Loss of Placental P-Glycoprotein May Be a Common Pathophysiologic Pathway for First Trimester Spontaneous Miscarriages

Abstract

Introduction P-glycoprotein the highly conserved mammalian adenosine triphosphate-binding cassette transmembrane multidrug protein transporter is involved in peri-implantation events and fetal placental development. Greater expression in early versus late pregnancy and localization in both syncytio- and cytotrophoblast indicate that P-glycoprotein transports substances across the uterine epithelium during early pregnancy and protects the conceptus from toxic substances during implantation and early embryogenesis. We hypothesized that P-glycoprotein is involved in the physiologic maintenance of early pregnancy and that P-glycoprotein dysregulation may be involved in early pregnancy pathologies. Methods First trimester dilation and curettage specimens were selected retrospectively from the archives of the Department of Pathology from spontaneous miscarriages (n = 36) and elective termination of pregnancy (n = 20). Two P-glycoprotein specific monoclonal antibodies JSB1and C219 were used on formalin-fixed, paraffin-embedded 5µ tissue sections. The location, intensity, and percentage of P-glycoprotein chorionic villous immunostaining were semiquantitated. Results Spontaneous miscarriages demonstrated absence or significant reduction in P-glycoprotein compared to elective terminations; 75% (27/36) showed total absence of P-glycoprotein, 19% (7/36) showed only rare villi with discontinuous immunostaining, and 6% (2/36) showed weak immunostaining. In contrast, 90% of elective terminations (18/20) showed positive immunostaining for P-glycoprotein and only 10% (2/20) showed loss of P-glycoprotein expression ( P < .0001). Discussion We report a dramatic loss/decrease of P-glycoprotein in first trimester spontaneous miscarriages. This finding in conjunction with the known high expression of P-glycoprotein in normal first trimester placental tissues suggests an important role of P-glycoprotein in the maintenance of early pregnancy.