To what extent does prenatal folate status modify associations between early pregnancy perfluoroalkyl and polyfluoroalkyl substance exposure and birth outcomes?

In a recent article published in JAMA Network Open, researchers evaluated the relationship between perfluoroalkyl and polyfluoroalkyl substance (PFAS) exposure during early pregnancy and birth outcomes.

Study: Association of Early Pregnancy Perfluoroalkyl and Polyfluoroalkyl Substance Exposure With Birth Outcomes. Image Credit: Makistock/Shutterstock.com

Background

PFAS exposure in early pregnancy could lead to poor birth outcomes, such as lower birth weight, shorter gestational age, and preterm birth. Preterm birth is defined as birth in less than 259 days with a weight of less than 2,500 grams.

Epidemiological studies like Project Viva have shown that higher folate concentrations lower blood PFAS concentrations in adolescents and adults. However, studies have not assessed modifiable factors that might decrease the harmful outcomes of PFAS exposure in pregnant women or other susceptible populations.

PFAS are synthetic chemicals found in nonstick cooking utensils, cosmetics, food packaging, etc., that persist in the environment and people. PFAS exposure and its presence harm a person’s overall health, especially reproductive health.

About the study

Researchers hypothesized that folate might confer protection against PFAS exposure because the two compounds share common transporters in the human placenta. Specifically the organic anion transporter family, solute carrier family, and the adenosine triphosphate–binding cassette family, implying a biological interaction between folate and PFAS.

A previous study showed an inverse association between folate and PFAS concentrations among the US population and how folate protects children from PFAS–related hazards.

Clinicians prescribe folic acid supplementation universally to prevent neural tube defects in the fetus, as folate helps in critical biological processes, such as deoxyribonucleic acid (DNA) synthesis and methylation.

Since prenatal PFAS exposure is related to epigenetic changes in cord blood, good folate status might also counteract epigenetic changes through its critical methyl-donor role in DNA methylation, thus mitigating the health hazards.

In the present study, researchers recruited mother-singleton pairs who enrolled in Project Viva, a large, pre-birth cohort study conducted in eastern Massachusetts, United States of America (USA). They examined whether the folate status of the expecting mother during early pregnancy modified the effect(s) of PFAS exposure on birth outcomes.

They used questionnaires and interviews to collect sociodemographic characteristics (e.g., maternal age, education,  race/ethnicity, annual household income), reproductive history (covered parity and infertility history), early pregnancy diet, and nutrient supplementation of all mother-singleton pairs enrolled in Project Viva.

The Alternative Healthy Eating Index for Pregnancy score reflected the diet quality in early pregnancy.

Specifically for folate measurements, they interviewed all participants at the time of study recruitment to enquire about their supplement intake for the three months before pregnancy detection.

Dietary folate equivalent (DFE) intake (micrograms/day) during early pregnancy covered natural and supplement intake. The researchers also accounted for the changes in folate intake by energy consumption.

Likewise, the team estimated birth outcome measurements like the birth weight in grams from medical records. They estimated gestational age using the last menstrual period (LMP) and birth weight z score standardized by infant sex and gestational age.

They also collected their nonfasting blood sample at recruitment to quantify eight PFAS compounds.

The team quantified the following eight PFAS compounds:

i) perfluorooctanoic acid (PFOA);

ii) perfluorooctane sulfonic acid (PFOS);

iii) perfluorohexane sulfonic acid;

iv) perfluorononanoate (PFNA);

v) 2-(N-ethyl-perfluorooctane sulfonamido) acetate (EtFOSAA);

vi) 2-(N-methyl-perfluorooctane sulfonamido) acetate (MeFOSAA);

vii) perfluorodecanoic acid (PFDeA); and

viii) perfluorooctane sulfonamide (PFOSA)

The researchers performed descriptive analyses on the study population and their PFAS distribution by folate groups between May 24 and October 25, 2022.

They calculated Spearman correlation coefficients of six PFAS and plasma folate concentrations and DFE intake after grouping the study population by quartiles.

They used multivariable linear regression models to assess differences in gestational age, birth weight, and birth weight z score for each doubling of plasma PFAS concentrations stratified by DFE intake or plasma folate concentration groups.

The researchers assessed the combined association of the cumulative PFAS mixture with continuous birth outcomes using quantile-based g computation (QGC) by folate groups.

They used likelihood ratio tests to determine the statistical significance of interaction terms in models with significant correlations.

Results

Of 14,00 pregnant women in this study cohort, 957 reported periconceptional folic acid supplement use. The study cohort characteristics were comparable across quartile groups stratified by plasma folate concentrations. However, mothers in the lowest quartile of the four DFE groups were less likely to use periconceptional folic acid supplements.

Yet, the authors detected six PFAS compounds in over 99% of samples, with correlation coefficients ranging between 0.18 and 0.74 for PFNA & EtFOSAA and PFOA and PFOS, respectively.

Early pregnancy exposure to PFAS compounds, such as PFOA, was correlated to lower birth weight in mothers with the lowest DFE intake. Likewise, the authors noted a correlation between plasma PFOA, PFOS, and PFNA concentrations and lower birth weight among mothers in the lowest quartile of plasma folate concentrations.

Mothers with lower folate status were also at an increased risk of lower birth weight z score and gestational age but not those with higher folate intake.

Notably, mothers in the lowest dietary folate quartile usually had lower socioeconomic status (SES), though SES was similar across quartile groups stratified by plasma folate concentrations.

The authors noted a correlation between lower birth weight z score and PFOA (not PFNA) and PFNA and lower gestational age in mothers whose folate status during the first trimester was in the lowest quartile range.

Conclusions

Note that the early pregnancy dietary folate intake broadly indicated its intake from the LMP to the first trimester, not the complete duration of pregnancy, due to varying food preferences.

Nonetheless, in this study, the researchers examined dietary intake of folate and folate as a plasma biomarker; thus, these two represented complementary folate assessments.

This study highlighted, in agreement with previous research, that adequate folate during preconception and pregnancy could counteract PFAS adverse effects apart from preventing neural tube defects in the fetus; thus, have important clinical implications.

The study results do not clarify how folate interacts with PFAS to influence birth outcomes; thus, this aspect warrants further investigation.