Brahmbhatt H, Sullivan D, Kigozi G, Askin F, Wabwire-Mangenm F, Serwadda D, et al. Association of HIV and malaria with mother-to-child transmission, birth outcomes, and child mortality. J Acqu Immune Defic Syn, 2008 Apr 1;47(4):472-6.
To assess the effect of malaria on mother-to-child transmission of HIV, preterm birth, low birth weight, and infant mortality.
Population-based cohort derived from a randomized controlled trial of treatment for sexually transmitted disease to reduce HIV transmission.
Rakai District, rural Uganda
Pregnant women and their infants enrolled in the Rakai Community Cohort Study (RCCS) between 1994 and 2000.(1,2)
Maternal malaria and HIV co-infection, low birth weight, preterm delivery, and infant mortality stratified by the presence or absence of plasmodia using placental and serologic diagnostic methods. The rate of maternal HIV transmission stratified by HIV viral load (above or below the median) and the independent risk of maternal HIV transmission associated with placental and serologic malarial infection adjusted for maternal HIV viral load.
The RCCS is a population-based cohort of 56 communities with an expected HIV incidence rate of two per 100 person-years of observation. Within the selected communities, households were enumerated and consenting residents aged 15-59 years were enrolled. Participants were followed annually, at which time they were administered a detailed questionnaire that collected demographic, behavioral, pregnancy and other health information. Participants also were tested for tested for HIV and other sexually transmitted diseases.
In the present study, pregnant women were identified either by interview or urine testing for human chorionic gonadotropin. Pregnant women were tested for HIV during pregnancy and postpartum using two independent enzyme immunoassays. Women were asked to place their placentas into buckets that contained preservatives immediately following delivery. The weight and chest, upper arm, and head circumference of infants were measured and the New Ballard Score(3) was used to determine preterm birth. Infants were assessed either the day of birth or between three days and six weeks of life (for unattended births). Seventy percent of women were assessed within three days of delivery.
Infants were tested for HIV using reverse transcriptase RNA-PCR. Intra-uterine and intra-partum transmission was defined as a positive HIV PCR test between birth and six weeks. Transmission from breast-feeding was diagnosed among infants who were HIV PCR negative at six weeks and HIV PCR positive sometime thereafter.
Maternal malaria was diagnosed using a rapid immunochromatographic test that detects Plasmodium falciparum and P. vivax antigens and P. falciparum-specific proteins and pan-Plasmodium aldolase antigens up to two weeks after the infection has cleared. Placenta malaria was diagnosed using hematoxylin and eosin staining and HRP-II immunohistochemistry with a monoclonal antibody to detect P. falciparum. Slides were read by microscopists who were blinded to information about the mother.
Of the 286 women in the study, 170 (59%) were infected with HIV. Thirty-two percent of the women had placental malaria but this proportion was significantly higher among HIV-infected than uninfected women (37.1% and 25%, respectively; P=0.039). The proportion of women with malaria who were identified using the serologic test for malaria was similar to the proportion who were identified with placental malaria (31.1%), but the test did not detect a difference between HIV-infected and uninfected women.
There were 109 women included in the analyses of mother-to-child transmission. Of the adverse birth outcomes examined, only low birth weight was positively associated with maternal malaria. Statistically significant differences were detected for women with positive results of both placental and serologic tests for malaria (compared to negative tests) and for women who tested positive only on the serologic test compared to women who tested negative.
Calculated using a generalized linear model with a logit link and binomial distribution, the univariate risk for maternal HIV transmission was significantly higher if the mother had placental malaria (relative risk [RR], 3.6; 95% confidence interval [CI], 1.3-10.1), if the mother had a positive serological test (RR, 3.2; 95% CI 1.14-9.2), and if the infant had low birth weight (RR, 6.3; 95% CI, 2.2 to 18.5). After adjustment for viral load, the risk of maternal HIV transmission in the presence of placental malaria increased significantly (RR, 7.9; 95% confidence limits [CL], 1.3) but not among those with serologic malaria (RR, 3.9; 95% CI, 0.78-19.5, P=0.09). The rate of HIV transmission was highest among women with placental malaria and HIV viral loads greater than the median (35.3%). Among women with placental malaria but viral loads lower than the median, transmission was higher than among women with higher viral loads but without placental malaria (28.6% and 11.1% respectively, X2 test for trend, P<0.001).
The authors conclude that co-infection with HIV and malaria are risk factors for low birth weight and mother-to-child transmission, suggesting that public health programs should emphasize an integrated approach focused on both prevention of mother-to-child transmission and malaria prophylaxis during pregnancy to help reduce the burden of HIV and adverse birth outcomes in children in rural Africa.
We used the Newcastle-Ottawa Quality Assessment Scale of Cohort Studies to evaluate this study. The manuscript itself provides a limited description of the methods used to establish the cohort because it had a secondary objective. Review of previous descriptions of the study design indicated that the study population was representative of rural communities in Uganda with high HIV prevalence rates and estimated HIV incidence rates of two per person year of observation. In this analysis the exposed and unexposed (HIV-infected women with and without malaria) were drawn from the same population. Ascertainment of HIV infection was done using standard methods. Diagnosis of malaria was done using two methods with greater sensitivity than those used in previous studies of the effect of malaria on mother-to-child transmission of HIV. Little information was provided on the characteristics of the women with and without malaria, making comparisons between the two groups limited essentially just to age. The follow-up timing and methodology were adequate, although only 70% of the women provided placentas for examination, and 16% of the children were not assessed for premature birth.
A limitation mentioned by the authors was using only maternal rapid test diagnosis at the postpartum visit, and consequently there was the inability to detect malaria episodes that may have resolved during pregnancy or to determine the effects of timing of malarial infection during gestation.
Studies of the impact of malaria on mother-to-child transmission of HIV have produced inconsistent results. An earlier study by the authors used a less sensitive method to diagnose malaria and, as such, was likely to have underestimated the risk of transmission associated with placental malaria.(4) The strength of the methods used in this study support a conclusion of increased mother-to-child HIV transmission in the presence of malaria. Other studies have suggested placental malaria may increase HIV transmission by increasing viral load;(5) however, this study, after adjusting for viral load, found that the risk of mother-to-child transmission associated with placental malaria remained high. This study also did not find higher malaria parasite density in the placenta to be associated with HIV viral load as it was in other studies.(6) Differences in study findings may be explained by the low sensitivity of malaria diagnoses used in previous studies,(4,5) variations in methodologies, and study locations; nevertheless, all suggest a correlation between placental malaria and mother-to-child transmission of HIV.
The increase in risk of mother-to-child HIV transmission in the presence of malaria highlights the need to prioritize malaria prevention efforts in Africa. The effect of malaria on mother-to-child transmission should be examined in the presence of antiretroviral therapy to prevent mother-to-child transmission.
- Gray RH, Wabwire-Mangen F, Kigozi G, et al. Randomized trial of presumptive sexually transmitted disease therapy during pregnancy in Rakai, Uganda. Am J Obstet Gynecol. 2001;185:1209-1217.
- Wawer MJ, Gray RH, Sewankambo NK, et al. A randomized, community trial of intensive sexually transmitted disease control for AIDS prevention, Rakai, Uganda. AIDS. 1998;12:1211-1225.
- Ballard JL, Khoury JC, Wedig K, et al. New Ballard Score, expanded to include extremely premature infants. J Pediatr. 1991;119:417-423.
- Brahmbhatt H, Kigozi G, Wabwire-Mangen F, et al. The effects of placental malaria on mother-to-child HIV transmission in Rakai, Uganda. AIDS. 2003;17:2539-2541.
- Inion I, Mwanyumba F, Gaillard P, et al. Placental malaria and perinatal transmission of human immunodeficiency virus type 1. J Infect Dis. 2003;188:1675-1678.
- ter Kuile FO, Parise ME, Verhoeff FH, et al. The burden of co-infection with human immunodeficiency virus type 1 and malaria in pregnant women in sub-Saharan Africa. Am J Trop Med Hyg. 2004;71(Suppl 2):41-54.