Large-Scale Proteomics in Early Pregnancy and Hypertensive Disorders of Pregnancy.

Importance: There is no consensus regarding the best method for prediction of hypertensive disorders of pregnancy (HDP), including gestational hypertension and preeclampsia. Objective: To determine predictive ability in early pregnancy of large-scale proteomics for prediction of HDP. Design, Setting, and Participants: This was a nested case-control study, conducted in 2022 to 2023, using clinical data and plasma samples collected between 2010 and 2013 during the first trimester, with follow-up until pregnancy outcome. This multicenter observational study took place at 8 academic medical centers in the US. Nulliparous individuals during first-trimester clinical visits were included. Participants with HDP were selected as cases; controls were selected from those who delivered at or after 37 weeks without any HDP, preterm birth, or small-for-gestational-age infant. Age, self-reported race and ethnicity, body mass index, diabetes, health insurance, and fetal sex were available covariates. Exposures: Proteomics using an aptamer-based assay that included 6481 unique human proteins was performed on stored plasma. Covariates were used in predictive models. Main Outcomes and Measures: Prediction models were developed using the elastic net, and analyses were performed on a randomly partitioned training dataset comprising 80% of study participants, with the remaining 20% used as an independent testing dataset. Primary measure of predictive performance was area under the receiver operating characteristic curve (AUC). Results: This study included 753 HDP cases and 1097 controls with a mean (SD) age of 26.9 (5.5) years. Maternal race and ethnicity were 51 Asian (2.8%), 275 non-Hispanic Black (14.9%), 275 Hispanic (14.9%), 1161 non-Hispanic White (62.8% ), and 88 recorded as other (4.8%), which included those who did not identify according to these designations. The elastic net model, allowing for forced inclusion of prespecified covariates, was used to adjust protein-based models for clinical and demographic variables. Under this approach, no proteins were selected to augment the clinical and demographic covariates. The predictive performance of the resulting model was modest, with a training set AUC of 0.64 (95% CI, 0.61-0.67) and a test set AUC of 0.62 (95% CI, 0.56-0.68). Further adjustment for study site yielded only minimal changes in AUCs. Conclusions and Relevance: In this case-control study with detailed clinical data and stored plasma samples available in the first trimester, an aptamer-based proteomics panel did not meaningfully add to predictive utility over and above clinical and demographic factors that are routinely available.

Approaches to protocol standardization and data harmonization in the ECHO-wide cohort study.

The United States (U.S.) National Institutes of Health-funded Environmental influences on Child Health Outcomes (ECHO)-wide Cohort was established to conduct high impact, transdisciplinary science to improve child health and development. The cohort is a collaborative research design in which both extant and new data are contributed by over 57,000 children across 69 cohorts. In this review article, we focus on two key challenging issues in the ECHO-wide Cohort: data collection standardization and data harmonization. Data standardization using a Common Data Model and derived analytical variables based on a team science approach should facilitate timely analyses and reduce errors due to data misuse. However, given the complexity of collaborative research designs, such as the ECHO-wide Cohort, dedicated time is needed for harmonization and derivation of analytic variables. These activities need to be done methodically and with transparency to enhance research reproducibility. IMPACT: Many collaborative research studies require data harmonization either prior to analyses or in the analyses of compiled data. The Environmental influences on Child Health Outcomes (ECHO) Cohort pools extant data with new data collection from over 57,000 children in 69 cohorts to conduct high-impact, transdisciplinary science to improve child health and development, and to provide a national database and biorepository for use by the scientific community at-large. We describe the tools, systems, and approaches we employed to facilitate harmonized data for impactful analyses of child health outcomes.

Association between Sleep Disordered Breathing and Neonatal Outcomes in Nulliparous Individuals.

OBJECTIVE: Our objective was to determine whether objectively measured sleep-disordered breathing (SDB) during pregnancy is associated with an increased risk of adverse neonatal outcomes in a cohort of nulliparous individuals. STUDY DESIGN: Secondary analysis of the nuMom2b sleep disordered breathing substudy was performed. Individuals underwent in-home sleep studies for SDB assessment in early (6-15 weeks' gestation) and mid-pregnancy (22-31 weeks' gestation). SDB was defined as an apnea-hypopnea index ≥5 events/h at either time point. The primary outcome was a composite outcome of respiratory distress syndrome, transient tachypnea of the newborn, or receipt of respiratory support, treated hyperbilirubinemia or hypoglycemia, large-for-gestational age, seizures treated with medications or confirmed by electroencephalography, confirmed sepsis, or neonatal death. Individuals were categorized into (1) early pregnancy SDB (6-15 weeks' gestation), (2) new onset mid-pregnancy SDB (22-31 weeks' gestation), and (3) no SDB. Log-binomial regression was used to calculate adjusted risk ratios (RR) and 95% confidence intervals (CIs) representing the association. RESULTS: Among 2,106 participants, 3% (n = 75) had early pregnancy SDB and 5.7% (n = 119) developed new-onset mid-pregnancy SDB. The incidence of the primary outcome was higher in the offspring of individuals with early (29.3%) and new onset mid-pregnancy SDB (30.3%) compared with individuals with no SDB (17.8%). After adjustment for maternal age, chronic hypertension, pregestational diabetes, and body mass index, new onset mid-pregnancy SDB conferred increased risk (RR = 1.43, 95% CI: 1.05, 1.94), where there was no longer statistically significant association between early pregnancy SDB and the primary outcome. CONCLUSION: New onset, mid-pregnancy SDB is independently associated with neonatal morbidity. KEY POINTS: · Sleep disordered breathing (SDB) is a common condition impacting pregnancy with known maternal risks.. · Objectively defined SDB in pregnancy was associated with a composite of adverse neonatal outcomes.. · New onset SDB in mid pregnancy conferred statistically significant increased risk..

Adverse Pregnancy Outcomes and Future Metabolic Syndrome.

Background: Metabolic syndrome (MetS) is associated with a history of gestational diabetes (GDM), hypertensive disorders of pregnancy (HDP), and preterm birth (PTB), but it is unclear whether this association is due to the pregnancy complication(s) or prepregnancy/early pregnancy confounders. The study examines the association of GDM, HDP, and PTB with MetS 2-7 years later, independent of early pregnancy factors. Materials and Methods: Large, diverse cohort of nulliparous pregnant people with singleton gestations enrolled during their first trimester and who attended a follow-up study visit 2-7 years after delivery. The longitudinal cohort was recruited from eight medical centers across the United States. Using standardized protocols, anthropometry, biospecimens, and surveys were collected at study visits and pregnancy outcomes were abstracted from medical records. We estimated the relative risk of prevalent MetS at the follow-up study visit for participants with GDM, HDP, or PTB (vs. no complications), adjusting for early pregnancy age, body mass index, self-reported race/ethnicity, insurance type, and smoking status. Results: Of 4,402 participants, 738 (16.8%) had MetS at follow-up: 13.1% (441/3,365) among those with no complications, and 27.9% (290/1,002) among those with complications. MetS occurred in 39.0% of GDM (73/187, adjusted relative risk [aRR] = 1.75; 95% confidence interval [CI] 1.42-2.16); 29.2% of HDP (176/603, aRR = 1.49; 95% CI 1.27-1.75); and 29.7% of PTB (113/380, aRR = 1.78; 95% CI 1.49-2.12). Those who had both HDP and PTB (n = 113) had an aRR = 1.95 (95% CI 1.50-2.54). Conclusions: People whose pregnancies were complicated by GDM, HDP, or PTB are at a higher risk of MetS within 2-7 years after delivery, independent of early pregnancy risk factors. The highest MetS risk follows pregnancies complicated by both HDP and PTB.

The Environmental Influences on Child Health Outcomes (ECHO)-Wide Cohort.

The Environmental Influences on Child Health Outcomes (ECHO)-Wide Cohort Study (EWC), a collaborative research design comprising 69 cohorts in 31 consortia, was funded by the National Institutes of Health (NIH) in 2016 to improve children's health in the United States. The EWC harmonizes extant data and collects new data using a standardized protocol, the ECHO-Wide Cohort Data Collection Protocol (EWCP). EWCP visits occur at least once per life stage, but the frequency and timing of the visits vary across cohorts. As of March 4, 2022, the EWC cohorts contributed data from 60,553 children and consented 29,622 children for new EWCP data and biospecimen collection. The median (interquartile range) age of EWCP-enrolled children was 7.5 years (3.7-11.1). Surveys, interviews, standardized examinations, laboratory analyses, and medical record abstraction are used to obtain information in 5 main outcome areas: pre-, peri-, and postnatal outcomes; neurodevelopment; obesity; airways; and positive health. Exposures include factors at the level of place (e.g., air pollution, neighborhood socioeconomic status), family (e.g., parental mental health), and individuals (e.g., diet, genomics).

Serum Cotinine and Adverse Cardiovascular Outcomes: A Cross-sectional Secondary Analysis of the nuMoM2b Heart Health Study.

OBJECTIVE: We aimed to (1) compare serum cotinine with self-report for ascertaining smoking status among reproductive-aged women; (2) estimate the relative odds of adverse cardiovascular (CV) outcomes among women by smoking status; (3) assess whether the association between adverse pregnancy outcomes (APOs) and CV outcomes varies by smoking status. STUDY DESIGN: We conducted a cross-sectional study of the nuMoM2b Heart Health Study. Women attended a study visit 2 to 7 years after their first pregnancy. The exposure was smoking status, determined by self-report and by serum cotinine. Outcomes included incident chronic hypertension (HTN), metabolic syndrome (MetS), and dyslipidemia. Multivariable logistic regression estimated odds ratios (ORs) for each outcome by smoking status. RESULTS: Of 4,392 women with serum cotinine measured, 3,610 were categorized as nonsmokers, 62 as secondhand smoke exposure, and 720 as smokers. Of 3,144 women who denied tobacco smoke exposure, serum cotinine was consistent with secondhand smoke exposure in 48 (1.5%) and current smoking in 131 (4.2%) After adjustment for APOs, smoking defined by serum cotinine was associated with MetS (adjusted OR [aOR] = 1.52, 95% confidence interval [CI]: 1.21, 1.91) and dyslipidemia (aOR = 1.28, 95% CI: 1.01, 1.62). When stratified by nicotine exposure, nonsmokers with an APO in their index pregnancy had higher odds of stage 1 (aOR = 1.64, 95% CI: 1.32, 2.03) and stage 2 HTN (aOR = 2.92, 95% CI: 2.17, 3.93), MetS (aOR = 1.76, 95% CI: 1.42, 2.18), and dyslipidemia (aOR = 1.55, 95% CI: 1.25, 1.91) relative to women with no APO. Results were similar when smoking exposure was defined by self-report. CONCLUSION: Whether determined by serum cotinine or self-report, smoking is associated with subsequent CV outcomes in reproductive-aged women. APOs are also independently associated with CV outcomes in women. KEY POINTS: · Cotinine was detected in 5.7% of reported nonsmokers.. · Smoking and APOs were independently associated with CV health.. · Smoking was associated with MetS and dyslipidemia..

Factors associated with duration of breastfeeding in women giving birth for the first time.

OBJECTIVE: To examine maternal, psychosocial, and pregnancy factors associated with breastfeeding for at least 6 months in those giving birth for the first time. METHODS: We performed a planned secondary analysis of an observational cohort study of 5249 women giving birth for the first time. Women were contacted at least 6 months after delivery and provided information regarding breastfeeding initiation, duration, and exclusivity. Maternal demographics, psychosocial measures, and delivery methods were compared by breastfeeding groups. RESULTS: 4712 (89.8%) of the women breastfed at some point, with 2739 (58.2%) breastfeeding for at least 6 months. Of those who breastfed, 1161 (24.7% of the entire cohort), breastfed exclusively for at least 6 months. In the multivariable model among those who ever breastfed, not smoking in the month prior to delivery (adjusted odds ratio [aOR] 2.04, 95%CI 1.19-3.45), having a Master's degree of higher (aOR 1.89, 95%CI 1.51-2.36), having a planned pregnancy (aOR 1.48, 95%CI 1.27-1.73), older age (aOR 1.02, 95% CI, 1.01-1.04), lower BMI (aOR 0.96 95% CI 0.95-0.97), and having less anxiety measured during pregnancy (aOR 0.990, 95%CI 0.983-0.998) were associated with breastfeeding for at least 6 months. Compared to non-Hispanic White women, Hispanic women, while being more likely to breastfeed initially (aOR 1.40, 95%CI 1.02-1.92), were less likely to breastfeed for 6 months (aOR 0.72, 95%CI 0.59-0.88). While non-Hispanic Black women were less likely than non-Hispanic White women to initiate breastfeeding (aOR 0.68, 95%CI 0.51-0.90), the odds of non-Hispanic Black women of continuing to breastfeed for at least 6 months was similar to non-Hispanic White women (aOR 0.92, 95%CI 0.71-1.19). CONCLUSIONS: In this cohort of women giving birth for the first time, duration of breastfeeding was associated with several characteristics which highlight groups at greater risk of not breastfeeding as long as currently recommended. TRIAL REGISTRATION: NCT01322529 (nuMoM2b) and NCT02231398 (nuMoM2b-Heart Health).

Placental protein levels in maternal serum are associated with adverse pregnancy outcomes in nulliparous patients.

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.

Use of a Doubly Robust Machine-Learning-Based Approach to Evaluate Body Mass Index as a Modifier of the Association Between Fruit and Vegetable Intake and Preeclampsia.

The Dietary Guidelines for Americans rely on summaries of the effect of dietary pattern on disease risk, independent of other population characteristics. We explored the modifying effect of prepregnancy body mass index (BMI; weight (kg)/height (m)2) on the relationship between fruit and vegetable density (cup-equivalents/1,000 kcal) and preeclampsia using data from a pregnancy cohort study conducted at 8 US medical centers (n = 9,412; 2010-2013). Usual daily periconceptional intake of total fruits and total vegetables was estimated from a food frequency questionnaire. We quantified the effects of diets with a high density of fruits (≥1.2 cups/1,000 kcal/day vs. <1.2 cups/1,000 kcal/day) and vegetables (≥1.3 cups/1,000 kcal/day vs. <1.3 cups/1,000 kcal/day) on preeclampsia risk, conditional on BMI, using a doubly robust estimator implemented in 2 stages. We found that the protective association of higher fruit density declined approximately linearly from a BMI of 20 to a BMI of 32, by 0.25 cases per 100 women per each BMI unit, and then flattened. The protective association of higher vegetable density strengthened in a linear fashion, by 0.3 cases per 100 women for every unit increase in BMI, up to a BMI of 30, where it plateaued. Dietary patterns with a high periconceptional density of fruits and vegetables appear more protective against preeclampsia for women with higher BMI than for leaner women.

Sleep-disordered Breathing in Pregnancy and after Delivery: Associations with Cardiometabolic Health.

Rationale: Knowledge gaps exist regarding health implications of sleep-disordered breathing (SDB) identified in pregnancy and/or after delivery. Objectives: To determine whether SDB in pregnancy and/or after delivery is associated with hypertension (HTN) and metabolic syndrome (MS). Methods: nuMoM2b-HHS (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be Heart Health Study) (N = 4,508) followed participants initially recruited during their first pregnancy. Participants returned for a visit 2-7 years after pregnancy. This study examined a subgroup who underwent SDB assessments during their first pregnancy (n = 1,964) and a repeat SDB assessment after delivery (n = 1,222). Two SDB definitions were considered: 1) apnea-hypopnea index (AHI) ⩾ 5 and 2) oxygen desaturation index (ODI) ⩾ 5. Associations between SDB and incident HTN and MS were evaluated with adjusted risk ratios (aRRs). Measurements and Main Results: The aRR for MS given an AHI ⩾ 5 during pregnancy was 1.44 (95% confidence interval [CI], 1.08-1.93), but no association with HTN was found. ODI ⩾ 5 in pregnancy was associated with both an increased risk for HTN (aRR, 2.02; 95% CI, 1.30-3.14) and MS (aRR, 1.53; 95% CI, 1.19-1.97). Participants with an AHI ⩾ 5 in pregnancy that persisted after delivery were at higher risk for both HTN (aRR, 3.77; 95% CI, 1.84-7.73) and MS (aRR, 2.46; 95% CI, 1.59-3.76). Similar associations were observed for persistent ODI ⩾ 5 after delivery. Conclusions: An AHI ⩾ 5 in pregnancy was associated with an increased risk of MS. An ODI ⩾ 5 in pregnancy was significantly associated with both HTN and MS. Participants with persistent elevations in AHI and ODI during pregnancy and at 2-7 years after delivery were at the highest risk for HTN and MS. Clinical trial registered with www.clinicaltrials.gov (NCT02231398).

Association between aspirin use during pregnancy and cardiovascular risk factors 2-7 years after delivery: The nuMoM2b Heart Health Study.

OBJECTIVES: To evaluate the association between aspirin use during first pregnancy and later maternal cardiovascular risk. STUDY DESIGN: In this secondary analysis of a prospective cohort, we included participants who carried their first pregnancy to 20 + weeks, had data regarding aspirin use, and attended a study visit 2-7 years following delivery. The exposure was aspirin use during the first pregnancy. We calculated aspirin use propensity scores from logistic regression models including baseline variables associated with aspirin use in pregnancy and cardiovascular risk. Outcomes of interest were incident cardiovascular-related diagnoses 2-7 years following delivery. Robust Poisson regression calculated the risk of outcomes by aspirin exposure, adjusting for the aspirin use propensity score. MAIN OUTCOME MEASURES: The primary outcome was a composite of incident cardiovascular diagnoses at the time of the study visit: cardiovascular events, chronic hypertension, metabolic syndrome, prediabetes or type 2 diabetes, dyslipidemia, and chronic kidney disease. RESULTS: Of 4,480 women included, 84 (1.9%) reported taking aspirin during their first pregnancy. 52.6% of participants in the aspirin-exposed group and 43.0% in the unexposed group had the primary outcome. After adjusting for the aspirin use propensity scores, aspirin use during the first pregnancy was not associated with any of the outcomes. CONCLUSION: We did not detect an association between aspirin use during the first pregnancy and cardiovascular-related diagnoses 2-7 years later. Our study was only powered to detect a large difference in relative risk, so we cannot rule out a smaller difference that may be clinically meaningful.

Perinatal Outcomes in Obese Women with One Abnormal Value on 3-Hour Oral Glucose Tolerance Test.

OBJECTIVE: This study aimed to determine if one abnormal value of four on the diagnostic 3-hour oral glucose tolerance test (OGTT) is associated with adverse perinatal outcomes in obese women. STUDY DESIGN: This is a secondary analysis of a prospective study of nulliparous women in eight geographic regions. Women with body mass index <30 kg/m2 and pregestational diabetes mellitus (GDM) were excluded. Four groups were compared: (1) normal 50-g 1-hour glucose screen, (2) elevated 1-hour glucose screen with normal 100-g 3-hour diagnostic OGTT, (3) elevated 1-hour glucose screen and one of four abnormal values on 3-hour OGTT, and (4) GDM. Using multivariable logistic regression adjusting for covariates, the women in the groups with dysglycemia were compared with those in the normal screen group for maternal and neonatal outcomes. RESULTS: Among 1,713 obese women, 1,418 (82.8%) had a normal 1-hour glucose screen, 125 (7.3%) had a normal 3-hour diagnostic OGTT, 72 (4.2%) had one abnormal value on their diagnostic OGTT, and 98 (5.7%) were diagnosed with GDM. The one abnormal value group had increased risk of large for gestational age (LGA) neonates (adjusted odds ratio [aOR] = 2.24, 95% confidence interval [CI]: 1.31-3.82), cesarean delivery (aOR = 2.19, 95% CI: 1.34-3.58), and hypertensive disorders of pregnancy (aOR = 2.19, 95% CI: 1.32-3.63) compared with normal screens. The one abnormal value group also had an increased risk of preterm birth <37 weeks (aOR = 2.63, 95% CI: 1.43-4.84), neonatal respiratory support (aOR = 2.38, 95% CI: 1.23-4.60), and neonatal hyperbilirubinemia (aOR = 2.00, 95% CI: 1.08-3.71). There was no association between one abnormal value with shoulder dystocia and neonatal hypoglycemia. CONCLUSION: For obese women, one abnormal value on the 3-hour OGTT confers increased perinatal adverse outcomes. These women should be studied further to determine if nutrition counseling and closer fetal monitoring improve outcomes even in the absence of a diagnosis of GDM. KEY POINTS: · Study of obese women with one abnormal value on OGTT.. · Adverse maternal and neonatal outcomes were found, including more LGA neonates.. · Neonates were not at increased risk of hypoglycemia..

Variation in self-identified most stressful life event by outcome of previous pregnancy in a population-based sample interviewed 6-36 months following delivery.

The majority of health research uses a deductive approach to measure stressful life events, despite evidence that perception of what is stressful varies. The goal of this project was to 1) describe the distribution of self-identified most stressful life events in a cohort of women who experienced a perinatal loss (stillbirth or neonatal death) or live birth in the previous three years and 2) test how childhood adversity influences participant selection of their most stressful life event. We used data from 987 women (282 with stillbirth, 657 without loss, and 48 with a neonatal death in the first 28 days) in the Stillbirth Collaborative Research Network - OASIS (Outcomes after Study Index Stillbirth) follow-up study, a population-based sample set in five U.S. states in 2009. We applied an inductive coding process to open-ended responses to a question about the most stressful event or major crisis that participants had ever experienced, resulting in a set of 15 categories. We compare psychologic wellbeing across self-identified most stressful life event, accounting for sampling and loss-to-follow-up weights. Overall, stillbirth was most commonly identified as the most stressful event (18.3% [95% CI: 15.6, 21.5]), followed by loss by death of someone other than a child (17.25% [95% CI: 13.9, 20.3]). For participants who experienced a perinatal loss, we fit multivariable logistic regression models to quantify the association between report of childhood maltreatment and identifying the perinatal loss as the most stressful life event, calculating risk ratios (RRs). Reporting any moderate or severe childhood maltreatment was associated with 24% lower risk of identifying the perinatal loss as the most stressful life event (adjusted RR: 0.76 [95% CI: 0.58, 1.01]), after adjusting for race/ethnicity, age, and education. These results demonstrate the value of combining standardized measures with open-ended, inductive approaches to measuring stress in large, population-based studies.

Objectively assessed sleep-disordered breathing during pregnancy and infant birthweight.

BACKGROUND: Sleep-disordered breathing (SDB) in pregnancy is associated with adverse maternal outcomes. The relationship between SDB and infant birthweight is unclear. This study's primary aim is to determine if objectively measured SDB in pregnancy is associated with infant birthweight. METHODS: We measured SDB objectively in early (6-15 weeks' gestation) and mid (22-31 weeks' gestation) pregnancy in a large cohort of nulliparous women. SDB was defined as an Apnea-Hypopnea Index ≥5 and in secondary analyses we also examined measures of nocturnal hypoxemia. We used a modified Poisson regression approach to estimate relative risks (RR) of large-for-gestational-age (LGA: >90th percentile for gestational age) and small-for-gestational-age (SGA: <10th percentile for gestational age) birthweights. RESULTS: The prevalence of early-pregnancy SDB was nearly 4%. The incidence of mid-pregnancy SDB was nearly 6.0%. The prevalence of LGA and SGA was 7.4% and 11.9%, respectively. Early-pregnancy SDB was associated with a higher risk of LGA in unadjusted models (RR 2.2, 95% CI 1.3-3.5) but not BMI-adjusted models (aRR 1.0, 95% CI 0.6-1.8). Mid-pregnancy SDB was not associated with SGA or LGA. Mid-pregnancy nocturnal hypoxemia (% of sleep time <90% oxygen saturation) and increasing nocturnal hypoxemia from early to mid-pregnancy were associated with a higher risk of LGA in BMI-adjusted models. SDB and nocturnal hypoxemia were not associated with SGA. CONCLUSIONS: SDB in pregnancy was not associated with an increased risk of LGA or SGA birthweight, independent of BMI. Some measures nocturnal hypoxemia were associated with an increase in LGA risk, independent of BMI. ClinicalTrials.gov Registration number NCT02231398.

Early Pregnancy Atherogenic Profile in a First Pregnancy and Hypertension Risk 2 to 7 Years After Delivery.

Background Cardiovascular risk in young adulthood is an important determinant of lifetime cardiovascular disease risk. Women with adverse pregnancy outcomes (APOs) have increased cardiovascular risk, but the relationship of other factors is unknown. Methods and Results Among 4471 primiparous women, we related first-trimester atherogenic markers to risk of APO (hypertensive disorders of pregnancy, preterm birth, small for gestational age), gestational diabetes mellitus (GDM) and hypertension (130/80 mm Hg or antihypertensive use) 2 to 7 years after delivery. Women with an APO/GDM (n=1102) had more atherogenic characteristics (obesity [34.2 versus 19.5%], higher blood pressure [systolic blood pressure 112.2 versus 108.4, diastolic blood pressure 69.2 versus 66.6 mm Hg], glucose [5.0 versus 4.8 mmol/L], insulin [77.6 versus 60.1 pmol/L], triglycerides [1.4 versus 1.3 mmol/L], and high-sensitivity C-reactive protein [5.6 versus 4.0 nmol/L], and lower high-density lipoprotein cholesterol [1.8 versus 1.9 mmol/L]; P<0.05) than women without an APO/GDM. They were also more likely to develop hypertension after delivery (32.8% versus 18.1%, P<0.05). Accounting for confounders and factors routinely assessed antepartum, higher glucose (relative risk [RR] 1.03 [95% CI, 1.00-1.06] per 0.6 mmol/L), high-sensitivity C-reactive protein (RR, 1.06 [95% CI, 1.02-1.11] per 2-fold higher), and triglycerides (RR, 1.27 [95% CI, 1.14-1.41] per 2-fold higher) were associated with later hypertension. Higher physical activity was protective (RR, 0.93 [95% CI, 0.87-0.99] per 3 h/week). When evaluated as latent profiles, the nonobese group with higher lipids, high-sensitivity C-reactive protein, and insulin values (6.9% of the cohort) had increased risk of an APO/GDM and later hypertension. Among these factors, 7% to 15% of excess RR was related to APO/GDM. Conclusions Individual and combined first-trimester atherogenic characteristics are associated with APO/GDM occurrence and hypertension 2 to 7 years later. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02231398.

Association of second trimester uterine artery Doppler parameters with maternal hypertension 2-7 years after delivery.

BACKGROUND: Reduced uterine artery compliance is associated with adverse pregnancy outcomes (APOs) and may indicate underlying maternal cardiovascular pathology. We investigated associations between second trimester uterine artery Doppler (UAD) parameters and incident maternal hypertension 2-7 years after delivery. METHODS: A cohort of 10,038 nulliparous US participants was recruited early in pregnancy. A subgroup of 3739, without baseline hypertension and with complete follow-up visits 2-7 years after delivery, were included in this analysis. We investigated UAD indicators of compliance including: 1) early diastolic notch; 2) resistance index (RI); and 3) pulsatility index (PI). We defined hypertension as systolic blood pressure ≥130 mmHg, diastolic ≥80 mmHg, or antihypertensive medication use. We calculated odds ratios (OR) and 95 % confidence intervals (95%CI) for associations between UAD parameters and hypertension, adjusting for age, obesity, race/ethnicity, insurance, smoking, and APOs. RESULTS: A total of 187 (5 %) participants developed hypertension after the index pregnancy. Presence of early diastolic notch on UAD was not associated with incident hypertension. Increased RI and PI correlated with higher odds of hypertension (RI: adjusted OR 1.15 [95 % CI 1.03-1.30]; PI: adjusted OR 1.03 [95%CI 1.01-1.05] for each 0.1 unit increase). Maximum RI above 0.84 or maximum PI above 2.3 more than doubled the odds of incident hypertension (RI: adjusted OR 2.49, 95%CI 1.45-4.26; PI: adjusted OR 2.36, 95%CI 1.45-3.86). CONCLUSION: Higher resistance and pulsatility indices measured on second trimester UAD were associated with increased odds of incident hypertension 2-7 years later, and may be biomarkers of higher maternal cardiovascular risk.

Causal Genetic Variants in Stillbirth.

BACKGROUND: In the majority of cases, the cause of stillbirth remains unknown despite detailed clinical and laboratory evaluation. Approximately 10 to 20% of stillbirths are attributed to chromosomal abnormalities. However, the causal nature of single-nucleotide variants and small insertions and deletions in exomes has been understudied. METHODS: We generated exome sequencing data for 246 stillborn cases and followed established guidelines to identify causal variants in disease-associated genes. These genes included those that have been associated with stillbirth and strong candidate genes. We also evaluated the contribution of 18,653 genes in case-control analyses stratified according to the degree of depletion of functional variation (described here as "intolerance" to variation). RESULTS: We identified molecular diagnoses in 15 of 246 cases of stillbirth (6.1%) involving seven genes that have been implicated in stillbirth and six disease genes that are good candidates for phenotypic expansion. Among the cases we evaluated, we also found an enrichment of loss-of-function variants in genes that are intolerant to such variation in the human population (odds ratio, 2.15; 95% confidence interval [CI], 1.46 to 3.06). Loss-of-function variants in intolerant genes were concentrated in genes that have not been associated with human disease (odds ratio, 2.22; 95% CI, 1.41 to 3.34), findings that differ from those in two postnatal clinical populations that were also evaluated in this study. CONCLUSIONS: Our findings establish the diagnostic utility of clinical exome sequencing to evaluate the role of small genomic changes in stillbirth. The strength of the novel risk signal (as generated through the stratified analysis) was similar to that in known disease genes, which indicates that the genetic cause of stillbirth remains largely unknown. (Funded by the Institute for Genomic Medicine.).

Psychosocial and Sociodemographic Contributors to Breastfeeding Intention in First-Time Mothers.

OBJECTIVE: Breastfeeding has multiple benefits for women and babies. Understanding factors contributing to intention to exclusively breastfeed may allow for improving the rates in first-time mothers. The study objective was to examine factors associated with a woman's intention to breastfeed her first child. METHODS: A secondary analysis of the prospective "Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be" (nuMoM2b) study of nulliparous women in the U.S. with singleton pregnancies was performed. Sociodemographic and psychosocial factors were analyzed for associations with breastfeeding intention. RESULTS: For the 6443 women with complete information about breastfeeding intention and all factors under consideration, women who intended to breastfeed (either exclusively or any breastfeeding) were more likely to be older, not black, have reached a higher level of education, have higher incomes, have a lower body mass index (BMI), and be nonsmokers. Reporting a planned pregnancy and several psychosocial measures were also associated with intention to breastfeed. In the multivariable analysis for exclusive breastfeeding, in addition to age, BMI, race, income, education, and smoking, of the psychosocial measures assessed, only women with higher hassle intensity ratios on the Pregnancy Experience Scale had lower odds of exclusive breastfeeding intention (OR 0.71, 95% CI 0.55-0.92). Other psychosocial measures were not associated with either exclusive breastfeeding or any breastfeeding after controlling for demographic characteristics. CONCLUSIONS FOR PRACTICE: Several sociodemographic factors, having a planned pregnancy, and fewer intense pregnancy hassles compared to uplifts are associated with intention to exclusively breastfeed. Identifying these factors may allow providers to identify women for focused, multilevel efforts to enhance breastfeeding rates.

Quality of periconceptional dietary intake and maternal and neonatal outcomes.

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.

Associations of perceived prenatal stress and adverse pregnancy outcomes with perceived stress years after delivery.

Maternal stress is a risk factor for adverse pregnancy outcomes (APOs). This study evaluates the associations of prenatal stress and APOs with maternal stress years after pregnancy. The 10-item Perceived Stress Scale (PSS) (0-40 range) was completed in the first and third trimesters, and 2-7 years after delivery among a subsample (n = 4161) of nulliparous women enrolled at eight US medical centers between 2010 and 2013 in a prospective, observational cohort study. Demographics, medical history, and presence of APOs (gestational diabetes (GDM), hypertensive disorders of pregnancy (HDP), preeclampsia (PE), and medically indicated or spontaneous preterm birth (miPTB, sPTB)) were obtained. The associations of prenatal PSS and the presence of APOs with PSS scores years after delivery were estimated using multivariable linear regression. Mean PSS scores were 12.5 (95% CI 12.3, 12.7) and 11.3 (95% CI 11.1, 11.5) in the first and third trimesters respectively and 14.9 (95% CI 14.7, 15.1) 2-7 years later, an average increase of 2.4 points (95% CI 2.2, 2.6) from the start of pregnancy. Regressing PSS scores after delivery on first-trimester PSS and PSS increase through pregnancy showed positive associations, with coefficients (95% CI) of 2.8 (2.7, 3.0) and 1.5 (1.3, 1.7) per 5-point change, respectively. Adding APO indicator variables separately showed higher PSS scores for women with HDP (0.7 [0.1, 1.3]), PE (1.3 [0.6, 2.1]), and miPTB (1.3 [0.2, 2.4]), but not those with GDM or sPTB. In this geographically and demographically diverse sample, prenatal stress and some APOs were positively associated with stress levels 2-7 years after pregnancy.ClinicalTrials.gov Registration number NCT02231398.