Randomization-Based Inference Within Principal Strata

In randomized studies, treatment comparisons conditional on intermediate post-randomization outcomes using standard analytic methods do not have a causal interpretation. An alternate approach entails treatment comparisons within principal strata defined by the potential outcomes for the intermediate outcome that would be observed under each treatment assignment. In this paper, we develop methods for randomization-based inference within principal strata. The proposed methods are compared with existing large-sample methods as well as traditional intent-to-treat approaches. This research is motivated by HIV prevention studies where few infections are expected and inference is desired within the always-infected principal stratum, i.e., all individuals who would become infected regardless of randomization assignment

The relationship between birth intervals and adverse maternal and neonatal outcomes in six low and lower-middle income countries

Background: Due to high fertility rates in some low and lower-middle income countries, the interval between pregnancies can be short, which may lead to adverse maternal and neonatal outcomes.Methods: We analyzed data from women enrolled in the NICHD Global Network Maternal Newborn Health Registry (MNHR) from 2013 through 2018. We report maternal characteristics and outcomes in relationship to the inter-delivery interval (IDI, time from previous delivery [live or stillborn] to the delivery of the index birth), by category of 6-17 months (short), 18-36 months (reference), 37-60 months, and 61-180 months (long). We used non-parametric tests for maternal characteristics, and multivariable logistic regression models for outcomes, controlling for differences in baseline characteristics.Results: We evaluated 181,782 women from sites in the Democratic Republic of Congo, Zambia, Kenya, Guatemala, India, and Pakistan. Women with short IDI varied by site, from 3% in the Zambia site to 20% in the Pakistan site. Relative to a 18-36 month IDI, women with short IDI had increased risk of neonatal death (RR = 1.89 [1.74, 2.05]), stillbirth (RR = 1.70 [1.56, 1.86]), low birth weight (RR = 1.38 [1.32, 1.44]), and very low birth weight (RR = 2.35 [2.10, 2.62]). Relative to a 18-36 month IDI, women with IDI of 37-60 months had an increased risk of maternal death (RR 1.40 [1.05, 1.88]), stillbirth (RR 1.14 [1.08, 1.22]), and very low birth weight (RR 1.10 [1.01, 1.21]). Relative to a 18-36 month IDI, women with long IDI had increased risk of maternal death (RR 1.54 [1.10, 2.16]), neonatal death (RR = 1.25 [1.14, 1.38]), stillbirth (RR = 1.50 [1.38, 1.62]), low birth weight (RR = 1.22 [1.17, 1.27]), and very low birth weight (RR = 1.47 [1.32,1.64]). Short and long IDIs were also associated with increased risk of obstructed labor, hemorrhage, hypertensive disorders, fetal malposition, infection, hospitalization, preterm delivery, and neonatal hospitalization.Conclusions: IDI varies by site. When compared to 18-36 month IDI, women with both short IDI and long IDI had increased risk of adverse maternal and neonatal outcomes.Trial registration: The MNHR is registered at NCT01073475

Association of parity with birthweight and neonatal death in five sites: The global network\u27s maternal newborn health registry study

Background: Nulliparity has been associated with lower birth weight (BW) and other adverse pregnancy outcomes, with most of the data coming from high-income countries. In this study, we examined birth weight for gestational age z-scores and neonatal (28-day) mortality in a large prospective cohort of women dated by first trimester ultrasound from multiple sites in low and middle-income countries.Methods: Pregnant women were recruited during the first trimester of pregnancy and followed through 6 weeks postpartum from Maternal Newborn Health Registry (MNHR) sites in the Democratic Republic of Congo (DRC), Guatemala, Belagavi and Nagpur, India, and Pakistan from 2017 and 2018. Data related to the pregnancy and its outcomes were collected prospectively. First trimester ultrasound was used for determination of gestational age; (BW) was obtained in grams within 48 h of delivery and later transformed to weight for age z-scores (WAZ) adjusted for gestational age using the INTERGROWTH-21st standards.Results: 15,121 women were eligible and included. Infants of nulliparous women had lower mean BWs (males: 2676 gr, females: 2587 gr, total: 2634 gr) and gestational age adjusted weight for age z-scores (males: - 0.73, females: - 0.77, total: - 0.75,) than women with one or more previous pregnancies. The largest differences were between zero and one previous pregnancies among female infants. The associations of parity with BW and z-scores remained even after adjustment for maternal age, maternal height, maternal education, antenatal care visits, hypertensive disorders, and socioeconomic status. Nulliparous women also had a significantly higher \u3c 28-day neonatal mortality rate (27.7 per 1,000 live births) than parous women (17.2 and 20.7 for parity of 1-3 and ≥ 4 respectively). Risk of preterm birth was higher among women with ≥ 4 previous pregnancies (15.5%) compared to 11.3% for the nulliparous group and 11.8% for women with one to three previous pregnancies (p = 0.0072).Conclusions: In this large sample from diverse settings, nulliparity was independently associated with both lower BW and WAZ scores as well as higher neonatal mortality compared to multiparity

Evaluating the effect of care around labor and delivery practices on early neonatal mortality in the global network\u27s maternal and newborn health registry

Background: Neonatal deaths in first 28-days of life represent 47% of all deaths under the age of five years globally and are a focus of the United Nation\u27s (UN\u27s) Sustainable Development Goals. Pregnant women are delivering in facilities but that does not indicate quality of care during delivery and the postpartum period. The World Health Organization\u27s Essential Newborn Care (ENC) package reduces neonatal mortality, but lacks a simple and valid composite index that measures its effectiveness.Methods: Data on 5 intra-partum and 3 post-partum practices (indicators) recommended as part of ENC, routinely collected in NICHD\u27s Global Network\u27s (GN) Maternal Newborn Health Registry (MNHR) between 2010 and 2013, were included. We evaluated if all 8 practices (Care around Delivery - CAD), combined as an index was associated with reduced early neonatal mortality rates (days 0-6 of life).Results: A total of 150,848 live births were included in the analysis. The individual indicators varied across sites. All components were present in 19.9% births (range 0.4 to 31% across sites). Present indicators (8 components) were associated with reduced early neonatal mortality [adjusted RR (95% CI):0.81 (0.77, 0.85); p \u3c 0.0001]. Despite an overall association between CAD and early neonatal mortality (RR \u3c 1.0 for all early mortality): delivery by skilled birth attendant; presence of fetal heart and delayed bathing were associated with increased early neonatal mortality.Conclusions: Present indicators (8 practices) of CAD were associated with a 19% reduction in the risk of neonatal death in the diverse health facilities where delivery occurred within the GN MNHR. These indicators could be monitored to identify facilities that need to improve compliance with ENC practices to reduce preventable neonatal deaths. Three of the 8 indicators were associated with increased neonatal mortality, due to baby being sick at birth. Although promising, this composite index needs refinement before use to monitor facility-based quality of care in association with early neonatal mortality. Trial registration The identifier of the Maternal Newborn Health Registry at ClinicalTrials.gov is NCT01073475

Neonatal deaths in infants born weighing ≥ 2500 g in low and middle-income countries

Background: Babies born weighing ≥ 2500 g account for more than 80% of the births in most resource-limited locations and for nearly 50% of the 28-day neonatal deaths. In contrast, in high-resource settings, 28-day neonatal mortality among this group represents only a small fraction of the neonatal deaths. Yet mortality risks for birth weight of ≥ 2500 g is limited. Knowledge regarding the factors associated with mortality in these babies will help in identifying interventions that can reduce mortality.Methods: The Global Network\u27s 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 that has been conducted in research sites in six low-middle income countries (India, Pakistan, Democratic Republic of Congo, Guatemala, Kenya and Zambia). Study staff enroll all pregnant women as early as possible during pregnancy and conduct follow-up visits to ascertain delivery and 28-day neonatal outcomes. We analyzed the neonatal mortality rates (NMR) and risk factors for deaths by 28 days among all live-born babies with a birthweight ≥ 2500 g from 2010 to 2018 across the Global Network sites.Results: Babies born in the Global Network sites from 2010 to 2018 with a birthweight ≥ 2500 g accounted for 84.8% of the births and 45.4% of the 28-day neonatal deaths. Among this group, the overall NMR was 13.1/1000 live births. The overall 28-day NMR for ongoing clusters was highest in Pakistan (29.7/1000 live births) and lowest in the Zambian/Kenyan sites (9.3/1000) for ≥ 2500 g infants. ≥ 2500 g NMRs declined for Zambia/Kenya and India. For Pakistan and Guatemala, the NMR remained almost unchanged over the period. The ≥ 2500 g risks related to maternal, delivery and newborn characteristics varied by site. Maternal factors that increased risk and were common for all sites included nulliparity, hypertensive disease, previous stillbirth, maternal death, obstructed labor, severe postpartum hemorrhage, and abnormal fetal presentation. Neonatal characteristics including resuscitation, hospitalization, congenital anomalies and male sex, as well as lower gestational ages and birthweights were also associated with increased mortality.Conclusions: Nearly half of neonatal deaths in the Global Network sites occurred in infants born weighing ≥ 2500 g. The NMR for those infants was 13.1 per 1000 live births, much higher than rates usually seen in high-income countries. The changes in NMR over time varied across the sites. Even among babies born ≥ 2500 g, lower gestational age and birthweight were largely associated with increased risk of mortality. Since many of these deaths should be preventable, attention to preventing mortality in these infants should have an important impact on overall NMR.Trial registration: https://ClinicalTrials.gov Identifier: NCT01073475

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

Multiple HIV-1-specific IgG3 responses decline during acute HIV-1: implications for detection of incident HIV infection

Different HIV-1 antigen specificities appear in sequence after HIV-1 transmission and the immunoglobulin G (IgG) subclass responses to HIV antigens are distinct from each other. The initial predominant IgG subclass response to HIV-1 infection consists of IgG1 and IgG3 antibodies with a noted decline in some IgG3 antibodies during acute HIV-1 infection. Thus, we postulate that multiple antigen-specific IgG3 responses may serve as surrogates for the relative time since HIV-1 acquisition

Neonatal deaths in rural Karnataka, India 2014-2018: a prospective population-based observational study in a low-resource setting.

BACKGROUND: Neonatal mortality causes a substantial proportion of the under-5 mortality in low and middle-income countries (LMIC). METHODS: We undertook a prospective, population-based research study of pregnant women residing in defined geographic areas in the Karnataka State of India, a research site of the Global Network for Women\u27s and Children\u27s Health Research. Study staff collected demographic and health care characteristics on eligible women enrolled with neonatal outcomes obtained at delivery and day 28. Cause of neonatal mortality at day 28 was assigned by algorithm using prospectively defined variables. RESULTS: From 2014 to 2018, the neonatal mortality rate was 24.5 per 1,000 live births. The cause of the 28-day neonatal deaths was attributed to prematurity (27.9%), birth asphyxia (25.1%), infection (23.7%) and congenital anomalies (18.4%). Four or more antenatal care (ANC) visits was associated with a lower risk of neonatal death compared to fewer ANC visits. In the adjusted model, compared to liveborn infants ≥ 2500 g, infants born weighing \u3c 1000 g RR for mortality was 25.6 (95%CI 18.3, 36.0), for 1000-1499 g infants the RR was 19.8 (95% CI 14.2, 27.5) and for 1500-2499 g infants the RR was 3.1 (95% CI 2.7, 3.6). However, more than one-third (36.8%) of the deaths occurred among infants with a birthweight ≥ 2500 g. Infants born preterm (\u3c 37 weeks) were also at higher risk for 28-day mortality (RR 7.9, 95% CI 6.9, 9.0) compared to infants ≥ 37 weeks. A one-week decrease in gestational age at delivery was associated with a higher risk of mortality with a RR of 1.3 (95% CI 1.3, 1.3). More than 70% of all the deliveries occurred at a hospital. Among infants who died, 50.3% of the infants had received bag/mask ventilation, 47.3% received antibiotics, and 55.6% received oxygen. CONCLUSIONS: Consistent with prior research, the study found that infants who were preterm and low-birth weight remained at highest risk for 28-day neonatal mortality in India. Although most of births now occur within health facilities, a substantial proportion are not receiving basic life-saving interventions. Further efforts to understand the impact of care on infant outcomes are needed. Study registration The trial is registered at clinicaltrials.gov. ClinicalTrial.gov Trial Registration: NCT01073475

Delayed and Interrupted Ventilation with Excess Suctioning after Helping Babies Breathe with Congolese Birth Attendants

There is a substantial gap in our understanding of resuscitation practices following Helping Babies Breathe (HBB) training. We sought to address this gap through an analysis of observed resuscitations following HBB 2nd edition training in the Democratic Republic of the Congo. This is a secondary analysis of a clinical trial evaluating the effect of resuscitation training and electronic heart rate monitoring on stillbirths. We included in-born, liveborn neonates ≥28 weeks gestation whose resuscitation care was directly observed and documented. For the 2592 births observed, providers dried/stimulated before suctioning in 97% of cases and suctioned before ventilating in 100%. Only 19.7% of newborns not breathing well by 60 s (s) after birth ever received ventilation. Providers initiated ventilation at a median 347 s (>five minutes) after birth; no cases were initiated within the Golden Minute. During 81 resuscitations involving ventilation, stimulation and suction both delayed and interrupted ventilation with a median 132 s spent drying/stimulating and 98 s suctioning. This study demonstrates that HBB-trained providers followed the correct order of resuscitation steps. Providers frequently failed to initiate ventilation. When ventilation was initiated, it was delayed and interrupted by stimulation and suctioning. Innovative strategies targeting early and continuous ventilation are needed to maximize the impact of HBB

Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants

BACKGROUND: Preterm infants with respiratory distress syndrome (RDS) given inositol had reduced bronchopulmonary dysplasia (BPD), death and severe retinopathy of prematurity (ROP). We assessed the safety and pharmacokinetics of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization. METHODS: Infants ≤ 29 wk GA (n = 122, 14 centers) were randomized and treated with placebo or inositol at 10, 40, or 80 mg/kg/d. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 wk, 34 wk postmenstrual age (PMA) or discharge. Serum collection employed a sparse sampling population pharmacokinetics design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored. RESULTS: At 80 mg/kg/d mean serum levels reached 140 mg/l, similar to Hallman's findings. Levels declined after 2 wk, converging in all groups by 6 wk. Analyses showed a mean volume of distribution 0.657 l/kg, clearance 0.058 l/kg/h, and half-life 7.90 h. Adverse events and comorbidities were fewer in the inositol groups, but not significantly so. CONCLUSION: Multiple dose inositol at 80 mg/kg/d was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a phase III trial