Measures

The placenta displays typical macroscopic features after delivery at term [1]. The term placenta shows a round disc‐like appearance, with the insertion of the umbilical cord in a slightly eccentric position on the fetal side of the placenta. The average measurements of a delivered placenta at term are as follows: diameter 22 cm, central thickness 2.5 cm, and weight 450–500 g. One has to keep in mind, though, that considerable variation in gross placental structure can occur in normal term pregnancies. In part, this is due to the fact that the human placenta comprises 30–50 operational units termed placentomes, whose aggregated shape may vary without compromise to the function of individual units.

Trophoblast lineage

At the transition between morula and blastocyst, the trophoblast lineage is the first to differentiate from the inner cell mass or embryoblast (Fig. 2.2) [1]. Following attachment of the blastocyst to the endometrial epithelium, further differentiation of the trophoblast occurs. Exact knowledge of the underlying molecular processes in the human is still lacking, but at this stage the first event is the creation of an outer layer of fused trophoblast cells, termed the outer syncytiotrophoblast. This outer syncytiotrophoblast generated by fused trophoblasts is in direct contact with maternal tissues and thus is the first layer from the conceptus to encounter and subsequently penetrate the uterine epithelium capillaries (Fig. 2.2).

Prelacunar stage

At day 7–8 post conception, the blastocyst has completely crossed the uterine epithelium to become embedded within the decidualized endometrial stroma. The developing embryo is completely surrounded by the growing placenta, which at that stage consists of the two fundamental subtypes of the trophoblast. The multinucleated syncytiotrophoblast is in direct contact with maternal tissues, while the mononucleated cytotrophoblast as the stem cell layer of the trophoblast is directed towards the embryo.

All the differentiation and developmental stages of the placenta described so far take place before fluid‐filled spaces within the syncytiotrophoblast develop. This is why this stage is termed ‘prelacunar’ [1].

Lacunar stage

At day 8–9 post conception, the syncytiotrophoblast generates a number of fluid‐filled spaces within its mass (lacunar stage) [1]. These spaces flow together forming larger lacunae, and finally embed parts of the syncytiotrophoblast (trabeculae) that cross the syncytial mass from the embryonic to the maternal side.

At the end of this stage, at day 12 post conception, the process of implantation is completed. The developing embryo with its surrounding extraembryonic tissues is completely embedded in the decidualized endometrium, and the syncytiotrophoblast surrounds the whole surface of the conceptus. Mesenchymal cells derived from the embryo spread over the inner surface of the trophoblast (extraembryonic mesoderm), thus generating an additional mesenchymal layer on top of the inner surface of the trophoblast, termed chorion.

The development of the lacunar system subdivides the placenta into its three compartments.

1. The embryonically oriented part of the trophoblast together with the extraembryonic mesoderm (chorion) will develop into the chorionic plate.
   
2. The trabeculae will become the anchoring villi, attaching the placenta proper to the uterine wall. The side branches growing out of the trabeculae will develop into floating villi. The lacunae surrounding the villi will turn into the intervillous space that will subsequently fill with maternal blood at the end of the first trimester.
   
3. The maternally oriented part of the trophoblast together with components of maternal decidual tissues will develop into the basal plate.

Early villous stage

Very early in pregnancy, specific types of villi develop as the forerunners of the placental villous tissues seen later in pregnancy [1]. Starting at day 12 post conception, proliferation of cytotrophoblast pushes trophoblasts to penetrate the syncytial trabeculae, reaching the maternal side of the syncytiotrophoblast by day 14. Further proliferation of trophoblasts inside the trabeculae (day 13) stretches the trabeculae, resulting in the development of syncytial side branches filled with cytotrophoblasts (primary villi).

Shortly after, the mesenchymal cells from the chorion follow the cytotrophoblast and penetrate the trabeculae and the primary villi, thus generating secondary villi with a mesenchymal core. At this stage, there is always a complete cytotrophoblast layer between penetrating mesenchyme and syncytiotrophoblast.

Around day 20–21 post conception, vascularization (development of new vessels from haemangioblastic precursor cells) within the villous mesenchyme gives rise to the formation of the first placental vessels (tertiary villi). Only later will the proximal connection to the vascular system of the embryo proper be established via the umbilical cord.

Placental villi are organized in villous trees that cluster together into a series of spherical units known as lobules or placentomes. Each placentome originates from the chorionic plate by a thick villous trunk stemming from a trabecula. Continuous branching of the main trunk results in the formation of floating villi that branch and end freely as terminal villi in the intervillous space.

Trophoblastic cell columns

During penetration of the syncytial trabeculae, the cytotrophoblasts reach the maternal decidual tissues while the subsequently penetrating mesenchymal cells do not infiltrate to the tips of the trabeculae [1]. Hence, at the tips of the anchoring villi multiple layers of cytotrophoblasts develop, referred to as trophoblastic cell columns (Fig. 2.3) [1]. Only those cytotrophoblasts remain as proliferative stem cells that are in direct contact with the basement membrane separating trophoblast from mesenchyme of the anchoring villi.

Subtypes of extravillous trophoblast

The formation of cell columns does not always result in a complete layer of trophoblastic shell but rather may be organized as separated columns from which extravillous trophoblasts invade into maternal uterine tissues (Fig. 2.3). All these cells migrate as interstitial trophoblast into the decidual stroma [1]. The interstitial trophoblast invades the whole thickness of the decidua and penetrates the inner third of the myometrium. Here, invasion normally stops and no extravillous trophoblast can be seen in the outer third of the myometrium.

Following this main direction of invasion, extravillous trophoblasts may invade via other specific routes. One subset of interstitial trophoblasts penetrates the walls of uterine spiral arteries and veins (intramural trophoblast), finally reaching the vessel lumen (endovascular trophoblast) (Fig. 2.3) [2]. Another subset of interstitial trophoblasts penetrates the walls of uterine glands, finally opening such glands towards the intervillous space (endoglandular trophoblast) (Fig. 2.4) [3]. Finally, some of the interstitial trophoblasts may fuse and thus develop into multinucleated trophoblast giant cells (Fig. 2.4) at the boundary between endometrium/decidua and myometrium [1].

Plugging of spiral arteries

Invasion of extravillous trophoblasts is the ultimate means to transform maternal arteries into large‐bore conduits to enable adequate supply of oxygen and nutrients to the placenta and the fetus [1,2]. However, free transfer of maternal blood to the intervillous space is only established at the end of the first trimester of pregnancy [4]. Before that, the extent of invasion and thus the number of endovascular trophoblasts is so great that the trophoblasts aggregate within the arterial lumen, plugging the distal segments of the spiral arteries (Fig. 2.3). Hence, before about 12 weeks of gestation, the intervillous space contains mostly a plasma filtrate that is free of maternal blood cells. To aid in nutritional support of the embryo, glandular secretion products from eroded uterine glands (histiotrophic nutrition) add to the fluids filling the intervillous space (Fig. 2.3) [3,5].

The reason for such paradoxical plugging of already eroded and transformed arteries may be because the lack of blood cells keeps the placenta and the embryo in a low oxygen environment of less than 20 mmHg in the first trimester of pregnancy. This low oxygen environment may be necessary to drive angiogenesis and at the same time reduce formation of free radicals that could damage the growing embryo in this critical stage of tissue and organ development [6].

Onset of maternal blood flow

At the end of the first trimester trophoblastic plugs within the spiral arteries break up to allow maternal blood cells to enter the intervillous space, thereby establishing the first arterial blood flow to the placenta (haemotrophic nutrition) [4]. The inflow starts in those upper parts of the placenta that are closer to the endometrial epithelium (the abembryonic pole of the placenta) (Fig. 2.3) [6]. These sites are characterized by a slight delay in development since the deeper parts at the embryonic pole have been the first to develop directly after implantation (Fig. 2.3). Therefore, at these upper sites the plugs inside the vessels contain fewer cells, enabling blood cells to penetrate the plugs earlier, and blood flow starts at these sites first, maybe even weeks prior to the embryonic pole. Because of the massive increase in oxygenation at this time (around weeks 8–10) at the abembryonic pole, placental villi degenerate in larger parts and the chorion becomes secondarily smooth. The regression leads to the formation of the fetal membrane or chorion laeve [6]. The remaining part of the placenta develops into the chorion frondosum, the definitive disc‐shaped placenta.