Early administration of inhaled corticosteroids for preventing chronic lung disease in very low birth weight preterm neonates

Vibhuti S Shah; Arne Ohlsson<sup>a</sup>; Henry L Halliday; Michael Dunn

doi:10.1002/14651858.CD001969.pub4

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Forest plot of comparison: 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), outcome: 1.1 CLD at 36 weeks' PMA.

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Figure 5

Forest plot of comparison: 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), outcome: 1.6 Death by or CLD at 36 weeks' PMA.

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Figure 6

Forest plot of comparison: 2 Early inhaled steroid (< 2 weeks) vs. placebo (among survivors), outcome: 2.1 CLD at 36 weeks' PMA.

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Analysis 1.1

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 1 CLD at 36 weeks PMA.

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Analysis 1.2

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 2 CLD at 28 days of age.

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Analysis 1.3

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 3 Death by 28 days of age.

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Analysis 1.4

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 4 Death by 36 weeks PMA.

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Analysis 1.5

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 5 Death by or CLD at 28 days of age.

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Analysis 1.6

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 6 Death by or CLD at 36 weeks PMA.

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Analysis 1.7

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 7 Survival to hospital discharge without CLD.

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Analysis 1.8

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 8 Death during hospital stay.

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Analysis 1.9

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 9 Culture proven infection during hospital stay.

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Analysis 1.10

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 10 Hyperglycaemia.

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Analysis 1.11

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 11 Hypertension.

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Analysis 1.12

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 12 Gastrointesinal bleeding.

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Analysis 1.13

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 13 Cataract.

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Analysis 1.14

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 14 Intraventricular haemorrhage.

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Analysis 1.15

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 15 Periventricular leukomalacia.

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Analysis 1.16

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 16 Brain injury.

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Analysis 1.17

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 17 Necrotizing enterocolitis.

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Analysis 1.18

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 18 Retinopathy of prematurity (any stage).

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Analysis 1.19

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 19 Patent ductus arteriosus.

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Analysis 1.20

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 20 Reintubation.

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Analysis 1.21

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 21 Requirement for systemic steroids.

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Analysis 1.22

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 22 Failure to extubate within 14 days.

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Analysis 1.23

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 23 Death or oxygen dependency at discharge.

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Analysis 1.24

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 24 Death or severe BPD.

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Analysis 1.25

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 25 Death or grade 3 or 4 IVH.

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Analysis 1.26

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 26 Death or PVL.

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Analysis 1.27

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 27 Death or NEC.

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Analysis 1.28

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 28 Death or sepsis.

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Analysis 1.29

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 29 Death or ROP (stage not stated).

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Analysis 1.30

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 30 Death or neurodevelopmental impairment at 18 months PMA.

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Analysis 1.31

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 31 Death or neurodevelopmental impairment at 3 years of age.

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Analysis 1.32

Comparison 1 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised), Outcome 32 Death or cerebral palsy at 3 years of age.

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Analysis 2.1

Comparison 2 Early inhaled steroid (< 2 weeks) vs. placebo (among survivors), Outcome 1 CLD at 36 weeks PMA.

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Analysis 2.2

Comparison 2 Early inhaled steroid (< 2 weeks) vs. placebo (among survivors), Outcome 2 CLD at 28 days of age.

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Analysis 2.3

Comparison 2 Early inhaled steroid (< 2 weeks) vs. placebo (among survivors), Outcome 3 Cerebral palsy.

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Analysis 2.4

Comparison 2 Early inhaled steroid (< 2 weeks) vs. placebo (among survivors), Outcome 4 Mean developmental index on BSID‐II < 2 SD of the mean.

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Analysis 2.5

Comparison 2 Early inhaled steroid (< 2 weeks) vs. placebo (among survivors), Outcome 5 Respiratory readmission.

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Summary of findings for the main comparison. Early inhaled steroids (< 2 weeks) compared to placebo (among all randomised) for preventing chronic lung disease in very low birth weight preterm neonates

Early inhaled steroids (< 2 weeks) compared to placebo (among all randomised) for preventing chronic lung disease in very low birth weight preterm neonates
Patient or population: very low birth weight preterm neonates Settings: neonatal intensive care units Intervention: early inhaled steroids (< 2 weeks after birth) Comparison: placebo (among all randomised)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo (among all randomised)	Early inhaled steroids (< 2 weeks)
CLD at 36 weeks' PMA oxygen dependency at 36 weeks' PMA	Study population		RR 0.97 (0.62 to 1.52)	429 (5 studies)	⊕⊕⊕⊝ moderate
	152 per 1000	148 per 1000 (94 to 231)
	Moderate
	115 per 1000	112 per 1000 (71 to 175)
Death by, or CLD at, 36 weeks' PMA Death or oxygen dependency at 36 weeks' PMA	Study population		RR 0.86 (0.75 to 0.99)	1285 (6 studies)	⊕⊕⊕⊝ moderate¹
	403 per 1000	346 per 1000 (302 to 398)
	Moderate
	350 per 1000	301 per 1000 (262 to 347)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Method of sequence generation was unclear in all included studies except for the study by Bassler 2015. In the studies by Fok 1999, Jangaard 2002, Merz 1999 and Yong 1999 blinding of outcome assessment was unclear. Except for the study by Bassler 2015, none of the included studies were registered and we were unable to identify whether there was selective reporting or not.

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Summary of findings 2. Early inhaled steroid (< 2 weeks) compared to placebo (among survivors) for preventing chronic lung disease in very low birth weight preterm neonates

Early inhaled steroid (< 2 weeks) compared to placebo (among survivors) for preventing chronic lung disease in very low birth weight preterm neonates
Patient or population: Very low birth weight preterm neonates Settings: Neonatal intensive care units Intervention: Early inhaled steroid (< 2 weeks after birth) Comparison: placebo (among survivors)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo (among survivors)	Early inhaled steroid (< 2 weeks)
CLD at 36 weeks' PMA	Study population		RR 0.76 (0.63 to 0.93)	1088 (6 studies)	⊕⊕⊕⊝ moderate
	314 per 1000	239 per 1000 (198 to 292)
	Moderate
	188 per 1000	143 per 1000 (118 to 175)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Summary of findings 2. Early inhaled steroid (< 2 weeks) compared to placebo (among survivors) for preventing chronic lung disease in very low birth weight preterm neonates

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Comparison 1. Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 CLD at 36 weeks PMA Show forest plot	5	429	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.62, 1.52]

2 CLD at 28 days of age Show forest plot	5	429	Risk Difference (M‐H, Random, 95% CI)	0.03 [‐0.08, 0.14]

3 Death by 28 days of age Show forest plot	5	429	Risk Difference (M‐H, Fixed, 95% CI)	‐0.04 [‐0.09, 0.01]

4 Death by 36 weeks PMA Show forest plot	6	1285	Risk Difference (M‐H, Fixed, 95% CI)	0.01 [‐0.03, 0.05]

5 Death by or CLD at 28 days of age Show forest plot	5	429	Risk Difference (M‐H, Fixed, 95% CI)	‐0.02 [‐0.11, 0.07]

6 Death by or CLD at 36 weeks PMA Show forest plot	6	1285	Risk Ratio (M‐H, Fixed, 99% CI)	0.86 [0.75, 0.99]

7 Survival to hospital discharge without CLD Show forest plot	1	86	Risk Difference (M‐H, Fixed, 95% CI)	0.14 [‐0.06, 0.34]

8 Death during hospital stay Show forest plot	1	86	Risk Difference (M‐H, Fixed, 95% CI)	0.07 [‐0.07, 0.21]

9 Culture proven infection during hospital stay Show forest plot	6	1121	Risk Difference (M‐H, Fixed, 95% CI)	0.05 [‐0.00, 0.11]

9.1 Positive blood or CSF culture	2	896	Risk Difference (M‐H, Fixed, 95% CI)	0.05 [‐0.01, 0.11]
9.2 Positive blood culture	4	225	Risk Difference (M‐H, Fixed, 95% CI)	0.05 [‐0.06, 0.16]
10 Hyperglycaemia Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10.1 Hyperglycaemia	3	116	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.49, 1.44]
10.2 Hyperglycaemia requiring insulin treatment	1	856	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.74, 1.27]
11 Hypertension Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

11.1 Hypertension	3	116	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.36, 3.99]
11.2 Hypertension requiring treatment	1	856	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.21, 1.57]
12 Gastrointesinal bleeding Show forest plot	1	253	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.04, 3.34]

13 Cataract Show forest plot	1	253	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.01, 8.56]

14 Intraventricular haemorrhage Show forest plot	2	306	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.77, 1.41]

15 Periventricular leukomalacia Show forest plot	2	306	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.59, 3.46]

16 Brain injury Show forest plot	1	838	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.94, 1.65]

17 Necrotizing enterocolitis Show forest plot	3	1162	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.68, 1.24]

18 Retinopathy of prematurity (any stage) Show forest plot	3	1030	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.93, 1.21]

19 Patent ductus arteriosus Show forest plot	1	53	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.57, 1.17]

20 Reintubation Show forest plot	1	856	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.35, 0.96]

21 Requirement for systemic steroids Show forest plot	8	1403	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.77, 1.02]

22 Failure to extubate within 14 days Show forest plot	5	193	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.76, 1.24]

23 Death or oxygen dependency at discharge Show forest plot	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.35, 1.15]

24 Death or severe BPD Show forest plot	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.70, 1.25]

25 Death or grade 3 or 4 IVH Show forest plot	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.65, 1.68]

26 Death or PVL Show forest plot	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.41, 1.93]

27 Death or NEC Show forest plot	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.46, 2.06]

28 Death or sepsis Show forest plot	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.44, 1.40]

29 Death or ROP (stage not stated) Show forest plot	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.79, 1.40]

30 Death or neurodevelopmental impairment at 18 months PMA Show forest plot	1	187	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.70, 1.70]

31 Death or neurodevelopmental impairment at 3 years of age Show forest plot	1	179	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.68, 1.56]

32 Death or cerebral palsy at 3 years of age Show forest plot	1	190	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.64, 1.96]

Comparison 1. Early inhaled steroids (< 2 weeks) vs. placebo (among all randomised)

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Comparison 2. Early inhaled steroid (< 2 weeks) vs. placebo (among survivors)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 CLD at 36 weeks PMA Show forest plot	6	1088	Risk Difference (M‐H, Fixed, 95% CI)	‐0.07 [‐0.13, ‐0.02]

2 CLD at 28 days of age Show forest plot	5	380	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.78, 1.21]

3 Cerebral palsy Show forest plot	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.33, 5.42]

4 Mean developmental index on BSID‐II < 2 SD of the mean Show forest plot	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.37, 4.17]

5 Respiratory readmission Show forest plot	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.44, 2.29]

Comparison 2. Early inhaled steroid (< 2 weeks) vs. placebo (among survivors)

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