By Ahizechukwu C. Eke, MD, PhD, MPH
Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: The neonatal advantages of prenatal dexamethasone administration seem to increase with longer administration-to-birth intervals than previously believed in women at risk of preterm birth before 34 weeks of gestation.
SOURCE: WHO ACTION Trials Collaborators. Effect of dexamethasone on newborn survival at different administration-to-birth intervals: A secondary analysis of the WHO ACTION (Antenatal CorticosTeroids for Improving Outcomes in Preterm Newborn)-I trial. EClinicalMedicine 2022;53:101744.
Preterm birth continues to be the most common cause of neonatal morbidity and mortality globally.1 It is estimated that approximately 1 million newborns die every year as a result of preterm birth-related complications.2 Respiratory distress syndrome (RDS), an acute lung condition linked to immaturity of the fetal lungs (specifically, surfactant deficit), is the most frequent cause of respiratory failure and death in preterm infants. There exists a strong inverse relationship between gestational age and RDS incidence, risk, and severity.2,3 Surfactant production, when insufficient, can lead to reduced pulmonary compliance, increased alveolar surface tension, alveolar collapse, hypoxia, and hypercapnia.3
The most effective intervention for the prevention of RDS, minimizing early newborn death and morbidity, is antenatal steroid therapy for women who are at risk of preterm delivery.4 The majority of glucocorticoid hormones, both natural and synthetic, have the ability to cross the placenta and initiate the maturational process that causes surfactant to be produced and released into the fetal alveoli.5 The benefits of antenatal steroids have been established in low-, middle-, and high-income countries for the prevention of RDS, but the optimal time interval between the administration of steroids and maximal clinical benefits have been a subject of debate.6
Data from high-income countries demonstrate maximum clinical benefits between seven and 14 days after steroid administration, but these do not take into consideration significant variables, such as gestational age at the time of steroid administration, or analyze and report the timepoints linked with the highest risk reductions for certain negative outcomes.4 In this study, Oladapo and colleagues evaluated the effect of dexamethasone compared to placebo (by the administration-to-birth interval) on neonatal mortality and severe respiratory morbidity outcomes to identify the interval with the greatest clinical benefits (i.e., an optimal interval) in low-income countries.7 Dexamethasone was chosen because it is more widely available, less expensive, and is on the WHO Essential Medicines List.
This was a secondary analysis of the WHO ACTION-I trial, a multi-country, multi-center, randomized clinical trial conducted at 29 sites in five countries (Nigeria, India, Pakistan, Kenya, and Bangladesh).8 Inclusion criteria were pregnant women with singleton or multiple gestations, between 260 weeks and 336 weeks of gestational age, at high risk for imminent preterm birth, defined as planned or expected birth within 48 hours (either from preterm labor or provider-initiated). Women were excluded if they had clinical signs of severe infection, had suspicion or evidence of clinical chorioamnionitis, had major congenital fetal anomalies, had concurrent or recent use of systemic steroids, were participating in another maternal or newborn health trial, had a repeat course of dexamethasone, or had a contraindication to steroid use.
The outcomes of interest were stillbirth or neonatal death, severe neonatal respiratory distress within 24 hours, and severe neonatal respiratory distress within the first week of birth (168 hours). Subgroup analyses were conducted by stratifying the study population (by pre-defined categories of administration-to-birth intervals of 0-6 hours, > 6 to < 12 hours, ≥ 12 hours to < 24 hours, ≥ 24 hours to < 1 week, and ≥ 1 week). The relative risks (RRs) of dexamethasone compared to placebo for each newborn outcome and for each interval category were calculated. The study employed multivariate logistic regression to evaluate the effect of dexamethasone compared to placebo on neonatal mortality, stillbirth, and severe respiratory distress at 24 hours and 168 hours. The use of RRs was employed to determine the administration-to-birth interval that yielded the most advantageous effects of dexamethasone in comparison to a placebo, specifically in relation to the results observed in newborns.
During the period spanning from Dec. 24, 2017, to Nov. 21, 2019, a total of 2,852 women and their 3,070 infants were registered for participation in the WHO ACTION-I study. Among these participants, a subset of 1,332 women (with 1,464 infants) were assigned to the dexamethasone group, while 1,306 women (with 1,440 infants) were assigned to the placebo group. The baseline characteristics of populations of women in the dexamethasone and placebo arms were similar. The risk of neonatal mortality decreased as the period between the initiation of dexamethasone treatment and birth increased: RR, 1.08 (0.83, 1.41); RR, 0.89 (0.63, 1.28); RR, 1.02 (0.67, 1.56); RR, 0.77 (0.60, 0.98; P < 0.05); and RR, 0.65 (0.39, 1.08) for administration-to-birth intervals of 0-6 hours, > 6 to < 12 hours, ≥ 12 hours to < 24 hours, ≥ 24 hours to < 1 week, and ≥ 1 week, respectively.
The greatest reduction in neonatal mortality (a 23% reduction) was observed between 24 hours and 1 week after steroid administration (RR, 0.77 [0.60, 0.98; P < 0.05]), after which the effect gradually diminished. This pattern was consistent regardless of the gestational age at which dexamethasone was administered, and was true for severe respiratory distress at 24 hours and at 168 hours after steroid administration.
COMMENTARY
The administration of prenatal corticosteroids is a well-accepted and implemented treatment for preterm pregnancies that are > 23 weeks and < 37 weeks of gestation across the world.9 Although there are many steroidal formulations, dexamethasone and betamethasone are the two that have been extensively researched and favored for use in facilitating fetal lung maturity in the face of imminent delivery. Thus, both are considered the recommended corticosteroid for clinical use because of their resistance to degradation by placental metabolic enzymes.
Both steroids pass through the placental-fetal barrier in their active state, exhibit a deficiency in mineralocorticoid activity, possess relatively limited immunosuppressive effect when used for a short duration, and exhibit almost comparable biological activity. Although both dexamethasone and betamethasone exhibit a structural similarity, they differ just by the presence of a single methyl group. The pharmacologic difference in methylation accounts for dexamethasone’s shorter half-life, more rapid onset of action, increased clearance, and smaller volume of distribution compared to betamethasone.4,10
The timing and dosing of antenatal steroids is critically important. The recommended treatment regimen involves the administration of either four intramuscular doses of dexamethasone, each containing 6 mg, with a 12-hour interval between doses, or two intramuscular doses of betamethasone, each containing 12 mg, with a 24-hour interval between doses.4 The optimal time frame for the administration of corticosteroids to yield the maximum benefit often is observed within a range of two to seven days following the initial dosage. The same applies to cases of preterm premature rupture of fetal membranes and multiple gestations.11 Because of the potential risks to both the mother and the fetus, as well as the need to carefully evaluate the trade-off between risks and benefits, it is not advisable to pursue planned multiple courses.
Results from studies comparing the effects of single vs. multiple courses of prenatal steroids have demonstrated a decrease in birth weight, a higher prevalence of newborns classified as small for gestational age (particularly in cases where four courses of corticosteroids were administered), and a reduction in fetal and neonatal head circumference following repeated steroid administration.12,13 Thus, the administration of corticosteroids should be reserved for cases where there is a significant clinical indication of imminent preterm birth, and there should be no more than two courses (four doses) when indicated during any pregnancy.
Conducting a clinical trial using dexamethasone compared to a normal saline placebo, when dexamethasone already has been proven to work and is considered the standard of care for fetal lung maturity, raises ethical concerns. However, conducting such a trial might be ethically justifiable in this instance because the investigators questioned the efficacy and safety of dexamethasone for women and newborn babies in hospitals in resource-limited settings (a question of equipoise). This question into the efficacy and safety of dexamethasone might be ethically defensible. In addition, the trial included appropriate safeguards to participants in the placebo arm and ensured that they received the standard of care (dexamethasone) if their condition worsened.
The findings from this study by Oladapo et al is consistent with the guidelines set forth by the American College of Obstetricians and Gynecologists (ACOG), which advises that pregnant women who are at risk of preterm delivery within seven days, including those with ruptured membranes and multiple gestations, between the gestational ages of 24 0/7 weeks and 33 6/7 weeks, should receive a single course of corticosteroids.4,7
Additionally, it is worth considering the potential application of antenatal steroid for pregnant women who are at a gestational age of 23 0/7 weeks and are deemed to be at a heightened risk of experiencing preterm birth within a span of seven days, as well as pregnant women at a gestational age between 34 0/7 weeks and 36 6/7 weeks who are at risk of preterm birth and have not previously received a course of corticosteroids during prenatal care.4 ACOG also advises administering a second (rescue) course of prenatal steroids to pregnant women who are at a gestational age of < 34 0/7 weeks and face a potential risk of delivering prematurely within a week, and whose initial course of antenatal corticosteroids was administered more than 14 days prior.4 The administration of a rescue course of corticosteroids may be initiated as early as seven days following the previous dosage.
REFERENCES
- Manuck TA, Rice MM, Bailit JL, et al. Preterm neonatal morbidity and mortality by gestational age: A contemporary cohort. Am J Obstet Gynecol 2016;215:103.e1-103.e14.
- Blencowe H, Cousens S, Chou D, et al. Born too soon: The global epidemiology of 15 million preterm births. Reprod Health 2013;10 (Suppl 1):S2.
- Yadav S, Lee B, Kamity R. Neonatal Respiratory Distress Syndrome. StatPearls [Internet]. StatPearls Publishing; July 25, 2023.
- American College of Obstetricians and Gynecologists' Committee on Practice Bulletins--Obstetrics. Practice Bulletin No. 171: Management of Preterm Labor. Obstet Gynecol 2016;128:e155-164.
- Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2017;3:CD004454.
- McDougall ARA, Aboud L, Lavin T, et al. Effect of antenatal corticosteroid administration-to-birth interval on maternal and newborn outcomes: A systematic review. EClinicalMedicine 2023;58:101916.
- WHO ACTION Trials Collaborators. Effect of dexamethasone on newborn survival at different administration-to-birth intervals: A secondary analysis of the WHO ACTION (Antenatal CorticosTeroids for Improving Outcomes in Preterm Newborn)-I trial. EClinicalMedicine 2022;53:101744.
- WHO ACTION Trials Collaborators. The World Health Organization ACTION-I (Antenatal CorTicosteroids for Improving Outcomes in preterm Newborns) Trial: A multi-country, multi-centre, two-arm, parallel, double-blind, placebo-controlled, individually randomized trial of antenatal corticosteroids for women at risk of imminent birth in the early preterm period in hospitals in low-resource countries. Trials 2019;20:507.
- Bonanno C, Wapner RJ. Antenatal corticosteroids in the management of preterm birth: Are we back where we started? Obstet Gynecol Clin North Am 2012;39:47-63.
- Mushkat Y, Ascher-Landsberg J, Keidar R, et al. The effect of betamethasone versus dexamethasone on fetal biophysical parameters. Eur J Obstet Gynecol Reprod Biol 2001;97:50-52.
- Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006;3:CD004454.
- Wapner RJ, Sorokin Y, Thom EA, et al. Single versus weekly courses of antenatal corticosteroids: Evaluation of safety and efficacy. Am J Obstet Gynecol 2006;195:633-642.
- Thorp JA, Jones PG, Knox E, Clark RH. Does antenatal corticosteroid therapy affect birth weight and head circumference? Obstet Gynecol 2002;99:101-108.
