OBJECTIVE:A multi-centre international trial (A-PLUS), demonstrated that a single dose of 2 g oral azithromycin in labour reduced the risk of maternal sepsis or death, but not neonatal mortality. We aimed to determine whether the efficacy of azithromycin in prevention of any maternal infection or neonatal infection varied by time interval from azithromycin administration to delivery. DESIGN:This is a secondary analysis of a randomized controlled trial. SETTING:Multi-centre international randomized controlled trial. POPULATION:Pregnant patients ≥ 28 weeks gestation (singleton or multiple gestation) presenting in labour for planned vaginal delivery. OUTCOMES:The primary outcome for this secondary analysis was maternal infection and the secondary outcome was any neonatal infection. METHODS:The estimated relative risks (and 95% confidence interval) of any maternal or neonatal infection comparing azithromycin to placebo were obtained by fitting a Poisson model adjusting for site, treatment arm, hours between drug administration and delivery (as continuous measure, and ≤ 12 or > 12 h for maternal and ≤ 9 or > 9 h for neonatal), and the two-way interaction between treatment arm and hours between drug administration and delivery. RESULTS:Included in the analysis were n = 14 569 randomized to azithromycin and n = 14 667 to placebo. There was no evidence that the benefit of azithromycin on reducing the risk of any maternal infection varied by time from dose to delivery (RR 0.71 (0.64-0.79) and RR 0.71 (0.54-0.94) for ≤ 12 and > 12 h respectively, interaction p = 0.987), although there was an observed interaction in Sub-Saharan Africa subgroup with reduced risk observed with administration > 12 vs. ≤ 12 (RR 0.21 (0.08-0.54) vs. RR 0.52 (0.41-0.66), interaction p = 0.03). There was no benefit observed in prevention of infant infection regardless of time from dose to delivery (≤ 9 or > 9 h) (RR 1.00 (0.95-1.06) and RR 1.01 (0.88-1.15) interaction p = 0.997). CONCLUSION:The benefit observed with a single intrapartum dose of azithromycin for prevention of any maternal infection in the setting of planned vaginal delivery was not observed to vary by time interval from azithromycin administration to delivery, although in some populations there may be greater benefit with delivery > 12 h from administration. Pregnant patients presenting for planned vaginal birth benefit from a single dose of 2 g azithromycin regardless of how soon delivery is anticipated.

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.

Background Postpartum haemorrhage is a leading cause of maternal death globally. To support earlier diagnosis and treatment of the condition, in 2025, WHO introduced new diagnostic criteria based on objectively measured blood loss of 300 mL or more with any abnormal haemodynamic sign, or 500 mL or more, whichever occurs first within 24 h after birth. Our study aimed to assess the feasibility, fidelity, acceptability, clinical outcomes, management practices, and cost implications of applying the new criteria. Methods We conducted a prospective, multi-country, mixed-methods study in 18 primary, secondary, and tertiary facilities across Colombia, India, Kenya, Nigeria, Tanzania, and Thailand between July 24 and Oct 1, 2025. Eligible health workers received training on the diagnostic criteria and postpartum haemorrhage first-response treatment bundle. Observers prospectively recorded blood loss, haemodynamic signs, postpartum haemorrhage diagnoses, and treatments for all births over 5 consecutive weeks. Health workers completed pre-training and post-implementation surveys and participated in semi-structured interviews. Descriptive statistics were used for quantitative data and mean-unit-cost per woman was estimated. Quantitative and qualitative findings were integrated to generate triangulated inferences. Findings 5264 births were observed across the 18 participating facilities during the 5-week implementation period. 33·2% of births occurred in India, 20·4% in Tanzania, 16·3% in Kenya, 11·6% in Nigeria, 9·9% in Colombia, and 8·5% in Thailand. More than half (53·2%) of all births took place in tertiary-level facilities, 31·9% in secondary-level facilities, and 15·0% in primary care facilities. Objective blood loss volume and at least one postpartum clinical assessment were recorded for 82·8% (4361 of 5264) of births during the study period. Health workers considered the new criteria feasible (97·6%; 528 of 541) and acceptable (96·8%; 338 of 349). Overall incidence of postpartum haemorrhage was 20·8% (908 of 4361) using the new criteria compared with 14·7% (701 of 4760) using the conventional 500 mL or more threshold. Postpartum haemorrhage incidence with the new criteria was more than double for caesarean (30·7%; 560 of 1823) compared with vaginal birth (13·7%; 348 of 2538). During the 5-week implementation period, overall adherence with the new diagnostic criteria was 54·1% (491 of 908) but was much higher for vaginal (85·6%; 298 of 348) than caesarean births (34·5%; 193 of 560). All women diagnosed with postpartum haemorrhage received treatment. The additional weighted mean cost per woman treated was US$4·6 (range 1·9–8·9) while mean cost of escalating care was $70·1 with great variation based on countries’ practices (4·0–307·9). Health workers emphasised the need for reliable supply chains, strong leadership, and national procurement mechanisms to ensure that the criteria are consistently applied. Interpretation In routine clinical care settings, implementing the new postpartum haemorrhage diagnostic criteria was feasible and acceptable, and increased early diagnosis with modest additional treatment costs. Adherence observed in the short term suggests meaningful uptake although strengthened implementation processes, particularly for caesarean births, will be required to support sustained use and scale-up. Funding The Gates Foundation and the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, a co-sponsored programme executed by WHO.

Background:Screening for, detecting, and managing pregnancy hypertension is a core function of antenatal care. To reduce both training requirements and the risks of measurement error in blood pressure (BP) values, automated and semiautomated BP devices have been validated in pregnant women with normal BP and pregnant women with hypertension and introduced for serial antenatal measurement of BP. objectives:The study aimed to (1) determine whether or not repeated BP measurements reduced the presence of terminal digit preference and (2) discern whether or not there was evidence of threshold avoidance in the Community-Level Interventions for Preeclampsia (CLIP) trials compared with the purely observational Pregnancy Care Integrating Translational Science, Everywhere (PRECISE) cohorts. Methods:The BP 3AS1-2 and CRADLE Vital Signs Alert low-cost Microlife BP devices were used by trained research staff in the CLIP trials conducted in India, Mozambique, Nigeria (pilot trial only), and Pakistan and the PRECISE cohorts of unselected pregnant women and nonpregnant women of reproductive age recruited in the Gambia, Kenya, and Mozambique. Both devices algorithmically calculate systolic blood pressure and diastolic blood pressure values displayed on digital read-outs. All BP readings were entered manually into a digital platform, which averaged them as the BP for that visit; the first and second readings were averaged unless they were more than 10 mm Hg different, which triggered a third reading, and the second and third readings were averaged. Results:A total of 51,875 participants had their BP measured 438,404 times. Using raw BP values, there was terminal digit preference (129,539/911,500, 14.21% vs 10%; P<.001 values ended in zero). A total of 28,929 out of 437,446 (6.61%) dBP values were 62 mm Hg, compared with 9310 of 195,349 (4.77%) from the averaged values (P<.001); errors were obviated by averaging BP values. There was evidence of both threshold preference and avoidance in the CLIP trials and the PRECISE cohort. Conclusions:Given the excess of 62 mm Hg values, there is a shared inherent algorithmic error in the calculation of dBP in the BP 3AS1-2 and CRADLE Vital Signs Alert devices. Averaged BP measurements are important to reduce the impact of user errors in manually recording BP values. We recommend that automated and semiautomated BP devices should be connected wirelessly to automatically transfer readings to digital health records to further optimize care.

OBJECTIVE:To identify risk factors for bag and mask ventilation (BMV) and compare mortality outcomes between infants who did and did not receive BMV. STUDY DESIGN:Secondary analysis of data from the seven sites of the Global Network Maternal Newborn Health registry, including fresh stillbirths and live births ≥ 1500 grams from 2017 to 2023. RESULTS:A total of 171 279 births (98.9% live births, 1.1% fresh stillbirths) were included. BMV was administered in 3.9% of cases. Maternal education, labor complications, delivery location, and prematurity were identified as major risk factors for receiving BMV. Adjusted relative risks (95% CI) for very early neonatal mortality with BMV was 26.18 (23.02-29.79), early neonatal mortality 19.08 (17.40-20.93), neonatal mortality 14.23 (13.08,15.49, mortality < 42 days 12.86 (11.84,13.97) and asphyxia-related deaths was and 2.42 (2.11, 2.77). CONCLUSION:These finding underscore the importance of early identification of maternal and perinatal factors associated with receiving BMV to improve neonatal outcomes.

OBJECTIVE:To evaluate the association between 2 g of intrapartum azithromycin given to laboring mothers and neurodevelopmental outcomes after birth asphyxia. METHODS:This was a neurodevelopmental follow-up study of children born at 34 weeks of gestation or later who had concern for asphyxia and whose mothers were enrolled in A-PLUS (the Azithromycin Prevention in Labor Use Study). Mothers in A-PLUS were randomized to receive a single oral dose of azithromycin (2 g) or placebo during labor. This follow-up to A-PLUS spanned six sites across five countries (India [two sites], Pakistan, Zambia, Democratic Republic of Congo, and Guatemala). Asphyxia was defined as 5-minute Apgar score less than 7 or the need for bag-and-mask ventilation at birth. The primary outcome was the CCS (Cognitive Composite Score) of the BSID-III (Bayley Scales of Infant and Toddler Development, 3rd Edition) at a corrected age of 24±1 months. Secondary outcomes included the LCS (Language Composite Score) and MCS (Motor Composite Score) of the BSID-III at a corrected age of 24±1 months. Masked examiners administered the BSID-III and the ASQ-3 (Ages & Stages Questionnaires, 3 rd Edition). Outcomes were analyzed using a generalized linear model and were adjusted for site, gestational age at delivery, and maternal and child baseline characteristics that differed between treatment groups. RESULTS:Of 529 eligible mother-child dyads screened, 403 (197 in the azithromycin arm and 206 in the placebo arm) were enrolled and completed the neurodevelopmental follow-up at a corrected age of 24±1 months. The primary outcome, the CCS of the BSID-III, did not differ significantly between groups (azithromycin: 90.9±11.2 vs placebo: 90.9±11.7; mean difference: 0.29; 95% CI, -1.77 to 2.34). No significant differences were observed between treatment arms in the BSID-III's LCS and MCS or in the total scores of the ASQ-3's five domains. Subgroup analysis by region (sub-Saharan Africa vs South Asia) also showed no differences in BSID-III or ASQ-3 scores between the azithromycin and placebo groups. CONCLUSION:In this follow-up study, a single oral dose of azithromycin given to laboring mothers who delivered neonates with birth asphyxia did not improve neurodevelopmental outcomes at 2 years of age. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, NCT03871491.

OBJECTIVE:The randomized trial of azithromycin to reduce maternal and neonatal sepsis (the A-PLUS Trial) found substantial reduction in maternal sepsis among women receiving azithromycin and substantial non-study antibiotic use. This secondary analysis explored the effect modification of non-study antibiotics on azithromycin versus placebo on maternal and newborn infection among A-PLUS participants. METHODS:Women ≥28 weeks gestation in labor and planning a vaginal delivery at a study hospital in seven low- and middle-income countries (Bangladesh, India [two sites], Pakistan, Guatemala, Kenya, Democratic Republic of Congo, and Zambia) were eligible for inclusion. Non-study antibiotic use was collected prospectively. We estimated the interaction of non-study antibiotics with azithromycin versus placebo on maternal and newborn sepsis. RESULTS:A total of 29 287 participants were randomized (14 590 to azithromycin; 14 688 to placebo). Maternal infection was reduced among the azithromycin group compared to placebo among those who did not receive non-study antibiotics, with estimated relative risk (RR) 0.58 (95% confidence interval [CI] 0.48, 0.70), and among those who received non-study antibiotics, with RR 0.80 (95% CI 0.70, 0.91). Similar results were observed for maternal sepsis. Neonatal infection was not significantly reduced in any group. These results were similar when stratified by African and Asian region but not statistically significant. CONCLUSION:Our results suggest a benefit of azithromycin in reducing maternal infection or sepsis across all groups, with a larger reduction in risk among participants who had not received other antibiotics. Given the concerns of inappropriate use of antibiotics, further research is warranted to determine the most effective strategies of reducing risk of infection.

OBJECTIVE:A single oral dose of azithromycin (AZM) given during labor to women planning a vaginal delivery reduced maternal infections including sepsis, with a stronger effect in sub-Saharan Africa than South Asia. Since maternal infection contributes to labor dysfunction and postpartum hemorrhage (PPH), we evaluated the effect of AZM on the risk of PPH and blood transfusion. METHODS:This was an unplanned secondary analysis of the Azithromycin Prevention in Labor Use Study (A-PLUS) randomized controlled trial at eight sites in seven low- and middle-income countries in sub-Saharan Africa, South Asia, and Latin America. The population consisted of pregnant women in labor at ≥28 weeks' gestation in health facilities randomized to either 2 g AZM or placebo. Based on an intent-to-treat analysis, the risk of PPH and blood transfusion was compared between AZM and placebo arms using Poisson regression adjusting for arm and site as fixed effects. The main outcome measures were (1) PPH (500 mL or greater) after delivery; and (2) postpartum blood transfusion after delivery. RESULTS:A total of 29 278 participants were randomized to APLUS; 14 590 to AZM and 14 688 to placebo. The risk of PPH did not significantly differ between AZM and placebo arms (1.4% in AZM; 1.6% in placebo; relative risk [RR] = 0.88; 95% confidence interval [CI]: 0.73, 1.07). The risk of blood transfusion also did not significantly differ between AZM and placebo arms (0.5% in AZM; 0.5% in placebo; RR = 0.90; 95% CI: 0.65, 1.25). There was also evidence indicating that the effect of AZM on the risk of blood transfusion, but not PPH, was beneficial in sub-Saharan Africa but not in South Asia (P value for two-way interaction = 0.002). CONCLUSION:A single intrapartum oral dose of AZM did not significantly reduce the overall risk of PPH or blood transfusion. CLINICALTRIALS:gov Identifier: NCT03871491.

Globally, more than two million perinatal deaths occur annually attributable to the intrapartum period, the vast majority occurring in low- and middle-income countries (LMICs). We sought to ascertain the incidence of adverse neonatal intrapartum-related outcomes and associated risk factors in tertiary referral centers in LMICs. The Limiting Adverse Birth Outcomes in Resource-limited settings (LABOR) Study was a prospective intrapartum observational cohort of women and their fetuses in Ghana, India and Zambia enrolled from 2019 to 2022 and followed through 42 days postpartum. Women with a singleton pregnancy admitted to the labor ward for a vaginal birth were eligible for inclusion; additionally, women admitted for a cesarean birth were eligible if they also had signs/symptoms of labor, elevated blood pressure or fever on admission. Among the 16,369 eligible participants, all 16,369 were approached; of these, 2315 refused and 1982 were excluded. Of the 12,072 enrolled, we excluded an additional 1736 with pre-labor Cesarean birth, analyzing a cohort of 10,336 women for this manuscript. Our primary outcome was a composite of these secondary outcomes: intrapartum stillbirth, neonatal death, intrapartum-related neonatal encephalopathy and culture-proven early onset neonatal sepsis. We estimated the incidence of outcomes using binomial proportions and the adjusted risk of outcomes associated with baseline factors using generalized linear models. We included 10,336 women with a median age of 27; 1788 (17·3

ABSTRACT Objectives Limited population‐based data have evaluated COVID‐19 infections during pregnancy in low‐ and middle‐income countries (LMICs). We updated COVID‐19 antibody positivity rates and relationships to pregnancy outcomes in unvaccinated women in LMICs. Design COVID‐19 antibody testing was conducted for pregnant women at delivery. We evaluated pregnancy outcomes using data collected in a prospective registry. Setting The Maternal and Newborn Health Registry (MNHR) is a prospective, population‐based study in specific geographic communities in Kenya, Zambia, the Democratic Republic of the Congo (DRC), Bangladesh, Pakistan, India, and Guatemala. Methods From October 2020 to October 2021, we conducted COVID‐19 antibody testing at delivery among women enrolled in the MNHR ( n = 14 015). Results include women delivering from November 2021 to July 2022 ( n = 8204). Outcomes among women who were COVID‐19 positive versus negative at delivery were compared among women unvaccinated for COVID‐19. Outcome Measures COVID‐19 antibody positivity rates, stillbirth, neonatal mortality, maternal mortality, and morbidity. Results Vaccination among pregnant women increased from < 1% (October 2020–October 2021) to 30.4% (November 2021–June 2022). In the final period, COVID‐19 vaccination rates ranged from 0.1% in DRC to 67.4% in Guatemala. Among unvaccinated women, the antibody positivity rate overall was 14.0% (October 2020–December 2020), increasing to 69.5% during May–July 2022. Over time, antibody positivity rates increased until January 2022 for women in all sites, when the positivity rates remained relatively stable through July 2022. In the final period, antibody positivity rates ranged from 59.4% (DRC) to 88.0% (India). After adjusting for site and maternal characteristics, antibody positivity was not associated with any adverse fetal/neonatal outcome. Conclusions In the pregnant populations across seven LMICs, COVID‐19 infections occurred in over 50% of unvaccinated women overall. Adverse pregnancy outcomes, including preterm birth, low birthweight, stillbirth, neonatal death, and antepartum hemorrhage, were not increased in women who were antibody positive compared to women who were antibody negative in either time period.

BackgroundProphylactic oral azithromycin vs. placebo reduced maternal, but not neonatal, mortality/sepsis in the A-PLUS Randomized Trial. While prophylactic intrapartum azithromycin reduces maternal mortality/sepsis, it may promote antimicrobial resistance (AMR) in commensal bacteria,.MethodsRandomly selected women and their infants participating in A-PLUS were enrolled in a longitudinal cross-sectional sub-study to assess the presence of azithromycin resistance in selected bacteria in nasal cultures. Staphylococcus aureus and Streptococcus pneumoniae were cultured on selective agar, then azithromycin-containing agar to select for azithromycin resistant bacteria, identified biochemically. Azithromycin susceptibility was assessed by E-test. Nasal cultures were collected from women and infants between August 11, 2021 and September 18, 2023 during labor/day 1, day 7, 6 weeks, and 3, 6 and 12 months after delivery.ResultsThe study enrolled 911 women and 915 liveborn infants at 8 sites in 7 countries. Azithromycin resistance in S aureus was higher and azithromycin susceptibility was lower in women receiving azithromycin compared with those receiving placebo on day 7 (P < 0.001), 6 weeks (P < 0.001) and 3 months (P = 0.009) after delivery. Azithromycin resistance in S aureus was also higher and azithromycin susceptibility was lower 6 weeks after delivery (P < 0.001) in infants born to women receiving azithromycin, Azithromycin resistance in S. pneumoniae was too sparse to interpret.ConclusionsThere was an increase in prevalence of azithromycin resistance (or reduction in azithromycin susceptibility) in commensal nasal S. aureus between day 7, 6 weeks and 3 months in women exposed to azithromycin vs. placebo and only at 6 weeks in infants exposed to azithromycin vs. placebo. These differences between the azithromycin and placebo groups were no longer detected at 6 and 12 months post-partum in the women and after 6 weeks through 12 months in the infants.

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.

OBJECTIVE:To evaluate if the effect of low-dose aspirin (LDA) commenced between 6 and 13 weeks of gestational age (GA) on preterm delivery (PTD) is modified by total exposure. DESIGN:Post hoc analysis of a randomized controlled trial. SETTING:Hospitals in low-resource settings in Africa, Asia and Latin America. POPULATION:Outcomes were obtained for 11 908/11943 women at 6 0/7 to 13 6/7 weeks' GA randomized. METHODS:Women received prepackaged two-week medication allotments. Adherence was assessed by pill counts every 2 weeks. Estimated relative risk and 95% confidence interval data for each outcome at each GA of treatment initiation weeks were obtained by fitting a Poisson model to each outcome, adjusting for site, treatment arm and GA at treatment initiation. MAIN OUTCOMES MEASURES:The primary outcome was PTD. Secondary outcomes included PTD < 34 weeks and perinatal mortality including analysis by region. RESULTS:The median gestational age at treatment initiation was 10.1 weeks (IQR 8.6, 12.0). 85.5% of the mothers had over 90% adherence to treatment. For each 1 week increase of GA at treatment initiation, the treatment risk ratio did not change for PTD [RR 0.97 (95% CI, 0.93, 1.02)], PTD < 34 weeks [< 0.98 (0.89, 1.07)] or perinatal mortality [1.04 (0.96, 1.12)], with no evidence of effect modification. For each 5% increase in adherence, the treatment risk ratio did not change for PTD [1.01 (0.99, 1.04)], PTD < 34 weeks [< 0.99 (0.95, 1.03)] or perinatal mortality [1.02 (0.98, 1.06)], indicating no meaningful interaction with adherence. There was no effect modification by region. CONCLUSIONS:This analysis shows that the results of PTD, PTD < 34 weeks and perinatal mortality were not dependent on the timing of the initiation or adherence to treatment. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT02409680.

Background:India contributed to 17.3% of the global stillbirth burden in 2019 and anaemia, an important risk factor for stillbirth, affects nearly half of pregnant women in the country. To understand the relationship between maternal anaemia and stillbirth, we analysed a diverse multicohort dataset from the Stillbirth Pooled Indian Cohort Consortium (ICMR-SPIC) from India. Methods:This was a secondary analysis of the ICMR-SPIC dataset, which includes individual-level data from eight observational studies and two randomised controlled trials conducted across ten states in India. Most cohorts recruited participants between 2010 and 2023, except for the Pune Maternal Nutrition Study (PMNS), which recruited participants between 1994 and 1996. A total of 214,709 singleton pregnant women with known birth outcomes and haemoglobin measurements during pregnancy were included. Unadjusted and adjusted risk ratios for the association between maternal anaemia and stillbirth were estimated using modified Poisson regression for each cohort and pooled using a random-effects meta-analysis. Kaplan-Meier survival curves were estimated for foetal survival beyond 28 weeks of gestation across categories of anaemia severity. Findings:The median maternal age of the women was 23 years (IQR 21-25). There were 108,982 (52%) women with moderate to severe anaemia (haemoglobin [Hb] <10 g/dL) and 3595 (1.7%) stillbirths. We found that moderate to severe anaemia at any point during pregnancy was associated with a higher risk of stillbirth after 28 weeks of gestation (aRR 1.27, 95% CI 1.07-1.51). The risk ratio for severe anaemia (<7 g/dL) was 3.12 (95% CI 2.46-3.97), and for moderate anaemia it was 1.20 (95% CI 1.02-1.40) at any gestational age, compared to women with no or mild anaemia. We found that stillbirths occurred around the 29th week of gestation among pregnant women with severe anaemia, compared to around 31 weeks of gestation among other women. Interpretation:These findings highlight that maternal anaemia is an important and potentially modifiable risk factor for stillbirth, with severe anaemia associated with early occurrence of stillbirth. Policies aimed at reducing stillbirths should prioritise comprehensive anaemia prevention and treatment strategies among pregnant women. Funding:Indian Council of Medical Research.

Though low-dose aspirin (LDA) has increasingly been broadly implemented into clinical practice for the prevention of preeclampsia and other adverse pregnancy outcomes, its impact on reducing the overall rate of preeclampsia has been modest (10-20% decrease). When examined more closely, the clinical impact of LDA may actually be to the apparent delay of early onset preeclampsia before 34 weeks (EOPE). The findings may be the result of both pre-eclampsia and pre-term pre-eclampsia being a common phenotype of differing disease processes that are responsive to aspirin. Given that EOPE drives the majority of maternal and fetal/neonatal morbidity and mortality, such prevention may confer outsized long-term benefits for both mother and child.

BACKGROUND:In 2023, the Azithromycin Prevention in Labor Use (A-PLUS) trial showed intrapartum azithromycin reduces maternal sepsis or death in women with planned vaginal delivery in low-resource settings, but whether it reduces maternal infection is unknown. We aimed to evaluate the effectiveness of intrapartum azithromycin in reducing maternal infection. METHODS:We performed a post-hoc analysis of the multicentre, facility-based, randomised, double-blind, placebo-controlled A-PLUS trial. This trial compared prophylactic intrapartum single oral dose of 2 g azithromycin versus placebo on maternal morbidity and mortality in low-resource settings in southeast Asia and Africa from Sept 9, 2020, to Aug 18, 2022. The trial enrolled women in labour at 28 weeks' gestation (or later) at eight sites in the Democratic Republic of the Congo, Kenya, Zambia, Bangladesh, India, Pakistan, and Guatemala and found that azithromycin reduced the incidence of maternal sepsis or death. The primary outcome of the present analysis was the incidence of any maternal infection in the azithromycin versus placebo groups, which was defined as one or more of these infections after randomisation: chorioamnionitis, endometritis, perineal or caesarean wound infection, abdominopelvic abscess, mastitis or breast abscess, and other infections. Any neonatal infection was also analysed. All analyses were by intention to treat in all those with data available for that outcome. Relative risks (RRs) and 95% CIs were estimated with a Poisson model adjusted for treatment group and site. Subgroup analyses included a two-way interaction test between intervention group and subgroup. A-PLUS was registered at ClinicalTrials.gov, number NCT03871491. FINDINGS:29 278 women were randomly assigned to groups: 14 590 to receive azithromycin, 14 688 to receive placebo. Baseline characteristics were similar between the azithromycin and placebo groups (43·3% vs 43·4% primiparous, 8·5% vs 8·7% high risk for infection). The presence of any maternal infection occurred less often in the azithromycin group (580 [4·0%] of 14 558) compared with the placebo group (824 [5·6%] of 14 661 women; RR 0·71, 95% CI 0·64-0·79, p<0·0001). Any neonatal infection did not differ between treatment groups. Adverse events were not detected. INTERPRETATION:Among women planning vaginal delivery, this analysis provides evidence indicating that intrapartum azithromycin is associated with a lower incidence of maternal infections than placebo. FUNDING:The Eunice Kennedy Shriver National Institute of Child Health and Human Development and Bill and Melinda Gates Foundation via Foundation of National Institutes of Health. TRANSLATIONS:For the French and Spanish translations of the abstract see Supplementary Materials section.

Existing international consortia for drug trials in maternal and perinatal health have focused largely on pragmatic trials using off-label medicines. This study aimed to identify and assess the capacity and experience of sites in low- and middle-income countries (LMICs) for conducting trials for regulatory approval of medicines for pregnancy-related conditions. We systematically reviewed site assessment checklists across any disease area to develop a maternal trial site assessment checklist. The checklist was pretested, revised and used to collect data from trial sites in LMICs. Sites were systematically identified from a scoping review of maternal trials conducted in LMICs, known networks and snowball searching. Data reported by sites were verified against publicly accessible sources (clinical trial registries and published articles). We contacted 106 sites in 30 countries, of which 49 (46.2%) sites in 21 countries completed the checklist. Sites were from five regions—Sub-Saharan Africa (37), South Asia (6), Latin America and the Caribbean (4), Middle East and North Africa (1) and East Asia and the Pacific (1). More than 70% of responding sites had the requisite physical infrastructure, clinical and research staff, ethics, participant recruitment and data management services to conduct randomised trials. Respondents collectively identified 52 completed, ongoing or planned maternal trials across their sites. Of these 52 trials, 16 (30.8%) were Good Clinical Practice-compliant, 22 (42.3%) were phase III and one was a regulatory trial. 14 trials were conducted by a collaborative group established mostly for a specific trial or a small group of related trials. Only two of these groups were pre-established trial networks. While there is some capacity to conduct high-quality maternal drug trials in LMICs, effective research collaborations are needed to further strengthen and expand this capacity. Establishing a sustainable LMIC-based trial network will accelerate the development and testing of novel drugs to improve maternal and newborn health outcomes in these regions.