Placental Conditions With Consequences for the Fetal Brain

Extravillous Trophoblast Development

The tips of the villous trophoblast adhere to the decidual surface, anchoring the villous tree and becoming multilayered, and then give rise to extravillous trophoblasts that differentiate into two lineages and migrate into the decidua along two routes. The interstitial trophoblasts (see Fig. 10.3 ) migrate into the decidual stroma guided by maternal signaling molecules, where their primary role is to degrade and remodel the spiral artery walls. The endarterial trophoblasts (see Fig. 10.3 ) migrate directly and profusely into the lumina of spiral arteries, where they form luminal plugs for most of the first trimester, temporarily blocking premature entry of blood and oxygen into the intervillous spaces and preventing oxidative stress. Failure of normal spiral artery remodeling and luminal plugging by the extravillous trophoblasts plays a fundamental role in placentation insufficiency and underlies a number of the major obstetric syndromes , including preeclampsia, fetal growth restriction, and placental abruption, all conditions associated with significant risk for disrupted development and injury to the developing fetal brain.

In summary , the normal villous and syncytiotrophoblast populations are principally involved in development of the fetal components of the placenta, whereas the extravillous lineages (discussed later) are involved in events on the maternal side.

Development of the Placental Vasculature

The placental vascular system consists of a uteroplacental (maternal) and a fetoplacental system, interfacing at the intervillous sinuses (see Fig. 10.1C ). As discussed previously, growth of the developing embryo and placenta is independent of blood and oxygen supply through much of the first trimester. This low-oxygen environment with oxygen partial pressure levels ~20 mm Hg is physiological and not hypoxic, serving a protective role against damaging reactive oxygen species during a period when embryonic and placental antioxidant systems are underdeveloped. In fact, premature opening of the spiral arteries with influx of oxygenated blood flow into the intervillous space at a time when antioxidant defenses are underdeveloped causes oxidative injury and is a major cause of spontaneous miscarriages in the late first trimester.

Development of the Uteroplacental Vasculature

The uterine vasculature extends from the uterine arteries to the ends of the spiral arteries where the uteroplacental circulation enters the intervillous spaces. Spiral artery remodeling starts when interstitial and endarterial trophoblasts enter the decidua (discussed earlier) where they work in combination to remodel the spiral arteries. This remodeling is achieved through cellular lytic, apoptotic, and dedifferentiation actions in the endothelial, muscularis, and perivascular layers of the spiral arteries, thereby transforming them into patulous, passive conduits (see Fig. 10.4A ). The increased caliber and reduced vasoconstrictive capacity of the normal remodeled spiral artery system leads to an overall decrease in uteroplacental resistance and loss of the normal diastolic dicrotic notch (discussed later; see Fig. 10.8 ). The reduction in blood flow velocity into, and transit through, the intervillous spaces thereby optimizes maternal-fetal oxygen and nutrient transfer while minimizing mechanical trauma to the villous structures. Spiral artery transformation is deepest (i.e., into the junctional zone of the myometrium) (see Fig. 10.4A ) at the center of the placenta. Failure of such “deep placentation” is seen in preeclampsia (discussed later) and is frequently associated with arterial thrombosis. The major invasion of endarterial trophoblasts into the spiral arteries occludes their lumina with villous plugs, which persist until 8 to 10 weeks gestation (discussed earlier) (see Fig. 10.1C ), after which these plugs commence a gradual breakdown. By the end of the first trimester, blood flow is established between the spiral arteries and the intervillous compartment.

Remodeling of larger uterine arteries during the first 20 weeks of gestation results in a two-fold increase in their diameter. This progressive vasodilation of the larger uterine blood vessels is trophoblast-independent and mediated by substances such as progesterone, estrogen, placental growth factor, human chorionic gonadotrophin, endothelial nitric oxide, and vascular endothelial growth factor. In contrast to the remodeled spiral arteries, which decrease blood flow velocity into the intervillous space, the larger upstream arteries regulate volumetric blood flow into the intervillous system. Disturbances in radial artery adaptation have been implicated in later pregnancy disorders, such as preeclampsia and placental abruption.

Development of the Fetoplacental Vasculature ( Fig. 10.5 )

The fundamental structure of the fetoplacental vascular tree is formed over the first 6 gestational weeks (GW), followed by phases of rapid branching angiogenesis (between 6 to 24 GW) and nonbranching angiogenesis (after 24 GW), both supported by the mesenchymal stromal cells (see Fig. 10.5 ). Conditions like placental failure with fetal growth restriction (discussed later) are in part due to impaired angiogenesis in early gestation, resulting in decreased vascular branching, vascular volume, and exchange capacity, as well as increased resistance to blood flow.

The Maternal-Fetal Circulatory Interface

The vasculosyncytial membrane consists of the syncytiotrophoblast layer and fetal capillary endothelium and abuts the intervillous space; that is, the terminal extent of maternal-placental perfusion (see Figs. 10.5 and 10.6 ). The syncytiotrophoblast has two polarized plasma membranes, the maternal-facing apical microvillous plasma membrane and the fetal-facing basal plasma membrane. The so-called interhemal barrier between maternal blood in the intervillous spaces and the fetal blood in the villous capillaries consists of the two syncytiotrophoblast membranes, basement membranes, stromal villous mesenchymal tissues, and the capillary endothelium (see Fig. 10.5 ). The interhemal barrier determines the efficiency of placental transfer, primarily through its overall surface area and its thickness. At ~32 weeks GA the interhemal barrier simplifies to a two-layered vasculosyncytial membrane, thereby decreasing its thickness and bringing the maternal and fetal circulations into closer proximity, enhancing oxygen-nutrient transfer during the major increase in late gestational fetal demand. Placental pathologies, such as distal villous hypoplasia, infarcts, or avascular villi, will decrease the effective total surface area of the interhemal barrier, whereas others, such as maternal diabetes with delayed villous maturation, and hydrops fetalis with villous edema, will increase its thickness and thereby the diffusion distance.

Development of the Fetal Circulation

The fetal circulation has lower oxygen content than that of the newborn, but the fetus is not hypoxic. In fact, the fetus has a considerable intrinsic margin of safety for oxygen, because its supply exceeds its requirements owing to factors such as generous blood flow to the fetal tissues and enhanced oxygen binding with fetal hemoglobin. Furthermore, the fetal brain is privileged in receiving the highest regional oxygen supply, through the anatomical and physiological arrangement of the fetal circulation .

Distribution of Fetal Blood Flow

Unlike the postnatal circulatory system, that of the fetus consists of two arterial circulations operating in parallel and connected by intra- and extracardiac shunts, the patency of which is critical for normal fetal development (see Fig. 10.7 ). The primary connection between the two fetal arterial systems is at the aortic isthmus, which is the circulatory watershed between the more oxygenated brain–upper body circulation (supplied by the left ventricle) and that of the less oxygenated subdiaphragmatic tissues and placenta (supplied by the right ventricle via the ductus arteriosus). The normal streaming of ductus arteriosus flow in the fetus results from the resistance differential between pulmonary (high resistance) and placental (low resistance) circulations. In normal circumstances, this arrangement provides preferential oxygen-substrate delivery to the aorta and the developing brain . Prior to 32 GW the placenta receives about one-third of the cardiac output, decreasing to one quarter across the rest of gestation. Conversely, placental insufficiency in conditions such as fetal growth restriction and preeclampsia leads to changes in vascular resistance in the two circulations, altering the volume and oxygen-substrate content of perfusion delivered through the fetal shunts. Superimposed upon these pathophysiologic changes are compensatory responses aimed at sustaining the developing brain’s privileged oxygen supply, achieved through hypoxemic vasodilation and reduction of the cerebral vascular resistance. These compensatory responses are capable of maintaining cerebral oxygenation for long periods of mild-to-moderate hypoxemia.

Distribution of Fetal Oxygenation

The umbilical vein has the highest blood oxygen content in the fetus, with normal oxyhemoglobin saturation around 85% to 90%. To minimize oxygen-nutrient extraction en route to the brain, about half the umbilical vein blood flow bypasses the liver through the ductus venosus into the right atrium and across the foramen ovale to the left heart and aorta (see Fig. 10.7 ). Consequently, the oxyhemoglobin saturation of the cerebral arterial circulation is approximately 65%, whereas that in the descending aorta (from the right ventricle and ductus arteriosus) is between 50% to 55%. In placental failure there are significant changes in regional fetal blood flow and oxygen distribution (discussed later).

Fetal Myocardial Function

Compared with that of the term newborn, the fetal myocardium is limited in both its systolic and diastolic function. Specifically, the fetal myocardial response to stretch generates lower active tension, thereby limiting systolic function, whereas decreased diastolic relaxation results in higher resting tension and reduced diastolic filling, thereby limiting diastolic performance. Although the fetal myocardium follows the basic Frank-Starling model, fetal cardiac output is more dependent on heart rate than that of the normal term newborn. Furthermore, autonomic innervation of the fetal heart, especially sympathetic function, is immature and limited .