Martin Gauster and Gernot Desoye
The term “great obstetrical syndromes” was coined about a decade ago (1). It describes conditions that have multiple etiologies and result from maternal-fetal interactions involving the genome and the environment. The most frequent obstetrical syndromes as they were understood earlier are fetal growth restriction and preeclampsia, both rooted in problems with placentation and trophoblast invasion, biological processes mainly of the first trimester of pregnancy (2). Less common are preterm labor and preterm rupture of membranes as well as stillbirth. Later on, gestational diabetes mellitus (GDM) was also added to this list (3) because of the placental contribution to both the etiology of the maternal condition and fetal phenotype (4). Development of the fetoplacental unit in the first trimester of pregnancy has received attention because early placental changes may also have an effect on placental development later in pregnancy (5). In recent years, studies into the origins of these conditions have received attention, and attempts have been made to predict them and prevent them from occurring (6). Identification of early biomarkers has become one focus of clinical research (7,8).
In this chapter, we discuss the biological processes involved in anchoring the fetoplacental unit in the uterus, the changes in the decidual arteries, and how a defect in any of these processes may lead to fetal growth restriction and preeclampsia. We further describe how the placenta may contribute to maternal metabolic changes underlying GDM and the placental involvement in phenotypic changes in the fetus.
Implantation and trophoblast invasion
In human pregnancy, embryo implantation is initiated by apposition of the blastocyst with its embryonic pole, bearing the inner cell mass, to the endometrial epithelium. While the inner cell mass gives rise to the embryo, the outer cell mass—referred to as trophoblast cells—forms the wall of the blastocyst, thus mediating initial adherence to the uterine wall and later forming the placenta. Apposition and adherence of the blastocyst are followed by intercellular fusion of trophoblasts that are in contact with the endometrial epithelium, to form the multinucleated syncytiotrophoblast (9). At that very early stage of embryo implantation, the syncytiotrophoblast is equipped with an enzymatic endowment that enables crossing of the endometrial epithelium and penetration of the underlying stroma. The endometrium from now on may be referred to as decidua, which provides the breeding ground for the growing embryo and the developing placenta. Once the blastocyst has completely penetrated the decidua, the mass of syncytiotrophoblast rapidly increases by ongoing proliferation and fusion of underlying cytotrophoblasts. The syncytiotrophoblast forms a complete layer over the surface of the blastocyst, whereas the site at the implantation pole achieves considerable thickness and develops extensions that deeply invade the decidua.
After implantation, primary placental villi, composed of a cytotrophoblast core with a covering of syncytiotrophoblast, are being developed (10). At the distal ends of the developing villi, cytotrophoblasts penetrate the syncytiotrophoblast and form cell columns, which attach the developing placenta to the decidua. With ongoing placentation, trophoblasts detach from cell columns, adopt an invasive phenotype, and invade as “extravillous trophoblasts” (EVTs), the decidual interstitium up to the first third of the myometrium. Previous, rather simplified dogmas suggest that EVTs invade the decidual interstitium with the aim to accumulate and form cellular plugs in decidual spiral arteries, where they obstruct the maternal arterial blood flow into the intervillous space until the end of the first trimester of pregnancy. With disaggregation of trophoblast plugs at the end of the first trimester, maternal blood flow is initiated into the intervillous space. Recent microanatomical surveys on first trimester decidua basalis sections challenged this doctrine and extended the current view by showing extravillous trophoblast subpopulations in several luminal structures, including uterine spiral arteries, veins, glands, and to a minor extent, uterine lymphatic vessels (10–12). While the functional significance for invasion into lymphatic vessels remains unclear, arteries, veins, and glands have to be connected to the intervillous space to guarantee successful placentation. However, the type of invasion into arteries may differ compared to invasion into uterine veins and glands. According to a recent opinion, uterine veins and glands are invaded to be connected to the intervillous space of the placenta without a massive remodeling of their vessel walls (13). In contrast, spiral arteries are remarkably converted by EVTs, leading to depletion of smooth muscle cells in their walls and loss of their elastic lamina. The consequence of the spiral artery conversion is that distal segments of the vessels dilate and are converted into flaccid conduits (Figure 3.1a), enabling reduction of the velocity of incoming maternal blood and thereby preventing damage to delicate villous trees (14–16).
Figure 3.1 Consequences of inadequate spiral artery remodeling. In normal pregnancy, trophoblast invasion into the maternal decidua gives rise to conversion of distal segments of spiral arteries into widened conduits (a) Aberrant trophoblast invasion and inadequate spiral artery remodeling, with absence of any dilation at the distal ends of the arteries, leads to high-speed jets that enter the intervillous space (b).
Consequences of inadequate invasion and spiral artery remodeling
Many placenta-associated pregnancy complications, such as recurrent pregnancy loss, intrauterine growth restriction (IUGR), and preeclampsia, have been associated with aberrant conversion of the spiral arteries in the placental bed, which is the part of the uterine wall underlying the placenta. Recent computational modeling of flow in spiral arteries suggests that inadequate spiral artery remodeling and the absence of any dilation at the distal ends of the arteries gives rise to turbulent, very high speed jets that enter the intervillous space, which surrounds the chorionic placental villi (Figure 3.1b) (14). While these high-speed jets can nowadays be visualized reliably using pulsed-wave Doppler ultrasonography, computational models of blood flow from spiral artery openings suggest that jets of flow observed by ultrasound are likely correlated with increased porosity of the intervillous space near the opening of the spiral arteries (15). Accordingly, mega-jets, which penetrate more than half the placental thickness, may only be possible when spiral arteries open to regions of the placenta with very sparse villous structures (15). This assumption further suggests that the velocity of the incoming blood flow from converted spiral arteries influences development and architecture of villous trees. The turbulent blood flow, including high-velocity jets and vortices combined with elevated blood pressure in the proximal intervillous space may contribute to an increased wall shear stress at the villous surface. Increased shear stress at the villous surface has been associated with elevated trophoblast shedding, as observed in an in toto embedded IUGR placenta. Histological examinations revealed potential villous damage, which appeared as cytokeratin-positive particles in the intervillous space, but in a more pronounced way in veins of intercotyledonary septa that drain the intervillous space (16).
Inadequate spiral artery remodeling may be the result of both shallow invasion and a reduced number of invaded trophoblasts. This assumption is based on numerous histological surveys on hysterectomy and postmortem specimens of uteri with in situ placentas as well as placental bed biopsies, consisting of both decidual and myometrial tissue. Among such studies, severely impaired trophoblast invasion has been shown in full-thickness uterine wall samples obtained from early onset preeclamptic pregnancies combined with intrauterine growth restriction (17). However, the detailed underlying mechanisms, regulating EVT invasion in vivo and how EVTs enable the extensive remodeling of the, in total, approximately 30–60 spiral arteries of the placental bed, remain largely unknown. In recent years, maternal immune cells such as uterine natural killer cells and macrophages have been suggested as key regulators of both EVT invasion and spiral artery remodeling in the placental bed (18,19). A plethora of soluble factors, including cytokines, chemokines, and growth factors, is secreted from decidual macrophages and stromal cells, as well as uterine natural killer cells and even uterine glandular epithelial cells. A balanced cocktail of these factors may drive initial proliferation of trophoblast cell columns and subsequent detachment and invasion of EVTs into the placental bed (20). Moreover, these factors could regulate recruitment of macrophages and natural killer cells as well as other less abundant immune cells into the placental bed. At the same time, decidual stroma cells are suggested to secrete some anti-invasive factors that might be essential to counteract the effects of invasion-promoting factors and restrain exaggerated invasion. Thus, the decidua may provide a timely, balanced production of invasion promoting and inhibiting factors enabling a well-coordinated EVT invasion (21).
Beside high-velocity jets, fluctuations in placental oxygen concentrations resulting from intermittent perfusion of the intervillous space are currently discussed as a consequence of inadequate spiral artery remodeling (22). While fluctuations in intervillous blood flow can be explained by periodic vasoconstriction of spiral arteries that might even occur during normal human pregnancies, it seems reasonable that such events occur more frequently and more pronounced in placental beds with less remodeled spiral arteries, due to the preservation of smooth muscle within their distal ends. The consequence of such fluctuations may be a decreased oxygen tension within the affected area, which probably could not be compensated by supply from adjacent spiral arteries. However, when vasoconstriction of spiral arteries declines, inflow in the intervillous space is restored, and the local oxygen tension steeply rises. Importantly, such fluctuations in oxygen tension are associated with an ischemia-reperfusion type of injury, which is well documented for other organs such as heart and brain (22). Ischemia-reperfusion generates high concentrations of reactive oxygen species (ROS), which in turn exert cytotoxic effects on the exposed syncytiotrophoblast, giving rise to placenta-associated pregnancy pathologies. In line with this assumption, recent analysis of stress-signaling pathways in placental tissues from complicated pregnancies together with in vitro experiments with trophoblasts suggest that placental oxidative stress may contribute to the pathophysiology of early onset preeclampsia and IUGR (23).
Gestational diabetes mellitus: Role of the placenta
GDM is a condition of hyperglycemia in the mother because of maternal ß-cell failure to compensate insulin resistance. Insulin resistance is a physiological condition in the second half of pregnancy in order to facilitate maternal catabolism to provide macronutrients for the fetus to sustain its growth. In normal pregnancies, this is accompanied by an increase in fasting insulin levels rising between weeks 25 and 33 of pregnancy (24), a result of structural, i.e., increasing ß-cell mass with progressing gestation (25), and functional changes of the pancreatic islets (26). If the degree of insulin resistance exceeds ß-cell capacity to mount adequate responses, i.e., release more and enough insulin to achieve the same effect as in the absence of insulin resistance, then GDM ensues (27). In many instances, the ß-cell defect is already present before pregnancy (28), and pregnancy only unmasks this defect. However, in a subgroup of GDM women, mostly obese women, ß-cell function is inadequate only temporarily during pregnancy. Insulin resistance can already be present early in gestation. If associated with hyperglycemia, then maternal risk for later GDM development increases (29). In obese women, a considerable proportion (23%) is already insulin resistant around week 15 of pregnancy (30). This requires ß-cell adaptation beyond that of a pregnancy that begins without insulin resistance.
Both insulin resistance and ß-cell adaptation in pregnancy are, among others, determined by placental hormones (31). Among these, human placental lactogen (hPL), the placental variant of human growth factor (hGH-V), and human chorionic gonadotropin (hCG) have received the most attention, although others such as hepatic growth factor, leptin, and kisspeptin may also play a role (32) (Figure 3.2). Many of the studies have been conducted in rodent models and may have limited validity for humans because of distinct species differences in islets and ß-cells (33) as well as in lactogenic hormones and their receptors (34). Evidence in humans is less convincing, but recent studies using human material have also supported the role of placental peptides and hormones to facilitate islet and ß-cell adaptation to pregnancy (32,35,36).
Figure 3.2 Hypothesized role of placental hormones in regulating maternal (glucose) homeostasis. Several placental hormones and peptides are involved in establishing physiologic maternal insulin resistance and pancreatic changes characteristic of the catabolic phase in the second half of pregnancy. Any homeostatic dysregulation reflected by augmented insulin resistance vis-à-vis inadequate pancreatic adaptation or ß-cell compensation, respectively, contributes to GDM.