Extravillous trophoblast invasion in placenta accreta is associated with differential local expression of angiogenic and growth factors: across-sectional study

ObjectivePlacenta accreta is clinically associated with maternal uterine scar. Our objective was to investigate the biochemical contribution of maternal scarring to hyperinvasive trophoblast. We hypothesised that trophoblast over-invasion in placenta accreta is associated with aberrant invasion-site signalling of growth and angiogenic factors known to be involved in wound healing and promotion of cell invasion through the epithelial to mesenchymal cellular programme. DesignCross-sectional series. SettingYale-New Haven Hospital. PopulationWomen with histologically confirmed normal and abnormal placentation. MethodsPlacental invasion site tissue sections were immunostained for endoglin and other angiogenic regulators, and transforming growth factor (TGF) proteins. Maternal serum endoglin, and the vascular endothelial growth factor (VEGF) mediators hypoxia-inducible factor-1 (HIF1) and endostatin, were assessed using immunoassay. Main outcome measuresDifferences in median H-score by immunostaining and in mean serum level by immunoassay. ResultsBy immunostaining, placenta accreta samples demonstrated intervillous endoglin shedding and increased trophoblast expression of its cleavage protein matrix metalloproteinase-14. Absent decidual HIF1 and endostatin were observed in areas of VEGF upregulation. TGF1 was present in myocytes but not in collagen bundles into which accreta trophoblast invaded. Maternal serum endoglin decreased in praevia and accreta when corrected for gestational age. ConclusionAngiogenic and growth factors at the placental invasion site are altered in accreta, both by decidual absence and within myometrial scar. We postulate this promotes the invasive phenotype of placenta accreta by activating hyperinvasive trophoblast and by dysregulating placental vascular remodelling. FundingYale Department of Obstetrics, Gynecology and Reproductive Sciences funds. Tweetable abstractPlacenta accreta histology shows dysregulation of angiogenic and growth factors. Tweetable abstract Placenta accreta histology shows dysregulation of angiogenic and growth factors. This article includes Author Insights, a video abstract available at