Early identification of preterm neonates at birth with a Tablet App for the Simplified Gestational Age Score (T-SGAS) when ultrasound gestational age dating is unavailable: A validation study.

BACKGROUND: In low resource settings recall of the date of the mother's last menstrual period may be unreliable and due to limited availability of prenatal ultrasound, gestational age of newborns may not be assessed reliably. Preterm babies are at high risk of morbidity and mortality so an alternative strategy is to identify them soon after birth is needed for early referral and management. OBJECTIVE: The objective of this study was to assess the accuracy in assessing prematurity of newborn, over and above birthweight, using a pictorial Simplified Gestational Age Score adapted for use as a Tablet App. METHODS: Two trained nurse midwives, blinded to each other's assessment and the actual gestational age of the baby used the app to assess gestational age at birth in 3 hospitals based on the following 4 parameters-newborn's posture, skin texture, breast and genital development. Inter-observer variation was evaluated and the optimal scoring cut-off to detect preterm birth was determined. Sensitivity and specificity of gestational age score using the tablet was estimated using combinations of last menstrual period and ultrasound as reference standards to assess preterm birth. The predictive accuracy of the score using the area under a receiver operating characteristic curve was also determined. To account for potential reference standard bias, we also evaluated the score using latent class models. RESULTS: A total of 8,591 live singleton births whose gestational age by last menstrual period and ultrasound was within 1 weeks of each other were enrolled. There was strong agreement between assessors (concordance correlation coefficient 0.77 (95% CI 0.76-0.78) and Fleiss' kappa was 0.76 (95% CI 0.76-0.78). The optimal cut-off for the score to predict preterm was 13. Irrespective of the reference standard, the specificity of the score was 90% and sensitivity varied from 40-50% and the predictive accuracy between 74%-79% for the reference standards. The likelihood ratio of a positive score varied between 3.75-4.88 while the same for a negative likelihood ratio consistently varied between 0.57-0.72. Latent class models showed similar results indicating no reference standard bias. CONCLUSION: Gestational age scores had strong inter-observer agreement, robust prediction of preterm births simplicity of use by nurse midwives and can be a useful tool in resource-limited scenarios. TRIAL REGISTRATION: The Tablet App for the Simplified Gestational Age Score (T-SGAS) study was registered at ClinicalTrials.gov NCT02408783.

Early Identification of Preterm Neonates at Birth With a Tablet App for the Simplified Gestational Age Score (T-SGAS) When Ultrasound Gestational Age Dating Is Unavailable: Protocol for a Validation Study.

BACKGROUND: Although rates of preterm birth continue to increase globally, identification of preterm from low birth weight infants remains a challenge. The burden of low birth weight vs preterm is greatest in resource-limited settings, where gestational age (GA) prior to delivery is frequently not known because ultrasound in early pregnancy is not available and estimates of the date of the mother's last menstrual period (LMP) may not be reliable. An alternative option is to assess GA at birth to optimize referral and care of preterm newborns. We previously developed and pilot-tested a system to measure the simplified gestational age score (SGAS) based on 4 easily observable neonatal characteristics. OBJECTIVE: The objective of this study is to adapt the scoring system as a tablet app (potentially scalable approach) to assess feasibility of use and to validate whether the scoring system accurately predicts prematurity by itself, over and above birth weight in a large sample of newborns. METHODS: The study is based in Nagpur, India, at the Research Unit of the National Institute of Child Health and Human Development's Global Network for Women's and Children's Health Research. The Android tablet app for the SGAS (T-SGAS) displays de-identified photographs of skin, breasts, and genitalia across a range of GAs and line drawings of infant posture. Each item is associated with a score. The user is trained to choose the photograph or line drawing that most closely matches the newborn being evaluated, and the app determines the neonate's GA category (preterm or term) from the cumulative score. The validation study will be conducted in 3 second level care facilities (most deliveries in India occur in hospitals, and women known to be at risk of preterm birth are referred to second level care facilities). Within 24 hours of delivery, women and their babies who are stable will be enrolled in the study. Two auxiliary nurse midwives (ANMs) blinded to prior GA assessments will use the T-SGAS to estimate the GA status of the newborn. An independent data collector will abstract the GA from the ultrasound recorded in the hospital chart and record the date of the mother's LMP. Eligibility for analysis is determined by the ultrasound and LMP data being collected within 1 week of each other to have a rigorous assessment of true GA. RESULTS: Publication of the results of the study is anticipated in 2019. CONCLUSIONS: Until GA dating by ultrasound is universally available and easy to use in resource-limited settings, and where there are restrictions on ultrasound use due to their use for sex determination and abortion of female fetuses, this study will determine whether the T-SGAS app can accurately assess GA in risk categories at birth. TRIAL REGISTRATION: ClinicalTrials.gov NCT02408783; https://clinicaltrials.gov/ct2/show/NCT02408783 (Archived by Webcite at http://www.webcitation.org/75S2kmr3T). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/11913.

A Prospective, Population-Based Study of Trends in Operative Vaginal Delivery Compared to Cesarean Delivery Rates in Low- and Middle-Income Countries, 2010-2016.

OBJECTIVE: Few data are available on cesarean delivery and operative vaginal delivery trends in low- and middle-income countries. Our objective was to analyze a prospective population-based registry including eight sites in seven low- and middle-income countries to observe trends in operative vaginal delivery versus cesarean delivery rates over time, across sites. STUDY DESIGN: A prospective population-based study, including home and facility births among women enrolled from 2010 to 2016, was performed in communities in Argentina, Democratic Republic of Congo, Guatemala, India, Kenya, Pakistan, and Zambia. Women were enrolled during pregnancy and delivery outcome data were collected. RESULTS: We analyzed 354,287 women; 4,119 (1.2%) underwent an operative vaginal delivery and 45,032 (11.2%) delivered by cesarean. Across all sites with data for 7 years, rates of operative vaginal delivery decreased from 1.6 to 0.3%, while cesarean delivery increased from 6.4 to 14.4%. Similar trends were seen when individual country data were analyzed. Operative vaginal delivery rates decreased in both hospitals and clinics, except in the hospital setting at one of the Indian sites. CONCLUSION: In low- and middle-income countries, operative vaginal delivery is becoming less utilized while cesarean delivery is becoming an increasingly common mode of delivery.

Malpresentation in low- and middle-income countries: Associations with perinatal and maternal outcomes in the Global Network.

INTRODUCTION: Uncertainty exists regarding the impact of malpresentation on pregnancy outcomes and the optimal mode of delivery in low- and middle-income countries. We sought to compare outcomes between cephalic and non-cephalic pregnancies. MATERIAL AND METHODS: Using the NICHD Global Network's prospective, population-based registry of pregnancy outcomes from 2010 to 2016, we studied outcomes in 436 112 singleton pregnancies. Robust Poisson regressions were used to estimate the risk of adverse outcomes associated with malpresentation. We examined rates of cesarean delivery for malpresentation and compared outcomes between cesarean and vaginal delivery by region. RESULTS: Across all regions, stillbirth and neonatal mortality rates were higher among deliveries with malpresentation. In adjusted analysis, malpresentation was significantly associated with stillbirth (adjusted relative risk [aRR] 4.0, 95% confidence interval [CI] 3.7-4.5) and neonatal mortality (aRR 2.3, 95% CI 2.1-2.6). Women with deliveries complicated by malpresentation had higher rates of morbidity and mortality. Rates of cesarean delivery for malpresentation ranged from 27% to 87% among regions. Compared with cesarean delivery, vaginal delivery for malpresentation was associated with increased maternal risk, especially postpartum hemorrhage (aRR 5.0, 95% CI; 3.6-7.1). CONCLUSIONS: In a cohort of deliveries in low- and middle-income countries, malpresentation was associated with increased perinatal and maternal risk. Further research is needed to determine the best management of these pregnancies.

Trends and determinants of stillbirth in developing countries: results from the Global Network's 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' 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 < 20 years and age > 35 years. Compared to parity 1-2, zero parity and parity > 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 .

The Relationship between Body Mass Index in Pregnancy and Adverse Maternal, Perinatal, and Neonatal Outcomes in Rural India and Pakistan.

OBJECTIVE: The objective of this study was to describe the relationship between early pregnancy body mass index (BMI) and maternal, perinatal, and neonatal outcomes in rural India and Pakistan. STUDY DESIGN: In a prospective, population-based pregnancy registry implemented in communities in Thatta, Pakistan and Nagpur and Belagavi, India, we obtained women's BMI prior to 12 weeks' gestation (categorized as underweight, normal, overweight, and obese following World Health Organization criteria). Outcomes were assessed 42 days postpartum. RESULTS: The proportion of women with an adverse maternal outcome increased with increasing maternal BMI. Less than one-third of nonoverweight/nonobese women, 47.2% of overweight women, and 56.0% of obese women experienced an adverse maternal outcome. After controlling for site, maternal age and parity, risks of hypertensive disease/severe preeclampsia/eclampsia, cesarean/assisted delivery, and antibiotic use were higher among women with higher BMIs. Overweight women also had significantly higher risk of perinatal and early neonatal mortality compared with underweight/normal BMI women. Overweight women had a significantly higher perinatal mortality rate. CONCLUSION: High BMI in early pregnancy was associated with increased risk of adverse maternal, perinatal, and neonatal outcomes in rural India and Pakistan. These findings present an opportunity to inform efforts for women to optimize weight prior to conception to improve pregnancy outcomes.

Maternal near miss in low-resource areas.

OBJECTIVE: To describe the Global Network Near-Miss Maternal Mortality System and its application in seven sites. METHODS: In a population-based study, pregnant women eligible for enrollment in the Maternal and Newborn Health Registry at seven sites (Democratic Republic of the Congo; Guatemala; Belagavi and Nagpur, India; Kenya; Pakistan; and Zambia) between January 2014 and April 2016 were screened to identify those likely to have a near-miss event. The WHO maternal near-miss criteria were modified for low-resource settings. The ratio of near-miss events to maternal deaths was calculated. RESULTS: Among 122 707 women screened, 18 307 (15.0%) had a potential near-miss event, of whom 4866 (26.6%; 4.0% of all women) had a near-miss maternal event. The overall maternal mortality ratio was 155 per 100 000 live births. The ratio of near-miss events to maternal deaths was 26 to 1. The most common factors involved in near-miss cases were the hematologic/coagulation system, infection, and cardiovascular system. CONCLUSION: By using the Global Network Near-Miss Maternal Mortality System, large numbers of women were screened for near-miss events, including those delivering at home or a low-level maternity clinic. The 4.0% incidence of near-miss maternal mortality is similar to previously reported data. The ratio of 26 near-miss cases to 1 maternal death suggests that near miss might evaluate the impact of interventions more efficiently than maternal mortality.

A description of the methods of the aspirin supplementation for pregnancy indicated risk reduction in nulliparas (ASPIRIN) study.

BACKGROUND: Preterm birth (PTB) remains the leading cause of neonatal mortality and long term disability throughout the world. Though complex in its origins, a growing body of evidence suggests that first trimester administration of low dose aspirin (LDA) may substantially reduce the rate of PTB. METHODS: Hypothesis: LDA initiated in the first trimester reduces the risk of preterm birth. Study Design Type: Prospective randomized, placebo-controlled, double-blinded multi-national clinical trial conducted in seven low and middle income countries. Trial will be individually randomized with one-to-one ratio (intervention/control) Population: Nulliparous women between the ages of 14 and 40, with a singleton pregnancy between 6 0/7 weeks and 13 6/7 weeks gestational age (GA) confirmed by ultrasound prior to enrollment, no more than two previous first trimester pregnancy losses, and no contraindications to aspirin. INTERVENTION: Daily administration of low dose (81 mg) aspirin, initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA, compared to an identical appearing placebo. Compliance and outcomes will be assessed biweekly. OUTCOMES: Primary outcome: Incidence of PTB (birth prior to 37 0/7 weeks GA). Secondary outcomes Incidence of preeclampsia/eclampsia, small for gestational age and perinatal mortality. DISCUSSION: This study is unique as it will examine the impact of LDA early in pregnancy in low-middle income countries with preterm birth as a primary outcome. The importance of developing low-cost, high impact interventions in low-middle income countries is magnified as they are often unable to bear the financial costs of treating illness. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02409680 Date: March 30, 2015.

Evaluation of Focused Obstetric Ultrasound Examinations by Health Care Personnel in the Democratic Republic of Congo, Guatemala, Kenya, Pakistan, and Zambia.

Prior studies have suggested that obstetrical (OB) ultrasound in low- and middle-income countries has aided in detection of high-risk conditions, which in turn could improve OB management. We are participating in a cluster-randomized clinical trial of OB ultrasound, which is designed to assess the effect of basic OB ultrasound on maternal mortality, fetal mortality, neonatal mortality, and maternal near-miss in 5 low-income countries. We designed a 2-week course in basic OB ultrasound, followed by 12 weeks of oversight, to train health care professionals with no prior ultrasound experience to perform basic OB ultrasound to screen for high-risk pregnancies. All patients with high-risk pregnancies identified by the trainees were referred to higher-level health facilities where fully trained sonographers confirmed the diagnoses before any actions were taken. Although there have been several published studies on basic OB ultrasound training courses for health care workers in low- and middle-income countries, quality control reporting has been limited. The purpose of this study is to report on quality control results of these trainees. Health care workers trained in similar courses could have an adjunctive role in ultrasound screening for high-risk OB conditions where access to care is limited. After completion of the ultrasound course, 41 trainees in 5 countries performed 3801 ultrasound examinations during a 12-week pilot period. Each examination was reviewed by ultrasound trainers for errors in scanning parameters and errors in diagnosis, using predetermined criteria. Of the 32,480 images comprising the 3801 examinations, 94.8% were rated as satisfactory by the reviewers. There was 99.4% concordance between trainee and reviewer ultrasound diagnosis. The results suggest that trained health care workers could play a role in ultrasound screening for high-risk OB conditions.

The global network antenatal corticosteroids trial: impact on stillbirth.

BACKGROUND: Antenatal corticosteroids are commonly used to reduce neonatal mortality, but most research to date has been in high-resource settings and few studies have evaluated its impact on stillbirth. In the Antenatal Corticosteroids Trial (ACT), a multi-country trial to assess impact of a multi-faceted intervention including antenatal corticosteroids to reduce neonatal mortality associated with preterm birth, we found an overall increase in 28-day neonatal mortality and stillbirth associated with the intervention. METHODS: The ACT was a cluster-randomized trial conducted in 102 clusters across 7 research sites in 6 countries (India [2 sites], Pakistan, Zambia, Kenya, Guatemala and Argentina), comparing an intervention to train birth attendants at all levels of the health system to identify women at risk of preterm birth, administer corticosteroids and refer women at risk. Because of inadequate gestational age dating, the <5(th) percentile birth weight was used as a proxy for preterm birth. A pre-specified secondary outcome of the trial was stillbirth. RESULTS: After adjusting for the pre-trial imbalance in stillbirth rates, the ACT intervention was associated with a non-significant increased risk of stillbirth (aRR 1.08, 95 % CI, 0.99-1.17, p-0.073). Additionally, the stillbirth rate was higher in the term births (1.20 95 % CI 1.06-1.37, 0.004) and among those with signs of maceration (RR 1.18 (1.04-1.35), p = 0.013) in the intervention vs. control clusters. Differences in obstetric care favored the control clusters and maternal infection was likely more common in the intervention clusters. CONCLUSIONS: In this pragmatic trial, limited data were available to identify the causes of the increase in stillbirths in the intervention clusters. A higher rate of stillbirth in the intervention clusters prior to the trial, differences in obstetric care and an increase in maternal infection are potential explanations for the observed increase in stillbirths in the intervention clusters during the trial. TRIAL REGISTRATION: clinicaltrials.gov (NCT01084096).

The Antenatal Corticosteroids Trial (ACT)'s explanations for neonatal mortality - a secondary analysis.

BACKGROUND: The Antenatal Corticosteroid Trial assessed the feasibility, effectiveness, and safety of a multifaceted intervention to increase the use of antenatal corticosteroids (ACS) in mothers at risk of preterm birth at all levels of care in low and middle-income countries. The intervention effectively increased the use of ACS but was associated with an overall increase in neonatal deaths. We aimed to explore plausible pathways through which this intervention increased neonatal mortality. METHODS: We conducted a series of secondary analyses to assess whether ACS or other components of the multifaceted intervention that might have affected the quality of care contributed to the increased mortality observed: 1) we compared the proportion of neonatal deaths receiving ACS between the intervention and control groups; 2) we compared the antenatal and delivery care process in all births between groups; 3) we compared the rates of possible severe bacterial infection between groups; and 4) we compared the frequency of factors related to ACS administration or maternal high risk conditions at administration between the babies who died and those who survived 28 days among all births in the intervention group identified as high risk for preterm birth and received ACS. RESULTS: The ACS exposure among the infants who died up to 28 days was 29 % in the intervention group compared to 6 % in controls. No substantial differences were observed in antenatal and delivery care process between groups. The risk of pSBI plus neonatal death was significantly increased in intervention clusters compared to controls (2.4 % vs. 2.0 %, adjusted RR 1.17, 95 % CI 1.04-1.30, p = 0.008], primarily for infants with birth weight at or above the 25(th) percentile. Regarding factors related to ACS administration, term infants who died were more likely to have mothers who received ACS within 7 days of delivery compared to those who survived 28 days (26.5 % vs 17.9 %, p = 0.014), and their mothers were more likely to have been identified as high risk for hypertension and less likely for signs of preterm labor. CONCLUSIONS: These results suggest that ACS more than other components of the intervention may have contributed to the overall increased neonatal mortality. ACS may have also been involved in the observed increased risk of neonatal infection and death. Further trials are urgently needed to clarify the effectiveness and safety of ACS on neonatal health in low resource settings.

A multi-faceted intervention including antenatal corticosteroids to reduce neonatal mortality associated with preterm birth: a case study from the Guatemalan Western Highlands.

BACKGROUND: The Global Network for Women's and Children's Health Research undertook a cluster-randomized trial to assess the impact of a multi-faceted intervention to identify women at high-risk of preterm birth at all levels of care, to administer corticosteroids to women and refer for facility delivery compared with standard care. Of the seven sites that participated in the ACT trial, only two sites had statistically significant reductions in the neonatal mortality among the target group of <5th percentile infants, and of the two, Guatemala's improvement in neonatal mortality was by far the largest. METHODS: We used data available from the ACT trial as well as pretrial data in an attempt to understand why neonatal mortality may have decreased in the intervention clusters in <5(th) percentile infants in Chimaltenango, Guatemala. The intervention and control clusters were compared in regards to ACS use, the various types of medical care, outcomes in facility and community births and among births in various birth weight categories. RESULTS: Neonatal mortality decreased to a greater extent in the intervention compared to the control clusters in the <5(th) percentile infants in Guatemala during the ACT Trial. ACS use for the <5(th) percentile infants in the intervention clusters was 49.1 % compared to 13.8 % in the control clusters. Many measures of the quality of obstetric and neonatal care improved to a greater extent in the intervention compared to the control clusters during the trial. Births in facilities and births weighing 1500 to 2500 g had the greatest reduction in neonatal mortality. CONCLUSIONS: The combination of improved care and greater ACS use may potentially account for the observed difference in neonatal mortality between the intervention and control clusters. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01084096 .

An Intervention to Enhance Obstetric and Newborn Care in India: A Cluster Randomized-Trial.

OBJECTIVES: This study assessed whether community mobilization and interventions to improve emergency obstetric and newborn care reduced perinatal mortality (PMR) and neonatal mortality rates (NMR) in Belgaum, India. METHODS: The cluster-randomised controlled trial was conducted in Belgaum District, Karnataka State, India. Twenty geographic clusters were randomized to control or the intervention. The intervention engaged and mobilized community and health authorities to leverage support; strengthened community-based stabilization, referral, and transportation; and aimed to improve quality of care at facilities. RESULTS: 17,754 Intervention births and 15,954 control births weighing ≥1000 g, respectively, were enrolled and analysed. Comparing the baseline period to the last 6 months period, the NMR was lower in the intervention versus control clusters (OR 0.60, 95% CI 0.34-1.06, p = 0.076) as was the PMR (OR 0.74, 95% CI 0.46-1.19, p = 0.20) although neither reached statistical significance. Rates of facility birth and caesarean section increased among both groups. There was limited influence on quality of care measures. CONCLUSIONS FOR PRACTICE: The intervention had large but not statistically significant effects on neonatal and perinatal mortality. Community mobilization and increased facility care may ultimately improve neonatal and perinatal survival, and are important in the context of the global transition towards institutional delivery.

Institutional deliveries and perinatal and neonatal mortality in Southern and Central India.

BACKGROUND: Skilled birth attendance and institutional delivery have been advocated for reducing maternal, perinatal and neonatal mortality (PMR and NMR). India has successfully implemented various strategies to promote skilled attendance and incentivize institutional deliveries in the last 5 years. OBJECTIVES: The study evaluates the trends in institutional delivery, PMR, NMR, and their risk factors in two Eunice Kennedy Shriver NICHD Global Network for Women's and Children's Health Research sites, in Belgaum and Nagpur, India, between January 2010 and December 2013. DESIGN/METHODS: Descriptive data stratified by level of delivery care and key risk factors were analyzed for 36 geographic clusters providing 48 months of data from a prospective, population-based surveillance system that registers all pregnant permanent residents in the study area, and their pregnancy outcomes irrespective of where they deliver. Log binomial models with generalized estimating equations to control for correlation of clustered observations were used to test the trends significance RESULTS: 64,803 deliveries were recorded in Belgaum and 39,081 in Nagpur. Institutional deliveries increased from 92.6% to 96.1% in Belgaum and from 89.5% to 98.6% in Nagpur (both p<0.0001); hospital rates increased from 63.4% to 71.0% (p=0.002) and from 63.1% to 72.0% (p<0.0001), respectively. PMR declined from 41.3 to 34.6 (p=0.008) deaths per 1,000 births in Belgaum and from 47.4 to 40.8 (p=0.09) in Nagpur. Stillbirths also declined, from 22.5 to 16.3 per 1,000 births in Belgaum and from 29.3 to 21.1 in Nagpur (both p=0.002). NMR remained unchanged. CONCLUSIONS: Significant increases in institutional deliveries, particularly in hospitals, were accompanied by reductions in stillbirths and PMR, but not by NMR.

Data quality monitoring and performance metrics of a prospective, population-based observational study of maternal and newborn health in low resource settings.

BACKGROUND: To describe quantitative data quality monitoring and performance metrics adopted by the Global Network's (GN) Maternal Newborn Health Registry (MNHR), a maternal and perinatal population-based registry (MPPBR) based in low and middle income countries (LMICs). METHODS: Ongoing prospective, population-based data on all pregnancy outcomes within defined geographical locations participating in the GN have been collected since 2008. Data quality metrics were defined and are implemented at the cluster, site and the central level to ensure data quality. Quantitative performance metrics are described for data collected between 2010 and 2013. RESULTS: Delivery outcome rates over 95% illustrate that all sites are successful in following patients from pregnancy through delivery. Examples of specific performance metric reports illustrate how both the metrics and reporting process are used to identify cluster-level and site-level quality issues and illustrate how those metrics track over time. Other summary reports (e.g. the increasing proportion of measured birth weight compared to estimated and missing birth weight) illustrate how a site has improved quality over time. CONCLUSION: High quality MPPBRs such as the MNHR provide key information on pregnancy outcomes to local and international health officials where civil registration systems are lacking. The MNHR has measures in place to monitor data collection procedures and improve the quality of data collected. Sites have increasingly achieved acceptable values of performance metrics over time, indicating improvements in data quality, but the quality control program must continue to evolve to optimize the use of the MNHR to assess the impact of community interventions in research protocols in pregnancy and perinatal health. TRIAL REGISTRATION NUMBER: NCT01073475.

Risk factors for maternal death and trends in maternal mortality in low- and middle-income countries: a prospective longitudinal cohort analysis.

BACKGROUND: Because large, prospective, population-based data sets describing maternal outcomes are typically not available in low- and middle-income countries, it is difficult to monitor maternal mortality rates over time and to identify factors associated with maternal mortality. Early identification of risk factors is essential to develop comprehensive intervention strategies preventing pregnancy-related complications. Our objective was to describe maternal mortality rates in a large, multi-country dataset and to determine maternal, pregnancy-related, delivery and postpartum characteristics that are associated with maternal mortality. METHODS: We collected data describing all pregnancies from 2010 to 2013 among women enrolled in the multi-national Global Network for Women's and Children's Health Research Maternal and Neonatal Health Registry (MNHR). We reported the proportion of mothers who died per pregnancy and the maternal mortality ratio (MMR). Generalized linear models were used to evaluate the relationship of potential medical and social factors and maternal mortality and to develop point and interval estimates of relative risk associated with these factors. Generalized estimating equations were used to account for the correlation of outcomes within cluster to develop appropriate confidence intervals. RESULTS: We recorded 277,736 pregnancies and 402 maternal deaths for an MMR of 153/100,000 live births. We observed an improvement in the total MMR from 166 in 2010 to 126 in 2013. The MMR in Latin American sites (91) was lower than the MMR in Asian (178) and African sites (125). When adjusted for study site and the other variables, no formal education (RR 3.2 [1.5, 6.9]), primary education only (RR 3.4 [1.6, 7.5]), secondary education only (RR 2.5 [1.1, 5.7]), lack of antenatal care (RR 1.8 [1.2, 2.5]), caesarean section delivery (RR 1.9 [1.3, 2.8]), hemorrhage (RR 3.3 [2.2, 5.1]), and hypertensive disorders (RR 7.4 [5.2, 10.4]) were associated with higher risks of death. CONCLUSIONS: The MNHR identified preventable causes of maternal mortality in diverse settings in low- and middle-income countries. The MNHR can be used to monitor public health strategies and determine their association with reducing maternal mortality. TRIAL REGISTRATION: clinicaltrials.gov NCT01073475.

Stillbirth rates in low-middle income countries 2010 - 2013: a population-based, multi-country study from the Global Network.

BACKGROUND: Stillbirth rates remain nearly ten times higher in low-middle income countries (LMIC) than high income countries. In LMIC, where nearly 98% of stillbirths worldwide occur, few population-based studies have documented characteristics or care for mothers with stillbirths. Non-macerated stillbirths, those occurring around delivery, are generally considered preventable with appropriate obstetric care. METHODS: We undertook a prospective, population-based observational study of all pregnant women in defined geographic areas across 7 sites in low-resource settings (Kenya, Zambia, India, Pakistan, Guatemala and Argentina). Staff collected demographic and health care characteristics with outcomes obtained at delivery. RESULTS: From 2010 through 2013, 269,614 enrolled women had 272,089 births, including 7,865 stillbirths. The overall stillbirth rate was 28.9/1000 births, ranging from 13.6/1000 births in Argentina to 56.5/1000 births in Pakistan. Stillbirth rates were stable or declined in 6 of the 7 sites from 2010-2013, only increasing in Pakistan. Less educated, older and women with less access to antenatal care were at increased risk of stillbirth. Furthermore, women not delivered by a skilled attendant were more likely to have a stillbirth (RR 2.8, 95% CI 2.2, 3.5). Compared to live births, stillbirths were more likely to be preterm (RR 12.4, 95% CI 11.2, 13.6). Infants with major congenital anomalies were at increased risk of stillbirth (RR 9.1, 95% CI 7.3, 11.4), as were multiple gestations (RR 2.8, 95% CI 2.4, 3.2) and breech (RR 3.0, 95% CI 2.6, 3.5). Altogether, 67.4% of the stillbirths were non-macerated. 7.6% of women with stillbirths had cesarean sections, with obstructed labor the primary indication (36.9%). CONCLUSIONS: Stillbirth rates were high, but with reductions in most sites during the study period. Disadvantaged women, those with less antenatal care and those delivered without a skilled birth attendant were at increased risk of delivering a stillbirth. More than two-thirds of all stillbirths were non-macerated, suggesting potentially preventable stillbirth. Additionally, 8% of women with stillbirths were delivered by cesarean section. The relatively high rate of cesarean section among those with stillbirths suggested that this care was too late or not of quality to prevent the stillbirth; however, further research is needed to evaluate the quality of obstetric care, including cesarean section, on stillbirth in these low resource settings. STUDY REGISTRATION: Clinicaltrials.gov (ID# NCT01073475).

A prospective observational description of frequency and timing of antenatal care attendance and coverage of selected interventions from sites in Argentina, Guatemala, India, Kenya, Pakistan and Zambia.

BACKGROUND: The Global Network for Women's and Children's Health Research is one of the largest international networks for testing and generating evidence-based recommendations for improvement of maternal-child health in resource-limited settings. Since 2009, Global Network sites in six low and middle-income countries have collected information on antenatal care practices, which are important as indicators of care and have implications for programs to improve maternal and child health. We sought to: (1) describe the quantity of antenatal care attendance over a four-year period; and (2) explore the quality of coverage for selected preventative, screening, and birth preparedness components. METHODS: The Maternal Newborn Health Registry (MNHR) is a prospective, population-based birth and pregnancy outcomes registry in Global Network sites, including: Argentina, Guatemala, India (Belgaum and Nagpur), Kenya, Pakistan, and Zambia. MNHR data from these sites were prospectively collected from January 1, 2010 - December 31, 2013 and analyzed for indicators related to quantity and patterns of ANC and coverage of key elements of recommended focused antenatal care. Descriptive statistics were generated overall by global region (Africa, Asia, and Latin America), and for each individual site. RESULTS: Overall, 96% of women reported at least one antenatal care visit. Indian sites demonstrated the highest percentage of women who initiated antenatal care during the first trimester. Women from the Latin American and Indian sites reported the highest number of at least 4 visits. Overall, 88% of women received tetanus toxoid. Only about half of all women reported having been screened for syphilis (49%) or anemia (50%). Rates of HIV testing were above 95% in the Argentina, African, and Indian sites. The Pakistan site demonstrated relatively high rates for birth preparation, but for most other preventative and screening interventions, posted lower coverage rates as compared to other Global Network sites. CONCLUSIONS: Results from our large, prospective, population-based observational study contribute important insight into regional and site-specific patterns for antenatal care access and coverage. Our findings indicate a quality and coverage gap in antenatal care services, particularly in regards to syphilis and hemoglobin screening. We have identified site-specific gaps in access to, and delivery of, antenatal care services that can be targeted for improvement in future research and implementation efforts. TRIAL REGISTRATION: Registration at Clinicaltrials.gov (ID# NCT01073475).

A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: the ACT cluster-randomised trial.

BACKGROUND: Antenatal corticosteroids for pregnant women at risk of preterm birth are among the most effective hospital-based interventions to reduce neonatal mortality. We aimed to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of antenatal corticosteroids at all levels of health care in low-income and middle-income countries. METHODS: In this 18-month, cluster-randomised trial, we randomly assigned (1:1) rural and semi-urban clusters within six countries (Argentina, Guatemala, India, Kenya, Pakistan, and Zambia) to standard care or a multifaceted intervention including components to improve identification of women at risk of preterm birth and to facilitate appropriate use of antenatal corticosteroids. The primary outcome was 28-day neonatal mortality among infants less than the 5th percentile for birthweight (a proxy for preterm birth) across the clusters. Use of antenatal corticosteroids and suspected maternal infection were additional main outcomes. This trial is registered with ClinicalTrials.gov, number NCT01084096. FINDINGS: The ACT trial took place between October, 2011, and March, 2014 (start dates varied by site). 51 intervention clusters with 47,394 livebirths (2520 [5%] less than 5th percentile for birthweight) and 50 control clusters with 50,743 livebirths (2258 [4%] less than 5th percentile) completed follow-up. 1052 (45%) of 2327 women in intervention clusters who delivered less-than-5th-percentile infants received antenatal corticosteroids, compared with 215 (10%) of 2062 in control clusters (p<0·0001). Among the less-than-5th-percentile infants, 28-day neonatal mortality was 225 per 1000 livebirths for the intervention group and 232 per 1000 livebirths for the control group (relative risk [RR] 0·96, 95% CI 0·87-1·06, p=0·65) and suspected maternal infection was reported in 236 (10%) of 2361 women in the intervention group and 133 (6%) of 2094 in the control group (odds ratio [OR] 1·67, 1·33-2·09, p<0·0001). Among the whole population, 28-day neonatal mortality was 27·4 per 1000 livebirths for the intervention group and 23·9 per 1000 livebirths for the control group (RR 1·12, 1·02-1·22, p=0·0127) and suspected maternal infection was reported in 1207 (3%) of 48,219 women in the intervention group and 867 (2%) of 51,523 in the control group (OR 1·45, 1·33-1·58, p<0·0001). INTERPRETATION: Despite increased use of antenatal corticosteroids in low-birthweight infants in the intervention groups, neonatal mortality did not decrease in this group, and increased in the population overall. For every 1000 women exposed to this strategy, an excess of 3·5 neonatal deaths occurred, and the risk of maternal infection seems to have been increased. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Global network for women's and children's health research: a system for low-resource areas to determine probable causes of stillbirth, neonatal, and maternal death.

BACKGROUND: Determining cause of death is needed to develop strategies to reduce maternal death, stillbirth, and newborn death, especially for low-resource settings where 98% of deaths occur. Most existing classification systems are designed for high income settings where extensive testing is available. Verbal autopsy or audits, developed as an alternative, are time-intensive and not generally feasible for population-based evaluation. Furthermore, because most classification is user-dependent, reliability of classification varies over time and across settings. Thus, we sought to develop classification systems for maternal, fetal and newborn mortality based on minimal data to produce reliable cause-of-death estimates for low-resource settings. RESULTS: In six low-resource countries (India, Pakistan, Guatemala, DRC, Zambia and Kenya), we evaluated data which are collected routinely at antenatal care and delivery and could be obtained with interview, observation, or basic equipment from the mother, lay-health provider or family to inform causes of death. Using these basic data collected in a standard way, we then developed an algorithm to assign cause of death that could be computer-programmed. Causes of death for maternal (trauma, abortion, hemorrhage, infection and hypertensive disease of pregnancy), stillbirth (birth trauma, congenital anomaly, infection, asphyxia, complications of preterm birth) and neonatal death (congenital anomaly, infection, asphyxia, complications of preterm birth) are based on existing cause of death classifications, and compatible with the World Health Organization International Classification of Disease system. CONCLUSIONS: Our system to assign cause of maternal, fetal and neonatal death uses basic data from family or lay-health providers to assign cause of death by an algorithm to eliminate a source of inconsistency and bias. The major strengths are consistency, transparency, and comparability across time or regions with minimal burden on the healthcare system. This system will be an important contribution to determining cause of death in low-resource settings.