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Early Path Medical Consultation Services
Pathology Services Working for Safer Pregnancies

Placental Pathology - Medical Student Lecture 2001
Carolyn M. Salafia, MD
Professor of Pathology and Pediatrics

CONTENTS

5. INTRAUTERINE INFECTION

6. MULTIFETAL PREGNANCY

GOALS OF THE LECTURE

Discuss the normal development of the placenta across gestation.
Discuss the major functions of the placenta, and how those functions may change across gestation.
Discuss major points of how the baby grows in utero, abnormal growth patterns (symmetric and asymmetric small for dates, and large for dates), and how they can be caused
Discuss one specific common clinical condition that leads to pregnancy complications (Example: preeclampsia).
Demonstrate the pathways of intrauterine infection: (ascending or bacterial infection, versus transplacental or hematogenous viral infection).
Illustrate the anatomy of multiple gestations, and discuss the most common complications.

OBJECTIVES FOR THE STUDENT

The student should:

Understand and be able to discuss basic aspects of normal placental anatomy.
Understand the main functions of the placenta.
Recognize several common gross and microscopic abnormalities of the placenta, and understand how they can affect the fetus.
Understand how abnormal implantation jeopardizes pregnancy.
Understand the relationship between fetal growth and the placenta across gestation.
Identify the most common and typical placental features of preeclampsia, and how it contributes to the maternal and fetal/neonatal complications.
Understand the difference between "monozygous" and "dizygous" twins, how these 2 types of twins can often be distinguished by placental study, and how multiple gestations have increased risk of complications.

INTRODUCTION

In the simplest physiologic terms, the placenta's function is to exchange nutrients. The three determiners of placental function are: maternal blood flow, fetal-placental blood flow, and placental trophoblast membrane permeability. The placenta transfers molecules from the mother's blood stream into the fetoplacental pool proportionally to their concentrations in the maternal circulation (e.g., high maternal blood sugar levels lead to high fetal blood sugar levels). Placental nutrient and oxygen exchange can be impaired or reduced by:(1) reduced maternal perfusion of the placenta, (2) abnormal blood flow between placenta and fetus, (3) reduced permeability of the placental membranes, and (4) increased placental metabolic needs. The main maternal adaptation favoring fetal oxygenation is high uterine blood flow. Uniform fetal perfusion of the placenta, production of a fetal hemoglobin with greater oxygen affinity than maternal hemoglobin, high fetal cardiac activity and increased fetal tissue perfusion are the main ways fetus optimizes its oxygenation. Normal placental growth and development will maximize placental efficiency while controlling its metabolic demands.

To establish a flourishing intrauterine pregnancy, (1) the trophoblast shell must be able to attach to the decidualized endometrium, and (2) the maternal/uteroplacental vasculature must be adapted for dramatic and progressive increases in blood flow. As the placenta "implants", it both destroys and remodels the uterine epithelium and supporting stroma, and must establish some level of nutrient supply from the maternal tissues and circulation. (Figure 1) Invasive endovascular trophoblast contribute to the destruction of the fibromuscular decidual spiral vessels, and help to remodel these blood vessels not only in the endometrium (at which level blood vessels would be shed at the end of a normal, non-pregnant menstrual cycle), but also deep into the superficial 1/3 of the myometrium. Thus, even "permanent" arterial segments are invaded and temporarily remodeled by the pregnancy. Decidual spiral arteries after trophoblast invasion (now called uteroplacental arteries) have increased caliber, reflecting their increased compliance and distensibility, and are not responsive to vasomotor stimuli. (Figure 2) Uteroplacental vessels terminate in the basal plate of the placenta, and empty their blood into the intervillous space. After trophoblast remodeling of spiral vessels, the intervillous space is a high-capacitance, low-resistance system (blood pressure of approximately 10-12 mmHg). (Figure 3)

The second major function of the maternal/uteroplacental remodeling process is to establish a degree of immune toleration of the mother to the semi-allogeneic conceptus. As in the mouse, placental cells preferentially express paternal genes, while the embryo preferentially expresses maternally-derived genes. Despite the preferential expression of non-self antigens, the placenta is not rejected by the pregnant mother, although during pregnancy she will reject a paternal organ or even skin transplant. Despite decades of intense research, the mechanisms of immune tolerance of the conceptus are poorly understood at best, but may involve ontologically primitive immune recognition through NK cells, or trophoblast expression of specific antigens.

The placenta is composed of a chorionic shell, off which project villi, finger-like outgrowths of placental epithelium (trophoblast) and blood vessels with their supportive connective tissue stroma. The placental epithelium, or trophoblast, is the "skin" covering the conceptus. It is composed of two cell types, the cytotrophoblast and the syncytiotrophoblast. Cytotrophoblast proliferate off the tips of the very primitive villi in the first weeks of gestation, and contribute to the invasive component of trophoblast that is critical to the vascular and immune parts of normal implantation. The villous cytotrophoblast is also the proliferating or stem cell that matures into the multinucleate syncytiotrophoblast. The villous cytotrophoblast cell layer is a continuous layer in the first trimester. Later in gestation, when placental growth plateaus (and rapid acquisition of large volumes of new syncytiotrophoblast ceases), the cytotrophoblast becomes much sparser, and may be hard to identify in mature villi at term in the absence of chronic placental injury. Late in pregnancy, cytotrophoblast probably only does little more than replace senescent syncytiotrophoblast. If there are any conditions causing abnormal/excess trophoblast injury, cytotrophoblast, the reparative layer, will naturally remain more prominent than it normally would be late in pregnancy.

The syncytiotrophoblast is a multinucleate cell. Some believe that all syncytotrophoblast are actually part of a enormous single cell barrier to infectious agents or maternal immune effector cells circulating in the intervillous space. Ultrastructural studies suggest that this single cell may be regionally specialized; one example of this would be the vasculosyncytial membrane, an area specialized for optimum diffusion and nutrient exchange efficiency (see below). Other specialized syncytial structures, the syncytial sprouts, may break off the villous surface, and be carried off into the maternal circulation to be trapped in the pulmonary capillary bed. In this site, these semi-allogeneic cells die without eliciting an inflammatory response, a process that may be important part of maternal tolerance of the conceptus.

Villi grow throughout gestation, and their anatomy changes as they grow and mature. Early in pregnancy, primitive blood vessel channels develop in the embryo, yolk sac, and primitive villi. (Figure 4) By the end of the fifth week of gestation, a beating embryonic heart begins to pump nucleated erythrocytes from the yolk sac throughout the embryo-placental circulation. Villi originally develop over the entire 360 degree sphere of the conceptus. During the first trimester, physiologic atrophy of parietal villi forms the chorion laeve, or bald chorion. (Figure 5) The mature villous functional unit is a barrel, with the staves formed by the large fetal stem vessels, and the smaller branches of the villous tree arborizing toward the center. The "youngest", or most recently formed, villi are in the center.

Early in pregnancy, villous vessels are situated deep in the villous stroma (see for example, Figure 6), with mean distance from intervillous space to villous vessel of 24-27 microns. Thanks in part of this wide diffusion distance, the early conceptus is relatively oxygen poor. If placental functional efficiency remained the same throughout gestation, one could reasonably expect a 7-pound baby to be delivered with a more than 200-pound placenta! Obviously, this would not work for the human woman, and accordingly, placental structure changes throughout gestation to directly cause improved functional efficiency. Functional efficiency involves both more efficient nutrient and oxygen capture from the maternal circulation and high volume/low resistance transport to the fetus. The placental vasculature increases in complexity, with increasing numbers of capillary outlines per villus, until about 36 weeks gestation. Grossly this correlates with a change in placental color from pale tan in the first trimester, to deep red by term, parallel with the increased proportion of the placenta that is composed of placental blood vessels. (Figure 6a-b) Second, from first trimester to term, there is progressive reduction in the thickness of the placental "skin", the trophoblast epithelium, narrowing the distance between the intervillous space (the maternal blood space) and the fetoplacental capillary. The most specialized area of optimum diffusion, the vasculosyncytial membrane (Figure 7), is the area in which villous capillaries actually abut the trophoblast basement membrane, with trophoblast nuclei clustering at the side. The membrane itself measures only 0.5 to 1.0 microns in thickness, <5% the diffusion distance in the first trimester. Finally, the villous surface area of exchange increases throughout gestation, a third means of meeting increasing fetal metabolic demands with a smaller placental mass. The syncytial microvillous surface increases until about 36 weeks gestation. Progressively improved placental permeability leads to a "flow-limited" placental transfer capacity at term. Given these adjustments, the fetoplacental weight ratio is able to shift from 1:1 at about 16 weeks to about 7:1 by term, a "bearable" weight for the human mother.

To summarize, the placental structure changes dramatically across gestation. Placental implantation, and the invasion of maternal decidua (uterine lining) by placental trophoblast cells are central to establish an adequate immune and nutrient provision environment. The development of the villous placenta itself is one directed towards progressively improved placental nutrient exchange efficiency. The extraplacental membranes, the area of the chorion where villi fail to elaborate, become progressively thinner. They maintain sufficient tensile strength until term to retain the amniotic fluid around the developing fetus. This fluid, to a large degree produced by fetal lung secretions and urine production, contains a number of trophic factors believed to be important for normal growth and development, and provides a space in which the developing fetus may move more or less unrestrained except by its umbilical cord "tether". Amniotic fluid is also includes a number of bacteriostatic and/or bacteriocidal molecules that may make some contribution to the sterility of the intrauterine environment. Fetal and amniotic epithelial cells desquamated into the amniotic fluid can, after amniocentesis, be coaxed to proliferate in vitro, and yield a diagnostic fetal karyotype.