The irony of the HIV-1 pandemic in children is that antiretroviral agents, which are the most effective measures for prevention and treatment of HIV-1 infections, have become available in regions where global proportions of the disease are the smallest, whereas in countries which bear the heaviest burdens , prophylaxis and care are scarcely affordable and mostly unavailable. No African country has yet provided antiretroviral agents for the prevention of mother-to-child transmission of HIV-1 on a nation-wide basis. The reasons for this are mostly, although not exclusively, related to questions of cost; even the cheapest course of these drugs (4 weeks of zidovudine as used in the Centers for Disease Control and Prevention trial in Thailand ), at $80, is beyond the entire per capita health expenditure of many African countries. It is therefore urgent that alternative strategies more relevant to poorer populations be evaluated. One such alternative is vitamin A. Vitamin A is cheap, easily provided through existing health services, and has been shown to be capable of reducing child mortality by approximately 30% . Given the affordability of this intervention, even substantially lesser degrees of benefit than those achieved for child morbidity and mortality may be acceptable to developing countries.
HIV infection is accompanied by multiple nutritional deficiencies , including deficiencies in vitamin A [5-7]. We have recently reported that in Durban, HIV-infected mothers at delivery had significantly lower serum retinol levels compared with a suitably selected control group of HIV-negative mothers . Semba et al. showed that in Malawi maternal vitamin A deficiency was associated with an increased risk of mother-to-child transmission of HIV .
The aim of this study was to test this association in a randomized, double-blind trial of the effect of vitamin A supplementation on mother-to-child transmission of HIV. In order to incorporate the antioxidant role of b-carotene (vitamin A precursor), both b-carotene and retinyl palmitate were included in the vitamin A supplement. The study was undertaken at two hospitals in Durban, South Africa. These hospitals are situated in KwaZulu-Natal, the province at the centre of the epidemic in South Africa; current figures for HIV prevalence at antenatal clinics in the province are 30%. Here we report the study results at a time-point at which all children had been followed-up to at least 3 months of age. These early results are important for policy makers and others in developing countries in considering affordable options for reducing mother-to-child transmission of HIV in developing countries.
Patients and methods
HIV-seropositive women identified through antenatal screening programmes at two hospitals in Durban, South Africa (King Edward VIII Hospital and McCords Hospital) were eligible for the study. Women were recruited between July 1995 and April 1998 and were randomized to receive vitamin A or placebo. Vitamin A treatment comprised a daily vitamin A supplement containing 5000IU retinyl palmitate and 30mg b-carotene; treatment commenced between 28 and 32 weeks gestation. At delivery, women in the vitamin A group received a dose of 200000IU (megadose) of retinyl palmitate; those in the control group received placebo on the same schedule. No woman on the study received any antiretroviral therapy. All the women enrolled were black Africans; most were Zulu-speaking.
Mothers were asked to attend a follow-up clinic when their infants were 1 week, 6 weeks and 3 months of age and thereafter every 3 months. At each paediatric follow-up visit mothers were asked about breastfeeding practices and infants were examined clinically and morbidity details were documented.
Venous blood was drawn from mothers on entry to the study for baseline differential count and lymphocyte subset analysis. The CD4 T-cell subset was enumerated by flow cytometry on a Coulter EPICS Profile 2 Flow Cytometer (Coulter Electronics, Miami, Florida, USA) using specific monoclonal antibodies. Baseline serum vitamin A concentrations were determined by reverse-phase high-pressure liquid chromatography . Infant venous blood was drawn within 48 h of delivery and again at 1 week, 6 weeks and 3 months of age and every 3 months thereafter until 15 months of age. If the mother was still breastfeeding, infant venous blood was drawn at 3 months after cessation of breastfeeding. Plasma was separated within 5 h and stored at -70°C for possible subsequent quantitative assay of HIV viral RNA by PCR (Roche Molecular Systems, Branchburg, New Jersey, USA)  at the National Institute of Virology, South Africa. Child samples taken at 9 months of age and older were tested by enzyme-linked immunosorbent assay (ELISA) for HIV antibodies (Abbott Laboratories, Chicago, Illinois, USA) and if negative were not tested for HIV RNA by PCR. These children were assumed to be uninfected at the age of their last negative ELISA test. If ELISA tests were positive at 9 months or older, the earliest available plasma sample for that child was tested, followed by the next available sample, and so on until two samples tested positive for HIV RNA by PCR or until no further samples were available. In children who had not yet reached 9 months of age, the last two available samples were tested for HIV RNA. If both were negative, the child was considered uninfected at the age of their last negative PCR. If one or both was positive, the earliest available sample was tested, and each sequential sample until two samples tested positive or until no further samples were available. Thus, children with at least one positive HIV RNA assay were considered infected although 75% were confirmed positive on one or more subsequent tests. The remainder were either lost to follow-up or still eligible for further follow-up at the time this analysis was conducted. No child with a positive HIV RNA PCR test result had a subsequent negative ELISA or PCR result.
The study was approved by the Ethics Committee of the University of Natal. Written informed consent was obtained from all women who participated in the trial. Enrolment was completed by the time the Thai, zidovudine trial results were released and we therefore did not need to switch our placebo arm to a zidovudine treatment arm.
Primary analyses were based on intent-to-treat comparisons of the two groups as randomized. All-cause mortality was compared between the two groups by life-table Kaplan-Meier methods and tested using log-rank tests. Surviving children were censored at the age they were last seen alive. Comparability of the groups was assessed by t test for continuous characteristics and c2 test for categorical characteristics. Because data on the risk of mother-to-child transmission was collected prospectively and not all children were followed for the same duration (some were lost to follow-up, others died, and others are still eligible to be followed further), the probability of infection in the child was calculated using Kaplan-Meier methods as used in the analysis of the ACTG 076 trial . The time to a first positive PCR was considered the time to an HIV end-point among those with at least one positive PCR. All other children were censored at their last negative test. The outcomes of twins were considered to be independent in this analysis.
Recruitment and vital status (see trial profile)
From July 1995 until April 1998, 728 pregnant women were enrolled at the two hospitals (344 at King Edward VIII Hospital and 384 at McCord Hospital). On entry to the study 11 women showed evidence of one or more clinical AIDS-related symptoms, the rest (98.5%) were clinically asymptomatic. Three-hundred and sixty-eight women were randomized to receive vitamin A treatment and 360 to receive placebo. Of the 728 enrolled women, 10 women experienced foetal loss before delivery (six singletons in the vitamin A group and three singletons and one twin pair in the placebo group) and an additional two women (in the placebo group) lost one foetus each of twin pregnancies but delivered the surviving twin. Of the 13 foetal deaths, one died before 28 weeks, 10 after 28 weeks but before term, and three were term stillbirths. An additional 57 women (27 in the vitamin A group and 30 in the placebo group) did not return to deliver at the study hospital and could not be traced. Thus, 661 women gave birth up to August 1998 to live-born infants (335 women in the vitamin A group and 326 women in the placebo group). The 661 women gave birth to 689 infants [631 singletons and 58 twins (28 complete pairs and two single survivors of twin pregnancies)]. Of the 689 live-born infants, no HIV test results were available for 57 (8.3%): nine of these infants subsequently died (seven before 1 month of age, one at 3 months, and one at 4 months of age). Therefore, 632 children were available for the Kaplan-Meier transmission analysis. Data for this analysis included results from all study visits up to November 1998. Thus all children had the opportunity to have completed at least 3 months of post-natal follow-up and 502 (79%) had HIV test results at 3 months or older.
At the time of the analysis, three study mothers were known to have died, one in the vitamin A group and two in the placebo group.
Comparability of the vitamin A and placebo groups
Women were recruited at a mean of 28 weeks gestation (range, 17-39 weeks) and received on average 8 weeks of their assigned treatment (range, 0-12). Most women (97.6%) received their megadose at delivery. The extent of compliance with treatment regime did not differ among those in the vitamin A and placebo groups. There were no statistically significant differences between women in the two groups at baseline pre-supplementation in serum retinol, haemoglobin, CD4 T-lymphocyte counts, or CD4:CD8 cell ratios. Before supplementation 30.6% of women had serum retinol levels <20μg/dl. There were also no differences between the two groups in maternal age, parity, syphilis screening test results, delivery characteristics, or feeding practices (Table 1).
Pregnancy outcomes by treatment assignment
Children born to mothers assigned to the vitamin A group were less likely to be born preterm (11.4% born £37 weeks) than children born to mothers in the placebo group (17.4% born £37 weeks; P=0.03). There were no other significant differences in neonatal characteristics by treatment assignment (Table 2). Preterm delivery was not associated with baseline serum retinol levels in either the vitamin A or placebo group, but was significantly higher in those with baseline haemoglobin <10g/dl (25% preterm) than haemoglobin ≥10g/dl (12% preterm) in the placebo group. In the vitamin A group, those with low baseline haemoglobin levels had similar rates of preterm delivery (8.9%) to those with higher levels (12.7%). Among singletons alone, preterm delivery was less common in the vitamin A group than in the placebo group (9.5 versus 12.3%) but the difference did not reach significance.
Transmission probabilities by treatment assignment
The primary analysis of the effect of vitamin A treatment on HIV transmission detectable by 3 months of age included all 632 children (319 in the vitamin A group and 313 in the placebo group) with at least one HIV test result. One-hundred and forty children (70 in each group) had at least one positive PCR test. There were 410 children (208 in the vitamin A group and 202 in the placebo group) who never had a positive PCR test but had their last negative test at 3 months or older. On the basis of the Kaplan-Meier analysis at 3 months of age, the estimated transmission probability was 20.3% [95% confidence interval (CI), 15.7-24.9] among the vitamin A group and 22.3% (95% CI, 17.5-27.1) among the placebo group. The estimated probability of infection by 1 day of age was 7.2% and 6.1% and by 1 month of age 12.0% and 16.1% among the vitamin A and placebo recipients respectively (Fig. 1).
In the subgroup of 80 preterm deliveries, those assigned to the vitamin A group had a lower probability of infection by 3 months of age (17.9%; 95% CI, 3.5-32.2) than those assigned to the placebo group (33.8%; 95% CI, 19.8-47.8). The preterm deliveries in the vitamin A and placebo groups were not, however, strictly comparable; there were small (non-significant) differences in patterns of feeding (67.9% were breast-fed in the vitamin A group, 73.3% in the placebo group), rates of Caesarean section (46.9% in the vitamin A group and 33.3% in the placebo group), anaemia (23.3% in the vitamin A group and 40.0% in the placebo group), and low CD4 cell counts (62.1% <500¥106/l in the vitamin A group and 41.0% <500¥106/l in the placebo group). The magnitude of the point estimate of the reduction in mother-to-child transmission in preterm infants associated with vitamin A supplementation (an approximate 50% reduction) was similar after adjustment for these factors; however, the adjusted estimate of reduction was not statistically significant. The estimated probability of infection by 1 day of age was 6.3% and 8.3% and by 1 month of age 13.8% and 24.1% among the vitamin A and placebo recipients respectively.
There were no significant differences in the probability of early HIV transmission by treatment assignment in other subgroups defined by baseline, maternal serum retinol level, haemoglobin, CD4 cell count, CD4:CD8 cell ratio, or by mode of delivery or by feeding practices (Table 3). For example, among 363 pregnant women with serum retinol levels <30μg/dl, the probability of infection by 3 months of age was 24.8% (95% CI, 18.2-31.4) in the vitamin A group, and 25.3% (95% CI, 18.8-31.7) in the placebo group. Probabilities of infection by 3 months were lower overall in women with higher baseline serum retinol levels (>30ug/dL), but again did not differ by treatment assignment: 15.3% (95% CI, 7.3-23.4) in the vitamin A group, and 16.0% (95% CI, 8.6-23.5) in the placebo group.
Infant mortality by treatment assignment
Of 689 live-born infants, 50 were known to have died later. The life-table estimates of all mortality among the vitamin A and placebo groups by 1 month of age were 2.35% and 3.24% respectively, at 3 months 5.52% and 5.44%, and at 12 months 9.26% and 9.99% (log-rank test P=0.903). Thirty-three of the 50 children who died had at least one prior positive HIV test, eight died subsequent to at least one negative HIV test not followed by a positive test (six of these tests were on samples collected at less than 2 weeks of age and two on samples collected at more than 6 weeks of age), and nine had no test results. There were no differences in survival between the vitamin A and placebo groups among the subgroup with at least one positive HIV test: 22.9% in the vitamin A group had died by 6 months of age and 23.3% in the placebo group (log-rank test P=0.786), nor were there any differences among the subgroup with no positive HIV tests: 2.7% in the vitamin A group had died by 6 months of age and 4.8% in the placebo group (log-rank test P=0.218) (Fig. 2).
The results of this trial suggest that vitamin A given from around the 28th week of pregnancy may reduce preterm delivery among HIV-infected African women and may decrease the risk of transmission among these deliveries. The incidence of preterm deliveries was reduced from 17.4% in the mothers on placebo to 11.4% in the treated group (P=0.03). Vitamin A appeared to counteract the adverse effects of anaemia (haemoglobin <10g/l) during gestation which increased the risk of preterm deliveries. In the placebo group, women with anaemia had a 25% incidence of prematurity, compared to 12% in non-anaemic women; there were similar rates among anaemic and non-anaemic women in the vitamin A treatment arm. Moreover, a reduction in the mother-to-child transmission of HIV with vitamin A supplementation was detected in preterm babies. Among 80 preterm deliveries those assigned to vitamin A treatment had a lower probability of HIV infection by 3 months of age (17.9%; 95% CI, 3.5-32.2) than those on placebo (33.8%; CI, 19.8-47.8). This is a 47% decrease in mother-to-child transmission, but the number of subjects is small and the CI are large.
The difference in transmission rates between the vitamin A and placebo groups among preterm deliveries was more obvious at 1 month of age than at 1 day of age. This would imply that the reduction observed is due to a reduction in intrapartum and early postnatal transmission rates. Explanations for this observation are discussed below.
Mucosal surfaces and skin are thinner and more permeable in preterm babies than in term babies [13,14]. Vitamin A supplementation during pregnancy may have improved vitamin A status of infants in the treatment arm resulting in better integrity of epithelial tissues. In addition vitamin A supplementation may improve the integrity of cervical and vaginal epithelium in the treated mothers so reducing the risk of the vulnerable, preterm infant coming into contact with infectious material during delivery; vitamin A deficiency was associated with a higher risk of viral shedding in lower genital tract infections in two studies from Kenya [15,16]. Another explanation relates to the foetal/neonatal immune response. Preterm neonates have lower levels of IgG; IgG is acquired transplacentally and is dependent on the gestational age of the infant and to a lesser extent, the level of maternal IgG . Vitamin A has been shown to play an important role in immune response  and it is possible that it may influence the transfer of IgG in the preterm neonates who are already at risk for lowered IgG and thereby, lower the rate of transmission as observed.
For the study population of babies as a whole (term and preterm), there was no effect of antenatal and intrapartum vitamin A on mother-to-child transmission of HIV-1. Mother-to-child transmission in the intervention and placebo arms were similar whether measured 1 day after birth, at 1 month of age or at 3 months. Our method for estimating the risk of HIV transmission by each age may slightly under-estimate transmission given the delay between actual and detectable infection; this under-estimation may be greater for breastfeeding- associated transmission, but would be equivalent in both the treated and placebo groups. Our analysis focused on infection detectable by 3 months of age which would include intrauterine, intrapartum and early post-natal infection. As the last dose of vitamin A was given at delivery, we are pessimistic that vitamin A would have consequences on late post-natal transmission long after it was given if it had no effect on transmission closer in time to the last dose. This lack of an effect is unlikely to be due to a failure of randomization: at baseline, the characteristics of the women in the two groups were similar; except for the features discussed above the subsequent maternal, delivery and neonatal characteristics were comparable by treatment assignment. In addition, a positive effect of supplementation could be anticipated in the patients studied as just under one-third had low levels (<20μg/dl) of vitamin A pre-supplementation. Women with low serum retinol levels at baseline (<30μg/dl) had a higher transmission rates than those with higher serum retinol levels, an observation first reported by Semba et al.  and which prompted this study. Two other observational studies which have examined this association in the USA provided conflicting results: low serum retinol was associated with a higher risk of mother-to-child transmission in one study , but not the other . However, even in the subgroup with low serum retinol at baseline, there was no apparent effect of intervention.
The lack of a strong effect of vitamin A supplementation on reducing mother-to-child transmission of HIV in our clinical trial, despite the association of low serum retinol levels with increased risk of transmission, suggests that serum retinol concentrations may be markers of HIV-1 disease progression rather than being causally related to mother-to-child transmission of HIV. Serum retinol is known to be depressed by the acute phase response to infection, even in the presence of adequate liver stores . It is unlikely that the lack of a strong effect was related to insufficient vitamin A supplementation as a high dose of b-carotene as well as a relatively high dose of preformed vitamin A was used (this was considered the safest way to avoid any possible teratogenicity) .
Our results as well as those of others offer intriguing suggestions that vitamin A supplementation, although not able to reduce transmission, may be of some benefit for other pregnancy outcomes. Semba‚s group, working in Malawi in southern Africa, reported a reduction in incidence of low birth weight deliveries among HIV-infected women supplemented with vitamin A compared with those on placebo . Fawzi‚s group in Tanzania  found large positive effects of multivitamins on perinatal outcomes (foetal mortality, low birth weight, preterm births) in HIV-infected women although vitamin A supplementation alone had no effect. A study from Nepal which supplemented all women (not only those infected by HIV) reported no effects of vitamin A on new-born characteristics but a major impact on maternal mortality (reduced by 44%) . These differing results are not entirely unexpected. Indeed, in their diversity they resemble some of the variability of outcomes in the field studies of vitamin A supplementation in pre-school children in developing countries .
In Durban , anaemia in seropositive pregnant women was shown to be a major risk factor for mother-to-child transmission of HIV-1; it is not known whether this is a primary nutritional intake problem or whether it reflects HIV disease activity. Vitamin A supplements have been shown to play a role in improving haemoglobin levels and indices of iron metabolism . Based on the results of this study maternal supplements of vitamin A may be helpful to pregnant women at risk of preterm delivery.
In conclusion, vitamin A supplementation to a population of HIV-infected pregnant women, many of whom had low vitamin A levels, was associated with a decreased number of preterm births and with reduced mother-to-child transmission of HIV in preterm babies, but was not associated with a reduction in HIV transmission overall. The results of this study need further investigation as there is potential for a substantial impact, given that the rate of preterm deliveries in HIV-infected women is known to be high; in a recent dissertation reviewing available data on preterm births in HIV-1-infected women the rates of preterm deliveries ranged from 15% in Europe to 33% in the USA and 42% in Rwanda . Data expected soon from the UNAIDS PETRA trial will reveal the most representative data on preterm delivery rates in Africa. We may have failed to detect a significant difference because of small sample size; pooling of the results on mother-to-child transmission of HIV in preterm babies from the other current vitamin A intervention trials in Africa may therefore be useful. Vitamin A may even be useful in industrial countries to counter the effects of antiretroviral therapy which appears to increase the risk of preterm deliveries .
The authors thank: H. Holst, superintendent, McCord Hospital, for valuable cooperation and allowing us access to patients in the antenatal clinic; I. Dwarkapersad, chief medical superintendent, King Edward VIII Hospital, for permission to conduct the study; nursing staff at McCord and King Edward Hospitals, for invaluable assistance and cooperation; T. Ngubane, T. Buthelezi, J. Sibanyoni, for providing counselling to the women in the study; D. Naicker, A. Mngadi, J. Mshentshela, for assistance with the follow-up clinics; I. Elson, Analytical Unit, University of Natal, for vitamin A analysis; A. Smith, D. York, S. Madurai, Department of Virology, University of Natal, for HIV testing; Z. Stein, Gertrude H Sergievsky Center, Columbia University, New York, for valuable discussions about study design and interpretation of data. Finally we thank the mothers and their children for participating in the study.
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Additional members of the South African Vitamin A Study Group
G. Sinclair, A. Mburu, N. Mngqundaniso, K. Uebel, I. Coetzee, K. Annamalai, T. Doorasamy, U. Govender, J. Willumsen, N. Rollins, J. Moodley and D. Moodley.
Members of the Data Safety and Monitoring Board
S. Abdool. Karim, E. Gouws, J. Levin and I. Kleinschmidt.