van Eijk AM, Ayisi JG, Ter Kuile FO, Slutsker L, Shi YP, Udhayakumar V, et al. HIV, malaria, and infant anemia as risk factors for postneonatal infant mortality among HIV-seropositive women in Kisumu, Kenya. J Infect Dis 2007 Jul 1;196(1):30-7. Epub 2007 May 16.
To examine the association of placental malaria, and of infant malaria, anemia, and HIV status on post-neonatal infant mortality (PNIM) among infants born to HIV-seropositive women.
A descriptive prospective cohort study with one year of follow-up. From June 1996 and August 2001, infants born to HIV-positive mothers were monitored and followed for one year.
Nyanza Provincial General Hospital in Kisumu, western Kenya.
Eight hundred thirty-five sero-positive mothers and their infants were identified; 265 were excluded (primarily because they failed all follow-up visits), leaving 570 mother-infant pairs in the follow-up study; 68% completed the study. Infants who had their first positive PCR test after four months were excluded. Among mothers, 26% were <20 years old; 63% had maternal anemia (Hbg <11g/dL) at delivery; 36% had a CD4+ cell count <500 cells/µL; and 21% had a maternal viral load >10,000 copies/mL.
There was no intervention. Patients were followed up at routine visits. Infants were scheduled to be seen every four weeks until one year of age or death. Infants with malaria parasitemia were treated with sulfadoxine-pyrimethamine (SP) or amodiaquine. Clinical staff treated infants with anemia or other complaints in accordance with their findings.
The primary outcome was post-neonatal infant mortality (PNIM), defined as death from 29 to 394 days post-delivery. Primary variables of interest were placental malaria, maternal mean viral load, infant anemia (<8 g/dL), and infant parasitemia on thick smear.
One month postpartum, maternal blood was collected for CD4+ cell counts. Maternal HIV load at delivery was determined using a quantitative assay with a limit of 400 copies/ml. At every four-week visit, information was obtained on infant health, and capillary blood was obtained for a malaria smear, Hbg and HIV PCR testing. CD4+ cell counts were not determined in infants. If a routine visit was missed, the patient was visited at home. Information on infant deaths was obtained using verbal autopsy.
Among infants born to HIV-infected mothers, 6.3% were of low birth weight, and 19.6% were HIV-positive. Placental malaria was detected among 25% of women, and parasitemia in 13% of infants at some time during follow-up.
Postnatal infant mortality: 13.2% of infants died during the postnatal period. Significant risk factors for PNIM were low/medium SES (adjusted hazards ratio (aHR) 2.1 [95% confidence interval (CI) 1.0-4.2]), maternal CD4+ cell count <500 cells/µL (aHR 1.9 [CI 1.2-3.1]); infant HIV sero-positivity (aHR 4.6 [CI 2.9-7.3]); low birth weight (aHR 2.2 [CI 1.1-4.4]); infant malaria (aHR 0.35 [CI 0.14-0.90]); and infant hemoglobin <8g/dL (aHR 2.2 [CI 1.1-4.5]). HIV-positive infants born to mothers with placental malaria were more likely to survive compared to HIV-positive infants born to mothers without malaria (AHR 0.34, 95% CI 0.10-1.10). Placental malaria was not associated with survival in HIV-negative infants.
Infant anemia and parasitemia: Moderate to severe anemia was a risk factor for PNIM among HIV-negative but not among HIV-positive infants. The combination of anemia and parasitemia was not significantly associated with PNIM (AHR 1.13 [CI, 0.15-8.53]; p=9), whereas anemia alone (without parasitemia) was a risk factor (AHR 5.80 [CI 2.19-15.38]; p<.01). Malaria parasitemia alone suggested a protective effect, but was not statistically significant (AHR 0.49 [CI, 0.12-2.08]; p=.3).
Maternal viral load and PNIM: Among women who transmitted HIV and whose infants survived, maternal viral load was higher when placental malaria was present. However, it was not significantly higher in mothers who had HIV-negative infants who died.
The authors conclude that in this study population, placental malaria and infant parasitemia were not risk factors for postnatal mortality among infants born to HIV-sero-positive women. Placental malaria may change the association between a high maternal viral load and HIV progression in the infected infant. The prevention of infant anemia may decrease PNIM among HIV-negative infants of HIV-seropositive women.
Based on the Newcastle-Ottawa quality rating system for prospective cohort studies, this study is of good quality. The study had the following limitations. Only HIV-infected women without AIDS-defining symptoms were enrolled. Infant mortality among those with mothers with more progressive HIV disease is likely to be higher than in this study. Also, a fairly large number of mother-infant pairs (265) were excluded from the analysis, either due to loss to follow-up, non-participation after the first visit, or sero-conversion. There may have been some misclassification of low-density parasitemias. The number of HIV-infected infants born to mothers with placental malaria was small, reducing the power of the study.
The authors did not find that placental malaria was a risk factor for PNIM among infants of HIV sero-positive women. This is in contrast to an earlier study by Bloland et al,(1) but consistent with another study reporting a non-significant protective effect of placental malaria among infants born to HIV-sero-positive women (HR, 0.39 [CI, 0.11-1.38]).(2) Another study reported that MTCT was also significantly lower in infants of mothers with placental malaria.(3) Several explanations may help explain these findings. Maternal exposure to malaria probably modulates immune responses to malaria in utero.(4,5,6,7) It has recently become known that HIV-mediated disease progression is correlated with down-regulation of a regulatory T cell (Treg) subset, which may be critical for maintaining CD4+ cell counts.(8) Placental malaria increases the number of Treg cells in cord blood, and this may help protect against any rapid decrease in CD4+ cell counts in infants.(9) Other studies have shown that HIV/malaria co-infection up-regulates certain chemokines (compared with HIV-positive, malaria-negative women), including macrophage inflammatory protein (MIP)-1b, which compete with CCR5 receptor for HIV entry.(9, 10)
Malaria parasitemia in infants was not a risk factor for PNIM-in fact, median survival was higher among HIV-infected children with at least one documented malaria episode than in children with no malaria, which is consistent with the results of a previous study in Uganda. (11)
This study does not have strong programmatic implications, except that correction of infant anemia may improve survival. However, the role of placental malaria in the context of HIV and its impact on PNIM should be further studied to better understand the relationship between maternal and infant immune response to malaria and HIV.
- Bloland PB, Wirima JJ, Steketee RW, Chilima B, Hightower A, Breman JG. Maternal HIV infection and infant mortality in Malawi: evidence for increased mortality due to placental malaria infection. AIDS 1995 Jul;9(7):721-6.
- Verhoeff FH, Le Cessie S, Kalanda BF, Kazembe PN, Broadhead RL, Brabin BJ. Post-neonatal infant mortality in Malawi: the importance of maternal health. Ann Trop Paediatr 2004 Jun;24(2):161-9.
- Ayisi JG, van Eijk AM, Newman RD, ter Kuile FO, Shi YP, Yang C, et al. Maternal malaria and perinatal HIV transmission, western Kenya. Emerg Infect Dis 2004 Apr;10(4):643-52.
- King et al. Acquired immune response in neonates from Cameroon. (No abstract available.)
- Fievet N, Ringwald P, Bickii J, Dubois B, Maubert B, Le Hesran JY, et al. Malaria cellular immune responses in neonates from Cameroon. Parasite Immunol 1996 Oct;18(10):483-90.
- Malhotra I, Mungai P, Muchiri E, Ouma J, Sharma S, Kazura JW, et al. Distinct Th1- and Th2-Type prenatal cytokine responses to Plasmodium falciparum erythrocyte invasion ligands. Infect Immun 2005 Jun;73(6):3462-70.
- Brustoski K, Moller U, Kramer M, Hartgers FC, Kremsner PG, Krzych U, et al. Reduced cord blood immune effector-cell responsiveness mediated by CD4+ cells induced in utero as a consequence of placental Plasmodium falciparum infection. J Infect Dis 2006 Jan 1;193(1):146-54.
- Oswald-Richter K, Grill SM, Shariat N, Leelawong M, Sundrud MS, Haas DW, et al. HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells. PLoS Biol 2004 Jul;2(7):E198.
- Chaisavaneeyakorn S, Moore JM, Othoro C, Otieno J, Chaiyaroj SC, Shi YP, et al. Immunity to placental malaria. IV. Placental malaria is associated with up-regulation of macrophage migration inhibitory factor in intervillous blood. J Infect Dis 2002 Nov 1;186(9):1371-5.
- Ned RM, Moore JM, Chaisavaneeyakorn S, Udhayakumar V. Modulation of immune responses during HIV-malaria co-infection in pregnancy. Trends Parasitol 2005 Jun;21(6):284-91. (Review.)
- Kalyesubula I, Musoke-Mudido P, Marum L, Bagenda D, Aceng E, Ndugwa C, et al. Effects of malaria infection in human immunodeficiency virus type 1-infected Ugandan children. Pediatr Infect Dis J 1997 Sep;16(9):876-81.