Review question: Are the effects of corticosteroids on the outcomes 'mortality, pulmonary morbidity and neurodevelopmental outcome' in preterm infants modulated by the dosage regimen administrated?
Background: Preterm infants have an increased risk of developing chronic lung disease (CLD) or bronchopulmonary dysplasia (BPD). Inflammation in the lung seems to play a central role in the development of BPD, and for this reason studies have investigated the anti-inflammatory drugs called corticosteroids. These studies showed that corticosteroid treatment reduces the risk of BPD, but is also associated with serious adverse effects on neurodevelopment outcome. To reduce these side effects, clinicians have looked for alternative regimens such as postponing corticosteroid administration, lowering its cumulative dose, giving pulse rather than continuous doses, or individualizing the dose according to the respiratory condition of the infant.
Study characteristics: Searching all electronic databases to 21 March 2016 revealed 14 studies investigating two or more different corticosteroid regimens in preterm infants. The investigated regimens differed in the used cumulative dose, timing of initiation and duration of therapy.
Key results: Those studies comparing a high versus a lower-dosage regimen showed an increased risk of BPD and adverse neurodevelopmental outcome for infants receiving a lower cumulative dose. Those studies investigating an early versus later administration of steroids did not show any difference in outcome. Furthermore, pulse regimens showed inferior results for the outcome BPD compared with continuous treatment. An individualized dosage regimen showed no differences compared to the standard tapering course.
Quality of evidence: Most of the studies had important methodological weaknesses, preventing any recommendations on the optimal corticosteroid dosage regimen for preterm infants at risk of BPD. More studies are urgently needed.
Despite the fact that some studies reported a modulating effect of treatment regimens in favor of higher-dosage regimens on the incidence of BPD and neurodevelopmental impairment, recommendations on the optimal type of corticosteroid, the optimal dosage, or the optimal timing of initiation for the prevention of BPD in preterm infants cannot be made based on current level of evidence. A well-designed large RCT is urgently needed to establish the optimal systemic postnatal corticosteroid dosage regimen.
Cochrane systematic reviews show that systemic postnatal corticosteroids reduce the risk of bronchopulmonary dysplasia (BPD) in preterm infants. However, corticosteroids have also been associated with an increased risk of neurodevelopmental impairment. It is unknown whether these beneficial and adverse effects are modulated by differences in corticosteroid treatment regimens.
To assess the effects of different corticosteroid treatment regimens on mortality, pulmonary morbidity, and neurodevelopmental outcome in very low birth weight (VLBW) infants.
We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2) in the Cochrane Library (searched 21 March 2016), MEDLINE via PubMed (1966 to 21 March 2016), Embase (1980 to 21 March 2016), and CINAHL (1982 to 21 March 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials.
Randomized controlled trials (RCTs) comparing two or more different treatment regimens of systemic postnatal corticosteroids in preterm infants at risk for BPD, as defined by the original trialists. Studies investigating one treatment regimen of systemic corticosteroids to a placebo or studies using inhalation corticosteroids were excluded.
Two authors independently assessed eligibility and quality of trials and extracted data on study design, participant characteristics and the relevant outcomes. We asked the original investigators to verify if data extraction was correct and, if possible, to provide any missing data. The primary outcomes to be assessed were: mortality at 36 weeks' postmenstrual age (PMA) or at hospital discharge; BPD defined as oxygen dependency at 36 weeks' PMA; long-term neurodevelopmental sequelae, including cerebral palsy, measured by the Bayley Mental Developmental Index (MDI); and blindness or poor vision. Secondary outcomes were: duration of mechanical ventilation and failure to extubate at day 3 and 7 after initiating therapy; rescue treatment with corticosteroids outside the study period; and the incidence of hypertension, sepsis and hyperglycemia during hospitalizations. Data were analyzed using Review Manager 5 (RevMan 5). We used the GRADE approach to assess the quality of evidence.
Fourteen studies were included in this review. Only RCTs investigating dexamethasone were identified. Eight studies enrolling a total of 303 participants investigated the cumulative dosage administered; three studies contrasted a high versus a moderate and five studies a moderate versus a low cumulative dexamethasone dose.
Analysis of the studies investigating a moderate dexamethasone dose versus a high-dosage regimen showed an increased risk of BPD (typical risk ratio (RR) 1.50, 95% confidence interval (CI) 1.01 to 2.22; typical risk difference (RD) 0.26, 95% CI 0.03 to 0.49; number needed to treat for an additional harmful outcome (NNTH) 4, 95% CI 1.9 to 23.3; I² = 0%, 2 studies, 55 infants) as well as an increased risk of abnormal neurodevelopmental outcome (typical RR 8.33, 95% CI 1.63 to 42.48; RD 0.30, 95% CI 0.14 to 0.46; NNTH 4, 95% CI 2.2 to 7.3; I² = 68%, 2 studies, 74 infants) when using a moderate cumulative-dosage regimen. The composite outcomes of death or BPD and death or abnormal neurodevelopmental outcome showed similar results although the former only reached borderline significance.
There were no differences in outcomes between a moderate- and a low-dosage regimen.
Four other studies enrolling 762 infants investigated early initiation of dexamethasone therapy versus a moderately early or delayed initiation and showed no significant differences in the primary outcomes. The two RCTs investigating a continuous versus a pulse dexamethasone regimen showed an increased risk of the combined outcome death or BPD when using the pulse therapy. Finally, two trials investigating a standard regimen versus a participant-individualized course of dexamethasone showed no difference in the primary outcome and long-term neurodevelopmental outcomes.
The quality of evidence for all comparisons discussed above was assessed as low or very low, because the validity of all comparisons is hampered by small samples of randomized infants, heterogeneity in study population and design, non-protocolized use of ‘rescue’ corticosteroids and lack of long-term neurodevelopmental data in most studies.