In the present study, we examined the association of maternal vitamin D status at baseline (12–27 weeks’ gestation) with adverse pregnancy outcomes, MTCT of HIV, and child mortality. No association was observed between a low maternal vitamin D level (<32 ng/mL) and such adverse pregnancy outcomes as low birth weight, preterm birth, and small-for-gestational-age status. An increased risk of being HIV infected or of dying at birth was observed for children born to women with a low vitamin D level at baseline; a low maternal vitamin D level was also associated with HIV transmission via breast-feeding and with higher infant mortality during follow-up.
The role of maternal vitamin D status in pregnancy outcomes of HIV-infected women has not been previously studied; however, there is some literature suggesting a benefit of vitamin D in pregnant women who are not HIV infected. For example, Marya et al [40
] conducted a study of Asian-Indian women, randomizing them to receive either 600,000 IU of vitamin D twice (once each during the seventh and eighth months of pregnancy) or no vitamin D supplements. Infants of mothers who received vitamin D had greater intrauterine growth and a higher birth weight than did infants of women who did not receive vitamin D supplements. However, the beneficial effects of vitamin D have been observed with relatively large doses of vitamin D supplements, which may lead to serum vitamin D levels that are much higher than those observed in our cohort. This could be a potential explanation for the lack of any observed association with vitamin D levels and pregnancy outcomes in this cohort. Furthermore, the rates of adverse pregnancy outcomes appear to be higher in HIV-infected women than in HIV-uninfected women. For example, in another trial involving 8468 HIV-uninfected pregnant women in Tanzania, our group determined that the incidence of preterm birth was only 17%, compared with the 27% incidence noted in the current analysis [41
]. Thus, it is possible that the adverse effect of HIV infection on perinatal outcomes may mask the beneficial effect of vitamin D on these outcomes, if any.
The association of maternal vitamin D status with HIV transmission and death among children has not been previously studied. However, our results are in accordance with some small studies of nonpregnant HIV-infected populations that have shown an association between low vitamin D levels and increased HIV disease progression and higher mortality [5
]. For example, in one longitudinal study in Norway, HIV-infected patients with 1,25(OH)D levels of <25 ng/L at baseline (n
= 9) had a significantly shorter survival time than did patients with levels in the range considered to be normal (n
= 44), after adjustment for CD4 cell counts [42
Recent research has highlighted the role of vitamin D in the regulation of the immune system, particularly innate immunity, which might explain this finding [43
]. Vitamin D is also known to have other immunomodulatory effects, such as improving the phagocytic capacity of macrophages, increasing the number of natural killer cells, and boosting cell-mediated immunity [6
]. Vitamin D is known to contribute to the development of the fetal immune system; a stronger immune system may be more resistant to HIV infection and may explain the decreased risk of MTCT observed in the present study. This finding would also likely correlate with fewer infections and opportunistic illnesses during follow-up and, consequently, with decreased mortality. In addition, there is increasing evidence supporting the role of vitamin D in fighting tuberculosis; tuberculosis is one of the primary killers in HIV-infected populations [18
Vitamin D may also decrease MTCT of HIV or child mortality by reducing inflammation; in this cohort, we observed an association between a low vitamin D level and a higher CD8 cell count and erythrocyte sedimentation rate (S.M., D.S., S. Aboud, E.L.G., G.I.M., E.H., F.M.M., D.J.H., and W.W.F., unpublished data). Although the conventional role of CD8 cells is to function as cytotoxic killer cells, they may also be the effector cells in inflammation [44
]. The involvement of vitamin D in modulating CD8 cells is also indicated by the fact that, of the major immune cells (CD8, CD4, and B cells and macrophages), CD8 cells express the highest concentration of vitamin D receptor [45
The present study includes important and informative findings, considering the lack of similar data in other studies reported to date, as well as implications for potential interventions for the prevention of MTCT of HIV and child mortality. However, we had limited power to examine the exact timing of MTCT of HIV. We also do not know whether the levels of vitamin D may be depressed as a result of HIV disease and thus may be a consequence of an advanced stage of HIV disease and/or accelerated viral replication and not the cause thereof. However, most women in our analysis did not have advanced HIV disease at baseline (>80% had stage 1 disease). The association observed in the present study may be different in other populations with a different underlying nutritional or immunologic status, as well as in populations with access to antiretroviral therapy, and therefore the findings may not be fully generalizable. One limitation of our analysis is that we had only one measurement of vitamin D levels at baseline; however, data from other studies suggest that there is a positive correlation between vitamin D levels in cord blood and vitamin D levels at baseline [29
]. Therefore, it may be reasonable to assume that vitamin D levels at baseline are predictive of vitamin D levels in the postpartum period.
Another limitation of the present study is that the assay that we used to assess vitamin D status does not measure vitamin D2 accurately; however, this form of vitamin D is obtained through supplements, the use of which was unlikely in this population. In addition, our choice of a cutoff level for vitamin D is to make the results clinically more relevant and comparable to those of other studies. However, estimates of a similar effect were obtained for such major outcomes as overall HIV transmission and overall child mortality, by use of quintiles of vitamin D, on the basis of its distribution in this population (data not shown).
Recent studies estimated that 1 billion people worldwide have vitamin D insufficiency [28
]. Daily intake of at least 800–1000 IU of vitamin D may be needed in the absence of adequate sun exposure, to maintain a circulating level of 25(OH)D >32 ng/mL [28
]. If demonstrated to be effective in intervention studies, vitamin D supplementation could prove to be a relatively simple and inexpensive method to lower mortality among children and to help prevent MTCT of HIV as an adjunct to antiretroviral therapy.