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Vitamin A: the enigmatic magic bullet

Vitamin A: the enigmatic magic bullet. Betty Kirkwood Dept of Nutrition & Public Health Intervention Research Faculty of Epidemiology & Population Health LSHTM. Metabolic roles Vision Maintenance of epithelial cells Immune system Growth Fertility Clinical deficiency Nightblindness

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Vitamin A: the enigmatic magic bullet

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  1. Vitamin A:the enigmatic magic bullet Betty Kirkwood Dept of Nutrition & Public Health Intervention Research Faculty of Epidemiology & Population Health LSHTM

  2. Metabolic roles Vision Maintenance of epithelial cells Immune system Growth Fertility Clinical deficiency Nightblindness Xerophthalmia: Dry eye disease Blindness Vitamin A: An essential micronutrient

  3. Preformed vitamin A (Retinol) Only in Animal Sources Fatty fish liver oils Meat (lambs liver) Dairy produce Breast milk Pro-vitamin A (β-Carotene) Red & orange fruits & vegetables Mango/papaya Red palm oil Carrot Dark green leafy vegetables, eg. spinach Vitamin A: 2 principal forms Stored in liver Capsules: Single large dose (200,000 iu) lasts 4-6 months Pro-vitamin A converted to retinol in 6:1 ratio

  4. Increased Mortality in Indonesian Children with Mild Vitamin A Deficiency Deaths/1000 child years “ … the results suggest that mild xerophthalmia justifies community-wide intervention as much to reduce child mortality as to prevent blindness from vitamin A deficiency” (Al Sommer et al, 1983)

  5. Vitamin A and child mortality:controversy in the late 1980’s The Lancet, May 24, 1986Vitamin A supplements decreased childhood mortality by 34% in Sumatra, Indonesia (Al Sommer et al) This finding is at odds with much of the conventional wisdom on the aetiology of childhood death in developing countries(Richard Feachem, Bull HygTropDis 1986)

  6. Meta-analysis (1993): overall reduction of 23% in child mortality 8 RCTs GHANA VAST Impact on mortality, hospital admissions, clinic attendances & on severity but not on incidence of diarrhoea Indonesia India Nepal Sudan Ghana Vitamin A supplementation became key element of child survival strategies

  7. An interesting policy response • World Development Report, 1993Investing in Health • Vitamin A supplementation a “Best Buy” • Linked to first three doses of DPT at 6, 10 and 14 weeks of age • WHO/UNICEF planning to recommend for adoption at EPI Global Advisory Group meeting in Philipines • BUTtrials demonstrated impact in 6-59 month age range

  8. BUTtrials demonstrated impact in children aged 6-59 months Meta-analysis from all RCT’s 0-5 months RR=0.97 (0.73-1.29) 6-11 months RR=0.69 (0.54-0.90) Pneumonia & Vitamin A Working Group (Bull WHO)

  9. EPI- linked Vitamin A supplementation: RCTs in Ghana, India & Peru Impact on Infant Mortality Impact on Vitamin A status Deaths/1000 % retinol <0.70µmol/L Age (months) Maternal DPT1-3 Measles suppl. & Polio 1-3 WHO/CHD Immunisation-Linked Vitamin A Supplementation Study Group

  10. Nepal trial: VAS of women of reproductive age • Keith West et al: IVACG 1998 & BMJ 1999 • Weekly low dose supplements (of either retinol or beta-carotene) to all women of childbearing age • No impact on infant mortality BUT44% reduction in pregnancy related mortality(95%CI =16-63%), P<0.005 • Implications for Safe Motherhood Programmes: • Potential for impact in short-medium term • Compared with emergency obstetric care & skilled birth attendance at delivery: requires considerable health system strengthening

  11. Trial in Nepal shows 44% reduction in pregnancy-related deaths: TWO views 1. Start implementing right away: “Why waste 10 more years on research as was done with Vitamin A and child health?” 2. Need to replicate before investing: • Does it really work? If not, we waste money and divert resources away from improving access and coverage to EOC • Even if it works, can we translate research findings into programmes?

  12. Vitamin A & maternal mortality:New trials • Ghana: All women childbearing age, • Bangladesh: Pregnant women • Indonesia: Multivitamins & pregnant women

  13. Ghana ObaapaVitA trial • Cluster randomised double-blind placebo controlled trial of weekly VAS (25,000 IU) • All women aged 15-45 years in 6 districts in BrongAhafo region • 4 weekly home surveillance • to monitor pregnancies, births, deaths (women and infants), migration • to distribute capsules • Clusters: Geographically contiguous compounds of 100-200 women • Additional data collection activities (verbal post-mortems for cause of death, hospital data capture) • IEC Strategy to maximise adherence to capsules • GIS Mapping

  14. ObaapaVitA cluster randomised trial Funded by UK DfID(& USAID) Vitamin A provided by Roche

  15. Summary of Impact of Weekly Vitamin A Supplements CONCLUSIVE RESULTS: NO IMPACT in rural Ghana

  16. Maternal mortality and VAS:Nepal & Ghana - CONTRASTING FINDINGS ALL WOMEN OF REPRODUCTIVE AGE Nepal NNIPS-2 Ghana ObaapaVitA • Lower maternal mortality in Ghana • 377 vs 704 deaths/100,000 pregnancies • Nightblindness: • Rare in Ghana vs10% pregnant women in Nepal • BUT subclinical levels VAD in pregnancy similar: 15% vs 19% • Child trials: impact seen where largely sub-clinical VAD PREGNANT WOMEN Bangladesh JiVitA Indonesia SUMMIT 1 RR (95%CI)

  17. Maternal mortality and VAS:Nepal & Ghana - CONTRASTING FINDINGS ALL WOMEN OF REPRODUCTIVE AGE Nepal NNIPS-2 Ghana ObaapaVitA • VAS didn’t improve serum retinol in Ghana • Dose recommended as safe for pregnant women • Capsule analysis confirmed stable content in field • IEC approach in Ghana, DOS in Nepal • Adherence data suggest Ghanaian women taking capsules (average 82% over 1 year in serum survey) • In Nepal VAS improved serum retinol, BUT β-carotene didn’t PREGNANT WOMEN Bangladesh JiVitA Indonesia SUMMIT 1 RR (95%CI)

  18. Maternal mortality and VAS:Nepal & Ghana - CONTRASTING FINDINGS ALL WOMEN OF REPRODUCTIVE AGE Nepal NNIPS-2 Ghana ObaapaVitA PREGNANT WOMEN • High rates of migration/change of treatment arm • In ITT analysis: • Women in same arm 32 months on average • 81% women in same arm > 1year • Pure ITT analysis, excluding data after change: • Odds ratio increased from 0.92 to 0.99 Bangladesh JiVitA Indonesia SUMMIT 1 RR (95%CI)

  19. Maternal mortality and VAS:Nepal & Ghana - CONTRASTING FINDINGS ALL WOMEN OF REPRODUCTIVE AGE Nepal NNIPS-2 Ghana ObaapaVitA PREGNANT WOMEN • Anomalous finding in Nepal • Highest reductions in deaths from injuries & unknown or uncertain causes • Smaller reductions for obstetric causes or infection • What about deaths unrelated to pregnancy? Bangladesh JiVitA Indonesia SUMMIT 1 RR (95%CI)

  20. Maternal mortality & VAS:Summary of evidence ALL WOMEN OF REPRODUCTIVE AGE Nepal NNIPS-2 Ghana ObaapaVitA PREGNANT WOMEN Bangladesh JiVitA Indonesia SUMMIT 1 RR (95%CI) Evidence does not support inclusion of low dose VAS of women in either safe motherhood or child survivalstrategies

  21. VAS of newborns: Another controversial area NEW TRIALS:Ghana, India, Tanzania (100,000 newborns)

  22. Vitamin A:the enigmatic magic bullet • Vitamin A: key child survival strategy • Saves lives of children aged 6-59 months

  23. Vitamin A Research: 24 years Ghana Health Service/LSHTM collaboration

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