Prenatal phthalate exposure in relation to placental corticotropin releasing hormone (pCRH) in the CANDLE cohort

Abstract

Context: Phthalates may disrupt maternal-fetal-placental endocrine pathways, affecting pregnancy outcomes and child development. Placental corticotropin releasing hormone (pCRH) is critical for healthy pregnancy and child development, but understudied as a target of endocrine disruption.

Objective: To examine phthalate metabolite concentrations (as mixtures and individually) in relation to pCRH.

Design: Secondary data analysis from a prospective cohort study.

Setting: Prenatal clinics in Tennessee, USA.

Patients: 1018 pregnant women (61.4% non-Hispanic Black, 32% non-Hispanic White, 6.6% other) participated in the CANDLE study and provided data. Inclusion criteria included: low-medical-risk singleton pregnancy, age 16-40, and gestational weeks 16-29.

Intervention: None.

Main outcome measures: Plasma pCRH at two visits (mean gestational ages 23.0 and 31.8 weeks) and change in pCRH between visits (ΔpCRH).

Results: In weighted quantile sums (WQS) regression models, phthalate mixtures were associated with higher pCRH at Visit 1 (β = 0.07, 95 %CI: 0.02, 0.11) but lower pCRH at Visit 2 (β = -0.08, 95 %CI: -0.14, -0.02). In stratified analyses, among women with gestational diabetes (n = 59), phthalate mixtures were associated with lower pCRH at Visit 1 (β = -0.17, 95 %CI: -0.35, 0.0006) and Visit 2 (β = -0.35, 95 %CI: -0.50, -0.19), as well as greater ΔpCRH (β = 0.16, 95 %CI: 0.07, 0.25). Among women with gestational hypertension (n = 102), phthalate mixtures were associated with higher pCRH at Visit 1 (β = 0.20, 95 %CI: 0.03, 0.36) and Visit 2 (β = 0.42; 95 %CI: 0.19, 0.64) and lower ΔpCRH (β = -0.17, 95 %CI: -0.29, -0.06). Significant interactions between individual phthalate metabolites and pregnancy complications were observed.

Conclusions: Phthalates may impact placental CRH secretion, with differing effects across pregnancy. Differences in results between women with and without gestational diabetes and gestational hypertension suggest a need for further research examining whether women with pregnancy complications may be more vulnerable to endocrine-disrupting effects of phthalates.

Keywords: Corticotropin releasing hormone; Endocrine disrupting chemicals; Phthalates; Placenta; Pregnancy complications.

Figure 1.

WQS regression coefficients and weights for associations between phthalate mixtures and log(pCRH) in pg/mL^1,2. The forest plots show WQS regression means and 95% CIs in the negative and positive directions. Permutation test p-value (PTp) indicates p-values after the application of the permutation test. WQS weights for all phthalate metabolites are indicated on the heat maps³. 1 Models adjusted for gestational age at sample collection, cotinine, maternal age, maternal race and ethnicity, marital status, fetal sex, maternal education, pre-pregnancy BMI, parity, gestational diabetes, gestational hypertension, and maternal childhood traumatic life events. Models examining the outcome ΔpCRH are additionally adjusted for the change in gestational age between the visits. 2 Exposure is Visit 1 phthalate metabolite concentrations for the outcome Visit 1 log(pCRH). Exposure is Visit 2 phthalate metabolite concentrations for the outcomes Visit 2 log(pCRH) and ΔpCRH. 3 The WQS regression coefficient and weight estimates in the negative direction for the V1 pCRH outcome are de-emphasized since these model results were derived from <100 (<10%) of the total bootstrap iterations within the WQS regression. These bootstrap iterations in a given direction are used to derive mixture weights and to compile to WQS mixture index, and so estimates based on only a few iterations in the desired direction may be unstable and should be interpreted with caution

Figure 2.

WQS regression coefficients and weights for associations between phthalate mixtures and log(pCRH) in models stratified by gestational diabetes (GDM) status (in pg/mL)^1,2. The forest plots show WQS regression means and 95% CIs in the negative and positive directions. Asterisks denote permutation test p-values < 0.05. WQS weights for all phthalate metabolites are indicated on the heat maps³. 1 Models adjusted for gestational age at sample collection, cotinine, maternal age, maternal race and ethnicity, marital status, fetal sex, maternal education, pre-pregnancy BMI, parity, gestational diabetes, gestational hypertension, and maternal childhood traumatic life events. Models examining the outcome ΔpCRH are additionally adjusted for the change in gestational age between the visits. 2 Exposure is Visit 1 phthalate metabolite concentrations for the outcome Visit 1 log(pCRH). Exposure is Visit 2 phthalate metabolite concentrations for the outcomes Visit 2 log(pCRH) and ΔpCRH. 3 For participants with diabetes, the WQS regression for ΔpCRH in the negative direction and for V2 pCRH in the positive direction found no bootstrapped mixture coefficients in the desired direction and therefore returned no estimate for those respective directions and outcomes, and therefore no estimates are presented for those models on the plots. Some WQS regression estimates (e.g., the negative mixture association with V1 pCRH for participants without diabetes) are de-emphasized since these model results were derived from <100 (<10%) of the total bootstrap iterations within the WQS regression. These bootstrap iterations in a given direction are used to derive mixture weights and to compile to WQS mixture index, and so estimates based on only a few iterations in the desired direction may be unstable and should be interpreted with caution.

Figure 3.

WQS regression coefficients and weights for associations between phthalate mixtures and log(pCRH) in models stratified by gestational hypertension (GHTN) status (in pg/mL)^1,2. The forest plots show WQS regression means and 95% CIs in the negative and positive directions. Asterisks denote permutation test p-values < 0.05. WQS weights for all phthalate metabolites are indicated on the heat maps³. 1 Models adjusted for gestational age at sample collection, cotinine, maternal age, maternal race and ethnicity, marital status, fetal sex, maternal education, pre-pregnancy BMI, parity, gestational diabetes, gestational hypertension, and maternal childhood traumatic life events. Models examining the outcome ΔpCRH are additionally adjusted for the change in gestational age between the visits. 2 Exposure is Visit 1 phthalate metabolite concentrations for the outcome Visit 1 log(pCRH). Exposure is Visit 2 phthalate metabolite concentrations for the outcomes Visit 2 log(pCRH) and ΔpCRH. 3 Some WQS regression estimates (e.g., the negative mixture association with V1 pCRH for participants without GHTN) are de-emphasized since these model results were derived from <100 (<10%) of the total bootstrap iterations within the WQS regression. These bootstrap iterations in a given direction are used to derive mixture weights and to compile to WQS mixture index, and so estimates based on only a few iterations in the desired direction may be unstable and should be interpreted with caution.