Organophosphate Ester Flame Retardants and Plasticizers in Relation to Fetal Growth in the LIFECODES Fetal Growth Study

Abstract

Background: Organophosphate esters (OPEs), used ubiquitously as flame retardants and plasticizers in consumer products, are suspected of having developmental toxicity.

Objectives: Our study aimed to estimate associations between prenatal exposure to OPEs and fetal growth, including both ultrasound (head circumference, abdominal circumference, femur length, and estimated fetal weight) and delivery [birth weight z-score, small-for-gestational age (SGA), and large-for-gestational age (LGA)] measures of growth.

Methods: In the LIFECODES Fetal Growth Study (2008-2018), an enriched case-cohort of 900 babies born at the small and large ends of the growth spectrum, we quantified OPE biomarkers in three urine samples per pregnant participant and abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-averaged log-transformed OPE biomarkers and repeated ultrasound measures of fetal growth using linear mixed-effects models, and delivery measures of fetal growth using linear (birth weight) and logistic (SGA and LGA) regression models.

Results: Most OPE biomarkers were positively associated with at least one ultrasound measure of fetal growth, but associations with delivery measures were largely null. For example, an interquartile range (IQR; $1.31\text{ng}/\mathrm{mL}$) increase in bis(2-chloroethyl) phosphate concentration was associated with larger z-scores in head circumference [mean difference (difference): 0.09; 95% confidence interval (CI): 0.01, 0.17], abdominal circumference (difference: 0.10; 95% CI: 0.02, 0.18), femur length (difference: 0.11; 95% CI: 0.03, 0.19), and estimated fetal weight (difference: 0.13; 95% CI: 0.04, 0.22) but not birth weight (difference: 0.04; 95% CI: $-0.08$, 0.17). At delivery, an IQR ($1.00\text{ng}/\mathrm{mL}$) increase in diphenyl phosphate (DPHP) concentration was associated with an SGA birth (odds ratio: 1.46; 95% CI: 1.10, 1.94).

Conclusions: In a large prospective cohort, gestational OPE exposures were associated with larger fetal size during pregnancy, but associations at delivery were null. DPHP concentrations were associated with heightened risk of an SGA birth. These findings suggest that OPE exposure may affect fetal development. https://doi.org/10.1289/EHP14647.

Figure 1.

Study flow diagram for the LIFECODES Fetal Growth Study (2008–2018). Note: AGA, appropriate-for-gestational age; LGA, large-for-gestational age; SGA, small-for-gestational age.

Figure 2.

Adjusted mean z-score differences and 95% CIs for an IQR-increase in average urinary concentrations of OPE biomarkers and fetal during gestation in the LIFECODES Fetal Growth Study (2008–2018; $n=900$). Note: Corresponding numeric results can be found in supplemental Table 2. Mean z-score differences estimated by linear mixed-effects models adjusted for participant age, prepregnancy BMI, educational attainment, race and ethnicity, insurance status, year of conception, parity, alcohol and smoking during pregnancy, season of enrollment, and fetal sex assigned at birth. Models incorporate both inverse probability of sampling weights and weights according to number of ultrasounds received during pregnancy. IQRs of log-transformed continuous biomarkers were: BCEP [$1.31\log \left(\text{ng}/\mathrm{mL}\right)$], BCIPP [$0.97\log \left(\text{ng}/\mathrm{mL}\right)$], BDCIPP [$1.32\log \left(\text{ng}/\mathrm{mL}\right)$], DnBP [$0.57\log \left(\text{ng}/\mathrm{mL}\right)$], DPhP [$1.00\log \left(\text{ng}/\mathrm{mL}\right)$]. BCEP, bis(2-chloroethyl) phosphate; BCIPP, bis(1-chloro-2-propyl) phosphate; BDCIPP, bis(1,3-dichloro-2-propyl) phosphate; BMI, body mass index; CI, confidence interval; DnBP, di-n-butyl phosphate; DPHP, diphenyl phosphate; IQR, interquartile range; OPE, organophosphate esters.

Figure 3.

Adjusted point estimates and 95% CIs for an IQR-increase in average urinary concentrations of OPE biomarkers and size at delivery in the LIFECODES Fetal Growth Study (2008–2018; $n=900$). Note: Corresponding numeric results can be found in Supplemental Table 7. Point estimates estimated by linear and logistic regression models incorporated inverse probability weights of selection and were adjusted for participant age, prepregnancy BMI, educational attainment, race and ethnicity, insurance status, year of conception, parity, alcohol and smoking during pregnancy, season of enrollment, and fetal sex assigned at birth. $n=247$ SGA births, $n=241$ LGA births, and $n=412$ AGA controls. IQRs of log-transformed continuous biomarkers were: BCEP [$1.31\log \left(\text{ng}/\mathrm{mL}\right)$], BCIPP [$0.97\log \left(\text{ng}/\mathrm{mL}\right)$], BDCIPP [$1.32\log \left(\text{ng}/\mathrm{mL}\right)$], DnBP [$0.57\log \left(\text{ng}/\mathrm{mL}\right)$], DPhP [$1.00\log \left(\text{ng}/\mathrm{mL}\right)$]. AGA, appropriate-for-gestational age; BCEP, bis(2-chloroethyl) phosphate; BCIPP, bis(1-chloro-2-propyl) phosphate; BDCIPP, bis(1,3-dichloro-2-propyl) phosphate; BMI, body mass index; CI, confidence interval; DnBP, di-n-butyl phosphate; DPHP, diphenyl phosphate; IQR, interquartile range; LGA, large-for-gestational age; MD, mean difference; OPE, organophosphate esters; OR, odds ratio; SGA, small-for-gestational age.

Figure 4.

(A) Predicted mean (95% CI) estimated fetal weights for SGA subtypes. (B) Adjusted ORs and 95% CIs for an IQR-increase in average urinary concentrations of OPE biomarkers and subtypes of SGA relative to AGA births in the LIFECODES Fetal Growth Study (2008–2018; $n=659$). Note: Corresponding numeric results can be found in Supplemental Table 13. Adjusted ORs estimated from logistic regression models adjusted for participant age, prepregnancy BMI, educational attainment, race and ethnicity, insurance status, year of conception, parity, alcohol and smoking during pregnancy, season of enrollment, and fetal sex assigned at birth. IQRs of log-transformed continuous biomarkers were: BCEP [$1.31\log \left(\text{ng}/\mathrm{mL}\right)$], BCIPP [$0.97\log \left(\text{ng}/\mathrm{mL}\right)$], BDCIPP [$1.32\log \left(\text{ng}/\mathrm{mL}\right)$], DnBP [$0.57\log \left(\text{ng}/\mathrm{mL}\right)$], DPhP [$1.00\log \left(\text{ng}/\mathrm{mL}\right)$]. SGA subtypes were determined among SGA births only, and the referent category for analysis was AGA births, for which the median (25th, 75th percentiles) observed EFW z-score at 20, 25, 30, and 35 wk of gestation was $-0.60$ ($-1.12$, $-0.02$), $-0.37$ ($-0.74$, $-0.02$), $-0.08$ ($-0.76$, 0.42), $-0.09$ ($-0.64$, 0.40). AGA, appropriate-for-gestational age; BCEP, bis(2-chloroethyl) phosphate; BCIPP, bis(1-chloro-2-propyl) phosphate; BDCIPP, bis(1,3-dichloro-2-propyl) phosphate; BMI, body mass index; CI, confidence interval; DnBP, di-n-butyl phosphate; DPHP, diphenyl phosphate; EFW, estimated fetal weight; IQR, interquartile range; OPE, organophosphate esters; OR, odds ratio; SGA, small-for-gestational age.