1. Objectives

To estimate the effect of maternal vitamin A supplementation on the risk of mother-to-child transmission of HIV as well as infant and maternal mortality and morbidity

2. How studies were identified

The following databases were searched in June 2010:

• CENTRAL (The Cochrane Library)
• PubMed
• EMBASE
• AIDS Education Global Information System (AEGIS)
• WHO International Clinical Trials Registry Platform

Reference lists were also searched and the authors directly contacted researchers and organizations

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials

3.2 Study participants

HIV-infected pregnant or breastfeeding women of any age, any clinical stage of HIV disease, and in any setting

(HIV infection was confirmed by an antibody test)

3.3 Interventions

Vitamin A supplementation compared to placebo

3.4 Primary outcomes

• HIV infection status of the child

Secondary outcomes included infant death, stillbirth, neonatal sepsis, neonatal admission to neonatal unit, death by 24 months of age, side effects in the child, preterm delivery (<37 weeks’ gestation), very preterm delivery (<34 weeks’ gestation), birth weight, low birth weight (<2500 g), very low birth weight (<2000 g), long term side effects, in the child, maternal death, postpartum infection, side effects in the mother, cost of the intervention, acceptability of the intervention

4. Main results

4.1 Included studies

Five randomized controlled trials, enrolling 7528 HIV-infected women, were included in this review

• Four studies were placebo-controlled, while one study compared vitamin A supplementation to standard care
• Four trials supplemented women in the antenatal period; two of these trials also supplemented women randomized to vitamin A treatment with high dose vitamin A (200,000 IU) at delivery, and in another study all women received 100,000 IU at six weeks’ postpartum, as per standard care in the region. Oral daily doses of vitamin A ranged from 3000 to 10,000 IU, and women were additionally supplemented with beta-carotene from 0 to 30 mg/day
• One trial was conducted in the postpartum period only, supplementing women with a single high dose of vitamin A (400,000 IU) or placebo, and also supplemented infants with a single high dose of vitamin A (50,000 IU) or placebo in a 2 x 2 factorial design
• Co-interventions included iron, folic acid and multivitamins; however, the use of antiretroviral agents was not well reported

4.2 Study settings

• Malawi, South Africa, the United Republic of Tanzania, and Zimbabwe (2 trials)
• Vitamin A deficiency in pregnant women was a moderate to severe public health problem in all included countries, as estimated in the WHO Global Database on Vitamin A Deficiency (2009)

4.3 Study settings

How the data were analysed
Vitamin A supplementation of HIV-infected women during pregnancy or the postpartum period was compared to placebo control or standard care. In pooled analysis, relative risks (RR) were calculated for dichotomous outcomes and mean differences (MD) were calculated for continuous outcomes, with corresponding 95% confidence intervals (CI). Where statistically significant heterogeneity was detected (p<0.1), random-effects meta-analysis was used; all other analyses were conducted using fixed-effects models. Subgroup analyses were conducted by timing of maternal vitamin A supplementation, i.e., in the antenatal or postpartum period.

Results
Mother-to-child transmission of HIV
Overall, in pooled analysis there was no evidence for an effect of vitamin A supplementation on the risk of mother-to-child transmission of HIV (RR 1.04, 95% CI [0.87 to 1.24], p=0.69; 4 trials/6517 women), and substantial heterogeneity was observed (I²=68%, p=0.02). The effect remained non-statistically significant when restricted to studies with antenatal supplementation (RR 1.05, 95% CI [0.78 to 1.41], p=0.75; 3 trials/2022 women) or postnatal supplementation only (RR 0.99, 95% CI [0.91 to 1.09], p=0.91; 1 trial/4495 women). In one trial, antenatal vitamin A supplementation increased the risk of mother-to-child HIV transmission by a statistically significant 35% (RR 1.35, 95% CI [1.10 to 21.65]; 898 women) at 24 months.

Additional outcomes
Infant outcomes
Birth weight was statistically significantly greater with maternal vitamin A supplementation by almost 90 g (MD 89.78 g, 95% CI [84.73 to 94.83], p<0.00001; 3 trials/1809 infants). There was no evidence for an effect of vitamin A supplementation on the risk of stillbirth (RR 0.99, 95% CI [0.68 to 1.43], p=0.95; 4 trials/2855 women), preterm birth (RR 0.88, 95% CI [0.65 to 1.19], p=0.40; 3 trials/2110 infants), very preterm birth (RR 0.69, 95% CI [0.24 to 2.00], p=0.5; 2 trials/1578 infants), low birth weight (RR 0.83, 95% CI [0.68 to 1.01], p=0.067; 3 trials/2606 infants), very low birth weight (RR 0.72, 95% CI [0.41 to 1.27], p=0.26; 2 trials/1483 infants), or death by 24 months of age (RR 1.03, 95% CI [0.88 to 1.20], p=0.72; 2 trials/1635 infants).

Maternal outcomes
Postpartum CD4 levels (MD -4.00, 95% CI [-51.06 to 43.06], p=0.87) and maternal death (RR 0.49, 95%CI [0.04 to 5.37], p=0.56) were not affected by treatment with vitamin A in one trial of 728 women.

5. Additional author observations*

Due to the differences in results across individual studies, the pooled effect for the main outcome of mother-to-child transmission of HIV displayed substantial heterogeneity, and therefore the quality of this evidence was regarded as moderate. Thus, although current evidence does not support a reduction in the risk of mother-to-child HIV transmission with maternal vitamin A supplementation, the possibility that a benefit exists cannot be completely excluded. In addition, the possibility that maternal vitamin A supplementation confers a harmful effect on the risk of mother-to-child transmission of HIV cannot be excluded, and none of the included trials reported on adverse events.

The quality of the evidence for the effect of the vitamin A supplementation of HIV-infected pregnant women on birth weight was high; however, the quality of the evidence for other outcomes was regarded as very low to moderate.

Further research utilizing a placebo-controlled, randomized design with appropriate power may be needed to investigate whether an additional benefit of maternal vitamin A supplementation exits for the prevention of mother-to-child HIV transmission in the context of antiretroviral therapy.