Overview of the Global and US Burden of Preterm Birth.

Preterm birth (PTB) is the leading cause of morbidity and mortality in children globally, yet its prevalence has been difficult to accurately estimate due to unreliable methods of gestational age dating, heterogeneity in counting, and insufficient data. The estimated global PTB rate in 2020 was 9.9% (95% confidence interval: 9.1, 11.2), which reflects no significant change from 2010, and 81% of prematurity-related deaths occurred in Africa and Asia. PTB prevalence in the United States in 2021 was 10.5%, yet with concerning racial disparities. Few effective solutions for prematurity prevention have been identified, highlighting the importance of further research.

Estimating Gestational Age and Prediction of Preterm Birth Using Metabolomics Biomarkers.

Preterm birth (PTB) is a leading cause of morbidity and mortality in children aged under 5 years globally, especially in low-resource settings. It remains a challenge in many low-income and middle-income countries to accurately measure the true burden of PTB due to limited availability of accurate measures of gestational age (GA), first trimester ultrasound dating being the gold standard. Metabolomics biomarkers are a promising area of research that could provide tools for both early identification of high-risk pregnancies and for the estimation of GA and preterm status of newborns postnatally.

Maternal Larp6 controls oocyte development, chorion formation and elevation.

La-related protein 6 (Larp6) is a conserved RNA-binding protein found across eukaryotes that has been suggested to regulate collagen biogenesis, muscle development, ciliogenesis, and various aspects of cell proliferation and migration. Zebrafish have two Larp6 family genes: larp6a and larp6b Viable and fertile single and double homozygous larp6a and larp6b zygotic mutants revealed no defects in muscle structure, and were indistinguishable from heterozygous or wild-type siblings. However, larp6a mutant females produced eggs with chorions that failed to elevate fully and were fragile. Eggs from larp6b single mutant females showed minor chorion defects, but chorions from eggs laid by larp6a;larp6b double mutant females were more defective than those from larp6a single mutants. Electron microscopy revealed defective chorionogenesis during oocyte development. Despite this, maternal zygotic single and double mutants were viable and fertile. Mass spectrometry analysis provided a description of chorion protein composition and revealed significant reductions in a subset of zona pellucida and lectin-type proteins between wild-type and mutant chorions that paralleled the severity of the phenotype. We conclude that Larp6 proteins are required for normal oocyte development, chorion formation and egg activation.

Geospatial variations in trends of reproductive, maternal, newborn and child health and nutrition indicators at block level in Bihar, India, during scale-up of Ananya program interventions.

BACKGROUND: Geographical variations in the levels and trajectory of health indicators at local level can inform the adaptation of interventions and development of targeted approaches for efficient scale-up of intervention impact. We examined the hypothesis that time trends of a set of reproductive, maternal, newborn, and child health and nutrition (RMNCHN) indicators varied at block-level during the statewide scale-up phase of the Ananya program in Bihar, India. METHODS: We used data on 22 selected indicators from four rounds of the Community-based Household Survey carried out between 2014 and 2017. Indicator levels at each round were estimated for each block. We used hierarchical Bayesian spatiotemporal modelling to smooth the raw estimates for each block with the estimates from its neighbouring blocks, and to examine space-time interaction models for evidence of variations in trends of indicators across blocks. We expressed the uncertainty around the smoothed levels and the trends with 95% credible intervals. RESULTS: There was evidence of variations in trends at block level in all but three indicators: facility delivery, public facility delivery, and age-appropriate initiation of complementary feeding. Fifteen indicators showed trends in opposite directions (increases in some blocks and declines in others). All blocks had at least 97.5% probability of a rise in immediate breastfeeding, early pregnancy registration, and having at least four antenatal care visits. All blocks had at least 97.5% probability of a decline in seeking care for pregnancy complications. CONCLUSIONS: The findings underscore the value of monitoring and evaluation at local level for targeted implementation of RMNCHN interventions. There is a need for identifying systematic factors leading to universal trends, or variable contextual or implementation factors leading to variable trends, in order to optimise primary health care program impact. STUDY REGISTRATION: ClinicalTrials.gov number NCT02726230.

Impact of mHealth interventions for reproductive, maternal, newborn and child health and nutrition at scale: BBC Media Action and the Ananya program in Bihar, India.

BACKGROUND: Mobile health (mHealth) tools have potential for improving the reach and quality of health information and services through community health workers in low- and middle-income countries. This study evaluates the impact of an mHealth tool implemented at scale as part of the statewide reproductive,maternal, newborn and child health and nutrition (RMNCHN) program in Bihar, India. METHODS: Three survey-based data sets were analysed to compare the health-related knowledge, attitudes and behaviours amongst childbearing women exposed to the Mobile Kunji and Dr. Anita mHealth tools during their visits with frontline workers compared with those who were unexposed. RESULTS: An evaluation by Mathematica (2014) revealed that exposure to Mobile Kunji and Dr. Anita recordings were associated with significantly higher odds of consuming iron-folic acid tablets (odds ratio (OR) = 2.3, 95% confidence interval (CI) = 1.8-3.1) as well as taking a set of three measures for delivery preparedness (OR = 2.8, 95% CI = 1.9-4.2) and appropriate infant complementary feeding (OR = 1.9, 95% CI = 1.0-3.5). CARE India's Community-based Household Surveys (2012-2017) demonstrated significant improvements in early breastfeeding (OR = 1.64, 95% CI = 1.5-1.78) and exclusive breastfeeding (OR = 1.46, 95% CI = 1.33-1.62) in addition to birth preparedness practices. BBC Media Action's Usage & Engagement Survey (2014) demonstrated a positive association between exposure to Mobile Kunji and Dr. Anita and exclusive breastfeeding (58% exposed vs 43% unexposed, P < 0.01) as well as maternal respondents' trust in their frontline worker. CONCLUSIONS: Significant improvements in RMNCHN-related knowledge and behaviours were observed for Bihari women who were exposed to Mobile Kunji and Dr. Anita. This analysis is unique in its rigorous evaluation across multiple data sets of mHealth interventions implemented at scale. These results can help inform global understanding of how best to use mHealth tools, for whom, and in what contexts. STUDY REGISTRATION: ClinicalTrials.gov number NCT02726230.

Health impact of self-help groups scaled-up statewide in Bihar, India.

BACKGROUND: The objective of this study was to assess the impact of self-help groups (SHGs) and subsequent scale-up on reproductive, maternal, newborn, child health, and nutrition (RMNCHN) and sanitation outcomes among marginalised women in Bihar, India from 2014-2017. METHODS: We examined RMNCHN and sanitation behaviors in women who were members of any SHGs compared to non-members, without differentiating between types of SHGs. We analysed annual surveys across 38 districts of Bihar covering 62 690 women who had a live birth in the past 12 months. All analyses utilised data from Community-based Household Surveys (CHS) rounds 6-9 collected in 2014-2017 by CARE India as part of the Bihar Technical Support Program funded by the Bill & Melinda Gates Foundation. We examined 66 RMNCHN and sanitation indicators using survey logistic regression; the comparison group in all cases was age-comparable women from the geographic contexts of the SHG members but who did not belong to SHGs. We also examined links between discussion topics in SHGs and changes in relevant behaviours, and stratification of effects by parity and mother's age. RESULTS: SHG members had higher odds compared to non-SHG members for 60% of antenatal care indicators, 22% of delivery indicators, 70% of postnatal care indicators, 50% of nutrition indicators, 100% of family planning and sanitation indicators and no immunisation indicators measured. According to delivery platform, most FLW performance indicators (80%) had increased odds, followed by maternal behaviours (57%) and facility care and outreach service delivery (22%) compared to non-SHG members. Self-report of discussions within SHGs on specific topics was associated with increased related maternal behaviours. Younger SHG members (<25 years) had attenuated health indicators compared to older group members (≥25 years), and women with more children had more positive indicators compared to women with fewer children. CONCLUSIONS: SHG membership was associated with improved RMNCHN and sanitation indicators at scale in Bihar, India. Further work is needed to understand the specific impacts of health layering upon SHGs. Working through SHGs is a promising vehicle for improving primary health care. STUDY REGISTRATION: ClinicalTrials.gov number NCT02726230.

Evaluation of a large-scale reproductive, maternal, newborn and child health and nutrition program in Bihar, India, through an equity lens.

BACKGROUND: Despite increasing focus on health inequities in low- and middle income countries, significant disparities persist. We analysed impacts of a statewide maternal and child health program among the most compared to the least marginalised women in Bihar, India. METHODS: Utilising survey-weighted logistic regression, we estimated programmatic impact using difference-in-difference estimators from Mathematica data collected at the beginning (2012, n = 10 174) and after two years of program implementation (2014, n = 9611). We also examined changes in disparities over time using eight rounds of Community-based Household Surveys (CHS) (2012-2017, n = 48 349) collected by CARE India. RESULTS: At baseline for the Mathematica data, least marginalised women generally performed desired health-related behaviours more frequently than the most marginalised. After two years, most disparities persisted. Disparities increased for skilled birth attendant identification [+16.2% (most marginalised) vs +32.6% (least marginalized), P < 0.01) and skin-to-skin care (+14.8% vs +20.4%, P < 0.05), and decreased for immediate breastfeeding (+10.4 vs -4.9, P < 0.01). For the CHS data, odds ratios compared the most to the least marginalised women as referent. Results demonstrated that disparities were most significant for indicators reliant on access to care such as delivery in a facility (OR range: 0.15 to 0.48) or by a qualified doctor (OR range: 0.08 to 0.25), and seeking care for complications (OR range: 0.26 to 0.64). CONCLUSIONS: Disparities observed at baseline generally persisted throughout program implementation. The most significant disparities were observed amongst behaviours dependent upon access to care. Changes in disparities largely were due to improvements for the least marginalised women without improvements for the most marginalised. Equity-based assessments of programmatic impacts, including those of universal health approaches, must be undertaken to monitor disparities and to ensure equitable and sustainable benefits for all. STUDY REGISTRATION: ClinicalTrials.gov number NCT02726230.

Trends in reproductive, maternal, newborn and child health and nutrition indicators during five years of piloting and scaling-up of Ananya interventions in Bihar, India.

BACKGROUND: The Ananya program in Bihar implemented household and community-level interventions to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) in two phases: a first phase of intensive ancillary support to governmental implementation and innovation testing by non-government organisation (NGO) partners in eight focus districts (2012-2014), followed by a second phase of state-wide government-led implementation with techno-managerial assistance from NGOs (2014 onwards). This paper examines trends in RMNCHN indicators in the program's implementation districts from 2012-2017. METHODS: Eight consecutive rounds of cross-sectional Community-based Household Surveys conducted by CARE India in 2012-2017 provided comparable data on a large number of indicators of frontline worker (FLW) performance, mothers' behaviours, and facility-based care and outreach service delivery across the continuum of maternal and child care. Logistic regression, considering the complex survey design and sample weights generated by that design, was used to estimate trends using survey rounds 2-5 for the first phase in the eight focus districts and rounds 6-9 for the second phase in all 38 districts statewide, as well as the overall change from round 2-9 in focus districts. To aid in contextualising the results, indicators were also compared amongst the formerly focus and the non-focus districts at the beginning of the second phase. RESULTS: In the first phase, the levels of 34 out of 52 indicators increased significantly in the focus districts, including almost all indicators of FLW performance in antenatal and postnatal care, along with mother's birth preparedness, some breastfeeding practices, and immunisations. Between the two phases, 33 of 52 indicators declined significantly. In the second phase, the formerly focus districts experienced a rise in the levels of 14 of 50 indicators and a decline in the levels of 14 other indicators. There was a rise in the levels of 22 out of 50 indicators in the non-focus districts in the second phase, with a decline in the levels of 13 other indicators. CONCLUSIONS: Improvements in indicators were conditional on implementation support to program activities at a level of intensity that was higher than what could be achieved at scale so far. Successes during the pilot phase of intensive support suggests that RMNCHN can be improved statewide in Bihar with sufficient investments in systems performance improvements. STUDY REGISTRATION: ClinicalTrials.gov number NCT02726230.

Impact of the Ananya program on reproductive, maternal, newborn and child health and nutrition in Bihar, India: early results from a quasi-experimental study.

BACKGROUND: The Government of Bihar (GoB) in India, the Bill and Melinda Gates Foundation and several non-governmental organisations launched the Ananya program aimed to support the GoB to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) statewide. Here we summarise changes in indicators attained during the initial two-year pilot phase (2012-2013) of implementation in eight focus districts of approximately 28 million population, aimed to inform subsequent scale-up. METHODS: The quasi-experimental impact evaluation included statewide household surveys at two time points during the pilot phase: January-April 2012 ("baseline") including an initial cohort of beneficiaries and January-April 2014 ("midline") with a new cohort. The two arms were: 1) eight intervention districts, and 2) a comparison arm comprised of the remaining 30 districts in Bihar where Ananya interventions were not implemented. We analysed changes in indicators across the RMNCHN continuum of care from baseline to midline in intervention and comparison districts using a difference-in-difference analysis. RESULTS: Indicators in the two arms were similar at baseline. Overall, 40% of indicators (20 of 51) changed significantly from baseline to midline in the comparison districts unrelated to Ananya; two-thirds (n = 13) of secular indicator changes were in a direction expected to promote health. Statistically significant impact attributable to the Ananya program was found for 10% (five of 51) of RMNCHN indicators. Positive impacts were most prominent for mother's behaviours in contraceptive utilisation. CONCLUSIONS: The Ananya program had limited impact in improving health-related outcomes during the first two-year period covered by this evaluation. The program's theories of change and action were not powered to observe statistically significant differences in RMNCHN indicators within two years, but rather aimed to help inform program improvements and scale-up. Evaluation of large-scale programs such as Ananya using theory-informed, equity-sensitive (including gender), mixed-methods approaches can help elucidate causality and better explain pathways through which supply- and demand-side interventions contribute to changes in behaviour among the actors involved in the production of population-level health outcomes. Evidence from Bihar indicates that deep structural constraints in health system organisation and delivery of interventions pose substantial limitations on behaviour change among health care providers and beneficiaries. STUDY REGISTRATION: ClinicalTrials.gov number NCT02726230.

Improving primary health care delivery in Bihar, India: Learning from piloting and statewide scale-up of Ananya.

In 2010, the Bill and Melinda Gates Foundation (BMGF) partnered with the Government of Bihar (GoB), India to launch the Ananya program to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) outcomes. The program sought to address supply- and demand-side barriers to the adoption, coverage, quality, equity and health impact of select RMNCHN interventions. Approaches included strengthening frontline worker service delivery; social and behavior change communications; layering of health, nutrition and sanitation into women's self-help groups (SHGs); and quality improvement in maternal and newborn care at primary health care facilities. Ananya program interventions were piloted in approximately 28 million population in eight innovation districts from 2011-2013, and then beginning in 2014, were scaled up by the GoB across the rest of the state's population of 104 million. A Bihar Technical Support Program provided techno-managerial support to governmental Health as well as Integrated Child Development Services, and the JEEViKA Technical Support Program supported health layering and scale-up of the GoB's SHG program. The level of support at the block level during statewide scale-up in 2014 onwards was approximately one-fourth that provided in the pilot phase of Ananya in 2011-2013. This paper - the first manuscript in an 11-manuscript and 2-viewpoint collection on Learning from Ananya: Lessons for primary health care performance improvement - seeks to provide a broad description of Ananya and subsequent statewide adaptation and scale-up, and capture the background and context, key objectives, interventions, delivery approaches and evaluation methods of this expansive program. Subsequent papers in this collection focus on specific intervention delivery platforms. For the analyses in this series, Stanford University held key informant interviews and worked with the technical support and evaluation grantees of the Ananya program, as well as leadership from the India Country Office of the BMGF, to analyse and synthesise data from multiple sources. Capturing lessons from the Ananya pilot program and statewide scale-up will assist program managers and policymakers to more effectively design and implement RMNCHN programs at scale through technical assistance to governments.