Publications by authors named "Katherine L Grantz"

108 Publications

Longitudinal Plasma Metabolomics Profile in Pregnancy-A Study in an Ethnically Diverse U.S. Pregnancy Cohort.

Nutrients 2021 Sep 1;13(9). Epub 2021 Sep 1.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20817, USA.

Amino acids, fatty acids, and acylcarnitine metabolites play a pivotal role in maternal and fetal health, but profiles of these metabolites over pregnancy are not completely established. We described longitudinal trajectories of targeted amino acids, fatty acids, and acylcarnitines in pregnancy. We quantified 102 metabolites and combinations (37 fatty acids, 37 amino acids, and 28 acylcarnitines) in plasma samples from pregnant women in the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singletons cohort ( = 214 women at 10-14 and 15-26 weeks, 107 at 26-31 weeks, and 103 at 33-39 weeks). We used linear mixed models to estimate metabolite trajectories and examined variation by body mass index (BMI), race/ethnicity, and fetal sex. After excluding largely undetected metabolites, we analyzed 77 metabolites and combinations. Levels of 13 of 15 acylcarnitines, 7 of 25 amino acids, and 18 of 37 fatty acids significantly declined over gestation, while 8 of 25 amino acids and 10 of 37 fatty acids significantly increased. Several trajectories appeared to differ by BMI, race/ethnicity, and fetal sex although no tests for interactions remained significant after multiple testing correction. Future studies merit longitudinal measurements to capture metabolite changes in pregnancy, and larger samples to examine modifying effects of maternal and fetal characteristics.
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http://dx.doi.org/10.3390/nu13093080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471130PMC
September 2021

Developmental outcomes in small-for-gestational age twins using a singleton vs twin birthweight reference in Upstate KIDS.

Am J Obstet Gynecol MFM 2021 Aug 18;3(6):100465. Epub 2021 Aug 18.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD (Drs Gleason, Yeung, Mendola, Vafai, Robinson, Putnick, and Grantz). Electronic address:

Background: Limited data exist about the potential developmental delays in appropriately grown twins; furthermore, twins may be at higher risk of developmental delay than singletons. Small-for-gestational age is a risk factor for developmental delay and is based on singleton birthweight references, which may misclassify small-for-gestational age in a subset of appropriately grown twins.

Objective: This study aimed to evaluate the risk of developmental delay in twins classified as small-for-gestational age according to the twin and singleton birthweight references (<10th percentile).

Study Design: In a birth cohort (2008-2010) of twins (n=1790) and singletons (n=3829) where parents completed Ages & Stages Questionnaires for child development between 4 and 36 months, we used a US population-based birthweight reference to categorize singletons and twins as small-for-gestational age. Uncertain small-for-gestational age twins were defined as small-for-gestational age by a singleton reference (<10th percentile) and not by a twin reference, and twin-reference small-for-gestational age twins were defined as small-for-gestational age by a twin reference. Adjusted generalized linear mixed-effects models were used to estimate the odds of failure on any Ages & Stages Questionnaires domain and on each of the 5 domains (fine motor, gross motor, communication, personal-social, and problem-solving domains); random intercepts accounted for repeated measures and twin clustering.

Results: Compared with non-small-for-gestational age twins (>10th percentile), uncertain small-for-gestational age twins did not have higher odds of Ages & Stages Questionnaires failure (adjusted odds ratio, 1.28; 95% confidence interval, 0.91-1.80). Compared with non-small-for-gestational age singletons, both twin-reference and uncertain small-for-gestational age twins had higher odds of Ages & Stages Questionnaires failure, with the highest risk conferred to twin-reference small-for-gestational age twins (twin-reference adjusted odds ratio, 3.14 [95% confidence interval, 1.94-5.10]; uncertain adjusted odds ratio, 2.35 [95% confidence interval, 1.69-3.26]; P<.01 for trend). Results remained consistent when limiting analyses to term births (≥37 weeks' gestation).

Conclusion: Although a singleton reference may overestimate small-for-gestational age in twins, the findings indicated that a singleton birthweight reference may be appropriate for twins because it identifies more twins at risk of developmental delay than a twin reference.
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http://dx.doi.org/10.1016/j.ajogmf.2021.100465DOI Listing
August 2021

Acute ambient air pollution exposure and placental Doppler results in the NICHD fetal growth studies - Singleton cohort.

Environ Res 2021 Jul 21;202:111728. Epub 2021 Jul 21.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA; Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA. Electronic address:

Background: Increased placental vascular resistance is a proposed mechanism by which air pollution exposure during pregnancy lowers birth weight and increases pregnancy-induced hypertensive disorders.

Objective: To examine the impact of acute air pollution exposure during pregnancy on uterine and umbilical artery Doppler indicators of placental vascular resistance.

Methods: After a first ultrasound to confirm gestational age, 2562 pregnant women recruited in 12 clinics throughout the United States underwent up to five standardized ultrasounds with Doppler measurements. Exposures to 11 air pollutants were estimated for the hour of ultrasound and each of the 2 h prior to ultrasound at the clinics using the National Air Quality Forecast Capability reanalysis products. We used mixed logistic regression to study the longitudinal odds ratio (OR) of any, uni- or bi-lateral systolic and diastolic uterine artery notching compared to no notching and the longitudinal OR of abnormal end diastolic flow of the umbilical artery compared to forward flow. Uterine and umbilical artery resistance indexes were studied using linear mixed models.

Results: Each inter-quartile range (IQR) increase of particulate matter < 2.5 μm, nitrate, ammonium, primary organic matter (POM) and nitrogen dioxide during the hour of ultrasound was associated with a decreased risk of unilateral systolic notch and with increased resistance index of the left uterine artery. For the umbilical artery, each IQR increase in ozone was associated with decreased resistance index (b: -0.26, 95 % CI: -0.52, -0.01) and with a decreased risk of abnormal end diastolic flow (OR: 0.36, 95 % CI: 0.14, 0.94); while each IQR increase of elemental carbon and POM was associated with increased risk of abnormal end diastolic flow (OR: 1.47, 95 % CI: 1.02, 2.13 and OR: 1.67, 95 % CI: 1.17, 2.39, respectively).

Discussion: Our results suggest acute air pollution exposure may influence placental vascular resistance.
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http://dx.doi.org/10.1016/j.envres.2021.111728DOI Listing
July 2021

Gestational age at term delivery and children's neurocognitive development.

Int J Epidemiol 2021 Jul 15. Epub 2021 Jul 15.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Background: Preterm birth is associated with lower neurocognitive performance. However, whether children's neurodevelopment improves with longer gestations within the full-term range (37-41 weeks) is unclear. Given the high rate of obstetric intervention in the USA, it is critical to determine whether long-term outcomes differ for children delivered at each week of term.

Methods: This secondary analysis included 39 199 live-born singleton children of women who were admitted to the hospital in spontaneous labour from the US Collaborative Perinatal Project (1959-76). At each week of term gestation, we evaluated development at 8 months using the Bayley Scales of Infant Development, 4 years using the Stanford-Binet IQ (SBIQ) domains and 7 years using the Wechsler Intelligence Scales for Children (WISC) and Wide-Range Achievement Tests (WRAT).

Results: Children's neurocognitive performance improved with each week of gestation from 37 weeks, peaking at 40 or 41 weeks. Relative to those delivered at 40 weeks, children had lower neurocognitive scores at 37 and 38 weeks for all assessments except SBIQ and WISC Performance IQ. Children delivered at 39 weeks had lower Bayley Mental (β = -1.18; confidence interval -1.77, -0.58) and Psychomotor (β = -1.18; confidence interval -1.90, -0.46) scores. Results were similar for within-family analyses comparing siblings, with the addition of lower WRAT scores at 39 weeks.

Conclusions: The improvement in development scores across assessment periods indicates that each week up to 40 or 41 weeks of gestation is important for short- and long-term cognitive development, suggesting 40-41 weeks may be the ideal delivery window for optimal neurodevelopmental outcomes.
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http://dx.doi.org/10.1093/ije/dyab134DOI Listing
July 2021

Maternal Moderate-to-Vigorous Physical Activity before and during Pregnancy and Maternal Glucose Tolerance: Does Timing Matter?

Med Sci Sports Exerc 2021 Jun 16. Epub 2021 Jun 16.

Department of Foundational Sciences and Research, East Carolina University, Greenville, NC Department of Obstetrics and Gynecology, East Carolina University, Greenville, NC Department of Kinesiology, East Carolina University, Greenville, NC Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

Purpose: To assess prospective associations between moderate-to-vigorous physical activity (MVPA) from preconception through pregnancy and glucose metabolism.

Methods: The sample consisted of 2,388 women from the NICHD Fetal Growth Studies-Singletons, which enrolled U.S. pregnant women between 8-13 weeks of gestation. Women recalled their MVPA in periconception (past 12 months, inclusive of 1st trimester), early-to-mid (13-20 weeks of gestation), and mid-to-late 2nd trimester (20-29 weeks). These data were obtained at study visits that occurred at enrollment (8-13 weeks) and at follow-up visits at 16-22 and 24-29 weeks. MVPA was recalled using the Pregnancy Physical Activity Questionnaire. Glucose challenge test and oral glucose tolerance test results and gestational diabetes diagnosis (defined by the Carpenter-Coustan criteria) were extracted from medical records. ANCOVA and Poisson regression with robust error variance were performed to estimate associations between MVPA and glucose concentrations and gestational diabetes risk, respectively, controlling for age, race/ethnicity, and pre-pregnancy body mass index.

Results: Women achieving higher levels of MVPA (≥75th percentile; 760.5 MET·min·wk-1) in early-to-mid 2nd trimester had lower glucose concentrations (β = -3.9 mg/dL, 95%CI: -7.4,-0.5) compared to their least-active counterparts (≤25th percentile; ≤117.0 MET·min·wk-1). Women maintaining recommended levels of MVPA from preconception & 1st trimester through 2nd trimester (early-to-mid: β = -3.0 mg/dL, -5.9,-0.1; mid-to-late: β = -4.2 mg/dL,-8.4,-0.1) or maintaining sufficient activity throughout 2nd trimester exhibited lower glucose levels (β = -5.6 mg/dL, -9.8,-1.4) compared to their inactive counterparts. No statistically significant associations with gestational diabetes were observed.

Conclusions: These findings demonstrate that achieving MVPA of at least 760.0 MET·min·week-1 in early-to-mid 2nd trimester or maintaining at least 500 MET ·min·week-1 from preconception through 2nd trimester may be related to improved maternal glucose metabolism in the 2nd trimester.
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http://dx.doi.org/10.1249/MSS.0000000000002730DOI Listing
June 2021

Healthy dietary patterns and common pregnancy complications: a prospective and longitudinal study.

Am J Clin Nutr 2021 09;114(3):1229-1237

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Background: Adherence to alternate Healthy Eating Index (AHEI), alternate Mediterranean diet (AMED), and Dietary Approaches to Stop Hypertension (DASH) has been linked to lower risks of chronic diseases. However, their associations with common pregnancy complications are unclear.

Objectives: This study investigates the associations of AHEI, AMED, and DASH during periconception and pregnancy with common pregnancy complication risks.

Methods: The study included 1887 pregnant women from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons. Women responded to an FFQ at 8-13 gestational weeks, and they performed a 24-h dietary recall at 16-22 and 24-29 wk. Gestational diabetes (GDM), gestational hypertension, preeclampsia, and preterm delivery were ascertained using medical records.

Results: Healthier diet indicated by higher AHEI, AMED, and DASH scores was generally related to lower risks of pregnancy complications. Significant inverse associations were observed between AHEI score reported at 16-22 wk and GDM risk [adjusted RR (95% CI), highest (Q4) vs. lowest quartile (Q1): 0.32 (0.16, 0.66), P-trend = 0.002]; DASH score reported at both 8-13 [adjusted RR (95% CI), Q4 vs. Q1: 0.45 (0.17, 1.17), P-trend = 0.04] and 16-22 wk [adjusted RR (95% CI), Q4 vs. Q1: 0.19 (0.05, 0.65), P-trend = 0.01] and gestational hypertension risk; AHEI score reported at 24-29 wk and preeclampsia risk [adjusted RR (95% CI), Q4 vs. Q1: 0.31 (0.11, 0.87), P-trend = 0.03]; AMED score reported at 8-13 wk [adjusted RR (95% CI), Q4 vs. Q1: 0.50 (0.25, 1.01), P-trend = 0.03] and DASH score reported at 24-29 wk [adjusted RR (95% CI), Q4 vs. Q1: 0.50, (0.26, 0.96), P-trend = 0.03] and preterm delivery risk.

Conclusions: Adherence to AHEI, AMED, or DASH during periconception and pregnancy was related to lower risks of GDM, gestational hypertension, preeclampsia, and preterm delivery.This study was registered at ClinicalTrials.gov as NCT00912132.
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http://dx.doi.org/10.1093/ajcn/nqab145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408886PMC
September 2021

Changes in Diet and Exercise in Pregnant Women after Diagnosis with Gestational Diabetes: Findings from a Longitudinal Prospective Cohort Study.

J Acad Nutr Diet 2021 May 18. Epub 2021 May 18.

Background: Lifestyle changes are recommended for women diagnosed with gestational diabetes mellitus (GDM), yet there are few data available documenting whether women change their diet and exercise after GDM diagnosis.

Objective: The aim of this study was to assess whether, and to what extent, pregnant women receiving usual prenatal care change their diet and exercise after a GDM diagnosis.

Design: This study was a post-hoc secondary analysis using data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons (2009-2013), a prospective pregnancy cohort study.

Participants/setting: Pregnant US women without major chronic medical conditions were enrolled from 12 participating hospital centers at 8 to 13 weeks' gestation. Diet analyses were based on 5,194 dietary recalls from 1,371 women. Exercise analyses were based on 6,440 physical activity assessments from 1,875 women. GDM was ascertained from medical records according to Carpenter and Coustan criteria. Women completed 24-hour dietary recalls and exercise assessments at weeks 16 to 22, 24 to 29, 30 to 33, 34 to 37, and 38 to 41 (exercise only).

Main Outcome Measures: The main outcome was the diet and exercise change from before to after GDM diagnosis or screening.

Statistical Analyses: Diet and exercise changes with 95% CIs from before to after GDM diagnosis or screening for women with and without GDM were estimated using weighted multivariable linear mixed models.

Results: Women with GDM (n = 72) significantly reduced their total energy intake (-184 kcal/d; 95% CI -358 to -10 kcal/d) and carbohydrate intake (-47.6 g/d; 95% CI -71.4 to -23.7 g/d) from before to after GDM diagnosis; these changes were unique to women with GDM and not observed among women without GDM (n = 1,299). Women with GDM decreased intakes of juice (-0.4 cups/d; 95% CI -0.7 to -0.2 cups/d) and added sugar (-3.2 teaspoons/d; 95% CI -5.5 to -0.5 teaspoons/d) and increased cheese (0.3 cups/d; 95% CI 0.1 to 0.6 cups/d) and artificially sweetened beverages (0.2 cups/d; 95% CI 0.0 to 0.3 cups/d). Women with GDM (n = 84) did not change their exercise duration after diagnosis; women without GDM (n = 1,791) significantly decreased moderate (-19.5 min/wk; 95% CI -24.7 to -14.3 min/wk) and vigorous exercise (-8.8 min/wk; 05% CI -10.6 to -6.9 min/wk) after GDM screening.

Conclusions: Women with GDM made modest dietary improvements and maintained their prediagnosis exercise routine, yet opportunities remain to further improve dietary intake and exercise after a diagnosis of GDM.
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http://dx.doi.org/10.1016/j.jand.2021.04.014DOI Listing
May 2021

Fetal Growth Curves: Is There a Universal Reference?

Obstet Gynecol Clin North Am 2021 Jun;48(2):281-296

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6710B Rockledge Drive, MSC 7004, Bethesda, MD 20892, USA. Electronic address:

Three modern cohort studies have an advantage over historical fetal growth references because they included diverse populations. Despite similar inclusion criteria, estimated fetal weight percentiles for gestational age varied among studies, which result in different proportions of fetuses as being classified below or above a cutoff point. A universal reference would make comparison of fetal growth simpler for clinical use and for comparison across populations but may misclassify small-for-gestational-age or large-for-gestational-age fetuses. It is important to know how a growth reference performs in a local population in relation to fetal morbidity and mortality when implementing in clinical practice.
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http://dx.doi.org/10.1016/j.ogc.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454882PMC
June 2021

Combination of Fundal Height and Ultrasound to Predict Small for Gestational Age at Birth.

Am J Perinatol 2021 May 3. Epub 2021 May 3.

Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Objective:  The objective of the study was to determine whether adding longitudinal measures of fundal height (FH) to the standard cross-sectional FH to trigger third trimester ultrasound estimated fetal weight (EFW) would improve small for gestational age (SGA) prediction.

Study Design:  We developed a longitudinal FH calculator in a secondary analysis of a prospective cohort study of 1,939 nonobese pregnant women who underwent serial FH evaluations at 12 U.S. clinical sites. We evaluated cross-sectional FH measurement ≤ -3 cm at visit 3 (mean: 32.0 ± 1.6 weeks) versus the addition of longitudinal FH up to and including visit 3 to trigger an ultrasound to diagnose SGA defined as birthweight <10th percentile. If the FH cut points were not met, the SGA screen was classified as negative. If FH cut points were met and EFW was <10th percentile, the SGA screen was considered positive. If EFW was ≥10th percentile, the SGA screen was also considered negative. Sensitivity, specificity, and positive predictive value (PPV) and negative predictive value (NPV) were computed.

Results:  In a comparison of methods, 5.8% of women were classified as at risk of SGA by both cross-sectional and longitudinal classification methods; cross-sectional FH identified an additional 4.0%, and longitudinal fundal height identified a separate, additional 4.5%.Using cross-sectional FH as an ultrasound trigger, EFW had a PPV and NPV for SGA of 69 and 92%, respectively. After adding longitudinal FH, PPV increased to 74%, whereas NPV of 92% remained unchanged; however, the number of women who underwent triggered EFW decreased from 9.7 to 5.7%.

Conclusion:  An innovative approach for calculating longitudinal FH to the standard cross-sectional FH improved identification of SGA birthweight, while simultaneously reducing the number of triggered ultrasounds. As an essentially free-of-charge screening test, our novel method has potential to decrease costs as well as perinatal morbidity and mortality (through better prediction of SGA).

Key Points: · We have developed an innovative calculator for fundal height trajectory.. · Longitudinal fundal height improves detection of SGA.. · As a low cost screening test, the fundal height calculator may decrease costs and morbidity through better prediction of SGA..
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http://dx.doi.org/10.1055/s-0041-1728837DOI Listing
May 2021

Asthma Medication Regimens in Pregnancy: Longitudinal Changes in Asthma Status.

Am J Perinatol 2021 Apr 21. Epub 2021 Apr 21.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Objective:  This study aimed to assess the impact of common asthma medication regimens on asthma symptoms, exacerbations, lung function, and inflammation during pregnancy.

Study Design:  A total of 311 women with asthma were enrolled in a prospective pregnancy cohort. Asthma medication regimen was categorized into short-acting β agonist (SABA) alone, SABA + inhaled corticosteroid (ICS), SABA + ICS + long-acting β agonist (LABA), and no asthma medications (reference). We evaluated asthma control at enrollment (< 15 weeks' gestation) and its change into trimesters 2 and 3, including per cent predicted forced expiratory volume in 1 second (%FEV1) and peak expiratory flow (%PEF), pulse oximetry, fractional exhaled nitric oxide (FeNO), asthma symptoms (asthma attacks/month, night symptoms/week), and severe exacerbations. Linear mixed models adjusted for site, age, race, annual income, gestational age, body mass index, and smoking, and propensity scores accounted for asthma control status at baseline.

Results:  Women taking SABA + ICS and SABA + ICS + LABA had better first trimester %PEF (83.5% [75.7-91.3] and 84.6% [76.9-92.3], respectively) compared with women taking no asthma medications (72.7% [66.0-79.3]). Women taking SABA + ICS + LABA also experienced improvements in %FEV1 (+11.1%,  < 0.01) in the third trimester and FeNO in the second (-12.3 parts per billion [ppb],  < 0.01) and third (-11.0 ppb,  < 0.01) trimesters as compared with the trajectory of women taking no medications. SABA + ICS use was associated with increased odds of severe exacerbations in the first (odds ratio [OR]: 2.22 [1.10-4.46]) and second (OR: 3.15 [1.11-8.96]) trimesters, and SABA + ICS + LABA use in the second trimester (OR: 7.89 [2.75-21.47]). Women taking SABA alone were similar to those taking no medication.

Conclusion:  Pregnant women taking SABA + ICS and SABA + ICS + LABA had better lung function in the first trimester. SABA + ICS + LABA was associated with improvements in lung function and inflammation across gestation. However, both the SABA + ICS and SABA + ICS + LABA groups had a higher risk of severe exacerbation during early to mid-pregnancy.

Key Points: · Medication regimens may affect perinatal asthma control.. · Intensive regimens improved lung function/inflammation.. · Women on intensive regimens had more acute asthma events..
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http://dx.doi.org/10.1055/s-0041-1727233DOI Listing
April 2021

Air pollution exposure and risk of adverse obstetric and neonatal outcomes among women with type 1 diabetes.

Environ Res 2021 06 18;197:111152. Epub 2021 Apr 18.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6710B Rockledge Drive, Bethesda, MD, 20892, USA; Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, 401 Kimball Tower, Buffalo, NY, 14214, USA.

Aims/hypothesis: Women with type 1 diabetes have increased risk for poor obstetric outcomes. Prenatal air pollution exposure is also associated with adverse outcomes for women and infants. We examined whether women with type 1 diabetes are more vulnerable than other women to pollution-associated risks during pregnancy.

Methods: In singleton deliveries from the Consortium on Safe Labor (2002-2008), obstetric and neonatal outcomes were compared for women with type 1 diabetes (n = 507) and women without autoimmune disease (n = 204,384). Preconception, trimester, and whole pregnancy average air pollutant exposure (ozone (O), carbon monoxide (CO), particulate matter >10 μm (PM), PM > 2.5 μm (PM), sulfur dioxide (SO), nitrogen oxides (NO)) were estimated using modified Community Multiscale Air Quality models. Poisson regression models with diabetes*pollutant interaction terms estimated relative risks and 95% confidence intervals for adverse outcomes, adjusted for maternal characteristics and geographic region.

Results: For whole pregnancy exposure to SO, women with type 1 diabetes had 15% increased risk (RR:1.15 95%CI:1.01,1.31) and women without autoimmune disease had 5% increased risk (RR:1.05 95%CI:1.05,1.06) for small for gestational age birth (p = 0.09). Additionally, whole pregnancy O exposure was associated with 10% increased risk (RR:1.10 95%CI:1.02,1.17) among women with type 1 diabetes and 2% increased risk (RR:1.02 95%CI:1.00,1.04) among women without autoimmune disease for perinatal mortality (p = 0.08). Similar patterns were observed between PM exposure and spontaneous preterm birth.

Conclusions: Pregnant women with type 1 diabetes may be at greater risk for adverse outcomes when exposed to air pollution than women without autoimmune disease.
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http://dx.doi.org/10.1016/j.envres.2021.111152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190832PMC
June 2021

Association Between Maternal Caffeine Consumption and Metabolism and Neonatal Anthropometry: A Secondary Analysis of the NICHD Fetal Growth Studies-Singletons.

JAMA Netw Open 2021 03 1;4(3):e213238. Epub 2021 Mar 1.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Importance: Higher caffeine consumption during pregnancy has been associated with lower birth weight. However, associations of caffeine consumption, based on both plasma concentrations of caffeine and its metabolites, and self-reported caffeinated beverage intake, with multiple measures of neonatal anthropometry, have yet to be examined.

Objective: To evaluate the association between maternal caffeine intake and neonatal anthropometry, testing effect modification by fast or slow caffeine metabolism genotype.

Design, Setting, And Participants: A longitudinal cohort study, the National Institute of Child Health and Human Development Fetal Growth Studies-Singletons, enrolled 2055 nonsmoking women at low risk for fetal growth abnormalities with complete information on caffeine consumption from 12 US clinical sites between 2009 and 2013. Secondary analysis was completed in 2020.

Exposures: Caffeine was evaluated by both plasma concentrations of caffeine and paraxanthine and self-reported caffeinated beverage consumption measured/reported at 10-13 weeks gestation. Caffeine metabolism defined as fast or slow using genotype information from the single nucleotide variant rs762551 (CYP1A2*1F).

Main Outcomes And Measures: Neonatal anthropometric measures, including birth weight, length, and head, abdominal, arm, and thigh circumferences, skin fold and fat mass measures. The β coefficients represent the change in neonatal anthropometric measure per SD change in exposure.

Results: A total of 2055 participants had a mean (SD) age of 28.3 (5.5) years, mean (SD) body mass index of 23.6 (3.0), and 580 (28.2%) were Hispanic, 562 (27.4%) were White, 518 (25.2%) were Black, and 395 (19.2%) were Asian/Pacific Islander. Delivery occurred at a mean (SD) of 39.2 (1.7) gestational weeks. Compared with the first quartile of plasma caffeine level (≤28 ng/mL), neonates of women in the fourth quartile (>659 ng/mL) had lower birth weight (β = -84.3 g; 95% CI, -145.9 to -22.6 g; P = .04 for trend), length (β = -0.44 cm; 95% CI, -0.78 to -0.12 cm; P = .04 for trend), and head (β = -0.28 cm; 95% CI, -0.47 to -0.09 cm; P < .001 for trend), arm (β = -0.25 cm; 95% CI, -0.41 to -0.09 cm: P = .02 for trend), and thigh (β = -0.29 cm; 95% CI, -0.58 to -0.04 cm; P = .07 for trend) circumference. Similar reductions were observed for paraxanthine quartiles, and for continuous measures of caffeine and paraxanthine concentrations. Compared with women who reported drinking no caffeinated beverages, women who consumed approximately 50 mg per day (~ 1/2 cup of coffee) had neonates with lower birth weight (β = -66 g; 95% CI, -121 to -10 g), smaller arm (β = -0.17 cm; 95% CI, -0.31 to -0.02 cm) and thigh (β = -0.32 cm; 95% CI, -0.55 to -0.09 cm) circumference, and smaller anterior flank skin fold (β = -0.24 mm; 95% CI, -0.47 to -0.01 mm). Results did not differ by fast or slow caffeine metabolism genotype.

Conclusions And Relevance: In this cohort study, small reductions in neonatal anthropometric measurements with increasing caffeine consumption were observed. Findings suggest that caffeine consumption during pregnancy, even at levels much lower than the recommended 200 mg per day of caffeine, are associated with decreased fetal growth.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.3238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994948PMC
March 2021

Shoulder dystocia and composite adverse outcomes for the maternal-neonatal dyad.

Am J Obstet Gynecol MFM 2021 07 20;3(4):100359. Epub 2021 Mar 20.

Department of Obstetrics, Gynecology and Reproductive Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX (Drs Mendez-Figueroa, Blackwell, and Chauhan). Electronic address:

Background: Although the neonatal morbidity associated with shoulder dystocia are well known, the maternal morbidity caused by this obstetrical emergency is infrequently reported.

Objective: This study aimed to assess the composite adverse maternal and neonatal outcomes among vaginal deliveries (at 34 weeks or later) with and without shoulder dystocia.

Study Design: This is a secondary analysis of the Consortium of Safe Labor, an observational obstetrical cohort of all vaginal deliveries occurring at 19 hospitals (from 2002-2008) and for which data on the occurrence of shoulder dystocia were available. The composite adverse maternal outcome included third- or fourth-degree perineal laceration, postpartum hemorrhage (>500 cc blood loss for a vaginal delivery and >1000 cc blood loss for cesarean delivery), blood transfusion, chorioamnionitis, endometritis, thromboembolism, admission to intensive care unit, or maternal death. The composite adverse neonatal outcome included an Apgar score of <7 at 5 minutes, a birth injury, neonatal seizure, hypoxic ischemic encephalopathy, or neonatal death. A multivariable Poisson regression was used to estimate the adjusted relative risks with 95% confidence intervals. The area under the receiver operating characteristic curve was constructed to determine if clinical factors would identify shoulder dystocia.

Results: Of the 228,438 women in the overall cohort, 130,008 (59.6%) met the inclusion criteria, and among them, shoulder dystocia was documented in 2159 (1.7%) cases. The rate of composite maternal morbidity was significantly higher among deliveries with shoulder dystocia (14.7%) than without (8.6%; adjusted relative risk, 1.71; 95% confidence interval, 1.64-2.01). The most common maternal morbidity with shoulder dystocia was a third- or fourth-degree laceration (adjusted relative risk, 2.82; 95% confidence interval, 2.39-3.31). The risk of composite neonatal morbidity with shoulder dystocia (12.2%) was also significantly higher than without shoulder dystocia (2.4%) (adjusted relative risk, 5.18; 95% confidence interval, 4.60-5.84). The most common neonatal morbidity was birth injury (adjusted relative risk, 5.39; 95% confidence interval, 4.71-6.17). The area under the curve for maternal characteristics to identify shoulder dystocia was 0.66 and it was 0.67 for intrapartum factors.

Conclusion: Although shoulder dystocia is unpredictable, the associated morbidity affects both mothers and newborns. The focus should be on concurrently averting the composite morbidity for the maternal-neonatal dyad with shoulder dystocia.
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http://dx.doi.org/10.1016/j.ajogmf.2021.100359DOI Listing
July 2021

Maternal diet patterns during early pregnancy in relation to neonatal outcomes.

Am J Clin Nutr 2021 07;114(1):358-367

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Background: Research has established that maternal diet influences fetal growth and preterm birth, but most studies only evaluate single nutrients. Relations between dietary patterns and neonatal outcomes are understudied.

Objective: We evaluated associations of neonatal outcomes with maternal diet patterns derived using 3 a priori diet scores [Alternative Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean diet score (aMed), and Dietary Approaches to Stop Hypertension (DASH)] as well as principal components analysis (PCA).

Methods: We studied 1948 women from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons, a racially diverse multisite cohort of pregnant women in the USA (2009-2013). Diet in the past 3 mo was assessed using a self-administered FFQ at 8-13 weeks of gestation. Birthweight was abstracted from medical records and neonatal anthropometry measured postdelivery using standardized protocols.

Results: All 3 a priori scores were significantly associated with increased birthweight, and aMed was also associated with reduced odds of low birthweight [quartile 4 versus 1: ORadj = 0.42; 95% CI: 0.18, 1.00 (P-trend = 0.02)]. Greater aMed and DASH scores were significantly associated with increased length [aMed: quartile 4 versus 1: 0.54 cm; 95% CI: 0.10, 0.99 (P-trend = 0.006); DASH: quartile 4 versus 1: 0.62 cm; 95% CI: 0.25, 0.99 (P-trend = 0.006)] and upper arm length. Neither diet pattern derived from PCA was significantly associated with birthweight.

Conclusion: Among mostly low-risk pregnant women, pre- and early pregnancy healthful diet quality indices, particularly the aMed score, were associated with larger neonatal size across the entire birthweight distribution. In the absence of generally accepted pregnancy-specific diet quality scores, these results provide evidence for an association between maternal diet patterns and neonatal outcomes.
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http://dx.doi.org/10.1093/ajcn/nqab019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246623PMC
July 2021

Prenatal medication use in a prospective pregnancy cohort by pre-pregnancy obesity status.

J Matern Fetal Neonatal Med 2021 Mar 11:1-8. Epub 2021 Mar 11.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Background: The association between obesity (body mass index (BMI) ≥ 30 kg/m) and pattern of medication use during pregnancy in the United States is not well-studied. Higher pre-pregnancy BMI may be associated with increases or decreases in medication use across pregnancy as symptoms (e.g. reflux) or comorbidities (e.g. gestational diabetes) requiring treatment that may be associated with higher BMI could also change with advancing gestation.

Objectives: To determine whether prenatal medication use, by the number and types of medications, varies by pre-pregnancy obesity status.

Methods: In a secondary data analysis of a racially/ethnically diverse prospective cohort of pregnant women with low risk for fetal abnormalities enrolled in the first trimester of pregnancy and followed to delivery (singleton, 12 United States clinical sites), free text medication data were obtained at enrollment and up to five follow-up visits and abstracted from medical records at delivery.

Results: In 436 women with obesity and 1750 women without obesity (pre-pregnancy BMI, 19-29.9 kg/m), more than 70% of pregnant women (77% of women with and 73% of women without obesity) reported taking at least one medication during pregnancy, respectively (adjusted risk ratio (aRR)=1.10, 95% confidence interval (CI)=1.01, 1.20), with 81% reporting two and 69% reporting three or more. A total of 17 classes of medications were identified. Among medication classes consumed by at least 5% of all women, the only class that differed between women with and without obesity was hormones and synthetic substitutes (including steroids, progesterone, diabetes, and thyroid medications) in which women with obesity took more medications (11 vs. 5%, aRR = 1.9, 95% CI = 1.38, 2.61) compared to women without obesity. Within this class, a higher percentage of women with obesity took diabetes medications (2.3 vs. 0.7%) and progesterone (3.4 vs. 1.3%) than their non-obese counterparts. Similar percentages of women with and without obesity reported consuming medications in the remaining medication classes including central nervous system agents (50 and 46%), gastrointestinal drugs (43 and 40%), anti-infective agents (23 and 21%), antihistamines (20 and 17%), autonomic drugs (10 and 9%), and respiratory tract agents (7 and 6%), respectively ( > 0.05 for all adjusted comparisons). There were no differences in medication use by obesity status across gestation. Since the study exclusion criteria limited the non-obese group to women without thyroid disease, in a sensitivity analysis we excluded all women who reported thyroid medication intake and still a higher proportion of women with obesity took the hormones and synthetic substitutes class compared to women without obesity.

Conclusion: Our findings suggest that pre-pregnancy obesity in otherwise healthy women is associated with a higher use of only selected medications (such as diabetes medications and progesterone) during pregnancy, while the intake of other more common medication types such as analgesics, antibiotics, and antacids does not vary by pre-pregnancy obesity status. As medication safety information for prenatal consumption is insufficient for many medications, these findings highlight the need for a more in-depth examination of factors associated with prenatal medication use.
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http://dx.doi.org/10.1080/14767058.2021.1893296DOI Listing
March 2021

Admixture mapping identifies African and Amerindigenous local ancestry loci associated with fetal growth.

Hum Genet 2021 Jul 15;140(7):985-997. Epub 2021 Feb 15.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6710B Rockledge Dr, 6710B-3204, Bethesda, MD, 20892-7004, USA.

Fetal growth is an important determinant of cardiometabolic disease risk during childhood and adulthood. The genetic architecture of fetal growth remains largely understudied in ancestrally diverse populations. We conducted genome-wide admixture mapping scan and analysis of genetic ancestry among Hispanic American, African American, European American, and Asian American pregnant women to identify genetic loci associated with fetal growth measures across 13-40 weeks gestation. Fetal growth measures were associated with genome-wide average African, European, Amerindigenous and East Asian ancestry proportions (P ranged from10 to 4.8 × 10). Admixture mapping analysis identified ten African ancestry loci and three Amerindigenous ancestry loci significantly associated with fetal growth measures at Bonferroni-corrected levels of significance (P ranged from 2.18 × 10 to 3.71 × 10). At the chr2q23.3-24.2 locus in which higher African ancestry was associated with long bone (femur and humerus) lengths, the T allele of rs13030825 (GALNT13) was associated with longer humerus length in African Americans (β = 0.44, P = 6.25 × 10 at week 27; β = 0.39, P = 7.72 × 10 at week 40). The rs13030825 SNP accounted for most of the admixture association at the chr2q23.3-24.2 locus and has substantial allele frequency difference between African and European reference samples (F = 0.55, P = 0.03). Regulatory annotation shows that rs13030825 overlaps with the serum response factor (SRF) transcription factor previously implicated in postnatal bone development of mice. Overall, we identified ancestry-related maternal genetic loci that influence fetal growth, shedding light on molecular pathways that regulate fetal growth and potential effects on health across the lifespan.Clinical trials registration ClinicalTrials.gov, NCT00912132.
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http://dx.doi.org/10.1007/s00439-021-02265-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197736PMC
July 2021

Nutrition during Pregnancy: Findings from the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton Cohort.

Curr Dev Nutr 2021 Jan 24;5(1):nzaa182. Epub 2020 Dec 24.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.

Background: Accumulating evidence indicates that maternal diets are important for optimizing maternal and offspring health. Existing research lacks comprehensive profiles of maternal diets throughout pregnancy, especially in a racially/ethnically diverse obstetrical population.

Objective: The aim was to characterize diets in a longitudinal US pregnancy cohort by trimester, race/ethnicity, and prepregnancy BMI.

Methods: Data were obtained from pregnant women in the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton cohort (2009-2013). A food-frequency questionnaire (FFQ) at 8-13 wk of gestation assessed periconception and first-trimester diet (= 1615). Automated, self-administered, 24-h dietary recalls targeted at 16-22, 24-29, 30-33, and 34-37 wk of gestation assessed second- and third-trimester diets (= 1817 women/6791 recalls). The Healthy Eating Index-2010 (HEI-2010) assessed diet quality (i.e., adherence to US Dietary Guidelines). Variations in weighted energy-adjusted means for foods and nutrients were examined by trimester, self-identified race/ethnicity, and self-reported prepregnancy BMI.

Results: Mean (95% CI) HEI-2010 was 65.9 (64.9, 67.0) during periconception to the first trimester assessed with an FFQ and 51.6 (50.8, 52.4) and 51.5 (50.7, 52.3) during the second trimester and third trimester, respectively, assessed using 24-h recalls. No significant differences were observed between the second and third trimester in macronutrients, micronutrients, foods, or HEI-2010 components (≥ 0.05). Periconception to first-trimester HEI-2010 was highest among Asian/Pacific Islander [67.2 (65.9, 68.6)] and lowest among non-Hispanic Black [58.7 (57.5, 60.0)] women and highest among women with normal weight [67.2 (66.1, 68.4)] and lowest among women with obesity [63.5 (62.1, 64.9)]. Similar rankings were observed in the second/third trimesters.

Conclusions: Most pregnant women in this cohort reported dietary intakes that, on average, did not meet US Dietary Guidelines for nonpregnant individuals. Also, diet differed across race/ethnic groups and by prepregnancy BMI, with the lowest overall dietary quality in all trimesters among non-Hispanic Black women and women with obesity. No meaningful changes in dietary intake were observed between the second and third trimesters.
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http://dx.doi.org/10.1093/cdn/nzaa182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846139PMC
January 2021

Vegetarian diets during pregnancy, and maternal and neonatal outcomes.

Int J Epidemiol 2021 03;50(1):165-178

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Background: Vegetarian diets are becoming increasingly popular in the USA. Limited research has examined the health consequences of vegetarian diets during pregnancy. We comprehensively examined associations of vegetarianism during pregnancy with maternal and neonatal outcomes.

Methods: We used data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Fetal Growth Studies-Singletons, a prospective multi-site cohort of 1948 low-risk pregnant women of four races/ethnicities (White, Black, Hispanic, Asian/Pacific Islander) in the USA (2009-2013). Vegetarianism was self-reported and also defined based on dietary patterns measured using a self-administered first-trimester food-frequency questionnaire (full [lacto-ovo and vegan], pesco-, semi- and non-vegetarians). Neonatal outcomes included birthweight and neonatal anthropometric measures, small for gestational age, small for gestational age with neonatal morbidity and preterm delivery. Maternal outcomes included gestational weight gain, gestational diabetes, hypertensive disorders of pregnancy and gestational anaemia.

Results: Ninety-nine (6.2%) women self-reported being vegetarian. The diet-based definition identified 32 (2.0%) full vegetarians, 7 (0.6%) pesco-vegetarians and 301 (17.6%) semi-vegetarians. Neonates of diet-based full vegetarians had higher odds of being small for gestational age [adjusted odds ratio (ORadj) = 2.51, 95% confidence interval: 1.01, 6.21], but not of being small for gestational age with a postnatal morbidity. Full vegetarians had marginally increased the odds of inadequate second-trimester gestational weight gain (ORadj = 2.24, 95% confidence interval: 0.95, 5.27).

Conclusion: Vegetarian diets during pregnancy were associated with constitutionally smaller neonatal size, potentially via the mothers' reduced gestational weight gain. Notably, vegetarianism was not associated with small-for-gestational-age-related morbidities or other adverse maternal outcomes.
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http://dx.doi.org/10.1093/ije/dyaa200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938506PMC
March 2021

Maternal Socioeconomic Factors and Racial/Ethnic Differences in Neonatal Anthropometry.

Int J Environ Res Public Health 2020 10 7;17(19). Epub 2020 Oct 7.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

Disparities in birthweight by maternal race/ethnicity are commonly observed. It is unclear to what extent these disparities are correlates of individual socioeconomic factors. In a prospective cohort of 1645 low-risk singleton pregnancies included in the NICHD Fetal Growth Study (2009-2013), neonatal anthropometry was measured by trained personnel using a standard protocol. Socioeconomic characteristics included employment status, marital status, health insurance, annual income, and education. Separate adjusted generalized linear models were fit to both test the effect of race/ethnicity and the interaction of race/ethnicity and socioeconomic characteristics on neonatal anthropometry. Mean infant birthweight, length, head circumference, and abdominal circumference all differed by race/ethnicity ( 0.001). We observed no statistically significant interactions between race/ethnicity and full-time employment/student status, marital status, insurance, or education in association with birthweight, neonatal exam weight, length, or head or abdominal circumference at examination. The interaction between income and race/ethnicity was significant only for abdominal circumference ( 0.027), with no other significant interactions for other growth parameters, suggesting that racial/ethnic differences in neonatal anthropometry did not vary by individual socioeconomic factors in low-risk women. Our results do not preclude structural factors, such as lifetime exposure to poverty, as an explanation for racial/ethnic disparities.
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http://dx.doi.org/10.3390/ijerph17197323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579630PMC
October 2020

Racial/Ethnic Differences in Prenatal Supplement and Medication Use in Low-Risk Pregnant Women.

Am J Perinatol 2020 Oct 8. Epub 2020 Oct 8.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Objective:  This study aimed to describe the overall quantity and type of supplements and medications used during pregnancy in a low-risk cohort and to examine any racial/ethnic differences in intake.

Study Design:  We used data from 2,164 racially/ethnically diverse, nonobese, and low-risk pregnant women participating without pre-pregnancy chronic conditions in a prospective cohort study at 12 sites across the United States. Medication data were self-reported as free text in enrollment, follow-up visit questionnaires, and abstracted from medical records at delivery. Supplements and medications data were mapped to their active ingredients and categorized into corresponding classes using the Slone Drug Dictionary. The total number and classes of supplements and medications consumed during pregnancy were calculated. Modified Poisson regression models were used to estimate the racial/ethnic differences in supplements and medications intake. All models were adjusted for maternal sociodemographic factors and study site.

Results:  98% of women took at least one supplement during pregnancy, with prenatal vitamins/multivitamins being most common. While only 31% reported taking no medications during pregnancy, 23% took one, 18% took two, and 28% took three or more. The percentage of women taking at least one medication during pregnancy was highest among non-Hispanic white women and lowest among Asians (84 vs. 55%,  < 0.001). All racial/ethnic groups reported taking the same top four medication classes including central nervous system agents, gastrointestinal drugs, anti-infective agents, and antihistamines. Compared with non-Hispanic white women, Hispanic (adjusted relative risk [aRR]: 0.84, 95% confidence interval [CI]: 0.71-0.98), and Asian women (aRR: 0.83, 95% CI: 0.70-0.98) were less likely to take central nervous system agents, as well as gastrointestinal drugs (Hispanics aRR: 0.79, 95% CI: 0.66-0.94; Asians aRR = 0.75, 95% CI: 0.63-0.90), and antihistamines (Hispanics aRR: 0.65, 95% CI: 0.47-0.92).

Conclusion:  Supplement intake was nearly universal. Medication use was also common among this low-risk pregnancy cohort and differed by race/ethnicity. CLINICALTRIALS.

Gov Identifier:  NCT00912132.

Key Points: · In women without chronic conditions, medication use is common.. · Racial/ethnic differences exist in prenatal medications use.. · Almost all women use supplements during pregnancy..
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http://dx.doi.org/10.1055/s-0040-1717097DOI Listing
October 2020

Maternal mortality in the United States: research gaps, opportunities, and priorities.

Am J Obstet Gynecol 2020 10 17;223(4):486-492.e6. Epub 2020 Jul 17.

Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.

Maternal mortality and severe maternal morbidity are urgent issues in the United States. It is important to establish priority areas to address these public health crises. On April 8, 2019, and May 2 to 3, 2019, the Eunice Kennedy Shriver National Institute of Child Health and Human Development organized and invited experts with varied perspectives to 2 meetings, a community engagement forum and a scientific workshop, to discuss underlying themes involved in the rising incidence of maternal mortality in the United States. Experts from diverse disciplines reviewed current data, ongoing activities, and identified research gaps focused on data measurement and reporting, obstetrical and health system factors, social determinants and disparities, and the community perspective and engagement. Key scientific opportunities to reduce maternal mortality and severe maternal morbidity include improved data quality and measurement, understanding the populations affected as well as the numerous etiologies, clinical research to confirm preventive and interventional strategies, and engagement of community participation in research that will lead to the reduction of maternal mortality in the United States. This article provides a summary of the workshop presentations and discussions.
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http://dx.doi.org/10.1016/j.ajog.2020.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564012PMC
October 2020

Early pregnancy dyslipidemia is associated with placental DNA methylation at loci relevant for cardiometabolic diseases.

Epigenomics 2020 06 17;12(11):921-934. Epub 2020 Jul 17.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD 20892-7004, USA.

To identify placental DNA methylation changes that are associated with early pregnancy maternal dyslipidemia. We analyzed placental genome-wide DNA methylation (n = 262). Genes annotating differentially methylated CpGs were evaluated for gene expression in placenta (n = 64). We found 11 novel significant differentially methylated CpGs associated with high total cholesterol, low-density lipoprotein cholesterol and triglycerides, and low high-density lipoprotein cholesterol. High triglycerides were associated with decreased methylation of cg02785814 () and decreased expression of in placenta. Genes annotating the differentially methylated CpGs play key roles in lipid metabolism and were enriched in dyslipidemia pathways. Functional annotation found -methylation quantitative trait loci for genetic loci in and . Our findings lend novel insights into potential placental epigenetic mechanisms linked with maternal dyslipidemia. ClinicalTrials.gov, NCT00912132.
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http://dx.doi.org/10.2217/epi-2019-0293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466909PMC
June 2020

Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy.

PLoS Genet 2020 05 14;16(5):e1008747. Epub 2020 May 14.

Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States of America.

Abnormal fetal growth is a risk factor for infant morbidity and mortality and is associated with cardiometabolic diseases in adults. Genetic influences on fetal growth can vary at different gestation times, but genome-wide association studies have been limited to birthweight. We performed trans-ethnic genome-wide meta-analyses and fine mapping to identify maternal genetic loci associated with fetal weight estimates obtained from ultrasound measures taken during pregnancy. Data included 1,849 pregnant women from four race/ethnic groups recruited through the NICHD Fetal Growth Studies. We identified a novel genome-wide significant association of rs746039 [G] (ITPR1) with reduced fetal weight from 24 to 33 weeks gestation (P<5x10-8; log10BF>6). Additional tests revealed that the SNP was associated with head circumference (P = 4.85x10-8), but not with abdominal circumference or humerus/femur lengths. Conditional analysis in an independent sample of mother-offspring pairs replicated the findings and showed that the effect was more likely maternal but not fetal. Trans-ethnic approaches successfully narrowed down the haplotype block that contained the 99% credible set of SNPs associated with head circumference. We further demonstrated that decreased placental expression of ITPR1 was correlated with increased placental epigenetic age acceleration, a risk factor for reduced fetal growth, among male fetuses (r = -0.4, P = 0.01). Finally, genetic risk score composed of known maternal SNPs implicated in birthweight among Europeans was associated with fetal weight from mid-gestation onwards among Whites only. The present study sheds new light on the role of common maternal genetic variants in the inositol receptor signaling pathway on fetal growth from late second trimester to early third trimester. Clinical Trial Registration: ClinicalTrials.gov, NCT00912132.
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http://dx.doi.org/10.1371/journal.pgen.1008747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252673PMC
May 2020

Adverse maternal and neonatal outcomes among women with preeclampsia with severe features <34 weeks gestation with versus without comorbidity.

Pregnancy Hypertens 2020 Apr 10;20:75-82. Epub 2020 Mar 10.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Bethesda, MD), United States.

Objectives: To determine adverse maternal and neonatal outcomes among women with preeclampsia with severe features who delivered <34 weeks comparing those with versus without a comorbid condition.

Study Design: A retrospective analysis from the U.S. Consortium on Safe Labor Study of deliveries <34 weeks with preeclampsia with severe features. We examined the association of each comorbid condition versus none with adverse maternal and neonatal outcomes. The comorbidities (not mutually exclusive) were chronic hypertension, pregestational diabetes, gestational diabetes, twin gestation, and fetal growth restriction.

Main Outcomes: Maternal outcome: eclampsia, thromboembolism, ICU admission, and/or death; and neonatal outcome: intracranial/periventricular hemorrhage, hypoxic-ischemic encephalopathy/periventricular leukomalacia, stillbirth, and/or perinatal death.

Results: Among 2217 deliveries, 50% had a comorbidity, namely chronic hypertension (30%), pregestational diabetes (8%), gestational diabetes (8%), twin gestation (10%), and fetal growth restriction (7%). Adverse maternal and neonatal outcomes occurred in 10% and 12% of pregnancies, respectively. Pregnancies with preeclampsia with severe features delivered <34 weeks complicated by gestational diabetes (adjusted risk difference, aRD: -4.9%, 95%CI: -9.11 to -0.71), twin gestation (aRD: -5.1%, 95%CI: -8.63 to -1.73), and fetal growth restriction (aRD: -4.7%, 95%CI: -7.96 to -1.62) were less likely to result in adverse maternal outcome compared to pregnancies without comorbidity, but not chronic hypertension and pregestational diabetes. A pregnancy complicated by fetal growth restriction (aRD: 12.2%, 95%CI: 5.48 to 19.03) was more likely to result in adverse neonatal outcome, but not other comorbid conditions.

Conclusions: Preeclampsia with severe features <34 weeks complicated by comorbidity was generally not associated with an increased risk of adverse maternal and neonatal outcomes, with the exception of fetal growth restriction.
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http://dx.doi.org/10.1016/j.preghy.2020.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293899PMC
April 2020

Gestational Age at Birth and Risk of Developmental Delay: The Upstate KIDS Study.

Am J Perinatol 2021 08 6;38(10):1088-1095. Epub 2020 Mar 6.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.

Objective: The aim of this study is to model the association between gestational age at birth and early child development through 3 years of age.

Study Design: Development of 5,868 children in Upstate KIDS (New York State; 2008-2014) was assessed at 7 time points using the Ages and Stages Questionnaire (ASQ). The ASQ was implemented using gestational age corrected dates of birth at 4, 8, 12, 18, 24, 30, and 36 months. Whether children were eligible for developmental services from the Early Intervention Program was determined through linkage. Gestational age was based on vital records. Statistical models adjusted for covariates including sociodemographic factors, maternal smoking, and plurality.

Results: Compared with gestational age of 39 weeks, adjusted odds ratios (aOR) and 95% confidence intervals of failing the ASQ for children delivered at <32, 32-34, 35-36, 37, 38, and 40 weeks of gestational age were 5.32 (3.42-8.28), 2.43 (1.60-3.69), 1.38 (1.00-1.90), 1.37 (0.98-1.90), 1.29 (0.99-1.67), 0.73 (0.55-0.96), and 0.51 (0.32-0.82). Similar risks of being eligible for Early Intervention Program services were observed (aOR: 4.19, 2.10, 1.29, 1.20, 1.01, 1.00 [ref], 0.92, and 0.78 respectively for <32, 32-34, 37, 38, 39 [ref], 40, and 41 weeks).

Conclusion: Gestational age was inversely associated with developmental delays for all gestational ages. Evidence from our study is potentially informative for low-risk deliveries at 39 weeks, but it is notable that deliveries at 40 weeks exhibited further lower risk.
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http://dx.doi.org/10.1055/s-0040-1702937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507972PMC
August 2021

Glycaemic status during pregnancy and longitudinal measures of fetal growth in a multi-racial US population: a prospective cohort study.

Lancet Diabetes Endocrinol 2020 04 2;8(4):292-300. Epub 2020 Mar 2.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background: The timepoint at which fetal growth begins to differ by maternal glycaemic status is not well understood. To address this lack of data, we examined gestational diabetes, impaired glucose tolerance, and early pregnancy glucose concentrations in relation to fetal growth trajectories.

Methods: This cohort study included 2458 pregnant women from the NICHD Fetal Growth Studies-Singletons study, which took place between 2009 and 2013. Women were recruited from 12 clinical centres in the USA. Women aged 18-40 years without major chronic conditions when entering pregnancy were included and those with records of neither glucose screening test or glucose tolerance test were excluded from the study. Women were enrolled at gestational weeks 8-13 and randomly assigned to four ultrasonogram schedules (Group A; weeks 16, 24, 30, 34; Group B: weeks 18, 26, 31, 35, 39; Group C: weeks 20, 28, 32, 36; Group D: weeks 22, 29, 33, 37, 41) to capture weekly fetal growth. Gestational diabetes, impaired glucose tolerance, and normal glucose tolerance were defined by medical record review. Glucose was measured in a subsample of women at weeks 10-14. We modelled fetal growth trajectories using linear mixed models with cubic splines. This study is registered with ClinicalTrials.gov, NCT00912132.

Findings: Of the 2458 women included in this study, 107 (4·4%) had gestational diabetes, 118 (4·8%) had impaired glucose tolerance, and 2020 (82·2%) had NGT. 213 women were excluded from the main analysis. The cohort with gestational diabetes was associated with a larger estimated fetal weight that started at week 20 and was significant at week 28-40 (at week 37: 3061 g [95% CI 2967-3164] for women with gestational diabetes vs 2943 g [2924-2962] for women with normal glucose tolerance, adjusted p=0·02). In addition, glucose levels at weeks 10-14 were positively associated with estimated fetal weight starting at week 23 and the association became significant at week 27 (at week 37: 3073 g [2983-3167] in the highest tertile vs 2853 g [2755-2955] in the lowest tertile, adjusted p=0·0009.

Interpretation: Gestational diabetes was associated with a larger fetal size that started at week 20 and became significant at gestational week 28. Efforts to mitigate gestational diabetes-related fetal overgrowth should start before 24-28 gestational weeks, when gestational diabetes is typically screened for in the USA.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/S2213-8587(20)30024-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676113PMC
April 2020

Differential DNA Methylation in Placenta Associated With Maternal Blood Pressure During Pregnancy.

Hypertension 2020 04 10;75(4):1117-1124. Epub 2020 Feb 10.

From the Epidemiology Branch (T.W., M.O., D.S., K.L.G., F.T.-A.).

Abnormal blood pressure during pregnancy is associated with impaired fetal growth, predisposing the offspring to cardiometabolic abnormalities over the life-course. Placental DNA methylation may be the regulatory pathway through which maternal blood pressure influences fetal and adult health outcomes. Epigenome-wide association study of 301 participants with placenta sample examined associations between DNA methylation and millimetre of mercury increases in systolic and diastolic blood pressure in each trimester. Findings were further examined using gene expression, gene pathway, and functional annotation analyses. Cytosine-(phosphate)-guanine (CpGs) known to be associated with cardiometabolic traits were evaluated. Increased maternal systolic and diastolic blood pressure were associated with methylation of 3 CpGs in the first, 6 CpGs in the second, and 15 CpGs in the third trimester at 5% false discovery rate ( values ranging from 6.6×10 to 2.3×10). Several CpGs were enriched in pathways including cardiovascular-metabolic development (=1.0×10). Increased systolic and diastolic blood pressure were associated with increased CpG methylation and gene expression at , a collagen family gene known for regulatory functions in the heart. Out of 304 previously reported CpGs known to be associated with cardiometabolic traits, 36 placental CpGs were associated with systolic and diastolic blood pressure in our data. The present study provides the first evidence for associations between placental DNA methylation and increased maternal blood pressure during pregnancy at genes implicated in cardiometabolic diseases. Identification of blood pressure-associated methylated sites in the placenta may provide clues to early origins of cardiometabolic dysfunction and inform guidelines for early prevention. Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00912132.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122078PMC
April 2020

Maternal preconception lipid profile and gestational lipid changes in relation to birthweight outcomes.

Sci Rep 2020 Jan 28;10(1):1374. Epub 2020 Jan 28.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6710B Rockledge Drive, MSC 7004, Bethesda, MD, 20892, United States.

In 575 women with 1-2 prior pregnancy losses; total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were evaluated preconception and throughout pregnancy to evaluate whether previously observed associations between third trimester maternal lipid profile and birthweight outcomes are driven by preconception lipids or lipid changes during pregnancy. Lipid trajectories were compared by pre-pregnancy body mass index (BMI) <25 or ≥25 kg/m; logistic regression models evaluated preconception lipid concentration and change from preconception to 28 weeks with adjusted odds of large- or small-for-gestational age (LGA or SGA) neonate by BMI group. Preconception lipid concentrations and gestational lipid trajectories varied by BMI group (P < 0.001). Preconception lipids were not associated with LGA or SGA in either group. A 10 mg/dL increase in HDL-C change from preconception to 28 weeks was associated with decreased odds of LGA (odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.46, 0.86) and 10 mg/dL increase in TG change associated with increased odds of LGA (OR = 1.05, 95% CI: 1.01, 1.1) overall. For ≥25 BMI only, 10 mg/dL increase in HDL-C change was associated with decreased SGA odds (OR = 0.35, 95% CI: 0.19, 0.64). Gestational lipid trajectories differed by BMI group and were differentially associated with birthweight outcomes, with HDL-C more strongly associated with healthy birthweight in women with BMI ≥25.
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http://dx.doi.org/10.1038/s41598-019-57373-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987205PMC
January 2020

Association of Maternal Exposure to Persistent Organic Pollutants in Early Pregnancy With Fetal Growth.

JAMA Pediatr 2020 02;174(2):149-161

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland.

Importance: Prenatal exposure to persistent organic pollutants (POPs) has been associated with birth size, but data on fetal growth and among racially/ethnically diverse pregnant women remain scarce.

Objectives: To assess the association between maternal plasma POPs in early pregnancy and fetal growth and by infant sex and maternal race/ethnicity.

Design, Setting, And Participants: This cohort study used the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort, which recruited nonobese, low-risk pregnant women before 14 weeks' gestation between July 1, 2009, and January 31, 2013, in 12 community-based clinics throughout the United States. Participants self-identified their race/ethnicity, self-reported their behavioral risk factors, and were followed up throughout their pregnancy. Data were analyzed from July 31, 2018, to June 3, 2019.

Exposures: Levels of 76 POPs in early gestation plasma were measured: 11 perfluoroalkyl and polyfluoroalkyl substances, 1 polybrominated biphenyl, 9 polybrominated diphenyl ethers (PBDEs), 44 polychlorinated biphenyls (PCBs), and 11 organochlorine pesticides (OCPs). The bayesian kernel machine regression method was used to examine chemical class mixtures, and generalized additive mixed model was used to analyze individual chemicals.

Main Outcomes And Measures: Fourteen fetal biometrics were measured, including head circumference, abdominal circumference, and femur length, within 5 ultrasonography appointments.

Results: A total of 2284 low-risk pregnant women were included: 606 women (26.5%) self-identified as white with a mean (SD) age of 30.3 (4.4) years, 589 (25.8%) as black with a mean (SD) age of 25.5 (5.5) years, 635 (27.8%) as Hispanic with a mean (SD) age of 27.1 (5.5) years, and 454 (19.9%) as Asian with a mean (SD) age of 30.5 (4.5) years. A comparison between the 75th and 25th percentile of exposure revealed that the OCP mixture was negatively associated with most fetal growth measures, with a reduction of 4.7 mm (95% CI, -6.7 to -2.8 mm) in head circumference, 3.5 mm (95% CI, -4.7 to -2.2 mm) in abdominal circumference, and 0.6 mm (95% CI, -1.1 to -0.2 mm) in femur length. Higher exposure to the PBDE mixture was associated with reduced abdominal circumference (-2.4 mm; 95% CI, -4.0 to -0.5 mm) and femur length (-0.5 mm; 95% CI, -1.0 to -0.1 mm), and the dioxin-like PCB mixture was associated with reduced head circumference (-6.4 mm; 95% CI, -8.4 to -4.3 mm) and abdominal circumference (-2.4 mm; 95% CI, -3.9 to -0.8 mm). Associations with individual chemicals were less consistent. There were some interactions by fetal sex, although most of the results did not vary by maternal race/ethnicity. For example, oxychlordane (-0.98 mm; 95% CI, -1.60 to -0.36 mm; P for interaction <.001), trans-nonachlor (-0.31 mm; 95% CI, -0.54 to -0.08 mm; P for interaction = .005), and p,p'-dichlorodiphenyldichloroethylene (-0.19 mm; 95% CI, -0.22 to -0.09 mm; P for interaction = .006) were associated with shorter femur length among boys only.

Conclusions And Relevance: This study found that, among pregnant women with low POP levels, a mixture of OCPs was negatively associated with most fetal growth measures and that mixtures of PBDEs and dioxin-like PCBs were associated with reduced abdominal circumference. These findings suggested that, although exposures may be low, associations with fetal growth are apparent.
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http://dx.doi.org/10.1001/jamapediatrics.2019.5104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990715PMC
February 2020

Vital Status Ascertainment for a Historic Diverse Cohort of U.S. Women.

Epidemiology 2020 03;31(2):310-316

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD.

Background: Studies linking large pregnancy cohorts with mortality data can address critical questions about long-term implications of gravid health, yet relevant US data are scant. We examined the feasibility of linking the Collaborative Perinatal Project, a large multiracial U.S. cohort study of pregnant women (n = 48,197; 1959-1966), to death records.

Methods: We abstracted essential National Death Index (NDI) (1979-2016) (n = 46,428). We performed a linkage to the Social Security Administration Death Master File through 2016 (n = 46,450). Genealogists manually searched vital status in 2016 for a random sample of women (n = 1,249). We conducted agreement analyses for women with abstracted data among the three sources. As proof of concept, we calculated adjusted associations between mortality and smoking and other sociodemographic factors using Cox proportional hazards regression.

Results: We successfully abstracted identifying information for most of the cohort (97%). National Death Index identified the greatest proportion of participants deceased (35%), followed by genealogists (31%) and Death Master File (23%). Estimates of agreement (κ [95% confidence interval]) between National Death Index and Death Master File were lower (0.52 [0.51, 0.53]) than for National Death Index and genealogist (0.66 [0.61, 0.70]). As expected, compared with nonsmokers, smoking ≥1 pack per day was associated with elevated mortality for all vital sources and was strongest for National Death Index.

Conclusions: Linking this historic cohort with mortality records was feasible and agreed reasonably on vital status when compared with other data sources. Such linkage enables future examination of pregnancy conditions in relation to mortality in a diverse U.S. cohort.
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http://dx.doi.org/10.1097/EDE.0000000000001134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042706PMC
March 2020
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