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Summary Background Women with HIV face an increased risk of preterm birth. 17 alpha-hydroxyprogesterone caproate (17P) has been shown in some trials to reduce early delivery among women with a history of spontaneous preterm birth. We investigated whether 17P would reduce this risk among women with HIV. Methods We did a randomised, double-blind, placebo-controlled trial in pregnant women with HIV at the University Teaching Hospital and Kamwala District Health Centre in Lusaka, Zambia. Eligible patients were women aged 18 years or older with confirmed HIV-1 infection, viable intrauterine singleton pregnancy at less than 24 weeks of gestation, and were receiving or intending to commence antiretroviral therapy during pregnancy. Exclusion criteria were major uterine or fetal anomaly; planned or in situ cervical cerclage; evidence of threatened miscarriage, preterm labour, or ruptured membranes at screening; medical contraindication to 17P; previous participation in the trial; or history of spontaneous preterm birth. Eligible participants provided written informed consent and were randomly assigned (1:1) to receive 250 mg intramuscular 17P or placebo once per week, starting between 16 and 24 weeks of gestation until delivery, stillbirth, or reaching term (37 weeks). Participants and study staff were masked to assignment, except for pharmacy staff who did random assignment and prepared injections but did not interact with participants. The primary outcome was a composite of delivery before 37 weeks or stillbirth at any gestational age. Patients attended weekly visits for study drug injections and antenatal care. We estimated the absolute and relative difference in risk of the primary outcome and safety events between treatment groups by intention to treat. This trial is registered with ClinicalTrials.gov , NCT03297216 , and is complete. Findings Between Feb 7, 2018 and Jan 13, 2020, we assessed 1042 women for inclusion into the study. 242 women were excluded after additional assessments, and 800 eligible patients were enrolled and randomly assigned to receive intramuscular 17P (n=399) or placebo (n=401). Baseline characteristics were similar between groups. Adherence to study drug injections was 98% in both groups, no patients were lost to follow-up, and the final post-partum visit was on Aug 6, 2020. 36 (9%) of 399 participants assigned to 17P had preterm birth or stillbirth, compared with 36 (9%) of 401 patients assigned to placebo (risk difference 0·1, 95% CI −3·9 to 4·0; relative risk 1·0, 95% CI 0·6 to 1·6; p=0·98). Intervention-related adverse events were reported by 140 (18%) of 800 participants and occurred in similar proportions in both randomisation groups. No serious adverse events were reported. Interpretation Although 17P seems to be safe and acceptable to participants, available data do not support the use of the drug to prevent preterm birth among women whose risk derives solely from HIV infection. The low risk of preterm birth in both randomisation groups warrants further investigation. Funding US National Institutes of Health and the Bill and Melinda Gates Foundation.

Background Adequate gestational weight gain (GWG) is essential for healthy fetal growth. However, in low- and middle-income countries, where malnutrition is prevalent, little information is available about GWG and how it might be modified by nutritional status and interventions. Objective We describe GWG and its associations with fetal growth and birth outcomes. We also examined the extent to which prepregnancy BMI, and preconception and early weight gain modify GWG, and its effects on fetal growth. Methods This was a secondary analysis of the Women First Trial, including 2331 women within the Democratic Republic of Congo (DRC), Guatemala, India, and Pakistan, evaluating weight gain from enrollment to ∼12 weeks of gestation and GWG velocity (kg/wk) between ∼12 and 32 weeks of gestation. Adequacy of GWG velocity was compared with 2009 Institute of Medicine recommendations, according to maternal BMI. Early weight gain (EWG), GWG velocity, and adequacy of GWG were related to birth outcomes using linear and Poisson models. Results GWG velocity (mean ± SD) varied by site: 0.22 ± 0.15 kg/wk in DRC, 0.30 ± 0.23 in Pakistan, 0.31 ± 0.14 in Guatemala, and 0.39 ± 0.13 in India, (P

OBJECTIVE Stillbirths occur 10-20 times more frequently in low-income settings compared with high-income settings. We created a methodology to define the proportion of stillbirths that are potentially preventable in low-income settings and applied it to stillbirths in sites in India and Pakistan. DESIGN Prospective observational study. SETTING Three maternity hospitals in Davangere, India and a large public hospital in Karachi, Pakistan. POPULATION All cases of stillbirth at ≥20 weeks of gestation occurring from July 2018 to February 2020 were screened for participation; 872 stillbirths were included in this analysis. METHODS We prospectively defined the conditions and gestational ages that defined the stillbirth cases considered potentially preventable. Informed consent was sought from the parent(s) once the stillbirth was identified, either before or soon after delivery. All information available, including obstetric and medical history, clinical course, fetal heart sounds on admission, the presence of maceration as well as examination of the stillbirth after delivery, histology, and polymerase chain reaction for infectious pathogens of the placenta and various fetal tissues, was used to assess whether a stillbirth was potentially preventable. MAIN OUTCOME MEASURES Whether a stillbirth was determined to be potentially preventable and the criteria for assignment to those categories. RESULTS Of 984 enrolled, 872 stillbirths at ≥20 weeks of gestation met the inclusion criteria and were included; of these, 55.5% were deemed to be potentially preventable. Of the 649 stillbirths at ≥28 weeks of gestation and ≥1000 g birthweight, 73.5% were considered potentially preventable. The most common conditions associated with a potentially preventable stillbirth at ≥28 weeks of gestation and ≥1000 g birthweight were small for gestational age (SGA) (52.8%), maternal hypertension (50.2%), antepartum haemorrhage (31.4%) and death that occurred after hospital admission (15.7%). CONCLUSIONS Most stillbirths in these sites were deemed preventable and were often associated with maternal hypertension, antepartum haemorrhage, SGA and intrapartum demise. TWEETABLE ABSTRACT Most stillbirths are preventable by better care for women with hypertension, growth restriction and antepartum haemorrhage.

Background Preconceptional maternal small-quantity lipid-based nutrient supplementation (SQLNS) improved intrauterine linear growth in low-resource countries as demonstrated by the Women First Preconception Maternal Nutrition Trial (WF). Fetal growth is dependent on nutrient availability and regulated by insulin-like growth factor 1 (IGF-1) through changes in placental transfer capacity, mediated by the mechanistic target of rapamycin (mTOR) pathway. Objectives Our objective was to evaluate the role of placental mTOR and IGF-1 signaling on fetal growth in women from 2 low-resource countries with high rates of stunting after they received preconceptional SQLNS. Methods We studied 48 women from preconception through delivery who were from Guatemala and Pakistan and received SQLNS or not, as part of the WF study. Placental samples were obtained at delivery (control, n = 24; SQLNS, n = 24). Placental protein or mRNA expression of eukaryotic translation initiation factor binding protein-1 (4E-BP1), ribosomal protein S6 (rpS6), AMP-activated protein kinase α (AMPKA), IGF-1, insulin-like growth factor receptor (IGF-1R), and pregnancy associated plasma protein (PAPP)-A, and DNA methylation of the IGF1 promoter were determined. Maternal serum IGF-1, insulin-like growth factor binding protein (IGFBP)-3, IGFBP-4, IGFBP-5, PAPP-A, PAPP-A2, and zinc were measured. Results Mean ± SEM maternal prepregnancy BMI differed between participants in Guatemala (26.5 ± 1.3) and Pakistan (19.8 ± 0.7) (P

Background Preterm birth continues to be a major public health problem contributing to 75% of the neonatal mortality worldwide. Low birth weight (LBW) is an important but imperfect surrogate for prematurity when accurate assessment of gestational age is not possible. While there is overlap between preterm birth and LBW newborns, those that are both premature and LBW are at the highest risk of adverse neonatal outcomes. Understanding the epidemiology of preterm birth and LBW is important for prevention and improved care for at risk newborns, but in many countries, data are sparse and incomplete. Methods We conducted data analyses using the Global Network’s (GN) population-based registry of pregnant women and their babies in rural communities in six low- and middle-income countries (Democratic Republic of Congo, Kenya, Zambia, Guatemala, India and Pakistan). We analyzed data from January 2014 to December 2018. Trained study staff enrolled all pregnant women in the study catchment area as early as possible during pregnancy and conducted follow-up visits shortly after delivery and at 42 days after delivery. We analyzed the rates of preterm birth, LBW and the combination of preterm birth and LBW and studied risk factors associated with these outcomes across the GN sites. Results A total of 272,192 live births were included in the analysis. The overall preterm birth rate was 12.6% (ranging from 8.6% in Belagavi, India to 21.8% in the Pakistani site). The overall LBW rate was 13.6% (ranging from 2.7% in the Kenyan site to 21.4% in the Pakistani site). The overall rate of both preterm birth and LBW was 5.5% (ranging from 1.2% in the Kenyan site to 11.0% in the Pakistani site). Risk factors associated with preterm birth, LBW and the combination were similar across sites and included nulliparity [RR − 1.27 (95% CI 1.21–1.33)], maternal age under 20 [RR 1.41 (95% CI 1.32–1.49)] years, severe antenatal hemorrhage [RR 5.18 95% CI 4.44–6.04)], hypertensive disorders [RR 2.74 (95% CI − 1.21–1.33], and 1–3 antenatal visits versus four or more [RR 1.68 (95% CI 1.55–1.83)]. Conclusions Preterm birth, LBW and their combination continue to be common public health problems at some of the GN sites, particularly among young, nulliparous women who have received limited antenatal care services. Trial registration The identifier of the Maternal and Newborn Health Registry at ClinicalTrials.gov is NCT01073475.Trial registration: The identifier of the Maternal and Newborn Health Registry at ClinicalTrials.gov is NCT01073475.

OBJECTIVE To characterize stillbirths associated with pregestational diabetes and gestational diabetes mellitus (GDM) in a large, prospective, U.S. case-control study. METHODS A secondary analysis of stillbirths among patients enrolled in a prospective; multisite; geographically, racially, and ethnically diverse case-control study in the United States was performed. Singleton gestations with complete information regarding diabetes status and with a complete postmortem evaluation were included. A standard evaluation protocol for stillbirth cases included postmortem evaluation, placental pathology, clinical testing as performed at the discretion of the health care professional, and a recommended panel of tests. A potential cause of death was assigned to stillbirth cases using a standardized classification tool. Demographic and delivery characteristics among women with pregestational diabetes and GDM were compared with characteristics of women with no diabetes in pairwise comparisons using χ or two-sample t tests as appropriate. Sensitivity analysis was performed excluding pregnancies with genetic conditions or major fetal malformations. RESULTS Of 455 stillbirth cases included in the primary analysis, women with stillbirth and diabetes were more likely to be older than 35 years and have a higher body mass index. They were also more likely to have a gestational hypertensive disorder than women without diabetes (28% vs 9.1%; P

Background While the relationship between hemoglobin (Hb) concentrations and pregnancy outcomes has been studied often, most reports have focused on a specific Hb cutoff used to define anemia. Fewer studies have evaluated pregnancy outcomes across the entire range of Hb values. Moreover, to date, most studies of the relationship of Hb concentrations to pregnancy outcomes have been done in high-income countries. Thus, we have sought to determine the relationship between the range of maternal Hb concentrations and adverse birth outcomes among South Asian pregnant women. Methods For this study, we used data collected from two South Asian countries (Pakistan – Sindh Province and two sites in India - Belagavi and Nagpur) in a prospective maternal and newborn health registry study. To assess the association between Hb concentrations and various maternal and fetal outcomes, we classified the Hb concentrations into seven categories. Regression analyses adjusting for multiple potential confounders were performed to assess adverse pregnancy outcomes across the range of Hb concentrations. Findings Between January 2012 and December 2018, 130,888 pregnant women were enrolled in the South Asian sites had a Hb measurement available, delivered and were included in the analyses. Overall, the mean Hb concentration of pregnant women from the sites was 9.9 g/dL, 10.0 g/dL in the Indian sites and 9.5 g/dL in the Pakistan site. Hb concentrations 35 years of age, women with ≥4 children and those who enrolled in the third trimester were more likely to have Hb concentrations of Interpretation This study documented the relationship between maternal Hb concentrations and adverse pregnancy outcomes in women from the Pakistani and Indian sites across the range of Hb values. Both low and high Hb concentrations were associated with risk of at least some adverse outcomes. Hence, both low and high values of Hb should be considered risk factors for the mother and fetus.

IntroductionSmokeless tobacco (SLT) consumption during pregnancy has adverse consequences for the mother and fetus. We aimed to investigate the effects of maternal pre-pregnancy SLT consumption on maternal and fetal outcomes in the district of Thatta, Pakistan.Aims and MethodsWe conducted a secondary data analysis of an individual randomized controlled trial of preconception maternal nutrition. Study participants were women of reproductive age (WRA) residing in the district of Thatta, Pakistan. Participants were asked questions regarding the usage of commonly consumed SLT known as gutka (exposure variable). Study outcomes included maternal anemia, miscarriage, preterm births, stillbirths, and low birth weight. We performed a cox-regression analysis by controlling for confounders such as maternal age, education, parity, working status, body mass index, and geographic clusters.ResultsThe study revealed that 71.5% of the women reported using gutka, with a higher proportion residing in rural areas as compared with urban areas in the district of Thatta, Pakistan. In the multivariable analysis, we did not find a statistically significant association between gutka usage and anemia [(relative risk, RR: 1.04, 95% confidence interval, CI (0.92 to 1.16)], miscarriage [(RR: 1.08, 95% CI (0.75 to 1.54)], preterm birth [(RR: 1.37, 95% CI (0.64 to 2.93)], stillbirth [(RR: 1.02, 95% CI (0.39 to 2.61)], and low birth weight [(RR: 0.96, 95% CI (0.72 to 1.28)].ConclusionsThe study did not find an association between gutka usage before pregnancy and adverse maternal and fetal outcomes. In the future, robust epidemiological studies are required to detect true differences with a dose–response relationship between gutka usage both before and during pregnancy and adverse fetomaternal outcomes.ImplicationsWhile most epidemiological studies conducted in Pakistan have focused on smoking and its adverse outcomes among males, none of the studies have measured the burden of SLT among WRA and its associated adverse outcomes. In addition, previously conducted studies have primarily assessed the effect of SLT usage during pregnancy rather than before pregnancy on adverse fetal and maternal outcomes. The current study is unique because it provides an insight into the usage of SLT among WRA before pregnancy and investigates the association between pre-pregnancy SLT usage and its adverse fetomaternal outcomes in rural Pakistan.

OBJECTIVE Marijuana use is associated with placenta-mediated adverse pregnancy outcomes including fetal growth restriction, but the mechanism remains uncertain. The objective was to evaluate the association between maternal marijuana use and the feto-placental weight ratio (FPR). Secondarily, we aimed to compare placental histology of women who used marijuana to those who did not. STUDY DESIGN This was a secondary analysis of singleton pregnancies enrolled in a multicenter and case-control stillbirth study. Prior marijuana use was detected by electronic medical record abstraction or cord homogenate positive for 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid. Prior tobacco use was detected by self-report or presence of maternal serum cotinine. Stillbirths and live births were considered separately. The primary outcome was FPR. Association of marijuana use with FPR was estimated with multivariable linear modeling adjusted for fetal sex, preterm birth, and tobacco use. Comparisons between groups for placental histology were made using Chi-square and stratified by live birth and stillbirth, term and preterm deliveries, and fetal sex. RESULTS Of 1,027 participants, 224 were stillbirths and 803 were live births. Overall, 41 (4%) women used marijuana during the pregnancy. The FPR ratio was lower among exposed offspring but reached statistical significance only for term stillbirths (mean 6.84 with marijuana use vs. mean 7.8 without use, p

Background In the majority of cases, the cause of stillbirth remains unknown despite detailed clinical and laboratory evaluation. Approximately 10 to 20% of stillbirths are attributed to c...

Background: Low dose aspirin (LDA) is an effective strategy to reduce preterm birth. However, LDA might have differential effects globally, based on the etiology of preterm birth. In some regions, malaria in pregnancy could be an important modifier of LDA on birth outcomes and anemia. Methods: This is a sub-study of the ASPIRIN trial, a multi-national, randomized, placebo controlled trial evaluating LDA effect on preterm birth. We enrolled a convenience sample of women in the ASPIRIN trial from the Democratic Republic of Congo (DRC), Kenya and Zambia. We used quantitative polymerase chain reaction to detect malaria. We calculated crude prevalence proportion ratios (PRs) for LDA by malaria for outcomes, and regression modelling to evaluate effect measure modification. We evaluated hemoglobin in late pregnancy based on malaria infection in early pregnancy. Findings: 1,446 women were analyzed, with a malaria prevalence of 63% in the DRC site, 38% in the Kenya site, and 6% in the Zambia site. Preterm birth occurred in 83 (LDA) and 90 (placebo) women, (PR 0.92, 95% CI 0.70, 1.22), without interaction between LDA and malaria (p=0.75). Perinatal mortality occurred in 41 (LDA) and 43 (placebo) pregnancies, (PR 0.95, 95% CI 0.63, 1.44), with an interaction between malaria and LDA (p=0.014). Hemoglobin was similar by malaria and LDA status. Interpretation: Malaria in early pregnancy did not modify the effects of LDA on preterm birth, but modified the effect of LDA on perinatal mortality. This effect measure modification deserves continued study as LDA is used in malaria endemic regions. Clinical Trial Registration Details: This is a sub-study of the ASPIRIN trial, a multi-national, randomized, placebo controlled trial evaluating LDA effect on preterm birthThe ASPIRIN trial was registered in clinicaltrials.gov (NCT02409680). Funding Information: NICHD (UG1HD076465, UG1HD078437, UG1HD076461). Declaration of Interests: We declare no competing interests. Ethics Approval Statement: This study was approved by the relevant ethics committees at the institutions conducting the study at each site prior to the initiation of study activities. The study was also approved by the ethics committees at the partner U.S.-based institutions (University of North Carolina at Chapel Hill, Columbia University, University of Alabama at Birmingham and Indiana University) and by RTI International, the data coordinating center. All women provided informed consent prior to their participation in the sub-study.

OBJECTIVES: Understanding the interactions between nutrition and climate-driven health outcomes is increasingly necessary. Employing data from the Women First trial conducted in Thatta, Pakistan, we examined the interactions between maternal nutritional deficits and heat stress (HS) on birth outcomes. METHODS: Women of child-bearing age either consumed a small quantity lipid-based nutrition supplement (sqLNS) prior to conception (Arm 1), from 12 wk of gestation until delivery (Arm 2); or were not supplemented with sqLNS (Arm 3). At the Pakistan site, samples sizes with birth outcomes obtained within 48 h of delivery for Arms 1, 2 and 3 were 157,150 and 138, respectively. Daily maximal air temperatures were used to were compute the average daily maximal temperatures (T(max)) for each infant over four 90-day windows representing each trimester of gestation and 3 mo preconception. The number of days in each period when the T(max) was > 39°C was computed to assess ‘heat stress days’. RESULTS: Linear regression models assessing the associations between heat exposure and outcome variables (gestational age adjusted Z-scores of birth length (LGAZ), birth weight (WGAZ) and head circumference (HCGAZ) revealed a striking negative association of both ambient temperature and HS days in the first trimester on birth length (LGAZ) and head circumference (HCGAZ) (p

OBJECTIVE To evaluate the association between maternal fructosamine levels at the time of delivery and stillbirth. DESIGN Secondary analysis of a case-control study. SETTING Multicentre study of five geographic catchment areas in the USA. POPULATION All singleton stillbirths with known diabetes status and fructosamine measurement, and representative live birth controls. MAIN OUTCOME MEASURES Fructosamine levels in stillbirths and live births among groups were adjusted for potential confounding factors, including diabetes. Optimal thresholds of fructosamine to discriminate stillbirth and live birth. RESULTS A total of 529 women with a stillbirth and 1499 women with a live birth were included in the analysis. Mean fructosamine levels were significantly higher in women with a stillbirth than in women with a live birth after adjustment (177 ± 3.05 versus 165 ± 2.89 μmol/L, P

Background As an evidence-based intervention to prevent maternal and neonatal morbidity and mortality, cesarean birth at rates of under 2%, which is the case in rural Southwest Ethiopia, is an unacceptable public health problem and represents an important disparity in the use of this life-saving treatment compared to more developed regions. The objective of this study is to explore an innovative clinical solution (a mobile cesarean birth center) to low cesarean birth rates resulting from the Three Delays to emergency obstetric care in isolated and underserved regions of Ethiopia, and the world. Methods We will use mixed but primarily qualitative methods to explore and prepare the mobile cesarean birth center for subsequent implementation in communities in Bench Sheko and West Omo Zones. This will involve interviews and focus groups with key stakeholders and retreat settings for user-centered design activities. We will present stakeholders with a prototype surgical truck that will help them conceive of the cesarean birth center concept and discuss implementation issues related to staffing, supplies, referral patterns, pre- and post-operative care, and relationship to locations for vaginal birth. Discussion Completion of our study aims will allow us to describe participants’ perceptions about barriers and facilitators to cesarean birth and their attitudes regarding the appropriateness, acceptability, and feasibility of a mobile cesarean birth center as a solution. It will also result in a specific, measurable, attainable, relevant, and timely (SMART) implementation blueprint(s), with implementation strategies defined, as well as recruitment plans identified. This will include the development of a logic model and process map, a timeline for implementation with strategies selected that will guide implementation, and additional adaptation/adjustment of the mobile center to ensure fit for the communities of interest. Trial registration There is no healthcare intervention on human participants occurring as part of this research, so the study has not been registered.

Eclampsia-related conditions are the second leading direct cause of obstetric deaths in Bangladesh. Efforts to prevent such deaths in low- and middle-income countries are increasingly focused on task shifting at the primary care level to enable frontline providers to screen and initiate treatment for women with preeclampsia, severe preeclampsia, and eclampsia (PE/SPE/E). The MaMoni Health Systems Strengthening project (funded by the United States Agency for International Development) implemented a magnesium sulfate intervention at primary care facilities in 4 Bangladesh districts in 2016 and 2017.The project trained frontline providers through a cascade approach from the national to the union level. A PE/SPE/E patient algorithm, digital blood pressure machines, and eclampsia kits with magnesium sulfate were supplied to service providers at each facility. We conducted a retrospective record review of facility-level data to assess the degree to which newly trained frontline providers adhered to a protocol that incorporated the use of magnesium sulfate for SPE/E in primary care settings.In total, 283 women were found to have PE/SPE/E. Fifty-four percent were managed according to the protocol. The required supplies were present at each facility, but some issues existed with regard to availability and functionality of blood pressure apparatuses.Challenges related to recordkeeping and service quality limited the analysis. Frontline providers need refresher trainings, ongoing supervision, properly calibrated blood pressure devices, and performance monitoring support in order to improve screening and management of PE/SPE/E in primary care facilities.

OBJECTIVE: To determine risk factors associated with cesarean delivery among nulliparous women in spontaneous labor with a single, cephalic, term pregnancy (Robson group 1). METHODS: Data were assessed from the WHO Global Survey of Maternal and Perinatal Health conducted in 2004–2008. RESULTS: Among 82 280 women in Robson group 1, 67 698 (82.3%) had vaginal and 14 578 (17.7%) had cesarean delivery. In adjusted analyses, maternal factors associated with cesarean included age older than 18 years, being overweight or obese, being married or cohabitating, attending four prenatal visits or more, and being medically high risk (P

Stillbirths account for 2.6 million deaths annually. 98% occur in low- and lower middle-income countries. Accurate classification of stillbirths in low-resource settings is challenged by poor pregnancy dating and infrequent access to electronic heart rate monitoring for both the newborn and fetus. In these settings, liveborn infants may be misclassified as stillbirths, and stillbirths may be misclassified as miscarriages. Causation is available for only 3% of stillbirths globally due to the absence of registration systems. In low-resource settings where culture and autopsy are infrequently available, clinical course is used to assign cause of stillbirth. This method may miss rare or subtle causes, as well as those with non-specific clinical presentations. Verbal autopsy is another technique for assigning cause of stillbirth when objective medical data are limited. This method requires family engagement and physician attribution of cause. As interventions to reduce stillbirths in LMICs are increasingly implemented, attention to accurate classification and assignment of causes of stillbirth are critical to charting progress.

Cesarean birth (CB) rates are rising, globally. The global burden of CB is having a mixed effect on pregnancy outcomes and requires significant clinical and economic resources. The context of CB care in low- and middle-income countries is further complicated by barriers to facility-based care itself, followed by issues with quality and delivery of care in these resource-limited settings. The objective of this commentary is to propose an original, new, flexible, comprehensive care model for delivering SAFE cesarean delivery care in very low-resource settings. This model, the SAFEmodel for cesarean delivery care in low- and middle-income countries, developed by the authors, does not assume the current care model is working. It does not assume that even traditional hospital settings are what is needed to solve the problem of delivering high-quality, easily accessible CB care in the most remote and geographically isolated communities. The novel model promotes a decentralized care program that brings emergency obstetric care to women instead of the converse through four concepts: the care should be cloSe (community-based), it should be very dedicated to Action (transfer of care), it should be Focused on and highly specific to labor and delivery (cesarean birth center), and finally, it should be committed to high-quality care through iterative Evidence-based quality improvement programming and data collection.

Background Stillbirth, defined as foetal death ≥20 weeks' gestation, is associated with poor foetal growth and is often attributed to placental abnormalities, which are also associated with poor foetal growth. Evaluating inter-relationships between placental abnormalities, poor foetal growth, and stillbirth may improve our understanding of the underlying mechanisms for some causes of stillbirth. Objective Our primary objective was to determine whether poor foetal growth, operationalised as small for gestational age (SGA), mediates the relationship between placental abnormalities and stillbirth. Methods We used data from the Stillbirth Collaborative Research Network study, a population-based case-control study conducted from 2006-2008. Our analysis included 266 stillbirths and 1135 livebirths. We evaluated associations of stillbirth with five types of placental characteristics (developmental disorders, maternal and foetal inflammatory responses, and maternal and foetal circulatory disorders) and examined mediation of these relationships by SGA. We also assessed exposure-mediator interaction. Models were adjusted for maternal age, race/ethnicity, education, body mass index, parity, and smoking status. Results All five placental abnormalities were more prevalent in cases than controls. After adjustment for potential confounders, maternal inflammatory response (odds ratio [OR] 2.58, 95% confidence interval [CI] 1.77, 3.75), maternal circulatory disorders OR 4.14, 95% CI 2.93, 5.84, and foetal circulatory disorders OR 4.58, 95% CI 3.11, 6.74 were strongly associated with stillbirth, and the relationships did not appear to be mediated by SGA status. Associations for developmental disorders and foetal inflammatory response diverged for SGA and non-SGA births, and strong associations were only observed when SGA was not present. Conclusions Foetal growth did not mediate the relationships between placental abnormalities and stillbirth. The relationships of stillbirth with maternal and foetal circulatory disorders and maternal inflammatory response appear to be independent of poor foetal growth, while developmental disorders and foetal inflammatory response likely interact with foetal growth to affect stillbirth risk.

Fibromyalgia (FM) is a common chronic pain disorder that presents diagnostic challenges for clinicians. Several classification, diagnostic and screening criteria have been developed over the years, but there continues to be a need to develop criteria that reflect the current understanding of FM and are practical for use by clinicians and researchers. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration (FDA) and the American Pain Society (APS) initiated the ACTTION-APS Pain Taxonomy (AAPT) to develop a diagnostic system that would be clinically useful and consistent across chronic pain disorders. The AAPT established an international FM working group consisting of clinicians and researchers with expertise in FM to generate core diagnostic criteria for FM and apply the multidimensional diagnostic framework adopted by AAPT to FM. The process for developing the AAPT criteria and dimensions included literature reviews and synthesis, consensus discussions, and analyses of data from large population-based studies conducted in the United Kingdom. The FM working group established a revised diagnosis of FM and identified risk factors, course, prognosis, and pathophysiology of FM. Future studies will assess the criteria for feasibility, reliability, and validity. Revisions of the dimensions will also be required as research advances our understanding of FM. PERSPECTIVE: The ACTTION-APS FM taxonomy provides an evidence-based diagnostic system for FM. The taxonomy includes diagnostic criteria, common features, comorbidities, consequences, and putative mechanisms. This approach might improve the recognition of FM in clinical practice.

Each year, an estimated 15 million babies are born preterm, a global burden borne disproportionately by families in lower-income countries. Maternal HIV infection increases a woman’s risk of delivering prematurely, and antiretroviral therapy (ART) may compound this risk. While prenatal progesterone prophylaxis prevents preterm birth among some high-risk women, it is unknown whether HIV-infected women could benefit from this therapy. We are studying the efficacy of progesterone supplementation to reduce the risk of preterm birth among pregnant women with HIV in Lusaka, Zambia. The Improving Pregnancy Outcomes with Progesterone (IPOP) study is a Phase III double-masked, placebo-controlled, randomized trial of intramuscular 17-alpha hydroxprogesterone caproate (17P) to prevent preterm birth in HIV-infected women. A total of 800 women will be recruited prior to 24 weeks of gestation and randomly allocated to 17P or placebo administered by weekly intramuscular injection. The primary outcome will be a composite of live birth prior to 37 completed gestational weeks or stillbirth at any gestational age. Secondary outcomes will include very preterm birth (

Recent World Health Organization (WHO) antenatal care recommendations include an ultrasound scan as a part of routine antenatal care. The First Look Study, referenced in the WHO recommendation, subsequently shows that the routine use of ultrasound during antenatal care in rural, low-income settings did not improve maternal, fetal or neonatal mortality, nor did it increase women's use of antenatal care or the rate of hospital births. This article reviews the First Look Study, reconsidering the assumptions upon which it was built in light of these results, a supplemental descriptive study of interviews with patients and sonographers that participated in the First Look study intervention, and a review of the literature. Two themes surface from this review. The first is that focused emphasis on building the pregnancy risk screening skills of rural primary health care personnel may not lead to adaptations in referral hospital processes that could benefit the patient accordingly. The second is that agency to improve the quality of patient reception at referral hospitals may need to be manufactured for obstetric ultrasound screening, or remote pregnancy risk screening more generally, to have the desired impact. Stemming from the literature, this article goes on to examine the potential for complementarity between obstetric ultrasound screening and another approach encouraged by the WHO, the maternity waiting home. Each approach may address existing shortcomings in how the other is currently understood. This paper concludes by proposing a path toward developing and testing such a hybrid approach.

Antibiotics administered just before delivery or during the intrapartum period is common globally and recommendations for increased use continue to expand. Before the introduction of maternal screening and treatment for Group B Streptococcus (GBS) colonization to prevent neonatal GBS sepsis in the 1990's, maternal antibiotic treatment at delivery was used rarely, usually for confirmed maternal infections. With maternal screening for GBS, including a 20-25% positivity rate in the United States (US), antibiotic use at delivery increased substantially.(1) Antibiotics at delivery were subsequently recommended for women with prolonged membrane rupture and preterm labor. Recommendations expanded further with evidence that antibiotics reduced post-partum maternal infections associated with cesarean delivery.(2) And now, following a trial in The Gambia that suggested reduced maternal and neonatal infections, several large trials in low- and middle-income countries (LMICs) are evaluating whether widespread azithromycin treatment, not only for women undergoing cesarean delivery, but among all pregnant women, reduces maternal and neonatal morbidity and mortality.(3).

Low birth weight is associated with perinatal and long-term morbidity and mortality, and may be a result of abnormal placental development and function. In studies of singletons, associations have been reported between features of placental morphology and birth weight. Evaluating similar associations within twin pairs offers a unique opportunity to control for key confounders shared within a twin pair, including gestational age, parental characteristics, and intrauterine environment. Data from 3 studies in the United States that were completed from 2012 to 2013, 2006 to 2008, and 1959 to 1966 were used in our analysis of 208 sets of dichorionic twins with unfused placentas. We used linear regression to model difference in birth weight within a twin pair as a function of differences in placental characteristics (i.e., thickness, 2-dimensional surface area, intraplacental difference in diameter). After controlling for sex discordance, a 75.3- cm(2) difference in placental surface area, which reflects the interquartile range, was associated with a difference in birth weight of 142.1 g (95% confidence interval (CI): 62.9, 221.3). The magnitude of the association also may be larger for same-sex male pairs than same-sex female pairs (males: 265.8 g, 95% CI: 60.8, 470.8; females: 133.0 g, 95% CI: 15.7, 250.3). Strong associations between surface area and birth weight are consistent with reported results for singleton pregnancies.

Background: South Asia contributes more than one-third of all global stillbirths, yet the cause of stillbirth remains largely unstudied in this region. New investigations, including novel assessment of placental and fetal tissues, facilitate more precise determination of the underlying causes of stillbirth. We sought to assess underlying and contributing causes of stillbirth from settings in India and Pakistan. Methods: The Project to Understand and Reduce Stillbirth and Preterm birth in Southeast Asia (PURPOSe) was established in hospitals in central India and south Pakistan to collect standardized, prospective data from women delivering in those health facilities to better understand causes of stillbirth and causes of death in preterm newborns. Here, we analyzed data from stillbirths. An expert panel reviewed available data for all stillbirths eligible for the study to determine the primary and contributing maternal, placental, and fetal causes of death. Findings: Between September 2018 and February 2020, 981 eligible stillbirths were enrolled and, of those, 611 had their cases reviewed by the expert panel. The primary maternal causes of stillbirth were hypertensive disease (36·1%), followed by severe anemia (10·8%) while the primary placental causes were maternal and fetal vascular malperfusion (47·9%). The primary fetal cause of stillbirth was intrauterine hypoxia (71·5%). When we assessed the overlap of main causes, 18·9% of all stillbirths had intrauterine hypoxia, placental malperfusion, and eclampsia/pre-eclampsia indicated as primary causes of death. Infection, including of the placenta, its membranes and in the fetus, as well as congenital anomalies also were causative for stillbirth. Interpretation: In South Asia, fetal asphyxia is the major cause of stillbirth. Several placental lesions, especially those associated with maternal and fetal vascular malperfusion and placental abruption play an important role in the pathway through asphyxia to fetal death. Maternal hypertension and especially preeclampsia is often the primary maternal condition associated with this pathway. Funding: Bill & Melinda Gates Foundation Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: The study was reviewed and approved by the ethics review committees at the Aga Khan University (Karachi, Pakistan), KLE Academy of Higher Education and Research (Belagavi, India), J.J.M. Medical College (Davangere, India), and RTI International (Durham, NC US). All women provided informed written consent prior to participation in the study.

Background Quality assurance (QA) is a process that should be an integral part of research to protect the rights and safety of study participants and to reduce the likelihood that the results are affected by bias in data collection. Most QA plans include processes related to study preparation and regulatory compliance, data collection, data analysis and publication of study results. However, little detailed information is available on the specific procedures associated with QA processes to ensure high-quality data in multi-site studies. Methods The Global Network for Women’s and Children’s Health Maternal Newborn Health Registy (MNHR) is a prospective population-based registry of pregnancies and deliveries that is carried out in 8 international sites. Since its inception, QA procedures have been utilized to ensure the quality of the data. More recently, a training and certification process was developed to ensure that standardized, scientifically accurate clinical definitions are used consistently across sites. Staff complete a web-based training module that reviews the MNHR study protocol, study forms and clinical definitions developed by MNHR investigators and are certified through a multiple choice examination prior to initiating study activities and every six months thereafter. A standardized procedure for supervision and evaluation of field staff is carried out to ensure that research activites are conducted according to the protocol across all the MNHR sites. Conclusions We developed standardized QA processes for training, certification and supervision of the MNHR, a multisite research registry. It is expected that these activities, together with ongoing QA processes, will help to further optimize data quality for this protocol.

Background Babies born weighing ≥ 2500 g account for more than 80% of the births in most resource-limited locations and for nearly 50% of the 28-day neonatal deaths. In contrast, in high-resource settings, 28-day neonatal mortality among this group represents only a small fraction of the neonatal deaths. Yet mortality risks for birth weight of ≥ 2500 g is limited. Knowledge regarding the factors associated with mortality in these babies will help in identifying interventions that can reduce mortality. Methods The Global Network’s Maternal Newborn Health Registry (MNHR) is a prospective, population-based observational study that includes all pregnant women and their pregnancy outcomes in defined geographic communities that has been conducted in research sites in six low-middle income countries (India, Pakistan, Democratic Republic of Congo, Guatemala, Kenya and Zambia). Study staff enroll all pregnant women as early as possible during pregnancy and conduct follow-up visits to ascertain delivery and 28-day neonatal outcomes. We analyzed the neonatal mortality rates (NMR) and risk factors for deaths by 28 days among all live-born babies with a birthweight ≥ 2500 g from 2010 to 2018 across the Global Network sites. Results Babies born in the Global Network sites from 2010 to 2018 with a birthweight ≥ 2500 g accounted for 84.8% of the births and 45.4% of the 28-day neonatal deaths. Among this group, the overall NMR was 13.1/1000 live births. The overall 28-day NMR for ongoing clusters was highest in Pakistan (29.7/1000 live births) and lowest in the Zambian/Kenyan sites (9.3/1000) for ≥ 2500 g infants. ≥ 2500 g NMRs declined for Zambia/Kenya and India. For Pakistan and Guatemala, the NMR remained almost unchanged over the period. The ≥ 2500 g risks related to maternal, delivery and newborn characteristics varied by site. Maternal factors that increased risk and were common for all sites included nulliparity, hypertensive disease, previous stillbirth, maternal death, obstructed labor, severe postpartum hemorrhage, and abnormal fetal presentation. Neonatal characteristics including resuscitation, hospitalization, congenital anomalies and male sex, as well as lower gestational ages and birthweights were also associated with increased mortality. Conclusions Nearly half of neonatal deaths in the Global Network sites occurred in infants born weighing ≥ 2500 g. The NMR for those infants was 13.1 per 1000 live births, much higher than rates usually seen in high-income countries. The changes in NMR over time varied across the sites. Even among babies born ≥ 2500 g, lower gestational age and birthweight were largely associated with increased risk of mortality. Since many of these deaths should be preventable, attention to preventing mortality in these infants should have an important impact on overall NMR. Trial registration: https://ClinicalTrials.gov Identifier: NCT01073475

Background Due to high fertility rates in some low and lower-middle income countries, the interval between pregnancies can be short, which may lead to adverse maternal and neonatal outcomes. Methods We analyzed data from women enrolled in the NICHD Global Network Maternal Newborn Health Registry (MNHR) from 2013 through 2018. We report maternal characteristics and outcomes in relationship to the inter-delivery interval (IDI, time from previous delivery [live or stillborn] to the delivery of the index birth), by category of 6–17 months (short), 18–36 months (reference), 37–60 months, and 61–180 months (long). We used non-parametric tests for maternal characteristics, and multivariable logistic regression models for outcomes, controlling for differences in baseline characteristics. Results We evaluated 181,782 women from sites in the Democratic Republic of Congo, Zambia, Kenya, Guatemala, India, and Pakistan. Women with short IDI varied by site, from 3% in the Zambia site to 20% in the Pakistan site. Relative to a 18–36 month IDI, women with short IDI had increased risk of neonatal death (RR = 1.89 [1.74, 2.05]), stillbirth (RR = 1.70 [1.56, 1.86]), low birth weight (RR = 1.38 [1.32, 1.44]), and very low birth weight (RR = 2.35 [2.10, 2.62]). Relative to a 18–36 month IDI, women with IDI of 37–60 months had an increased risk of maternal death (RR 1.40 [1.05, 1.88]), stillbirth (RR 1.14 [1.08, 1.22]), and very low birth weight (RR 1.10 [1.01, 1.21]). Relative to a 18–36 month IDI, women with long IDI had increased risk of maternal death (RR 1.54 [1.10, 2.16]), neonatal death (RR = 1.25 [1.14, 1.38]), stillbirth (RR = 1.50 [1.38, 1.62]), low birth weight (RR = 1.22 [1.17, 1.27]), and very low birth weight (RR = 1.47 [1.32,1.64]). Short and long IDIs were also associated with increased risk of obstructed labor, hemorrhage, hypertensive disorders, fetal malposition, infection, hospitalization, preterm delivery, and neonatal hospitalization. Conclusions IDI varies by site. When compared to 18–36 month IDI, women with both short IDI and long IDI had increased risk of adverse maternal and neonatal outcomes. Trial registration The MNHR is registered at NCT01073475.

Objective Approximately 10% of stillbirths are attributed to fetal anomalies, but anomalies are also common in live births. We aimed to assess the relationship between anomalies, by system and stillbirth. Design Secondary analysis of a prospective, case-control study. Setting Multicentre, 59 hospitals in five regional catchment areas in the USA. Population or sample All stillbirths and representative live birth controls. Methods Standardised postmortem examinations performed in stillbirths, medical record abstraction for stillbirths and live births. Main outcome measures Incidence of major anomalies, by type, compared between stillbirths and live births with univariable and multivariable analyses using weighted analysis to account for study design and differential consent. Results Of 465 singleton stillbirths included, 23.4% had one or more major anomalies compared with 4.3% of 1871 live births. Having an anomaly increased the odds of stillbirth; an increasing number of anomalies was more highly associated with stillbirth. Regardless of organ system affected, the presence of an anomaly increased the odds of stillbirth. These relationships remained significant if stillbirths with known genetic abnormalities were excluded. After multivariable analyses, the adjusted odds ratio (aOR) of stillbirth for any anomaly was 4.33 (95% CI 2.80-6.70) and the systems most strongly associated with stillbirth were cystic hygroma (aOR 29.97, 95% CI 5.85-153.57), and thoracic (aOR16.18, 95% CI 4.30-60.94) and craniofacial (aOR 35.25, 95% CI 9.22-134.68) systems. Conclusions In pregnancies affected by anomalies, the odds of stillbirth are higher with increasing numbers of anomalies. Anomalies of nearly any organ system increased the odds of stillbirth even when adjusting for gestational age and maternal race. Tweetable abstract Stillbirth risk increases with anomalies of nearly any organ system and with number of anomalies seen.

BackgroundAnemia is a major public health concern among women of reproductive age leading to high maternal mortality in low- and middle-income countries. Of the prior studies conducted in Pakistan, most focused on large urban areas and did not explore the determinants of anemia among women of reproductive age (WRA) across socio-demographic, dietary, reproductive, and biological domains. Thus, we aimed to study the prevalence and determinants of anemia among WRA in rural Pakistan.MethodsWe conducted a cross-sectional study in the Thatta district of Pakistan from September 2018 to January 2019 and enrolled 150 non-pregnant, married women. Data collectors administered a structured questionnaire to collect sociodemographic, reproductive and dietary data from women, who also provided stool and blood samples. We classified all WRA as anemic if their hemoglobin was ResultsIn our study, 61.3% of the enrolled women were anemic. In the multivariable analysis, we found that factors such as serum iron levels of less than 50 μg/dl (aOR: 7.17; 95% CI (2.94, 17.47)), history of breastfeeding (aOR: 2.43; 95% CI (1.04, 5.72)), living in a katcha house (aOR: 6.61; 95% CI (2.21, 19.87)), no consumption of meat (aOR: 4.18; 95% CI (1.66, 9.96)) were significantly associated with anemia among WRA. A history of more than one abortion (aOR: 0.06; 95% CI (0.01, 0.33) appeared protective for its association with anemia.ConclusionOur findings demonstrate a high burden of anemia and its complex determinants among WRA in rural Pakistan. A combination of nutritional and educational strategies should be designed to encourage rural women to consume iron-rich foods in their diet with an access to adequate food. Breastfeeding women should be encouraged to consume extra calories with sufficient intake of the food to continue exclusive breastfeeding and reserve the iron stores through amenorrhea to prevent themselves from becoming anemic.

Objective. To determine the hematologic profile of preterm infants with regard to different diseases. Methods. A prospective, cross-sectional, observational study, conducted in 5 hospitals in Ethiopia from July 2016 to May 2018. Preterm babies 3, and 159 340 cells/mm3, respectively. Early onset neonatal sepsis (EONS) 1433 (37%), asphyxia 266 (6.9%), and respiratory distress syndrome (RDS) 1738 (45.3%) were common reasons for admission. The WBC count was 3 for 8.8%, 9.0%, and 11.1% of neonates with EONS, asphyxia and RDS, respectively. The hemoglobin value was 3 for 16.8%, 17.7%, and 19.8% of preterms admitted with a diagnosis of EONS, asphyxia, and RDS, respectively. Conclusion. WBC and platelet counts were the most common to be associated with EONS, asphyxia, and RDS. Further study is recommended to determine the effect of abnormal hematologic profile on the outcome of preterm babies.

Background In Pakistan, there is a dearth of literature on the perceptions of anemia among women of reproductive age (WRA). This study was undertaken to explore the perceptions of women, their husbands, and healthcare providers about anemia, its possible causes, and how anemia impacts maternal and child health in Thatta, Pakistan. Methods A qualitative study was conducted in Thatta, Pakistan from September to December 2018. Using a pre-tested semi-structured interview (SSI), we collected data to understand their definitions of anemia through ten focus group discussions (FGDs) with women and their partners and ten primary informant interviews (KIIs) with healthcare providers. We identified six major themes: (I) Knowledge and awareness of anemia, (II) Causes and consequences of Anemia, (III) Dietary practices, (IV) Knowledge and practices regarding the use of iron-folic acid supplements, (V) Factors influencing prevention and control of anemia and (VI) Women’s health behavior. We analyzed the data through thematic analysis using NVivo 10 software. Results Most community members were not aware of the term anemia but described anemia as a condition characterized by ‘blood deficiency’ in the body. All study participants perceived anemia as an important health problem tending to cause adverse outcomes among WRA and their children. Study participants perceived gutka (chewable tobacco) consumption as an important cause of anemia. Healthcare providers identified short inter-pregnancy intervals, lack of family planning, poor health-seeking behavior, and consumption of unhealthy food as causes of anemia in the district. Consumption of unhealthy food might not be related to related to a poorer knowledge of iron-deficient foods, but economic constraints. This was further endorsed by the healthcare providers who mentioned that most women were too poor to afford iron-rich foods. All men and women were generally well versed with the sources of good nutrition to be consumed by WRA to prevent anemia. Conclusion The findings suggest that the government should plan to develop strategies for poverty-stricken and vulnerable rural women and plan health awareness programs to improve dietary practices, compliance with supplements, and health-seeking behavior among women of reproductive age. There is a need to develop effective counseling strategies and context-specific health education sessions to improve the health-seeking behavior of women and men in the Thatta district of Pakistan. Besides, there is need to address social determinants of health such as poverty that pushes women of poorer socioeconomic strata to eat less nutritious foods and have more anaemia. Therefore, a comprehensive and robust strategic plan need to be adopted by government that focuses not only on the awareness programs, but also aim to reduce inequities that lead to pregnant women eat iron-poor foods, which, in turn, forces them to become anemic.

BackgroundPreterm infants have high risk of developing growth restriction and long-term complications. Enteral feeding is often delayed in neonatal intensive care units (NICUs) for the fear of feeding intolerance and the associated necrotising enterocolitis, and recent advances in nutritional support are unavailable in low-income countries.ObjectiveThe aim of this study was to assess the incidence and associated factors of extrauterine growth restriction (EUGR) among preterm infants in selected NICUs in Ethiopia.MethodThis was a cross-sectional study involving a subgroup analysis of preterm infants admitted to hospitals, from a multicentre descriptive study of cause of illness and death in preterm infants in Ethiopia, conducted from 2016 to 2018. EUGR was defined as weight at discharge Z-scores ResultFrom 436 preterm infants included in the analysis, 223 (51%) were male, 224 (51.4%) very low birth weight (VLBW) and 185 (42.4%) small for gestational age (SGA). The mean (SD) of weight for corrected age Z-score at the time of discharge was −2.5 (1.1). The incidence of EUGR was 86.2%. Infants who were SGA, VLBW and longer hospital stay over 21 days had increased risk of growth restriction (p-valueConclusionThe majority of the infants had EUGR at the time of discharge from the hospital, which indicates suboptimal nutrition. Revision of national guidelines for preterm infants feeding and improvement in clinical practice is highly required.

In this issue of The Journal , Gibson, et al have demonstrated that certain subscales of the Multidimensional Health Assessment Questionnaire (MDHAQ) can be combined to provide clues to the diagnosis of comorbid fibromyalgia (FM) in patients with rheumatic diseases1. An FM assessment screening tool (FAST) compared favorably to the 2011 self-report FM criteria, developed for clinical and epidemiologic studies2, and both agreed moderately with the clinical diagnosis of FM. The authors suggest that because MDHAQ is already frequently used in rheumatology centers, adapting the FAST indices can alert clinicians to concurrent FM without adding new self-administered screening instruments. This paper also reconsiders a number of important issues involving rheumatologists and FM. First, rheumatologists have become more aware of the frequency and effect of FM in every rheumatic disease. Whether using the FAST indices, the 2011 FM criteria, or the gold standard (Dr. Gibson’s clinical diagnosis), FM was present in about 20–30% of patients with rheumatic disease. This is consistent with reports of FM in 13–40% of cases of rheumatoid arthritis (RA)3,4, 10–20% of osteoarthritis (OA)5, 10–30% with psoriatic arthritis or a spondyloarthropathy [SpA; such … Address correspondence to Dr. D.L. Goldenberg, 1125 NW 12th Ave., Unit 107, Portland, Oregon 97209, USA. E-mail: dongoldenberg44{at}gmail.com

PurposeThe aim of this study was to assess morbidity and mortality pattern of small for gestational age (SGA) preterm infants in comparison to appropriate for gestational age (AGA) preterm infants of similar gestational age.MethodWe compared neonatal outcomes of 1336, 1:1 matched, singleton SGA and AGA preterm infants based on their gestational age using data from the study ‘Causes of Illness and Death of Preterm Infants in Ethiopia (SIP)’. Data were analysed using SPSS V.23. ORs and 95% CIs and χ2tests were done, p value of ResultThe majority of the infants (1194, 89%) were moderate to late preterm (32–36 weeks of gestation), 763 (57%) were females. Male preterm infants had higher risk of being SGA than female infants (pConclusionNeonatal complications such as hypoglycaemic, NEC, LOS, polycythaemia and prolonged hospitalisation are more common in SGA infants, while rates of RDS and mortality are similar in SGA and AGA groups. Early recognition of SGA status, high index of suspicion and screening for complications associated and timely intervention to prevent complications need due consideration.

Objective Umbilical cord abnormalities are commonly cited as a cause of stillbirth, but details regarding these stillbirths are rare. Our objective was to characterize stillbirths associated with umbilical cord abnormalities using rigorous criteria and to examine associated risk factors. Methods The Stillbirth Collaborative Research Network conducted a case-control study of stillbirth and live births from 2006 to 2008. We analyzed stillbirths that underwent complete fetal and placental evaluations and cause of death analysis using the INCODE (Initial Causes of Fetal Death) classification system. Umbilical cord abnormality was defined as cord entrapment (defined as nuchal, body, shoulder cord accompanied by evidence of cord occlusion on pathologic examination); knots, torsions, or strictures with thrombi, or other obstruction by pathologic examination; cord prolapse; vasa previa; and compromised fetal microcirculation, which is defined as a histopathologic finding that represents objective evidence of vascular obstruction and can be used to indirectly confirm umbilical cord abnormalities when suspected as a cause for stillbirth. We compared demographic and clinical factors between women with stillbirths associated with umbilical cord abnormalities and those associated with other causes, as well as with live births. Secondarily, we analyzed the subset of pregnancies with a low umbilical cord index. Results Of 496 stillbirths with complete cause of death analysis by INCODE, 94 (19%, 95% CI 16-23%) were associated with umbilical cord abnormality. Forty-five (48%) had compromised fetal microcirculation, 27 (29%) had cord entrapment, 26 (27%) knots, torsions, or stricture, and five (5%) had cord prolapse. No cases of vasa previa occurred. With few exceptions, maternal characteristics were similar between umbilical cord abnormality stillbirths and non-umbilical cord abnormality stillbirths and between umbilical cord abnormality stillbirths and live births, including among a subanalysis of those with hypo-coiled umbilical cords. Conclusion Umbilical cord abnormalities are an important risk factor for stillbirth, accounting for 19% of cases, even when using rigorous criteria. Few specific maternal and clinical characteristics were associated with risk.

Background Oligohydramnios is a condition of abnormally low amniotic fluid volume that has been associated with poor pregnancy outcomes. To date, the prevalence of this condition and its outcomes has not been well described in low and low-middle income countries (LMIC) where ultrasound use to diagnose this condition in pregnancy is limited. As part of a prospective trial of ultrasound at antenatal care in LMICs, we sought to evaluate the incidence of and the adverse maternal, fetal and neonatal outcomes associated with oligohydramnios. Methods We included data in this report from all pregnant women in community settings in Guatemala, Pakistan, Zambia and the Democratic Republic of Congo (DRC) who received a third trimester ultrasound as part of the First Look Study, a randomized trial to assess the value of ultrasound at antenatal care. Using these data, we conducted a planned secondary analysis to compare pregnancy outcomes of women with to those without oligohydramnios. Oligohydramnios was defined as measurement of an Amniotic Fluid Index less than 5 cm in at least one ultrasound in the third trimester. The outcomes assessed included maternal morbidity and fetal and neonatal mortality, preterm birth and low-birthweight. We used pairwise site comparisons with Tukey-Kramer adjustment and multivariable logistic models using general estimating equations to account for the correlation of outcomes within cluster. Results Of 12,940 women enrolled in the clusters in Guatemala, Pakistan, Zambia and the DRC in the First Look Study who had a third trimester ultrasound examination, 87 women were diagnosed with oligohydramnios, equivalent to 0.7% of those studied. Prevalence of detected oligohydramnios varied among study sites; from the lowest of 0.2% in Zambia and the DRC to the highest of 1.5% in Pakistan. Women diagnosed with oligohydramnios had higher rates of hemorrhage, fetal malposition, and cesarean delivery than women without oligohydramnios. We also found unfavorable fetal and neonatal outcomes associated with oligohydramnios including stillbirths (OR 5.16, 95%CI 2.07, 12.85), neonatal deaths Conclusions Oligohydramnos was associated with worse neonatal, fetal and maternal outcomes in LMIC. Further research is needed to assess effective interventions to diagnose and ultimately to reduce poor outcomes in these settings. Trial registration NCT01990625.

Objectives To assess deviations in longitudinally measured cytokines with preterm birth (PTB). Methods Prospective longitudinal study targeting 80 subjects. Phlebotomy specimens for broad panel of cytokine analysis were obtained at three time (T) intervals: first trimester (T1: 8–14 weeks’ gestation), second trimester (T2: 18–22 weeks’ gestation), and third trimester (T3: 28–32 weeks’ gestation). Important demographics and outcomes were tracked. Data were stratified and the target groups were analyzed as follows: “Uncomplicated” (delivered ≥37 weeks) or “Preterm Birth” ( Results Complete data replete with phlebotomy at all three visits were obtained on 80 women. Birth outcomes were as follows: 11 Uncomplicated Term Birth (UTB), 28 PTB, 4 low birth weight (LBW), 16 OB complications (OBC), 11 current infections (IFN), and 10 mixed complications (MC=2 or more of the above). 28 PTB were compared to 11 uncomplicated term deliveries. In both groups, T helper type 1 (TH1) cytokine (IL-1β), pleiotrophic pro-inflammatory cytokine (IL-6), and counter-regulatory cytokine (IL-10) responses decreased over gestation, but rates of change in IL-1β, IL-6, and IL-10 were significantly different. Stratification of women by smoking status additionally demonstrated significant variance in immune status over the course of pregnancy Conclusions Women delivering PTB demonstrated significant differences in cytokine trajectory over pregnancy; these data further validate key role played by immune regulation in directing pregnancy outcome. Likewise, smoking impacts longitudinal trajectory of cytokines over pregnancy.

Globally, more than 5 million stillbirths and neonatal deaths occur annually. For many, the cause of death (CoD) is unknown. Minimally invasive tissue sampling (MITS) has been increasingly used in postmortem examinations for ascertaining the CoD in stillbirths and neonates. Our study compared the counseling and consent methods used in MITS projects in five countries in Africa and south Asia. Key informant interviews were conducted with researchers to describe the characteristics and backgrounds of counselors, the environment and timing of consent and perceived facilitators and barriers encountered during the consent process. Counselors at all sites had backgrounds in social science, psychology and counseling or clinical expertise in obstetrics/gynecology or pediatrics. All counsellors received training about techniques for building rapport and offering emotional support to families; training duration and methods differed across sites. Counselling environments varied significantly; some sites allocated a separate room, others counselled families at the bedside or nursing stations. All counsellors had a central role in explaining the MITS procedure to families in their local languages. Most sites did not use visual aids during the process, relying solely on verbal descriptions. In most sites, parents were approached within one hour of death. The time needed for decision making by families varied from a few minutes to 24 h. In most sites, extended family took part in the decision making. Because many parents wanted burial as soon as possible, counsellors ensured that MITS would be conducted promptly after receiving consent. Barriers to consent included decreased comprehension of information due to the emotional and psychological impact of grief. Moreover, having more family members engaged in decision-making increased the complexity of counselling and achieving consensus to consent for the procedure. While each site adapted their approach to fit the context, consistencies and similarities across sites were observed.

Background The objectives of this analysis were to document trends in and risk factors associated with the cesarean birth rate in low- and middle-income country sites participating in the Global Network for Women’s and Children’s Health Research (Global Network). Methods This is a secondary analysis of a prospective, population-based study of home and facility births conducted in the Global Network sites. Results Cesarean birth rates increased uniformly across all sites between 2010 and 2018. Across all sites in multivariable analyses, women younger than age twenty had a reduced risk of cesarean birth (RR 0.9 [0.9, 0.9]) and women over 35 had an increased risk of cesarean birth (RR 1.1 [1.1, 1.1]) compared to women aged 20 to 35. Compared to women with a parity of three or more, less parous women had an increased risk of cesarean (RR 1.2 or greater [1.2, 1.4]). Four or more antenatal visits (RR 1.2 [1.2, 1.3]), multiple pregnancy (RR 1.3 [1.3, 1.4]), abnormal progress in labor (RR 1.1 [1.0, 1.1]), antepartum hemorrhage (RR 2.3 [2.0, 2.7]), and hypertensive disease (RR 1.6 [1.5, 1.7]) were all associated with an increased risk of cesarean birth, p Conclusion Cesarean birth rates continue to rise within the Global Network. The proportions of cesarean birth are higher among women with no history of cesarean birth in the African sites and among women with primary elective cesarean, primary cesarean after induction, and repeat cesarean in the non-African sites.

Background Nulliparity has been associated with lower birth weight (BW) and other adverse pregnancy outcomes, with most of the data coming from high-income countries. In this study, we examined birth weight for gestational age z-scores and neonatal (28-day) mortality in a large prospective cohort of women dated by first trimester ultrasound from multiple sites in low and middle-income countries. Methods Pregnant women were recruited during the first trimester of pregnancy and followed through 6 weeks postpartum from Maternal Newborn Health Registry (MNHR) sites in the Democratic Republic of Congo (DRC), Guatemala, Belagavi and Nagpur, India, and Pakistan from 2017 and 2018. Data related to the pregnancy and its outcomes were collected prospectively. First trimester ultrasound was used for determination of gestational age; (BW) was obtained in grams within 48 h of delivery and later transformed to weight for age z-scores (WAZ) adjusted for gestational age using the INTERGROWTH-21st standards. Results 15,121 women were eligible and included. Infants of nulliparous women had lower mean BWs (males: 2676 gr, females: 2587 gr, total: 2634 gr) and gestational age adjusted weight for age z-scores (males: − 0.73, females: − 0.77, total: − 0.75,) than women with one or more previous pregnancies. The largest differences were between zero and one previous pregnancies among female infants. The associations of parity with BW and z-scores remained even after adjustment for maternal age, maternal height, maternal education, antenatal care visits, hypertensive disorders, and socioeconomic status. Nulliparous women also had a significantly higher Conclusions In this large sample from diverse settings, nulliparity was independently associated with both lower BW and WAZ scores as well as higher neonatal mortality compared to multiparity.

South Asia has >50% of the global burden of low birth weight (LBW). The objective was to determine the extent to which maternal nutrition interventions commenced before conception or in the 1st trimester improved fetal growth in this region. This was a secondary analysis of combined newborn anthropometric data for the South Asian sites (India and Pakistan) in the Women First Preconception Maternal Nutrition Trial. Participants were 972 newborn of mothers who were poor, rural, unselected on basis of nutritional status, and had been randomized to receive a daily lipid-based micronutrient supplement commencing ≥3 months prior to conception (Arm 1), in the 1st trimester (Arm 2), or not at all (Arm 3). An additional protein-energy supplement was provided if BMI

OBJECTIVE: To better characterize infection stillbirth in terms of pathogenesis and microbiology. METHODS: We conducted a secondary analysis of 512 stillbirths in a prospective, multisite, geographically, racially and ethnically diverse, population-based study of stillbirth in the United States. Cases underwent evaluation that included maternal interview, chart abstraction, biospecimen collection, fetal autopsy, and placental pathology. Recommended evaluations included syphilis and parvovirus serology. Each case was assigned probable and possible causes of death using the INCODE Stillbirth Classification System. Cases where infection was assigned as a probable or possible cause of death were reviewed. For these cases, clinical scenario, autopsy, maternal serology, culture results and placental pathology were evaluated. RESULTS: For 66 (12.9%) cases of stillbirth, infection was identified as a probable or possible cause of death. Of these, 36% (95% CI 35% - 38%) were categorized as a probable and 64% (95% CI 62% - 65%) as a possible cause of death. Infection-related stillbirth occurred earlier than non-infection related stillbirth (median gestational age 22 weeks vs 28 weeks, p= 0.001). Fetal bacterial culture results were available in 47 cases (71%), of which 35 (53%) grew identifiable organisms. The predominant species were Escherichia coli (19; 29%), group B streptococcus (8; 12%), and enterococcus (8; 12%). Placental pathology revealed chorioamnionitis in 50 (76%), funisitis in 27 (41%), villitis in 11 (17%), deciduitis in 35 (53%), necrosis in 27 (41%), and viral staining in 7 (11%) cases. Placental pathology found inflammation or evidence of infection in 65 (99%) cases and fetal autopsy in 26 (39%) cases. In infection stillbirth cases, the likely causative non-bacterial organisms identified were parvovirus in 2 (3%) cases, syphilis in 1 (2%) case, cytomegalovirus in 5 (8%) cases and herpes in 1 (2%) case. CONCLUSIONS: Of infection-related stillbirth cases in a large U.S. cohort, E. coli, group B streptococcus and enterococcus were the most common bacterial pathogens and cytomegalovirus the most common viral pathogen.

Antenatal corticosteroids are standard of care for pregnancies at risk of preterm delivery between 24-34 weeks' gestational age. Recent trials demonstrate modest benefits from antenatal corticosteroids for late preterm and elective cesarean deliveries, and antenatal corticosteroids for periviable deliveries should be considered with family discussion. However, many women with threatened preterm deliveries receive antenatal corticosteroids but do not deliver until >34 weeks or at term. The net effect is that a substantial fraction of the delivery population will be exposed to antenatal corticosteroids. There are gaps in accurate assessments of benefits of antenatal corticosteroids because the randomized controlled trials were performed prior to about 1990 in pregnancies generally >28 weeks. The care practices for the mother and infant survival were different than today. The randomized controlled trial data also do not strongly support the optimal interval from antenatal corticosteroid treatment to delivery of 1-7 days. Epidemiology-based studies using large cohorts with >85% of at-risk pregnancies treated with antenatal corticosteroids probably overestimate the benefits of antenatal corticosteroids. Although most of the prematurity-associated mortality is in low-resource environments, the efficacy and safety of antenatal corticosteroids in those environments remain to be evaluated. The short-term benefits of antenatal corticosteroids for high-risk pregnancies in high-resource environments certainly justify antenatal corticosteroids as few risks have been identified over many years. However, cardiovascular and metabolic abnormalities have been identified in large animal models and cohorts of children exposed to antenatal corticosteroids that are consistent with fetal programming for adult diseases. These late effects of antenatal corticosteroids suggest caution for the expanded use of antenatal corticosteroids beyond at-risk pregnancies at 24-34 weeks. A way forward is to develop noninvasive fetal assessments to identify pregnancies across a wider gestational age that could benefit from antenatal corticosteroids.

Preterm birth remains a common cause of neonatal mortality, with a disproportionately high burden in low-income and middle-income countries. Meta-analyses of low-dose aspirin to prevent pre-eclampsia suggest that the incidence of preterm birth might also be decreased, particularly if initiated before 16 weeks of gestation.ASPIRIN was a randomised, multicountry, double-masked, placebo-controlled trial of low-dose aspirin (81 mg daily) initiated between 6 weeks and 0 days of pregnancy, and 13 weeks and 6 days of pregnancy, in nulliparous women with an ultrasound confirming gestational age and a singleton viable pregnancy. Participants were enrolled at seven community sites in six countries (two sites in India and one site each in the Democratic Republic of the Congo, Guatemala, Kenya, Pakistan, and Zambia). Participants were randomly assigned (1:1, stratified by site) to receive aspirin or placebo tablets of identical appearance, via a sequence generated centrally by the data coordinating centre at Research Triangle Institute International (Research Triangle Park, NC, USA). Treatment was masked to research staff, health providers, and patients, and continued until 36 weeks and 7 days of gestation or delivery. The primary outcome of incidence of preterm birth, defined as the number of deliveries before 37 weeks' gestational age, was analysed in randomly assigned women with pregnancy outcomes at or after 20 weeks, according to a modified intention-to-treat (mITT) protocol. Analyses of our binary primary outcome involved a Cochran-Mantel-Haenszel test stratified by site, and generalised linear models to obtain relative risk (RR) estimates and associated confidence intervals. Serious adverse events were assessed in all women who received at least one dose of drug or placebo. This study is registered with ClinicalTrials.gov, NCT02409680, and the Clinical Trial Registry-India, CTRI/2016/05/006970.From March 23, 2016 to June 30, 2018, 14 361 women were screened for inclusion and 11 976 women aged 14-40 years were randomly assigned to receive low-dose aspirin (5990 women) or placebo (5986 women). 5780 women in the aspirin group and 5764 in the placebo group were evaluable for the primary outcome. Preterm birth before 37 weeks occurred in 668 (11·6%) of the women who took aspirin and 754 (13·1%) of those who took placebo (RR 0·89 [95% CI 0·81 to 0·98], p=0·012). In women taking aspirin, we also observed significant reductions in perinatal mortality (0·86 [0·73-1·00], p=0·048), fetal loss (infant death after 16 weeks' gestation and before 7 days post partum; 0·86 [0·74-1·00], p=0·039), early preterm delivery (34 weeks; 0·75 [0·61-0·93], p=0·039), and the incidence of women who delivered before 34 weeks with hypertensive disorders of pregnancy (0·38 [0·17-0·85], p=0·015). Other adverse maternal and neonatal events were similar between the two groups.In populations of nulliparous women with singleton pregnancies from low-income and middle-income countries, low-dose aspirin initiated between 6 weeks and 0 days of gestation and 13 weeks and 6 days of gestation resulted in a reduced incidence of preterm delivery before 37 weeks, and reduced perinatal mortality.Eunice Kennedy Shriver National Institute of Child Health and Human Development.

The objective of this secondary analysis was to identify maternal characteristics that modified the effect of maternal supplements on newborn size. Participants included 1465 maternal&ndash, newborn dyads in Guatemala, India, and Pakistan. Supplementation commenced before conception (Arm 1) or late 1st trimester (Arm 2), Arm 3 received usual care. Characteristics included body mass index (BMI), stature, anemia, age, education, socio-economic status (SES), parity, and newborn sex. Newborn outcomes were z-scores for length (LAZ), weight (WAZ), and weight to length ratio-for-age (WLRAZ). Mixed-effect regression models included treatment arm, effect modifier, and arm * effect modifier interaction as predictors, controlling for site, characteristics, and sex. Parity (para-0 vs. para &ge, 1), anemia (anemia/no anemia), and sex were significant effect modifiers. Effect size (95% CI) for Arm 1 vs. 3 was larger for para-0 vs. &ge, 1 for all outcomes (LAZ 0.56 (0.28, 0.84, p &lt, 0.001), WAZ 0.45 (0.20, 0.07, p &lt, WLRAZ 0.52 (0.17, 0.88, p &lt, 0.01) but only length for Arm 2 vs. 3. Corresponding effects for para &ge, 1 were &gt, 0.02. Arm 3 z-scores were all very low for para-0, but not para &ge, 1. Para-0 and anemia effect sizes for Arm 1 were &gt, Arm 2 for WAZ and WLRAZ, but not LAZ. Arm 1 and 2 had higher WAZ for newborn boys vs. girls. Maternal nulliparity and anemia were associated with impaired fetal growth that was substantially improved by nutrition intervention, especially when commenced prior to conception.

The Jawaharlal Nehru Medical College (JNMC) Women’s and Children’s Health Research Unit (WCHRU) of the Karnataka Lingayat Education (KLE) Academy of Higher Education and Research Deemed-to-be-University and its collaborators convened the ‘2nd International Conference on Maternal and Newborn Health -Translating Research Evidence to Practice’ to address the common theme of improving maternal and newborn health in low- and middle- income countries (LMIC). This supplement, including 16 manuscripts, reflects much of the research presented at the conference, including analyses of the state of knowledge, as well as completed, ongoing and planned research in these areas conducted by the WCHRU in India together with many collaborators across high-income and LMIC. The first paper reviews maternal, fetal and neonatal mortality in low-income countries, considers their causes, as well as evidence for potential interventions to reduce mortality. A second paper addresses near miss maternal mortality. Several manuscripts address the research conducted by WCHRU and their colleagues in a multi-center research network. One study examines rates of miscarriage and medically terminated pregnancy in India and the risk factors for these occurrences. Another paper addresses stillbirth and its risk factors, both in India as well as in other LMIC. Haemorrhage and preeclampsia/eclampsia, important causes of maternal mortality, stillbirth and neonatal morbidity in LMIC, are addressed in a series of papers summarizing trials of interventions to reduce improve outcomes associated with these conditions. Poor maternal and infant nutritional status, which contribute to adverse outcomes, are addressed through papers which describe a number of important studies that the WCHRU and their colleagues have conducted to attempt to improve nutritional status. Another paper describes a study to investigate causes of stillbirth and deaths among preterm births, which will utilize new techniques to investigate the infectious causes of these deaths. Finally, the supplement addresses the process for dissemination of research results to inform public policy. Together these manuscripts represent a body of research to inform interventions to reduce maternal, fetal and newborn mortality and illustrates what a dedicated research group together with institutional support can accomplish.

Background Stillbirth rates remain high, especially in low and middle-income countries, where rates are 25 per 1000, ten-fold higher than in high-income countries. The United Nations’ Every Newborn Action Plan has set a goal of 12 stillbirths per 1000 births by 2030 for all countries. Methods From a population-based pregnancy outcome registry, including data from 2010 to 2016 from two sites each in Africa (Zambia and Kenya) and India (Nagpur and Belagavi), as well as sites in Pakistan and Guatemala, we evaluated the stillbirth rates and rates of annual decline as well as risk factors for 427,111 births of which 12,181 were stillbirths. Results The mean stillbirth rates for the sites were 21.3 per 1000 births for Africa, 25.3 per 1000 births for India, 56.9 per 1000 births for Pakistan and 19.9 per 1000 births for Guatemala. From 2010 to 2016, across all sites, the mean stillbirth rate declined from 31.7 per 1000 births to 26.4 per 1000 births for an average annual decline of 3.0%. Risk factors for stillbirth were similar across the sites and included maternal age 35 years. Compared to parity 1–2, zero parity and parity > 3 were both associated with increased stillbirth risk and compared to women with any prenatal care, women with no prenatal care had significantly increased risk of stillbirth in all sites. Conclusions At the current rates of decline, stillbirth rates in these sites will not reach the Every Newborn Action Plan goal of 12 per 1000 births by 2030. More attention to the risk factors and treating the causes of stillbirths will be required to reach the Every Newborn Action Plan goal of stillbirth reduction. Trial registration NCT01073475.