Vitamin A:

the enigmatic magic bullet

Betty Kirkwood
Dept of Nutrition & Public Health Intervention Research Faculty of Epidemiology & Population Health LSHTM

Vitamin A: An essential micronutrient

Metabolic roles
Vision Maintenance of epithelial cells Immune system Growth Fertility

Clinical deficiency Nightblindness Xerophthalmia: Dry eye disease Blindness

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 (-Carotene)
Red & orange fruits & vegetables
Mango/papaya Red palm oil Carrot

Dark green leafy vegetables, eg. spinach Pro-vitamin A converted to retinol in 6:1 ratio

Stored in liver
Capsules: Single large dose (200,000 iu) lasts 4-6 months

Increased Mortality in Indonesian Children with Mild Vitamin A Deficiency

Deaths/1000 child years
50 45 40 35 30 25 20 15 10 5 0 RR=8.6 RR=6.6

RR=2.7 RR=1.0

Normal

Night Blind

Bitot's Spot

NB + BS

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)

Vitamin A and child mortality: controversy in the late 1980s

The Lancet, May 24, 1986

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)

Meta-analysis (1993): overall reduction of 23% in child mortality

1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0

8 RCTs

RR (95% CI)

GHANA VAST
Impact on mortality, hospital admissions, clinic attendances & on severity but not on incidence of diarrhoea
Aceh 1986 Bogor 1988 Tamil Nadu Hyderabad 1990 1990 Sarlahi 1991 Jumla 1992 Khartoum 1992 UER 1993 Summary Beaton et al, 1993

Indonesia

India

Nepal

Sudan

Ghana

Vitamin A supplementation became key element of child survival strategies

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

BUT trials demonstrated impact in children aged 6-59 months

Meta-analysis from all RCTs
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)

EPI- linked Vitamin A supplementation: RCTs in Ghana, India & Peru

Impact on Infant Mortality
Deaths/1000

Impact on Vitamin A status

% retinol <0.70mol/L
90 80 70 60 50 40 30 20 10 0

Control group Vitamin A

Age (months) Maternal DPT1-3 suppl. & Polio 1-3 Measles

6wk

6mo

9mo

12mo

WHO/CHD Immunisation-Linked Vitamin A Supplementation Study Group

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

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?

Vitamin A & maternal mortality: New trials

Ghana: All women childbearing age,
Bangladesh: Pregnant women Indonesia: Multivitamins & pregnant women

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 Brong Ahafo 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

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

Summary of Impact of Weekly Vitamin A Supplements

Outcome Pregnancy-related mortality Adult female mortality Hospital morbidity (any of 12) Adjusted RR 0.92 (0.73, 1.17) 1.01 (0.93, 1.09) 0.98 (0.89, 1.09) 1.04 (0.96, 1.13) 1.01 (0.94, 1.08) 0.95 (0.87, 1.04) 0.98 (0.91, 1.05)

Stillbirths Perinatal mortality Neonatal mortality Infant mortality

CONCLUSIVE RESULTS: NO IMPACT in rural Ghana

Maternal mortality and VAS: Nepal & Ghana - CONTRASTING FINDINGS

ALL WOMEN OF REPRODUCTIVE AGE
Nepal NNIPS-2 VAS -carotene

Ghana ObaapaVitA

Lower maternal mortality in Ghana PREGNANT WOMEN 377 vs 704 deaths/100,000 pregnancies Nightblindness: Rare in Ghana vs 10% pregnant women in Nepal Indonesia SUMMIT BUT subclinical levels VAD in pregnancy similar: 15% 1 0.2vs 19% 2 RR (95%CI) Child trials: impact seen where largely sub-clinical VAD
Bangladesh JiVitA

Maternal mortality and VAS: Nepal & Ghana - CONTRASTING FINDINGS

ALL WOMEN OF REPRODUCTIVE AGE
Nepal NNIPS-2 VAS -carotene

Ghana ObaapaVitA

VAS didnt improve PREGNANT WOMEN serum retinol in Ghana

Dose recommended as safe for pregnant women Bangladesh JiVitA Capsule analysis confirmed stable content in field IEC approach Ghana, DOS in Nepal Indonesia in SUMMIT Adherence data suggest Ghanaian women taking 0.2 2 survey) capsules (average RR 82% over 11year in serum (95%CI) In Nepal VAS improved serum retinol, BUT -carotene didnt

Maternal mortality and VAS: Nepal & Ghana - CONTRASTING FINDINGS

ALL WOMEN OF REPRODUCTIVE AGE
Nepal NNIPS-2 VAS

-carotene Ghana ObaapaVitA

PREGNANT High rates ofWOMEN migration/change of treatment arm

In ITT analysis: Bangladesh JiVitA Women in same arm 32 months on average 81% women in same arm > 1year Indonesia SUMMIT Pure ITT analysis, excluding data after change: Odds ratio increased from 0.92 to 0.99 1
0.2 RR (95%CI) 2

Maternal mortality and VAS: Nepal & Ghana - CONTRASTING FINDINGS

ALL WOMEN OF REPRODUCTIVE AGE
Nepal NNIPS-2 VAS -carotene Ghana ObaapaVitA

Anomalous finding in Nepal

HighestBangladesh reductions in deaths from injuries & unknown or JiVitA uncertain causes
SUMMIT SmallerIndonesia reductions for obstetric causes or infection

PREGNANT WOMEN

0.2 What about deaths unrelated to 1 pregnancy? 2

RR (95%CI)

Maternal mortality & VAS: Summary of evidence

ALL WOMEN OF REPRODUCTIVE AGE
Nepal NNIPS-2

Ghana ObaapaVitA

PREGNANT WOMEN
Bangladesh JiVitA

VAS -carotene MMN

Indonesia SUMMIT 1

0.2

RR (95%CI)

Evidence does not support inclusion of low dose VAS of women in either safe motherhood or child survival strategies

VAS of newborns: Another controversial area

Study ID ES (95% CI) % Weight male Humphrey 1996 M Rahmathullah 2003 M Benn 2008 M Klemm 2008 M Benn 2010 M Humprey unpublished M Subtotal (I-squared = 71.4%, p = 0.004) . female Humphrey 1996 F Rahmathullah 2003 F Klemm 2008 F Benn 2008 F Benn 2010 F Humprey unpublished F Subtotal (I-squared = 45.1%, p = 0.105) . Overall (I-squared = 58.6%, p = 0.005) NOTE: Weights are from random effects analysis .03 1 33.3 0.93 (0.80, 1.07) 100.00 0.84 (0.26, 2.77) 0.87 (0.65, 1.17) 0.81 (0.65, 1.00) 1.39 (0.90, 2.14) 1.42 (0.94, 2.15) 0.93 (0.78, 1.14) 0.98 (0.82, 1.17) 1.36 9.97 12.34 6.71 7.09 13.15 50.62 0.15 (0.03, 0.68) 0.70 (0.52, 0.94) 0.84 (0.55, 1.27) 0.89 (0.72, 1.10) 0.74 (0.45, 1.22) 1.19 (1.00, 1.42) 0.84 (0.65, 1.09) 0.81 9.91 6.99 12.45 5.60 13.61 49.38

NEW TRIALS: Ghana, India, Tanzania (100,000 newborns)

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 Maternal VAS in pregnancy (& before) Newborn supplement ??? 2013-4

Vitamin A Research: 24 years

Ghana Health Service/LSHTM collaboration