Multiomics Characterization of Preterm Birth in Low- and Middle-Income Countries.

Importance: Worldwide, preterm birth (PTB) is the single largest cause of deaths in the perinatal and neonatal period and is associated with increased morbidity in young children. The cause of PTB is multifactorial, and the development of generalizable biological models may enable early detection and guide therapeutic studies. Objective: To investigate the ability of transcriptomics and proteomics profiling of plasma and metabolomics analysis of urine to identify early biological measurements associated with PTB. Design, Setting, and Participants: This diagnostic/prognostic study analyzed plasma and urine samples collected from May 2014 to June 2017 from pregnant women in 5 biorepository cohorts in low- and middle-income countries (LMICs; ie, Matlab, Bangladesh; Lusaka, Zambia; Sylhet, Bangladesh; Karachi, Pakistan; and Pemba, Tanzania). These cohorts were established to study maternal and fetal outcomes and were supported by the Alliance for Maternal and Newborn Health Improvement and the Global Alliance to Prevent Prematurity and Stillbirth biorepositories. Data were analyzed from December 2018 to July 2019. Exposures: Blood and urine specimens that were collected early during pregnancy (median sampling time of 13.6 weeks of gestation, according to ultrasonography) were processed, stored, and shipped to the laboratories under uniform protocols. Plasma samples were assayed for targeted measurement of proteins and untargeted cell-free ribonucleic acid profiling; urine samples were assayed for metabolites. Main Outcomes and Measures: The PTB phenotype was defined as the delivery of a live infant before completing 37 weeks of gestation. Results: Of the 81 pregnant women included in this study, 39 had PTBs (48.1%) and 42 had term pregnancies (51.9%) (mean [SD] age of 24.8 [5.3] years). Univariate analysis demonstrated functional biological differences across the 5 cohorts. A cohort-adjusted machine learning algorithm was applied to each biological data set, and then a higher-level machine learning modeling combined the results into a final integrative model. The integrated model was more accurate, with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% CI, 0.72-0.91) compared with the models derived for each independent biological modality (transcriptomics AUROC, 0.73 [95% CI, 0.61-0.83]; metabolomics AUROC, 0.59 [95% CI, 0.47-0.72]; and proteomics AUROC, 0.75 [95% CI, 0.64-0.85]). Primary features associated with PTB included an inflammatory module as well as a metabolomic module measured in urine associated with the glutamine and glutamate metabolism and valine, leucine, and isoleucine biosynthesis pathways. Conclusions and Relevance: This study found that, in LMICs and high PTB settings, major biological adaptations during term pregnancy follow a generalizable model and the predictive accuracy for PTB was augmented by combining various omics data sets, suggesting that PTB is a condition that manifests within multiple biological systems. These data sets, with machine learning partnerships, may be a key step in developing valuable predictive tests and intervention candidates for preventing PTB

Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort study.

BACKGROUND: More than 500 000 neonatal deaths per year result from possible serious bacterial infections (pSBIs), but the causes are largely unknown. We investigated the incidence of community-acquired infections caused by specific organisms among neonates in south Asia. METHODS: From 2011 to 2014, we identified babies through population-based pregnancy surveillance at five sites in Bangladesh, India, and Pakistan. Babies were visited at home by community health workers up to ten times from age 0 to 59 days. Illness meeting the WHO definition of pSBI and randomly selected healthy babies were referred to study physicians. The primary objective was to estimate proportions of specific infectious causes by blood culture and Custom TaqMan Array Cards molecular assay (Thermo Fisher, Bartlesville, OK, USA) of blood and respiratory samples. FINDINGS: 6022 pSBI episodes were identified among 63 114 babies (95·4 per 1000 livebirths). Causes were attributed in 28% of episodes (16% bacterial and 12% viral). Mean incidence of bacterial infections was 13·2 (95% credible interval [CrI] 11·2-15·6) per 1000 livebirths and of viral infections was 10·1 (9·4-11·6) per 1000 livebirths. The leading pathogen was respiratory syncytial virus (5·4, 95% CrI 4·8-6·3 episodes per 1000 livebirths), followed by Ureaplasma spp (2·4, 1·6-3·2 episodes per 1000 livebirths). Among babies who died, causes were attributed to 46% of pSBI episodes, among which 92% were bacterial. 85 (83%) of 102 blood culture isolates were susceptible to penicillin, ampicillin, gentamicin, or a combination of these drugs. INTERPRETATION: Non-attribution of a cause in a high proportion of patients suggests that a substantial proportion of pSBI episodes might not have been due to infection. The predominance of bacterial causes among babies who died, however, indicates that appropriate prevention measures and management could substantially affect neonatal mortality. Susceptibility of bacterial isolates to first-line antibiotics emphasises the need for prudent and limited use of newer-generation antibiotics. Furthermore, the predominance of atypical bacteria we found and high incidence of respiratory syncytial virus indicated that changes in management strategies for treatment and prevention are needed. Given the burden of disease, prevention of respiratory syncytial virus would have a notable effect on the overall health system and achievement of Sustainable Development Goal. FUNDING: Bill & Melinda Gates Foundation

Rates and determinants of neonatal mortality in two rural sub-districts of Sylhet, Bangladesh.

INTRODUCTION:Reducing neonatal mortality rate (NMR) is a challenge in many low- and middle-income countries including Bangladesh. In 2014, the estimated NMR in this country was 28 per 1,000 live births. This rate is higher in rural regions compared to the national average. Currently, Sylhet Division has the highest NMR in Bangladesh. Investigating rates and determinants of neonatal mortality in rural regions of this high-risk division is particularly important to implement evidence-based programs. This study examined rates and determinants of neonatal deaths in a large rural cohort in Sylhet Division. METHODS:We analyzed data from a multi-country cohort study, Aetiology of Neonatal Infections in South Asia. From November 2011 to December 2013, this study was conducted in two rural sub-districts in Sylhet Division. Community health workers followed 28,960 pregnant women and their newborns up to two months postpartum and collected data on pregnancy outcomes and newborns' survival status. The NMR was obtained by dividing total number of neonatal deaths with all studied newborns. Logistic regression was employed to calculate adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for factors associated with neonatal mortality. Stata 14.0 was used for data analysis. RESULTS:This study analyzed data of 21,227 newborns. The NMR was 43.4 (95% CI: 39.3-48.0) per 1,000 live births (N = 922). Multivariable analysis showed that the odds of neonatal mortality were significantly higher among male newborns (AOR: 1.5, 95% CI: 1.2-1.8), babies born before 34 weeks of gestation (AOR: 5.0, 95% CI: 4.1-6.1), those who were twins or triplets (AOR: 6.2, 95% CI: 3.6-10.9), and first-born child (AOR: 2.9, 95% CI: 1.6-5.3). Additionally, maternal age 30-35 years (AOR: 1.4, 95% CI: 1.-1.8), history of child death (AOR: 1.6, 95% CI: 1.2-2.2), and delivery complications (AOR: 2.1, 95% CI: 1.6-2.6) had positive associations with neonatal deaths. CONCLUSION:Public health programs in Bangladesh need to adopt a comprehensive strategy to address the individual, maternal, and intrapartum factors associated with neonatal mortality in rural regions. Interventions should aim to prioritize managing pre-term deliveries, first-born child, and delivery complications among pregnant women

Effect of a package of integrated demand- and supply-side interventions on facility delivery rates in rural Bangladesh: Implications for large-scale programs

<div><p>Background</p><p>According to the Bangladesh Demographic and Health Survey 2014, only approximately 37 percent of women deliver in a health facility. Among the eight administrative divisions of Bangladesh, the facility delivery rate is lowest in the Sylhet division (22.6 percent) where we assessed the effect of integrated supply- and demand-side interventions on the facility-based delivery rate.</p><p>Methods</p><p>Population-based cohort data of pregnant women from an ongoing maternal and newborn health improvement study being conducted in a population of ~120,000 in Sylhet district were used. The study required collection and processing of biological samples immediately after delivery. Therefore, the project assembled various strategies to increase institutional delivery rates. The supply-side intervention included capacity expansion of the health facilities through service provider refresher training, 24/7 service coverage, additions of drugs and supplies, and incentives to the providers. The demand-side component involved financial incentives to cover expenses, a provision of emergency transport, and referral support to a tertiary-level hospital. We conducted a before-and-after observational study to assess the impact of the intervention in a total of 1,861 deliveries between December 2014 and November 2016.</p><p>Results</p><p>Overall, implementation of the intervention package was associated with 52.6 percentage point increase in the proportions of facility-based deliveries from a baseline rate of 25.0 percent to 77.6 percent in 24 months. We observed lower rates of institutional deliveries when only supply-side interventions were implemented. The proportion rose to 47.1 percent and continued increasing when the project emphasized addressing the financial barriers to accessing obstetric care in a health facility.</p><p>Conclusions</p><p>An integrated supply- and demand-side intervention was associated with a substantial increase in institutional delivery. The package can be tailored to identify which combination of interventions may produce the optimum result and be scaled. Rigorous implementation research studies are needed to draw confident conclusions and to provide information about the costs, feasibility for scale-up and sustainability.</p></div

Study flow chart.

<p>Study flow chart.</p

Trends in proportions of pregnant women delivered in a health facility.

<p>Trends in proportions of pregnant women delivered in a health facility.</p

Facility_Delivery_PONE-D-17-08125

<p>We report the effect of an integrated demand- and supply-side intervention undertaken as part of an ongoing maternal and newborn health improvement study on facility delivery rates over a 24-month period in a rural population in Sylhet district, Bangladesh.</p

Patterns and Determinants of Care-Seeking for Antepartum and Intrapartum Complications in Rural Bangladesh: Results from a Cohort Study.

The burden of maternal complications during antepartum and intrapartum periods is high and care seeking from a trained provider is low, particularly in low middle income countries of sub-Saharan Africa and South Asia. Identification of barriers to access to trained care and development of strategies to address them will contribute to improvements in maternal health. Using data from a community-based cohort of pregnant women, this study identified the prevalence of antepartum and intrapartum complications and determinants of care-seeking for these complications in rural Bangladesh.The study was conducted in 24,274 pregnant women between June 2011 and December 2013 in rural Sylhet district of Bangladesh. Women were interviewed during pregnancy to collect data on demographic and socioeconomic characteristics; prior miscarriages, stillbirths, live births, and neonatal deaths; as well as data on their ability to make decision to go to health center alone. They were interviewed within the first 7 days of child birth to collect data on self-reported antepartum and intrapartum complications and care seeking for those complications. Bivariate analysis was conducted to explore association between predisposing (socio-demographic), enabling (economic), perceived need, and service related factors with care-seeking for self-reported antepartum and intrapartum complications. Multivariable multinomial logistic regression was performed to examine the association of selected factors with care-seeking for self-reported antepartum and intrapartum complications adjusting for co-variates.Self-reported antepartum and intrapartum complications among women were 14.8% and 20.9% respectively. Among women with any antepartum complication, 58.9% sought care and of these 46.5% received care from a trained provider. Of the women with intrapartum complications, 61.4% sought care and of them 46.5% did so from a trained provider. Care-seeking for both antepartum and intrapartum complications from a trained provider was significantly higher for women with higher household wealth status, higher literacy level of both women and their husbands, and for those living close to a health facility (<10 km). Women's decision making ability to go to health centre alone was associated with untrained care only for antepartum complications, but was associated with both trained and untrained care for intrapartum complications.Nearly 40.0% of the women who experienced either an antepartum or intrapartum complications did not seek care from any provider and 11.5% -14.9% received care from untrained providers, primarily because of economic and geographic barriers to access. Development and evaluation of context specific, cost-effective, and sustainable strategies that will address these barriers to access to care for the maternal complications will enhance care seeking from trained health care providers and improve maternal health

Conceptual framework.

<p>Note: Adapted from Andersen RM. Revisiting the behavioral Model and access to Medical Care: Does It Matter? Journal of Health and Social Behaviour 1995, vol. 36 (March): 1–10.</p

Care seeking behavior for self-reported intrapartum complications by selected characteristics of women.

<p>Care seeking behavior for self-reported intrapartum complications by selected characteristics of women.</p