Zinc Supplementation Initiated Prior to or During Pregnancy Modestly Impacted Maternal Status and High Prevalence of Hypozincemia in Pregnancy and Lactation: The Women First Preconception Maternal Nutrition Trial.

BACKGROUND: Data regarding effects of small-quantity-lipid-based nutrient supplements (SQ-LNS) on maternal serum zinc concentrations (SZC) in pregnancy and lactation are limited. OBJECTIVES: The objectives of this study were to evaluate the effect of preconception compared with prenatal zinc supplementation (compared with control) on maternal SZC and hypozincemia during pregnancy and early lactation in women in low-resource settings, and assess associations with birth anthropometry. METHODS: From ∼100 women/arm at each of 3 sites (Guatemala, India, and Pakistan) of the Women First Preconception Maternal Nutrition trial, we compared SZC at 12- and 34-wk gestation (n = 651 and 838, respectively) and 3-mo postpartum (n = 742) in women randomly assigned to daily SQ-LNS containing 15 mg zinc from ≥3 mo before conception (preconception, arm 1), from ∼12 wk gestation through delivery (early pregnancy, arm 2) or not at all (control, arm 3). Birth anthropometry was examined for newborns with ultrasound-determined gestational age. Statistical analyses were performed separately for each time point. RESULTS: At 12-wk gestation and 3-mo postpartum, no statistical differences in mean SZC were observed among arms. At 34-wk, mean SZC for arms 1 and 2 were significantly higher than for arm 3 (50.3, 50.8, 47.8 µg/dL, respectively; P = 0.005). Results were not impacted by correction for inflammation or albumin concentrations. Prevalence of hypozincemia at 12-wk (<56 µg/dL) was 23% in Guatemala, 26% in India, and 65% in Pakistan; at 34 wk (<50 µg/dL), 36% in Guatemala, 48% in India, and 74% in Pakistan; and at 3-mo postpartum (<66 µg/dL) 79% in Guatemala, 91% in India, and 92% in Pakistan. Maternal hypozincemia at 34-wk was associated with lower birth length-for-age Z-scores (all sites P = 0.013, Pakistan P = 0.008) and weight-for-age Z-scores (all sites P = 0.017, Pakistan P = 0.022). CONCLUSIONS: Despite daily zinc supplementation for ≥7 mo, high rates of maternal hypozincemia were observed. The association of hypozincemia with impaired fetal growth suggests widespread zinc deficiency in these settings. This trial is registered at clinicaltrials.gov as #NCT01883193.

RAPIDIRON Trial follow-up study - the RAPIDIRON-KIDS Study: protocol of a prospective observational follow-up study.

BACKGROUND: Anemia is a worldwide problem with iron deficiency being the most common cause. When anemia occurs in pregnancy, it increases the risk of adverse maternal, fetal, and postnatal outcomes. It induces preterm births and low birth weight (LBW) deliveries, long-term neurodevelopmental sequelae, and an increased risk of earlier onset of postnatal iron deficiency. Anemia rates are among the highest in South Asia, and India's National Family Health Survey (NFHS-5) for 2019-2021 indicated that over half of pregnant women, and more than 65% of children, in the country are classified as anemic (Sciences IIfP, National Family Health Survey-5, 2019-21, India Fact Sheet). In 2021, the parent RAPIDIRON Trial (Derman et al., Trials 22:649, 2021) was initiated in two states in India, with the goal of assessing whether a dose of intravenous (IV) iron given to anemic women during early pregnancy results in a greater proportion of participants with normal hemoglobin concentrations in the third trimester and a lower proportion of participants with LBW deliveries compared to oral iron. As a follow-up to the RAPIDIRON Trial, the RAPIDIRON-KIDS Study will follow the offspring of previously randomized mothers to assess, neurobehavioral, hematological, and health outcomes. METHODS: This prospective observational cohort study will follow a subset of participants previously randomized as part of the RAPIDIRON Trial and their newborns. Study visits occur at birth, 6 weeks, 4 months, 12 months, 24 months, and 36 months and include blood sample collection with both maternal and infant participants and specific neurobehavioral assessments conducted with the infants (depending on the study visit). The primary outcomes of interest are (1) infant iron status as indicated by both hemoglobin and ferritin (a) at birth and (b) at 4 months of age and (2) the developmental quotient (DQ) for the cognitive domain of the Bayley Scales of Infant Development Version IV (BSID-IV) at 24 months of age. DISCUSSION: This RAPIDIRON-KIDS Study builds upon its parent RAPIDIRON Trial by following a subset of the previously randomized participants and their offspring through the first 3 years of life to assess neurodevelopmental and neurobehavioral (infants, children), hematological, and health outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05504863 , Registered on 17 August 2022. Clinical Trials Registry - India CTRI/2022/05/042933 . Registered on 31 May 2022.

Pathophysiology and management of iron deficiency anaemia in pregnancy: a review.

According to World Health Organization (WHO), iron deficiency anaemia (IDA) is considered the most prevalent nutritional deficiency worldwide, affecting approximately 30% of the global population. While gastrointestinal bleeding and menstruation in women are the primary causes of IDA, insufficient dietary iron intake and reduced iron absorption contribute to the condition. The aim of IDA treatment is to restore iron stores and normalise haemoglobin levels in affected patients. Iron plays a critical role in various cellular mechanisms, including oxygen delivery, electron transport, and enzymatic activity. During pregnancy, the mother's blood volume increases, and the growing foetus requires a significant increase in iron. Iron deficiency during pregnancy is associated with adverse outcomes such as maternal illness, low birth weight, preterm birth, and intrauterine growth restriction. Iron supplementation is commonly used to treat IDA; however, not all patients benefit from this therapy due to factors such as low compliance and ineffectiveness. In the past, IV iron therapy was underutilised due to its unfavourable and occasionally unsafe side effects. Nevertheless, the development of new type II and III iron complexes has improved compliance, tolerability, efficacy, and safety profiles. This article aims to provide an updated overview of the diagnosis and management of IDA during pregnancy. It will discuss the advantages and limitations of oral versus intravenous iron and the pathophysiology, diagnosis, treatment, and overall management of IDA in pregnancy.

Placental inflammation and pregnancy outcomes: A prospective, observational study in South Asia: The PURPOSe study.

OBJECTIVE: To examine inflammatory lesions in placentas of stillbirths, preterm neonatal deaths and term controls in India and Pakistan. DESIGN: Prospective, observational study. SETTING: Three hospitals in India and a large maternity hospital in Pakistan. POPULATION: The enrolled participants with placentas available for histology evaluation included stillbirths (n = 814), preterm live births who died within 28 days of birth (n = 618) and term live birth controls (n = 201). From this same population, polymerase chain reaction (PCR) analysis for pathogens was performed on 809 stillbirth placentas, 614 neonatal death placentas and the placentas of 201 term controls. Placentas from preterm infants who lived beyond day 28 (n = 1432) were only available from India. METHODS: A prospective observational study of placental inflammatory lesions defined by the Amsterdam criteria and on the same placentas, multiplex PCR evaluation for 75 pathogens using TaqMan Array Cards. MAIN OUTCOME MEASURES: Any placental inflammatory lesions, including chorioamnionitis, funisitis, villitis and intervillitis and their association with various pathogens. RESULTS: In the Indian liveborn preterm infants, placental inflammation of any kind was present in 26.2% of those who died versus 16.6% of those who lived (p = 0.0002). Chorioamnionitis was present in 25.8% of those who died versus 16.3% of those who lived (p = 0.0002) and funisitis was present in 4.1% of those who died versus 1.5% of those who lived, (p = 0.005). Across all three sites, in the placentas of the 201 term controls, 18.9% had any inflammation, 16.9% had chorioamnionitis, 5.5% had funisitis, 0.5% had intervillitis and none had villitis. Overall, for stillbirths, any inflammation was observed in 30.2%, chorioamnionitis in 26.9%, funisitis in 5.7%, intervillitis in 6.0% and villitis in 2.2%. For the neonatal deaths, any inflammation was present in 24.9%, chorioamnionitis in 23.3%, funisitis in 8.1%, intervillitis in 1.9% and villitis in 0.5%. Compared with the placentas of term controls, in neonatal deaths, only chorioamnionitis was significantly increased (23.3% versus 16.9%, p = 0.05). Among stillbirths, the rates of any inflammation, chorioamnionitis, intervillitis and villitis were similar across the birthweight groups. However, funisitis was more common in the placentas of stillborn fetuses weighing 2500 g or more (13.8%) compared with 1.0% for those weighing less than 1000 g and 4.8% for stillborn fetuses weighing 1000-2499 g. In the PCR studies, Ureaplasma spp. were by far the most common pathogens found and generally were more commonly found in association with inflammatory lesions. CONCLUSIONS: Chorioamnionitis was the most common type of placental inflammatory lesion regardless of whether the placentas evaluated were from term controls, stillbirths or neonatal deaths. For stillbirths, inflammation in each inflammation category was more common than in the term controls and significantly more so for any inflammation, chorioamnionitis, intervillitis and villitis. For neonatal deaths, compared with the placentas of term controls, all inflammation categories were more common, but only significantly so for chorioamnionitis. Ureaplasma spp. were the most common organisms found in the placentas and were significantly associated with inflammation.

Group B streptococcal prevalence in internal organs and placentas of deceased neonates and stillbirths in South Asia.

OBJECTIVE: Group B streptococcus (GBS) has been associated with adverse pregnancy outcomes, but few prospective studies have assessed its prevalence in low- and middle-income country settings. We sought to evaluate the prevalence of GBS by polymerase chain reaction (PCR) in internal organ tissues and placentas of deceased neonates and stillbirths. DESIGN: This was a prospective, observational study. SETTING: The study was conducted in hospitals in India and Pakistan. POPULATION: Pregnant women with stillbirths or preterm births were recruited at delivery, as was a group of women with term, live births, to serve as a control group. METHODS: A rectovaginal culture was collected from the women in Pakistan to assess GBS carriage. Using PCR, we evaluated GBS in various tissues of stillbirths and deceased neonates and their placentas, as well as the placentas of live-born preterm and term control infants. MAIN OUTCOME MEASURES: GBS identified by PCR in various tissues and the placentas; rate of stillbirths and 28-day neonatal deaths. RESULTS: The most obvious finding from this series of analyses from India and Pakistan was that no matter the country, the condition of the subject, the tissue studied or the methodology used, the prevalence of GBS was low, generally ranging between 3% and 6%. Among the risk factors evaluated, only GBS positivity in primigravidae was increased. CONCLUSIONS: GBS diagnosed by PCR was identified in <6% of internal organs of stillbirths and neonatal deaths, and their placentas, and control groups in South Asian sites. This is consistent with other reports from South Asia and is lower than the reported GBS rates from the USA, Europe and Africa.

Morphological study of the placenta in deliveries with pre-eclampsia: Results from a prospective, observational study in India and Pakistan (PURPOSe).

OBJECTIVE: To compare placental findings in women with and without pre-eclampsia. DESIGN: The PURPOSe study included women with stillbirths, women with preterm births and women at term as controls. The placenta of each case was evaluated using the Amsterdam criteria. SETTING: Two sites and five tertiary care hospitals of south Asia (Three in India and two in Pakistan). POPULATION: Pregnancies in India and Pakistan with placental histology including women with documented hypertension and documented proteinuria and women with neither hypertension nor proteinuria. METHODS: We compared the placental findings of the two groups using the Amsterdam criteria and further evaluated the placental findings in women with and without pre-eclampsia who had a stillbirth, preterm live birth, or term live birth (control). MAIN OUTCOME MEASURES: The main outcome measures were the frequency of maternal and fetal vascular malperfusion and the frequency of placental inflammation and its components, chorioamnionitis, funisitis, villitis and intervillitis in women with and without pre-eclampsia. RESULTS: A total of 733 women had pre-eclampsia and 2334 women had neither hypertension nor proteinuria. In the placentas of women with pre-eclampsia, 57.3% had maternal vascular malperfusion compared with 37.1% in women without pre-eclampsia (p < 0.0001). There was not a significant difference in the prevalence of fetal vascular hypertension between mothers with (17.1%) and without (14.8%, p = 0.6118) pre-eclampsia. When placentas were classified as 'histologically normal' or not, 61.3% of those from pre-eclamptic pregnancies were classified as abnormal, whereas if there was no pre-eclampsia, only 45.0% were classified as histologically abnormal (p < 0.0001). We also considered rates of placental maternal vascular malperfusion in women with and without pre-eclampsia with stillbirth, preterm neonatal death, and term live birth. In women at term with no pre-eclampsia, 16.7% of the placentas had features of maternal vascular malperfusion. This occurred in 79.9% of women with stillbirths with pre-eclampsia compared with 51.8% of those without pre-eclampsia. Maternal vascular malperfusion was present in 49.7% of preterm live births with pre-eclampsia compared with 33.8% without pre-eclampsia. We also evaluated the inflammatory lesions by whether the mother had or did not have pre-eclampsia. When all inflammatory lesions were considered, women with pre-eclampsia had significantly fewer inflammatory lesions than those women without pre-eclampsia (17.1% versus 23.6% p = 0.001). Each of the specific inflammatory lesions was less common in placentas of women with pre-eclampsia than those with chorioamnionitis (16.1% versus 21.9%, p = 0.004) and funisitis (1.5% versus. 5.1%, p = 0.0004). CONCLUSIONS: Of placental lesions in women with pre-eclampsia, maternal vascular malperfusion was the most common. Inflammatory lesions were less common in women with pre-eclampsia.

The PURPOSe cause of death study in stillbirths and neonatal deaths in India and Pakistan: A review.

The PURPOSe study was a prospective, observational study conducted in India and Pakistan to determine the cause of death for stillbirths and preterm neonatal deaths, using clinical data together with minimally invasive tissue sampling (MITS) and the histologic and polymerase chain reaction (PCR) evaluation of fetal/neonatal tissues and the placenta. After evaluating all available data, an independent panel chose a maternal, a placental and a fetal/neonatal cause of death. Here, we summarise the major results. Among the most important findings were that most stillbirths were caused by fetal asphyxia, often preceded by placental malperfusion, and clinically associated with pre-eclampsia, placental abruption and a small-for-gestational-age fetus. The preterm neonatal deaths were primarily caused by birth asphyxia, followed by various infections. An important finding was that many of the preterm neonatal deaths were caused by a nosocomial infection acquired after neonatal intensive care (NICU) admission; the most common organisms were Acinetobacter baumannii, followed by Klebsiella pneumoniae, Escherichia coli/Shigella and Haemophilus influenzae. Group B streptococcus was less commonly present in the placentas or internal organs of the neonatal deaths.

Associations between ambient temperature and pregnancy outcomes from three south Asian sites of the Global Network Maternal Newborn Health Registry: A retrospective cohort study.

OBJECTIVE: Growing evidence suggests that environmental heat stress negatively influences fetal growth and pregnancy outcomes. However, few studies have examined the impact of heat stress on pregnancy outcomes in low-resource settings. We combined data from a large multi-country maternal-child health registry and meteorological data to assess the impacts of heat stress. DESIGN: Retrospective cohort study. SETTING: Three sites based in south Asia as part of the Global Network for Women's and Children's Health research in India (Belagavi and Nagpur) and Pakistan (Thatta). POPULATION OR SAMPLE: Data from women enrolled between 2014 and 2020 in the Global Network's Maternal Newborn Health Registry (MNHR), a prospective, population-based registry of pregnancies, were used. METHODS: A total of 126 273 pregnant women were included in this analysis. Daily maximal air temperatures (Tmax ) were acquired from local meteorological records. Associations between averages of daily maximal temperatures for each trimester and main outcomes were analysed using a modified Poisson regression approach. MAIN OUTCOMES MEASURES: Incidence of stillbirth, preterm birth, low birthweight (<2500 g) or evidence of pregnancy hypertension or pre-eclampsia. RESULTS: In the overall cohort, risk of preterm birth was positively associated with greater temperature in the second trimester (relative risk [RR] 1.05, 95% CI 1.02-1.07, p = 0.0002). Among individual sites, the risk of preterm birth was greatest in Nagpur (RR 1.07, 95% CI 1.03-1.11, p = 0.0005) and associated with second-trimester temperature. The overall risk of low birthweight was associated with ambient temperature in second trimester (RR 1.02, 95% CI 1.01-1.04, p = 0.01). The risk for LBW was associated with first-trimester heat in Thatta and with second-trimester heat in Nagpur. Finally, the overall risk of gestational hypertensive disease was associated with greater temperature in the third trimester among all sites (RR 1.07, 95% CI 1.02-1.12, p = 0.005) and was particularly significant for Nagpur (RR 1.13, 95% CI 1.05-1.23, p = 0.002). These findings highlight the increased risk of detrimental obstetric and neonatal outcomes with greater temperature. CONCLUSION: In a multi-country, community-based study, greater risk of adverse outcomes was observed with increasing temperature. The study highlights the need for deeper understanding of covarying factors and intervention strategies, especially in regions where high temperatures are common.

Neonatal mortality among preterm infants admitted to neonatal intensive care units in India and Pakistan: A prospective study.

OBJECTIVE: To explore potential reasons for differences in preterm neonatal mortality in neonatal intensive care units (NICUs) in India and Pakistan. DESIGN: A prospective observational study, the Project to Understand and Research Stillbirth and Preterms in Southeast Asia (PURPOSe) was conducted July 2018 to February 2020. SETTING: Three hospitals in Davangere, India, and a large public hospital in Karachi, Pakistan. POPULATION: Of a total of 3,202 preterm infants enrolled, 1,512 were admitted to a study NICU. METHODS: We collected data for neonates, including length of stay, diagnoses, and diagnostic tests. MAIN OUTCOME MEASURES: Neonatal mortality, tests performed, diagnoses ascertained. RESULTS: For infants of equivalent weights and gestational ages, neonatal mortality in Pakistan was twice that in the Indian NICU. The mean newborn length of stay in Pakistan was 2 days compared with 10 days for India. Fewer diagnostics and other investigations were used to determine neonatal condition or guide treatment in the Pakistani NICU. Because of limited information from testing in Pakistan concerning clinical respiratory distress, respiratory distress syndrome appeared to be over-diagnosed, whereas other conditions including pneumonia, sepsis, necrotising entercolitis and intraventricular haemorrhage were rarely diagnosed. CONCLUSION: In the Pakistani site, the limited resources available to the NICU appeared related to a shorter length of stay and decreased diagnostic testing, likely explaining the higher mortality. With improved care, reduction in mortality among preterm neonates should be achievable.

Pregnancy outcomes in preterm multiple gestations: Results from a prospective study in India and Pakistan (PURPOSe).

OBJECTIVE: To evaluate perinatal outcomes in preterm multiple compared with singleton pregnancies in India and Pakistan. DESIGN: Prospective, observational study. SETTINGS: Study hospitals in India and Pakistan. POPULATION: We evaluated 3897 preterm pregnancies. These mothers gave birth to 3615 (92.8%) singleton infants, 267 (6.8%) sets of twins, 14 (0.4%) sets of triplets and one set of quadruplets. MAIN OUTCOME MEASURES: Neonatal mortality, stillbirth, cause of death. RESULTS: Of the singleton infants, 691 (19.1%) were stillborn and 2924 (80.9%) live born. Of the 534 infants from twin pregnancies, 41 (7.7%) were stillborn and 493 (92.3%) were live born. Of the 267 sets of twins, in 14 cases (5.2%) both were stillborn, in 13 cases (4.8%) one was stillborn and one live born, and in 240 cases (90.0%) both were live born. In both preterm twins and preterm singletons, the three most common causes of death were intrauterine hypoxia, infections acquired prior to birth and infections acquired at or after birth. The preterm twins appeared less likely to have died from intrauterine hypoxia but more likely to have died from infections acquired at or after birth. Respiratory distress syndrome (RDS) was less likely considered by the panel to be the primary cause of death in either the twins (9.6%) or singletons (9.7%). Congenital anomalies were also not often judged to be the cause of death in either the preterm twins 2 (2.4%) or singletons 27 (5.3%). CONCLUSION: In the PURPOSe study, neonatal mortality rates in preterm twins compared with singletons when evaluated by sex, GA, birthweight and SGA, were generally similar to rates of preterm singleton neonatal mortality in those groups. Thus, the higher rate of mortality in live-born twin infants is related to the fact that these infants were more likely to be born earlier rather than to any inherent characteristics of the babies themselves.

COVID-19 symptoms and antibody positivity among unvaccinated pregnant women: An observational study in seven countries from the Global Network.

OBJECTIVE: To determine the relation of COVID-19 symptoms to COVID-19 antibody positivity among unvaccinated pregnant women in low- and middle-income countries (LMIC). DESIGN: COVID-19 infection status measured by antibody positivity at delivery was compared with the symptoms of COVID-19 in the current pregnancy in a prospective, observational cohort study in seven LMICs. SETTING: The study was conducted among women in the Global Network for Women's and Children's Health's Maternal and Newborn Health Registry (MNHR), a prospective, population-based study in Kenya, Zambia, the Democratic Republic of the Congo (DRC), Bangladesh, Pakistan, India (Belagavi and Nagpur sites) and Guatemala. POPULATION: Pregnant women enrolled in the ongoing pregnancy registry at study sites. METHODS: Data on COVID-19 symptoms during the current pregnancy were collected by trained staff between October 2020 and June 2022. COVID-19 antibody testing was performed on samples collected at delivery. The relation between COVID-19 antibody positivity and symptoms was assessed using generalised linear models with a binomial distribution adjusting for site and symptoms. MAIN OUTCOME MEASURES: COVID-19 antibody status and symptoms of COVID-19 among pregnant women. RESULTS: Among 19 218 non-vaccinated pregnant women who were evaluated, 14.1% of antibody-positive women had one or more symptoms compared with 13.4% in antibody-negative women. Overall, 85.3% of antibody-positive women reported no COVID-19 symptoms during the present pregnancy. Reported fever was significantly associated with antibody status (relative risk [RR] 1.10, 95% CI 1.03-11.18; P = 0.008). A multiple variable model adjusting for site and all eight symptoms during pregnancy showed similar results (RR 1.13, 95% CI 1.04-1.23; P = 0.012). None of the other symptoms was significantly related to antibody positivity. CONCLUSIONS: In a population-based cohort in LMICs, unvaccinated pregnant women who were antibody-positive had slightly more symptoms during their pregnancy and a small but significantly greater increase in fever. However, for prevalence studies, evaluating COVID-19-related symptoms does not appear to be useful in differentiating pregnant women who have had a COVID-19 infection.

Aspirin delays the onset of hypertensive disorders of pregnancy among nulliparous pregnant women: A secondary analysis of the ASPIRIN trial.

OBJECTIVE: To assess the impact of low-dose aspirin (LDA) starting in early pregnancy on delaying preterm hypertensive disorders of pregnancy. DESIGN: Non-prespecified secondary analysis of a randomised masked trial of LDA. SETTING: The study was conducted among women in the Global Network for Women's and Children's Health's Maternal and Newborn Health Registry (MNHR) clusters, a prospective, population-based study in Kenya, Zambia, the Democratic Republic of the Congo (DRC), Pakistan, India (two sites-Belagavi and Nagpur) and Guatemala. POPULATION: Nulliparous singleton pregnancies between 6+0 weeks and 13+6 weeks in six low-middle income countries (Democratic Republic of Congo, Guatemala, India, Kenya, Pakistan, Zambia) enrolled in the ASPIRIN Trial. METHODS: We compared the incidence of HDP at delivery at three gestational age periods (<28, <34 and <37 weeks) between women who were randomised to aspirin or placebo. Women were included if they were randomised and had an outcome at or beyond 20 weeks (Modified Intent to Treat). MAIN OUTCOME MEASURES: Our primary outcome was pregnancies with HDP associated with preterm delivery (HDP@delivery) before <28, <34 and <37 weeks. Secondary outcomes included small for gestational age (SGA) <10th percentile, <5th percentile, and perinatal mortality. RESULTS: Among the 11 976 pregnancies, LDA did not significantly lower HDP@delivery <28 weeks (relative risk [RR] 0.18, 95% confidence interval [CI] 0.02-1.52); however, it did lower HDP@delivery <34 weeks (RR 0.37, 95% CI 0.17-0.81) and HDP@delivery <37 weeks (RR 0.66, 95% CI 0.49-0.90). The overall rate of HDP did not differ between the two groups (RR 1.08, 95% CI 0.94-1.25). Among those pregnancies who had HDP, SGA <10th percentile was reduced (RR 0.81, 95% CI 0.67-0.99), though SGA <5th percentile was not (RR 0.84, 95% CI 0.64-1.09). Similarly, perinatal mortality among pregnancies with HDP occurred less frequently (RR 0.55, 95% CI 0.33-0.92) in those receiving LDA. Pregnancies randomised to LDA delivered later with HDP compared with those receiving placebo (median gestational age 38.5 weeks vs. 37.9 weeks; p = 0.022). CONCLUSIONS: In this secondary analysis of a study of low-risk nulliparous singleton pregnancies, early administration of LDA resulted in lower rates of preterm HDP and delivery before 34 and 37 weeks but not in the overall rate of HDP. These results suggest that LDA works in part by delaying HDP.

Pathogens identified in the internal tissues and placentas of stillbirths: results from the prospective, observational PURPOSe study.

OBJECTIVE: To examine internal organ tissues and placentas of stillbirths for various pathogens. DESIGN: Prospective, observational study. SETTINGS: Three study hospitals in India and a large maternity hospital in Pakistan. POPULATION: Stillborn infants delivered in a study hospital. METHODS: A prospective observational study. MAIN OUTCOME MEASURES: Organisms identified by pathogen polymerase chain reaction (PCR) in internal organs and placental tissues of stillbirths. RESULTS: Of 2437 stillbirth internal tissues, 8.3% (95% CI 7.2-9.4) were positive. Organisms were most commonly detected in brain (12.3%), cerebrospinal fluid (CSF) (9.5%) and whole blood (8.4%). Ureaplasma urealyticum/parvum was the organism most frequently detected in at least one internal organ (6.4% of stillbirths and 2% of all tissues). Escherichia coli/Shigella was the next most common (4.1% one or more internal organ tissue sample and 1.3% of tissue samples), followed by Staphylococcus aureus in at least one internal organ tissue (1.9% and 0.9% of all tissues). None of the other organisms was found in more than 1.4% of the tissue samples in stillbirths or more than 0.6% of the internal tissues examined. In the placenta tissue, membrane or cord blood combined, 42.8% (95% CI 40.2-45.3) had at least one organism identified, with U. urealyticum/parvum representing the most commonly identified (27.8%). CONCLUSIONS: In about 8% of stillbirths, there was evidence of a pathogen in an internal organ. Ureaplasma urealyticum/parvum was the most common organism found in the placenta and in the internal tissues, especially in the fetal brain.

Considering Risks to Researchers and Staff in Low-Resource Settings during Public Health Crises: A Proposed Conceptual Model.

Human subjects research protections have historically focused on mitigating risk of harm and promoting benefits for research participants. In many low-resource settings (LRS), complex and often severe challenges in daily living, poverty, geopolitical uprisings, sociopolitical, economic, and climate crises increase the burdens of even minimal risk research. While there has been important work to explore the scope of ethical responsibilities of researchers and research teams to respond to these wider challenges and hidden burdens in global health research, less attention has been given to the ethical dilemmas and risk experienced by frontline researcher staff as they perform research-related activities in LRS. Risks such as job insecurity, moral distress, infection, or physical harm can be exacerbated during public health crises, as recently highlighted by the COVID-19 pandemic. We highlight the layers of risk research staff face in LRS and present a conceptual model to characterize drivers of this risk, with particular attention to public health crises. A framework by which funders, institutions, principal investigators, and/or research team leaders can systematically consider these additional layers of risk to researchers and frontline staff is an important and needed addition to routine research proposals and protocol review.

Pathogens Identified by Minimally Invasive Tissue Sampling in India and Pakistan From Preterm Neonatal Deaths: The PURPOSE Study.

BACKGROUND: We identified pathogens found in internal organs and placentas of deceased preterm infants cared for in hospitals in India and Pakistan. METHODS: Prospective, observational study conducted in delivery units and neonatal intensive care units. Tissue samples from deceased neonates obtained by minimally invasive tissue sampling and placentas were examined for 73 different pathogens using multiplex polymerase chain reaction (PCR). RESULTS: Tissue for pathogen PCR was obtained from liver, lung, brain, blood, cerebrospinal fluid, and placentas from 377 deceased preterm infants. Between 17.6% and 34.1% of each type of tissue had at least 1 organism identified. Organism detection was highest in blood (34.1%), followed by lung (31.1%), liver (23.3%), cerebrospinal fluid (22.3%), and brain (17.6%). A total of 49.7% of the deceased infants had at least 1 organism. Acinetobacter baumannii was in 28.4% of the neonates compared with 14.6% for Klebsiella pneumoniae, 11.9% for Escherichia coli/Shigella, and 11.1% for Haemophilus influenzae. Group B streptococcus was identified in only 1.3% of the neonatal deaths. A. baumannii was rarely found in the placenta and was found more commonly in the internal organs of neonates who died later in the neonatal period. The most common organism found in placentas was Ureaplasma urealyticum in 34% of the samples, with no other organism found in >4% of samples. CONCLUSIONS: In organ samples from deceased infants in India and Pakistan, evaluated with multiplex pathogen PCR, A. baumannii was the most commonly identified organism. Group B streptococcus was rarely found. A. baumannii was rarely found in the placentas of these deceased neonates.

The causes of preterm neonatal deaths in India and Pakistan (PURPOSe): a prospective cohort study.

BACKGROUND: Preterm birth remains the major cause of neonatal death worldwide. South Asia contributes disproportionately to deaths among preterm births worldwide, yet few population-based studies have assessed the underlying causes of deaths. Novel evaluations, including histological and bacteriological assessments of placental and fetal tissues, facilitate more precise determination of the underlying causes of preterm deaths. We sought to assess underlying and contributing causes of preterm neonatal deaths in India and Pakistan. METHODS: The project to understand and research preterm pregnancy outcomes and stillbirths in South Asia (PURPOSe) was a prospective cohort study done in three hospitals in Davangere, India, and two hospitals in Karachi, Pakistan. All pregnant females older than 14 years were screened at the time of presentation for delivery, and those with an expected or known preterm birth, defined as less than 37 weeks of gestation, were enrolled. Liveborn neonates with a weight of 1000 g or more who died by 28 days after birth were included in analyses. Placentas were collected and histologically evaluated. In addition, among all neonatal deaths, with consent, minimally invasive tissue sampling was performed for histological analyses. PCR testing was performed to assess microbial pathogens in the placental, blood, and fetal tissues collected. An independent panel reviewed available data, including clinical description of the case and all clinical maternal, fetal, and placental findings, and results of PCR bacteriological investigation and minimally invasive tissue sampling histology, from all eligible preterm neonates to determine the primary and contributing maternal, placental, and neonatal causes of death. FINDINGS: Between July 1, 2018, and March 26, 2020, of the 3470 preterm neonates enrolled, 804 (23%) died by 28 days after birth, and, of those, 615 were eligible and had their cases reviewed by the panel. Primary maternal causes of neonatal death were hypertensive disease (204 [33%] of 615 cases), followed by maternal complication of pregnancy (76 [12%]) and preterm labour (76 [11%]), whereas the primary placental causes were maternal and fetal vascular malperfusion (172 [28%] of 615) and chorioamnionitis, funisitis, or both (149 [26%]). The primary neonatal cause of death was intrauterine hypoxia (212 [34%] of 615) followed by congenital infections (126 [20%]), neonatal infections (122 [20%]), and respiratory distress syndrome (126 [20%]). INTERPRETATION: In south Asia, intrauterine hypoxia and congenital infections were the major causes of neonatal death among preterm babies. Maternal hypertensive disorders and placental disorders, especially maternal and fetal vascular malperfusion and placental abruption, substantially contributed to these deaths. FUNDING: Bill & Melinda Gates Foundation.

The causes of stillbirths in south Asia: results from a prospective study in India and Pakistan (PURPOSe).

BACKGROUND: South Asia contributes more than a third of all global stillbirths, yet the causes remain largely unstudied in this region. New investigations, including novel assessments 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: In this prospective cohort study (PURPOSe), we report the cause of death in stillbirths in hospitals in central India and south Pakistan (Davangere, India [three public and private hospitals] and Karachi, Pakistan [one public maternity and one children's hospital]). Women aged 15 years or older and with a known stillbirth (defined as a pregnancy at 20 or more weeks of gestation with the in-utero death of a fetus) weighing 1000 g or more were included in the study. Maternal clinical factors, placental evaluation, fetal tissue evaluation (from minimally invasive tissue sampling), and PCR for microbial pathogens were used to identify the causes of death. An expert panel reviewed available data for all stillbirths to identify the primary and contributing maternal, placental, and fetal causes of stillbirth. FINDINGS: Between Sept 1, 2018, and Feb 12, 2020, 981 stillborns were included and, of those, 611 were reviewed by the expert panel. The primary maternal causes of stillbirth were hypertensive disease in 221 (36%) of 611 stillbirths, followed by severe anaemia in 66 (11%) stillbirths. The primary placental causes were maternal and fetal vascular malperfusion, in 289 (47%) stillbirths. The primary fetal cause of stillbirth was intrauterine hypoxia, in 437 (72%) stillbirths. We assessed the overlap of main causes and 116 (19%) stillbirths had intrauterine hypoxia, placental malperfusion, and eclampsia or pre-eclampsia indicated as primary causes of death. Infection (including of the placenta, its membranes, and in the fetus) and congenital anomalies also were causative of 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, have an important role in asphyxia and fetal death. Maternal hypertension, and especially pre-eclampsia, is often the primary maternal condition associated with this pathway. FUNDING: Bill & Melinda Gates Foundation.

Birth asphyxia is under-rated as a cause of preterm neonatal mortality in low- and middle-income countries: A prospective, observational study from PURPOSe.

OBJECTIVE: To assess respiratory distress syndrome (RDS) compared with birth asphyxia as the cause of death in preterm newborns, assigned by the neonatal intensive care unit (NICU) physician at the time of death and assigned by a panel with complete obstetric history, placental evaluation, tissue histology and microbiology. DESIGN: Prospective, observational study. SETTINGS: Study NICUs in India and Pakistan. POPULATION: Preterm infants delivered in study facility. METHODS: A total of 410 preterm infants who died in the NICU with cause of death ascertained by the NICU physicians and independently by expert panels. We compared the percentage of cases assigned RDS versus birth asphyxia as cause of death by the physician and the panel. MAIN OUTCOME MEASURES: RDS and birth asphyxia. RESULTS: Of 410 preterm neonatal deaths, the discharging NICU physicians found RDS as a cause of death among 83.2% of the cases, compared with the panel finding RDS in only 51.0%. In the same neonatal deaths, the NICU physicians found birth asphyxia as a cause of death in 14.9% of the deaths, whereas the panels found birth asphyxia in 57.6% of the deaths. The difference was greater in Pakistan were the physicians attributed 89.7% of the deaths to RDS and less than 1% to birth asphyxia whereas the panel attributed 35.6% of the deaths to RDS and 62.7% to birth asphyxia. CONCLUSIONS: NICU physicians who reported cause of death in deceased preterm infants less often attributed the death to birth asphyxia, and instead more often chose RDS, whereas expert panels with more extensive data attributed a greater proportion of deaths to birth asphyxia than did the physicians.

The impact of low-dose aspirin on markers of inflammation and placental function: an ancillary study of the ASPIRIN trial.

OBJECTIVE: To determine the impact of low-dose aspirin (81 mg) on markers of maternal inflammation and placental function. SETTING: Rural Southern India. POPULATION: Nulliparous women with a singleton pregnancy dated by ultrasound who were enrolled in the ASPIRIN (Aspirin Supplementation for Pregnancy Indicated risk Reduction In Nulliparas) Trial. METHODS: We performed a case-control study to elucidate the impact of low dose aspirin (LDA) on markers of placental function and maternal inflammation among women who delivered prematurely compared to term controls in women enrolled in the ASPIRIN trial. Women were prospectively enrolled in an ancillary observational trial wherein maternal serum was collected and measured between 10 to 13 weeks and 17 to 21 weeks of gestation after initiation of aspirin or an identical placebo. RESULTS: From 2016-18 with a total of 666 n women enrolled in this ancillary trial of whom 269 were selected for analyte analysis. Women who received LDA had lower levels of Alpha Feto-Protein (AFP) at 10 to 13 weeks than women who received placebo (Placebo) (LDA 18.3 ng/mL vs 21.4 ng/mL -P 0.001). AFP was similar between the two groups at 17 to 21 weeks. No other differences were seen in C-Reactive protein or Anti-Mullerian Hormone. CONCLUSION: Low-dose aspirin administration lowers AFP early in pregnancy.