1. Objectives

To evaluate the effects of vitamin A supplementation in: i) breastfeeding mothers, and ii) infants under six months of age, on infant morbidity, mortality and adverse effects until one year of age in low- and middle-income countries

2. How studies were identified

The following databases were searched in October 2010:

• CENTRAL (The Cochrane Library 2010, Issue 3)
• MEDLINE
• EMBASE
• ClinicalTrials.gov

Other trial registration websites and reference lists were also searched, and the authors directly contacted relevant researchers and agencies

3. Criteria for including studies in the review

3.1 Study type

Randomized or quasi-randomized controlled trials, including cluster-randomized trials

3.2 Study participants

i) Breastfeeding mothers from low- and middle-income countries, irrespective of antenatal vitamin A supplementation, and ii) apparently healthy infants from low- and middle-income countries, breastfed or non-breastfed, and irrespective of maternal vitamin A supplementation during pregnancy and lactation

(Studies that exclusively enrolled infants who were sick or hospitalized, infants with very low birth weight (<1500 g), or infants with HIV-infected mothers were excluded)

3.3 Interventions

i) Oral synthetic vitamin A supplementation of lactating mothers initiated in the first six weeks postpartum, compared to placebo, whose infants were not supplemented with vitamin A; and ii) oral synthetic vitamin A supplementation of infants under six months of age, compared to placebo, whose mothers should have received identical vitamin A supplementation to the control group or none at all

(Studies that evaluated food fortification, consumption of vitamin A rich foods or beta-carotene supplementation were excluded)

3.4 Primary outcomes

Mortality

• During infancy, until one year of age
• During the neonatal period, until one month of age

Secondary outcomes included cause-specific mortality due to diarrhoea, acute respiratory infections, and other causes; infant morbidity until one year of age due to diarrhoea, acute respiratory infection or respiratory difficultly, cough or running nose, ear infection, fever, and vomiting; and adverse effects within one week following the intervention including bulging fontanelle, vomiting, irritability, diarrhoea, and fever

4. Main results

4.1 Included studies

Eighteen randomized controlled trials, including more than 150,000 participants, were included in this review

• Eight trials contributed to the maternal supplementation comparison and 15 trials contributed to the infant supplementation comparison; four trials were cluster-randomized
• In maternal supplementation studies reporting on the primary outcome of infant mortality (seven trials), maternal postpartum cumulative doses were ≤200,000 IU in one trial and >200,000 all remaining trials; in three trials women were also supplemented antenatally; and in four trials vitamin A supplementation was administered as a single dose
• In infant supplementation studies reporting on the primary outcome of infant mortality (nine trials, ten analytical components), supplementation had been initiated between birth and one month of age in seven analytic components, and between one and six months of age in three components; simultaneous maternal postpartum supplementation occurred in four of the ten analytical components; and the cumulative vitamin A dose received by the infant in the first six months was ≤50,000 IU in seven analytic components and >50,000 in three

4.2 Study settings

• Maternal supplementation studies were located in Bangladesh, Ghana (2 trials), India (2 trials), Kenya, Nepal, and Zimbabwe
• Infant supplementation studies were conducted in Bangladesh (3 trials), Ghana, Guinea-Bissau (3 trials), India (2), Indonesia (2 trials), Kenya, Nepal, and Zimbabwe, and one multinational trial was set in Ghana, India, and Peru
• Trials were conducted in both rural and urban areas, and all studies were conducted in low- and middle-income countries with endemic vitamin A deficiency

4.3 Study settings

How the data were analysed
Two comparisons were made: i) maternal vitamin A supplementation initiated during the first six weeks postpartum compared to placebo, and ii) infant vitamin A supplementation initiated during the first six months of age compared to placebo. In studies assessing different doses of vitamin A and placebo, the intervention groups were combined for analysis. Risk ratios (RR) were generated for dichotomous outcomes with corresponding 95% confidence intervals (CI). Data from cluster-randomized trials were adjusted for clustering. Random-effects meta-analysis was employed with results from fixed-effects models also provided for comparison in some cases. Subgroup analyses were planned for the primary outcome of infant mortality as follows:

• By cumulative maternal dose of vitamin A: low dose (≤200,000 IU) versus high dose (>200,000 IU) (maternal supplementation comparison only)
• By age of vitamin A supplementation initiation: neonatal period (zero to one month) versus post-neonatal period (one to six months) (infant supplementation comparison only)
• By cumulative infant dose of vitamin A up to the age of six months: low dose (≤50,000 IU) versus high dose (>50,000 IU) (infant supplementation comparison only)
• By maternal postpartum vitamin A supplementation: none versus any (infant supplementation comparison only)
• By baseline maternal vitamin A status: prevalence of maternal night blindness low (<5%) versus high (≥5%), and mean maternal antenatal or postpartum serum retinol levels ≤1.1 micromol/L (low) versus >1.1 micromol/L (high) (both comparisons)
• By birth weight: low (<2500 g) versus normal (≥2500 g) (both comparisons)

Results
Maternal postpartum vitamin A supplementation
Infant mortality
Overall, there was no evidence of an effect of maternal postpartum vitamin A supplementation on infant mortality in the first year of life, with a pooled RR of 1.00 (95% CI [0.94 to 1.06], p=0.9; 7 studies/96,203 participants). The finding did not differ when restricted to data on infant death in the first month of life (RR 0.98, 95% CI [0.87 to 1.11], p=0.47; 2 studies/84,537 participants). Subgroup analyses showed no significant effect of vitamin A on the risk of infant mortality in groups with a low or high prevalence of maternal night blindness, low or high cumulative maternal vitamin A dose, or low or high maternal serum retinol concentration. Disaggregated data were not available for subgroup analysis by birth weight.

Additional outcomes
Two trials reported on cause-specific infant mortality, in which no statistically significant effect of maternal postpartum vitamin A supplementation on the risk of death due to respiratory (RR 1.59, 95% CI [0.84 to 2.99]), diarrhoeal (RR 2.57, 95% CI [0.72 to 9.12]), or other causes (RR 0.62, 95% CI [0.09 to 4.09]) was observed. In one trial reporting on infant morbidity, maternal vitamin A supplementation did not reduce the risk of diarrhoea (RR 1.08, 95% CI [0.94 to 1.24]) or acute respiratory infection (RR 1.08, 95% CI [0.98 to 1.19]) relative to placebo before six months of age, or between six and 12 months of age (RR for diarrhoea 1.10, 95% CI [0.99 to 1.23], and RR for acute respiratory infection 0.96, 95% CI [0.85 to 1.08]).

Adverse effects in the first week
In the two trials reporting on adverse effects in the week following supplementation, no events were observed in either the treatment or control group.

Infant vitamin A supplementation
Infant mortality
Overall, infant vitamin A supplementation did not reduce the risk of mortality in infants up to one year of age compared to placebo (RR 0.97, 95% CI [0.83 to 1.12], p=0.65; 9 trials/59,402 infants), or reduce the risk of death in infants up to one month of age (RR 0.90 (95% CI [0.75 to 1.08], p=0.27; 3 trials). In subgroup analyses on the risk of mortality up to one year of age, results did not differ when the treatment was administered in the first month of life or between one and six months. Subgroup analysis by cumulative infant dose of vitamin A also did not differ, nor did further subgroup analyses by concomitant maternal vitamin A supplementation, prevalence of maternal night blindness or infant birth weight.

Additional outcomes
Pooled analysis of data from nine trials on cause-specific mortality in the first year of life indicated no difference between treatment and control groups in the risk of death due to diarrhoeal (RR 1.01, 95%CI [0.72 to 1.41]), respiratory (RR 1.12, 95% CI [0.91 to 1.39]), or other causes (RR 0.81, 95% CI [0.64 to 1.02]). However, in one trial conducted in India, fatalities linked to diarrhoea and fever were statistically significantly lower in the vitamin A group compared to the placebo group (RR 0.50, 95% CI [0.27 to 0.90], and RR 0.60, 95% CI [0.40 to 0.88], respectively). No differences were noted in pooled analysis of trials reporting on infant morbidity in the first year of life for the outcomes of diarrhoea (RR 1.02, 95% CI [0.99 to 1.06]), respiratory infection/distress (RR 1.04, 95% CI [0.95 to 1.15]), cough/running nose (RR 0.98, 95% CI [0.85 to 1.13]), or fever (RR 0.92, 95% CI [0.76 to 1.11]).

Adverse effects
Overall, in 10 trials reporting on the risk of a bulging fontanelle, the pooled RR for the treatment group compared to control group was 1.55 (95% CI [1.05 to 2.28], p=0.03). The risk appeared to increase for doses subsequent to the first, with a pooled RR of 1.37 (95% CI [0.98 to 1.91]) for the first dose, 3.60 (95% CI [1.65 to 7.87] for the second dose, and 3.14 (95% CI [1.72 to 5.74] for the third dose. No differences between treatment and control groups were noted for other adverse effects.

5. Additional author observations*

Despite all trials being conducted in low- and middle-income countries with endemic vitamin A deficiency and high rates of infant mortality, few trials reported data restricted to high-risk groups, such as those with a high prevalence of maternal night blindness or low birth weight infants. For trials involving maternal postpartum supplementation with vitamin A, the quality of the evidence for the primary outcome of infant mortality in the first year of life was high, although for neonatal mortality the evidence was regarded as moderate due to evidence of publication bias. For other outcomes, evidence was regarded as being of very low quality or of uninterpretable quality. Due to unexplained heterogeneity (I²=49%), the effect of infant vitamin A supplementation on infant mortality was regarded as moderate, while for neonatal mortality the evidence was regarded as being of very low quality. Evidence for other outcomes, including the risk of a bulging fontanelle, was regarded as low to moderate, due to study design limitations, imprecision, heterogeneity and publication bias.

While benefits may exist for maternal and infant vitamin A status, for the purposes of reducing infant mortality and morbidity, current evidence does not support either maternal vitamin A supplementation in the first six weeks postpartum or infant vitamin A supplementation in the first six months of life. In addition, there is some low quality evidence for an increased risk of a bulging fontanelle with infant vitamin A supplementation in the first six months of life.

Further research on the effect of maternal postpartum vitamin A supplementation on infant mortality is warranted in high-risk groups, and further research is also warranted on its effect on infant morbidity and adverse reactions. At the time of this review, four ongoing trials were expected to address information gaps in the findings related to infant vitamin A supplementation.