Vitamin A Supplementation at Birth Might Prime the Response to Subsequent Vitamin A Supplements in Girls. Three Year Follow-Up of a Randomized Trial Tolerance of young infants to a single, large dose of vitamin A: a randomized community trial in Nepal. Safety of one 52-mumol (50,000 IU) oral dose of vitamin A administered to neonates. Childhood mortality after a high dose of vitamin A in a high risk population. Effect of 50 000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial Efficacy of early neonatal vitamin A supplementation in reducing mortality during infancy in Ghana, India and Tanzania: study protocol for a randomized controlled trial Impact of vitamin A supplementation on prevalence and incidence of xerophthalmia in Nepal. Mortality of infants < 6 mo of age supplemented with vitamin A: a randomized, double-masked trial in Nepal. Vitamin A supplementation at birth delays pneumococcal colonization in South Indian infants. Effect of vitamin A supplementation with BCG vaccine at birth on vitamin A status at 6 wk and 4 mo of age. Effect of postpartum maternal or neonatal vitamin A supplementation on infant mortality among infants born to HIV-negative mothers in Zimbabwe. Effect of maternal and neonatal vitamin A supplementation and other postnatal factors on anemia in Zimbabwean infants: a prospective, randomized study. Neonatal vitamin A supplementation: effect on development and growth at 3 y of age. Effect of high-dose vitamin A supplementation on the immune response to Bacille Calmette-Guerin vaccine. Newborn vitamin A dosing reduces the case fatality but not incidence of common childhood morbidities in South India. A double blind randomized controlled trial in neonates to determine the effect of vitamin A supplementation on immune responses: The Gambia protocol Effect of early neonatal vitamin A supplementation on mortality during infancy in Ghana (Neovita): a randomised, double-blind, placebo-controlled trial The effect of neonatal vitamin A supplementation on growth in the first year of life among low-birth-weight infants in Guinea-Bissau: two by two factorial randomised controlled trial Effect of neonatal vitamin A supplementation on mortality in infants in Tanzania (Neovita): a randomised, double-blind, placebo-controlled trial The Effect of 50 000 IU Vitamin A with BCG Vaccine at Birth on Growth in the First Year of Life Maternal supplementation with retinyl palmitate during immediate postpartum period: potential consumption by infants. Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India 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. Efficacy of early neonatal supplementation with vitamin A to reduce mortality in infancy in Haryana, India (Neovita): a randomised, double-blind, placebo-controlled trial No adverse events after simultaneous administration of 50 000 IU vitamin A and Bacille Calmette-Guerin vaccination to normal-birth-weight newborns in Guinea-Bissau Two different doses of supplemental vitamin A did not affect mortality of normal-birth-weight neonates in Guinea-Bissau in a randomized controlled trial. Effect of administration of 200,000 IU of vitamin A to women within 24 hrs after delivery on response to PPV administered to the newborn. Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates: two by two factorial randomised controlled trial Newborn Vitamin A Supplementation Reduced Infant Mortality in Rural Bangladesh The effect of at-birth vitamin A supplementation on differential leucocyte counts and in vitro cytokine production: an immunological study nested within a randomised trial in Guinea-Bissau. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. Does early neonatal vitamin a supplementation reduce infant mortality? Administration of 25,000 IU vitamin A doses at routine immunisation in young infants. Neonatal vitamin A supplementation associated with increased atopy in girls Newborn vitamin A supplementation does not affect nasopharyngeal carriage of Streptococcus pneumoniae in Bangladeshi infants at age 3 months. Effect of vitamin A supplementation in women of reproductive age on maternal survival in Ghana (ObaapaVitA): a cluster-randomised, placebo-controlled trial The effect of high-dose vitamin A supplementation given with bacille Calmette-Guérin vaccine at birth on infant rotavirus infection and diarrhea: a randomized prospective study from Guinea-Bissau. The effect of newborn vitamin A supplementation on infant immune functions: trial design, interventions, and baseline data.
Objectives Within a r and omised trial of neonatal vitamin A supplementation ( VAS ) in Guinea-Bissau , neonatal VAS did not affect overall  infant mortality . We conducted a post-hoc analysis to test the hypothesis that neonatal VAS primes the response to subsequent vitamin A. Methods All trial children were offered VAS after follow-up ended at 1 year of age ( FU-VAS ) . We compared mortality between 1 and 3 years of age according to initial r and omization to neonatal VAS or placebo in Cox-regression models ; we expected that children r and omized to neonatal VAS compared with those r and omized to placebo would have lower mortality after reception of FU-VAS . Results Of 4345 infants enrolled in the original trial , 3646 lived in the study area at 1 year of age and 2958 received FU-VAS .  Between 1 and 3 years of age , 112 children died . After FU-VAS , neonatal VAS was associated with lower mortality than placebo : Mortality Rate Ratio ( MRR ) = 0.54 ( 95%CI : 0.31–0.94 ) . The effect was more pronounced in girls ( MRR = 0.37 ( 0.16–0.89 ) ) than boys ( MRR = 0.73 ( 0.35–1.51 ) ) . The beneficial effect of neonatal VAS may have been particularly strong for girls who received both VAS in a campaign and FU-VAS ( MRR = 0.15 ( 0.03–0.67 ) ) . Among children who had not received FU-VAS , mortality in the second and third year of life did not differ according to reception of neonatal VAS or placebo . Hence , in the second and third year of life the effect of neonatal VAS versus placebo was different in girls who had or had not received FU-VAS ( p for homogeneity = 0.01 ) . Conclusions The present results suggest that neonatal VAS primes the response in girls such that they get a beneficial effect after a subsequent dose of VAS . Trial Registration Clinical trials.gov A r and omized , double-masked trial was carried out in rural Nepal to investigate the incidence and severity of acute side-effects among neonates ( < 1 month of age ) and infants aged 1 - 6 months who received a large , oral dose of vitamin A ( 15,000 retinol equivalents ( RE ) ( 50,000 IU ) and 30,000 RE ( 100,000 IU ) , respectively ) or placebo ( 75 RE ( 250 IU ) and 150 RE ( 500 IU ) , respectively ) in oil . Infants ( vitamin A group , n = 1461 ; controls , n = 1379 ) were assessed for vomiting , loose stools , fever , and irritability during the 24 hours before and after dosing . Fontanelles were palpated 24 hours after dosing . Neonates exhibited no excess risk of adverse side-effects after receiving 15,000 RE . Compared with controls the older infants who ingested 30,000 RE had a 1.6 % excess rate of vomiting ( 95 % confidence interval ( CI ) : 0.2 - 3.0 % ) and a 0.5 % excess rate ( 95 % CI : -0.1 to 1.1 % ) in the occurrence of bulging fontanelles . There were no other significant differences in the older infants . The controlled , periodic distribution of a single 15,000 RE dose of vitamin A therefore confers no apparent acute risk to young infants ; a 30,000 RE dose is associated with a minimum risk of transient , acute side-effects A placebo-controlled trial was carried out among 2067 Indonesian neonates to assess the safety of administering one oral 52-mumol ( 50,000 IU ) dose of vitamin A.  Infants were assessed for potential acute side-effects before and throughout 48 hours after the dose . The first 965 infants were examined by cranial ultrasound before and at 24 hours after dosing to rule out intracranial haemorrhage and determine the resistive index ( RI ) of the anterior cerebral artery using duplex Doppler . Groups were comparable at the baseline . A bulging fontanelle occurred in the control and vitamin A groups , respectively , among 2.7 % and 4.6 % of the infants at 24 hours , and 2.4 % and 4.5 % of the infants at 48 hours . The groups did not differ in any other sign or symptom assessed . No infant developed intracranial haemorrhage . Mean RI values were normal and not different between groups at baseline or at 24 hours . Mean RI fell during the 24 hours , as normally occurs ; the mean decrease was nearly identical in the two groups . A bulging fontanelle was not associated with increased rates of any sign or symptom or with an increase in RI . The 52-mumol dose of oral vitamin A may cause a small increase in intracranial volume in a small proportion of infants , but no increase in intracranial pressure . Acute side-effects following this intervention were rare and mild OBJECTIVES --To determine whether a single high dose of vitamin A given to all children in communities with high mortality and malnutrition could affect mortality and to assess whether periodic community wide supplementation could be readily incorporated into an ongoing primary health programme . DESIGN --Opportunistic controlled trial . SETTING --Jumla district , Nepal . SUBJECTS -- All children aged under 5 years ; 3786 in eight subdistricts given single dose of vitamin A and 3411 in remaining eight subdistricts given no supplementation .  MAIN OUTCOME MEASURES --Mortality and cause of death in the five months after supplementation . RESULTS --Risk of death for children aged 1 - 59 months in supplemented communities was 26 % lower ( relative risk 0.74 , 95 % confidence interval 0.55 to 0.99 ) than in unsupplemented communities . The reduction in mortality was greatest among children aged 6 - 11 months : death rate ( deaths/1000 child years at risk ) was 133.8 in supplemented children and 260.8 in unsupplemented children ( relative risk 0.51 , 0.30 to 0.89 ) . The death rate from diarrhoea was also reduced ( 63.5 supplemented v 97.5 unsupplemented ; relative risk 0.65 , 0.44 to 0.95 ) . The extra cost per death averted was about $ 11 . CONCLUSION --The results support a role for Vitamin A in increasing child survival . The supplementation programme was readily integrated with the ongoing community health programme at little extra cost Objective To investigate the effect of high dose vitamin A supplementation given with BCG vaccine at birth in an African setting with high infant mortality . Design R and omised placebo controlled trial . Setting B and i m Health Project ’s demographic surveillance system in Guinea-Bissau , covering approximately 90 000 inhabitants . Participants 4345 infants due to receive BCG . Intervention Infants were r and omised to 50 000 IU vitamin A or placebo and followed until age 12 months . Main outcome measure Mortality rate ratios . Results 174 children  died during follow-up ( mortality=47/1000 person-years ) . Vitamin A supplementation was not significantly associated with mortality ; the mortality rate ratio was 1.07 ( 95 % confidence interval 0.79 to 1.44 ) . The effect was 1.00 ( 0.65 to 1.56 ) during the first four months and 1.13 ( 0.75 to 1.68 ) from 4 to 12 months of age . The mortality rate ratio in boys was 0.84 ( 0.55 to 1.27 ) compared with 1.39 ( 0.90 to 2.14 ) in girls ( P for interaction=0.10 ) . An explorative analysis revealed a strong interaction between vitamin A and season of administration . Conclusions Vitamin A supplementation given with BCG vaccine at birth had no significant benefit in this African setting . Although little doubt exists that vitamin A supplementation reduces mortality in older children , a global recommendation of supplementation for all newborn infants may not contribute to better survival . Trial registration Clinical trials NCT00168597 Background Vitamin A supplementation of 6 - 59 month old children is currently recommended by the World Health Organization based on evidence that it reduces mortality . There has been considerable interest in determining the benefits of neonatal vitamin A supplementation , but the results of existing trials are conflicting . A technical consultation convened by WHO pointed to the need for larger scale studies in Asia and Africa to inform global policy on the use of neonatal vitamin A supplementation . Three trials were therefore initiated in Ghana , India and Tanzania to determine if vitamin A supplementation ( 50,000 IU ) given to neonates once orally on the day of birth or within the next two days will reduce mortality in the period from supplementation to 6 months of age compared to placebo . Methods / Design The trials are individually r and omized , double masked , and placebo controlled . The required sample size is 40,200 in India and 32,000 each in Ghana and Tanzania . The study participants are neonates who fulfil age eligibility , whose families are likely to stay in the study area for the next 6 months , who are able to feed orally , and whose parent(s ) provide informed written consent to participate in the study . Neonates r and omized to the intervention group receive 50,000 IU vitamin A and the ones r and omized to the control group receive placebo at the time of enrolment . Mortality and morbidity information are collected through periodic home visits by a study worker during infancy . The primary outcome of the study is mortality from supplementation to 6 months of age . The secondary outcome of the study is mortality from supplementation to 12 months of age . The three studies will be analysed independent of each other . Subgroup analysis will be carried out to determine the effect by birth weight , sex , and timing of DTP vaccine , socioeconomic groups and maternal large-dose vitamin A supplementation . Discussion The three ongoing studies are the largest studies evaluating the efficacy of vitamin A supplementation to neonates . Policy formulation will be based on the results of efficacy of the intervention from the ongoing r and omized controlled trials combined with results of previous studies .Trial Registration Ghana : Australian New Zeal and Clinical Trials Registry ( ANZCTR ) - ACTRN12610000582055 ; India : CLINICAL TRIALS.GOV - NCT01138449 ; Tanzania : Australian New Zeal and Clinical Trials Registry ( ANZCTR ) - ACTRN12610000636055 PURPOSE To assess the impact of vitamin A supplementation at 4-month intervals on the prevalence and incidence of xerophthalmia among preschool-age children . METHODS A stratified , r and om sample of 40 wards with 4766 children in Sarlahi district of Nepal was selected to participate in a r and omized , controlled , community trial . In the vitamin A group , at 4-month intervals , neonates received 50,000 IU , 1- to 11-month-old infants received 100,000 IU , and children 1 through 4 years of age received 200,000 IU . Children underwent eye examination before the intervention and 16 months later . RESULTS Before the intervention , 4318 children were examined for xerophthalmia .  The prevalence was 2.3 % in the  vitamin A group and 3.3 % in the placebo group . All children with xerophthalmia were treated with vitamin A at the time of the examination . Of those examined at baseline , 38 in the vitamin A group and 48 in the placebo group died in the 16 months after intervention . There were 1871 ( 84 % ) surviving children in the vitamin A group and 1711 ( 85 % ) in the placebo group examined at follow-up . After adjustment for the baseline prevalence of xerophthalmia , vitamin A reduced the prevalence at follow-up by 63 % ( 95 % confidence interval , 21 % to 83 % ) . The apparent incidence was 3.2/1000 per year in the vitamin A group and 9.2/1000 per year in the placebo group , an adjusted reduction of 62 % ( 95 % confidence interval , 0 % to 86 % ) . CONCLUSIONS Supplementation was effective at reducing the prevalence and incidence of xerophthalmia The effect of supplementing 11,918 infants < 1 mo and 1 - 5 mo of age with vitamin A ( 15,000 and 30,000 micrograms retinol equivalents or 50,000 and 100,000 IU , respectively ) or a placebo on subsequent 4-mo mortality was assessed in a r and omized , double-masked community trial in the rural plains of Nepal . There were 130 deaths ( 51.6/1000 child-y ) in the control group and 150 deaths ( 57.1/1000 child-y ) in the vitamin A group , yielding a relative risk of 1.11 ( 95 % CI : 0.86 , 1.42 ) , which is indicative of no overall effect on early infant mortality . There was a tendency for the relative risk of mortality among vitamin A recipients to rise with improved nutritional status . These results suggest that distribution of a large oral dose of vitamin A to infants < 5 - 6 mo of age may not benefit short-term survival . This is in contrast with the results of trials in which older infants and children in this same population were supplemented Nasopharyngeal colonization is a risk factor for pneumococcal disease , a leading cause of complications and death in infants . We assessed the impact of vitamin A supplementation in reducing pneumococcal colonization in infants from an area with endemic vitamin A deficiency . We recruited 464 2-mo-old infants from a rural area in South India . Infants were r and omly assigned to receive two 7000-microg retinol equivalent doses of vitamin A ( n = 239 ) or placebo ( n = 225 ) orally at birth , and nasopharyngeal specimens were collected at ages 2 , 4 and 6 mo . We studied the effect of vitamin A on culture-confirmed pneumococcal colonization and on the distribution of pneumococcal serotypes . Analyses were conducted by intention-to-treat . The risk of colonization among infants aged 4 mo who were not colonized by age 2 mo was significantly reduced in the vitamin A group compared with the placebo group [ odds ratio 0.51 ( 0.28 , 0.92 ) , P = 0.02 ) . The odds of colonization were 27 % lower in the treatment group than in the placebo group [ odds ratio 0.73 ( 0.48 , 1.1 ) , P = 0.13 ] . No differences were detected in the prevalence of invasive serotypes . The risk of colonization with penicillin-resistant isolates was 74 % lower in the vitamin A group than in the placebo group at 2 mo of age . However , the prevalence of penicillin-resistant isolates was only 4 % . Neonatal vitamin A supplementation may play a role in lowering morbidity rates associated with pneumococcal disease by delaying the age at which colonization occurs BACKGROUND The effect of vitamin A supplementation ( VAS ) at birth on subsequent vitamin A status has not been studied . OBJECTIVE The objective was to study the effect of 50,000 IU vitamin A administered with BCG vaccine at birth on vitamin A status in both sexes . DESIGN Within a r and omized placebo-controlled trial of VAS , we obtained blood from 614 children at 6 wk of age and from 369 mother-infant pairs at 4 mo of age . We assessed vitamin A status on the basis of serum retinol-binding protein ( RBP ) and measured serum C-reactive protein to monitor for concurrent infections . RESULTS RBP concentrations indicated vitamin A deficiency in 32 % of the children at age 6 wk and in 16 % at age 4 mo . VAS was not associated with higher RBP concentrations overall or in either sex . However , the effect of VAS varied with maternal education ( P for interaction = 0.004 ) : At age 6 wk , VAS was associated with higher ( 9 % ; 95 % CI : 2 , 17 % ) RBP concentrations in children of noneducated mothers but not in children of educated mothers . Overall , RBP concentrations increased between 6 wk and 4 mo of age . The increase correlated inversely with the number of diphtheria-tetanus-pertussis ( DTP  ) vaccines received in the interval ( P = 0.009 ) , particularly in girls ( P for interaction = 0.01 ) and in vitamin A recipients ( P = 0.01 ) . CONCLUSIONS Overall , VAS at birth had no effect on vitamin A status . However VAS may temporarily improve vitamin A status in the subgroup of children of noneducated mothers . In vitamin A recipients , subsequent DTP vaccines affected vitamin A status negatively . The main trial was registered at clinical trials.gov as NCT00168597 BACKGROUND Young infants are at risk of vitamin A deficiency . Supplementation of breastfeeding mothers improves the vitamin A status of their infants , but there are no data regarding its effect on infant mortality , and data on the effect of directly supplementing infants during the first few weeks of life are conflicting . OBJECTIVE The objective was to measure the effect on infant mortality of supplementing neonates and their HIV-negative mothers with single , large doses of vitamin A during the immediate postpartum period . DESIGN A r and omized , placebo-controlled , 2-by-2 factorial design trial was conducted in 14,110 mothers and their infants ; 9208 of the mothers were HIV-negative at delivery , remained such during the postpartum year , and were retained in the current analysis . The infants were r and omly assigned within 96 h of delivery to 1 of 4 treatment groups : mothers and infants received vitamin A ( Aa ) , mothers received vitamin A and infants received placebo ( Ap ) , mothers received placebo and infants received vitamin A ( Pa ) , and both mothers and infants received placebo ( Pp ) . The vitamin A dose in the mothers was 400,000 IU and in the infants was 50,000 IU . The mother-infant pairs were followed to 12 mo . RESULTS Hazard ratios ( 95 % CI ) for 12 mo mortality among infants in the maternal-supplemented and infant-supplemented groups were 1.17 ( 0.87 , 1.58 ) and 1.08 ( 0.80 , 1.46 ) , respectively . Hazard ratios ( 95 % CI ) for the Aa , Ap , and Pa groups compared with the Pp group were 1.28 ( 0.83 , 1.98 ) , 1.27 ( 0.82 , 1.97 ) , and 1.18 ( 0.76 , 1.83 ) , respectively . These data indicate no overall effect . Serum retinol concentrations among a sub sample of women were similar to reference norms . CONCLUSION Postpartum maternal or neonatal vitamin A supplementation may not reduce infant mortality in infants of HIV-negative women with an apparently adequate vitamin A status BACKGROUND Anemia is prevalent in infants in developing countries . Its etiology is multifactorial and includes vitamin A deficiency . OBJECTIVE Our primary aim was to measure the effect of maternal or neonatal vitamin A supplementation ( or both ) on hemoglobin and anemia in Zimbabwean infants . Our secondary aim was to identify the underlying causes of postnatal anemia . DESIGN A r and omized , placebo-controlled trial was conducted in 14 110 mothers and their infants ; 2854 infants were r and omly selected for the anemia sub study , of whom 1592 were successfully observed for 8 - 14 mo and formed the study sample . Infants were r and omly assigned within 96 h of delivery to 1 of 4 treatment groups : mothers and infants received vitamin A ; mothers received vitamin A and infants received placebo ; mothers received placebo and infants received vitamin A ; and mothers and infants received placebo . The vitamin A doses were 400,000 and 50,000 IU in the mothers and infants , respectively . RESULTS Vitamin A supplementation had no effect on hemoglobin or anemia ( hemoglobin < 105 g/L ) in unadjusted or adjusted analyses . Infant HIV infection independently increased anemia risk > 6-fold . Additional predictors of anemia  in HIV-negative and -positive infants were male sex and lower total body iron at birth . In addition , in HIV-positive infants , the risk of anemia increased with early infection , low maternal CD4 + lymphocyte count at recruitment , and frequent morbidity . Six-month plasma ferritin concentrations < 12 microg/L were a risk factor in HIV-negative but not in HIV-positive infants . Maternal HIV infection alone did not cause anemia . CONCLUSION Prevention of infantile anemia should include efforts to increase the birth endowment of iron and prevent HIV infection We reported recently that neonatal supplementation with 52 micromol vitamin A reduced infant mortality by 64 % ; acute side effects were limited to a 3 % excess rate of a bulging fontanelle . The current study was conducted to identify developmental changes at 3 y of age associated with neonatal vitamin A supplementation or a bulging fontanelle . Children who had a bulging fontanelle ( n = 91 ) and 432 children who had normal fontanelles after receiving vitamin A or placebo were evaluated with the Bayley Scales of Infant Development . Mean scores for the mental , psychomotor , and behavioral rating scale ( BRS ) plus 3 subscales of the BRS were not significantly different for treatment-fontanelle-specific groups . In regression models predicting each score , a bulging fontanelle had a small negative effect in all models ; when 1 child who was injured from birth was removed from the analysis the effect of a bulging fontanelle was not significant in any model ( P > or = 0.35 ) . Vitamin A supplementation had a small beneficial effect on all developmental scores , which was significant for one of the BRS subscales ( orientation-engagement ) and also for a second ( motor quality ) when the outlier child was removed . Compared with children with normal fontanelles in the placebo group , children with a bulging fontanelle in the vitamin A group tended to grow less ( -0.5 cm , P = 0.33 ) , whereas those with normal fontanelles in the vitamin A group grew significantly more ( 0.68 cm , P < 0.05 ) , over the first 3 y of life . This study provides no evidence that neonatal vitamin A supplementation is associated with biologically significant adverse growth or developmental sequelae BACKGROUND Vitamin A supplementation ( VAS ) at birth has been associated with decreased mortality in Asia .  Bacille Calmette-Guérin ( BCG ) vaccine is given at birth in tuberculosis-endemic countries . Previous studies suggest that VAS may influence the immune response to vaccines . OBJECTIVE Our objective was to examine whether VAS influences the immune response to simultaneously administered BCG vaccine . DESIGN Within a r and omized trial of 50,000 IU vitamin A or placebo given with BCG vaccine at birth in Guinea-Bissau , 2710 infants were examined for BCG scar formation and delayed-type hypersensitivity ( DTH ) to purified protein derivative of Mycobacterium tuberculosis ( PPD ) at 2 and 6 mo of age . The ex vivo cytokine response to PPD was measured in 607 infants . RESULTS At 2 mo of age , 39 % ( 43 % of the boys and 34 % of the girls ) responded to PPD . The prevalence ratio of a measurable PPD reaction for VAS compared with placebo recipients was 0.90 ( 95 % CI : 0.80 , 1.02 ) for all infants , 0.81 ( 95 % CI : 0.69 , 0.95 ) for boys , and 1.04 ( 95 % CI : 0.86 , 1.26 ) for girls . At 6 mo of age , 42 % of the infants responded to PPD . No difference was observed between VAS and placebo recipients . The prevalence of BCG scar was not affected by VAS . The ex vivo interferon-gamma response to PPD was increased by VAS ( means ratio : 1.40 ; 95 % CI : 1.03 , 1.91 ) . CONCLUSIONS VAS with BCG vaccination does not appear to interfere with the long-term immune response to BCG . However , VAS temporarily altered the DTH reaction to PPD in boys at 2 mo of age , suggesting sex differences in the immunologic response to VAS given with BCG . This trial was registered at www . clinical trials.gov as # NCT00168597 Vitamin A supplementation reduces mortality in young children in areas of endemic vitamin A deficiency . However , it has no impact on the incidence of common morbidities . This discrepancy has been explained by an impact on case fatality , although with the exception of hospitalized measles cases , there is little direct evidence to support this hypothesis . We assessed the impact of newborn dosing with vitamin A on the incidence and case fatality of common childhood morbidities in early infancy in a community-based , r and omized trial in South India . Morbidity for each day in the previous 2 wk was assessed for the first 6 mo of life . A total of 11,619 live-born infants were enrolled and r and omized to receive either 48,000 IU ( 50.4 micromol retinol ) of oral vitamin A or placebo following delivery . There was no difference between treatment groups in the incidence of acute or chronic diarrhea , dysentery , or fever but a small increased incidence of acute respiratory illness ( ARI ) . Case fatality for diarrhea and fever were significantly reduced in the vitamin A group compared with placebo ( relative case fatality [ 95 % CI ] of 0.50 [ 0.27 , 0.90 ] and 0.60 [ 0.40 , 0.88 ] , respectively ) . There was a trend in reduction of case fatality for various definitions of ARI , but the evidence for this effect was modest . Survival analysis among those with morbid episodes confirmed the case fatality analysis . This trial demonstrated that the reduction in overall mortality due to newborn vitamin A dosing was driven primarily by a reduction in case fatality among infants Background Vitamin A supplementation significantly reduces all-cause mortality when given between 6–59 months of age , but has a null or detrimental effect when given between 1–5 months . Studies of  neonatal vitamin A supplementation  conducted across Africa and South Asia have produced conflicting findings . These age-pattern variations might result from immunological interactions between vitamin A supplementation and vaccines . Knowledge on the potential immunological sequelae of human neonatal vitamin A supplementation is so scarce that the foremost aim of this study is to seek indicative data on aspects of immunity likely to be affected by neonatal vitamin A supplementation . The objective of this trial is to test whether human neonatal vitamin A supplementation modulates immune function including improved thymic maturation in infancy and improved systemic immune responses to routine immunization . Methods / design In an area of moderate vitamin A deficiency in a peri-urban area of The Gambia , 200 mother – infant pairs were enrolled in a double-blind r and omised controlled trial . Within 48 hours of birth , neonates were r and omised with stratification by birth weight and sex to receive either an oral dose of 50,000 IU vitamin A or placebo . Exp and ed Programme of Immunisation birth vaccinations were administered after supplementation , with subsequent vaccinations administered at 8 , 12 and 16 weeks of age . A range of immunological outcomes were examined up to 17 weeks of age , with additional morbidity and anthropometry follow-up carried out throughout the first year of life . The primary endpoint of this trial is the frequency of circulating T regulatory ( Treg ) cells expressing gut homing receptors in infants at 17 week post-supplementation , with secondary outcomes including thymus maturation and B cell immune responses . Discussion Indicative immunological data from this trial ( and its Bangladeshi counterpart ) , will complement the larger r and omised controlled trials ( conducted in India , Tanzania and Ghana ) , on the effectiveness and safety of neonatal vitamin A supplementation in improving infant survival . Combined these trials , in addition to the existing trials , will inform policy . Trial registration clinical trials.gov BACKGROUND Results of r and omised controlled trials of newborn ( age 1 - 3 days ) vitamin A supplementation  have been inconclusive . The WHO is coordinating three large r and omised trials in Ghana , India , and Tanzania ( Neovita trials ) . We present the findings of the Neovita trial in Ghana . METHODS This study was a population -based , individually r and omised , double-blind , placebo-controlled trial in the Brong Ahafo region of Ghana . The trial participants were infants aged at least 2 h , identified at home or facilities on the day of birth or in the next 2 days , able to feed orally , and likely to stay in the study area for at least 6 months . They were r and omly assigned ( ratio 1:1 ) to receive either one oral dose of vitamin A ( 50,000 IU ) or placebo immediately after recruitment . The research team and parents of the infants were masked to treatment assignment . Follow-up home visits were undertaken every 4 weeks , when data were recorded for deaths , facility use , and care seeking . The primary outcome was post-supplementation mortality to 6 months of age . Analysis was by intention to treat . Potential adverse events were recorded at 1 and 3 days after supplementation . This trial is registered with the Australian New Zeal and Clinical Trials Registry (ANZCTR)CTRN12610000582055 . FINDINGS We assessed 26,414 livebirths for eligibility between Aug 16 , 2010 , and Nov 7 , 2011 . We recruited 22,955 newborn infants , with 11,474 r and omly assigned to receive vitamin A and 11,481 to receive placebo . Loss to follow-up was low with vital status at 6 months of age reported for 22,698 ( 98·9 % ) infants . We recorded 278 post-supplementation deaths to 6 months of age in the vitamin A group ( mortality risk 24·5 in 1000 supplemented infants ) and 248 deaths in the placebo group ( mortality risk 21·8 per 1000 supplemented infants ) , relative risk ( RR ) 1·12 ( 95 % CI 0·95 - 1·33 ; p=0·183 ) and risk difference ( RD ) 2·66 ( 95 % CI -1·25 to 6·57 ; p=0·18 ) . Adverse events within 3 days of supplementation did not differ by trial group . 122 infants died in the first 3 days after supplementation ; 70 ( 0·6 % ) in the vitamin A and 52 ( 0·5 % ) in the placebo group ( risk ratio [ RR ] 1·35 , 95 % CI 0·94 - 1·93 , p=0·102 ) . 53 infants were reported to have a bulging fontanelle ; 32 ( 0·3 % ) in the vitamin A group and 21 ( 0·2 % ) in the placebo group ( RR 1·53 , 0·88 - 2·62 , p=0·130 ) . INTERPRETATION The results of this trial do not support inclusion of newborn vitamin A supplementation as a child survival strategy in Ghana . FUNDING Bill & Melinda Gates Foundation grant to the WHO Background Vitamin A supplementation ( VAS ) may amplify the effect of vaccines . We therefore investigated if neonatal VAS given with and without Bacille Calmette-Guérin ( BCG ) vaccine to low-birth-weight ( LBW ) neonates had an effect on growth in the first year of life . We hypothesised that VAS would be particularly beneficial when provided with BCG . Methods We conducted a r and omised two-by-two factorial trial in Guinea-Bissau ; 1,717 LBW neonates were r and omly allocated to VAS or placebo at birth as well as early or the usual postponed BCG vaccination .  Anthropometric measurements were obtained at 2 , 6 , and 12 months after inclusion . Results Overall there was no effect of neonatal VAS on growth in the first year of life . By 2 months , VAS tended to have a beneficial effect on weight and head circumference when given with BCG but not when given without BCG ( interaction : weight-for-age p = 0.07 and head circumference-for-age : p = 0.06 ) . By 6 months , there was a beneficial effect of VAS on head circumference and weight among children who had not received DTP vaccine 2 months after inclusion ( weight : 0.18 ( 0.00 ; 0.36 ) and head circumference 0.27 ( 0.06 ; 0.48 ) ) , but no beneficial effect among those who had received DTP . Conclusion The results support other trials indicating that neonatal VAS does not have consistent effects on childhood growth and if anything the effects seem to be temporary . They also show that the effect may differ by vaccination status , being beneficial when given with BCG at birth and when DTP is delayed . Trial registration http://www . Clinical Trials.gov ( NCT00168610 BACKGROUND Supplementation of vitamin A in children aged 6 - 59 months improves child survival and is implemented as global policy . Studies of the efficacy of supplementation of infants in the neonatal period have inconsistent results . We aim ed to assess the efficacy of oral supplementation with vitamin A given to infants in the first 3 days of life to reduce mortality between supplementation and 180 days ( 6 months ) . METHODS We did an individually r and omised , double-blind , placebo-controlled trial of infants born in the Morogoro and Dar es Salaam regions of Tanzania . Women were identified during antenatal clinic visits or in the labour wards of public health facilities in Dar es Salaam . In Kilombero , Ulanga , and Kilosa districts , women were seen at home as part of the health and demographic surveillance system . Newborn infants were eligible for r and omisation if they were able to feed orally and if the family intended to stay in the study area for at least 6 months . We r and omly assigned infants to receive one dose of 50,000 IU of vitamin A or placebo in the first 3 days after birth . Infants were r and omly assigned in blocks of 20 , and investigators , participants ' families , and data analysis teams were masked to treatment assignment . We assessed infants on day 1 and day 3 after dosing , as well as at 1 , 3 , 6 , and 12 months after birth . The primary endpoint was mortality at 6 months , assessed by field interviews . The primary analysis included only children who were not lost to follow-up . This trial is registered with the Australian New Zeal and Clinical Trials Registry ( ANZCTR ) , number ACTRN12610000636055 . FINDINGS Between Aug 26 , 2010 , and March 3 , 2013 , 31,999 newborn babies were r and omly assigned to receive vitamin A ( n=15,995 ) or placebo ( n=16,004 ; 15,428 and 15,464 included in analysis of mortality at 6 months , respectively ) . We did not find any evidence for a beneficial effect of vitamin A  supplementation on mortality in infants at 6 months ( 26 deaths per 1000 livebirths in vitamin A vs 24 deaths per 1000 livebirths in placebo group ; risk ratio 1·10 , 95 % CI 0·95 - 1·26 ; p=0·193 ) . There was no evidence of a differential effect for vitamin A supplementation on mortality by sex ; risk ratio for mortality at 6 months for boys was 1·08 ( 0·90 - 1·29 ) and for girls was 1·12 ( 0·91 - 1·39 ) . There was also no evidence of adverse effects of supplementation within 3 days of dosing . INTERPRETATION Neonatal vitamin A supplementation did not result in any immediate adverse events , but had no beneficial effect on survival in infants in Tanzania . These results strengthen the evidence against a global policy recommendation for neonatal vitamin A supplementation . FUNDING Bill & Melinda Gates Foundation to WHO Vitamin A supplements may interact with diphtheria-tetanus-pertussis ( DTP ) vaccine causing increased female mortality . In a r and omised trial of neonatal vitamin A supplementation ( VAS ) , we examined growth during the first year of life in 808 children , pursuing the hypothesis that a negative interaction between VAS and DTP in girls would be reflected in growth . Length and weight were measured at 6 weekly visits and WHO-growth-reference z-scores derived . Neonatal VAS had no effect on anthropometric measures at 12 months , but may interact sex differentially with routine vaccines . While BCG was the most recent vaccine , neonatal VAS benefitted growth ( difference in weight-for-length z-score ( dWFL : 0.31(95 % CI : 0.03–0.59 ) ) . While DTP was the most recent vaccine , VAS tended to affect growth adversely in girls ( dWFL = −0.21 ( −0.48–0.06 ) ) . After measles vaccine ( MV ) there was no overall effect of neonatal VAS . The VAS effect differed significantly between the BCG and DTP windows ( P = 0.03 ) , and the difference was borderline significant between the DTP and MV windows for girls ( P = 0.09 ) OBJECTIVE To assess the effect of maternal supplementation with a single dose of retinyl palmitate during the postpartum period , in order to provide vitamin A for the infant . METHODS A clinical trial was conducted in Natal ( Northern Brazil ) , between March and December 2007 , on 85 women distributed r and omly into two groups . The postpartum supplements of retinyl palmitate consisted of a single dose of 200,000 IU ( experimental group ) and zero IU ( control group ) . The retinol levels in milk were quantified using high performance liquid chromatography . Based on the retinol concentrations obtained in breast milk and through simulations , vitamin A consumption among infants 24 hours and 30 days postpartum was calculated . RESULTS The daily provision of retinol to newborns through colostrum , 24 hours postpartum , was 1.63 micromol for the controls and 2.9 micromol for the experimental group , taking adequate intake to be 1.40 micromol/day and the milk volume consumed to be 500 ml/day . Thirty days postpartum , these values were 0.64 micromol/day ( controls ) and 0.89 micromol/day ( experimental group ) , corresponding to a 39 % increase in retinol concentration in the experimental group , in relation to the control group , or 64 % of the recommendation for infants aged zero to six months . CONCLUSIONS Maternal supplementation with 200,000 IU of retinyl palmitate during the immediate post-partum period , and promotion of breastfeeding practice s , are efficient for increasing the nutritional status of vitamin A for the mother-child pair Abstract Objective To assess the impact of supplementing newborn infants with vitamin A  on  mortality at age 6 months . Design Community based , r and omised , double blind , placebo controlled trial . Setting Two rural districts of Tamil Nadu , southern India . Participants 11 619 newborn infants allocated 24 000 IU  oral vitamin A or placebo on days 1 and 2 after delivery . Main outcome measure Primary outcome measure was mortality at age 6 months . Results Infants in the vitamin A group had a 22 % reduction in total mortality ( 95%confidence interval 4 % to 37 % ) compared with those in the placebo group . Vitamin A had an impact on mortality between two weeks and three months after treatment , with no additional impact after three months . Conclusion Supplementing newborn infants with vitamin A can significantly reduce early infant mortality BACKGROUND Low maternal serum retinol level is a risk factor for mother-to-child transmission ( MTCT ) of human immunodeficiency virus ( HIV ) . Multiple-large-dose vitamin A supplementation of HIV-positive children reduces mortality . The World Health Organization recommends single-large-dose vitamin A supplementation for postpartum women in areas of prevalent vitamin A deficiency ; neonatal dosing is under consideration . We investigated the effect that single-large-dose maternal/neonatal vitamin A supplementation has on MTCT , HIV-free survival , and mortality in HIV-exposed infants . METHODS A total of 14,110 mother-infant pairs were enrolled < or = 96 h after delivery , and both mother and infant , mother only , infant only , or neither received vitamin A supplementation in a r and omized , placebo-controlled trial with a 2 x 2 factorial design . All but 4 mothers initiated breast-feeding . A total of 4495 infants born to HIV-positive women were included in the present analysis . RESULTS Neither maternal nor neonatal vitamin A supplementation significantly affected postnatal MTCT or overall mortality between baseline and 24 months . However , the timing of infant HIV infection modified the effect that supplementation had on mortality .  Vitamin A supplementation had no effect in infants who were polymerase chain reaction ( PCR ) positive [ corrected ] for HIV at baseline . In infants who were PCR negative at baseline and PCR positive at 6 weeks , neonatal supplementation reduced mortality by 28 % ( P=.01 ) , but maternal supplementation had no effect . In infants who were PCR negative at 6 weeks , all 3 vitamin A regimens were associated with ~2-fold higher mortality ( P < or = .05 ) . CONCLUSIONS Targeted vitamin A supplementation of HIV-positive children prolongs their survival . However , postpartum maternal and neonatal vitamin A supplementation may hasten progression to death in breast-fed children who are PCR negative at 6 weeks . These findings raise concern about universal maternal or neonatal vitamin A supplementation in HIV-endemic areas BACKGROUND Vitamin A supplementation in children aged 6 months to 5 years has been shown to reduce mortality . The efficacy of neonatal supplementation with vitamin A to reduce mortality in the first 6 months of life is plausible but not established . We aim ed to assess the efficacy of neonatal oral supplementation with vitamin A to reduce mortality between supplementation and 6 months of age . METHODS We undertook an individually r and omised , double-blind , placebo-controlled trial in Haryana , India . We identified pregnant women through a surveillance programme undertaken every 3 months of all female residents in two districts of Haryana , India , aged 15 - 49 years , and screened every identified livebirth . Eligible participants were neonates whose parents consented to participate , were likely to stay in the study area until at least 6 months of age , and were able to feed orally at the time of enrolment . Participants were r and omly assigned to receive oral capsules containing vitamin A ( retinol palmitate 50,000 IU plus vitamin E 9·5 - 12·6 IU ) or placebo ( vitamin E 9·5 - 12·6 IU ) within 72 h of birth . R and omisation was in blocks of 20 according to a r and omisation list prepared by a statistician not otherwise involved with the trial . Investigators , participants ' families , and the data analysis team were masked to treatment allocation . The primary outcome was mortality between supplementation and 6 months of age . Analysis included all participants assigned to study groups . This trial is registered with Clinical Trials.gov , number NCT01138449 , and the Indian Council of Medical Research Clinical Trial Registry , number CTRI/2010/091/000220 . FINDINGS Between June 24 , 2010 , and July 1 , 2012 we screened 47,777 neonates and r and omly assigned 44,984 to receive vitamin A ( 22,493 ) or placebo ( 22,491 ) . Between supplementation and 6 months of age , 656 infants died in the vitamin A group compared with 726 in the placebo group ( 29·2 per 1000 vs 32·3 per 1000 ; difference -3·1 per 1000 , 95 % CI -6·3 to 0·1 ; risk ratio 0·90 , 95 % CI 0·81 to 1·00 ) . We noted no significant interactions between the intervention effect and sex on mortality at 6 months ( p=0·409 ) . Supplementation with 50,000 IU vitamin A within the first 72 h of life was generally safe and well tolerated , with the exception of a small excess risk of transient bulging fontanelle ( 205 cases in the vitamin A group confirmed by physician vs 80 cases in the placebo group , risk ratio 2·56 [ 95 % CI 1·98 - 3·32 ] ) . INTERPRETATION The findings of this study , done in a population in which vitamin A deficiency is a moderate public health problem , are consistent with a modest reduction in mortality between supplementation and 6 months of age . These findings must be viewed together with similar trials in other population s to enable determination of appropriate public health policy . FUNDING Bill & Melinda Gates Foundation to WHO Objective : To determine whether the combined intervention of 50 000 IU vitamin A administered together with Bacille Calmette-Guerin ( BCG ) vaccination at birth was associated with adverse events , in particular bulging fontanels and adverse reactions to BCG.Subjects/ Methods : From an ongoing trial , 2145 infants r and omized to 50 000 IU vitamin A or placebo with BCG vaccination were recruited .  Adverse events were monitored in two different ways : ( A ) daily clinical examinations by a medical doctor during the first 3 days post supplementation ; ( B ) weekly interviews by a trained assistant during the first month post supplementation . Results : In part A , 1271 infants were enrolled , in part B 2078 .  Vitamin A supplementation ( VAS ) was associated with a relative risk ( RR ) of bulging fontanels of 1.16 ( 95 % confidence interval (CI)=0.82–1.65 ) . The rate of health care contacts and various symptoms during the first month were comparable between the groups . VAS was associated with larger peak local reactions to BCG vaccination in boys , but not in girls ( P-value for test of interaction between VAS and sex=0.02 ) . Conclusion : 50 000 IU vitamin A with BCG was not associated with adverse events . The observed sex-differential effect of VAS on local reaction to BCG is in line with other observations of sex-differential effects of VAS Whether neonatal vitamin A supplementation ( NVAS ) should be policy in areas with vitamin A deficiency is debated . We observed that a smaller dose of vitamin A may decrease mortality more than a larger dose and conducted a r and omized , double-blind , placebo-controlled trial in Guinea-Bissau with the primary aim of comparing the effect of 50,000 with 25,000 IU neonatal vitamin A on infant mortality . The secondary aim was to study the effect of NVAS vs. placebo , including a combined analysis of NVAS trials . Between 2004 and 2007 , normal-birth-weight neonates were r and omly assigned in a 1:1:1 ratio to be administered 2 different doses of vitamin A ( 50,000 or 25,000 IU ) or placebo .  Infant mortality rates ( MRs ) were compared in Cox models providing MR ratios ( MRRs ) . Among 6048 children enrolled , there were 160 deaths in 4125 person-years ( MR = 39/1000 ) . There was no difference in mortality between the 2 dosage groups : the MRR for 25,000 vs. 50,000 IU was 0.96 ( 95 % CI : 0.67 , 1.38 ) . Neither dose of NVAS was associated with lower mortality than placebo ( MRR = 1.28 ; 95 % CI : 0.91 , 1.81 ) . In a combined analysis of the present trial and 2 previous NVAS trials in Guinea-Bissau , the effect of receiving NVAS ( any dose ) vs. placebo was 1.13 ( 95 % CI : 0.94 , 1.36 ) and differed significantly ( P = 0.01 ) between boys ( 0.80 ; 95 % CI : 0.58 , 1.09 ) and girls ( 1.35 ; 95 % CI : 1.04 , 1.75 ) . We could not confirm that a smaller dose of neonatal vitamin A reduces mortality more than a larger dose . We confirmed 2 other trials in Guinea-Bissau that showed no beneficial effect of NVAS . This trial was registered at clinical trials.gov as NCT00168610 OBJECTIVE To explore the effect of maternal supplementation of vitamin A on the immune response to oral polio vaccine  in breastfed infants . DESIGN R and omized controlled trial . SETTING Hospital based . METHODS One hundred mothers having uncomplicated deliveries r and omly received either 200,000 IU vitamin A orally ( Experimental ) or placebo ( Control ) . All the newborns were given a dose of oral polio vaccine within 72 hours after birth and were breastfed . Type specific neutralizing antibodies to polio viruses in test sera diluted from 1:4 to 1:512 and serum retinol levels were determined from the cord blood and at the age of 6 weeks . Breast milk retinol levels were determined at 3 , 10 , 30 , 45 and 90 days of lactation . RESULTS Seroconversion to OPV and geometric means of antibody titers to the three types of polio viruses were comparable between the groups of infants belonging to the experimental and control mothers . Breast milk retinol levels were significantly higher in the experimental group upto 45 - 90 days of lactation . Majority of the infants at birth had serum retinol levels < 15 micrograms/dl which improved significantly by 6 weeks irrespective of the maternal supplementation status . CONCLUSIONS Maternal vitamin A supplementation soon after delivery improves vitamin A intakes of breastfed infants during the first 3 months and has no interference with the seroconversion to a neonatal dose of OPV . OPV administered to newborn in turn has no adverse effect on the vitamin A status of the breastfed infants Objective To investigate the effect of vitamin A supplementation and BCG vaccination at birth in low birthweight neonates . Design R and omised , placebo controlled , two by two factorial trial . Setting Bissau , Guinea-Bissau . Participants 1717 low birthweight neonates born at the national hospital . Intervention Neonates who weighed less than 2.5 kg were r and omly assigned to 25 000 IU vitamin A or placebo , as well as to early BCG vaccine or the usual late BCG vaccine , and were followed until age 12 months . Main outcome measure Mortality , calculated as mortality rate ratios ( MRRs ) , after follow-up to 12 months of age for infants who received vitamin A supplementation compared with those who received placebo . Results No interaction was observed between vitamin A supplementation and BCG vaccine allocation ( P=0.73 ) . Vitamin A supplementation at birth was not significantly associated with mortality : the MRR of vitamin A supplementation compared with placebo , controlled for r and omisation to “ early BCG ” versus “ no early BCG ” was 1.08 ( 95 % CI 0.79 to 1.47 ) . Stratification by sex revealed a significant interaction between vitamin A supplementation and sex ( P=0.046 ) , the MRR of vitamin A supplementation being 0.74 ( 95 % CI 0.45 to 1.22 ) in boys and 1.42 ( 95 % CI 0.94 to 2.15 ) in girls . When these data were combined with data from a complementary trial among normal birthweight neonates in Guinea-Bissau , the combined estimate of the effect of neonatal vitamin A supplementation on mortality was 1.08 ( 95 % CI 0.87 to 1.33 ) ; 0.80 ( 95 % CI 0.58 to 1.10 ) in boys and 1.41 ( 95 % CI 1.04 to 1.90 ) in girls ( P=0.01 for interaction between neonatal vitamin A and sex ) . Conclusions The combined results of this trial and the complementary trial among normal birthweight neonates have now shown that , overall , it would not be beneficial to implement a neonatal vitamin A supplementation policy in Guinea-Bissau . Worryingly , the trials show that vitamin A supplementation at birth can be harmful in girls . Previous studies and future trials should investigate the possibility that vitamin A supplementation has sex differential effects . Trial registration Clinical Trials.gov NCT00168610 OBJECTIVES . We assessed the effect of supplementing newborns with 50000 IU of vitamin A on all-cause infant mortality  through 24 weeks of age . PATIENTS AND METHODS . This was a community-based , double-masked , cluster-r and omized , placebo-controlled trial conducted in 19 unions in rural northwest Bangladesh . The study was nested into and balanced across treatment arms of an ongoing placebo-controlled , weekly maternal vitamin A or β-carotene supplementation trial . Study -defined sectors ( N = 596 ) were evenly r and omized for newborns of participating mothers to receive a single , oral supplement of vitamin A ( 50000 IU ) or placebo as droplets of oil squeezed from a gelatinous capsule . Mothers provided informed consent for newborn participation at ∼28 weeks ' gestation . After birth , typically at home ( where > 90 % of births occurred ) , infants were supplemented and their vital status was followed through 24 weeks of age . The main outcome measure was mortality through 24 weeks of age . RESULTS . We obtained maternal consent to dose 17116 live-born infants ( 99.8 % of all eligible ) among whom 15937 ( 93.1 % ) were visited to be supplemented < 30 days after birth and for whom vital status at 24 weeks of age was known . Dosed infants ( n = 15902 [ 99.8 % ] ) received their study supplement at a median age of 7 hours . Relative to control subjects , the risk of death in vitamin A – supplemented infants was 0.85 , reflecting a 15 % reduction in all-cause mortality . Protective relative risks were indistinguishable by infant gender , gestational age , birth weight , age at dosing , maternal age , parity , or across the 3 treatment arms of the maternal supplementation trial . CONCLUSIONS . Newborn vitamin A dosing improved infant survival through the first 6 months of life in Bangladesh . These results corroborate previous findings from studies in Indonesia and India and provide additional evidence that vitamin A supplementation shortly after birth can reduce infant mortality in South Asia Vitamin A supplementation ( VAS ) at birth was not associated with improved survival in a r and omised , placebo-controlled trial in Guinea-Bissau . However , a negative sex-differential effect , which became evident after diphtheria-tetanus-pertussis ( DTP ) vaccination , was noted ; among girls who had received DTP , VAS at birth was associated with two-fold higher mortality than placebo . The objective of the present study was to investigate the immunological effects of VAS at birth within a subgroup of participants in the r and omised trial . Guided by the mortality results , we further explored whether VAS had a differential effect according to sex and DTP status . At 6 weeks after r and omisation and supplementation , we measured differential leucocyte counts and TNF-α , interferon-γ , IL-10 , IL-13 and IL-5 production in a whole-blood culture assay . A total of 471 children were included .  VAS compared with placebo at birth was associated with a higher proportion of monocytes ( relative risk ratio 1·26 , 95 % CI 1·07 , 1·49 , P=0·04 ) , while spontaneous TNF-α production was lower in the VAS group ( geometric mean ratio 0·54 , 95 % CI , 0·37 , 0·78 , P=0·001 ) . Stratified analysis showed that VAS was associated with lower TNF-α and IL-10 production for girls without DTP and boys with DTP , result ing in significant three-way interactions between VAS , sex and DTP vaccination status ( P=0·03 and P=0·04 , respectively ) for spontaneous TNF-α and IL-10 production . The results substantiate the potential role of VAS as an immunomodulatory intervention , which has different effects depending on concomitant health interventions and the sex of the recipient OBJECTIVE To determine whether vitamin A supplementation at birth could reduce  infant morbidity and mortality .  STUDY DESIGN We conducted a placebo-controlled trial among 2067 Indonesian neonates who received either 52 micromol ( 50,000 IU ) orally administered vitamin A or placebo on the first day of life . Infants were followed up at 1 year to determine the impact of this intervention on infant mortality . A subgroup ( n = 470 ) was also examined at 4 and 6 months of age to examine the impact on morbidity . RESULTS Vital status was confirmed in 89 % of infants in both groups at 1 year . There were 19 deaths in the control group and 7 in the vitamin A group ( relative risk = 0.36 ; 95 % confidence interval = 0.16 , 0.87 ) . The impact was stronger among boys , infants of normal compared with low birth weight , and those of greater ponderal index . Among infants examined at 4 months of age , the 1-week period prevalence of common morbidities was similar for vitamin A and control infants . However , during this same 4-month period , 73 % and 51 % more control infants were brought for medical treatment for cough ( p = 0.008 ) and fever ( p = 0.063 ) , respectively . CONCLUSIONS Neonatal vitamin A supplementation may reduce the infant mortality rate and the prevalence of severe respiratory infection among young infants Summary In this individually r and omized , double-blind , placebocontrolled trial in Haryana , India , 44,984 neonates were r and omly assigned to receive oral capsules containing vitamin A ( retinol palmitate 50,000 IU plus vitamin E 9·5–12·6 IU ; n=22,493 ) or placebo ( vitamin E 9·5–12·6 IU ; n=22 491 ) within 72 h of birth . The primary outcome was mortality between supplementation and 6 months of age . Between supplementation and 6 months of age , 656 infants  died in the vitamin A group compared with 726 in the placebo group ( 29·2 per 1000 vs 32·3 per 1000 ; difference −3·1 per 1000 , 95 % CI −6·3 to 0·1 ; risk ratio 0·90 , 95 % CI 0·81 to 1·00 ) . There was a small excess risk of transient bulging fontanelle ( 205 cases in the vitamin A group vs 80 cases in the placebo group ; RR 2·56 , 95 % CI 1·98 , 3·32 ) OBJECTIVE To investigate whether monthly administration of vitamin A at routine immunisation produces any side-effects , and to examine the effect of this supplementation on the vitamin A nutrition status of infants . DESIGN A double-blind r and omised  placebo-controlled clinical trial . SETTING Immunisation clinic of a large diarrhoea treatment centre . SUBJECTS Infants aged 6 - 17 weeks who will receive their first diphtheria-pertussis-tetanus/oral polio vaccine ( DPT/OPV ) dose . METHODS Infants were r and omly assigned to receive either  25,000 IU vitamin A or placebo . Three such doses were given with each immunisation dose at monthly intervals . Infants were examined by a physician before and during 24 h after the doses and any signs of toxicity were recorded . Venous blood was drawn at entry and 1 month after the 3rd dose for retinol assay . RESULTS One hundred and one infants received vitamin A and 98 received placebo .  Decreased feeding , irritability , diarrhoea , and vomiting were comparable between the two groups . In the vitamin A group five infants developed bulging fontanelle ; three of them developed it once ( after 1st , 2nd and 3rd dose respectively ) , one developed it twice ( after both the 2nd and 3rd dose ) , and the other infant after all three doses . In the placebo group a single child developed bulging fontanelle after the 3rd dose . In all the cases the bulging disappeared within 48 h of onset except in one infant , in whom it subsided at 60 h. The total bulging episodes in the vitamin A and placebo groups were 8 and 1 respectively ( RR = 7.7 ; P < 0.04 ) . However , none of these infants had irritability . At entry fasting retinol level was < 10 micrograms/dl in 35 % infants and in 87 % infants it was < 20 micrograms/dl . After the third dose fasting retinol level was marginally better in the vitamin A group ( mean + /- s.d . : 21.9 + /- 8.2 vs 19.2 + /- 7.8 ; P = 0.05 ) . However , 47 % infants receiving supplementation still had serum retinol level < 20 micrograms/dl . CONCLUSION The results suggest that administration of 25,000 IU of vitamin A in young infants along with routine immunisations , though associated with increased incidence of transient bulging fontanelle without any associated adverse signs or symptoms , may still be inadequate to prevent deficiency in this population . SPONSORSHIP This study was funded by the United States Agency for International Development ( USAID ) under grant no. DPE-5986-A-1009 - 00 with the International Centre for Diarrhoeal Disease Research , Bangladesh ( ICDDR , B ) . The ICDDR , B is supported by countries and agencies which share its concern for the health problems of developing countries Neonatal vitamin A supplementation ( NVAS ) is currently being considered as policy in countries at risk of deficiency . A previous study suggested that NVAS may be associated with increased atopy . We examined the effect of  NVAS on atopy by conducting long‐term follow‐up of a previous r and omized controlled trial in Guinea‐Bissau Nasopharyngeal ( NP ) carriage of S. pneumoniae ( Spn ) is a risk factor for pneumococcal disease and its transmission . We assessed the impact of vitamin A ( VA ) supplementation shortly after birth in reducing Spn colonization in early infancy in rural Bangladesh . We recruited 500 infants participating in a cluster-r and omized trial that reported a 15 % reduction in mortality following receipt of an oral dose of VA ( 52.25 μmol ) compared to placebo . NP specimens were collected at the age of 3 mo to study the effect of VA on the prevalence of culture-confirmed Spn . Analyses were conducted by intention to treat . Spn carriage prevalence did not differ between VA and placebo recipients [ OR = 0.83 ( 95 % CI : 0.55 - 1.27 ) ; P = 0.390 ] . Spn carriage at the age of 3 mo was not lowered by VA given at birth . Results are similar to those from an Indian study in which impact on Spn carriage was assessed at the age of 4 mo [ OR = 0.73 ( 95 % CI : 0.48 - 1.10 ) ; P = 0.128 ] . The point estimate of the pooled effect size for the 2 studies is OR = 0.78 [ ( 95 % CI : 0.58 - 1.04 ) ; P = 0.095 ] , which may imply a modest impact on carriage . If so , then the evidence thus far would suggest that Spn carriage reduction is unlikely to be a primary ancillary benefit of newborn VA supplementation BACKGROUND A previous trial in Nepal showed that supplementation with vitamin A or its precursor ( betacarotene ) in women of reproductive age reduced pregnancy-related mortality by 44 % ( 95 % CI 16 - 63 ) . We assessed the effect of vitamin A supplementation in women in Ghana . METHODS ObaapaVitA was a cluster-r and omised , double-blind , placebo-controlled trial undertaken in seven districts in Brong Ahafo Region in Ghana . The trial area was divided into 1086 small geographical clusters of compounds with fieldwork areas consisting of four contiguous clusters . All women of reproductive age ( 15 - 45 years ) who gave informed consent and who planned to remain in the area for at least 3 months were recruited . Participants were r and omly assigned by cluster of residence to receive a vitamin A supplement ( 25 000 IU retinol equivalents ) or placebo capsule orally once every week . R and omisation was blocked and based on an independent , computer-generated list of numbers , with two clusters in each fieldwork area allocated to vitamin A supplementation and two to placebo . Capsules were distributed during home visits undertaken every 4 weeks , when data were gathered on pregnancies , births , and deaths . Primary outcomes were pregnancy-related mortality and all-cause female mortality . Cause of death was established by verbal post mortems . Analysis was by intention to treat ( ITT ) with r and om-effects regression to account for the cluster-r and omised design . Adverse events were synonymous with the trial outcomes . This trial is registered with Clinical Trials.gov , number NCT00211341 . FINDINGS 544 clusters ( 104 484 women ) were r and omly assigned to vitamin A supplementation and 542 clusters ( 103 297 women ) were assigned to placebo . The main reason for participant drop out was migration out of the study area . In the ITT analysis , there were 39 601 pregnancies and 138 pregnancy-related deaths in the vitamin A supplementation group ( 348 deaths per 100 000 pregnancies ) compared with 39 234 pregnancies and 148 pregnancy-related deaths in the placebo group ( 377 per 100 000 pregnancies ) ; adjusted odds ratio 0.92 , 95 % CI 0.73 - 1.17 ; p=0.51 . 1326 women died in 292 560 woman-years in the vitamin A supplementation group ( 453 deaths per 100 000 years ) compared with 1298 deaths in 289 310 woman-years in the placebo group ( 449 per 100 000 years ) ; adjusted rate ratio 1.01 , 0.93 - 1.09 ; p=0.85 . INTERPRETATION The body of evidence , although limited , does not support inclusion of vitamin A supplementation for women in either safe motherhood or child survival strategies . FUNDING UK Department for International Development , and USAID BACKGROUND Prophylactic vitamin A supplementation ( VAS ) reduces mortality and may reduce morbidity associated with diarrhea in children > 6 months of age . Rotavirus is the most common cause of acute dehydrating diarrhea among children worldwide . METHODS In a r and omized placebo-controlled study of 50,000 IU of vitamin A versus placebo given with bacille Calmette-Guérin vaccine at birth , 287 infants were followed up with weekly interviews and stool sample obtainment to test the hypothesis that VAS reduced the risk of rotavirus infection . RESULTS VAS was associated with increased risk of rotavirus infection and diarrhea ( incidence rate ratio [ IRR ] of infection , 1.72 [ 95 % confidence interval ( CI ) , 1.04 - 2.85 ] ; IRR of diarrhea , 3.74 [ 95 % CI , 1.40 - 9.98 ] ) among children < 6 months of age . There was no effect in older children . VAS had a beneficial effect on nonrotavirus diarrhea in boys < 6 months of age ( IRR , 0.51 ; 95 % CI , 0.27 - 0.95 ) and a detrimental effect in girls > 6 months of age ( IRR , 1.84 ; 95 % CI , 0.96 - 3.55 ) . CONCLUSION VAS at birth did not reduce rotavirus morbidity . The effect of VAS on nonrotavirus diarrhea may differ by sex , being more beneficial in boys . Clinical trials registration . NCT00168597 In recent years , neonatal vitamin A supplementation is considered as an essential infant-survival intervention but the evidence is not conclusive . This r and omized controlled clinical trial was conducted to evaluate the effect of vitamin A on immune competence in early infancy . Results would provide a mechanistic basis for underst and ing the effect of this intervention on infant survival . Within 2 days of birth , infants born at one maternity clinic located in a poor slum area of Dhaka city were supplemented with either 50,000 IU vitamin A or placebo . Live attenuated oral polio vaccine ( OPV ) and BCG vaccine were provided after supplementation . Infants also receive diphtheria , pertussis , tetanus ( TT ) , hepatitis B ( HBV ) and Haemophilus influenzae B vaccines ( pentavalent combination ) along with OPV at 6 , 10 and 14 weeks of age . Infant thymus size , anthropometry , feeding practice and morbidity data were collected at regular interval . Infant blood sample s were collected to determine T-cell-receptor excision circle ( TREC ) , total , naïve and memory T cells and mucosal targeting lymphocytes including Treg cells . TT- , HBV- , BCG- and OPV-specific T cell blastogenic , cytokine and plasma cell antibody responses were also measured . In 16 mo enrollment period , 306 newborns , equal number of boys and girls , were enrolled . ~95 % completed the 4-month follow-up period . Baseline characteristics are presented here . Anthropometry and immune assays with fresh blood sample s were completed immediately while stored sample s were analyzed in single batches at the end of the trial . Connecting different aspects of immunological data in early infancy will help eluci date immune competence for protecting infection . Trial registration Clinical Trials.gov : NCT01583972
BACKGROUND Vitamin A deficiency is a major public health problem in low and middle income countries .
Vitamin A supplementation in children six months of age and older has been found to be beneficial , but no effect of supplementation has been noted for children between one and five months of age .
Supplementation during the neonatal period has been suggested to have an impact by increasing body stores in early infancy .
OBJECTIVES To evaluate the role of vitamin A supplementation for term neonates in low and middle income countries with respect to prevention of mortality and morbidity .
AUTHORS ' CONCLUSIONS Given the high burden of death among children younger than five years of age in low and middle income countries , and the fact that mortality in infancy is a major contributory cause , it is critical to obtain sound scientific evidence of the effect of vitamin A supplementation during the neonatal period on infant mortality and morbidity .