Publications by authors named "Stephanie M Engel"

107 Publications

Gestational blood levels of toxic metal and essential element mixtures and associations with global DNA methylation in pregnant women and their infants.

Sci Total Environ 2021 Sep 8;787:147621. Epub 2021 May 8.

Norwegian Institute of Public Health, Oslo, Norway.

Background: Pregnant women and their fetuses are exposed to multiple toxic metals that together with variations in essential element levels may alter epigenetic regulation, such as DNA methylation.

Objectives: The aim of the study was to investigate the associations between gestational levels of toxic metals and essential elements and mixtures thereof, with global DNA methylation levels in pregnant women and their newborn children.

Methods: Using 631 mother-child pairs from a prospective birth cohort (The Norwegian Mother, Father and Child Cohort Study), we measured maternal blood concentration (gestation week ~18) of five toxic metals and seven essential elements. We investigated associations as individual exposures and two-way interactions, using elastic net regression, and total mixture, using quantile g-computation, with blood levels of 5-methylcytocine (5mC) and 5-hydroxymethylcytosine (5hmC) in mothers during pregnancy and their newborn children (cord blood). Multiple testing was adjusted for using the Benjamini and Hochberg false discovery rate (FDR) approach.

Results: The most sensitive marker of DNA methylation appeared to be 5mC levels. In pregnant mothers, elastic net regression indicated associations between 5mC and selenium and lead (non-linear), while in newborns results indicated relationships between maternal selenium, cobalt (non-linear) and mercury and 5mC, as well as copper (non-linear) and 5hmC levels. Several possible two-way interactions were identified (e.g. arsenic and mercury, and selenium and maternal smoking in newborns). None of these findings met the FDR threshold for multiple testing. No net effect was observed in the joint (mixture) exposure-approach using quantile g-computation.

Conclusion: We identified few associations between gestational levels of several toxic metals and essential elements and global DNA methylation in pregnant mothers and their newborn children. As DNA methylation dysregulation might be a key mechanism in disease development and thus of high importance for public health, our results should be considered as important candidates to investigate in future studies.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147621DOI Listing
September 2021

Pregnancy exposure to organophosphate esters and the risk of attention-deficit hyperactivity disorder in the Norwegian mother, father and child cohort study.

Environ Int 2021 Sep 25;154:106549. Epub 2021 Apr 25.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Organophosphate esters (OPEs) are a class of flame retardants in common use. OPEs can easily leach from materials, resulting in human exposure. Increasing concentrations have been reported in human populations over the past decade. Recent studies have linked prenatal OPE exposure to hyperactivity and attention problems in children. Such behaviors are often found among children with attention-deficit hyperactivity disorder (ADHD), however, no study has investigated OPEs in relation to clinically assessed ADHD.

Objective: To evaluate prenatal exposure to OPEs as risk factors for clinically assessed ADHD using a case-cohort study nested within the Norwegian Mother, Father, and Child Cohort Study (MoBa).

Methods: We included in the case group 295 ADHD cases obtained via linkage with the Norwegian Patient Registry, and the sub-cohort group 555 children sampled at baseline, irrespective of their ADHD case status. Prenatal concentrations of OPE metabolites were measured in maternal urine collected at 17 weeks of gestation, and included diphenyl phosphate (DPHP), di-n-butyl phosphate (DNBP), bis(2-butoxyethyl) hydrogen phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP). We estimated risk ratios and the corresponding 95% confidence intervals [95% CI] using logistic regression, adjusting for season of urine collection, child sex, birth year, and maternal depression, education, and sum of urinary di(2-ethylhexyl) phthalate metabolites (∑DEHP) concentration during pregnancy. To assess the overall impact of simultaneously decreasing exposure to all chemical constituents of an OPE-phthalate mixture, quantile based g-computation was implemented. The mixture constituents included OPE and phthalate metabolites commonly detected in our study. In all models, we considered effect measure modification by child sex and polymorphisms in genes encoding paraoxonase 1 (PON1) and cytochrome P450 (P450) enzymes. Mediation analysis was conducted using thyroid function biomarkers estimated from maternal blood collected at 17 weeks of gestation.

Results: DPHP was detected in nearly all samples (97.2%), with a higher geometric mean among the case group (0.70 µg/L) as compared to the sub-cohort (0.52 µg/L). DNBP was commonly detected as well (93.8%), while BBOEP (52.9%) and BDCIPP (22.9%) were detected less frequently. A higher risk of ADHD was observed in children with greater than median exposure to DPHP during pregnancy (risk ratio: 1.38 [95% CI: 0.96, 1.99]), which was slightly higher among girls (2.04 [1.03, 4.02]) and children of mothers with PON1 Q192R genotype QR (1.69 [0.89, 3.19]) or PON1 Q192R genotype RR (4.59 [1.38, 15.29]). The relationship between DPHP and ADHD (total risk ratio: 1.34 [0.90, 2.02]) was partially mediated through total triiodothyronine to total thyroxine ratio (natural direct effect: 1.29 [0.87, 1.94]; natural indirect effect: 1.04 [1.00, 1.10]; 12.48% mediated). We also observed an elevated risk of ADHD in relation to BDCIPP detection during pregnancy (1.50 [0.98, 2.28]). We did not observe notable differences in ADHD by DNBP (0.88 [0.62, 1.26]) or BBOEP (1.03 [0.73, 1.46]) during pregnancy. Simultaneously decreasing all constituents of common-detect OPE-phthalate mixture, specifically DPHP, DNBP, and 6 phthalate metabolites, by a quartile resulted in an ADHD risk ratio of 0.68 [0.64, 0.72].

Conclusion: Prenatal exposure to DPHP and BDCIPP may increase the risk of ADHD. For DPHP, we observed potential modification by child sex and maternal PON1 Q192R genotype and partial mediation through maternal thyroid hormone imbalance at 17 weeks gestation.
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http://dx.doi.org/10.1016/j.envint.2021.106549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217330PMC
September 2021

Epigenetically mediated electrocardiographic manifestations of sub-chronic exposures to ambient particulate matter air pollution in the Women's Health Initiative and Atherosclerosis Risk in Communities Study.

Environ Res 2021 07 22;198:111211. Epub 2021 Apr 22.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA; Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.

Background: Short-duration exposure to ambient particulate matter (PM) air pollution is associated with cardiac autonomic dysfunction and prolonged ventricular repolarization. However, associations with sub-chronic exposures to coarser particulates are relatively poorly characterized as are molecular mechanisms underlying their potential relationships with cardiovascular disease.

Materials And Methods: We estimated associations between monthly mean concentrations of PM < 10 μm and 2.5-10 μm in diameter (PM PM) with time-domain measures of heart rate variability (HRV) and QT interval duration (QT) among U.S. women and men in the Women's Health Initiative and Atherosclerosis Risk in Communities Study (n = 82,107; n = 76,711). Then we examined mediation of the PM-HRV and PM-QT associations by DNA methylation (DNAm) at three Cytosine-phosphate-Guanine (CpG) sites (cg19004594, cg24102420, cg12124767) with known sensitivity to monthly mean PM concentrations in a subset of the participants (n = 7,169; n = 6,895). After multiply imputing missing PM, electrocardiographic and covariable data, we estimated associations using attrition-weighted, linear, mixed, longitudinal models adjusting for sociodemographic, behavioral, meteorological, and clinical characteristics. We assessed mediation by estimating the proportions of PM-HRV and PM-QT associations mediated by DNAm.

Results: We found little evidence of PM-HRV association, PM-QT association, or mediation by DNAm.

Conclusions: The findings suggest that among racially/ethnically and environmentally diverse U.S. populations, sub-chronic exposures to coarser particulates may not exert appreciable, epigenetically mediated effects on cardiac autonomic function or ventricular repolarization. Further investigation in better-powered studies is warranted, with additional focus on shorter duration exposures to finer particulates and non-electrocardiographic outcomes among relatively susceptible populations.
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http://dx.doi.org/10.1016/j.envres.2021.111211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179344PMC
July 2021

Pregnancy exposure to common-detect organophosphate esters and phthalates and maternal thyroid function.

Sci Total Environ 2021 Aug 24;782:146709. Epub 2021 Mar 24.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Contemporary human populations are exposed to elevated concentrations of organophosphate esters (OPEs) and phthalates. Some metabolites have been linked with altered thyroid function, however, inconsistencies exist across thyroid function biomarkers. Research on OPEs is sparse, particularly during pregnancy, when maintaining normal thyroid function is critical to maternal and fetal health. In this paper, we aimed to characterize relationships between OPEs and phthalates exposure and maternal thyroid function during pregnancy, using a cross-sectional investigation of pregnant women nested within the Norwegian Mother, Father, and Child Cohort (MoBa).

Methods: We included 473 pregnant women, who were euthyroid and provided bio-samples at 17 weeks' gestation (2004-2008). Four OPE and six phthalate metabolites were measured from urine; six thyroid function biomarkers were estimated from blood. Relationships between thyroid function biomarkers and log-transformed concentrations of OPE and phthalate metabolites were characterized using two approaches that both accounted for confounding by co-exposures: co-pollutant adjusted general linear model (GLM) and Bayesian Kernal Machine Regression (BKMR).

Results: We restricted our analysis to common-detect OPE and phthalate metabolites (>94%): diphenyl phosphate (DPHP), di-n-butyl phosphate (DNBP), and all phthalate metabolites. In GLM, pregnant women with summed di-isononyl phthalate metabolites (∑DiNP) concentrations in the 75th percentile had a 0.37 ng/μg lower total triiodothyronine (TT3): total thyroxine (TT4) ratio (95% credible interval: [-0.59, -0.15]) as compared to those in the 25th percentile, possibly due to small but diverging influences on TT3 (-1.99 ng/dL [-4.52, 0.53]) and TT4 (0.13 μg/dL [-0.01, 0.26]). Similar trends were observed for DNBP and inverse associations were observed for DPHP, monoethyl phthalate, mono-isobutyl phthalate, and mono-n-butyl phthalate. Most associations observed in co-pollutants adjusted GLMs were attenuated towards the null in BKMR, except for the case of ∑DiNP and TT3:TT4 ratio (-0.48 [-0.96, 0.003]).

Conclusions: Maternal thyroid function varied modestly with ∑DiNP, whereas results for DPHP varied by the type of statistical models.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146709DOI Listing
August 2021

Clustering Longitudinal Blood Pressure Trajectories to Examine Heterogeneity in Outcomes Among Preeclampsia Cases and Controls.

Hypertension 2021 Jun 5;77(6):2034-2044. Epub 2021 Apr 5.

Department of Epidemiology (K.R.R., S.M.E.), University of North Carolina at Chapel Hill.

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119318PMC
June 2021

Metal and essential element concentrations during pregnancy and associations with autism spectrum disorder and attention-deficit/hyperactivity disorder in children.

Environ Int 2021 07 22;152:106468. Epub 2021 Mar 22.

Division of Mental and Physical Health, Norwegian Institute of Public Health, PO Box 222 Skøyen, 0213 Oslo, Norway.

Background: Prenatal exposure to toxic metals or variations in maternal levels of essential elements during pregnancy may be a risk factor for neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in offspring.

Objectives: We investigated whether maternal levels of toxic metals and essential elements measured in mid-pregnancy, individually and as mixtures, were associated with childhood diagnosis of ADHD or ASD.

Methods: This study is based on the Norwegian Mother, Father and Child Cohort Study and included 705 ADHD cases, 397 ASD cases and 1034 controls. Cases were identified through linkage with the Norwegian Patient Registry. Maternal concentrations of 11 metals/elements were measured in blood at week 17 of gestation; cadmium; cesium; cobalt; copper; lead; magnesium; manganese; selenium; zinc; total arsenic; and total mercury. Multivariable adjusted logistic regression models were used to examine associations between quartile levels of individual metals/elements and outcomes. We also investigated non-linear associations using restricted cubic spline models. The joint effects of the metal/element mixture on ASD and ADHD diagnoses were estimated using a quantile-based g-computation approach.

Results: For ASD, we identified positive associations (increased risks) in the second quartile of arsenic [OR = 1.77 (CI: 1.26, 2.49)] and the fourth quartiles of cadmium and manganese [OR = 1.57 (CI: 1.07 2.31); OR = 1.84 (CI: 1.30, 2.59)], respectively. In addition, there were negative associations between cesium, copper, mercury, and zinc and ASD. For ADHD, we found increased risk in the fourth quartiles of cadmium and magnesium [OR = 1.59 (CI: 1.15, 2.18); [OR = 1.42 (CI: 1.06, 1.91)]. There were also some negative associations, among others with mercury. In addition, we identified non-linear associations between ASD and arsenic, mercury, magnesium, and lead, and between ADHD and arsenic, copper, manganese, and mercury. There were no significant findings in the mixture approach analyses.

Conclusion: Results from the present study show several associations between levels of metals and elements during gestation and ASD and ADHD in children. The most notable ones involved arsenic, cadmium, copper, mercury, manganese, magnesium, and lead. Our results suggest that even population levels of these compounds may have negative impacts on neurodevelopment. As we observed mainly similarities among the metals' and elements' impact on ASD and ADHD, it could be that the two disorders share some neurochemical and neurodevelopmental pathways. The results warrant further investigation and replication, as well as studies of combined effects of metals/elements and mechanistic underpinnings.
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http://dx.doi.org/10.1016/j.envint.2021.106468DOI Listing
July 2021

The Adolescent and Young Adult (AYA) Horizon Study: An AYA Cancer Survivorship Cohort.

Cancer Epidemiol Biomarkers Prev 2021 May 22;30(5):857-866. Epub 2021 Feb 22.

Division of Research, Kaiser Permanente Northern California, Oakland, California.

Background: In the United States, >45,000 adolescent and young adult (AYA) women are diagnosed with cancer annually. Reproductive issues are critically important to AYA cancer survivors, but insufficient information is available to address their concerns. The AYA Horizon Study was initiated to contribute high-quality, contemporary evidence on reproductive outcomes for female cancer survivors in the United States.

Methods: The study cohort includes women diagnosed with lymphoma, breast, melanoma, thyroid, or gynecologic cancer (the five most common cancers among women ages 15-39 years) at three study sites: the state of North Carolina and the Kaiser Permanente health systems in Northern and Southern California. Detailed information on cancer treatment, fertility procedures, and pregnancy (e.g., miscarriage, live birth) and birth (e.g., birth weight, gestational length) outcomes are leveraged from state cancer registries, health system databases and administrative insurance claims, national data on assisted reproductive technology procedures, vital records, and survey data.

Results: We identified a cohort of 11,072 female AYA cancer survivors that includes >1,200 African American women, >1,400 Asian women, >1,600 Medicaid enrollees, and >2,500 Hispanic women using existing data sources. Active response to the survey component was low overall ( = 1,679), and notably lower among minority groups compared with non-Hispanic white women.

Conclusions: Passive data collection through linkage reduces participant burden and prevents systematic cohort attrition or potential selection biases that can occur with active participation requirements.

Impact: The AYA Horizon study will inform survivorship planning as fertility and parenthood gain increasing recognition as key aspects of high-quality cancer care.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102328PMC
May 2021

Neurotoxicity of Ortho-Phthalates: Recommendations for Critical Policy Reforms to Protect Brain Development in Children.

Am J Public Health 2021 04 18;111(4):687-695. Epub 2021 Feb 18.

Stephanie M. Engel is with the Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill. Heather B. Patisaul is with the Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh. Charlotte Brody is with Healthy Babies Bright Futures, Charlottesville, VA. Russ Hauser is with the Department of Environmental Health at the Harvard T. H. Chan School of Public Health, Boston, MA. Ami R. Zota is with the Department of Environmental and Occupational Health, George Washington University Milken School of Public Health, Washington, DC. Deborah H. Bennet is with the Department of Public Health Sciences, School of Medicine, University of California at Davis. Maureen Swanson is with The Arc of the United States, Washington, DC. Robin M. Whyatt is with the Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY.

Robust data from longitudinal birth cohort studies and experimental studies of perinatally exposed animals indicate that exposure to ortho-phthalates can impair brain development and increase risks for learning, attention, and behavioral disorders in childhood. This growing body of evidence, along with known adverse effects on male reproductive tract development, calls for immediate action.Exposures are ubiquitous; the majority of people are exposed to multiple ortho-phthalates simultaneously. We thus recommend that a class approach be used in assessing health impacts as has been done with other chemical classes. We propose critically needed policy reforms to eliminate ortho-phthalates from products that lead to exposure of pregnant women, women of reproductive age, infants, and children. Specific attention should be focused on reducing exposures among socially vulnerable populations such as communities of color, who frequently experience higher exposures.Ortho-phthalates are used in a vast array of products and elimination will thus necessitate a multipronged regulatory approach at federal and state levels. The fact that manufacturers and retailers have already voluntarily removed ortho-phthalates from a wide range of products indicates that this goal is feasible.
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http://dx.doi.org/10.2105/AJPH.2020.306014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958063PMC
April 2021

Prenatal phthalate exposures and executive function in preschool children.

Environ Int 2021 04 29;149:106403. Epub 2021 Jan 29.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Prenatal phthalate exposure has been linked with altered neurodevelopment, including externalizing behaviors and attention-deficit hyperactivity disorder (ADHD). However, the implicated metabolite, neurobehavioral endpoint, and child sex have not always been consistent across studies, possibly due to heterogeneity in neurodevelopmental instruments. The complex set of findings may be synthesized using executive function (EF), a construct of complex cognitive processes that facilitate ongoing goal-directed behaviors. Impaired EF can be presented with various phenotypes of poor neurodevelopment, differently across structured conditions, home/community, or preschool/school. We evaluated the relationship between prenatal phthalate exposure and comprehensive assessment of preschool EF.

Methods: Our study comprised 262 children with clinically significant/subthreshold ADHD symptoms and 78 typically developing children who were born between 2003 and 2008 and participated in the Preschool ADHD Substudy, which is nested within a population-based prospective cohort study, the Norwegian Mother, Father, and Child Cohort (MoBa). Twelve phthalate metabolites were measured from urine samples that their mothers had provided during pregnancy, at 17 weeks' gestation. All children, at approximately 3.5-years, took part in a detailed clinical assessment that included parent-and teacher-rated inventories and administered tests. We used instruments that measured constructs related to EF, which include a parent-and teacher-reported Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P) and three performance-based tests: A Developmental NEuroPSYchological Assessment (NEPSY), Stanford-Binet intelligence test V (SB5), and the cookie delay task (CDT). The standard deviation change in test score per interquartile range (IQR) increase in phthalate metabolite was estimated with multivariable linear regression. We applied weighting in all models to account for the oversampling of children with clinically significant or subthreshold symptoms of ADHD. Additionally, we assessed modification by child sex and potential co-pollutant confounding.

Results: Elevated exposure to mono-benzyl phthalate (MBzP) during pregnancy was associated with poorer EF, across all domains and instruments, in both sex. For example, an IQR increase in MBzP was associated with poorer working memory rated by parent (1.23 [95% CI: 0.20, 2.26]) and teacher (1.13 [0.14, 2.13]) using BRIEF-P, and administered tests such as SB5 (no-verbal: 0.19 [0.09, 0.28]; verbal: 0.13 [0.01, 0.25]). Adverse associations were also observed for mono-n-butyl phthalate (MnBP) and mono-iso-butyl phthalate (MiBP), although results varied by instruments. EF domains reported by parents using BRIEF-P were most apparently implicated, with stronger associations among boys (e.g., MnBP and inhibition: 2.74 [1.77, 3.72]; MiBP and inhibition: 1.88 [0.84, 2.92]) than among girls (e.g., MnBP and inhibition: -0.63 [-2.08, 0.83], interaction p-value: 0.04; MiBP and inhibition: -0.15 [-1.04, 0.74], interaction p-value: 0.3). Differences by sex, however, were not found for the teacher-rated BRIEF-P or administered tests including NEPSY, SB5, and CDT.

Conclusion And Relevance: Elevated mid-pregnancy MBzP, MiBP, and MnBP were associated with more adverse profiles of EF among preschool-aged children across a range of instruments and raters, with some associations found only among boys. Given our findings and accumulating evidence of the prenatal period as a critical window for phthalate exposure, there is a timely need to expand the current phthalate regulations focused on baby products to include pregnancy exposures.
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http://dx.doi.org/10.1016/j.envint.2021.106403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945722PMC
April 2021

Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.

Nat Commun 2020 11 25;11(1):5976. Epub 2020 Nov 25.

Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.
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http://dx.doi.org/10.1038/s41467-020-19733-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688949PMC
November 2020

Ondansetron use in early pregnancy and the risk of late pregnancy outcomes.

Pharmacoepidemiol Drug Saf 2021 02 9;30(2):114-125. Epub 2020 Nov 9.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Background: The effects of ondansetron, used off-label to treat nausea and vomiting during pregnancy, on common pregnancy complications are understudied. Modest effects of a commonly used drug could result in adverse events for large numbers of pregnant women. Therefore, our objective was to compare the risk of stillbirth, preterm birth, gestational hypertensive disorders, small for gestational age, and differences in birth weight between women prescribed ondansetron and women prescribed alternative antiemetics in early pregnancy.

Methods: A cohort of pregnant women receiving a prescription for ondansetron or comparator antiemetics (metoclopramide or promethazine) during the first 20 weeks of pregnancy was identified using electronic health record data from a health care system in North Carolina, USA. Confounding by multiple covariates was controlled using stabilized inverse probability of treatment weights. Weighted hazard ratios (HR) and 95% confidence intervals (CI) accounted for competing events.

Results: We identified 2677 eligible pregnancies with antiemetic orders, 66% for ondansetron. The small number of stillbirths (n = 15) resulted in an imprecise estimate of the association with ondansetron (HR = 1.60; 95%CI 0.51, 4.97). No association was observed for preterm birth (HR = 0.90; 95%CI 0.67, 1.20) or gestational hypertensive disorders (HR = 0.87; 95%CI 0.68, 1.12). We observed an association with small for gestational age (HR = 1.37; 95%CI 0.98, 1.90), however mean birth weight among term births was similar between groups.

Conclusions: Our results do not suggest that ondansetron increases the risk of preterm birth or gestational hypertensive disorders. The weak association observed between ondansetron use and small for gestational age warrants further investigation.
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http://dx.doi.org/10.1002/pds.5151DOI Listing
February 2021

Ondansetron use in early pregnancy and the risk of miscarriage.

Pharmacoepidemiol Drug Saf 2021 02 12;30(2):103-113. Epub 2020 Oct 12.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Background: Ondansetron is commonly used to treat nausea and vomiting in pregnancy despite inconclusive evidence of its safety. Previous studies have reported no increase in risk of miscarriage but relied on methods that failed to account for gestational weeks at risk and non-user comparators, which may increase the potential for unmeasured confounding. Our objective was to estimate the risk of miscarriage among women prescribed ondansetron vs alternative antiemetics during the first 20 weeks of pregnancy.

Methods: A pregnancy cohort was created using electronic health record data from a health care system in North Carolina. Women were classified as exposed to either ondansetron or comparator antiemetics (metoclopramide or promethazine) based on the first antiemetic prescription received in the first 20 weeks of gestation. Cumulative incidence of miscarriage at 20 weeks was estimated in each antiemetic group. Hazard ratios (HR) were estimated with 95% confidence intervals and measured confounding was controlled using inverse probability of treatment weights. Sensitivity analyses assessed the potential impact of exposure misclassification, latency period, and selection bias.

Results: We identified 2620 eligible pregnancies with antiemetic orders; 65% had a first ondansetron order and 35% had a first comparator antiemetic order. In total, 95 women had a miscarriage. After adjustment, there was no difference in risk of miscarriage (HR 1.21, 95% CI 0.77, 1.90). Results from the per-protocol and other sensitivity analyses were similar to the main analysis.

Conclusions: We did not observe an increase in the risk of miscarriage for pregnancies exposed to ondansetron vs comparator antiemetics.
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http://dx.doi.org/10.1002/pds.5143DOI Listing
February 2021

Prenatal maternal organophosphorus pesticide exposures, paraoxonase 1, and childhood adiposity in the Mount Sinai Children's Environmental Health Study.

Environ Int 2020 09 26;142:105858. Epub 2020 Jun 26.

Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address:

Background: Animal studies suggest that organophosphorus pesticides (OPs) may be environmental obesogens. While prenatal OP exposures have been associated with altered infant glucose metabolism, associations with pediatric adiposity remain unknown.

Methods: We summed concentrations of three dimethylphosphate (∑DMP) and three diethylphosphate (∑DEP) metabolites of OPs measured in third trimester spot urine samples collected from pregnant women enrolled in New York City, 1998-2002. We measured percent fat mass using bio-electrical impedance analysis and calculated age- and sex-standardized body mass index (BMI) z-scores from anthropometric measurements collected at approximately 4, 6, and 7-9 years of age (166 children, 333 observations). We assessed covariate-adjusted associations of OPs with repeated adiposity measures using linear mixed models and evaluated effect measure modification (EMM) by sex and paroxonase (PON) 1 -108C/T and Q192R polymorphisms measured in maternal peripheral blood samples.

Results: The geometric mean urinary concentration of ∑DMP metabolites (29.9 nmol/L, IQR: 105.2 nmol/L) was higher than ∑DEP metabolites (8.8 nmol/L, IQR: 31.2 nmol/L). Adjusted associations were null, with differences in fat mass per 10-fold increase in prenatal ∑DMP and ∑DEP concentrations of 0.7% (95% CI: -0.6, 2.0) and 0.8% (95% CI: -0.4, 2.0), respectively. Maternal PON1-108C/T polymorphisms modified relationships of prenatal ∑DMP with percent fat mass (EMM p-value = 0.18) and ∑DEP with BMI z-scores (EMM p-value = 0.12). For example, ∑DMP was modestly associated with increased percent fat mass among children of mothers with the at-risk CT or TT genotype (β = 1.2%, 95% CI: -0.6, 3.0) but not among those whose mothers had the CC genotype (β = -0.4%, 95% CI: -2.4, 1.5). Associations were not modified by sex or maternal PON1 Q192R polymorphisms.

Conclusions: We observed little evidence of a relationship between prenatal OP exposures and child adiposity, although there was some suggestion of increased risk among offspring of mothers who were slow OP metabolizers. Larger studies are warranted to further evaluate possible associations of prenatal OP exposures with child adiposity and differences by maternal PON1 genotype, which regulates OP metabolism and may increase susceptibility to exposure.
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http://dx.doi.org/10.1016/j.envint.2020.105858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340581PMC
September 2020

Neonatal thyroid-stimulating hormone and association with attention-deficit/hyperactivity disorder.

Paediatr Perinat Epidemiol 2020 09 18;34(5):590-596. Epub 2020 Feb 18.

Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway.

Background: Normal brain development is dependent on maternal, fetal and neonatal thyroid function. Measuring neonatal thyroid-stimulating hormone (TSH) 48-72 hours after birth screens for congenital hypothyroidism, allowing early treatment to avoid serious impairment. However, even within sub-clinical ranges, disrupted thyroid homeostasis during brain development has been linked to adverse neurodevelopmental outcomes, including attention-deficit/hyperactivity disorder (ADHD).

Objectives: To estimate the association between neonatal TSH below threshold for potential congenital hypothyroidism and subsequent ADHD diagnosis using a population-based birth cohort.

Methods: Children with a diagnosis of ADHD in the Norwegian Mother, Father and Child Cohort Study (MoBa) were identified through linkage with the Norwegian Patient Registry using ICD-10 codes for hyperkinetic disorders. The study included 405 ADHD cases and 1,092 controls (born 2003-2008) with available neonatal TSH concentrations below 10 mU/L (cut-off for potential congenital hypothyroidism) measured in dried blood spots sampled 48-72 hours after birth.

Results: In multivariable, quintile models the relationship appeared to follow a U-shaped pattern with elevated odds ratios (OR) at lower and higher TSH levels. Among children with TSH in the lowest quintile, odds of ADHD was approximately 1.5-fold higher than children in the middle quintile (OR 1.60, 95% CI 1.09, 2.34), which was driven by substantially elevated risk among girls, with no association among boys (P = 0.02; girls OR 3.10, 95% CI 1.53, 6.30; boys OR 1.16, 95% CI 0.73, 1.84).

Conclusions: ADHD risk appeared to be elevated among newborns with low TSH levels (i.e. with hyperthyroid status), and this association was mainly found among girls. Because our findings are suggestive of increased risk at very low TSH concentrations, where analytical accuracy is low, future studies should employ highly sensitive assays capable of accurate quantitation at very low concentrations. Also, larger studies are needed to investigate these associations at higher neonatal TSH concentrations where data are more widely distributed.
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http://dx.doi.org/10.1111/ppe.12643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431377PMC
September 2020

Associations between urine phthalate metabolites and thyroid function in pregnant women and the influence of iodine status.

Environ Int 2020 04 7;137:105509. Epub 2020 Feb 7.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina and Chapel Hill, Chapel Hill, NC, USA.

Background: Human populations, including susceptible subpopulations such as pregnant women and their fetuses, are continuously exposed to phthalates. Phthalates may affect the thyroid hormone system, causing concern for pregnancy health, birth outcomes and child development. Few studies have investigated the joint effect of phthalates on thyroid function in pregnant women, although they are present as a mixture with highly inter-correlated compounds. Additionally, no studies have investigated if the key nutrient for thyroid health, iodine, modifies these relationships.

Methods: In this study, we examined the cross-sectional relationships between concentrations of 12 urinary phthalate metabolites and 6 plasma thyroid function biomarkers measured mid-pregnancy (~17 week gestation) in pregnant women (N = 1072), that were selected from a population-based prospective birth cohort, The Norwegian Mother, Father and Child Cohort study (MoBa). We investigated if the phthalate metabolite-thyroid function biomarker associations differed by iodine status by using a validated estimate of habitual dietary iodine intake based on a food frequency questionnaire from the 22nd gestation week. We accounted for the phthalate metabolite mixture by factor analyses, ultimately reducing the exposure into two uncorrelated factors. These factors were used as predictors in multivariable adjusted linear regression models with thyroid function biomarkers as the outcomes.

Results: Factor 1, which included high loadings for mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), and monobenzyl phthalate (MBzP), was associated with increased total triiodothyronine (TT3) and free T3 index (fT3i). These associations appeared to be driven primarily by women with low iodine intake (<150 µg/day, ~70% of our sample). Iodine intake significantly modified (p-interaction < 0.05) the association of factor 1 with thyroid stimulating hormone (TSH), total thyroxine (TT4) and free T4 index (fT4i), such that only among women in the high iodine intake category (≥150 µg/day, i.e. sufficient) was this factor associated with increased TSH and decreased TT4 and FT4i, respectively. In contrast, factor 2, which included high loadings for di-2-ethylhexyl phthalate metabolites (∑DEHP) and di-iso-nonyl phthalate metabolites (∑DiNP), was associated with a decrease in TT3 and fT3i, which appeared fairly uniform across iodine intake categories.

Conclusion: We find that phthalate exposure is associated with thyroid function in mid-pregnancy among Norwegian women, and that iodine intake, which is essential for thyroid health, could influence some of these relationships.
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http://dx.doi.org/10.1016/j.envint.2020.105509DOI Listing
April 2020

Leukocyte Traits and Exposure to Ambient Particulate Matter Air Pollution in the Women's Health Initiative and Atherosclerosis Risk in Communities Study.

Environ Health Perspect 2020 01 6;128(1):17004. Epub 2020 Jan 6.

Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina.

Background: Inflammatory effects of ambient particulate matter (PM) air pollution exposures may underlie PM-related increases in cardiovascular disease risk and mortality, although evidence of PM-associated leukocytosis is inconsistent and largely based on small, cross-sectional, and/or unrepresentative study populations.

Objectives: Our objective was to estimate PM-leukocyte associations among U.S. women and men in the Women's Health Initiative and Atherosclerosis Risk in Communities study ().

Methods: We based the PM-leukocyte estimations on up to four study visits per participant, at which peripheral blood leukocytes and geocoded address-specific concentrations of , , and in diameter (, , and , respectively) were available. We multiply imputed missing data using chained equations and estimated PM-leukocyte count associations over daily to yearly PM exposure averaging periods using center-specific, linear, mixed, longitudinal models weighted for attrition and adjusted for sociodemographic, behavioral, meteorological, and geographic covariates. In a subset of participants with available data (), we also estimated PM-leukocyte proportion associations in compositional data analyses.

Results: We found a (95% confidence interval: , 33) higher leukocyte count, a 1.2% (0.6%, 1.8%) higher granulocyte proportion, and a (, ) lower T-cell proportion per increase in 1-month mean . However, shorter-duration exposures were inversely and only modestly associated with leukocyte count.

Discussion: The -leukocyte estimates, albeit imprecise, suggest that among racially, ethnically, and environmentally diverse U.S. populations, sustained, ambient exposure to fine PM may induce subclinical, but epidemiologically important, inflammatory effects. https://doi.org/10.1289/EHP5360.
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http://dx.doi.org/10.1289/EHP5360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015624PMC
January 2020

Comparative effectiveness of metformin versus insulin for gestational diabetes in New Zealand.

Pharmacoepidemiol Drug Saf 2019 12 6;28(12):1609-1619. Epub 2019 Nov 6.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Purpose: To measure the comparative effectiveness of metformin versus insulin for initial pharmacological management of gestational diabetes mellitus (GDM).

Methods: We conducted a population-based retrospective cohort study using administrative claims, maternity care, and laboratory result data from New Zealand. We followed pregnant women aged 15 to 45 from GDM diagnosis through delivery and assessed outcomes using maternity care and hospitalization data. We adjusted for covariates using inverse probability of treatment weights and multiple imputation for missing covariate information. We estimated unadjusted and adjusted risk ratios (RRs), risk differences (RDs) per 100, and 95% confidence intervals (CIs). Linear regression was used to estimate the association of treatment with birthweight. We stratified analyses by ethnicity and infant sex in prespecified sensitivity analyses.

Results: We compared 3818 metformin-treated pregnancies with 3450 insulin-treated pregnancies. We observed differences in treatment initiation by ethnicity, socioeconomic status, region, and calendar year. Treatment groups were similar in age, body mass index (BMI), and timing of diagnosis/treatment initiation. After adjustment, metformin was associated with reduced absolute risk of planned elective c-section (RD = -2.3, 95% CI, -4.3 to -0.3), large for gestational age (RD = -3.7, 95% CI, -5.5 to -1.8), and neonatal hypoglycemia (RD = -5.0, 95% CI, -6.9 to -3.2) compared with insulin. There were no clinically meaningful differences in average birthweight between metformin- and insulin-treated pregnancies. We observed variation in estimates by ethnicity and infant sex for some neonatal outcomes.

Conclusion: Metformin appears to be an effective treatment for women with GDM and may reduce risk of some adverse neonatal outcomes when compared with insulin.
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http://dx.doi.org/10.1002/pds.4907DOI Listing
December 2019

Prenatal exposure to perfluoroalkyl substances and associations with symptoms of attention-deficit/hyperactivity disorder and cognitive functions in preschool children.

Int J Hyg Environ Health 2020 01 22;223(1):80-92. Epub 2019 Oct 22.

Norwegian Institute of Public Health, PO Box 222, Skøyen, N-0213, Oslo, Norway.

Background: Perfluoroalkyl substances (PFASs) are persistent organic pollutants that are suspected to be neurodevelopmental toxicants, but epidemiological evidence on neurodevelopmental effects of PFAS exposure is inconsistent. We investigated the associations between prenatal exposure to PFASs and symptoms of attention-deficit/hyperactivity disorder (ADHD) and cognitive functioning (language skills, estimated IQ and working memory) in preschool children, as well as effect modification by child sex.

Material And Methods: This study included 944 mother-child pairs enrolled in a longitudinal prospective study of ADHD symptoms (the ADHD Study), with participants recruited from The Norwegian Mother, Father and Child Cohort Study (MoBa). Boys and girls aged three and a half years, participated in extensive clinical assessments using well-validated tools; The Preschool Age Psychiatric Assessment interview, Child Development Inventory and Stanford-Binet (5th revision). Prenatal levels of 19 PFASs were measured in maternal blood at week 17 of gestation. Multivariable adjusted regression models were used to examine exposure-outcome associations with two principal components extracted from the seven detected PFASs. Based on these results, we performed regression analyses of individual PFASs categorized into quintiles.

Results: PFAS component 1 was mainly explained by perfluoroheptane sulfonate (PFHpS), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS) and perfluorooctanoic acid (PFOA). PFAS component 2 was mainly explained by perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA) and perfluorononanoic acid (PFNA). Regression models showed a negative association between PFAS component 1 and nonverbal working memory [β = -0.08 (CI: -0.12, -0.03)] and a positive association between PFAS component 2 and verbal working memory [β = 0.07 (CI: 0.01, 0.12)]. There were no associations with ADHD symptoms, language skills or IQ. For verbal working memory and PFAS component 2, we found evidence for effect modification by child sex, with associations only for boys. The results of quintile models with individual PFASs, showed the same pattern for working memory as the results in the component regression analyses. There were negative associations between nonverbal working memory and quintiles of PFOA, PFNA, PFHxS, PFHpS and PFOS and positive associations between verbal working memory and quintiles of PFOA, PFNA, PFDA and PFUnDA, with significant relationships mainly in the highest concentration groups.

Conclusions: Based on our results, we did not find consistent evidence to conclude that prenatal exposure to PFASs are associated with ADHD symptoms or cognitive dysfunctions in preschool children aged three and a half years, which is in line with the majority of studies in this area. Our results showed some associations between PFASs and working memory, particularly negative relationships with nonverbal working memory, but also positive relationships with verbal working memory. The relationships were weak, as well as both positive and negative, which suggest no clear association - and need for replication.
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http://dx.doi.org/10.1016/j.ijheh.2019.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922090PMC
January 2020

Neonatal jaundice in association with autism spectrum disorder and developmental disorder.

J Perinatol 2020 02 6;40(2):219-225. Epub 2019 Aug 6.

Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.

Objective: To examine the association between neonatal jaundice and autism spectrum disorder (ASD) and non-ASD developmental disorder (DD).

Study Design: We analyzed data from the Study to Explore Early Development, a US multisite, case-control study conducted from 2007 to 2011. Developmental assessment classified children aged 2-5 years into: ASD (n = 636), DD (n = 777), or controls (POP; n = 926). Neonatal jaundice (n = 1054) was identified from medical records and maternal interviews. We examined associations between neonatal jaundice and ASD and DD using regression models to obtain adjusted odds ratios (aOR).

Results: Our results showed interaction between gestational age and neonatal jaundice. Neonatal jaundice was associated with ASD at 35-37 weeks (aOR = 1.83, 95%CI 1.05, 3.19), but not ≥38 weeks gestation (aOR = 0.97, 95%CI 0.76, 1.24). Similar results were observed with DD.

Conclusions: Further exploration of timing and severity of neonatal jaundice and ASD/DD is warranted.
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http://dx.doi.org/10.1038/s41372-019-0452-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031756PMC
February 2020

Neuroblastoma in relation to joint effects of vitamin A and maternal and offspring variants in vitamin A-related genes: A report of the Children's Oncology Group.

Cancer Epidemiol 2019 08 4;61:165-171. Epub 2019 Jul 4.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States.

Background: There is evidence vitamin A plays a role in neuroblastoma. Not only is 13-cis-retinoic acid used as maintenance therapy for high-risk cases, but prenatal vitamin intake use may decrease neuroblastoma risk. We hypothesized that single nucleotide polymorphisms (SNPs) in vitamin A-related genes are may be associated with neuroblastoma risk and potentially be modified by vitamin A intake.

Methods: The Neuroblastoma Epidemiology in North America (NENA) study recruited 563 case-parent sets through the Children's Oncology Group's Childhood Cancer Research Network. We ascertained dietary nutrient intake through questionnaires and genotyped 463 SNPs in vitamin A-related genes from saliva DNA. Offspring and maternal log-additive risk ratios (RR) and stratum-specific RR for gene-environment interaction were estimated with a log-linear model. We avoided false positives due to multiple testing by using the false discovery rate (FDR).

Results: When all neuroblastoma cases were considered together, no offspring variants met the significance criteria (FDR Q-value < 0.2). One maternal SNP (rs12442054) was associated with decreased risk of neuroblastoma (RR: 0.61; 95% Confidence Interval (CI): 0.47-0.79, Q = 0.076). When the cases were categorized according to prognostic risk category and age at onset, nine offspring SNPs were significantly associated with intermediate-risk neuroblastoma. Maternal rs6776706 was associated with (RR: 0.49; 95% CI: 0.33-0.72, Q = 0.161) high-risk neuroblastoma and maternal rs11103603 (RR: 0.60; 95% CI: 0.45-0.79, Q = 0.127) was associated with neuroblastoma aged <1 year. For gene-environment interaction, maternal rs729147 was associated with decreased risk of neuroblastoma among mothers with vitamin A consumption above the recommendation.

Conclusions: Although there is biologic plausibility for the role of vitamin A in neuroblastoma, we found weak evidence of a relationship between vitamin A related genes and neuroblastoma.
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http://dx.doi.org/10.1016/j.canep.2019.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730673PMC
August 2019

Methylome-wide association study provides evidence of particulate matter air pollution-associated DNA methylation.

Environ Int 2019 11 14;132:104723. Epub 2019 Jun 14.

Laboratory of Environmental Epigenetics, Departments of Environmental Health Sciences and Epidemiology, Columbia University Mailman School of Public Health, New York, NY, USA.

Background: DNA methylation (DNAm) may contribute to processes that underlie associations between air pollution and poor health. Therefore, our objective was to evaluate associations between DNAm and ambient concentrations of particulate matter (PM) ≤2.5, ≤10, and 2.5-10 μm in diameter (PM; PM; PM).

Methods: We conducted a methylome-wide association study among twelve cohort- and race/ethnicity-stratified subpopulations from the Women's Health Initiative and the Atherosclerosis Risk in Communities study (n = 8397; mean age: 61.5 years; 83% female; 45% African American; 9% Hispanic/Latino American). We averaged geocoded address-specific estimates of daily and monthly mean PM concentrations over 2, 7, 28, and 365 days and 1 and 12 months before exams at which we measured leukocyte DNAm in whole blood. We estimated subpopulation-specific, DNAm-PM associations at approximately 485,000 Cytosine-phosphate-Guanine (CpG) sites in multi-level, linear, mixed-effects models. We combined subpopulation- and site-specific estimates in fixed-effects, inverse variance-weighted meta-analyses, then for associations that exceeded methylome-wide significance and were not heterogeneous across subpopulations (P < 1.0 × 10; P > 0.10), we characterized associations using publicly accessible genomic databases and attempted replication in the Cooperative Health Research in the Region of Augsburg (KORA) study.

Results: Analyses identified significant DNAm-PM associations at three CpG sites. Twenty-eight-day mean PM was positively associated with DNAm at cg19004594 (chromosome 20; MATN4; P = 3.33 × 10). One-month mean PM and PM were positively associated with DNAm at cg24102420 (chromosome 10; ARPP21; P = 5.84 × 10) and inversely associated with DNAm at cg12124767 (chromosome 7; CFTR; P = 9.86 × 10). The PM-sensitive CpG sites mapped to neurological, pulmonary, endocrine, and cardiovascular disease-related genes, but DNAm at those sites was not associated with gene expression in blood cells and did not replicate in KORA.

Conclusions: Ambient PM concentrations were associated with DNAm at genomic regions potentially related to poor health among racially, ethnically and environmentally diverse populations of U.S. women and men. Further investigation is warranted to uncover mechanisms through which PM-induced epigenomic changes may cause disease.
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http://dx.doi.org/10.1016/j.envint.2019.03.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754789PMC
November 2019

Maternal diabetes and hypertensive disorders in association with autism spectrum disorder.

Autism Res 2019 06 10;12(6):967-975. Epub 2019 Apr 10.

The University of North Carolina, Chapel Hill, North Carolina.

Previous studies have shown complications of pregnancy, often examined in aggregate, to be associated with autism spectrum disorder (ASD). Results for specific complications, such as maternal diabetes and hypertension, have not been uniformly consistent and should be investigated independently in relation to ASD in a large community-based sample. The Study to Explore Early Development (SEED), a US multisite case-control study, enrolled children born in 2003-2006 at 2-5 years of age. Children were classified into three groups based on confirmation of ASD (n = 698), non-ASD developmental delay (DD; n = 887), or controls drawn from the general population (POP; n = 979). Diagnoses of any diabetes or hypertensive disorder during pregnancy were identified from prenatal medical records and maternal self-report. Logistic regression models estimated adjusted odds ratios (aOR) and confidence intervals (CI) adjusting for maternal age, race/ethnicity, education, smoking during pregnancy, and study site. Models for hypertension were additionally adjusted for parity and plurality. Among 2,564 mothers, we identified 246 (9.6%) with any diabetes and 386 (15.1%) with any hypertension in pregnancy. After adjustment for covariates, any diabetes during pregnancy was not associated with ASD (aOR = 1.10 [95% CI 0.77, 1.56]), but any hypertension was associated with ASD (aOR = 1.69 [95% CI 1.26, 2.26]). Results were similar for DD, and any diabetes (aOR = 1.29 [95% CI 0.94, 1.78]) or any hypertension (aOR = 1.71 [95% CI 1.30, 2.25]). Some pregnancy complications, such as hypertension, may play a role in autism etiology and can possibly serve as a prompt for more vigilant ASD screening efforts. Autism Res 2019, 12: 967-975. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We studied if common complications in pregnancy are associated with autism spectrum disorder (ASD) in a large sample of mothers and children. Our results show an association between conditions marked by high blood pressure and ASD, but no association with conditions marked by high blood sugar and ASD. Associations were similar for children who had a developmental disorder that was not ASD, suggesting that this relationship may not be specific to ASD.
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http://dx.doi.org/10.1002/aur.2105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546522PMC
June 2019

Prenatal exposure to organophosphate esters and behavioral development in young children in the Pregnancy, Infection, and Nutrition Study.

Neurotoxicology 2019 07 3;73:150-160. Epub 2019 Apr 3.

Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, 2101 McGavran-Greenberg Hall, Chapel Hill, NC, 27599, USA.

Organophosphate esters (OPEs) are commonly used as plasticizers and flame retardants in consumer products, and exposure is relatively ubiquitous in most populations studied. This may be of concern as some OPEs may be neurotoxic, endocrine-disrupting, and interfere with behavioral development; however, observational evidence is limited. We used data from the Pregnancy, Infection, and Nutrition Study, a prospective birth cohort study, to investigate associations between maternal OPE metabolite concentrations during pregnancy and behavioral development in offspring. Women provided a urine sample during pregnancy that was analyzed for concentrations of OPE metabolites, including diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl phosphate) (BDCIPP), isopropyl-phenyl phenyl phosphate (ip-PPP), and 1-hydroxyl-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP). Offspring's behavioral development was assessed by the Behavioral Assessment System for Children (2nd Edition) (BASC-2) at approximately 36 months. Linear regression was used to estimate associations between tertiles in specific gravity-corrected OPE metabolite concentrations and children's scores on the BASC-2, adjusted for maternal age, maternal BMI, maternal race, maternal education, familial income, maternal depression, quality of the home environment, and sex. Higher BDCIPP concentrations were associated with higher scores on the Behavioral Symptoms Index (1st vs. 3rd tertile: β = 3.03; 95% CI = 0.40, 5.67) and Externalizing Problems (1st vs. 3rd tertile: β = 2.49; 95% CI: -0.12, 5.10) composites. Among BASC-2 scales, BDCIPP was most strongly associated with Withdrawal, Attention Problems, Depression, Hyperactivity, and Aggression. DPHP concentrations were also associated with higher scores on the Externalizing Problems and Behavioral Symptoms Index composites, but not as strongly as BDCIPP. Conversely, higher concentrations of ip-PPP were associated with fewer adverse behavioral symptoms, including an inverse association with the Internalizing Problems composite (1st vs. 3rd tertile: β = -3.74; 95% CI = -6.75, -0.74) and constituent scales. BCIPHIPP was not strongly associated with any measured behavioral outcomes. Our results suggest that greater maternal exposure to tris(1,3-dichloro-2-propyl phosphate) (TDCIPP, parent compound of BDCIPP) and, to a lesser degree, triphenyl phosphate (TPHP, parent compound of DPHP) during pregnancy is associated with adverse behavioral development in children. Our study contributes to the growing body of evidence pertaining to adverse developmental effects of prenatal OPE exposure and highlights the need for further research to characterize risks associated with this ubiquitous family of chemicals.
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http://dx.doi.org/10.1016/j.neuro.2019.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635002PMC
July 2019

Association of Long-term Child Growth and Developmental Outcomes With Metformin vs Insulin Treatment for Gestational Diabetes.

JAMA Pediatr 2019 02;173(2):160-168

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill.

Importance: Metformin is an emerging option for treating gestational diabetes (GDM). However, because metformin crosses the placenta, patients and clinicians are concerned with its long-term effect on child health.

Objective: To estimate the association of treating GDM with metformin vs insulin with child growth and development.

Design, Setting, And Participants: Population-based cohort study of New Zealand women treated with metformin or insulin for GDM from 2005 to 2012 and their children. This study linked national health care data to create a cohort of mothers and their children, including data from maternity care, pharmaceutical dispensing, hospitalizations, demographic records, and the B4 School Check (B4SC) preschool health assessment. Women treated pharmacologically with metformin or insulin during pregnancy were included. We excluded pregnancies with evidence of diabetes and deliveries prior to 2013. Liveborn infants were linked to their B4SC results. Data were analyzed between January 2017 and May 2018.

Exposures: Pharmacologic treatment for GDM with metformin or insulin, measured using pharmaceutical claims data.

Main Outcomes And Measures: Child growth (weight and height) and Strengths and Difficulties Questionnaire (SDQ) scores for behavioral development. All outcomes were derived from the B4SC screening program. Linear and log-binomial regression with inverse probability of treatment weighting was used to estimate the association of child growth and psychosocial outcomes with metformin vs insulin treatment for GDM.

Results: In both treatment groups, the mean (SD) maternal age was 32 (5) years. A large proportion of mothers who were treated with insulin identified as New Zealand European (867 [44.9%]) while 576 mothers who were treated with metformin (28.9%) identified as New Zealand European. Approximately one-third of mothers who were treated with metformin (n = 639) identified as Asian. We identified 3928 pregnancies treated with metformin (n = 1996) or insulin (n = 1932). After adjustment, we observed no meaningful difference in weight for height z scores between children exposed to metformin compared with insulin (mean difference, -0.10; 95% CI, -0.20 to 0.01). Risk of being 85th percentile or greater for weight for height was similar between treatment groups (adjusted risk ratio, 0.92; 95% CI, 0.83-1.02). Mean SDQ scores were not meaningfully different between the treatment groups, Children of metformin-treated mothers were not significantly more likely to have parent-reported SDQ scores of 14 or more (adjusted risk ratio, 1.13; 95% CI, 0.88-1.46) than those of insulin-treated mothers.

Conclusions And Relevance: Our study compares long-term outcomes among school-aged children following maternal use of metformin vs insulin treatment for GDM. Children of metformin-treated mothers were indistinguishable on growth and developmental assessments from those of insulin-treated mothers. These results will help inform future GDM treatment guidelines.
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http://dx.doi.org/10.1001/jamapediatrics.2018.4214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439608PMC
February 2019

Prenatal exposure to organophosphate esters and cognitive development in young children in the Pregnancy, Infection, and Nutrition Study.

Environ Res 2019 02 30;169:33-40. Epub 2018 Oct 30.

Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, 2101 McGavran-Greenberg Hall, Chapel Hill, NC 27599, USA.

Organophosphate esters (OPEs) are a class of chemicals commonly used as flame retardants and plasticizers. OPEs are applied to a wide variety of consumer products and have a propensity to leach from these products. Consequently, OPEs are ubiquitous contaminants in many human environments and human exposure is pervasive. Accumulating evidence suggests that OPEs are capable of interfering with childhood cognitive development through both neurologic- and endocrine-mediated mechanisms. However, observational evidence of cognitive effects is limited. We used data collected in the third phase of the Pregnancy, Infection, and Nutrition Study to investigate cognitive effects of prenatal exposure to OPEs. In a spot prenatal maternal urine sample, we measured the following OPE metabolites: diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl phosphate) (BDCIPP), isopropyl-phenyl phenyl phosphate (ip-PPP), and 1-hydroxyl-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP). We assessed children's language and multi-faceted and overall cognitive development between two and three years of age using the MacArthur-Bates Communicative Development Inventories (MB-CDI) and the Mullen Scales of Early Learning (MSEL). We used linear regression to estimate the change in children's scores on these developmental assessments per interquartile range (IQR) increase in log-transformed, specific-gravity-corrected prenatal OPE metabolite concentrations, adjusted for maternal age, education, income, race/ethnicity, BMI, and child's sex. A total of 149 children had both OPE metabolite measurements and MB-CDI scores, and 227 children had both OPE metabolite measurements and MSEL scores. We observed that higher concentrations of ip-PPP (ng/ml) were associated with lower scores on the MSEL Cognitive Composite Score (β = -2.61; 95% CI: -5.69, 0.46), and separately on two of the four MSEL Scales that comprise the Cognitive Composite, specifically the Fine Motor Scale (β = -3.08; 95% CI: -5.26, -0.91) and the Expressive Language Scale (β = -1.21; 95% CI: -2.91, 0.49). We similarly observed that prenatal ip-PPP concentrations were inversely associated with age-standardized scores on the MB-CDI Vocabulary assessment (β = -1.19; 95% CI: -2.53, 0.16). Other OPE metabolites were not strongly associated with performance on either assessment. Our results suggest that isopropylated triarylphosphate isomers, the presumed parent compounds of ip-PPP, may adversely impact cognitive development, including fine motor skills and early language abilities. Our study contributes to the growing body of observational evidence that suggests prenatal exposure to OPEs may adversely affect cognitive development.
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http://dx.doi.org/10.1016/j.envres.2018.10.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347494PMC
February 2019

Maternal Thyroid Function During Pregnancy or Neonatal Thyroid Function and Attention Deficit Hyperactivity Disorder: A Systematic Review.

Epidemiology 2019 01;30(1):130-144

From the Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC.

Background: Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in children, yet its etiology is poorly understood. Early thyroid hormone disruption may contribute to the development of ADHD. Disrupted maternal thyroid hormone function has been associated with adverse neurodevelopmental outcomes in children. Among newborns, early-treated congenital hypothyroidism has been consistently associated with later cognitive deficits.

Methods: We systematically reviewed literature on the association between maternal or neonatal thyroid hormones and ADHD diagnosis or symptoms. We searched Embase, Pubmed, Cinahl, PsycInfo, ERIC, Medline, Scopus, and Web of Science for articles published or available ahead of print as of April 2018.

Results: We identified 28 eligible articles: 16 studies of maternal thyroid hormones, seven studies of early-treated congenital hypothyroidism, and five studies of neonatal thyroid hormones. The studies provide moderate evidence for an association between maternal thyroid hormone levels and offspring ADHD, some evidence for an association between early-treated congenital hypothyroidism and ADHD, and little evidence for an association between neonatal thyroid hormone levels and later ADHD.

Conclusions: The reviewed articles suggest an association between maternal thyroid function and ADHD, and possibly between early-treated congenital hypothyroidism and ADHD. Study limitations, however, weaken the conclusions in our systematic review, underlining the need for more research. Importantly, there was much variation in the measurement of thyroid hormone function and of ADHD symptoms. Recommendations for future research include using population-based designs, attending to measurement issues for thyroid hormones and ADHD, considering biologically relevant covariates (e.g., iodine intake), and assessing nonlinear dose-responses.
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http://dx.doi.org/10.1097/EDE.0000000000000937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359926PMC
January 2019

Preconceptional Cardiovascular Health and Pregnancy Outcomes in Women with Systemic Lupus Erythematosus.

J Rheumatol 2019 01 15;46(1):70-77. Epub 2018 Jul 15.

From the Department of Epidemiology, and the Department of Biostatistics, University of North Carolina Chapel Hill Gillings School of Global Public Health, Chapel Hill, North Carolina; School of Nursing, University of Virginia, Charlottesville, Virginia; Division of Rheumatology, Department of Medicine, Duke University Medical Center, Durham, North Carolina; Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Objective: To estimate the effects of preconceptional cardiovascular (CV) health, measured by American Heart Association (AHA) guidelines, on pregnancy outcomes in women with systemic lupus erythematosus (SLE).

Methods: The study included patients in the Hopkins Lupus Pregnancy Cohort. Body mass index (BMI), total cholesterol, and blood pressure (BP) in the most recent clinic visit prior to conception or first trimester were used to determine CV health (ideal, intermediate, or poor health) based on AHA definitions. Outcomes included preterm birth, gestational age at birth, and small for gestational age (SGA). Multivariable linear and logistic regression models with generalized estimating equations estimated the association of each CV health factor and outcome.

Results: The analysis included 309 live births. There were 95 preterm births (31%), and of the 293 pregnancies with birth weights, 18% were SGA. Ideal BMI, total cholesterol, and BP were reported in 56%, 85%, and 51% of pregnancies, respectively. Intermediate BMI was associated with decreased odds of SGA (OR 0.26, 95% CI 0.11-0.63), adjusted for race and prednisone use. Intermediate/poor total cholesterol was associated with increased odds of preterm birth (OR 2.21, 95% CI 1.06-4.62). Intermediate/poor BP was associated with decreased gestational age at birth (β -0.96, 95% CI -1.62 to -0.29).

Conclusion: Poor/intermediate preconception CV health affects pregnancy outcomes of preterm birth and SGA infants among women with SLE. Efforts to maintain BMI, total cholesterol, and BP within the recommended ideal range prior to pregnancy is important to improve pregnancy outcomes in women with SLE.
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http://dx.doi.org/10.3899/jrheum.171066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314889PMC
January 2019

Vitamin D and risk of pregnancy related hypertensive disorders: mendelian randomisation study.

BMJ 2018 06 20;361:k2167. Epub 2018 Jun 20.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.

Objective: To use mendelian randomisation to investigate whether 25-hydroxyvitamin D concentration has a causal effect on gestational hypertension or pre-eclampsia.

Design: One and two sample mendelian randomisation analyses.

Setting: Two European pregnancy cohorts (Avon Longitudinal Study of Parents and Children, and Generation R Study), and two case-control studies (subgroup nested within the Norwegian Mother and Child Cohort Study, and the UK Genetics of Pre-eclampsia Study).

Participants: 7389 women in a one sample mendelian randomisation analysis (751 with gestational hypertension and 135 with pre-eclampsia), and 3388 pre-eclampsia cases and 6059 controls in a two sample mendelian randomisation analysis.

Exposures: Single nucleotide polymorphisms in genes associated with vitamin D synthesis (rs10741657 and rs12785878) and metabolism (rs6013897 and rs2282679) were used as instrumental variables.

Main Outcome Measures: Gestational hypertension and pre-eclampsia defined according to the International Society for the Study of Hypertension in Pregnancy.

Results: In the conventional multivariable analysis, the relative risk for pre-eclampsia was 1.03 (95% confidence interval 1.00 to 1.07) per 10% decrease in 25-hydroxyvitamin D level, and 2.04 (1.02 to 4.07) for 25-hydroxyvitamin D levels <25 nmol/L compared with ≥75 nmol/L. No association was found for gestational hypertension. The one sample mendelian randomisation analysis using the total genetic risk score as an instrument did not provide strong evidence of a linear effect of 25-hydroxyvitamin D on the risk of gestational hypertension or pre-eclampsia: odds ratio 0.90 (95% confidence interval 0.78 to 1.03) and 1.19 (0.92 to 1.52) per 10% decrease, respectively. The two sample mendelian randomisation estimate gave an odds ratio for pre-eclampsia of 0.98 (0.89 to 1.07) per 10% decrease in 25-hydroxyvitamin D level, an odds ratio of 0.96 (0.80 to 1.15) per unit increase in the log(odds) of 25-hydroxyvitamin D level <75 nmol/L, and an odds ratio of 0.93 (0.73 to 1.19) per unit increase in the log(odds) of 25-hydroxyvitamin D levels <50 nmol/L.

Conclusions: No strong evidence was found to support a causal effect of vitamin D status on gestational hypertension or pre-eclampsia. Future mendelian randomisation studies with a larger number of women with pre-eclampsia or more genetic instruments that would increase the proportion of 25-hydroxyvitamin D levels explained by the instrument are needed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008987PMC
http://dx.doi.org/10.1136/bmj.k2167DOI Listing
June 2018

Goodness-Of-Fit Test for Nonparametric Regression Models: Smoothing Spline ANOVA Models as Example.

Comput Stat Data Anal 2018 Jun 31;122:135-155. Epub 2018 Jan 31.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.

Nonparametric regression models do not require the specification of the functional form between the outcome and the covariates. Despite their popularity, the amount of diagnostic statistics, in comparison to their parametric counter-parts, is small. We propose a goodness-of-fit test for nonparametric regression models with linear smoother form. In particular, we apply this testing framework to smoothing spline ANOVA models. The test can consider two sources of lack-of-fit: whether covariates that are not currently in the model need to be included, and whether the current model fits the data well. The proposed method derives estimated residuals from the model. Then, statistical dependence is assessed between the estimated residuals and the covariates using the HSIC. If dependence exists, the model does not capture all the variability in the outcome associated with the covariates, otherwise the model fits the data well. The bootstrap is used to obtain p-values. Application of the method is demonstrated with a neonatal mental development data analysis. We demonstrate correct type I error as well as power performance through simulations.
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http://dx.doi.org/10.1016/j.csda.2018.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983390PMC
June 2018

Prenatal Phthalates, Maternal Thyroid Function, and Risk of Attention-Deficit Hyperactivity Disorder in the Norwegian Mother and Child Cohort.

Environ Health Perspect 2018 05 10;126(5):057004. Epub 2018 May 10.

Norwegian Institute of Public Health, Oslo, Norway.

Background: There is growing concern that phthalate exposures may have an impact on child neurodevelopment. Prenatal exposure to phthalates has been linked with externalizing behaviors and executive functioning defects suggestive of an attention-deficit hyperactivity disorder (ADHD) phenotype.

Objectives: We undertook an investigation into whether prenatal exposure to phthalates was associated with clinically confirmed ADHD in a population-based nested case-control study of the Norwegian Mother and Child Cohort (MoBa) between the years 2003 and 2008.

Methods: Phthalate metabolites were measured in maternal urine collected at midpregnancy. Cases of ADHD (=297) were obtained through linkage between MoBa and the Norwegian National Patient Registry. A random sample of controls (=553) from the MoBa population was obtained.

Results: In multivariable adjusted coexposure models, the sum of di-2-ethylhexyl phthalate metabolites (∑DEHP) was associated with a monotonically increasing risk of ADHD. Children of mothers in the highest quintile of ∑DEHP had almost three times the odds of an ADHD diagnosis as those in the lowest [OR=2.99 (95% CI: 1.47, 5.49)]. When ∑DEHP was modeled as a log-linear (natural log) term, for each log-unit increase in exposure, the odds of ADHD increased by 47% [OR=1.47 (95% CI: 1.09, 1.94)]. We detected no significant modification by sex or mediation by prenatal maternal thyroid function or by preterm delivery.

Conclusions: In this population-based case-control study of clinical ADHD, maternal urinary concentrations of DEHP were monotonically associated with increased risk of ADHD. Additional research is needed to evaluate potential mechanisms linking phthalates to ADHD. https://doi.org/10.1289/EHP2358.
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http://dx.doi.org/10.1289/EHP2358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071976PMC
May 2018