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.

Association of maternal prenatal copper concentration with gestational duration and preterm birth: a multicountry meta-analysis.

BACKGROUND: Copper (Cu), an essential trace mineral regulating multiple actions of inflammation and oxidative stress, has been implicated in risk for preterm birth (PTB). OBJECTIVES: This study aimed to determine the association of maternal Cu concentration during pregnancy with PTB risk and gestational duration in a large multicohort study including diverse populations. METHODS: Maternal plasma or serum samples of 10,449 singleton live births were obtained from 18 geographically diverse study cohorts. Maternal Cu concentrations were determined using inductively coupled plasma mass spectrometry. The associations of maternal Cu with PTB and gestational duration were analyzed using logistic and linear regressions for each cohort. The estimates were then combined using meta-analysis. Associations between maternal Cu and acute-phase reactants (APRs) and infection status were analyzed in 1239 samples from the Malawi cohort. RESULTS: The maternal prenatal Cu concentration in our study samples followed normal distribution with mean of 1.92 µg/mL and standard deviation of 0.43 µg/mL, and Cu concentrations increased with gestational age up to 20 wk. The random-effect meta-analysis across 18 cohorts revealed that 1 µg/mL increase in maternal Cu concentration was associated with higher risk of PTB with odds ratio of 1.30 (95% confidence interval [CI]: 1.08, 1.57) and shorter gestational duration of 1.64 d (95% CI: 0.56, 2.73). In the Malawi cohort, higher maternal Cu concentration, concentrations of multiple APRs, and infections (malaria and HIV) were correlated and associated with greater risk of PTB and shorter gestational duration. CONCLUSIONS: Our study supports robust negative association between maternal Cu and gestational duration and positive association with risk for PTB. Cu concentration was strongly correlated with APRs and infection status suggesting its potential role in inflammation, a pathway implicated in the mechanisms of PTB. Therefore, maternal Cu could be used as potential marker of integrated inflammatory pathways during pregnancy and risk for PTB.

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.

Development and external validation of machine learning algorithms for postnatal gestational age estimation using clinical data and metabolomic markers.

BACKGROUND: Accurate estimates of gestational age (GA) at birth are important for preterm birth surveillance but can be challenging to obtain in low income countries. Our objective was to develop machine learning models to accurately estimate GA shortly after birth using clinical and metabolomic data. METHODS: We derived three GA estimation models using ELASTIC NET multivariable linear regression using metabolomic markers from heel-prick blood samples and clinical data from a retrospective cohort of newborns from Ontario, Canada. We conducted internal model validation in an independent cohort of Ontario newborns, and external validation in heel prick and cord blood sample data collected from newborns from prospective birth cohorts in Lusaka, Zambia and Matlab, Bangladesh. Model performance was measured by comparing model-derived estimates of GA to reference estimates from early pregnancy ultrasound. RESULTS: Samples were collected from 311 newborns from Zambia and 1176 from Bangladesh. The best-performing model accurately estimated GA within about 6 days of ultrasound estimates in both cohorts when applied to heel prick data (MAE 0.79 weeks (95% CI 0.69, 0.90) for Zambia; 0.81 weeks (0.75, 0.86) for Bangladesh), and within about 7 days when applied to cord blood data (1.02 weeks (0.90, 1.15) for Zambia; 0.95 weeks (0.90, 0.99) for Bangladesh). CONCLUSIONS: Algorithms developed in Canada provided accurate estimates of GA when applied to external cohorts from Zambia and Bangladesh. Model performance was superior in heel prick data as compared to cord blood data.

Early Life Environmental Exposure to Cadmium, Lead, and Arsenic and Age at Menarche: A Longitudinal Mother-Child Cohort Study in Bangladesh.

BACKGROUND: Several metals act as endocrine disruptors, but there are few large longitudinal studies about associations with puberty onset. OBJECTIVES: We evaluated whether early life cadmium, lead, and arsenic exposure was associated with timing of menarche. METHODS: In a mother-child cohort in rural Bangladesh (n=935), the exposure was assessed by concentrations in maternal erythrocytes in early pregnancy and in girls' urine at 5 and 10 years of age using inductively coupled plasma mass spectrometry. The girls were interviewed twice, at average ages 13.3 [standard deviation (SD)=0.43] and 13.8 (SD=0.43) y, and the date of menarche, if present, was recorded. Associations were assessed using Kaplan-Meier analysis and multivariable-adjusted Cox regression. RESULTS: In total, 77% of the girls (n=717) had reached menarche by the second follow-up. The median age of menarche among all girls was 13.0 y (25th-75th percentiles: 12.4-13.7 y). At 10 years of age, median urinary cadmium was 0.25µg/L (5th-95th percentiles: 0.087-0.72µg/L), lead 1.6µg/L (0.70-4.2µg/L), and arsenic 54µg/L (19-395µg/L). Given the same age, girls in the highest quartile of urinary cadmium at 5 and 10 years of age had a lower rate of menarche than girls in the lowest quartile, with an adjusted hazard ratio of (HR) 0.80 (95% CI: 0.62, 1.01) at 5 years of age, and 0.77 (95% CI: 0.60, 0.98) at 10 years of age. This implies that girls in the highest cadmium exposure quartile during childhood had a higher age at menarche. Comparing girls in the highest to the lowest quartile of urinary lead at 10 years of age, the former had a higher rate of menarche [adjusted HR = 1.23 (95% CI: 0.97, 1.56)], implying lower age at menarche, whereas there was no association with urinary lead at 5 years of age. Girls born to mothers in the highest quartile of erythrocyte arsenic during pregnancy were less likely to have attained menarche than girls born to mothers in the lowest quartile [adjusted HR= 0.79 (95% CI: 0.62, 0.99)]. No association was found with girls' urinary arsenic exposure. DISCUSSION: Long-term childhood cadmium exposure was associated with later menarche, whereas the associations with child lead exposure were inconclusive. Maternal exposure to arsenic, but not cadmium or lead, was associated with later menarche. https://doi.org/10.1289/EHP11121.

Dietary patterns and indicators of cardiometabolic risk among rural adolescents: A cross-sectional study at 15-year follow-up of the MINIMat cohort.

Background: Diet being a modifiable factor, its relationship with cardiometabolic risk is of public health interest. The vast majority of studies on associations of dietary patterns with cardiometabolic risk indicators among adolescents are from high-income countries and urban settings. We sought to describe dietary patterns and examine their associations with selected cardiometabolic risk indicators-waist circumference (WC), systolic blood pressure, fasting lipid profile and insulin resistance-along with its gender stratification among adolescents in a low-income, rural setting. Methods: This cross-sectional study utilized data from the 15-year follow-up of the Maternal and Infant Nutrition Interventions in Matlab (MINIMat) cohort in southeast Bangladesh. The children who were born as singletons to the mothers randomized in the MINIMat trial and had valid birth anthropometrics were eligible for the follow-up. We employed a single, qualitative 24-hour recall to assess diet. Dietary patterns were derived from simple K-means cluster analysis, and calculation of dietary diversity score (DDS) using a validated instrument. Anthropometric parameters and systolic blood pressure were recorded. Fasting plasma triglyceride, total cholesterol, low- and high-density lipoproteins, insulin and glucose levels were measured. We calculated insulin resistance using the Homeostasis Model Assessment equation (HOMA-IR). Three right-skewed outcome variables were natural log (Ln) transformed: WC, triglyceride and HOMA-IR. Omnibus and gender-specific multiple linear regression models were fitted. Results: Among 2,253 adolescents (52.1% girls, 7.1% overweight/obese), we identified four diet clusters: Traditional, Fish-dominant, Meat-dominant, and High-variety. No significant associations were found between the clusters and indicators. On gender-stratification, triglyceride levels were lower among boys in the Fish-dominant (Ln-triglyceride ßadjusted: -0.09; 95% confidence interval (CI): -0.15, -0.02) and Meat-dominant (Ln-triglyceride ßadjusted: -0.08; 95% CI: -0.15, -0.004) clusters than among boys in the Traditional cluster. Compared to boys in the bottom quartile of DDS, boys in the top quartile had 2.1 mm of Hg (95% CI: 0.5, 3.6) higher systolic blood pressure and 1.9% (95% CI: 0.01-3.8%) higher WC. Conclusion: While statistically significant, the gender-specific differences in triglyceride, systolic blood pressure, and waist circumference across dietary patterns were small. Associations between dietary patterns and cardiometabolic risk indicators may require a time lag beyond mid-adolescence to manifest in a rural setting. Prospective studies are warranted to delineate the magnitude and direction of those associations.

Gender and socio-economic stratification of ultra-processed and deep-fried food consumption among rural adolescents: A cross-sectional study from Bangladesh.

BACKGROUND: Although consumption of ultra-processed and deep-fried foods among adolescents is a global health concern, little is known about its gender and socio-economic stratification in rural settings of low- and middle-income countries. We, thus, aimed to describe ultra-processed and deep-fried food consumption among rural adolescents by gender and socio-economic factors, and to explore their relative importance in shaping consumption. METHODS: This cross-sectional study drew on data from a household survey in Matlab, a rural sub-district in Bangladesh. The analytic sample comprised 2463 adolescents. We assessed consumption of four ultra-processed food groups: ready-to-eat or "instant" foods; confectionery, sweets and similar packaged products; savory snacks; sugar-sweetened beverage; and of deep-fried foods with a 24-hour, qualitative recall. Asset scores were constructed. Proportion of consumption was calculated and compared by gender and household wealth. Logistic regression models were fitted to isolate socio-demographic variables associated with consumption. RESULTS: Approximately 83% (81.5-84.4) adolescents consumed at least one ultra-processed or deep-fried item. Confectioneries were the most consumed (53.5%), whereas sugar-sweetened beverage was the least consumed (12%) group. Boys had greater odds of consumption than girls for all food groups. The association was strongest for sugar-sweetened beverage (adjusted odds ratio = 2.57; 95% CI: 1.97, 3.37), followed by deep-fried foods (adjusted odds ratio = 1.96; 95% CI: 1.66, 2.32) and ready-to-eat foods (adjusted odds ratio = 1.85; 95% CI: 1.45, 2.38). Belonging to the richest households was associated with ready-to-eat food consumption (adjusted odds ratio = 1.55; 95% CI: 1.12, 2.16). Adolescents with higher educational attainment had lower odds of consuming sugar-sweetened beverage (adjusted odds ratio = 0.73; 95% CI: 0.54, 0.98). CONCLUSION: Consumption of packaged confectioneries, savory snacks, and deep-fried foods appeared common, while SSB consumption was relatively low. Role of gender was pre-eminent as consumption was more likely among boys across the food groups. This may disproportionately expose them to the risk of diet-related non-communicable diseases.

Prediction of gestational age using urinary metabolites in term and preterm pregnancies.

Assessment of gestational age (GA) is key to provide optimal care during pregnancy. However, its accurate determination remains challenging in low- and middle-income countries, where access to obstetric ultrasound is limited. Hence, there is an urgent need to develop clinical approaches that allow accurate and inexpensive estimations of GA. We investigated the ability of urinary metabolites to predict GA at time of collection in a diverse multi-site cohort of healthy and pathological pregnancies (n = 99) using a broad-spectrum liquid chromatography coupled with mass spectrometry (LC-MS) platform. Our approach detected a myriad of steroid hormones and their derivatives including estrogens, progesterones, corticosteroids, and androgens which were associated with pregnancy progression. We developed a restricted model that predicted GA with high accuracy using three metabolites (rho = 0.87, RMSE = 1.58 weeks) that was validated in an independent cohort (n = 20). The predictions were more robust in pregnancies that went to term in comparison to pregnancies that ended prematurely. Overall, we demonstrated the feasibility of implementing urine metabolomics analysis in large-scale multi-site studies and report a predictive model of GA with a potential clinical value.

Determinants of utilization of antenatal and delivery care at the community level in rural Bangladesh.

BACKGROUND: Timely utilization of antenatal care and delivery services supports the health of mothers and babies. Few studies exist on the utilization and determinants of timely ANC and use of different types of health facilities at the community level in Bangladesh. This study aims to assess the utilization, timeliness of, and socio-demographic determinants of antenatal and delivery care services in two sub-districts in Bangladesh. METHODS: This cross-sectional study used data collected through a structured questionnaire in the eRegMat cluster-randomized controlled trial, which enrolled pregnant women between October 2018-June 2020. We undertook univariate and multivariate logistic regression analysis to determine the associations of socio-demographic variables with timely first ANC, four timely ANC visits, and facility delivery. We considered the associations in the multivariate logistic regression as statistically significant if the p-value was found to be <0.05. Results are presented as adjusted odds ratios (AOR) with 95% confidence intervals (CI). RESULTS: Data were available on 3293 pregnant women. Attendance at a timely first antenatal care visit was 59%. Uptake of four timely antenatal care visits was 4.2%. About three-fourths of the women delivered in a health facility. Women from all socio-economic groups gradually shifted from using public health facilities to private hospitals as the pregnancy advanced. Timely first antenatal care visit was associated with: women over 30 years of age (AOR: 1.52, 95% CI: 1.05-2.19); nulliparity (AOR: 1.30, 95% CI: 1.04-1.62); husbands with >10 years of education (AOR: 1.40, 95% CI: 1.09-1.81) and being in the highest wealth quintile (AOR: 1.49, 95% CI: 1.18-1.89). Facility deliveries were associated with woman's age; parity; education; the husband's education, and wealth index. None of the available socio-demographic factors were associated with four timely antenatal care visits. CONCLUSIONS: The study observed socio-demographic inequalities associated with increased utilization of timely first antenatal care visit and facility delivery. The pregnant women, irrespective of wealth shifted from public to private facilities for their antenatal care visits and delivery. To increase the health service utilization and promote good health, maternal health care programs should pay particular attention to young, multiparous women, of low socio-economic status, or with poorly educated husbands. CLINICAL TRIAL REGISTRATION: ISRCTN69491836; https://www.isrctn.com/. Registered on December 06, 2018. Retrospectively registered.

Association of maternal prenatal selenium concentration and preterm birth: a multicountry meta-analysis.

BACKGROUND: Selenium (Se), an essential trace mineral, has been implicated in preterm birth (PTB). We aimed to determine the association of maternal Se concentrations during pregnancy with PTB risk and gestational duration in a large number of samples collected from diverse populations. METHODS: Gestational duration data and maternal plasma or serum samples of 9946 singleton live births were obtained from 17 geographically diverse study cohorts. Maternal Se concentrations were determined by inductively coupled plasma mass spectrometry analysis. The associations between maternal Se with PTB and gestational duration were analysed using logistic and linear regressions. The results were then combined using fixed-effect and random-effect meta-analysis. FINDINGS: In all study samples, the Se concentrations followed a normal distribution with a mean of 93.8 ng/mL (SD: 28.5 ng/mL) but varied substantially across different sites. The fixed-effect meta-analysis across the 17 cohorts showed that Se was significantly associated with PTB and gestational duration with effect size estimates of an OR=0.95 (95% CI: 0.9 to 1.00) for PTB and 0.66 days (95% CI: 0.38 to 0.94) longer gestation per 15 ng/mL increase in Se concentration. However, there was a substantial heterogeneity among study cohorts and the random-effect meta-analysis did not achieve statistical significance. The largest effect sizes were observed in UK (Liverpool) cohort, and most significant associations were observed in samples from Malawi. INTERPRETATION: While our study observed statistically significant associations between maternal Se concentration and PTB at some sites, this did not generalise across the entire cohort. Whether population-specific factors explain the heterogeneity of our findings warrants further investigation. Further evidence is needed to understand the biologic pathways, clinical efficacy and safety, before changes to antenatal nutritional recommendations for Se supplementation are considered.

An Electronic Registry for Improving the Quality of Antenatal Care in Rural Bangladesh (eRegMat): Protocol for a Cluster Randomized Controlled Trial.

BACKGROUND: Digital health interventions (DHIs) can alleviate several barriers to achieving better maternal and child health. The World Health Organization's guideline recommendations for DHIs emphasize the need to integrate multiple DHIs for maximizing impact. The complex health system of Bangladesh provides a unique setting for evaluating and understanding the role of an electronic registry (eRegistry) for antenatal care, with multiple integrated DHIs for strengthening the health system as well as improving the quality and utilization of the public health care system. OBJECTIVE: The aim of this study is to assess the effect of an eRegistry with DHIs compared with a simple digital data entry tool without DHIs in the community and frontline health facilities. METHODS: The eRegMat is a cluster-randomized controlled trial conducted in the Matlab North and Matlab South subdistricts in the Chandpur district, Bangladesh, where health facilities are currently using the eRegistry for digital tracking of the health status of pregnant women longitudinally. The intervention arm received 3 superimposed data-driven DHIs: health worker clinical decision support, health worker feedback dashboards with action items, and targeted client communication to pregnant women. The primary outcomes are appropriate screening as well as management of hypertension during pregnancy and timely antenatal care attendance. The secondary outcomes include morbidity and mortality in the perinatal period as well as timely first antenatal care visit; successful referrals for anemia, diabetes, or hypertension during pregnancy; and facility delivery. RESULTS: The eRegistry and DHIs were co-designed with end users between 2016 and 2018. The eRegistry was implemented in the study area in July 2018. Recruitment for the trial started in October 2018 and ended in June 2020, followed by an 8-month follow-up period to capture outcome data until February 2021. Trial results will be available for publication in June 2021. CONCLUSIONS: This trial allows the simultaneous assessment of multiple integrated DHIs for strengthening the health system and aims to provide evidence for its implementation. The study design and outcomes are geared toward informing the living review process of the guidelines for implementing DHIs. TRIAL REGISTRATION: ISRCTN Registry ISRCTN69491836; https://www.isrctn.com/ISRCTN69491836. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/26918.

A cohort study of the association between prenatal arsenic exposure and age at menarche in a rural area, Bangladesh.

BACKGROUND: Millions of individuals worldwide, particularly in Bangladesh, are exposed to arsenic, mainly through drinking water from tube wells. Arsenic is a reproductive toxicant, but there is limited knowledge of whether it influences pubertal development. OBJECTIVES: We evaluated the association between prenatal arsenic exposure and age at menarche. METHODS: This prospective study was based on data from two studies conducted in Matlab, Bangladesh-the Maternal and Infant Nutrition Interventions in Matlab (MINIMat) trial and the Health Consequences of Arsenic in Matlab (AsMat) study. We included 809 MINIMat girls who participated in assessing age at menarche from July 2016 to June 2017 and had prenatal arsenic exposure data through the AsMat study via measurements in tube well water used by the mothers during pregnancy. The exposure was categorized into <10, 10-49, 50-99, 100-199, and ≥200 µg/L. We used Kaplan-Meier and Cox proportional hazards analyses with adjustment for potential confounders to evaluate the association between arsenic exposure and age at menarche. The results were presented by adjusted hazards ratio (aHR) with a 95% confidence interval (CI). RESULTS: The median arsenic concentration in tube well water consumed by pregnant women was 80 µg/L (interquartile range 2-262 µg/L), and 55% drank water with concentrations above Bangladesh's acceptable value of 50 µg/L. The median age at menarche was 13.0 years. The unadjusted analysis revealed 3.2 months delay in menarche for girls exposed to arsenic concentrations ≥200 µg/L compared with the girl exposed to arsenic concentrations <10 µg/L. Girls exposed to the same higher arsenic concentrations were 23% (aHR 0.77, 95% CI: 0.63-0.95) less likely to have reached menarche than girls exposed to low arsenic concentrations. CONCLUSIONS: Increased levels of prenatal arsenic exposure were associated with older age at menarche. This delay may indicate endocrine disruptions that could potentially result in adverse health consequences in later life. This finding, along with other severe adverse health reinforces the need for arsenic mitigation at the population level.

Developing targeted client communication messages to pregnant women in Bangladesh: a qualitative study.

BACKGROUND: Timely and appropriate evidence-based practices during antenatal care improve maternal and neonatal health. There is a lack of information on how pregnant women and families perceive antenatal care in Bangladesh. The aim of our study was to develop targeted client communication via text messages for increasing antenatal care utilization, as part of an implementation of an electronic registry for maternal and child health. METHODS: Using a phenomenological approach, we conducted this qualitative study from May to June 2017 in two sub-districts of Chandpur district, Bangladesh. We selected study participants by purposive sampling. A total of 24 in-depth interviews were conducted with pregnant women (n = 10), lactating women (n = 5), husbands (n = 5), and mothers-in-law (n = 4). The Health Belief Model (HBM) was used to guide the data collection. Thematic analysis was carried out manually according to the HBM constructs. We used behavior change techniques to inform the development of targeted client communication based on the thematic results. RESULTS: Almost no respondents mentioned antenatal care as a preventive form of care, and only perceived it as necessary if any complications developed during pregnancy. Knowledge of the content of antenatal care (ANC) and pregnancy complications was low. Women reported a variety of reasons for not attending ANC, including the lack of information on the timing of ANC; lack of decision-making power; long-distance to access care; being busy with household chores, and not being satisfied with the treatment by health care providers. Study participants recommended phone calls as their preferred communication strategy when asked to choose between the phone call and text message, but saw text messages as a feasible option. Based on the findings, we developed a library of 43 automatically customizable text messages to increase ANC utilization. CONCLUSIONS: Pregnant women and family members had limited knowledge about antenatal care and pregnancy complications. Effective health information through text messages could increase awareness of antenatal care among the pregnant women in Bangladesh. This study presents an example of designing targeted client communication to increase antenatal care utilization within formal scientific frameworks, including a taxonomy of behavior change techniques. TRIAL REGISTRATION: ISRCTN69491836 . Registered on December 06, 2018. Retrospectively registered.

Congo red test for identification of preeclampsia: Results of a prospective diagnostic case-control study in Bangladesh and Mexico.

BACKGROUND: Misfolded proteins in the urine of women with preeclampsia bind to Congo Red dye (urine congophilia). We evaluated a beta prototype of a point-of-care test for the identification of urine congophilia in preeclamptic women. METHODS: Prospective diagnostic case-control study conducted in 409 pregnant women (n = 204 preeclampsia; n = 205 uncomplicated pregnancies) presenting for delivery in two tertiary level hospitals located in Bangladesh and Mexico. The GV-005, a beta prototype of a point-of-care test for detecting congophilia, was performed on fresh and refrigerated urine samples. The primary outcome was the prevalence of urine congophilia in each of the two groups. Secondary outcome was the likelihood of the GV-005 (index test) to confirm and rule-out preeclampsia based on an adjudicated diagnosis (reference standard). FINDINGS: The GV-005 was positive in 85% of clinical cases (83/98) and negative in 81% of clinical controls (79/98) in the Bangladesh cohort. In the Mexico cohort, the GV-005 test was positive in 48% of clinical cases (51/106) and negative in 77% of clinical controls (82/107). Adjudication confirmed preeclampsia in 92% of Bangladesh clinical cases (90/98) and 61% of Mexico clinical cases (65/106). The odds ratio of a urine congophilia in adjudicated cases versus controls in the Bangladesh cohort was 34.5 (14.7 - 81.1) (p<0.001) compared to 4.2 (2.1 - 8.4; p<0.001) in the Mexico cohort. INTERPRETATION: The GV-005, a beta prototype of a point-of-care test for detection of urine congophilia, is a promising tool for rapid identification of preeclampsia. FUNDING: Saving Lives at Birth.

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.

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.

Determinants of care-seeking practice for neonatal illnesses in rural Bangladesh: A community-based cross-sectional study.

BACKGROUND: Proper utilization of skilled care services in neonatal illnesses is crucial to reduce neonatal morbidity and mortality. The study aimed to evaluate the level and factors associated with seeking care from skilled healthcare service providers for reported neonatal illnesses in rural Matlab, Bangladesh. METHODS: This community based cross-sectional study was based on data from a randomly selected sample comprised of 2223 women who delivered live-born babies in 2014. Data were collected from June to October 2015 through a structured questionnaire. We used a multivariable logistic regression model and presented the results by adjusted odds ratios (AOR) with 95% confidence intervals (CI). RESULTS: Of the neonates, 1361 (61.2%) suffered from at least one complication, and among these, 479 (35.2%) sought care from skilled healthcare service providers. In the multivariable logistic regression analysis, the participants' husbands' educational level, number of antenatal care visits, and place of childbirth were significantly associated with seeking skilled care for reported neonatal illnesses. The care-seeking from skilled healthcare service providers for neonatal illness was more than two times higher (AOR = 2.26, 95% CI = 1.51-3.39) in the group in which the participants' husband had attended school for more than 10 years as compared to the group in which they had attended school for less than six years. The AORs of seeking skilled care were 1.93 (95% CI = 1.42-2.62) and 2.26 (95% CI = 1.51-3.39) with the mothers receiving two to three and four or more antenatal care services, respectively, compared to the mothers with no or one antenatal care visit. Women who gave birth at a health facility were three times (AOR = 3.24, 95% CI = 2.50-4.19) more likely to seek skilled care for sick neonates compared to those who gave birth at home. CONCLUSION: The utilization of skilled care for neonatal sicknesses was low in this rural setting in Bangladesh. The participants' husbands' higher school attendance, increased number of ANC visits, and facility delivery were positively associated with care-seeking from skilled healthcare providers for neonatal illness. The husbands with low school attendance should be targeted for intervention, and continue efforts to increase ANC coverage and facility delivery to improve neonatal health in this country's rural area.