Key messages
· In this review, we used network meta-analysis (NMA), a relatively new tool that allows comparisons between all relevant treatment options, including those that have not been directly compared with each other in previous clinical trials.
· NMA was able to add a small amount of information to the existing data, most notably with comparisons between the effects of different corticosteroid doses for the prevention of bronchopulmonary dysplasia (BPD) in infants born prematurely.
· The optimal way to deliver corticosteroids remains unknown, as there is not enough evidence on harmful long-term outcomes to fully guide decision-making.
What is BPD?
Infants born very prematurely can develop lung injury know as bronchopulmonary dysplasia (BPD), which can have serious and lasting harmful effects.
How can BPD be prevented?
Anti-inflammatory drugs known as corticosteroids can decrease the development of BPD through their anti-inflammatory properties, but they also have their own potential risks. The optimal corticosteroid treatment plan to balance these benefits and risks is unknown, including which type of corticosteroid (options include dexamethasone and hydrocortisone), what dose of corticosteroid, and at what age to start treatment.
What did we want to find out?
In this review, we wanted to compare the benefits and risks of different corticosteroid treatment regimens (the type of corticosteroid, dose, and timing) delivered to premature infants systemically, that is through the vein.
What did we do?
We included trials that evaluated corticosteroid treatment in infants born preterm with risk for the development of BPD, and we reported on any of our predefined outcome measures. We included 59 studies, involving 6441 infants, in our analyses. We chose to compare early (before seven days after birth) and late (seven days or more after birth) corticosteroid treatments separately, as these treatments likely address different patient populations.
What did we find?
Of the many different corticosteroid treatment regimens we compared for treating infants born preterm, two different regimens seem to be most beneficial in helping infants survive without developing BPD:
· treatment beginning late, after 7 days of life, with a higher dose of dexamethasone (at or above 4 mg/kg of body weight);
· treatment beginning early, before 7 days of life, with a moderate dose of dexamethasone (at or above 2 mg/kg but below 4 mg/kg of body weight).
More studies are needed comparing these different treatments and considering their long-term effects.
What are the limitations of the evidence?
Our certainty in the evidence was generally low.
How up to date is this evidence?
We searched for evidence through February 2022.
While early treatment with moderate-dose dexamethasone or late treatment with high-dose dexamethasone may lead to the best effects for survival without BPD, the certainty of the evidence is low. There is insufficient evidence to guide this therapy with regard to plausible adverse long-term outcomes. Further RCTs with direct comparisons between systemic corticosteroid treatments are needed to determine the optimal treatment approach, and these studies should be adequately powered to evaluate survival without major neurosensory disability.
Despite considerable improvement in outcomes for preterm infants, rates of bronchopulmonary dysplasia (BPD) remain high, affecting an estimated 33% of very low birthweight infants, with corresponding long-term respiratory and neurosensory issues. Systemic corticosteroids can address the inflammation underlying BPD, but the optimal regimen for prevention of this disease, balancing of the benefits with the potentially meaningful risks of systemic corticosteroids, continues to be a medical quandary.
Numerous studies have shown that systemic corticosteroids, particularly dexamethasone and hydrocortisone, effectively treat or prevent BPD. However, concerning short and long-term side effects have been reported and the optimal approach to corticosteroid treatment remains unclear.
To determine whether differences in efficacy and safety exist between high-dose dexamethasone, moderate-dose dexamethasone, low-dose dexamethasone, hydrocortisone, and placebo in the prevention of BPD, death, the composite outcome of death or BPD, and other relevant morbidities, in preterm infants through a network meta-analysis, generating both pairwise comparisons between all treatments and rankings of the treatments.
We searched the Cochrane Library for all systematic reviews of systemic corticosteroids for the prevention of BPD and searched for completed and ongoing studies in the following databases in January 2023: Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and clinical trial databases.
We included randomized controlled trials (RCTs) in preterm infants (< 37 weeks’ gestation) at risk for BPD that evaluated systemic corticosteroids (high-dose [≥ 4 mg/kg cumulative dose] dexamethasone, moderate-dose [≥ 2 to < 4 mg/kg] dexamethasone, low-dose [< 2 mg/kg] dexamethasone, or hydrocortisone) versus control or another systemic corticosteroid.
Our main information sources were the systematic reviews, with reference to the original manuscript only for data not included in these reviews. Teams of two paired review authors independently performed data extraction, with disagreements resolved by discussion. Data were entered into Review Manager 5 and exported to R software for network meta-analysis (NMA). NMA was performed using a frequentist model with random-effects. Two separate networks were constructed, one for early (< seven days) initiation of treatment and one for late (≥ seven days) treatment initiation, to reflect the different patient populations evaluated. We assessed the certainty of evidence derived from the NMA for our primary outcomes using principles of the GRADE framework modified for application to NMA.
We included 59 studies, involving 6441 infants, in our analyses.
Only six of the included studies provided direct comparisons between any of the treatment (dexamethasone or hydrocortisone) groups, forcing network comparisons between treatments to rely heavily on indirect evidence through comparisons with placebo/no treatment groups. Thirty-one studies evaluated early corticosteroid treatment, 27 evaluated late corticosteroid treatment, and one study evaluated both early and late corticosteroid treatments.
Early treatment (prior to seven days after birth):
Benefits: NMA for early treatment showed only moderate-dose dexamethasone to decrease the risk of BPD at 36 weeks' postmenstrual age (PMA) compared with control (RR 0.56, 95% CI 0.39 to 0.80; moderate-certainty evidence), although the other dexamethasone dosing regimens may have similar effects compared with control (high-dose dexamethasone, RR 0.71, 95% CI 0.50 to 1.01; low-certainty evidence; low-dose dexamethasone, RR 0.83, 95% CI 0.67 to 1.03; low-certainty evidence). Other early treatment regimens may have little or no effect on the risk of death at 36 weeks' PMA. Only moderate-dose dexamethasone decreased the composite outcome of death or BPD at 36 weeks' PMA compared with control (RR 0.77, 95% CI 0.60 to 0.98; moderate-certainty evidence).
Harms: Low-dose dexamethasone increased the risk for cerebral palsy (RR 1.92, 95% CI 1.12 to 3.28; moderate-certainty evidence) compared with control. Hydrocortisone may decrease the risk of major neurosensory disability versus low-dose dexamethasone (RR 0.65, 95% CI 0.41 to 1.01; low-certainty evidence).
Late treatment (at seven days or later after birth):
Benefits: NMA for late treatment showed high-dose dexamethasone to decrease the risk of BPD both versus hydrocortisone (RR 0.66, 95% CI 0.51 to 0.85; low-certainty evidence) and versus control (RR 0.72, CI 0.59 to 0.87; moderate-certainty evidence). The late treatment regimens evaluated may have little or no effect on the risk of death at 36 weeks' PMA. High-dose dexamethasone decreased risk for the composite outcome of death or BPD compared with all other treatments (control, RR 0.69, 95% CI 0.59 to 0.80, high-certainty evidence; hydrocortisone, RR 0.69, 95% CI 0.58 to 0.84, low-certainty evidence; low-dose dexamethasone, RR 0.73, 95% CI 0.60 to 0.88, low-certainty evidence; moderate-dose dexamethasone, RR 0.76, 95% CI 0.62 to 0.93, low-certainty evidence).
Harms: No effect was observed for the outcomes of major neurosensory disability or cerebral palsy.
The evidence for the primary outcomes was of overall low certainty, with notable deductions for imprecision and heterogeneity across the networks.