Dataset Information

Antenatal Dexamethasone for Early Preterm Birth in Low-Resource Countries.

ABSTRACT:

Background

The safety and efficacy of antenatal glucocorticoids in women in low-resource countries who are at risk for preterm birth are uncertain.

Methods

We conducted a multicountry, randomized trial involving pregnant women between 26 weeks 0 days and 33 weeks 6 days of gestation who were at risk for preterm birth. The participants were assigned to intramuscular dexamethasone or identical placebo. The primary outcomes were neonatal death alone, stillbirth or neonatal death, and possible maternal bacterial infection; neonatal death alone and stillbirth or neonatal death were evaluated with superiority analyses, and possible maternal bacterial infection was evaluated with a noninferiority analysis with the use of a prespecified margin of 1.25 on the relative scale.

Results

A total of 2852 women (and their 3070 fetuses) from 29 secondary- and tertiary-level hospitals across Bangladesh, India, Kenya, Nigeria, and Pakistan underwent randomization. The trial was stopped for benefit at the second interim analysis. Neonatal death occurred in 278 of 1417 infants (19.6%) in the dexamethasone group and in 331 of 1406 infants (23.5%) in the placebo group (relative risk, 0.84; 95% confidence interval [CI], 0.72 to 0.97; P?=?0.03). Stillbirth or neonatal death occurred in 393 of 1532 fetuses and infants (25.7%) 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 4.8% and 6.3%, respectively (relative risk, 0.76; 95% CI, 0.56 to 1.03). There was no significant between-group difference in the incidence of adverse events.

Conclusions

Among women in low-resource countries who were at risk for early preterm birth, the use of dexamethasone resulted in significantly lower risks of neonatal death alone and stillbirth or neonatal death 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-India number, CTRI/2017/04/008326.).

SUBMITTER: WHO ACTION Trials Collaborators

PROVIDER: S-EPMC7660991 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

Antenatal Dexamethasone for Early Preterm Birth in Low-Resource Countries.

Oladapo Olufemi T OT Vogel Joshua P JP Piaggio Gilda G Nguyen My-Huong MH Althabe Fernando F Gülmezoglu A Metin AM Bahl Rajiv R Rao Suman P N SPN De Costa Ayesha A Gupta Shuchita S Baqui Abdullah H AH Khanam Rasheda R Shahidullah Mohammod M Chowdhury Saleha B SB Ahmed Salahuddin S Begum Nazma N D Roy Arunangshu A Shahed M A MA Jaben Iffat A IA Yasmin Farida F Rahman M Mozibur MM Ara Anjuman A Khatoon Soofia S Ara Gulshan G Akter Shaheen S Akhter Nasreen N Dey Probhat R PR Sabur M Abdus MA Azad Mohammad T MT Choudhury Shahana F SF Matin M A MA Goudar Shivaprasad S SS Dhaded Sangappa M SM Metgud Mrityunjay C MC Pujar Yeshita V YV Somannavar Manjunath S MS Vernekar Sunil S SS Herekar Veena R VR Bidri Shailaja R SR Mathapati Sangamesh S SS Patil Preeti G PG Patil Mallanagouda M MM Gudadinni Muttappa R MR Bijapure Hidaytullah R HR Mallapur Ashalata A AA Katageri Geetanjali M GM Chikkamath Sumangala B SB Yelamali Bhuvaneshwari C BC Pol Ramesh R RR Misra Sujata S SS Das Leena L Nanda Saumya S Nayak Rashmita B RB Singh Bipsa B Qureshi Zahida Z Were Fredrick F Osoti Alfred A Gwako George G Laving Ahmed A Kinuthia John J Mohamed Hafsa H Aliyan Nawal N Barassa Adelaide A Kibaru Elizabeth E Mbuga Margaret M Thuranira Lydia L Githua Njoroge J NJ Lusweti Bernadine B Ayede Adejumoke I AI Falade Adegoke G AG Adesina Olubukola A OA Agunloye Atinuke M AM Iyiola Oluwatosin O OO Sanni Wilfred W Ejinkeonye Ifeyinwa K IK Idris Hadiza A HA Okoli Chinyere V CV Irinyenikan Theresa A TA Olubosede Omolayo A OA Bello Olaseinde O Omololu Olufemi M OM Olutekunbi Olanike A OA Akintan Adesina L AL Owa Olorunfemi O OO Oluwafemi Rosena O RO Eniowo Ireti P IP Fabamwo Adetokunbo O AO Disu Elizabeth A EA Agbara Joy O JO Adejuyigbe Ebunoluwa A EA Kuti Oluwafemi O Anyabolu Henry C HC Awowole Ibraheem O IO Fehintola Akintunde O AO Kuti Bankole P BP Isah Anthony D AD Olateju Eyinade K EK Abiodun Olusanya O Dedeke Olabisi F OF Akinkunmi Francis B FB Oyeneyin Lawal L Adesiyun Omotayo O Raji Hadijat O HO Ande Adedapo B A ABA Okonkwo Ikechukwu I Ariff Shabina S Soofi Sajid B SB Sheikh Lumaan L Zulfiqar Saima S Omer Sadia S Sikandar Raheel R Sheikh Salma S Giordano Daniel D Gamerro Hugo H Carroli Guillermo G Carvalho Jose J Neilson James J Molyneux Elizabeth E Yunis Khalid K Mugerwa Kidza K Chellani Harish K HK

The New England journal of medicine 20201023 26

<h4>Background</h4>The safety and efficacy of antenatal glucocorticoids in women in low-resource countries who are at risk for preterm birth are uncertain.<h4>Methods</h4>We conducted a multicountry, randomized trial involving pregnant women between 26 weeks 0 days and 33 weeks 6 days of gestation who were at risk for preterm birth. The participants were assigned to intramuscular dexamethasone or identical placebo. The primary outcomes were neonatal death alone, stillbirth or neonatal death, and ...[more]

PMID: 33095526

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Project description:BackgroundAntenatal corticosteroids (ACS) have long been regarded as a cornerstone intervention in mitigating the adverse effects of a preterm birth. However, the safety and efficacy of ACS in hospitals in low-resource countries has not been established in an efficacy trial despite their widespread use. Findings of a large cluster-randomized trial in six low- and middle-income countries showed that efforts to scale up ACS use in low-resource settings can lead to harm. There is equipoise regarding the benefits and harms of ACS use in hospitals in low-resource countries. This randomized controlled trial aims to determine whether ACS are safe and efficacious when given to women at risk of imminent birth in the early preterm period, in hospitals in low-resource countries.Methods/designThe trial design is a parallel, two-arm, double-blind, individually randomized, placebo-controlled trial of ACS (dexamethasone) for women at risk of imminent preterm birth. The trial will recruit 6018 women in participating hospitals across five low-resource countries (Bangladesh, India, Kenya, Nigeria and Pakistan). The primary objectives are to compare the efficacy of dexamethasone with placebo on survival of the baby and maternal infectious morbidity. The primary outcomes are: 1) neonatal death (to 28 completed days of life); 2) any baby death (any stillbirth postrandomization or neonatal death); and 3) a composite outcome to assess possible maternal bacterial infections. The trial will recruit eligible, consenting pregnant women from 26 weeks 0 days to 33 weeks 6 days gestation with confirmed live fetuses, in whom birth is planned or expected within 48 h. The intervention comprises a regimen of intramuscular dexamethasone sodium phosphate. The comparison is an identical placebo regimen (normal saline). A total of 6018 women will be recruited to detect a reduction of 15% or more in neonatal deaths in a two-sided 5% significance test with 90% power (including 10% loss to follow-up).DiscussionFindings of this trial will guide clinicians, programme managers and policymakers on the safety and efficacy of ACS in hospitals in low-resource countries. The trial findings will inform updating of the World Health Organization's global recommendations on ACS use.Trial registrationACTRN12617000476336 . Registered on 31 March 2017.

Project description:BackgroundThere is currently insufficient evidence on the safety and efficacy of antenatal corticosteroids in preventing mortality and severe morbidity amongst late preterm newborns in low-resource countries.MethodsWe conducted a double-blind, randomized trial in four hospitals in India between 26 December 2017 to 21 May 2020. Pregnant women at risk of imminent preterm birth between 34 weeks 0 days and 36 weeks 0 days of gestation were recruited. Women were randomly assigned (1:1) to a course of 6 mg intramuscular dexamethasone or an identical placebo. All trial participants, research staff and outcome assessors were masked to allocation. Primary outcomes were neonatal death, any baby death (stillbirth or neonatal death), severe neonatal respiratory distress and possible maternal bacterial infection. The study was registered with ANZCTR (ACTRN12617001494325) and CTRI (CTRI/2017/05/008721).FindingsWe randomized 782 women, 391 to each arm. Neonatal death occurred in 11 of 412 liveborn babies (2.7%) in the dexamethasone group and 12 of 425 liveborn babies (2.8%) in the placebo group (RR 0.95; 95% CI 0.42-2.12). Any baby death occurred in 16 of 417 infants (3.8%) in the dexamethasone group and 19 of 432 infants (4.4%) in the placebo group (RR 0.87; 95% CI 0.45-1.67). Severe neonatal respiratory distress was infrequent in both groups (0.8% vs 0.5%; RR 1.56; 95% CI 0.26-9.29). Possible maternal bacterial infection did not differ between groups (2.3% vs. 3.8%, RR 0.60; 95% CI 0.27-1.35). Fewer neonates in the dexamethasone group required resuscitation at birth (RR 0.38, CI 0.15-0.97). Other secondary outcomes were similar in the two arms. The trial was stopped due to lower than expected prevalence of primary outcomes and slow recruitment.InterpretationAntenatal dexamethasone did not result in a reduction in neonatal death, stillbirth or neonatal death, or severe neonatal respiratory distress in this trial. The overall trend of effects suggests that potential benefit of dexamethasone in late preterm cannot be excluded, and further trials are required.FundingThis trial was primarily funded by the Bill and Melinda Gates Foundation (Grant OPP1136821). Additional support was provided by UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Sexual and Reproductive Health and Research; and Department of Maternal, Newborn, Child, Adolescent Health, and Ageing, of the World Health Organization, Geneva, Switzerland.

Project description:ImportanceWorldwide, preterm birth (PTB) is the single largest cause of deaths in the perinatal and neonatal period and is associated with increased morbidity in young children. The cause of PTB is multifactorial, and the development of generalizable biological models may enable early detection and guide therapeutic studies.ObjectiveTo investigate the ability of transcriptomics and proteomics profiling of plasma and metabolomics analysis of urine to identify early biological measurements associated with PTB.Design, setting, and participantsThis diagnostic/prognostic study analyzed plasma and urine samples collected from May 2014 to June 2017 from pregnant women in 5 biorepository cohorts in low- and middle-income countries (LMICs; ie, Matlab, Bangladesh; Lusaka, Zambia; Sylhet, Bangladesh; Karachi, Pakistan; and Pemba, Tanzania). These cohorts were established to study maternal and fetal outcomes and were supported by the Alliance for Maternal and Newborn Health Improvement and the Global Alliance to Prevent Prematurity and Stillbirth biorepositories. Data were analyzed from December 2018 to July 2019.ExposuresBlood and urine specimens that were collected early during pregnancy (median sampling time of 13.6 weeks of gestation, according to ultrasonography) were processed, stored, and shipped to the laboratories under uniform protocols. Plasma samples were assayed for targeted measurement of proteins and untargeted cell-free ribonucleic acid profiling; urine samples were assayed for metabolites.Main outcomes and measuresThe PTB phenotype was defined as the delivery of a live infant before completing 37 weeks of gestation.ResultsOf the 81 pregnant women included in this study, 39 had PTBs (48.1%) and 42 had term pregnancies (51.9%) (mean [SD] age of 24.8 [5.3] years). Univariate analysis demonstrated functional biological differences across the 5 cohorts. A cohort-adjusted machine learning algorithm was applied to each biological data set, and then a higher-level machine learning modeling combined the results into a final integrative model. The integrated model was more accurate, with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% CI, 0.72-0.91) compared with the models derived for each independent biological modality (transcriptomics AUROC, 0.73 [95% CI, 0.61-0.83]; metabolomics AUROC, 0.59 [95% CI, 0.47-0.72]; and proteomics AUROC, 0.75 [95% CI, 0.64-0.85]). Primary features associated with PTB included an inflammatory module as well as a metabolomic module measured in urine associated with the glutamine and glutamate metabolism and valine, leucine, and isoleucine biosynthesis pathways.Conclusions and relevanceThis study found that, in LMICs and high PTB settings, major biological adaptations during term pregnancy follow a generalizable model and the predictive accuracy for PTB was augmented by combining various omics data sets, suggesting that PTB is a condition that manifests within multiple biological systems. These data sets, with machine learning partnerships, may be a key step in developing valuable predictive tests and intervention candidates for preventing PTB.

Project description:BackgroundPreterm neonatal mortality (NM) has remained high and unchanged for many years in Tanzania, a resource-limited country. Major causes of mortality include birth asphyxia, respiratory insufficiency and infections. Antenatal corticosteroids (ACS) have been shown to significantly reduce mortality in developed countries. There is inconsistent use of ACS in Tanzania.ObjectiveTo determine whether implementation of a care bundle that includes ACS, maternal antibiotics (MA), neonatal antibiotics (NA) and avoidance of moderate hypothermia (temperature < 36°C) targeting infants of estimated gestational age (EGA) 28 to 34 6/7 weeks would reduce NM (< 7 days) by 35%.MethodsA Pre (September 2014 to May 2015) and Post (June 2015 to June 2017) Implementation strategy was used and introduced at three University-affiliated and one District Hospital. Dexamethasone, as the ACS, was added to the national formulary in May 2015, facilitating its free use down to the district level.FindingsNM was reduced 26% from 166 to 122/1000 livebirths (P = 0.005) and fresh stillbirths (FSB) 33% from 162/1000 to 111/1000 (p = 0.0002) Pre versus Post Implementation. Medications including combinations increased significantly at all sites (p<0.0001). By logistic regression, combinations of ACS, maternal and NA (odds ratio (OR) 0.33), ACS and NA (OR 0.30) versus no treatment were significantly associated with reduced NM. NM significantly decreased per 250g birthweight increase (OR 0.59), and per one week increase in EGA (OR 0.87). Moderate hypothermia declined pre versus post implementation (p<0.0001) and was two-fold more common in infants who died versus survivors.InterpretationA low-cost care bundle, ~$6 per patient, was associated with a significant reduction in NM and FSB rates. The former presumably by reducing respiratory morbidity with ACS and minimizing infections with antibiotics. If these findings can be replicated in other resource-limited settings, the potential for further reduction of <5 year mortality rates becomes enormous.

Project description:ObjectiveTo describe discordance in antenatal corticosteroid use and resuscitation following extremely preterm birth and its relationship with infant survival and neurodevelopment.Study designA multicenter cohort study of 4858 infants 22-26 weeks of gestation born 2006-2011 at 24 US hospitals participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, with follow-up through 2013. Survival and neurodevelopmental outcomes were available at 18-22 months of corrected age for 4576 (94.2%) infants. We described antenatal interventions, resuscitation, and infant outcomes. We modeled the effect on infant outcomes of each hospital increasing antenatal corticosteroid exposure for resuscitated infants born at 22-24 weeks of gestation to rates observed at 25-26 weeks of gestation.ResultsDiscordant antenatal corticosteroid use and resuscitation, where one and not the other occurred, were more frequent for births at 22 and 23 but not 24 weeks (rate ratio [95% CI] at 22 weeks: 1.7 [1.3-2.2]; 23 weeks: 2.6 [2.2-3.2]; 24 weeks: 1.0 [0.8-1.2]) when compared with 25-26 weeks. Among infants resuscitated at 23 weeks, adjusting each hospital's rate of antenatal corticosteroid use to the average at 25-26 weeks (89.2%) was projected to increase infant survival by 7.1% (95% CI 5.4-8.8%) and survival without severe impairment by 6.4% (95% CI 4.7-8.1%). No significant change in outcomes was projected for infants resuscitated at 22 weeks, where few (n = 22) resuscitated infants received antenatal corticosteroids.ConclusionsInfants born at 23 weeks were more frequently resuscitated without antenatal corticosteroids than other extremely preterm infants. When resuscitation is intended, consistent provision of antenatal corticosteroids may increase infant survival and survival without impairment.Trial registrationClinicalTrials.govNCT00063063 (Generic Database) and NCT00009633 (Follow-Up Study).

Project description:BACKGROUND:Low birthweight (LBW) and preterm birth (PB) remain the leading cause of morbidity and mortality in neonates worldwide. The aim of this study was to identify maternal demographic and antenatal factors associated with PB and LBW among low socio-economic communities. METHODS:Pregnant women (n?=?1099) were recruited in the first trimester into the Mother and Child in the Environment (MACE) birth cohort in Durban, South Africa. Maternal factors such as demographic information, health status, residential area, occupational, personal and environmental smoking and biomass fuel use were obtained through standardised interviews, while clinical status was obtained in each trimester and antenatal information on HIV status and treatment, syphilis and conditions such as pregnancy induced hypertension, diabetes etc. was extracted from the antenatal assessments. Key outcomes of interest were preterm birth and low birthweight. The latter data was obtained from the clinical assessments performed by midwives at delivery. Logistic regression models identified factors associated with PB and LBW. RESULTS:Of the 760 live births, 16.4 and 13.5% were preterm and LBW, respectively. Mothers who delivered by caesarean section had an increased odds of having LBW babies (Adjusted odds ratio (AOR): 1.7; 95% CI: 1.1-2.7) and PB (AOR: 1.7, 95% CI: 1.1-2.7) versus normal vaginal deliveries. Mothers >?30?years (AOR: 1.8, 95% CI: 1.1-2.9) and current smokers (AOR: 2.7, 95% CI: 1.3-5.8) had an increased odds of having PB babies. Compared to younger mothers and non-smokers respectively. An effect of PB and LBW was seen among mothers with high BMI (25.0-29.9?kg/m2) (PB: AOR: 0.5, 95% CI: 0.3-0.9 and LBW: AOR: 0.5, 0.5, CI: 0.3-0.8), and obese BMI (>?30?kg/m2) (PB: AOR: 0.5, 95% CI: 0.3-0.9 and LBW: AOR: 0.4, CI: 0.2-0.7). Maternal HIV (PB AOR: 1.4 and LBW AOR: 1.2) and history of sexually transmitted infections (PB AOR: 2.7 and LBW AOR: 4.2) were not statistically significant. CONCLUSION:Maternal age, cigarette smoking and caesarean delivery were associated with LBW and PB. Findings highlight the need of maternal health interventions to improve new-born health outcomes.

Dataset Information

Antenatal Dexamethasone for Early Preterm Birth in Low-Resource Countries.

Background

Methods

Results

Conclusions

Publications

Antenatal Dexamethasone for Early Preterm Birth in Low-Resource Countries.

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