ABSTRACT
Placental malaria (PM) is a major cause of fetal growth restriction, yet the underlying mechanism is unclear. Complement C5a and C5a receptor levels are increased with PM. C5a is implicated in fetal growth restriction in non-infection-based animal models. In a case-control study of 492 pregnant Malawian women, we find that elevated C5a levels are associated with an increased risk of delivering a small-for-gestational-age infant. C5a was significantly increased in PM and was negatively correlated with the angiogenic factor angiopoietin-1 and positively correlated with angiopoietin-2, soluble endoglin, and vascular endothelial growth factor. Genetic or pharmacological blockade of C5a or its receptor in a mouse model of PM resulted in greater fetoplacental vessel development, reduced placental vascular resistance, and improved fetal growth and survival. These data suggest that C5a drives fetal growth restriction in PM through dysregulation of angiogenic factors essential for placental vascular remodeling resulting in placental vascular insufficiency.
Subject(s)
Complement Activation , Complement C5a/metabolism , Fetal Growth Retardation/pathology , Gene Expression Regulation, Developmental , Malaria/pathology , Placental Insufficiency/pathology , Pregnancy Complications, Parasitic/pathology , Adolescent , Animals , Biomarkers/metabolism , Case-Control Studies , Disease Models, Animal , Female , Fetal Growth Retardation/metabolism , Fetal Growth Retardation/parasitology , Gestational Age , Humans , Malaria/metabolism , Male , Mice , Mice, Inbred BALB C , Neovascularization, Pathologic/metabolism , Placenta/blood supply , Placenta/parasitology , Placental Insufficiency/metabolism , Placental Insufficiency/parasitology , Plasmodium berghei/pathogenicity , Pregnancy , Receptor, Anaphylatoxin C5a , Receptors, Complement/metabolism , Signal Transduction , Transcription, Genetic , Young AdultABSTRACT
UNLABELLED: Acute placental dysfunction induced by malaria is characterized by umbilical artery resistance increase and cerebral artery resistance decrease during the crisis. The objective was to evaluate the sensitivity and specificity of fetal Doppler indices and crisis duration for predicting abnormal fetal heart rate (aFHR) at delivery several weeks after the crisis. METHOD: Every day during the crisis, the umbilical and cerebral resistance indices were measured by Doppler. These indices allowed evaluation of the amplitude of the fetal flow redistribution (C/U = cerebral resistance/umbilical resistance ratio), the duration of the flow redistribution period (i.e. crisis duration) and the Hypoxic index (HI) (mean %C/U change x crisis duration). POPULATION: 46 pregnancies. Mean duration of the flow redistribution period 8+/-3.2 days, mean C/U change -9%+/-6; Hypoxic index -86+/-75; prematures 48%; aFHR 30%). Hypoxic index >150 predicted occurrence of aFHR with high sensitivity and specificity (83%/88%). The presence of abnormal flow distribution (C/U<1.1) and the duration of the period with flow disturbance (>8 days) predicted aFHR at delivery with a sensitivity of 45 and 48% and a specificity of 82 and 84%. CONCLUSION: The Hypoxic index was more predictive of aFHR at delivery than the amplitude or the duration of the fetal flow redistribution triggered by placental insufficiency.
