Original Article

Antenatal Dexamethasone for Early Preterm Birth in Low-Resource Countries

List of authors.
  • The WHO ACTION Trials Collaborators

Abstract

Background

The safety and efficacy of antenatal glucocorticoids in women in low-resources countries who are at hazard for preterm nascency are uncertain.

Methods

Nosotros conducted a multicountry, randomized trial involving pregnant women between 26 weeks 0 days and 33 weeks 6 days of gestation who were at take a chance for preterm birth. The participants were assigned to intramuscular dexamethasone or identical placebo. The primary outcomes were neonatal death alone, stillbirth or neonatal decease, and possible maternal bacterial infection; neonatal death lone and stillbirth or neonatal death were evaluated with superiority analyses, and possible maternal bacterial infection was evaluated with a noninferiority analysis with the employ of a prespecified margin of ane.25 on the relative calibration.

Results

A total of 2852 women (and their 3070 fetuses) from 29 secondary- and 3rd-level hospitals across Bangladesh, India, Kenya, Nigeria, and Pakistan underwent randomization. The trial was stopped for do good at the 2nd interim analysis. Neonatal expiry occurred in 278 of 1417 infants (nineteen.6%) in the dexamethasone group and in 331 of 1406 infants (23.five%) in the placebo group (relative risk, 0.84; 95% confidence interval [CI], 0.72 to 0.97; P=0.03). Stillbirth or neonatal decease occurred in 393 of 1532 fetuses and infants (25.seven%) and in 444 of 1519 fetuses and infants (29.2%), respectively (relative risk, 0.88; 95% CI, 0.78 to 0.99; P=0.04); the incidence of possible maternal bacterial infection was 4.eight% and 6.iii%, respectively (relative risk, 0.76; 95% CI, 0.56 to 1.03). There was no significant between-group departure in the incidence of adverse events.

Conclusions

Among women in depression-resources countries who were at risk for early preterm nascency, the use of dexamethasone resulted in significantly lower risks of neonatal death lone and stillbirth or neonatal expiry than the use of placebo, without an increase in the incidence of possible maternal bacterial infection. (Funded by the Bill and Melinda Gates Foundation and the World Health Organization; Australian and New Zealand Clinical Trials Registry number, ACTRN12617000476336; Clinical Trials Registry–Bharat number, CTRI/2017/04/008326.)

Introduction

Preterm birth is a leading cause of expiry in infants and children younger than 5 years of historic period globally.ane Infants born preterm are also at increased risk for a wide range of short-term and long-term respiratory, infectious, metabolic, and neurologic weather, with higher risks amid those born during the early preterm menses.2,3

On the basis of trials conducted largely in high-resource countries, antenatal glucocorticoids accept long been promoted every bit the key intervention for reducing preterm infant mortality and morbidity.4,v Nevertheless, the generalizability of this prove to depression-resource settings was called into question in 2015, when a large population-based trial conducted in six low-resource countries showed that efforts to scale up the use of antenatal glucocorticoids could lead to harm.six In that trial, scaling up of glucocorticoids did not reduce mortality amid infants who were below the fifth percentile for birth weight (a proxy for preterm birth) and unexpectedly was associated with an increase in the incidence of neonatal decease, stillbirth, and suspected maternal infection in the population overall. These findings reopened the fence about the safety and efficacy of antenatal glucocorticoids in depression-resource countries.7,8

Because of these considerations, in 2015 the Earth Wellness Organization (WHO) recommended that antenatal glucocorticoids should exist used only nether sure conditions, including the authentic assessment of gestational age, imminent preterm birth, the absenteeism of maternal infection, and acceptable care for childbirth and preterm newborns.ix The guideline console and an expert console that was after convened by the WHO identified the behave of efficacy trials in hospitals in low-resource countries as a research priority in club to resolve this controversy and guide clinicians and policymakers on the use of antenatal glucocorticoids.vii,8 Nosotros conducted the WHO Activeness-I (Antenatal Corticosteroids for Improving Outcomes in Preterm Newborns) trial, a randomized trial to assess the prophylactic and efficacy of dexamethasone in women in hospitals in depression-resource countries who were at risk for early preterm nascence.

Methods

Trial Design and Oversight

We designed a multicountry, multicenter, parallel-group, double-blind, individually randomized, placebo-controlled trial to compare intramuscular dexamethasone with identical placebo in women at risk for imminent preterm birth. We conducted the trial at 29 secondary- and 3rd-level hospitals across six trial sites in Bangladesh, India, Kenya, Nigeria, and Pakistan. The trial protocol, which has been published previously,10 is available with the full text of this article at NEJM.org. It was approved past the relevant ethics committees and regulatory agencies in each state and by the WHO Ethics Review Committee. WHO was the trial sponsor. A steering group comprising a trial coordinating unit, principal investigators, and technical advisors provided trial oversight.

Fresenius Kabi–Labesfal (Portugal) produced dexamethasone sodium phosphate and identical placebo, which were packaged and shipped to the trial sites by Ivers–Lee Clinical Supplies Management (Switzerland). Fresenius Kabi–Labesfal had no part in the trial blueprint, the collection, analysis, and estimation of the information, the writing of the manuscript, or the decision to submit the manuscript for publication. The first, 2nd, third, and seventh members of the writing committee vouch for the accuracy and abyss of the data and for the fidelity of the trial to the protocol.

Trial Setting

The trial hospitals were selected through a standardized cess of maternal and newborn wellness care services (Table S1 in the Supplementary Appendix, bachelor at NEJM.org) to ensure that the WHO criteria for antenatal glucocorticoid treatment could be reasonably met.8,9 To make the trial procedures consistent and to ensure that the trial participants received at least the minimum quality of care, ultrasonographic systems (Philips HD5, the netherlands), continuous positive airway pressure (CPAP) machines (DiaMedica UK, United Kingdom), pulse oximeters (Masimo International, Switzerland), and glucometers were procured for all the hospitals. Standardized training was provided to all research and clinical staff.

Screening and Recruitment

Pregnant women who had confirmed live fetuses between 26 weeks 0 days and 33 weeks six days of gestation and who were at adventure for preterm birth were eligible for inclusion. The inclusion criteria were planned or expected birth in the side by side 48 hours (either provider-initiated preterm birth or afterwards preterm, prelabor rupture of membranes or spontaneous labor). Gestational historic period was determined by the earliest ultrasonographic examination or an ultrasonographic examination performed at admission. Women were excluded if they had clinical signs of astringent infection, major congenital fetal anomalies, concurrent or recent (within the previous ii weeks) use of systemic glucocorticoids, or a contraindication to glucocorticoids or if they were participating in some other trial. Written informed consent was obtained from all the participants before randomization.

Randomization and Trial Regimens

The participants were randomly assigned in a ane:1 ratio to a course of intramuscular injections of either 6 mg of dexamethasone or identical placebo administered every 12 hours, for a maximum of four doses, or until infirmary discharge or nascence. The women were eligible for a repeat course if they had not given birth afterwards 7 completed days but however met the inclusion criteria. The echo class was identical to the first course and the aforementioned as the initial assignment.

Site-stratified individual randomization with counterbalanced permuted blocks of 10 were used. The calculator-generated randomization sequence was prepared centrally at the WHO. All the sites received serially numbered identical packs containing ampules of 4 mg per milliliter of dexamethasone or placebo for two full courses. The trial participants, intendance providers, and investigators were unaware of the trial-group assignments.

The participants received either dexamethasone or placebo immediately afterwards randomization. Clinical care was provided according to local guidelines. Follow-upwards of the fetuses was conducted until 28 days afterward birth or until death (stillbirth or neonatal death), whichever came first, and follow-upwardly of the women was conducted until 28 days after they gave birth or until expiry, whichever came kickoff. Trained research staff collected data during the infirmary admission or admissions and during customs-level visits.

Trial Outcomes

The 3 master outcomes were neonatal death (death of a live-born infant within 28 completed days of life), stillbirth or neonatal decease, and a composite of possible maternal bacterial infection, defined as maternal fever (temperature ≥38°C) or clinically suspected or confirmed infection for which therapeutic antibiotics were used. The secondary outcomes were maternal and newborn mortality and morbidity as well as process-of-care outcomes (a listing and definitions of these outcomes are provided in the Statistical Methods section in the Supplementary Appendix).

All trial-related information was stored deeply at the trial sites. Information were double-entered into a Web-based data-management platform and centrally managed by Centro Rosarino de Estudios Perinatales (Argentina).

Statistical Analysis

Nosotros estimated that 6018 women would accept to exist recruited to detect a subtract in the risk of neonatal decease of 15.00% or more than, from 25.00% to 21.25%, in a two-sided 5% significance test with 90% power and x% loss to follow-up. The estimated sample size would provide more than 80% power at the ii.v% significance level to notice whether dexamethasone is noninferior to placebo for maternal infection, inside a noninferiority margin of ane.25 on the relative calibration. The noninferiority margin was based on the consideration that a maximum increase of 25% over a ten% baseline incidence of maternal bacterial infection could exist accepted for a fetal or infant mortality do good.

For the primary outcomes, intention-to-care for analyses were to be performed. We hypothesized that the utilise of dexamethasone would result in a decrease in the risk of neonatal death and stillbirth or neonatal death without increasing the take chances of maternal infection. Therefore, nosotros applied a superiority hypothesis to neonatal death and stillbirth or neonatal death, and we applied a noninferiority hypothesis to maternal infection. Analyses were first performed on all available information, and sensitivity analyses were so performed with the use of multiple imputationxi to guess the effect of missing data. Analyses of principal outcomes were corrected for multiplicity with the false-discovery-rate arroyo.12 The dexamethasone grouping was compared with the placebo group for the principal outcomes with the utilize of relative risks with 95% conviction intervals, according to a logistic model with a binomial distribution and a log link to obtain relative risks. The stratifying variable — trial site — was included in the model, as well equally a clustering characteristic for multiple births for neonatal outcomes. For continuous variables, ways and standard deviations or medians and interquartile ranges according to grouping were reported. The trial groups were compared with mean or median differences and 95% conviction intervals according to a general linear model that included trial site as the stratifying variable. Carve up models were fitted for each of the primary and secondary outcomes.

The master outcomes were analyzed in prespecified subgroups (encounter the Statistical Methods department in the Supplementary Appendix). The results for all secondary outcomes and subgroup analyses are presented as point estimates and 95% conviction intervals. No correction was made for multiplicity, and the width of the confidence intervals should not exist used to infer handling furnishings. All the models were fitted with the use of SAS software, version 9.4 (SAS Constitute).

Three interim analyses by the data and safety monitoring lath were planned. The board members were to inform the steering grouping chair if, in their view, in that location was proof beyond a incertitude that dexamethasone was indicated or contraindicated on the basis of statistical considerations (using the Haybittle–Peto stopping rule13 for the primary outcomes for fetuses and infants) or clinical considerations, practical issues, or new external information. Subsequently the second acting analysis involving 2304 women and 2536 fetuses and infants, with complete follow-up of primary outcomes, the data and rubber monitoring board decided to unblind the trial and recommended that the trial be stopped for fetus and infant mortality benefits and strong bear witness of a graded dose–response event, in the context of existing evidence of benefits of antenatal glucocorticoids.4 Recruitment was stopped beyond all sites on November 21, 2019, and all ethics committees and regulatory regime were informed. The funders had no role in the decision to finish the trial.

Results

Participant Characteristics

Screening, Enrollment, Randomization, and Follow-up.

Women could take more than one reason for not meeting eligibility criteria.

 Characteristics of the Participants at Trial Entry.

From Dec 2017 through Nov 2019, of the 7008 women who were screened for eligibility, 2852 underwent randomization (1429 to the dexamethasone group and 1423 to the placebo grouping) (Figure one). The well-nigh common reason for ineligibility was that nascency was not planned or expected in the adjacent 48 hours. A total of 90.0% of the infants in the dexamethasone group and xc.eight% of those in the placebo group were born before 37 weeks. More than 99.0% of the women who underwent randomization and their infants completed follow-upwardly. The characteristics of the dexamethasone and placebo groups were similar at trial entry (Table 1 and Table S2).

Adherence to Assigned Trial Regimen

All the women except 1 received at least one dose of dexamethasone or placebo (Figure ane). A total of 815 of 1429 women (57.0%) in the dexamethasone group and 756 of 1423 women (53.1%) in the placebo group received all four doses in the get-go grade. The echo course was administered to 61 women in the dexamethasone group and 74 women in the placebo group, of whom 46 and 47 women, respectively, received 4 doses. The virtually mutual reason that a scheduled dose was not administered was the occurrence of nascence between the administration of doses.

Primary Outcomes

Primary Outcomes.

There were 278 neonatal deaths among 1417 alive-born infants in the dexamethasone group (19.6%) and 331 neonatal deaths amongst 1406 alive-born infants in the placebo group (23.5%) (relative risk, 0.84; 95% conviction interval [CI], 0.72 to 0.97; P=0.03) (Tabular array ii). We determined that 25 women would need to exist treated with dexamethasone to forbid 1 neonatal expiry (95% CI, xiv to 110). The incidence of stillbirth or neonatal death was besides significantly lower in the dexamethasone group than in the placebo group (25.7% vs. 29.2%; relative risk, 0.88; 95% CI, 0.78 to 0.99; P=0.04).

Possible maternal bacterial infection occurred in 68 of 1416 women (iv.8%) in the dexamethasone group and in 89 of 1412 women (vi.three%) in the placebo group (relative take a chance, 0.76; 95% CI, 0.56 to one.03; P=0.002 for noninferiority); this result was consistent with noninferiority at the prespecified margin of 1.25 (Table two). In the per-protocol population, possible maternal bacterial infection occurred in 63 of 1393 women (4.5%) in the dexamethasone group and in 89 of 1385 women (half-dozen.four%) in the placebo group (relative risk, 0.70; 95% CI, 0.51 to 0.96); this result was besides consequent with noninferiority. Multiple imputation for missing values11 yielded identical results for all the primary outcomes (Tabular array S3).

Prespecified Subgroup Analyses of Master Neonatal Outcomes.

Shown are the results of the assay of neonatal death (Panel A) and stillbirth or neonatal death (Panel B) (the primary neonatal outcomes) in prespecified subgroups. The widths of the confidence intervals were not adjusted for multiplicity, so the intervals should not exist used to infer definitive treatment effects. The size of each black square is proportional to the total number of fetuses, infants, or both in the subgroup.

The results according to the prespecified subgroups are shown in Effigy 2 and Figure S1. Analyses of neonatal decease, according to the time from the first dose of dexamethasone or placebo to nativity, stratified co-ordinate to gestational age, suggest greater benefit with increasing time from the first dose to birth and increasing gestational historic period at the first dose (from 26 to 32 weeks) (Fig. S2). In a post hoc analysis of the causes of neonatal death, the frequency of neonatal death caused by respiratory distress syndrome was lower in the dexamethasone group than in the placebo group (Tabular array S4).

Secondary Neonatal Outcomes

Secondary Maternal and Neonatal Outcomes.

The results with respect to early neonatal death, astringent respiratory distress at 24 hours after nativity, neonatal hypoglycemia at 6 hours after birth, major resuscitation at nativity, the utilise of CPAP, and the duration of oxygen therapy provide back up for the primary findings. Other secondary and procedure-of-intendance outcomes were similar in the dexamethasone and placebo groups (Table iii and Table S5).

Secondary Maternal Outcomes

The secondary maternal outcomes were similar in the dexamethasone and placebo groups (Table 3). Five women died in the dexamethasone group, and four women died in the placebo group.

Adverse Events

Prespecified maternal and neonatal outcomes were excluded from the reporting of serious adverse events. There was no pregnant between-group difference in the incidence of serious agin events, which occurred in ane.1% of the women in both groups (Tabular array S6). No serious adverse events were reported in the neonates.

Discussion

In this infirmary-based randomized trial conducted in depression-resource countries, nosotros found that the administration of dexamethasone to women who were at take a chance for early preterm nascency reduced the incidences of neonatal decease and stillbirth or neonatal expiry without increasing the incidence of maternal bacterial infection. Dexamethasone had no outcome on stillbirth, but the findings for several secondary outcomes, including early on neonatal expiry, severe respiratory distress, and the use of major neonatal resuscitation and CPAP were consistent with the overall results for neonatal deaths by 28 days. These clinical benefits were observed even though 45% of the participants received fewer than 4 doses of their assigned medication.

Our findings are generally consistent with the results of a meta-analysis of 22 trials that were mostly conducted in high-resource settings. That meta-analysis showed a substantial subtract in the incidence of neonatal death among infants of women who received glucocorticoids.4 Previous efforts to increment the low apply of antenatal glucocorticoids in women at chance for preterm nascency in low-resources countries14 were challenged past the results of the Antenatal Corticosteroids Trial (ACT).half-dozen,15 ACT was a cluster-randomized trial of an implementation strategy that included provider grooming and tools to identify women who were eligible to receive dexamethasone at all levels of care, including principal health care and care at the community level.

In dissimilarity to ACT, which selected women for treatment on the basis of their last menstrual menstruum or measurement of uterine height and included clinical settings where resources for neonatal intendance were inadequate, the hospitals in our trial selected patients for whom handling was warranted (through cess by obstetrical physicians and verification of gestational age by ultrasonographic examination) and provided minimum standards of neonatal care, including access to oxygen and CPAP. In the current trial, ninety% of the infants who were exposed to dexamethasone were born preterm, whereas only 16% of the infants exposed to dexamethasone in the ACT intervention clusters had a nativity weight below the 5th percentile. The depression incidence of apparent preterm birth among infants exposed to dexamethasone in Act indicates substantial overtreatment, which may explain at least in part the lack of mortality benefit and overall impairment observed. Appropriate selection of participants and the provision of a minimum standard of intendance appear to be critical in achieving benefits and preventing potential harms from glucocorticoids and should be incorporated into future implementation strategies.

The results of our trial provide reassurance regarding the beneficial effects of glucocorticoids with respect to reducing neonatal mortality in low-resource settings, and they expand the deficient body of evidence from depression- and middle-income countries.xvi-xx Although smaller trials conducted in depression- and middle-income countries take suggested benefits, nigh of them were not placebo-controlled trials.17,19,20

The utilise of dexamethasone in our trial did not increase the risk of maternal or neonatal infection; this finding is consistent with those of previous trials conducted in low- and middle-income countries,16-xx where the baseline risks of such infections are high.21-23 The lack of effect on the overall incidence of neonatal hypoglycemia and the proposition of a reduced run a risk of early hypoglycemia with the utilise of dexamethasone, nonetheless, were unexpected. Studies in animals and pharmacokinetic studies accept indicated that neonatal hypoglycemia is a potential complication of the utilise of standard doses of dexamethasone.24 Moreover, in the Antenatal Late Preterm Steroids trial, the assistants of betamethasone to women with a singleton pregnancy at 34 weeks 0 days to 36 weeks five days of gestation who were at chance for preterm nascency increased the incidence of neonatal hypoglycemia by sixty%.25 The effects of maternal glucocorticoid administration on preterm infants have been inconsistent across studies26,27 and may differ in infants with early on preterm birth and those with late preterm birth.

The current trial is larger than previous placebo-controlled trials assessing the efficacy and safety of antenatal glucocorticoids in low-resource countries, and nosotros used broad eligibility criteria. We assessed neonatal death according to the standard definition (which was largely unspecified or restricted to in-infirmary deaths in previous trials7), and we carefully selected hospitals that could reasonably meet minimum preconditions for glucocorticoid use. The loss to follow-up of trial participants and the per centum of participants with missing primary effect data were very depression despite the need for follow-upwardly in the community. The trial was limited by the challenges in standardizing maternal and neonatal care across trial sites and the use of ultrasonographic examination to appraise gestational age for a substantial percent of the participants in the third trimester.

Farther study is warranted to make up one's mind the most appropriate dosing regimen28,29 and the rubber and efficacy of administering glucocorticoids in belatedly preterm pregnancy,30 particularly in low-resource countries. The observed benefits with respect to neonatal mortality appeared to increment with tocolysis and with the duration of fetal exposure to dexamethasone; the part of tocolytic agents in safely delaying early on preterm nascency in women who are eligible for the use of antenatal glucocorticoids also merits further investigation.

The utilise of antenatal dexamethasone that was targeted to women at hazard for imminent preterm birth in hospitals with minimum resources for maternal and preterm newborn intendance resulted in significantly lower risks of neonatal death and stillbirth or neonatal death than did the apply of placebo, without whatever testify of harm to women or newborns.

Funding and Disclosures

Supported past a grant (OPP1136821) from the Nib and Melinda Gates Foundation and by the United Nations Evolution Program–Un Population Fund–United nations Children'south Fund–World Health Organization–World Banking concern Special Programme of Enquiry, Evolution, and Research Training in Man Reproduction, Section of Sexual and Reproductive Health and Research and the Department of Maternal, Newborn, Child, Boyish Health and Ageing, World Health Arrangement, Geneva.

The members of the writing commission are as follows: Olufemi T. Oladapo, M.D., Chiliad.P.H., Joshua P. Vogel, One thousand.B., B.Southward., Ph.D., Gilda Piaggio, Ph.D., My-Huong Nguyen, M.D., Ph.D., Fernando Althabe, M.D., A. Metin Gülmezoglu, M.D., Ph.D., Rajiv Bahl, One thousand.D., Ph.D., Suman P.Northward. Rao, M.B., B.S., G.D., D.K., Ayesha De Costa, M.D., Ph.D., Shuchita Gupta, K.B., B.Southward., Yard.D., M.P.H., Ph.D., Abdullah H. Baqui, M.B., B.S., M.P.H., DoctorP.H., Rasheda Khanam, M.B., B.Due south., M.P.H., Ph.D., Mohammod Shahidullah, One thousand.B., B.S., Saleha B. Chowdhury, M.B., B.S., Salahuddin Ahmed, M.B., B.S., Nazma Begum, One thousand.A., Dip.Comp.Sc., Arunangshu D. Roy, M.B., B.S., M.A. Shahed, M.B., B.S., Iffat A. Jaben, 1000.B., B.S., Yard.P.H., Farida Yasmin, M.B., B.Due south., One thousand. Mozibur Rahman, G.B., B.S., Anjuman Ara, M.B., B.S., Soofia Khatoon, M.B., B.S., Thou.H.P.Ed., Gulshan Ara, M.B., B.South., Shaheen Akter, M.B., B.S., M.D., Nasreen Akhter, M.B., B.S., Probhat R. Dey, M.B., B.S., M.D., M. Abdus Sabur, M.B., B.S., Mohammad T. Azad, 1000.B., B.S., M.D., Shahana F. Choudhury, M.B., B.S., M.A. Matin, M.B., B.S., Shivaprasad South. Goudar, K.D., Sangappa M. Dhaded, M.D., Mrityunjay C. Metgud, Thousand.D., Yeshita V. Pujar, Thousand.D., Manjunath Southward. Somannavar, M.D., Sunil S. Vernekar, M.D., Veena R. Herekar, Grand.D., Shailaja R. Bidri, M.D., Sangamesh S. Mathapati, M.D., Preeti K. Patil, D.N.B., Mallanagouda M. Patil, Thousand.D., Muttappa R. Gudadinni, M.D., Hidaytullah R. Bijapure, G.D., Ashalata A. Mallapur, Yard.D., Geetanjali M. Katageri, 1000.Due south., Sumangala B. Chikkamath, M.D., Bhuvaneshwari C. Yelamali, M.D., Ramesh R. Pol, M.D., Sujata Southward. Misra, M.D., Leena Das, Grand.D., Saumya Nanda, M.D., Rashmita B. Nayak, M.D., Bipsa Singh, M.D., Zahida Qureshi, Thousand.B., B.Due south., Fredrick Were, M.B., Ch.B., Ph.D., Alfred Osoti, M.B., Ch.B., M.P.H., Ph.D., George Gwako, 1000.B., Ch.B., Ahmed Laving, M.B., Ch.B., John Kinuthia, G.B., Ch.B., M.P.H., Hafsa Mohamed, Yard.B., Ch.B., Nawal Aliyan, One thousand.B., Ch.B., Adelaide Barassa, Thou.B., Ch.B., Elizabeth Kibaru, 1000.B., Ch.B., Margaret Mbuga, G.B., Ch.B., Lydia Thuranira, M.B., Ch.B., Njoroge J. Githua, Chiliad.B., Ch.B., Bernadine Lusweti, M.B., Ch.B., Adejumoke I. Ayede, M.B., B.Southward., Adegoke G. Falade, M.B., B.Southward., 1000.D., Olubukola A. Adesina, G.B., B.Southward., Atinuke G. Agunloye, Thou.B., B.South., Oluwatosin O. Iyiola, M.B., Ch.B., Wilfred Sanni, B.Yard., B.Ch., Ifeyinwa K. Ejinkeonye, M.B., B.S., Hadiza A. Idris, M.B., B.S., M.R.H., Chinyere V. Okoli, M.B., B.South., M.P.H., Theresa A. Irinyenikan, M.B., B.S., M.P.H., Omolayo A. Olubosede, Chiliad.B., B.South., M.P.H., Olaseinde Bello, M.B., Ch.B., Olufemi M. Omololu, Yard.B., B.S., Olanike A. Olutekunbi, K.B., B.S., Adesina L. Akintan, M.B., B.Southward., Olorunfemi O. Owa, M.B., B.S., M.P.A., Rosena O. Oluwafemi, M.B., Ch.B., M.P.H., Ireti P. Eniowo, Yard.B., B.S., Adetokunbo O. Fabamwo, M.B., B.South., Elizabeth A. Disu, M.B., B.Ch., Joy O. Agbara, Yard.B., B.Due south., Ebunoluwa A. Adejuyigbe, Thousand.B., Ch.B., Oluwafemi Kuti, M.B., B.S., Henry C. Anyabolu, Chiliad.B., B.S., Ibraheem O. Awowole, M.B., Ch.B., Akintunde O. Fehintola, Thou.B., B.Due south., M.P.H., Bankole P. Kuti, M.B., Ch.B., Anthony D. Isah, 1000.B., B.S., Eyinade 1000. Olateju, M.B., B.S., Olusanya Abiodun, 1000.B., Ch.B., Olabisi F. Dedeke, G.B., B.S., M.P.H., Francis B. Akinkunmi, M.B., Ch.B., Lawal Oyeneyin, Yard.B., B.S., Omotayo Adesiyun, Yard.B., B.Southward., Hadijat O. Raji, M.B., B.S., Adedapo B.A. Ande, M.B., Ch.B., K.P.H., Ikechukwu Okonkwo, M.B., B.Southward., Shabina Ariff, M.B., B.South., Sajid B. Soofi, Thousand.B., B.South., Lumaan Sheikh, Chiliad.B., B.S., Saima Zulfiqar, Chiliad.B., B.S., Sadia Omer, M.B., B.Southward., Raheel Sikandar, M.B., B.S., Salma Sheikh, Yard.B., B.Southward., Daniel Giordano, B.Sc., Hugo Gamerro, B.Sc., Guillermo Carroli, Chiliad.D., Jose Carvalho, B.Sc., Thou.Sc., Ph.D., James Neilson, One thousand.D., Elizabeth Molyneux, 1000.B., B.S., Khalid Yunis, Chiliad.D., Kidza Mugerwa, G.B., Ch.B., and Harish K. Chellani, M.D.

This is the New England Journal of Medicine version of record, which includes all Periodical editing and enhancements. The Author Final Manuscript, which is the author'due south version after external peer review and before publication in the Journal, is available nether a CC By license at PMC7660991.

This article was published on October 23, 2020, at NEJM.org.

A information sharing statement provided by the authors is available with the full text of this commodity at NEJM.org.

We thank the women and infants who participated in this trial; the physicians, midwives, pharmacists, data managers, and research administration who helped comport the trial in each of the five countries (in Bangladesh, Mohammad A. Mannan, Begum Nasrin, Saima Sultana, Saria Tasnim, Sumia Bari, Murshed A. Chowdhury, Dilip K. Bhowmik, and Jamila K. Chowdhury; in India, Vishwanath L. Machakanur, Shruti S. Andola, Yogesh Kumar S., Umesh C. Charantimath, Avinash Kavi, Saraswati A. Welling, Bhavana B. Lakhkar, Umesh Ramadurg, Maya Padhi, Lucy Das, Madhusmita J. Pradhan, Girija-Shankar G. Mohanty, and Paresh Sahoo; in Republic of kenya, Msuo Omar, Mwanapazia Hassan, Joachim Ogindo, Salome Waweru, and Grace Ochieng; in Nigeria [Ibadan], Bukola Fawole [deceased], Oluwakemi F. Ashubu, Olukemi Tongo, Olubunmi O. Busari, Michael A. Okunlola, Olatunji Lawal, Collins Kalu, Francisca North. Ali, Kenneth Nwachukwu, Fatima A. Sallau, Lilian O. Ekwem, Anastasia Due east. Ajuwan, Folarin B. Jimoh, Felix F. Akindeju, Olugbenga Runsewe, Abimbola O. Oladeji, Olumide Alao, and Madise-wobo Akpoembele; in Nigeria [Ile-Ife], Adebanjo B. Adeyemi, Olusola C. Famurewa, Nosakhare O. Enaruna, Olufunmilayo V. Adebara, Aboyeji A. Peter, and Mokuolu Olugbenga; and in Pakistan, Mubarak Ali, Saleem Laghari, Jamal Anwar, Shazia Memon, Nida Najmi, Shazia Rani, Farrukh Raza, Masawar Hussain, Amjad Hussain, and Imran Ahmed); the members of the information and prophylactic monitoring board (Betty Kirkwood [chair], Jon Deeks [contained statistician], Siddarth Ramji, Elizabeth Bukusi, and Robert Pattinson [who served from 2015–2019], and G. Justus Hofmeyr [who began to serve in 2019]) for their role in monitoring the overall behave and quality of the trial; Cynthia Pileggi-Castro for trial protocol development; Liana Campodonico and Gabriela Camacho Garcia for data management; Vania A. Nilsson and Luciana Abreu for statistical programming and assay; Lynn Coppola, Sandhya Maranna, and Devasenathipathy Kandasamy for obstetrical and neonatal ultrasonography training and quality assurance; Adam Devall for preparing the subgroup analysis figures; and Janna Patterson, Jerker Liljestrand, and Hilary Gammill for their technical input and back up as program managers for the WHO ACTION Trials Collaboration at the Bill and Melinda Gates Foundation.

Writer Affiliations

The affiliations of the members of the writing committee are as follows: World Health Organization, Geneva (O.T.O., J.P.V., G.P., M.-H.Due north., F.A., A.K.G., R.B., S.P.Due north.R., A.D.C., S.G.); Johns Hopkins Bloomberg School of Public Health, Baltimore (A.H.B., R.Chiliad.); Bangabandhu Sheikh Mujib Medical University (1000.Due south., S.B. Chowdhury), Projahnmo Research Foundation (S. Ahmed, North.B., A.D.R., G.A. Shahed, I.A.J.), Institute of Child and Mother Health (F.Y., M.M.R.), Center for Woman and Child Health (A.A., S.K.), and Enam Medical Higher and Hospital (G.A., S. Akter), Dhaka, and Sylhet Muhammad Ataul Gani Osmani Medical College Hospital (N. Akhter, P.R.D.), Jalalabad Ragib–Rabeya Medical College Hospital (M.A. Sabur, M.T.A.), and Sylhet Women'south Medical College Hospital (S.F.C., M.A.Yard.), Sylhet — both in Bangladesh; KLE Academy of Higher Education and Inquiry, Jawaharlal Nehru Medical College, Belagavi (Southward.S.Chiliad., Southward.M.D., G.C.M., Y.V.P., Grand.S.S., S.S.V., Five.R.H.), Shri B.M. Patil Medical College, Vijayapura (Southward.R.B., S.Due south. Mathapati, P.G.P., M.M.P., Grand.R.Thou., H.R.B.), Southward. Nijalingappa Medical College, Bagalkot (A.A.M., G.M.M., S.B. Chikkamath, B.C.Y., R.R.P.), Srirama Chandra Bhanja Medical Higher, Cuttack (South.S. Misra, L.D., S.N., R.B.Due north., B.Due south.), and Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi (H.G.C.) — all in Bharat; University of Nairobi (Z.Q., F.Due west., A. Osoti, 1000.G., A.L.) and Kenyatta National Hospital (J.K.), Nairobi, Coast Provincial General Hospital, Mombasa (H.Thousand., N. Aliyan), Nakuru Level 5 Hospital, Nakuru (A.B., Due east.K.), Kiambu Level 5 Hospital, Kiambu (1000.M., L.T.), and Thika Level 5 Hospital, Thika (Due north.J.M., B.L.) — all in Kenya; the College of Medicine, University of Ibadan, and University College Hospital, Ibadan (A.I.A., A.G.F., O.A.A., A.M.A., O.O.I.), Kubwa Full general Hospital, Kubwa (Westward.South., I.K.E.), Nyanya General Hospital, Nyanya (H.A.I., C.V.O.), Land Specialist Hospital (T.A.I., O.A. Olubosede, O.B.) and Mother and Child Hospital (A.50.A., O.O.O., R.O.O., I.P.E.), Akure, Lagos Island Maternity Hospital (O.Grand.O., O.A. Olutekunbi), and Lagos Land Academy Teaching Hospital (A.O. Fabamwo, E.A.D., J.O.A.), Lagos, Obafemi Awolowo University, Ile-Ife (E.A.A., O.K., H.C.A., I.O.A., A.O. Fehintola, B.P.K.), University of Abuja, Abuja (A.D.I., Due east.K.O.), Sacred Heart Hospital, Abeokuta (O. Abiodun, O.F.D.), Female parent and Child Infirmary, Ondo (F.B.A., L.O.), Academy of Ilorin, Ilorin (O. Adesiyun, H.O.R.), and University of Benin, Benin City (A.B.A.A., I.O.) — all in Nigeria; Aga Khan University, Karachi (South. Ariff, South.B.S., L.S.), Sheikh Zayed Medical Higher and Infirmary, Rahim Yar Khan (S.Z., Southward.O.), and Liaquat University Hospital, Hyderabad (R.S., S.S.) — all in Pakistan; Centro Rosarino de Estudios Perinatales, Rosario, Argentina (D.G., H.G., G.C.); Statistika Consultoria, Campinas, Brazil (J.C.); University of Liverpool, Liverpool, U.k. (J.N.); College of Medicine, University of Malawi, Blantyre (E.M.); American University of Beirut, Beirut, Lebanon (K.Y.); and the Makerere University College of Health Sciences, Kampala, Republic of uganda (One thousand.M.).

Address reprint requests to Dr. Oladapo at the United Nations Evolution Plan–United Nations Population Fund–Un Children'southward Fund–World Health Organisation–World Bank Special Program of Research, Development, and Research Training in Man Reproduction, Department of Sexual and Reproductive Wellness and Inquiry, World Health System, 20 Ave. Appia, Geneva, Switzerland, or at [electronic mail protected]; or to Dr. Bahl at the Department of Maternal, Newborn, Child, Boyish Health and Ageing, World Health Organization, 20 Ave. Appia, Geneva, Switzerland, or at [email protected].

Supplementary Fabric

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