Vitamin D Lecture

7/27/2019 Vitamin D Lecture

1/23

Vitamin A:

the enigmatic magic bullet

Betty Kirkwood

Dept of Nutrition & Public Health Intervention Research

Faculty of Epidemiology & Population HealthLSHTM


2/23

Vitamin A: An essential micronutrient

Metabolic roles Vision

Maintenance of epithelial cells

Immune system

Growth

Fertility

Clinical deficiency

Nightblindness

Xerophthalmia: Dry eye disease

Blindness


3/23

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. spinachPro-vitamin A converted

to retinol in 6:1 ratio

Stored in liverCapsules: Single large

dose (200,000 iu) lasts

4-6 months


4/23


5/23

Vitamin A and child mortality:

controversy in the late 1980s

The Lancet, May 24, 1986

Vitamin A supplements decreasedchildhood mortality by 34% in Sumatra,Indonesia (Al Sommer et al)

This finding is at odds with much of theconventional wisdom on the aetiology of

childhood death in developing countries

(Richard Feachem, Bull Hyg Trop Dis 1986)


6/23

Meta-analysis (1993): overall reduction

of 23% in child mortality

Indonesia India Nepal Sudan Ghana

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

Aceh

1986

Bogor

1988

Tamil Nadu

1990

Hyderabad

1990

Sarlahi

1991

Jumla

1992

Khartoum

1992

UER

1993

Summary

Beaton etal, 1993

RR(9

5%C

I)

Vitamin A supplementation became key

element of child survival strategies

8 RCTs

GHANA VAST

Impact on mortality, hospital admissions,

clinic attendances & on severity but not on

incidence of diarrhoea


7/23

An interesting policy response

World Development Report, 1993Investing in Health

VitaminA supplementation a Best Buy

Linked to first three doses of DPT at 6, 10 and14 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


8/23

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)

BUTtrials demonstrated impact in

children aged 6-59 months


9/23

EPI- linked Vitamin A supplementation:

RCTs in Ghana, India & PeruDeaths/1000

Maternal DPT1-3 Measles

suppl. & Polio 1-3

Age (months)0

10

20

30

40

50

60

70

80

90

6wk 6mo 9mo 12mo

Control groupVitamin A

WHO/CHD Imm unisat ion-Linked Vitamin A Sup plementat ion Study Grou p

Impact on Infant Mortality Impact on Vitamin A status

% retinol


10/23

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% reductionin pregnancy related mortality(95%CI =16-63%),

P


11/23

1. Start implementing right away:

Why waste 10 more years on research as was

done with Vitamin A and child health?

Trial in Nepal shows 44% reduction in

pregnancy-related deaths: TWO views

2. Need to replicate before investing:

Does it really work? If not, we waste moneyand divert resources away from improvingaccess and coverage to EOC

Even if it works, can we translate researchfindings into programmes?


12/23

Vitamin A & maternal mortality:

New trials

Ghana: All women childbearing age,

Bangladesh: Pregnant women Indonesia: Multivitamins & pregnant women


13/23

Ghana ObaapaVitA trial

Cluster randomised double-blindplacebo controlled trial of weeklyVAS (25,000 IU)

All women aged 15-45 years in 6districts in Brong Ahafo region

4 weekly home surveillance

to monitor pregnancies, births, deaths(women and infants), migration

to distribute capsules

Clusters: Geographically contiguouscompounds of 100-200 women

Additional data collection activities(verbal post-mortems for cause ofdeath, hospital data capture)

IEC Strategy to maximise adherenceto capsules GIS Mapping


14/23

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


15/23

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


16/23

Maternal mortality and VAS:

Nepal & Ghana - CONTRASTING FINDINGS

0.2 2

VAS

-carotene

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


17/23

0.2 2

VAS

-carotene

Nepal NNIPS-2

Ghana ObaapaVitA

Bangladesh JiVitA

Indonesia SUMMIT


PREGNANT WOMEN

RR (95%CI)1

VAS didnt 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 -carotene

didnt




18/23


19/23

0.2 2

VAS

-carotene

Nepal NNIPS-2

Ghana ObaapaVitA

Bangladesh JiVitA

Indonesia SUMMIT


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?




20/23

Maternal mortality & VAS:

Summary of evidence

0.2 2

VAS

-carotene

MMN

Nepal NNIPS-2

Ghana ObaapaVitA

Bangladesh JiVitA

Indonesia SUMMIT


PREGNANT WOMEN

RR (95%CI)1

Evidence does not support inclusion of low dose VAS of

women in eithersafe motherhood orchild survivalstrategies


21/23

NOTE: Weights are from random effects analysis

.

.

Overall (I-squared = 58.6%, p = 0.005)

Klemm 2008 M

Humprey unpublished M

Rahmathullah 2003 M

Klemm 2008 F

ID

Rahmathullah 2003 F

Benn 2010 M

female

Humphrey 1996 F

Subtotal (I-squared = 45.1%, p = 0.105)

Benn 2010 F

Benn 2008 F

Subtotal (I-squared = 71.4%, p = 0.004)

Study

Benn 2008 M

Humphrey 1996 M

Humprey unpublished F

male

0.93 (0.80, 1.07)

0.89 (0.72, 1.10)

1.19 (1.00, 1.42)

0.70 (0.52, 0.94)

0.81 (0.65, 1.00)

ES (95% CI)

0.87 (0.65, 1.17)

0.74 (0.45, 1.22)

0.84 (0.26, 2.77)

0.98 (0.82, 1.17)

1.42 (0.94, 2.15)

1.39 (0.90, 2.14)

0.84 (0.65, 1.09)

0.84 (0.55, 1.27)

0.15 (0.03, 0.68)

0.93 (0.78, 1.14)

100.00

12.45

13.61

9.91

12.34

Weight

9.97

5.60

1.36

50.62

7.09

6.71

49.38

%

6.99

0.81

13.15

0.93 (0.80, 1.07)

0.89 (0.72, 1.10)

1.19 (1.00, 1.42)

0.70 (0.52, 0.94)

0.81 (0.65, 1.00)

ES (95% CI)

0.87 (0.65, 1.17)

0.74 (0.45, 1.22)

0.84 (0.26, 2.77)

0.98 (0.82, 1.17)

1.42 (0.94, 2.15)

1.39 (0.90, 2.14)

0.84 (0.65, 1.09)

0.84 (0.55, 1.27)

0.15 (0.03, 0.68)

0.93 (0.78, 1.14)

100.00

12.45

13.61

9.91

12.34

Weight

9.97

5.60

1.36

50.62

7.09

6.71

49.38

%

6.99

0.81

13.15

1.03 1 33.3

VAS of newborns:

Another controversial area

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


22/23

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


23/23

Vitamin A Research: 24 yearsGhana Health Service/LSHTM collaboration

Documents

Vitamin D Lecture