Correction: Longitudinal Profiles of Thyroid Hormone Parameters in Pregnancy and Associations with Preterm Birth.

[This corrects the article DOI: 10.1371/journal.pone.0169542.].

Associations between mixtures of urinary phthalate metabolites with gestational age at delivery: a time to event analysis using summative phthalate risk scores.

BACKGROUND: Preterm birth is a significant public health concern and exposure to phthalates has been shown to be associated with an increased odds of preterm birth. Even modest reductions in gestational age at delivery could entail morbid consequences for the neonate and analyzing data with this additional information may be useful. In the present analysis, we consider gestational age at delivery as our outcome of interest and examine associations with multiple phthalates. METHODS: Women were recruited early in pregnancy as part of a prospective, longitudinal birth cohort at the Brigham and Women's Hospital in Boston, Massachusetts. Urine samples were collected at up to four time points during gestation for urinary phthalate metabolite measurement, and birth outcomes were recorded at delivery. From this population, we selected all 130 cases of preterm birth (< 37 weeks of gestation) as well as 352 random controls. We conducted analysis with both geometric average of the exposure concentrations across the first three visits as well as using repeated measures of the exposure. Two different time to event models were used to examine associations between nine urinary phthalate metabolite concentrations and time to delivery. Two different approaches to constructing a summative phthalate risk score were also considered. RESULTS: The single-pollutant analysis using a Cox proportional hazards model showed the strongest association with a hazard ratio (HR) of 1.21 (95% confidence interval (CI): 1.09, 1.33) per interquartile range (IQR) change in average log-transformed mono-2-ethyl-5-carboxypentyl phthalate (MECPP) concentration. Using the accelerated failure time model, we observed a 1.19% (95% CI: 0.26, 2.11%) decrease in gestational age in association with an IQR change in average log-transformed MECPP. We next examined associations with an environmental risk score (ERS). The fourth quartile of ERS was significantly associated with a HR of 1.44 (95% CI: 1.19, 1.75) and a reduction of 2.55% (95% CI: 0.76, 4.30%) in time to delivery (in days) compared to the first quartile. CONCLUSIONS: On average, pregnant women with higher urinary metabolite concentrations of individual phthalates have shorter time to delivery. The strength of the observed associations are amplified with the risk scores when compared to individual pollutants.

Subclinical Changes in Maternal Thyroid Function Parameters in Pregnancy and Fetal Growth.

Context: Overt thyroid disease in pregnancy is a known risk factor for abnormal fetal growth and development. Data on the effects of milder forms of variation in maternal thyroid function on intrauterine growth are less well examined. Objective: We explored these associations using repeated thyroid hormone and ultrasound measurements. Design, Setting, and Participants: Data were obtained from 439 pregnant women without diagnosed thyroid disease who were participants in a case-control study of preterm birth nested within an ongoing prospective birth cohort in Boston, Massachusetts. Main Outcome Measures: Ultrasound and delivery indices of fetal growth were standardized to those measured in a larger population. Results: At median 10, 18, and 26 weeks of gestation, we observed significant inverse associations between free thyroxine (FT4) and birth weight z scores, with the strongest association detected at median 10 weeks, at which time a 10% increase in FT4 was associated with a 0.02 z score decrease (∼8.5 g) in birth weight (ß = -0.41 for ln-transformed FT4; 95% confidence interval, -0.64 to -0.18). FT4 was also inversely associated with repeated measurements of estimated fetal weight, head circumference, and abdominal circumference. We observed weaker inverse associations for total T4 and a positive relationship between total triiodothyronine and birth weight z scores. We did not observe any associations for thyroid-stimulating hormone. Conclusion: In pregnant women without overt thyroid disease, subclinical changes in thyroid function parameters may influence fetal growth.

Urinary BPA and Phthalate Metabolite Concentrations and Plasma Vitamin D Levels in Pregnant Women: A Repeated Measures Analysis.

BACKGROUND: In addition to its well-established role in maintaining skeletal health, vitamin D has essential regulatory functions in female reproductive and pregnancy outcomes. Phthalates and bisphenol A (BPA) are endocrine disruptors, and previous research has suggested that these chemical agents may disrupt circulating levels of total 25(OH)D in adults. OBJECTIVES: We investigated the relationships between repeated measures of urinary phthalate metabolites and BPA and circulating total 25(OH)D in a prospective cohort of pregnant women. METHODS: The present study population includes participants (n=477) in a nested case-control study of preterm birth drawn from a prospective birth cohort of pregnant women at Brigham and Women's Hospital in Boston, Massachusetts. Urine and blood samples were collected for biomarker measurements at median 10 wk and 26 wk of gestation. RESULTS: In repeated measures analysis, we observed that an interquartile range (IQR) increase in urinary mono-3-carboxypropyl phthalate (MCPP) was associated with a 4.48% decrease [95% confidence interval (CI): -7.37, -1.58] in total 25(OH)D. We also detected inverse associations for metabolites of di(2-ethylhexyl) phthalate (DEHP) [percent difference (%Δ)=-2.83 to -2.16]. For BPA, we observed a nonsignificant inverse association with total 25(OH)D in the overall population. Our sensitivity analysis revealed that the associations for some metabolites (e.g., MEHP) varied by race/ethnicity, which may reflect potential differences in susceptibility. In agreement with findings from repeated measures analysis, we reported that DEHP metabolites and BPA were significantly associated with an approximate 20% increase in the odds of vitamin D deficiency (≤20 ng/mL) [odds ratio (95% CI): 1.19 (1.06, 1.35) for molar sum of DEHP metabolites and 1.22 (1.01, 1.47) for BPA] at median 10 wk and 26 wk, respectively. CONCLUSIONS: Our results provide suggestive evidence of the potential for environmental exposure to phthalates and/or BPA to disrupt circulating vitamin D levels in pregnancy. https://doi.org/10.1289/EHP1178.

Thyroid hormone parameters during pregnancy in relation to urinary bisphenol A concentrations: A repeated measures study.

BACKGROUND: Maternal supply of thyroid hormones during pregnancy serves a critical role in fetal development. Although animal and in vitro studies provide evidence for thyroid hormone disruption as a result of bisphenol A (BPA) exposure, there is still a lack of evidence in human studies, particularly in the context of pregnancy. OBJECTIVES: We aimed to explore the associations between urinary BPA concentrations and plasma thyroid hormone parameters during gestation in pregnant women, and also investigated potential windows of vulnerability during gestation. METHODS: Our study population included 116 cases of preterm birth and 323 controls from a nested case-control study. We measured BPA in urine and thyroid hormone parameters in plasma samples collected at up to four study visits during pregnancy (median for each visit: 9.64, 17.9, 26.0, and 35.1weeks gestation). We used linear mixed models for repeated measures analyses, and multivariate linear regression models stratified by study visit to explore potential windows of susceptibility. RESULTS: In our repeated measures analysis, BPA and thyrotropin (TSH) were inversely associated. An interquartile range (IQR) increase in BPA was associated with an 8.21% decrease in TSH (95% confidence interval [CI]: -14.2, -1.83), and a 4.79% increase in free T4 (95% CI: 0.82, 8.92). BPA and TSH were also inversely associated in our cross-sectional analyses at visits 3 and 4. CONCLUSIONS: Our results suggest that TSH is inversely associated with urinary BPA in a consistent manner across pregnancy. Disruption of TSH levels during pregnancy can potentially impact child development and interfere with normal birth outcomes.

Longitudinal Profiles of Thyroid Hormone Parameters in Pregnancy and Associations with Preterm Birth.

INTRODUCTION: Overt thyroid disease in pregnancy is associated with numerous maternal and neonatal complications including preterm birth. Less is known about the contribution of trimester-specific subclinical alterations in individual thyroid hormones, especially in late gestation, on the risk of preterm birth. Herein, we examined the associations between subclinical changes in maternal thyroid hormone concentrations (TSH, total T3, free and total T4), measured at multiple time points in pregnancy, and the odds of preterm birth in pregnant women without clinical thyroid disease. PARTICIPANTS AND METHODS: Data were obtained from pregnant women participating in a nested case-control study of preterm birth within on ongoing birth cohort study at Brigham and Women's Hospital in Boston, MA (N = 439; 116 cases and 323 controls). We measured thyroid hormones in plasma collected at up to four time points in pregnancy (median = 10, 18, 26, and 35 weeks). We used multivariate logistic regression models stratified by study visit of sample collection to examine associations. To reveal potential biological pathways, we also explored these relationships by obstetric presentation of preterm birth (e.g., spontaneous preterm delivery) that have been previously hypothesized to share common underlying mechanisms. RESULTS: In samples collected at median 10 and 26 weeks of gestation, we found inverse associations between FT4 and the odds of overall preterm birth (odds ratio [OR] = 0.57, 95% confidence interval (CI) = 0.33, 1.00; and OR = 0.53, 95% CI = 0.34, 0.84, respectively). Positive associations were detected for total T3 at these same time points (OR = 2.52, 95% CI = 1.20, 5.31; and OR = 3.40, 95% CI = 1.56, 7.40, respectively). These effect estimates were stronger for spontaneous preterm birth. CONCLUSIONS: Our results suggest that subclinical alterations in individual maternal thyroid hormones may influence the risk of preterm birth, and the strength of these associations vary by gestational age.

Relationships Between Urinary Phthalate Metabolite and Bisphenol A Concentrations and Vitamin D Levels in U.S. Adults: National Health and Nutrition Examination Survey (NHANES), 2005-2010.

CONTEXT: Recent research suggests that environmental exposure to endocrine-disrupting chemicals may alter circulating 25-hydroxyvitamin D [25(OH)D] levels in humans. To date, no studies have assessed the associations between phthalates and bisphenol A (BPA) and total 25(OH)D in the U.S. general population. OBJECTIVE: To explore relationships between urinary concentrations of 11 phthalate metabolites and BPA and serum total 25(OH)D in a representative sample of U.S. adults. DESIGN: A cross-sectional study. SETTING: U.S. National Health and Nutrition Examination Survey, 2005-2010. PATIENTS OR OTHER PARTICIPANTS: U.S. general adult population (aged ≥20 years). INTERVENTIONS: None Main Outcome Measures: Serum total 25(OH)D measured by liquid chromatography-tandem mass spectrometry. RESULTS: Metabolites of di(2-ethylhexyl) phthalate (DEHP) were consistently inversely associated with total 25(OH)D in the overall study population and in gender-stratified models. In the overall population, we detected a significant inverse relationship for the molar sum of DEHP metabolites (ΣDEHP), where an interquartile range increase in ΣDEHP was associated with a 1.90% decrease (95% confidence interval [CI], -3.64, -0.17) in total 25(OH)D. A positive association was detected for monoethyl phthalate. For BPA, we found a statistically significant inverse relationship in women, but not in men. In women, an interquartile range increase in urinary BPA was associated with a 3.71% decrease (95% CI, -6.41, -1.02) in total 25(OH)D. CONCLUSIONS: Overall, our results provide suggestive evidence that environmental exposure to phthalates and BPA may alter circulating levels of total 25(OH)D in adults. Future human and animal studies are required to resolve the direction, temporality, and impact of these relationships.

Exploratory analysis of the potential relationship between urinary molybdenum and bone mineral density among adult men and women from NHANES 2007-2010.

Human exposure to molybdenum (Mo) may play a role in reducing bone mineral density (BMD) by interfering with steroid sex hormone levels. To begin to address gaps in the literature on this topic, the potential relationship between urinary Mo (U-Mo) and BMD at the femoral neck (FN-BMD) and lumbar spine (LS-BMD) was explored in a sample of 1496 adults participating in the 2007-2010 cycles of the National Health and Nutrition Examination Survey. Associations were assessed using multiple linear regression models stratified on sex and age. In adjusted models for 50-80+ year-old women, there was a statistically significant inverse relationship between natural log-U-Mo and LS-BMD (p-value: 0.002), and a statistically significant dose-dependent decrease in LS-BMD with increasing U-Mo quartiles (trend p-value: 0.002). A suggestive (trend p-value: 0.08), dose-dependent decrease in FN-BMD with increasing U-Mo quartiles was noted in this group of women as well. All other adjusted models revealed no statistically significant or suggestive relationships between U-Mo and FN-BMD or LS-BMD. Bone health is important for overall human health and well-being and, given the exploratory nature of this work, additional studies are needed to confirm the results in other populations, and clarify the potential underlying mechanisms of Mo on BMD.

Phenols and parabens in relation to reproductive and thyroid hormones in pregnant women.

INTRODUCTION: Phenols and parabens are ubiquitous environmental contaminants. Evidence from animal studies and limited human data suggest they may be endocrine disruptors. In the current study, we examined associations of phenols and parabens with reproductive and thyroid hormones in 106 pregnant women recruited for the prospective cohort, "Puerto Rico Testsite for Exploring Contamination Threats (PROTECT)". METHODS: Urinary exposure biomarkers (bisphenol A, triclosan, benzophenone-3, 2,4-dichlorophenol, 2,5-dichlorophenol, butyl, methyl and propyl paraben) and serum hormone levels (estradiol, progesterone, sex hormone-binding globulin (SHBG), free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone) were measured at up to two time points during pregnancy (16-20 weeks and 24-28 weeks). We used linear mixed models to assess relationships between exposure biomarkers and hormone levels across pregnancy, controlling for urinary specific gravity, maternal age, BMI and education. In sensitivity analyses, we evaluated cross-sectional relationships between exposure and hormone levels stratified by study visit using linear regression. RESULTS: An IQR increase in methyl paraben was associated with a 7.70% increase (95% CI 1.50, 13.90) in SHBG. Furthermore, an IQR increase in butyl paraben as associated with an 8.46% decrease (95% CI 16.92, 0.00) in estradiol, as well as a 9.34% decrease (95% CI -18.31,-0.38) in estradiol/progesterone. Conversely, an IQR increase in butyl paraben was associated with a 5.64% increase (95% CI 1.26, 10.02) in FT4. Progesterone was consistently negatively associated with phenols, but none reached statistical significance. After stratification, methyl and propyl paraben were suggestively negatively associated with estradiol at the first time point (16-20 weeks), and suggestively positively associated with estradiol at the second time point (24-28 weeks). CONCLUSIONS: Within this ongoing birth cohort, certain phenols and parabens were associated with altered reproductive and thyroid hormone levels during pregnancy. These changes may contribute to adverse health effects in mothers or their offspring, but additional research is required.

Associations between Repeated Measures of Maternal Urinary Phthalate Metabolites and Thyroid Hormone Parameters during Pregnancy.

BACKGROUND: Maintaining thyroid homeostasis during pregnancy is essential for normal fetal growth and development. Growing evidence suggests that phthalates interfere with normal thyroid function. Few human studies have investigated the degree to which phthalates may affect thyroid hormone levels in particularly susceptible populations such as pregnant women. OBJECTIVES: We examined the associations between repeated measures of urinary phthalate metabolites and plasma thyroid hormone levels in samples collected at up to four time points per subject in pregnancy. Additionally, we investigated the potential windows of susceptibility to thyroid hormone disturbances related to study visit of sample collection. METHODS: Data were obtained from pregnant women (n = 439) participating in a nested case-control study of preterm birth with 116 cases and 323 controls. We measured 9 phthalate metabolite concentrations in urine samples collected at up to four study visits per subject during pregnancy (median = 10, 18, 26, and 35 weeks of gestation, respectively). We also measured a panel of thyroid function markers in plasma collected at the same four time points per subject during pregnancy. RESULTS: Although our results were generally null, in repeated measures analyses we observed that phthalate metabolites were largely inversely associated with thyrotropin and positively associated with free and total thyroid hormones. Cross-sectional analyses by study visit revealed that the magnitude and/or direction of these relationships varied by timing of exposure during gestation. CONCLUSIONS: These results support previous reports showing the potential for environmental phthalate exposure to alter circulating levels of thyroid hormones in pregnant women. Citation: Johns LE, Ferguson KK, McElrath TF, Mukherjee B, Meeker JD. 2016. Associations between repeated measures of maternal urinary phthalate metabolites and thyroid hormone parameters during pregnancy. Environ Health Perspect 124:1808-1815; http://dx.doi.org/10.1289/EHP170.

Exposure assessment issues in epidemiology studies of phthalates.

PURPOSE: The purpose of this paper is to review exposure assessment issues that need to be addressed in designing and interpreting epidemiology studies of phthalates, a class of chemicals commonly used in consumer and personal care products. Specific issues include population trends in exposure, temporal reliability of a urinary metabolite measurement, and how well a single urine sample may represent longer-term exposure. The focus of this review is on seven specific phthalates: diethyl phthalate (DEP); di-n-butyl phthalate (DBP); diisobutyl phthalate (DiBP); butyl benzyl phthalate (BBzP); di(2-ethylhexyl) phthalate (DEHP); diisononyl phthalate (DiNP); and diisodecyl phthalate (DiDP). METHODS: Comprehensive literature search using multiple search strategies. RESULTS: Since 2001, declines in population exposure to DEP, BBzP, DBP, and DEHP have been reported in the United States and Germany, but DEHP exposure has increased in China. Although the half-lives of various phthalate metabolites are relatively short (3 to 18h), the intraclass correlation coefficients (ICCs) for phthalate metabolites, based on spot and first morning urine samples collected over a week to several months, range from weak to moderate, with a tendency toward higher ICCs (greater temporal stability) for metabolites of the shorter-chained (DEP, DBP, DiBP and BBzP, ICCs generally 0.3 to 0.6) compared with those of the longer-chained (DEHP, DiNP, DiDP, ICCs generally 0.1 to 0.3) phthalates. Additional research on optimal approaches to addressing the issue of urine dilution in studies of associations between biomarkers and different type of health effects is needed. CONCLUSIONS: In conclusion, the measurement of urinary metabolite concentrations in urine could serve as a valuable approach to estimating exposure to phthalates in environmental epidemiology studies. Careful consideration of the strengths and limitations of this approach when interpreting study results is required.

Serum Biomarkers of Exposure to Perfluoroalkyl Substances in Relation to Serum Testosterone and Measures of Thyroid Function among Adults and Adolescents from NHANES 2011-2012.

Perfluoroalkyl substances (PFASs) are a group of environmentally-persistent chemicals that have been widely used in many industrial applications. There is human and animal evidence that PFASs may alter levels of reproductive and thyroid-related hormones. However, human studies on the potential age-related effects of PFASs on these outcomes among males and females are limited. We explored the relationship between serum PFASs and serum total testosterone (T), thyroid stimulating hormone (TSH), and free and total triiodothyronine (FT3, TT3) and thyroxine (FT4, TT4) among males and females 12 to 80 years of age from the 2011-2012 cycle of the National Health and Nutrition Examination Survey. Associations were assessed using multiple linear regression models that were stratified on sex and age categories. Effect estimates from the majority of the adjusted models were not statistically significant. However, exposure to PFASs may be associated with increases in FT3, TT3, and FT4 among adult females, but during adolescence, PFASs may be related to increases in TSH among males and decreases in TSH among females. No significant relationships were observed between PFASs and T in any of the models. These findings suggest that exposure to PFASs may disrupt thyroid hormone homeostasis.

Urinary phthalate metabolites in relation to maternal serum thyroid and sex hormone levels during pregnancy: a longitudinal analysis.

BACKGROUND: Increasing scientific evidence suggests that exposure to phthalates during pregnancy may be associated with an elevated risk of adverse reproductive outcomes such as preterm birth. Maternal endocrine disruption across pregnancy may be one pathway mediating some of these relationships. We investigated whether urinary phthalate metabolites were associated with maternal serum thyroid (free thyroxine [FT4], free triiodothyronine [FT3], and thyroid-stimulating hormone [TSH]), and sex (estradiol, progesterone, and sex hormone-binding globulin [SHBG]) hormone levels at multiple time points during pregnancy. METHODS: Preliminary data (n = 106) were obtained from an ongoing prospective birth cohort in Northern Puerto Rico. We collected urine and serum sample at the first and third study visits that occurred at 18 +/- 2 and 26 +/- 2 weeks of gestation, respectively. To explore the longitudinal relationships between urinary phthalate metabolites and serum thyroid and sex hormone concentrations, we used linear mixed models (LMMs) adjusted for prepregnancy body mass index (BMI) and maternal age. An interaction term was added to each LMM to test whether the effect of urinary phthalate metabolites on serum thyroid and sex hormone levels varied by study visit. In cross-sectional analyses, we stratified BMI- and age-adjusted linear regression models by study visit. RESULTS: In adjusted LMMs, we observed significant inverse associations between mono-3-carboxypropyl phthalate (MCPP) and FT3 and between mono-ethyl phthalate (MEP) and progesterone. In cross-sectional analyses by study visit, we detected stronger and statistically significant inverse associations at the third study visit between FT3 and MCPP as well as mono-carboxyisooctyl phthalate (MCOP); also at the third study visit, significant inverse associations were observed between FT4 and metabolites of di-(2-ethylhexyl) phthalate (DEHP). The inverse association between MEP and progesterone was consistent across study visits. CONCLUSIONS: In this group of pregnant women, urinary phthalate metabolites may be associated with altered maternal serum thyroid and sex hormone levels, and the magnitude of these effects may depend on the timing of exposure during gestation.

A case study of the impact of inaccurate cause-of-death reporting on health disparity tracking: New York City premature cardiovascular mortality.

OBJECTIVES: Heart disease death overreporting is problematic in New York City (NYC) and other US jurisdictions. We examined whether overreporting affects the premature (< 65 years) heart disease death rate disparity between non-Hispanic Blacks and non-Hispanic Whites in NYC. METHODS: We identified overreporting hospitals and used counts of premature heart disease deaths at reference hospitals to estimate corrected counts. We then corrected citywide, age-adjusted premature heart disease death rates among Blacks and Whites and a White-Black premature heart disease death disparity. RESULTS: At overreporting hospitals, 51% of the decedents were White compared with 25% at reference hospitals. Correcting the heart disease death counts at overreporting hospitals decreased the age-adjusted premature heart disease death rate 10.1% (from 41.5 to 37.3 per 100,000) among Whites compared with 4.2% (from 66.2 to 63.4 per 100,000) among Blacks. Correction increased the White-Black disparity 6.1% (from 24.6 to 26.1 per 100,000). CONCLUSIONS: In 2008, NYC's White-Black premature heart disease death disparity was underestimated because of overreporting by hospitals serving larger proportions of Whites. Efforts to reduce overreporting may increase the observed disparity, potentially obscuring any programmatic or policy-driven advances.

Neighborhood social cohesion and posttraumatic stress disorder in a community-based sample: findings from the Detroit Neighborhood Health Study.

PURPOSE: Posttraumatic stress disorder (PTSD) is common and debilitating. Although research has identified individual-level risk factors for PTSD, the role of macro-social factors in PTSD etiology remains unknown. This study tests whether perceived neighborhood social cohesion (NSC), measured at the both the individual and neighborhood levels, plays a role in determining past-year risk of PTSD among those exposed to trauma. METHODS: Data (n = 1,221) were obtained from an ongoing prospective epidemiologic study in the city of Detroit. Assessment of traumatic event exposure and PTSD was consistent with DSM-IV criteria. Generalized estimating equations (GEE) and logistic regression models were used to estimate the association of neighborhood-level perceived NSC with the risk of PTSD, adjusting for individual-level perceptions of NSC and other covariates. RESULTS: The odds of past-year PTSD were significantly higher among those residing in a neighborhood with low social cohesion compared to high (OR = 2.44, 95 % CI: 1.58, 3.78), independent of individual sociodemographic characteristics, number of traumas, and individual-level perceptions of NSC. The odds of past-year PTSD were not significantly associated with individual-level perceptions of NSC. CONCLUSIONS: These results demonstrate that social context shapes risk of PTSD and suggest that changing the social context may shift vulnerability to this disorder.