Child Health Research Project Research Results and Policy Formulation on Nutrition and Micronutrients

Selective Presentation of CHR Research and Policy Activities in Nutrition and Micronutrients Breastfeeding/Complementary Feeding Underweight (“PEM”) Vitamin A Zinc Iron/Multiple micronutrients

Breastfeeding - Importance Not breastfeeding increases risk of death < 6 mo 6-23 mo - ≈ 2x Diarrhea – 6.1x Pneumonia – 2.4x Not breastfeeding increases risk of death < 6 mo 6-23 mo - ≈ 2x Diarrhea – 6.1x Pneumonia – 2.4x Not exclusively breastfeeding for 4 mo (compared with partial breastfeeding) increases risk of death Diarrhea – 3.9x Pneumonia – 2.4x Not exclusively breastfeeding for 4 mo (compared with partial breastfeeding) increases risk of death Diarrhea – 3.9x Pneumonia – 2.4x From WHO Collaborative Study Team, Lancet 2000 and Arifeen et al., Pediatrics 2001

Research Results with IMCI Nutritional Counseling Clinic-based intervention in Brazil improved diet and weight gain Clinic-based intervention in Brazil improved diet and weight gain Clinic and community intervention in India increased breastfeeding in 0-3 mo. olds from 14% to 73% Clinic and community intervention in India increased breastfeeding in 0-3 mo. olds from 14% to 73% Clinical and community intervention in Peru reduced stunting by < 70% Clinical and community intervention in Peru reduced stunting by < 70% From Santos et al, J Nutr 2001 (Brazil), others unpublished)

Nutrition Policy Formulation WHO recommends exclusive breastfeeding for first 6 mo. of life WHO recommends exclusive breastfeeding for first 6 mo. of life WHO meeting in December 2001 develops Global Strategy for Infant and Young Child Feeding (to protect, promote and support optimal infant and young child feeding) WHO meeting in December 2001 develops Global Strategy for Infant and Young Child Feeding (to protect, promote and support optimal infant and young child feeding)

Underweight (Low Weight for Age) Causes and Prevalence in Children < 5y Old Caused by IUGR, inadequate breastfeeding/complementary feeding and zinc intake and by infectious disease morbidity Caused by IUGR, inadequate breastfeeding/complementary feeding and zinc intake and by infectious disease morbidity Prevalence varies from 5% in middle income countries in Latin America to 46% in low income countries of South Asia Prevalence varies from 5% in middle income countries in Latin America to 46% in low income countries of South Asia

Increased Risk of Morbidity and Mortality for Underweight Children Infectious disease morbidity (< -2z) Infectious disease morbidity (< -2z) Diarrhea Diarrhea - RR 1.25 Pneumonia Pneumonia - RR 1.86 Mortality (- 1z to -2z; -2z to -3z; < -3z) Mortality (- 1z to -2z; -2z to -3z; < -3z) Diarrhea Diarrhea - RR 2.3 → Pneumonia Pneumonia - RR 2.0 → Malaria Malaria - RR 2.1 → Measles Measles - RR 1.7 →

Sources: For cause-specific mortality: EIP/WHO using 1999 data. For deaths associated with malnutrition: Caulfield LE, Black RE. Malnutrition and the global burden of disease: underweight and cause-specific mortality. Paper in preparation; NOT FOR CITATION. Deaths associated with undernutrition 60% Major causes of death among children under five, global, 2000

Contribution of undernutrition to under-five mortality by cause, for 2000 Sources: For cause-specific mortality: EIP/WHO using 1999 data. For deaths associated with malnutrition: Caulfield LE, Black RE. Malnutrition and the global burden of disease: underweight and cause-specific mortality. Paper in preparation; NOT FOR CITATION.

Vitamin A Deficiency Prevalence and Disease Risk in Children < 5y Old Prevalence varies from 16% in middle income countries in Latin America to 48% in low income countries of Asia Prevalence varies from 16% in middle income countries in Latin America to 48% in low income countries of Asia Infectious disease morbidity (incidence) Malaria - RR 1.43 Infectious disease morbidity (incidence) Malaria - RR 1.43 Mortality Diarrhea - RR 1.47 Measles - RR 1.35 Mortality Diarrhea - RR 1.47 Measles - RR 1.35

Safety of Delivery of Vitamin A with EPI RCT in 9424 mother-infant pairs in Ghana, India and Peru RCT in 9424 mother-infant pairs in Ghana, India and Peru Mothers 200,000 IU vitamin A post-partum, infants 25,000 IU at 6, 10, 14 weeks with immunizations Mothers 200,000 IU vitamin A post-partum, infants 25,000 IU at 6, 10, 14 weeks with immunizations No adverse effects No adverse effects Small reduction in vitamin A deficiency at 6 mo of age Small reduction in vitamin A deficiency at 6 mo of age From WHO/CHD Immunization-Linked Vitamin A Supplementation Group, Lancet 1998

Zinc Deficiency Prevalence in Children < 5y Old Estimated using FAO food balance sheets to determine prevalence of inadequate availability of zinc per capita to meet zinc requirements Estimated using FAO food balance sheets to determine prevalence of inadequate availability of zinc per capita to meet zinc requirements Prevalence up to 72% in South Asia (31% global) Prevalence up to 72% in South Asia (31% global) From International Zinc Consultative Group

Risk of Child Morbidity and Mortality with Zinc Deficiency Infectious disease morbidity (incidence) Diarrhea- RR 1.28 Pneumonia- RR 1.69 Malaria- RR 1.56 Infectious disease morbidity (incidence) Diarrhea- RR 1.28 Pneumonia- RR 1.69 Malaria- RR 1.56 Mortality – likely greater risk than for incidence since also effect on severity Mortality – likely greater risk than for incidence since also effect on severity Published 2/3 ↓ in mortality in 1-9 mo old SGA infants (Sazawal, Pediatrics 2001) Published 2/3 ↓ in mortality in 1-9 mo old SGA infants (Sazawal, Pediatrics 2001)

Process of Priority Setting, Research Implementation and Policy Formulation Regarding Zinc Deficiency CHR meeting Nov reviewed evidence and published research priorities CHR meeting Nov reviewed evidence and published research priorities Pooled analyses of existing studies conducted – Pooled analyses of existing studies conducted – Research undertaken – 1997-present Research undertaken – 1997-present Recommendations made – 1998-present Recommendations made – 1998-present

Zinc in Therapy of Persistent Diarrhea 5 published trials: 29% ↓ in duration, 40% ↓ in treatment failure or death 5 published trials: 29% ↓ in duration, 40% ↓ in treatment failure or death WHO recommends zinc be used in treatment of persistent diarrhea WHO recommends zinc be used in treatment of persistent diarrhea From Zinc Investigators’ Collaborative Group, Am J Clin Nutr 2000

Zinc in Therapy of Acute Diarrhea 7 published trials: 22% ↓ in duration, plus reduction in stool output 7 published trials: 22% ↓ in duration, plus reduction in stool output 4 of 6 additional trials show similar benefit 4 of 6 additional trials show similar benefit Controlled trial (12,000 child-years) shows 19% ↓ diarrhea hospitalization, 51% ↓ in mortality and 62% ↓ in antibiotic use Controlled trial (12,000 child-years) shows 19% ↓ diarrhea hospitalization, 51% ↓ in mortality and 62% ↓ in antibiotic use

Zinc in Therapy of Acute Diarrhea: Policy and Needed Research WHO meeting in May 2001 concludes that zinc supplementation is efficacious in reducing severity and duration WHO meeting in May 2001 concludes that zinc supplementation is efficacious in reducing severity and duration Effectiveness studies needed to assess strategies for delivering zinc supplementation to children with diarrhea Effectiveness studies needed to assess strategies for delivering zinc supplementation to children with diarrhea Initiating 5-site study of acceptability and 2-site study of effectiveness and impact Initiating 5-site study of acceptability and 2-site study of effectiveness and impact

Zinc Supplements in Prevention of Morbidity (Incidence) 9 trials with diarrhea outcome: 22% ↓ 9 trials with diarrhea outcome: 22% ↓ 4 trials with pneumonia outcome: 41% ↓ 4 trials with pneumonia outcome: 41% ↓ 2 trials with malaria (clinic visits) outcome: 36% ↓ 2 trials with malaria (clinic visits) outcome: 36% ↓ 3 mortality impact trails underway in India, Nepal, Zanzibar 3 mortality impact trails underway in India, Nepal, Zanzibar From Zinc Investigators’ Collaborative Group, J Pediatrics 1999

Alternatives for Increasing Zinc Intake Supplements – dispersible tablet with zinc or zinc/iron highly acceptable and costs 1 U.S. cent or less Supplements – dispersible tablet with zinc or zinc/iron highly acceptable and costs 1 U.S. cent or less “Sprinkle” with multiple micronutrients “Sprinkle” with multiple micronutrients Fully fortified (i.e. RDA) sachet of food Fully fortified (i.e. RDA) sachet of food Fortified staple foods, e.g. maize flour in Mexico Fortified staple foods, e.g. maize flour in Mexico

Iron Deficiency Prevalence and Disease Risk Prevalence of anemia in children up to 63% in South Asia and 50% thought to be IDA; estimates of risk per gram decrease in hemoglobin Prevalence of anemia in children up to 63% in South Asia and 50% thought to be IDA; estimates of risk per gram decrease in hemoglobin AF of maternal mortality – 20% AF of maternal mortality – 20% AF of early neonatal mortality – 22% AF of early neonatal mortality – 22% AF of mental retardation – 18% AF of mental retardation – 18%

Meta-analyses of Effects of Oral Iron Supplements in Infectious Disease Morbidity 50% ↑ clinical malaria and other infectious diseases in malarious areas (Oppenheimer, J Nutrition 2001) 50% ↑ clinical malaria and other infectious diseases in malarious areas (Oppenheimer, J Nutrition 2001) 17%↑ P. falciparum infection; non sig. 9% ↑ clinical malaria (Shankar, submitted) 17%↑ P. falciparum infection; non sig. 9% ↑ clinical malaria (Shankar, submitted) 11% ↑ diarrhea, no difference in other morbidity (Gera, submitted) 11% ↑ diarrhea, no difference in other morbidity (Gera, submitted)

Effects of Multiple Micronutrients vs. Zinc Supplementation in Peru RCT compared daily zinc (10 mg) or multiple micronutrients with placebo in 6-24 mo old infants RCT compared daily zinc (10 mg) or multiple micronutrients with placebo in 6-24 mo old infants Supplement for 6 mo, home visits by workers 5 d/wk to give supplement and record morbidity Supplement for 6 mo, home visits by workers 5 d/wk to give supplement and record morbidity

Effects of Multiple Micronutrients (MN) vs. Zinc, Iron or Zinc/Iron Supplementation on Diarrhea of Moderate Severity in Bangladesh RCT compared weekly zinc (20 mg), iron, zinc/iron, or MN with placebo in 6-11 mo old infants RCT compared weekly zinc (20 mg), iron, zinc/iron, or MN with placebo in 6-11 mo old infants Infants < -1z W/A: diarrhea reduced 19% by zinc and 17% by zinc/iron (borderline sig.) and increased 10% by MN (not sig.) Infants < -1z W/A: diarrhea reduced 19% by zinc and 17% by zinc/iron (borderline sig.) and increased 10% by MN (not sig.) All infants: diarrhea same in zinc, iron or zinc/iron, but increased by 18% in MN (sig.) All infants: diarrhea same in zinc, iron or zinc/iron, but increased by 18% in MN (sig.)

Continuing Challenges/Research Questions Can we successfully implement programs to improve BF/CF and thus enhance nutritional status? Can we successfully implement programs to improve BF/CF and thus enhance nutritional status? Can we devise sustainable means to improve nutrition/micronutrient status where dietary approaches are not sufficient? Can we devise sustainable means to improve nutrition/micronutrient status where dietary approaches are not sufficient? What are the positive and negative interactions of micronutrients provided in supplements? What are the positive and negative interactions of micronutrients provided in supplements?

Continuing Challenges/Research Questions How should programs be implemented to use zinc for treatment of diarrhea? How should programs be implemented to use zinc for treatment of diarrhea? How can zinc and iron deficiencies be prevented? How can zinc and iron deficiencies be prevented? What are the nutritional/micronutrient effects in malaria, TB, HIV/AIDS? What are the nutritional/micronutrient effects in malaria, TB, HIV/AIDS?