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Micronutrients and vertical transmission of HIV-1^1,2,3

¹ From the Departments of Nutrition (MLD and WWF) and Epidemiology (WWF), Harvard School of Public Health, Boston.

² Supported by the National Institute of Child Health and Human Development (NICHD R01 32257) and a training grant from the National Institutes of Health (DK07703).

³ Address reprint requests to ML Dreyfuss, Department of Population and Family Health Sciences, The Johns Hopkins University, Bloomberg School of Public Health, 615 North Wolfe Street, Room W4033, Baltimore, MD 21205. E-mail:
mdreyfus{at}jhsph.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MICRONUTRIENTS AND VERTICAL... POTENTIAL MECHANISMS OF ACTION... MICRONUTRIENTS AND SYSTEMIC... MICRONUTRIENTS AND HIV DISEASE... MICRONUTRIENTS AND PLACENTAL AND... MICRONUTRIENTS AND BREAST... MICRONUTRIENTS AND POOR BIRTH... MICRONUTRIENTS AND... SUMMARY REFERENCES

 
ABSTRACT Vertical transmission of HIV from mother to infant can occur during pregnancy, at the time of delivery, or post-natally through breast-feeding and is a major factor in the continu-ing spread of HIV infection. Inadequate nutritional status may increase the risk of vertical HIV transmission by influencing mater-nal and child factors for transmission. The potential effects on these factors include impaired systemic immune function in preg-nant women, fetuses, and children; an increased rate of clinical, immunologic, and virologic disease progression; impaired epithe-lial integrity of the placenta and genital tract; increased viral shed-ding in breast milk from inflammation of breast tissue; increased risk of low birth weight and preterm birth; and impaired gastroin-testinal immune function and integrity in fetuses and children. Micronutrient deficiencies are prevalent in many HIV-infected pop-ulations, and numerous studies have reported that these deficien-cies impair immune responses, weaken epithelial integrity, and are associated with accelerated HIV disease progression. Although low serum vitamin A concentrations were shown to be associated with an increased risk of vertical HIV transmission in prospective cohort studies, randomized, placebo-controlled trials have reported that vitamin A and other vitamin supplements do not appear to have an effect on HIV transmission during pregnancy or the intrapartum period. However, the ability of prenatal and postpartum micronu-trient supplements to reduce transmission during the breast-feeding period is still unknown. Am J Clin Nutr 2002;75:959-70.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MICRONUTRIENTS AND VERTICAL... POTENTIAL MECHANISMS OF ACTION... MICRONUTRIENTS AND SYSTEMIC... MICRONUTRIENTS AND HIV DISEASE... MICRONUTRIENTS AND PLACENTAL AND... MICRONUTRIENTS AND BREAST... MICRONUTRIENTS AND POOR BIRTH... MICRONUTRIENTS AND... SUMMARY REFERENCES

 
More than 36 million persons worldwide were infected with HIV by the end of 2000, and 5.3 million new cases were identified during the past year (1). About 95% of HIV infections are found in developing countries; sub-Saharan Africa, south Asia, and Southeast Asia have been most severely affected by the AIDS epidemic. More than 10% of adults, including 15–30% of women attending prenatal clinics in urban centers of sub-Saharan Africa, are infected with HIV.

Transmission of HIV from mother to infant can occur during pregnancy, at the time of delivery, or postnatally through breast-feeding. Vertical transmission rates of HIV in the absence of preventive measures are estimated to be 25–35% in developing countries compared with 15–25% in industrialized countries (2). An estimated 570000 children became infected with HIV during 1999, and 90% of these infections were acquired in utero, during delivery, or through breast-feeding from their HIV-infected mothers (3).

Both maternal and child factors influence vertical transmission, and many of these factors relate to nutritional status. Systemic cell-mediated immune function in pregnant women is a determinant of disease progression and may also protect against vertical transmission. Clinical, immunologic, and virologic factors of maternal disease progression increase the risk of vertical HIV transmission. Impaired epithelial integrity of the placenta and genital tract may increase the risk of transplacental and intrapartum transmission, respectively. Increased viral shedding in breast milk from inflammation of breast tissue may contribute to vertical transmission through breast-feeding. Low birth weight and preterm birth are risk factors for transmission during delivery and the breast-feeding period, or conversely, they may be consequences of transmission in utero. Systemic and gastrointestinal mucosal immune function in fetuses and children may also prevent vertical transmission.

Micronutrient deficiencies are prevalent in many HIV-infected populations, and numerous studies have reported that these deficiencies impair immune responses, weaken epithelial integrity, and are associated with accelerated HIV disease progression. Strong evidence from observational studies has led to interest in the potential of micronutrient supplementation as a cost-effective strategy for preventing vertical HIV transmission, particularly in countries where antiretroviral and prophylactic drugs are unavailable. In this article, we review the direct epidemiologic evidence that micronutrient status influences vertical HIV transmission and then discuss the potential mechanisms by which micronutrients might have an effect on transmission.

	MICRONUTRIENTS AND VERTICAL TRANSMISSION OF HIV

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Prospective studies
Many prospective cohort studies have examined the relation of nutritional status and vertical transmission of HIV, both in developed and developing countries. Their findings provide some evidence that low serum vitamin A concentrations among HIV-infected pregnant women are associated with an increased risk of vertical transmission. The first studies to identify this association were conducted among cohorts in sub-Saharan Africa where poor nutritional status among pregnant women is prevalent. In Malawi, a study of 338 HIV-infected pregnant women reported that the risk of vertical transmission to infants surviving to 1 y of age was significantly lower among women with higher serum vitamin A concentrations, ranging from 32% among women with moderate to severe vitamin A deficiency (serum retinol < 0.70 µmol/L) to 7% among women with normal vitamin A concentrations (serum retinol > 1.04 µmol/L) (Table 1) (4). A higher serum vitamin A concentration was also associated with a lower infant mortality rate among the offspring of this population of HIV-infected mothers. The mortality rates of infants born to women with moderate or severe vitamin A deficiency were 2–4 times those of infants born to women with higher serum vitamin A concentrations (9). A study from Rwanda reported that HIV-infected women with low serum vitamin A concentrations during pregnancy were more likely than were women with normal vitamin A concentrations to have an infant who died or was HIV-positive (5).

Two recent case-control studies reported conflicting results regarding vitamin A deficiency and heterosexual HIV transmission. In India, a low ß-carotene concentration was strongly associated with subsequent seroconversion among male and female patients from clinics that treat sexually transmitted diseases (10). In contrast, a low serum retinol concentration was independently associated with a decreased risk of seroconversion among Kenyan men with genital ulcers (11).

Alternative explanations should be considered when reviewing the association between maternal vitamin A concentrations and vertical HIV transmission. HIV infection could lead to vitamin A deficiency by adversely affecting nutrient absorption and metabolism. Furthermore, serum retinol, a biochemical indicator of vitamin A status, is depressed during the acute phase response to infection, even when liver stores are adequate (12). Therefore, rather than leading to a higher risk of vertical transmission, low serum vitamin A concentrations may be a result of advanced HIV disease, and this disease progression may account for the increased risk of transmission observed. The observed association could also be explained by residual confounding by other predictors of vertical transmission. Although most of the studies adjusted for indicators of disease progression, such as the CD4⁺ cell count and clinical symptoms of HIV infection, other factors (eg, access to care, opportunistic infections, and prevalence of other micronutrient deficiencies) were not assessed. Differing lengths of follow-up time may also have been a source of bias in these studies. The stage of disease or the length of follow-up time of infected women may have differed between vitamin A–sufficient and vitamin A–deficient persons so that vitamin A–deficient women were more likely to develop AIDS and to be excluded from the study cohort (13). Finally, a limitation in the design of some of these studies is that they did not take into account that the association of maternal vitamin A status and vertical HIV transmission may vary by the route of transmission. These studies determined infant HIV status at different times in the postpartum period; therefore, a distinction between transmission by the transplacental, intrapartum, or breast-feeding routes could not be made. In addition, mothers in the US cohorts were not breast-feeding, so the association between the risk of transmission via this route and vitamin A deficiency could not be assessed.

Supplementation trials
In light of the observational evidence of an association between vitamin A status and the risk of vertical transmission of HIV, randomized, placebo-controlled trials were conducted to assess the efficacy of micronutrient supplements in reducing the risk of vertical transmission. In Malawi, 697 HIV-infected pregnant women were randomly assigned to receive 3000 µg retinol equivalents (RE) preformed vitamin A (10000 IU) or placebo daily during pregnancy. Supplementation had no significant effect on vertical transmission assessed at 6 wk or at 12 mo postpartum (14). In a South African trial, pregnant women received vitamin A [1667 µg RE (5000 IU) preformed vitamin A plus 30 mg (5000 µg RE) ß-carotene] or placebo daily during their third trimester (15). Vertical transmission of HIV was not significantly different between the offspring (at 3 mo of age) of these 2 groups: 20.3% in the vitamin A group and 22.3% in the placebo group. Among infants born preterm, vitamin A supplements reduced the risk of transmission by 50%, but this effect was not significant after multivariate adjustment for other predictors of transmission not balanced between the treatment groups. A placebo-controlled trial in Tanzania randomly assigned HIV-positive pregnant women at 12–27 wk gestation to receive daily prenatal supplements of vitamin A [1667 µg RE (5000 IU) preformed vitamin A plus 30 mg (5000 µg RE) ß-carotene], multivitamins (including folate, thiamine, riboflavin, niacin, and vitamins B-6, B-12, C, and E), both, or neither in a 2 x 2 factorial design (16). Neither vitamin A (relative risk: 1.06; 95% CI: 0.81, 1.39) nor multivitamins (relative risk: 0.95; 95% CI: 0.73, 1.24) had a significant effect on the risk of HIV transmission or survival through 6 wk postpartum. However, multivitamin supplements, but not vitamin A, reduced the risk of fetal death by 40% (17). Because the HIV status of fetal deaths was not known, it is not possible to distinguish whether this effect was due to prevention of transplacental transmission or to other determinants of fetal death.

There are currently 2 other placebo-controlled trials being conducted in Zimbabwe to evaluate the efficacy of nutritional supplements on vertical HIV transmission (18). In one trial, investigators at the Ministry of Health in Zimbabwe, the Johns Hopkins University, and McGill University are testing the efficacy of a single, large dose of vitamin A given to women or their infants at birth on the risk of transmission through breast-feeding and on other health outcomes in infants. This study plans to enroll 4000 women. In the second trial, researchers at the University of Zimbabwe and the Royal Veterinary and Agricultural University in Denmark are examining the efficacy of a multivitamin supplement or a placebo during pregnancy to reduce the vertical transmission risk among 600 HIV-positive women.

	POTENTIAL MECHANISMS OF ACTION FOR MICRONUTRIENTS IN THE VERTICAL TRANSMISSION OF HIV

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There are numerous biological mechanisms by which adequate nutrition could reduce the risk of vertical transmission of HIV (Table 2). Micronutrients can improve systemic humoral and cellular immune function in women and their infants and reduce the rate of clinical, immunologic, and virologic HIV disease progression. Micronutrients may also strengthen the epithelial integrity of the placenta and the lower genital tract, reduce the risk of placental infection, and enhance mucosal genital tract immunity to protect against fetal exposure to HIV. Improved nutritional status may reduce inflammation of breast tissue that is associated with HIV viral shedding in breast milk and thereby reduce the risk of vertical transmission through breast-feeding. Rates of low birth weight and preterm birth can be reduced by micronutrient supplementation, and systemic and gastrointestinal immune function in fetuses and children may also benefit from micronutrients, providing additional defenses against vertical transmission. Evidence for these potential mechanisms of action are given below.

	MICRONUTRIENTS AND SYSTEMIC IMMUNITY AND INFECTION

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Animal and human studies provide evidence that various B vitamins influence both cellular and humoral immune function. Animal studies have found that vitamin B-6 deficiency is associated with reduced lymphocyte proliferation and cell-mediated cytotoxicity, delayed-type hypersensitivity (DTH) skin responses, and reduced antibody production. Vitamin B-6 depletion in the elderly resulted in decreases in lymphocyte production, mitogenic responses of peripheral blood lymphocytes to B and T cell mitogens, and interleukin 2 (IL-2) production (30). A study in HIV-positive patients reported that vitamin B-6 deficiency is associated with a reduced lymphocytic response to mitogens and natural killer cell cytotoxicity, but lymphocyte counts and serum antibody concentrations did not vary by vitamin B-6 status (31). In vitro, low concentrations of folic acid were shown to impair neutrophil phagocytosis, and folic acid repletion improved neutrophil activity (32). Neutrophil function was also reduced in clinical studies of vitamin B-12 deficiency, and vitamin B-12 supplementation improved antibody immunity and mitogenic responses in animal and in vitro studies (32).

Antioxidant vitamins are important enhancers of immune function. Vitamin E deficiency is associated with impairment of cell-mediated immune functions, such as the DTH skin response, neutrophil phagocytosis, and lymphocyte proliferation in human and animal studies (33). Vitamin E supplementation has immunostimulatory benefits in AIDS-infected mice, including increased IL-2 production and natural killer cell cytotoxicity and a reduced production of inflammatory cytokines such as tumor necrosis factor and IL-6 (34,35). Short-term, high-dose vitamin E supplementation in elderly subjects significantly increased lymphocyte proliferation from mitogen stimulation, IL-2 production, and the DTH response (36). Longer-term vitamin E supplementation at lower dosages also increased the DTH response and improved the antibody response to T cell–dependent vaccines (37). Vitamin C deficiency negatively affects cellular immune responses in animal studies (33). Vitamin C supplementation has improved T- and B-lymphocyte proliferative responses in some human studies (33), and the incidence of infection was lower among elderly subjects with enhanced vitamin C status (38). In a study of patients with cystic fibrosis, poor vitamin C status was associated with a higher concentration of proinflammatory cytokines, including IL-6 and ₁-acid glycoprotein (39).

Zinc deficiency has widespread negative effects on immunity and increases the risk of infections because of zinc's central role in many aspects of immune function (40). Zinc is necessary for the normal function of neutrophils, natural killer cells, and macrophages and for the production and activity of T and B lymphocytes. Zinc supplementation trials in children showed significant reductions in diarrheal and respiratory infections and malaria (41). Selenium is an essential structural component of the antioxidant enzyme glutathione peroxidase, and it has numerous important functions in the maintenance of humoral and cell-mediated immunity (42). Selenium deficiency inhibits neutrophil function, the cytoxicity of T lymphocytes and natural killer cells, lymphocyte proliferation in response to mitogens, the DTH response, antibody production, and resistance to pathogens (42). In a small study of selenium depletion and supplementation in patients with gut failure and receiving parenteral nutrition, 2–4 mo of supplementation with a moderate dose of selenium improved lymphocyte responses to various mitogens and antigens (43).

Some trials examined the effects of multivitamin and mineral supplementation on immune function and illness. A short-term trial among elderly patients of supplementation with vitamins A, C, and E significantly increased the number of T lymphocytes and the proliferation response to phytohemagglutinin (44). In a longer-term randomized, placebo-controlled trial among healthy elderly followed for 12 mo, multivitamin and mineral supplementation had wide-ranging positive effects on humoral and cell-mediated immune function and on the risk of infection. Subjects in the supplemented group had a greater number of CD4⁺ and CD3⁺ T lymphocytes and natural killer cells; a better lymphocyte proliferation response to mitogens; a greater natural killer cell activity, IL-2 production, and antibody responses to vaccine; and 50% fewer days of infectious illness than did the placebo group (45).

	MICRONUTRIENTS AND HIV DISEASE PROGRESSION

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It is important to elucidate the potential benefits of micronutrients in slowing clinical, immunologic, and virologic disease progression because the stage of HIV disease is a key determinant of vertical transmission. Longitudinal studies to assess the role of micronutrients in progression of HIV disease have examined dietary intake and biochemical concentrations of micronutrients. Two long-term prospective studies, the Multicenter AIDS Cohort Study (MACS; 46) and the San Francisco Men's Health Study (SFMHS; 47), recruited and followed cohorts of HIV-positive homosexual or bisexual men. The nutritional intakes and the status of the men were assessed at baseline and linked with subsequent HIV disease progression. The MACS also assessed serum micronutrient concentrations at baseline. There were also 2 large randomized trials in sub-Saharan Africa that were designed to examine the effects of micronutrient supplementation on the vertical transmission of HIV. These trials evaluated the effect of vitamin supplements on clinical, immunologic, and virologic disease progression. In the South African study, the effects of prenatal vitamin A supplements were studied, whereas the study in Tanzania compared the effects of prenatal vitamin A, multivitamins, or both with those of placebo. A summary of evidence of the relation between micronutrients and HIV disease progression is given in Table 3.

Randomized trials
In contrast with evidence from prospective studies, randomized trials have not shown that vitamin A supplementation slows HIV disease progression among adults. In short-term trials, a single, large dose of vitamin A did not alter the load of HIV or CD4⁺ cell counts among HIV-infected intravenous drug users in the United States (52,53). Analysis of a subsample of women from the trial in South Africa on vertical HIV transmission showed that vitamin A and ß-carotene supplementation during the third trimester of pregnancy has no effect on the load of HIV (54) and that vitamin A supplementation does not slow the immunologic progression of HIV disease. In the large randomized trial among HIV-infected pregnant women in Tanzania, daily vitamin A supplementation had no significant effect on CD4⁺, CD8⁺, and CD3⁺ cell counts during pregnancy (17).

ß-Carotene
Prospective studies
Some observational and experimental studies have examined the specific role of ß-carotene in HIV progression because it has unique antioxidant properties in addition to its role as a contributor to body stores of vitamin A. The dietary intake of ß-carotene was not associated with immunologic or clinical progression of HIV among subjects in the SFMHS (48). Among HIV-infected men in the MACS cohort, subjects with ß-carotene intakes in the third quartile had improved survival relative to those with intakes below the median (55). A high ß-carotene intake was not protective, mirroring the U-shaped association with progression (49) and mortality risk (55) observed with vitamin A intake in this population.

Randomized trials
Intervention studies have also yielded equivocal results. A small randomized crossover study of 21 HIV-positive subjects reported that 4 wk of daily ß-carotene supplementation resulted in significant increases in white blood cell counts, the percentage change in CD4⁺ cell counts, and the percentage change in the ratio of CD4⁺ to CD8⁺ cells, and these indexes decreased when subjects were switched to placebo (59). However, a larger randomized, placebo-controlled trial (n = 72) by the same investigators using the same dose of ß-carotene failed to show any effect after 3 mo of supplementation (60). However, all subjects in this trial were also given daily multivitamin supplements that included 1667 µg RE (5000 IU) vitamin A, and the authors suggest that this may explain why the additional 180 mg (30000 µg RE) ß-carotene had no effect. In another study with nonplacebo control subjects, 52 HIV-positive patients with CD4⁺ cells counts <400 x 10⁶/L were randomly assigned to receive 60 mg (10000 µg RE) ß-carotene or 250 µg Se/d for 1 y (61). Neither micronutrient had an effect on the CD4⁺ cell count, although various measures of oxidative stress improved.

B vitamins
Intakes of thiamine, riboflavin, and niacin were positively associated with the CD4⁺ cell count and inversely associated with HIV disease progression among men in the SFMHS cohort (48). In the MACS, higher intakes of these same vitamins, along with vitamin B-6, were associated with a slower progression to AIDS, but only niacin remained significantly associated in the multivariate model (49). A high intake of B vitamins and use of vitamin B supplements were also associated with improved survival in this cohort (55). Vitamin B-12 and folate intakes were not related to progression or survival. However, subjects from the MACS cohort with low serum vitamin B-12 concentrations progressed to AIDS in approximately half the time that subjects with adequate serum vitamin B-12 concentrations did (62). Low serum folate and vitamin B-6 concentrations were not associated with disease progression or with a decrease in the CD4⁺ cell count. In an 18-mo prospective study of HIV-infected men in Miami, CD4⁺ cell counts decreased significantly among subjects developing vitamin B-12 deficiency and increased significantly among those whose serum vitamin B-12 concentrations normalized during the same period (51). A retrospective case-control analysis among HIV-infected patients in South Africa reported that patients who took B vitamins more than doubled their progression time to AIDS and increased their survival time by 120 wk (65). Experimental trials of B vitamin supplementation alone have not been conducted.

Vitamins C and E
Progression to AIDS was slower with a higher intake of vitamins C and E among subjects in the SFMHS (48). In the MACS cohort, subjects with the highest quartile of vitamin C intake had significantly more AIDS-free time than did those with lower intakes, but no significant difference was observed with intakes of vitamin E (49). Time to death did not vary by intake of either nutrient in this cohort (55). However, the serum vitamin E concentration in the highest quartile was associated with a 34% decrease in the risk of progression to AIDS compared with the lowest quartile in this population (50). Nevertheless, the serum vitamin E concentration was not correlated with changes in CD4⁺ counts over time (50,51) or with risk of death (58). In a randomized, placebo-controlled trial among HIV-infected patients, large daily doses of vitamin C and E reduced the load of HIV during 3 mo of supplementation, whereas the viral load increased in the placebo group (63).

Trace elements
Trace elements may also have an effect on the progression of HIV disease. The dietary intake of iron but not zinc was positively associated with CD4⁺ cell counts at baseline and inversely associated with HIV disease progression in the SFMHS cohort (48). However, the risk of disease progression (49) and of mortality (55) progressively increased with increasing zinc intakes in the MACS cohort. Zinc supplement use also increased the risk of mortality (55). A nested case-control study from the MACS cohort did not find dietary intake or tissue concentrations of zinc and copper to be associated with AIDS progression (64). However, lower serum zinc and higher serum copper concentrations significantly predicted progression, and the study's authors hypothesized that serum concentrations of these nutrients are markers of disease progression and are not causally related. Another study among HIV-positive homosexual men found that normalization of serum zinc concentrations during 18 mo of follow-up was associated with a significant increase in CD4⁺ cell counts (51). Among a cohort of male and female drug users in Miami, zinc and selenium deficiencies were each associated with an increased risk of mortality in univariate analyses, but only selenium remained an independent predictor of mortality after multivariate adjustment (58).

Multivitamin and mineral supplements
Daily multivitamin and mineral supplement use by subjects in the SFMHS cohort reduced the risk of a low CD4⁺ cell count and of HIV disease progression by 40% and 31%, respectively (48). In the randomized trial in Tanzania, prenatal multivitamin supplementation (excluding vitamin A) significantly improved CD4⁺, CD8⁺, and CD3⁺ cell counts of HIV-infected women during pregnancy (17).

Summary
Although higher nutrient intakes and serum concentrations were associated with slower disease progression in many prospective studies, the few experimental studies conducted yielded equivocal results. Moderate vitamin A intake slowed clinical disease progression and death. A low serum vitamin A concentration was associated with increased risk of death. However, both vitamin A and ß-carotene supplements had no significant effects on T lymphocyte counts or on the load of HIV during pregnancy. Intakes of B vitamins—particularly thiamine, riboflavin, and niacin—and serum vitamin B-12 concentrations were associated with a reduced rate of clinical and immunologic HIV disease progression and improved survival. A higher intake of the antioxidant vitamins C and E was associated with improved CD4⁺ cell counts and a slower disease progression, and supplementation with both vitamins at the same time reduced the load of HIV. Zinc intake was associated with accelerated disease progression and an increased risk of death, but the direction of the association with serum zinc concentration was the opposite. Few data are available on selenium and disease progression, but one prospective study reported that low serum selenium concentrations are associated with an increased risk of death among HIV-infected subjects, independent of other risk factors and nutrient deficiencies. Finally, observational data indicate that multivitamin and mineral supplement use slowed the clinical and immunologic progression of HIV disease, and a randomized intervention of multivitamin supplementation showed significant improvements in T lymphocyte subsets, but its effect on clinical outcomes remains to be examined.

Most of the evidence presented on micronutrients and HIV disease progression comes from observational cohort studies. Although most of the cohort studies described above adjusted for potential confounders of the relation between micronutrients and HIV progression, such as CD4⁺ cell counts, antiretroviral use, and energy intake, residual confounding is still possible and may explain the findings. As in the observational studies of vertical transmission, these studies of HIV disease progression were conducted among seroprevalent rather than seroincident cohorts. There may have been bias in these studies because of the variation in duration of infection among subjects with and without micronutrient deficiencies, which were unknown and therefore not adjusted for in the analyses. In addition, in studies using biochemical measures, low serum concentrations of some nutrients may be indicators of rather than contributors to infection and disease progression.

	MICRONUTRIENTS AND PLACENTAL AND LOWER GENITAL TRACT FACTORS

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Maternal nutritional status may have an effect on mucosal immunity and the epithelial integrity of the placenta and lower genital tract that increases the risk of vertical HIV transmission. Evidence from animal studies indicates that vitamin A–deficient rats have reduced placental integrity (66). Placental membrane inflammation increased the risk of vertical HIV transmission in many observational studies (67–69). Chorioamnionitis may increase placental permeability to the HIV virus and could result in a higher viral load in amniotic fluid and an increase in transplacental transmission. Lower genital tract and ascending vaginal infections also increase the risk of chorioamnionitis and lead to an increased viral load in the amniotic cavity. Therefore, an increased prevalence of chorioamnionitis may explain the association of premature rupture of membranes and preterm birth with perinatal transmission (70). The mucosal lining of the genital tract may be part of the body's defense against genital infections, including HIV, and there is evidence that nutritional status may affect its functioning. Studies in rats showed that vitamin A deficiency leads to keratinization of the epithelium of the lower genital tract (71,72). Therefore, nutritional deficiency may increase the risk of injury and bleeding of the cervix during delivery and subsequent exposure of the infant to infectious material.

Genital mucosal immunity may also play a role in the vertical transmission of HIV, and may be influenced by micronutrient status. Mucosal secretions in the lower genital tract include immunologic factors that can both enhance and prevent the vertical transmission of HIV (73). Two studies from Kenya showed that vitamin A deficiency is associated with an increased risk of viral shedding in genital secretions (74,75). In one of these studies, selenium deficiency was also associated with an increased risk of HIV shedding in genital mucosa independent of vitamin A deficiency and CD4⁺ cell counts (76).

	MICRONUTRIENTS AND BREAST-FEEDING FACTORS

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The breast milk of HIV-positive women is known to contain HIV (77,78), and the transmission rate of HIV through breast-feeding is 5–15% (79,80). Among HIV-infected mothers, 40% have HIV RNA in their breast milk, but only a small proportion of this HIV RNA is believed to be infectious (81).

There are many specific and nonspecific immunologic factors in human breast milk that may protect against HIV infection in infants, including immunoglobins, lactoferrin, lysozyme, secretory leukocyte protease inhibitor (SLPI), oligosaccharides, glycosaminoglycans, RANTES (regulated on activation normal T cell expressed and secreted), and IL-8. Among 18-mo old infants of HIV-infected women in Rwanda, a lack of persistence of immunoglobulin M in breast milk increased the risk of infant HIV infection (82). Lactoferrin from breast milk showed anti-HIV effects in vitro by binding the V3 domain of the HIV envelope protein gp120 (83). Glycosaminoglycans were shown to inhibit the binding of the HIV gp120 protein to CD4⁺ cell receptors (84). SLPI binds to human monocytes to prevent infection by HIV in vitro (85). The chemokine RANTES interacts with an HIV coreceptor on CD4⁺ lymphocytes to inhibit HIV infection in vitro (86). Many of these immunologic properties of human breast milk and the nutritional quality of human milk, particularly the concentrations of fat and micronutrients, are affected by the nutritional status of women (87). Therefore, micronutrient supplementation to improve maternal nutritional status may improve breast-milk quality and confer nutritional and immunologic benefits to breast-fed infants.

Mastitis is an inflammatory condition of breast tissue characterized by elevated concentrations of leukocytes and sodium in breast milk because of the opening of paracellular pathways between mammary cells (88). There is evidence that HIV-infected cells enter breast milk via these pathways during inflammation, thereby increasing the HIV load and the risk of vertical transmission. A study among HIV-infected women in Malawi found that elevated sodium concentrations in breast milk indicative of mastitis were associated with significantly higher HIV loads in breast milk and a higher risk of HIV transmission to infants (89). Higher concentrations of immunologic and inflammatory factors such as lactoferrin, SLPI, IL-8, and RANTES were also found in women with symptoms of mastitis (90).

Evidence from animal research suggests that oxidative stress and immune dysfunction are associated with mastitis, and that micronutrient deficiencies may increase the susceptibility to mastitis by contributing to these conditions (91). Nutritional supplementation with antioxidant micronutrients such as vitamin E and selenium has been shown to reduce the incidence of mastitis in cows (91). There is some evidence that micronutrient supplementation may reduce the risk of mastitis in humans. Postpartum vitamin A supplementation did not have an effect on subclinical mastitis among Bangladeshi women, although low body stores of vitamin A at baseline were associated with an elevated ratio of sodium to potassium, a proxy for mastitis (92). However, in a randomized dietary supplementation trial of pregnant women in Tanzania, vitamin E–rich sunflower oil but not vitamin A–rich red palm oil significantly reduced the risk of mastitis at 3 mo postpartum (93). The HIV status of subjects in both studies was not assessed, so the potential beneficial effects of supplementation on HIV viral load in breast milk and vertical transmission could not be examined. One observational study of HIV-infected lactating Kenyan women directly examined the relation of micronutrient status with the presence of HIV in breast milk and reported a significant association between low serum vitamin A during pregnancy and HIV shedding in breast milk among women with CD4⁺ cell counts <400 x 10⁶/L (94). However, the study was observational rather than experimental, and the limitations of this type of study, as discussed previously (eg, bias from confounding factors not adjusted for in the analyses and the limitations of serum retinol as a marker of vitamin A status in the presence of infection), apply here as well.

	MICRONUTRIENTS AND POOR BIRTH OUTCOMES

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Micronutrient supplementation during pregnancy has been shown in a few studies to reduce the risk of low birth weight and preterm birth. These birth outcomes may be risk factors for vertical HIV transmission during delivery or breast-feeding. Use of multivitamin and mineral supplements by low-income pregnant women in the United States is associated with a 41% reduction in the risk of low birth weight and a 34% reduction in the risk of preterm birth (95). There was no significant effect on the risk of small-for-gestational-age births. However, supplement use was not randomized so there may have been residual confounding of the observed associations despite multivariate adjustment for known confounders such as parity, prepregnancy body mass index, gestational weight gain, smoking, and previous poor birth outcome.

In the trial of prenatal vitamin A and multivitamin supplementation in Tanzania described earlier, the effect of supplements on pregnancy outcomes was also evaluated (17). All subjects were given daily supplements of iron and folate and weekly doses of chloroquine phosphate as malaria prophylaxis per standard care practices in Tanzania. Multivitamin supplementation resulted in statistically significant reductions of 40% in fetal loss, low birth weight, severe preterm birth, and small-for-gestational age birth (17). Vitamin A supplementation had a much smaller effect on these pregnancy outcomes, which was not statistically significant. A randomized, placebo-controlled trial of weekly vitamin A or ß-carotene supplementation of >20000 women in Nepal reported a maternal mortality rate that was 40% lower in the women who received vitamin A or ß-carotene than in the placebo group (96). However, neither supplement had a significant effect on low birth weight, preterm birth, or small-for-gestational age birth among a 10% subsample of pregnancies for which birth outcomes data were collected (97). By contrast, prenatal vitamin A supplementation of HIV-infected women reduced the risk of preterm birth by 34% in South Africa (15) and the risk of low birth weight by 30% in Malawi (14). Among low-income pregnant women with low serum zinc concentration in Alabama, prenatal zinc supplementation resulted in significantly increased birth weights and marginally increased gestational age (98). However, zinc supplementation had no effect on the risk of low birth weight or preterm birth in a trial in Peru (99). In the Alabama study, all women also took prenatal multivitamin and mineral supplements that did not contain zinc, whereas iron-folate supplements were consumed by all participants in the Peru trial.

	MICRONUTRIENTS AND GASTROINTESTINAL MUCOSAL IMMUNITY IN FETUSES AND CHILDREN

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Evidence suggests that vertical transmission of HIV in utero or through breast-feeding can be influenced by the epithelial integrity of the gastrointestinal mucosal lining of fetuses and infants. The risk of transmission from HIV-infected amniotic fluid or breast milk may be reduced by the barrier function of the gastrointestinal mucosal epithelium and by the immune response in the gut. Vitamin A and zinc deficiencies are associated with epithelial impairment in the gastrointestinal tract. Vitamin A deficiency is associated with a decrease in goblet cells (100), a decrease in luminal mucus (101), and a decrease in cellular division and differentiation (102) in animal studies. Zinc deficiency leads to ultrastructural changes in mucosal cell morphology and impaired epithelial cell growth (103). Two randomized, placebo-controlled trials of vitamin A supplementation in India—one a community-based study among healthy infants and the other a study among hospitalized infants—showed that vitamin A supplementation improved gastrointestinal epithelial integrity on the basis of the results of the lactulose-mannitol dual-sugar intestinal permeability test, which is an indicator of barrier function in the gut (104). A similar trial conducted among Bangladeshi infants with acute or persistent diarrhea observed that 2 wk of zinc supplementation improved intestinal permeability and aided in the recovery from diarrhea (103). The HIV status of the infants in these studies was unknown. Both zinc and vitamin A supplementation were shown to significantly reduce the severity and duration of diarrhea in children (29m41).

Mucosal immunity of the gastrointestinal tract involves both cellular and humoral immune responses. Secretory immunoglobulin A comprises the humoral immune response in the gut, where it binds microorganisms to prevent their attachment to intestinal epithelium (105). Cell-mediated mucosal immunity in the gastrointestinal tract includes intraepithelial and lamina propria lymphocytes. Intraepithelial lymphocytes are cytotoxic suppressor T cells (CD8⁺ cells), whereas lamina propria lymphocytes are a combination of CD4⁺ and CD8⁺ cells at a ratio (2:1) similar to that found in peripheral blood (105). Intraepithelial lymphocytes have various types of cytotoxic activity for fighting viral infections in the gastrointestinal tract, including antibody-dependent cell-mediated cytotoxicity, in which immunoglobulin A (IgA) also plays a role. An epidemiologic study of Kenyan preschool children investigating the relation of HIV infection to intestinal mucosal immunity reported that HIV-infected children had lower CD4⁺ and higher CD8⁺ cell counts, lower phagocytic activity, lower intestinal IgA concentrations, and more severe diarrhea than did uninfected children (106). Poor nutritional status is associated with an increased risk of gastrointestinal infections and is believed to impair mucosal, humoral, and cellular immune defenses. Protein-energy malnutrition and vitamin A deficiency are associated with lower concentrations of secretory IgA, lower numbers of intraepithelial lymphocytes, decreased natural killer cell activity, and increased binding of bacteria to epithelial cells in the gut (107).

	SUMMARY

TOP ABSTRACT INTRODUCTION MICRONUTRIENTS AND VERTICAL... POTENTIAL MECHANISMS OF ACTION... MICRONUTRIENTS AND SYSTEMIC... MICRONUTRIENTS AND HIV DISEASE... MICRONUTRIENTS AND PLACENTAL AND... MICRONUTRIENTS AND BREAST... MICRONUTRIENTS AND POOR BIRTH... MICRONUTRIENTS AND... SUMMARY REFERENCES

 
Deficiencies and sometimes excesses of vitamins and minerals can potentially influence the vertical transmission of HIV through many maternal, fetal, and child risk factors that were reviewed above. Micronutrients may bolster the systemic immune function of women and infants and reduce the clinical, virologic, and immunologic progression of disease. Adequate micronutrient status to reduce the risk of placental infection, enhance mucosal genital tract immunity, and maintain the epithelial integrity of the placenta, genital tract, and breast tissue may lead to reduced viral shedding in genital secretions and breast milk. Micronutrient supplements during pregnancy can reduce the risk of low birth weight and preterm birth among HIV-infected women and may also improve systemic and gastrointestinal immune function of fetuses and children. These factors may be important mechanisms for vertical transmission during the breast-feeding period.

Randomized, placebo-controlled trials provide evidence that prenatal vitamin A or multivitamin supplementation is unlikely to reduce the risk of vertical HIV transmission through transplacental and intrapartum routes. However, vitamin A and multivitamin supplementation in the Tanzania trial has continued during the postpartum period, allowing for an extended evaluation of the effect of supplementation on HIV transmission through breast-feeding. The 2 trials currently underway in Zimbabwe—one assessing vitamin A supplementation in women and infants at birth and the other assessing prenatal multivitamin supplement use—will provide further information regarding the potential benefits of micronutrients for reducing the vertical transmission of HIV. The effects of other micronutrients, such as zinc and selenium, on vertical HIV transmission have not yet been investigated.

It is possible that the vitamin doses used in these trials were insufficient to have a positive effect on vertical transmission, and that higher doses are necessary to observe any effects. However, the micronutrient doses used in the Tanzania, South Africa, and Malawi interventions were multiples of the recommended dietary allowance for individual nutrients, so this explanation is unlikely. Another possible reason for the lack of an effect on vertical transmission is that the timing of supplementation was not appropriate. In all 3 trials, women usually began supplementation at their first prenatal visit at 20 wk gestation. Programming of the fetal immune system may occur very early in gestation, and adequate nutritional status may be required during this critical period to ensure its successful formation and function. Preliminary evidence of the role of micronutrient deficiencies in fetal programming comes from a study in mice. Zinc-deprived pregnant mice gave birth to offspring with impaired immune function that persisted in 2 generations of offspring fed nutritionally adequate diets (108). Although similar data are not available for other micronutrients, these findings suggest that zinc, and possibly other micronutrient deficiencies during pregnancy, can adversely affect the development of and have lasting effects on immune function in infants. If so, micronutrient supplementation among HIV-infected women may need to begin before or during the periconceptional period to provide benefits for fetal immune system development and function.

The burden of HIV infection among adults continues to increase worldwide, particularly in developing countries, and high rates of vertical HIV transmission exacerbate this trend by contributing to the vast majority of childhood infections. There were 500000 child deaths from AIDS during 2000 alone (1). Virtually all infections in early childhood come from exposure to maternal infection during pregnancy, delivery, or the postpartum period. Recent clinical trials have shown the efficacy of short-course antiretroviral drug regimens given to women and their infants during labor and delivery in reducing vertical HIV transmission (109–111). These lower-cost prophylactic alternatives are encouraging prevention options for developing countries faced with high vertical transmission rates. However, the inputs required to implement an effective prevention program are considerable. Not all pregnant women receive antenatal care, HIV testing and counseling services are not universally accepted, many women do not deliver their infants with the assistance of trained medical personnel, and the costs of developing and maintaining an effective program to provide these drugs to infected women are high (112). Furthermore, antiretroviral regimens given during pregnancy and delivery are less efficacious in breast-feeding populations, so it is important to continue to investigate alternatives for reducing transmission during breast-feeding. Evidence exists that multivitamin supplementation during pregnancy improves hematologic status and immunocompetence and reduces the incidence of poor pregnancy outcomes among HIV-infected women. The effects of prenatal multivitamin supplementation along with other nutritional interventions on vertical transmission from breast-feeding continue to be investigated. Postpartum micronutrient supplementation—either directly to the infant or indirectly through breast milk—to prevent HIV transmission is also important to consider given the evidence of its prevention of HIV disease progression and risk of morbidity (113) and mortality (114) among HIV-infected infants and children. The Zimbabwe trial currently underway is assessing the effects of postpartum vitamin A supplementation in women and infants on the vertical transmission of HIV from breast-feeding, but the effect of postpartum supplementation with other micronutrients remains to be evaluated. Consideration should also be given to the possibility of interactions, both synergistic and antagonistic, from the simultaneous administration of micronutrient supplements and antiretroviral drugs. This issue is a priority for future research given the importance of both types of interventions in improving health outcomes in HIV-infected populations.

In conclusion, prenatal vitamin supplements do not appear to reduce the rate of vertical HIV transmission in utero or during the intrapartum period. Whether micronutrient supplementation needs to be started earlier in pregnancy or before conception to provide benefits that would prevent HIV transmission is not yet known. Postpartum micronutrient supplementation of breast-feeding women and their infants should continue to be explored as a potential nutritional intervention for preventing HIV transmission through breast milk. Even as research on these issues continues, the public health community should implement existing interventions—such as prenatal micronutrient supplementation and short-course antiretroviral prophylaxis—because they have demonstrable benefits for the health outcomes of pregnant women and their infants. However, research is needed to demonstrate the safety and efficacy of providing these interventions simultaneously in HIV-infected populations.

	REFERENCES

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