Stephanie M. Engel

Prenatal Phenol and Phthalate Exposures and Birth Outcomes

BACKGROUNDnMany phthalates and phenols are hormonally active and are suspected to alter the course of development.nnnOBJECTIVEnWe investigated prenatal exposures to phthalate and phenol metabolites and their associations with body size measures of the infants at birth.nnnMETHODSnWe measured 5 phenol and 10 phthalate urinary metabolites in a multiethnic cohort of 404 women in New York City during their third trimester of pregnancy and recorded size of infants at birth.nnnRESULTSnMedian urinary concentrations were > 10 microg/L for 2 of 5 phenols and 6 of 10 phthalate monoester metabolites. Concentrations of low-molecular-weight phthalate monoesters (low-MWP) were approximately 5-fold greater than those of high-molecular-weight metabolites. Low-MWP metabolites had a positive association with gestational age [0.97 day gestational age per ln-biomarker; 95% confidence interval (CI), 0.07-1.9 days, multivariate adjusted] and with head circumference. Higher prenatal exposures to 2,5-dichlorophenol (2,5-DCP) predicted lower birth weight in boys (-210 g average birth weight difference between the third tertile and first tertile of 2,5-DCP; 95% CI, 71-348 g). Higher maternal benzophenone-3 (BP3) concentrations were associated with a similar decrease in birth weight among girls but with greater birth weight in boys.nnnCONCLUSIONSnWe observed a range of phthalate and phenol exposures during pregnancy in our population, but few were associated with birth size. The association of 2,5-DCP and BP3 with reduced or increased birth weight could be important in very early or small-size births. In addition, positive associations of urinary metabolites with some outcomes may be attributable partly to unresolved confounding with maternal anthropometric factors.

Prenatal Phthalate Exposure Is Associated with Childhood Behavior and Executive Functioning

Background Experimental and observational studies have reported biological consequences of phthalate exposure relevant to neurodevelopment. Objective Our goal was to examine the association of prenatal phthalate exposure with behavior and executive functioning at 4–9 years of age. Methods The Mount Sinai Children’s Environmental Health Study enrolled a multiethnic prenatal population in New York City between 1998 and 2002 (n = 404). Third-trimester maternal urines were collected and analyzed for phthalate metabolites. Children (n = 188, n = 365 visits) were assessed for cognitive and behavioral development between the ages of 4 and 9 years. Results In multivariate adjusted models, increased loge concentrations of low molecular weight (LMW) phthalate metabolites were associated with poorer scores on the aggression [β = 1.24; 95% confidence interval (CI), 0.15– 2.34], conduct problems (β = 2.40; 95% CI, 1.34–3.46), attention problems (β = 1.29; 95% CI, 0.16– 2.41), and depression (β = 1.18; 95% CI, 0.11–2.24) clinical scales; and externalizing problems (β = 1.75; 95% CI, 0.61–2.88) and behavioral symptom index (β = 1.55; 95% CI, 0.39–2.71) composite scales. Increased loge concentrations of LMW phthalates were also associated with poorer scores on the global executive composite index (β = 1.23; 95% CI, 0.09–2.36) and the emotional control scale (β = 1.33; 95% CI, 0.18– 2.49). Conclusion Behavioral domains adversely associated with prenatal exposure to LMW phthalates in our study are commonly found to be affected in children clinically diagnosed with conduct or attention deficit hyperactivity disorders.

Endocrine disruptors and childhood social impairment.

Prenatal exposure to endocrine disruptors has the potential to impact early brain development. Neurodevelopmental toxicity in utero may manifest as psychosocial deficits later in childhood. This study investigates prenatal exposure to two ubiquitous endocrine disruptors, the phthalate esters and bisphenol A (BPA), and social behavior in a sample of adolescent inner-city children. Third trimester urines of women enrolled in the Mount Sinai Childrens Environmental Health Study between 1998 and 2002 (n=404) were analyzed for phthalate metabolites and BPA. Mother-child pairs were asked to return for a follow-up assessment when the child was between the ages of 7 and 9 years. At this visit, mothers completed the Social Responsiveness Scale (SRS) (n=137), a quantitative scale for measuring the severity of social impairment related to Autistic Spectrum Disorders (ASD) in the general population. In adjusted general linear models increasing log-transformed low molecular weight (LMW) phthalate metabolite concentrations were associated with greater social deficits (β=1.53, 95% CI 0.25-2.8). Among the subscales, LMWP were also associated with poorer Social Cognition (β=1.40, 95% CI 0.1-2.7); Social Communication (β=1.86, 95% CI 0.5-3.2); and Social Awareness (β=1.25, 95% CI 0.1-2.4), but not for Autistic Mannerisms or Social Motivation. No significant association with BPA was found (β=1.18, 95% CI -0.75, 3.11). Prenatal phthalate exposure was associated with childhood social impairment in a multiethnic urban population. Even mild degrees of impaired social functioning in otherwise healthy individuals can have very important adverse effects over a childs lifetime. These results extend our previous finding of atypical neonatal and early childhood behaviors in relation to prenatal phthalate exposure.

Prenatal phthalate exposure and performance on the Neonatal Behavioral Assessment Scale in a multiethnic birth cohort

We investigated the relationship between prenatal maternal urinary concentrations of phthalate metabolites and neonatal behavior in their 295 children enrolled in a multiethnic birth cohort between 1998 and 2002 at the Mount Sinai School of Medicine in New York City. Trained examiners administered the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) to children within 5 days of delivery. We measured metabolites of 7 phthalate esters in maternal urine that was collected between 25 and 40 weeks gestation. All but two phthalate metabolites were over 95% detectable. We summed metabolites on a molar basis into low and high molecular weight phthalates. We hypothesized the existence of sex-specific effects from phthalate exposure a priori given the hormonal activity of these chemicals. Overall we found few associations between individual phthalate metabolites or their molar sums and most of the BNBAS domains. However, we observed significant sex-phthalate metabolite interactions (p<0.10) for the Orientation and Motor domains and the overall Quality of Alertness score. Among girls, there was a significant linear decline in adjusted mean Orientation score with increasing urinary concentrations of high molecular weight phthalate metabolites (B=-0.37, p=0.02). Likewise, there was a strong linear decline in their adjusted mean Quality of Alertness score (B=-0.48, p<0.01). In addition, boys and girls demonstrated opposite patterns of association between low and high molecular weight phthalate metabolite concentrations and motor performance, with some indication of improved motor performance with increasing concentration of low molecular weight phthalate metabolites among boys. This is the first study to report an association between prenatal phthalate exposure and neurological effects in humans or animals, and as such requires replication.

Prenatal Pesticide and PCB Exposures and Birth Outcomes

Evidence is inconsistent or poorly understood for links between polychlorinated biphenyls (PCBs), 1,1′-dichloro-2,2′-bis(4-chlorophenyl)ethylene (DDE), and organophosphate (OP) pesticides and adverse pregnancy outcomes, although they are known developmental toxicants. We measured biomarkers of maternal exposure to DDE, PCB, and OP metabolites in the third trimester of pregnancy among 404 mothers in a multiethnic cohort in New York City. We also determined maternal paraoxonase (PON1), butyrylcholinesterase (BuChe), and PON1Q192R gene variant. Higher multivariate-adjusted DDE levels (but not PCB) were associated with lower birth weight (–98 g/log10 DDE, p = 0.096) and head circumference (–0.54 cm/log10 DDE, p = 0.030). DDE and PCB levels were not related to birth length, Ponderal index, or gestational age. Birth length was shorter for mothers with PON192RR slow genotype compared with PON192QQ (p = 0.026), and head circumference was inversely associated with maternal PON1 activity (p = 0.004). With slow-activity PON1 or PON192, urinary diethylphosphates (ΣDEPs) were associated with lower birth weight and dimethylphosphates (ΣDMPs) with shorter birth length. No associations were found between birth outcomes and BuChe. In summary, we found suggestive relationships between prenatal environmental biomarkers and birth outcomes in this population. Maternal susceptibility factors including PON1 and maternal weight contributed to the observed effects.

The Effect of Maternal PTSD Following in Utero Trauma Exposure on Behavior and Temperament in the 9-Month-Old Infant

Abstract:u2002 In view of evidence of in utero glucocorticoid programming, and our prior observation of lower cortisol levels in 9‐month‐old infants of mothers with posttraumatic stress disorder (PTSD) compared to mothers without PTSD, we undertook an examination of the effect of in utero maternal stress, as determined by PTSD symptom severity, and maternal cortisol levels on behavioral outcomes in the infant. Methods: Ninety‐eight pregnant women directly exposed to the World Trade Center (WTC) collapse on 9/11 provided salivary cortisol samples and completed a PTSD symptom questionnaire and a behavior rating scale to measure infant temperament, including distress to limitations, and response to novelty. Results: Mothers who developed PTSD in response to 9/11 had lower morning and evening salivary cortisol levels, compared to mothers who did not develop PTSD. Maternal morning cortisol levels were inversely related to their rating of infant distress and response to novelty (i.e., loud noises, new foods, unfamiliar people). Also, mothers who had PTSD rated their infants as having greater distress to novelty than did mothers without PTSD (t= 2.77, df= 61, P= 0.007). Conclusion: Longitudinal studies are needed to determine how the association between maternal PTSD symptoms and cortisol levels and infant temperament reflect genetic and/or epigenetic mechanisms of intergenerational transmission.

Peripheral Blood Cytokine Profiling During Pregnancy and Post-partum Periods

Citation Kraus TA, Sperling RS, Engel SM, Lo Y, Kellerman L, Singh T, Loubeau M, Ge Y, Garrido JL, Rodríguez‐García M, Moran TM. Peripheral blood cytokine profiling during pregnancy and post‐partum periods. Am J Reprod Immunol 2010; 64: 411–426

Bayesian Selection and Clustering of Polymorphisms in Functionally Related Genes

In epidemiologic studies, there is often interest in assessing the relationship between polymorphisms in functionally related genes and a health outcome. For each candidate gene, single nucleotide polymorphism (SNP) data are collected at a number of locations, resulting in a large number of possible genotypes. Because instabilities can result in analyses that include all the SNPs, dimensionality is typically reduced by conducting single SNP analyses or attempting to identify haplotypes. This article proposes an alternative Bayesian approach for reducing dimensionality. A multilevel Dirichlet process prior is used for the distribution of the SNP-specific regression coefficients within genes, incorporating a variable selection-type mixture structure to allow SNPs with no effect. This structure allows simultaneous selection of important SNPs and soft clustering of SNPs having similar impact on the health outcome. The methods are illustrated using data from a study of pro- and anti-inflammatory cytokine polymorphisms and spontaneous preterm birth.

Maternal Smoking, Preeclampsia, and Infant Health Outcomes in New York City, 1995–2003

A number of previous studies have reported an inverse association between maternal smoking and preeclampsia. Additionally, some have suggested that smokers who develop preeclampsia have worse maternal and fetal outcomes than nonsmokers who develop preeclampsia. The authors examined the relation of smoking to preeclampsia among 674,250 singleton pregnancies in New York City between 1995 and 2003. Although smoking was associated with a reduced risk of preeclampsia overall (adjusted odds ratio = 0.88, 95% confidence interval: 0.82, 0.94), no association was found for preeclampsia superimposed on chronic hypertension (adjusted odds ratio = 1.04, 95% confidence interval: 0.90, 1.21). Furthermore, the apparent protection conferred by maternal smoking was restricted to women aged < or =30 years. Contrary to previous reports, the authors found evidence of a negative interaction between smoking and preeclampsia with respect to preterm delivery and birth weight; smokers who developed preeclampsia had a lower risk of preterm delivery, and a lower adjusted mean difference in birth weight, than would have been expected based on the independent effects of smoking and preeclampsia. These data suggest that smoking is only protective against preeclampsia without pre gestational hypertension, and even then principally among younger women. Additionally, smokers who develop these disorders have no increased risk of adverse birth outcomes relative to nonsmokers who develop the same conditions.

Maternal ethnic ancestry and adverse perinatal outcomes in New York City.

OBJECTIVEnWe sought to examine the association between narrowly defined subsets of maternal ethnicity and birth outcomes.nnnSTUDY DESIGNnWe analyzed 1995-2003 New York City birth certificates linked to hospital discharge data for 949,210 singleton births to examine the multivariable associations between maternal ethnicity and preterm birth, subsets of spontaneous and medically indicated preterm birth, term small for gestational age, and term birthweight.nnnRESULTSnCompared with non-Hispanic whites, Puerto Ricans had an elevated odds ratio (1.9; 95% confidence interval, 1.9-2.0) for delivering at 32-36 weeks (adjusted for nativity, maternal age, parity, education, tobacco use, prepregnancy weight, and birth year). We found an excess of adverse outcomes among most Latino groups. Outcomes also varied within regions, with North African infants nearly 100 g (adjusted) heavier than sub-Saharan African infants.nnnCONCLUSIONnThe considerable heterogeneity in risk of adverse perinatal outcomes is obscured in broad categorizations of maternal race/ethnicity and may help to formulate etiologic hypotheses.