813 Am. J. Trop. Med. Hyg., 59(5), 1998, pp. 813–822 Copyright  1998 by The American Society of Tropical Medicine and Hygiene EFFICACY OF SULFADOXINE-PYRIMETHAMINE FOR PREVENTION OF PLACENTAL MALARIA IN AN AREA OF KENYA WITH A HIGH PREVALENCE OF MALARIA AND HUMAN IMMUNODEFICIENCY VIRUS INFECTION MONICA E. PARISE, JOHN G. AYISI, BERNARD L. NAHLEN, LINDA J. SCHULTZ, JACQUELIN M. ROBERTS, AMBROSE MISORE, RICHARD MUGA, AGGREY J. OLOO, AND RICHARD W. STEKETEE Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; Kenya Medical Research Institute, Kisian, Kenya; Kenya Ministry of Health, Kisumu, Kenya Abstract. A fever case management (CM) approach using sulfadoxine-pyrimethamine (SP) was compared with two presumptive intertmittent SP treatment regimens in the second and third trimesters in pregnant primigravidae and secundigravidae in an area of intense Plasmodium falciparum malaria transmission in western Kenya. The investi- gation evaluated efficacy of the antimalarial regimens for prevention of placental malaria and examined the effect of human immunodeficiency virus (HIV) infection on antimalarial drug efficacy and adverse drug reactions. Twenty- seven percent (93 of 343) of pregnant women in the CM group had placental malaria compared with 12% (38 of 330; P  0.001) of women who received two doses of SP and compared with 9% (28 of 316; P  0.001) of women who received monthly SP. Fourteen percent (49 of 341) of women in the CM group delivered low birth weight (LBW) infants compared with 8% (27 of 325; P = 0.118) of women who received two doses of SP and compared with 8% (26 of 331; P = 0.078) of women who received monthly SP. Seven percent (7 of 99) of the HIV-negative women on the two-dose SP regimen had placental malaria compared with 25% (10 of 39; P = 0.007) of HIV-positive women on the same regimen; the rate of placental malaria in HIV-positive women was reduced to 7% (2 of 28; P = 0.051) for women on the monthly SP regimen. Less than 2% of women reported adverse drug reactions, with no statistically significant differences between HIV-positive and HIV-negative women. Intermittent treatment with SP is safe and efficacious for the prevention of placental malaria in pregnant primigravidae and secundigravidae in sub-Saharan Africa. While a two-dose SP regimen may be effective in areas with low HIV seroprevalence, administration of SP monthly during the second and third trimesters of pregnancy should be considered in areas of high HIV seroprevalence to prevent the effects of maternal malaria on the newborn. In sub-Saharan Africa, pregnant women are more likely than their non-pregnant counterparts to become infected with Plasmodium falciparum malaria and have a higher density of parasitemia. 1,2 In areas of high P. falciparum transmission, infection in pregnant women is frequently asymptomatic but can lead to parasite sequestration and altered placental in- tegrity. 3–5 Placental malaria is a risk factor for low birth weight (LBW), 6–8 presumably through decreased nutrient transport across the placenta. Additionally, malaria parasit- emia may contribute to maternal anemia, 9,10 also a risk factor for LBW. 11 Low birth weight is the single greatest risk factor for neonatal and infant mortality. 12 In areas with high P. falciparum malaria transmission, where women may have substantial acquired antimalarial immunity, women in their first and second pregnancies are most at risk of malaria 8,13 and of malaria-associated LBW. 1,12,13 In these same sub-Saharan African settings, human im- munodeficiency virus (HIV) infection has become increas- ingly prevalent in women of reproductive age. 14–16 Recent studies suggest that HIV infection may diminish a pregnant woman’s capacity to control P. falciparum infection 17 and thus may lead to decreased efficacy of antimalarial interven- tions. The presence of placental malaria in HIV-positive women may also increase the risk of vertical transmission of HIV. 18 In addition, infection with HIV may predispose the woman to adverse events associated with sulfa-containing antimalarials. Adverse drug reactions (ADRs), 19 including fatal ones, 20 have been reported in HIV-positive persons us- ing sulfadoxine-pyrimethamine (SP) for prophylaxis against Pneumocystis carinii pneumonia. Case-fatality rates for ADRs, particularly severe cutaneous adverse reactions, have been reported to be higher after administration of drugs with long elimination half-lives, such as SP, compared with drugs with shorter half-lives. 21 Because of the consequences of P. falciparum infection dur- ing pregnancy, the World Health Organization recommends that women living in malarious areas receive chemoprophylaxis during pregnancy. 22 The choice of an efficacious and safe reg- imen has, however, become increasingly challenging because of widespread chloroquine (CQ) resistance. In 1992, Schultz and others 23 demonstrated that two treatment doses of SP, ad- ministered once in the second and once in the third trimester, was efficacious in decreasing placental malaria in an area where persons receive, on average, 50 infective mosquito bites/year. Important remaining questions include whether such a two-dose SP regimen would be sufficiently efficacious in an area with even higher malaria transmission and where malaria transmis- sion is less seasonal than at the Malawi study site and, addi- tionally, whether SP would be effective in an area with a high prevalence of HIV infection. In western Kenya, where women receive 200–300 infec- tive mosquito bites/year, 24 the standard of care at the time of this study was to provide fever case management (CM), that is, antimalarial treatment for febrile episodes accompanied by parasitemia during pregnancy. In this investigation we compared CM to two presumptive intermittent SP-treatment regimens. The objectives of the study were to determine the efficacy of the different regimens in the prevention of pla- cental malaria, to examine for adverse effects associated with SP use, and to assess the effect of HIV infection on antimalarial efficacy and ADRs. METHODS Study site. The study was conducted from December 1994 through July 1996 in Kisumu District in western Ke-