Urinary phthalate metabolite and bisphenol A associations with ultrasound and delivery indices of fetal growth

doi:10.1016/j.envint.2016.06.013

Environment International

Volume 94, September 2016, Pages 531-537

https://doi.org/10.1016/j.envint.2016.06.013 Get rights and content

Highlights

•
Exposure to phthalates and BPA in pregnancy may impact development of the fetus.
•
We measured exposure biomarkers at 4 visits during gestation on 482 women.
•
We used ultrasound scans from pregnancy and birthweight to examine fetal growth.
•
Urinary di-2-ethylhexyl phthalate metabolites were associated with reduced growth.
•
This is the first study with a robust repeated measures design to detect this relationship.

Abstract

Growth of the fetus is highly sensitive to environmental perturbations, and disruption can lead to problems in pregnancy as well as later in life. This study investigates the relationship between maternal exposure to common plasticizers in pregnancy and fetal growth. Participants from a longitudinal birth cohort in Boston were recruited early in gestation and followed until delivery. Urine samples were collected at up to four time points and analyzed for concentrations of phthalate metabolites and bisphenol A (BPA). Ultrasound scans were performed at four time points during pregnancy for estimation of growth parameters, and birthweight was recorded at delivery. Growth measures were standardized to a larger population. For the present analysis we examined cross-sectional and repeated measures associations between exposure biomarkers and growth estimates in 482 non-anomalous singleton pregnancies. Cross-sectional associations between urinary phthalate metabolites or BPA and growth indices were imprecise. However, in repeated measures models, we observed significant inverse associations between di-2-ethylhexyl phthalate (DEHP) metabolites and estimated or actual fetal weight. An interquartile range increase in summed DEHP metabolites was associated with a 0.13 standard deviation decrease in estimated or actual fetal weight (95% confidence interval = − 0.23, − 0.03). Associations were consistent across different growth parameters (e.g., head circumference, femur length), and by fetal sex. No consistent associations were observed for other phthalate metabolites or BPA. Maternal exposure to DEHP during pregnancy was associated with decreased fetal growth, which could have repercussive effects.

Section snippets

1. Introduction

Reduced fetal growth is a well-recognized pregnancy endpoint of concern. While definitions and origins may differ, low birthweight, small for gestational age, and intrauterine growth restriction are all associated with increased risk of neonatal mortality and morbidity and have been linked to adverse health effects later in life (Barker et al., 2002, McCormick, 1985). The process of fetal development is highly sensitive to perturbations from environmental toxicant exposures (Wigle et al., 2008

2.1. Study population

Pregnant women were recruited in Boston as part of the LIFECODES birth cohort study. Individuals were eligible for participation if they were < 15 weeks pregnant, were carrying a singleton non-anomalous fetus, and were planning to deliver at Brigham and Women's Hospital. At the initial study visit subjects provided informed consent and completed questionnaires detailing demographic information, personal and family health histories, and characteristics of pregnancy. Gestational age was calculated

3. Results

Demographic characteristics are presented in Table 1 for the 482 subjects in this study population. As previously reported, the participants were primarily White (59%), had private health insurance providers (81%), indicating high socioeconomic status, and many were college graduates (41%) (Ferguson et al., 2014b). With weightings, the populations had a preterm delivery rate that was similar to that observed in the general US population (12%). Concentrations of cumulative phthalate metabolite

4. Discussion

When we applied a longitudinal analysis to examine the relationship between average exposure measures and growth we observed inverse associations between head and abdominal circumferences, femur length, and estimated fetal weight and ∑ DEHP metabolites. Within the DEHP metabolites, associations were strongest for MECPP. An IQR increase in ∑ DEHP was associated with a 0.13 SD decrease in estimated fetal weight in reference to the standard population. No consistent associations were observed for

5. Conclusions

We observed associations between maternal exposure to DEHP metabolites and decreased fetal growth during pregnancy. This is the first study to detect such associations in a population with repeated measures of urinary phthalate metabolite measurements as well as combined ultrasound and birth indices of growth. Due to our study design, these results may be specific to pregnancies for which ultrasound examinations are clinically indicated later in pregnancy, but this limitation in

Acknowledgements

We thank Gerry Pace and colleagues at NSF International (Ann Arbor, MI) for their analysis of urinary phthalate metabolites. Initial funding for the recruitment of the birth cohort was provided by Abbott Diagnostics (9MZ-04-06N03). All other funding was provided by the National Institute of Environmental Health Sciences, National Institutes of Health (R01ES018872, P42ES017198, P01ES022844, P50ES026049, and P30ES017885). Support for Dr. Ferguson was provided in part by the Intramural Research

References (51)

L. Casas et al.
Urinary concentrations of phthalates and phenols in a population of Spanish pregnant women and children
Environ. Int.
(2011)
K.K. Ferguson et al.
Variability in urinary phthalate metabolite levels across pregnancy and sensitive windows of exposure for the risk of preterm birth
Environ. Int.
(2014)
F.P. Hadlock et al.
Estimation of fetal weight with the use of head, body, and femur measurements–a prospective study
Am. J. Obstet. Gynecol.
(1985)
U. Heudorf et al.
Phthalates: toxicology and exposure
Int. J. Hyg. Environ. Health
(2007)
P.-C. Huang et al.
Association between prenatal exposure to phthalates and the health of newborns
Environ. Int.
(2009)
M. Hulak et al.
In vitro effects of bisphenol A on the quality parameters, oxidative stress, DNA integrity and adenosine triphosphate content in sterlet (Acipenser ruthenus) spermatozoa
Comp. Biochem. Physiol. C: Toxicol. Pharmacol.
(2013)
W. Huo et al.
Maternal urinary bisphenol A levels and infant low birth weight: a nested case–control study of the Health Baby Cohort in China
Environ. Int.
(2015)
L.E. Johns et al.
Exposure assessment issues in epidemiology studies of phthalates
Environ. Int.
(2015)
B.-E. Lee et al.
Prenatal bisphenol A and birth outcomes: MOCEH (Mothers and Children's Environmental Health) study
Int. J. Hyg. Environ. Health
(2014)
R.C. Lewis et al.
Predictors of urinary bisphenol A and phthalate metabolite concentrations in Mexican children
Chemosphere
(2013)

Y. Suzuki et al.

Prenatal exposure to phthalate esters and PAHs and birth outcomes

Environ. Int.

(2010)

R. Tang et al.

Associations of prenatal exposure to phenols with birth outcomes

Environ. Pollut.

(2013)

L.M. Tetz et al.

Mono-2-ethylhexyl phthalate induces oxidative stress responses in human placental cells in vitro

Toxicol. Appl. Pharmacol.

(2013)

J. Troisi et al.

Placental concentrations of bisphenol A and birth weight from births in the Southeastern US

Placenta

(2014)

X. Ye et al.

Urinary metabolite concentrations of organophosphorous pesticides, bisphenol A, and phthalates among pregnant women in Rotterdam, the Netherlands: the Generation R study

Environ. Res.

(2008)

Y. Zhang et al.

Phthalate levels and low birth weight: a nested case-control study of Chinese newborns

J. Pediatr.

(2009)

J.J. Adibi et al.

Prenatal exposures to phthalates among women in New York City and Krakow, Poland

Environ. Health Perspect.

(2003)

I. Aguilera et al.

Prenatal exposure to traffic-related air pollution and ultrasound measures of fetal growth in the INMA Sabadell cohort

Environ. Health Perspect.

(2010)

D.J. Barker et al.

Fetal origins of adult disease: strength of effects and biological basis

Int. J. Epidemiol.

(2002)

J.M. Braun et al.

Variability of urinary phthalate metabolite and bisphenol A concentrations before and during pregnancy

Environ. Health Perspect.

(2012)

A.M. Calafat et al.

Optimal exposure biomarkers for nonpersistent chemicals in environmental epidemiology

Environ. Health Perspect.

(2015)

D.E. Cantonwine et al.

Urinary bisphenol A levels during pregnancy and risk of preterm birth

Environ. Health Perspect.

(2015)

D.E. Cantonwine et al.

Utilizing Longitudinal Measures of Fetal Growth to Create a Standard Method to Assess the Impacts of Maternal Disease and Environmental Exposure

PLoS One

(2016)

M. Casas et al.

Exposure to bisphenol A and phthalates during pregnancy and ultrasound measures of fetal growth in the INMA-Sabadell cohort

Environ. Health Perspect.

(2015)

W.-C. Chou et al.

Biomonitoring of bisphenol A concentrations in maternal and umbilical cord blood in regard to birth outcomes and adipokine expression: a birth cohort study in Taiwan

Environ. Health

(2011)

Cited by (63)

Analyzing the impact of phthalate and DINCH exposure on fetal growth in a cohort with repeated urine collection
2024, Environment International
Most previous studies investigating the associations between prenatal exposure to phthalates and fetal growth relied on measurements of phthalate metabolites at a single time point. They also focused on weight at birth without assessing growth over pregnancy, preventing the identification of potential periods of fetal vulnerability. We examined the associations between pregnancy urinary phthalate metabolites and fetal growth outcomes measured twice during pregnancy and at birth.
For 484 pregnant women, we assessed 13 phthalate and two 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH) metabolite concentrations from two within-subject weekly pools of up to 21 urine samples (median of 18 and 34 gestational weeks, respectively). Fetal biparietal diameter, femur length, head and abdominal circumferences were measured during two routine pregnancy follow-up ultrasonographies (median 22 and 32 gestational weeks, respectively) and estimated fetal weight (EFW) was calculated. Newborn weight, length, and head circumference were measured at birth. Associations between phthalate/DINCH metabolite and growth parameters were investigated using adjusted linear regression and Bayesian kernel machine regression models.
Detection rates were above 99 % for all phthalate/DINCH metabolites. While no association was observed with birth measurements, mono-iso-butyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) were positively associated with most fetal growth parameters measured at the second trimester. Specifically, MiBP was positively associated with biparietal diameter, head and abdominal circumferences, while MnBP was positively associated with EFW, head and abdominal circumferences, with stronger associations among males. Pregnancy MnBP was positively associated with biparietal diameter and femur length at third trimester. Mixture of phthalate/DINCH metabolites was positively associated with EFW at second trimester.
In this pregnancy cohort using repeated urine samples to assess exposure, MiBP and MnBP were associated with increased fetal growth parameters. Further investigation on the effects of phthalates on child health would be relevant for expanding current knowledge on their long-term effects.
Association between phthalate metabolite mixture in neonatal cord serum and birth outcomes
2024, Science of the Total Environment
Prenatal exposure to phthalates (PAEs) is ubiquitous among Chinese neonates. PAEs entering the body will be transformed to various hydrolyzed and oxidated PAE metabolites (mPAEs). PAEs and mPAEs exposure may lead to adverse birth outcomes through disruption of multiple hormone signaling pathways, induction of oxidative stress, and alterations in intracellular signaling processes. In this study, the concentrations of 11 mPAEs in 318 umbilical cord serum samples from neonates in Jinan were quantified with HPLC-ESI-MS. Multiple linear regression, Bayesian kernel machine regression, and quantile g-computation models were utilized to investigate the effects of both individual mPAE and mPAE mixture on birth outcomes. Stratified analysis was performed to explore whether these effects were gender-specific. mPAE mixture was negatively associated with birth length (BL) z-score, birth weight (BW) z-score, head circumference (HC) z-score, and ponderal index (PI). Mono(2-ethylhexyl) phthalate (MEHP) manifested negative associations with BL(z-score), BW(z-score), HC(z-score), and PI, whereas mono(2-carboxymethylhexyl) phthalate (MCMHP) was negatively associated with BW(z-score) and PI within the mPAE mixture. Stratified analysis revealed that the negative associations between mPAE mixture and four birth outcomes were attenuated in female infants, while the positive impact of mono(2-ethyl-5carboxypentyl) phthalate (MECPP) on BL(z-score) and BW(z-score) could be detected only in females. In summary, our findings suggest that prenatal exposure to phthalates may be associated with intrauterine growth restriction, and these effects vary according to the gender of the infant.
Maternal urinary bisphenols and phthalates in relation to estimated fetal weight across mid to late pregnancy
2023, Environment International
Bisphenols and phthalates are high production volume chemicals used as additives in a variety of plastic consumer products leading to near ubiquitous human exposure. These chemicals have established endocrine disrupting properties and have been linked to a range of adverse reproductive and developmental outcomes. Here, we investigated exposure in relation to fetal growth.
Participants included 855 mother-fetal pairs enrolled in the population-based New York University Children’s Health and Environment Study (NYU CHES). Bisphenols and phthalates were measured in maternal urine collected repeatedly during pregnancy. Analyses included 15 phthalate metabolites and 2 bisphenols that were detected in 50 % of participants or more. Fetal biometry data were extracted from electronic ultrasonography records and estimated fetal weight (EFW) was predicted for all fetuses at 20, 30, and 36 weeks gestation. We used quantile regression adjusted for covariates to model exposure-outcome relations across percentiles of fetal weight at each gestational timepoint. We examined sex differences using stratified models.
Few statistically significant associations were observed across chemicals, gestational time periods, percentiles, and sexes. However, within gestational timepoints, we found that among females, the molar sums of the phthalates DiNP and DnOP were generally associated with decreases in EFW among smaller babies and increases in EFW among larger babies. Among males, the opposite trend was observed. However, confidence intervals were generally wide at the tails of the distribution.
In this sample, exposure to bisphenols and phthalates was associated with small sex-specific shifts in fetal growth; however, few associations were observed at the median of fetal weight and confidence intervals in the tails were wide. Findings were strongest for DiNP and DnOP, which are increasingly used as replacements for DEHP, supporting the need for future research on these contaminants.
Sex-specific associations between maternal exposure to parabens, phenols and phthalates during pregnancy and birth size outcomes in offspring
2022, Science of the Total Environment
Current evidence on the effects of prenatal exposure to endocrine disrupting chemicals on birth size remains largely inconclusive. We aimed to investigate sex-specific associations between maternal exposure to parabens, phenols and phthalates during pregnancy and birth weight, length and head/abdominal circumferences. We performed a prospective study of 88 pregnant women who underwent amniocentesis in the period 2012 to 2014. Maternal urine samples were collected during pregnancy in weeks 12 to 36 (median: 18 weeks). The concentrations of parabens, phenols and individual phthalate diester metabolites were analyzed by isotope-diluted liquid chromatography-tandem mass spectrometry and osmolality adjusted. Linear regression models estimated the associations between urinary levels of selected compounds (tertile(T2-T3)_medium/high versus T1_low exposure) and birth size, stratified by offspring sex. A total of three parabens, two phenols, four individual phthalate metabolites and four sums of diester metabolites were detectable above limits of detection in at least 60% of urine samples. Overall, we observed few statistically significant associations, but medium/high exposure to bisphenol A (BPA) in male offspring was associated with statistically significant lower birth size across most outcomes [birth weight: −428 g (95% CI −756 to −99.4); birth length: −1.76 cm (95% CI −3.28 to −0.25); abdominal circumference: −1.97 cm (95% CI −3.55 to −0.39)]. Similarly, medium/high exposure to methyl paraben (MeP) in male offspring was associated with lower birth weight (−661 g, 95% CI −1251 to −70.7) and length (−3.11 cm, 95% CI −5.76 to −0.46) compared to low exposure. None of these associations were statistically significant in female offspring. Across all compounds, individual exposures were associated with more negative estimates of birth weight for male than for female offspring. Our study indicates that prenatal exposure to BPA and MeP may negatively affect birth size outcomes, with a possible sex effect. Given the small sample size, these findings need to be replicated in future larger studies.
Urinary phthalate metabolite mixtures in pregnancy and fetal growth: Findings from the infant development and the environment study
2022, Environment International
Citation Excerpt :
Few prior studies have examined ultrasound-derived measures of fetal growth in relation to phthalate exposure (Kamai et al., 2019). Four studies (van den Dries et al., 2021; Santos, 2021; Ferguson et al., 2016; Botton et al., 2016) have reported that phthalates were associated with lower fetal weight during pregnancy and one study (Zhao, 2014) reported phthalates were associated with intrauterine growth restriction; not all studies have confirmed these findings (Casas et al., 2016). We found little evidence for an association between phthalates and ultrasound-derived measures of fetal growth.
Prenatal phthalate exposure has been linked to reductions in fetal growth in animal and laboratory studies, but epidemiologic evidence is equivocal.
Examine the association between prenatal phthalate metabolite mixtures and fetal growth and evaluate whether that association is modified by fetal sex or omega-3 intake during pregnancy.
Analyses included 604 singleton pregnancies from TIDES, a prospective pregnancy cohort with spot urine samples and questionnaires collected in each trimester. Pregnancy-averaged phthalate exposure estimates were calculated as the geometric means of specific-gravity corrected phthalate metabolites. Fetal growth outcomes included birthweight and length, and ultrasound-derived size and velocity of estimated fetal weight, femur length, abdominal and head circumferences in the second and third trimesters. We used a novel application of quantile g-computation to estimate the joint association between pregnancy-averaged phthalate exposure and fetal growth, and to examine effect modification of that association by infant sex or omega-3 intake during pregnancy.
There were few statistically significant differences in birth size and fetal growth by exposure. A one-quartile increase in the phthalate mixture was modestly associated with reduced birthweight (β [95% confidence interval)]: −54.6 [−128.9, 19.7] grams; p = 0.15) and length (−0.2 [−0.6, 0.2] centimeters; p = 0.40). A one-quartile increase in the phthalate mixture was associated with reduced birth length in males (−0.5 [−1.0, 0.0] centimeters) but not for females (0.1 [−0.2, 0.3] centimeters); interaction p = 0.05. The phthalate metabolite mixture was inversely associated with ultrasound-derived fetal growth among those with adequate omega-3 intake. For example, a one-quartile increase in the phthalate mixture was associated with reduced abdominal circumference in the third trimesters in those with adequate omega-3 intake (−3.3 [−6.8, 0.1] millimeters) but not those with inadequate omega-3 intake (1.8 [−0.8, 4.5] millimeters); interaction p = 0.01.
Prenatal phthalate exposure was not significantly associated with fetal growth outcomes, with some exceptions for certain subgroups.
The associations of birth outcome differences in twins with prenatal exposure to bisphenol A and its alternatives
2021, Environmental Research
Bisphenol A (BPA) and its alternatives, including BPF and BPS, exhibit endocrine disruption activities. However, the effects of bisphenols on fetal growth in twins remain unclear.
To explore the associations of prenatal BPA, BPF, and BPS exposure with birth outcome differences in twins.
We recruited 289 twin pregnant women who visited the hospital for prenatal examination during the first trimester from 2013 to 2016. Urinary bisphenol levels were determined during the first, second, and third trimesters. The associations of maternal exposure to bisphenols with birth outcome differences in twins were analyzed after stratification by different trimesters. We applied the multiple informant model to estimate trimester-specific associations between urinary bisphenol concentrations and birth outcome differences in twins.
We found low reproducibility (ICC<0.40) for maternal urinary BPA and moderate reproducibility (0.40 < ICC<0.75) for BPF and BPS. Urinary BPA concentrations were positively associated with within-pair twin birth weight difference when comparing the third vs. the first tertile in each of the three trimesters (i.e., 133.06 g, 95% CI: 68.19, 197.94; 144.5 g, 95%CI: 81.82–207.18 g; and 135.04 g, 95%CI: 71.37–198.71 g for the 1st, 2nd, and 3rd trimester, respectively). The effect of urinary BPA concentration on increased birth length difference within-pair twins were also observed across different trimesters (All P for trends < 0.05). Urinary BPA levels were positively associated with the within-pair birth weight and birth length differences across pregnancy trimesters (All of Type 3 P for values < 0.05).
Maternal BPA exposure appeared to influence birth wight and birth length differences in twins. Our results warrant further confirmation.

View all citing articles on Scopus

View full text

Published by Elsevier Ltd.

Urinary phthalate metabolite and bisphenol A associations with ultrasound and delivery indices of fetal growth

Highlights

Abstract

Section snippets

1. Introduction

2.1. Study population

3. Results

4. Discussion

5. Conclusions

Acknowledgements

Environ. Int.

Environ. Int.

Am. J. Obstet. Gynecol.

Int. J. Hyg. Environ. Health

Environ. Int.

Comp. Biochem. Physiol. C: Toxicol. Pharmacol.

Environ. Int.

Environ. Int.

Int. J. Hyg. Environ. Health

Chemosphere

Environ. Int.

Environ. Pollut.

Toxicol. Appl. Pharmacol.

Placenta

Environ. Res.

J. Pediatr.

Prenatal exposures to phthalates among women in New York City and Krakow, Poland

Environ. Health Perspect.

Prenatal exposure to traffic-related air pollution and ultrasound measures of fetal growth in the INMA Sabadell cohort

Environ. Health Perspect.

Fetal origins of adult disease: strength of effects and biological basis

Int. J. Epidemiol.

Variability of urinary phthalate metabolite and bisphenol A concentrations before and during pregnancy

Environ. Health Perspect.

Optimal exposure biomarkers for nonpersistent chemicals in environmental epidemiology

Environ. Health Perspect.

Urinary bisphenol A levels during pregnancy and risk of preterm birth

Environ. Health Perspect.

Utilizing Longitudinal Measures of Fetal Growth to Create a Standard Method to Assess the Impacts of Maternal Disease and Environmental Exposure

PLoS One

Exposure to bisphenol A and phthalates during pregnancy and ultrasound measures of fetal growth in the INMA-Sabadell cohort

Environ. Health Perspect.

Biomonitoring of bisphenol A concentrations in maternal and umbilical cord blood in regard to birth outcomes and adipokine expression: a birth cohort study in Taiwan

Environ. Health