Published online July 1, 2008
PEDIATRICS Vol. 122 No. 1 July 2008, pp. e242-e250 (doi:10.1542/peds.2007-3448)
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ARTICLE

Newborn Vitamin A Supplementation Reduced Infant Mortality in Rural Bangladesh

Rolf D.W. Klemm, MPH, DrPHa, Alain B. Labrique, MSc, MHS, PhDa, Parul Christian, MPH, DrPHa, Mahbubur Rashid, MBBS, MSc, MBAb, Abu Ahmed Shamim, MScb, Joanne Katz, MS, ScDa, Alfred Sommer, MD, MHSa and Keith P. West, Jr, DrPH, MPH, RDa

a Center for Human Nutrition, Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
b JiVitA Maternal and Infant Health and Nutrition Research Project, Rangpur, Bangladesh


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
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-randomized, 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 randomized 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.

Key Words: vitamin A • infant mortality • neonatal mortality • community trial • Bangladesh • supplementation

Abbreviations: IQR—interquartile range • DSMB—data safety and monitoring board • RR—relative risk • CI—confidence interval • GEE—generalized estimating equation • NEC—necrotizing enterocolitis

Reducing infant mortality remains a major public health challenge in developing countries. In recent years, attention has turned to reaching newborns with safe, efficacious interventions to improve survival.1,2 Long known to reduce child mortality over 6 months of age,3 new observations have emerged in recent years that vitamin A, if given as an oral supplement shortly after birth, can reduce infant mortality. Two randomized, placebo-controlled trials in South Asia have, to date, reported significant reductions in infant mortality after receipt of a large, oral dose of vitamin A (~50000 IU) within several hours to several days after birth. In Indonesia, Humphrey et al4 reported a 64% reduction in mortality in a trial among 2067 hospital-born infants, and in south India, Rahmathullah et al5 observed a 22% reduction in mortality through 6 months of age in a community-based trial among 11619 infants. Both studies found newborn supplementation with vitamin A to be safe with respect to short-term adverse effects6 and, in Indonesia, with respect to effects on early childhood development and growth through the first 3 years of life.7 However, the findings are in contrast to an apparent lack of survival benefit in undernourished populations when single, large doses of vitamin A are given postnatally through the fifth month of age.8,9 Reasons for a differential effect of vitamin A by age at dosing remain unclear. Studies in other species suggest that maternal-fetal vitamin A deficiency can lead to postnatal maturational delays and functional deficits in lung and airways,10–13 gastrointestinal tract,14–16 kidney,10,17,18 heart cardiovasculature,11,19 and the immune system.20,21 In (vitamin A-deficient) preterm infants, a group believed to be nearly universally deficient in vitamin A, neonatal vitamin A receipt has been shown to lower risks of bronchopulmonary dysplasia22 and apparent oxidative stress.23 In India, community-based newborn vitamin A supplementation reduced risks of nasopharyngeal streptococcal colonization24 and fatality related to diarrhea and febrile illness through 6 months of age.25 The potential effect of newborn vitamin A receipt merits public health attention, particularly in South Asia, where infant mortality remains high26,27 and infantile vitamin A deficiency is widespread28–31 and persistent29,32 during the first several months of life. To further address this issue, we conducted a field trial in northwest Bangladesh to assess the efficacy of supplementing newborns orally with a 50000 IU dose of vitamin A in reducing infant mortality through 6 months of life.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Design and Population
The study, called JiVitA-2, was the second large trial conducted by a rural nutrition and health research project, called JiVitA. The project operates in a contiguous, rural area of ~435 sq km with a population of ~650000, composed of 19 unions of the northwest districts of Gaibandha and Rangpur, Bangladesh. Based on health survey data, the area is typical of lower socioeconomic rural communities in the country with respect to levels of infrastructure, maternal and child nutrition, socioeconomic and health status, and patterns of health care use.33,34 The area was, however, previously identified as one with a high prevalence of maternal night blindness,33 a condition that can arise during pregnancy as a result of vitamin A deficiency.35 The study, begun in January 2004, was a double-masked, cluster-randomized, placebo-controlled trial that assessed the efficacy of newborn, oral vitamin A receipt (50000 IU) in reducing all-cause infant mortality during the first 6 months of life. The trial was nested into an ongoing, placebo-controlled, weekly, low-dose vitamin A or β-carotene supplementation trial among pregnant women, underway since August 2001, to evaluate effects on pregnancy-related mortality.36

Randomization and Eligibility
Community maps of the area were developed, homes were issued numeric addresses, and married women of reproductive age were enumerated and issued unique study identification numbers. The study area was divided into 596 smaller community groups of comparable size, each with a median number of households of 228 (interquartile range [IQR]: 200–263), called "sectors," which served as units of randomization. Sectors were listed in geographically contiguous order and were randomized in blocks of 4 within each of 3 previously randomized maternal supplementation trial treatment arms (ie, vitamin A, β-carotene, and placebo, each ~200 sectors) for newborns to receive 50000 IU of vitamin A or placebo in oil as soon as possible after birth. This process produced 2 infant supplement groups, each with 298 sectors, that were balanced across the maternal supplementation trial treatment arms. Infants born to consenting mothers who were participating in the parent trial were eligible for inclusion in the study. We excluded from analysis infants of consenting mothers who had died before they could be supplemented by staff, those who were born outside of the study area, and infants who could not be reached to receive a supplement after repeated staff visits during the first 30 days after birth.

Pregnancy Recruitment and Maternal Assessments
Pregnant women were identified and recruited into the parent trial via a 5-weekly, home-visit surveillance system that was based on a history of the last menstrual period combined with pregnancy urine testing.36 On enrollment into the parent trial, women were interviewed at ~9 weeks' gestation about household sociodemographic characteristics and recent morbidity history, including night blindness, dietary intake, and other risk factors, and were measured for midupper arm circumference as an indicator of wasting malnutrition. At ~28 weeks of age, women were asked for permission to visit and dose their newborns with a study supplement that was either vitamin A or a placebo. As a service, all of the women approached for consent were offered a health advice card on recommended newborn care. At ~32 weeks' gestation, mothers were again interviewed about recent morbidity history, dietary intake, and other risk factors and were measured for midupper arm circumference. A similar maternal assessment was repeated at ~3 months postpartum.

In a substudy area consisting of 32 contiguous study clusters (~3% of the study population), consenting mothers (at first and third trimesters and at 3 months postpartum) and their infants (at 3 months of age) were assessed clinically and biochemically after phlebotomy and heel stick (collecting blood on Millipore cards), respectively, to document differences in health and vitamin A status (retinol concentrations in plasma and on dried blood spots, respectively). Biochemical analysis of maternal plasma for vitamin A was performed at the nutrition laboratory of the Institute of Nutrition, Mahidol University (Bangkok, Thailand).

Intervention and Infant Assessments
Live-born infants of consented mothers were visited by field staff as soon as possible after birth (median: 7 hours of age [IQR: 2–18 hours]) and administered a sector-coded supplement containing either 50000 IU of vitamin A or placebo. The supplements for both groups were opaque gelatinous capsules identical in shape, size, and color containing edible oil. After cutting the nipple portion of the capsule with a clean pair of scissors, the contents were squeezed into the newborn's mouth. Before field use, supplements were stored in a temperature-controlled warehouse to help maintain potency. Supplements stored under field and warehouse conditions were sampled and analyzed for potency approximately every 3 months, the results of which indicated ~97% potency (mean ± SD: 49088 ± 638 IU of vitamin A).

After supplementation, 1 of a trained team of 56 female anthropometrists conducted a home visit to measure the infant for weight, length, and midupper arm, head, and chest circumferences at a median age of 18 hours (IQR: 9–36 hours). Birth weight was measured to the nearest 10 g using a Tanita BD-585 digital pediatric scale (Tanita Corporation, Tokyo, Japan). Length was measured to the nearest 0.1 cm using an affixed headboard and movable footplate that had been fashioned for use with the Tanita scale. Circumferential measurements were made with a Ross insertion tape (Abbott Laboratories, Columbus, OH). At the home visit, anthropometrists also asked mothers if they had noticed any rise in the soft spot on the top of an infant's head since birth and if the swelling was still present at the time of the visit. Maternal report of a bulge present at the time of the visit prompted notification of a study physician by cell phone and a follow-up clinical examination at the home, usually within 24 hours of the anthropometrist's report (median: 1 day [IQR: 0–1 days]).

Infant vital status was assessed weekly at home for the first 12 weeks of life by field staff and then again at 24 weeks of age. At 12 and 24 weeks of age, risk factor interviews were conducted related to infant breast and complementary feeding and morbidity in the previous 12 weeks as reported by parents.

Ethical approval for the study was provided by the Bangladesh Medical Research Council, an autonomous body, under the Ministry of Health and Family Welfare, government of Bangladesh, and the institutional review board at the Johns Hopkins Bloomberg School of Public Health. An independent data safety and monitoring board (DSMB) was formed and met 4 times (before the outset of the trial and at 13, 21, and 34 months after start-up) to review trial procedures and data related to primary outcomes and safety.

Sample Size
We planned to enroll a total of ~20000 infants to detect a minimum reduction of 15% in 6-month infant mortality with 80% power given an expected 6-month mortality rate in the study area of ~64 deaths per 1000 live births, after adjusting for a 1% design effect because of cluster randomization (based on previous data collected in the study area). Unknown was the number of deaths that would occur before infants would be visited by field staff to be supplemented for the study. In early December 2006, the DSMB recommended halting the study for reasons of efficacy of the intervention in reducing infant mortality. The DSMB made this decision after reviewing outcome data for 14823 infants (n taking vitamin A = 7394; n taking placebo = 7429) followed through 24 weeks of life that showed 286 and 343 deaths in the vitamin A and placebo groups, respectively, representing a relative risk (RR) of 0.84 (95% confidence interval [CI]: 0.70–0.99; P = .03). Procedures were subsequently initiated to close out the trial. In consultation with the DSMB, the formal analytic database was defined to include infants whose 24-week vital status was known as of December 31, 2006, yielding a total of 15937 infants in the study. The placebo supplement was withdrawn, and the study intervention was ceased in January 2007. Subsequently, infants born to mothers who had consented during pregnancy were given vitamin A at birth.

Statistical Analysis
Characteristics of the pregnant women and their newborn infants were compared across treatment groups with respect to community, household, and individual risk factors. The primary outcome was mortality within the first 24 weeks of life among infants who had been visited at home and offered a supplement. All of the analyses were done on an intention-to-treat basis; that is, infants randomly assigned to each group and visited were included in the survival analysis, irrespective of dosage receipt. Multiple births (n = 106) were included in the analysis. RRs with 95% CIs for comparing 24-week mortality rates of the treatment versus control groups were calculated by using a generalized estimating equation (GEE) logistic regression model with log link and exchangeable correlation37 to adjust for the design effect. The design effect from the observed data was 0.9%. In addition, stratified analyses by infant and maternal factors and treatment arms of the maternal supplementation trial (vitamin A, β-carotene, or placebo) and other variables were performed to explore particular subgroups of infants who may have been differentially affected by vitamin A receipt. Using GEE logistic regression analyses, interaction terms for RR estimation were tested at the 5% significance level.

Kaplan-Meier survival analysis was used to compare differences in the survival probabilities of live-born infants followed through 24 weeks of life according to treatment group, using the log rank test to assess statistical significance. All of the analyses were performed by using Stata 9.1 (Stata Corp, College Station, TX).


   RESULTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Over the 2.5-year period of recruitment and follow-up, 17155 infants were born to mothers who had been approached for consent at ~28 weeks' gestation, 8545 in the vitamin A and 8610 in the placebo control groups. Among these, mothers for 39 refused consent to have their newborns supplemented, 888 (5.20%) survived but could not be visited and given a study supplement before 30 days of age, 280 (1.60%) died before the home visit at which they were to be dosed, and 11 (0.01%) were lost to follow-up, leaving 15937 infants in the trial cohort followed to 24 weeks of age (n taking vitamin A = 7953; n taking placebo = 7984). Included in the cohort were 35 infants whose initially consenting parents refused to let their infants be dosed once born (Fig 1). Losses and reasons for losses of infants were balanced across the 2 treatment groups.


Figure 1
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  		FIGURE 1 a Trial profile infants who were born by July 20, 2006, and followed for 24 weeks through December 31, 2006. b Of the 298 sectors allocated to each newborn supplementation treatment arm, 100, 99, and 99 were placebo, β-carotene, and vitamin A sectors, respectively, from the parent maternal supplementation trial. c Data include 57 and 49 sets of twins for the vitamin A and placebo groups, respectively; d data include 23 and 12 infants whose parents refused the supplement at the postnatal dosing visit for the vitamin A and placebo groups, respectively.

 
Baseline characteristics of mothers and households of study infants were comparable by treatment group (Table 1). In both groups, 41% of mothers were <20 years of age at the time of their pregnancy, 42% had no formal education, 30% had a left midupper arm circumference <22 cm (reflecting wasting malnutrition),38 and ~10% reported having had night blindness during their most recent previous pregnancy that had ended in a live birth. In the substudy area, first trimester serum retinol concentrations (mean ± SD) of mothers of enrolled infants in the vitamin A and control groups were 1.13 ± 0.27 and 1.17 ± 0.34 µmol/L, respectively, with ~41% and 36% in each respective group having concentrations <1.05 µmol/L, a conventional cutoff for suboptimal vitamin A status.39 Approximately 38%, 42%, and 46% of mothers in both groups lived in households that owned a bicycle, ≥1 head of cattle, and cultivatable land, respectively. Fifty-eight percent of mothers in both groups had ≥1 previous pregnancy, of whom in both groups ~25% reported having had ≥1 end as a fetal loss and ~25% having had ≥1 infant die (data not shown).


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  		TABLE 1 Maternal and Household Characteristics of Recruited Infants According to Treatment Group

 
Characteristics related to delivery were comparable in the 2 treatment groups. More than 90% of births took place at home, whereas <7% were attended by a trained health professional (physician or nurse; Table 2). Slightly more infants were boys than girls. Approximately 23% of the infants were born preterm (ie, gestational age <37 weeks), based on prospectively obtained histories of the mother's last menstrual period. The mean (SD) birth weight was 2432 g (429 g) in the vitamin A group and 2428 g (429 g) in the placebo group; ~54% of infants weighed <2500 g, and ~14% weighed <2000 g in both groups. Mean (SD) newborn length and head, chest, and midupper arm circumferences were 46.4 (2.5) cm, 32.4 (1.7) cm, 30.4 (2.2) cm, and 9.3 (0.9) cm, none of which differed by treatment group (data not shown). Breastfeeding was initiated within 12 hours of birth in nearly half of all of the infants, and 95% of mothers who had initiated breastfeeding reported feeding colostrum. Seventy-nine percent of newborns in both groups received a study supplement within the first 24 hours of life, whereas 11% were dosed between 1 and 7 days of age. The remaining 10% of infants in each group were dosed between 8 and 29 days of age, inclusive.


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  		TABLE 2 Delivery Characteristics, Newborn Care Practices, and Age at Supplement Receipt Among Infants According to Treatment Group

 
A bulging fontanelle was infrequently reported by mothers when questioned by trained field anthropometrists who visited infants at a median time of <12 hours after dosing. In the vitamin A and control groups, 154 (1.9%) and 178 (2.2%), respectively, who reported bulging fontanel were obtained from mothers by field staff, of which 11 and 21 cases, respectively, were clinically confirmed ~1 day later on examination by a study physician. There were no parental reports or clinician findings of other adverse effects. Approximately 77% of infants had received an immunization including coverage with ≥1 dose of Bacille Calmette-Guerin vaccine (~72%); diphtheria, pertussis, and tetanus vaccine (~65%); or polio vaccine (~73%; data not shown).

A total of 666 infants died by 24 weeks of age within the trial cohort, yielding mortality rates of 38.5 and 45.1 deaths per 1000 live births in the vitamin A–supplemented (306 of 7953) and placebo-supplemented (360 of 7984) groups, respectively. The resultant RR for mortality in the vitamin A-assigned group was 0.85 (95% CI: 0.73–1.00; P = .045; Table 3). The survival probabilities of infants in the 2 groups were significantly different (P = .037), with the curves diverging after the first week of life (Fig 2). By 16 weeks of age, the 2 curves seem to be parallel, indicating little additional treatment effect beyond that age.


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  		TABLE 3 Rates and RRs of Infant Mortality by 24 Weeks of Age According to Treatment Group and Selected Infant and Maternal Factors

 

Figure 2
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  		FIGURE 2 Kaplan-Meier curves depicting the survival of infants through 24 weeks of age according to treatment group. N = 15937; log-rank test: 4.36; P = .037.

 
Vitamin A receipt seemed protective against neonatal (0–28 days; RR: 0.89) and postneonatal (29–168 days; RR: 0.77) mortality through 24 weeks of age, although neither was statistically distinguishable from the other, and the 95% CIs for RR estimates in both strata were >1.00 (Table 3). Protective RRs related to vitamin A receipt were observed among infants of both genders and in preterm and term born infants, although upper 95% confidence limits were ≤1.00 only for girls and term infants, whose gestational ages were 37 to 44 weeks at birth (Table 3). Protective RR estimates for vitamin A receipt were observed in low (<2500 g) and normal birth weight infants and for each postnatal dosing time interval (Table 3). Tests for interactions by logistic regression analysis across levels of each of the above infant factors yielded nonsignificant results (.96 > P > .13). Protective RRs were also observed for vitamin A–supplemented infants born to mothers of varying age, parity, and randomized parent trial supplement allocation, with RR estimates ranging from 0.76 to 0.92 and P values for interaction ranging from .35 to .74.


   DISCUSSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Infants are born with low body vitamin A stores,40 especially if preterm.41,42 In well-nourished populations of infants with low burdens of infection, serum retinol seems to steadily improve toward adult concentrations in the first several months of life,43,44 whereas in undernourished settings, low-to-deficient vitamin A status at birth is likely to persist or worsen because of combined effects of low breast milk vitamin A content,29,45 complementary foods of low vitamin A density,46 and frequent infection47 throughout infancy.44 In this rural Bangladesh setting, supplementing newborns with 50000 IU of vitamin A within days of being born significantly reduced mortality under 6 months of age by 15% relative to placebo-supplemented infants. Our findings are consistent with those from 2 previous trials in South Asia, specifically Indonesia4 and south India,5 where infant mortality was reduced by 64% and 23%, respectively, after receipt of a similar dosage of vitamin A shortly after birth. As observed in both earlier trials, in Bangladesh, infant survival in the vitamin A–supplemented group began to improve beyond the first week of life, with the survival curves of the 2 groups diverging until week 16 of life, after which little effect was observed. The estimated percentages of reduction in mortality risk in the first month and next 5 months of life were 11% and 23%, respectively, although CIs for these age-stratified estimates included unity. Across the 3 South Asian sites, the data were consistent in revealing a period of efficacy of ~4 months in reducing mortality.

We were unable to identify particular risk factor strata in which the effect of vitamin A on infant survival varied significantly. There was stronger evidence of protection, compared with the null, among girls, term infants, and infants born to mothers of parity 1 or higher, but risk ratios in these strata were not significantly different from protective effect estimates in boys, preterm infants, and newborns of multiparous women. Unlike the studies in India, which observed improved survival among infants of low birth weight,5 and Indonesia,4 where the effect concentrated in infants of normal birth weight, the effect of vitamin A on survival was indistinguishable across our observed range of birth weight. Variation in efficacy across subgroups from trial to trial may reflect actual population differences in responsiveness to vitamin A or could be because of chance.

Analysis of the effect of newborn vitamin A dosing on cause-specific mortality as determined by verbal autopsy will be reported separately. However, studies elsewhere in Bangladesh reveal that acute lower respiratory infections and diarrhea are major causes of postneonatal death.48 In Indonesia, clinic visits for cough and fever, suggestive of pneumonia, were reduced in vitamin A–supplemented infants.4 In India, neonatal vitamin A reduced case fatality related to febrile disease by 40%, although the effect was weaker when fever was combined with symptoms of respiratory infections.25 However, a study that was nested into the same trial population observed a significant ~2-month delay in the risk of nasopharyngeal colonization with Streptococcus pneumoniae,24 a leading cause of infantile respiratory infection49 and meningitis50 and a common neonatal respiratory pathogen in Bangladesh.51 These findings are consistent with known protective roles of vitamin A against infection by maintaining epithelial integrity (the "barrier function")52 and immune competence53 but are also consistent with essential roles of vitamin A in regulating lung development and function and, thus, susceptibility to damage from the embryonic period through neonatal life in a number of mammalian species.11,13,54–56 Neonatal vitamin A receipt may also reduce severity and risk of mortality from gastrointestinal disease. In Indian and Gambian52 infants supplemented with vitamin A, intestinal integrity improved, reflected by a lowered lactulose:mannitol intestinal permeability test, suggesting that neonatal repletion with vitamin A may protect the gut mucosa and increase resistance to infectious diarrhea. In Indonesia and south India, infant fatality because of diarrhea was reduced 50% to 60% compared with control subjects,4 significantly so in the Indian study.25 It is also plausible that necrotizing enterocolitis (NEC), a highly fatal disease characterized by intestinal inflammation and dysfunction, bacterial overgrowth of the bowel, and sepsis,57 may respond to vitamin A repletion. In the neonatal rabbit, a large dose of vitamin A has been shown to stimulate precocious maturation of parietal cells in the stomach16 and, in weanling rats, to influence differentiation and maturation of stomach and small intestinal epithelial cells,14 revealing a critical role for the vitamin in normalizing epithelialization of the bowel very early in life. Mimicked lesions of NEC in young rats, achieved by exposing the intestine to butyric acid, were ameliorated in pups treated with vitamin A compared with control subjects treated with saline.15

Early neonatal administration to high-risk infants may reduce oxidative stress-related pathways of disease. In humans, breath ethane levels declined in premature neonates given vitamin A relative to placebo controls, reflecting decreased lipid peroxidative stress associated with NEC23 and other diseases that involve excessive oxygen radical formation.58 Maternal vitamin A deficiency can also broadly affect perinatal size and structure or function of the kidney, liver, heart, and cardiovasculature,11 which could be relevant to mechanisms involved with improved survival after neonatal vitamin A supplementation.

Shifts in distributions in maternal nutritional status, gestational maturity, and infant size at birth; access to antenatal and obstetric care; and dominant infant disease patterns and mortality risks can be expected to affect the prophylactic efficacy of newborn nutritional interventions, including high-potency vitamin A for neonates. Such population differences may prove to be important as we increasingly evaluate variation in the efficacy of newborn vitamin A, for example, in Harare, Zimbabwe, where vitamin A supplementation shortly after birth did not favorably influence infant survival.59 Presently, there are insufficient data on the health and survival effects of newborn vitamin A supplementation in Africa.60

Age at dosing, serving as a proxy for organ system maturation, nutritional, disease, and other environmental exposures, seems to modify the survival advantage associated with vitamin A receipt in early infancy. For example, there has been little to no effect on mortality risk observed when infants participating in placebo-controlled trials in Nepal,8 India, Ghana, and Peru9 have been given supplements with high-potency vitamin A between 1 and 5 months of age. Thereafter, the efficacy of periodic vitamin A supplementation in reducing mortality in late infancy and early childhood is well established.3,61,62

Newborn vitamin A supplementation seems to be safe with respect to short- and long-term adverse effects. A bulge in the anterior fontanel, usually ascribed to benign cranial volume expansion, is an adverse effect often associated with high-potency vitamin A receipt.63 Excess rates of bulging fontanel of <1% to ~7% have been reported among infants <6 months of age dosed with vitamin A versus a placebo.44 When observed, a bulging fontanel after vitamin A supplementation has been clinically mild and self-limiting, typically disappearing on its own within 48 hours and almost entirely within 72 hours, without treatment or sequelae.63 The most comprehensive study of adverse effects associated with newborn vitamin A receipt to date found an excess rate of a self-limiting bulging fontanel of ~2% over subjects receiving placebo control (~4.5% vs 2.5%), in the absence of Doppler ultrasound-based evidence of intracranial hemorrhage.6 Follow-up of the trial cohort at 3 years of age revealed no evidence of adverse effects associated with having had a perinatal bulging fontanel in terms of cognitive, motor, and behavioral test outcomes.7 In the present study, which was not designed to definitively assess adverse effects, physician-confirmed parental reporting of a bulging fontanel at ~48 to 72 hours postdosing was <0.4% in both vitamin A and placebo control groups.


   CONCLUSIONS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The findings from this trial and others conducted in South Asia suggest that providing newborns with an oral supplement of 50000 IU of vitamin A within several days after birth can reduce mortality by ~15% or more. Adequate, timely, and effective newborn vitamin A dosing programs require innovative community approaches in South Asia, where typically >90% of infants are born at home.


   ACKNOWLEDGMENTS
 
This trial was conducted by the Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, under Global Research Activity cooperative agreement GHS-A-00-03-00019-00 between Johns Hopkins University and the Office of Health and Nutrition; the US Agency for International Development (Washington, DC); and Bill and Melinda Gates Foundation (Seattle, WA) grant 614 (Global Control of Micronutrient Deficiency). Additional direct or in-kind support was provided by Sight and Life (Basel, Switzerland), the Sight and Life Research Institute (Baltimore, MD), Nutrilite Health Institute (Nutrilite Division, Access Business Group, LLC, Buena Park, CA), the Canadian International Development Agency, and the National Integrated Population and Health Program of the Ministry of Health and Family Welfare of the government of the People's Republic of Bangladesh.

We especially thank members of the international DSMB: Drs Nancy Sloan, Anthony L. de Costello, James Tonascia, Mamunar Rashid, and Sameena Chowdhury. Additional appreciation goes to the JiVitA Project National Adviser, Dr Halida Akhter; senior JiVitA Project staff including Drs Barkat Ullah, Hasmot Ali, Shafiul Alam, Shahab Uddin, Rashedujjaman, and Sayeda Khatun Sharifa; Ummeh Taslima Arju; the JiVitA Field Management Team; and members of the Center for Human Nutrition Data Management team Allan Massie, Lee Shu-Fune Wu, Maithilee Mitra, and Andre Hackman.


   FOOTNOTES
 
Accepted Feb 8, 2008.

Address correspondence to Rolf D.W. Klemm, MPH, DrPH, Johns Hopkins University, Center for Human Nutrition, Department of International Health, Bloomberg School of Public Health, 615 North Wolfe St, Baltimore, MD 21205. E-mail: rklemm{at}jhsph.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

Drs Klemm, Christian, and West made primary contributions to the design, conduct, analysis, interpretation, and writing of this article; as corresponding author, Dr Klemm had full access to all of the data in the study and had final responsibility for the decision to submit for publication; Dr Labrique, Mr Rashid, and Mr Shamim made primary contributions to the implementation plan, conduct, field supervision, and quality control of the trial; Dr Katz contributed to the design of the trial and assisted with the data analysis and interpretation of the study results; and Dr Sommer contributed to the development and design of the trial and to the interpretation of the study results. All of the authors have reviewed and approved the article.

This trial has been registered at www.clinicaltrials.gov (identifier NCT00128557).


What's Known on This Subject

Previous evidence from South Asia has shown that providing vitamin A to infants at or near birth in deficient populations can reduce infant mortality.

 

What This Study Adds

The findings from this trial suggest that providing newborns with an oral supplement of 50 000 IU of vitamin A within several days after birth can reduce mortality by ~15% or more, which confirms previous findings from trials in South Asia.

 


   REFERENCES
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Martines J, Paul VK, Bhutta ZA, et al. Neonatal survival: a call for action. Lancet.2005; 365 (9465):1189 –1197[CrossRef][ISI][Medline]
  2. Darmstadt GL, Bhutta ZA, Cousens S, et al. Evidence-based, cost-effective interventions: How many newborn babies can we save? Lancet.2005; 365 (9463):977 –988[CrossRef][ISI][Medline]
  3. Sommer A, West KP. Vitamin A Deficiency: Health, Survival, and Vision. New York, NY: Oxford University Press;1996
  4. Humphrey JH, Agoestina T, Wu L, et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr.1996; 128 (4):489 –496[CrossRef][ISI][Medline]
  5. Rahmathullah L, Tielsch JM, Thulasiraj RD, et al. Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in Southern India. BMJ.2003; 327 (7409):254 –259[Abstract/Free Full Text]
  6. Agoestina T, Humphrey JH, Taylor GA, et al. Safety of one 52-mumol (50,000 IU) oral dose of vitamin A administered to neonates. Bull World Health Organ.1994; 72 (6):859 –868[ISI][Medline]
  7. Humphrey JH, Agoestina T, Juliana A, et al. Neonatal vitamin A supplementation: effect on development and growth at 3 y of age. Am J Clin Nutr.1998; 68 (1):109 –117[Abstract]
  8. West KP Jr, Katz J, Shrestha SR, et al. Mortality of infants < 6 mo of age supplemented with vitamin A: a randomized, double-masked trial in Nepal. Am J Clin Nutr.1995; 62 (1):143 –148[Abstract/Free Full Text]
  9. World Health Organization/Child Health and Development Division Immunisation-Linked Vitamin A Supplementation Study Group. Randomised trial to assess benefits and safety of vitamin A supplementation linked to immunisation in early infancy [published correction appears in Lancet. 1999;353(9147):154]. Lancet.1998; 352 (9136):1257 –1263[CrossRef][ISI][Medline]
  10. Antipatis C, Grant G, Ashworth CJ. Moderate maternal vitamin A deficiency affects perinatal organ growth and development in rats. Br J Nutr.2000; 84 (1):125 –132[ISI][Medline]
  11. Antipatis C, Ashworth CJ, Grant G, Lea RG, Hay SM, Rees WD. Effects of maternal vitamin A status on fetal heart and lung: changes in expression of key developmental genes. Am J Physiol.1998; 275 (6 pt 1):1184 –1191
  12. Biesalski HK. The significance of vitamin A for the development and function of the lung. Forum Nutr.2003; 56 :37 –40[Medline]
  13. Frey G, Egli E, Chailley-Heu B, et al. Effects of mild vitamin a deficiency on lung maturation in newborn rats: a morphometric and morphologic study. Biol Neonate.2004; 86 (4):259 –268[CrossRef][ISI][Medline]
  14. Bhat PV. Retinal dehydrogenase gene expression in stomach and small intestine of rats during postnatal development and in vitamin A deficiency. FEBS Lett.1998; 426 (2):260 –262[CrossRef][ISI][Medline]
  15. Nafday SM, Green RS, Chauvin SN, Holzman IR, Magid MS, Lin J. Vitamin A supplementation ameliorates butyric acid-induced intestinal mucosal injury in newborn rats. J Perinat Med.2002; 30 (2):121 –127[CrossRef][ISI][Medline]
  16. Karam SM, Ansari HR, Al-Dhaheri WS, Alexander G. Retinol enhances differentiation of the gastric parietal cell lineage in developing rabbits. Cell Physiol Biochem.2004; 14 (4–6):333 –342[CrossRef][ISI][Medline]
  17. McGowan SE, Takle EJ, Holmes AJ. Vitamin A deficiency alters the pulmonary parenchymal elastic modulus and elastic fiber concentration in rats. Respir Res.2005; 6 :77[CrossRef][Medline]
  18. Marín MP, Esteban-Pretel G, Alonso R, et al. Vitamin A deficiency alters the structure and collagen IV composition of rat renal basement membranes. J Nutr.2005; 135 (4):695 –701[Abstract/Free Full Text]
  19. Zile MH. Function of vitamin A in vertebrate embryonic development. J Nutr.2001; 131 (3):705 –708[Abstract/Free Full Text]
  20. Sankaranarayanan S, Ma Y, Bryson MC, Li NQ, Ross AC. Neonatal-age treatment with vitamin A delays postweaning vitamin A deficiency and increases the antibody response to T-cell dependent antigens in young adult rats fed a vitamin A-deficient diet. J Nutr.2007; 137 (5):1229 –1235[Abstract/Free Full Text]
  21. Stephensen CB. Vitamin A, infection, and immune function. Annu Rev Nutr.2001; 21 :167 –192[CrossRef][ISI][Medline]
  22. Shenai JP. Vitamin A supplementation in very low birth weight neonates: rationale and evidence. Pediatrics.1999; 104 (6):1369 –1374[Free Full Text]
  23. Schwarz KB, Cox JM, Sharma S, et al. Possible antioxidant effect of vitamin A supplementation in premature infants. J Pediatr Gastroenterol Nutr.1997; 25 (4):408 –414[CrossRef][ISI][Medline]
  24. Coles CL, Rahmathullah L, Kanungo R, et al. Vitamin A supplementation at birth delays pneumococcal colonization in South Indian infants. J Nutr.2001; 131 (2):255 –261[Abstract/Free Full Text]
  25. Tielsch JM, Rahmathullah L, Thulasiraj RD, et al. Newborn vitamin A dosing reduces the case fatality but not incidence of common childhood morbidities in South India. J Nutr.2007; 137 (11):2470 –2474[Abstract/Free Full Text]
  26. Bhutta ZA, Gupta I, de'Silva H, et al. Maternal and child health: is south Asia ready for change? BMJ.2004; 328 (7443):816 –819[Free Full Text]
  27. United Nations Population Fund, United Nations Economic Social Commission for Asia and the Pacific. Emerging Issues of Health and Mortality in the Asian and Pacific Region. New York, NY: United Nations Publications;2005
  28. Katz J, West KP Jr, Khatry SK, et al. Risk factors for early infant mortality in Sarlahi district, Nepal. Bull World Health Organ.2003; 81 (10):717 –725[ISI][Medline]
  29. Rice AL, Stoltzfus RJ, de Francisco A, Chakraborty J, Kjolhede CL, Wahed MA. Maternal vitamin A or beta-carotene supplementation in lactating Bangladeshi women benefits mothers and infants but does not prevent subclinical deficiency. J Nutr.1999; 129 (2):356 –365[Abstract/Free Full Text]
  30. Rahmathullah L, Raj MS, Chandravathi TS. Aetiology of severe vitamin A deficiency in children. Natl Med J India.1997; 10 (2):62 –65[Medline]
  31. Gupta M, Jora R, Bhatia R, Pareek A. Keratomalacia in a neonate secondary to maternal vitamin A deficiency. Indian J Pediatr.2005; 72 (10):881 –882[CrossRef][Medline]
  32. Wahed MA, Alvarez JO, Rahman MM, Hussain M, Jahan F, Habte D. Subclinical vitamin A deficiency in young infants from Bangladesh. Nutr Res.1997; 17 (4):591 –598[CrossRef][ISI]
  33. United Nations Children's Fund; Bangladesh Bureau of Statistics. Progotir Pathey on the Road to Progress. Dhaka, Bangladesh: United Nations Children's Fund and Bangladesh Bureau of Statistics;1998
  34. United Nations Children's Fund; Bangladesh Bureau of Statistics. Progotir Pathey 2003. Dhaka, Bangladesh: United Nations Children's Fund and Bangladesh Bureau of Statistics;2004
  35. Christian P, West KP Jr, Khatry SK, et al. Night blindness of pregnancy in rural Nepal: nutritional and health risks. Int J Epidemiol.1998; 27 (2):231 –237[Abstract/Free Full Text]
  36. West KP Jr, Christian P, Klemm RD, et al. The JiVitA Bangladesh project: research to improve nutrition and health among mothers and infants in rural south Asia. Sight Life Newslett.2006; 1 :10 –14
  37. Diggle PJ, Liang K, Zeger SL. Analysis of Longitudinal Data. New York, NY: Oxford University Press;1994
  38. James WP, Mascie-Taylor GC, Norgan NG, Bistrian BR, Shetty PS, Ferro-Luzzi A. The value of arm circumference measurements in assessing chronic energy deficiency in Third World adults. Eur J Clin Nutr.1994; 48 (12):883 –894[ISI][Medline]
  39. Pilch SM. Analysis of vitamin A data from the health and nutrition examination surveys. J Nutr.1987; 117 (4):636 –640[Abstract/Free Full Text]
  40. Humphrey JH, Rice AL. Vitamin A supplementation of young infants. Lancet.2000; 356 (9227):422 –424[CrossRef][ISI][Medline]
  41. Mactier H, Galloway P, Hamilton R, Weaver L. Inadequacy of IV vitamin A supplementation of extremely preterm infants? J Pediatr.2005; 146 (6):846 –847[ISI][Medline]
  42. Woodruff CW, Latham CB, Mactier H, Hewett JE. Vitamin A status of preterm infants: Correlation between plasma retinol concentration and retinol dose response. Am J Clin Nutr.1987; 46 (6):985 –988[Abstract/Free Full Text]
  43. Lindblad BS, Patel M, Hamadeh M, et al. Age and sex are important factors in determining normal retinol levels. J Trop Pediatr.1998; 44 (2):96 –99[CrossRef][ISI][Medline]
  44. West KP Jr. Public health impact of preventing vitamin A deficiency in the first six months of life. In: Delange FM, West KP Jr, eds. Micronutrient Deficiencies in the First Months of Life. Vevey, Switzerland: Karger;2003 :103 –128
  45. Stoltzfus RJ, Hakimi M, Miller KW, et al. High dose vitamin A supplementation of breast-feeding Indonesian mothers: effects on the vitamin A status of mother and infant. J Nutr.1993; 123 (4):666 –675[Abstract/Free Full Text]
  46. Brown KH, Dewey KG, Allen LH. Complementary Feeding of Young Children in Developing Countries: A Review of Current Scientific Knowledge. Geneva, Switzerland: World Health Organization:1998
  47. Mitra AK, Alvarez JO, Stephensen CB. Increased urinary retinol loss in children with severe infections. Lancet.1998; 351 (9108):1033 –1034[CrossRef][ISI][Medline]
  48. Baqui AH, Sabir AA, Begum N, Arifeen SE, Mitra SN, Black RE. Causes of childhood deaths in Bangladesh: an update. Acta Paediatr.2001; 90 (6):682 –690[ISI][Medline]
  49. Garenne M, Ronsmans C, Campbell H. The magnitude of mortality from acute respiratory infections in children under 5 years in developing countries. World Health Stat Q.1992; 45 (2–3):180 –191[Medline]
  50. Obaro SK, Monteil MA, Henderson DC. The pneumococcal problem. BMJ.1996; 312 (7045):1521 –1525[Abstract/Free Full Text]
  51. Saha SK, Baqui AH, Darmstadt GL, et al. Comparison of antibiotic resistance and serotype composition of carriage and invasive pneumococci among Bangladeshi children: implications for treatment policy and vaccine formulation. J Clin Microbiol.2003; 41 (12):5582 –5587[Abstract/Free Full Text]
  52. Thurnham DI, Northrop-Clewes CA, McCullough FS, Das BS, Lunn PG. Innate immunity, gut integrity, and vitamin A in Gambian and Indian infants. J Infect Dis.2000; 182 (suppl 1):S23 –S28[CrossRef][ISI][Medline]
  53. Ross AC. The relationship between immunocompetence and vitamin A status. In: Sommer A, West KP Jr, eds. Vitamin A Deficiency: Health, Survival, and Vision. New York, NY: Oxford University Press;1996 :251 –273
  54. Biesalski HK, Nohr D. Importance of vitamin-A for lung function and development. Mol Aspects Med.2003; 24 (6):431 –440[CrossRef][Medline]
  55. Zachman RD. Role of vitamin A in lung development. J Nutr.1995; 125 (6 suppl):1634S –1638S[Abstract/Free Full Text]
  56. Chailley-Heu B, Chelly N, Lelievre-Pegorier M, Barlier-Mur AM, Merlet-Benichou C, Bourbon JR. Mild vitamin A deficiency delays fetal lung maturation in the rat. Am J Respir Cell Mol Biol.1999; 21 (1):89 –96[Abstract/Free Full Text]
  57. Lin PW, Stoll BJ. Necrotising enterocolitis. Lancet.2006; 368 (9543):1271 –1283[CrossRef][ISI][Medline]
  58. Saugstad OD. Oxidative stress in the newborn: a 30-year perspective. Biol Neonate.2005; 88 (3):228 –236[CrossRef][ISI][Medline]
  59. Malaba LC, Iliff PJ, Nathoo KJ, et al. Effect of postpartum maternal or neonatal vitamin A supplementation on infant mortality among infants born to HIV-negative mothers in Zimbabwe. Am J Clin Nutr.2005; 81 (2):454 –4560[Abstract/Free Full Text]
  60. Sommer A. Innocenti micronutrient search report #1. Sight Life Newslett.2005; 3 :13 –18
  61. Beaton BH, Martorell R, Aronson K, et al. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. Presented at: the Administrative Committee on Coordination, Sub-Committee on Nutrition session; February 15–16,1993; Geneva, Switzerland
  62. Fawzi WW, Chalmers TC, Herrera MG, Mosteller F. Vitamin A supplementation and child mortality: a meta-analysis. JAMA.1993; 269 (7):898 –903[Abstract]
  63. Humphrey JH, Ichord RN. Safety of vitamin A supplementation of postpartum women and young children. Food Nutr Bull.2001; 22 (3):311 –319
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Vitamin A Deficiency and Clinical Disease: An Historical Overview
J. Nutr., October 1, 2008; 138(10): 1835 - 1839.
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