[WHO/CHD Immunization - Linked
Vitamin A Supplementation Study Group. Randomized trial to assess benefits and safety of Vita- min A supplementation linked to immunization in early infancy. Lancet 1998; 352: 1257- 1263].
Vitamin A is an essential nutrient required for normal reproduction,
embryogenesis, vision, growth, hematopoiesis, immune competence and ultimately survival. An estimated 5-10 million children develop xerophthalmia each year, of whom a quarter to a half million suffer corneal disease, half of whom go blind(1). However, xerophthalmia represents only the 'tip of the iceberg'; systemic (and largely 'subclinical') vitamin A deficiency affects an estimated 125 million pre-school
children in the world and because of its impact on infection, is
responsible for an estimated '1.2 to 2.5 million child deaths each year.
Additionally, maternal vitamin A deficiency appears to be widespread, with
potential consequences for reproductive health and fetal and infant survival, particularly in third world population(2).' Prevention of vitamin A deficiency is therefore an urgent international health priority to reach stated health goals by the year 2000 and beyond. Thus the search is on for various strategies for vitamin
supplementation which are efficacious, devoid of
side effects and at the same time achieving a
wide coverage especially through the existing
health care system in developing countries. A
schedule was suggested by an informal 'consultation covered by WHO's Nutrition Unit and the Expanded Programme on Immunizations (EPI), and the International Vitamin A Consultative Group (IVACG) on the basis of safety and operational simplicity. This schedule proposes the delivery of 25000
IU, starting from around the age of 6 weeks with the first DPT immunization, and then every 4 weeks until the third DPT dose, and a fourth dose of 100,000 IU at 9 months with measles immunization(3), along with one large 200,000 lU dose to the mother during the post partum period which improves the delivery of vitamin A to the breastfeeding infant by the 'age 6 months when the risk of vitamin A deficiency is high. The benefits and safety of this schedule were assessed in this randomized, double-blind, placebo-controlled trial.
From January 1995,9424 mother-infant pairs from Ghana, India and Peru were included into the trial.
mothers of infants in the vitamin A group received 200,000 IU vitamin A and their infants were given 25000 IU vitamin A with each of the first three doses of DPT/poliomyelitis immunization at 6, 10 and 14 weeks. In the control group 4708 mothers and their infants received placebo at the same time. At 9 months, with measles immunization, infants in the Vitamin A group were given a further dose of 25,000 IU and. those in the control group received 100,000 IU Vitamin A. Infants were followed upto age 12 months. The results showed that at 6 months follow-up, there was a small decrease in Vitamin A deficiency (assessed biochemically) in the Vitamin A group com- pared with controls (serum retinol <0.70 IlmollL-101 (29.9%) vs 122 (37.1%), 95% CI
of the difference being
- 14.3%-0.2%). This effect was no longer apparent at 9 months
and 12 months. There were no significant difference between the two groups in mortality throughout the study. Fewer than 1 % of infants had bulging fontanelles. There was no effect on anthropometric status or morbidity.
Periodic distribution or' an oral, high potency vitamin A supplement is currently being propagated as the most direct method to improve vitamin A status, prevent xerophthalmia and reduce associated mortality in pre-school children 6 months of age and 0Ider(4,5). Three delivery schemes are used, each representing increasingly wider cover- age. The first is the most restrictive and the least expensive approach by supplying Vitamin A to children suffering from xerophthalmia according to WHO treatment guide- lines. A second 'targeted' approach involves existing health services to provide high potency supplements to children whenever possible, that is during sickness and growth, monitoring visits and vaccination campaigns.
Though the cost of coverage is lower and a larger segment of population is
covered the, supplementation provided is often erratic. The third method, namely
the universal approach represents a community based distribution of Vitamin A to
all target children on a periodic basis usually every 6 months and is organized
as a coordinated national or regional campaigns. This distribution requires a great deal cifcoordination,
motivation, continuous funding and community involvement making universal
delivery difficult to sustain in the 'long run'. Thus the second approach
involving the existing health care systems and preferably combining
immunizations and Vitamin A supplementations may be the most viable option. The
currently recommended regime. involves a large dose Vitamin A administered
only at measles immunization at 9 months of age. Large scale field trials show that improving the Vitamin A status of children older than 6 months who live in areas where Vitamin A deficiel1cy is rife significantly reduces morbidity
and mortality(4). The effects of Vitamin A supplementation in younger infants less than 6 months of age is unclear. Due to widespread prevalence of respiratory ill- nesses in younger infants, large multicentric trials are in progress to assess the effective- ness of Vitamin A supplementation in reducing
morbidity and mortality in younger infants. The current study explored the effects of Vitamin A supplementation. in infants given along with the each of the three DPTI poliomyelitis immunization.
Though this trial confirmed the safety of
combined DPT/OPV immunization and
supplementation, no sustained benefits in term of Vitamin A status beyond age 6 months or infant growth, morbidity or mortality could be demonstrated. Further the additional'
benefits of maternal supplementation could not be proved. Regarding toxic effects, after each dose less than I % of infants in either group had bulging fontanelle which is much lower than the rates of about 10% reported . in Bangladesh but is similar to those reported in Guinea Bissau(6). Indonesia(7) and Nepal(8).
In the absence of any demonstrable clinical benefit of Vitamin A supplementation in the typical setting of a developing country, this .large trial raises a fundamental issue should poor countries invest a substantial portion of their health expenditure for this "magic bullet approach" to improve infant health. If this study is the yard stick, then all we are likely to achieve is a logical marginal biochemical benefit without a concomitant clinical advantage and the chance of a bulging fontanelle in <1 %, which certainly can not be
ignored. Hopefully this evidence will be noticed by the planners.
Department of Pediatrics,
Maulana Azad Medical College,
New Delhi 110 002,
Humphrey JH, West Jr KP, Sommer A. Vita- min A deficiency and attributable mortality among under 5 year Glds. Bull WHO 1992; 70: 225-232.
Semba RD, Miotti PG, Chiphangwi JD. Maternal Vitamin A deficiency and mother to child transmission of HIV -1. Lancet J 994; 343: 1593-1597.
World Health Organization. Using Immunization Contacts to Combat Vitamin A Deficiency. Report of an Informal Consultation: WHO, Geneva, June 30-July 1, 1992. WHO/
NVT/EPI/93.1 WHO: Geneva, 1993.
Sommer A, Tarwetjo I, Djuinaedi E. Impact of Vitamin A supplementation on childhood mortality: A randomized controlled community trial. Lancet 1986; 1: 1169-1173.
West Jr KP, Pokhrel RP, Katz J. Efficacy of Vitamin Ain reducing pre-school
child mortality in Nepal. Lancet 1991; 338: 67-71.
Stabell C, Bale C, Pedro da Silva A, Olsen J, Aaby P. No evidence of fontanelle
bulging episodes after vitamin A supplementation of 6 and 9 months old infants in Guinea Bissau. Eur J Clin Nutr 1995; 49: 73-74.
Humphrey JH, Agoestina T, Wu L. Impact of neonatal Vitamin A supplementation on infant morbidity and mortality. J Pediatr 1996; 128: 489-496.
West KP Jr, Khatry SK, Le Clerq SC. Tolerance of young infants to a single large
dose vitamin A: A randomized community trial in Nepal. Bull WHO 1992; 70: 733-739.