Different corticosteroids and regimens for accelerating fetal lung maturation for babies at risk of preterm birth

Despite the widespread use of antenatal corticosteroids to prevent respiratory distress syndrome (RDS) in preterm infants, there is currently no consensus as to the type of corticosteroid to use, dose, frequency, timing of use or the route of administration.  OBJECTIVES: To assess the effects on fetal and neonatal morbidity and mortality, on maternal morbidity and mortality, and on the child and adult in later life, of administering different types of corticosteroids (dexamethasone or betamethasone), or different corticosteroid dose regimens, including timing, frequency and mode of administration.

For this update, we searched Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (9 May 2022) and reference lists of retrieved studies.

We included all identified published and unpublished randomised controlled trials or quasi-randomised controlled trials comparing any two corticosteroids (dexamethasone or betamethasone or any other corticosteroid that can cross the placenta), comparing different dose regimens (including frequency and timing of administration) in women at risk of preterm birth. We planned to exclude cross-over trials and cluster-randomised trials. We planned to include studies published as abstracts only along with studies published as full-text manuscripts.

At least two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of included studies. Data were checked for accuracy. We assessed the certainty of the evidence using GRADE.

We included 11 trials (2494 women and 2762 infants) in this update, all of which recruited women who were at increased risk of preterm birth or had a medical indication for preterm birth. All trials were conducted in high-income countries. Dexamethasone versus betamethasone Nine trials (2096 women and 2319 infants) compared dexamethasone versus betamethasone. All trials administered both drugs intramuscularly, and the total dose in the course was consistent (22.8 mg or 24 mg), but the regimen varied. We assessed one new study to have no serious risk of bias concerns for most outcomes, but other studies were at moderate (six trials) or high (two trials) risk of bias due to selection, detection and attrition bias. Our GRADE assessments ranged between high- and low-certainty, with downgrades due to risk of bias and imprecision.  Maternal outcomes The only maternal primary outcome reported was chorioamnionitis (death and puerperal sepsis were not reported). Although the rate of chorioamnionitis was lower with dexamethasone, we did not find conclusive evidence of a difference between the two drugs (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.48 to 1.06; 1 trial, 1346 women; moderate-certainty evidence). The proportion of women experiencing maternal adverse effects of therapy was lower with dexamethasone; however, there was not conclusive evidence of a difference between interventions (RR 0.63, 95% CI 0.35 to 1.13; 2 trials, 1705 women; moderate-certainty evidence). Infant outcomes We are unsure whether the choice of drug makes a difference to the risk of any known death after randomisation, because the 95% CI was compatible with both appreciable benefit and harm with dexamethasone (RR 1.03, 95% CI 0.66 to 1.63; 5 trials, 2105 infants; moderate-certainty evidence). The choice of drug may make little or no difference to the risk of RDS (RR 1.06, 95% CI 0.91 to 1.22; 5 trials, 2105 infants; high-certainty evidence). While there may be little or no difference in the risk of intraventricular haemorrhage (IVH), there was substantial unexplained statistical heterogeneity in this result (average (a) RR 0.71, 95% CI 0.28 to 1.81; 4 trials, 1902 infants; I² = 62%; low-certainty evidence). We found no evidence of a difference between the two drugs for chronic lung disease (RR 0.92, 95% CI 0.64 to 1.34; 1 trial, 1509 infants; moderate-certainty evidence), and we are unsure of the effects on necrotising enterocolitis, because there were few events in the studies reporting this outcome (RR 5.08, 95% CI 0.25 to 105.15; 2 studies, 441 infants; low-certainty evidence). Longer-term child outcomes Only one trial consistently followed up children longer term, reporting  at two years' adjusted age. There is probably little or no difference between dexamethasone and betamethasone in the risk of neurodevelopmental disability at follow-up (RR 1.02, 95% CI 0.85 to 1.22; 2 trials, 1151 infants; moderate-certainty evidence). It is unclear whether the choice of drug makes a difference to the risk of visual impairment (RR 0.33, 95% CI 0.01 to 8.15; 1 trial, 1227 children; low-certainty evidence). There may be little or no difference between the drugs for hearing impairment (RR 1.16, 95% CI 0.63 to 2.16; 1 trial, 1227 children; moderate-certainty evidence), motor developmental delay (RR 0.89, 95% CI 0.66 to 1.20; 1 trial, 1166 children; moderate-certainty evidence) or intellectual impairment (RR 0.97, 95% CI 0.79 to 1.20; 1 trial, 1161 children; moderate-certainty evidence). However, the effect estimate for cerebral palsy is compatible with both an important increase in risk with dexamethasone, and no difference between interventions (RR 2.50, 95% CI 0.97 to 6.39; 1 trial, 1223 children; low-certainty evidence). No trials followed the children beyond early childhood. Comparisons of different preparations and regimens of corticosteroids We found three studies that included a comparison of a different regimen or preparation of either dexamethasone or betamethasone (oral dexamethasone 32 mg versus intramuscular dexamethasone 24 mg; betamethasone acetate plus phosphate versus betamethasone phosphate; 12-hourly betamethasone versus 24-hourly betamethasone). The certainty of the evidence for the main outcomes from all three studies was very low, due to  small sample size and  risk of bias. Therefore, we were limited in our ability to draw conclusions from any of these studies.

Overall, it remains unclear whether there are important differences between dexamethasone and betamethasone, or between one regimen and another.  Most trials compared dexamethasone versus betamethasone. While for most infant and early childhood outcomes there may be no difference between these drugs, for several important outcomes for the mother, infant and child the evidence was inconclusive and did not rule out significant benefits or harms. The evidence on different antenatal corticosteroid regimens was sparse, and does not support the use of one particular corticosteroid regimen over another.