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Newborn Vitamin A Dosing andNeonatal Mortality Why do the Results Differ?

David ThurnhamUniversity of Ulster, Northern Ireland Centre for Food and Health,Coleraine, UK and MRC Elsie Widdowson Laboratory, Cambridge, UK

Correspondence: David Thurnham, 46 High Street, LittleWilbraham, Cambridge CB21 5JY, UKEmail: di.thurnham@ulster.ac.uk

The primary purpose of this article is to provide adescription of the studies that examined early infantsurvival following vitamin A supplementation of new-born infants. These descriptions will provide a back-ground for the accompanying papers by Drs Benn andKlemm on the wider issues surrounding the vitamin Adosing of newborns. In addition, I will describe theeffects of the high dose of vitamin A on retinolreserves in the neonate, compare it with the amount ofvitamin A obtained from human colostrum, and exam-ine breast feeding practices in or near to the countrieswhere the vitamin A dosing studies were done. Tworecent studies have highlighted some of the conse-quences of delayed initiation of breast feeding on mor-tality of the neonate, and their results may be of rele-vance in the interpretation of the newborn vitamin Adosing trials.

The neonatal vitamin A supplementation trials

Three randomized, placebo-controlled trials, inIndonesia1, Bangladesh2 and South India3 all demon-strated a significant reduction in infant mortalityamong newborn infants who were supplemented with50,000 IU (52 µmol retinol equivalents (RE)) vita-min A within 48 hr of birth compared to controlgroups. In contrast, no reduction in mortality wasdetected in two similar studies in sub-Saharan Africa;in Guinea Bissau4 and in Zimbabwe.5

The first of the trials was done in a hospital inBandung, Indonesia. Mothers delivering in this hospi-tal were enrolled and if their infants were more than1,500 g and without any life-threatening illness, they

were given either the vitamin A (n=1,034) or control(n=1,033) treatments and followed up to 12 mo.1

There was a surprisingly large difference in infantmortality, with a relative risk ratio of 0.36 – that is,64% fewer deaths in the vitamin A group (n=19) com-pared with the controls (n=7) at 12 mo (Table 1). The

impact was greater in boys, infants of normal com-pared with low birth weight, and those of greater pon-deral index (kg/m3). Safety studies carried out at thesame time examined infants for potentially acute side-effects over the first 48 hr. The groups were compara-ble at baseline, but a bulging fontanel was observed at24 hr and 48 hr in the vitamin A (4.6%, 4.5%) andcontrol (2.7%, 2.4%) groups respectively. The authorsconcluded that neonatal vitamin A supplementation of50,000 IU had minimal side effects and appeared toreduce infant mortality rate and the prevalence ofsevere respiratory infection among young infants.

Vitamin A dosing of newborn infant

SIGHT AND LIFE Magazine 2010;1:19–26

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The next study was done byRahmathullah and colleagues inTamil Nadu, Southern India.3 Thiswas a community-based study inwhich 11,619 infants were allocat-ed to doses of 24,000 IU (25 µmol)oral vitamin A (n=5,786) or place-bo (n=5,733) on days 1 and 2 afterdelivery. After the first dose, thesupervisor revisited the householdto give the second dose and recordany adverse events. Adverse eventswere limited to vomiting (placebo,6; vitamin A, 3), and there were noreports of bulging fontanel. Projectstaff visited the households everytwo weeks to assess vital status andcollect morbidity data for up to sixmonths. There were 188 deaths in the placebo group and 146 in thevitamin A group. Supplementingnewborn infants with vitamin Awas associated with 22% less mor-tality and analysis of infant survivalcurves indicated that the placebogroup did progressively worse from

2 weeks to 3 months. Inter estinglythe protective effects of vitamin Awere stronger in boys (30%) andnot significant in girls (13%) andonly significant in those with birthweights <2,500 g (Table 1).

The third study to report lowermortality in neonates supplementedwith vitamin A was carried out inBangladesh. Infants were dosedwith oral vitamin A (50,000 IU,n=7953) or placebo (n=7984), and99.8% received their supplement ata median age of seven hours.2 Thestudy piggy-backed on a maternalvitamin A and �-carotene supple-mentation trial, but this did notappear to influence the results. Themain outcome measure was mortal-ity during the first 24 weeks, whichwas assessed at weekly visits forthe first 12 weeks and then again at24 weeks of age. There were fewadverse effects. Mothers reportedbulging fontanel in 154 (vitamin A,

1.9%) and 178 (control 2.2%), butof these only 11 and 21 casesrespectively were clinically con-firmed ~1 day later. The trial washalted when there had been 306(vitamin A) and 360 (control)deaths, representing a relative riskof 0.85 or 15% reduction attributa-ble to the vitamin A (Table 1).

There were other similaritiesbetween the studies in Bangladeshand Southern India,3 where mortal-ity rates were far greater than thosein Indonesia. The studies inBangladesh and Southern Indiawere both done in rural communi-ties, and infant survival in the con-trol group was progressively worsefrom one up to ~16 weeks.However, in contrast to SouthernIndia, there was stronger evidenceof protection among girls, terminfants, infants born to motherswith parity one or higher, and arelationship between survival and

Table 1: Mortality statistics in the newborn vitamin A supplementation trials

Study Sample size Total Mortality Relative Period of Survival Sub-groupsdeaths rate/1000 risk measure- difference benefiting

person/years ratio ment between from(95% CI) (months) groups vitamin A

Indonesia1 VA 1,034 7 7.2 0.36 (0.16, 0.87) 12 Better in VA Boys; normalC 1,033 19 19.8 group between birth weight;

2 wk and 4 mo greater ponderalindex

Southern VA 5,786 146 53.8 0.78 (0.63, 0.96) 6 Better in VA Boys;India3 C 5,833 188 69.1 group between birth weights

2 wk and 3–4 mo >2,500 gBangladesh2 VA 7,953 306 38.5 0.85 (0.73, 1.00) 6 Better in VA Girls;

C 7,984 360 45.1 group between term infants;2 wk and 4 mo mothers’ parity >1

Zimbabwe5 VA 4,592 88 21.0 1.08 (0.80, 1.46) 12 No period None reportedC 4,601 82 19.3 advantage of survival

Guinea Bissau4 VA 2,145 88 49.0 1.07 (0.79, 1.44) 12 No period Boys;C 2,200 86 45.6 of survival infants born

advantage in dry season1.00 (0.65, 1.56) First 4 mo

VA: Vitamin A; C: Control

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birth weight was not detected(Table 1).

Malaba and colleagues5 workingin Zimbabwe reported the firststudy to find no benefit of vitaminA given to neonates. The study wasa 2x2 factorial designed trial ofinfants from HIV-negative motherswhere mothers and infants wererandomized to receive vitamin A(mothers 400,000 and infants50,000 IU) or placebo. There wereapproximately 2,300 mother-infantpairs per group and 42–46 deaths inany group receiving vitamin Acompared with 36 deaths in thegroup where neither mothers norinfants received vitamin A.Mortality rates were similar withthose in Indonesia. Survival curvestended to be poorer in the threegroups receiving vitamin A, butnone of the differences from thegroup receiving no vitamin A weresignificant. Thus the authors con-cluded that vitamin A supplemen-tation of neonates and post-partumwomen was unlikely to reduceinfant mortality, and, the authorsadded, “in relatively well-nour-ished populations even when infec-tious diseases are the commonestcause of death” (Table 1).

Lastly Benn and colleagues4

reported no effects of 50,000 IUvitamin A on infant mortality whenthey randomized 4,345 infants whowere due to receive BCG vaccineat birth, with vitamin A or placebo.Their study was done in GuineaBissau, West Africa and excludedinfants below 2,500 g at birth.Infants were followed through theroutine registration system every 3mo and were visited by a specialteam at 12 mo. 174 children diedduring follow-up, and overall mor-tality rates were high and compara-ble with Bangladesh and SouthernIndia. However, the 12 mo mortali-ty risk ratio was 1.07. There wasalso no evidence of any survival

advantage for the vitamin A groupduring the first 4 mo when the ratiowas 1.0 and it was 1.13 betweenmo 4 to 8 (Table 1). So the groupfailed to find any important effectof vitamin A on overall mortality,but when the genders were exam-ined separately, the effect tended to beneficial for boys but harmfulfor girls i.e. a commonality withthe studies in Indonesian andBangladesh.1,3

Vitamin A status

In a previous article in SIGHTAND LIFE Magazine,6 Tielschand colleagues argue that a princi-ple factor explaining the differentoutcomes between the interventionstudies was the vitamin A status,

for it was reasonable to assumethat there was unlikely to be amortality benefit if the vitamin Astatus was good, as was found inthe two African studies.4,5

However, a major difficulty in thishypothesis was the lack of evi-dence of vitamin A deficiency inthe Indonesian study (Table 2).The Indonesia women recruitedwere relatively privileged in thatthey had access to, and made use

of, the health care system inchoosing to give birth in the hospi-tal1, and the retinol concentrationsin the trial women were compara-ble with those obtained fromwomen in industrialized countrieslike the UK7–10 and the USA.11

Please compare the mean retinolconcentration of the Indonesianmothers (Table 2) with that ofadult UK women in the Figure.However, there was certainly evi-dence of vitamin A deficiency inthe other two Asian studies, sincein Southern India 5–6% of thewomen reported a history of nightblindness,3 and in Bangladeshapproximately 10% of womenreported night blindness in a previ-ous pregnancy.2

The vitamin A status reported inthe two African studies was differ-ent to that in the Indian sub-conti-nent. In Zimbabwe, no womanreported night blindness, and theauthors suggest that the maternalplasma concentrations were similarto those of a reference Americanpopulation of reproductive age.How ever, comparison withNHANES 3 data11 which is essen-tially the same as that shown in the

Figure: Plasma retinol concentrations and age in England

2.2

0.6

2

1.6

3

1.8

1.4

1.2

0.8

1

5 8.5 12.5 16.5 18–65 Years

MaleFemale

Plas

ma

retin

ol µ

mol

/L

Mean plasma retinol concentrations at different ages for males and females obtained from three UK national surveys.8-10

Modified from Thurnham et al.7

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Figure suggests the mean Zim -babwean plasma retinol concentra-tions are ~30% lower thanAmerican data. Nevertheless suchdata are unlikely to indicate defi-cient liver stores of vitamin A, asrelative dose response tests carriedout on Thai women with slightlylower mean retinol concentrationsfound no evidence of deficient liverreserves.12 However, the relativelylow plasma retinol concentrationsof the Zimbabwean women couldwell impair milk retinol concentra-tions.13

In the case of the study inGuinea Bissau, the authors tookblood from sub-samples of mothersand infants at 6 weeks and 4 mo ofage. In general they measured vita-min A status using retinol bindingprotein (RBP). To convert theirdata to plasma retinol concentra-tions, they analysed a few samples

by HPLC and calculated a regres-sion equation. Using the authors’equation, the mean maternal retinolconcentrations they obtained were1.82 µmol/L (95% CI 1.77, 1.87),which, as they suggest, were equiv-alent to those of American women.Furthermore the mean retinol con-centrations of the infants at 6 weeksand 4 mo of age were ~0.96 and1.14 µmol/L respectively and wereequivalent to those of preschoolage children in England (Figure).Thus there was very little evidenceto suggest any vitamin A deficien-cy in Guinea Bissau apart from arelatively high proportion of infantswith low retinol concentrations.However the latter may be due toinflammation. The authors meas-ured CRP as a marker of inflamma-tion in the infant blood because ofthe high exposure to infection inthe community. There were ~23%with a CRP concentration >5 mg/L,

but the authors failed to measurethe marker of chronic inflammation�1-acid glycoprotein (AGP).Children with chronic inflamma-tion usually outnumber those withacute inflammation, as seen in therecent study in The Gambia whereat 6 mo there were 20% of infantswith a raised CRP but 50% with araised AGP concentration.14 Thusthe high proportion of low retinolresults in the infants may have beena consequence of chronic inflam-mation and not vitamin A deficien-cy, further emphasising the fact thatvitamin A status of this populationwas probably reasonably good.

In summary, in the two studieswhere night blindness was report-ed, vitamin A supplements wereassociated with lower neonatalmortality. However, vitamin A hasthe same effect in Indonesia, wherevitamin A status of the mothers was

Table 2: Vitamin A status and other socio-economic factors in the five neonatal vitamin A supplemen-tation trials

Study Blood levels Night blindness Socio-economic factorsIndonesia1 Mean maternal retinol Women had access to and chose

in a subsample (n=150) None reported to give birth in hospital. ~1.77 µmol/L Most infants (>80%) in Indonesia

are born at homeSouthern India3 No measurements 5–6% reported in current Study done in 2 rural

pregnancy districts in Tamil Nadu. Most infantsborn either at home (~37%) or at hospital (54%)

Bangladesh2 Mean (SD) maternal 10% reported history in Study done in 19 unions ofserum retinol (first trimester) previous pregnancy rural NW Bangladesh, typical lower~1.15 (0.32) µmol/L socio-economic community;

94% infants delivered at homeZimbabwe5 Mean maternal retinol None reported Study done in Harare;

of sub-groups 1.09–1.25 µmol/L Mothers HIV negative at delivery. National Survey found 36% of pre-school children had serum retinol <0.7 µmol/L in 1999

Guinea Bissau4 Mean RBP measurements None reported Bandim health project in 6equivalent to – maternal retinol suburban districts of G-B, 1.75, infants 0.82 (6 wk) malaria endemic, birth weight >2,500 g.and 0.98 µmol/L (4 mo) Infants born at home and in hospitals

RBP: Retinol binding protein

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good, but had no effect in the two African studies,where vitamin A status also appeared to be good. Thusthe presence of vitamin A deficiency in the communi-ty does not appear to be the main determinant for asuccessful reduction in mortality following neonataldosing with vitamin A.

Time of initiation of breast feeding and neonatalmortality

Two studies have recently shown that failure to pro-vide human milk to the neonate in the first hour afterdelivery will increase the risk of neonatal mortali-ty.15,16 It has been recognized for a long time that allinfants, irrespective of maternal vitamin A status, areborn with little or no reserves of vitamin A, and infantsare dependent on the vitamin A in breast milk to sup-ply their needs for growth and storage.17 In addition,breast milk, and especially the colostrum, is an impor-tant source of protein and immunoglobulins. The con-centration of these is highest on day one, halves by daytwo and then progressively decreases at a slow ratethereafter. Such factors may accelerate intestinal mat-uration, resistance to infection and epithelial recoveryafter infection.15

In Ghana, West Africa, 70% of infants were exclu-sively fed breast milk, and for another 27%, breastmilk was the predominant feed. Breast feeding wasinitiated by 71% of infants within the first day, and allbut 1.3% had started by day 3. However, it was breastfeeding within the first hour that reportedly saved 22%

of neonatal deaths, and 16% if all infants were breastfed from day 1. Late initiation (after day 1) was asso-ciated with a 2.4-fold higher risk of mortality and afour-fold higher risk in children given milk-based flu-ids or solids in addition to breast milk (Table 3).15

A similar pattern of the neonatal mortality risk wasassociated with breast feeding initiation in southernNepal.16 The authors suggested that 7.7 and 19.1% ofneonatal deaths may be avoided by universal initiationof breast feeding within the first day and hour respec-tively. However, when the confounders of birthweight and prematurity were taken into account, theeffects of early initiation were no longer significant,but the trend for a higher risk with longer initiationtimes was still significant (p<0.03). As also noted inGhana, partial as opposed to exclusive breast feedingwas associated with ~2-fold higher mortality (1.7795% CI 1.32, 2.39).

Does neonatal vitamin A supplementation substitute for the vitamin A in colostrum?

Many studies have shown that the vitamin A content ofhuman milk is high in the colostrum at birth and thendecreases by half to two thirds in mature milk. A reviewof the literature by Ross & Harvey18 suggested that thepotential amount of vitamin A from colostrum over thesix days from a mother living in a poor environment is~3.6 mg (12.5 µmol RE). If the mother receives vitaminA supplements during pregnancy, the potential amountincreases to 4.6 mg (16 µmol RE). These amounts arelower than the vitamin A obtained by an infant from avitamin A supplement (52 µmol RE, 50,000 IU), whereestimates suggest infant liver reserves increase by ~28µmol RE.19 However, the stimulus of early breast feed-ing is believed to increase rates of exclusive16 and sus-tained breast feeding through infancy15 to maintain thesupply of vitamin A. Thus early initiation of breastfeeding may provide equivalent health benefits to theneonatal vitamin A supplement.

Table 3: Influence of time of breast feed initiation and risk of neonatal mortality

Time of Percent of Potential deaths Total neonatal Mortality rateinitiation (hours) sample saved (%) deaths (48 hr to 28 d)

Nepal16

<1 3.4 19.1 297 12.6/1000<24 56.6 7.7

Ghana15

<1 43.5 22 145 13.3/1000<24 72 16

Two studies have recently shown thatfailure to provide human milk to the

neonate in the first hour after deliverywill increase the risk of

neonatal mortality

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Thus it is possible that where theneonatal vitamin A supplementappeared to lower mortality com-pared to the placebo treatment, thesupplement may have been makinggood a deficit in those advantagesobtained from colostrum. Thesecircumstances may have applied inSouthern India and Bangladesh andhence the vitamin A supplementlowered the mortality in the vita-min A group. In contrast, the rapid

initiation of breast feeding inZimbabwe lowered the efficacy ofthe vitamin A supplement, so nobenefit was seen even though moth-ers’ vitamin A status may haveslightly lowered the breast milkvitamin A content. In Indonesia,mothers’ vitamin A status was

good, but the early introduction ofnon-human milks may have influ-enced the mortality statistics, givingthe appearance of benefit from thevitamin A supplement. Lastly,there is no direct information on ini-tiation of breast feeding or of com-plementary feeding in the GuineaBissau study, so it is difficult toknow whether or not these factorsmay have influenced the outcome.The high vitamin A status and

potentially high prevalence ofinflammation may have precludedany benefit from the vitamin Atreatment, and this is to some extentsupported by the suggestion that thevitamin A supplement was of bene-fit to infants born in the dry season.Experience in The Gambia would

suggest that prevalence of inflam-mation was lower in the dry than inthe wet season.20

Breast feeding practices in theneonatal mortality trials

The benefits of earlier initiation ofbreast feeding, and especially ofreceiving colostrum, on neonatalmortality have only recently beendemonstrated15,16 and, unfortunate-ly, information on the breast feed-ing habits of the infants in theneonatal vitamin A supplementa-tion trials is incomplete (Table 4).

In Indonesia, although mostmothers gave breast milk to theirinfants, there is no information onfeeding habits in the first 12 hours,but up to 2% (n=41) of infants maynever have received breast milk, andat 4 mo 82% received complementa-ry foods. The authors report ~98%of infants in both the vitamin A andplacebo groups were breast fed atbaseline, but baseline was the timeof administering the supplement and

Table 4: Breast feeding habits reported in the vitamin A supplementation trials

Study Not breast fed Not breast fed at all Use of Other informationin first 12 hours complementary

foodsIndonesia1 No information 1–2% not BF or fed

<1 mo (2%, n=41)At 4 mo 82%receiving comple-mentary foods

Early introduction ofnon-breast-milk foodscustomary in Indonesia

SouthernIndia3

20% (n=1,157) in VAgroup18% (n=1,050) inplacebo group

11% (n=636) in VAgroup15% (n=875) in placebogroup

No information Median time to 1st doseVA was 26 h and moth-ers encouraged to BFimmediately after dose

Bangladesh2 52.8% (n=4,199) inVA group52.6% (n=4,200) inplacebo group

No information No information Approximately 5%(n=797) in both groupsdid not get anycolostrum

Zimbabwe5 2.4–3.0% (n~280) None No information

GuineaBissau4

No information No information No information Almost all children instudy area BF to at least18 mo

The benefits of earlier initiation of breast feeding, and especially of receiving colo strum, on neonatal

mortality have only recently been de mon strated

BF: Breast feeding

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~12% (n=248) had not receivedtheir supplement at 24 hr. The mor-tality rate in the Indonesian cohortwas relatively low (total 26 deaths)and delayed initiation of breast feed-ing, and early introduction of com-plementary feeding may both haveinfluenced mortality and not beenaccounted for in assessing theeffects of the vitamin A trial onmortality.

In the Southern India study3,approximately 19% of infants didnot receive breast milk in the first 12hours and 11–15% were not fedbreast milk at all (Table 4).Mothers were encouraged to breastfeed immediately following thetreatment to reduce losses of thesupplements, but median first-treat-ment time was 26 hours. There werea total of 334 deaths (146 VA; 188placebo) in those infants treatedwithin the first 48 hours, when itappeared vitamin A had its greatestbenefit (risk ratio 0.77; 95% CI0.61, 0.97), but this group will haveincluded a large number of infantsnot given colostrum in the first 12hours. Infant feeding habits do notappear to have been included in thedata analysis, thus delayed initiationof breast feeding may also have con-tributed to the neonatal mortalityand any differences between the twogroups may have not been entirelydue to vitamin A.

In the Bangladesh study, 79% oflive born infants were administeredthe supplement within 24 hours(median age 7, inter-quartile range2, 18 h) and new-born care practices(breast feed initiation, colostrumconsumption etc.) were comparablebetween the two treatment groups.However, more than half of allinfants did not receive breast milk inthe first 12 hours and there were 32more mothers in the vitamin A thanthe placebo group who reported giv-ing no colostrum. No relationshipbetween time of initiation of breast

feeding or colostrum consumptionand neonatal mortality was reportedby the authors. There were 54 fewerdeaths in the group who receivedvitamin A than the placebo treat-ment, and a more detailed analysisof breast feeding initiation andinfant mortality within the first 24 hmight be justified. This is particular-ly relevant if one considers the datafrom Zimbabwe, where ~40% ofmothers initiated breast feedingwithin 1 hr of delivery and 97%within 12 hr.5 These habits are insharp contrast to those in theSouthern India and Bangladeshstudies (Table 4).

In Guinea Bissau no informationis given on the time of breast feedinginitiation; only that mothers breastfed children to at least 18 mo.4

Guinea Bissau is in West Africa, andconcern has been expressed overbreast feeding practices in West andCentral Africa, which has some of

the highest malnutrition and mortal-ity rates in the world.21 In TheGambia, which is geographicallyclose to Guinea Bissau, initiation ofbreast feeding is reported to be usu-ally delayed until more than 24 hrafter delivery. In addition, pre-lacteal feeds are common, andexclusive breast feeding is rare.22 Ifbreast feeding initiation in GuineaBissau is similar to that reportedfrom The Gambia, then the highmortality rates reported in GuineaBissau (in spite of an apparentlywell-controlled vaccination schedulefor the infants) may share a similaretiology to mortality rates inBangladesh and Southern India.However, in Guinea Bissau therewas no overall effect on neonatalmortality of the vitamin A treatment,and this difference may have arisenbecause vitamin A status appeared tobe satisfactory in both mothers andinfants.

Key findings at a glance

• There was less infant mortality in Indonesia, Southern India andBangladesh after neonatal vitamin A supplementation with 50,000 IUcompared with placebo• Similar trials in Zimbabwe and Guinea Bissau in Africa had no effects oninfant mortality• Night blindness was evidence of poor vitamin A status in Southern Indiaand Bangladesh• Vitamin A status was moderate to good in Zimbabwe, Indonesia andGuinea Bissau• Delayed initiation of breast feeding was common in Southern India andBangladesh• Delayed initiation of breast feeding was associated with higher mortalityin two studies (Ghana, Nepal)• There was no delay in breast feeding in Zimbabwe, with ~40% startingwithin 1 hr of delivery, but no information for Indonesia and GuineaBissau• The cumulative effect on vitamin A status of feeding colostrum in the firsthour after birth may be similar to that of oral vitamin A dosing with50,000 IU vitamin A• Good vitamin A status, early initiation of breast feeding and vitamin Asupplements are associated with lower infant mortality• Late initiation of breast feeding, poor vitamin A status, early introductionof complementary feeds are associated with higher infant mortality

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Conclusions

Late initiation of breast feeding may be a major factorin the high neonatal mortality rates in Bangladesh,Southern India and Guinea Bissau, and in these cir-cumstances vitamin A status is particularly importantand, where it is poor, neonatal dosing with vitamin Areduced infant mortality. In the Zimbabwean andIndonesian studies, infant vitamin A status was rela-tively good due to early initiation of breast feeding inZimbabwe and the higher socio-economic status inIndonesia. In these circumstances, neonatal vitamin Asupplement provided no further benefit in Zimbabwebut did provide benefit in Indonesia, where there wasearly introduction of non-breast-milk foods.

References

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3. Rahmathullah L, Tielsch JM, Thulasiraj RD et al. Impact ofsupplementing newborn infants with vitamin A on early infantmortality: community based randomised trial in southern India.BMJ 2003; 327:254–260.

4. Benn CS, Diness BR, Roth A et al. Effect of 50,000 IU vitaminA given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial. BMJ 2008;336:1416–1420.

5. Malaba LC, Iliff PJ, Nathoo KJ et al. Effect of postpartummaternal or neonatal vitamin A supplementation on infant mor-tality among infants born to HIV-negative mothers inZimbabwe. Am J Clin Nutr 2005; 81:454–460.

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13. Stolfzfus RJ, Hakimi M, Miller KW et al. High dose vitamin Asupplementation of breast-feeding Indonesian mothers: effectson the vitamin A status of mother and infant. J Nutr 1993;123:666–675.

14. Darboe MK, Thurnham DI, Morgan G et al. Effectiveness ofthe new IVACG early high-dose vitamin A supplementationscheme compared to the standard WHO protocol: A ran-domised controlled trial in Gambian mothers and infants.Lancet 2007; 369:2088–2096.

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18. Ross JS, Harvey PW. Contribution of breastfeeding to vitaminA nutrition of infants: a simulation model. Bull WHO 2003;81:80–86.

19. Miller M, Humphrey JH, Johnson EJ et al. Why do childrenbecome vitamin A deficient? J Nutr 2002; 132:2867S–2880S.

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Newborn supplements