In this nested case-control study of rural Rwandan mothers followed from 1989 to 1994, we found that PM was independently associated with MTCT of HIV-1, particularly among primigravidae, before the regional availability of antiretroviral therapy or prophylaxis. Our results are consistent with a recently published study conducted in rural Rakai, Uganda,14
but differ from findings reported in Blantyre, Malawi,11
and Nyanza Province, Kenya.15
These differences may be explained in part by the varying dynamics of malaria infection and epidemiology in different settings and altitudes. The PM may have a greater effect on MTCT of HIV-1 in rural as opposed to urban areas, possibly caused by higher malaria disease burden among pregnant women or reduced access to malaria treatment in rural areas. Differences in PM diagnostic techniques may also account for some of the observed differences among studies. In this study, PM was diagnosed by H&E staining, Giemsa staining, and immunohistochemistry, which serve as markers for chronic infection and have been shown to be more sensitive than peripheral or placental blood films.26
The histopathological findings of our study are characteristic of chronic or acute active malarial infection.23
Our results suggest that PM may partially explain the observed seasonal variation in rates of MTCT in some settings.27
Primigravidae, among whom malaria tends to be most severe, may be at higher risk. Our finding that primigravidae with observed PM were at higher risk of MTCT of HIV than multigravidae may reflect a protective effect of pregnancy-specific malaria immunity, which has been shown to be absent in the first pregnancy.6
The PM may affect MTCT through several possible mechanisms, including up-regulation of CCR5 chemokine co-receptor expression on placental macrophages as a consequence of malaria infection.28
In addition, compromised integrity of the placenta caused by inflammation may increase tissue susceptibility to viral infection and promote increased placental virus load.11,29
We did not observe an association between HIV-1 MTCT and ultrasensitive p24 antigen level, a proxy for viral load, suggesting that local rather than systemic virus replication may be responsible for vertical transmission.
This study has several limitations, including its small sample size. In agreement with requirements from the Rwandan Ministry of Health, most specimens collected from cohort women and infants were kept at the National University of Rwanda project laboratory and these were all destroyed as a result of the civil war in April 1994, severely limiting the number of additional specimens that could be tested. Another limitation is the lack of data on maternal viral load as a measure of HIV disease severity (only ultrasensitive p24 antigen was available). The strengths of the study include the nested case-control design, random selection of control placentas, high follow-up rate of the cohort, high rate of placental retrieval after delivery, and precise exposure and outcome assessment, all of which serve to reduce selection and information bias and hence improve the precision of our findings. In addition, this analysis focused on data and placenta specimens from treatment-naive pregnant women and infants in rural East Africa, yielding results that could not be duplicated in the present-day highly active antiretroviral therapy (HAART) era.
Although antiretroviral prophylaxis and treatment have been shown to reduce rates of MTCT more than 10-fold,30
many HIV-infected pregnant women, especially in malaria-endemic rural areas of sub-Saharan Africa, do not yet have access to antiretroviral treatment or prophylaxis.31
Prevention and treatment of malaria among pregnant women through established interventions such as insecticide-treated bed nets and artemisinin combination anti-malarial treatment, as well as control strategies under development to interrupt parasite transmission dynamics, may reduce rates of MTCT of HIV-1, particularly in hyper-endemic areas with high rates of malaria transmission among rural households.32,33
Although no studies have reported on the association between PM and MTCT of HIV-1 in the context of maternal HAART during pregnancy, we speculate that the impact of placental malaria on the risk of MTCT of HIV-1 in these mothers may be limited, particularly among those with undetectable virus. However, the pathological changes caused by PM including focal villitis, cellular infiltration of the intervillous space, chorioamnionitis, and vasculitis could provide a portal of entry for infected maternal cells into the fetal circulation despite suppression of HIV-1 RNA. Additional studies in malaria-endemic settings among HIV-infected mothers may elucidate the relationship among HAART, PM, and MTCT of HIV-1 and the biological and epidemiological factors that underlie this relationship. In the current context of maternal and infant antiretroviral prophylaxis and treatment, studies of drug interactions and potential toxicities when antiretroviral therapy and antimalarials are co-administered in pregnancy are also needed.