The effects of placental malaria on mother-to-child HIV transmission in Rakai, Uganda

We examined the association of placental malaria and mother-to-child transmission (MTCT) of HIV in a prospective community-randomized trial in Rakai District, Uganda. In the 746 HIV-positive mother-infant pairs, the MTCT rate was 20.4%. Placental malaria was more common in HIV-positive than HIV-negative women. After multivariate adjustment for HIV viral load, the risk of MTCT associated with placental malaria was 2.89 and with HIV viral load the risk was 2.85. Interventions to prevent malaria during pregnancy could potentially reduce MTCT.

Malaria and HIV-1 are among the most prevalent infectious diseases in sub-Saharan Africa, and co-infections are common in endemic malarious areas. The frequency and severity of malaria is greater in pregnant compared with non-pregnant women [^1,2], and results in adverse pregnancy outcomes [¹]. Similarly, higher rates of low birthweight, preterm delivery and infant mortality occur in children born to HIV-positive compared with HIV-negative mothers [³]. Therefore, co-infection of malaria and HIV-1 during pregnancy may have severe consequences for morbidity and mortality of infants, and the prevention of these infections during pregnancy is a public health priority. To the best of our knowledge, no studies have assessed the effects of placental malaria on mother-to-child transmission (MTCT) of HIV.

From 1994 to 1999, we conducted a community-randomized trial of sexually transmitted disease (STD) control for HIV prevention, which included an assessment of the effects of STD treatment during pregnancy on maternal and infant health [⁴]. Consenting pregnant women were enrolled and randomly assigned to a STD intervention arm using presumptive antibiotic therapy, or a control arm-providing standard of care. Women were enrolled at varying gestational ages, interviewed and samples were collected for HIV and STD diagnoses. Mothers and infants were followed up postpartum to determine mother-infant STD infections, infant birthweight and gestational age, and infant HIV detected by RNA-polymerase chain reaction at 4-6 weeks postpartum using the Amplicor HIV-1 Monitor 1.5 Assay (Roche Molecular Systems, Branchburg, NJ, USA). Mothers retained their placentas in 10% iron-free formol saline for histopathology, including placental malaria diagnosed by the presence of pigment or parasites using haematoxilyn and eosin stain. At the time of this study, antiretroviral prophylaxis of MTCT was not available in rural Uganda. The study was reviewed and approved by institutional review boards in Uganda and the USA.

The main outcomes were malaria prevalence in HIV-positive and HIV-negative women, and MTCT in HIV-positive women. The adjusted risk ratios (RR) and 95% confidence intervals (CI) of MTCT associated with placental malaria were estimated by multivariate log binomial regression. Variables included in the models were the malaria exposures of interest, and potential confounders found to be associated with MTCT at P < 0.05 or RR greater than 2.0.

Histopathology was available for 668 placentas from women of known HIV status. Of the placentas examined, 62 (9.3%) were positive for malaria parasites or pigment. Among HIV-positive mothers, 13.6% (21/155) had placental malaria, compared with 8.0% (41/510) in HIV-negative mothers (P = 0.039) MTCT rates were 40% (6/15) with placental malaria and 15.4% (12/78) without malaria (P = 0.027). Univariate analyses showed that MTCT was significantly associated with maternal viral load (each log₁₀ increase in viral load, RR 2.32, 95% CI 1.66-3.24), and placental malaria infection (RR 2.60, 95% CI 1.16-5.84). Primagravidity was not significantly associated with MTCT (RR 1.17, 95% CI 0.74-2.34). The adjusted risk ratio of MTCT associated with placental malaria was RR 2.89, 95% CI 1.12-7.52 after adjustment for HIV viral load (RR 2.85, 95% CI 1.53-5.32, for each log₁₀ increase in viral load).

Among infants, the median infant HIV log₁₀ viral load was higher in infants whose mothers were also infected with malaria, compared with infants whose mothers were infected with HIV alone (log₁₀ copies/ml 4.58 versus 3.77, respectively, P = 0.13).

Our findings corroborate other studies, which observed that placental malaria infection was more prevalent in HIV-positive compared with HIV-negative mothers, and it is likely that immunodeficiency as a result of HIV may impair the immune response to malaria [^1,2]. Co-infection of malaria and HIV during pregnancy was significantly associated with increased MTCT, and this association was strengthened after controlling for maternal HIV viral load. Also, infant HIV viral load was higher in infected babies whose mothers had placental malaria, although this was not statistically significant.

Several mechanisms can be postulated to explain the increased risks of MTCT associated with placental malaria. Inflammation as a result of malaria infection may damage the placenta, increasing the exchange of maternal and fetal blood and facilitating in-utero HIV transmission. Malaria also increases HIV CCR5 chemokine co-receptor expression in maternal macrophages and fetal Hofbauer cells, possibly increasing susceptibility to infant HIV infection [⁵].

These findings could have potential public health relevance because interventions to prevent malaria during pregnancy might reduce MTCT, and this could augment current approaches using antiretroviral prophylaxis. Randomized trials of intensive malaria control in HIV-positive women are urgently needed.