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Background: Pregnancy malaria has a negative impact on fetal outcome. It is uncertain whether infections in early pregnancy have a clinical impact by impeding the development of the placental vasculature.Methods: Tanzanian women (n = 138) were closely monitored during pregnancy. Placentas collected at birth were investigated using stereology to establish the characteristics of placental villi and vessels. Placental vasculature measures were compared between women infected with malaria and controls.Results: Compared with controls, placentas from women infected with malaria before a gestational age (GA) of 15 weeks had a decreased volume of transport villi (mean decrease [standard deviation], 12.45 [5.39] cm3; P = .02), an increased diffusion distance in diffusion vessels (mean increase, 3.33 [1.27] µm; P = .01), and a compensatory increase in diffusion vessel surface area (mean increase, 1.81 [0.74 m2]; P = .02). In women who had malaria before a GA of 15 weeks diffusion vessel surface area and transport vessel length distance were positive predictors for birth weight (multilinear regression: P = .007 and P = .055 for diffusion surface area and transport length, respectively) and GA at delivery (P = .005 and P = .04).Conclusions: Malaria infection in early pregnancy impedes placental vascular development. The resulting phenotypic changes, which can be detected at delivery, are associated with birth weight and gestational length.Clinical Trials Registration: NCT02191683. [ABSTRACT FROM AUTHOR]