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

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

3. Vitamin A: 2 principal forms
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 -
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, Vitamin 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 Hyg Trop Dis 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, 1993 Investing 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
BUT trials demonstrated impact in 6-59 month age range

8. BUT trials demonstrated impact in children aged 6-59 months
Meta-analysis from all RCT’s
0-5 months RR=0.97 ( )
6-11 months RR=0.69 ( )
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 DPT 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 BUT 44% 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 years in 6 districts in Brong Ahafo region
4 weekly home surveillance
to monitor pregnancies, births, deaths (women and infants), migration
to distribute capsules
Clusters: Geographically contiguous compounds of 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
Dec 2000 – Oct 2008
1086 clusters
207,781 women
102,952 pregnancies
96,350 livebirths
683,025 women years
Funded by UK DfID (& USAID)
Vitamin A provided by Roche

15. Summary of Impact of Weekly Vitamin A Supplements
Outcome
Adjusted RR
Pregnancy-related mortality
0.92 (0.73, 1.17)
Adult female mortality
1.01 (0.93, 1.09)
Hospital morbidity (any of 12)
0.98 (0.89, 1.09)
Stillbirths
1.04 (0.96, 1.13)
Perinatal mortality
1.01 (0.94, 1.08)
Neonatal mortality
0.95 (0.87, 1.04)
Infant mortality
0.98 (0.91, 1.05)
CONCLUSIVE RESULTS:
NO IMPACT in rural Ghana

16. Maternal mortality and VAS: Nepal & Ghana - CONTRASTING FINDINGS
Nepal NNIPS-2
Ghana ObaapaVitA
Bangladesh JiVitA
Indonesia SUMMIT
ALL WOMEN OF REPRODUCTIVE AGE
PREGNANT WOMEN
RR (95%CI) 1
Lower maternal mortality in Ghana
377 vs 704 deaths/100,000 pregnancies
Nightblindness:
Rare in Ghana vs 10% pregnant women in Nepal
BUT subclinical levels VAD in pregnancy similar: 15% vs 19%
Child trials: impact seen where largely sub-clinical VAD

17. Maternal mortality and VAS: Nepal & Ghana - CONTRASTING FINDINGS
Nepal NNIPS-2
Ghana ObaapaVitA
Bangladesh JiVitA
Indonesia SUMMIT
ALL WOMEN OF REPRODUCTIVE AGE
PREGNANT WOMEN
RR (95%CI) 1
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

18. Maternal mortality and VAS: Nepal & Ghana - CONTRASTING FINDINGS
Nepal NNIPS-2
Ghana ObaapaVitA
Bangladesh JiVitA
Indonesia SUMMIT
ALL WOMEN OF REPRODUCTIVE AGE
PREGNANT WOMEN
RR (95%CI) 1
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

19. Maternal mortality and VAS: Nepal & Ghana - CONTRASTING FINDINGS
Nepal NNIPS-2
Ghana ObaapaVitA
Bangladesh JiVitA
Indonesia SUMMIT
ALL WOMEN OF REPRODUCTIVE AGE
PREGNANT WOMEN
RR (95%CI) 1
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?

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

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
Saving lives of infants aged <6 months
VAS linked to early immunisation Χ
Maternal VAS in pregnancy (& before)
Newborn supplement
???
2013-4

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