PRIOR EXPOSURE TO PLASMODIUM COATNEYI ON OUTCOME OF PREGNANCY: RHESUS MONKEYS

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Pregnant women with malaria due to infection with Plasmodium falciparum suffer more adverse consequences than P. falciparum-infected nonpregnant women. The more common and serious sequelae include anemia and severe malaria with central nervous system complications. Their infants suffer intrauterine growth retardation (IUGR), low birth weight (LBW), congenital infection and high infant mortality. Although much information has been gleaned from human trials, the conditions, and moral and ethical limitations of human studies of pregnancy preclude manipulation of the system and important data is often uninterpretable due to confounding variables. Due to its close similarity to the human in its clinical and immunological responses to Plasmodium, the nonhuman primate has been widely used as a model to study malaria. Nonhuman primates are also the only animals with a villous, hemochorial placenta like that of man and are, therefore, the animal model of choice in studies of pregnancy. During 1996, we established a model of malaria during pregnancy by intravenously inoculating 10 malaria naive rhesus monkeys (Macaca mulatta) during the first trimester with Plasmodium coatneyi, a "falciparum-type parasite". A manuscript describing these results is in press (The American Journal of Tropical Medicine and Hygiene). In a continuation of our model development, we examined the effect of a second exposure to P.coatneyi during a subsequent pregnancy in 5 of these monkeys, referred to as "semi-immune". This aspect of the study addressed questions relevant to the actual situation existing in malaria endemic areas. Women in these areas are chronically exposed to malaria prior to pregnancy and therefore develop some level of immunity to Plasmodium. To address the question of the effects of prior immunity on the outcome of pregnancy, all 5 previously exposed monkeys were inoculated early during the first trimester(gestation day 21-35) and weekly physical exams, CBCs, parasite determinations, and ultrasound examination of the fetus were performed throughout pregnancy. Only low levels of parasitemia occurred (276-12,800/mm3) in all 5 monkeys and took an average of 37 (vs. 14 in first study) days to appear. Fresh inoculum was more effective than frozen in infecting the monkeys. No significant anemia occurred in the semi-immune monkeys, despite levels and patterns of parasitemia similar to those in 4 naive monkeys with low parasitemia in our first study. Unlike the first study where dams lost weight during pregnancy, the dam's weight gain during pregnancy was the same as the controls. There was no early infant mortality, further strengthening our finding in the first study that persistent anemia during the later half of pregnancy correlates with infant mortality. Although there was no high parasitemia, significant anemia, or infant mortality in this group, adverse outcomes occurred in 4 of 5 infants. Intrauterine death with fetal resorption occurred in one infant. IUGR during the 3rd trimester occurred in a 2nd infant and this infant has been growth retarded for the past 6 mo. Low placental wt., LBW and congenital infection occurred in a 3rd infant. Clinical problems and weight loss occurred for the first month after birth in a 4th infant. The mean birth weight of the group was normal. However, these infants initially lost weight and the mean weight gain continues to be below that of the controls. The mean falls between the mean wt gain for controls and that for the group of infants born to naive monkeys. Congenital infection was identified in one infant (semi-immune dam) at 20 weeks of age and was transient, with one episode of low level parasitemia (12,000/mm3). The congenital infection in our first study occurred at 11 weeks, has had high parasitemia (120,000/mm3) and has been persistently infected for 22 months. The transiently infected infant may have received increased levels of passive protection from its semi-immune mother. The placentas from the semi-immune group are still being evaluated but the general pathology is not as severe as that observed in the naive group. Inoculation of one additional naive primigravid monkey with the same inoculum used in the semi-immune group resulted in very high chronic parasitemia, anemia, IUGR, and early infant death. Thus, the differences in outcome are not due to variability in the inoculum. A manuscript will be submitted to the American Journal of Tropical Medicine and Hygiene.