EBNEO Commentary: Antenatal Corticosteroids for Late Preterm Gestation in Low-Resource Countries

June 30, 2022


WHO ACTION Trials Collaborators. Antenatal dexamethasone for late preterm birth: A multi-centre, two-arm, parallel, double-blind, placebo-controlled, randomized trial. EClinicalMedicine. 2022 Feb 12; 44:101285. doi: 10.1016/j.eclinm.2022.101285. PMID: 35198915; PMCID: PMC8850324.


Nehad Nasef
Professor of Pediatrics,
Department of Pediatrics/Neonatology, Mansoura University Children’s Hospital, Mansoura, Egypt.

Islam Nour
Associate Professor of Pediatrics,
Department of Pediatrics/Neonatology, Mansoura University Children’s Hospital, Mansoura, Egypt.

Hesham Abdel-Hady
Professor of Pediatrics,
Department of Pediatrics/Neonatology, Mansoura University Children’s Hospital, Mansoura, Egypt.


Nehad Nasef
Professor of Pediatrics,
Department of Pediatrics/Neonatology, Mansoura University Children’s Hospital, Mansoura, Egypt.






Treatment / prevention.


(P)  In women at risk of imminent late-preterm delivery between 340/7 to 360/7 weeks’ gestation, (I) does intramuscular dexamethasone sodium phosphate to a maximum of four doses (C) compared to placebo, (O) reduce the risk of stillbirth, neonatal death, or severe neonatal respiratory distress in low resource countries? 


  • Design: Randomized controlled, double-blind, multicenter trial, 4 neonatal intensive care units in India.
  • Allocation: Eligible women were randomly assigned (1:1) with a computer-generated randomization system. The randomization was stratified by study center and balanced within randomly sized blocks of 10 infants in each center.
  • Blinding: Parents, caregivers and research staff were blinded to group assignment.
  • Follow-up period: Until death or discharge.
  • Setting: Four NICUs in a low resource country setting between December 2017 and May 2020.
  • Patients:
  • Inclusion criteria: Pregnant women at 34 weeks 0 days to 36 weeks 0 days of gestation, who were at risk for delivery within the upcoming 48 hours.
  • Exclusion criteria: Clinical signs of severe infection, chorioamnionitis, major congenital fetal anomalies, prior use of antenatal steroids within the past 2 weeks, contraindication to steroid, or enrollment in another clinical trial.
  • Intervention:
    • Women in the intervention group received a single course of intra-muscular dexamethasone sodium phosphate (maximum of 4 doses of 6 mg/12 hours) until birth or hospital discharge whichever came first.
    • In the control group, matching placebo was administered.
  • Outcomes:
  • Primary outcome: Neonatal death within 28 days, any death (stillbirth/ neonatal death), severe respiratory distress and suspected or confirmed maternal bacterial infection.
  • Secondary outcomes:
  • Neonatal outcomes: Stillbirth, early neonatal death, neonatal sepsis, severe intraventricular hemorrhage, hypoglycemia at 6 and 36 hours, Apgar score <7 at 5 min , major resuscitation at birth, duration of oxygen therapy, duration of CPAP, duration of mechanical ventilation , use of parenteral therapeutic antibiotics, need for surfactant, admission to a special care unit, and length of hospital stay.
  • Maternal outcomes: Maternal death, maternal fever, chorioamnionitis, endometritis, wound infection, non-obstetric infection, therapeutic antibiotics, any antibiotic use.
  • Analysis and Sample Size:
  • The authors adopted a superiority hypothesis to the primary neonatal outcomes, assuming that antenatal dexamethasone is superior to placebo, with a two-sided significance level 5%. For the primary outcome possible material infection, a non-inferiority hypothesis was applied with a prespecified non-inferiority margin of 2.5% on the absolute scale.
  • They estimated that the sample size of 22,589 women would provide a power of 90% to detect relative risk reduction of 15% of neonatal deaths, including 10% loss of follow up. This sample allows identifying a 20% reduction of severe neonatal respiratory distress rates with 90% power. Also, it would provide ˃ 99% power at the 2.5% significance level to perceive if antenatal steroids use is non-inferior to placebo for the maternal infection outcome.
  • Analysis had been performed on an intention-to-treat basis.
  • Patient follow-up:
  • The trial had been halted early due to lower than expected primary outcome of neonatal mortality and slow recruitment.
  • Of 1198 pregnant women assessed for eligibility, 782 were recruited. 391 women and their 417 babies were assigned to dexamethasone group and 391 women and their 432 babies to control group. The primary outcome of severe neonatal respiratory distress was analyzed for 378 and 393 infants, respectively.
  • A total of 152 of 391 women (38.9%) in the dexamethasone group and 140 of 391 (35.8%) in the control group received the pre-specified four-dosage regimen of study medication. All women received at least one dose of their assigned treatment.


  • The demographic data and clinical characteristics of enrolled women were matched in the 2 groups.
  • No statistically significant difference was noted between the studied groups as regard any of primary outcome items: (1) neonatal mortality was reported in 2.7% of the dexamethasone group versus 2.8% in the placebo group (RR 0.95; 95% CI 0.42−2.12; P = 0.89), (2) Any baby death occurrence rates was 3.8% in the dexamethasone group compared to 4.4% in the placebo group (RR 0.87; 95% CI 0.45−1.67; P = 0.89), (3) Few neonates exhibited severe neonatal respiratory distress within the whole cohort (0.8% vs 0.5%; RR 1.56; 95% CI 0.26−9.29; P = 0.89). (4) Possible maternal bacterial infection was 2.3% in dexamethasone group versus 3.8% in placebo group (RR 0.60; 95% CI 0.27−1.35; P = 0.002 for non-inferiority).
  • Neonates in dexamethasone group had significantly less need for resuscitation at birth compared to placebo (1.5% vs 3.8%; RR 0.38, 95% CI 0.15−0.97; P = 0.043)
  • No statistically significant difference between both arms regarding any of maternal or neonatal adverse events, including neonatal hypoglycemia.
  • The authors did a pooled analysis of the current trial (ACTION-II) with the Cochrane review that assessed the use of single course of corticosteroids to women prior to anticipated preterm birth to update meta-analyses and found no substantive changes in the strength or direction of risk estimates for neonatal death, perinatal death, or respiratory distress syndrome, both overall and for the subgroup of women receiving antenatal corticosteroids at 34 weeks gestation or greater. The updated meta-analysis results revealed that antenatal corticosteroids use, compared with placebo or no treatment, was associated with reduced incidence of neonatal mortality (RR 0.78, 95% CI 0.70 – 0.87; 11,446 infants; studies = 23; I2 = 10%). The mortality reducing effect of antenatal corticosteroids was not consistently reported among neonates ≥ 34 weeks’ gestation (RR 1.11, 95% CI 0.58 – 2.13; 4485 infant; studies = 5; I2 = 10%)


The authors conclude that antenatal dexamethasone use, compared with placebo, was not associated with reduced neonatal mortality or severe respiratory distress rates, however, it resulted less need for resuscitation at birth. Clinical benefits of antenatal steroid use cannot be excluded and further trials in low-resource countries are warranted.


Antenatal corticosteroids (ACS) therapy is the standard of care for pregnant women between 24+0 and 34+0 weeks of gestation who are at risk of preterm birth, as it significantly reduces perinatal mortality, respiratory distress syndrome (RDS) and intraventricular hemorrhage (1). The evidence for these benefits is based on studies conducted largely in high-resource countries. Recently, a multi-center study in five low-resource countries demonstrated that the administration of ACS to women who were at risk for early preterm birth reduced the incidences of neonatal death and stillbirth or neonatal death without increasing the incidence of maternal bacterial infection (2). Regarding late preterm infants, the administration of ACS at 34+0 to 36+6 weeks of gestation have been shown to reduce respiratory morbidity (3). The evidence for this was mainly dominated by the Antenatal Late Preterm Steroids Trial (ALPS) which was conducted in tertiary hospitals in the USA with a high standard of care provided to preterm infants and their mothers (4). The World Health Organization (WHO) recommended that ACS should only be used for pregnant women at risk of preterm birth from 24+0 to 34+0 weeks’ gestation due to a lack of evidence of the balance of benefits versus harms of ACS beyond 34 weeks in low-resource settings (5). This uncertainty of evidence represents the rationale for the current study.

The current study (ACTION-II trial) (6) was not able to demonstrate that ACS reduce neonatal death or severe respiratory morbidity owing to the small recruited sample size compared to the planned sample. However, ACS decreased the needs for neonatal resuscitation at birth without an evidence of maternal or newborn harms. The authors also pooled their findings with the Cochrane review on ACS for accelerating fetal lung maturation (1) and found no changes in the strength or direction of risk estimates of neonatal death in late preterm infants but suggested benefit for severe neonatal respiratory distress.

The current trial is strengthened by being the largest efficacy trial of ACS for late preterm infants conducted in low-resource countries, careful selection for inclusion based on standardized screening criteria, relatively high accuracy of gestational age assessment, selected study hospitals ensuring minimum standards of maternal and preterm newborn care, and minimal loss to follow-up to the reported outcomes. The authors acknowledged early termination of the study before recruiting the target sample, lack of statistical power to detect any difference in the primary mortality outcome, low rate of reported primary outcome compared to initial anticipation during sample size calculation, and subjective assessment of RDS by clinicians which may have accounted for the discrepancy between the low reported rate for RDS and the percentage of infants needed respiratory support as limitations of the current ACTION-II trial.

The authors attributed the lack of identified clinical benefit for their trial compared to the ALPS trial to the underpowered sample size together with the number of ACS doses administered and duration of fetal exposure prior to birth as 38.9% of women randomized to the ACTION-II trial delivered after receiving full course of dexamethasone while 59.6% of women randomized to the ALPS trial (4) delivered after receiving full course of betamethasone. Other possible explanations for the lack of ACS benefits in low-resource countries include lower accuracy in the identification of gestational age which may result in improper administration of ACS to more mature infants, the use of dexamethasone rather than betamethasone in low-resource countries, and variations in the level of antenatal and postnatal care of newborns (7). Moreover, both ACTION-II and ALPS trials did not report long-term neurodevelopmental outcomes for their infants. This represents a significant concern considering the potential inhibitory effect of corticosteroids on the exponential brain growth at late preterm gestation and the reported school follow-up of children included in the ASTECS trial of betamethasone therapy 48 hours before planned cesarean delivery at ≥37 weeks which revealed a lower achievement in the betamethasone group compared to the control (8).

In conclusion; the current study did not detect reductions in neonatal death or severe respiratory morbidity with the use of ACS when given to women at risk of late preterm birth, in hospitals in low-resource countries. Future studies to optimize the use of ACS in low-resource countries is justified, such studies should consider the composite outcome of death or developmental disability when exploring the benefit of ACS in this population.


  1. McGoldrick E, Stewart F, Parker R, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2020; 12:CD004454
  2. Oladapo OT, Vogel JP, Piaggio G, Nguyen MH, Althabe F, Gulmezoglu AM, et al. Antenatal Dexamethasone for Early Preterm Birth in Low-Resource Countries. N Engl J Med. 2020; 383:2514-25
  3. Saccone G, Berghella V. Antenatal corticosteroids for maturity of term or near term fetuses: systematic review and meta-analysis of randomized controlled trials. BMJ. 2016; 355:i5044
  4. Gyamfi-Bannerman C, Thom EA, Blackwell SC, Tita AT, Reddy UM, Saade GR, et al. Antenatal Betamethasone for Women at Risk for Late Preterm Delivery. N Engl J Med. 2016; 374:1311-20
  5. Vogel JP, Oladapo OT, Manu A, Gulmezoglu AM, Bahl R. New WHO recommendations to improve the outcomes of preterm birth. Lancet Glob Health. 2015; 3:e589-90
  6. WHO ACTION Trials Collaborators. Antenatal dexamethasone for late preterm birth: A multi-centre, two-arm, parallel, double-blind, placebo-controlled, randomized trial. EClinicalMedicine. 2022; 44:101285
  7. Althabe F, Belizan JM, McClure EM, Hemingway-Foday J, Berrueta M, Mazzoni A, et al. A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: the ACT cluster-randomised trial. Lancet. 2015; 385:629-39
  8. Stutchfield P, Whitaker R, Russell I. Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomised trial. BMJ. 2005; 331:662


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