DETERMINANTS OF NORMAL AND ABERRANT PLACENTAL GROWTH

Approximately 10% of the almost 4 million infants born each year in the United States are classified as low birth weight (LBW). Terminology used to describe the small fetus/newborn can be confusing. The term LBW is used clinically by pediatricians postnatally and is defined strictly as a birth weight less than 2500g with no regard for gestational age. The term “small for gestational age” (SGA) was originally defined by pediatricians as a newborn with a birth weight less than expected given gestational age and which can occur in a term or a preterm neonate. However, use of the term SGA subsequently expanded from the postnatal period to the antenatal period and is currently used interchangeably with intrauterine growth restriction (IUGR). For the purposes of this chapter, the use of the term SGA will be reserved for the newborn and IUGR, as implied by the name, will be restricted to the fetus. IUGR is more specifically defined later in the chapter. The fetus or newborn classified as IUGR or SGA, respectively, encompasses a group of fetuses-newborns that are small for a variety of reasons with varying prognoses, including congenital infections, congenital malformations, aneuploidy, uteroplacental insufficiency, and constitutionally small. It is important to recognize that not all fetuses or newborns that are classified as IUGR or SGA are small due to pathologic reasons (i.e., constitutionally small), but simply represent the smaller fetuses/newborns at the lower end of the bell-shaped distribution of the normal poulation. The prognosis for a given IUGR fetus is dependent on the etiology. Placental insufficiency accounts for the majority of IUGR fetuses. The scope of the problem with IUGR is quite broad, not just because it increases morbidity and mortality of the fetus, but also because it does so for the newborn and adult the fetus is destined to become. IUGR places the fetus at risk for hypoxemia, acidemia, antepartum death, and intrapartum distress. It places the neonate at risk for a number of metabolic disturbances, polycythemia, pulmonary transition difficulties, intraventricular hemorrhage, impaired cognitive function, and cerebral palsy. Several epidemiologic studies and animal studies in the early 1990s began to report on long-term sequelae of IUGR including adult hypertension, heart disease, stroke, and diabetes. The theory of fetal programming as the origin of adult disease was introduced by Barker and colleagues and is commonly referred to as the “Barker hypothesis.” The challenge in management of the IUGR fetus is to identify the condition and manage it such that adverse sequelae are minimized. The use of real-time ultrasound and Doppler velocimetry play pivotal roles in the diagnosis and management of IUGR. This chapter reviews normal placental–fetal growth, etiologies of the IUGR fetus, and practical uses of ultrasound and Doppler velocimetry in the diagnosis and management of the IUGR fetus.

Normal Placental Development

In most mammalian species, the placental and fetal mass increase exponentially for at least a portion of pregnancy. Normal growth of the fetus is in turn dependent on normal placentation and growth of the placenta. The placenta is a dynamic and multifaceted organ that serves as an interface between mother and fetus with the critical role of meeting the metabolic and circulatory demands of the growing fetus.

The roles of the placenta include:

Nutritional: Provides oxygen, glucose, amino acid, and volume (fluid) transfer.
Immunologic: Protects the fetus from pathogens and the maternal immune system.
Endocrinologic: Produces numerous hormones, growth factors, cytokines, and other vasoactive mediators.
Metabolic: Serves as the respiratory and the kidney organ for the fetus and is responsible for elimination of carbon dioxide, metabolic acids, and other waste products from the fetus to maintain acid–base balance.
Placentation must be normal in order for these functions to be met
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Research has begun to provide an understanding of the complexity of the implantation and placentation processes, which requires production and coordination of numerous angiogenic growth factors (fibroblast growth factor, hepatocyte growth factor, placental growth factor, vascular endothelial growth factor), cell-adhesion molecules, cytokines, nitric oxide, extracellular matrix metalloproteinases, hormones, and transcription factors (hypoxia inducible factor). This process of coordination begins very early in pregnancy and can dictate whether the pregnancy grows in a normal or abnormal direction. During the luteal phase of the menstrual cycle, the endometrium becomes decidualized in preparation for acceptance of the products of conception. Shortly after entering the uterine cavity on day 4 postconception, the morula becomes a blastocyst with an inner cell mass at one pole that is called the embryoblast and an outer cell mass that is called the trophoblast. On day 7 postconception, the trophoblast differentiates into the cytotrophoblast, which envelops the blastocyst circumferentially. Simultaneously, the newly developed cytotrophoblast cells further differentiate into a sheet of syncytiotrophoblast cells. The syncytiotrophoblast produces proteins and steroid hormones. The cytotrophoblast, made up of nucleated cells, continues to produce the anucleate syncytiotrophoblast throughout gestation primarily by mitotic activity and loss of cytotrophoblastic cell walls. By day 13, the cytotrophoblast layer has differentiated into invasive and noninvasive cytotrophoblast. The invasive cytotrophoblast forms invasive cell columns that invade the uterine epithelium to anchor the fetus and establish blood flow to the placenta and fetus. During this process, the invasive cytotrophoblast cells (extravillous trophoblast):

-migrate through the syncytiotrophoblast and into the decidualized endometrium and  myometrium
-invade the vessel walls of the maternal-based spiral arteries in these areas
-transform the spiral arteries from a high-resistance to a low-resistance vessel.

As the invasive cell columns of the cytotrophoblast penetrate the syncytiotrophoblast, spaces called lacunae are created, which subsequently fuse to form the intervillous space with intervening syncytiotrophoblast columns called trabeculae. The process of intervillous space formation and spiral artery transformation directs an increasing maternal cardiac output into the intervillous space. Loss of spiral artery vessel media is the mechanism by which the spiral arteries drop their resistance to blood flow. The syncytiotrophoblast-based trabeculae branch laterally to initiate placental villi formation on approximately day 13. The extent of vascularization of the villus architecture defines the villus as stem or primary villus, secondary villus. or tertiary villus. The stem villus is without vessels and only has trophoblast cells. The secondary villus is formed by central invasion of the primary villous core by the allantoic mesenchyme of the embryoblast. The tertiary villus forms during vasculogenesis, which is the development of de novo blood vessels from mesenchymal cells differentiating into hemangioblasts. Hemangioblasts are precursors of endothelial cells. This process begins in the 5th week of gestation.

These three villous types represent progressively smaller generations of villous branching with the terminal villi serving as the end point. The stem villi extend from the chorionic plate to the basal plate. The stem villi contain a single truncus that progressively branches into the rami chorii, which in turn branches into the ramuli chorii. It is from the ramuli chorii that the intermediate villi appear of which there are two types: The immature and mature intermediate villi. The terminal villi are the primary gas exchanging villi, which have actually been identified at all levels of branching. They account for 55% of the total number of cross-sectional villi in the peripheral villous tree. Smooth muscle staining shows that vessels coursing through the villi contain smooth muscle media down to the level of the immature villi. This distinguishes the stem and immature villi from the gas-exchanging mature and terminal villi. It has been noted that the intermediate villi, because of the smaller arterioles, venules, pre- and postcapillaries contained within, may serve a hemodynamic regulatory function (i.e., control of blood pressure and flow). The concept of blood flow control at this level is further supported by previously described sphincterlike precapillary structures.

In contrast to vasculogenesis, angiogenesis represents the formation of new blood vessels from endothelial cells and is classified into branching and nonbranching angiogenesis. Branching angiogenesis occurs primarily in the first and second trimesters and leads to the formation of the immature villous tree. Branching angiogenesis continues until the end of the second trimester when there is a transition to nonbranching angiogenesis. During this process there is a dramatic increase in mature intermediate and terminal villi. The nonbranching angiogenesis forms terminal capillary loops with minimal branching and provides the network of capillaries for the intermediate and terminal villi. A dramatic decrease in vascular resistance and an increase in blood flow through the placenta are coincident with this process. The progressive decline in vascular resistance is depicted by increased end-diastolic velocities in Doppler flow velocity waveforms of the umbilical artery.

Abnormal Placental Development

In pregnancies complicated by preeclampsia and IUGR, trophoblast invasion is limited to the decidualized endometrium, which results in failure of the spiral arteries to become low resistance vessels. The inability of spiral arteries to transition from high to low blood flow resistance can be detected by Doppler velocimetry of the uterine artery which supplies blood to the spiral arteries. The blood flow velocity waveforms in the uterine artery obtained with pulsed-wave Doppler velocimetry are reflective of the waveforms downstream at the spiral arteries. These abnormalities are identified on a Doppler flow velocity waveform (FVW) profile by a high resistance pattern (low velocity of flow at end-diastole relative to that at systole) and by a protodiastolic (early diastolic) notch. Failure of this process to occur on the maternal side of the circulation may lead to adverse effects on both the mother and the fetus. Maternal vascular endothelial dysfunction may lead to production of a variety of vasoactive mediators, which could subsequently lead to the development of preeclampsia. Poor growth of the placental–fetal unit may also result from poor invasion and remodeling of the spiral arteries by the cytotrophoblast.

A variety of villous and vascular abnormalities have been described in the placenta of the IUGR fetus. Placentas from IUGR pregnancies have fewer gas-exchanging villi. The gas-exchanging villi are also slender, elongated, poorly branched, and poorly capillarized. Vascular abnormalities include reduced branching of stem arteries and disorganized vascular patterns including less coiling as depicted by placental vascular cast studies. There are also fewer terminal villi with smaller lumens. The reduced branching seen in the villous vasculature creates abnormal blood flow and an increase in vascular resistance to flow that can be likened to that of an electric circuit—the fewer downstream tributaries that exist from the main supply line, the higher the resistance.

Danforth’s Obstetrics and Gynecology
Henry L. Galan and John C. Hobbins
Intrauterine Growth Restriction