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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. 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' 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. 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' gestation and before 7 days post partum; 0·86 [0·74–1·00], p=0·039), early preterm delivery (<34 weeks; 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. 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. Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Basic resuscitation practices, particularly bag-mask ventilation, reduce newborn deaths from respiratory depression. There is strong scientific premise for improving bag-mask ventilation with feedback strategies, but there are significant barriers to bedside feedback in low-resource settings. To address these barriers, we developed LIVEBORN, a mobile health application to support feedback for newborn resuscitations. LIVEBORN uses data on provider actions and the newborn’s condition entered in real-time by an observer to provide real-time guidance during resuscitation and support debriefing after resuscitation. In a pilot study, we designed and then evaluated strategies to incorporate LIVEBORN Feedback into clinical practice at two health facilities in the Democratic Republic of the Congo, with one facility allocated to real-time guidance and one to debriefing. Providers at each facility used a participatory research methodology called Trials of Improved Practices to design and refine their strategy prior to pilot testing. The primary outcome of the pilot study was the feasibility of observing resuscitation care with LIVEBORN, defined as the percentage of births observed using LIVEBORN with a threshold of at least 50% of births observed to achieve feasibility. We also evaluated usability with the System Usability Scale and explored midwives’ perceptions of LIVEBORN Feedback in focus group discussions. During the pilot test, we found both strategies to be feasible with 74% of births observed with LIVEBORN at the real-time guidance facility and 67% at the debriefing facility. The strategy was also sufficiently usable with a System Usability Scale median score of 68 (Q1 65, Q3 78). Midwives perceived LIVEBORN Feedback to be helpful and believed it could save lives, but sometimes disagreed with LIVEBORN Feedback’s guidance to ventilate. In conclusion, we identified context-specific, feasible strategies for incorporating LIVEBORN Feedback into clinical care. We are now evaluating the effectiveness of LIVEBORN Feedback in a randomized control trial.

Worldwide, an estimated five million children under the age of five die each year; 47% of these deaths occur during the neonatal period, and the vast majority in low- and middle-income countries. Events during labor are the cause of one quarter of neonatal deaths globally. Basic resuscitation with positive pressure ventilation reduces these deaths but is challenging to execute. To characterize barriers to implementation of basic neonatal resuscitation, we conducted a qualitative study using focus group discussions with midwives at three health facilities in Kinshasa, Democratic Republic of the Congo. We analyzed qualitative data using an inductive content approach in order to identify emergent themes and trends. Twenty-four midwives participated with a median age of 49 and over 80% with more than 10 years of clinical experience. We categorized challenges to implementing basic neonatal resuscitation into three themes with subthemes: 1) limited resources (subthemes: human resource limitations, inadequate and unprepared equipment, insufficient monitoring during labor); 2) inadequate simulated and clinical experience (subthemes: poor systems to support maintenance of skills, infrequent opportunity to resuscitate); 3) emotional burden of resuscitation (subthemes: decision-making under time pressure, tendency to stick to the routine, acute stress during resuscitation, moral distress after unsuccessful outcome). Our findings suggest that while simulation training is key, learning from clinical events may be a critical companion to address these barriers. We call for a new focus on developing and evaluating strategies that support providers in learning from every newborn resuscitation.

Legal, ethical, and regulatory requirements of medical research uniformly call for informed consent. We aimed to characterize and compare consent rates for neonatal randomized controlled trials in low- and lower middle-income countries versus high-income countries, and to evaluate the influence of study characteristics on consent rates. In this systematic review, we searched MEDLINE, EMBASE and Cochrane for randomized controlled trials of neonatal interventions in low- and lower middle-income countries or high-income countries published 01/01/2013 to 01/04/2018. Our primary outcome was consent rate, the proportion of eligible participants who consented amongst those approached, extracted from the article or email with the author. Using a generalised linear model for fractional dependent variables, we analysed the odds of consenting in low- and lower middle-income countries versus high-income countries across control types and interventions. We screened 3523 articles, yielding 300 eligible randomized controlled trials with consent rates available for 135 low- and lower middle-income country trials and 65 high-income country trials. Median consent rates were higher for low- and lower middle-income countries (95.6%; interquartile range (IQR) 88.2-98.9) than high-income countries (82.7%; IQR 68.6-93.0; p<0.001). In adjusted regression analysis comparing low- and lower middle-income countries to high-income countries, the odds of consent for no placebo-drug/nutrition trials was 3.67 (95% Confidence Interval (CI) 1.87-7.19; p = 0.0002) and 6.40 (95%CI 3.32-12.34; p<0.0001) for placebo-drug/nutrition trials. Neonatal randomized controlled trials in low- and lower middle-income countries report consistently higher consent rates compared to high-income country trials. Our study is limited by the overrepresentation of India among randomized controlled trials in low- and lower middle-income countries. This study raises serious concerns about the adequacy of protections for highly vulnerable populations recruited to clinical trials in low- and lower middle-income countries.

Background Preterm birth continues to be a major public health problem contributing to 75% of the neonatal mortality worldwide. Low birth weight (LBW) is an important but imperfect surrogate for prematurity when accurate assessment of gestational age is not possible. While there is overlap between preterm birth and LBW newborns, those that are both premature and LBW are at the highest risk of adverse neonatal outcomes. Understanding the epidemiology of preterm birth and LBW is important for prevention and improved care for at risk newborns, but in many countries, data are sparse and incomplete. Methods We conducted data analyses using the Global Network’s (GN) population-based registry of pregnant women and their babies in rural communities in six low- and middle-income countries (Democratic Republic of Congo, Kenya, Zambia, Guatemala, India and Pakistan). We analyzed data from January 2014 to December 2018. Trained study staff enrolled all pregnant women in the study catchment area as early as possible during pregnancy and conducted follow-up visits shortly after delivery and at 42 days after delivery. We analyzed the rates of preterm birth, LBW and the combination of preterm birth and LBW and studied risk factors associated with these outcomes across the GN sites. Results A total of 272,192 live births were included in the analysis. The overall preterm birth rate was 12.6% (ranging from 8.6% in Belagavi, India to 21.8% in the Pakistani site). The overall LBW rate was 13.6% (ranging from 2.7% in the Kenyan site to 21.4% in the Pakistani site). The overall rate of both preterm birth and LBW was 5.5% (ranging from 1.2% in the Kenyan site to 11.0% in the Pakistani site). Risk factors associated with preterm birth, LBW and the combination were similar across sites and included nulliparity [RR − 1.27 (95% CI 1.21–1.33)], maternal age under 20 [RR 1.41 (95% CI 1.32–1.49)] years, severe antenatal hemorrhage [RR 5.18 95% CI 4.44–6.04)], hypertensive disorders [RR 2.74 (95% CI − 1.21–1.33], and 1–3 antenatal visits versus four or more [RR 1.68 (95% CI 1.55–1.83)]. Conclusions Preterm birth, LBW and their combination continue to be common public health problems at some of the GN sites, particularly among young, nulliparous women who have received limited antenatal care services. Trial registration The identifier of the Maternal and Newborn Health Registry at ClinicalTrials.gov is NCT01073475.Trial registration: The identifier of the Maternal and Newborn Health Registry at ClinicalTrials.gov is NCT01073475.

Benefits of identifying risk factors for bronchopulmonary dysplasia in extremely premature infants include providing prognostic information, identifying infants likely to benefit from preventive strategies, and stratifying infants for clinical trial enrollment. To identify risk factors for bronchopulmonary dysplasia, and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based estimator using readily available clinical information to predict risk of bronchopulmonary dysplasia or death. We assessed infants of 23-30 weeks' gestation born in 17 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and enrolled in the Neonatal Research Network Benchmarking Trial from 2000-2004. Bronchopulmonary dysplasia was defined as a categorical variable (none, mild, moderate, or severe). We developed and validated models for bronchopulmonary dysplasia risk at six postnatal ages using gestational age, birth weight, race and ethnicity, sex, respiratory support, and Fi(O(2)), and examined the models using a C statistic (area under the curve). A total of 3,636 infants were eligible for this study. Prediction improved with advancing postnatal age, increasing from a C statistic of 0.793 on Day 1 to a maximum of 0.854 on Day 28. On Postnatal Days 1 and 3, gestational age best improved outcome prediction; on Postnatal Days 7, 14, 21, and 28, type of respiratory support did so. A Web-based model providing predicted estimates for bronchopulmonary dysplasia by postnatal day is available at https://neonatal.rti.org. The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.

Background Pakistan has among the poorest pregnancy outcomes worldwide, significantly worse than many other low-resource countries. The reasons for these differences are not clear. In this study, we compared pregnancy outcomes in Pakistan to other low-resource countries and explored factors that might help explain these differences. Methods The Global Network (GN) Maternal Newborn Health Registry (MNHR) is a prospective, population-based observational study that includes all pregnant women and their pregnancy outcomes in defined geographic communities in six low-middle income countries (India, Pakistan, Democratic Republic of Congo, Guatemala, Kenya, Zambia). Study staff enroll women in early pregnancy and follow-up soon after delivery and at 42 days to ascertain delivery, neonatal, and maternal outcomes. We analyzed the maternal mortality ratios (MMR), neonatal mortality rates (NMR), stillbirth rates, and potential explanatory factors from 2010 to 2018 across the GN sites. Results From 2010 to 2018, there were 91,076 births in Pakistan and 456,276 births in the other GN sites combined. The MMR in Pakistan was 319 per 100,000 live births compared to an average of 124 in the other sites, while the Pakistan NMR was 49.4 per 1,000 live births compared to 20.4 in the other sites. The stillbirth rate in Pakistan was 53.5 per 1000 births compared to 23.2 for the other sites. Preterm birth and low birthweight rates were also substantially higher than the other sites combined. Within weight ranges, the Pakistani site generally had significantly higher rates of stillbirth and neonatal mortality than the other sites combined, with differences increasing as birthweights increased. By nearly every measure, medical care for pregnant women and their newborns in the Pakistan sites was worse than at the other sites combined. Conclusion The Pakistani pregnancy outcomes are much worse than those in the other GN sites. Reasons for these poorer outcomes likely include that the Pakistani sites' reproductive-aged women are largely poorly educated, undernourished, anemic, and deliver a high percentage of preterm and low-birthweight babies in settings of often inadequate maternal and newborn care. By addressing the issues highlighted in this paper there appears to be substantial room for improvements in Pakistan’s pregnancy outcomes.

Few studies have assessed the impact of first-trimester malaria infection during pregnancy. We estimated this impact on adverse maternal and pregnancy outcomes. In a convenience sample of women from the ASPIRIN (Aspirin Supplementation for Pregnancy Indicated risk Reduction In Nulliparas) trial in Kenya, Zambia, and the Democratic Republic of the Congo, we tested for first-trimester Plasmodium falciparum infection using quantitative polymerase chain reaction. We estimated site-specific effects on pregnancy outcomes using parametric g-computation. Compared to uninfected women, we observed the adjusted site-specific prevalence differences (PDs) among women with first-trimester malaria of the following pregnancy outcomes: preterm birth among Congolese (aPD = 0.06 [99% CI: -0.04, 0.16]), Kenyan (0.03 [-0.04, 0.09]), and Zambian (0.00 [-0.10, 0.20]) women; low birth weight among Congolese (0.07 [-0.03, 0.16]), Kenyan (0.01 [-0.04, 0.06]) and Zambian (-0.04 [-0.13, 0.16]) women; spontaneous abortion among Congolese (0.00 [-0.05, 0.04]), Kenyan (0.00 [-0.04, 0.04]), and Zambian (0.02 [-0.07, 0.24]) women, and anemia later in pregnancy among Congolese (0.04 [-0.09, 0.16]), Kenyan (0.05 [-0.06, 0.17]), and Zambian (0.07 [-0.12, 0.36]) women. The pooled PD for anemia later in pregnancy (26-30 weeks) was 0.08 [99% CI: 0.00, 0.16]. First-trimester malaria was associated with increased prevalence of anemia later in pregnancy. We identified areas for further investigation including effects of first-trimester malaria on preterm birth and low birth weight.

Patent ductus arteriosus (PDA) is a common diagnosis among extremely premature infants, especially in those with lung disease. Treatments are often used to close the PDA. Despite nearly three decades of research, the question of whether the benefits of treatments to prevent ductal patency or promote closure outweigh the risks of these treatments remains unanswered. The authors rarely use treatments designed to close the PDA. This article reviews three considerations in support of this restrained approach: rates of spontaneous closure of the ductus arteriosus; adverse effect of persistent ductal patency; and benefits and risks of treatments for closure.

Improving neonatal resuscitation practices reduces neonatal mortality. In low- and middle-income countries (LMICs), granular details about provider actions during resuscitation are largely unknown; therefore, identifying targets for improvement is difficult. The International Liaison Committee on Resuscitation (ILCOR) recognizes the importance of uniform reporting of clinical neonatal resuscitation studies and published a guideline recommending specific variables to include. We established an open cohort study for newborn resuscitation in the Democratic Republic of the Congo (DRC) as a platform for developing and evaluating novel strategies to improve newborn resuscitation. We included all in-born neonates at two health facilities in Kinshasa, DRC. We gathered data on all enrollees via delivery registry and medical record abstraction. Using the Liveborn Observation app, we directly observed care at birth for a convenience sample. We collected heart rate data when providers used NeoBeat, a battery-operated heart rate meter. From September 2022 to August 2023, we abstracted delivery registry and medical record data for 6,414 newborns and gathered observational data on the infant’s breathing status and provider actions for 3,166 (49%). Our dataset includes 85% of ILCOR’s recommended core variables applicable to this setting, and 50% of ILCOR’s applicable supplemental variables. Our registry also contains variables beyond those recommended by ILCOR that are contextually important for evaluating resuscitation care in LMICs such as duration of suctioning, pauses in positive pressure ventilation and fresh stillbirth. Our experience establishing a resuscitation registry with novel tools in the DRC serves as a model for resuscitation research in low-resource settings. Our cohort study provides important insight to inform subsequent versions of ILCOR’s guideline on uniform reporting of neonatal resuscitations studies globally.