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Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection

  1. Wiysonge CU Shey,
  2. P Brocklehurst,
  3. JAC Sterne

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 22 APR 2002

DOI: 10.1002/14651858.CD003648

How to Cite

Shey WCU, Brocklehurst P, Sterne JAC. Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection. The Cochrane Database of Systematic Reviews 2002, Issue 2. Art. No.: CD003648. DOI: 10.1002/14651858.CD003648.

Author Information

*Dr Charles Shey Wiysonge, Department of Community Health, Ministry of Public Health, BP 25125 Messa, Yaoundé, CAMEROON.

Publication History

  1. Published Online: 22 APR 2002

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This is not the most recent version of the article. View current version (19 JAN 2011)

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support

HIV/AIDS has produced a global epidemic that is far more extensive than was predicted when the infection emerged two decades ago. UNAIDS and WHO estimate that 37.2 million adults were living with HIV/AIDS worldwide at the end of 2001, nearly half of whom were women of childbearing age (UNAIDS/WHO 2001). Mother-to-child transmission (MTCT) of HIV is the dominant mode of acquisition of HIV infection for children, currently resulting in about 1800 new paediatric HIV infections each day worldwide, 90% of which occur in Africa south of the Sahara. The risk of MTCT of HIV ranges from 15-30% in the well-resourced countries of Europe and North America, to 30-45% in the resource-limited countries of sub-Saharan Africa (De Cock 2000).

MTCT of HIV can occur during pregnancy, delivery and breastfeeding, and risk factors for transmission are both fetal/child and maternal (Mofenson 1994; Newell 1998). The increasing number of infected women of childbearing age makes the prevention of MTCT of HIV a public health priority in the hardest-hit developing countries with high antenatal HIV seroprevalence (UNAIDS/WHO 2001). Current strategies to reduce the risk of transmission include a short course of antiretroviral therapy (Brocklehurst 2002), Caesarean section delivery, and avoidance of breastfeeding (Newell 2000). Despite their benefits, these interventions are impractical in most resource-limited developing countries because they require the determination of the HIV status of pregnant women and are costly, complex, and require skilled personnel. Simple, inexpensive, and effective interventions that could potentially be implemented in the absence of prenatal HIV testing programmes would be valuable.

Vitamin A supplementation during pregnancy is one low-cost intervention that has been suggested (Newell 2000). Vitamin A is the generic name for a group of fat-soluble compounds, which have the biological activity of the primary alcohol, retinol. The vitamin is involved in the regulation and promotion of growth and differentiation of many cells and maintains the integrity of the epithelial cells of the respiratory and digestive tracts. Vitamin A is necessary for formation of the photosensitive visual pigment in the retina, and reproductive functions. In the 1920s the vitamin was considered to be an anti-infective agent (Green 1928) and there is increasing evidence that it is essential for normal immune function (Ross 1996; Semba 1998).

Vitamin A deficiency is most prevalent in areas where diets lack preformed vitamin A, such as in South and Southeast Asia, and Sahelian and sub-Saharan Africa (West 2001). An estimated 8-12 million pregnant women are deficient in vitamin A wordwide (Christian 1998). Vitamin A in pregnant women is associated with night blindness, severe anaemia, wasting, and malnutrition, and reproductive and infectious morbidity (Christian 1998a), and increase risk of mortality 1-2 years following delivery (Christian 2000).

Observational studies in sub-Saharan Africa have shown low serum vitamin A levels in HIV-infected women to be associated with significantly increased rates of MTCT of HIV (Semba 1994, Dushimimana 1992) and infant mortality (Dushimimana 1992, Semba 1995). However, four observational studies in the United States provided conflicting results: low serum vitamin A was associated with a higher risk of MTCT of HIV in two (Greenberg 1997, Landesmand 1996), but not the other two (Burger 1997, Burns 1999). However, these studies used different definitions for vitamin A deficiency (serum retinol levels <30mg/dl used by Semba et al (Burns 1999, Greenberg 1997); <20mg/dl used by Burger et al (Burger 1997) and had small sample sizes (e.g. in the Burger study, only 4/95 (4.2%) of women had serum retinol levels <20mg/dl).

Given the magnitude of the paediatric HIV epidemic in under-resourced countries (UNAIDS/WHO 2001) and the simplicity and low cost of vitamin A supplementation (Bell 1997), clarification of the role of vitamin A supplementation in MTCT of HIV is of considerable importance. This review aims to combine all high quality randomised trials comparing vitamin A supplementation with an appropriate control group conducted to date, to estimate the effect of vitamin A supplementation on MTCT of HIV, infant and maternal mortality and morbidity, as well as the tolerability of vitamin A supplementation. The ultimate goal is to determine whether vitamin A supplementation during pregnancy and lactation could be recommended as a public health policy to reduce MTCT of HIV. We have thus considered overall MTCT of HIV whether occurring during, before or after delivery.

This is one of a number of Cochrane reviews assessing the available evidence for decreasing the risk of HIV transmission from an infected mother to her child. Other topics include antiretroviral therapies (Brocklehurst 2002), vaginal disinfection (Shey Wiysonge 2002), delivery by Caesarean section, and avoidance of breastfeeding.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support

The primary objective of this review is to estimate the effect of vitamin A supplementation during pregnancy, compared to an appropriate control group, on the risk of mother-to-child transmission of HIV infection.

The secondary objectives are to estimate the effect of vitamin A supplementation on infant and maternal mortality and morbidity and to describe any side effects for the mother and the neonate.

 

Criteria for considering studies for this review

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support
 

Types of studies

Only randomised controlled trials were considered for this review.

 

Types of participants

Known HIV-infected women (as diagnosed by an antibody test): any age, any stage of pregnancy, any clinical stage of HIV disease, whether exposed to another intervention aimed at reducing mother-to-child transmission of HIV or not.

Trials assessing the effect of vitamin A supplementation on adverse pregnancy outcomes for HIV negative women and those of unknown HIV serostatus were not included in this review. A Cochrane review is on-going on this topic (Kulier 2002).

 

Types of intervention

Vitamin A supplementation during pregnancy compared with no vitamin A supplementation. The latter was either placebo or micronutrient supplementation when the intervention was a combination of vitamin A and micronutrients.

 

Types of outcome measures

The primary outcome measure is the HIV infection status of the child (as defined by the authors).

The secondary outcome measures are both fetal/infant and maternal:

Fetal/infant:
1. Infant death
2. Stillbirth
3. Neonatal sepsis (as defined by the authors)
4. Neonatal admission to neonatal unit
5. Later death of the child (as defined by the authors)
6. Side effects in the child (as defined by the authors)
7. Preterm delivery, less than 37 weeks of gestation
8. Very preterm delivery, less than 34 weeks of gestation
9. Birth weight
10. Low birth weight, less than 2500g
11. Very low birthweight, less than 2000g
12. Long term side effects in survivors

Mother:
1. Maternal death
2. Postpartum infection (as defined by the authors)
3. Side effects in the mother (as defined by the authors)
4. Cost of the intervention
5. Acceptability of the intervention.

 

Search strategy for identification of studies

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support

See: Cochrane HIV/AIDS Group search strategy

Electronic searches were undertaken in CENTRAL/CCTR (Cochrane Library Issue 1, 2002), Cochrane Pregnancy and Childbirth register, PubMed (2001 onwards), EMBASE, AIDSLINE, LILACS, AIDSTRIALS, AIDSDRUGS, using the following terms: (caroten* OR retinoic OR retinol OR vitamin* OR micronutrient*) AND (pregnancy OR pregnant OR antepartum OR antenatal OR prenatal OR prepart*). Standardised methodological filters for identifying controlled trials were applied (Lefebvre 2000; Clarke 2001), as appropriate. The methodological filter we used for PubMed was ("randomized controlled trial" [pt] OR "controlled clinical trial" [pt] OR "randomized controlled trials" [mh] OR "random allocation" [mh] OR "double-blind method" [mh] OR "single-blind method" [mh] OR "clinical trial" [pt] OR "clinical trials" [mh] OR (clinica* [tw] AND trial* [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR (latin [tw] AND square [tw]) OR placebos [mh] OR placebo* [tw] OR random* [tw] OR volunteer* [tw] OR "research design" [mh:noexp]) NOT (animal [mh] NOT human [mh]), and that for EMBASE was (CLINICAL-TRIAL (DE) OR RANDOMIZED-CONTROLLED-TRIAL (DE) OR trial* OR compar* OR DOUBLE-BLIND-PROCEDURE (DE) OR PLACEBO (DE) OR versus OR MULTICENTER-STUDY (DE) OR assign* OR allocat* OR singl* adj blind* OR CROSS-OVER-PROCEDURE (DE) OR PHASE-3-CLINICAL-TRIAL (DE) OR INTERMETHOD-COMPARISON (DE) OR volunteer* OR SINGLE-BLIND-PROCEDURE (DE)). The "Related articles" feature of PubMed was also used.

The above search strategy was supplemented by searching reference lists of identified articles and abstracts or proceedings of the International Conference on AIDS, the Conference on Retroviruses and Opportunistic Infections, the Conference on Global Strategies for the Prevention of HIV Transmission From Mothers to Infants, and the International Vitamin A Consultative Group Symposium. Investigators of identified trials and other content experts, agencies, organisations, academic centres, and pharmaceutical companies were contacted to locate any further trials (completed or ongoing, published or not) that may not have been included in the electronic databases or presented at the conferences and symposia. Relevant editorials, expert opinions and letters to the editor were also scrutinised for any additional relevant studies or unpublished data.

There were no language restrictions to our search.

 

Methods of the review

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support

Three reviewers (CSW, JS and PB) undertook the review. CSW conducted the literature search, noting the date each database was searched and years covered by the search, and JS and PB were informed of its progress.

Studies identified by the search strategy were scrutinised independently for eligibility by CSW and PB. Studies were included if they were controlled trials (study design) comparing vitamin A supplementation with no vitamin A supplementation (intervention) in HIV infected pregnant women (participants) and information was available on any of the outcome variables. CSW and PB then independently assessed included studies for methodological quality. Quality assessment was based on the method of assigning participants to interventions (Clarke 2001) as follows:

Category A - Adequate allocation concealment (such as centralised or pharmacy-controlled randomisation; pre-numbered or coded identical containers administered serially to patients; on-site computer system combined with allocations kept in a locked unreadable computer file that can be accessed only after the characteristics of an enrolled participant have been entered; sequentially numbered, sealed, opaque envelopes);

Category B - Uncertainty about whether the allocation was adequately concealed (for example, merely stating that a list or table was used, that sealed envelopes were used, or that the participants were randomly assigned); and

Category C - Inadequate allocation concealment: if the approach used was alternation; use of case record numbers, dates of birth, day of the week, open list of random numbers, etc.

After quality assessment, the two reviewers extracted the data. We designed forms for data extraction and for requesting additional information from the investigators. On data abstraction forms was noted the review title, study reference and publication status, date of extraction, and reviewer's initials. Data were extracted under the following subheadings in the form: methods (method of randomisation and allocation concealment, blinding of those receiving and providing care and outcome assessors, losses to follow-up and how they were handled), participants (setting; number of women randomised, baseline vitamin A level, gestational age at initiation of supplementation), interventions (supplementation dose, length of supplementation, type of control group, co-interventions), outcomes (children infected with HIV, infant death, stillbirth, neonatal sepsis, neonatal admission to neonatal unit, later death of the child, side effects in the child, preterm delivery, very preterm delivery, birth weight, low birth weight, very low birth weight, long term side effects in survivors, maternal death, maternal postpartum infection, side effects in the mother, cost of the intervention, number of complaints), and other notes. If data were available on MTCT of HIV at two or more periods, the more complete or later one was taken into account. The data extracted for dichotomous variables were the number of affected participants and the number of participants in the comparison group; and for continuous variables, the mean, the standard deviation and the number of participants in the comparison group. Missing data were sought from the investigators.

Disagreement between reviewers on the eligibility or quality of a trial, data extracted, or other aspects of the review was resolved by discussion. When more information was needed, we wrote to first authors of main trial reports. Any study that satisfied the design, intervention and participant criteria but for which none of the pre-specified outcomes could be obtained is referenced as one awaiting assessment. When we obtain the required information, the trials will be included in the next update of the review. Reviewers assessing study eligibility and quality were not blinded to the names of the authors, their institutions, journals of publication, and results of the study.

Meta-analysis was undertaken using the latest version of Review Manager (RevMan). Study results for dichotomous data were expressed as odds ratios and combined using a fixed effect (Mantel-Haenszel) method. Heterogeneity between studies was examined by graphical inspection of results followed by a chi-square test of homogeneity. We planned to use meta-regression to explore the effect of trial quality and other trial characteristics (including adequacy of baseline vitamin A intake, presence or not of co-interventions, and type of control group) on estimated treatment effects, but the number of trials was not sufficient. We did not plan subgroup analyses based on patient characteristics, a priori, as these are better investigated using individual patient-data meta-analysis.

 

Description of studies

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support

See Table 'Characteristics of Included Studies' for complete description of trials.

 

Methodological quality

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support

Coutsoudis 1999
The method of allocation concealment is not clear from trial reports. The trial is reported as "double-blind" and "randomised", but the exact method is not reported. Fifty seven (7.8%) of 728 women for whom outcomes were not available were excluded from the analysis.

Fawzi 1998a
There was adequate allocation concealment from the trial reports. Randomisation was done in blocks of 20. At enrollment, each eligible woman was assigned the next numbered bottle of study drug. Fifty four (5%) of 1085 women were lost to follow-up, and excluded from the analysis.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support

We identified five eligible trials, only two of which included an estimate of the effect of vitamin A on at least one of the pre-specified outcomes. For the other three (Friis 1997; Semba 1997; ZVITAMBO Project), we are awaiting information requested from the investigators.

Based on the two included trials, with a total of 1813 participants, there is no evidence that vitamin A supplementation has an effect on mother-to-child transmission of HIV (odds ratio (OR) 1.09, 95% confidence interval (CI) 0.81 to 1.45). There is no evidence of heterogeneity between the trials (p = 0.37), and no evidence of an effect of vitamin A supplementation in HIV-infected pregnant women on stillbirths (OR 1.07, 95% CI 0.63 to 1.80), very preterm births, i.e. born less than 34 weeks gestation (OR 0.86, 95% CI 0.57 to 1.31), all preterm births, i.e. born less than 37 weeks gestation (OR 0.88, 95% CI 0.68 to 1.13), low birth weight, i.e. weighing less than 2500g (OR 0.86, 95% CI 0.64 to 1.17), and very low birthweight, i.e. weighing less than 2000g (OR 0.71, 95% CI 0.40 to 1.28), and postpartum CD4 levels (weighted mean difference -4.00, 95% CI -51.06 to 43.06). In the study by Coutsoudis and collaborators (Coutsoudis 1999), vitamin A supplementation reduced MTCT of HIV in preterm infants. This finding is suspect given differences between the vitamin A and placebo groups, e.g. a smaller proportion of preterm deliveries in the vitamin A group compared to those born in the placebo group were breastfed, born by Caesarean section, had aneamia, and higher CD4+ cell counts.

The effect of vitamin A supplementation on maternal mortality could not be assessed, as there were only three maternal deaths.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support

Vitamin A is postulated to reduce MTCT of HIV by affecting several maternal, fetal, and/or child risk factors for transmission (Fawzi 1998; Fawzi 2000) including the clinical, immunological, or viral stage of HIV disease among pregnant women; the integrity of the epithelial lining of the placenta, maternal lower genital tract, or breast; the occurrence of prematurity and low birth weight; and the status of the systemic and digestive mucosal immune systems of the fetus and the child.

Overall, the two trials did not show a significant effect of vitamin A supplementation on the frequency of low birth weight and preterm delivery among HIV-infected pregnant women. One trial which compared vitamin A supplementation to placebo (Coutsoudis 1999), suggests significant reductions in the frequency of preterm birth (OR 0.60, 95% CI 0.39 to 0.93 for all preterm births and OR 0.36, 95% CI 0.14 to 0.93 for very preterm births) and non-significant reductions for low birth weight. The other trial which compared vitamin A plus micronutrient supplementation with micronutrient supplementation alone (Fawzi 1998a) is compatible with a modest protective effect of vitamin A against low birth weight, although this result is not statistically significant, and combining the data from both trials suggests no significant effect of vitamin A on these outcomes. There was no significant effect of supplementation on postpartum CD4 cell counts, for the trial that reported this outcome.

The two trials show no evidence that antenatal and intrapartum vitamin A supplementation has an effect on MTCT of HIV. However, the sample sizes of these trials were calculated for an expected reduction of MTCT of HIV rate of 30% with a baseline risk of 30% and thus have limited power to detect vitamin A benefits on adverse pregnancy outcomes with a lower incidence. The situation should become clearer when data from future trials are combined. One trial suggested significant reductions of MTCT of HIV in preterm babies. We did not plan subgroup analyses based on patient characteristics in this systematic review as these are better investigated using individual patient-data meta-analyses.

There was no statistically significant effect on stillbirths. The effect of vitamin A supplementation on maternal mortality could not be assessed, as there were only three maternal deaths. A large, high quality randomised placebo-controlled trial in women of unknown HIV status in Nepal (West 1999) showed a significant 40% reduction in maternal mortality with supplementation.

Vitamin A is a known teratogen, with a suggested dose-response effect. Although the doses of vitamin A used in the trials were within the currently recommended safe low doses (IVACG 1998; WHO 1998), neither trial reported information on the potential adverse effects of vitamin A.

In developed countries the incorporation of the three-pronged approach of (a) zidovudine or combination antiretroviral regimens (Brocklehurst 2002), (b) elective Caesarean section delivery and (c) formula feeding into clinical practice coupled with increased prenatal HIV-1 counselling and testing has resulted in MTCT of HIV rates of 2% or less in those countries (Mofenson 2000). However, due to their complexity, cost and other constraints many less-developed countries are having difficulties implementing these interventions (Shey Wiysonge 2001; McIntyre 2002); thus there is a need for simpler and less costly options.

Vitamin A is easily provided through existing health services, and has been shown to be effective in reducing child mortality by approximately 30% (Fawzi 1993; Glasziou 1993). Using data from Tanzania, Bell and Sacks (Bell 1997) estimated that the savings in health care costs and lost productivity associated with HIV exceed the vitamin A programme expenditures if a 3% reduction in MTCT of HIV is achieved. The cost-effectiveness was based on, but not sensitive to, an antenatal seroprevalence of 12.5%, a compliance of 60%, and baseline transmission of 32%. Therefore, given the cost-efffectiveness of a vitamin A supplementation programme for reducing MTCT of HIV (Bell 1997), even substantially lesser degrees of benefit on MTCT of HIV and pregnancy outcomes than those achieved for childhood mortality may be acceptable to less-developed countries. Vitamin A deficiency is common in most populations of less-developed countries (WHO 1995) and preventing the deficiency through natural dietary means is unrealistic in most of these populations. It is thus necessary to clarify the effect of vitamin A supplementation on MTCT of HIV and infant and maternal mortality. Such clarification is important to programme managers and policy-makers considering affordable options for reducing MTCT of HIV and improving reproductive health care in resource-limited countries.

We identified five eligible trials, only two of which included an estimate of the effect of vitamin A on at least one of the pre-specified outcomes. For the other three (Friis 1997, Semba 1997, ZVITAMBO Project) we are awaiting information requested from the investigators. Once we obtain the required information, the trials will be included in the next update of the review.

Data from only two trials may be insufficient in providing conclusive evidence on the effects of vitamin A on MTCT of HIV, but the association between low serum vitamin A levels and increased risk of MTCT of HIV seen in observational studies (Dushimimana 1992; Semba 1994; Landesmand 1996; Greenberg 1997) could have other explanations. For example, low serum vitamin A levels may be a marker of advanced HIV-1 infection and not causally related to MTCT of HIV (Burger 1997; Burns 1999).

The effects of antenatal and intrapartum supplementation of HIV-infected women on MTCT of HIV and pregnancy outcomes will become more precisely known as more trials report their findings.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support

 

Implications for practice

At the present time there is no conclusive evidence that the antenatal and intrapartum use of vitamin A supplementation to reduce mother-to-child transmission of HIV and adverse pregnancy outcomes should be recommended.

 
Implications for research

The current review will be updated as soon as data from other studies (Friis 1997; Semba 1997; ZVITAMBO Project) become available. This review and the review in progress on vitamin A supplementation in pregnant women of seronegative/unknown HIV status (Kulier 2002) should be considered together in order to shed more light on the effect of vitamin A supplementation on non-HIV related adverse pregnancy outcomes.

 

Potential conflict of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support

None known

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support

We are grateful to Prof Aubrey Sheiham, Sir Iain Chalmers, Dr Phil Alderson, Prof Alfred Sommer, Prof Justus Hofmeyr, the staff of the Cochrane Collaboration Secretariat and the UK Cochrane Centre, and the editorial base of the Cochrane HIV/AIDS and Pregnancy and Childbirth Groups for their support in the course of preparing this review.

 

Characteristics of included studies

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support


StudyCoutsoudis 1999

MethodsDescribed as randomised double-blind.
Eight percent of mother-infant pairs lost to follow-up and excluded from the analysis.

Participants728 HIV-infected women at 17-39 weeks' gestation in KwaZulu-Natal province of South Africa; 30.6% of whom had serum retinol levels < 20 µg/dl.

InterventionsDaily oral vitamin A (5000 IU retinyl palmitate and 30 mg beta-carotene) or placebo. At delivery, women in the vitamin A group received a dose of 200,000 IU of retinyl palmitate while the placebo arm received an identical placebo.

OutcomesStillbirths, HIV infection in the child, neonatal deaths, preterm birth, birthweight, low birthweight.

NotesNo woman received any antiretroviral therapy. It is not stated in the trial reports whether the women also received iron, folic acid, and/or chloroquine.

Allocation concealmentB






StudyFawzi 1998a

MethodsRandomised, placebo-controlled, double-blind.
Five percent of mother-infant pairs were lost to follow-up and excluded from the analysis.

Participants1085 pregnant HIV-infected women at 12-27 weeks' gestation resident in Dar es Salam, Tanzania.
The prevalence of vitamin A deficiency at baseline is not stated.

InterventionsDaily oral dose of one of: vitamin A (30mg beta carotene + 5000 IU retinyl palmitate) alone, multivitamins ( 20mg B1, 20mg B2, 25mg B6, 100mg niacin, 50microg B12, 500mg C, 30 mg E, and 0.8 mg folic) plus vitamin A, multivitamins without vitamin A, or placebo. At delivery, women receiving any vitamin A were given an additional 200,000 IU oral dose of vitamin A while the others received an extra dose of placebo.

OutcomesStillbirths, HIV infection in child, preterm delivery, low birthweight, postpartum CD4 levels.

NotesIt is not mentioned in this trial whether any woman received antiretroviral therapy.
All women were given daily oral doses of iron and folic acid, and weekly doses of chloroquine.

Allocation concealmentA



 

Characteristics of ongoing studies

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support


StudyZVITAMBO Project

Trial name or titleZimbabwe Vitamin A for Mothers and Babies Project (ZVITAMBO).

Participants14,100 mother-infant pairs (32.5% of mothers HIV-positive) enrolled at delivery from maternity units in Greater Harare, Zimbabwe.

InterventionsA single oral dose of vitamin A given to mothers (400,000 IU) and/or neonates (50,000 IU) within 96 hours of delivery.

OutcomesInfant mortality, mother-to-child transmission of HIV, and incident HIV infections in women post-partum.

Starting dateNovember 1997

Contact informationZVITAMBO Project, 21 Van Praagh Avenue, Milton Park, Harare, Zimbabwe.
Email: zvitambo@icon.co.zv

NotesPrimary results expected in early 2002



 

Graphs

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support

 
Comparison 01. Vitamin A supplementation versus no vitamin A supplementation

Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size

01 HIV infection in child
 FigureFigure 1. 01 HIV infection in child
21085Odds Ratio (Fixed) 95% CI1.09 [0.81, 1.45]

02 Stillbirth
 FigureFigure 2. 02 Stillbirth
21692Odds Ratio (Fixed) 95% CI1.07 [0.63, 1.80]

03 Preterm less than 34 weeks
 FigureFigure 3. 03 Preterm less than 34 weeks
21578Odds Ratio (Fixed) 95% CI0.86 [0.57, 1.31]

04 Preterm less than 37 weeks
 FigureFigure 4. 04 Preterm less than 37 weeks
21577Odds Ratio (Fixed) 95% CI0.88 [0.68, 1.13]

05 Low birth weight less than 2500g
 FigureFigure 5. 05 Low birth weight less than 2500g
21486Odds Ratio (Fixed) 95% CI0.86 [0.64, 1.17]

06 Low birthweight less than 2000g
 FigureFigure 6. 06 Low birthweight less than 2000g
21483Odds Ratio (Fixed) 95% CI0.71 [0.40, 1.28]

07 Birthweight
 FigureFigure 7. 07 Birthweight
1689Weighted Mean Difference (Fixed) 95% CI16.00 [-68.76, 100.76]

08 Maternal death
 FigureFigure 8. 08 Maternal death
1728Odds Ratio (Fixed) 95% CI0.49 [0.04, 5.40]

09 Postpartum CD4 count
 FigureFigure 9. 09 Postpartum CD4 count
1727Weighted Mean Difference (Fixed) 95% CI-4.00 [-51.06, 43.06]

10 Neonatal sepsis
 FigureFigure 10. 10 Neonatal sepsis
00Odds Ratio (Fixed) 95% CINot estimable

11 Neonatal admission to neonatal unit
 FigureFigure 11. 11 Neonatal admission to neonatal unit
00Odds Ratio (Fixed) 95% CINot estimable

12 Later death of the child
 FigureFigure 12. 12 Later death of the child
00Odds Ratio (Fixed) 95% CINot estimable

13 Side effects in child
 FigureFigure 13. 13 Side effects in child
00Odds Ratio (Fixed) 95% CINot estimable

14 Long term side effects in survivors
 FigureFigure 14. 14 Long term side effects in survivors
00Odds Ratio (Fixed) 95% CINot estimable

15 Maternal post-partum infection
 FigureFigure 15. 15 Maternal post-partum infection
00Odds Ratio (Fixed) 95% CINot estimable

16 Acceptance of supplementation
 FigureFigure 16. 16 Acceptance of supplementation
00Odds Ratio (Fixed) 95% CINot estimable

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Criteria for considering studies for this review
  5. Search strategy for identification of studies
  6. Methods of the review
  7. Description of studies
  8. Methodological quality
  9. Results
  10. Discussion
  11. Authors' conclusions
  12. Potential conflict of interest
  13. Acknowledgements
  14. Characteristics of included studies
  15. Characteristics of ongoing studies
  16. Graphs
  17. Sources of support
 

External sources of support

  • Aubrey Sheiham Cochrane Collaboration Scholarship (CSW) UK
  • Department of Health (PB) UK

 

Internal sources of support

  • Department of Social Medicine, University of Bristol (JS) UK
  • Ministry of Public Health (CSW) CAMEROON

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Criteria for considering studies for this review
  6. Search strategy for identification of studies
  7. Methods of the review
  8. Description of studies
  9. Methodological quality
  10. Results
  11. Discussion
  12. Authors' conclusions
  13. Potential conflict of interest
  14. Acknowledgements
  15. Characteristics of included studies
  16. Characteristics of ongoing studies
  17. Graphs
  18. Sources of support
  19. References to studies included in this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
Coutsoudis 1999{published data only}
  • Coutsoudis A, Bobat RA, Coovadia HM, et al. The effects of vitamin A supplementation on the morbidity of children born to HIV-infected women. Am J Public Health 1995;85:1076-81.
  • Coutsoudis A, Moodley D, Pillay K, et al. Effects of vitamin A supplementation on viral load in HIV-1-infected pregnant women. J Acquir Immune Defic Syndr Hum Retrovirol 1997;15:86-87.
  • Coutsoudis A, Pillay K, Spooner E, et al. Randomized trial testing the effect of vitamin A supplementation on pregnancy outcomes and early mother-to-child transmission of HIV-1 in Durban, South Africa. AIDS 1999;13:1517-1524.
  • Filteau S, Rollins NC, Coutsoudis A, et al. The effect of antenatal vitamin A and Beta-carotene supplementation on gut integrity of infants of HIV-infected South African Women. J Pediatr Gastroenterol 2001;32:464-470.
  • Kennedy CM, Coutsoudis A, Kuhn L, et al. Randomized controlled trial assessing the effect of vitamin A supplementation on maternal morbidity during pregnancy and postpartum among HIV-infected women. J Acquir Immune Defic Syn 2000;24:37-44.
Fawzi 1998a{published data only}

References to studies awaiting assessment

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Criteria for considering studies for this review
  6. Search strategy for identification of studies
  7. Methods of the review
  8. Description of studies
  9. Methodological quality
  10. Results
  11. Discussion
  12. Authors' conclusions
  13. Potential conflict of interest
  14. Acknowledgements
  15. Characteristics of included studies
  16. Characteristics of ongoing studies
  17. Graphs
  18. Sources of support
  19. References to studies included in this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
Friis 1997
  • Friis H, Gomo E, Nyazema N, et al. The effect of maternal multimicronutrient supplementation. A conference on global strategies for the prevention of HIV transmission from mothers to infants. Washington, DC: 1997:87.
Semba 1997
  • Semba RD, Kumwenda N, Taha ET, et al. Plasma and breast milk vitamin A as indicators of vitamin A status in pregnant women. Int J Vitam Nutr Res 2000;7:271-277.
  • Semba RD, Kumwenda N, Taha TE, et al. Impact of vitamin A supplementation on anaemia and plasma erythropoietin concentrations in pregnant women: a controlled trial. Eur J Haematol 2001;66:389-395.
  • Semba RD, Miotti PG, Taha TE, et al. Maternal vitamin A supplementation and mother-to-child transmission of HIV. International Vitamin A Consultative Group Meeting. Cairo September 1997.

References to ongoing studies

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Criteria for considering studies for this review
  6. Search strategy for identification of studies
  7. Methods of the review
  8. Description of studies
  9. Methodological quality
  10. Results
  11. Discussion
  12. Authors' conclusions
  13. Potential conflict of interest
  14. Acknowledgements
  15. Characteristics of included studies
  16. Characteristics of ongoing studies
  17. Graphs
  18. Sources of support
  19. References to studies included in this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
ZVITAMBO Project
  • Zimbabwe Vitamin A for Mothers and Babies Project (ZVITAMBO).. Ongoing study November 1997.
  • Humphrey J, Ilif P, Nathoo K, et al. Rationale and design of the ZVITAMBO trial (Zimbabwe vitamin A for mothers and babies). Int Conf AIDS 2000;July 9-14:abstract no TuPeB3257.
  • Malaba L, Mbuya N, Miller M, et al. Haemoglobin distribution of HIV positive and HIV negative women during the immedate postpartum period in Harare, Zimbabwe. Int Conf AIDS 2000;July 9-14:abstract no ThPeB5042.

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Criteria for considering studies for this review
  6. Search strategy for identification of studies
  7. Methods of the review
  8. Description of studies
  9. Methodological quality
  10. Results
  11. Discussion
  12. Authors' conclusions
  13. Potential conflict of interest
  14. Acknowledgements
  15. Characteristics of included studies
  16. Characteristics of ongoing studies
  17. Graphs
  18. Sources of support
  19. References to studies included in this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
Bell 1997
  • Bell J, Sacks HS. Cost-effectiveness analysis of vitamin A supplementation to reduce perinatal transmission of HIV in developing countries. Conf Retroviruses Opportunistic Infect 1997, Jan 22-26;abstract no 520.
Brocklehurst 2002
Burger 1997
  • Burger H, Kovacs A, Weiser B, et al. Maternal serum vitamin A levels are not associated with mother-to-child transmission of HIV-1 in the United States. J Acquir Immune Defic Syndr Hum Retrovirol 1997;14:321-6.
Burns 1999
  • Burns DN, FitzGerald G, Semba RD, et al. Vitamin A deficiency and other nutritional indices during pregnancy in human immunodeficiency virus infection: prevalence, clinical correlates, and outcome. Clin Infect Dis 1999 1999;29:328-34.
Christian 1998
Christian 1998a
  • Christian P, Schulze K, Stoltzfus RJ, et al. Hyporetinolemia, illness symptoms, and acute phase protein response in pregnant women with and without night blindness. Am J Clin Nutr 1998;67:1237-1243.
Christian 2000
  • Christian P, West KP Jr, Khatry SK. Night blindness during pregnancy and subsequent mortality among women in nepal: effects of vitamin A and beta-carotene supplementation. Am J Epidemiol 2000;152:542-547.
Clarke 2001
  • Clarke M, Oxman AD, editors. Cochrane Reviewers' Handbook 4.1.4 [Updated October 2001]. Cochrane Library Issue 4, 2001. Oxford: Update software. Updated quarterly,
De Cock 2000
  • De Cock KM, Fowler MG, Mercier E, et al. Prevention of mother-to-child HIV transmission in resource-poor countries: translating research into policy and practice. JAMA 2000;283:1175-82.
Dushimimana 1992
  • Dushimimana A, Graham MN, Humphrey JH, et al. Maternal vitamin A levels and HIV-related birth outcome in Rwanda. Int Conf AIDS. Amsterdam 1992 Jul 19-24;abstract no POC 4221.
Fawzi 1993
Fawzi 1998
Fawzi 2000
Filteau 2001
  • Filteau SM, Rollins NC, Coutsoudis, et al. The effect of vitamin A and beta-carotene supplementation on gut integrity of infants of HIV-infected South African women. J Pediatr Gastroenterol 2001;32:464-70.
Glasziou 1993
Green 1928
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Greenberg 1997
IVACG 1998
  • International Vitamin A Consultative Group. IVACG Statement. Safe doses of vitamin A during pregnancy and lactation. International Vitamin A Consultative Group. Washington, IVACG 1998.
Kulier 2002
  • Kulier R, Gülmezoglu M, de Onis M, Villar J. Vitamin A supplementation during pregnancy (Protocol for a Cochrane Review). In: Cochrane Library, 1, 2002. Oxford: Update Software. 10.1002/14651858.CD001996
Landesmand 1996
  • Landesmand S. [Vitamin A relationships to mortality in HIV disease and effects on HIV infection: and late breaking studies]. Bethesda, MD: National Institutes of Health (Lawton Chiles International House) 1996.
Lefebvre 2000
  • Lefebvre C, Clarke MJ. Identifying randomised trials. In: Egger M, Davey Smith G, Altman DG, editor(s). Systematic reviews in health care: meta-analysis in context. London: BMJ Books, 2000.
McIntyre 2002
Mofenson 1994
  • Mofenson L. Epidemiology and determinants of vertical transmission of HIV. Sem Pediatr Infect Dis 1994;5:490-496].
Mofenson 2000
Newell 1998
Newell 2000
Rice 1998
  • Rice AL, Stolzfus RJ, De Francisco A, et al. Maternal vitamin A or beta-carotene supplementation in lactating Bangledashi women benefits mothers and infants but does not prevent sub clinical deficiency. J Nutr 1998;129:356-65.
Ross 1996
Semba 1995
Semba 1994
Semba 1998
Shey Wiysonge 2001
  • Shey Wiysonge C, Cunin P, Ayouba A, et al. Preventing vertical transmission of HIV-1: Cameroon's experience. Global Health Council's 28th Annual Conference. Washington DC, USA 2001, May 28 - June 04.
Shey Wiysonge 2002
UNAIDS/WHO 2001
  • UNAIDS/WHO. AIDS epidemic update. Geneva: Joint United Nations Programme on HIV/AIDS. UNAIDS/01.74-WHO/CDS/CSR/NCS/2001.2 (English original, December 2001).
West 1999
  • West KP Jr, Katz J, Khatry SJ, et al. Double blind, cluster randomised trial of low dose supplementation with vitamin A or beta carotene on mortality related to pregnancy in Nepal. The NNIPS-2 Study Group. BMJ 1999;318:570-575.
West 2001
  • West K, Darnton-Hill I. Vitamin A deficiency. In: Semba R, Bloem M, editor(s). Nutrition and Health in Developing Countries. Totowa, NJ: Humana Press, Inc, 2001:267-306.
WHO 1995
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WHO 1998
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