Young Infant Mortality Associated with Preterm and Small-for-Gestational-Age Births in Rural Bangladesh: A Prospective Cohort Study.

OBJECTIVE: To assess the relative risk of mortality in infants born preterm and small for gestational age (SGA) during the first and second months of life in rural Bangladesh. STUDY DESIGN: We analyzed data from a cohort of pregnant women and their babies in Sylhet, Bangladesh, assembled between 2011 and 2014. Community health workers visited enrolled babies up to 10 times from birth to age 59 days. Survival status was recorded at each visit. Gestational age was estimated from mother's reported last menstrual period. Birth weights were measured within 72 hours of delivery. SGA was defined using the INTERGROWTH-21st standard. We estimated unadjusted and adjusted hazard ratios (HRs) and corresponding 95% CIs for babies born preterm and SGA separately for the first and second month of life using bivariate and multivariable weighted Cox regression models. RESULTS: The analysis included 17 643 singleton live birth babies. Compared with infants born at term-appropriate for gestational age, in both unadjusted and adjusted analyses, infants born preterm-SGA had the greatest risk of death in the first (HR 13.25, 95% CI 8.65-20.31; adjusted HR 12.05, 95% CI 7.82-18.57) and second month of life (HR 4.65, 95% CI 1.93-11.23; adjusted HR 4.1, 95% CI 1.66-10.15), followed by infants born preterm-appropriate for gestational age and term-SGA. CONCLUSIONS: The risk of mortality in infants born preterm and/or SGA is increased and extends through the second month of life. Appropriate interventions to prevent and manage complications caused by prematurity and SGA could improve survival during and beyond the neonatal period.

Does the implementation of revised American College of Cardiology and American Heart Association (ACC/AHA) guidelines improve the identification of stillbirths and preterm births in hypertensive pregnancies: a population-based cohort study from South Asia and sub-Saharan Africa.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) are a significant cause of maternal mortality worldwide. The classification and treatment of hypertension in pregnancy remain debated. We aim to compare the effectiveness of the revised 2017 ACC/AHA blood pressure threshold in predicting adverse pregnancy outcomes. METHODS: We conducted a secondary data analysis of the Alliance for Maternal and Newborn Health Improvement (AMANHI) biorepository study, including 10,001 pregnant women from Bangladesh, Pakistan, and Tanzania. Blood pressure was measured using validated devices at different antenatal care visits. The blood pressure readings were categorized as: normal blood pressure (systolic blood pressure (sBP) < 120 mm Hg and diastolic blood pressure (dBP) < 80 mm Hg), elevated blood pressure (sBP 120-129 and dBP < 80), stage 1 hypertension (sBP 130-139 or dBP 80-89, or both), and stage 2 hypertension (sBP ≥ 140 or dBP ≥ 90, or both). We estimated risk ratios for stillbirths and preterm births, as well as diagnostic test properties of both the pre-existing JNC7 (≥ 140/90) and revised ACC/AHA (≥ 130/80) thresholds using normal blood pressure as reference group. RESULTS: From May 2014 to June 2018, blood pressure readings were available for 9,448 women (2,894 in Bangladesh, 2,303 in Pakistan, and 4,251 in Tanzania). We observed normal blood pressure in 70%, elevated blood pressure in 12.4%, stage 1 hypertension in 15.2%, and stage 2 hypertension in 2.5% of the pregnant women respectively. Out of these, 310 stillbirths and 9,109 live births were recorded, with 887 preterm births. Using the ACC/AHA criteria, the stage 1 hypertension cut-off revealed 15.3% additional hypertension diagnoses as compared to JNC7 criteria. ACC/AHA defined hypertension was significantly associated with stillbirths (RR 1.8, 95% CI 1.4, 2.3). The JNC 7 hypertension cut-off of ≥ 140/90 was significantly associated with a higher risk of preterm births (RR 1.6, 95% CI 1.2, 2.2) and stillbirths (RR 3.6, 95% CI 2.5, 5.3). Both criteria demonstrated low sensitivities (8.4 for JNC-7 and 28.1 for ACC/AHA) and positive predictive values (11.0 for JNC7 and 5.2 for ACC/AHA) in predicting adverse outcomes. CONCLUSION: The ACC/AHA criteria (≥ 130/80) identified additional cases of hypertension but had limited predictive accuracy for stillbirths and preterm births, highlighting the ongoing need for improved criteria in managing pregnancy-related hypertension.

Direct maternal morbidity and the risk of pregnancy-related deaths, stillbirths, and neonatal deaths in South Asia and sub-Saharan Africa: A population-based prospective cohort study in 8 countries.

BACKGROUND: Maternal morbidity occurs several times more frequently than mortality, yet data on morbidity burden and its effect on maternal, foetal, and newborn outcomes are limited in low- and middle-income countries. We aimed to generate prospective, reliable population-based data on the burden of major direct maternal morbidities in the antenatal, intrapartum, and postnatal periods and its association with maternal, foetal, and neonatal death in South Asia and sub-Saharan Africa. METHODS AND FINDINGS: This is a prospective cohort study, conducted in 9 research sites in 8 countries of South Asia and sub-Saharan Africa. We conducted population-based surveillance of women of reproductive age (15 to 49 years) to identify pregnancies. Pregnant women who gave consent were include in the study and followed up to birth and 42 days postpartum from 2012 to 2015. We used standard operating procedures, data collection tools, and training to harmonise study implementation across sites. Three home visits during pregnancy and 2 home visits after birth were conducted to collect maternal morbidity information and maternal, foetal, and newborn outcomes. We measured blood pressure and proteinuria to define hypertensive disorders of pregnancy and woman's self-report to identify obstetric haemorrhage, pregnancy-related infection, and prolonged or obstructed labour. Enrolled women whose pregnancy lasted at least 28 weeks or those who died during pregnancy were included in the analysis. We used meta-analysis to combine site-specific estimates of burden, and regression analysis combining all data from all sites to examine associations between the maternal morbidities and adverse outcomes. Among approximately 735,000 women of reproductive age in the study population, and 133,238 pregnancies during the study period, only 1.6% refused consent. Of these, 114,927 pregnancies had morbidity data collected at least once in both antenatal and in postnatal period, and 114,050 of them were included in the analysis. Overall, 32.7% of included pregnancies had at least one major direct maternal morbidity; South Asia had almost double the burden compared to sub-Saharan Africa (43.9%, 95% CI 27.8% to 60.0% in South Asia; 23.7%, 95% CI 19.8% to 27.6% in sub-Saharan Africa). Antepartum haemorrhage was reported in 2.2% (95% CI 1.5% to 2.9%) pregnancies and severe postpartum in 1.7% (95% CI 1.2% to 2.2%) pregnancies. Preeclampsia or eclampsia was reported in 1.4% (95% CI 0.9% to 2.0%) pregnancies, and gestational hypertension alone was reported in 7.4% (95% CI 4.6% to 10.1%) pregnancies. Prolonged or obstructed labour was reported in about 11.1% (95% CI 5.4% to 16.8%) pregnancies. Clinical features of late third trimester antepartum infection were present in 9.1% (95% CI 5.6% to 12.6%) pregnancies and those of postpartum infection in 8.6% (95% CI 4.4% to 12.8%) pregnancies. There were 187 pregnancy-related deaths per 100,000 births, 27 stillbirths per 1,000 births, and 28 neonatal deaths per 1,000 live births with variation by country and region. Direct maternal morbidities were associated with each of these outcomes. CONCLUSIONS: Our findings imply that health programmes in sub-Saharan Africa and South Asia must intensify their efforts to identify and treat maternal morbidities, which affected about one-third of all pregnancies and to prevent associated maternal and neonatal deaths and stillbirths. TRIAL REGISTRATION: The study is not a clinical trial.

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.

Pregnancy intervals after stillbirth, neonatal death and spontaneous abortion and the risk of an adverse outcome in the next pregnancy in rural Bangladesh.

BACKGROUND: Studies have revealed associations between preceding short and long birth-to-birth or birth-to-pregnancy intervals and poor pregnancy outcomes. Most of these studies, however, have examined the effect of intervals that began with live births. Using data from Bangladesh, we examined the effect of inter-outcome intervals (IOI) starting with a non-live birth or neonatal death, on outcomes in the next pregnancy. Pregnancy spacing behaviors in rural northeast Bangladesh have changed little since 2004. METHODS: We analyzed pregnancy histories for married women aged 15-49 years who had outcomes between 2000 and 2006 in Sylhet, Bangladesh. We examined the effects of the preceding outcome and the IOI length on the risk of stillbirth, neonatal death and spontaneous abortion using multinomial logistic regression models. RESULTS: Data included 64,897 pregnancy outcomes from 33,495 mothers. Inter-outcome intervals of 27-50 months and live births were baseline comparators. Stillbirths followed by IOI's <=6 months, 7-14 months or overall <=14 months had increased risks for spontaneous abortion with adjusted relative risk ratios (aRRR) and 95% confidence intervals = 29.6 (8.09, 108.26), 1.84 (0.84, 4.02) and 2.53 (1.19, 5.36), respectively. Stillbirths followed by IOIs 7-14 months had aRRR 2.00 (1.39, 2.88) for stillbirths. Neonatal deaths followed by IOIs <=6 months had aRRR 28.2 (8.59, 92.63) for spontaneous abortion. Neonatal deaths followed by IOIs 7-14 and 15-26 months had aRRRs 3.08 (1.82, 5.22) and 2.32 (1.38, 3.91), respectively, for stillbirths; and aRRRs 2.81 (2.06, 3.84) and 1.70 (1.24, 3.84), respectively, for neonatal deaths. Spontaneous abortions followed by IOIs <=6 months and 7-14 months had, respectively, aRRRs 23.21 (10.34, 52.13) and 1.80 (0.98, 3.33) for spontaneous abortion. CONCLUSION: In rural northeast Bangladesh, short inter-outcome intervals after stillbirth, neonatal death and spontaneous abortion were associated with a high risk of a similar outcome in the next pregnancy. These findings are aligned with other studies from Bangladesh. Two studies from similar settings have found benefits of waiting six months before conceiving again, suggesting that incorporating this advice into programs should be considered. Further research is warranted to confirm these findings.

Prevalence of and risk factors for abnormal vaginal flora and its association with adverse pregnancy outcomes in a rural district in north-east Bangladesh.

INTRODUCTION: The role of screening and treatment for abnormal vaginal flora (AVF) on adverse pregnancy outcomes remains unclear. Using data from women who participated in a population-based cluster randomized trial who were screened and treated for AVF, we report risk factors for AVF and association of persistent AVF with adverse perinatal outcomes. MATERIAL AND METHODS: Pregnant women (n = 4221) <19 weeks of gestation provided self-administered mid-vaginal swabs; smears were Nugent-scored. AVF was treated with oral clindamycin; if AVF was present 3 weeks after treatment, persistent AVF was re-treated. We examined risk factors for AVF and the association of persistent AVF with adverse pregnancy outcomes. RESULTS: The prevalence of AVF was 16.5%: 9.8% of women had bacterial vaginosis and 6.8% had intermediate flora. Lower economic and educational status of women were associated with increased risk of AVF. One-third of women with AVF had persistent abnormal flora; these women had a higher risk of a composite measure of adverse pregnancy outcomes from 20 to <37 weeks (preterm live birth, preterm still birth, late miscarriage) (relative risk [RR] 1.33, 95% confidence interval [CI] 1.07-1.65) and of late miscarriage alone (RR 4.15, 95% CI 2.12-8.12) compared to women without AVF. CONCLUSIONS: In this study in Sylhet District, Bangladesh, rates of AVF and persistent AVF were high and persistent AVF was associated with adverse pregnancy outcomes, with an especially high associated risk for late miscarriage. Further characterization of the microbiome and relative bacterial species density associated with persistent AVF is needed.

Urinary tract infections in pregnancy in a rural population of Bangladesh: population-based prevalence, risk factors, etiology, and antibiotic resistance.

BACKGROUND: Urinary tract infection (UTI) in pregnancy, including asymptomatic bacteriuria, is associated with maternal morbidity and adverse pregnancy outcomes, including preterm birth and low birthweight. In low-middle income countries (LMICs), the capacity for screening and treatment of UTIs is limited. The objective of this study was to describe the population-based prevalence, risk factors, etiology and antimicrobial resistance patterns of UTIs in pregnancy in Bangladesh. METHODS: In a community-based cohort in Sylhet district, Bangladesh, urine specimens were collected at the household level in 4242 pregnant women (< 20 weeks gestation) for culture and antibiotic susceptibility testing. Basic descriptive analysis was performed, as well as logistic regression to calculate adjusted odds ratios (aOR) for UTI risk factors. RESULTS: The prevalence of UTI was 8.9% (4.4% symptomatic UTI, 4.5% asymptomatic bacteriuria). Risk factors for UTI in this population included maternal undernutrition (mid-upper arm circumference <23 cm: aOR= 1.29, 95% CI: 1.03-1.61), primiparity (aOR= 1.45, 95% CI: 1.15-1.84), and low paternal education (no education: aOR= 1.56, 95% CI: 1.09-2.22). The predominant uro-pathogens were E. coli (38% of isolates), Klebsiella (12%), and staphyloccocal species (23%). Group B streptococcus accounted for 5.3% of uro-pathogens. Rates of antibiotic resistance were high, with only two-thirds of E. coli susceptible to 3rd generation cephalosporins. CONCLUSIONS: In Sylhet, Bangladesh, one in 11 women had a UTI in pregnancy, and approximately half of cases were asymptomatic. There is a need for low-cost and accurate methods for UTI screening in pregnancy and efforts to address increasing rates of antibiotic resistance in LMIC.

The association between daily 500 mg calcium supplementation and lower pregnancy-induced hypertension risk in Bangladesh.

BACKGROUND: Evidence suggests that daily supplementation of 1500 to 2000 mg of calcium during pregnancy reduces pregnancy-induced hypertension (PIH). However, the evidence on the efficacy of low-dose calcium supplementation on PIH is limited. This paper assesses the longitudinal correlation between low-dose calcium intake (500 mg daily) and change in blood pressure during pregnancy among a homogeneous population in terms of hypertension and pre-eclampsia. METHODS: The study followed a retrospective cohort study design, and was carried out among 11,387 pregnant women from 10 rural upazilas (sub-districts) of Bangladesh where maternal nutrition initiative (MNI), implemented by Building Resources Across Communities (BRAC), was ongoing. The modified Poisson regression model was used to estimate the association (risk ratio) between consumption of calcium tablets and PIH. RESULTS: The present research found that women who consumed 500 mg/d calcium tablets for more than 6 months during their pregnancy had a 45% lower risk of developing hypertension compared to those who consumed less calcium (RR = 0.55, 95% CI = 0.33-0.93). CONCLUSIONS: Daily supplementation of 500 mg oral calcium during pregnancy for at least 180 tablets is associated with a considerably reduced risk of PIH, but this study is unable to confirm whether this association is causal. The causal relationship needs to be confirmed through a large scale randomized controlled trial.

Neonatal mortality within 24 hours of birth in six low- and lower-middle-income countries.

OBJECTIVE: To estimate neonatal mortality, particularly within 24 hours of birth, in six low- and lower-middle-income countries. METHODS: We analysed epidemiological data on a total of 149 570 live births collected between 2007 and 2013 in six prospective randomized trials and a cohort study from predominantly rural areas of Bangladesh, Ghana, India, Pakistan, the United Republic of Tanzania and Zambia. The neonatal mortality rate and mortality within 24 hours of birth were estimated for all countries and mortality within 6 hours was estimated for four countries with available data. The findings were compared with published model-based estimates of neonatal mortality. FINDINGS: Overall, the neonatal mortality rate observed at study sites in the six countries was 30.5 per 1000 live births (range: 13.6 in Zambia to 47.4 in Pakistan). Mortality within 24 hours was 14.1 per 1000 live births overall (range: 5.1 in Zambia to 20.1 in India) and 46.3% of all neonatal deaths occurred within 24 hours (range: 36.2% in Pakistan to 65.5% in the United Republic of Tanzania). Mortality in the first 6 hours was 8.3 per 1000 live births, i.e. 31.9% of neonatal mortality. CONCLUSION: Neonatal mortality within 24 hours of birth in predominantly rural areas of six low- and lower-middle-income countries was higher than model-based estimates for these countries. A little under half of all neonatal deaths occurred within 24 hours of birth and around one third occurred within 6 hours. Implementation of high-quality, effective obstetric and early newborn care should be a priority in these settings.

Screening and treatment of maternal genitourinary tract infections in early pregnancy to prevent preterm birth in rural Sylhet, Bangladesh: a cluster randomized trial.

BACKGROUND: Approximately half of preterm births are attributable to maternal infections, which are commonly undetected and untreated in low-income settings. Our primary aim is to determine the impact of early pregnancy screening and treatment of maternal genitourinary tract infections on the incidence of preterm live birth in Sylhet, Bangladesh. We will also assess the effect on other adverse pregnancy outcomes, including preterm birth (stillbirth and live birth), late miscarriage, maternal morbidity, and early onset neonatal sepsis. METHODS/DESIGN: We are conducting a cluster randomized controlled trial that will enroll 10,000 pregnant women in Sylhet district in rural northeastern Bangladesh. Twenty-four clusters, each with ~4000 population (120 pregnant women/year) and served by a community health worker (CHW), are randomized to: 1) the control arm, which provides routine antenatal and postnatal home-based care, or 2) the intervention arm, which includes routine antenatal and postnatal home-based care plus screening and treatment of pregnant women between 13 and 19 weeks of gestation for abnormal vaginal flora (AVF) and urinary tract infection (UTI). CHWs conduct monthly pregnancy surveillance, make 2 antenatal and 4 postnatal home visits for all enrolled pregnant women and newborns, and refer mothers or newborns with symptoms of serious illness to the government sub-district hospital. In the intervention clusters, CHWs perform home-based screening of AVF and UTI. Self-collected vaginal swabs are plated on slides, which are Gram stained and Nugent scored. Women with AVF (Nugent score ≥4) are treated with oral clindamycin, rescreened and retreated, if needed, after 3 weeks. Urine culture is performed and UTI treated with nitrofurantoin. Repeat urine culture is performed after 1 week for test of cure. Gestational age is determined by maternal report of last menstrual period at study enrollment using prospectively completed study calendars, and in a subset by early (<20 week) ultrasound. CHWs prospectively collect data on all pregnancy outcomes, maternal and neonatal morbidity and mortality. IMPLICATIONS/DISCUSSION: Findings will enhance our understanding of the burden of AVF and UTI in rural Bangladesh, the impact of a maternal screening-treatment program for genitourinary tract infections on perinatal health, and help formulate public health recommendations for infection screening in pregnancy in low-resource settings. TRIAL REGISTRATION: The study was registered on ClinicalTrials.gov:NCT01572532 on December 15, 2011. The study was funded by NICHD: R01HD066156 .

Infectious aetiologies of neonatal illness in south Asia classified using WHO definitions: a primary analysis of the ANISA study.

BACKGROUND: Globally, neonatal mortality accounts for almost half of all deaths in children younger than 5 years. Aetiological agents of neonatal infection are difficult to identify because the clinical signs are non-specific. Using data from the Aetiology of Neonatal Infections in south Asia (ANISA) cohort, we aimed to describe the spectrum of infectious aetiologies of acute neonatal illness categorised post-hoc using the 2015 WHO case definitions of critical illness, clinical severe infection, and fast breathing only. METHODS: Eligible infants were aged 0-59 days with possible serious bacterial infection and healthy infants enrolled in the ANISA study in Bangladesh, India, and Pakistan. We applied a partial latent class Bayesian model to estimate the prevalence of 27 pathogens detectable on PCR, pathogens detected by blood culture only, and illness not attributed to any infectious aetiology. Infants with at least one clinical specimen available were included in the analysis. We assessed the prevalence of these aetiologies according to WHO's case definitions of critically ill, clinical severe infection, and infants with late onset, isolated fast breathing. For the clinical severe definition, we compared the prevalence of signs by bacterial versus viral aetiology. FINDINGS: There were 934 infants (992 episodes) in the critically ill category, 3769 (4000 episodes) in the clinical severe infection category, and 738 (771 episodes) in the late-onset isolated fast breathing category. We estimated the proportion of illness attributable to bacterial infection was 32·7% in infants in the critically ill group, 15·6% in the clinical severe infection group, and 8·8% among infants with late-onset isolated fast breathing group. An infectious aetiology was not identified in 58-82% of infants in these categories. Among 4000 episodes of clinical severe infection, those with bacterial versus viral attribution had higher proportions of hypothermia, movement only when stimulated, convulsions, and poor feeding. INTERPRETATION: Our modelled results generally support the revised WHO case definitions, although a revision of the most severe case definition could be considered. Clinical criteria do not clearly differentiate between young infants with and without infectious aetiologies. Our results highlight the need for improved point-of-care diagnostics, and further study into neonatal deaths and episodes with no identified aetiology, to ensure antibiotic stewardship and targeted interventions. FUNDING: The Bill and Melinda Gates Foundation.

Risk factors for community-acquired bacterial infection among young infants in South Asia: a longitudinal cohort study with nested case-control analysis.

OBJECTIVE: Risk factors predisposing infants to community-acquired bacterial infections during the first 2 months of life are poorly understood in South Asia. Identifying risk factors for infection could lead to improved preventive measures and antibiotic stewardship. METHODS: Five sites in Bangladesh, India and Pakistan enrolled mother-child pairs via population-based pregnancy surveillance by community health workers. Medical, sociodemographic and epidemiological risk factor data were collected. Young infants aged 0-59 days with signs of possible serious bacterial infection (pSBI) and age-matched controls provided blood and respiratory specimens that were analysed by blood culture and real-time PCR. These tests were used to build a Bayesian partial latent class model (PLCM) capable of attributing the probable cause of each infant's infection in the ANISA study. The collected risk factors from all mother-child pairs were classified and analysed against the PLCM using bivariate and stepwise logistic multivariable regression modelling to determine risk factors of probable bacterial infection. RESULTS: Among 63 114 infants born, 14 655 were assessed and 6022 had signs of pSBI; of these, 81% (4859) provided blood samples for culture, 71% (4216) provided blood samples for quantitative PCR (qPCR) and 86% (5209) provided respiratory qPCR samples. Risk factors associated with bacterial-attributed infections included: low (relative risk (RR) 1.73, 95% credible interval (CrI) 1.42 to 2.11) and very low birth weight (RR 5.77, 95% CrI 3.73 to 8.94), male sex (RR 1.27, 95% CrI 1.07 to 1.52), breathing problems at birth (RR 2.50, 95% CrI 1.96 to 3.18), premature rupture of membranes (PROMs) (RR 1.27, 95% CrI 1.03 to 1.58) and being in the lowest three socioeconomic status quintiles (first RR 1.52, 95% CrI 1.07 to 2.16; second RR 1.41, 95% CrI 1.00 to 1.97; third RR 1.42, 95% CrI 1.01 to 1.99). CONCLUSION: Distinct risk factors: birth weight, male sex, breathing problems at birth and PROM were significantly associated with the development of bacterial sepsis across South Asian community settings, supporting refined clinical discernment and targeted use of antimicrobials.

Gender-specific prevalence and associated factors of hypertension among elderly Bangladeshi people: findings from a nationally representative cross-sectional survey.

OBJECTIVE: We aimed to estimate the gender-specific prevalence and associated factors of hypertension among elderly people in Bangladesh. DESIGN AND METHOD: We analysed data from the food security and nutrition surveillance round 2018-2019. The multistage cluster sampling method was used to select the study population. Hypertension was defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg and/or having a history of hypertension. We carried out the descriptive analysis, bivariate and multivariable logistic regression to report the weighted prevalence of hypertension as well as crude and adjusted ORs with 95% CI. A p value<0.05 was considered statistically significant. SETTING: The study was conducted in 82 clusters (57 rural, 15 non-slum urban and 10 slums) in all eight administrative divisions of Bangladesh. PARTICIPANTS: A total of 2482 males and 2335 females aged ≥60 years were included in this analysis. RESULTS: The weighted prevalence of hypertension was 42% and 56% among males and females, respectively. The prevalence was higher among females across all sociodemographic, behavioural and clinical strata. Factors associated with higher odds of hypertension (adjusted OR (AOR) (95% CI) for males and females, respectively) were age ≥70 years (1.32 (1.09, 1.60) and 1.40 (1.15, 1.71)); insufficient physical activity (1.50 (1.25, 1.81) and 1.38 (1.15, 1.67)); higher waist circumference (2.76 (2.22, 3.43) and 2.20 (1.82, 2.67)); and self-reported diabetes (1.36 (1.02, 1.82) and 1.82 (1.35, 2.45)). Additionally, living in slums decreased (0.71 (0.52, 0.96)) and education >10 years increased odds of hypertension (1.83 (1.38, 2.44)) among males. CONCLUSION: In Bangladesh, half of the elderly persons were hypertensive, with a higher prevalence in females. In both sexes, odds of hypertension was higher among persons with older age (≥70 years), insufficient physical activity, higher waist circumference and self-reported diabetes. The Ministry of Health of Bangladesh should consider these findings while designing and implementing health programmes for elderly population.

Validation of community health worker identification of maternal puerperal sepsis using a clinical diagnostic algorithm in Bangladesh and Pakistan.

BACKGROUND: Puerperal sepsis (PP sepsis) is a leading cause of maternal mortality globally. The majority of maternal sepsis cases and deaths occur at home and remain undiagnosed and under-reported. In this paper, we present findings from a nested case-control study in Bangladesh and Pakistan which sought to assess the validity of community health worker (CHW) identification of PP sepsis using a clinical diagnostic algorithm with physician assessment and classification used as the gold standard. METHODS: Up to 300 postpartum women were enrolled in each of the 3 sites 1) Sylhet, Bangladesh (n = 278), 2) Karachi, Pakistan (n = 278) and 3) Matiari, Pakistan (n = 300). Index cases were women with suspected PP Sepsis as diagnosed by CHWs clinical assessment of one or more of the following signs and symptoms: temperature (recorded fever ≥38.1°C, reported history of fever, lower abdominal or pelvic pain, and abnormal or foul-smelling discharge. Each case was matched with 3 control women who were diagnosed by CHWs to have no infection. Cases and controls were assessed by trained physicians using the same algorithm implemented by the CHWs. Using physician assessment as the gold standard, Kappa statistics for reliability and diagnostic validity (sensitivity and specificity) are presented with 95% CI. Sensitivity and specificity were adjusted for verification bias. RESULTS: The adjusted sensitivity and specificity of CHW identification of PP sepsis across all sites was 82% (Karachi: 78%, Matiari: 78%, Sylhet: 95%) and 90% (Karachi: 95%, Matiari: 85%, Sylhet: 90%) respectively. CHW-Physician agreement was highest for moderate and high fever (range across sites: K = 0.84-0.97) and lowest for lower abdominal pain (K = 0.30-0.34). The clinical signs and symptoms for other conditions were reported infrequently, however, the CHW-physician agreement was high for all symptoms except severe headache/ blurred vision (K = 0.13-0.38) and reported "lower abdominal pain without fever" (K = 0.39-0.57). CONCLUSION: In all sites, CHWs with limited training were able to identify signs and symptoms and to classify cases of PP sepsis with high validity. Integrating postpartum infection screening into existing community-based platforms and post-natal visits is a promising strategy to monitor women for PP sepsis - improving delivery of cohesive maternal and child health care in low resource settings.

Provider performance and facility readiness for managing infections in young infants in primary care facilities in rural Bangladesh.

BACKGROUND: Neonatal infections remain a leading cause of newborn deaths globally. In 2015, WHO issued guidelines for managing possible serious bacterial infection (PSBI) in young infants (0-59 days) using simplified antibiotic regimens when compliance with hospital referral is not feasible. Bangladesh was one of the first countries to adopt WHO's guidelines for implementation. We report results of an implementation research study that assessed facility readiness and provider performance in three rural sub-districts of Bangladesh during August 2015-August 2016. METHODS: This study took place in 19 primary health centers. Facility readiness was assessed using checklists completed by study staff at three time points. To assess provider performance, we extracted data for all infection cases from facility registers and compared providers' diagnosis and treatment against the guidelines. We plotted classification and dosage errors across the study period and superimposed a locally weighted smoothed (LOWESS) curve to analyze changes in performance over time. Focus group discussions (N = 2) and in-depth interviews (N = 28) with providers were conducted to identify barriers and facilitators for facility readiness and provider performance. RESULTS: At baseline, none of the facilities had adequate supply of antibiotics. During the 10-month period, 606 sick infants with signs of infection presented at the study facilities. Classification errors were identified in 14.9% (N = 90/606) of records. For infants receiving the first dose(s) of antibiotic treatment (N = 551), dosage errors were identified in 22.9% (N = 126/551) of the records. Distribution of errors varied by facility (35.7% [IQR: 24.7-57.4%]) and infection severity. Errors were highest at the beginning of the study period and decreased over time. Qualitative data suggest errors in early implementation were due to changes in providers' assessment and treatment practices, including confusion about classifying an infant with multiple signs of infection, and some providers' concerns about the efficacy of simplified antibiotic regimens. CONCLUSIONS: Strategies to monitor early performance and targeted supports are important for enhancing implementation fidelity when introducing complex guidelines in new settings. Future research should examine providers' assessment of effectiveness of simplified treatment and address misconceptions about superiority of broader spectrum antibiotics for treating community-acquired neonatal infections in this context.

Caregiver acceptability of the guidelines for managing young infants with possible serious bacterial infections (PSBI) in primary care facilities in rural Bangladesh.

INTRODUCTION: Many infants with possible serious bacterial infections (PSBI) do not receive inpatient treatment because hospital care may not be affordable, accessible, or acceptable for families. In 2015, WHO issued guidelines for managing PSBI in young infants (0-59 days) with simpler antibiotic regimens when hospital care is not feasible. Bangladesh adopted WHO's guidelines for implementation in outpatient primary health centers. We report results of an implementation research study that assessed caregiver acceptability of the guidelines in three rural sub-districts of Bangladesh during early implementation (October 2015-August 2016). METHODS: We included 19 outpatient primary health centers involved in the initial rollout of the infection management guidelines. We extracted data for all PSBI cases (N = 192) from facility registers to identify gaps in referral feasibility, simplified antibiotic treatment, and follow-up. Focus group discussions (FGD) and in-depth interviews (IDI) were conducted with both caregivers (6 FGDs; 23 IDIs) and providers (2 FGDs; 28 IDIs) to assess caregiver acceptability of the guidelines. RESULTS: Referral to the hospital was not feasible for many families (83.3%; N = 160/192) and acceptance varied by infection severity. Barriers to referral feasibility included economic and household factors, and previous experiences with poor quality of care at the sub-district hospital. Conversely, providers and caregivers indicated high acceptability of simplified antibiotic treatment. 80% (N = 96/120) of infants with clinical severe infection for whom referral was not feasible returned to the facility for the second antibiotic injection. Some providers reported developing local solutions-including engaging informal providers in treatment of the infant-to address organizational barriers and promote treatment compliance. Follow-up of young infants receiving simplified treatment is critical, but only 67.4% (N = 87/129) of infants received fourth day follow-up. Some providers' reported deviations from the guidelines that shifted responsibility of follow-up to the caregiver, which may have contributed to lapses. CONCLUSION: Caregivers' perception of trust and communication with providers were influential in caregiver acceptability of care. Few caregivers accepted referral to the sub-district hospital, suggesting low acceptability of this option. When referral was not feasible, many caregivers reported satisfaction with simplified antibiotic treatment. Local solutions described by providers require further examination in this context to assess the safety and potential value of these strategies in outpatient treatment. Our findings suggest strengthening providers' interpersonal skills could improve caregiver acceptability of the guidelines.

Population-based incidence and serotype distribution of invasive pneumococcal disease prior to introduction of conjugate pneumococcal vaccine in Bangladesh.

BACKGROUND: Bangladesh introduced the 10-valent pneumococcal conjugate vaccine (PCV-10) in 2015. We measured population-based incidence of invasive pneumococcal disease (IPD) prior to introduction of PCV-10 to provide a benchmark against which the impact of PCV-10 can be assessed. METHODS: We conducted population, facility and laboratory-based surveillance in children 0-59 months of age in three rural sub-districts of Sylhet district of Bangladesh from January 2014 to June 2015. All children received two-monthly home visits with one week recall for morbidity and care seeking. Children attending the three Upazilla Health Complexes (UHC, sub-district hospitals) in the surveillance area were screened for suspected IPD. Blood samples were collected from suspected IPD cases for culture and additionally, cerebrospinal fluid (CSF) was collected from suspected meningitis cases for culture and molecular testing. Pneumococcal isolates were serotyped by Quellung. Serotyping of cases detected by molecular testing was done by sequential multiplex polymerase chain reaction. RESULTS: Children under surveillance contributed to 126,657 child years of observations. Sixty-three thousand three hundred eighty-four illness episodes were assessed in the UHCs. Blood specimens were collected from 8,668 suspected IPD cases and CSF from 177 suspected meningitis cases. Streptococcus pneumoniae was isolated from 46 cases; 32 (70%) were vaccine serotype. The population-based incidence of IPD was 36.3/100,000 child years of observations. About 80% of the cases occurred in children below two years of age. DISCUSSION: IPD was common in rural Bangladesh suggesting the potential benefit of an effective vaccine. Measurement of the burden of IPD requires multiple surveillance modalities.

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.

Maternal short stature and under-weight status are independent risk factors for preterm birth and small for gestational age in rural Bangladesh.

BACKGROUND/OBJECTIVES: To estimate the risks of term-small for gestational age (SGA), preterm-appropriate for gestational age (AGA), and preterm SGA associated with maternal height and body mass index (BMI) and to calculate the population attributable fractions (PAF) of term SGA, preterm AGA, and preterm SGA associated with maternal short stature. SUBJECTS/METHODS: A population-based cohort of 13,230 women with pre-pregnancy height and weight followed from 2012 to 2016 in Sylhet, Bangladesh. We analyzed data of 2655 singleton live born infants. The babies born <37 weeks of gestation were considered preterm and weight <10th percentile of Intergrowth sex-specific gestational age were considered SGA. Risk factors for term SGA, preterm AGA, and preterm SGA were examined using multinomial logistic regression that estimated relative risk ratios (RRR) and 95% confidence intervals (CI). RESULTS: Maternal short stature <145 cm was significantly associated with term SGA (RRR 1.88, 95% CI 1.37, 2.58; p < 0.001), preterm AGA (RRR 1.45, 95% CI 1.02, 2.05; p < 0.05), and preterm SGA (RRR 14.40, 95% CI 1.82, 113.85; p < 0.05). Maternal underweight status (BMI < 18.5 kg/m2) was significant predictor of term SGA (RRR 1.32, 95% CI 1.10, 1.59; p < 0.01), and preterm AGA (RRR 1.39, 95% CI 1.12, 1.71; p < 0.01). PAF for maternal short stature were 23.2, 7.3, and 73.9% for term SGA, preterm AGA, and preterm SGA, respectively. CONCLUSIONS: To address the problem of undernutrition, Bangladesh needs to strengthen implementation of its multi-sectoral nutrition program comprising nutrition specific and sensitive interventions. Implementation of the program with high coverage and quality would improve maternal nutrition and perinatal outcomes including preterm births and SGA.

Effect of population-based antenatal screening and treatment of genitourinary tract infections on birth outcomes in Sylhet, Bangladesh (MIST): a cluster-randomised clinical trial.

BACKGROUND: One-third of preterm births are attributed to pregnancy infections. We implemented a community-based intervention to screen and treat maternal genitourinary tract infections, with the aim of reducing the incidence of preterm birth. METHODS: We did an unblinded cluster-randomised controlled trial in two subdistricts of Sylhet, Bangladesh. Clusters were defined as the contiguous area served by a single community health worker, and each cluster comprised several contiguous villages, contained roughly 4000 people, and had about 120 births per year. Eligible participants within clusters were all ever-married women and girls of reproductive age (ie, aged 15-49 years) who became pregnant during the study period. Clusters were randomly assigned (1:1) to the intervention or control groups via a restricted randomisation procedure. In both groups, community health workers made home visits to identify pregnant women and girls and provide antenatal and postnatal care. Between 13 and 19 weeks' gestation, participants in the intervention group received home-based screening for abnormal vaginal flora and urinary tract infections. A random 10% of the control group also received the intervention to examine the similarity of infection prevalence between groups. If present, abnormal vaginal flora (ie, Nugent score ≥4 was treated with oral clindamycin (300 mg twice daily for 5 days) and urinary tract infections with cefixime (400 mg once daily for 3 days) or oral nitrofurantoin (100 mg twice daily for 7 days). Both infections were retreated if persistent. The primary outcome was the incidence of preterm livebirths before 37 weeks' gestation among all livebirths. This trial is registered with ClinicalTrials.gov, number NCT01572532. The trial is closed to new participants, with follow-up completed. FINDINGS: Between Jan 2, 2012, and July 28, 2015, 9712 pregnancies were enrolled (4840 in the intervention group, 4391 in the control group, and 481 in the control subsample). 3818 livebirths in the intervention group and 3557 livebirths in the control group were included in the primary analysis. In the intervention group, the prevalence of abnormal vaginal flora was 16·3% (95% CI 15·1-17·6) and that of urinary tract infection was 8·6% (7·7-9·5). The effective coverage of successful treatment in the intervention group was 58% in participants with abnormal vaginal flora (ie, abnormal vaginal flora resolved in 361 [58%] of the 622 participants who initially tested positive), and 71% in those with urinary tract infections (ie, resolution in 224 [71%] of the 317 participants who initially tested positive). Overall, the incidence of preterm livebirths before 37 weeks' gestation did not differ significantly between the intervention and control groups (21·8% vs 20·6%; relative risk 1·07 [95% CI 0·91-1·24]). INTERPRETATION: A population-based antenatal screening and treatment programme for genitourinary tract infections did not reduce the incidence of preterm birth in Bangladesh. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development and Saving Lives at Birth Grand Challenges.