Vitamin A supplements linked to high HIV levels in breast milk

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Research in Tanzania shows that women with HIV who took vitamin A and beta-carotene (VA/BC) supplements had more HIV in their breast milk than those who did not, while women who took multivitamins were more likely to develop mastitis. Both are major risk factors for HIV transmission during breastfeeding

The discovery of an association between vitamin A supplementation and HIV in breast milk may help to explain an unexpected finding from an earlier study of the same group of women.

After enrolling 1078 HIV-positive pregnant women into intervention and control arms to investigate the potential benefits of nutritional supplementation, researchers observed that children born to mothers in the VA/BC arm were more likely to acquire HIV during breastfeeding.

Glossary

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

subclinical

Describes an infection or disease which is not severe enough to present definite or readily observable symptoms.

p-value

The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret. 

observational study

A study design in which patients receive routine clinical care and researchers record the outcome. Observational studies can provide useful information but are considered less reliable than experimental studies such as randomised controlled trials. Some examples of observational studies are cohort studies and case-control studies.

inflammation

The general term for the body’s response to injury, including injury by an infection. The acute phase (with fever, swollen glands, sore throat, headaches, etc.) is a sign that the immune system has been triggered by a signal announcing the infection. But chronic (or persisting) inflammation, even at low grade, is problematic, as it is associated in the long term to many conditions such as heart disease or cancer. The best treatment of HIV-inflammation is antiretroviral therapy.

Earlier observational studies had suggested that low maternal vitamin A levels might increase the likelihood of mother-to-child transmission of HIV, raising the question of whether supplementation could have a protective effect. The latest findings, published online by The American Journal of Clinical Nutrition on August 25th, instead provide further evidence of adverse consequences.

HIV-positive pregnant women in the Tanzanian cohort were randomly assigned to four arms: one receiving VA/BC (5000 IU preformed vitamin A plus 30 mg beta-carotene); one receiving VA/BC along with multivitamins (20 mg thiamine, 20 mg riboflavin, 25 mg vitamin B-6, 100 mg niacin, 50 mg vitamin B-12, 500 mg vitamin C, 30 mg vitamin E, and 0.8 mg folic acid); one receiving placebo along with the multivitamin regimen; and one receiving only placebo.

The recently published study sought to examine the effects of VA/BC and multivitamins on HIV shedding in breast milk. Researchers randomly selected 720 research participants from the larger cohort, then eliminated those who had not provided adequate breast milk samples for analysis. The resulting substudy population was comprised of 594 women.

When researchers compared the pooled group of women from the two VA/BC treatment arms (VA/BC alone and VA/BC plus multivitamin) to the pooled group of women from the two non-VA/BC arms (placebo plus multivitamin and placebo alone), they found significant differences.

Detectable viral load levels were found in the breast milk samples of 51.5% of women in the VA/BC group, but in those of only 44.8% of women in the non-VA/BC group (p=0.02). The lower limit of detection was 100 viral copies/mL.

Women participating in the study had been asked to provide breast milk samples approximately every three months postpartum. While not everyone had done so, enough samples were available from throughout the postpartum period for researchers to look at whether the effect of VA/BC changed with time.

Significant viral load differences associated with VA/BC were not evident until six months postpartum; from that point onward, women in the VA/BC group were 34% more likely than their counterparts to have detectable viral load levels in breast milk (95% confidence interval, 4% – 73%).

A related study published online by the Journal of Nutrition on August 25th implicates both VA/BC and multivitamins in subclinical (asymptomatic) mastitis, which is known to be a risk factor for HIV.

Women are most likely to develop mastitis, an inflammation of the breast tissue, while breastfeeding. Although breastfeeding is not recommended for HIV-positive women who have the option of using infant formula, many HIV-positive women in developing countries breastfeed out of necessity.

The study looked for a biological marker of subclinical mastitis in breast milk samples from the cohort of 1078 Tanzanian women. Six hundred and seventy-four women had provided one or more samples, and a total of 1642 samples underwent testing.

Researchers compared the original three intervention arms (VA/BC alone; VA/BC plus multivitamin; placebo plus multivitamin) to the placebo arm.

The risk of severe subclinical mastitis was found to be 45% higher in the VA/BC arm than in the placebo arm (p=0.03).

Additionally, women in the placebo-plus-multivitamin arm were 33% more likely than women in the placebo arm to have any subclinical mastitis (p=0.005), and 75% more likely to have severe subclinical mastitis (p=0.0006).

Similar analyses were performed after stratifying women into two CD4 cell count levels: <350 cells/mm3 and ≥350 cells/mm3. The only intervention arm to show a significant difference was the multivitamin arm, in which women with higher CD4 cell counts had a 49% higher risk of any subclinical mastitis (p=0.006).

The finding of more subclinical mastitis among women taking VA/BC fits with the association between VA/BC and HIV transmission during breastfeeding, and in fact points to a possible biological pathway for that outcome.

However, researchers were surprised to see the apparently negative impact of taking multivitamins during pregnancy and breastfeeding. They speculated that multivitamins might have enhanced the women’s inflammatory response to the infection causing the mastitis.

Members of the same research group previously documented a number of important health benefits for both mothers and infants when women took multivitamins. The most recent findings thus raise the question of whether or not potential benefits outweigh potential risks.

References

Arsenault JE et al. Vitamin Supplementation Increases Risk of Subclinical Mastitis in HIV-Infected Women. J Nutr, advance online publication, August 27, 2010. DOI: 10.3945/jn.110.122713.

Villamor E et al. Effect of vitamin supplements on HIV shedding in breast milk. Am J Clin Nutr: advance online publication, August 27, 2010. DOI: 10.3945/ajcn.2010.29339.