Importance Scalable interventions are urgently needed to mitigate the adverse effects of heat on pregnancy and newborn health. Objective To evaluate whether low-dose aspirin modifies the association between heat exposure and preterm birth. Design, Setting, and Participants This secondary analysis of the Global Network for Women’s and Children’s Health Research Aspirin Supplementation for Pregnancy Indicated Risk Reduction in Nulliparas (ASPIRIN) randomized, double-blinded, placebo-controlled clinical trial was conducted from March 2016 to June 2018. Statistical analyses were performed from June 2024 to June 2025. The study settings included the Democratic Republic of Congo, Zambia, Kenya, Guatemala, Pakistan, and Belagavi and Nagpur, India. Participants included nulliparous individuals between 6 and 13 weeks’ gestation recruited through local clinics and communities, with delivery at 20 or more weeks’ gestation. Exposures Prenatal care site–specific daily maximum humid heat averaged across gestation and by gestational week, and randomization to aspirin or placebo. Main Outcome and Measure The main outcome was preterm birth (delivery between 20 and <37 weeks’ gestation) with gestational age confirmed by enrollment ultrasonography. Results Of 11 558 participants (mean [SD] age, 20.9 [3.3] years), 5787 were randomized to receive aspirin and 5771 to receive placebo. Preterm birth occurred among 754 placebo recipients (13.1%) and 668 aspirin recipients (11.6%). In mixed-effects pooled logistic regression, each 1 °C increase in mean daily maximum shaded wet-bulb globe temperature across gestation was associated with a 5% increased odds of preterm birth (adjusted odds ratio, 1.05; 95% CI, 1.01-1.10). In stratified analyses, this increased risk was observed only among placebo recipients (adjusted odds ratio [AOR], 1.07; 95% CI, 1.02-1.13), not among aspirin recipients (AOR, 1.03; 95% CI, 0.97-1.10). In pooled mixed-effects logistic distributed lag models, increased odds of preterm birth were observed 17 to 19 weeks before delivery among individuals whose daily maximum shaded wet-bulb globe temperature exceeded the site-specific 75th percentile compared with the lowest 3 quartiles. This vulnerability was not observed among aspirin recipients. In contrast, the association of heat with perinatal mortality was observed only among those receiving aspirin (AOR, 1.15; 95% CI, 1.05-1.26) and not among those receiving placebo (AOR, 1.03; 95% CI, 0.96-1.11). Conclusions and Relevance The findings of this secondary analysis of the Global Network ASPIRIN trial suggest that low-dose aspirin initiated early in pregnancy among nulliparous individuals may mitigate the effects of heat exposure on preterm birth. The increasing global prevalence of heat stress warrants testing its efficacy more broadly among pregnant people as well as its safety with respect to perinatal mortality. Trial Registration ClinicalTrials.gov Identifier: NCT02409680

OBJECTIVES:Fetal death is a major pregnancy complication, with rates of 5.5 per 1,000 births in the United States and substantially higher in India (24.7/1,000) and Pakistan (44.5/1,000). Maternal vascular malperfusion (MVM) is the most frequent placental lesion associated with fetal death, occurring in 58 % of fetal deaths and 31 % of preterm neonatal deaths in South Asia. Angiogenic imbalance, characterized by a low placental growth factor (PlGF) to soluble fms-like tyrosine kinase-1 (sFlt-1) ratio, has been associated with MVM and fetal death in high-income countries. We examined whether maternal serum concentrations of PlGF, sFlt-1, and their ratio differ between mothers with and without MVM among stillbirths and preterm neonatal deaths in India and Pakistan. METHODS:This retrospective cohort analysis used data from the PURPOSe study (Project to Understand and Research Preterm Pregnancy Outcomes and Stillbirths in South Asia). Maternal blood was collected at delivery, and placental histopathology was classified according to the Amsterdam criteria. Serum PlGF and sFlt-1 were measured using Elecsys® immunoassays, with analyses stratified by gestational age. RESULTS:Placental MVM was present in 44-57 % of stillbirths and 31-38 % of preterm neonatal deaths. Between 28 and 36 weeks, women with MVM had significantly lower PlGF and higher sFlt-1 and sFlt-1/PlGF ratios (p<0.001). A tenfold decrease in PlGF or increase in the ratio was associated with MVM (OR 0.5 and 1.7, respectively). CONCLUSIONS:The maternal sFlt-1/PlGF ratio identifies pregnancies with fetal or neonatal death associated with placental MVM, particularly between 28 and 36 weeks' gestation.

To develop effective HIV prevention strategies to guide public health policy the main sources of infection in HIV prevention studies must be identified. Accordingly, we devised a statistical approach that estimates the relative contribution of different sources of infection in community-randomized trials of infectious disease prevention using deep- (or next generation) sequenced pathogen data. We applied this approach to the Botswana Combination Prevention Project (BCPP) and estimated that 90% [95% Confidence Interval (CI): 80-94] of new infections in communities that received combination prevention (including universal HIV test-and-treat) originated from individuals residing in communities outside the trial area. We estimate from our model that the relative benefit of providing the BCPP intervention to all communities nationwide would be a 59% [3-87] reduction in transmissions to recipients in trial communities, exceeding the 30% reduction observed when providing the BCPP intervention to trial communities only. Our results suggest that the impact of the BCPP trial intervention was curtailed by sources of transmission outside the trial area and could be considerably larger if applied nationally. We recommend that the impact of sources of transmission beyond the reach of the intervention be considered when designing and evaluating interventions to inform public health programs.

Importance:Scalable interventions are urgently needed to mitigate the adverse effects of heat on pregnancy and newborn health. Objective:To evaluate whether low-dose aspirin modifies the association between heat exposure and preterm birth. Design, Setting, and Participants:This secondary analysis of the Global Network for Women's and Children's Health Research Aspirin Supplementation for Pregnancy Indicated Risk Reduction in Nulliparas (ASPIRIN) randomized, double-blinded, placebo-controlled clinical trial was conducted from March 2016 to June 2018. Statistical analyses were performed from June 2024 to June 2025. The study settings included the Democratic Republic of Congo, Zambia, Kenya, Guatemala, Pakistan, and Belagavi and Nagpur, India. Participants included nulliparous individuals between 6 and 13 weeks' gestation recruited through local clinics and communities, with delivery at 20 or more weeks' gestation. Exposures:Prenatal care site-specific daily maximum humid heat averaged across gestation and by gestational week, and randomization to aspirin or placebo. Main Outcome and Measure:The main outcome was preterm birth (delivery between 20 and <37 weeks' gestation) with gestational age confirmed by enrollment ultrasonography. Results:Of 11 558 participants (mean [SD] age, 20.9 [3.3] years), 5787 were randomized to receive aspirin and 5771 to receive placebo. Preterm birth occurred among 754 placebo recipients (13.1%) and 668 aspirin recipients (11.6%). In mixed-effects pooled logistic regression, each 1 °C increase in mean daily maximum shaded wet-bulb globe temperature across gestation was associated with a 5% increased odds of preterm birth (adjusted odds ratio, 1.05; 95% CI, 1.01-1.10). In stratified analyses, this increased risk was observed only among placebo recipients (adjusted odds ratio [AOR], 1.07; 95% CI, 1.02-1.13), not among aspirin recipients (AOR, 1.03; 95% CI, 0.97-1.10). In pooled mixed-effects logistic distributed lag models, increased odds of preterm birth were observed 17 to 19 weeks before delivery among individuals whose daily maximum shaded wet-bulb globe temperature exceeded the site-specific 75th percentile compared with the lowest 3 quartiles. This vulnerability was not observed among aspirin recipients. In contrast, the association of heat with perinatal mortality was observed only among those receiving aspirin (AOR, 1.15; 95% CI, 1.05-1.26) and not among those receiving placebo (AOR, 1.03; 95% CI, 0.96-1.11). Conclusions and Relevance:The findings of this secondary analysis of the Global Network ASPIRIN trial suggest that low-dose aspirin initiated early in pregnancy among nulliparous individuals may mitigate the effects of heat exposure on preterm birth. The increasing global prevalence of heat stress warrants testing its efficacy more broadly among pregnant people as well as its safety with respect to perinatal mortality. Trial Registration:ClinicalTrials.gov Identifier: NCT02409680.

ObjectiveTo describe the intrapartum and postpartum use of non-study antibiotics in low- and middle-income countries (LMICs) during the double-blinded NICHD Global Network Azithromycin in Labor (A-PLUS) trial.DesignThe antibiotic use sub-study was a planned prospective, observational sub-study of the A-PLUS trial.SettingsThe study was carried out in hospitals or health centres affiliated with eight sites of the Global Network for Women's and Children's Health Research (Global Network) in seven countries: Bangladesh, Pakistan, India (two sites), Kenya, Zambia, The Democratic Republic of the Congo (DRC) and Guatemala.PopulationTotally, 29 278 pregnant women enrolled in the A-PLUS trial.MethodsWe collected data on 29 278 pregnant women admitted to a facility for delivery related to non-study antibiotic use overall and during three time periods: (1) in the facility prior to delivery, (2) after delivery until facility discharge and (3) after discharge to 42 days post-partum.Main Outcome MeasuresNon-study antibiotic use overall and for treatment or prophylaxis by the site during the three time periods.ResultsOf the 29 278 women in the study, 5020 (17.1%; 95% CI 16.7%-17.6%) received non-study antibiotics in the facility prior to delivery, 11 956 (40.8%; 95% CI 40.3%-41.4%) received non-study antibiotics in the facility after delivery, and 13 390 (47.6%; 95% CI 47.0%-48.2%) women received non-study antibiotics after delivery and after facility discharge. Antibiotics were prescribed more often among women in the Asian and Guatemalan sites than in the African sites. In the three time-periods, among those receiving antibiotics, prophylaxis was the indication in 82.3%, 97.7% and 90.7% of the cases, respectively. The type of antibiotics used varied substantially by time-period and site, but generally, penicillin-type drugs, cephalosporin-type drugs and metronidazole were used more frequently than other types.ConclusionsAcross the eight sites of the Global Network, in the facility before delivery, and in the post-partum periods before and after facility discharge, antibiotics were used frequently, but use was highly variable by site and time-period.

Background The Azithromycin Prevention in Labor Use Study (A-PLUS), a large, multi-national randomized trial, was performed to evaluate the improvement of maternal and newborn outcomes following a single dose of azithromycin (AZ) given during labor. However, the immediate and long-term impact of this single dose on the microbiome and the development or prevalence of antimicrobial resistance are unknown. We designed a sub-study to assess AZ resistance of bacterial isolates from clinical infections and of three target bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli) from the serial surveillance of the nasopharynx and rectum. Additionally, the serially surveilled samples will be evaluated for changes to the microbiome and the resistome of the nasopharynx and rectum. Methods and Analysis As part of the large, randomized APLUS trial, maternal and neonatal clinical infections were monitored for up to 42 days postpartum, and samples collected for culture using site-specific routine methods. For this sub-study, cultured bacterial isolates will be assessed for AZ resistance using an antibiotic susceptibility method. Additionally, a random subset of maternal-neonatal dyads from the main trial will be selected for serial surveillance with aseptic swab collections of the nasopharynx and the rectum at baseline, and subsequently at 1-week, 6-weeks, 3-months, 6-months, and 12-months postpartum. The serial samples will undergo selective culturing of sentinel bacterial species and screened for AZ resistance. An additional set of serial samples will be stored for future microbiome and resistome analyses. Ethics and Dissemination The study protocol was reviewed, and ethics approval obtained from all the relevant ethical review boards at each research site. All participants will provide informed written consent prior to their enrollment. Results of the trial will be disseminated through peer-reviewed publications, presentations at relevant conferences, and at dissemination meetings with the ministries of health and local stakeholders at each research site. Trial Registration NCT03871491.

To develop effective HIV prevention strategies that can guide public health policy it is important to identify the main sources of infection in HIV prevention studies. Accordingly, we devised a statistical approach that leverages deep– (or next generation) sequenced pathogen data to estimate the relative contribution of different sources of infection in community–randomized trials of infectious disease prevention. We applied this approach to the Botswana Combination Prevention Project (BCPP) and estimated that 90% [95% Confidence Interval (CI): 81 – 93] of new infections that occurred in individuals in communities that received combination prevention (including universal HIV test–and–treat) originated from individuals residing in communities outside of the trial area. We estimate that the relative impact of the intervention was greater in rural geographically isolated communities with limited opportunity for imported infections compared to communities neighboring major urban centers. Treating people with HIV limits the spread of infection to uninfected individuals; accordingly, counterfactual modeling scenarios estimated that a nationwide application of the intervention could have reduced transmissions to recipients in trial communities by 59% [3 – 87], much higher than the observed 30% reduction. Our results suggest that the impact of the BCPP trial intervention was substantially limited by sources of transmission outside the trial area, and that the impact of the intervention could be considerably larger if applied nationally. We recommend that studies of infectious disease prevention consider the impact of sources of transmission beyond the reach of the intervention when designing and evaluating interventions to inform public health programs. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT01965470 ### Funding Statement This study was supported by the National Institute of General Medical Sciences (U54GM088558); the Fogarty International Center (FIC) of the U.S. National Institutes of Health (D43 TW009610); and the President′s Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention (CDC) (Cooperative agreements U01 GH000447 and U2G GH001911), NIH K24 AI131928 as well as the Morris-Singer Fund, the VK Fund for the Harvard Center for Communicable Disease Dynamics and the Bill and Melinda Gates Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial was given ethical approval by the Botswana Health Research and Development Committee, the institutional review board of the Centers for Disease Control and Prevention and the Harvard School of Public Health Office of Regulatory Affairs and Research Compliance; and was monitored by a data and safety monitoring board and Westat. Written informed consent for enrollment in the trial and viral HIV genotyping was obtained from all participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All relevant data are within the paper, figures and tables. A code repository has been made available at the following URL: https://github.com/magosil86/spillover-infections

The corona virus disease (COVID-19) pandemic disrupted daily life worldwide, and its impact on child well-being remains a major concern. Neighborhood characteristics affect child well-being, but how these associations were affected by the pandemic is not well understood. We analyzed data from 1039 children enrolled in the Environmental influences on Child Health Outcomes Program whose well-being was assessed using the Patient-Reported Outcomes Measurement Information System Global Health questionnaire and linked these data to American Community Survey (ACS) data to evaluate the impacts of neighborhood characteristics on child well-being before and during the pandemic. We estimated the associations between more than 400 ACS variables and child well-being t-scores stratified by race/ethnicity (non-Hispanic white vs. all other races and ethnicities) and the timing of outcome data assessment (pre-vs. during the pandemic). Network graphs were used to visualize the associations between ACS variables and child well-being t-scores. The number of ACS variables associated with well-being t-scores decreased during the pandemic period. Comparing non-Hispanic white with other racial/ethnic groups during the pandemic, different ACS variables were associated with child well-being. Multiple ACS variables representing census tract-level housing conditions and neighborhood racial composition were associated with lower well-being t-scores among non-Hispanic white children during the pandemic, while higher percentage of Hispanic residents and higher percentage of adults working as essential workers in census tracts were associated with lower well-being t-scores among non-white children during the same study period. Our study provides insights into the associations between neighborhood characteristics and child well-being, and how the COVID-19 pandemic affected this relationship.

Background: Hypertensive disorders of pregnancy (HDP) remain a primary contributor for maternal and perinatal death and results in long-term health risks for both the mother and child. Heterogeneous studies have evaluated the possible benefit of low dose aspirin (50 to 150 mg per day) in pregnancy to minimize the risk of HDP. Objective: To assess the impact of low-dose Aspirin (LDA) starting in early pregnancy on delaying preterm hypertensive disorders of pregnancy. Methodology: This was a non-prespecified secondary analysis of a randomized masked trial of Low-dose Aspirin (LDA). Nulliparous singleton pregnancies between 6 weeks and 0 days and 13 weeks 6 days in 6 low- middle income countries (Democratic Republic of Congo, Guatemala, India, Kenya, Pakistan, Zambia) enrolled in the ASPIRIN Trial were included. The incidence of HDP at delivery at three gestational age periods (< 37 weeks) between women who were randomized to Aspirin or Placebo. Women were included if they were randomized and had an outcome at or beyond 20 weeks (Modified Intent to Treat). Results: Amongst the 11,976 pregnancies, LDA did not significantly lower HDP at delivery. Conclusion: In low-risk nulliparous singleton pregnancies, early administration of LDA resulted in lower rates of preterm HDP and delivery before 34 and 37 weeks. LDA works in part by delaying HDP.

BackgroundFew studies have assessed the impact of first-trimester malaria infection during pregnancy. We estimated this impact on adverse maternal and pregnancy outcomes.MethodsIn a convenience sample of women from the ASPIRIN (Aspirin Supplementation for Pregnancy Indicated risk Reduction In Nulliparas) trial in Kenya, Zambia, and the Democratic Republic of the Congo, we tested for first-trimester Plasmodium falciparum infection using quantitative polymerase chain reaction. We estimated site-specific effects on pregnancy outcomes using parametric g-computation.ResultsCompared to uninfected women, we observed the adjusted site-specific prevalence differences (PDs) among women with first-trimester malaria of the following pregnancy outcomes: preterm birth among Congolese (aPD = 0.06 [99% CI: -0.04, 0.16]), Kenyan (0.03 [-0.04, 0.09]), and Zambian (0.00 [-0.10, 0.20]) women; low birth weight among Congolese (0.07 [-0.03, 0.16]), Kenyan (0.01 [-0.04, 0.06]) and Zambian (-0.04 [-0.13, 0.16]) women; spontaneous abortion among Congolese (0.00 [-0.05, 0.04]), Kenyan (0.00 [-0.04, 0.04]), and Zambian (0.02 [-0.07, 0.24]) women, and anemia later in pregnancy among Congolese (0.04 [-0.09, 0.16]), Kenyan (0.05 [-0.06, 0.17]), and Zambian (0.07 [-0.12, 0.36]) women. The pooled PD for anemia later in pregnancy (26-30 weeks) was 0.08 [99% CI: 0.00, 0.16].ConclusionsFirst-trimester malaria was associated with increased prevalence of anemia later in pregnancy. We identified areas for further investigation including effects of first-trimester malaria on preterm birth and low birth weight.

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.

OBJECTIVES:Antibiotic use is increasing in low- and middle-income countries (LMIC); however, few studies have examined the rates of use in a population. The use of antibiotics for liveborn infants in LMIC was examined. DESIGN:The study, a planned prospective, observational secondary analysis of the A-PLUS randomised controlled trial of azithromycin, was conducted in Global Network sites in seven countries: Bangladesh, Pakistan, India (two sites), Kenya, Zambia, the Democratic Republic of Congo and Guatemala. The analyses included liveborn infants of women planning a vaginal delivery who were enrolled in the A-PLUS trial. METHODS:Data were collected on liveborn infants related to non-study antibiotic use in two time-periods: (i) after delivery while in the facility, and (ii) after discharge until 42 days post-partum. Antibiotic use was also examined in preterm and term infants. The most commonly used antibiotics were classified into three groups: penicillins, cephalosporins and aminoglycosides. Antibiotics used in <1% of infants are not presented. RESULTS:Of the 29,354 eligible infants in the study, 2224 (7.6%, 95% CI 7.3-7.9) received non-study antibiotics in the facility after delivery, and 3847 (13.1%, 95% CI 12.7-13.5) received non-study antibiotics after facility discharge until Day 42. In the facility, antibiotics were given to newborns more frequently in sites in Asia and less frequently in sites in Africa and Guatemala. Similarly, after facility discharge, infants were more likely to receive antibiotics in the Asian sites and less so in the African sites and Guatemala. In the facilities, antibiotics were used predominately for prophylaxis (70.7%) but after facility discharge antibiotics were given more often for treatment (56.8%). Preterm infants received more non-study antibiotics than term infants. The antibiotics used varied substantially by time-period and site but, in general, penicillins, cephalosporins and aminoglycosides were the antibiotic categories used more frequently. CONCLUSIONS:Across the Global Network sites, which represent a range of LMIC, nearly 8% of infants received non-study antibiotics more often for prophylaxis, with 13% of infants receiving non-study antibiotics following hospital discharge. With concerns about increasing antimicrobial resistance worldwide, further attention should be given to appropriate antibiotic use.

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.

Guidelines recommend prescribing low-dose aspirin (LDA) to at-risk pregnant women for the prevention of preeclampsia; however, the impact of antenatal LDA on neurodevelopment is limited. We therefore sought to determine if there were differences in neurodevelopment in children whose mothers had been antenatally randomized to LDA or a placebo. We performed a non-inferiority masked neurodevelopmental follow-up study of a randomly selected subset of children between 33 and 39 months of age in five Low-Middle Income Countries whose mothers had participated in a randomized trial of daily LDA (81mg) or an identical placebo, initiated between 6 weeks and 0 days and 13 weeks and 6 days of pregnancy. LDA was continued to 36 weeks of gestation or birth if it occurred earlier. Children were excluded if they had a significant congenital anomaly that would preclude testing. Children were evaluated using the Bayley Scale of Infant Development-III (BSID-III) and the Ages and Stages Questionnaire 3rd Edition (ASQ-3). Our primary outcome was the cognitive composite score of the BSID-III with the threshold of non-inferiority being defined as a ≥ 4-point difference. A total of 644 children (330 LDA and 314 placebo) were evaluated. Maternal and delivery characteristics did not differ between the two groups (table 1). The cognitive composite score of the BSID-III was non-inferior and did not differ between the two groups (LDA 96± 10 SD vs. Placebo 97± 10, p=0.25). No differences were seen in the BSID-III language composite score (LDA 101± 13 SD vs. Placebo 100± 14, p=0.38) or BSID-III the motor composite score (LDA 99± 13 SD vs. Placebo 100± 14, p=0.50). No differences in the communication, gross motor, fine motor, problem solving and personal-social components of the ASQ-3 were detected. Breastfeeding rates, breastfeeding duration, maternal education, and home environment as measured by the Family Care Indicators did not differ between the two groups. Antenatal LDA exposure beginning as early 6 weeks gestation is not associated with neurodevelopmental delay at 33 to 39 months of age.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

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.

BACKGROUND:The Aspirin Supplementation for Pregnancy Indicated Risk Reduction In Nulliparas trial was a landmark study that demonstrated a reduction in preterm birth and hypertensive disorders of pregnancy in nulliparous women who received low-dose aspirin. All women in the study had at least 1 moderate-risk factor for preeclampsia (nulliparity). Unlike current US Preventative Service Task Force guidelines, which recommend low-dose aspirin for ≥2 moderate-risk factors, women in this study were randomized to receive low-dose aspirin regardless of the presence or absence of an additional risk factor. OBJECTIVE:This study aimed to compare how low-dose aspirin differentially benefits nulliparous women with and without additional preeclampsia risk factors for the prevention of preterm birth and hypertensive disorders of pregnancy. STUDY DESIGN:This was a non-prespecified secondary analysis of the Aspirin Supplementation for Pregnancy Indicated Risk Reduction In Nulliparas trial that randomized nulliparous women with singleton pregnancies from 6 low-middle-income countries to receive low-dose aspirin or placebo. Our primary exposure was having an additional preeclampsia risk factor beyond nulliparity. Our primary outcome was preterm birth before 37 weeks of gestation, and our secondary outcomes included preterm birth before 34 weeks of gestation, preterm birth before 28 weeks of gestation, hypertensive disorders of pregnancy, and perinatal mortality. RESULTS:Among 11,558 nulliparous women who met the inclusion criteria, 66.8% had no additional risk factors. Low-dose aspirin similarly reduced the risk of preterm birth at <37 weeks of gestation in women with and without additional risk factors (relative risk: 0.75 vs 0.85; P=.35). Additionally for our secondary outcomes, low-dose aspirin similarly reduced the risk of preterm birth at <28 weeks of gestation, hypertensive disorders of pregnancy, and perinatal mortality in women with and without additional risk factors. The reduction of preterm birth at <34 weeks of gestation with low-dose aspirin was significantly greater in women without additional risk factors than those with an additional risk factor (relative risk: 0.69 vs 1.04; P=.04). CONCLUSION:Low-dose aspirin's ability to prevent preterm birth, hypertensive disorders of pregnancy, and perinatal mortality was similar in nulliparous women with and without additional risk factors. Professional societies should consider recommending low-dose aspirin to all nulliparous women.

Objective To better understand maternal morbidity, using quality data from low- and middle-income countries (LMICs), including out-of-hospital deliveries. Additionally, to compare to the WHO estimate that maternal morbidity occurs in 15% of pregnancies, which is based largely on hospital-level data. Methods The Global Network for Women's and Children's Health Research Maternal Newborn Health Registry collected data on all pregnancies from seven sites in six LMICs between 2015 and 2020. Rates of maternal mortality and morbidity and the differences in morbidity across delivery location and birth attendant type were evaluated. Results Among the 280 584 deliveries included in the present analysis, the overall maternal mortality ratio was 138 per 100 000, while 11.7% of women experienced at least one morbidity. Rates of morbidity were generally higher for deliveries occurring within hospitals (19.8%) and by physicians (23.6%). The lowest rates of morbidity were noted among women delivering in non-hospital healthcare facilities (5.6%) or with non-physician clinicians (e.g. nurses, midwives [5.4%]). Conclusion The present study shows important differences in reported maternal morbidity across delivery sites, with a trend towards lower morbidity in non-hospital healthcare facilities and among non-physician clinicians.

Background Premature birth is associated with an increased risk of mortality and morbidity, and strategies to prevent preterm birth are few in number and resource intensive. In 2020, the ASPIRIN trial showed the efficacy of low-dose aspirin (LDA) in nulliparous, singleton pregnancies for the prevention of preterm birth. We sought to investigate the cost-effectiveness of this therapy in low-income and middle-income countries. Methods In this post-hoc, prospective, cost-effectiveness study, we constructed a probabilistic decision tree model to compare the benefits and costs of LDA treatment compared with standard care using primary data and published results from the ASPIRIN trial. In this analysis from a health-care sector perspective, we considered the costs and effects of LDA treatment, pregnancy outcomes, and neonatal health-care use. We did sensitivity analyses to understand the effect of the price of the LDA regimen, and the effectiveness of LDA in reducing both preterm birth and perinatal death. Findings In model simulations, LDA was associated with 141 averted preterm births, 74 averted perinatal deaths, and 31 averted hospitalisations per 10 000 pregnancies. The reduction in hospitalisation resulted in a cost of US$248 per averted preterm birth, $471 per averted perinatal death, and $15middot95 per disability-adjusted life year. Interpretation LDA treatment in nulliparous, singleton pregnancies is a low-cost, effective treatment to reduce preterm birth and perinatal death. The low cost per disability-adjusted life year averted strengthens the evidence in support of prioritising the implementation of LDA in publicly funded health care in low-income and middle-income countries. Lancet 11: See Department University Chapel USA International, Triangle (S J Jawaharlal College, Belagavi, (Prof M Department Gynecology, University, USA Department

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.