Impact of neonatal vitamin A supplementation on infant morbidity and mortality. Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh. Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India. Efficacy of vitamin A in reducing preschool child mortality in Nepal. Mortality of infants < 6 mo of age supplemented with vitamin A: a randomized, double-masked trial in Nepal. Vitamin A supplementation and child survival. Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network.
To determine whether vitamin A supplementation at birth could reduce infant morbidity and mortality.
                We conducted a placebo-controlled trial among 2067 Indonesian neonates who received either 52 micromol (50,000 IU) orally administered vitamin A or placebo on the first day of life. Infants were followed up at 1 year to determine the impact of this intervention on infant mortality. A subgroup (n = 470) was also examined at 4 and 6 months of age to examine the impact on morbidity.
                Vital status was confirmed in 89% of infants in both groups at 1 year. There were 19 deaths in the control group and 7 in the vitamin A group (relative risk = 0.36; 95% confidence interval = 0.16, 0.87). The impact was stronger among boys, infants of normal compared with low birth weight, and those of greater ponderal index. Among infants examined at 4 months of age, the 1-week period prevalence of common morbidities was similar for vitamin A and control infants. However, during this same 4-month period, 73% and 51% more control infants were brought for medical treatment for cough (p = 0.008) and fever (p = 0.063), respectively.
                Neonatal vitamin A supplementation may reduce the infant mortality rate and the prevalence of severe respiratory infection among young infants. We assessed the effect of supplementing newborns with 50000 IU of vitamin A on all-cause infant mortality through 24 weeks of age.
                This was a community-based, double-masked, cluster-randomized, placebo-controlled trial conducted in 19 unions in rural northwest Bangladesh. The study was nested into and balanced across treatment arms of an ongoing placebo-controlled, weekly maternal vitamin A or beta-carotene supplementation trial. Study-defined sectors (N = 596) were evenly randomized for newborns of participating mothers to receive a single, oral supplement of vitamin A (50000 IU) or placebo as droplets of oil squeezed from a gelatinous capsule. Mothers provided informed consent for newborn participation at approximately 28 weeks' gestation. After birth, typically at home (where >90% of births occurred), infants were supplemented and their vital status was followed through 24 weeks of age. The main outcome measure was mortality through 24 weeks of age.
                We obtained maternal consent to dose 17116 live-born infants (99.8% of all eligible) among whom 15937 (93.1%) were visited to be supplemented <30 days after birth and for whom vital status at 24 weeks of age was known. Dosed infants (n = 15902 [99.8%]) received their study supplement at a median age of 7 hours. Relative to control subjects, the risk of death in vitamin A-supplemented infants was 0.85, reflecting a 15% reduction in all-cause mortality. Protective relative risks were indistinguishable by infant gender, gestational age, birth weight, age at dosing, maternal age, parity, or across the 3 treatment arms of the maternal supplementation trial.
                Newborn vitamin A dosing improved infant survival through the first 6 months of life in Bangladesh. These results corroborate previous findings from studies in Indonesia and India and provide additional evidence that vitamin A supplementation shortly after birth can reduce infant mortality in South Asia. To assess the impact of supplementing newborn infants with vitamin A on mortality at age 6 months.
                Community based, randomised, double blind, placebo controlled trial.
                Two rural districts of Tamil Nadu, southern India.
                11 619 newborn infants allocated 24 000 IU oral vitamin A or placebo on days 1 and 2 after delivery.
                Primary outcome measure was mortality at age 6 months.
                Infants in the vitamin A group had a 22% reduction in total mortality (95% confidence interval 4% to 37%) compared with those in the placebo group. Vitamin A had an impact on mortality between two weeks and three months after treatment, with no additional impact after three months.
                Supplementing newborn infants with vitamin A can significantly reduce early infant mortality. Community trials of the efficacy of vitamin A supplementation in reducing preschool childhood mortality have produced conflicting results. To resolve the question, a randomised, double-masked, placebo-controlled community trial of 28,630 children aged 6-72 months was carried out in rural Nepal, an area representative of the Gangetic flood plain of South Asia. Randomisation was carried out by administrative ward; the vitamin-A-supplemented children received 60,000 retinol equivalents every 4 months and placebo-treated children received identical capsules containing 300 retinol equivalents. After 12 months, the relative risk of death in the vitamin-A-supplemented compared with the control group was 0.70 (95% confidence interval 0.56-0.88), equivalent to a 30% reduction in mortality. The trial, which had been planned to last 2 years, was discontinued. The reduction in mortality was present in both sexes (relative risk for boys 0.77; for girls 0.65), at all ages (range of relative risks 0.83-0.50), and throughout the year (0.76-0.67). The reduction in mortality risk was not affected by acute nutritional status, as measured by arm circumference. Thus, periodic vitamin A delivery in the community can greatly reduce child mortality in developing countries. The effect of supplementing 11,918 infants < 1 mo and 1-5 mo of age with vitamin A (15,000 and 30,000 micrograms retinol equivalents or 50,000 and 100,000 IU, respectively) or a placebo on subsequent 4-mo mortality was assessed in a randomized, double-masked community trial in the rural plains of Nepal. There were 130 deaths (51.6/1000 child-y) in the control group and 150 deaths (57.1/1000 child-y) in the vitamin A group, yielding a relative risk of 1.11 (95% CI: 0.86, 1.42), which is indicative of no overall effect on early infant mortality. There was a tendency for the relative risk of mortality among vitamin A recipients to rise with improved nutritional status. These results suggest that distribution of a large oral dose of vitamin A to infants < 5-6 mo of age may not benefit short-term survival. This is in contrast with the results of trials in which older infants and children in this same population were supplemented. Previous studies of the effect of 6-monthly vitamin A supplementation on child mortality have given conflicting results. In other trials, more frequent doses of vitamin A have significantly reduced mortality among children at risk of vitamin A deficiency. We have done a double-blind, placebo-controlled trial of vitamin A supplementation in the Sudan among 28,753 children aged 9-72 months at risk of vitamin A deficiency. Children were assigned to receive either 200,000 IU vitamin A and 40 IU vitamin E every 6 months (vitamin A group) or 40 IU vitamin E alone (placebo group). During the 18 months of follow-up, there were 120 deaths (8.4/1000) in the vitamin A group and 112 (7.9/1000) in the placebo group (relative risk 1.06, 95% confidence interval 0.82-1.37). Controlling for geographic site, round of observation, anthropometry, morbidity, dietary intake of vitamin A, sex, and all baseline differences between the two groups did not change the results. Children living in poor and unsanitary environments, younger children, and those sick, stunted, wasted, or consuming diets low in vitamin A were at a significantly higher risk of dying. The lack of an effect of large-dose vitamin A supplementation on mortality, despite a clear association between dietary vitamin A and mortality, underscores the need to identify factors that modify the efficacy of vitamin A supplements as a public-health measure. Reducing poverty, improvements in sanitation, and access to adequate diets should remain the main goals to improve child survival. Vitamin A supplementation may reduce the risk of chronic lung disease and sepsis in extremely-low-birth-weight infants. The results of our pilot study suggested that a dose of 5000 IU administered intramuscularly three times per week for four weeks was more effective than the lower doses given in past trials.
                We performed a multicenter, blinded, randomized trial to assess the effectiveness and safety of this regimen as compared with sham treatment in 807 infants in need of respiratory support 24 hours after birth. The mean birth weight was 770 g in the vitamin A group and 769 g in the control group, and the respective gestational ages were 26.8 and 26.7 weeks.
                By 36 weeks' postmenstrual age, 59 of the 405 infants (15 percent) in the vitamin A group and 55 of the 402 infants (14 percent) in the control group had died. The primary outcome - death or chronic lung disease at 36 weeks' postmenstrual age - occurred in significantly fewer infants in the vitamin A group than in the control group (55 percent vs. 62 percent; relative risk, 0.89; 95 percent confidence interval, 0.80 to 0.99). Overall, 1 additional infant survived without chronic lung disease for every 14 to 15 infants who received vitamin A supplements. The proportions of infants in the vitamin A group and the control group who had signs of potential vitamin A toxicity were similar. The proportion of infants with serum retinol values below 20 microg per deciliter (0.70 micromol per liter) was lower in the vitamin A group than in the control group (25 percent vs. 54 percent, P<0.001).
                Intramuscular administration of 5000 IU of vitamin A three times per week for four weeks reduced biochemical evidence of vitamin A deficiency and slightly decreased the risk of chronic lung disease in extremely-low-birth-weight infants.
Considering mortality in early infancy being a major contributory cause of overall child mortality for the under five year old group in developing countries, it is critical to obtain sound scientific evidence of the effect of vitamin A supplementation in neonates. Evidence provided in this review does indicate a potential beneficial effect of supplementing neonates with vitamin A at birth for reducing mortality in the first half of infancy. Considering the absence of a clear indication of the biological mechanism and conflicting findings from individual studies in settings with varying levels of maternal vitamin A deficiency and infant mortality, and given four additional ongoing trials with approximately 100,000 neonates being enrolled, we propose a delay in any policy recommendations for neonatal vitamin A supplementation.