$, $-0.02$) were associated with hCG in the single chemical and mixture analyses. The PFAS mixture was negatively associated with $\text{hCG}\alpha$ and positively with $\text{hCG}\beta$. Subgroup analyses revealed that PFAS associations with hCG differed by maternal race/ethnicity and education. Perfluoropentanoic acid (PFPeA) was associated with $\text{hCG}\beta$ only in Black participants ($-0.23$; 95% CI: $-0.37$, $-0.09$) and in participants with high school education or less ($-0.14$; 95% CI: $-0.26$, $-0.02$); conversely, perfluorononanoic acid (PFNA) was negatively associated with $\text{hCG}\alpha$ only in White participants ($-0.15$; 95% CI: $-0.27$, $-0.03$) and with $\text{hCG}\beta$ only in participants with a college education or greater ($-0.19$; 95% CI: $-0.36$, $-0.01$). These findings were robust to testing for selection bias, confounding bias, and left truncation bias where PFAS detection frequency was $<100\%$. Two associations were negative in male (and null in female) pregnancies: Perfluoroundecanoic acid (PFUnDA) with $\text{hCG}\alpha$, and PFNA with h-hCG.

Conclusions: Evidence was strongest for the association between PFHxS and PFDA with hCG in all participants and for PFPeA and PFNA within subgroups defined by social determinants and fetal sex. PFAS mixture associations with $\text{hCG}\alpha$ and $\text{hCG}\beta$ differed, suggesting subunit-specific types of toxicity and/or regulation. Future studies will evaluate the biological, clinical and public health significance of these findings. https://doi.org/10.1289/EHP12950.

Figure 1.

Causal diagram to identify association of maternal PFAS levels and placental hCG, adapted from Howe et al. Italicized nodes are unmeasured in the current study. Underlined nodes indicate potential points of intervention to modify PFAS exposure risk. Note: hCG, human chorionic gonadotropin; PFAS, per- and polyfluoroalkyl substances.

Figure 2.

Associations of serum perfluoroalkyl substances (PFAS, log) and four forms of 1st trimester hCG as log MoM, in participants of the UPSIDE study ($n=286$). Models were adjusted for prepregnancy maternal body mass index, age, race/ethnicity, income, education level, and smoking status. Dots represent point estimates of the beta coefficient and lines represent their 95% CIs. Dotted line is the null value. Beta coefficients and CIs are in Table S4. Note: CI, confidence interval; hCG, human chorionic gonadotropin; MoM, multiple of median; PFDA, perfluorodecanoic acid; PFHxS, perfluorohexanesulfonic acid; PFNA, perfluorononanoic acid; PFOA, perfluorooctanoic acid; PFOS, perfluorooctanesulfonic acid; PFPeA, perfluoropentanoic acid; PFUnDA, perfluoroundecanoic acid; UPSIDE, Understanding Pregnancy Signals and Infant Development.

Figure 3.

Overall PFAS mixture effect, estimated by BKMR, on (A) $\text{hCG}\mathrm{\alpha }$; (B) $\text{hCG}\mathrm{\beta }$; (C) h-hCG; (D) intact hCG, adjusted for prepregnancy maternal body mass index, age, race/ethnicity, education level, and smoking status in participants of the UPSIDE study. The plot shows the estimated differences in hCG and 95% CrIs per quantile increase in all PFAS, in comparison with when all PFAS are held at their median levels. Supporting data for the BKMR analysis are in Table 2 and Figures S1 and S2; numeric data can be found in Table S19. Note: BKMR, Bayesian kernel machine regression; CI, credible interval; hCG, human chorionic gonadotropin; $\text{hCG}\mathrm{\alpha }$, human chorionic gonadotropin alpha; $\text{hCG}\mathrm{\beta }$, human chorionic gonadotropin beta; h-hCG, hyperglycosylated hCG; UPSIDE, Understanding Pregnancy Signals and Infant Development.