OBJECTIVES

To assess effects of enteral “low” dose (daily doses of ≤10 000 international unit) vitamin A supplementation compared with no vitamin A supplementation in human milk-fed preterm and low birth weight (LBW) infants.

DATA SOURCES

Cochrane Central Register of Controlled Trials; Medline, Embase, Scopus, Web of Science, CINAHL from inception to 16 March 2021.

STUDY SELECTION

Randomized trials were screened. Primary outcomes were mortality, morbidity, growth, neurodevelopment. Secondary outcomes were feed intolerance and duration of hospitalization. We also assessed the dose and timing of vitamin A supplementation. Data were extracted and pooled with fixed and random-effects models.

RESULTS

Four trials including 800 very LBW <1.5 kg or <32 weeks’ gestation infants were found. At latest follow-up, we found little or no effect on: mortality, sepsis, bronchopulmonary dysplasia, retinopathy of prematurity, duration of hospitalisation. However, we found a increased level of serum retinol mean difference of 4.7 μg/ml (95% CI 1.2 to 8.2, I2 =0.00%, one trial, 36 participants,). Evidence ranged from very low to moderate certainty. There were no outcomes reported for length, head circumference or neurodevelopment.

LIMITATIONS

Heterogeneity and small sample size in the included studies.

CONCLUSIONS

Low-dose vitamin A increased serum retinol concentration among very LBW and very preterm infants but had no effect on other outcomes. More trials are needed to assess effects on clinical outcomes and to assess effects in infants 1.5 to 2.4 kg or 32 to 26 weeks’ gestation.

Vitamin A plays an important role in embryonic development and maintenance of differentiation of cells in humans. Preterm (<37 weeks’ gestation) and low birth weight (LBW) (<2.5 kg) infants are born with low cord blood and liver storage of vitamin A,1  and have lower concentrations of plasma retinol-binding protein than term infants.

Supplementation with vitamin A has been reported to reduce bronchopulmonary dysplasia (BPD) in preterm and LBW infants in some studies.1,2  Low-dose enteral vitamin A (ie, daily doses of ≤10 000 international unit [IU]) is commonly given to preterm and LBW infants as part of multivitamin vitamin supplementations.

The World Health Organization currently does not recommend enteral vitamin A supplementation for LBW infants who are fed mother's own milk or donor human milk because of insufficient evidence.3  The European Society for Pediatric Gastroenterology Hepatology and Nutrition recommends 400 to 1000 μg/kg per day for stable preterm infants.4  However, there have been new studies since these recommendations were made.

Thus, our primary objective was to assess the effects of enteral low-dose (dose ≤10 000 IU per day) vitamin A supplementation compared with no supplementation on mortality, morbidity, growth, and neurodevelopmental outcomes. Secondary objectives were to understand the optimal dose and timing of vitamin A supplementation.

The protocol for this review was registered in PROSPERO (2021 #CRD42021239191).5 

We selected randomized controlled trials and nonrandomized trials (quasi-randomized) in which preterm or LBW infants fed mother's own milk or donor human milk were either allocated to receive enteral vitamin A supplementation or no supplementation. Data comparing dosage, duration, and timing of initiation were also included. Studies in which enteral vitamin A supplementation was provided for the treatment of any disease were excluded. Outcome definitions can be found in Appendix 3.

We searched Cochrane Central Register of Controlled Trials in the Cochrane Library via the Cochrane Register of Studies Online, PubMed and Embase from inception to March 16, 2021 (Appendix 1  for search strategy). We used standard methods to screen and extract data. We extracted data using the modified Cochrane Effective Practice and Organization of Care Group data collection checklist.6  Screening and data extraction were managed using the Web-based software, Covidence.7 

The assessment of the methodological quality of the included studies was done by using the standard methods of Revised Cochrane risk of bias (ROB) tool for randomized trials (RoB 2) and ROB in nonrandomized studies of interventions (ROBINS-I) tool for nonrandomized studies.8  We planned to use funnel plots and Egger’s tests for all outcomes with >10 studies.9 

We used standard methods for statistical analysis.8  For each outcome, studies were pooled at the latest follow-up if there was >1 study. We reported individual study effect size if a single study had multiple time points of the outcome. The effect of interventions on outcomes was estimated through a meta-analysis using the “meta” command in Stata 16.10  We reported relative risk (RR) for categorical outcomes and mean difference (MD) for continuous outcomes. The individual infant was the unit of analysis for all the studies. We used adjusted results whenever possible. Fixed-effect meta-analysis (inverse variance method) was used to combine data when studies were estimating the same underlying treatment effects. High heterogeneity was defined as an I2 value >50%.11  In cases of high heterogeneity, the random effects model Restricted Maximum Likelihood Method was used.

We planned a priori a subgroup analysis to assess gestational age (very preterm [VPT], <32 weeks) and birth weight (very LBW [VLBW], or <1500 g) for the important outcomes.

We evaluated the certainty of the evidence using the standard Grading of Recommendations Assessment, Development, and Evaluation approach and Grading of Recommendations Assessment, Development, and Evaluation Pro software.12 

A total of 7051 records were identified from the search and 4 trials (800 participants) were included which compared enteral vitamin A with no vitamin A or placebo (Appendix 2 , Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart).1316  Studies were conducted in 3 countries (India, China, United Kingdom) in hospital settings. All infants were VLBW (<1.5 kg) or VPT (<32 weeks). Three trials had low ROB,13,14,16  and 1 had some concerns15  (Appendix 4 ). The daily dose of vitamin A ranged between 1500 and 5000 IU and commenced between 0 and 4 days of birth. All 4 trials used placebo (mostly soyabean oil) in the comparator group. No studies were located that compared the dose or timing of vitamin A supplementation.

Primary outcome data are summarized in Table 1 and Appendix 3. At the latest follow-up (median 10 weeks), we found an RR of 0.74 for all-cause mortality in infants who received enteral vitamin A supplementation compared with infants who received no supplementation (95% confidence interval [CI] 0.53–1.02, I2 = 43.5%, 4 trials, 800 participants, moderate certainty evidence). At the latest follow-up (median 16 weeks), we found an RR of 0.87 for sepsis (95% CI 0.64–1.19, I2 = 0.00%, 3 trials, 646 participants, low certainty evidence). At latest follow-up (median 13 weeks), we found an RR of 0.77 for BPD (95% CI 0.50–1.16, I2 = 61.4%, 22 trials, 746 participants, very low certainty evidence).

TABLE 1

Effect of Enteral Low-Dose Vitamin A Supplementation Versus Placebo on Mortality, Morbidity, and Growth

Low-Dose Vitamin A Compared With Placebo for Preterm and/or LBW Infants
OutcomesNo. of Participants (Studies) Follow-UpCertainty of the Evidence (GRADE)Relative Effect (95% CI)Anticipated Absolute Effects
Risk With PlaceboRisk Difference With Low Dose Vitamin A
Length of hospital stay mean (SD):12.5 (6.3) wk 450 (2 RCTs) ⨁◯◯◯ Very lowa — The mean length of hospital stay was 69.3 (36.8) d 8.76 d lower (32.1 lower–14.58 higher) 
Mortality follow-up: latest mean (SD):10.3 (7.2) wk 800 (4 RCTs) ⨁⨁⨁◯ Moderateb RR 0.74 (0.53–1.02) 153 per 1000 40 fewer per 1000 (72 fewer–3 more) 
Pulmonary hemorrhage follow-up: latest (10 wk) 154 (1 RCT) ⨁⨁◯◯ Lowc RR 0.60 (0.30–1.21) 143 per 1000 57 fewer per 1000 (100 fewer–30 more) 
Sepsis follow-up: latest mean (SD):12.3 (7.2) wk 646 (3 RCTs) ⨁⨁◯◯ Lowd RR 0.87 (0.64–1.19) 196 per 1000 25 fewer per 1000 (70 fewer–37 more) 
Necrotizing enterocolitis follow-up: latest mean (SD): 12.33 (4.04) wk 604 (3 RCTs) ⨁◯◯◯ Very lowe RR 1.05 (0.71–1.57) 66 per 1000 3 more per 1000 (19 fewer–38 more) 
BPD follow-up: latest mean (SD):11.75 (6.02) wk 746 (4 RCTs) ⨁⨁◯◯ Lowf RR 0.77 (0.50–1.16) 338 per 1000 78 fewer per 1000 (169 fewer–54 more) 
Retinopathy of prematurity follow-up: latest mean (SD):11.75 (6.02) wk 742 (4 RCTs) ⨁⨁◯◯ Lowf RR 0.69 (0.37–1.30) 174 per 1000 54 fewer per 1000 (110 fewer–52 more) 
Patent ductus arteriosus follow-up: latest mean (SD): 7 (4.24) wk 350 (2 RCTs) ⨁⨁◯◯ Lowf RR 0.66 (0.21–2.06) 206 per 1000 70 fewer per 1000 (163 fewer–218 more) 
Seizures follow-up: latest (10 wk) 154 (1 RCT) ⨁⨁◯◯ Lowc RR 0.82 (0.54 to 1.25) 260 per 1000 47 fewer per 1000 (119 fewer–65 more) 
Pneumothorax follow-up: latest (10 wk) 154 (1 RCT) ⨁⨁◯◯ Lowc RR 0.75 (0.46–1.21) 221 per 1000 55 fewer per 1000 (119 fewer–46 more) 
Periventricular leukomalacia follow-up: latest 17 wk 262 (1 RCT) ⨁⨁◯◯ Lowc RR 0.66 (0.38–1.14) 208 per 1000 71 fewer per 1000 (129 fewer–29 more) 
Intraventricular hemorrhage follow-up: latest mean (SD): 13.5 (4.95) wk 450 (2 RCTs) ⨁◯◯◯ Very lowe RR 1.00 (0.46–2.17) 54 per 1000 0 fewer per 1000 (29 fewer–63 more) 
Weight follow-up: latest (at discharge, 16 wk) 188 (1 RCT) ⨁⨁◯◯ Lowc — The mean weight was 3.08 (0.77) kg MD 0.02 kg higher (0.21 lower–0.24 higher) 
Neurodevelopment No trials — —   
Serum retinol concentration follow-up: latest (8 wk) 36 (1 RCT) ⨁⨁◯◯g — The mean serum retinol concentration was 16.4 (6.36) μg/mL MD 4.7 μg/mL higher (1.2 higher–8.2 higher) 
Low-Dose Vitamin A Compared With Placebo for Preterm and/or LBW Infants
OutcomesNo. of Participants (Studies) Follow-UpCertainty of the Evidence (GRADE)Relative Effect (95% CI)Anticipated Absolute Effects
Risk With PlaceboRisk Difference With Low Dose Vitamin A
Length of hospital stay mean (SD):12.5 (6.3) wk 450 (2 RCTs) ⨁◯◯◯ Very lowa — The mean length of hospital stay was 69.3 (36.8) d 8.76 d lower (32.1 lower–14.58 higher) 
Mortality follow-up: latest mean (SD):10.3 (7.2) wk 800 (4 RCTs) ⨁⨁⨁◯ Moderateb RR 0.74 (0.53–1.02) 153 per 1000 40 fewer per 1000 (72 fewer–3 more) 
Pulmonary hemorrhage follow-up: latest (10 wk) 154 (1 RCT) ⨁⨁◯◯ Lowc RR 0.60 (0.30–1.21) 143 per 1000 57 fewer per 1000 (100 fewer–30 more) 
Sepsis follow-up: latest mean (SD):12.3 (7.2) wk 646 (3 RCTs) ⨁⨁◯◯ Lowd RR 0.87 (0.64–1.19) 196 per 1000 25 fewer per 1000 (70 fewer–37 more) 
Necrotizing enterocolitis follow-up: latest mean (SD): 12.33 (4.04) wk 604 (3 RCTs) ⨁◯◯◯ Very lowe RR 1.05 (0.71–1.57) 66 per 1000 3 more per 1000 (19 fewer–38 more) 
BPD follow-up: latest mean (SD):11.75 (6.02) wk 746 (4 RCTs) ⨁⨁◯◯ Lowf RR 0.77 (0.50–1.16) 338 per 1000 78 fewer per 1000 (169 fewer–54 more) 
Retinopathy of prematurity follow-up: latest mean (SD):11.75 (6.02) wk 742 (4 RCTs) ⨁⨁◯◯ Lowf RR 0.69 (0.37–1.30) 174 per 1000 54 fewer per 1000 (110 fewer–52 more) 
Patent ductus arteriosus follow-up: latest mean (SD): 7 (4.24) wk 350 (2 RCTs) ⨁⨁◯◯ Lowf RR 0.66 (0.21–2.06) 206 per 1000 70 fewer per 1000 (163 fewer–218 more) 
Seizures follow-up: latest (10 wk) 154 (1 RCT) ⨁⨁◯◯ Lowc RR 0.82 (0.54 to 1.25) 260 per 1000 47 fewer per 1000 (119 fewer–65 more) 
Pneumothorax follow-up: latest (10 wk) 154 (1 RCT) ⨁⨁◯◯ Lowc RR 0.75 (0.46–1.21) 221 per 1000 55 fewer per 1000 (119 fewer–46 more) 
Periventricular leukomalacia follow-up: latest 17 wk 262 (1 RCT) ⨁⨁◯◯ Lowc RR 0.66 (0.38–1.14) 208 per 1000 71 fewer per 1000 (129 fewer–29 more) 
Intraventricular hemorrhage follow-up: latest mean (SD): 13.5 (4.95) wk 450 (2 RCTs) ⨁◯◯◯ Very lowe RR 1.00 (0.46–2.17) 54 per 1000 0 fewer per 1000 (29 fewer–63 more) 
Weight follow-up: latest (at discharge, 16 wk) 188 (1 RCT) ⨁⨁◯◯ Lowc — The mean weight was 3.08 (0.77) kg MD 0.02 kg higher (0.21 lower–0.24 higher) 
Neurodevelopment No trials — —   
Serum retinol concentration follow-up: latest (8 wk) 36 (1 RCT) ⨁⨁◯◯g — The mean serum retinol concentration was 16.4 (6.36) μg/mL MD 4.7 μg/mL higher (1.2 higher–8.2 higher) 

The risk in the intervention group (and its 95% CI) is on the basis of the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Grading of Recommendations Assessment, Development, and Evaluation working group grades of evidence: high certainty, we are very confident that the true effect lies close to that of the estimate of the effect; moderate certainty, we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; low certainty, our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect; very low certainty, we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. Patient or population: preterm and/or LBW infants. Setting: any setting. Intervention: low-dose vitamin A. Comparison: placebo. GRADE, Grading of Recommendations Assessment, Development, and Evaluation; RCT, randomized controlled trial. —, not applicable.

a

Downgraded 3 levels for: serious inconsistency (high heterogeneity); very serious imprecision (suboptimal sample size, wide CI).

b

Downgraded 1 level for: serious imprecision (wide CI).

c

Downgraded 2 levels for: serious inconsistency (small number of studies); serious imprecision (wide CI).

d

Downgraded 2 levels for: serious ROB; serious imprecision (wide CI).

e

Downgraded 3 levels for: serious ROB; serious inconsistency (high heterogeneity); serious imprecision (wide CI).

f

Downgraded 2 levels for: serious inconsistency (high heterogeneity); serious imprecision (wide CI).

g

Downgraded 2 levels for: serious inconsistency (small number of studies); serious imprecision (suboptimal sample size).

At the latest follow-up (median 13 weeks), we found an RR of 0.77 for retinopathy of prematurity (95% CI 0.37–1.30, I2 = 55.4%, 4 trials, 742 participants, very low certainty evidence). At the latest follow-up (median 7 weeks), we found an RR of 0.66 for patent ductus arteriosus (95% CI 0.21–2.06, I2 = 61.4%, 2 trials, 350 participants, low certainty evidence).

At 10 weeks follow-up, we found an RR of RR 0.82 for seizures (95% CI 0.54–1.25, 1 trial, 154 participants, low certainty evidence). Data on other morbidities (pulmonary hemorrhage, pneumothorax, intraventricular hemorrhage periventricular leukomalacia, necrotizing enterocolitis) can be found in Appendix 9.

At 4 weeks follow-up, we found an RR of 0.60 for feed intolerance (95% CI 0.23–1.58, I2 = 0.00%, 1 trial, 196 participants, low certainty evidence). At latest follow-up (median 12.5 weeks), we found an MD of −8.76 for duration of hospitalization (95% CI −32.1 to 14.58, I2 = 61.4%, 2 trials, 450 participants, very low certainty evidence).

At 8 weeks follow-up, we found a serum retinol MD of 4.7 μg/mL (95% CI 1.2–8.2, I2 = 0.00%, 1 trial, 36 participants, low certainty evidence). At latest follow-up (median 7 weeks), we found 2 trials (646 participants) that assessed bulging fontanelle, and no cases of bulging fontanelle were found in either trial.

Three of the 4 studies (Wardle 2001; Rakshasbhuvankar 2021; Sun 2019) recruited infants <1000 g or <28 weeks’ gestation. The remaining study (Basu 2019) recruited 20% infants <1000 g and 40% between 1000 and 1499 g. We did a sensitivity analysis excluding the Basu study and results were similar (Appendix 11 ). Sensitivity analysis excluding the 1 high-income country study (Wardle 2001) also showed little change to the results (Appendix 12 ).

Our systematic review included 4 trials enrolling 800 VLBW (<1.5k g) and VPT infants <32 weeks’ gestation. Overall, we showed that daily low-dose (≤10 000 IU) vitamin A may decrease mortality (RR 0.75, 95% CI 0.53–1.02) and may decrease other morbidities. However, all our estimates for mortality, morbidities, and growth outcomes crossed the line of no effect and included both appreciable benefit and appreciable harm. Our review also found no effect on growth outcome on the basis of a single trial (MD 0.02 kg, 95% CI −0.21 to 0.24). Our effect on retinol was also on the basis of 1 trial. All evidence was of very low to moderate certainty. There were no trials that compared the timing of initiation and duration of supplementation.

A recent systematic review published in 2021 has also reported on the effects of enteral and parenteral vitamin A supplementation in VPT infants <32 weeks’ gestation.1  The review reported that enteral vitamin A supplementation did not reduce mortality RR 0.94 (95% CI 0.63–1.40). The review also reported that enteral vitamin A supplementation reduced BPD at 36 weeks’ postmenstrual age (4 trials, 746 participants, RR 0.82, 95% CI 0.67–0.99) and that parenteral vitamin A supplementation reduced retinopathy of prematurity (4 trials, 463 participants, RR 0.60, 95% CI 0.48–0.76).

We did not find these effects in our study; however, we reported our primary outcomes at the latest follow-up (median 10 weeks) in line with the a priori specification in our protocol. In contrast, the 2021 systematic review reported outcomes at 3 earlier time points (28 days, 36 weeks’ postmenstrual age, and at discharge). It is possible that vitamin A has early effects that diminish with time. However, the effects of vitamin A supplementation on respiratory and ocular outcomes do have biological plausibility because vitamin A has been shown in animal models to protect against hyperoxia-associated lung injury and impaired alveolarization leading to BPD.17  Animal models also suggest that restoration of adequate vitamin A status might reverse necrotizing trachea-bronchiolitis and squamous metaplasia pulmonary epithelium caused by vitamin A deficiency.18 

Our review had some limitations. The studies were heterogeneous with respect to dose and had small sample sizes. The studies were conducted in VLBW and VPT infants only. The daily doses in the included studies (1500–5000 IU) were higher than is currently recommended and available in multivitamin preparations (400–1000 IU), also limiting generalizability. The mortality analysis did not achieve an optimal information size. Only 800 babies were included in the analysis and the CIs were wide and crossed the line of no effect; thus, we downgraded 1 level for serious imprecision. However, strengths of our search include our extensive literature search and rigorous methods for assessing and synthesizing data.

In conclusion, we showed an increase in retinol levels in VLBW and VPT infants from enteral vitamin A supplementation and little effect on mortality and morbidity outcomes. More randomized controlled trials are required to understand effects on mortality, morbidity, growth, and neurodevelopmental outcomes, especially studies including larger preterm and LBW infants above 1.5 kg.

The Society for Applied Studies thanks the core support provided by the Department of Maternal, Newborn, Child, and Adolescent Health, World Health Organization, Geneva (World Health Organization Collaborating Centre IND–158).

Drs Manapurath and Kumar conceptualized and designed the study, drafted the initial manuscript, designed the data collection instruments, collected data, conducted the initial analyses, and reviewed and revised the manuscript; Dr Pathak conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Upadhyay designed the data collection instruments, collected data, conducted the initial analyses, provided the overall supervision and the necessary technical guidance, critically reviewed the manuscript for important intellectual content, and reviewed and revised the manuscript; Drs Chowdhury, Sinha, Choudhary, Chandola, Mazumdar, Taneja, and Bhandari critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

This systematic review is registered at PROSPERO, #CRD42021239191, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021239191. Data are available in public domain.

FUNDING: Funded by the Department of Maternal, Newborn, Child and Adolescent Health, and Ageing, World Health Organization (WHO). The sponsor (WHO) commissioned the review for a guideline development group meeting for development of WHO recommendations on care of the preterm or low birth weight infant. The sponsor formulated the research question and provided inputs on the synthesis of the results and manuscript.

CONFLICT OF INTEREST DISCLAIMER: The authors have indicated they have no conflicts relevant to this article to disclose.

     
  • BPD

    bronchopulmonary dysplasia

  •  
  • CI

    confidence interval

  •  
  • IU

    international unit

  •  
  • LBW

    low birth weight

  •  
  • MD

    mean difference

  •  
  • ROB

    risk of bias

  •  
  • RR

    relative risk

  •  
  • VLBW

    very low birth weight

  •  
  • VPT

    very preterm

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Supplementary data