Prenatal exposure to consumer product chemical mixtures and size for gestational age at delivery.

BACKGROUND: While fetal growth is a tightly regulated process, it is sensitive to environmental exposures that occur during pregnancy. Many commonly used consumer products contain chemicals that can disturb processes underlying fetal growth. However, mixtures of these chemicals have been minimally examined. We investigated associations between prenatal exposure to 33 consumer product chemicals (nine organophosphate ester flame retardant [OPE] metabolites, 12 phthalate metabolites, and 12 phenols) and the odds of small- or large-for-gestational age (SGA and LGA) births. METHODS: This case-control study was comprised of SGA (N = 31), LGA (N = 28), and appropriate for gestational age control (N = 31) births selected from the larger LIFECODES cohort. Biomarkers of exposure to consumer product chemicals were quantified in maternal urine collected from up to three study visits during pregnancy. In a single-pollutant approach, odds ratios (OR) and 95% confidence intervals (CI) of SGA and LGA associated with an interquartile range (IQR)-increase in exposure biomarkers were estimated using multinomial logistic regression. In a multi-pollutant approach, quantile g-computation was used to jointly estimate the OR (95% CI) of SGA and LGA per simultaneous one quartile-change in all biomarkers belonging to each chemical class. RESULTS: Among the 33 biomarkers analyzed, 20 were detected in at least 50% of the participants. After adjusting for potential confounders, we observed reduced odds of LGA in association with higher urinary concentrations of several exposure biomarkers. For example, an IQR-increase in the OPE metabolite, diphenyl phosphate, was associated with lower odds of LGA (OR: 0.40 [95% CI: 0.18, 0.87]). Using quantile g-computation, we estimated lower odds of an LGA birth for higher OPE metabolite concentrations (OR: 0.49 [95% CI: 0.27, 0.89]) and phthalate metabolite concentrations (OR: 0.23 [95% CI: 0.07, 0.73]). Associations between consumer product chemicals and SGA were largely null. CONCLUSIONS: Joint exposure to OPEs and phthalates was associated with lower odds of delivering LGA. Associations with LGA could indicate a specific impact of these exposures on the high end of the birth weight spectrum. Future work to understand this nuance in the associations between consumer product chemical mixtures and fetal growth is warranted.

Identification of pathologically small fetuses using customized, ultrasound and population-based growth norms.

OBJECTIVES: Fetal growth restriction is a strong risk factor for stillbirth. We compared the performance of three fetal growth curves - customized, ultrasound (Hadlock) and population - in identifying abnormally grown fetuses at risk of stillbirth. METHODS: We performed a case-control study of singleton stillbirths (delivered between 2000 and 2010) at one center. Four liveborn controls were randomly identified for each stillbirth. Ultrasound-estimated fetal weight within 1 month prior to delivery was used to calculate growth percentiles for each fetus using three fetal growth norms. Sensitivities and odds ratios for stillbirth, as well as odds of abnormal growth according to formula, were calculated. RESULTS: There were 49 stillbirths and 197 live births. Using the customized norms, growth of the fetuses destined to be stillborn was bimodal, with both more small-for-gestational-age (SGA; < 10(th) percentile) and large-for-gestational-age (LGA; ≥ 90(th) percentile) fetuses. Odds of being abnormally grown were significantly higher using ultrasound compared with population norms (P = 0.02) but were not statistically different using ultrasound and customized norms (P = 0.21). Sensitivity for identification of SGA on ultrasound as a predictor of stillbirth was higher using customized (39%; 95% CI, 24-54%) or ultrasound (33%; 95% CI, 19-47%), rather than population (14%; 95% CI, 4-25%), norms. CONCLUSIONS: Among fetuses destined to be stillborn, customized and ultrasound norms identified a greater proportion of both SGA and LGA estimated fetal weights. The customized norms performed best in identifying death among SGA fetuses. These results should be interpreted within the limitations of the study design.

Temporal trends and predictors of phthalate, phthalate replacement, and phenol biomarkers in the LIFECODES Fetal Growth Study.

BACKGROUND: Exposure to many phthalates and phenols is declining as replacements are introduced. There is little information on temporal trends or predictors of exposure to these newer compounds, such as phthalate replacements, especially among pregnant populations. OBJECTIVE: Examine temporal trends and predictors of exposure to phthalates, phthalate replacements, and phenols using single- and multi-pollutant approaches. METHODS: We analyzed data from 900 singleton pregnancies in the LIFECODES Fetal Growth Study, a nested case-cohort with recruitment from 2007 to 2018. We measured and averaged concentrations of 12 phthalate metabolites, four phthalate replacement metabolites, and 12 phenols in urine at three timepoints during pregnancy. We visualized and analyzed temporal trends and predictors of biomarker concentrations. To examine chemical mixtures, we derived clusters of individuals with shared exposure profiles using a finite mixture model and examined temporal trends and predictors of cluster assignment. RESULTS: Exposure to phthalates and most phenols declined across the study period, while exposure to phthalate replacements (i.e., di(isononyl) cyclohexane-1,2-dicarboxylic acid, diisononyl ester [DINCH] and di-2-ethylhexyl terephthalate [DEHTP]) and bisphenol S (BPS) increased. For example, the sum of DEHTP biomarkers increased multiple orders of magnitude, with an average concentration of 0.92 ng/mL from 2007 to 2008 and 61.9 ng/mL in 2017-2018. Biomarkers of most chemical exposures varied across sociodemographic characteristics, with the highest concentrations observed in non-Hispanic Black or Hispanic participants relative to non-Hispanic White participants. We identified five clusters with shared exposure profiles and observed temporal trends in cluster membership. For example, at the end of the study period, a cluster characterized by high exposure to phthalate replacements was the most prevalent. SIGNIFICANCE: In a large and well-characterized pregnancy cohort, we observed exposure to phthalate replacements and BPS increased over time while exposure to phthalates and other phenols decreased. Our results highlight the changing nature of exposure to consumer product chemical mixtures.

Temporal trends and predictors of gestational exposure to organophosphate ester flame retardants and plasticizers.

BACKGROUND: Organophosphate esters (OPEs), used as flame retardants and plasticizers, are chemicals of concern for maternal and infant health. Prior studies examining temporal trends and predictors of OPE exposure are primarily limited by small sample sizes. OBJECTIVES: Characterize temporal trends and predictors of OPE exposure biomarkers. METHODS: We determined urinary concentrations of eight biomarkers of OPE exposure at three timepoints during pregnancy for participants in the LIFECODES Fetal Growth Study (n = 900), a nested case-cohort recruited between 2007 and 2018. We examined biomarker concentrations, their variability during pregnancy, and temporal trends over the study period. In addition, we identified sociodemographic and pregnancy characteristics associated with biomarker concentrations. Analyses were conducted using both the within-subject pregnancy geometric means and biomarker concentrations measured at individual study visits. RESULTS: Five OPE biomarkers were detected in at least 60% of the study participants. Biomarkers were not strongly correlated with one another and intraclass correlation coefficients, measuring within-subject variability during pregnancy, ranged from 0.27 to 0.51. Biomarkers exhibited varying temporal trends across study years. For example, bis(1-chloro-2-propyl) phosphate (BCIPP) increased monotonically, whereas bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP), displayed non-monotonic trends with concentrations that peaked between 2011 and 2014. We observed associations between sociodemographic characteristics and OPE biomarkers. In general, concentrations of most OPE biomarkers were higher among participants from racial and ethnic minority populations, participants who were younger, had higher pre-pregnancy body mass index (BMI), and less than a college degree. We observed consistent results using either averaged or visit-specific biomarker concentrations. SIGNIFICANCE: We observed widespread exposure to several OPEs and OPE biomarkers displayed varying temporal trends in pregnant people from 2007 to 2018. Concentrations of most OPE biomarkers varied according to sociodemographic factors, suggesting higher burdens of exposure among participants with higher pre-pregnancy BMI, those belonging to racial and ethnic minority populations, and lower educational attainment.

Provider practices for the prevention of eclampsia and attitudes toward magnesium sulfate: results of a nationwide survey.

OBJECTIVE: To survey OB-GYNs regarding their practice patterns and perspectives when it comes to using magnesium sulfate (magnesium) in the prevention of eclampsia. STUDY DESIGN: We conducted a cross-sectional web-based 18-item survey given to 564 practicing OB-GYNs in the Pregnancy-Related Care Research Network. The survey used clinical scenarios to look at provider practices for preventing eclampsia in patients who have preeclampsia and relative contraindications to magnesium. Next, we assessed provider attitudes toward magnesium and inquired about their experiences with complications related to its use. The survey also contained an embedded educational component that addressed the signs and symptoms of magnesium toxicity followed by a 2-item quiz for those providers who self-identified as having never treated magnesium toxicity. RESULTS: Nearly 30% of OB-GYNs contacted completed the survey. For patients with preeclampsia and a contraindication to magnesium such as myasthenia gravis, 44.4% of respondents would administer an alternative antiepileptic and 42.5% of them would administer no antiepileptic at all. For patients with pulmonary edema complicating preeclampsia, 32.5% would give magnesium at the usual dose, 33.1% would give magnesium at less than the usual dose, 12.3% would give an alternative antiepileptic and 22.1% would give no antiepileptic at all. For patients with laboratory evidence of renal compromise complicating preeclampsia, most respondents (89.6%) said they would give magnesium at less than the usual dose. Regarding complications of magnesium that clinicians have encountered, over one-third of respondents have administered calcium gluconate for magnesium toxicity in patients with preeclampsia. For those providers who have not treated magnesium toxicity and were prompted to receive the educational component and quiz, all knew the correct initial bolus dosing of magnesium and the majority were able to identify symptoms of toxicity. The majority (81.8%) of respondents said that continuous magnesium infusions cause an increased demand for dedicated personnel to care for the patients on them. Almost 57% of respondents endorsed the need for an alternative antiepileptic to magnesium in the prevention of eclampsia. Most write-in responses supporting this need cited a concern with magnesium's safety and side effects. CONCLUSION: There is wide variation among OB-GYNs regarding the prevention of eclampsia and complications of magnesium are not uncommon. The survey revealed that OB-GYNs are using alternative antiepileptics in scenarios where there is concern for magnesium's safety profile. In addition, over half of those surveyed believe there is a need for validated antiepileptics other than magnesium for the prevention of eclampsia in patients with preeclampsia. These findings suggest that OB-GYNs would support further research into alternative antiepileptics in the prevention of eclampsia.

Analysis of changes in maternal circulating angiogenic factors throughout pregnancy for the prediction of preeclampsia.

OBJECTIVE: To assess whether changes in maternal angiogenic factors throughout pregnancy predict the development of preeclampsia. STUDY DESIGN: Placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 receptor (sFlt-1) were measured in 2355 women at 10, 18, 26 and 35 weeks gestation. Receiver operator characteristic analysis was used to calculate test characteristics for changes in analytes between time points. Linear mixed-effects models generated slopes of analytes throughout pregnancy, which in turn were used as predictors in adjusted logistic regression models. RESULT: Changes in analytes yielded positive predictive values of 9 to 19% and negative predictive values of 93 to 97%. Individuals with lowest quartile slopes in PlGF had sixfold greater odds (95% confidence interval (CI): 3.5, 10.2) of preeclampsia compared with individuals in the highest quartile. With respect to sFlt-1, the highest quartile had 5.1 times greater odds (95% CI: 3.1, 8.4) than the lowest quartile. CONCLUSION: Measuring the trend in PlGF and sFlt-1 across pregnancy segregates women at increased risk of preeclampsia. However, changes in these factors throughout pregnancy lack clinically useful predictive power.

Phthalate metabolites and bisphenol-A in association with circulating angiogenic biomarkers across pregnancy.

INTRODUCTION: Phthalates and bisphenol-a (BPA) are endocrine disrupting compounds with widespread exposure that have been linked to adverse birth outcomes and developmental effects. We hypothesized that these associations may be mediated in part through altered placental development and function consequent to exposure. To investigate this question, we examined associations between plasma biomarkers of angiogenesis and urinary biomarkers of exposure to phthalates and bisphenol-a (BPA) measured at repeated time points across pregnancy. METHODS: We utilized a nested case-control population of 130 mothers who delivered preterm and 352 who delivered term from a prospective birth cohort. Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured in plasma samples collected from up to four visits during pregnancy (median 10, 18, 26, and 35 weeks). Phthalate metabolites and BPA were measured in urine samples collected at the same visits as indices of exposure. RESULTS: In linear mixed effects models adjusted for urine dilution and gestational age at sample collection, oxidized di-2-ethylhexyl phthalate (DEHP) metabolites were associated with decreases in PlGF as well as increases in the sFlt-1 to PlGF ratio. These results were slightly attenuated in fully adjusted models. Other phthalate metabolites did not show consistent relationships with either sFlt-1 or PlGF. BPA, however, was associated with increased sFlt-1 as well as the sFlt-1 to PlGF ratio in both crude and adjusted models. DISCUSSION: We observed associations between urinary DEHP metabolites and BPA and biomarkers of angiogenesis during pregnancy that may be indicative of disrupted placental development and/or function during gestation.