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Supplementing newborn infants with Vitamin A reduces mortality at age 6 months
EVIDENCE -BASED PUBLIC HEALTH
Supplementing newborn infants with vitamin A reduces mortality at age 6 months Abstracted from: Rahmathullah L,Tielsch JM,Thulasiraj RD et al. Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India. BMJ 2003; 327: 254.
BACKGROUND V|tamin A supplementation significantly reduces mortality, particularly in children aged 6 months or older. However the e¡ect of supplementation at birth on mortality at age 6 months is not known. OBJECTIVE To examine the e¡ects of supplementing newborn infants with vitamin A on mortality at 6 months. SETTING Two rural districts of Tamil Nadu, southern India; June 1998 to March 2001.
OUTCOMES Mortality within the ¢rst 6 months of life. MAIN RESULTS V|tamin A supplementation signi¢cantly reduced mortality within the ¢rst 6 months of life compared with placebo (reduction in total mortality, vitamin A versus placebo 22%, 95% CI 4 to 37%; RR of mortality 0.78, 95% CI 0.63 to 0.97).
METHOD Randomised controlled trial.
AUTHORS’ CONCLUSIONS V|tamin A supplementation within 48 h of birth signi¢cantly reduced early infant mortality.
PARTICIPANTS 11, 619 newborn infants. All liveborn infants within participating villages were eligible for inclusion. Pregnant women were recruited prior to delivery and were randomised at recruitment. Post-randomisation exclusions included: stillbirths, miscarriages, delivery 420 km outside of the study area and infants who died before arrival of the study team.
Sources of funding: This study was funded by the Center for Human Nutrition (Bloomberg School of Public Health, John Hopkins University) and the O⁄ce of Health and Nutrition (USAgency for International Development, Washington DC), the Bill and Miranda Gates Foundation (Seattle Washington), and Task Force Sight and Life (Basel, Switzerland)
INTERVENTION V|tamin A (two oral doses of 24,000 IU with a 24h interval) or placebo within 48 h after birth. In order to ensure consumption of the
Commentary 1 Vitamin A deficiency disorders (VADD) are a major public health problem in118 countries, especially in Asia and Africa, specifically among pre-school aged children, pregnant and lactating women. 250 000 to 500 000 vitamin A-deficient children become blind every year, half of them dying within 12 months of losing their sight. It has been estimated that VADD affects between 100 and 140 million children and is one of the most important underlying causes of childhood mortality.1,2 A meta-analysis of large trials carried out in both Asia and in Africa established that vitamin A supplementation of children aged 6 to 59 months can reduce mortality
30
complete dose, mothers were encouraged to breast feed the infant immediately after treatment.
Evidence-based Healthcare (2004) 8, 30 ^32 doi:10.1016/j.ehbc.2003.12.012
Correspondenceto: JM T|elsch, Departmentof International Health, Bloomberg School of Public Health, John Hopkins University, Baltimore, Maryland, USA. E-mail: [email protected] Abstract provided by Bazian Ltd., London
by 23%.Vitamin A supplementation of young children is one of the most cost-effective and safest strategies for child survival. 3,4 The effect of vitamin A supplementation during the first 6 months of life is, however, not clear.Two studies showed no benefits of vitamin A supplementation on childhood mortality during the first 6 months of life.5,6 There is only one study which showed a 64% reduction in infant mortality and severe respiratory infections through the administration of a single 50,000 IU dose of vitamin A on the first day of life. 7 Rahmathullah and her colleagues carried out a communitybased randomized trial to study the impact of vitamin A supplementation among newborn infants on early infant mortality.They 1462-9410/$ - see front matter & 2004 Published by Elsevier Ltd.
reported a 22% reduction in total mortality between 2 weeks and 3 months after treatment (95% CI 4 to 37%) compared with the placebo group.The impact was found particularly among the low-birth-weight children. Low birth weight is strongly associated with fetal, neonatal and post-neonatal mortality.8 These results confirmed the previously mentioned study by Humphrey et al. 7 The studies among children aged 6 ^59 months have clearly shown that the mechanism for reducing mortality among this age group is mainly through improved immunity resulting from vitamin A supplementation.However, the e¡ect of vitamin A supplementation at birth may be explained by a di¡erent mechanism; for example, through an improved di¡erentiation and maturation of the lungs and gut, particularly of low-birth-weight infants.9 Vitamin A deficiency and low birth weight are major public health problems in many developing countries. This study may, therefore, have major consequences for change in public health policy on vitamin A supplementation at birth. However, there is still a need for another study specifically in the African continent to support the universality of these findings as well as reconciliation with the practice of exclusive breastfeeding. Martin W Bloem, MD, PhD Helen Keller Worldwide Singapore Literature cited 1. World Health Organization/United Nations International Children’s Emergency Fund/International Vitamin A Consultative Group (WHO/UNICEF/IVACG) The global prevalence
Commentary 2 Observational associations abound between vitamin A deficiency and potential childhood illness. In poor populations, vitamin A supplementation for children aged over 6 months could reduce childhood mortality by about a quarter.1 Three randomised controlled trials have addressed supplementation for infants under 6 months. In Nepal, supplementation at 2 to 3 weeks did not affect subsequent mortality.2 Supplementation during immunisation contacts in Ghana, India and Peru had no demonstrable effect on infant morbidity.3 An Indonesian trial in which most infants received supplements on the first day of life, however, showed a 64% reduction in infant mortality.4 Supplementation during pregnancy does not appear to reduce either neonatal mortality5 or infant mortality up to 6 months of age.6 The double-blind randomised controlled trial reported by Rahmathullah and colleagues raises two questions: are vitamin A supplements beneficial to infants younger than 6 months, and should they be given to all newborn infants in populations at risk, or to a subgroup? We may take as read the debate on the relative merits of poverty reduction, female education, general dietary improvement, food fortification, multiple micronutrient supplementation, and targeted vitamin A supplementation. The study was of good quality and involved a population in which such an intervention might be considered. 80% of infants received 48,000 IU vitamin A or placebo starting within 48 hours of birth.The vitamin A recipient group showed a mortality reduction of 22% over the first 6 months, most of the effect appearing
of vitamin A deficiency. MDIS working paper 2 WHO/NUT/95.3, WHO, Geneva, Switzerland,1995. 2. West KP, Darnton-Hill, I.Vitamin A deficiency. In: Semba, R & Bloem MW (eds) Nutrition and Health in Developing Countries Totowa NJ: Humana Press, 2001: 267^306. 3. Beaton GH, Martorell R, Aronson KJ et al. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. State of the Art Series, Nutrition Policy Discussion Paper No 13. Geneva: Administrative Committee on Coordination/Subcommittee on Nutrition, United Nations, December 1993. 4. Ross D. Recommendations for vitamin A supplementation. J Nutr 2002; 131: 2902S-2906S. 5. West KP, Katz J, Shrestha SR et al. Mortality of infants under six months of age supplementation with vitamin A: a randomized, double masked trial in Nepal. Am J Clin Nutr 1995; 62: 143^148. 6. WHO/CHD Immunization-Linked Vitamin A Supplementation Study Group. Randomized trial to assess benefits and safety of vitamin A supplementation linked to immunization in early infancy. Lancet 1998; 353: 1257^1263. 7. Humphrey JH, Agoestina T, Wu L et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr 1996;128: 489^ 496. 8. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985; 312: 82^90. 9. Shenai JP, Kennedy KA, Chytil F, Stahlman MT. Clinical trial of vitamin A supplementation in infants susceptible to bronchopulmonary dysplasia. J Pediatr 1987; 111: 269-277.
in the first 3 months. After stratification, it appeared that the mortality benefit was seen in low birth weight infants. This may have been driven by benefits to preterm infants,7,8 but the differentiation of infants into preterm and term groups is not presented. Although another trial showed a converse effect ^ on infants of normal birth weight4 ^ neither study hypothesised or attained the statistical power for such subgroup analysis, and we should be cautious about either developing or criticising these f|ndings. The original design underestimated the number of infants who would die before enrolment.The 22% reduction in mortality refers to a‘post-early neonatal death, 6 month infant mortality rate’ which, though viable for the analysis, is unconventional and difficult to interpret from a public health standpoint. The published figures imply a perinatal mortality rate of roughly 50 per thousand births, but we are not able to infer early neonatal mortality. The study suggests that early neonatal vitamin A supplementation could reduce infant mortality, but more work is required on efficacy, subgroup risks and population effectiveness. David Osrin, MRCPCH International Perinatal Care Unit, Institute of Child Health University College London, UK Literature cited 1. Beaton G, Martorell R, Aronson K et al. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. ACC/SCN Evidence-based Healthcare (2004) 8, 30 ^32
31
State-of-the-Art Series, Nutrition Policy Discussion Paper No.13. Administrative Committee on Coordination/Subcommittee on Nutrition, Toronto: United Nations,1993. 2. West K, Katz J, Shrestha S et al. Mortality of infants o6 months of age supplemented with vitamin A: a randomized, double-masked trial in Nepal. Am J Clin Nutr 1995; 62:143^148. 3. WHO/CHD immunisation-Linked Vitamin A Supplementation Study Group.Randomised trial to assess benefits and safety of vitamin A supplementation linked to immunisation in early infancy. Lancet 1998; 352:1257^1263. 4. Humphrey J, AgoestinaT, Wu L et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr 1996; 128: 489^ 496.
32
Evidence-based Healthcare (2004) 8, 30 ^32
5. Katz J, West K, Khatry S et al. Maternal low-dose vitamin A or beta-carotene supplementation has no effect on fetal loss and early infant mortality: a randomized cluster trial in Nepal. Am J Clin Nutr 2000; 71: 1570 ^1576. 6. Christian P, West K, Khatry S et al. Maternal night blindness increases risk of mortality in the first 6 months of life among infants in Nepal. J Nutr 2001; 131: 1510 ^1512. 7. Shenai J, Chytil F, Jhaveri A, Stahlman M. Plasma vitamin A and retinol-binding protein in premature and term neonates. J Pediatr 1981; 99: 302^305. 8. Yasmin S, Osrin D, Paul E, Costello A. Neonatal mortality of low-birth-weight infants in Bangladesh. Bull WHO 2001; 79: 608 ^ 614.
Supplementing newborn infants with vitamin A reduces mortality at age 6 months Abstracted from: Rahmathullah L,Tielsch JM,Thulasiraj RD et al. Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India. BMJ 2003; 327: 254.
BACKGROUND V|tamin A supplementation significantly reduces mortality, particularly in children aged 6 months or older. However the e¡ect of supplementation at birth on mortality at age 6 months is not known. OBJECTIVE To examine the e¡ects of supplementing newborn infants with vitamin A on mortality at 6 months. SETTING Two rural districts of Tamil Nadu, southern India; June 1998 to March 2001.
OUTCOMES Mortality within the ¢rst 6 months of life. MAIN RESULTS V|tamin A supplementation signi¢cantly reduced mortality within the ¢rst 6 months of life compared with placebo (reduction in total mortality, vitamin A versus placebo 22%, 95% CI 4 to 37%; RR of mortality 0.78, 95% CI 0.63 to 0.97).
METHOD Randomised controlled trial.
AUTHORS’ CONCLUSIONS V|tamin A supplementation within 48 h of birth signi¢cantly reduced early infant mortality.
PARTICIPANTS 11, 619 newborn infants. All liveborn infants within participating villages were eligible for inclusion. Pregnant women were recruited prior to delivery and were randomised at recruitment. Post-randomisation exclusions included: stillbirths, miscarriages, delivery 420 km outside of the study area and infants who died before arrival of the study team.
Sources of funding: This study was funded by the Center for Human Nutrition (Bloomberg School of Public Health, John Hopkins University) and the O⁄ce of Health and Nutrition (USAgency for International Development, Washington DC), the Bill and Miranda Gates Foundation (Seattle Washington), and Task Force Sight and Life (Basel, Switzerland)
INTERVENTION V|tamin A (two oral doses of 24,000 IU with a 24h interval) or placebo within 48 h after birth. In order to ensure consumption of the
Commentary 1 Vitamin A deficiency disorders (VADD) are a major public health problem in118 countries, especially in Asia and Africa, specifically among pre-school aged children, pregnant and lactating women. 250 000 to 500 000 vitamin A-deficient children become blind every year, half of them dying within 12 months of losing their sight. It has been estimated that VADD affects between 100 and 140 million children and is one of the most important underlying causes of childhood mortality.1,2 A meta-analysis of large trials carried out in both Asia and in Africa established that vitamin A supplementation of children aged 6 to 59 months can reduce mortality
30
complete dose, mothers were encouraged to breast feed the infant immediately after treatment.
Evidence-based Healthcare (2004) 8, 30 ^32 doi:10.1016/j.ehbc.2003.12.012
Correspondenceto: JM T|elsch, Departmentof International Health, Bloomberg School of Public Health, John Hopkins University, Baltimore, Maryland, USA. E-mail: [email protected] Abstract provided by Bazian Ltd., London
by 23%.Vitamin A supplementation of young children is one of the most cost-effective and safest strategies for child survival. 3,4 The effect of vitamin A supplementation during the first 6 months of life is, however, not clear.Two studies showed no benefits of vitamin A supplementation on childhood mortality during the first 6 months of life.5,6 There is only one study which showed a 64% reduction in infant mortality and severe respiratory infections through the administration of a single 50,000 IU dose of vitamin A on the first day of life. 7 Rahmathullah and her colleagues carried out a communitybased randomized trial to study the impact of vitamin A supplementation among newborn infants on early infant mortality.They 1462-9410/$ - see front matter & 2004 Published by Elsevier Ltd.
reported a 22% reduction in total mortality between 2 weeks and 3 months after treatment (95% CI 4 to 37%) compared with the placebo group.The impact was found particularly among the low-birth-weight children. Low birth weight is strongly associated with fetal, neonatal and post-neonatal mortality.8 These results confirmed the previously mentioned study by Humphrey et al. 7 The studies among children aged 6 ^59 months have clearly shown that the mechanism for reducing mortality among this age group is mainly through improved immunity resulting from vitamin A supplementation.However, the e¡ect of vitamin A supplementation at birth may be explained by a di¡erent mechanism; for example, through an improved di¡erentiation and maturation of the lungs and gut, particularly of low-birth-weight infants.9 Vitamin A deficiency and low birth weight are major public health problems in many developing countries. This study may, therefore, have major consequences for change in public health policy on vitamin A supplementation at birth. However, there is still a need for another study specifically in the African continent to support the universality of these findings as well as reconciliation with the practice of exclusive breastfeeding. Martin W Bloem, MD, PhD Helen Keller Worldwide Singapore Literature cited 1. World Health Organization/United Nations International Children’s Emergency Fund/International Vitamin A Consultative Group (WHO/UNICEF/IVACG) The global prevalence
Commentary 2 Observational associations abound between vitamin A deficiency and potential childhood illness. In poor populations, vitamin A supplementation for children aged over 6 months could reduce childhood mortality by about a quarter.1 Three randomised controlled trials have addressed supplementation for infants under 6 months. In Nepal, supplementation at 2 to 3 weeks did not affect subsequent mortality.2 Supplementation during immunisation contacts in Ghana, India and Peru had no demonstrable effect on infant morbidity.3 An Indonesian trial in which most infants received supplements on the first day of life, however, showed a 64% reduction in infant mortality.4 Supplementation during pregnancy does not appear to reduce either neonatal mortality5 or infant mortality up to 6 months of age.6 The double-blind randomised controlled trial reported by Rahmathullah and colleagues raises two questions: are vitamin A supplements beneficial to infants younger than 6 months, and should they be given to all newborn infants in populations at risk, or to a subgroup? We may take as read the debate on the relative merits of poverty reduction, female education, general dietary improvement, food fortification, multiple micronutrient supplementation, and targeted vitamin A supplementation. The study was of good quality and involved a population in which such an intervention might be considered. 80% of infants received 48,000 IU vitamin A or placebo starting within 48 hours of birth.The vitamin A recipient group showed a mortality reduction of 22% over the first 6 months, most of the effect appearing
of vitamin A deficiency. MDIS working paper 2 WHO/NUT/95.3, WHO, Geneva, Switzerland,1995. 2. West KP, Darnton-Hill, I.Vitamin A deficiency. In: Semba, R & Bloem MW (eds) Nutrition and Health in Developing Countries Totowa NJ: Humana Press, 2001: 267^306. 3. Beaton GH, Martorell R, Aronson KJ et al. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. State of the Art Series, Nutrition Policy Discussion Paper No 13. Geneva: Administrative Committee on Coordination/Subcommittee on Nutrition, United Nations, December 1993. 4. Ross D. Recommendations for vitamin A supplementation. J Nutr 2002; 131: 2902S-2906S. 5. West KP, Katz J, Shrestha SR et al. Mortality of infants under six months of age supplementation with vitamin A: a randomized, double masked trial in Nepal. Am J Clin Nutr 1995; 62: 143^148. 6. WHO/CHD Immunization-Linked Vitamin A Supplementation Study Group. Randomized trial to assess benefits and safety of vitamin A supplementation linked to immunization in early infancy. Lancet 1998; 353: 1257^1263. 7. Humphrey JH, Agoestina T, Wu L et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr 1996;128: 489^ 496. 8. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985; 312: 82^90. 9. Shenai JP, Kennedy KA, Chytil F, Stahlman MT. Clinical trial of vitamin A supplementation in infants susceptible to bronchopulmonary dysplasia. J Pediatr 1987; 111: 269-277.
in the first 3 months. After stratification, it appeared that the mortality benefit was seen in low birth weight infants. This may have been driven by benefits to preterm infants,7,8 but the differentiation of infants into preterm and term groups is not presented. Although another trial showed a converse effect ^ on infants of normal birth weight4 ^ neither study hypothesised or attained the statistical power for such subgroup analysis, and we should be cautious about either developing or criticising these f|ndings. The original design underestimated the number of infants who would die before enrolment.The 22% reduction in mortality refers to a‘post-early neonatal death, 6 month infant mortality rate’ which, though viable for the analysis, is unconventional and difficult to interpret from a public health standpoint. The published figures imply a perinatal mortality rate of roughly 50 per thousand births, but we are not able to infer early neonatal mortality. The study suggests that early neonatal vitamin A supplementation could reduce infant mortality, but more work is required on efficacy, subgroup risks and population effectiveness. David Osrin, MRCPCH International Perinatal Care Unit, Institute of Child Health University College London, UK Literature cited 1. Beaton G, Martorell R, Aronson K et al. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. ACC/SCN Evidence-based Healthcare (2004) 8, 30 ^32
31
State-of-the-Art Series, Nutrition Policy Discussion Paper No.13. Administrative Committee on Coordination/Subcommittee on Nutrition, Toronto: United Nations,1993. 2. West K, Katz J, Shrestha S et al. Mortality of infants o6 months of age supplemented with vitamin A: a randomized, double-masked trial in Nepal. Am J Clin Nutr 1995; 62:143^148. 3. WHO/CHD immunisation-Linked Vitamin A Supplementation Study Group.Randomised trial to assess benefits and safety of vitamin A supplementation linked to immunisation in early infancy. Lancet 1998; 352:1257^1263. 4. Humphrey J, AgoestinaT, Wu L et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr 1996; 128: 489^ 496.
32
Evidence-based Healthcare (2004) 8, 30 ^32
5. Katz J, West K, Khatry S et al. Maternal low-dose vitamin A or beta-carotene supplementation has no effect on fetal loss and early infant mortality: a randomized cluster trial in Nepal. Am J Clin Nutr 2000; 71: 1570 ^1576. 6. Christian P, West K, Khatry S et al. Maternal night blindness increases risk of mortality in the first 6 months of life among infants in Nepal. J Nutr 2001; 131: 1510 ^1512. 7. Shenai J, Chytil F, Jhaveri A, Stahlman M. Plasma vitamin A and retinol-binding protein in premature and term neonates. J Pediatr 1981; 99: 302^305. 8. Yasmin S, Osrin D, Paul E, Costello A. Neonatal mortality of low-birth-weight infants in Bangladesh. Bull WHO 2001; 79: 608 ^ 614.