PLACENTAL CHANGES ASSOCIATED W/ FETAL OUTCOME IN PLASMODIUM COATNEYI: MALARIA

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To achieve our goal of establishing the P. coatneyi-infected pregnant rhesus monkey as a comprehensive model of malaria during pregnancy, the placentas from one intrauterine death and 7 term pregnancies from monkeys inoculated with P. coatneyi during the first trimester were evaluated and the results were correlated with maternal parasitemia, morbidity and fetal/infant outcome. Controls consisted of 5 placentas from monkeys with no history of Plasmodium exposure collected and treated in the same manner. The general placental pathology from P. coatneyi-infected monkeys resembled that seen in P. falciparum-infected humans including focal syncytiotrophhoblast necrosis, irregular thickening of the trophoblast basement membrane, the presence of parasitized erythrocytes and aggregates of leukocytes (including macrophages) within the intervillous space (IVS), macrophages containing malaria pigment, malaria pigment deposits in fibrin and fibrinoid deposits, and fibrinoid necrosis of villi. Placental weights were lower than controls ( p=.0220). The 7 placentas from Plasmodium-infected dams had more significant pathologic changes than did the placentas from 5 control animals when median scores were compared (Mann Whitney Test) for the following parameters (all had p<.05) Distinct fibrinoid lesions, Generalized finbrinoid necrosis, Infarcts, Inflammatory infiltrates, Syncytiotrophoblast layer disruption and Placental damage. When the means were compared (Students T-test), the Plasmodium-infected placentas also had significantly higher numbers of activated (LN5+ Zymed) maternal macrophages in the IVS and Hofbaur cells in fetal villi than the controls (p=0.0173, p=0.0014 respectively). Fetal death occurred 7 days PI at 37 days gestation, in one monkey and appeared to be due to placental infarction. Parasitized erythrocytes were sequestered in endometrial capillaries, particularly toward the placenta. The basal plate was infarcted and the intervillous space contained fibrinoid material with IRBC and malaria pigment. Macrophages associated with these areas contained P. coatneyi and malaria pigment. These areas were associated with fibrinoid necrosis of villi. Placentas from Plasmodium-infected monkeys Associations between Parameters Examined and Fetal/Infant Outcome- Associations between placental parameter scores, the sums of parameter scores, total parasite load during pregnancy, parasite load during individual trimesters, and various fetal outcomes, were compared by Spearman Rank correlates (rs) analysis. Parasite inoculations during trimester 1, resulting in high parasite load during early gestation, were more likely to result in acute fetal demise (p=0.0476). High fibrinoid lesion scores and high placental damage scores were not associated with intrauterine growth retardation (IUGR) (p=0.4286), low birth weight (LBW) (rs=-0.2594), or early infant mortality (p=1.000). LBW and IUGR were associated with high pigment scores and high numbers of activated macrophages in the IVS. The relationships between pigment scores, activated macrophages and infant weight were highly significant. As total pigment increased, infant weight decreased (rs= -0.8524, p<0.05). As activated macrophages increased, infant weight decreased (rs= -0.8524, p<0.05). Of the three monkeys with the highest levels of activated macrophages and the highest total pigment scores, 2 gave birth to infants which died at 3 and 5 days of age. One infant had severe IUGR, LBW and the lowest weight placenta and the other delivered a LBW infant with IUGR which survived, but had congenital malaria diagnosed at 3 months of age. This infant's placenta contained the most activated macrophages in our study. Plasmodium-infected fetal RBCs were identified in fetal vessels in 4 monkeys with the highest total parasite loads (>150,000/ mm3) but not in 3 with low total parasite load (<55,000). This was significant (p= 0.0286). As activated maternal macrophages increased, the number of fetal RBCs containing parasites increased (rs= 0.7769, p<0.05). CONCLUSIONS In the P.coatneyi-infected rhesus monkey model, both parasitemia, and the stage of gestation at which it occurs, are important factors related to specific types of placental lesions and fetal/infant outcome. High parasite loads prior to gestation day 65 resulted in placental infarction and abortion. Intuitively, one would expect the highest total parasite load during pregnancy to be related to high placental damage scores, and this in turn to be associated with, IUGR, LBW and congenital infection. This was not the case in this study. IUGR, LBW, congenital infection and, to some degree early infant mortality, were associated with high parasite loads during trimesters 2 and 3 combined. High levels of activated macrophages within the intervillous space, along with heavy deposits of malaria pigment within fibrin and macrophages, were the histopathologic markers