Phthalate and phthalate replacement concentrations in relationship to adiposity in a multi-racial cohort of children.

BACKGROUND/OBJECTIVE: Phthalates and phthalate replacements are used in multiple everyday products, making many of them bioavailable to children. Experimental studies suggest that phthalates and their replacements may be obesogenic, however, epidemiologic studies remain inconsistent. Therefore, our objective was to examine the association between phthalates, phthalate replacements and childhood adiposity/obesity markers in children. SUBJECTS/METHODS: A cross-sectional study was conducted in 630 racial/ethnically diverse children ages 4-8 years. Urinary oxidative metabolites of DINCH and DEHTP, three low molecular weight (LMW) phthalates, and eleven high molecular weight (HMW) phthalates were measured. Weight, height, waist circumference and % body fat were measured. Composite molar sum groups (nmol/ml) were natural log-transformed. Linear regression models adjusted for urine specific gravity, sex, age, race-ethnicity, birthweight, breastfeeding, reported activity level, mother's education and pre-pregnancy BMI. RESULTS: All children had LMW and HMW phthalate metabolites and 88% had DINCH levels above the limit of detection. One unit higher in the log of DINCH was associated with 0.106 units lower BMI z-score [ß = -0.106 (95% CI: -0.181, -0.031)], 0.119 units lower waist circumference z-score [ß = -0.119 (95% CI: -0.189, -0.050)], and 0.012 units lower percent body fat [ß = -0.012 (95% CI: -0.019, -0.005)]. LMW and HMW group values were not associated with adiposity/obesity. CONCLUSIONS: We report an inverse association between child urinary DINCH levels, a non-phthalate plasticizer that has replaced DEHP in several applications, and BMI z-score, waist circumference z-score and % body fat in children. Few prior studies of phthalates and their replacements in children have been conducted in diverse populations. Moreover, DINCH has not received a great deal of attention or regulation, but it is a common exposure. In summary, understanding the ubiquitous nature of these chemical exposures and ultimately their sources will contribute to our understanding of their relationship with obesity.

Multiethnic growth standards for fetal body composition and organ volumes derived from 3D ultrasonography.

BACKGROUND: A major goal of contemporary obstetrical practice is to optimize fetal growth and development throughout pregnancy. To date, fetal growth during prenatal care is assessed by performing ultrasonographic measurement of 2-dimensional fetal biometry to calculate an estimated fetal weight. Our group previously established 2-dimensional fetal growth standards using sonographic data from a large cohort with multiple sonograms. A separate objective of that investigation involved the collection of fetal volumes from the same cohort. OBJECTIVE: The Fetal 3D Study was designed to establish standards for fetal soft tissue and organ volume measurements by 3-dimensional ultrasonography and compare growth trajectories with conventional 2-dimensional measures where applicable. STUDY DESIGN: The National Institute of Child Health and Human Development Fetal 3D Study included research-quality images of singletons collected in a prospective, racially and ethnically diverse, low-risk cohort of pregnant individuals at 12 U.S. sites, with up to 5 scans per fetus (N=1730 fetuses). Abdominal subcutaneous tissue thickness was measured from 2-dimensional images and fetal limb soft tissue parameters extracted from 3-dimensional multiplanar views. Cerebellar, lung, liver, and kidney volumes were measured using virtual organ computer aided analysis. Fractional arm and thigh total volumes, and fractional lean limb volumes were measured, with fractional limb fat volume calculated by subtracting lean from total. For each measure, weighted curves (fifth, 50th, 95th percentiles) were derived from 15 to 41 weeks' using linear mixed models for repeated measures with cubic splines. RESULTS: Subcutaneous thickness of the abdomen, arm, and thigh increased linearly, with slight acceleration around 27 to 29 weeks. Fractional volumes of the arm, thigh, and lean limb volumes increased along a quadratic curvature, with acceleration around 29 to 30 weeks. In contrast, growth patterns for 2-dimensional humerus and femur lengths demonstrated a logarithmic shape, with fastest growth in the second trimester. The mid-arm area curve was similar in shape to fractional arm volume, with an acceleration around 30 weeks, whereas the curve for the lean arm area was more gradual. The abdominal area curve was similar to the mid-arm area curve with an acceleration around 29 weeks. The mid-thigh and lean area curves differed from the arm areas by exhibiting a deceleration at 39 weeks. The growth curves for the mid-arm and thigh circumferences were more linear. Cerebellar 2-dimensional diameter increased linearly, whereas cerebellar 3-dimensional volume growth gradually accelerated until 32 weeks followed by a more linear growth. Lung, kidney, and liver volumes all demonstrated gradual early growth followed by a linear acceleration beginning at 25 weeks for lungs, 26 to 27 weeks for kidneys, and 29 weeks for liver. CONCLUSION: Growth patterns and timing of maximal growth for 3-dimensional lean and fat measures, limb and organ volumes differed from patterns revealed by traditional 2-dimensional growth measures, suggesting these parameters reflect unique facets of fetal growth. Growth in these three-dimensional measures may be altered by genetic, nutritional, metabolic, or environmental influences and pregnancy complications, in ways not identifiable using corresponding 2-dimensional measures. Further investigation into the relationships of these 3-dimensional standards to abnormal fetal growth, adverse perinatal outcomes, and health status in postnatal life is warranted.

Nutritional Intake in Dichorionic Twin Pregnancies: A Descriptive Analysis of a Multisite United States Cohort.

INTRODUCTION: Twin gestations have greater nutritional demands than singleton gestations, yet dietary intakes of women with twin gestations have not been well described. METHODS: In a prospective, multi-site US study of 148 women with dichorionic twin gestations (2012-2013), we examined longitudinal changes in diet across pregnancy. Women completed a food frequency questionnaire during each trimester of pregnancy. We examined changes in means of total energy and energy-adjusted dietary components using linear mixed effects models. RESULTS: Mean energy intake (95% CI) across the three trimesters was 2010 kcal/day (1846, 2175), 2177 kcal/day (2005, 2349), 2253 kcal/day (2056, 2450), respectively (P = 0.01), whereas the Healthy Eating Index-2010 was 63.9 (62.1, 65.6), 64.5 (62.6, 66.3), 63.2 (61.1, 65.3), respectively (P = 0.53). DISCUSSION: Women with twin gestations moderately increased total energy as pregnancy progressed, though dietary composition and quality remained unchanged. These findings highlight aspects of nutritional intake that may need to be improved among women carrying twins.

Fetal Growth and Antenatal Testing in Uncomplicated Multiple Gestations.

Multiple gestations experience a slowing of fetal growth in the third trimester and have been described as having a higher risk of growth restriction. Whether this increased diagnosis of fetal growth restriction is physiological or pathologic is controversial. In an attempt to better identify those fetuses most at risk, twin-specific growth charts have been developed and tested. In addition, there are data to suggest that multiple gestations experience an increased risk of unexpected third-trimester stillbirth in apparently uncomplicated pregnancies. This chapter reviews the current data and recommendations for fetal growth assessment, antenatal surveillance, and delivery timing in uncomplicated multiple gestations.

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

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 birth weight <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 birth weight, 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..

Association between gestational PFAS exposure and Children's adiposity in a diverse population.

Perfluoroalkyl substances (PFAS) are widely distributed suspected obesogens that cross the placenta. However, few data are available to assess potential fetal effects of PFAS exposure on children's adiposity in diverse populations. To address the data gap, we estimated associations between gestational PFAS concentrations and childhood adiposity in a diverse mother-child cohort. We considered 6 PFAS in first trimester blood plasma, measured using ultra-high-performance liquid chromatography with tandem mass spectrometry, collected from non-smoking women with low-risk singleton pregnancies (n = 803). Body mass index (BMI), waist circumference (WC), fat mass, fat-free mass, and % body fat were ascertained in 4-8 year old children as measures of adiposity. We estimated associations of individual gestational PFAS with children's adiposity and overweight/obesity, adjusted for confounders. There were more non-Hispanic Black (31.7 %) and Hispanic (42.6 %) children with overweight/obesity, than non-Hispanic white (18.2 %) and Asian/Pacific Islander (16.4 %) children (p < 0.0001). Perfluorooctane sulfonate (PFOS; 5.3 ng/mL) and perfluorooctanoic acid (2.0 ng/mL) had the highest median concentrations in maternal blood. Among women without obesity (n = 667), greater perfluoroundecanoic acid (PFUnDA) was associated with their children having higher WC z-score (ß = 0.08, 95%CI: 0.01, 0.14; p = 0.02), fat mass (ß = 0.55 kg, 95%CI: 0.21, 0.90; p = 0.002), and % body fat (ß = 0.01 %; 95%CI: 0.003, 0.01; p = 0.004), although the association of PFUnDA with fat mass attenuated at the highest concentrations. Among women without obesity, the associations of PFAS and their children's adiposity varied significantly by self-reported race-ethnicity, although the direction of the associations was inconsistent. In contrast, among the children of women with obesity, greater, PFOS, perfluorononanoic acid, and perfluorodecanoic acid concentrations were associated with less adiposity (n = 136). Our results suggest that specific PFAS may be developmental obesogens, and that maternal race-ethnicity may be an important modifier of the associations among women without obesity.

Fetal Growth Biometry as Predictors of Shoulder Dystocia in a Low-Risk Obstetrical Population.

OBJECTIVE: This study aimed to evaluate fetal biometrics as predictors of shoulder dystocia (SD) in a low-risk obstetrical population. STUDY DESIGN: Participants were enrolled as part of a U.S.-based prospective cohort study of fetal growth in low-risk singleton gestations (n = 2,802). Eligible women had liveborn singletons ≥2,500 g delivered vaginally. Sociodemographic, anthropometric, and pregnancy outcome data were abstracted by research staff. The diagnosis of SD was based on the recorded clinical impression of the delivering physician. Simple logistic regression models were used to examine associations between fetal biometrics and SD. Fetal biometric cut points, selected by Youden's J and clinical determination, were identified to optimize predictive capability. A final model for SD prediction was constructed using backward selection. Our dataset was randomly divided into training (60%) and test (40%) datasets for model building and internal validation. RESULTS: A total of 1,691 women (98.7%) had an uncomplicated vaginal delivery, while 23 (1.3%) experienced SD. There were no differences in sociodemographic or maternal anthropometrics between groups. Epidural anesthesia use was significantly more common (100 vs. 82.4%; p = 0.03) among women who experienced SD compared with those who did not. Amniotic fluid maximal vertical pocket was also significantly greater among SD cases (5.8 ± 1.7 vs. 5.1 ± 1.5 cm; odds ratio = 1.32 [95% confidence interval: 1.03,1.69]). Several fetal biometric measures were significantly associated with SD when dichotomized based on clinically selected cut-off points. A final prediction model was internally valid with an area under the curve of 0.90 (95% confidence interval: 0.81, 0.99). At a model probability of 1%, sensitivity (71.4%), specificity (77.5%), positive (3.5%), and negative predictive values (99.6%) did not indicate the ability of the model to predict SD in a clinically meaningful way. CONCLUSION: Other than epidural anesthesia use, neither sociodemographic nor maternal anthropometrics were significantly associated with SD in this low-risk population. Both individually and in combination, fetal biometrics had limited ability to predict SD and lack clinical usefulness. KEY POINTS: · SD unpredictable in low-risk women.. · Fetal biometry does not reliably predict SD.. · Epidural use associated with increased SD risk.. · SD prediction models clinically inefficient..

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

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%, p < 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. 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..

Dichorionic twin-specific vs singleton growth references for diagnosis of fetal growth restriction.

BACKGROUND: Fetal growth restriction is associated with an increased risk for adverse neonatal outcomes. The Hadlock singleton growth reference is widely used to determine the estimated fetal weight percentile for both twin and singleton gestations. The Eunice Kennedy Shriver National Institute of Child Health and Human Development's twin-specific growth reference accounts for the different growth trajectory that twins follow during gestation. There is a lack of research comparing these different growth references in their ability to identify fetal growth restriction that is associated with adverse neonatal outcomes in dichorionic twin gestations. OBJECTIVE: This study aimed to compare a twin-specific growth reference (the Eunice Kennedy Shriver National Institute of Child Health and Human Development's twin-specific growth reference) and a singleton growth reference (Hadlock) in their ability to identify fetal growth restriction associated with adverse neonatal outcomes in dichorionic twin gestations. STUDY DESIGN: This was a retrospective cohort study of dichorionic twin gestations at ≥32 weeks' gestation delivered at a single institution between 2004 and 2019 with the serial growth ultrasounds and neonatal outcomes data available for analysis. Using their last growth ultrasound before delivery, twins were classified into the following 3 categories: fetal growth restriction according to both the Hadlock and Eunice Kennedy Shriver National Institute of Child Health and Human Development references, fetal growth restriction according to the Hadlock reference only, and no fetal growth restriction according to either reference, with fetal growth restriction defined as an estimated fetal weight of <10th percentile for gestational age. Multivariable generalized linear mixed models were used to assess the adverse neonatal outcomes via pair-wise comparisons between the groups, with a random-effects component to account for twin-pair correlations. RESULTS: A total of 1460 dichorionic twin infants were included with 8.1% (n=118) of cases classified as fetal growth restricted by both the Eunice Kennedy Shriver National Institute of Child Health and Human Development and Hadlock references, 8.8% (n=129) of cases classified as fetal growth restricted by the Hadlock reference only, and 83.1% (n=1213) of cases classified as no fetal growth restriction by either reference. Compared with twins with no fetal growth restriction by either reference, twins with fetal growth restriction by both references were more likely to experience mild (adjusted odds ratio, 2.38; confidence interval, 1.38-4.13) or severe (adjusted odds ratio, 2.82; confidence interval, 1.16-6.88) composite neonatal morbidity. Compared with twins with fetal growth restriction according to the Hadlock reference only, twins with fetal growth restriction according to both references were more likely to experience mild (adjusted odds ratio, 2.03; confidence interval, 1.00-4.14) but not severe (adjusted odds ratio, 3.70; confidence interval, 0.72-18.90) composite neonatal morbidity. Composite neonatal morbidity was not different between twins with fetal growth restriction according to the Hadlock reference only and those with no fetal growth restriction by either growth reference. CONCLUSION: The Eunice Kennedy Shriver National Institute of Child Health and Human Development's twin-specific growth reference better identifies the risk for adverse neonatal outcomes in dichorionic twin gestations diagnosed with fetal growth restriction. The use of the Hadlock singleton growth reference more than doubles the number of dichorionic twins identified with fetal growth restriction who seem to be at a low-risk for neonatal morbidity, leading to unnecessary maternal anxiety, increased antenatal testing, and possibly iatrogenic preterm delivery.

Association between gestational phthalate exposure and newborn head circumference; impacts by race and sex.

Observational and experimental studies report associations between gestational phthalate exposure and fetal development, yet few data exist to characterize phthalate effects on head circumference (HC) or to estimate the impact of race or sex. To address this data gap, we enrolled 152 African American and 158 white mothers with uncomplicated singleton pregnancies from the Charleston, South Carolina (USA) metropolitan area in a prospective birth cohort. Study participants provided up to two urine specimens during mid and late gestation, completed a study questionnaire, and allowed access to hospital birth records. We measured eight phthalate monoester metabolites using liquid chromatography with tandem mass spectrometry, and calculated molar sums of phthalate parent diesters. After specific gravity correction, we tested for associations between phthalates and neonatal HC (cm) and cephalization index (cm/g) using multiple informant linear regression with inverse probability weighting to account for selection bias between repeated urine sampling, adjusted for maternal race, age, body mass index, education, and smoking. We explored interactions by maternal race and infant sex. A doubling of urinary monoethyl phthalate (MEP) concentration was associated with a -0.49% (95%CI: -0.95%, -0.02%) smaller head circumference, although seven other phthalate metabolites were null. There were no statistically significant associations with cephalization index. HC was larger for whites than African American newborns (p < 0.0001) but similar for males and females (p = 0.16). We detected interactions for maternal race with urinary monobutyl phthalate (MBP; p = 0.03), monobenzyl phthalate (MBzP; p = 0.01), monoethylhexyl phthalate (MEHP; p = 0.05), monomethyl phthalate (MMP; p = 0.02), and the sum of dibutyl phthalate metabolites (∑DBP; p = 0.05), in which reduced HC circumference associations were stronger among whites than African Americans, and interactions for sex with MBP (p = 0.08) and MiBP (p = 0.03), in which associations were stronger for females than males. Our results suggest that gestational phthalate exposure is associated with smaller neonatal HC and that white mothers and female newborns have greater susceptibility.

Placental growth factor predicts time to delivery in women with signs or symptoms of early preterm preeclampsia: a prospective multicenter study.

BACKGROUND: There is a robust association between altered angiogenic factor concentrations, which includes placental growth factor and clinically recognized preeclampsia. Alterations in concentrations of angiogenic factors precede the clinical onset of preeclampsia by several weeks. The temporal relationship between the measured angiogenic factors and the time to delivery in women with suspected preeclampsia at <35 weeks gestation, however, remains to be clarified. OBJECTIVE: The purposes of this study were to examine the relationship between placental growth factor and time to delivery in women at <35 weeks gestation with signs or symptoms of preeclampsia and to compare the performance of placental growth factor to other clinical markers for prediction of time to delivery in preeclampsia. STUDY DESIGN: Women with signs or symptoms of preeclampsia between 20.0 and 35.0 weeks gestation were enrolled in a prospective, observational study at 24 centers. Blood was collected at presentation for placental growth factor, and subjects were evaluated and treated according to local protocols. Clinical outcomes were obtained, and all final diagnoses were adjudicated by an independent expert panel according to 2013 American College of Obstetricians and Gynecologists' Hypertension in Pregnancy criteria. Placental growth factor was measured retrospectively on the Alere, Inc, triage platform. A normal placental growth factor was defined as >100 pg/mL; the assay's limit of detection is 12 pg/mL. Two-by-2 tables were constructed for comparison of test outcomes that included negative predictive value; time-to-delivery was analyzed by survival curves and Cox regression. RESULTS: Seven hundred fifty-three subjects were enrolled; 538 (71%) had a final diagnosis of preeclampsia; 542 (72%) delivered at <37 weeks gestation, and 358 (47%) delivered at <34 weeks gestation. Among the 279 women (37%) with a normal placental growth factor at presentation, the negative predictive value for preeclampsia delivered within 14 days or within 7 days was 90% and 93%, respectively. Compared with women with normal placental growth factor, women with placental growth factor ≤100 pg/mL have a hazard ratio of 7.17 (confidence interval, 5.08-10.13) in Cox regression for time to delivery after adjustment for both gestational age at enrollment and the final diagnosis of preeclampsia. The placental growth factor levels of normal (>100 pg/mL), low (12-100 pg/mL), and very low (<12 pg/mL) have well-separated distributions of time to delivery, with median values of 45, 10, and 2 days, respectively. Subjects with placental growth factor ≤100 pg/mL have a perinatal death rate of 5.7% and a small-for-gestational-age rate of 51.7%; subjects with placental growth factor >100 pg/mL have a perinatal death rate of 0% (no observations in this cohort) and an a small-for-gestational-age rate of 16.8%. CONCLUSION: In women with suspected preeclampsia at <35.0 weeks gestation, a low placental growth factor was correlated strongly with preterm delivery independent of a diagnosis of preeclampsia or gestational age at presentation, whereas a normal placental growth factor was associated with pregnancy prolongation, even in patients who ultimately had a final diagnosis of preeclampsia. This suggests that placental growth factor levels are superior to clinical markers in the prediction of adverse pregnancy in women with suspected preeclampsia.

Intrauterine growth discordance across gestation and birthweight discordance in dichorionic twins.

BACKGROUND: Although intertwin size difference is an important measure of fetal growth, the appropriate cut point to define discordance is unclear. Few studies have assessed intertwin differences in estimated fetal weight longitudinally or in relation to size differences at birth. OBJECTIVES: The objectives of the study were to estimate the magnitude of percentage differences in estimated fetal weight across gestation in dichorionic twins in relation to a fixed discordance cut point and compare classification of aberrant fetal growth by different measures (estimated fetal weight differences, birthweight discordance, small for gestational age). STUDY DESIGN: Women aged 18-45 years from 8 US centers with dichorionic twin pregnancies at 8 weeks 0 days to 13 weeks 6 days gestation planning to deliver in participating hospitals were recruited into the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Dichorionic Twins study and followed through delivery (n = 140; 2012-2013). Ultrasounds were conducted at 6 targeted study visits to obtain fetal biometrics and calculate estimated fetal weight. Percent estimated fetal weight and birthweight differences were calculated: ([weightlarger - weightsmaller]/weightlarger)*100; discordance was defined as ≥18% for illustration. Birth sizes for gestational age (both, 1, or neither small for gestational age) were determined; twins were categorized into combined birthweight plus small for gestational age groups: birthweight discordance ≥18% (yes, no) with both, 1, or neither small for gestational age. Linear mixed-models estimated percentiles of estimated fetal weight percent differences across gestation and compared estimated fetal weight differences between combined birthweight discordance and small for gestational age groups. A Fisher exact test compared birthweight discordance and small for gestational age classifications. RESULTS: Median estimated fetal weight percentage difference increased across gestation (5.9% at 15.0, 8.4% at 38.0 weeks), with greater disparities at higher percentiles (eg, 90th percentile: 15.6% at 15.0, 26.3% at 38.0 weeks). As gestation advanced, an increasing percentage of pregnancies were classified as discordant using a fixed cut point: 10% at 27.0, 15% at 34.0, and 20% at 38.0 weeks. Birthweight discordance and small for gestational age classifications differed (P = .002); for birthweight discordance ≥18% vs <18%: 44% vs 71% had neither small for gestational age; 56% vs 18% had 1 small for gestational age; no cases (0%) vs 11% had both small for gestational age, respectively. Estimated fetal weight percent difference varied across gestation by birthweight discordance plus small for gestational age classification (P = .040). Estimated fetal weight percentage difference increased with birthweight discordance ≥18% (neither small for gestational age: 0.46%/week [95% confidence interval, 0.08-0.84]; 1 small for gestational age: 0.57%/week [95% confidence interval, 0.25-0.90]) but less so without birthweight discordance (neither small for gestational age: 0.17%/week [95% confidence interval, 0.06-0.28]; 1 small for gestational age: 0.03%/week [95% confidence interval, -0.17 to 0.24]); both small for gestational age: 0.10%/week [95% confidence interval, -0.15 to 0.36]). CONCLUSION: The percentage of dichorionic pregnancies exceeding a fixed discordance cut point increased over gestation. A fixed cut point for defining twin discordance would identify an increasing percentage of twins as discordant as gestation advances. Small for gestational age and percentage weight differences assess distinct aspects of dichorionic twin growth. A percentile cut point may be more clinically useful for defining discordance, although further study is required to assess whether any specific percentile cut point correlates to adverse outcomes.

Fetal growth patterns in pregnancy-associated hypertensive disorders: NICHD Fetal Growth Studies.

BACKGROUND: Fetal growth patterns in pregnancy-associated hypertensive disorders is poorly understood because prospective longitudinal data are lacking. OBJECTIVE: The objective of the study was to compare longitudinal fetal growth trajectories between normotensive women and those with pregnancy-associated hypertensive disorders. STUDY DESIGN: This is a study based on data from a prospective longitudinal cohort study of fetal growth performed at 12 US sites (2009-2013). Project gestational age was confirmed by ultrasound between 8 weeks 0 days and 13 weels 6 days, and up to 6 ultrasounds were performed across gestation. Hypertensive disorders were diagnosed based on 2002 American College of Obstetricians and Gynecologists guidelines and grouped hierarchically as severe preeclampsia (including eclampsia or HELLP [hemolysis, elevated liver enzymes, and low platelet count] syndrome), mild preeclampsia, severe gestational hypertension, mild gestational hypertension, or unspecified hypertension. Women without any hypertensive disorder constituted the normotensive group. Growth curves for estimated fetal weight and individual biometric parameters including biparietal diameter, head circumference, abdominal circumference, and femur and humerus length were calculated for each group using linear mixed models with cubic splines. Global and weekly pairwise comparisons were performed between women with a hypertensive disorder compared with normotensive women to analyze differences while adjusting for confounding variables. Delivery gestational age and birthweights were compared among groups. RESULTS: Of 2462 women analyzed, 2296 (93.3%) were normotensive, 63 (2.6%) had mild gestational hypertension, 54 (2.2%) mild preeclampsia, 32 (1.3%) severe preeclampsia, and 17 (0.7%) unspecified hypertension. Compared with normotensive women, those with severe preeclampsia had estimated fetal weights that were reduced between 22 and 38 weeks (all weekly pairwise values of P < .008). Women with severe preeclampsia compared with those without hypertension also had significantly smaller fetal abdominal circumference between 23-31 and 33-37 weeks' gestation (weekly pairwise values of P < .04). Scattered weekly growth differences were noted on other biometric parameters between these 2 groups. The consistent differences in estimated fetal weight and abdominal circumference were not observed between women with other hypertensive disorders and those who were normotensive. Women with severe preeclampsia delivered significantly earlier (mean gestational age 35.9 ± 3.2 weeks) than the other groups (global P < .0001). Birthweights in the severe preeclampsia group were also significantly lower (mean -949.5 g [95% confidence interval, -1117.7 to -781.2 g]; P < .0001) than in the normotensive group. CONCLUSION: Among women with pregnancy-associated hypertensive disorders, only those destined to develop severe preeclampsia demonstrated a significant and consistent difference in fetal growth (ie, smaller estimated fetal weight and abdominal circumference) when compared with normotensive women.

Associations between estimated foetal weight discordance and clinical characteristics within dichorionic twins: The NICHD Fetal Growth Studies.

BACKGROUND: Birthweight discordance is well studied, with less known about longitudinal inter-twin differences in foetal growth. OBJECTIVE: To examine inter-twin per cent differences in EFW (EFW% ), head (HC% ) and abdominal circumference (AC% ), and femur length (FL% ) across gestation in dichorionic twin gestations and explore associated characteristics. METHODS: Foetal biometrics were assessed by ultrasound and EFW calculated at ≤6 study visits among women with dichorionic twin pregnancies enrolled in the NICHD Fetal Growth Studies cohort (US, 2012-2013). Inter-twin per cent difference was defined: ([Sizelarger twin  - Sizesmaller twin ]/Sizelarger twin  × 100). Linear mixed models evaluated per cent differences in foetal biometrics at 15 weeks and their change per week overall and by maternal/neonatal characteristics in unadjusted and adjusted models. RESULTS: In 140 pregnancies, inter-twin per cent differences increased across gestation for EFW (0.18%/week, 95% confidence interval [CI] 0.10, 0.27), HC (0.03%/week, 95% CI 0.00, 0.06), and AC (0.03%/week, 95%CI -0.01, 0.08) but decreased for FL (-0.03%/week, 95% CI -0.09, 0.02). After adjustment, change in EFW% difference across gestation differed by pre-pregnancy body mass index (BMI [kg/m2 ]; underweight [<18.5]; normal weight [18.5-24.9]; overweight [25.0-29.9]; obese [≥30.0]; Pinteraction  = .022); and conception method (in vitro fertilisation [IVF], intrauterine insemination, ovulation induction medication, donor egg/embryo, none; Pinteraction  = .060). While EFW% difference increased with normal pre-pregnancy BMI (0.24%/week, 95% CI 0.12, 0.37), little change was noted with pre-pregnancy obesity (0.01%/week, 95% CI -0.15, 0.17). EFW% difference increased in conceptions without fertility treatments (0.23%/week, 95% CI 0.11, 0.34) but not IVF conceptions (-0.00%/week, 95% CI -0.16, 0.16). Similar patterns of differences across gestation were noted for HC% by conception method (Pinteraction  = .026) and AC% by pre-pregnancy BMI (Pinteraction  = .071); changes in HC% differed by parity (nulliparous, multiparous; Pinteraction  = .004). CONCLUSIONS: EFW% difference increased across gestation in dichorionic twins, but remained stable with pre-pregnancy obesity or IVF conception, patterns mirrored for HC and AC. Research is needed to understand pathologic versus physiologic differential twin growth trajectories.

In utero effects of maternal phthalate exposure on male genital development.

BACKGROUND: Phthalates are used extensively in commercial and personal care products and maternal exposure is ubiquitous. Phthalates are anti-androgenic, but the potential effects of phthalates on male penile development have not been assessed in utero. OBJECTIVE: The study aims to investigate the association between early pregnancy phthalate exposure and fetal penile development, overall and by race. METHODS: Prospective cohort study of women with singleton pregnancies presenting for prenatal ultrasound between 18 and 22 weeks' gestation. Maternal urine samples were assayed for eight phthalate monoester metabolites. We used maternal phthalate levels at 18 to 22 weeks' gestation as predictors of fetal size using multiple linear regression models, adjusted for fetal gestational age, maternal age, race, smoking, and education. We incorporated a phthalate by race interaction into a second set of regression models. RESULTS: We detected statistically significant race interactions for continuous phthalates with penile width. Race interactions were also suggested for penile length and volume using tertiles of phthalates with point estimates generally positive for whites and negative for African Americans. CONCLUSION: Penile development is significantly influenced by race, and the impact of maternal phthalates on penile measurements also varies by race. Maternal phthalate exposure can adversely affect in utero penile growth and development, especially among African Americans.

Longitudinal changes in maternal anthropometry in relation to neonatal anthropometry.

OBJECTIVE: To characterize the association of longitudinal changes in maternal anthropometric measures with neonatal anthropometry and to assess to what extent late-gestational changes in maternal anthropometry are associated with neonatal body composition. DESIGN: In a prospective cohort of pregnant women, maternal anthropometry was measured at six study visits across pregnancy and after birth, neonates were measured and fat and lean mass calculated. We estimated maternal anthropometric trajectories and separately assessed rate of change in the second (15-28 weeks) and third trimester (28-39 weeks) in relation to neonatal anthropometry. We investigated the extent to which tertiles of third-trimester maternal anthropometry change were associated with neonatal outcomes. SETTING: Women were recruited from twelve US sites (2009-2013).ParticipantsNon-obese women with singleton pregnancies (n 2334). RESULTS: A higher rate of increase in gestational weight gain was associated with larger-birth-weight infants with greater lean and fat mass. In contrast, higher rates of increase in maternal anthropometry measures were not associated with infant birth weight but were associated with decreased neonatal lean mass. In the third trimester, women in the tertile of lowest change in triceps skinfold (-0·57 to -0·06 mm per week) had neonates with 35·8 g more lean mass than neonates of mothers in the middle tertile of rate of change (-0·05 to 0·06 mm per week). CONCLUSIONS: The rate of change in third-trimester maternal anthropometry measures may be related to neonatal lean and fat mass yet have a negligible impact on infant birth weight, indicating that neonatal anthropometry may provide additional information over birth weight alone.

Patterns of gestational weight gain and birthweight outcomes in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons: a prospective study.

BACKGROUND: Inadequate or excessive total gestational weight gain is associated with increased risks of small- and large-for-gestational-age births, respectively, but evidence is sparse regarding overall and trimester-specific patterns of gestational weight gain in relation to these risks. Characterizing the interrelationship between patterns of gestational weight gain across trimesters can reveal whether the trajectory of gestational weight gain in the first trimester sets the path for gestational weight gain in subsequent trimesters, thereby serving as an early marker for at-risk pregnancies. OBJECTIVE: We sought to describe overall trajectories of gestational weight gain across gestation and assess the risk of adverse birthweight outcomes associated with the overall trajectory and whether the timing of gestational weight gain (first vs second/third trimester) is differentially associated with adverse outcomes. STUDY DESIGN: We conducted a secondary analysis of a prospective cohort of 2802 singleton pregnancies from 12 US prenatal centers (2009 through 2013). Small and large for gestational age were calculated using sex-specific birthweight references <5th, <10th, or ≥90th percentiles, respectively. At each of the research visits, women's weight was measured following a standardized anthropometric protocol. Maternal weight at antenatal clinical visits was also abstracted from the prenatal records. Semiparametric, group-based, latent class, trajectory models estimated overall gestational weight gain and separate first- and second-/third-trimester trajectories to assess tracking. Robust Poisson regression was used to estimate the relative risk of small- and large-for-gestational-age outcomes by the probability of trajectory membership. We tested whether relationships were modified by prepregnancy body mass index. RESULTS: There were 2779 women with a mean of 15 (SD 5) weights measured across gestation. Four distinct gestational weight gain trajectories were identified based on the lowest Bayesian information criterion value, classifying 10.0%, 41.8%, 39.2%, and 9.0% of the population from lowest to highest weight gain trajectories, with an inflection at 14 weeks. The average rate in each trajectory group from lowest to highest for 0-<14 weeks was -0.20, 0.04, 0.21, and 0.52 kg/wk and for 14-39 weeks was 0.29, 0.48, 0.63, and 0.79 kg/wk, respectively; the second lowest gaining trajectory resembled the Institute of Medicine recommendations and was designated as the reference with the other trajectories classified as low, moderate-high, or high. Accuracy of assignment was assessed and found to be high (median posterior probability 0.99, interquartile range 0.99-1.00). Compared with the referent trajectory, a low overall trajectory, but not other trajectories, was associated with a 1.55-fold (95% confidence interval, 1.06-2.25) and 1.58-fold (95% confidence interval, 0.88-2.82) increased risk of small-for-gestational-age <10th and <5th, respectively, while a moderate-high and high trajectory were associated with a 1.78-fold (95% confidence interval, 1.31-2.41) and 2.45-fold (95% confidence interval, 1.66-3.61) increased risk of large for gestational age, respectively. In a separate analysis investigating whether early (<14 weeks) gestational weight gain tracked with later (≥14 weeks) gestational weight gain, only 49% (n = 127) of women in the low first-trimester trajectory group continued as low in the second/third trimester, and had a 1.59-fold increased risk of small for gestational age; for the other 51% (n = 129) of women without a subsequently low second-/third-trimester gestational weight gain trajectory, there was no increased risk of small for gestational age (relative risk, 0.75; 95% confidence interval, 0.47-1.38). Prepregnancy body mass index did not modify the association between gestational weight gain trajectory and small for gestational age (P = 0.52) or large for gestational age (P = .69). CONCLUSION: Our findings are reassuring for women who experience weight loss or excessive weight gain in the first trimester; however, the risk of small or large for gestational age is significantly increased if women gain weight below or above the reference trajectory in the second/third trimester.

Dichorionic twin trajectories: the NICHD Fetal Growth Studies.

BACKGROUND: Systematic evaluation and estimation of growth trajectories in twins require ultrasound measurements across gestation that are performed in controlled clinical settings. Currently, there are few such data for contemporary populations. There is also controversy about whether twin fetal growth should be evaluated with the use of the same benchmarks as singleton growth. OBJECTIVES: Our objective was to define the trajectory of fetal growth in dichorionic twins empirically using longitudinal 2-dimensional ultrasonography and to compare the fetal growth trajectories for dichorionic twins with those based on a growth standard that was developed by our group for singletons. STUDY DESIGN: A prospective cohort of 171 women with twin gestations was recruited from 8 US sites from 2012-2013. After an initial sonogram at 11 weeks 0 days-13 weeks 6 days of gestation during which dichorionicity was confirmed, women were assigned randomly to 1 of 2 serial ultrasonography schedules. Growth curves and percentiles were estimated with the use of linear mixed models with cubic splines. Percentiles were compared statistically at each gestational week between the twins and 1731 singletons, after adjustment for maternal age, race/ethnicity, height, weight, parity, employment, marital status, insurance, income, education, and infant sex. Linear mixed models were used to test for overall differences between the twin and singleton trajectories with the use of likelihood ratio tests of interaction terms between spline mean structure terms and twin-singleton indicator variables. Singleton standards were weighted to correspond to the distribution of maternal race in twins. For those ultrasound measurements in which there were significant global tests for differences between twins and singletons, we tested for week-specific differences using Wald tests that were computed at each gestational age. In a separate analysis, we evaluated the degree of reclassification in small for gestational age, which was defined as <10th percentile that would be introduced if fetal growth estimation for twins was based on an unweighted singleton standard. RESULTS: Women underwent a median of 5 ultrasound scans. The 50th percentile abdominal circumference and estimated fetal weight trajectories of twin fetuses diverged significantly beginning at 32 weeks of gestation; biparietal diameter in twins was smaller from 34-36 weeks of gestation. There were no differences in head circumference or femur length. The mean head circumference/abdominal circumference ratio was progressively larger for twins compared with singletons beginning at 33 weeks of gestation, which indicated a comparatively asymmetric growth pattern. At 35 weeks of gestation, the average gestational age at delivery for twins, the estimated fetal weights for the 10th, 50th, and 90th percentiles were 1960, 2376, and 2879 g for dichorionic twins, respectively, and 2180, 2567, and 3022 g for the singletons, respectively. At 32 weeks of gestation, the initial week when the mean estimated fetal weight for twins was smaller than that of singletons, 34% of twins would be classified as small for gestational age with the use of a singleton, non-Hispanic white standard. By 35 weeks of gestation, 38% of twins would be classified as small for gestational age. CONCLUSION: The comparatively asymmetric growth pattern in twin gestations, initially evident at 32 weeks of gestation, is consistent with the concept that the intrauterine environment becomes constrained in its ability to sustain growth in twin fetuses. Near term, nearly 40% of twins would be classified as small for gestational age based on a singleton growth standard.