Seven studies including 51,446 neonates were included in this review.
The study by Humphrey et al was conducted in a single tertiary care hospital in Indonesia (Humphrey 1996) as a safety trial for vitamin A supplementation at the time of birth. This was a randomised double blind placebo controlled trial of 2067 infants with birthweight > 1500 g and without any critical illness. The infants were randomly assigned to receive a single oral dose of vitamin A (50,000 IU) or placebo within 24 hours of delivery. The two groups were similar at baseline for maternal, infant and household characteristics.
The study conducted by West et al (West 1995) in Nepal was part of a large cluster randomised, double blind, placebo controlled trial of vitamin A supplementation in preschool children. A total of 11,918 infants less than six months of age, of which 1621 were neonates, were enrolled and administered vitamin A (50,000 IU in < one month old infants and 100,000 in one to five month old infants) or placebo. Baseline characteristics of the two groups were similar.
The study conducted in India by Rahmatullah et al (Rahmathullah 2003) was also a randomised, double blind, placebo controlled trial in which all live born infants resulting from pregnancies within the participating villages were eligible for inclusion. A total of 11,619 newborn infants born to consenting mothers who were residing in the study area were enrolled. Infants were given two doses of vitamin A or placebo with the first dose being administered within the first 48 hours of delivery and the second dose within 24 hours of the first dose. Baseline characteristics of the families, mothers and infants were similar between the treatment groups.
The Zimbabwe study (Malaba 2005) was a randomised, double bind, placebo controlled trial using a two by two factorial design. Mother-infant pairs were eligible for inclusion if the mother planned to reside in the study area after delivery. None of the two had any life threatening illness and the infant's birthweight was > 1500 g. Around 14,110 infant-mother pairs were enrolled within 96 hours of delivery and were assigned to either of the following groups: Aa (vitamin A supplementation to both the mother and infant), Ap (vitamin A to the mother and placebo to infant), pa (placebo to mother and vitamin A to infant) and pp (placebo to both the mother and infant). The vitamin A dose for mothers was 400,000 IU and for infants it was 50,000 IU. All the treatment groups were similar at baseline for maternal, household and other related variables.
The study conducted by Klemm et al in Bangladesh (Klemm 2008) was a cluster randomised, double bind, placebo controlled trial which was nested within an ongoing parent trial of vitamin A supplementation in pregnant women. All infants born to consenting mothers of the original trial were included in the current trial. A total of 15,948 infants were administered vitamin A (50,000 IU) or placebo at home as soon as possible after birth. Baseline characteristics of the mothers and infants in this study were comparable at baseline.
Two studies were conducted in Guinea Bissau by Benn et al. Benn 2008 was a randomised, double blind, placebo controlled trial which included 4345 normal birthweight infants (birthweight at least 2500 g). For births occurring at the national hospital or local health centres, mothers were invited to participate in the study at the time of Bacille Calmette-Guérin (BCG) vaccination. For home births, mothers were invited to participate at the time of their visit to the local health centres for BCG vaccination. All infants with birthweight at least 2500 g, without any serious medical condition or malformation, for whom parental consent was available were randomised to either oral drops of vitamin A (50,000 IU) or placebo. The treatment groups were similar at baseline for various baseline characteristics. The other study by these investigators was conducted in parallel with Benn 2008. Benn 2010 was a two by two factorial, randomised, double blind, placebo controlled trial in low birth weight neonates (birthweight < 2500 g). This study included 1736 neonates randomised to either 25,000 IU vitamin A or placebo, as well as to early BCG vaccine or the usual late BCG vaccine.
See the table 'Characteristics of included studies' for further details.
There are four ongoing studies that are being conducted in Pakistan, India, Ghana and Tanzania. All four studies are randomised, double blind, placebo controlled trials, with the one in Pakistan using a cluster randomised design.
The inclusion criteria for Pakistan 2008 were live born infants without congenital malformations or serious birth injury from all pregnancies within participating villages, with a sample size of 7,400 infants. The study was designed as an effectiveness trial with vitamin A delivery through the Lady Health Workers program of the government of Pakistan. Intervention included routine postpartum care and vitamin A supplementation (50,000 IU) to the newborn within 48 to 72 hours of birth whereas the control group received routine postpartum care only. Outcomes to be evaluated were all-cause and cause-specific infant mortality at six months, incidence of serious infections (sepsis, pneumonia and diarrhoea), measurement of serum retinol values and rates of breastfeeding in the two groups. Recruitment and follow up for this study have been completed and data analysis is in progress.
The studies being planned in India, Ghana and Tanzania also aim to evaluate the effect of supplementation of 50,000 IU of vitamin A against control. The Indian study is being conducted in two districts in the state of Haryana with an estimated sample size of 40,200 neonates (India 2010). All births in the study area contacted by the enrolment team within the eligible age window and with the parent's consent to participate will be included. The eligible age window has been defined as up to 60 hours after birth. Outcomes that will be evaluated include infant mortality at six months, mortality in the neonatal period (during the first month of life); incidence of severe morbidity, defined as hospitalizations due to any illness in the first six months of infancy; potential adverse effects of vitamin A; and vitamin A status in a subgroup of newborns at two weeks and three months of age and their caregivers.
The methodologies of the studies in Ghana and Tanzania were found to be similar. The Ghana study will be conducted in seven contiguous districts in the Brong Ahafo region of central rural Ghana (Ghana 2010) with a target sample size of 28,000 neonates. The Tanzanian study will be conducted in Dar-es-Salaam and the Kilombero and Ulanga districts in Ifakara (Tanzania 2010). The estimated sample size for this study is 32,000 neonates. Inclusion criteria in both studies are all births in the study area that are contacted by the study team on the day of birth or in the next two days. Both singleton and multiple births are eligible for inclusion and each infant will be provided a unique identification number. Intervention includes vitamin A 50,000 IU once orally within the first three days of life, keeping a minimum period of two hours between birth and dosing. Similar outcomes will be evaluated in the two studies, which are all-cause infant mortality assessed at six months of age, all-cause neonatal mortality assessed at one month of age, incidence of severe morbidity defined as hospitalisations due to any illness in the first six months of infancy, potential adverse effects of vitamin A, and vitamin A and C reactive protein (CRP) status in a subsample of infants at two weeks and three months of age.
See the table 'Characteristics of ongoing studies' for further details.
Two studies were excluded from the review (Bezzera 2009; Bhaskaram 1998). Bezzera 2009 included vitamin A supplementation of mothers only in the immediate postpartum period; their neonates were not supplemented. Bhaskaram 1998 supplemented mothers only with vitamin A within 24 hours of delivery while all neonates were given oral poliovirus vaccine (OPV) between 48 and 72 hours after birth.