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Meta-Analysis
. 2016 Aug 22;2016(8):CD000501.
doi: 10.1002/14651858.CD000501.pub4.

Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birth weight infants

Brian A Darlow  1 , P J Graham, Maria Ximena Rojas-Reyes
Affiliations
Meta-Analysis

Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birth weight infants

Brian A Darlow et al. Cochrane Database Syst Rev. .

Abstract

Background: Vitamin A is necessary for normal lung growth and the integrity of respiratory tract epithelial cells. Preterm infants have low vitamin A status at birth and this has been associated with an increased risk of developing chronic lung disease.

Objectives: To evaluate supplementation with vitamin A on the incidence of death or neonatal chronic lung disease and long-term neurodevelopmental disability in very low birth weight (VLBW) infants compared with a control (placebo or no supplementation), and to consider the effect of the supplementation route, dose, and timing.

Search methods: For the original review and subsequent updates, we searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, Science Citation Index, and the Oxford Database of Perinatal Trials. The reference lists of relevant trials, paediatric and nutrition journals, and conference abstracts and proceedings were handsearched up to 2010.For the 2016 update, we used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 4), MEDLINE via PubMed (1 May 2016), EMBASE (1 May 2016), and CINAHL (1 May 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection criteria: Randomised controlled trials comparing vitamin A supplementation with a control (placebo or no supplementation) or other dosage regimens in VLBW infants (birth weight ≤ 1500 grams or less than 32 weeks' gestation).

Data collection and analysis: Two review authors screened the search results, extracted data, and assessed the trials for risk of bias. Results were reported as risk ratios (RR), risk differences (RD), and number needed to treat to benefit (NNTB), all with 95% confidence intervals (CI). Trialists were contacted for additional data.

Main results: Eleven trials met the inclusion criteria. Ten trials (1460 infants) compared vitamin A supplementation with a control and one (120 infants) compared different regimens of vitamin A supplementation. Compared to the control group, vitamin A appeared to have a small benefit in reducing the risk of death or oxygen requirement at one month of age (typical RR 0.93, 95% CI 0.88 to 0.99; typical RD -0.05, 95% CI -0.10 to -0.01; NNTB 20, 95% CI 10 to 100; 6 studies, 1165 infants) and the risk of chronic lung disease (oxygen requirement) at 36 weeks' postmenstrual age (typical RR 0.87, 95% CI 0.77 to 0.99; typical RD -0.07, 95% CI -0.13 to -0.01; NNTB 11, 95% CI 6 to 100; 5 studies, 986 infants) (moderate-quality evidence). There was a marginal reduction of the combined outcome of death or chronic lung disease (typical RR 0.92, 95% CI 0.84 to 1.01; typical RD -0.05, 95% CI -0.11 to 0.01; 4 studies, 1089 infants). Neurodevelopmental assessment of 88% of the surviving infants in the largest trial showed no difference between the groups at 18 to 22 months of age, corrected for prematurity (low-quality evidence). There is no evidence to support different vitamin A dosing regimens. No adverse effects of vitamin A supplementation were reported, but it was noted that intramuscular injections of vitamin A were painful.

Authors' conclusions: Whether clinicians decide to utilise repeat intramuscular doses of vitamin A to prevent chronic lung disease may depend upon the local incidence of this outcome and the value attached to achieving a modest reduction in the outcome balanced against the lack of other proven benefits and the acceptability of the treatment. Information on long-term neurodevelopmental status suggests no evidence of either benefit or harm from the intervention.

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Conflict of interest statement

None known.

Figures

1
1
Study flow diagram: review update
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: 1 Supplemental vitamin A versus no supplementation, outcome: 1.1 Death (before 1 month).
4
4
Forest plot of comparison: 1 Supplemental vitamin A versus no supplementation, outcome: 1.2 Chronic lung disease (oxygen use at 28 days in survivors).
5
5
Forest plot of comparison: 1 Supplemental vitamin A versus no supplementation, outcome: 1.3 Death or chronic lung disease (oxygen use at 28 days).
6
6
Forest plot of comparison: 1 Supplemental vitamin A versus no supplementation, outcome: 1.4 Death before 36 weeks' postmenstrual age.
7
7
Forest plot of comparison: 1 Supplemental vitamin A versus no supplementation, outcome: 1.5 Chronic lung disease (oxygen use at 36 weeks' postmenstrual age in survivors).
1.1
1.1. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 1 Death (before 1 month).
1.2
1.2. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 2 Chronic lung disease (oxygen use at 28 days in survivors).
1.3
1.3. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 3 Death or chronic lung disease (oxygen use at 28 days).
1.4
1.4. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 4 Death before 36 weeks' postmenstrual age.
1.5
1.5. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 5 Chronic lung disease (oxygen use at 36 weeks' postmenstrual age in survivors).
1.6
1.6. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 6 Death or chronic lung disease (oxygen use at 36 weeks' postmenstrual age).
1.7
1.7. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 7 Death before 18 to 22 months.
1.8
1.8. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 8 Neurodevelopmental impairment at 18 to 22 months.
1.9
1.9. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 9 Death or neurodevelopmental impairment at 18 to 22 months.
1.10
1.10. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 10 Failure of ductal closure or treatment by day 14.
1.11
1.11. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 11 Sepsis (≥ 1 episodes).
1.12
1.12. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 12 Necrotising enterocolitis.
1.13
1.13. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 13 Intraventricular haemorrhage.
1.14
1.14. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 14 Periventricular leukomalacia.
1.15
1.15. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 15 Retinopathy of prematurity (any grade).
1.16
1.16. Analysis
Comparison 1 Supplemental vitamin A versus no supplementation, Outcome 16 Retinopathy of prematurity requiring laser therapy.
2.1
2.1. Analysis
Comparison 2 Vitamin A regimens: higher dose (10,000 IU) versus standard dose (5000 IU); both intramuscular and 3 x week for 4 weeks, Outcome 1 Death before 36 weeks' postmenstrual age.
2.2
2.2. Analysis
Comparison 2 Vitamin A regimens: higher dose (10,000 IU) versus standard dose (5000 IU); both intramuscular and 3 x week for 4 weeks, Outcome 2 Oxygen use at 36 weeks' postmenstrual age in survivors.
2.3
2.3. Analysis
Comparison 2 Vitamin A regimens: higher dose (10,000 IU) versus standard dose (5000 IU); both intramuscular and 3 x week for 4 weeks, Outcome 3 Death or oxygen use at 36 weeks' postmenstrual age.
2.4
2.4. Analysis
Comparison 2 Vitamin A regimens: higher dose (10,000 IU) versus standard dose (5000 IU); both intramuscular and 3 x week for 4 weeks, Outcome 4 Retinol concentration on study day 28 (μg/L).
2.5
2.5. Analysis
Comparison 2 Vitamin A regimens: higher dose (10,000 IU) versus standard dose (5000 IU); both intramuscular and 3 x week for 4 weeks, Outcome 5 Retinol < 200 μg/L on day 28 (%).
2.6
2.6. Analysis
Comparison 2 Vitamin A regimens: higher dose (10,000 IU) versus standard dose (5000 IU); both intramuscular and 3 x week for 4 weeks, Outcome 6 Necrotising enterocolitis.
2.7
2.7. Analysis
Comparison 2 Vitamin A regimens: higher dose (10,000 IU) versus standard dose (5000 IU); both intramuscular and 3 x week for 4 weeks, Outcome 7 Retinopathy of prematurity (any grade).
2.8
2.8. Analysis
Comparison 2 Vitamin A regimens: higher dose (10,000 IU) versus standard dose (5000 IU); both intramuscular and 3 x week for 4 weeks, Outcome 8 Retinopathy of prematurity (threshold disease).
2.9
2.9. Analysis
Comparison 2 Vitamin A regimens: higher dose (10,000 IU) versus standard dose (5000 IU); both intramuscular and 3 x week for 4 weeks, Outcome 9 Sepsis (≥ 1 episodes).
3.1
3.1. Analysis
Comparison 3 Vitamin A regimens: once‐a‐week (15,000 IU) versus standard dose (5000 IU 3 x week); both intramuscular and for 4 weeks, Outcome 1 Death before 36 weeks' postmenstrual age.
3.2
3.2. Analysis
Comparison 3 Vitamin A regimens: once‐a‐week (15,000 IU) versus standard dose (5000 IU 3 x week); both intramuscular and for 4 weeks, Outcome 2 Oxygen use at 36 weeks' postmenstrual age in survivors.
3.3
3.3. Analysis
Comparison 3 Vitamin A regimens: once‐a‐week (15,000 IU) versus standard dose (5000 IU 3 x week); both intramuscular and for 4 weeks, Outcome 3 Death or oxygen use at 36 weeks' postmenstrual age.
3.4
3.4. Analysis
Comparison 3 Vitamin A regimens: once‐a‐week (15,000 IU) versus standard dose (5000 IU 3 x week); both intramuscular and for 4 weeks, Outcome 4 Retinol concentration on study day 28 (μg/L).
3.5
3.5. Analysis
Comparison 3 Vitamin A regimens: once‐a‐week (15,000 IU) versus standard dose (5000 IU 3 x week); both intramuscular and for 4 weeks, Outcome 5 Retinol < 200 μg/L on day 28 (%).
3.6
3.6. Analysis
Comparison 3 Vitamin A regimens: once‐a‐week (15,000 IU) versus standard dose (5000 IU 3 x week); both intramuscular and for 4 weeks, Outcome 6 Necrotising enterocolitis.
3.7
3.7. Analysis
Comparison 3 Vitamin A regimens: once‐a‐week (15,000 IU) versus standard dose (5000 IU 3 x week); both intramuscular and for 4 weeks, Outcome 7 Retinopathy of prematurity (any grade).
3.8
3.8. Analysis
Comparison 3 Vitamin A regimens: once‐a‐week (15,000 IU) versus standard dose (5000 IU 3 x week); both intramuscular and for 4 weeks, Outcome 8 Retinopathy of prematurity (threshold disease).
3.9
3.9. Analysis
Comparison 3 Vitamin A regimens: once‐a‐week (15,000 IU) versus standard dose (5000 IU 3 x week); both intramuscular and for 4 weeks, Outcome 9 One or more episodes of sepsis.
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Update of

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References to other published versions of this review

Darlow 1998
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