Early prediction of preeclampsia in pregnancy with cell-free RNA.

Liquid biopsies that measure circulating cell-free RNA (cfRNA) offer an opportunity to study the development of pregnancy-related complications in a non-invasive manner and to bridge gaps in clinical care1-4. Here we used 404 blood samples from 199 pregnant mothers to identify and validate cfRNA transcriptomic changes that are associated with preeclampsia, a multi-organ syndrome that is the second largest cause of maternal death globally5. We find that changes in cfRNA gene expression between normotensive and preeclamptic mothers are marked and stable early in gestation, well before the onset of symptoms. These changes are enriched for genes specific to neuromuscular, endothelial and immune cell types and tissues that reflect key aspects of preeclampsia physiology6-9, suggest new hypotheses for disease progression and correlate with maternal organ health. This enabled the identification and independent validation of a panel of 18 genes that when measured between 5 and 16 weeks of gestation can form the basis of a liquid biopsy test that would identify mothers at risk of preeclampsia long before clinical symptoms manifest themselves. Tests based on these observations could help predict and manage who is at risk for preeclampsia-an important objective for obstetric care10,11.

RNA profiles reveal signatures of future health and disease in pregnancy.

Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden1. Yet the ability to assess underlying pathophysiology before clinical presentation to enable identification of pregnancies at risk remains elusive. Here we demonstrate the ability of plasma cell-free RNA (cfRNA) to reveal patterns of normal pregnancy progression and determine the risk of developing pre-eclampsia months before clinical presentation. Our results centre on comprehensive transcriptome data from eight independent prospectively collected cohorts comprising 1,840 racially diverse pregnancies and retrospective analysis of 2,539 banked plasma samples. The pre-eclampsia data include 524 samples (72 cases and 452 non-cases) from two diverse independent cohorts collected 14.5 weeks (s.d., 4.5 weeks) before delivery. We show that cfRNA signatures from a single blood draw can track pregnancy progression at the placental, maternal and fetal levels and can robustly predict pre-eclampsia, with a sensitivity of 75% and a positive predictive value of 32.3% (s.d., 3%), which is superior to the state-of-the-art method2. cfRNA signatures of normal pregnancy progression and pre-eclampsia are independent of clinical factors, such as maternal age, body mass index and race, which cumulatively account for less than 1% of model variance. Further, the cfRNA signature for pre-eclampsia contains gene features linked to biological processes implicated in the underlying pathophysiology of pre-eclampsia.

Placental transcriptomic signatures of spontaneous preterm birth.

BACKGROUND: Spontaneous preterm birth accounts for most preterm births and leads to significant morbidity in the newborn and childhood period. This subtype of preterm birth represents an increasing proportion of all preterm births when compared with medically indicated preterm birth, yet it is understudied in omics analyses. The placenta is a key regulator of fetal and newborn health, and the placental transcriptome can provide insight into pathologic changes that lead to spontaneous preterm birth. OBJECTIVE: This analysis aimed to identify genes for which placental expression was associated with spontaneous preterm birth (including early preterm and late preterm birth). STUDY DESIGN: The ECHO PATHWAYS consortium extracted RNA from placental samples collected from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood and the Global Alliance to Prevent Prematurity and Stillbirth studies. Placental transcriptomic data were obtained by RNA sequencing. Linear models were fit to estimate differences in placental gene expression between term birth and spontaneous preterm birth (including gestational age subgroups defined by the American College of Obstetricians and Gynecologists). Models were adjusted for numerous confounding variables, including labor status, cohort, and RNA sequencing batch. This analysis excluded patients with induced labor, chorioamnionitis, multifetal gestations, or medical indications for preterm birth. Our combined cohort contained gene expression data for 14,023 genes in 48 preterm and 540 term samples. Genes and pathways were considered statistically significantly different at false discovery rate-adjusted P value of <.05. RESULTS: In total, we identified 1728 genes for which placental expression was associated with spontaneous preterm birth with more differences in expression in early preterm samples than late preterm samples when compared with full-term samples. Of those, 9 genes were significantly decreased in both early and late spontaneous preterm birth, and the strongest associations involved placental expression of IL1B, ALPL, and CRLF1. In early and late preterm samples, we observed decreased expression of genes involved in immune signaling, signal transduction, and endocrine function. CONCLUSION: This study provides a comprehensive assessment of the differences in the placental transcriptome associated with spontaneous preterm birth with robust adjustment for confounding. Results of this study are in alignment with the known etiology of spontaneous preterm birth, because we identified multiple genes and pathways for which the placental and chorioamniotic membrane expression was previously associated with prematurity, including IL1B. We identified decreased expression in key signaling pathways that are essential for placental growth and function, which may be related to the etiology of spontaneous preterm birth. We identified increased expression of genes within metabolic pathways associated exclusively with early preterm birth. These signaling and metabolic pathways may provide clinically targetable pathways and biomarkers. The findings presented here can be used to understand underlying pathologic changes in premature placentas, which can inform and improve clinical obstetrics practice.

Assessment of feasibility and acceptability of family-centered care implemented at a neonatal intensive care unit in India.

BACKGROUND: A family-centered care (FCC) parent participation program that ensures an infant is not separated from parents against their will was developed for the caring of their small or sick newborn at a neonatal intensive care unit (NICU) in Delhi, India. Healthcare provider sensitization training directed at psychosocial and tangible support and an audio-visual training tool for parent-attendants were developed that included: 1) handwashing, infection prevention, protocol for entry; 2) developmentally supportive care, breastfeeding, expression of breastmilk and assisted feeding; 3) kangaroo mother care; and 4) preparation for discharge and care at home. The study aimed to examine the feasibility and acceptability of the FCC model in a NICU in India. METHODS: A prospective cohort design collected quantitative data on each parent-attendant/infant dyad at enrollment, during the NICU stay, and at discharge. Feasibility of the FCC program was measured by assessing the participation of parent-attendants and healthcare providers, and whether training components were implemented as intended. Acceptability was measured by the proportion of parent-attendants who participated in the trainings and their ability to accurately complete program activities. RESULTS: Of 395 NICU admissions during the study period, eligible participants included 333 parent-attendant/infant dyads, 24 doctors, and 21 nurses. Of the 1242 planned parent-attendant training sessions, 939 (75.6%) were held, indicating that program fidelity was high, and the majority of trainings were implemented as intended. While 50% of parent-attendants completed all 4 FCC training sessions, 95% completed sessions 1 and 2; 60% of the total participating parent-attendants completed session 3, and 75% completed session 4. Compliance rates were over 96% for 5 of 10 FCC parent-attendant activities, and 60 to 78% for the remaining 5 activities. CONCLUSIONS: FCC was feasible to implement in this setting and was acceptable to participating parent-attendants and healthcare providers. Parents participated in trainings conducted by NICU providers and engaged in essential care to their infants in the NICU. A standard care approach and behavior norms for healthcare providers directed psychosocial and tangible support to parent-attendants so that a child is not separated from his or her parents against their will while receiving advanced care in the NICU.

Sexually Transmitted Infections in Pregnancy and Reproductive Health: Proceedings of the STAR Sexually Transmitted Infection Clinical Trial Group Programmatic Meeting.

The goal of the STAR Sexually Transmitted Infection Clinical Trial Group (STI CTG) Programmatic meeting on Sexually Transmitted Infections (STIs) in Pregnancy and Reproductive Health in April 2018 was to review the latest research and develop recommendations to improve prevention and management of STIs during pregnancy. Experts from academia, government, nonprofit, and industry discussed the burden of STIs during pregnancy; the impact of STIs on adverse pregnancy and birth outcomes; interventions that work to reduce STIs in pregnancy, and the evidence, policy, and technology needed to improve STI care during pregnancy. Key points of the meeting are as follows: (i) alternative treatments and therapies for use during pregnancy are needed; (ii) further research into the relationship between the vaginal microbiome and STIs during pregnancy should be supported; (iii) more research to determine whether STI tests function equally well in pregnant as nonpregnant women is needed; (iv) development of new lower cost, rapid point-of-care testing assays could allow for expanded STI screening globally; (v) policies should be implemented that create standard screening and treatment practices globally; (vi) federal funding should be increased for STI testing and treatment initiatives supported by the Centers for Disease Control and Prevention (CDC), the Centers of Excellence in STI Treatment, public STD clinics, and the President's Emergency Plan for AIDS Relief (PEPFAR).

Referral systems for preterm, low birth weight, and sick newborns in Ethiopia: a qualitative assessment.

BACKGROUND: A responsive and well-functioning newborn referral system is a cornerstone to the continuum of child health care; however, health system and client-related barriers negatively impact the referral system. Due to the complexity and multifaceted nature of newborn referral processes, studies on newborn referral systems have been limited. The objective of this study was to assess the barriers for effective functioning of the referral system for preterm, low birth weight, and sick newborns across the primary health care units in 3 contrasting regions of Ethiopia. METHODS: A qualitative assessment using interviews with mothers of preterm, low birth weight, and sick newborns, interviews with facility leaders, and focus group discussions with health care providers was conducted in selected health facilities. Data were coded using an iteratively developed codebook and synthesized using thematic content analysis. RESULTS: Gaps and barriers in the newborn referral system were identified in 3 areas: transport and referral communication; availability of, and adherence to newborn referral protocols; and family reluctance or refusal of newborn referral. Specifically, the most commonly noted barriers in both urban and rural settings were lack of ambulance, uncoordinated referral and return referral communications between providers and between facilities, unavailability or non-adherence to newborn referral protocols, family fear of the unknown, expectation of infant death despite referral, and patient costs related to referral. CONCLUSIONS: As the Ethiopian Federal Ministry of Health focuses on averting early child deaths, government investments in newborn referral systems and standardizing referral and return referral communication are urgently needed. A complimentary approach is to lessen referral overload at higher-level facilities through improvements in the scope and quality of services at lower health system tiers to provide basic and advanced newborn care.

Health system readiness to support facilities for care of preterm, low birth weight, and sick newborns in Ethiopia: a qualitative assessment.

BACKGROUND: Preterm birth is a worldwide challenge with the highest burden in low- and middle-income countries. Despite availability of low-cost interventions to decrease mortality of preterm, low birth weight, and sick newborns, these interventions are not well integrated in the health systems of low- and middle-income countries. The aim of this study was to assess, from the perspective of key stakeholders comprising leaders in the public health system, the health system readiness to support health care facilities in the care provided to preterm, low birth weight, and sick newborns in different regions of Ethiopia. METHODS: A qualitative assessment using in-depth interviews with health facility leaders was conducted in health facilities in 3 regions of Ethiopia from December 2017 to February 2018. The interview guide was developed using a modified version of the World Health Organization health system building blocks. RESULTS: Across the public health system, adequate and reliable space, power, and water were problematic. Human resource issues (training, staffing, and retention) were critical to being able to properly care for preterm, low birth weight, and sick newborns. Problems with functional equipment and equipment distribution systems were widespread. Funds were lacking to support preterm, low birth weight, and sick newborn needs in facilities. Data collection practices, data quality, and data utilization were all problematic. There were gaps in the availability of guidelines and protocols, specifically targeting preterm, low birth weight, and sick newborn care. Key facilitators, information disseminators, and influencers identified in the study were the Health Development Army, community and religious leaders, and mothers and families who had had positive experiences or outcomes of care. CONCLUSIONS: The Ethiopian health system has opportunities across all 7 World Health Organization health system building blocks to strengthen readiness to support health facilities to provide quality care and improve outcomes for preterm, low birth weight, and sick newborns.

Transcriptomic comparison of in vitro models of the human placenta.

Studying the human placenta through in vitro cell culture methods is necessary due to limited access and amenability of human placental tissue to certain experimental methods as well as distinct anatomical and physiological differences between animal and human placentas. Selecting an in vitro culture model of the human placenta is challenging due to representation of different trophoblast cell types with distinct biological roles and limited comparative studies that define key characteristics of these models. Therefore, the aim of this research was to create a comprehensive transcriptomic comparison of common in vitro models of the human placenta compared to bulk placental tissue from the CANDLE and GAPPS cohorts (N=1083). We performed differential gene expression analysis on publicly available RNA sequencing data from 6 common in vitro models of the human placenta (HTR-8/SVneo, BeWo, JEG-3, JAR, Primary Trophoblasts, and Villous Explants) and compared to CANDLE and GAPPS bulk placental tissue or cytotrophoblast, syncytiotrophoblast, and extravillous trophoblast cell types derived from bulk placental tissue. All in vitro placental models had a substantial number of differentially expressed genes (DEGs, FDR<0.01) compared to the CANDLE and GAPPS placentas (Average DEGs=10,873), and the individual trophoblast cell types (Average DEGs=5,346), indicating that there are vast differences in gene expression compared to bulk and cell-type specific human placental tissue. Hierarchical clustering identified 53 gene clusters with distinct expression profiles across placental models, with 22 clusters enriched for specific KEGG pathways, 7 clusters enriched for high-expression placental genes, and 7 clusters enriched for absorption, distribution, metabolism, and excretion genes. In vitro placental models were classified by fetal sex based on expression of Y-chromosome genes that identified HTR-8/SVneo cells as being of female origin, while JEG-3, JAR, and BeWo cells are of male origin. Overall, none of the models were a close approximation of the transcriptome of bulk human placental tissue, highlighting the challenges with model selection. To enable researchers to select appropriate models, we have compiled data on differential gene expression, clustering, and fetal sex into an accessible web application: "Comparative Transcriptomic Placental Model Atlas (CTPMA)" which can be utilized by researchers to make informed decisions about their selection of in vitro placental models.

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.

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.

Qualitative Assessment of the Quality of Care for Preterm, Low Birth Weight, and Sick Newborns in Ethiopia.

This study assesses the quality of care for preterm, low birth weight (LBW), and sick newborns across the public health care system levels in 3 regions of Ethiopia. Qualitative data based on the WHO framework to assess provision and experience of care was collected using in-depth interviews and focus group discussions with women who recently delivered preterm, LBW, and sick newborns, as well as health care providers and health extension workers, and facility administrators associated with study health facilities. This qualitative approach revealed perspectives of patients, health care providers and facility administrators to assess what is actually happening in facilities. Clinical guidelines for the care of preterm, LBW, and sick newborns were not available in many facilities, and even when available, often not followed. Most providers reported little or no communication with parents following hospital discharge. Human resource challenges (shortage of skilled staff, motivation and willingness, lack of supervision, and poor leadership) inhibited quality of care. Participants reported widespread shortages of equipment and supplies, medication, physical space, water, electricity, and infrastructure. Economic insecurity was a critical factor affecting parents' experience. Acceptance by users was impacted by the perceived benefits and cost. Users reported they were less likely to accept interventions if they perceived that there would be financial costs they couldn't afford. The quality of care for preterm, LBW, and sick newborns in Ethiopia as reported by recently delivered women, health care providers and facility administrators is compromised. Improving quality of care requires attention to process of care, experience of care, and health system capacity, structure, and resources.

Readiness to Provide Antenatal Corticosteroids for Threatened Preterm Birth in Public Health Facilities in Northern India.

INTRODUCTION: In 2014, the Government of India (GOI) released operational guidelines on the use of antenatal corticosteroids (ACS) in preterm labor. However, without ensuring the quality of childbirth and newborn care at facilities, the use of ACS in low- and middle-income countries is potentially harmful. This study assessed the readiness to provide ACS at primary and secondary care public health facilities in northern India. METHODS: A cross-sectional study was conducted in 37 public health facilities in 2 districts of Haryana, India. Facility processes and program implementation for ACS delivery were assessed using pretested study tools developed from the World Health Organization (WHO) quality of care standards and WHO guidelines for threatened preterm birth. RESULTS: Key gaps in public health facilities' process of care to provide ACS for threatened preterm birth were identified, particularly concerning evidence-based practices, competent workforce, and actionable health information system. Emphasis on accurate gestational age estimation, quality of childbirth care, and quality of preterm care were inadequate. Shortage of trained staff was widespread, and a disconnect was found between knowledge and attitudes regarding ACS use. ACS administration was provided only at district or subdistrict hospitals, and these facilities did not uniformly record ACS-specific indicators. All levels lacked a comprehensive protocol and job aids for identifying and managing threatened preterm birth. CONCLUSIONS: ACS operational guidelines were not widely disseminated or uniformly implemented. Facilities require strengthened supervision and standardization of threatened preterm birth care. Facilities need greater readiness to meet required conditions for ACS use. Increasing uptake of a single intervention without supporting it with adequate quality of maternal and newborn care will jeopardize improvement in preterm birth outcomes. We recommend updating and expanding the existing GOI ACS operational guidelines to include specific actions for the safe and effective use of ACS in line with recent scientific evidence.

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.

Implementing the Family-Led Care model for preterm and low birth weight newborns in Malawi: Experience of healthcare workers.

BACKGROUND: Every Preemie-SCALE developed and piloted the Family-Led Care model, an innovative, locally developed model of care for preterm and low birth weight babies receiving kangaroo mother care. AIM: The aim of this study was to describe healthcare workers' experience using Family-Led Care. SETTING: This study was conducted in five health facilities and their catchment areas in Balaka district, Malawi. METHODS: The mixed-methods design, with two data collection periods, included record reviews, observations and questionnaires for facility staff and qualitative interviews with health workers of these facilities and their catchment areas. The total convenience sample comprised 123 health professionals, support staff and non-professional community health workers. RESULTS: Facility-based staff generally had positive perceptions of Family-Led Care (83%). Knowledge and application-of-knowledge scores were 69% and 52%, respectively. A major change between the first and the second data periods was improvement in client record-keeping. Documentation of newborn vital signs increased from 62% to 92%. Themes emerging from the qualitative interview analysis were the following: benefits of Family-Led Care; activities supporting the implementation of Family-Led Care; own care practices; and families' reaction to and experience of Family-Led Care. CONCLUSION: This article reports improved quality of care through better documentation and better follow-up of preterm and low birth weight babies receiving kangaroo mother care according to the Family-Led Care model. Overall, health workers were positive about their involvement, and they reported positive reactions from families. Lessons learned have been incorporated into a universal Family-Led Care package that is available for adaptation by other countries.

Prediction of gestational age with symphysis-fundal height and estimated uterine volume in a pregnancy cohort in Sylhet, Bangladesh.

OBJECTIVE: To improve the accuracy of the prediction of gestational age (GA) before birth with the standardised measurement of symphysis-fundal height (SFH), estimation of uterine volume, and statistical modelling including maternal anthropometrics and other factors. DESIGN: Prospective pregnancy cohort study. SETTING: Rural communities in Sylhet, Bangladesh. PARTICIPANTS: 1516 women with singleton pregnancies with early pregnancy ultrasound dating (<20 weeks); 1486 completed follow-up. METHODS: SFH and abdominal girth were measured at subsequent antenatal care (ANC) visits by community health workers at 24 to 28, 32 to 36, and/or >37 weeks gestation. An estimated uterine volume (EUV) was calculated from these measures. Data on pregnancy characteristics and other maternal anthropometrics were also collected. PRIMARY OUTCOME MEASURE: GA at subsequent ANC visits, as defined by early ultrasound dating. RESULTS: 1486 (98%) women had at least one subsequent ANC visit, 1102 (74%) women had two subsequent ANC visits, and 748 (50%) had three visits. Using the common clinical practice of approximating the GA (in weeks) with the SFH measurement (cm), SFH systematically underestimated GA in late pregnancy (mean difference -4.4 weeks, 95% limits of agreement -12.5 to 3.7). For the classification of GA <28 weeks, SFH <26 cm had 85% sensitivity and 81% specificity; and for GA <34 weeks, SFH <29 cm had 83% sensitivity and 71% specificity. EUV had similar diagnostic accuracy. Despite rigorous statistical modelling of SFH, accounting for repeated longitudinal measurements and additional predictors, the best model without including a known last menstrual period predicted 95% of pregnancy dates within ±7.4 weeks of early ultrasound dating. CONCLUSIONS: We were unable to predict GA with a high degree of accuracy before birth using maternal anthropometric measures and other available maternal characteristics. Efforts to improve GA dating in low- and middle-income countries before birth should focus on increasing coverage and training of ultrasonography. TRIAL REGISTRATION NUMBER: NCT01572532.

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.

Antenatal Corticosteroids for Women at Risk of Imminent Preterm Birth in 7 sub-Saharan African Countries: A Policy and Implementation Landscape Analysis.

BACKGROUND: Every year approximately 15 million babies are born prematurely and nearly 1 million die due to preterm birth complications. Evidence shows that antenatal corticosteroids (ACS) can be used to improve preterm birth outcomes in particular clinical settings. We conducted a policy and implementation landscape analysis of ACS use for women at risk of imminent preterm birth in 7 low-income countries. METHODS: A study framework and situation analysis tool were developed based on the World Health Organization (WHO) recommendation for ACS use among women at risk of preterm birth. The study was conducted in the Democratic Republic of the Congo, Ethiopia, Malawi, Nigeria, Sierra Leone, Tanzania, and Uganda. Primary data were collected through key informant interviews. Secondary data were gathered from publicly available sources, a survey of health management information system indicators, and demographic data from the Every Preemie-SCALE country profiles for preterm and low birth weight prevention and care. RESULTS: All 7 countries are using ACS for women at risk of imminent preterm birth. The majority of countries include language on ACS use in clinical protocols or standard treatment guidelines; however, none include language on accurately measuring gestational age. For 2 of the 5 countries with national standards for ACS use, the upper gestational age limit for ACS use exceeded the WHO recommendation of 34 weeks. There are gaps in national guidance on how to determine if a woman is at risk of imminent preterm birth. Few countries include guidance that indicates ACS is contraindicated in the presence of infection. The majority of countries reported that facilities providing ACS meet comprehensive emergency obstetric and newborn care standards, and all countries reported the availability of some form of special newborn care or neonatal intensive care units at facilities providing ACS. CONCLUSIONS: Countries recognize challenges to access to high-quality maternal and newborn care that fulfill clinical care preconditions required for safe and effective ACS use. Key informants recommended support for clinical guidelines and provider training on ACS use, inclusion of obstetric indications for dexamethasone and betamethasone in national essential medicine lists, collecting and using ACS-related data, and improving the quality of maternal and newborn care, including specialized newborn care.

Tracking facility-based perinatal deaths in Tanzania: Results from an indicator validation assessment.

BACKGROUND: Globally, an estimated 2.7 million babies die in the neonatal period annually, and of these, about 0.7 million die from intrapartum-related events. In Tanzania 51,000 newborn deaths and 43,000 stillbirths occur every year. Approximately two-thirds of these deaths could be potentially prevented with improvements in intrapartum and neonatal care. Routine measurement of fetal intrapartum deaths and newborn deaths that occur in health facilities can help to evaluate efforts to improve the quality of intrapartum care to save lives. However, few examples exist of indicators on perinatal mortality in the facility setting that are readily available through health management information systems (HMIS). METHODS: From November 2016 to April 2017, health providers at 10 government health facilities in Kagera region, Tanzania, underwent refresher training on perinatal death classification and training on the use of handheld Doppler devices to assess fetal heart rate upon admission to maternity services. Doppler devices were provided to maternity services at the study facilities. We assessed the validity of an indicator to measure facility-based pre-discharge perinatal mortality by comparing perinatal outcomes extracted from the HMIS maternity registers to a gold standard perinatal death audit. RESULTS: Sensitivity and specificity of the HMIS neonatal outcomes to predict gold standard audit outcomes were both over 98% based on analysis of 128 HMIS-gold standard audit pairs. After this validation, we calculated facility perinatal mortality indicator from HMIS data using fresh stillbirths and pre-discharge newborn death as the numerator and women admitted in labor with positive fetal heart tones as the denominator. Further emphasizing the validity of the indicator, FPM values aligned with expected mortality by facility level, with lowest rates in health centers (range 0.3%- 0.5%), compared to district hospitals (1.5%- 2.9%) and the regional hospital (4.2%). CONCLUSION: This facility perinatal mortality indicator provides an important health outcome measure that facilities can use to monitor levels of perinatal deaths occurring in the facility and evaluate impact of quality of care improvement activities.

The Zambian Preterm Birth Prevention Study (ZAPPS): Cohort characteristics at enrollment.

Background:Sub-Saharan Africa bears a disproportionate burden of preterm birth and other adverse outcomes. A better understanding of the demographic, clinical, and biologic underpinnings of these adverse outcomes is urgently needed to plan interventions and inform new discovery.  Methods:The Zambian Preterm Birth Prevention Study (ZAPPS) is a prospective observational cohort established at the Women and Newborn Hospital (WNH) in Lusaka, Zambia. We recruit pregnant women from district health centers and the WNH and offer ultrasound examination to determine eligibility. Participants receive routine obstetrical care, lab testing, midtrimester cervical length measurement, and serial fetal growth monitoring. At delivery, we assess gestational age, birthweight, vital status, and sex and assign a delivery phenotype. We collect blood, urine, and vaginal swab specimens at scheduled visits and store them in an on-site biorepository. In September 2017, enrollment of the ZAPPS Phase 1 - the subject of this report - was completed. Phase 2 - which is limited to HIV-uninfected women - reopened in January 2018.  Results:Between August 2015 and September 2017, we screened 1784 women, of whom 1450 (81.2%) met inclusion criteria and were enrolled. The median age at enrollment was 27 years (IQR 23-32) and thee median gestational age was 16 weeks (IQR 13-18). Among parous women (N=866; 64%), 21% (N=182) reported a prior miscarriage, 49% (N=424) reported a prior preterm birth, and 13% (N=116) reported a prior stillbirth. The HIV seroprevalence was 24%. Discussion:We have established a large cohort of pregnant women and newborns at the WHN to characterize the determinants of adverse birth outcomes in Lusaka, Zambia. Our overarching goal is to elucidate biological mechanisms in an effort to identify new strategies for early detection and prevention of adverse outcomes. We hope that findings from this cohort will help guide future studies, clinical care, and policy.