Vitamin A Supplementation in Newborns Study
Condition: Infant, Newborn
Study type: Interventional
Phase: Phase 3

Summary: 
      This study was a randomized, community-based trial testing whether dosing newborn infants in
      the first few days after delivery with a large dose of vitamin A could reduce early infant
      morbidity, mortality and improve growth. Pregnant women in 2 districts of Tamil Nadu State in
      southern India were identified and recruited for participation. When the child was born,
      study staff were notified and traveled to the house to collect information and provide the
      vitamin A or placebo dose. Children were visited every two weeks until they were 6 months of
      age to collect information about vital status and morbidity. All children were discharged
      from the study at 6 months after growth was assessed and they received a 100,000 IU dose of
      vitamin A.
    

Detailed description: 
      I. Background

      A variety of studies over the past 15 years have demonstrated that clinical vitamin A
      deficiency is associated with increased mortality in pre-school aged children (1,2) and that
      supplementation of populations with endemic sub-clinical vitamin A deficiency can
      significantly reduce total mortality (3-8). A recent meta-analysis of 8 clinical trials
      showed that vitamin A supplementation of children 6 months through 5 years of age reduced
      mortality by an average of 23% (9). While the average impact was 23%, there was significant
      variation in the results of these studies. The impact was as high as 54% among children in an
      underprivileged area of Tamil Nadu supplemented with small weekly doses of vitamin A (4).

      While the story of the impact of vitamin A supplementation in children 6 months and older is
      clear, such is not the case for younger infants. Traditionally, it has been thought that the
      full-time breast feeding practices associated with early infancy protected the infant from
      becoming vitamin A deficient. It was not until the onset of weaning or the misuse of
      bottle-feeding that clinical signs of xerophthalmia appeared (1). Recent evidence from a
      variety of locations suggests that these traditional assumptions about the adequacy of breast
      -feeding in assuring adequate vitamin A nutriture are suspect and likely unfounded. It is
      well known that infants are born with very low body stores of vitamin A and they depend on
      regular breast feeding or other sources to build body stores (13, 14). Therefore, if the
      mother's breast milk has a lower than normal concentration of vitamin A, the infant will not
      be able to meet daily requirements and increase body reserves. It has become clear that many
      women in developing countries have poor vitamin A status themselves and that their breast
      milk concentrations may be only half that found among women with adequate vitamin A status
      (15). In addition, it has been shown in Indonesia that supplementation of women post-partum
      can improve the vitamin A concentration in their blood and breast milk (16).

      While it is becoming clearer that young infants in developing countries with endemic vitamin
      A deficiency are at significant risk of being vitamin A deficient in spite of adequate breast
      feeding behaviour, there is little data concerning the impact of supplementing this group
      with vitamin A. Two major studies have addressed this issue, both done by the same group at
      Johns Hopkins University, with opposite findings. Humphrey et al. have reported, in a
      randomized clinical trial of 2067 infants born in a hospital in Bandung, Indonesia, that
      direct supplementation of newborn infants within 24 hours of birth with 50,000 IU of vitamin
      A was safe (10) and associated with a 64% reduction in infant mortality (11). In contrast,
      West et al. studied over 11,000 infants under six months of age in their large intervention
      trial in southern Nepal (17). They found no difference in mortality between those
      supplemented with vitamin A versus those given placebo (relative risk =1.11, 95% CI 0.86 -
      1.42). However, there were significant and potentially important differences between these
      two studies. First, the time of dosing was different. The Indonesian study dosed infants
      within 24 hours of birth whereas the Nepal study dosed infants when they were first
      identified to the study during their distribution rounds every four months. On average then,
      the age at first dosing was 2 months after the highest risk period and exposure to dietary
      and other environmental factors. It may be that the time of dosing is critically important
      for the development of early immune function or other protective mechanisms. Support for the
      Indonesian findings has come from a recently discussed study in Bangladesh where
      supplementation of mothers' post-partum was associated with a reduction in infant mortality
      (12).

      Given the apparent controversy in the scientific literature on early infant dosing with
      vitamin A and the fact that this remains the highest risk period for mortality during
      childhood, more data are urgently needed to resolve this confusion. If the Indonesian
      findings can be replicated, the policy implications for developing countries are clear. An
      expansion of the "safe delivery" concept to include supplementation of the infant and mother
      with vitamin A would enhance nutrition and safe motherhood program impact in an extremely
      cost-efficient fashion. As practices in India move increasingly in the direction of attended
      childbirth, the opportunity to intervene becomes easier with significant potential for having
      a dramatic impact on infant mortality.

      Goals and Specific Aims

      The overall goal of this project is to improve the health and survival of young children in
      India through improvement in vitamin A status. More specifically this project will:

        1. Evaluate the efficacy of vitamin A supplementation of newborn infants (50,000 IU) on
           mortality within the first 6 months of life using a community-based distribution and
           outcome assessment strategy.

        2. Evaluate the efficacy of vitamin A supplementation of newborn infants (50,000) on the
           incidence and severity of morbidity within the first 6 months of life. Specific
           morbidities of interest include diarrhea and acute respiratory infections.

        3. Evaluate the efficacy of vitamin A supplementation of newborn infants (50,000 IU) on
           growth of infants over the first 6 months of life.

      These specific aims will be accomplished by conducting a community-based, randomized trial of
      vitamin A supplementation to newborn infants within 48 hours of birth in underprivileged
      rural communities of Tamil Nadu.

      II. Study Protocol

      Overview: The overall design of this study will be that of a randomized, community-based
      clinical trial. The intervention to be tested for impact on infant mortality, morbidity and
      growth is supplementation of 50,000 IU of vitamin A to the newborn within 48 hours after
      delivery. Outcomes of interest are mortality within the first 6 months of life, the incidence
      and severity of diarrhea and acute respiratory infections, and growth.

      This study will be population-based such that all live births within a defined population
      will be enrolled. Women residing in study villages will be identified by village-based field
      staff when they become pregnant. Informed consent will be obtained at that time as well as
      baseline data regarding family and household characteristics. In addition, field workers for
      the study will ask the woman where she plans to deliver the child, at home, in a maternity
      home, or in the hospital. The woman will be assigned a study number and randomized at the
      time of enrollment to either the vitamin A or placebo groups. Actual supplementation will
      occur at the time of delivery.

      Study staff will attend all deliveries within 24 hours of the birth. At that time, the child
      will be dosed with either vitamin A or placebo according to their treatment assignment. Birth
      weight will be measured, and details of the delivery will be collected. Following delivery, a
      short vital status and morbidity assessment will be conducted every two weeks for the first 6
      months of life. If a child death is reported, supervisors will be dispatched to the household
      to verify the death and to conduct a verbal autopsy. All children will receive 200,000 IU
      oral vitamin A at the time of the 6 month visit and discharged from the study (200,000 IU is
      the dose currently provided by the government of Tamil Nadu to children 6 months of age and
      older).

      The analysis will focus on estimation of mortality rates for the vitamin A and placebo
      groups. These will be compared using a person-time approach as well as survival analysis
      techniques. The two groups will be compared on baseline characteristics and any imbalance
      will be controlled using standard adjustment techniques including logistic regression and
      proportional hazards models. Results will be reported in the scientific literature, at
      national and international meetings.

      Study Population:

      The study population chosen for this project will include all villages in two rural blocks in
      Tamil Nadu. The two blocks chosen for inclusion in the study are Kariaypatti and Natham.
      ASSEFA (Association for Sarva Seva Farm) is a non-governmental organisation involved in
      community development, education, and health programs for underprivileged rural communities.
      Within the ASSEFA area of a block, the health activities consist of a maternal and child
      health program, which runs antenatal clinics and produces and delivers weaning foods to young
      children and pregnant women. The engine for this program is the Health Committee in each
      village. In most ASSEFA program areas, registration of pregnant women by ASSEFA staff or
      volunteers is virtually complete. Non-ASSEFA villages are slightly better off and served
      primarily through a variety of government programmes.

      Eligibility: In order to maximise the generalisability of the results of this study, the
      criteria for eligibility will be broad and inclusive. All pregnancies that occur within the
      geographic boundaries of the participating villages, which result in a live born infant(s),
      will be eligible for recruitment. This will include multiple births, those with congenital
      anomalies, and those born early or with low birth weight. Provision of informed consent will
      be the only eligibility criterion in addition to geographic eligibility.

      Recruitment and enrollment: Pregnant women will be identified from a variety of sources, the
      ASSEFA Health Committee Members, the antenatal care clinics run on a monthly basis by ASSEFA
      or the government in the study areas, and other women's development workers in the area. Once
      a pregnant woman is identified, the cluster worker will explain the study and attempt to
      enroll the subject. If she agrees, then the cluster worker will proceed with the assignment
      of a study ID number and completion of baseline data collection form, including a
      determination of where the women plans to deliver her child.

      For those women who are registered, but plan to deliver outside the village, special actions
      will be taken. There are three types of these women:

      i) Those who go outside the village to deliver their child and are not reachable by our study
      teams (more than 20 kms away from the village). These women will be excluded from
      participation in the trial, but these babies will be followed after they return to the
      village, only for 6-month mortality.

      ii) Those who go outside the village to deliver in another study village. These women will be
      transferred to the appropriate Cluster Worker so the treatment doses can be given as per
      protocol and the infants will be following in this location until they return to their home
      village. At this time, the file will be transferred back to the appropriate Cluster Worker in
      the home village.

      iii) Those who go outside the village, not to study villages, but who are reachable by
      special efforts of our study supervisory staff. Reachable will be defined as being within 20
      km of the Block Office. These women will be treated and infants dosed by the supervisor of
      the cluster worker. They will not be followed for morbidity, but will be followed for
      mortality based on home village family reports until they return to the village. After
      returning to the home village, they will continue to be followed for mortality and growth
      only (not morbidity).

      A fourth special situation are those women who move into one of our study villages
      temporarily to deliver from outside the study area. These women will be included and enrolled
      as soon as they arrive in our study villages and they will be followed for morbidity and
      mortality after birth until they return home. After they leave the village, mortality only
      will be followed by reports from the family in the study village.

      Randomisation: Randomisation will be conducted at the individual level, stratified by
      geographic area and randomized in blocks of size four to insure equal numbers of babies in
      each treatment group. Each pregnant woman will be assigned a unique study number at the time
      of enrollment. Each set of capsules (two 25,000 IU capsules for the newborn) will be packaged
      separately and labelled with the woman's name, address, and ID number to avoid mix-ups at the
      time of delivery. Treatment assignment codes will be kept in a locked filing cabinet in a
      sealed envelope at a location separate from the study headquarters.

      Definition and Measurement of Outcomes: There are one primary and two secondary outcomes that
      will be evaluated in this study. The primary outcome is vital status within the first 6
      months of life. Deaths will be ascertained during the vital status and morbidity assessments
      conducted every two weeks during a home visit. Any child found to have died within the
      preceding two weeks will initiate the process of death verification and cause of death
      determination. Cause of death determination will identify both immediate and underlying
      causes by two independent reviews of the verbal autopsy information by paediatricians. If
      there is disagreement regarding the cause of death, a third paediatrician will review the
      data and conduct a consensus meeting to arrive at an agreed upon cause of death.

      Secondary outcomes include the incidence and severity of diarrhea and acute respiratory
      infections over the first six months of life, clinic utilisation for illnesses during the
      first six months, and growth over the first six months. Episodes of diarrhea, dysentery,
      acute respiratory illness (ARI), and clinic utilisation will be based on a maternal interview
      conducted every two weeks. Diarrhea will be defined as 6 or more loose, watery stools in a 24
      hour period. Dysentery will be defined as diarrhea with the additional history of blood or
      mucus in the stool. The incidence of episodes as well as their duration will be assessed
      during the data collection process. Growth will be assessed only at the six-month visit where
      weight, length, and mid-upper arm circumference will be assessed using standard protocols.

      Sample Size Requirements: Previous research on the impact of vitamin A supplementation among
      young infants in Tamil Nadu and Indonesia suggests that we may expect a mortality reduction
      of between 30% and 50%. Because even the lower end of this range of impact would be of
      significant importance, sample size calculations have been done using a minimal detectable
      reduction of 30%.

      The infant mortality rate (IMR) in Tamil Nadu as a whole is approximately 60/1000 live
      births. The population selected for inclusion in this study is poorer economically and has
      worse health status than the average for Tamil Nadu. It is likely, therefore, that the infant
      mortality rate in this area is higher than the state as a whole. We have estimated it at
      70/1000 live births. The study design for this project calls for vital status assessment to
      conclude at 6 months of age. Therefore the expected mortality rate in the first six months
      will be lower than the total IMR. Mortality rates decline dramatically with age, even in the
      first year of life. Reasonable estimates are that 75% of total infant mortality occurs in the
      first six months of life. Applying this figure to the estimated IMR of 70/1000 live births
      gives a 6-month infant mortality rate (IMR-6) of 52.5/1000 live births.

      Assuming a type I error of 5% (2-sided), 80% power, an IMR-6 of 52.5/1000 in the placebo
      group, and a minimum detectable reduction of 30% in the vitamin A group, the sample size
      required in each group is approximately 2700 live births. If we assume a 10% loss to
      follow-up this brings the number required in each group to approximately 3000, or a total of
      6000 live births.

      The crude birth rate in Tamil Nadu is approximately 20/1000 population. In order to enroll
      6000 live births in one year, we must ascertain all births in a total population of
      approximately 300,000 or a population of 150,000 over a two-year enrollment period. We have
      chosen to enroll deliveries for a period of 24 months.

      References

        1. Sommer A. Nutritional Blindness. New York, Oxford University Press, 1983.

        2. Sommer A, Tarwotjo I, Hussaini G, et al. Increased mortality in children with mild
           vitamin A deficiency. Lancet 1983; 2:585-588.

        3. Sommer A, Tarwotjo I, Djunaedi E, et al. Impact of vitamin A supplementation on
           childhood mortality. A randomized controlled community trial. Lancet 1986; 1:1169-1173.

        4. Rahmathullah L, Underwood BA, Thulasiraj RD, et al. Reduced mortality among children in
           southern India receiving a small weekly dose of vitamin A. N Eng J Med 1990; 33:929-935.

        5. Daulaire NMP, Starbuck ES, Houston RM et al. Childhood mortality after a high dose of
           vitamin A in a high risk population. Brit Med J 1992; 304:207-210.

        6. West KP Jr, Pokhrel RP, Katz J, et al. Efficacy of vitamin A in reducing pre-school
           child mortality in Nepal. Lancet 1991; 338:67-71.

        7. Muhilal, Permeisih D, Idjradinata YR, et al. Vitamin A fortified monosodium glutamate
           and health, growth, and survival of children: a controlled field trial. Am J Clin Nutr
           1988; 48:1271-1276.

        8. Ghana VAST Study Team. Vitamin A supplementation in northern Ghana: effects on clinic
           attendances, hospital admissions, and child mortality. Lancet 1993;342:7-12.

        9. Beaton GH, Martorell R, Aronson KJ, et al. Effectiveness of vitamin A supplementation in
           the control of young child morbidity and mortality in developing countries. ACC/SCN
           State of the Art Series, Nutrition Policy Discussion Paper No. 13, December 1993,
           Geneva.

       10. Agoestina T, Humphrey JH, Taylor GA, et al. Safety of one 52 umol (50,000 IU) oral dose
           of vitamin A administered to neonates. Bull WHO 1994;72(6):859-868.

       11. Humphrey JH, Agoestina T, Wu L, et al. Impact of neonatal vitamin A supplementation on
           infant morbidity and mortality. J Pediatrics 1996;128:489-496.

       12. de Francisco A, Yasui Y, Chakraborty J. Vitamin A supplementation given to mothers after
           delivery reduces infant mortality and increases symptoms of morbidity. Presented at the
           XVI IVACG Meeting, October 24-28, 1994, Chiang Rai, Thailand.

       13. Olson JA. Liver vitamin A reserves of neonates, pre-school children and adults dying of
           various causes in Salvador, Brazil. Arch Latinoam Nutr 1979; 29:521-545.

       14. Olson JA, Gunning DB, Tilton RA. Liver concentrations of vitamin A and carotenoids as a
           function of age and other parameters of American children who died of various causes. Am
           J Clin Nutr 1984; 39:903-910.

       15. Wallingford JC, Underwood BA. Vitamin A deficiency in pregnancy, lactation and the
           nursing child. In Bauernfeind JC (ed). Vitamin A Deficiency and Its Control. Orlando,
           Florida, Academic Press, 1986: 101-152.

       16. 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; 123:666-675.

       17. West KP Jr, Katz J, Shrestha SR, et al. Mortality of infants under six months of age
           supplemented with vitamin A: a randomized, double-masked trial in Nepal. Am J Clin Nutr
           1995; 62:143-148.
    

Intervention name(s): Vitamin A
Intervention type(s): Drug
Other intervention name(s): vitamin A (retinol palmitate) oral, 48,000 IU
Intervention MeSH terms: Vitamins; Vitamin A; Retinol palmitate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: vitamin A; mortality; newborn; liveborn infants