The expanded spectrum of human disease associated with GREB1L likely includes complex congenital heart disease.

OBJECTIVE: GREB1L has been linked prenatally to Potter's sequence, as well as less severe anomalies of the kidney, uterus, inner ear, and heart. The full phenotypic spectrum is unknown. The purpose of this study was to characterize known and novel pre- and postnatal phenotypes associated with GREB1L. METHODS: We solicited cases from the Fetal Sequencing Consortium, screened a population-based genomic database, and conducted a comprehensive literature search to identify disease cases associated with GREB1L. We present a detailed phenotypic spectrum and molecular changes. RESULTS: One hundred twenty-seven individuals with 51 unique pathogenic or likely pathogenic GREB1L variants were identified. 24 (47%) variants were associated with isolated kidney anomalies, 19 (37%) with anomalies of multiple systems, including one case of hypoplastic left heart syndrome, five (10%) with isolated sensorineural hearing loss, two (4%) with isolated uterine agenesis; and one (2%) with isolated tetralogy of Fallot. CONCLUSION: GREB1L may cause complex congenital heart disease (CHD) in humans. Clinicians should consider GREB1L testing in the setting of CHD, and cardiac screening in the setting of GREB1L variants.

Monogenic conditions and central nervous system anomalies: A prospective study, systematic review and meta-analysis.

OBJECTIVES: Determine the incremental diagnostic yield of prenatal exome sequencing (pES) over chromosome microarray (CMA) or G-banding karyotype in fetuses with central nervous system (CNS) abnormalities. METHODS: Data were collected via electronic searches from January 2010 to April 2022 in MEDLINE, Cochrane, Web of Science and EMBASE. The NHS England prenatal exome cohort was also included. Incremental yield was calculated as a pooled value using a random-effects model. RESULTS: Thirty studies were included (n = 1583 cases). The incremental yield with pES for any CNS anomaly was 32% [95%CI 27%-36%; I2 = 72%]. Subgroup analysis revealed apparent incremental yields in; (a) isolated CNS anomalies; 27% [95%CI 19%-34%; I2 = 74%]; (b) single CNS anomaly; 16% [95% CI 10%-23%; I2 = 41%]; (c) more than one CNS anomaly; 31% [95% Cl 21%-40%; I2 = 56%]; and (d) the anatomical subtype with the most optimal yield was Type 1 malformation of cortical development, related to abnormal cell proliferation or apoptosis, incorporating microcephalies, megalencephalies and dysplasia; 40% (22%-57%; I2 = 68%). The commonest syndromes in isolated cases were Lissencephaly 3 and X-linked hydrocephalus. CONCLUSIONS: Prenatal exome sequencing provides a high incremental diagnostic yield in fetuses with CNS abnormalities with optimal yields in cases with multiple CNS anomalies, particularly those affecting the midline, posterior fossa and cortex.

Prevalence and Clinical Significance of Commonly Diagnosed Genetic Disorders in Preterm Infants.

Background and Objectives: Preterm infants (<34 weeks' gestation) experience high rates of morbidity and mortality before hospital discharge. Genetic disorders substantially contribute to morbidity and mortality in related populations. The prevalence and clinical impact of genetic disorders is unknown in this population. We sought to determine the prevalence of commonly diagnosed genetic disorders in preterm infants, and to determine the association of disorders with morbidity and mortality. Methods: This was a retrospective multicenter cohort study of infants born from 23 to 33 weeks' gestation between 2000 and 2020. Genetic disorders were abstracted from diagnoses present in electronic health records. We excluded infants transferred from or to other health care facilities prior to discharge or death when analyzing clinical outcomes. We determined the adjusted odds of pre-discharge morbidity or mortality after adjusting for known risk factors. Results: Of 320,582 infants, 4196 (1.3%) had genetic disorders. Infants with trisomy 13, 18, 21, or cystic fibrosis had greater adjusted odds of severe morbidity or mortality. Of the 17,427 infants who died, 566 (3.2%) had genetic disorders. Of the 65,968 infants with a severe morbidity, 1319 (2.0%) had genetic disorders.ConclusionsGenetic disorders are prevalent in preterm infants, especially those with life-threatening morbidities. Clinicians should consider genetic testing for preterm infants with severe morbidity and maintain a higher index of suspicion for life-threatening morbidities in preterm infants with genetic disorders. Prospective genomic research is needed to clarify the prevalence of genetic disorders in this population, and the contribution of genetic disorders to preterm birth and subsequent morbidity and mortality. Article Summary: Genetic disorders were found in 1.3% of preterm infants and at a higher rate (2.0%) in infants who died or developed severe morbidity. What's Known on This Subject: Previous research described the prevalence and associated short-term morbidity and mortality of trisomy 13, 18, and 21 in preterm infants. The prevalence of other commonly diagnosed genetic disorders and associated short-term morbidity and mortality in preterm infants is unknown. What This Study Adds: In a multicenter, retrospective cohort of 320,582 preterm (<34 weeks' gestation) infants, we found that 1.3% had genetic disorders diagnosed through standard care. Multiple disorders were associated with increased adjusted odds of morbidities or mortality prior to hospital discharge. Contributors Statement Page: Selin S. Everett conceptualized and designed the study, conducted analyses, drafted the initial manuscript, and critically reviewed and revised the manuscript.Dr. Thomas Hays conceptualized and designed the study, drafted the initial manuscript, and critically reviewed and revised the manuscript.Miles Bomback conceptualized and designed the study and critically reviewed and revised the manuscript.Drs. Veeral N. Tolia and Reese H. Clark coordinated and supervised data collection and critically reviewed and revised the manuscript.Dr. Rakesh Sahni conceptualized and designed the study and critically reviewed and revised the manuscript.Dr. Alex Lyford conducted analyses and critically reviewed and revised the manuscript. Dr. Ronald J. Wapner reviewed and critically revised the manuscript.All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Maternal and Delivery Characteristics and Self-Reported Perceived Control During Labor.

OBJECTIVE: To evaluate the association between maternal and delivery characteristics and self-reported perceived control during childbirth. METHODS: A secondary analysis of a multicenter randomized trial was conducted to compare labor induction at 39 weeks of gestation with expectant management in low-risk nulliparous people. Six to 96 hours after delivery, participants who experienced labor completed the Labor Agentry Scale, a validated self-administered questionnaire to ascertain perceived control during childbirth. Scores range from 29 to 203, with higher scores indicating a sense of greater control. Multivariable linear regression was used to determine which maternal and delivery characteristics were associated with the Labor Agentry Scale score. Eligible characteristics included age, self-reported race and ethnicity, marital status, employment status, type of insurance, previous pregnancy loss before 20 weeks of gestation, body mass index (BMI), smoking, alcohol use, mode of delivery, labor pain (0-10 points), and a composite of perinatal death or severe neonatal complications. Significant variables ( P <.05) were retained in the final multivariable model, and adjusted mean differences (95% CIs) between groups were estimated. RESULTS: Of 6,106 people enrolled in the trial, 6,038 experienced labor, of whom 5,750 (95.2%) completed the Labor Agentry Scale and were included in this analysis. Mean [95% CI] adjusted Labor Agentry Scale scores were significantly lower among those who identified as Asian (-6.4 [-10.5 to -2.3]) or Hispanic (-3.7 [-5.7 to -1.7]) compared with White, smoked compared with did not smoke (-2.8 [-5.5 to -0.1]), had BMIs of 35 or higher compared with less than 30 (-2.0 [-3.8 to -0.2]), were unemployed (-3.15 [-4.76 to -1.55]), did not have private health insurance (-2.61 [-4.47 to -0.76]), underwent operative vaginal (-5.1 [-7.7 to -2.6]) or cesarean (-14.4 [-16.1 to -12.6]) delivery compared with spontaneous vaginal delivery, and reported greater labor pain score of 8 or higher compared with less than 8 (-11.9 [-13.4 to -10.4]). Mean [95% CI] adjusted Labor Agentry Scale scores were significantly higher among people who were employed compared with unemployed (3.2 [1.6-4.8]) and had private compared with nonprivate insurance (2.6 [0.76-4.5]). CONCLUSION: In nulliparous people at low risk, unemployment, lack of private health insurance, Asian race, Hispanic ethnicity, smoking, operative delivery, and more labor pain were associated with lower perceived control during labor. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT01990612.

Maternal Morbidity Risk Factors in Nulliparas.

OBJECTIVE: For every incidence of maternal mortality, maternal morbidity is thought to occur in another 50 to 100 individuals in the United States. Multiple risk factors for severe maternal morbidity have been identified, but counseling about specific risk in pregnancy remains difficult, particularly nulliparous individuals as prior obstetric history is one of the factors influencing risk for severe maternal morbidity. The objective of this study is to examine the association between sociodemographic and laboratory assessments in the first trimester and maternal morbidity in nulliparas. STUDY DESIGN: This was a secondary analysis of a large, multicenter prospective observational cohort of nulliparas. The primary maternal outcome was a composite of hypertensive disorders of pregnancy (HDP), hemorrhage (transfusion, hemorrhage, hysterectomy, other surgery, readmission for bleeding), infection (endometritis, wound infection or dehiscence, pneumonia, sepsis, infection during labor and delivery, readmission for infection through day 14), venous thromboembolic events (VTE) (deep venous thrombosis, or pulmonary embolus), or maternal death within 14 days of delivery. Sociodemographic and clinical factors were compared between people with and without maternal morbidity. Relative risk and 95% confidence interval for maternal morbidity was calculated using log-binomial regression, adjusted for baseline characteristics that had a significant independent relationship with maternal morbidity with a p-value <0.05. RESULTS: Of 9,445 pregnant people in the analysis, 18.2% (n = 1,716) experienced the composite maternal morbidity; the most common component was HDP (13.1%, n = 1,244) followed by infection (4.43%, n = 420), hemorrhage (2.27%, n = 215), VTE (0.12%, n = 11), and death (0.01%, n = 1). In a multivariable model, self-identified Black race, first trimester obesity, pregestational diabetes, chronic hypertension, and chronic kidney disease were significantly associated with the primary maternal outcome. CONCLUSION: More than one in six nulliparas experienced the composite maternal morbidities. Maternal morbidity was associated with self-identified Black race, obesity, and multiple preexisting medical comorbidities. KEY POINTS: · One in six nulliparas experience maternal morbidity in their first pregnancy related to hypertensive disorders of pregnancy, infection, hemorrhage, and venous thromboembolism.. · Risk factors for maternal morbidity in nulliparas include Black race, prepregnancy body mass index, and preexisting medical conditions.. · The preexisting medical conditions with the strongest association with maternal morbidity included pregestational diabetes, chronic hypertension, and chronic kidney disease..

Short-term neonatal outcomes of pregnancies complicated by maternal obesity.

BACKGROUND: Maternal obesity complicates a high number of pregnancies. The degree to which neonatal outcomes are adversely affected is unclear. OBJECTIVE: This study aimed to evaluate neonatal outcomes of pregnancies complicated by maternal obesity. STUDY DESIGN: This study was a secondary analysis of a cohort of deliveries occurring on randomly selected days at 25 hospitals from 2008 to 2011. Data were collected by certified abstractors. This analysis included singleton deliveries between 24 and 42 weeks of gestation. Body mass index was calculated on the basis of maternal height and most recent weight before delivery. Normal and overweight (reference group; body mass index, 18.5-29.9 kg/m2), obese (body mass index, 30.0-39.9 kg/m2), morbidly obese (body mass index, 40.0-49.9 kg/m2), and super morbidly obese (body mass index, ≥50 kg/m2) patients were compared. Patients in the reference group were matched in a 1:1 ratio with those in all other groups with obesity using the baseline characteristics of age, race and ethnicity, previous cesarean delivery, preexisting diabetes mellitus, chronic hypertension, parity, cigarette use, and insurance status. The primary outcome was composite neonatal morbidity, including fetal or neonatal death, hypoxic-ischemic encephalopathy, respiratory distress syndrome, intraventricular hemorrhage grade 3 or 4, necrotizing enterocolitis, sepsis, birth injury, seizures, or ventilator use. We used a modified Poisson regression to examine the associations between body mass index and composite neonatal outcome. Preterm delivery at <37 weeks of gestation and the presence of maternal preeclampsia or eclampsia were included in the final model because of their known associations with neonatal outcomes. RESULTS: Overall, 52,162 patients and their neonates were included after propensity score matching. Of these, 21,704 (41.6%) were obese, 3787 (7.3%) were morbidly obese, and 590 (1.1%) were super morbidly obese. A total of 2103 neonates (4.0%) had the composite outcome. Neonates born to pregnant people with morbid obesity had a 33% increased risk of composite neonatal morbidity compared with those in the reference group (adjusted odds ratio, 1.33; 95% confidence interval, 1.17-1.52), but no significant association was observed for persons with obesity (adjusted odds ratio, 1.05; 95% confidence interval, 0.97-1.14) or with super morbid obesity (adjusted odds ratio, 1.18; 95% confidence interval, 0.86-1.64). CONCLUSION: Compared with the reference group, gravidas with morbid obesity were at higher risk of composite neonatal morbidity.

Long-Term Maternal Metabolic and Cardiovascular Phenotypes after a Pregnancy Complicated by Mild Gestational Diabetes Mellitus or Obesity.

OBJECTIVE: The aim of this study was to evaluate the association of mild gestational diabetes mellitus (GDM) and obesity with metabolic and cardiovascular markers 5 to 10 years after pregnancy. STUDY DESIGN: This was a secondary analysis of 5- to 10-year follow-up study of a mild GDM treatment trial and concurrent observational cohort of participants ineligible for the trial with abnormal 1-hour glucose challenge test only. Participants with 2-hour glucose tolerance test at follow-up were included. The primary exposures were mild GDM and obesity. The outcomes were insulinogenic index (IGI), 1/homeostatic model assessment of insulin resistance (HOMA-IR), and cardiovascular markers vascular endothelial growth factor, (VEGF), vascular cell adhesion molecule 1 (VCAM-1), cluster of differentiation 40 ligand (CD40L), growth differentiation factor 15 (GDF-15), and suppression of tumorgenesis 2 (ST-2). Multivariable linear regression estimated the association of GDM and obesity with biomarkers. RESULTS: Of 951 participants in the parent study, 642 (68%) were included. Lower 1/HOMA-IR were observed in treated and untreated GDM groups, compared with non-GDM (mean differences, -0.24 and -0.15; 95% confidence intervals [CIs], -0.36 to -0.12 and -0.28 to -0.03, respectively). Lower VCAM-1 (angiogenesis) was observed in treated GDM group (mean difference, -0.11; 95% CI, -0.19 to -0.03). GDM was not associated with IGI or other biomarkers. Obesity was associated with lower 1/HOMA-IR (mean difference, -0.42; 95% CI, -0.52 to -0.32), but not other biomarkers. CONCLUSION: Prior GDM and obesity are associated with more insulin resistance but not insulin secretion or consistent cardiovascular dysfunction 5 to 10 years after delivery. KEY POINTS: · Mild GDM increases the risk of insulin resistance 5 to 10 years postpartum but not pancreatic dysfunction.. · Obesity increases the risk of insulin resistance 5 to 10 years postpartum but not pancreatic dysfunction.. · Neither mild GDM nor obesity increased the risk of cardiovascular dysfunction 5 to 10 years postpartum..

Racial and Ethnic Disparities in Adverse Perinatal Outcomes at Term.

OBJECTIVE: This study aimed to evaluate whether racial and ethnic disparities in adverse perinatal outcomes exist at term. STUDY DESIGN: We performed a secondary analysis of a multicenter observational study of 115,502 pregnant patients and their neonates (2008-2011). Singleton, nonanomalous pregnancies delivered from 37 to 41 weeks were included. Race and ethnicity were abstracted from the medical record and categorized as non-Hispanic White (White; referent), non-Hispanic Black (Black), non-Hispanic Asian (Asian), or Hispanic. The primary outcome was an adverse perinatal composite defined as perinatal death, Apgar score < 4 at 5 minutes, ventilator support, hypoxic-ischemic encephalopathy, subgaleal hemorrhage, skeletal fracture, infant stay greater than maternal stay (by ≥ 3 days), brachial plexus palsy, or facial nerve palsy. RESULTS: Of the 72,117 patients included, 48% were White, 20% Black, 5% Asian, and 26% Hispanic. The unadjusted risk of the primary outcome was highest for neonates of Black patients (3.1%, unadjusted relative risk [uRR] = 1.16, 95% confidence interval [CI]: 1.04-1.30), lowest for neonates of Hispanic patients (2.1%, uRR = 0.80, 95% CI: 0.71-0.89), and no different for neonates of Asian (2.6%), compared with those of White patients (2.7%). In the adjusted model including age, body mass index (BMI), smoking, obstetric history, and high-risk pregnancy, differences in risk for the primary outcome were no longer observed for neonates of Black (adjusted relative risk [aRR] = 1.06, 95% CI: 0.94-1.19) and Hispanic (aRR = 0.92, 95% CI: 0.81-1.04) patients. Adding insurance to the model lowered the risk for both groups (aRR = 0.85, 95% CI: 0.75-0.96 for Black; aRR = 0.68, 95% CI: 0.59-0.78 for Hispanic). CONCLUSION: Although neonates of Black patients have the highest frequency of adverse perinatal outcomes at term, after adjustment for sociodemographic factors, this higher risk is no longer observed, suggesting the importance of developing strategies that address social determinants of health to lessen extant health disparities. KEY POINTS: · Term neonates of Black patients have the highest crude frequency of adverse perinatal outcomes.. · After adjustment for confounders, higher risk for neonates of Black patients is no longer observed.. · Disparities in outcomes are strongly related to insurance status..

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..

Hypertensive disorders during pregnancy and polycystic ovary syndrome are associated with child communication and social skills in a sex-specific and androgen-dependent manner.

Prenatal exposure to testosterone is implicated in the etiology of autism spectrum disorder (ASD). Hypertensive disorders of pregnancy and polycystic ovary syndrome are associated with both hyperandrogenism and increased risk for ASD. We examined whether increased maternal testosterone mediates the relationship between these hyperandrogenic disorders (HDs) during pregnancy and child communication and social skills. Maternal plasma was collected during the second trimester and parent-report measures of child communication and social skills were obtained at 4.5-6.5 years of age from 270 participants enrolled in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b). Our retrospective frequency-matched cohort study design identified 58 mothers with one or both of the HDs and 58 matched controls. Women diagnosed with an HD who carried a female had higher testosterone levels compared to those carrying a male (t(56) = -2.70, p = 0.01). Compared to females controls, females born to women with an HD had significantly higher scores on the Social Communication Questionnaire (t(114) = -2.82, p =0.01). Maternal testosterone partially mediated the relationship between a diagnosis of an HD and SCQ scores among females. These findings point to sex-specific associations of two HDs - hypertensive disorders of pregnancy and polycystic ovary syndrome - on child communication and social skills and a mediating effect of maternal testosterone during pregnancy. Further research is needed to understand placental-mediated effects of maternal testosterone on child brain development and neurodevelopmental outcomes.

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).

Association of Maternal Body Mass Index and Maternal Morbidity And Mortality.

OBJECTIVE: This study aimed to assess the association of maternal body mass index (BMI) with a composite of severe maternal outcomes. STUDY DESIGN: Secondary analysis of a cohort of deliveries on randomly selected days at 25 hospitals from 2008 to 2011. Data on comorbid conditions, intrapartum events, and postpartum course were collected. The reference group (REF, BMI: 18.5-29.9kg/m2), obese (OB; BMI: 30-39.9kg/m2), morbidly obese (MO; BMI: 40-49.9kg/m2), and super morbidly obese (SMO; BMI ≥ 50kg/m2) women were compared. The composite of severe maternal outcomes was defined as death, intensive care unit (ICU) admission, ventilator use, deep venous thrombosis/pulmonary embolus (DVT/PE), sepsis, hemorrhage, disseminated intravascular coagulation (DIC), unplanned operative procedure, or stroke. Patients in the REF group were matched 1:1 with those in all other obesity groups based on propensity score using the baseline characteristics of age, race/ethnicity, previous cesarean, preexisting diabetes, chronic hypertension, parity, cigarette use, and insurance status. Multivariable Poisson's regression was used to estimate adjusted relative risks (aRRs) and 95% confidence intervals (CIs) for the association between BMI and the composite outcome. Because cesarean delivery may be in the causal pathway between obesity and adverse maternal outcomes, models were then adjusted for mode of delivery to evaluate potential mediation. RESULTS: A total of 52,162 pregnant patients are included in the analysis. Risk of composite maternal outcomes was increased for SMO compared with REF but not for OB and MO [OB: aRR=1.06, 95% CI: 0.99-1.14; MO: aRR=1.10, 95% CI: 0.97-1.25; SMO: aRR=1.32, 95% CI: 1.02-1.70]. However, in the mediation analysis, cesarean appears to mediate 46% (95% CI: 31-50%) of the risk of severe morbidity for SMO compared with REF. CONCLUSION: Super morbid obesity is significantly associated with increased serious maternal morbidity and mortality; however, cesarean appears to mediate this association. Obesity and morbid obesity are not associated with maternal morbidity and mortality. KEY POINTS: · Super morbid obesity is associated with increased morbidity.. · Cesarean appears to mediate the association between super morbid obesity and morbidity.. · Obesity and morbid maternal obesity are not associated with morbidity..

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.

Prediction of Cerebral Palsy or Death among Preterm Infants Who Survive the Neonatal Period.

OBJECTIVE: To assess whether neonatal morbidities evident by the time of hospital discharge are associated with subsequent cerebral palsy (CP) or death. STUDY DESIGN: This is a secondary analysis of data from a multicenter placebo-controlled trial of magnesium sulfate for the prevention of CP. The association between prespecified intermediate neonatal outcomes (n = 11) and demographic and clinical factors (n = 10) evident by the time of discharge among surviving infants (n = 1889) and the primary outcome of death or moderate/severe CP at age 2 (n = 73) was estimated, and a prediction model was created. RESULTS: Gestational age in weeks at delivery (odds ratio [OR]: 0.74, 95% confidence interval [CI]: 0.67-0.83), grade III or IV intraventricular hemorrhage (IVH) (OR: 5.3, CI: 2.1-13.1), periventricular leukomalacia (PVL) (OR: 46.4, CI: 20.6-104.6), and male gender (OR: 2.5, CI: 1.4-4.5) were associated with death or moderate/severe CP by age 2. Outcomes not significantly associated with the primary outcome included respiratory distress syndrome, bronchopulmonary dysplasia, seizure, necrotizing enterocolitis, neonatal hypotension, 5-minute Apgar score, sepsis, and retinopathy of prematurity. Using all patients, the receiver operating characteristic curve for the final prediction model had an area under the curve of 0.84 (CI: 0.78-0.89). Using these data, the risk of death or developing CP by age 2 can be calculated for individual surviving infants. CONCLUSION: IVH and PVL were the only neonatal complications evident at discharge that contributed to an individual infant's risk of the long-term outcomes of death or CP by age 2. A model that includes these morbidities, gestational age at delivery, and gender is predictive of subsequent neurologic sequelae. KEY POINTS: · Factors known at hospital discharge are identified which are independently associated with death or CP by age 2.. · A model was created and validated using these findings to counsel parents.. · The risk of death or CP can be calculated at the time of hospital discharge..

Prenatal Nicotine or Cannabis Exposure and Offspring Neurobehavioral Outcomes.

OBJECTIVE: To study the association between nicotine or cannabis metabolite presence in maternal urine and child neurodevelopmental outcomes. METHODS: We conducted a secondary analysis of two parallel multicenter randomized controlled trials of treatment for hypothyroxinemia or subclinical hypothyroidism among pregnant individuals enrolled at 8-20 weeks of gestation. All maternal-child dyads with a maternal urine sample at enrollment and child neurodevelopmental testing were included (N=1,197). Exposure was urine samples positive for nicotine (cotinine) or cannabis 11-nor-9-carboxy-delta-9-tetrahydrocannabinol [THC-COOH]) or both metabolites. Primary outcome was child IQ at 60 months. Secondary outcomes included cognitive, motor and language, attention, behavioral and social competency, and differential skills assessments at 12, 24, 36, and 48 months. Quantile regression analysis was performed with confounder adjustment. RESULTS: Of 1,197 pregnant individuals, 99 (8.3%) had positive cotinine samples and 47 (3.9%) had positive THC-COOH samples; 33 (2.8%) were positive for both. Groups differed in self-reported race and ethnicity, education, marital status, insurance, and thyroid status. Median IQ was similar between cotinine-exposed and -unexposed children (90 vs 95, adjusted difference in medians -2.47, 95% CI -6.22 to 1.29) and THC-COOH-exposed and -unexposed children (89 vs 95, adjusted difference in medians -1.35, 95% CI -7.76 to 5.05). In secondary outcome analysis, children with THC-COOH exposure compared with those unexposed had higher attention scores at 48 months of age (57 vs 49, adjusted difference in medians 6.0, 95% CI 1.11-10.89). CONCLUSIONS: Neither prenatal nicotine nor cannabis exposure was associated with a difference in IQ. Cannabis exposure was associated with worse attention scores in early childhood. Longitudinal studies assessing associations between child neurodevelopmental outcomes and prenatal nicotine and cannabis exposure with a focus on timing and quantity of exposure are needed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00388297.

Outcomes in Twins Compared With Singletons Subsequent to Preterm Prelabor Rupture of Membranes.

OBJECTIVE: To compare maternal and neonatal outcomes after preterm prelabor rupture of membranes (PROM) from 23 to 34 weeks of gestation in twin compared with singleton gestations. METHODS: We conducted a secondary analysis of an obstetric cohort of 115,502 individuals and their singleton or twin neonates born in 25 hospitals nationwide (2008-2011). Those with preterm PROM from 23 0/7 through 33 6/7 weeks of gestation were included; neonates with major fetal anomalies were excluded. The coprimary outcomes for this analysis were composite maternal morbidity (chorioamnionitis, blood transfusion, postpartum endometritis, wound infection, sepsis, venous thromboembolism, intensive care unit admission, or death) and composite major neonatal morbidity (persistent pulmonary hypertension, intraventricular hemorrhage grade III or IV, seizures, hypoxic-ischemic encephalopathy, necrotizing enterocolitis stage II or III, bronchopulmonary dysplasia, stillbirth subsequent to admission, or neonatal death before discharge). Logistic regression was used to estimate unadjusted and adjusted odds ratios (ORs) with 95% CIs for twin compared with singleton gestations. RESULTS: Of 1,531 (1.3%) individuals who met eligibility criteria for this analysis, 218 (14.2%) had twin gestations. The median gestational age at preterm PROM was similar between those with twins and singletons (31.2 weeks [interquartile range 27.4-32.9] vs 30.6 weeks [interquartile range 26.9-32.7], P=.23); however, those with twin gestations had a shorter median latency period (2.0 days [interquartile range 1.0-5.0] vs 3.0 days [interquartile range 2.0-8.0], P<.001). After adjustment for potential confounders, odds of experiencing composite maternal morbidity (17.9% vs 19.3%, adjusted OR 0.97, 95% CI 0.66-1.42) or composite neonatal morbidity (20.4% vs 20.5%, OR 0.97, 95% CI 0.72-1.31) did not differ between groups. CONCLUSION: In a large, diverse cohort, the likelihood of composite maternal or neonatal morbidity per fetus after preterm PROM was similar for twin and singleton gestations.

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.

Neonatal and Maternal Composite Adverse Outcomes Among Low-Risk Nulliparous Women Compared With Multiparous Women at 39-41 Weeks of Gestation.

OBJECTIVE: To estimate whether the frequency of adverse maternal and neonatal outcomes differs between low-risk nulliparous and multiparous women at 39-41 weeks of gestation. METHODS: This is a secondary analysis of an observational obstetrics cohort of maternal-neonatal dyads at 25 hospitals. Low-risk women with nonanomalous singletons who delivered between 39 0/7 and 41 6/7 weeks of gestation were included. The composite neonatal adverse outcome included 5-minute Apgar score less than five, ventilator support or cardiopulmonary resuscitation, seizure, hypoxic ischemic encephalopathy, sepsis, bronchopulmonary dysplasia, persistent pulmonary hypertension, necrotizing enterocolitis, birth injury or perinatal death. The composite maternal adverse outcome included infection, third- or fourth-degree perineal laceration, thromboembolism, transfusion of blood products, or maternal death. Small for gestational age (SGA), large for gestational age (LGA), and shoulder dystocia requiring maneuvers were also evaluated. Multivariable regression was used to estimate adjusted relative risks (aRRs) and adjusted odds ratios (aORs) with 95% CIs. RESULTS: Of the 115,502 women in the overall cohort, 39,870 (34.5%) met eligibility criteria for this analysis; 18,245 (45.8%) were nulliparous. The risk of the composite neonatal adverse outcome (1.5% vs 1.0%, aRR 1.80, 95% CI 1.48-2.19), composite maternal adverse outcome (15.1% vs 3.3%, aRR 5.04, 95% CI 4.62-5.49), and SGA (8.9% vs 5.8%, aOR 1.45, 95% CI 1.33-1.57) was significantly higher in nulliparous than multiparous patients. The risk of LGA (aOR 0.65, 95% CI 0.60-0.71) and shoulder dystocia with maneuvers (aRR 0.68, 95% CI 0.60-0.77) was significantly lower in nulliparous rather than multiparous patients. CONCLUSION: The risk of composite adverse outcomes and SGA among low-risk nulliparous women at 39-41 weeks of gestation is significantly higher than among multiparous counterparts. However, nulliparous women had a lower risk of shoulder dystocia with maneuvers and LGA.

Profile of Reported Alcohol, Tobacco, and Recreational Drug Use in Nulliparous Women.

OBJECTIVE: To estimate alcohol, tobacco, and recreational drug use during pregnancy among nulliparous women. METHODS: In a cohort of nulliparous women followed through pregnancy from the first-trimester nuMoM2b (Nulliparous Outcomes in Pregnancy: Monitoring Mothers to be) study, self-reported use of alcohol, tobacco, and drugs was chronicled longitudinally at four study visits in this secondary analysis. Rates of use before pregnancy, in each trimester (visit 1, visit 2, visit 3, approximating each trimester), and at the time of delivery (visit 4) were recorded. The amount of alcohol, tobacco, and drug exposure were recorded using validated measures, and trends across pregnancy were analyzed. RESULTS: Of the 10,038 study participants, 10,028 had information regarding alcohol, tobacco, and drug use at visit 1, 9,412 at visit 2, 9,217 at visit 3, and 7,167 at visit 4. The rates of drinking alcohol, which had been 64.6% in the 3 months before pregnancy, were lower in pregnancy (3.9% at visit 1, 5.6% at visit 2, 7.0% at visit 3, and 6.1% at visit 4, P<.001 for all). Rates later in pregnancy were all greater than in the first trimester (P<.01). The rate of smoking in the 3 months before pregnancy, which was 17.8%, also declined at visit 1 (5.9%), and continued to decline through pregnancy (5.3% at visit 2, 4.7% at visit 3, and 3.9% at visit 4, with all rates lower than that of visit 1 [P<.01]). Although recreational drug use was relatively common in the months before pregnancy (33.8%), it also declined during pregnancy (1.1% at visit 2, 0.7% at visit 3, 0.4% at visit 4). CONCLUSIONS: In this geographically and ethnically diverse cohort of nulliparous women, rates of self-reported alcohol, smoking, and recreational drug use were all significantly lower during than before pregnancy. Nonetheless, rates of alcohol use rose as pregnancy progressed, highlighting the need for continued counseling throughout all trimesters of pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01322529.

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.