Fetal and Maternal Factors Predictive of Primary Cesarean Delivery at Term in a Low-Risk Population: NICHD Fetal Growth Studies-Singletons.

OBJECTIVE: This study aimed to examine associations of fetal biometric and amniotic fluid measures with intrapartum primary cesarean delivery (PCD) and develop prediction models for PCD based on ultrasound parameters and maternal factors. STUDY DESIGN: Secondary analysis of the National Institute of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-singleton cohort (2009-2013) including patients with uncomplicated pregnancies and intent to deliver vaginally at ≥370/7 weeks. The estimated fetal weight, individual biometric parameters, fetal asymmetry measurements, and amniotic fluid single deepest vertical pocket assessed at the final scan (mean 37.5 ± 1.9 weeks) were categorized as <10th, 10th to 90th (reference), and >90th percentiles. Logistic regression analyses examined the association between the ultrasound measures and PCD. Fetal and maternal SuperLearner prediction algorithms were constructed for the full and nulliparous cohorts. RESULTS: Of the 1,668 patients analyzed, 249 (14.9%) had PCD. The fetal head circumference, occipital-frontal diameter, and transverse abdominal diameter >90th percentile (adjusted odds ratio [aOR] = 2.50, 95% confidence interval [95% CI]: 1.39, 4.51; aOR = 1.86, 95% CI: 1.02, 3.40; and aOR = 2.13, 95% CI: 1.16, 3.89, respectively) were associated with PCD. The fetal model demonstrated poor ability to predict PCD in the full cohort and in nulliparous patients (area under the receiver-operating characteristic curve [AUC] = 0.56, 95% CI: 0.52, 0.61; and AUC = 0.54, 95% CI: 0.49, 0.60, respectively). Conversely, the maternal model had better predictive capability overall (AUC = 0.79, 95% CI: 0.75, 0.82) and in the nulliparous subgroup (AUC = 0.72, 95% CI: 0.67, 0.77). Models combining maternal/fetal factors performed similarly to the maternal model (AUC = 0.78, 95% CI: 0.75, 0.82 in full cohort, and AUC = 0.71, 95% CI: 0.66, 0.76 in nulliparas). CONCLUSION: Although a few fetal biometric parameters were associated with PCD, the fetal prediction model had low performance. In contrast, the maternal model had a fair-to-good ability to predict PCD. KEY POINTS: · Fetal HC >90th percentile was associated with cesarean delivery.. · Fetal parameters did not effectively predict PCD.. · Maternal factors were more predictive of PCD.. · Maternal/fetal and maternal models performed similarly.. · Prediction models had lower performance in nulliparas..

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.

Comparing Fetal Ultrasound Biometric Measurements to Neonatal Anthropometry at the Extremes of Birthweight.

OBJECTIVE: Error in birthweight prediction by sonographic estimated fetal weight (EFW) has clinical implications, such as avoidable cesarean or misclassification of fetal risk in labor. We aimed to evaluate optimal timing of ultrasound and which fetal measurements contribute to error in fetal ultrasound estimations of birth size at the extremes of birthweight. STUDY DESIGN: We compared differences in head circumference (HC), abdominal circumference (AC), femur length, and EFW between ultrasound and corresponding birth measurements within 14 (n = 1,290) and 7 (n = 617) days of birth for small- (SGA, <10th percentile), appropriate- (AGA, 10th-90th), and large-for-gestational age (LGA, >90th) newborns. RESULTS: Average differences between EFW and birthweight for SGA neonates were: -40.2 g (confidence interval [CI]: -82.1, 1.6) at 14 days versus 13.6 g (CI: -52.4, 79.7) at 7 days; for AGA, -122.4 g (-139.6, -105.1) at 14 days versus -27.2 g (-50.4, -4.0) at 7 days; and for LGA, -242.8 g (-306.5, -179.1) at 14 days versus -72.1 g (-152.0, 7.9) at 7 days. Differences between fetal and neonatal HC were larger at 14 versus 7 days, and similar to patterns for EFW and birthweight, differences were the largest for LGA at both intervals. In contrast, differences between fetal and neonatal AC were larger at 7 versus 14 days, suggesting larger error in AC estimation closer to birth. CONCLUSION: Using a standardized ultrasound protocol, SGA neonates had ultrasound measurements closer to actual birth measurements compared with AGA or LGA neonates. LGA neonates had the largest differences between fetal and neonatal size, with measurements 14 days from delivery showing 3- to 4-fold greater differences from birthweight. Differences in EFW and birthweight may not be explained by a single fetal measurement; whether estimation may be improved by incorporation of other knowable factors should be evaluated in future research. KEY POINTS: · Ultrasound measurements may be inadequate to predict neonatal size at birth.. · Birthweight estimation error is higher for neonates >90th percentile.. · There is higher error in AC closer to birth..

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.

Placental accelerated aging in antenatal depression.

BACKGROUND: Antenatal maternal depression is associated with poor pregnancy outcomes and long-term effects on the offspring. Previous studies have identified links between antenatal depression and placental DNA methylation and between placental epigenetic aging and poor pregnancy outcomes, such as preterm labor and preeclampsia. The relationship between antenatal depression and poor pregnancy outcomes may be partly mediated via placental aging. OBJECTIVE: This study aimed to investigate whether antenatal depressive symptoms are associated with placental epigenetic age acceleration, an epigenetic aging clock measure derived from the difference between methylation age and gestational age at delivery. STUDY DESIGN: The study included 301 women who provided placenta samples at delivery as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies - Singletons that recruited participants from diverse race and ethnic groups at 12 US clinical sites (2009-2013). Women underwent depression screening using the Edinburgh Postnatal Depression Scale up to 6 times across the 3 trimesters of pregnancy. Depressive symptoms status was determined for each pregnancy trimester using an Edinburgh Postnatal Depression Scale score, in which a score of ≥10 was defined as having depressive symptoms and a score of <10 was defined as not having depressive symptoms. Placental DNA methylation was profiled from placenta samples. Placental epigenetic age was estimated using a methylation-based age estimator (placental "epigenetic clock") that has previously been found to have high placental gestational age prediction accuracy for uncomplicated term pregnancies. Placental age acceleration was defined to be the residual upon regressing the estimated epigenetic age on gestational age at delivery. Associations between an Edinburgh Postnatal Depression Scale score of ≥10 and an Edinburgh Postnatal Depression Scale score of <10 in the first, second, and third trimesters of pregnancy (ie, depressive symptoms vs none in each trimester) and placental age acceleration were tested using multivariable linear regression adjusting for maternal age, parity, race and ethnicity, and employment. RESULTS: There were 31 (10.3%), 48 (16%), and 49 (16.4%) women with depressive symptoms (ie, Edinburgh Postnatal Depression Scale score of ≥10) in the first, second, and third trimesters of pregnancy, respectively. Of these women, 21 (7.2%) had sustained first- and second-trimester depressive symptoms, 19 (7%) had sustained second- and third-trimester depressive symptoms, and 12 (4.8%) had sustained depressive symptoms throughout pregnancy. Women with depressive symptoms in the second trimester of pregnancy had 0.41 weeks higher placental age acceleration than women without depressive symptoms during the second trimester of pregnancy (ß=0.21 weeks [95% confidence interval, -0.17 to 0.58; P=.28] during the first trimester of pregnancy; ß=0.41 weeks [95% confidence interval, 0.10-0.71; P=.009] during the second trimester of pregnancy; ß=0.17 weeks [95% confidence interval, -0.14 to 0.47; P=.29] during the third trimester of pregnancy). Sustained first- and second-trimester depressive symptoms were associated with 0.72 weeks higher placental age acceleration (95% confidence interval, 0.29-1.15; P=.001) than no depressive symptom in the 2 trimesters. The association between second-trimester depressive symptoms and higher placental epigenetic age acceleration strengthened in the analysis of pregnancies with male fetuses (ß=0.53 weeks; 95% confidence interval, 0.06-1.08; P=.03) but was not significant in pregnancies with female fetuses. CONCLUSION: Antenatal depressive symptoms during the second trimester of pregnancy were associated with an average of 0.41 weeks of increased placental age acceleration. Accelerated placental aging may play an important role in the underlying mechanism linking antenatal depression to pregnancy complications related to placental dysfunction.

The NICHD Fetal 3D Study: A Pregnancy Cohort Study of Fetal Body Composition and Volumes.

There's a paucity of robust normal fractional limb and organ volume standards from a large and diverse ethnic population. The Fetal 3D Study was designed to develop research and clinical applications for fetal soft tissue and organ volume assessment. The NICHD Fetal Growth Studies (2009-2013) collected 2D and 3D fetal volumes. In the Fetal 3D Study (2015-2019), sonographers performed longitudinal 2D and 3D measurements for specific fetal anatomical structures in research ultrasounds of singletons and dichorionic twins. The primary aim was to establish standards for fetal body composition and organ volumes, overall and by maternal race/ethnicity, and determine whether these standards vary for twins versus singletons. We describe the study design, methods, and details about reviewer training. Basic characteristics of this cohort, with their corresponding distributions of fetal 3D measurements by anatomical structure, are summarized. This investigation is responsive to critical data gaps in understanding serial changes in fetal subcutaneous fat, lean body mass, and organ volume in association with pregnancy complications. In the future, this cohort can answer critical questions regarding the potential influence of maternal characteristics, lifestyle factors, nutrition, and biomarker and chemical data on longitudinal measures of fetal subcutaneous fat, lean body mass, and organ volumes.

History of multifetal gestation and long-term maternal mortality.

BACKGROUND: Multifetal gestation could be associated with higher long-term maternal mortality because it increases the risk of pregnancy complications such as preeclampsia and preterm birth, which are in turn linked to postpartum cardiovascular risk. OBJECTIVES: We examined whether spontaneously conceived multifetal versus singleton gestation was associated with long-term maternal mortality in a racially diverse U.S. METHODS: We ascertained vital status as of 2016 via linkage to the National Death Index and Social Security Death Master File of 44,174 mothers from the Collaborative Perinatal Project (CPP; 1959-1966). Cox proportional hazards models with maternal age as the time scale assessed associations between history of spontaneous multifetal gestation (in the last CPP observed pregnancy or prior pregnancy) and all-cause and cardiovascular mortality, adjusted for demographics, smoking status, and preexisting medical conditions. We calculated hazard ratios (HR) for all-cause and cause-specific mortality over the study period and until age 50, 60, and 70 years (premature mortality). RESULTS: Of eligible participants, 1672 (3.8%) had a history of multifetal gestation. Participants with versus without a history of multifetal gestation were older, more likely to have a preexisting condition, and more likely to smoke. By 2016, 51% of participants with and 38% of participants without a history of multifetal gestation had died (unadjusted all-cause HR 1.14, 95% confidence interval [CI] 1.07, 1.23). After adjustment for smoking and preexisting conditions, a history of multifetal gestation was not associated with all-cause (adjusted HR 1.00, 95% CI 0.93, 1.08) or cardiovascular mortality (adjusted HR 0.99, 95% CI 0.87, 1.11) over the study period. However, history of multifetal gestation was associated with an 11% lower risk of premature all-cause mortality (adjusted HR 0.89, 95% CI 0.82, 0.96). CONCLUSIONS: In a cohort with over 50 years of follow-up, history of multifetal gestation was not associated with all-cause mortality, but may be associated with a lower risk of premature mortality.

Comparing population-based fetal growth standards in a US cohort.

BACKGROUND: No fetal growth standard is currently endorsed for universal use in the United States. Newer standards improve upon the methodologic limitations of older studies; however, before adopting into practice, it is important to know how recent standards perform at identifying fetal undergrowth or overgrowth and at predicting subsequent neonatal morbidity or mortality in US populations. OBJECTIVE: To compare classification of estimated fetal weight that is <5th or 10th percentile or >90th percentile by 6 population-based fetal growth standards and the ability of these standards to predict a composite of neonatal morbidity and mortality. STUDY DESIGN: We used data from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be cohort, which recruited nulliparous women in the first trimester at 8 US clinical centers (2010-2014). Estimated fetal weight was obtained from ultrasounds at 16 to 21 and 22 to 29 weeks of gestation (N=9534 women). We calculated rates of fetal growth restriction (estimated fetal weight <5th and 10th percentiles; fetal growth restriction<5 and fetal growth restriction<10) and estimated fetal weight >90th percentile (estimated fetal weight>90) from 3 large prospective fetal growth cohorts with similar rigorous methodologies: INTERGROWTH-21, World Health Organization-sex-specific and combined, Eunice Kennedy Shriver National Institute of Child Health and Human Development race-ethnic-specific and unified, and the historic Hadlock reference. To determine whether differential classification of fetal growth restriction or estimated fetal weight >90 among standards was clinically meaningful, we then compared area under the curve and sensitivity of each standard to predict small for gestational age or large for gestational age at birth, composite perinatal morbidity and mortality alone, and small for gestational age or large for gestational age with composite perinatal morbidity and mortality. RESULTS: The standards classified different proportions of fetal growth restriction and estimated fetal weight>90 for ultrasounds at 16 to 21 (visit 2) and 22 to 29 (visit 3) weeks of gestation. At visit 2, the Eunice Kennedy Shriver National Institute of Child Health and Human Development race-ethnic-specific, World Health Organization sex-specific and World Health Organization-combined identified similar rates of fetal growth restriction<10 (8.4%-8.5%) with the other 2 having lower rates, whereas Eunice Kennedy Shriver National Institute of Child Health and Human Development race-ethnic-specific identified the highest rate of fetal growth restriction<5 (5.0%) compared with the other references. At visit 3, World Health Organization sex-specific classified 9.2% of fetuses as fetal growth restriction<10, whereas the other 5 classified a lower proportion as follows: World Health Organization-combined (8.4%), Eunice Kennedy Shriver National Institute of Child Health and Human Development race-ethnic-specific (7.7%), INTERGROWTH (6.2%), Hadlock (6.1%), and Eunice Kennedy Shriver National Institute of Child Health and Human Development unified (5.1%). INTERGROWTH classified the highest (21.3%) as estimated fetal weight>90 whereas Hadlock classified the lowest (8.3%). When predicting composite perinatal morbidity and mortality in the setting of early-onset fetal growth restriction, World Health Organization had the highest area under the curve of 0.53 (95% confidence interval, 0.51-0.53) for fetal growth restriction<10 at 22 to 29 weeks of gestation, but the areas under the curve were similar among standards (0.52). Sensitivity was generally low across standards (22.7%-29.1%). When predicting small for gestational age birthweight with composite neonatal morbidity or mortality, for fetal growth restriction<10 at 22 to 29 weeks of gestation, World Health Organization sex-specific had the highest area under the curve (0.64; 95% confidence interval, 0.60-0.67) and INTERGROWTH had the lowest (area under the curve=0.58; 95% confidence interval 0.55-0.62), though all standards had low sensitivity (7.0%-9.6%). CONCLUSION: Despite classifying different proportions of fetuses as fetal growth restriction or estimated fetal weight>90, all standards performed similarly in predicting perinatal morbidity and mortality. Classification of different percentages of fetuses as fetal growth restriction or estimated fetal weight>90 among references may have clinical implications in the management of pregnancies, such as increased antenatal monitoring for fetal growth restriction or cesarean delivery for suspected large for gestational age. Our findings highlight the importance of knowing how standards perform in local populations, but more research is needed to determine if any standard performs better at identifying the risk of morbidity or mortality.

Gestational weight change in a diverse pregnancy cohort and mortality over 50 years: a prospective observational cohort study.

BACKGROUND: High weight gain in pregnancy is associated with greater postpartum weight retention, yet long-term implications remain unknown. We aimed to assess whether gestational weight change was associated with mortality more than 50 years later. METHODS: The Collaborative Perinatal Project (CPP) was a prospective US pregnancy cohort (1959-65). The CPP Mortality Linkage Study linked CPP participants to the National Death Index and Social Security Death Master File for vital status to 2016. Adjusted hazard ratios (HRs) with 95% CIs estimated associations between gestational weight gain and loss according to the 2009 National Academy of Medicine recommendations and mortality by pre-pregnancy BMI. The primary endpoint was all-cause mortality. Secondary endpoints included cardiovascular and diabetes underlying causes of mortality. FINDINGS: Among 46 042 participants, 20 839 (45·3%) self-identified as Black and 21 287 (46·2%) as White. Median follow-up time was 52 years (IQR 45-54) and 17 901 (38·9%) participants died. For those who were underweight before pregnancy (BMI <18·5 kg/m2; 3809 [9·4%] of 40 689 before imputation for missing data]), weight change above recommendations was associated with increased cardiovascular mortality (HR 1·84 [95% CI 1·08-3·12]) but not all-cause mortality (1·14 [0·86-1·51]) or diabetes-related mortality (0·90 [0·13-6·35]). For those with a normal pre-pregnancy weight (BMI 18·5-24·9 kg/m2; 27 921 [68·6%]), weight change above recommendations was associated with increased all-cause (HR 1·09 [1·01-1·18]) and cardiovascular (1·20 [1·04-1·37]) mortality, but not diabetes-related mortality (0·95 [0·61-1·47]). For those who were overweight pre-pregnancy (BMI 25·0-29·9 kg/m2; 6251 [15·4%]), weight change above recommendations was associated with elevated all-cause (1·12 [1·01-1·24]) and diabetes-related (1·77 [1·23-2·54]) mortality, but not cardiovascular (1·12 [0·94-1·33]) mortality. For those with pre-pregnancy obesity (≥30·0 kg/m2; 2708 [6·7%]), all associations between gestational weight change and mortality had wide CIs and no meaningful relationships could be drawn. Weight change below recommended levels was associated only with a reduced diabetes-related mortality (0·62 [0·48-0·79]) in people with normal pre-pregnancy weight. INTERPRETATION: This study's novel findings support the importance of achieving healthy gestational weight gain within recommendations, adding that the implications might extend beyond the pregnancy window to long-term health, including cardiovascular and diabetes-related mortality. FUNDING: National Institutes of Health.

Longitudinal Child Growth Patterns in Twins and Singletons in the Upstate KIDS Cohort.

OBJECTIVES: To investigate childhood growth patterns in twins and to determine whether they show the same signs of excess growth as singletons born small-for-gestational age (SGA), which may confer future cardiometabolic risk. STUDY DESIGN: In the Upstate KIDS cohort of infants delivered from 2008 through 2010, we compared height, weight, and body mass index (BMI) z-scores at 0-3 and 7-9 years of age, as well as risk of rapid weight gain (RWG) in infancy and overweight/obesity beginning at 2 years, among appropriate-for-gestational age (AGA) twins (n = 1121), AGA singletons (n = 2684), and two groups of SGA twins: uncertain SGA twins (<10th percentile for birthweight by a singleton reference but >10th% by a population-based twin birthweight reference; n = 319) and true SGA twins (<10th% by a population-based twin reference; n = 144). RESULTS: Compared with AGA twins, both SGA twin groups had lower weight and BMI z-scores at both time points. By 7-9 years, both groups caught up in height with AGA twins. Compared with AGA singletons, z-score differences decreased between 0-3 and 7-9 years for uncertain SGA and true SGA twins, though true SGA twins had the lowest z-scores for all measures. During infancy, twins were more likely to display RWG compared with AGA singletons (RR = 2.06 to 2.67), which may reflect normal catch-up growth, as no twin group had higher prevalence of overweight/obesity at either time point. CONCLUSIONS: Though twins had lower height, weight, and BMI z-scores at birth and into toddlerhood, differences were reduced by 7-9 years, with no evidence of pathological growth and no group of twins showing elevated risk of overweight/obesity.

Associations of Pregnancy Per- and Polyfluoroalkyl Substance Concentrations and Uterine Fibroid Changes across Pregnancy: NICHD Fetal Growth Studies - Singletons Cohort.

BACKGROUND: Fibroids (hormonally responsive benign tumors) often undergo volume changes in pregnancy. Because per- and polyfluoroalkyl substances (PFAS) disrupt hormonal signaling, they might affect fibroid growth. We assessed associations between PFAS and fibroid changes in pregnancy. METHODS: We analyzed seven PFAS, including perfluorohexanesulfonic acid (PFHxS), perfluorooctanesulfonic acid (PFOS), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA), in plasma collected at 10-13 wk gestation from 2,621 women in the NICHD Fetal Growth Studies - Singletons cohort (2009-2013). Sonographers recorded fibroid number and volume of the three largest fibroids during up to six timed ultrasounds. Generalized linear models assessed associations of baseline log2-transformed PFAS and fibroid number, volume, and presence, and weighted quantile sum regression evaluated the PFAS mixture. Generalized linear mixed models with random intercepts assessed associations of PFAS and longitudinal fibroid number and total volume. Volume analyses were stratified by total volume at first visualization [equivalent to a fibroid <1cm (small), 1 to<3cm (medium), or ≥3cm (large) in diameter]. RESULTS: Fibroid prevalence was 9.4% (n=245 women). PFAS were not associated with changes in fibroid number, but were associated with volume trajectory, depending on baseline volume. Among women with small volume, PFAS were associated with fibroid growth: Each doubling in PFHxS and PFOS concentrations was associated with 3.6% [95% confidence interval (CI): 0.2, 7.0 and 5.2% (95% CI: -0.4, 11.1)] greater weekly fibroid growth, respectively. Among women with medium volume, PFAS were associated with shrinking: Doublings in PFOS, PFDA, and PFUnDA concentrations were associated with 1.9% (95% CI: 0.4, 3.3), 1.2% (95% CI: 0.1, 2.4), and 1.6% (95% CI: 0.4, 2.8) greater weekly fibroid volume reduction, respectively. DISCUSSION: Certain PFAS were associated with fibroid growth among women with small fibroids and decreases among women with medium fibroids. PFAS were not associated with fibroid prevalence or number; therefore, PFAS may influence prevalent fibroids rather than initiating fibroid development. https://doi.org/10.1289/EHP11606.

The Association of Periconception Asthma Medication Discontinuation with Adverse Obstetric Outcomes.

OBJECTIVE: This study aimed to investigate asthma medication reduction in the periconceptional period as it relates to asthma status and adverse outcomes in pregnancy. STUDY DESIGN: In a prospective cohort study, self-reported current and past asthma medications were collected and analyzes compared measures of asthma status in women who discontinued asthma medication in the 6 months prior to enrollment ("step-down") versus those who did not ("no change"). Evaluation of asthma was done at three study visits (one per trimester) and by daily diaries, including measures of lung function (percent predicted forced expiratory volume in 1 and 6 s [%FEV1, %FEV6], peak expiratory flow [%PEF], forced vital capacity [%FVC], FEV1 to FVC ratio [FEV1/FVC]), lung inflammation (fractional exhaled nitric oxide [FeNO], ppb), rate of asthma symptoms (activity limitation, night symptoms, rescue inhaler use, wheeze, shortness of breath, cough, chest tightness, chest pain), and rate of asthma exacerbations. Adverse pregnancy outcomes were also evaluated. Adjusted regression analyses examined whether adverse outcomes differed by periconceptional asthma medication changes. RESULTS: Of 279 participants included in analyses, 135 (48.4%) did not change asthma medication in the periconceptional period, whereas 144 (51.6%) reported a step down in medication. Those in the step-down group were more likely to have milder disease (88 [61.1%] in the step-down vs. 74 [54.8%] in the no change group), exhibited less activity limitation (rate ratio [RR]: 0.68, 95% confidence interval [CI]: 0.47-0.98), and experienced fewer asthma attacks (RR: 0.53, 95% CI: 0.34-0.84) during pregnancy. The step-down group had a nonsignificant increase in overall odds of experiencing an adverse pregnancy outcome (odds ratio: 1.62, 95% CI: 0.97-2.72). CONCLUSION: Over half of women with asthma reduce asthma medication in the periconceptional period. Although these women typically have milder disease, a step down in medication may be associated with an increased risk of adverse pregnancy outcomes. KEY POINTS: · Many women reduce their asthma medication in pregnancy.. · Reduction is more common among those with mild disease.. · Medication reduction may lead to adverse pregnancy outcomes..

A new method for customized fetal growth reference percentiles.

BACKGROUND: Customized fetal growth charts assume birthweight at term to be normally distributed across the population with a constant coefficient of variation at earlier gestational ages. Thus, standard deviation used for computing percentiles (e.g., 10th, 90th) is assumed to be proportional to the customized mean, although this assumption has never been formally tested. METHODS: In a secondary analysis of NICHD Fetal Growth Studies-Singletons (12 U.S. sites, 2009-2013) using longitudinal sonographic biometric data (n = 2288 pregnancies), we investigated the assumptions of normality and constant coefficient of variation by examining behavior of the mean and standard deviation, computed following the Gardosi method. We then created a more flexible model that customizes both mean and standard deviation using heteroscedastic regression and calculated customized percentiles directly using quantile regression, with an application in a separate study of 102, 012 deliveries, 37-41 weeks. RESULTS: Analysis of term optimal birthweight challenged assumptions of proportionality and that values were normally distributed: at different mean birthweight values, standard deviation did not change linearly with mean birthweight and the percentile computed with the normality assumption deviated from empirical percentiles. Composite neonatal morbidity and mortality rates in relation to birthweight < 10th were higher for heteroscedastic and quantile models (10.3% and 10.0%, respectively) than the Gardosi model (7.2%), although prediction performance was similar among all three (c-statistic 0.52-0.53). CONCLUSIONS: Our findings question normality and constant coefficient of variation assumptions of the Gardosi customization method. A heteroscedastic model captures unstable variance in customization characteristics which may improve detection of abnormal growth percentiles. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00912132.

Pregnancy Complications and Long-Term Mortality in a Diverse Cohort.

BACKGROUND: Pregnancy complications are associated with increased risk of development of cardiometabolic diseases and earlier mortality. However, much of the previous research has been limited to White pregnant participants. We aimed to investigate pregnancy complications in association with total and cause-specific mortality in a racially diverse cohort and evaluate whether associations differ between Black and White pregnant participants. METHODS: The Collaborative Perinatal Project was a prospective cohort study of 48 197 pregnant participants at 12 US clinical centers (1959-1966). The Collaborative Perinatal Project Mortality Linkage Study ascertained participants' vital status through 2016 with linkage to the National Death Index and Social Security Death Master File. Adjusted hazard ratios (aHRs) for underlying all-cause and cause-specific mortality were estimated for preterm delivery (PTD), hypertensive disorders of pregnancy, and gestational diabetes/impaired glucose tolerance (GDM/IGT) using Cox models adjusted for age, prepregnancy body mass index, smoking, race and ethnicity, previous pregnancies, marital status, income, education, previous medical conditions, site, and year. RESULTS: Among 46 551 participants, 45% (21 107 of 46 551) were Black, and 46% (21 502 of 46 551) were White. The median time between the index pregnancy and death/censoring was 52 years (interquartile range, 45-54). Mortality was higher among Black (8714 of 21 107 [41%]) compared with White (8019 of 21 502 [37%]) participants. Overall, 15% (6753 of 43 969) of participants had PTD, 5% (2155 of 45 897) had hypertensive disorders of pregnancy, and 1% (540 of 45 890) had GDM/IGT. PTD incidence was higher in Black (4145 of 20 288 [20%]) compared with White (1941 of 19 963 [10%]) participants. The following were associated with all-cause mortality: preterm spontaneous labor (aHR, 1.07 [95% CI, 1.03-1.1]); preterm premature rupture of membranes (aHR, 1.23 [1.05-1.44]); preterm induced labor (aHR, 1.31 [1.03-1.66]); preterm prelabor cesarean delivery (aHR, 2.09 [1.75-2.48]) compared with full-term delivery; gestational hypertension (aHR, 1.09 [0.97-1.22]); preeclampsia or eclampsia (aHR, 1.14 [0.99-1.32]) and superimposed preeclampsia or eclampsia (aHR, 1.32 [1.20-1.46]) compared with normotensive; and GDM/IGT (aHR, 1.14 [1.00-1.30]) compared with normoglycemic. P values for effect modification between Black and White participants for PTD, hypertensive disorders of pregnancy, and GDM/IGT were 0.009, 0.05, and 0.92, respectively. Preterm induced labor was associated with greater mortality risk among Black (aHR, 1.64 [1.10-2.46]) compared with White (aHR, 1.29 [0.97-1.73]) participants, while preterm prelabor cesarean delivery was higher in White (aHR, 2.34 [1.90-2.90]) compared with Black (aHR, 1.40 [1.00-1.96]) participants. CONCLUSIONS: In this large, diverse US cohort, pregnancy complications were associated with higher mortality nearly 50 years later. Higher incidence of some complications in Black individuals and differential associations with mortality risk suggest that disparities in pregnancy health may have life-long implications for earlier mortality.

Leiomyomata, neonatal anthropometry, and pregnancy outcomes in singleton pregnancies.

PURPOSE: To investigate the relationship of fibroids in pregnancy, preterm birth, and neonatal anthropometry. METHODS: Pregnant women (n = 2578) in the National Institute of Child Health and Human Development Fetal Growth Studies-Singletons cohort had up to six ultrasounds across pregnancy. Sonographers recorded fibroid number and volume of the three largest fibroids. Trained personnel measured neonatal anthropometry. Linear and logistic regression compared neonatal anthropometry and pregnancy outcomes among pregnancies with versus without fibroids. Causal mediation analysis evaluated preterm birth as a mediator. RESULTS: Average birthweight did not differ by fibroid status. However, compared with pregnancies without fibroids, neonates from pregnancies with single fibroids had 0.3- (95% confidence interval [CI], 0.0, 0.5) cm larger head circumferences; those with multiple fibroids had 0.3- (95% CI, 0.0, 0.6) cm larger arm circumferences; and those with small fibroid volume had 0.7- (95% CI, 0.3, 1.2) cm larger head, 0.4- (95% CI, 0.0, 0.8) cm larger arm, and 0.7- (95% CI, 0.1, 1.3) cm larger thigh circumferences. Presence versus absence of fibroids was associated with 1.73-2.65 times higher odds of preterm birth. Differences in preterm birth did not explain fibroid-anthropometry results. CONCLUSIONS: We found no evidence that fibroids negatively impacted fetal growth; instead, fibroids were associated with increased head, arm, and thigh circumferences. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00912132.

Prenatal social support in low-risk pregnancy shapes placental epigenome.

BACKGROUND: Poor social support during pregnancy has been linked to inflammation and adverse pregnancy and childhood health outcomes. Placental epigenetic alterations may underlie these links but are still unknown in humans. METHODS: In a cohort of low-risk pregnant women (n = 301) from diverse ethnic backgrounds, social support was measured using the ENRICHD Social Support Inventory (ESSI) during the first trimester. Placental samples collected at delivery were analyzed for DNA methylation and gene expression using Illumina 450K Beadchip Array and RNA-seq, respectively. We examined association between maternal prenatal social support and DNA methylation in placenta. Associated cytosine-(phosphate)-guanine sites (CpGs) were further assessed for correlation with nearby gene expression in placenta. RESULTS: The mean age (SD) of the women was 27.7 (5.3) years. The median (interquartile range) of ESSI scores was 24 (22-25). Prenatal social support was significantly associated with methylation level at seven CpGs (PFDR < 0.05). The methylation levels at two of the seven CpGs correlated with placental expression of VGF and ILVBL (PFDR < 0.05), genes known to be involved in neurodevelopment and energy metabolism. The genes annotated with the top 100 CpGs were enriched for pathways related to fetal growth, coagulation system, energy metabolism, and neurodevelopment. Sex-stratified analysis identified additional significant associations at nine CpGs in male-bearing pregnancies and 35 CpGs in female-bearing pregnancies. CONCLUSIONS: The findings suggest that prenatal social support is linked to placental DNA methylation changes in a low-stress setting, including fetal sex-dependent epigenetic changes. Given the relevance of some of these changes in fetal neurodevelopmental outcomes, the findings signal important methylation targets for future research on molecular mechanisms of effect of the broader social environment on pregnancy and fetal outcomes. TRIAL REGISTRATION: NCT00912132 ( ClinicalTrials.gov ).

Infant sex at birth and long-term maternal mortality.

BACKGROUND: Maternal adaptations may vary by foetal sex. Whether male infants influence long-term mortality in mothers remains uncertain. OBJECTIVE: The objective of the study was to examine whether male infants increase the risk of maternal mortality. METHODS: This study included pregnant women enrolled at 12 US sites from 1959 to 1966 in the Collaborative Perinatal Project (CPP). Collaborative Perinatal Project records were linked to the National Death Index and the Social Security Master Death File to ascertain deaths until 2016. Foetal sex was determined by infant sex at birth, defined as the total number of male or female infants in pregnancies prior to or during enrolment in the CPP. In secondary analyses, exposure was defined as infant sex at the last CPP delivery. Outcomes included all-cause and underlying causes of mortality. We used Cox proportional hazards models weighted by the number of prior live births and stratified our models by parity and race/ethnicity. RESULTS: Among 48,188 women, 50.8% had a male infant at their last registered CPP pregnancy and 39.0% had a recorded death after a mean follow-up of 47.8 years (SD 10.5 years). No linear association was found between the number of liveborn males and all-cause mortality (primipara women: HR 1.02, 95% CI 0.95, 1.09, multipara women, 1 prior live birth: HR 0.96, 95% CI 0.89, 1.03, multipara women, ≥2 prior live births: HR 0.97, 95% CI 0.85, 1.11). A similar trend was noted for cardiovascular- and cancer-related mortality. At the last delivery, women with a male infant did not have an increased risk of all-cause or cause-specific mortality compared to women with a female infant. These findings were consistent across racial/ethnic groups. CONCLUSIONS: Women who give birth to male infants, regardless of number, are not at increased risk of all-cause and cause-specific mortality. These findings suggest that giving birth to male infants may not independently influence the long-term health of women.

The association between first-trimester omega-3 fatty acid supplementation and fetal growth trajectories.

BACKGROUND: Prenatal omega-3 fatty acid supplementation, particularly docosahexaenoic acid and eicosapentaenoic acid, has been associated with greater birthweight in clinical trials; however, its effect on fetal growth throughout gestation is unknown. OBJECTIVE: This study aimed to examine the association between first-trimester docosahexaenoic acid and eicosapentaenoic acid supplementation and growth trajectories of estimated fetal weight and specific fetal biometrics measured longitudinally from the second trimester of pregnancy to delivery. STUDY DESIGN: In a multisite, prospective cohort of racially diverse, low-risk pregnant women, we used secondary data analysis to examine fetal growth trajectories in relation to self-reported (yes or no) first-trimester docosahexaenoic acid and eicosapentaenoic acid supplementation. Fetal ultrasonographic measurements, including abdominal circumference, biparietal diameter, femur length, head circumference, and humerus length, were measured at enrollment (8-13 weeks) and up to 5 follow-up visits. Estimated fetal weight and head circumference-to-abdominal circumference ratio (a measure of growth symmetry) were calculated. Fetal growth trajectories were modeled for each measure using a linear mixed model with cubic splines. If significant differences in fetal growth trajectories between groups were observed (global P<.05), weekly comparisons were performed to determine when in gestation these differences emerged. Analyses were adjusted for maternal sociodemographics, parity, infant sex, total energy consumption, and diet quality score. All analyses were repeated using dietary docosahexaenoic acid and eicosapentaenoic acid intake, dichotomized at the recommended cutoff for pregnant and lactating women (≥0.25 vs <0.25 g/d), among women who did not report supplement intake in the first trimester of pregnancy were repeated. RESULTS: Among 1535 women, 143 (9%) reported docosahexaenoic acid and eicosapentaenoic acid supplementation in the first trimester of pregnancy. Overall, first-trimester docosahexaenoic acid and eicosapentaenoic acid supplementation was associated with statistically significant differences (P-value <.05) in fetal growth trajectories during pregnancy. Specifically, estimated fetal weight was larger among women with docosahexaenoic acid and eicosapentaenoic acid supplementation than among those without supplementation (global P=.028) with significant weekly differences in median estimated fetal weight most apparent between 38 to 41 weeks of gestation (median estimated fetal weight difference at 40 weeks of gestation, 114 g). Differences in fetal growth trajectories for abdominal circumference (P=.003), head circumference (P=.003), and head circumference-to-abdominal circumference ratio (P=.0004) were also identified by supplementation status. In weekly comparisons, docosahexaenoic acid and eicosapentaenoic acid supplement use was associated with larger median abdominal circumference (changed from 2 to 9 mm) in midpregnancy onward (19 to 41 weeks), larger median head circumference between 30 to 33 weeks of gestation, and smaller median head circumference-to-abdominal circumference ratio in the second and third trimesters of pregnancy. There was no specific weekly difference in fetal femur length or humerus length by docosahexaenoic acid and eicosapentaenoic acid supplementation. First-trimester dietary sources of docosahexaenoic acid and eicosapentaenoic acid among women with no first-trimester docosahexaenoic acid and eicosapentaenoic acid supplementation (n=1392) were associated with differences in fetal biparietal diameter (P=.043), but not other metrics of fetal growth. At the recommended dietary docosahexaenoic acid and eicosapentaenoic acid levels compared with below-recommended levels, biparietal diameter was larger between 38 to 41 weeks of gestation. CONCLUSION: In this racially diverse pregnancy cohort, first-trimester docosahexaenoic acid and eicosapentaenoic acid supplementation was associated with significant increases in fetal growth, specifically greater estimated fetal abdominal circumference in the second and third trimesters of pregnancy.

Risk of adverse neonatal outcomes among pregnant women with disabilities.

BACKGROUND: To compare risk of neonatal morbidities between women with and without documented disability and to evaluate mediation of these associations by pre-term birth and caesarean delivery. METHODS: Using data from the Consortium on Safe Labor (2002-2008; n = 223 385), we evaluated risk of 22 neonatal outcomes among singleton deliveries using ICD-9 codes to define physical (n = 1733), sensory (n = 250) and intellectual disability (n = 91). Adjusted relative risk (aRR) was estimated for each outcome among each category of disability, and among women with any disability using Poisson regression models with robust variance. Causal mediation methods evaluated pre-term birth and caesarean delivery as mediators. RESULTS: Compared with no disability, neonates of women with any disability had higher risk of nearly all neonatal outcomes, including pre-term birth (aRR = 1.77; 95% CI 1.62-1.94), small for gestational age (SGA) (aRR = 1.25; CI 1.11-1.41), neonatal intensive care unit (NICU) admission (aRR = 1.70; CI 1.54-1.87), seizures (aRR = 2.81; CI 1.54-5.14), cardiomyopathy (aRR = 4.92; CI 1.15-20.95), respiratory morbidities (aRR ranged from 1.33-2.08) and death (aRR = 2.31; CI 1.38-3.87). Women with disabilities were more likely to have a maternal indication for pre-term delivery, including pre-pregnancy diabetes (aRR = 3.80; CI 2.84-5.08), chronic hypertension (aRR = 1.46; CI 0.95-2.25) and severe pre-eclampsia/eclampsia (aRR = 1.47; CI 1.19-1.81). Increased risk varied but was generally consistent across all disability categories. Most outcomes were partially mediated by pre-term birth, except SGA, and heightened risk remained for NICU admissions, respiratory distress syndrome, anaemia and a composite of any adverse outcome (aRR = 1.21; CI 1.10-1.32). CONCLUSION: Neonates of women with disabilities were at higher risk of a broad range of adverse neonatal outcomes, including death. Risks were not fully explained by pre-term birth.