Zooming in and out: a holistic framework for research on maternal, late foetal and newborn survival and health.

Research is needed to understand why some countries succeed in greater improvements in maternal, late foetal and newborn health (MNH) and reducing mortality than others. Pathways towards these health outcomes operate at many levels, making it difficult to understand which factors contribute most to these health improvements. Conceptual frameworks provide a cognitive means of rendering order to these factors and how they interrelate to positively influence MNH. We developed a conceptual framework by integrating theories and frameworks from different disciplines to encapsulate the range of factors that explain reductions in maternal, late foetal and neonatal mortality and improvements in health. We developed our framework iteratively, combining our interdisciplinary research team's knowledge, experience and review of the literature. We present a framework that includes health policy and system levers (or intentional actions that policy-makers can implement) to improve MNH; service delivery and coverage of interventions across the continuum of care; and epidemiological and behavioural risk factors. The framework also considers the role of context in influencing for whom and where health and non-health efforts have the most impact, to recognize 'the causes of the causes' at play at the individual/household, community, national and transnational levels. Our framework holistically reflects the range of interrelated factors influencing improved MNH and survival. The framework lends itself to studying how different factors work together to influence these outcomes using an array of methods. Such research should inform future efforts to improve MNH and survival in different contexts. By re-orienting research in this way, we hope to equip policy-makers and practitioners alike with the insight necessary to make the world a safer and fairer place for mothers and their babies

Open-label comparative clinical study of chlorproguanil-dapsone fixed dose combination (Lapdap) alone or with three different doses of artesunate for uncomplicated Plasmodium falciparum malaria.

UNLABELLED: The objective of this study was to determine the appropriate dose of artesunate for use in a fixed dose combination therapy with chlorproguanil-dapsone (CPG-DDS) for the treatment of uncomplicated falciparum malaria. METHODS: Open-label clinical trial comparing CPG-DDS alone or with artesunate 4, 2, or 1 mg/kg at medical centers in Blantyre, Malawi and Farafenni, The Gambia. The trial was conducted between June 2002 and February 2005, including 116 adults (median age 27 years) and 107 children (median age 38 months) with acute uncomplicated Plasmodium falciparum malaria. Subjects were randomized into 4 groups to receive CPG-DDS alone or plus 4, 2 or 1 mg/kg of artesunate once daily for 3 days. Assessments took place on Days 0-3 in hospital and follow-up on Days 7 and 14 as out-patients. Efficacy was evaluated in the Day 3 per-protocol (PP) population using mean time to reduce baseline parasitemia by 90% (PC90). A number of secondary outcomes were also included. Appropriate artesunate dose was determined using a pre-defined decision matrix based on primary and secondary outcomes. Treatment emergent adverse events were recorded from clinical assessments and blood parameters. Safety was evaluated in the intent to treat (ITT) population. RESULTS: In the Day 3 PP population for the adult group (N = 85), mean time to PC90 was 19.1 h in the CPG-DDS group, significantly longer than for the +artesunate 1 mg/kg (12.5 h; treatment difference -6.6 h [95%CI -11.8, -1.5]), 2 mg/kg (10.7 h; -8.4 h [95%CI -13.6, -3.2]) and 4 mg/kg (10.3 h; -8.7 h [95%CI -14.1, -3.2]) groups. For children in the Day 3 PP population (N = 92), mean time to PC90 was 21.1 h in the CPG-DDS group, similar to the +artesunate 1 mg/kg group (17.7 h; -3.3 h [95%CI -8.6, 2.0]), though the +artesunate 2 mg/kg and 4 mg/kg groups had significantly shorter mean times to PC90 versus CPG-DDS; 14.4 h (treatment difference -6.4 h [95%CI -11.7, -1.0]) and 12.8 h (-7.4 h [95%CI -12.9, -1.8]), respectively. An analysis of mean time to PC90 for the Day 14 PP and ITT populations was consistent with the primary analysis. Treatment emergent, drug-related adverse events were experienced in 35.3% (41/116) of adults and 70.1% (75/107) of children; mostly hematological and gastroenterological. The nature and incidence of adverse events was similar between the groups. No dose-related changes in laboratory parameters were observed. Nine serious adverse events due to any cause occurred in five subjects including two cases of hemolysis believed to be associated with drug treatment (one adult, one child). One adult died of anaphylactic shock, not associated with investigational therapy. CONCLUSIONS: CPG-DDS plus artesunate demonstrated advantages over CPG-DDS alone for the primary efficacy endpoint (mean time to PC90) except in children for the 1 mg/kg artesunate dose. Based on a pre-defined decision matrix, the primary endpoint in the child group supported an artesunate dose of 4 mg/kg. Secondary endpoints also supported a 4 mg/kg artesunate dose to take forward into the remainder of the development program. TRIAL REGISTRATION: ClinicalTrials.gov NCT00519467

Neonatal hyperbilirubinemia and Rhesus disease of the newborn: incidence and impairment estimates for 2010 at regional and global levels.

BACKGROUND: Rhesus (Rh) disease and extreme hyperbilirubinemia (EHB) result in neonatal mortality and long-term neurodevelopmental impairment, yet there are no estimates of their burden. METHODS: Systematic reviews and meta-analyses were undertaken of national prevalence, mortality, and kernicterus due to Rh disease and EHB. We applied a compartmental model to estimate neonatal survivors and impairment cases for 2010. RESULTS: Twenty-four million (18% of 134 million live births ≥ 32 wk gestational age from 184 countries; uncertainty range: 23-26 million) were at risk for neonatal hyperbilirubinemia-related adverse outcomes. Of these, 480,700 (0.36%) had either Rh disease (373,300; uncertainty range: 271,800-477,500) or developed EHB from other causes (107,400; uncertainty range: 57,000-131,000), with a 24% risk for death (114,100; uncertainty range: 59,700-172,000), 13% for kernicterus (75,400), and 11% for stillbirths. Three-quarters of mortality occurred in sub-Saharan Africa and South Asia. Kernicterus with Rh disease ranged from 38, 28, 28, and 25/100,000 live births for Eastern Europe/Central Asian, sub-Saharan African, South Asian, and Latin American regions, respectively. More than 83% of survivors with kernicterus had one or more impairments. CONCLUSION: Failure to prevent Rh sensitization and manage neonatal hyperbilirubinemia results in 114,100 avoidable neonatal deaths and many children grow up with disabilities. Proven solutions remain underused, especially in low-income countries

Preterm birth associated with maternal fine particulate matter exposure : A global, regional and national assessment

Reduction of preterm births (< 37 completed weeks of gestation) would substantially reduce neonatal and infant mortality, and deleterious health effects in survivors. Maternal fine particulate matter (PM2.5) exposure has been identified as a possible risk factor contributing to preterm birth. The aim of this study was to produce the first estimates of ambient PM2.5-associated preterm births for 183 individual countries and globally. To do this, national, population-weighted, annual average ambient PM2.5 concentration, preterm birth rate and number of livebirths were combined to calculate the number of PM2.5-associated preterm births in 2010 for 183 countries. Uncertainty was quantified using Monte-Carlo simulations, and analyses were undertaken to investigate the sensitivity of PM2.5-associated preterm birth estimates to assumptions about the shape of the concentration-response function at low and high PM2.5 exposures, inclusion of provider-initiated preterm births, and exposure to indoor air pollution. Globally, in 2010, the number of PM2.5-associated preterm births was estimated as 2.7 million (1.8–3.5 million, 18% (12–24%) of total preterm births globally) with a low concentration cut-off (LCC) set at 10 μg m− 3, and 3.4 million (2.4–4.2 million, 23% (16–28%)) with a LCC of 4.3 μg m− 3. South and East Asia, North Africa/Middle East and West sub-Saharan Africa had the largest contribution to the global total, and the largest percentage of preterm births associated with PM2.5. Sensitivity analyses showed that PM2.5-associated preterm birth estimates were 24% lower when provider-initiated preterm births were excluded, 38–51% lower when risk was confined to the PM2.5 exposure range in the studies used to derive the effect estimate, and 56% lower when mothers who live in households that cook with solid fuels (and whose personal PM2.5 exposure is likely dominated by indoor air pollution) were excluded. The concentration-response function applied here derives from a meta-analysis of studies, most of which were conducted in the US and Europe, and its application to the areas of the world where we estimate the greatest effects on preterm births remains uncertain. Nevertheless, the substantial percentage of preterm births estimated to be associated with anthropogenic PM2.5 (18% (13%–24%) of total preterm births globally) indicates that reduction of maternal PM2.5 exposure through emission reduction strategies should be considered alongside mitigation of other risk factors associated with preterm births

Estimating the birth prevalence and pregnancy outcomes of congenital malformations worldwide

Congenital anomaly registries have two main surveillance aims: firstly to define baseline epidemiology of important congenital anomalies to facilitate programme, policy and resource planning, and secondly to identify clusters of cases and any other epidemiological changes that could give early warning of environmental or infectious hazards. However, setting up a sustainable registry and surveillance system is resource-intensive requiring national infrastructure for recording all cases and diagnostic facilities to identify those malformations that that are not externally visible. Consequently, not all countries have yet established robust surveillance systems. For these countries, methods are needed to generate estimates of prevalence of these disorders which can act as a starting point for assessing disease burden and service implications. Here, we describe how registry data from high-income settings can be used for generating reference rates that can be used as provisional estimates for countries with little or no observational data on non-syndromic congenital malformations

Categorising interventions to levels of inpatient care for small and sick newborns: Findings from a global survey.

BACKGROUND: In 2017, 2.5 million newborns died, mainly from prematurity, infections, and intrapartum events. Preventing these deaths requires health systems to provide routine and emergency care at birth, and quality inpatient care for small and sick newborns. Defined levels of emergency obstetric care (EmOC) and standardised measurement of "signal functions" has improved tracking of maternal care in low- and middle-income countries (LMICs). Levels of newborn care, particularly for small and sick newborns, and associated signal functions are still not consistently defined or tracked. METHODS: Between November 2016-November 2017, we conducted an online survey of professionals working in maternal and newborn health. We asked respondents to categorise 18 clinical care interventions that could act as potential signal functions for small and sick newborns to 3 levels of care they thought were appropriate for health systems in LMICs to provide: "routine care at birth", "special care" and "intensive care". We calculated the percentage of respondents that classified each intervention at each level of care and stratified responses to look at variation by respondent characteristics. RESULTS: Six interventions were classified to specific levels by more than 50% of respondents as "routine care at birth," three interventions as "special care" and one as "intensive care". Eight interventions were borderline between these care levels. Responses were more consistent for interventions with relevant WHO clinical care guidelines while more variation in respondents' classification was observed in complex interventions that lack standards or guidelines. Respondents with experience in lower-income settings were more likely to assign a higher level of care for more complex interventions. CONCLUSIONS: Results were consistent with known challenges of scaling up inpatient care in lower-income settings and underline the importance of comprehensive guidelines and standards for inpatient care. Further work is needed to develop a shortlist of newborn signal functions aligned with emergency obstetric care levels to track universal health coverage for mothers and their newborns

Stillbirths:economic and psychosocial consequences

Despite the frequency of stillbirths, the subsequent implications are overlooked and underappreciated. We present findings from comprehensive, systematic literature reviews, and new analyses of published and unpublished data, to establish the effect of stillbirth on parents, families, health-care providers, and societies worldwide. Data for direct costs of this event are sparse but suggest that a stillbirth needs more resources than a livebirth, both in the perinatal period and in additional surveillance during subsequent pregnancies. Indirect and intangible costs of stillbirth are extensive and are usually met by families alone. This issue is particularly onerous for those with few resources. Negative effects, particularly on parental mental health, might be moderated by empathic attitudes of care providers and tailored interventions. The value of the baby, as well as the associated costs for parents, families, care providers, communities, and society, should be considered to prevent stillbirths and reduce associated morbidity

Birthweight: EN-BIRTH multi-country validation study.

BACKGROUND: Accurate birthweight is critical to inform clinical care at the individual level and tracking progress towards national/global targets at the population level. Low birthweight (LBW)  98% for four hospitals) and legible > 99.9%. Weighing of stillbirths varied by hospital, ranging from 12.5-89.0%. Observed LBW rate was 15.6%; survey-reported rate 14.3% (8.9-20.9%), sensitivity 82.9% (75.1-89.4%), specificity 96.1% (93.5-98.5%); register-recorded rate 14.9%, sensitivity 90.8% (85.9-94.8%), specificity 98.5% (98-99.0%). In surveys, "don't know" responses for birthweight measured were 4.7%, and 2.9% for knowing the actual weight. 95.9% of observed babies were weighed within 1 h of birth, only 14.7% with a digital scale. Weight heaping indices were around two-fold lower using digital scales compared to analogue. Observed heaping was almost 5% higher for births during the night than day. Survey-report further increased observed birthweight heaping, especially for LBW babies. Enablers to register birthweight measurement in qualitative interviews included digital scale availability and adequate staffing. CONCLUSIONS: Hospital registers captured birthweight and LBW prevalence more accurately than women's survey report. Even in large hospitals, digital scales were not always available and stillborn babies not always weighed. Birthweight data are being captured in hospitals and investment is required to further improve data quality, researching of data flow in routine systems and use of data at every level

Stillbirth With Group B Streptococcus Disease Worldwide: Systematic Review and Meta-analyses.

Background: There are an estimated 2.6 million stillbirths each year, many of which are due to infections, especially in low- and middle-income contexts. This paper, the eighth in a series on the burden of group B streptococcal (GBS) disease, aims to estimate the percentage of stillbirths associated with GBS disease. Methods: We conducted systematic literature reviews (PubMed/Medline, Embase, Literatura Latino-Americana e do Caribe em Ciências da Saúde, World Health Organization Library Information System, and Scopus) and sought unpublished data from investigator groups. Studies were included if they reported original data on stillbirths (predominantly ≥28 weeks' gestation or ≥1000 g, with GBS isolated from a sterile site) as a percentage of total stillbirths. We did meta-analyses to derive pooled estimates of the percentage of GBS-associated stillbirths, regionally and worldwide for recent datasets. Results: We included 14 studies from any period, 5 with recent data (after 2000). There were no data from Asia. We estimated that 1% (95% confidence interval [CI], 0-2%) of all stillbirths in developed countries and 4% (95% CI, 2%-6%) in Africa were associated with GBS. Conclusions: GBS is likely an important cause of stillbirth, especially in Africa. However, data are limited in terms of geographic spread, with no data from Asia, and cases worldwide are probably underestimated due to incomplete case ascertainment. More data, using standardized, systematic methods, are critical, particularly from low- and middle-income contexts where the highest burden of stillbirths occurs. These data are essential to inform interventions, such as maternal GBS vaccination

Service readiness for inpatient care of small and sick newborns: what do we need and what can we measure now?

BACKGROUND: Each year an estimated 2.6 million newborns die, mainly from complications of prematurity, neonatal infections, and intrapartum events. Reducing these deaths requires high coverage of good quality care at birth, and inpatient care for small and sick newborns. In low- and middle-income countries, standardised measurement of the readiness of facilities to provide emergency obstetric care has improved tracking of readiness to provide care at birth in recent years. However, the focus has been mainly on obstetric care; service readiness for providing inpatient care of small and sick newborns is still not consistently measured or tracked. METHODS: We reviewed existing international guidelines and resources to create a matrix of the structural characteristics (infrastructure, equipment, drugs, providers and guidelines) for service readiness to deliver a package of inpatient care interventions for small and sick newborns. To identify gaps in existing measurement systems, we reviewed three multi-country health facility survey tools (the Service Availability and Readiness Assessment, the Service Provision Assessment and the Emergency Obstetric and Newborn Care Assessment) against our service readiness matrix. FINDINGS: For service readiness to provide inpatient care for small and sick newborns, our matrix detailed over 600 structural characteristics. Our review of the SPA, the SARA and the EmONC assessment tools identified several measurement omissions to capture information on key intervention areas, such as thermoregulation, feeding and respiratory support, treatment of specific complications (seizures, jaundice), and screening and follow up services, as well as specialised staff and service infrastructure. CONCLUSIONS: Our review delineates the required inputs to ensure readiness to provide inpatient care for small and sick newborns. Based on these findings, we detail where questions need to be added to existing tools and describe how measurement systems can be adapted to reflect small and sick newborns interventions. Such work can inform investments in health systems to end preventable newborn death and disability as part of the Every Newborn Action Plan