High rates of placental inflammation among samples collected by the Multi-Omics for Mothers and Infants consortium.

BACKGROUND: The Multi-Omics for Mothers and Infants consortium aims to improve birth outcomes. Preterm birth is a major obstetrical complication globally and causes significant infant and childhood morbidity and mortality. OBJECTIVE: We analyzed placental samples (basal plate, placenta or chorionic villi, and the chorionic plate) collected by the 5 Multi-Omics for Mothers and Infants sites, namely The Alliance for Maternal and Newborn Health Improvement Bangladesh, The Alliance for Maternal and Newborn Health Improvement Pakistan, The Alliance for Maternal and Newborn Health Improvement Tanzania, The Global Alliance to Prevent Prematurity and Stillbirth Bangladesh, and The Global Alliance to Prevent Prematurity and Stillbirth Zambia. The goal was to analyze the morphology and gene expression of samples collected from preterm and uncomplicated term births. STUDY DESIGN: The teams provided biopsies from 166 singleton preterm (<37 weeks' gestation) and 175 term (≥37 weeks' gestation) deliveries. The samples were fixed in formalin and paraffin embedded. Tissue sections from these samples were stained with hematoxylin and eosin and subjected to morphologic analyses. Other placental biopsies (n=35 preterm, 21 term) were flash frozen, which enabled RNA purification for bulk transcriptomics. RESULTS: The morphologic analyses revealed a surprisingly high rate of inflammation that involved the basal plate, placenta or chorionic villi, and the chorionic plate. The rate of inflammation in chorionic villus samples, likely attributable to chronic villitis, ranged from 25% (Pakistan site) to 60% (Zambia site) of cases. Leukocyte infiltration in this location vs in the basal plate or chorionic plate correlated with preterm birth. Our transcriptomic analyses identified 267 genes that were differentially expressed between placentas from preterm vs those from term births (123 upregulated, 144 downregulated). Mapping the differentially expressed genes onto single-cell RNA sequencing data from human placentas suggested that all the component cell types, either singly or in subsets, contributed to the observed dysregulation. Consistent with the histopathologic findings, gene ontology analyses highlighted the presence of leukocyte infiltration or activation and inflammatory responses in both the fetal and maternal compartments. CONCLUSION: The relationship between placental inflammation and preterm birth is appreciated in developed countries. In this study, we showed that this link also exists in developing geographies. In addition, among the participating sites, we found geographic- and population-based differences in placental inflammation and preterm birth, suggesting the importance of local factors.

Healthcare seeking behavior and delays in case of Drug-Resistant Tuberculosis patients in Bangladesh: Findings from a cross-sectional survey.

The emergence of Drug-Resistant Tuberculosis (DR-TB) has become a major threat globally and Bangladesh is no exception. Delays in healthcare seeking, proper diagnosis and initiation of treatment cause continuous transmission of the resistant tubercule bacilli through the communities. This study aimed to assess the different health care-seeking behaviors and delays among DR-TB patients in Bangladesh. A prospective cross-sectional study was conducted from November to December 2018, among 92 culture positive and registered DR-TB patients in four selected hospitals in Bangladesh. Data were collected through face-to-face interviews with survey questionnaire as well as record reviews. Among the 92 study participants, the median patient delay was 7 (IQR 3, 15) days, the median diagnostic delay was 88 (IQR 36.5, 210), the median treatment delay was 7 (IQR 4,12) days, and the median total delay among DR-TB patients was 108.5 (IQR 57.5, 238) days. 81.32% sought initial care from informal healthcare providers. The majority (68.48%) of the informal healthcare providers were drug sellers while 60.87% of patients sought care from more than four healthcare points before being diagnosed with DR-TB. The initial care seeking from multiple providers was associated with diagnostic and total delays. In Bangladesh, DR-TB cases usually seek care from multiple providers, particularly from informal providers, and among them, alarmingly higher healthcare-seeking related delays were noted. Immediate measures should be taken both at the health system levels and, in the community, to curb transmission and reduce the burden of the disease.

Trends and risk of recurrent preterm birth in pregnancy cohorts in rural Bangladesh, 1990-2019.

INTRODUCTION: A history of preterm birth reportedly increases the risk of subsequent preterm birth. This association has primarily been studied in high-income countries and not in low-income settings in transition with rapidly descending preterm birth figures. We evaluated the population-based trends of preterm births and recurrent preterm births and the risk of preterm birth recurrence in the second pregnancy based on prospectively studied pregnancy cohorts over three decades in Matlab, Bangladesh. METHODS: A population-based cohort included 72 160 live births from 1990 to 2019. We calculated preterm birth and recurrent preterm birth trends. We assessed the odds of preterm birth recurrence based on a subsample of 14 567 women with live-born singletons in their first and second pregnancies. We used logistic regression and presented the associations by OR with a 95% CI. RESULTS: The proportion of preterm births decreased from 25% in 1990 to 13% in 2019. The recurrent preterm births had a similar, falling pattern from 7.4% to 3.1% across the same period, contributing 27% of the total number of preterm births in the population. The odds of second pregnancy preterm birth were doubled (OR 2.18; 95% CI 1.96 to 2.43) in women with preterm birth compared with the women with term birth in their first pregnancies, remaining similar over the study period. The lower the gestational age at the first birth, the higher the odds of preterm birth in the subsequent pregnancy (test for trend p<0.001). CONCLUSION: In this rural Bangladeshi setting, recurrent preterm births contributed a sizeable proportion of the total number of preterm births at the population level. The increased risk of recurrence remained similar across three decades when the total proportion of preterm births was reduced from 25% to 13%.

Comparative predictive power of serum vs plasma proteomic signatures in feto-maternal medicine.

BACKGROUND: Blood proteins are frequently measured in serum or plasma, because they provide a wealth of information. Differences in the ex vivo processing of serum and plasma raise concerns that proteomic health and disease signatures derived from serum or plasma differ in content and quality. However, little is known about their respective power to predict feto-maternal health outcomes. Predictive power is a sentinel characteristic to determine the clinical use of biosignatures. OBJECTIVE: This study aimed to compare the power of serum and plasma proteomic signatures to predict a physiological pregnancy outcome. STUDY DESIGN: Paired serum and plasma samples from 73 women were obtained from biorepositories of a multinational prospective cohort study on pregnancy outcomes. Gestational age at the time of sampling was the predicted outcome, because the proteomic signatures have been validated for such a prediction. Multivariate and cross-validated models were independently derived for serum and plasma proteins. RESULTS: A total of 1116 proteins were measured in 88 paired samples from 73 women with a highly multiplexed platform using proximity extension technology (Olink Proteomics Inc, Watertown, MA). The plasma proteomic signature showed a higher predictive power (R=0.64; confidence interval, 0.42-0.79; P=3.5×10-6) than the serum signature (R=0.45; confidence interval, 0.18-0.66; P=2.2×10-3). The serum signature was validated in plasma with a similar predictive power (R=0.58; confidence interval, 0.34-0.75; P=4.8×10-5), whereas the plasma signature was validated in serum with reduced predictive power (R=0.53; confidence interval, 0.27-0.72; P=2.6×10-4). Signature proteins largely overlapped in the serum and plasma, but the strength of association with gestational age was weaker for serum proteins. CONCLUSION: Findings suggest that serum proteomics are less informative than plasma proteomics. They are compatible with the view that the partial ex-vivo degradation and modification of serum proteins during sample processing are an underlying reason. The rationale for collecting and analyzing serum and plasma samples should be carefully considered when deriving proteomic biosignatures to ascertain that specimens of the highest scientific and clinical yield are processed. Findings suggest that plasma is the preferred matrix.

Multiomic signals associated with maternal epidemiological factors contributing to preterm birth in low- and middle-income countries.

Preterm birth (PTB) is the leading cause of death in children under five, yet comprehensive studies are hindered by its multiple complex etiologies. Epidemiological associations between PTB and maternal characteristics have been previously described. This work used multiomic profiling and multivariate modeling to investigate the biological signatures of these characteristics. Maternal covariates were collected during pregnancy from 13,841 pregnant women across five sites. Plasma samples from 231 participants were analyzed to generate proteomic, metabolomic, and lipidomic datasets. Machine learning models showed robust performance for the prediction of PTB (AUROC = 0.70), time-to-delivery (r = 0.65), maternal age (r = 0.59), gravidity (r = 0.56), and BMI (r = 0.81). Time-to-delivery biological correlates included fetal-associated proteins (e.g., ALPP, AFP, and PGF) and immune proteins (e.g., PD-L1, CCL28, and LIFR). Maternal age negatively correlated with collagen COL9A1, gravidity with endothelial NOS and inflammatory chemokine CXCL13, and BMI with leptin and structural protein FABP4. These results provide an integrated view of epidemiological factors associated with PTB and identify biological signatures of clinical covariates affecting this disease.

Body mass index in early-pregnancy and selected maternal health outcomes: Findings from two cohorts in Bangladesh.

BACKGROUND: Maternal nutrition is one of the most influential factors that affect the health of the mother and her offspring and remains a significant public health challenge globally. There is a lack of studies evaluating the trends of maternal nutrition and its impact on the burden of pregnancy complications from low-income countries, including Bangladesh. We aimed to determine the burden of early-pregnancy nutrition status based on body mass index (BMI), and the associations of nutritional status with pregnancy-induced hypertension (PIH), cesarean section (CS) delivery, perineal tear and postpartum hemorrhage (PPH) in a rural area in Bangladesh. METHODS: This prospective study analyzed data from two cohorts: the Maternal, Neonatal, and Child Health (MNCH) project carried out from January 2008 to June 2010, and the Preterm and Stillbirth Study, Matlab (PreSSMat) conducted from October 2015 to March 2018. In total, information of 9287 women who gave birth from the two cohorts was available for analysis. Early-pregnancy BMI was categorized into underweight, normal-weight, and overweight groups. The change in the burden of malnutrition between two cohort periods and the associations between women's BMI and maternal health outcomes were presented in odds ratios (ORs) with their 95% confidence interval (CI). RESULTS: Between the two cohort periods, the prevalence of underweight decreased from 17.5% to 15.4%, and overweight increased from 10.8% to 20.9%. The risk of being overweight in pregnant women was about two times (OR = 2.19; 95% CI = 1.94-2.46) higher in the PreSSMat cohort than in the MNCH cohort. After multivariate-adjustment for socio-demographic factors, the pooled ORs of PIH, CS delivery, perineal tear, and PPH were 2.41 (95% CI = 1.95-2.99), 2.12 (95% CI = 1.86-2.41), 2.46 (95% CI = 1.54-3.92), and 1.68 (95% CI = 1.12-2.53), respectively, in women with overweight compared to the normal-weight group. CONCLUSIONS: The results confirmed the existence of a double burden of malnutrition in rural women in Bangladesh. Women with overweight had an increased risk of selected pregnancy complications. The findings call for the adoption of appropriate prenatal counseling and preparedness tailored to women's nutritional status to prevent possible adverse health outcomes.

Association between antenatal care visit and preterm birth: a cohort study in rural Bangladesh.

BACKGROUND: Strengthening the antenatal care programme is suggested as one of the public health strategies to reduce preterm birth burden at a population level. However, the evidence so far available is inconclusive. OBJECTIVES: To evaluate the association between antenatal care (ANC) visit and preterm birth; and also to explore to what extent the increased usage of ANC after the initiation of the Maternal, Neonatal and Child Health (MNCH) project in Matlab, Bangladesh, contributed to the reduction of preterm birth. SETTING: This population-based cohort study was conducted in Matlab, a subdistrict under Chandpur. The analysis was based on data collected from 2005 to 2009. In 2007, an MNCH project was initiated in the area that strengthened the ongoing ANC services. PARTICIPANTS: In total, 12 980 live births with their mothers during the study period were included in the analysis. ANALYSIS: We performed logistic regression with generalised estimating equation models to evaluate the associations. OUTCOME MEASURES: Preterm birth. RESULTS: The number of ANC visits was associated with preterm birth in a dose-dependent way (p for linear trend <0.001). The adjusted odds of preterm birth were 2.4-times higher (OR 2.37, 95% CI 2.07 to 2.70) among women who received ≤1 ANC compared with women who received ≥3 ANC. We observed a significant reduction of preterm birth rates (OR 0.69, 95% CI 0.61 to 0.77) in the period after (2008 to 2009) MNCH project initiation in comparison to the period before (2005 to 2006). Controlling for ANC visits substantially attenuated this observed effect of the MNCH project on preterm birth (OR 0.88, 95% CI 0.77 to 0.99) (Sobel test of mediation p<0.001). CONCLUSIONS: ANC visits are associated with decreased occurrences of preterm births. Strengthening the ANC services should be prioritised in countries with high preterm birth rates to reduce the preterm birth burden at the population level.

Time trends and sociodemographic determinants of preterm births in pregnancy cohorts in Matlab, Bangladesh, 1990-2014.

INTRODUCTION: Preterm birth is the major cause of under-five mortality. Population-based data on determinants and proportions of children born preterm are limited, especially from low-income countries. This study aimed at assessing time trends and social, reproductive and environmental determinants of preterm births based on a population-based pregnancy cohort over 25 years in rural Bangladesh. METHODS: In this cohort study in Matlab, a rural area in Bangladesh, we used data from the Health and Demographic Surveillance System from 1990 to 2014. Gestational age at birth was based on the reported last menstrual period and verified by ultrasound assessments. Preterm birth proportions were assessed within strata of social and reproductive characteristics, and time series analysis was performed with decomposition for trend and seasonality. We also determined the prevented fractions of preterm birth reduction associated with social and demographic changes during the follow-up period. RESULTS: Analyses were based on 63 063 live births. Preterm birth decreased from 29% (95% CI 28.6 to 30.1) in 1990-1994 to 11% (95% CI 10.5 to 11.6) in 2010-2014. Low education, older age and multi-parity were associated with higher proportions of preterm births across the study period. Preterm births had a marked seasonal variation. A rapid increase in women's educational level and decrease in parity were associated with the decline in preterm births, and 27% of the reduction observed from 1990 to 2014 could be attributed to these educational and reproductive changes. CONCLUSION: The reduction in preterm birth was to a large extent associated with the sociodemographic transition, especially changes in maternal education and parity. The persistent seasonal variation in the proportion of preterm birth may reflect the environmental stressors for pregnant women across the study period. Continued investments in girls' education and family planning programmes may contribute to further reduction of preterm births in Bangladesh.

Associations between improved care during the second stage of labour and maternal and neonatal health outcomes in a rural hospital in Bangladesh.

OBJECTIVE: To evaluate the efficacy of care in the second stage of labour with a package of interventions that included (1) maintaining the birthing position according to the woman's choice, (2) adopting a spontaneous pushing technique and (3) using a support person, to reduce maternal and neonatal complications. DESIGN: Used the data collected from two cohorts- before and after an initiative to improve care during the second stage of labour. SETTING: A rural hospital in Bangladesh where 90-100 deliveries are conducted monthly and cesarean section provision is not available. PARTICIPANTS: One thousand and fifty-one singleton pregnancies who attended the hospital for giving birth in the first stage of labour before full dilatation of the cervix and with cephalic presentation. MEASUREMENTS AND FINDINGS: Data were collected through a structured checklist and questionnaire completed by research assistants; and also retrieved from hospital case record files, and the ongoing demographic surveillance system database. Coverage of adopting the upright or lateral position in the post-intervention period increased to 76% from about 1% in the pre-intervention period, and the spontaneous pushing technique increased to 97% from 77% in the same period. The odds of combined maternal and neonatal complications decreased by 46% between pre- and post-intervention periods (odds ratio: 0.54, 95% confidence interval: 0.43-0.70). Frequency of episiotomy (from 43% to 29%, P < 0.001), cervical tear (3.8% to 1.5%, P = 0.02), and median blood loss (200 ml to 150 ml; P < 0.001) were reduced significantly in the same period. No significant associations were observed in perineal tear or birth asphyxia occurrences. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The study suggests that there is a beneficial effect of care during the second stage of labour with a package of interventions in reducing maternal and neonatal complications, particularly in reducing the frequency of episiotomy, cervical tear, and blood loss during delivery. The preferred choice of posture during giving birth, adopting a spontaneous pushing technique and continuous presence of support person during the second stage of labour may be encouraged for better health outcomes.