Traditional and New Routes of Trophoblast Invasion and Their Implications for Pregnancy Diseases

Abstract

Historically, invasion of placental trophoblasts was thought to be extremely specific, only invading into the connective tissues of the maternal uterus and finally reaching and transforming the uterine spiral arteries. Only recently, identification of new routes of trophoblast invasion into different structures of the maternal uterus has been achieved. Thorough morphological analysis has resulted in the identification of trophoblasts invading into glands, veins, and lymph vessels of the uterine wall. These new routes pave the way for a re-evaluation of trophoblast invasion during normal placental development. Of course, such new routes of trophoblast invasion may well be altered, especially in pregnancy pathologies such as intra-uterine growth restriction, preeclampsia, early and recurrent pregnancy loss, stillbirth, and spontaneous abortion. Maybe one or more of these pregnancy pathologies show alterations in different pathways of trophoblast invasion, and, thus, etiologies may need to be redefined, and new therapies may be developed.

Keywords: intra-uterine growth restriction; invasion; placenta; pregnancy outcome; trophoblast; uterine glands; uterine milk.

Figure 1

(A) Image #7 of case 8020: Margin of the trophoblastic plate. Allen Enders explained: “Syncytial trophoblast with small nuclei has invaded the underlying endometrial gland. It is not known whether the small nuclear syncytium is synctiotrophoblast or is partially a heterokaryon involving fusion of trophoblast and uterine cells.” The black arrow points to invasion into a uterine gland. (B) Image #13 of case 8171: Early lacunar stage (stage 5B). Allen Enders’ explained: “Note that the appearance of endometrial glands is similar to that seen in one of the stage 5A sites.” He further explained (under image #14 of case 8171): “Note continuity of a capillary with a lacuna that anastomoses with other lacunae. Trophoblast appears to be invading a gland in the upper right.” The black arrow points to invasion into a uterine gland, while the blue arrow points to invasion into a uterine blood vessel. Image are provided by courtesy of Allen C. Enders and the Carnegie Collection.

Figure 2

Schematic representation of the routes of trophoblast invasion during normal pregnancy. (A) Very early in pregnancy, prior to six weeks of gestation, invasion of the early invading syncytiotrophoblast during implantation, as well as invasion of early extravillous trophoblasts, results in opening uterine glands and veins toward the intervillous space of the placenta. Endoglandular trophoblasts open uterine glands, to enable the flow of “uterine milk” toward the placenta. This is followed by invasion of endovenous trophoblasts into uterine veins, to enable backflow of fluids into the maternal system, including villous material and endoglandular trophoblasts (shown in vein). The arrows in gland and vein represent the material transported in these structures (green arrow: glandular secretion products). (B) Later, during the first trimester, endoarterial trophoblasts invade into uterine spiral arteries, transform their walls, and plug their lumen, to hinder flow of maternal blood into the placenta. At that stage, only blood plasma is seeping through the plugs (indicated by the dashed red arrow). During this stage of pregnancy, the backflow via utero–placental veins comprises glandular secretion products, plus plasma from the spiral arteries (green arrow plus dashed red arrow), including villous material plus endoglandular and endoarterial trophoblasts (shown in vein). (C) At the beginning of the second trimester, the arterial plugs disintegrate, and the flow of maternal blood into the placenta is finally established. So far, it is not clear at which time point the glandular input diminishes and disappears, but in the second half of pregnancy, respective glands can hardly be found. Hence, this schematic drawing only shows arteries and veins (red arrows: maternal blood). Now, the venous backflow contains villous material, as well as endoarterial trophoblasts (shown in vein). A, artery; G, gland; V, vein; GA, gestational age; ST, syncytiotrophoblast; vCT, villous cytotrophoblast; EVT, extravillous trophoblast.