Early pregnancy phthalates and replacements in relation to fetal growth: The human placenta and phthalates study

Abstract

Background: Pregnant persons are exposed ubiquitously to phthalates and increasingly to chemicals introduced to replace phthalates. In early pregnancy, exposure to these chemicals may disrupt fetal formation and development, manifesting adverse fetal growth. Previous studies examining the consequences of early pregnancy exposure relied on single spot urine measures and did not investigate replacement chemicals.

Objective: Characterize associations between urinary phthalate and replacement biomarkers in early pregnancy and fetal growth outcomes.

Methods: Analyses were conducted among 254 pregnancies in the Human Placenta and Phthalates Study, a prospective cohort with recruitment 2017-2020. Exposures were geometric mean concentrations of phthalate and replacement biomarkers quantified in two spot urine samples collected around 12- and 14-weeks of gestation. Outcomes were fetal ultrasound biometry (head and abdominal circumferences, femur length, estimated fetal weight) collected in each trimester and converted to z-scores. Adjusted linear mixed effects (single-pollutant) and quantile g-computation (mixture) models with participant-specific random effects estimated the difference, on average, in longitudinal fetal growth for a one-interquartile range (IQR) increase in individual (single-pollutant) or all (mixture) early pregnancy phthalate and replacement biomarkers.

Results: Mono carboxyisononyl phthalate and the sums of metabolites of di-n-butyl, di-iso-butyl, and di-2-ethylhexyl phthalate were inversely associated with fetal head and abdominal circumference z-scores. A one-IQR increase in the phthalate and replacement biomarker mixture was inversely associated with fetal head circumference (β: -0.36 [95% confidence interval: -0.56, -0.15]) and abdominal circumference (-0.31 [-0.49, -0.12]) z-scores. This association was mainly driven by phthalate biomarkers.

Conclusions: Urine concentrations of phthalate biomarkers, but not replacement biomarkers, in early pregnancy were associated with reductions in fetal growth. Though the clinical implications of these differences are unclear, reduced fetal growth contributes to excess morbidity and mortality across the lifecourse. Given widespread global exposure to phthalates, findings suggest a substantial population health burden resulting from early pregnancy phthalate exposure.

Keywords: Endocrine disruptors; Fetal weight; Phthalic acid; Pregnancy; Prospective studies.

Figure 1.. Study participation and design in the Human Placenta and Phthalates Study, 2017–2020.

Abbreviations: Number (No.)

Figure 2.. Single- and multi-pollutant model betas and 95% confidence intervals for the association of early pregnancy phthalate and replacement biomarker concentrations with fetal growth outcomes.

Betas represent the difference, on average, in fetal growth for a one-IQR increase in individual (single-pollutant) or all (mixture) phthalate and replacement biomarkers. Models included maternal age, BMI, race and ethnicity, highest education, parity, smoking, alcohol, drug use, infant sex, study site, and gestational age at outcome assessment. Abbreviations: Di-2-ethylhexyl phthalate (DEHP); Di-2-ethylhexyl terephthalate (DEHTP); Di-iso-butyl phthalate (DiBP); 1,2-Cyclohexane dicarboxylic acid, diisononyl ester (DINCH); Di-isononyl phthalate (DiNP); Di-n-butyl phthalate (DnBP); Interquartile range (IQR); Monobenzyl phthalate (MBzP); Monocarboxyisononyl phthalate (MCNP); Mono-3-carboxypropyl phthalate (MCPP); Monoethyl phthalate (MEP).

Figure 3.. Single- and multi-pollutant model betas and 95% CIs for the association of early pregnancy phthalate and replacement biomarkers with birthweight.

Betas represent the difference in birthweight for a one-IQR increase in individual (single-pollutant) or all (mixture) phthalate and replacement biomarkers. Models included maternal age, BMI, race and ethnicity, highest education, parity, smoking, alcohol, drug use, infant sex, study site, and gestational age at birth. Abbreviations: Di-2-ethylhexyl phthalate (DEHP); Di-2-ethylhexyl terephthalate (DEHTP); Di-iso-butyl phthalate (DiBP); 1,2-Cyclohexane dicarboxylic acid, diisononyl ester (DINCH); Di-isononyl phthalate (DiNP); Di-n-butyl phthalate (DnBP); Interquartile range (IQR); Monobenzyl phthalate (MBzP); Monocarboxyisononyl phthalate (MCNP); Mono-3-carboxypropyl phthalate (MCPP); Monoethyl phthalate (MEP).

Figure 4.. Trimester-specific single- and multi-pollutant model betas and 95% confidence intervals for the association of early pregnancy phthalate and replacement biomarkers with fetal growth outcomes.

Betas represent the difference, on average, in fetal growth outcomes in a given trimester for a one-IQR increase in individual (single-pollutant) or all (mixture) phthalate and replacement biomarkers. Models included maternal age, BMI, race and ethnicity, highest education, parity, smoking, alcohol, drug use, infant sex, and study site. Interaction term was between exposure biomarker and trimester of outcome assessment. Abbreviations: Di-2-ethylhexyl phthalate (DEHP); Di-2-ethylhexyl terephthalate (DEHTP); Di-iso-butyl phthalate (DiBP); 1,2-Cyclohexane dicarboxylic acid, diisononyl ester (DINCH); Di-isononyl phthalate (DiNP); Di-n-butyl phthalate (DnBP); Interquartile range (IQR); Monobenzyl phthalate (MBzP); Monocarboxyisononyl phthalate (MCNP); Mono-3-carboxypropyl phthalate (MCPP); Monoethyl phthalate (MEP).