Reducing neonatal mortality associated with preterm birth: gaps in knowledge of the impact of antenatal corticosteroids on preterm birth outcomes in low-middle income countries

The Global Network’s Antenatal Corticosteroids Trial (ACT), was a multi-country, cluster-randomized trial to improve appropriate use of antenatal corticosteroids (ACS) in low-resource settings in low-middle income countries (LMIC). ACT substantially increased ACS use in the intervention clusters, but the intervention failed to show benefit in the targeted < 5th percentile birth weight infants and was associated with increased neonatal mortality and stillbirth in the overall population. In this issue are six papers which are secondary analyses related to ACT that explore potential reasons for the increase in adverse outcomes overall, as well as site differences in outcomes. The African sites appeared to have increased neonatal mortality in the intervention clusters while the Guatemalan site had a significant reduction in neonatal mortality, perhaps related to a combination of ACS and improving obstetric care in the intervention clusters. Maternal and neonatal infections were increased in the intervention clusters across all sites and increased infections are a possible partial explanation for the increase in neonatal mortality and stillbirth in the intervention clusters, especially in the African sites. The analyses presented here provide guidance for future ACS trials in LMIC. These include having accurate gestational age dating of study subjects and having care givers who can diagnose conditions leading to preterm birth and predict which women likely will deliver in the next 7 days. All study subjects should be followed through delivery and the neonatal period, regardless of when they deliver. Clearly defined measures of maternal and neonatal infection should be utilized. Trials in low income country facilities including clinics and those without newborn intensive care seem to be of the highest priority.Fil: McClure, Elizabeth M.. RTI International; Estados UnidosFil: Goldenberg, Robert L.. Columbia University; Estados UnidosFil: Jobe, Alan H.. Cincinnati Children’s Hospital; Estados UnidosFil: Miodovnik, Menachem. Eunice Kennedy Shriver National Institute of Child and Human Development; Estados UnidosFil: Koso Thomas, Marion. Eunice Kennedy Shriver National Institute of Child and Human Development; Estados UnidosFil: Buekens, Pierre. University of Tulane; Estados UnidosFil: Belizan, Jose. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Althabe, Fernando. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Trends and determinants of stillbirth in developing countries: results from the Global Network\u27s Population-Based Birth Registry.

BACKGROUND: Stillbirth rates remain high, especially in low and middle-income countries, where rates are 25 per 1000, ten-fold higher than in high-income countries. The United Nations\u27 Every Newborn Action Plan has set a goal of 12 stillbirths per 1000 births by 2030 for all countries. METHODS: From a population-based pregnancy outcome registry, including data from 2010 to 2016 from two sites each in Africa (Zambia and Kenya) and India (Nagpur and Belagavi), as well as sites in Pakistan and Guatemala, we evaluated the stillbirth rates and rates of annual decline as well as risk factors for 427,111 births of which 12,181 were stillbirths. RESULTS: The mean stillbirth rates for the sites were 21.3 per 1000 births for Africa, 25.3 per 1000 births for India, 56.9 per 1000 births for Pakistan and 19.9 per 1000 births for Guatemala. From 2010 to 2016, across all sites, the mean stillbirth rate declined from 31.7 per 1000 births to 26.4 per 1000 births for an average annual decline of 3.0%. Risk factors for stillbirth were similar across the sites and included maternal age \u3c 20 years and age \u3e 35 years. Compared to parity 1-2, zero parity and parity \u3e 3 were both associated with increased stillbirth risk and compared to women with any prenatal care, women with no prenatal care had significantly increased risk of stillbirth in all sites. CONCLUSIONS: At the current rates of decline, stillbirth rates in these sites will not reach the Every Newborn Action Plan goal of 12 per 1000 births by 2030. More attention to the risk factors and treating the causes of stillbirths will be required to reach the Every Newborn Action Plan goal of stillbirth reduction. TRIAL REGISTRATION: NCT01073475

Decision-to-incision times and maternal and infant outcomes.

Journal ArticleOBJECTIVE: To measure decision-to-incision intervals and related maternal and neonatal outcomes in a cohort of women undergoing emergency cesarean deliveries at multiple university-based hospitals comprising the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. METHODS: All women undergoing a primary cesarean delivery at a Network center during a 2-year time span were prospectively ascertained. Emergency procedures were defined as those performed for umbilical cord prolapse, placental abruption, placenta previa with hemorrhage, nonreassuring fetal heart rate pattern, or uterine rupture. Detailed information regarding maternal and neonatal outcomes, including the interval from the decision time to perform cesarean delivery to the actual skin incision, was collected. RESULTS: Of the 11,481 primary cesarean deliveries, 2,808 were performed for an emergency indication. Of these, 1,814 (65%) began within 30 minutes of the decision to operate. Maternal complication rates, including endometritis, wound infection, and operative injury, were not related to the decision-to-incision interval. Measures of newborn compromise including umbilical artery pH less than 7 and intubation in the delivery room were significantly greater when the cesarean delivery was commenced within 30 minutes, likely attesting to the need for expedited delivery. Of the infants with indications for an emergency cesarean delivery who were delivered more than 30 minutes after the decision to operate, 95% did not experience a measure of newborn compromise. CONCLUSION: Approximately one third of primary cesarean deliveries performed for emergency indications are commenced more than 30 minutes after the decision to operate, and the majority were for nonreassuring heart rate tracings. In these cases, adverse neonatal outcomes were not increased. LEVEL OF EVIDENCE: II-2

Maternal safety of the delayed-release doxylamine and pyridoxine combination for nausea and vomiting of pregnancy; a randomized placebo controlled trial

Background: Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expecting mothers. In April 2013 the FDA approved the delayed release combination of doxylamine succinate and -pyridoxine hydrochloride (Diclegis®) for NVP, following a phase 3 randomized trial in pregnant women. The fetal safety of this medication has been proven by numerous studies. However, because it is the only FDA-approved medication for NVP that is likely to be used by a large number of pregnant women, its maternal safety is an important public health question. The Objective is to evaluate the maternal safety of doxylamine succinate -pyridoxine hydrochloride delayed-release preparation (Diclegis® as compared to placebo. Methods: We randomized women suffering from NVP to receive Diclegis® (n = 131) or placebo (n = 125) for 14 days at doses ranging from 2-4 tablets a day, based on a pre-specified titration protocol response to symptoms. Adverse events were collected through patient diaries, clinical examination and laboratory testing. Results: Doxylamine succinate 10 mg and pyridoxine hydrochloride 10 mg use was not associated with an increased rate of any adverse event over placebo, including CNS depression, gastrointestinal or cardiovascular involvement. Conclusions: Doxylamine succinate-pyridoxine hydrochloride delayed release combination is safe and well tolerated by pregnant women when used in the recommended dose of up to 4 tablets daily in treating nausea and vomiting of pregnancy. Trial Registration: Clinical Trial Registration No: NCT00614445

Prenatal Phthalate Exposure Is Associated with Childhood Behavior and Executive Functioning

Background: Experimental and observational studies have reported biological consequences of phthalate exposure relevant to neurodevelopment. Objective: Our goal was to examine the association of prenatal phthalate exposure with behavior and executive functioning at 4-9 years of age. Methods: The Mount Sinai Children's Environmental Health Study enrolled a multiethnic prenatal population in New York City between 1998 and 2002 (n = 404). Third-trimester maternal urines were collected and analyzed for phthalate metabolites. Children (n = 188, n = 365 visits) were assessed for cognitive and behavioral development between the ages of 4 and 9 years. Results: In multivariate adjusted models, increased loge concentrations of low molecular weight (LMW) phthalate metabolites were associated with poorer scores on the aggression [β = 1.24; 95% confidence interval (CI), 0.15- 2.34], conduct problems (β = 2.40; 95% CI, 1.34-3.46), attention problems (β = 1.29; 95% CI, 0.16- 2.41), and depression (β = 1.18; 95% CI, 0.11-2.24) clinical scales; and externalizing problems (β = 1.75; 95% CI, 0.61-2.88) and behavioral symptom index (β = 1.55; 95% CI, 0.39-2.71) composite scales. Increased loge concentrations of LMW phthalates were also associated with poorer scores on the global executive composite index (β = 1.23; 95% CI, 0.09-2.36) and the emotional control scale (β = 1.33; 95% CI, 0.18- 2.49). Conclusion: Behavioral domains adversely associated with prenatal exposure to LMW phthalates in our study are commonly found to be affected in children clinically diagnosed with conduct or attention deficit hyperactivity disorders

Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Preterm birth remains a common cause of neonatal mortality, with a disproportionately high burden in low-income and middle-income countries. Meta-analyses of low-dose aspirin to prevent pre-eclampsia suggest that the incidence of preterm birth might also be decreased, particularly if initiated before 16 weeks of gestation. METHODS: ASPIRIN was a randomised, multicountry, double-masked, placebo-controlled trial of low-dose aspirin (81 mg daily) initiated between 6 weeks and 0 days of pregnancy, and 13 weeks and 6 days of pregnancy, in nulliparous women with an ultrasound confirming gestational age and a singleton viable pregnancy. Participants were enrolled at seven community sites in six countries (two sites in India and one site each in the Democratic Republic of the Congo, Guatemala, Kenya, Pakistan, and Zambia). Participants were randomly assigned (1:1, stratified by site) to receive aspirin or placebo tablets of identical appearance, via a sequence generated centrally by the data coordinating centre at Research Triangle Institute International (Research Triangle Park, NC, USA). Treatment was masked to research staff, health providers, and patients, and continued until 36 weeks and 7 days of gestation or delivery. The primary outcome of incidence of preterm birth, defined as the number of deliveries before 37 weeks\u27 gestational age, was analysed in randomly assigned women with pregnancy outcomes at or after 20 weeks, according to a modified intention-to-treat (mITT) protocol. Analyses of our binary primary outcome involved a Cochran-Mantel-Haenszel test stratified by site, and generalised linear models to obtain relative risk (RR) estimates and associated confidence intervals. Serious adverse events were assessed in all women who received at least one dose of drug or placebo. This study is registered with ClinicalTrials.gov, NCT02409680, and the Clinical Trial Registry-India, CTRI/2016/05/006970. FINDINGS: From March 23, 2016 to June 30, 2018, 14 361 women were screened for inclusion and 11 976 women aged 14-40 years were randomly assigned to receive low-dose aspirin (5990 women) or placebo (5986 women). 5780 women in the aspirin group and 5764 in the placebo group were evaluable for the primary outcome. Preterm birth before 37 weeks occurred in 668 (11·6%) of the women who took aspirin and 754 (13·1%) of those who took placebo (RR 0·89 [95% CI 0·81 to 0·98], p=0·012). In women taking aspirin, we also observed significant reductions in perinatal mortality (0·86 [0·73-1·00], p=0·048), fetal loss (infant death after 16 weeks\u27 gestation and before 7 days post partum; 0·86 [0·74-1·00], p=0·039), early preterm delivery (\u3c34 \u3eweeks; 0·75 [0·61-0·93], p=0·039), and the incidence of women who delivered before 34 weeks with hypertensive disorders of pregnancy (0·38 [0·17-0·85], p=0·015). Other adverse maternal and neonatal events were similar between the two groups. INTERPRETATION: In populations of nulliparous women with singleton pregnancies from low-income and middle-income countries, low-dose aspirin initiated between 6 weeks and 0 days of gestation and 13 weeks and 6 days of gestation resulted in a reduced incidence of preterm delivery before 37 weeks, and reduced perinatal mortality. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development

Risk Factors and Outcome of Varicella-Zoster Virus Pneumonia in Pregnant Women

To determine the factors associated with an increased risk of developing varicella-zoster virus (VZV) pneumonia during pregnancy, a case-control analysis was done in which 18 pregnant women with VZV pneumonia were compared with 72 matched control subjects. VZV infection was identified clinically, and VZV pneumonia was diagnosed by dyspnea and findings on chest radiographs. Of 347 pregnant women with VZV infection, 18 (5.2%) had pneumonia treated with acyclovir, and none died. Mean gestational age at rash onset was 25.8 ± 8.8 weeks for patients with pneumonia and 17.7 ± 10.3 weeks for control subjects, which was not significant in the multivariable model. Women with VZV pneumonia were significantly more likely to be current smokers (odds ratio [OR], 5.1; 95% confidence interval [CI], 1.6–16.7) and to have \u3e100 skin lesions (OR, 15.9; 95% CI, 1.9–130.2). Pregnant women with VZV infection may be more likely to develop varicella pneumonia if they are smokers or manifest \u3e100 skin lesions

The Global Network Maternal Newborn Health Registry: a multi-national, community-based registry of pregnancy outcomes

Abstract Background The Global Network for Women's and Children's Health Research (Global Network) supports and conducts clinical trials in resource-limited countries by pairing foreign and U.S. investigators, with the goal of evaluating low-cost, sustainable interventions to improve the health of women and children. Accurate reporting of births, stillbirths, neonatal deaths, maternal mortality, and measures of obstetric and neonatal care is critical to efforts to discover strategies for improving pregnancy outcomes in resource-limited settings. Because most of the sites in the Global Network have weak registration within their health care systems, the Global Network developed the Maternal Newborn Health Registry (MNHR), a prospective, population-based registry of pregnancies at the Global Network sites to provide precise data on health outcomes and measures of care. Methods Pregnant women are enrolled in the MNHR if they reside in or receive healthcare in designated groups of communities within sites in the Global Network. For each woman, demographic, health characteristics and major outcomes of pregnancy are recorded. Data are recorded at enrollment, the time of delivery and at 42 days postpartum. Results From 2010 through 2013 Global Network sites were located in Argentina, Guatemala, Belgaum and Nagpur, India, Pakistan, Kenya, and Zambia. During this period, 283,496 pregnant women were enrolled in the MNHR; this number represented 98.8% of all eligible women. Delivery data were collected for 98.8% of women and 42-day follow-up data for 98.4% of those enrolled. In this supplement, there are a series of manuscripts that use data gathered through the MNHR to report outcomes of these pregnancies. Conclusions Developing public policy and improving public health in countries with poor perinatal outcomes is, in part, dependent upon understanding the outcome of every pregnancy. Because the worst pregnancy outcomes typically occur in countries with limited health registration systems and vital records, alternative registration systems may prove to be highly valuable in providing data. The MNHR, an international, multicenter, population-based registry, assesses pregnancy outcomes over time in support of efforts to develop improved perinatal healthcare in resource-limited areas. Study Registration: The Maternal Newborn Health Registry is registered at Clinicaltrials.gov (ID# NCT01073475)

Association of Polymorphisms in Neuroprotection and Oxidative Stress Genes and Neurodevelopmental Outcomes After Preterm Birth

To estimate the associations between neuronal homeostasis, neuroprotection, and oxidative stress candidate gene polymorphisms and neurodevelopmental disability