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Background: The Eunice Kennedy Shriver National Institute of Child Health and Human Development Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be was established to investigate the underlying causes and pathophysiological pathways associated with adverse pregnancy outcomes in nulliparous gravidas.Objective: This study aimed to study placental physiology and identify novel biomarkers concerning adverse pregnancy outcomes, including preterm birth (medically indicated and spontaneous), preeclampsia, small-for-gestational-age neonates, and stillbirth. We measured levels of placental proteins in the maternal circulation in the first 2 trimesters of pregnancy.Study Design: Maternal serum samples were collected at 2 study visits (6-13 weeks and 16-21 weeks), and levels of 9 analytes were measured. The analytes we measured were vascular endothelial growth factor, placental growth factor, endoglin, soluble fms-like tyrosine kinase-1, A disintegrin and metalloproteinase domain-containing protein 12, pregnancy-associated plasma protein A, free beta-human chorionic gonadotropin, inhibin A, and alpha-fetoprotein. The primary outcome was preterm birth between 20 0/7 and 36 6/7 weeks of gestation. The secondary outcomes were spontaneous preterm births, medically indicated preterm births, preeclampsia, small-for-gestational-age neonates, and stillbirth.Results: A total of 10,038 eligible gravidas were enrolled in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be cohort, from which a nested case-control study was performed comparing 800 cases with preterm birth (466 spontaneous preterm births, 330 medically indicated preterm births, and 4 unclassified preterm births), 568 with preeclampsia, 406 with small-for-gestational-age birth, and 49 with stillbirth with 911 controls who delivered at term without complications. Although levels of each analyte generally differed between cases and controls at 1 or 2 visits, the odds ratios revealed a <2-fold difference between cases and controls in all comparisons. Receiver operating characteristic curves, generated to determine the relationship between analyte levels and preterm birth and the other adverse pregnancy outcomes, resulted in areas under the receiver operating characteristic curves that were relatively low (range, 0.50-0.64) for each analyte. Logistic regression modeling demonstrated that areas under the receiver operating characteristic curves for predicting adverse pregnancy outcomes were greater using baseline clinical characteristics and combinations of analytes than baseline characteristics alone, but areas under the receiver operating characteristic curves remained relatively low for each outcome (range, 0.65-0.78).Conclusion: We have found significant associations between maternal serum levels of analytes evaluated early in pregnancy and subsequent adverse pregnancy outcomes in nulliparous gravidas. However, the test characteristics for these analytes do not support their use as clinical biomarkers to predict adverse pregnancy outcomes, either alone or in combination with maternal clinical characteristics. [ABSTRACT FROM AUTHOR]

Background: Periconceptional diet quality is commonly suboptimal and sociodemographic disparities in diet quality exist. However, it is unknown whether individual periconceptional diet quality is associated with obstetric outcomes.Objective: Our objective was to assess differences in maternal and neonatal outcomes according to maternal periconceptional diet quality.Study Design: This is a secondary analysis of a large, multicenter prospective cohort study of 10,038 nulliparous women receiving obstetrical care at 8 United States centers. Women underwent 3 antenatal study visits and had detailed maternal and neonatal data abstracted by trained research personnel. In the first trimester (between 6 and 13 weeks), women completed the modified Block 2005 Food Frequency Questionnaire, a semiquantitative assessment of usual dietary intake for the 3 months around conception. Responses were scored using the Healthy Eating Index-2010, which assesses adherence to the 2010 Dietary Guidelines for Americans. Higher scores on the Healthy Eating Index represent better adherence. Healthy Eating Index scores were analyzed by quartile; quartile 4 represents the highest dietary quality. Bivariable and multivariable analyses were performed to assess associations between diet quality and outcomes. A sensitivity analysis in which markers of socioeconomic status were included in the multivariable Poisson regression models was performed.Results: In the cohort of 8259 women with Healthy Eating Index data, the mean Healthy Eating Index score was 63 (±13) of 100. Women with the lowest quartile Healthy Eating Index scores were more likely to be younger, non-Hispanic black and Hispanic, publicly insured, low income, and tobacco users. They were more likely to have comorbidities (obesity, chronic hypertension, pregestational diabetes, mental health disorders), a higher prepregnancy body mass index, and less education. Women with lowest quartile scores experienced less frequent major perineal lacerations and more frequent postpartum hemorrhage requiring transfusion and hypertensive disorders of pregnancy, which persisted on multivariable analyses (controlling for age, body mass index, tobacco use, chronic hypertension, pregestational diabetes mellitus, and mental health disorders) comparing women in each quartile with quartile 4. Additionally, women in quartiles 1 and 2 experienced greater adjusted relative risk of cesarean delivery compared with women in quartile 4. Neonatal outcomes also differed by dietary quartile, with women in the lowest Healthy Eating Index quartile experiencing greater adjusted relative risk of preterm birth, neonatal intensive care unit admission, small for gestational age infant, and low birthweight, and lower risk of macrosomia; all neonatal findings also persisted in multivariable analyses. The sensitivity analysis with inclusion of markers of socioeconomic status (race/ethnicity, insurance status, marital status) in the multivariable models supported these findings.Conclusion: Periconceptional diet quality among women in the United States is poor. Poorer periconceptional dietary quality is associated with adverse maternal and neonatal outcomes, even after controlling for potential comorbidities and body mass index, suggesting periconceptional diet may be an important social or biological determinant of health underlying existing health disparities. [ABSTRACT FROM AUTHOR]

Background: Recently updated American College of Cardiology/ American Heart Association (ACC/AHA) guidelines redefine blood pressure categories as stage 1 hypertension (systolic, 130-139 mm Hg or diastolic, 80-89 mm Hg), elevated (systolic, 120-129 mm Hg and diastolic, <80 mm Hg), and normal (<120/<80 mm Hg), but their relevance to an obstetric population is uncertain.Objective: We sought to evaluate the risk of gestational hypertension or preeclampsia based on early pregnancy blood pressure category and trajectory.Study Design: We utilized data from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be cohort, a prospective observational study of nulliparous women with singleton pregnancies conducted at 8 clinical sites between 2010 and 2014. Women included in this analysis had no known history of prepregnancy hypertension (blood pressure, ≥140/90 mm Hg) or diabetes. We compared the frequency of hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension, among women based on ACC/AHA blood pressure category at a first-trimester study visit and blood pressure trajectory between study visits in the first and second trimesters. Blood pressure trajectories were categorized based on blood pressure difference between visits 1 and 2 as stable (<5 mm Hg difference), upward (≥5 mm Hg), or downward (≤-5 mm Hg). Associations of blood pressure category and trajectory with preeclampsia and gestational hypertension were assessed via univariate analysis and multinomial logistic regression analysis with covariates identified a priori.Results: A total of 8899 women were included in the analysis. Study visit 1 occurred at a mean gestational age of 11.6 ± 1.5 weeks and study visit 2 at a mean gestational age of 19.0 ± 1.6 weeks. First-trimester blood pressure category was significantly associated with both preeclampsia and gestational hypertension, with increasing blood pressure category associated with a higher risk of all hypertensive disorders of pregnancy. Elevated blood pressure was associated with an adjusted relative risk of 1.54 (95% confidence interval, 1.18-2.02) and stage 1 hypertension was associated with adjusted relative risk of 2.16 (95% confidence interval, 1.31-3.57) of any hypertensive disorder of pregnancy. Stage 1 hypertension was associated with the highest risk of preeclampsia with severe features, with an adjusted relative risk of 2.48 (95% confidence interval, 1.38-8.74). Both systolic and diastolic blood pressure trajectories were also significantly associated with the risk of hypertensive disorders of pregnancy independent of blood pressure category (P < .001). Women with a blood pressure categorized as normal and with an upward systolic trajectory had a 41% increased risk of any hypertensive disorder of pregnancy (adjusted relative risk, 1.41; 95% confidence interval, 1.20-1.65) compared to women with a downward systolic trajectory.Conclusion: In nulliparous women, blood pressure category and trajectory in early pregnancy are independently associated with risk of preeclampsia and gestational hypertension. Our study demonstrates that blood pressure categories with lower thresholds than those traditionally used to identify individuals as hypertensive may identify more women at risk for preeclampsia and gestational hypertension. [ABSTRACT FROM AUTHOR]

Background Sleep-disordered breathing (SDB) is common in pregnancy, but there are limited data on predictors. Objectives The objective of this study was to develop predictive models of sleep-disordered breathing during pregnancy. Study Design Nulliparous women completed validated questionnaires to assess for symptoms related to snoring, fatigue, excessive daytime sleepiness, insomnia, and restless leg syndrome. The questionnaires included questions regarding the timing of sleep and sleep duration, work schedules (eg, shift work, night work), sleep positions, and previously diagnosed sleep disorders. Frequent snoring was defined as self-reported snoring ≥3 days per week. Participants underwent in-home portable sleep studies for sleep-disordered breathing assessment in early (6–15 weeks gestation) and mid pregnancy (22–31 weeks gestation). Sleep-disordered breathing was characterized by an apnea hypopnea index that included all apneas, plus hypopneas with ≥3% oxygen desaturation. For primary analyses, an apnea hypopnea index ≥5 events per hour was used to define sleep-disordered breathing. Odds ratios and 95% confidence intervals were calculated for predictor variables. Predictive ability of the logistic models was estimated with area under the receiver-operating-characteristic curves, along with sensitivities, specificities, and positive and negative predictive values and likelihood ratios. Results Among 3705 women who were enrolled, data were available for 3264 and 2512 women in early and mid pregnancy, respectively. The corresponding prevalence of sleep-disordered breathing was 3.6% and 8.3%, respectively. At each time point in gestation, frequent snoring, chronic hypertension, greater maternal age, body mass index, neck circumference, and systolic blood pressure were associated most strongly with an increased risk of sleep-disordered breathing. Logistic regression models that included current age, body mass index, and frequent snoring predicted sleep-disordered breathing in early pregnancy, sleep-disordered breathing in mid pregnancy, and new onset sleep-disordered breathing in mid pregnancy with 10-fold cross-validated area under the receiver-operating-characteristic curves of 0.870, 0.838, and 0.809. We provide a supplement with expanded tables, integrated predictiveness, classification curves, and an predicted probability calculator. Conclusion Among nulliparous pregnant women, logistic regression models with just 3 variables (ie, age, body mass index, and frequent snoring) achieved good prediction of prevalent and incident sleep-disordered breathing. These results can help with screening for sleep-disordered breathing in the clinical setting and for future clinical treatment trials. [ABSTRACT FROM AUTHOR]

Background: Sleep-disordered breathing (SDB) is common in pregnancy, but there are limited data on predictors.Objectives: The objective of this study was to develop predictive models of sleep-disordered breathing during pregnancy.Study Design: Nulliparous women completed validated questionnaires to assess for symptoms related to snoring, fatigue, excessive daytime sleepiness, insomnia, and restless leg syndrome. The questionnaires included questions regarding the timing of sleep and sleep duration, work schedules (eg, shift work, night work), sleep positions, and previously diagnosed sleep disorders. Frequent snoring was defined as self-reported snoring ≥3 days per week. Participants underwent in-home portable sleep studies for sleep-disordered breathing assessment in early (6-15 weeks gestation) and mid pregnancy (22-31 weeks gestation). Sleep-disordered breathing was characterized by an apnea hypopnea index that included all apneas, plus hypopneas with ≥3% oxygen desaturation. For primary analyses, an apnea hypopnea index ≥5 events per hour was used to define sleep-disordered breathing. Odds ratios and 95% confidence intervals were calculated for predictor variables. Predictive ability of the logistic models was estimated with area under the receiver-operating-characteristic curves, along with sensitivities, specificities, and positive and negative predictive values and likelihood ratios.Results: Among 3705 women who were enrolled, data were available for 3264 and 2512 women in early and mid pregnancy, respectively. The corresponding prevalence of sleep-disordered breathing was 3.6% and 8.3%, respectively. At each time point in gestation, frequent snoring, chronic hypertension, greater maternal age, body mass index, neck circumference, and systolic blood pressure were associated most strongly with an increased risk of sleep-disordered breathing. Logistic regression models that included current age, body mass index, and frequent snoring predicted sleep-disordered breathing in early pregnancy, sleep-disordered breathing in mid pregnancy, and new onset sleep-disordered breathing in mid pregnancy with 10-fold cross-validated area under the receiver-operating-characteristic curves of 0.870, 0.838, and 0.809. We provide a supplement with expanded tables, integrated predictiveness, classification curves, and an predicted probability calculator.Conclusion: Among nulliparous pregnant women, logistic regression models with just 3 variables (ie, age, body mass index, and frequent snoring) achieved good prediction of prevalent and incident sleep-disordered breathing. These results can help with screening for sleep-disordered breathing in the clinical setting and for future clinical treatment trials. [ABSTRACT FROM AUTHOR]

Background: Trophoblastic invasion of the uterine spiral arteries substantially increases compliance to accommodate increased blood flow to the placenta. Failure of this process impedes uterine artery blood flow, and this may be detected by uterine artery Doppler flow studies. However, the clinical utility of uterine artery Doppler flow studies in the prediction of adverse pregnancy outcomes in a general population remains largely unknown.Objective: We sought to determine the utility of early second-trimester uterine artery Doppler studies as a predictor of small-for-gestational-age neonates.Study Design: Nulliparous women with a viable singleton pregnancy were recruited during their first trimester into an observational prospective cohort study at 8 institutions across the United States. Participants were seen at 3 study visits during pregnancy and again at delivery. Three indices of uterine artery Doppler flow (resistance index, pulsatility index, and diastolic notching) were measured in the right and left uterine arteries between 16 weeks 0 days' and 22 weeks 6 days' gestation. Test characteristics for varying thresholds in the prediction of small for gestational age (defined as birthweight <5th percentile for gestational age [Alexander growth curve]) were evaluated.Results: Uterine artery Doppler indices, birthweight, and gestational age at birth were available for 8024 women. Birthweight <5th percentile for gestational age occurred in 358 (4.5%) births. Typical thresholds for the uterine artery Doppler indices were all associated with birthweight <5th percentile for gestational age (P < .0001 for each), but the positive predictive values for these cutoffs were all <15% and areas under receiver operating characteristic curves ranged from 0.50-0.60. Across the continuous scales for these measures, the areas under receiver operating characteristic curves ranged from 0.56-0.62. Incorporating maternal age, early pregnancy body mass index, race/ethnicity, smoking status prior to pregnancy, chronic hypertension, and pregestational diabetes in the prediction model resulted in only modest improvements in the areas under receiver operating characteristic curves ranging from 0.63-0.66.Conclusion: In this large prospective cohort, early second-trimester uterine artery Doppler studies were not a clinically useful test for predicting small-for-gestational-age babies. [ABSTRACT FROM AUTHOR]

Background: Experimental and epidemiologic data suggest that among nonpregnant adults, sleep duration may be an important risk factor for chronic disease. Although pregnant women commonly report poor sleep, few studies objectively evaluated the quality of sleep in pregnancy or explored the relationship between sleep disturbances and maternal and perinatal outcomes.Objective: Our objective was to examine the relationship between objectively assessed sleep duration, timing, and continuity (measured via wrist actigraphy) and maternal cardiovascular and metabolic morbidity specific to pregnancy.Study Design: This was a prospective cohort study of nulliparous women. Women were recruited between 16 0/7 and 21 6/7 weeks' gestation. They were asked to wear a wrist actigraphy monitor and complete a daily sleep log for a period of 7 consecutive days. The primary sleep exposure variables were the averages of the following over the total valid nights (minimum 5, maximum 7 nights): short sleep duration during the primary sleep period (<7 h/night), late sleep midpoint (midpoint between sleep onset and sleep offset >5 am), and top quartile of minutes of wake time after sleep onset and sleep fragmentation index. The primary outcomes of interest were a composite of hypertensive disorders of pregnancy (mild, severe, or superimposed preeclampsia; eclampsia; or antepartum gestational hypertension) and gestational diabetes mellitus. We used χ2 tests to assess associations between sleep variables and categorical baseline characteristics. Crude odds ratios and 95% confidence intervals were estimated from univariate logistic regression models to characterize the magnitude of the relationship between sleep characteristics and hypertensive disorders of pregnancy and gestational diabetes. For associations significant in univariate analysis, multiple logistic regression was used to explore further the association of sleep characteristics with pregnancy outcomes.Results: In all, 901 eligible women consented to participate; 782 submitted valid actigraphy studies. Short sleep duration and a later sleep midpoint were associated with an increased risk of gestational diabetes (odds ratio, 2.24; 95% confidence interval, 1.11-4.53; and odds ratio, 2.58; 95% confidence interval, 1.24-5.36, respectively) but not of hypertensive disorders. A model with both sleep duration and sleep midpoint as well as their interaction term revealed that while there was no significant interaction between these exposures, the main effects of both short sleep duration and later sleep midpoint with gestational diabetes remained significant (adjusted odds ratio, 2.06; 95% confidence interval, 1.01-4.19; and adjusted odds ratio, 2.37; 95% confidence interval, 1.13-4.97, respectively). Additionally, after adjusting separately for age, body mass index, and race/ethnicity, both short sleep duration and later sleep midpoint remained associated with gestational diabetes. No associations were demonstrated between the sleep quality measures (wake after sleep onset, sleep fragmentation) and hypertensive disorders or gestational diabetes.Conclusion: Our results demonstrate a relationship between short sleep duration and later sleep midpoint with gestational diabetes. Our data suggest independent contributions of these 2 sleep characteristics to the risk for gestational diabetes in nulliparous women. [ABSTRACT FROM AUTHOR]

Background: An evaluation for heritable thrombophilias is recommended in the evaluation of stillbirth. However, the association between thrombophilias and stillbirth remains uncertain.Objective: We sought to assess the association between maternal and fetal/placental heritable thrombophilias and stillbirth in a population-based, case-control study in a geographically, racially, and ethnically diverse population.Study Design: We conducted secondary analysis of data from the Stillbirth Collaborative Research Network, a population-based case-control study of stillbirth. Testing for factor V Leiden, prothrombin G20210A, methylene tetrahydrofolate reductase C677T and A1298C, and plasminogen activating inhibitor (PAI)-1 4G/5G mutations was done on maternal and fetal (or placental) DNA from singleton pregnancies. Data analyses were weighted for oversampling and other aspects of the design. Odds ratios (OR) were generated from univariate models regressing stillbirth/live birth status on each thrombophilia marker.Results: Results were available for ≥1 marker in 488 stillbirths and 1342 live birth mothers and 405 stillbirths and 990 live birth fetuses. There was an increased odds of stillbirth for maternal homozygous factor V Leiden mutation (2/488; 0.4% vs 1/1380; 0.0046%; OR, 87.44; 95% confidence interval, 7.88-970.92). However, there were no significant differences in the odds of stillbirth for any other maternal thrombophilia, even after stratified analyses. Fetal 4G/4G PAI-1 (OR, 0.63; 95% confidence interval, 0.43-0.91) was associated with decreased odds of stillbirth. Other fetal thrombophilias were similar among groups.Conclusion: Most maternal and fetal thrombophilias were not associated with stillbirth. Maternal factor V Leiden was weakly associated with stillbirth, and the fetal PAI-1 4G/4G polymorphism was associated with live birth. Our data do not support routine testing for heritable thrombophilias as part of an evaluation for possible causes of stillbirth. [ABSTRACT FROM AUTHOR]

Objective: The primary aim of the "Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be" is to determine maternal characteristics, which include genetic, physiologic response to pregnancy, and environmental factors that predict adverse pregnancy outcomes.Study Design: Nulliparous women in the first trimester of pregnancy were recruited into an observational cohort study. Participants were seen at 3 study visits during pregnancy and again at delivery. We collected data from in-clinic interviews, take-home surveys, clinical measurements, ultrasound studies, and chart abstractions. Maternal biospecimens (serum, plasma, urine, cervicovaginal fluid) at antepartum study visits and delivery specimens (placenta, umbilical cord, cord blood) were collected, processed, and stored. The primary outcome of the study was defined as pregnancy ending at <37+0 weeks' gestation. Key study hypotheses involve adverse pregnancy outcomes of spontaneous preterm birth, preeclampsia, and fetal growth restriction.Results: We recruited 10,037 women to the study. Basic characteristics of the cohort at screening are reported.Conclusion: The "Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be" cohort study methods and procedures can help investigators when they plan future projects. [ABSTRACT FROM AUTHOR]

Objective: The objective of the Sleep Disordered Breathing substudy of the Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b) is to determine whether sleep disordered breathing during pregnancy is a risk factor for adverse pregnancy outcomes.Study Design: NuMoM2b is a prospective cohort study of 10,037 nulliparous women with singleton gestations that was conducted across 8 sites with a central Data Coordinating and Analysis Center. The Sleep Disordered Breathing substudy recruited 3702 women from the cohort to undergo objective, overnight in-home assessments of sleep disordered breathing. A standardized level 3 home sleep test was performed between 6(0)-15(0) weeks' gestation (visit 1) and again between 22(0)-31(0) weeks' gestation (visit 3). Scoring of tests was conducted by a central Sleep Reading Center. Participants and their health care providers were notified if test results met "urgent referral" criteria that were based on threshold levels of apnea hypopnea indices, oxygen saturation levels, or electrocardiogram abnormalities but were not notified of test results otherwise. The primary pregnancy outcomes to be analyzed in relation to maternal sleep disordered breathing are preeclampsia, gestational hypertension, gestational diabetes mellitus, fetal growth restriction, and preterm birth.Results: Objective data were obtained at visit 1 on 3261 women, which was 88.1% of the studies that were attempted and at visit 3 on 2511 women, which was 87.6% of the studies that were attempted. Basic characteristics of the substudy cohort are reported in this methods article.Conclusion: The substudy was designed to address important questions regarding the relationship of sleep-disordered breathing on the risk of preeclampsia and other outcomes of relevance to maternal and child health. [ABSTRACT FROM AUTHOR]

Objective: We sought to compare bile acids in women with and without stillbirth in a population-based study. Study Design: The Stillbirth Collaborative Research Network conducted a multisite, population-based case-control study of stillbirth (fetal deaths ≥20 weeks). Maternal sera were obtained at the time of enrollment and frozen at –80°C until assay for bile acids. Results: Assays were performed in 581 women with stillbirth and 1546 women with live births. Bile acid levels were slightly higher in women with stillbirth (geometric mean [95% confidence interval {CI}] = 3.2 [3.0–3.5]) compared to live births (2.9 [2.7–3.1], P = .0327). However, the difference was not significant after adjustment for baseline risk factors for stillbirth. The proportion of women with elevated levels (≥10 or ≥40 μmol/L) was similar in stillbirths and live births. Results were similar when the analysis was limited to subsets of stillbirths and live births. In women with stillbirths not associated with fetal anomalies or obstetric complications bile acid levels were higher than in women with term live births (geometric mean [95% CI] = 3.4 [3.0–3.8] vs 2.9 [2.7–3.0], P = .0152, unadjusted; P = .06, adjusted). However, a similar proportion of women in both groups had levels ≥10 μmol/L (10.7 vs 7.2%; odds ratio [OR], 1.54; 95% CI, 0.97–2.44; adjusted OR, 1.29; 95% CI, 0.78–2.15) and ≥40 μmol/L (1.7 vs 0.7%; OR, 2.58; 95% CI, 0.85–7.84; adjusted OR, 2.28; 95% CI, 0.79–6.56). Conclusion: Our data do not support testing for bile acids in cases of stillbirth in the absence of clinical evidence of intrahepatic cholestasis of pregnancy. [ABSTRACT FROM AUTHOR]