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Environmental phthalate exposure and preterm birth in the PROTECT birth cohort.

ABSTRACT: BACKGROUND:Preterm birth is a global public health issue and rates in Puerto Rico are consistently among the highest in the USA. Exposures to environmental contaminants might be a contributing factor. METHODS:In a preliminary analysis from the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) cohort (n?=?1090), we investigated the association between urinary phthalate metabolite concentrations measured at three study visits (targeted at 20, 24, and 28?weeks of gestation) individually and averaged over pregnancy with gestational age at delivery and preterm birth. We additionally assessed differences in associations by study visit and among preterm births with a spontaneous delivery. RESULTS:Compared to women in the general USA population, urinary concentrations of metabolites of di-n-butyl phthalate (DBP) and di-isobutyl phthalate (DiBP) were higher among pregnant women in Puerto Rico. Interquartile range (IQR) increases in pregnancy-averages of urinary metabolites of DBP and DiBP were associated with shorter duration of gestation and increased odds of preterm birth. An IQR increase in mono-n-butyl phthalate (MBP), a metabolite of DBP, was associated with 1.55?days shorter gestation (95% confidence interval [CI]?=?-2.68, -0.42) and an odds ratio (OR) of 1.42 (95% confidence interval [CI]: 1.07, 1.88) for preterm birth. An IQR increase in mono-isobutyl phthalate (MiBP), a metabolite of DiBP, was associated with 1.16?days shorter gestation (95% CI?=?-2.25, -0.08) and an OR of 1.32 (95% CI: 1.02, 1.71) for preterm birth. Associations were greatest in magnitude for urinary concentrations measured at the second study visit (median 23?weeks gestation). DiBP metabolite associations were greatest in magnitude in models of spontaneous preterm birth. No associations were detected with other phthalate metabolites, including those of di-2-ethylhexyl phthalate. CONCLUSION:Among pregnant women in the PROTECT cohort, DBP and DiBP metabolites were associated with increased odds of preterm birth. These exposures may be contributing to elevated rates of preterm birth observed in Puerto Rico.

SUBMITTER: Ferguson KK

PROVIDER: S-EPMC6754790 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Environmental phthalate exposure and preterm birth in the PROTECT birth cohort.

Ferguson Kelly K KK Rosen Emma M EM Rosario Zaira Z Feric Zlatan Z Calafat Antonia M AM McElrath Thomas F TF Vélez Vega Carmen C Cordero José F JF Alshawabkeh Akram A Meeker John D JD

Environment international 20190817

<h4>Background</h4>Preterm birth is a global public health issue and rates in Puerto Rico are consistently among the highest in the USA. Exposures to environmental contaminants might be a contributing factor.<h4>Methods</h4>In a preliminary analysis from the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) cohort (n = 1090), we investigated the association between urinary phthalate metabolite concentrations measured at three study visits (targeted at 20, 24, and 28 weeks of ges ...[more]

PMID: 31430608

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Project description:IMPORTANCE:Preterm birth is a leading cause of neonatal mortality, with a variety of contributing causes and risk factors. Environmental exposures represent a group of understudied, but potentially important, factors. Phthalate diesters are used extensively in a variety of consumer products worldwide. Consequently, exposure in pregnant women is highly prevalent. OBJECTIVE:To assess the relationship between phthalate exposure during pregnancy and preterm birth. DESIGN, SETTING, AND PARTICIPANTS:This nested case-control study was conducted at Brigham and Women's Hospital, Boston, Massachusetts. Women were recruited for a prospective observational cohort study from 2006-2008. Each provided demographic data, biological samples, and information about birth outcomes. From within this group, we selected 130 cases of preterm birth and 352 randomly assigned control participants, and we analyzed urine samples from up to 3 time points during pregnancy for levels of phthalate metabolites. EXPOSURE:Phthalate exposure during pregnancy. MAIN OUTCOMES AND MEASURES:We examined associations between average levels of phthalate exposure during pregnancy and preterm birth, defined as fewer than 37 weeks of completed gestation, as well as spontaneous preterm birth, defined as preterm preceded by spontaneous preterm labor or preterm premature rupture of the membranes (n?=?57). RESULTS:Geometric means of the di-2-ethylhexyl phthalate (DEHP) metabolites mono-(2-ethyl)-hexyl phthalate (MEHP) and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), as well as mono-n-butyl phthalate (MBP), were significantly higher in cases compared with control participants. In adjusted models, MEHP, MECPP, and? ??DEHP metabolites were associated with significantly increased odds of preterm birth. When spontaneous preterm births were examined alone, MEHP, mono-(2-ethyl-5-oxohexyl) phthalate, MECPP, ???DEHP, MBP, and mono-(3-carboxypropyl) phthalate metabolite levels were all associated with significantly elevated odds of prematurity. CONCLUSIONS AND RELEVANCE:Women exposed to phthalates during pregnancy have significantly increased odds of delivering preterm. Steps should be taken to decrease maternal exposure to phthalates during pregnancy.

Project description:Importance:Although phthalate exposure during pregnancy has been associated with preterm birth, the association of preconception exposure in either parent with preterm birth constitutes a knowledge gap. Objective:To examine the association of paternal and maternal preconception urinary concentrations of biomarkers of phthalates and phthalate substitutes with singleton preterm birth. Design, Setting, and Participants:This study, conducted at an academic fertility center in Boston, Massachusetts, included a prospective preconception cohort of subfertile couples comprising 419 mothers and 229 fathers and their 420 live-born singleton offspring born between January 1, 2005, and December 31, 2018. Statistical analysis was performed from August 1 to October 31, 2019. Exposures:Urinary concentrations of metabolites of phthalates and phthalate substitutes obtained before conception. Main Outcomes and Measures:Gestational age was abstracted from delivery records and validated using the American College of Obstetricians and Gynecologists guidelines for births after medically assisted reproduction. The risk ratio (RR) of preterm birth (live birth before 37 completed weeks' gestation) was estimated in association with urinary concentrations of 11 individual phthalate metabolites, the molar sum of 4 di-(2-ethylhexyl) phthalate (ΣDEHP) metabolites, and 2 metabolites of 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH, a nonphthalate plasticizer substitute) using modified Poisson regression models adjusted for covariates. Results:The mean (SD) age of the 419 mothers was 34.7 (4.0) years, the mean (SD) age of the 229 fathers was 36.0 (4.5) years, and the mean (SD) gestational age of the 420 singleton children (217 boys) was 39.3 (1.7) weeks, with 34 (8%) born preterm. In adjusted models, maternal preconception ΣDEHP concentrations (RR, 1.50; 95% CI, 1.09-2.06; P = .01) and cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH, a metabolite of DINCH) concentrations (RR, 1.70; 95% CI, 0.89-3.24; P = .11) were associated with an increased risk of preterm birth. After additional adjustment for prenatal ΣDEHP or MHiNCH concentrations, the association of maternal preconception exposure to ΣDEHP and preterm birth remained robust (RR, 1.69; 95% CI, 1.17-2.44; P = .006), while the association of maternal preconception exposure to MHiNCH and preterm birth was attenuated (RR, 1.17; 95% CI, 0.49-2.81; P = .72). The remaining urinary metabolites examined in either parent showed no association with preterm birth. Conclusions and Relevance:In this prospective cohort of subfertile couples, maternal preconception exposure to ΣDEHP metabolites was associated with an increased risk of preterm birth. The results suggest that female exposure to select phthalate plasticizers during the preconception period may be a potential risk factor for adverse pregnancy outcomes, which may need to be considered in preconception care strategies.

Project description:BackgroundGlyphosate (GLY) is the most heavily used herbicide in the world. Despite nearly ubiquitous exposure, few studies have examined prenatal GLY exposure and potentially adverse pregnancy outcomes. Preterm birth (PTB) is a risk factor for neonatal mortality and adverse health effects in childhood.ObjectivesWe examined prenatal exposure to GLY and a highly persistent environmental degradate of GLY, aminomethylphosphonic acid (AMPA), and odds of PTB in a nested case-control study within the ongoing Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) pregnancy cohort in northern Puerto Rico.MethodsGLY and AMPA in urine samples collected at 18±2 (Visit 1) and 26±2 (Visit 3) wk gestation (53 cases/194 randomly selected controls) were measured using gas chromatography tandem mass spectrometry. Multivariable logistic regression was used to estimate associations with PTB (delivery <37wk completed gestation).ResultsDetection rates in controls were 77.4% and 77.5% for GLY and 52.8% and 47.7% for AMPA, and geometric means (geometric standard deviations) were 0.44 (2.50) and 0.41 (2.56) μg/L for GLY and 0.25 (3.06) and 0.20 (2.87) μg/L for AMPA, for Visits 1 and 3, respectively. PTB was significantly associated with specific gravity-corrected urinary GLY and AMPA at Visit 3, whereas associations with levels at Visit 1 and the Visits 1-3 average were largely null or inconsistent. Adjusted odds ratios (ORs) for an interquartile range increase in exposure at Visit 3 were 1.35 (95% CI: 0.99, 1.83) and 1.67 (95% CI: 1.26, 2.20) for GLY and AMPA, respectively. ORs for Visit 1 and the visit average were closer to the null.DiscussionUrine GLY and AMPA levels in samples collected near the 26th week of pregnancy were associated with increased odds of PTB in this modestly sized nested case-control study. Given the widespread use of GLY, multiple potential sources of AMPA, and AMPA's persistence in the environment, as well as the potential for long-term adverse health effects in preterm infants, further investigation in other populations is warranted. https://doi.org/10.1289/EHP7295.

Project description:Background:Urinary phthalate metabolites and psychosocial stress in pregnancy have each been associated with preterm birth (PTB), but no study has examined the joint impact of these two environmental exposures. We hypothesized that there would be stronger associations between phthalate exposure and PTB in mothers with higher stress in pregnancy compared to mothers with lower stress.Methods:We addressed this question using data from The Infant Development and the Environment Study (TIDES), a prospective birth cohort conducted at four US sites (N?=?783). We examined urinary phthalate metabolite concentrations measured in samples collected from up to three trimesters of pregnancy. Mothers reported their exposure to stressful life events (SLE) in each trimester in a questionnaire administered in the third trimester. PTB was defined as delivery before 37?weeks completed gestation (n?=?71, 9.1%). We examined associations between urinary phthalate metabolite concentrations (individual time points and on average) and PTB using logistic regression models adjusted for maternal race, age, pre-pregnancy body mass index, education, specific gravity, and gestational age at sample collection. In addition, we created models stratified by whether or not mothers were exposed to any or no SLE in pregnancy.Results:Summed di-2-ethylhexyl phthalate (?DEHP) metabolites measured in urine samples from the third trimester, but not the first trimester, were associated with an increased odds ratio (OR) of PTB (OR?=?1.44, 95% confidence interval [CI]?=?1.06, 1.95). In models stratified by SLE, associations between third trimester ?DEHP concentrations and PTB were significant only for women experiencing one or more SLE during pregnancy (OR for ?DEHP: 2.09, 95% CI: 1.29, 3.37) but not for women with no SLE during pregnancy (OR for ?DEHP: 1.04, 95% CI: 0.66, 1.63) (p for interaction?=?0.07).Conclusions:We observed an association between urinary ?DEHP levels and PTB that was modified by whether a mother was exposed to one or more psychosocial stressors during pregnancy. Additional research to understand the joint impacts of chemical and non-chemical exposures, with an emphasis on timing of exposure, is needed in order to advance the state of the science on how the environment influences pregnancy.

Project description:BackgroundParental preconception exposure to select phenols and phthalates was previously associated with increased risk of preterm birth in single chemical analyses. However, the joint effect of phenol and phthalate mixtures on preterm birth is unknown.MethodsWe included 384 female and 211 male (203 couples) participants seeking infertility treatment in the Environment and Reproductive Health (EARTH) Study who gave birth to 384 singleton infants between 2005 and 2018. Mean preconception urinary concentrations of bisphenol A (BPA), parabens, and eleven phthalate biomarkers, including di(2-ethylhexyl) phthalate (DEHP) metabolites, were examined. We used principal component analysis (PCA) with log-Poisson regression and Probit Bayesian Kernel Machine Regression (BKMR) with hierarchical variable selection to examine maternal and paternal phenol and phthalate mixtures in relation to preterm birth. Couple-based BKMR model was fit to assess couples' joint mixtures in relation to preterm birth.ResultsPCA identified the same four factors for maternal and paternal preconception mixtures. Each unit increase in PCA scores of maternal (adjusted Risk Ratio (aRR): 1.36, 95%CI: 1.00, 1.84) and paternal (aRR: 1.47, 95%CI: 0.90, 2.42) preconception DEHP-BPA factor was positively associated with preterm birth. Maternal and paternal BKMR models consistently presented the DEHP-BPA factor with the highest group Posterior Inclusion Probability (PIP). BKMR models further showed that maternal preconception BPA and mono(2-ethyl-5-hydroxyhexyl) phthalate, and paternal preconception mono(2-ethylhexyl) phthalate were positively associated with preterm birth when the remaining mixture components were held at their median concentrations. Couple-based BKMR models showed a similar relative contribution of paternal (PIP: 61%) and maternal (PIP: 77%) preconception mixtures on preterm birth. We found a positive joint effect on preterm birth across increasing quantiles of couples' total mixture concentrations.ConclusionIn this prospective cohort of subfertile couples, maternal BPA and DEHP, and paternal DEHP exposure before conception were positively associated with preterm birth. Both parental windows jointly contributed to the outcome. These results suggest that preterm birth may be a couple-based pregnancy outcome.

Project description:BackgroundInfant non-nutritive suck (NNS), or sucking on a pacifier with no nutrients being delivered, has been used as in index of brain function and has been linked to subsequent neurodevelopment. Yet, no data are available connecting NNS to environmental exposures in utero. The goal of this study was to examine the relationship between gestational exposure to phthalates (a group of chemicals found in personal care products, PVC plastics, and other products) and NNS among infants in a birth cohort study in Puerto Rico.MethodsUrinary phthalate metabolite levels were measured in women at up to three time points in pregnancy as a measure of in utero exposure to the child. We calculated the geometric mean of each metabolite for each woman as a measure of exposure across gestation. Infants had their NNS sampled using our custom research pacifier between 4-6 (± 2 weeks) weeks of age, yielding the following NNS dependent measures: cycles/burst, frequency, amplitude, bursts/min, and cycles/min.ResultsTwo hundred and eight mother-infant dyads completed this study We used multiple linear regression to assess associations between individual phthalate metabolites and NNS measurements, adjusting for infant sex, birthweight, and urinary specific gravity. An interquartile range (IQR) increase in mono carboxyisononyl phthalate across pregnancy was associated with 3.5% (95%CI: -6.2, -0.8%) lower NNS frequency and 8.9% (0.6, 17.3%) higher NNS amplitude. Similarly, an IQR increase in mono-2-ethylhexyl phthalate was also associated with 3.4% (-6.5, -0.2%) lower NNS frequency, while an IQR increase in di-2-ethylhexyl terephthalate metabolites was associated with 11.2% (2.9, 19.5%) higher NNS amplitude. Gestational exposure to phthalates may alter NNS amplitude and frequency in full-term infants. These findings indicate that the infants may be increasing their NNS amplitude to compensate for their slower NNS frequency. These preliminary findings could have important clinical implications for earlier detection of exposure-related deficits in neurofunction as well as implications for subsequent neurodevelopment and related interventions.

Project description:BackgroundMediation analysis is useful for understanding mechanisms and has been used minimally in the study of the environment and disease.ObjectiveWe examined mediation of the association between phthalate exposure during pregnancy and preterm birth by oxidative stress.MethodsThis nested case-control study of preterm birth (n = 130 cases, 352 controls) included women who delivered in Boston, Massachusestts, from 2006 through 2008. Phthalate metabolites and 8-isoprostane, an oxidative stress biomarker, were measured in urine from three visits in pregnancy. We applied four counterfactual mediation methods: method 1, utilizing exposure and mediator averages; method 2, using averages but allowing for an exposure-mediator interaction; method 3, incorporating longitudinal measurements of the exposure and mediator; and method 4, using longitudinal measurements and allowing for an exposure-mediator interaction.ResultsWe observed mediation of the associations between phthalate metabolites and all preterm birth by 8-isoprostane, with the greatest estimated proportion mediated observed for spontaneous preterm births specifically. Fully utilizing repeated measures of the exposure and mediator improved precision of indirect (i.e., mediated) effect estimates, and including an exposure-mediator interaction increased the estimated proportion mediated. For example, for mono(2-ethyl-carboxy-propyl) phthalate (MECPP), a metabolite of di(2-ethylhexyl) phthalate (DEHP), the percent of the total effect mediated by 8-isoprostane increased from 47% to 60% with inclusion of an exposure-mediator interaction term, in reference to a total adjusted odds ratio of 1.67 or 1.48, respectively.ConclusionsThis demonstrates mediation of the phthalate-preterm birth relationship by oxidative stress, and the utility of complex regression models in capturing mediated associations when repeated measures of exposure and mediator are available and an exposure-mediator interaction may exist. Citation: Ferguson KK, Chen YH, VanderWeele TJ, McElrath TF, Meeker JD, Mukherjee B. 2017. Mediation of the relationship between maternal phthalate exposure and preterm birth by oxidative stress with repeated measurements across pregnancy. Environ Health Perspect 125:488-494; http://dx.doi.org/10.1289/EHP282.

Dataset Information

Environmental phthalate exposure and preterm birth in the PROTECT birth cohort.

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Environmental phthalate exposure and preterm birth in the PROTECT birth cohort.

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