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Meta-Analysis
. 2017 Jan 31;1(1):CD010941.
doi: 10.1002/14651858.CD010941.pub2.

Systemic corticosteroid regimens for prevention of bronchopulmonary dysplasia in preterm infants

Wes Onland  1 , Anne Pmc De Jaegere  1 , Martin Offringa  2 , Anton van Kaam  1
Affiliations
Meta-Analysis

Systemic corticosteroid regimens for prevention of bronchopulmonary dysplasia in preterm infants

Wes Onland et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: 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.

Objectives: To assess the effects of different corticosteroid treatment regimens on mortality, pulmonary morbidity, and neurodevelopmental outcome in very low birth weight (VLBW) infants.

Search methods: 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.

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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.

Authors' conclusions: 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.

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Conflict of interest statement

No financial disclosure to be declared. No potential conflicts of interest known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 1 Death or bronchopulmonary dysplasia at 36 weeks PMA.
1.2
1.2. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 2 Mortality at 36 weeks' PMA.
1.3
1.3. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 3 Mortality at hospital discharge.
1.4
1.4. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 4 Bronchopulmonary dysplasia at 36 weeks' PMA.
1.5
1.5. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 5 Failure to extubate 3 days after initiation.
1.6
1.6. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 6 Failure to extubate 7 days after initiation.
1.7
1.7. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 7 Days of mechanical ventilation.
1.8
1.8. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 8 Days on supplemental oxygen.
1.9
1.9. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 9 Hypertension.
1.10
1.10. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 10 Hyperglycemia.
1.11
1.11. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 11 Culture confirmed infection.
1.12
1.12. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 12 Clinical suspected infection.
1.13
1.13. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 13 Gastrointestinal hemorrhage.
1.14
1.14. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 14 Gastrointestinal perforation.
1.15
1.15. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 15 Necrotizing enterocolitis.
1.16
1.16. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 16 Intraventricular hemorrhage (> grade II).
1.17
1.17. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 17 Periventricular leukomalacia (PVL).
1.18
1.18. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 18 Open‐label corticosteroids.
1.19
1.19. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 19 Severe retinopathy of prematurity.
1.20
1.20. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 20 Cerebral palsy in survivors assessed.
1.21
1.21. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 21 Death or cerebral palsy.
1.22
1.22. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 22 Bayley's MDI < 2 SD.
1.23
1.23. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 23 Severe blindness.
1.24
1.24. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 24 Abnormal neurodevelopmental outcome in survivors assessed (various definitions).
1.25
1.25. Analysis
Comparison 1 Lower versus higher cumulative dose dexamethasone regimen, Outcome 25 Death or abnormal neurodevelopmental outcome (various definitions).
2.1
2.1. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 1 Death or bronchopulmonary dysplasia at 36 weeks' PMA.
2.2
2.2. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 2 Mortality at 28 days' PNA.
2.3
2.3. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 3 Mortality at 36 weeks' PMA.
2.4
2.4. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 4 Mortality at hospital discharge.
2.5
2.5. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 5 Bronchopulmonary dysplasia at 28 days' PNA.
2.6
2.6. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 6 Bronchopulmonary dysplasia at 36 weeks' PMA.
2.7
2.7. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 7 Failure to extubate 3 days after initiation.
2.8
2.8. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 8 Failure to extubate 7 days after initiation.
2.9
2.9. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 9 Days of mechanical ventilation.
2.10
2.10. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 10 Hypertension.
2.11
2.11. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 11 Hyperglycemia.
2.12
2.12. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 12 Culture confirmed infection.
2.13
2.13. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 13 Gastrointestinal hemorrhage.
2.14
2.14. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 14 Gastrointestinal perforation.
2.15
2.15. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 15 Necrotizing enterocolitis.
2.16
2.16. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 16 Patent ductus arteriosus requiring therapy.
2.17
2.17. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 17 Intraventricular hemorrhage (> grade II).
2.18
2.18. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 18 Open‐label corticosteroids.
2.19
2.19. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 19 Retinopathy of prematurity (any).
2.20
2.20. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 20 Severe retinopathy of prematurity.
2.21
2.21. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 21 Cerebral palsy in survivors assessed.
2.22
2.22. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 22 Death or cerebral palsy.
2.23
2.23. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 23 Severe blindness.
2.24
2.24. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 24 Abnormal neurodevelopmental outcome in survivors assessed (various definitions).
2.25
2.25. Analysis
Comparison 2 Later versus earlier initiation of dexamethasone therapy, Outcome 25 Death or abnormal neurodevelopmental outcome (various definitions).
3.1
3.1. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 1 Death or bronchopulmonary dysplasia at 36 weeks PMA.
3.2
3.2. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 2 Mortality at 28 days PNA.
3.3
3.3. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 3 Mortality at 36 weeks PMA.
3.4
3.4. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 4 Mortality at hospital discharge.
3.5
3.5. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 5 Bronchopulmonary dysplasia at 28 days PNA.
3.6
3.6. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 6 Bronchopulmonary dysplasia at 36 weeks PMA.
3.7
3.7. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 7 Hypertension.
3.8
3.8. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 8 Hyperglycemia.
3.9
3.9. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 9 Culture confirmed infection.
3.10
3.10. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 10 Clinical suspected infection.
3.11
3.11. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 11 Gastrointestinal hemorrhage.
3.12
3.12. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 12 Necrotizing enterocolitis.
3.13
3.13. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 13 Intraventricular hemorrhage (> grade II).
3.14
3.14. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 14 Open‐label corticosteroids.
3.15
3.15. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 15 Retinopathy of prematurity (any).
3.16
3.16. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 16 Severe retinopathy of prematurity.
3.17
3.17. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 17 Abnormal neurodevelopmental outcome in survivors assessed (various definitions).
3.18
3.18. Analysis
Comparison 3 Pulse versus continuous dexamethasone therapy, Outcome 18 Death or abnormal neurodevelopmental outcome (various definitions).
4.1
4.1. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 1 Death or bronchopulmonary dysplasia at 36 weeks PMA.
4.2
4.2. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 2 Mortality at 28 days PNA.
4.3
4.3. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 3 Mortality at 36 weeks PMA.
4.4
4.4. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 4 Mortality at hospital discharge.
4.5
4.5. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 5 Bronchopulmonary dysplasia at 28 days PNA.
4.6
4.6. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 6 Bronchopulmonary dysplasia at 36 weeks PMA.
4.7
4.7. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 7 Hypertension.
4.8
4.8. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 8 Hyperglycemia.
4.9
4.9. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 9 Days of mechanical ventilation.
4.10
4.10. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 10 Culture confirmed infection.
4.11
4.11. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 11 Gastrointestinal hemorrhage.
4.12
4.12. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 12 Necrotizing enterocolitis.
4.13
4.13. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 13 Intraventricular hemorrhage (> grade II).
4.14
4.14. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 14 Open‐label corticosteroids.
4.15
4.15. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 15 Retinopathy of prematurity (any).
4.16
4.16. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 16 Abnormal neurodevelopmental outcome in survivors assessed (various definitions).
4.17
4.17. Analysis
Comparison 4 Individual tailored versus continuous tapered dexamethasone regimen, Outcome 17 Death or abnormal neurodevelopmental outcome (various definitions).
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References

References to studies included in this review

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References to other published versions of this review

Onland 2008
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