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.

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.

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: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.

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.

BACKGROUND:Nutrition supplements such as multiple micronutrient-fortified small-quantity lipid-based nutrient supplementation (SQ-LNS) consumed either before or during pregnancy have been shown to improve intrauterine growth, but the mechanisms through which the supplements improve intrauterine growth remain unclear. OBJECTIVES:We examined whether hemoglobin (Hb) during pregnancy could be a potential mechanism through which multiple micronutrient-fortified SQ-LNS improve intrauterine growth. METHODS:We used data collected from women and newborns in a randomized controlled trial conducted in Pakistan, India, the Democratic Republic of the Congo, and Guatemala. Women were randomly assigned to consume multiple micronutrient-fortified SQ-LNS from preconception until birth (arm 1); consume the SQ-LNS from the second trimester of pregnancy until birth (arm 2); or no supplement (arm 3). Intrauterine growth, expressed as birth length, weight, and head circumference Z-scores, was the outcome. The mediator was Hb (g/dL) measured at 12 (n = 2075) and 32 wk of gestation (n = 2157). Causal mediation analysis was employed to estimate direct and indirect effects. RESULTS:Hb levels at 12 or 32 wk of gestation did not mediate the relation between the SQ-LNS and intrauterine growth. Indirect effects of preconception SQ-LNS (arm 1) compared with arm 3, mediated by Hb at 12 wk of gestation, were 0.02 [95% confidence interval (CI): -0.02, 0.01], 0.01 (95% CI: -0.01, 0.02), and 0.01 (95% CI: -0.01, 0.02) for length, weight, and head circumference Z-scores, respectively. The corresponding direct effects (95% CIs), not mediated by Hb, were 0.18 (0.09, 0.33), 0.12 (0.03, 0.23), and 0.06 (-0.03, 0.20), respectively. Site-specific and gestational age-adjusted data analyses at 12 and 32 wk of gestation confirmed the findings of no statistically significant mediated effects of Hb during pregnancy. CONCLUSIONS:The observed main effect of multiple micronutrient-fortified SQ-LNS on intrauterine growth was not mediated by Hb levels at 12 or 32 wk of gestation. The findings suggest exploring other pathways implicated in the association between the SQ-LNS and intrauterine growth. This trial was registered at clinicaltrials.gov as #NCT01883193 (https://clinicaltrials.gov/ct2/show/NCT01883193?term=01883193&rank=1).

OBJECTIVE:To evaluate similarities in pathways leading to preterm stillbirth and preterm neonatal death. DESIGN:Prospective observational study. SETTING:Study hospitals in India and Pakistan. POPULATION:Preterm stillbirths and neonatal deaths ≥ 1000 g delivered in a study facility and evaluated by an expert panel for cause of death. METHODS:An observational study of stillbirths and preterm neonatal deaths. MAIN OUTCOME MEASURES:Asphyxia, placental maternal vascular malperfusion (MVM), maternal hypertension, fetal growth restriction (FGR). RESULTS:There were 398 preterm stillbirths and 582 preterm neonatal deaths in our study population. Of these, the panel determined asphyxia as a cause of death for 80.2% of the preterm stillbirths and 57.4% of the preterm neonatal deaths. Of the 319 preterm stillbirths with asphyxia, 62.4% also had placental MVM, while only 38.0% of the preterm stillbirths without birth asphyxia had MVM. Maternal hypertension was present among 44.5% of the stillbirths and FGR in 35.2%. Among the stillbirths with hypertension, 64.4% had asphyxia and MVM compared to 38.5% among those without hypertension. Similar patterns were seen among neonatal deaths. CONCLUSIONS:Both MVM and birth asphyxia were commonly present among stillbirths and neonatal deaths, especially those associated with hypertension and FGR compared to stillbirths and neonatal deaths without those conditions. These findings suggest that MVM and fetal asphyxia are part of a common pathway for stillbirth and preterm neonatal deaths.

BACKGROUND:Sepsis is one of the leading causes of maternal mortality globally. In 2023, the Azithromycin Prevention in Labor Use (A-PLUS) trial showed intrapartum azithromycin for women planning a vaginal birth reduced the risk of maternal sepsis or death and infection. We aimed to evaluate the cost-effectiveness of intrapartum azithromycin for pregnant people planning a vaginal birth in low-income and middle-income countries (LMICs) using A-PLUS trial data. METHODS:We compared the benefits and costs of intrapartum azithromycin versus standard care across 100 000 model simulations using data from the A-PLUS trial and a probabilistic decision tree model that included 24 mutually exclusive scenarios. A-PLUS was a randomised, double-blind, placebo-controlled trial that enrolled 29 278 women in labour at 28 weeks' gestation or more at eight sites in the Democratic Republic of the Congo, Kenya, Zambia, Bangladesh, India, Pakistan, and Guatemala. Women randomly assigned to azithromycin received a single intrapartum 2 g oral dose. In this cost-effectiveness analysis, we considered the cost of azithromycin treatment and its effects on a composite outcome of maternal infection, sepsis, or death and its individual components, and health-care use. Our analysis had a health-care sector perspective. We summarised results as an average and 95% CI of the model simulations. We also conducted sensitivity analyses. A-PLUS was registered at ClinicalTrials.gov, number NCT03871491. FINDINGS:In model simulations, intrapartum azithromycin resulted in 1592·0 (95% CI 1139·7 to 2024·1) cases of maternal infection, sepsis, or death averted per 100 000 pregnancies, yielding 248·5 (95·3 to 403·7) facility readmissions averted, 866·8 (537·8 to 1193·2) unplanned clinic visits averted, and 1816·2 (1324·5 to 2299·7) antibiotic regimens averted. Using mean health-care costs across the A-PLUS sites, intrapartum azithromycin resulted in net savings of US$32 661 (-52 218 to 118 210) per 100 000 pregnancies and 13·2 (8·3 to 17·9) disability-adjusted life-years averted. The cost of facility readmission, cost of azithromycin, and probability of infection had the greatest impact on the incremental cost. INTERPRETATION:In most cases, intrapartum azithromycin is a cost-saving intervention for the prevention of maternal infection, sepsis, or death in LMICs. This evidence supports global consideration of intrapartum azithromycin as an economically efficient preventive therapy to reduce infection, sepsis, or death among women planning a vaginal birth in LMICs. FUNDING:Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Foundation for the National Institutes of Health through the Maternal, Newborn, and Child Health Discovery and Tools Initiative of the Bill & Melinda Gates Foundation TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.

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.

OBJECTIVE:Adverse pregnancy outcomes, including preterm birth and preeclampsia, are associated with worse cardiovascular outcomes for offspring. Examination of the placenta is important for understanding how the prenatal period shapes long-term cardiovascular health. We sought to investigate the association between placental vascular malperfusion and fetal cardiac structure. STUDY DESIGN:Data obtained from the Stillbirth Collaborative Research Network included stillbirths with placental pathology and autopsy. Stillbirths were classified in two ways: based on the severity of placental maternal vascular malperfusion (MVM) and based on the cause of death (MVM, fetal vascular malperfusion [FVM], or acute infection/controls). Organ weight and heart measures were standardized by gestational age (GA) and compared across groups. RESULTS:We included 329 stillbirths in the analysis by MVM severity and 76 in the analysis by cause of death (COD). While z-scores for most organ weights/heart measures were smaller when COD was attributed to MVM as compared with FVM or controls, heart weight and brain weight z-scores did not differ by COD (p > 0.05). In analyses accounting for body size, the difference between heart and body weight z-score was -0.05 (standard deviation [SD]: 0.53) among those with MVM as a COD and -0.20 (SD: 0.95) among those with severe MVM. Right and left ventricle thicknesses and tricuspid, pulmonary, mitral, and aortic valve circumferences were consistently as expected or larger than expected for GA and body weight. In the analysis investigating the severity of MVM, those with the most severe MVM had heart measures that were as expected or larger than expected for body weight while those with only mild to moderate MVM had heart measures that were generally small relative to body weight. CONCLUSION:When assessed as COD or based on severity, MVM was associated with heart measures that were as expected or larger than expected for GA and body weight, indicating possible heart sparing. KEY POINTS:· Fetal deaths with MVM show smaller organ weights.. · Heart weight sparing is seen with fetal death attributed to MVM.. · Heart weight sparing is more pronounced with severe MVM..

IntroductionFeeding infants a sub-optimal diet deprives them of critical nutrients for their physical and cognitive development. The objective of this study is to describe the intake of foods of low nutritional value (junk foods) and identify the association with growth and developmental outcomes in infants up to 18 months in low-resource settings.MethodsThis is a secondary analysis of data from an iron-rich complementary foods (meat versus fortified cereal) randomized clinical trial on nutrition conducted in low-resource settings in four low- and middle-income countries (Democratic Republic of the Congo, Guatemala, Pakistan, and Zambia). Mothers in both study arms received nutritional messages on the importance of exclusive breastfeeding up to 6 months with continued breastfeeding up to at least 12 months. This study was designed to identify the socio-demographic predictors of feeding infants’ complementary foods of low nutritional value (junk foods) and to assess the associations between prevalence of junk food use with neurodevelopment (assessed with the Bayley Scales of Infant Development II) and growth at 18 months.Results1,231 infants were enrolled, and 1,062 (86%) completed the study. Junk food feeding was more common in Guatemala, Pakistan, and Zambia than in the Democratic Republic of Congo. 7% of the infants were fed junk foods at 6 months which increased to 70% at 12 months. Non-exclusive breastfeeding at 6 months, higher maternal body mass index, more years of maternal and paternal education, and higher socioeconomic status were associated with feeding junk food. Prevalence of junk foods use was not associated with adverse neurodevelopmental or growth outcomes.ConclusionThe frequency of consumption of junk food was high in these low-resource settings but was not associated with adverse neurodevelopment or growth over the study period.