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Vitamin A supplements in newborns and child survival

BMJ 2008; 336 doi: https://doi.org/10.1136/bmj.39575.486609.80 (Published 19 June 2008) Cite this as: BMJ 2008;336:1385

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Neonatal vitamin A supplementation in South Asia: Rapid implementation or understanding the variation?

Neonatal vitamin A supplementation in South Asia: Rapid implementation or understanding the variation?

Five trials of neonatal vitamin A supplementation (VAS) have now been published. Three trials from South Asia showed beneficial effects on mortality of neonatal VAS (1-3). Two trials from Africa found no overall beneficial effect, the estimates going in the other direction (4-6).

 

When some trials have found a positive effect of neonatal VAS and others no effect, a subgroup VAS policy is only acceptable if there is convincing evidence that the subgroup encompasses the children who benefit, and not those who might be harmed. Apparently, many seem to accept the geographical area “South Asia” as a reasonable definition of such a subgroup. Several voices have been raised in favour of recommending blanket neonatal VAS in South Asia (7,8). Recently, as a comment to our neonatal VAS trial from Guinea-Bissau (6), Professor Tielsch wrote “Forpopulations in Asia who are deficient in vitamin A the evidencefor benefit is convincing” (9).

 

We think it might be premature to implement neonatal VAS in South Asia before we understand the background for the contradictory effects in existing trials (6,10). As argued below, there may be factors other than vitamin A deficiency that explain the effects of neonatal VAS.

 

According to Professor Tielsch differences in vitamin A status and baseline mortality in the five neonatal VAS trials is the best way of reconciling the contradiction between the trials. It is the common understanding that VAS has the greatest benefit inpopulations with endemic vitamin A deficiency (VAD) and high mortality, and intuitively it is a very appealing explanation. However, this may not fit the data very well. Even in the early studies of VAS to older children, there is no evidence for such associations (11). The five neonatal VAS trials do not support a strong association between vitamin A status and baseline mortality and the effect of VAS either. First, it is not easy to assess the vitamin A status since the trials have provided very different measurements of VAD (Table). We agree with Dr. Tielsch that the Indian and Bangladeshi trials probably had the highest degree of VAD and found a good effect of neonatal VAS (2). It is also noteworthy that none of the women in the African trials suffered from night blindness. However, it should be also noted – not dismissed as an outlier among five trials – that the Indonesian trial had a good vitamin A status for the mothers and a very good effect of VAS (1). Also, one of the Zimbabwean subgroups of 4,495 HIV positive women presumably suffered from VAD and neonatal VAS had no beneficial effect in that group; it even had a significantly negative effect in the large majority of the children who remained HIV-negative (5). Second, it is easier to assess the mortality level in the five trials though they had variable length of follow-up and this could have affected the mortality level (Table). Mortality was reduced in the Guinea-Bissau trial due to exclusion of low birth weight infants and free drugs and treatment of trial participants (9). However, the infant mortality rate in Guinea-Bissau was still higher than in the trials from Bangladesh and Indonesia. A plot of the effect of neonatal VAS as a function of baseline mortality in the placebo groups reveals no association (Figure available upon request).

Hence, though it may seem illogical, the existing evidence does not convincingly support that “Benefit depends on the setting, baseline infant mortality, andvitamin A deficiency“(9). The effect of VAS can not be predicted based alone on the level of VAD and baseline mortality, and there is no reason why it should be predicted based on the setting.

This is not to say that VAS does not prevent or treat VAD and prevent deaths for that reason. However, other environmental factors may modify the effect of VAS on mortality, making it impossible to predict its effect based on pre-existing degree of VAD and baseline mortality. Identifying such environmental factors could lead to optimised use of VAS. Importantly, VAS has been associated with increased mortality in some situations (5, 12-15). Identifying the underlying mechanisms is crucial in order to prevent the worst thinkable scenario: intervention-induced increased mortality.

 

We have proposed that the divergent results may be explained by differences in vaccination intensity in the five trials (10). Accumulating data suggests that VAS may interact negatively with DTP vaccine in girls (12-15). We have found that DTP has a negative effect for girls in areas with herd immunity to pertussis (16) and VAS may amplify this negative effect. In our trial from Guinea-Bissau, all children received BCG at the same time as VAS or placebo (6). Having received VAS tended to be beneficial as long as BCG was the last vaccine to be received, the mortality rate ratio being 0.86 (0.48-1.54). However, a post hoc analysis showed that once children received DTP vaccine, mortality in girls who had received VAS at birth was significantly 2-fold higher compared with girls who had received placebo at birth (14). Hence, in our experience VAS has a beneficial effect as long as BCG is the last vaccine but may have a negative effect for girls once they receive DTP (14). As a consequence the survival curves of VAS and placebo recipients should cross over once they start receiving DTP around two months of age if the coverage for DTP is high. This pattern is seen both in Guinea-Bissau and in Zimbabwe (4). An important question for further research is what happens when BCG and DTP are administered simultaneously as often happen in rural areas. We suspect that VAS in this situation will be more beneficial for girls since we have previously experienced that combined BCG and DTP vaccinations are better for girls than for boys (17).

 

Such vitamin A-vaccine interactions could help explain the variation in trial results. Vaccination intensity was high in Guinea-Bissau (14, Table) and probably also in Zimbabwe as judged by the national coverage data (18). This was not the case in the trials from India and Bangladesh, which were the only trials to provide data on vaccination coverage (Table). The trial from Indonesia was conducted 15 years ago when vaccination coverage may have been lower. Hence, existing data are compatible with the hypothesis that early DTP vaccination might interfere with the beneficial effect of neonatal VAS. Importantly, neonatal VAS-DTP interactions would be most important in settings which have high mortality throughout infancy. The Indian and Bangladeshi trials tended to have nearly all mortality concentrated in the first 1-2 months of life (Table), which would not be affected by a negative interaction between VAS and DTP. In contrast, the African trials continued to have high mortality throughout the 12-24 months of follow-up. High neonatal mortality combined with little mortality in the subsequent months may be a better indicator of populations in which neonatal VAS may be beneficial than “South Asia”. However, it would seem important to conduct trials with longer follow-up than 6 months to make sure that the effect does not cease to be beneficial and/or becomes negative.

 

If our hypothesis is correct and neonatal VAS is made a general policy in South Asia, the intervention may cease to be beneficial or even become detrimental as the DTP coverage increases and more children are vaccinated early in life, especially in populations in which mortality is not limited to the first months of life. However, there will be no way of knowing because it is considered unethical to conduct further trials once an intervention has become policy.

 

It will be up to the WHO to weigh the evidence for and against a neonatal VAS policy in South Asia. Hopefully, in the process, a consensus will be reached on how VAD data should be reported, and which potential effect modifiers should be examined. Based on our experience data on vitamin A effects should always be reported by sex and by vaccination status. So far there is limited scientific evidence for the interpretation that neonatal VAS is most beneficial in areas with highest degree of VAD and baseline mortality. We need better explanations for the contradictory results before we make subgroup policies.

 


References

1.      Humphrey JH, Agoestina T, Wu L, Usman A, Nurachim M, Subardja D, et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr 1996; 128:489-96.

2.      Rahmathullah L, Tielsch JM, Thulasiraj RD, Katz J, Coles C, Devi S, et al. Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India. BMJ 2003; 327:254.

3.      Klemm R, Labrique A, Christian P, Rashid M, Shamim AA, Wu L, et al. Efficacy of newborn vitamin A supplementation in reducing infant mortality in rural Bangladesh: The JIVITA-2 trial. Pediatrics 2008;

4.      Malaba LC, Iliff PJ, Nathoo KJ, Marinda E, Moulton LH, Zijenah LS, et al. Effect of postpartum maternal or neonatal vitamin A supplementation on infant mortality among infants born to HIV-negative mothers in Zimbabwe. Am J ClinNutr 2005; 81: 454-60.

5.      Humphrey JH, Iliff PJ, Marinda ET, Mutasa K, Moulton LH, Chidawanyika H, et al. Effects of a single large dose of vitamin A, given during the postpartum period to HIV-positive women and their infants, on child HIV infection, HIV-free survival, and mortality. J Infect Dis 2006; 193: 860-71.

6.      Benn CS, Diness BR, Roth A, Nante E, Fisker AB, Lisse IM, Whittle H, Rodrigues A, Yazdanbakhsh M, Aaby P. Randomised trial of the effect on mortality of 50,000 IU vitamin A given with BCG vaccine to infants in Guinea-Bissau, West-Africa BMJ 2008; 336(7658):1416-20.

7.      West Jr K, Sommer A. Newborn vitamin A dosing: Policy implications for Southern Asia and Africa. Abstract presented at the 1st Micronutrient Forum Meeting in Istanbul, Turkey, April 2007. (http://www.micronutrientforum.org/Meeting2007/MN%20Forum%20Program%20Part%20II_Abstracts.pdf, abstract T116).

8.      Bhutta ZA, Ahmed T, Black RE, Cousens S, Dewey K, Giugliani E, et al; Maternal and Child Undernutrition Study Group. What works? Interventions for maternal and child undernutrition and survival. Lancet 2008; 371: 417-40.

9.      Tielsch JM.  Editorial. Vitamin A supplements in newborns and child survival. BMJ 2008; 336(7658): 1385-1386.

10.  Benn CS, Fisker AB, Jørgensen MJ, Aaby P. Conflicting evidence for neonatal vitamin A supplementation. Vaccine 2008 Apr 30. [Epub ahead of print]

11.  Beaton GH, Martorell R, Aronson KJ, Edmonston B, McCabe G, Ross AC, et al. Effectiveness of Vitamin A Supplementation in the Control of Young Child Morbidity and Mortality in Developing Countries. International Nutrition Program. Department of Nutritional Sciences, Faculty of Medicine, University of Toronto. Toronto, Ontario, Canada. 1993.

12.  Benn CS, Balé C, Sommerfelt H, Friis H, Aaby P. Vitamin A supplementation and childhood mortality: Amplification of the non-specific effects of vaccines? Int J Epidemiol 2003; 32:822-8. 

13.  Benn CS, Martins C, Rodrigues A, Fisker AB, Christoffersen D, Aaby P. The effect of vitamin A supplementation administered with missing vaccines during national immunisation days in Guinea-Bissau (Int J Epidemiol, in review)

14.  Benn CS, Rodrigues A, Yazdanbakhsh M, Fisker AB, Ravn H, Whittle H, Aaby P. The effect of high-dose vitamin A supplementation administered with BCG vaccine at birth may be modified by subsequent DTP vaccination (Int J Epidemiol, in review)

15.  Benn CS, Fisker AB, Jørgensen MJ, Aaby P. Why worry: Vitamin A with DTP vaccine? Vaccine 2007; 25: 777-779.

16.  Aaby P,Jensen H, Samb B, Cisse B, Sodeman M, Jakobsen M, Poulsen A, Rodrigues A, Lisse IM, Simondon F, Whittle H. Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: a re-analysis of the West African studies.Lancet 2003;361: 2183-88

17.  Aaby P, Jensen H, Rodrigues A, Garly ML, Benn CS, Lisse IM, Simondon F. Divergent female-male mortality ratios associated with different routine vaccinations among female-male twin pairs.Int J Epidemiol 2004;33:367-73

18.  http://www.who.int/vaccines/globalsummary/immunization/countryprofileselect.cfm

19.  Moulton LH, Rahmathullah L, Halsey NA, Thulasiraj RD, Katz J,Tielsch JM. Evaluation of non-specific effects of infant immunizations on early infant mortality in a southern Indian population. Trop Med Intern Health 2005;10:1-9.

 

 


Table.Overview of the neonatal vitamin A supplementation (VAS) trials.

 

Partici-pants

Maternal supplement

Age at follow-up

Mortality rate

/1000 pyrs in control group

% deaths  during the first mo in control group

Level of vitamin A deficiency

Vaccine coverage information

Effect of VAS on mortality

ALL

Effect of VAS on mortality

BOYS

Effect of VAS on mortality

GIRLS

ASIAN TRIALS

 

Indonesia (1)

2,067

No

12 mo

20

(12 mo)

21 (1 mo) @

48 (2 mo) &

MMSR: 1.77 umol/L

 

0.36 (0.16-0.87)

0.15 (0.03-0.68)

0.84 (0.26-2.77)

India (2)

11,619

No

6 mo

69*

(6 mo)

61 (1 mo) &

70 (2 mo) &

5-6% NB in pregnancy

BCG: 59% DTP1: 66%

DTP3: 17%

(6 mo)(19)

0.78 (0.63-0.97)

0.70 (0.52-0.94)

0.87 (0.65-1.17)

Bangladesh (3)

15,937

Yes

(3*2 factorial)

5½ mo

45

(5½ mo)

69 (1 mo) @

82 (2 mo) &

 

MMSR in first trimester: 1.15 umol/L. 10% NB in last pregnancy

BCG: 72%

DTP1: 65%

(5½ mo**)

0.87 (0.67-1.12) $

0.89 (0.72-1.10)

0.81 (0.65-1.00)

AFRICAN TRIALS

 

Zimbabwe (4)

HIV negative mothers

9,208

Yes

(2*2 factorial)

12 mo

17

(12 mo)

53 (1 mo) &

65 (2 mo) &

 

MSR: 6%<_1.05 xmlns:wkso="urn:x-prefix:wkso" umol="umol" l="l" _6="_6" wkso:p="wkso:p"/>

No NB

 

1.18 (0.76-1.83)

N/A

N/A

Zimbabwe (5)

HIV positive mothers

4,495

Yes

(2*2 factorial)

24 mo

155

(2 yrs (all children))

28 (6 wks) ¤

 

 

MMSR: ~1.00 umol/L after delivery,

NoNB

1.21 (0.99-1.46) $

HIV positive:

0.88 (0.58-1.32)

HIV negative:

1.89 (1.05-3.40)

N/A

N/A

Zimbabwe (5) combined

14,110

Yes

(2*2 factorial)

N/A

N/A

N/A

NoNB

1.16 (0.98-1.38)

N/A

N/A

Guinea-Bissau (6)

4,345

No

12 mo

47

(12 mo)

53

(6 mo)

23 (1mo)

30 (2mo)

MMSR at 4 mo:

1.66 umol/L

Mean child SR:

0.95 umol/L (6 wks)

1.07 umol/L (4 mo)

BCG: 100% 

DTP1: 97%

DTP3: 90%

(6 mo) (17)

1.07 (0.79-1.44)

0.84 (0.55-1.27)

 

1.39 (0.90-2.14)

MMSR= Mean maternal serum retinol. NB=night blindness

* Note, mortality per 1000 live births **Estimates presented in the paper without any indication of when collected - presumably at age 5½ months.

@ Presented in paper & Based on extrapolation from mortality curves in papers ¤ 6 weeks, calculated from table 3 in paper, those without HIV infection

$ Effect in maternal placebo groups

 

Competing interests: None declared

Competing interests: No competing interests

11 July 2008
Christine S Benn
Senior researcher
Hilton Whittle, Ane Fisker, and Peter Aaby
Bandim Health Project, Statens Serum Institut, 2300 Copenhagen S, Denmark