Acetaminophen and Ibuprofen in Pediatric Central Nervous System Malaria: A Randomized Clinical Trial.

Importance: A third of children who survive malaria with neurological involvement (central nervous system [CNS] malaria) develop sequelae. A higher maximum temperature (Tmax) and seizures are risk factors for sequelae. Objective: To compare aggressive antipyretic therapy using scheduled acetaminophen and ibuprofen vs usual care with acetaminophen alone given only for a temperature of 38.5 °C or higher. Design, Setting, and Participants: This randomized clinical trial was conducted at inpatient pediatric services of 1 tertiary care and 1 district hospital in Zambia and a tertiary care center in Malawi. Included were children aged 2 to 11 years with CNS malaria (excluding those with creatinine >1.2 mg/dL), who were enrolled from 2019 to 2022. Data analysis took place from December 2022 to April 2023. Intervention: The aggressive antipyretic group received acetaminophen (30 mg/kg load, then 15 mg/kg) plus ibuprofen, 10 mg/kg, every 6 hours, regardless of clinical temperature for 72 hours. The usual care group received 15 mg/kg of acetaminophen as needed every 6 hours for a temperature of 38.5 °C or higher. Main Outcomes and Measures: The primary outcome variable was Tmax over 72 hours, the total duration of follow-up. Secondary outcomes included seizures and parasite clearance. Results: Five hundred fifty-three patients were screened, 226 (40.9%) were ineligible, and 57 (10.3%) declined. A total 256 participants (n = 128/group) had a mean (SD) age of 4.3 (2.1) years; 115 (45%) were female, and 141 (55%) were male. The aggressive antipyretic group had a lower Tmax, 38.6 vs 39.2 °C (difference, -0.62 °C; 95% CI, -0.82 to -0.42; P < .001) and lower odds of experiencing multiple or prolonged seizures, 10 (8%) vs 34 children (27%) in the usual care group (odds ratio [OR], 0.26; 95% CI, 0.12 to 0.56). No group difference in parasite clearance time was detected. Severe adverse events occurred in 40 children (15%), 25 (20%) in the usual care group and 15 (12%) in the aggressive antipyretic group, including 13 deaths (10 [8%] and 3 [2%], respectively). Increased creatinine resulted in study drug discontinuation in 8 children (6%) in the usual care group and 13 children (10%) in the aggressive antipyretic group (OR, 1.74; 95% CI, 0.63 to 5.07). Conclusions and Relevance: This study found that aggressive antipyretic therapy reduced mean Tmax to temperature levels comparable with the Tmax among children without neurological impairments in prior observational studies and improved acute seizure outcomes with no prolongation of parasitemia. Trial Registration: ClinicalTrials.gov Identifier: NCT03399318.

The prevalence of anemia during pregnancy and its correlates vary by trimester and hemoglobin assessment method in Eastern Maharashtra, India.

Approximately half of pregnant women in India are anemic, representing over 7.5 million women. Few studies have assessed the relationship between multiple micronutrient deficiencies and anemia during pregnancy or the trajectory of hemoglobin (Hb) during pregnancy in low-resource settings. We enrolled 200 pregnant women from the Maternal and Newborn Health (MNH) registry, a population-based pregnancy and birth registry in Eastern Maharashtra, India to address these gaps. The women provided capillary (finger-prick) and venous blood specimens at enrollment (<15 weeks), and a second capillary specimen in the 3rd trimester (>27 weeks). Capillary specimens were analyzed at the time of collection with a HemoCue Hb 201+; venous specimens were shipped on dry ice to a laboratory for cyanmethemoglobin assessment. In the 1st trimester, mean Hb concentration and anemia (Hb<11.0 g/dL) prevalence using capillary specimens were 10.9 ± 1.5 g/dL and 51.1%; mean Hb concentration using venous blood specimens was estimated to be 11.3 ± 1.3 g/dL and anemia prevalence was 37.5%. The prevalence of iron, vitamin B12 and folate deficiencies were 40%, 30% and 0%, respectively. Among women with anemia in the 1st trimester (venous blood), 56% had concurrent iron deficiency (inflammation-adjusted serum ferritin <15 µg/L) indicating that their anemia may be amenable to iron supplementation. In total, 21% of women had ID and anemia, 19% ID in the absence of anemia, 16.5% anemia in the absence of ID and 43.5% had neither. By the 3rd trimester, mean Hb from capillary specimens had declined to 10.1 ± 1.35 g/dL and anemia prevalence increased to 70.7%, despite 99.4% mothers reporting receipt of iron-folic acid (IFA) supplements during her current pregnancy, and 83.9% reporting IFA consumption the previous day. Significant predictors of anemia in the 1st trimester (both venous and capillary) included the number of weeks gestation at the time of Hb assessment and inflammation-adjusted serum ferritin. For 3rd trimester anemia, significant predictors included 1st trimester height, BMI and IFA consumption during the 3rd trimester (but not 1st trimester micronutrient biomarkers), indicating that IFA supplementation over the course of pregnancy may have influenced micronutrient status and anemia risk. Our findings highlight the severity of the burden of anemia and micronutrient deficiencies in Eastern Maharashtra, but also highlight that in many cases, ID and anemia affect different individuals. Preventing and managing anemia in pregnancy in India will require strengthening both clinical and community-based strategies targeting iron deficiency, as well as other causes of anemia.

Providing optimal care in the neonatal care units in India: How Covid-19 exacerbated existing barriers.

Nearly one quarter (600,000) of all neonatal deaths worldwide per year occur in India. To reduce neonatal mortality, the Indian Ministry of Health and Family Welfare established neonatal care units, including neonatal intensive care units and specialized neonatal care units to provide immediate care at birth, resuscitation for asphyxiation, postnatal care, follow up for high-risk newborns, immunization, and referral for additional or complex healthcare services. Despite these efforts, neonatal mortality remains high, and measures taken to reduce mortality have been severely challenged by multiple problems caused by the Covid-19 pandemic. In this qualitative study, we conducted seven focus group discussions with newborn care unit nurses and pediatric residents and 35 key informant interviews with pediatricians, residents, nurses, annual equipment maintenance contractors, equipment manufacturers, and Ministry personnel in the Vidarbha region of Maharashtra between December 2019 and November 2020. The goal of the study was to understand barriers and facilitators to providing optimal care to neonates, including the challenges imposed by the Covid-19 pandemic. Covid-19 exacerbated existing barriers to providing optimal care to neonates in these newborn care units. As a result of Covid-19, we found the units were even more short-staffed than usual, with trained pediatric nurses and essential equipment diverted from newborn care to attend to patients with Covid-19. Regular training of neonatal nursing staff was also disrupted due to Covid-19, leaving many staff without the skills to provide optimate care to neonates. Infection control was also exacerbated by Covid-19. This study highlights the barriers to providing optimal care for neonates were made even more challenging during Covid-19 because of the diversion of critically important neonatal equipment and staff trained to use that equipment to Covid-19 wards. The barriers at the individual, facility, and systems levels will remain challenging as the Covid-19 pandemic continues.

Protocol for a magnetic resonance imaging study of participants in the fever RCT: Does fever control prevent brain injury in malaria?

BACKGROUND: Despite eradication efforts, ~135,000 African children sustained brain injuries as a result of central nervous system (CNS) malaria in 2021. Newer antimalarial medications rapidly clear peripheral parasitemia and improve survival, but mortality remains high with no associated decline in post-malaria neurologic injury. A randomized controlled trial of aggressive antipyretic therapy with acetaminophen and ibuprofen (Fever RCT) for malarial fevers being conducted in Malawi and Zambia began enrollment in 2019. We propose to use neuroimaging in the context of the RCT to further evaluate neuroprotective effects of aggressive antipyretic therapy. METHODS: This observational magnetic resonance imaging (MRI) ancillary study will obtain neuroimaging and neurodevelopmental and behavioral outcomes in children previously enrolled in the Fever RCT at 1- and 12-months post discharge. Analysis will compare the odds of any brain injury between the aggressive antipyretic therapy and usual care groups based upon MRI structural abnormalities. For children unable to undergo imaging without deep sedation, neurodevelopmental and behavioral outcomes will be used to identify brain injury. DISCUSSION: Neuroimaging is a well-established, valid proxy for neurological outcomes after brain injury in pediatric CNS malaria. This MRI ancillary study will add value to the Fever RCT by determining if treatment with aggressive antipyretic therapy is neuroprotective in CNS malaria. It may also help elucidate the underlying mechanism(s) of neuroprotection and expand upon FEVER RCT safety assessments.

Increased susceptibility for nonsyndromic cleft lip with or without cleft palate by SLC19A1 80G>A genetic variation.

BACKGROUND: The disruption of craniofacial developmental pathways during early embryogenesis can lead to conditions such as nonsyndromic cleft lip with or without cleft palate (NSCL/P). Several lines of evidence indicate that inadequate maternal nutrition causes low folate levels during the periconceptional period, resulting in NSCL/P. Although substantial research has been conducted on the possible link between SLC19A1 genetic variants and NSCL/P, the association between SLC19A1 80G>A (rs1051266) and NSCL/P remains unclear. In the present study, the associations of SLC19A1 80G>A with NSCL/P risk were assessed by calculating the pooled odds ratios (ORs) and 95% confidence intervals (CIs) by meta-analyses. METHODS: Following the PRISMA guidelines, a meta-analysis was conducted on 10 studies assessing the NSCL/P risk associated with SLC19A1 80G>A variant. To ascertain the degree of relationship between the SLC19A1 80G>A genetic variant and the risk of NSCL/P, data were analyzed in allelic, recessive and dominant genetic models. CI of OR for each study and the pooled data were obtained. All statistical analyses were conducted utilizing the MetaGenyo software tool, which integrates the adjustment of P values for multiple testing through the Bonferroni method. RESULTS: The pooled analysis showed that SLC19A1 80G>A variant significantly increased the NSCL/P risk in the allelic model (OR 1.39; 95% CI 1.00-1.92), recessive model (OR 1.37; 95% CI 1.03-1.82) and dominant models (OR 1.7; 95% CI 1.05-2.90). Publication bias was not observed. CONCLUSIONS: This study supports that the SLC19A1 80G>A genetic variant is associated with NSCL/P risk.

Neurodevelopment of Children Whose Mothers Were Randomized to Low-Dose Aspirin During Pregnancy.

OBJECTIVE: Because low-dose aspirin is now commonly prescribed in pregnancy, we sought to assess the association between early antenatal exposure and child neurodevelopment. METHODS: We performed a noninferiority, masked, neurodevelopmental follow-up study of children between age 33 and 39 months whose mothers had been randomized to daily low-dose aspirin (81 mg) or placebo between 6 0/7 and 13 6/7 weeks of gestation through 37 weeks. Neurodevelopment was assessed with the Bayley-III (Bayley Scales of Infant and Toddler Development, 3rd Edition) and the ASQ-3 (Ages and Stages Questionnaire, 3rd Edition). The primary outcome was the Bayley-III cognitive composite score with a difference within 4 points demonstrating noninferiority. RESULTS: A total of 640 children (329 in the low-dose aspirin group, 311 in the placebo group) were evaluated between September 2021 and June 2022. The Bayley-III cognitive composite score was noninferior between the two groups (-1, adjusted mean -0.8, 95% CI, -2.2 to 0.60). Significant differences were not seen in the language composite score (difference 0.7, 95% CI, -0.8 to 2.1) or the motor composite score (difference -0.6, 95% CI, -2.5 to 1.2). The proportion of children who had any component of the Bayley-III score lower than 70 did not differ between the two groups. Similarly, the communication, gross motor, fine motor, problem-solving, and personal-social components of the ASQ-3 did not differ between groups. Maternal characteristics, delivery outcomes, breastfeeding rates, breastfeeding duration, and home environment as measured by the Family Care Indicators were similar. CONCLUSION: Antenatal low-dose aspirin exposure was not associated with altered neurodevelopmental outcomes at age 3 years. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT04888377.

Neonatal Respiratory Support Utilization in Low- and Middle-Income Countries: A Registry-Based Observational Study.

BACKGROUND: Newborns with hypoxemia often require life-saving respiratory support. In low-resource settings, it is unknown if respiratory support is delivered more frequently to term infants or preterm infants. We hypothesized that in a registry-based birth cohort in 105 geographic areas in seven low- and middle-income countries, more term newborns received respiratory support than preterm newborns. METHODS: This is a hypothesis-driven observational study based on prospectively collected data from the Maternal and Newborn Health Registry of the NICHD Global Network for Women's and Children's Health Research. Eligible infants enrolled in the registry were live-born between 22 and 44 weeks gestation with a birth weight ≥400 g and born from January 1, 2015, to December 31, 2018. Frequency data were obtained to report the number of term and preterm infants who received treatment with oxygen only, CPAP, or mechanical ventilation. Test for trends over time were conducted using robust Poisson regression. RESULTS: 177,728 (86.3%) infants included in this study were term, and 28,249 (13.7%) were preterm. A larger number of term infants (n = 5,108) received respiratory support compared to preterm infants (n = 3,287). Receipt of each mode of respiratory support was more frequent in term infants. The proportion of preterm infants who received respiratory support (11.6%) was higher than the proportion of term infants receiving respiratory support (2.9%, p < 0.001). The rate of provision of respiratory support varied between sites. CONCLUSIONS: Respiratory support was more frequently used in term infants expected to be at low risk for respiratory disorders compared to preterm infants.

Maternal age extremes and adverse pregnancy outcomes in low-resourced settings.

Introduction: Adolescent (<20 years) and advanced maternal age (>35 years) pregnancies carry adverse risks and warrant a critical review in low- and middle-income countries where the burden of adverse pregnancy outcomes is highest. Objective: To describe the prevalence and adverse pregnancy (maternal, perinatal, and neonatal) outcomes associated with extremes of maternal age across six countries. Patients and methods: We performed a historical cohort analysis on prospectively collected data from a population-based cohort study conducted in the Democratic Republic of Congo, Guatemala, India, Kenya, Pakistan, and Zambia between 2010 and 2020. We included pregnant women and their neonates. We describe the prevalence and adverse pregnancy outcomes associated with pregnancies in these maternal age groups (<20, 20-24, 25-29, 30-35, and >35 years). Relative risks and 95% confidence intervals of each adverse pregnancy outcome comparing each maternal age group to the reference group of 20-24 years were obtained by fitting a Poisson model adjusting for site, maternal age, parity, multiple gestations, maternal education, antenatal care, and delivery location. Analysis by region was also performed. Results: We analyzed 602,884 deliveries; 13% (78,584) were adolescents, and 5% (28,677) were advanced maternal age (AMA). The overall maternal mortality ratio (MMR) was 147 deaths per 100,000 live births and increased with advancing maternal age: 83 in the adolescent and 298 in the AMA group. The AMA groups had the highest MMR in all regions. Adolescent pregnancy was associated with an adjusted relative risk (aRR) of 1.07 (1.02-1.11) for perinatal mortality and 1.13 (1.06-1.19) for neonatal mortality. In contrast, AMA was associated with an aRR of 2.55 (1.81 to 3.59) for maternal mortality, 1.58 (1.49-1.67) for perinatal mortality, and 1.30 (1.20-1.41) for neonatal mortality, compared to pregnancy in women 20-24 years. This pattern was overall similar in all regions, even in the <18 and 18-19 age groups. Conclusion: The maternal mortality ratio in the LMICs assessed is high and increased with advancing maternal age groups. While less prevalent, AMA was associated with a higher risk of adverse maternal mortality and, like adolescence, was associated with adverse perinatal mortality with little regional variation.

Development of mobile phone-based dietary data collection applications in pregnant women and infants for the M-SAKHI trial.

In nutritional epidemiological studies, it is imperative to collect high-quality data to ensure accurate dietary assessment. However, dietary data collection using traditional paper forms has several limitations that may compromise data quality. The aim of this study was to propose novel methods to design and develop software applications (Apps) for dietary data collection to assess the nutritional status of pregnant women and infants. This study is part of the M-SAKHI (Mobile-Solutions for Aiding Knowledge for Health Improvement) cluster randomised controlled trial (cRCT) implemented in central India. Three tablet-based software Apps were developed in this study: the ACEC (Automated Coding and Energy Calculation) App to establish a generic cooked food recipe database, the FFQ (Food Frequency Questionnaire), and the IDR (24 h Infant Dietary Recall) Apps to collect dietary data from pregnant women and their infants from rural area of Bhandara and Nagpur districts. Regional food lists, recipes, and portion resource kits were developed to support the data collection using the Apps. In conclusion, the Apps were user-friendly, required minimal prior training, had built-in validation checks for erroneous data entry and provided automated calculations. The Apps were successfully deployed in low-resource rural settings to accurately collect high-quality regional cooked food data and individual-level dietary data of pregnant women and their infants.

Comparing the efficacy of electronic cognitive behavioral therapy to medication and combination therapy for generalized anxiety disorder: a quasi-experimental clinical trial.

Background: Generalized anxiety disorder (GAD) is a debilitating mental health disorder with first-line treatments include cognitive behavioral therapy (CBT) and pharmacotherapy. CBT is costly, time-consuming, and inaccessible. Electronic delivery (e-CBT) is a promising solution to address these barriers. However, due to the novelty of this intervention, more research testing the e-CBT efficacy independently and in conjunction with other treatments is needed. Objective: This study investigated the efficacy of e-CBT compared to and in conjunction with pharmacotherapy for GAD. Methods: This study employed a quasi-experimental design where patients selected their preferred treatment modality. Patients with GAD were enrolled in either e-CBT, medication, or combination arms. The 12-week e-CBT program was delivered through a digital platform. The medications followed clinical guidelines. The efficacy of each arm was evaluated using questionnaires measuring depression, anxiety, and stress severity, as well as quality of life. Results: There were no significant differences between arms (N e-CBT = 41; N Medication = 41; N Combination = 33) in the number of weeks completed or baseline scores. All arms showed improvements in anxiety scores after treatment. The medication and combination arms improved depression scores. The e-CBT and Combination arms improved quality of life, and the combination arm improved stress scores. There were no differences between the groups in depression, anxiety, or stress scores post-treatment. However, the combination arm had a significantly larger improvement in quality of life. Gender and treatment arm were not predictors of dropout, whereas younger age was. Conclusion: Incorporating e-CBT on its own or in combination with pharmaceutical interventions is a viable option for treating GAD. Treating GAD with e-CBT or medication appears to offer significant improvements in symptoms, with no meaningful difference between the two. Combining the treatments also offer significant improvements, while not necessarily superior to either independently. The findings suggest that all options are viable. Taking the patient's preferred treatment route based on their lifestyle, personality, and beliefs into account when deciding on treatment should be a priority for care providers.

Maternal and perinatal outcomes of women with vaginal birth after cesarean section compared to repeat cesarean birth in select South Asian and Latin American settings of the global network for women's and children's health research.

OBJECTIVE: Our objective was to analyze a prospective population-based registry including five sites in four low- and middle-income countries to observe characteristics associated with vaginal birth after cesarean versus repeat cesarean birth, as well as maternal and newborn outcomes associated with the mode of birth among women with a history of prior cesarean. HYPOTHESIS: Maternal and perinatal outcomes among vaginal birth after cesarean section will be similar to those among recurrent cesarean birth. METHODS: A prospective population-based study, including home and facility births among women enrolled from 2017 to 2020, was performed in communities in Guatemala, India (Belagavi and Nagpur), Pakistan, and Bangladesh. Women were enrolled during pregnancy, and delivery outcome data were collected within 42 days after birth. RESULTS: We analyzed 8267 women with a history of prior cesarean birth; 1389 (16.8%) experienced vaginal birth after cesarean, and 6878 (83.2%) delivered by a repeat cesarean birth. Having a repeat cesarean birth was negatively associated with a need for curettage (ARR 0.12 [0.06, 0.25]) but was positively associated with having a blood transfusion (ARR 3.74 [2.48, 5.63]). Having a repeat cesarean birth was negatively associated with stillbirth (ARR 0.24 [0.15, 0.49]) and, breast-feeding within an hour of birth (ARR 0.39 [0.30, 0.50]), but positively associated with use of antibiotics (ARR 1.51 [1.20, 1.91]). CONCLUSIONS: In select South Asian and Latin American low- and middle-income sites, women with a history of prior cesarean birth were 5 times more likely to deliver by cesarean birth in the hospital setting. Those who delivered vaginally had less complicated pregnancy and labor courses compared to those who delivered by repeat cesarean birth, but they had an increased risk of stillbirth. More large scale studies are needed in Low Income Country settings to give stronger recommendations. TRIAL REGISTRATION: NCT01073475, Registered February 21, 2010, https://clinicaltrials.gov/ct2/show/record/NCT01073475 .

Protocol for a Magnetic Resonance Imaging (MRI) Study of Participants in the Fever Randomized Controlled Trial: Does fever control prevent brain injury in malaria?

Background: Despite eradication efforts, ~135,000 African children sustained brain injuries as a result of central nervous system (CNS) malaria in 2021. Newer antimalarial medications rapidly clear peripheral parasitemia and improve survival, but mortality remains high with no associated decline in post-malaria neurologic injury. A randomized controlled trial of aggressive antipyretic therapy with acetaminophen and ibuprofen (Fever RCT) for malarial fevers being conducted in Malawi and Zambia began enrollment in 2019. We propose to use neuroimaging in the context of the RCT to further evaluate neuroprotective effects of aggressive antipyretic therapy. Methods: This observational magnetic resonance imaging (MRI) ancillary study will obtain neuroimaging and neurodevelopmental and behavioral outcomes in children previously enrolled in the Fever RCT at 1- and 12-months post discharge. Analysis will compare the odds of any brain injury between the aggressive antipyretic therapy and usual care groups based upon MRI structural abnormalities. For children unable to undergo imaging without deep sedation, neurodevelopmental and behavioral outcomes will be used to identify brain injury. Discussion: Neuroimaging is a well-established, valid proxy for neurological outcomes after brain injury in pediatric CNS malaria. This MRI ancillary study will add value to the Fever RCT by determining if treatment with aggressive antipyretic therapy is neuroprotective in CNS malaria. It may also help elucidate the underlying mechanism(s) of neuroprotection and expand upon FEVER RCT safety assessments.

Screening for developmental delay in urban Rwandan children: a cross sectional study.

BACKGROUND: Systematic or targeted screening for developmental delay (DD) is critical to the early identification of developmental disabilities. With limited available information for urban Rwandan children, this study aimed to determine the prevalence of DD and associated risk factors in infants aged 9 to 16 months living in the urban Rwandan city of Kigali. METHODS: A cross-sectional study was conducted in Rwanda from August to November 2019. A convenience sample of 376 Rwandan parents/caregivers and their children attending urban health centers for their routine immunization visits at 9 and 15 months of age was studied. Parents/caregivers completed the official Kinyarwandan version of the Ages and Stages Questionnaire (ASQ-3) and established cutoffs were used to identify DD. Frequency and percentages were used to summarise the data. Logistic regression analysis was used to identify factors associated with DD. RESULTS: Of the 358 children screened using the ASQ-3, the overall prevalence of DD was 24.6%, with a 27.2% prevalence among 9-10-month old children and 22.4% prevalence among 15-16-month old children. Delays in the combined group among the domains of gross motor, communication, fine motor, personal social, and problem solving were 12.8%, 2.5%, 8.4%, 1.7% and 7.5%, respectively. Gestational age at delivery and district of origin were most highly associated with DD, with preterm children at significantly higher risk of having DD compared to term children (Adjusted Odd Ratio AOR = 8.3; 95% CI = 2.5-27.4) and children from Nyarugenge District at high risk of DD compared to children from Gasabo district (AOR = 2.15; 95% CI = 1.2-3.9). CONCLUSIONS: The prevalence of ASQ-detectable DD among urban Rwandan children between 9 and 16 months of age was 24.6%, with a high correlation to a history of prematurity and district of origin. This study demonstrates the need for thoughtful health planning regarding integrated developmental surveillance for children, particularly those at high risk, to allow for earlier identification and intervention in the urban area of Kigali, Rwanda.

Can the date of last menstrual period be trusted in the first trimester? Comparisons of gestational age measures from a prospective cohort study in six low-income to middle-income countries.

OBJECTIVES: We examined gestational age (GA) estimates for live and still births, and prematurity rates based on last menstrual period (LMP) compared with ultrasonography (USG) among pregnant women at seven sites in six low-resource countries. DESIGN: Prospective cohort study SETTING AND PARTICIPANTS: This study included data from the Global Network's population-based Maternal and Newborn Health Registry which follows pregnant women in six low-income and middle-income countries (Democratic Republic of the Congo, Guatemala, India, Kenya, Pakistan and Zambia). Participants in this analysis were 42 803 women, including their 43 230 babies, who registered for the study in their first trimester based on GA estimated either by LMP or USG and had a live or stillbirth with an estimated GA of 20-42 weeks. OUTCOME MEASURES: GA was estimated in weeks and days based on LMP and/or USG. Prematurity was defined as GA of 20 weeks+0 days through 36 weeks+6 days, calculated by both USG and LMP. RESULTS: Overall, average GA varied ≤1 week between LMP and USG. Mean GA for live births by LMP was lower than by USG (adjusted mean difference (95% CI) = -0.23 (-0.29 to -0.17) weeks). Among stillbirths, a higher GA was estimated by LMP than USG (adjusted mean difference (95% CI)= 0.42 (0.11 to 0.72) weeks). Preterm birth rates for live births were significantly higher when dated by LMP (adjusted rate difference (95% CI)= 4.20 (3.56 to 4.85)). There was no significant difference in preterm birth rates for stillbirths. CONCLUSION: The small differences in GA for LMP versus USG in the Guatemalan and Indian sites suggest that LMP may be a useful alternative to USG for GA dating during the first trimester until availability of USG improves in those areas. Further research is needed to assess LMP for first-trimester GA dating in other regions with limited access to USG. TRIAL REGISTRATION NUMBER: NCT01073475.

Building a predictive model of low birth weight in low- and middle-income countries: a prospective cohort study.

BACKGROUND: Low birth weight (LBW, < 2500 g) infants are at significant risk for death and disability. Improving outcomes for LBW infants requires access to advanced neonatal care, which is a limited resource in low- and middle-income countries (LMICs). Predictive modeling might be useful in LMICs to identify mothers at high-risk of delivering a LBW infant to facilitate referral to centers capable of treating these infants. METHODS: We developed predictive models for LBW using the NICHD Global Network for Women's and Children's Health Research Maternal and Newborn Health Registry. This registry enrolled pregnant women from research sites in the Democratic Republic of the Congo, Zambia, Kenya, Guatemala, India (2 sites: Belagavi, Nagpur), Pakistan, and Bangladesh between January 2017 - December 2020. We tested five predictive models: decision tree, random forest, logistic regression, K-nearest neighbor and support vector machine. RESULTS: We report a rate of LBW of 13.8% among the eight Global Network sites from 2017-2020, with a range of 3.8% (Kenya) and approximately 20% (in each Asian site). Of the five models tested, the logistic regression model performed best with an area under the curve of 0.72, an accuracy of 61% and a recall of 72%. All of the top performing models identified clinical site, maternal weight, hypertensive disorders, severe antepartum hemorrhage and antenatal care as key variables in predicting LBW. CONCLUSIONS: Predictive modeling can identify women at high risk for delivering a LBW infant with good sensitivity using clinical variables available prior to delivery in LMICs. Such modeling is the first step in the development of a clinical decision support tool to assist providers in decision-making regarding referral of these women prior to delivery. Consistent referral of women at high-risk for delivering a LBW infant could have extensive public health consequences in LMICs by directing limited resources for advanced neonatal care to the infants at highest risk.

The Global Network COVID-19 studies: a review.

With the paucity of data available regarding COVID-19 in pregnancy in low- and middle-income countries (LMICs), near the start of the pandemic, the Global Network for Women's and Children's Health Research, funded by the National Institute of Child Health and Human Development (NICHD), initiated four separate studies to better understand the impact of the COVID-19 pandemic in eight LMIC sites. These sites included: four in Asia, in Bangladesh, India (two sites) and Pakistan; three in Africa, in the Democratic Republic of the Congo (DRC), Kenya and Zambia; and one in Central America, in Guatemala. The first study evaluated changes in health service utilisation; the second study evaluated knowledge, attitudes and practices of pregnant women in relationship to COVID-19 in pregnancy; the third study evaluated knowledge, attitude and practices related to COVID-19 vaccination in pregnancy; and the fourth study, using antibody status at delivery, evaluated changes in antibody status over time in each of the sites and the relationship of antibody positivity with various pregnancy outcomes. Across the Global Network, in the first year of the study there was little reduction in health care utilisation and no apparent change in pregnancy outcomes. Knowledge related to COVID-19 was highly variable across the sites but was generally poor. Vaccination rates among pregnant women in the Global Network were very low, and were considerably lower than the vaccination rates reported for the countries as a whole. Knowledge regarding vaccines was generally poor and varied widely. Most women did not believe the vaccines were safe or effective, but slightly more than half would accept the vaccine if offered. Based on antibody positivity, the rates of COVID-19 infection increased substantially in each of the sites over the course of the pandemic. Most pregnancy outcomes were not worse in women who were infected with COVID-19 during their pregnancies. We interpret the absence of an increase in adverse outcomes in women infected with COVID-19 to the fact that in the populations studied, most COVID-19 infections were either asymptomatic or were relatively mild.

Prevention of maternal and neonatal death/infections with a single oral dose of azithromycin in women in labour in low-income and middle-income countries (A-PLUS): a study protocol for a multinational, randomised placebo-controlled clinical trial.

INTRODUCTION: Maternal and neonatal infections are among the most frequent causes of maternal and neonatal mortality, and current antibiotic strategies have been ineffective in preventing many of these deaths. A randomised clinical trial conducted in a single site in The Gambia showed that treatment with an oral dose of 2 g azithromycin versus placebo for all women in labour reduced certain maternal and neonatal infections. However, it is unknown if this therapy reduces maternal and neonatal sepsis and mortality. In a large, multinational randomised trial, we will evaluate the impact of azithromycin given in labour to improve maternal and newborn outcomes. METHODS AND ANALYSIS: This randomised, placebo-controlled, multicentre clinical trial includes two primary hypotheses, one maternal and one neonatal. The maternal hypothesis is to test whether a single, prophylactic intrapartum oral dose of 2 g azithromycin given to women in labour will reduce maternal death or sepsis. The neonatal hypothesis will test whether this intervention will reduce intrapartum/neonatal death or sepsis. The intervention is a single, prophylactic intrapartum oral dose of 2 g azithromycin, compared with a single intrapartum oral dose of an identical appearing placebo. A total of 34 000 labouring women from 8 research sites in sub-Saharan Africa, South Asia and Latin America will be randomised with a one-to-one ratio to intervention/placebo. In addition, we will assess antimicrobial resistance in a sample of women and their newborns. ETHICS AND DISSEMINATION: The study protocol has been reviewed and ethics approval obtained from all the relevant ethical review boards at each research site. The results will be disseminated via peer-reviewed journals and national and international scientific forums. TRIAL REGISTRATION NUMBER: NCT03871491 (https://clinicaltrials.gov/ct2/show/NCT03871491?term=NCT03871491&draw=2&rank=1).

Trends over time in the knowledge, attitude and practices of pregnant women related to COVID-19: A cross-sectional survey from seven low- and middle-income countries.

OBJECTIVE: To understand trends in the knowledge, attitudes and practices (KAP) of pregnant women related to COVID-19 in seven low- and middle-income countries. DESIGN: Multi-country population-based prospective observational study. SETTING: Study sites in Bangladesh, the Demographic Republic of Congo (DRC), Guatemala, India (two sites), Kenya, Pakistan and Zambia. POPULATION: Pregnant women in the Global Network's Maternal and Neonatal Health Registry (MNHR). METHODS: Pregnant women enrolled in the MNHR were interviewed to assess their KAP related to COVID-19 from September 2020 through July 2022 across all study sites. MAIN OUTCOME MEASURES: Trends of COVID-19 KAP were assessed using the Cochran-Armitage test for trend. RESULTS: A total of 52 297 women participated in this study. There were wide inter-country differences in COVID-19-related knowledge. The level of knowledge of women in the DRC was much lower than that of women in the other sites. The ability to name COVID-19 symptoms increased over time in the African sites, whereas no such change was observed in Bangladesh, Belagavi and Guatemala. All sites observed decreasing trends over time in women avoiding antenatal care visits. CONCLUSIONS: The knowledge and attitudes of pregnant women related to COVID-19 varied substantially among the Global Network sites over a period of 2 years; however, there was very little change in knowledge related to COVID-19 over time across these sites. The major change observed was that fewer women reported avoiding medical care because of COVID-19 across all sites over time.

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.