I. Anatomy & Physiology of the Placenta

 A. The maternal component
    The maternal portion of the placenta arises from the endometrium that is transformed into decidua in part by high levels of progesterone.

       1. The decidua basalis is the portion of the decidua at the base of the chorion frondosum (the implantation site). In this area, the spiral arteries are converted in association with trophoblast invasion into the uteroplacental arteries. These re-modeled arteries without elastic or muscle components to their fibrinoid wall, are pressure passive and massively dilate in response to the increased uterine flow that is progressive throughout gestation. By the end of pregnancy, approximately 100-150 arteries are converted, supplying 40-60 placental functional units
       2. Nitabuch's fibrinoid layer is a predominantly acellular zone that develops at the interface between the chorionic villi and the decidua in the decidua basalis.
       3. The decidua capsularis is adjacent to the chorion laeve (bald chorion, see below) and eventually fuses with the decidua lining the rest of the myometrium, the decidua parietalis.
       4. The intervillous space can also be thought out as part of the maternal component of the placenta. This space is filled by maternal blood provided by the uteroplacental arteries. Fetal nutrient exchange occurs at the interface between the intervillous space and the chorionic villi. (See below).

B. Fetal component

1. The chorion is the outer "shell" of the conceptus. Originally a sphere, out-pouchings of the chorion form the primitive chorionic villi. The chorion villi formed on the chorion surface oriented towards the uterine lumen will atrophy, forming the chorion laeve (bald chorion). The definitive placental disc is called the chorion frondosum. The chorionic plate (continuous with the bald chorion) contains fetal arteries and veins that connect the umbilical circulation to smaller branches of chorionic arteries and veins. These intermediate vessels travel in fetal stem villi, and are connected to the capillary beds of the chorionic villi, where oxygen, nutrients, and waste exchange with the mother's circulation (in the intervillous space) occurs.
2. The amnion is the "inner shell" of the conceptus, embryologically continuous with the epithelium of the umbilical cord and the baby's skin. It forms a transparent membranous sac that is filled with amniotic fluid. The amnion allows some water, possibly nutrient and possibly hormonal exchanges between the mother's blood vessels in the decidua capsularis and the amniotic fluid. The intact amnion sac provides a buoyant environment that protects the fetus from trauma, and allows freedom of fetal movements (important to fetal musculoskeletal and pulmonary development). The amnion is
avascular.
 3. The umbilical cord is normally composed of two umbilical arteries and one umbilical vein. The connective tissue of the cord, Wharton's jelly, protects the cord blood vessels from mechanical trauma.

C. Structure and function of chorionic villi

The chorionic villi reflect progressive extension of the chorionic villous tree, beginning with main fetal stems branching off the chorionic plate early in pregnancy. Branching and formation of new chorionic villi continues in many placentas until term.

The bulk of the placental disc is composed of chorionic villi. Looking at the placenta from the maternal surface (the surface facing the uterine wall), this disc appears to be divided by septa (invaginations of maternal decidua that effectively are analogous to cerebral gyri) into 15-20 cotyledons . These cotyledons do not reflect actual functional placental units, and are probably not meaningful physiologically.

"Placental functional units" number approximately 40-60 in the term placenta. These are composed of villi arranged with the larger fetal stem villi at the periphery (like staves of a barrel). The chorionic villi branch towards the center of the barrel, with most of the nutrients and oxygen exchange areas located more centrally in terminal chorionic villi (anatomically equivalent to the alveoli of the lung).

The chorionic villi are composed of a trophoblast epithelium, fetal blood vessels, and supporting mesenchyme. The trophoblast is the "skin" of the placenta, and its cells diverge from those of the embryo very early. This leads to the potential for "confined placental mosaicism", which can confound analyses of chorionic villous sampling. The villous cytotrophoblasts are mononuclear stem cells from which the multinucleate (syncytial) synctiotrophoblasts develop. They are easiest to see in the first trimester, a time of very rapid placental growth and villous elaboration. By the third trimester, the cytotrophoblasts have far less obvious, except in certain types of complicated pregnancies. The syncytiotrophoblast is the barrier between the fetal vessels and the maternal blood in the intervillous space. The apical surface contains many microvilli that are important in nutrient and macromolecular transfer. Many hormones are also produced by the syncytiotrophoblast, including corticotropin-releasing hormone (CRH), which many be an important trigger of parturition (labor). In the third trimester, placental growth plateaus compared to fetal growth; therefore, more grams of fetus are supported by fewer grams of placenta. Maintenance of adequate fetal nutrition is achieved by increased functional efficiency of the placenta. The structure that allows this increased efficiency is the vasculosyncytial membrane (VSM). In this area, the syncytium is thinned, nuclei clustered at each side of the VSM, and the fetal capillary closely abuts the trophoblast basement membrane. The exchange area created is analogous in function and efficiency to the mature alveolus of the lung. VSM's are uncommon before the third trimester, and may not be as abundant later in gestation in certain disease states. Normal VSM formation requires both an intact syncytiotrophoblast layer and appropriate villous capillary growth, as well as appropriate maternal intervillous perfusion pressure and non-turbulent flow.

A third trophoblast cell is located extravillous, where it serves to anchor the placenta to the uterine lining, contributes to the formation of Nitabuch's fibrinoid, and participates in the remodeling of the endometrium and spiral arteries which is essential to normal pregnancy. Sometimes termed "intermediate trophoblast," extravillous trophoblast are believed to participate in the immune modulation of the maternal placental interaction, expressing an almost unique major histocompatibility locus antigen HLA-G. During the process of endovascular conversion, they play a role in the loss of spiral arterial vascular smooth muscle, elastica and endothelium, and contribute to the fibrinoid, that replaces the normal spiral arterial vascular structure. The endovascular trophoblast serve as a temporary endothelium to the maternal circulation during the active conversion process. After conversion is completed (extending down into the inner third of the myometrium), the endovascular trophoblast become embedded within the fibrinoid, and the maternal endothelium re-grows over the fibrinoid layer. Failure of re-endothelialization has been documented in pre-eclampsia (see below). The mononuclear extra villous trophoblast cells fuse, forming placental giant cells, after the conversion process is completed.

II. Placental abnormalities

  A. Umbilical cord insertion
The intervillous space is normally distended by maternal perfusion pressure, making the placenta approximately twice as thick in life as it is after delivery. This makes the chorionic plate a resilient, flexible surface. Umbilical cord inserted anywhere on the chorionic plate, therefore, have "protection" with the "give" of the chorionic plate maintaining normal arterial and venous perfusion from the umbilical cord to the chorionic plate and chorionic villi despite cord torsion or fetal movements.

The umbilical cord insertion reflects the intersections of embryo folding that form the human umbilicus. While the navel tends to be inserted in pretty much the same place on the abdominal wall, umbilical cord insertion on the placental disc is very variable. This reflects the frequency with which some degree of differential placental growth and development occurs after the establishment of the umbilical cord axis in the first trimester. Such differential placental growth and development is believed to be a response to regional variations in uterine perfusion and the local oxygen tension. If placental growth significantly shifts from the established axis, the umbilical cord insertion may be left at the margin of the placenta or on the membranes (velamentous). Marginal and velamentous cord insertion may be mechanically fragile, with umbilical cords inserted on and/or or chorionic vessels running in the reflected membranes (facing the myometrium) being more susceptible to mechanical compression.

 B. Single umbilical artery
The normal umbilical cord has two arteries and one vein. It is believed that arterial coiling around the vein provides the pressure to milk the umbilical venous blood back up from the placental capillary bed to the fetus. A single umbilical artery is more common in babies with other anomalies. Most babies with single umbilical arteries are anatomically normal. A single umbilical artery may be less efficient hemodynamically, and therefore has been anecdotally associated with fetal growth restriction, and infrequently fetal intolerance to labor.

 C. Umbilical cord knots
A false umbilical cord knot is actually a varicose vessel, and is not of any known clinical significance.

A true umbilical cord knot may cause impedance to venous perfusion, and less commonly to umbilical arterial flow. The lower pressure in the umbilical vein compared to the umbilical artery causes venous return to the fetus to be compromised before arterial perfusion of the placenta ceases. A cord knot that functionally obstructs a beating fetal heart should be associated with peri-venous lesions (edema, hemorrhage, or thrombus) on the placental side of the knot, and peri-arterial lesions on the fetal side of the knot. After fetal death in utero, vaginal delivery can pull a loose knot tight, since the umbilical cord is now flaccid and fetal descent during delivery occurs while the placenta remains tethered in the uterus.

  D. Membrane insertion
Marginal insertion of the membranes is normal. Circumvallate insertion is grossly seen as a folding over of the membranes on the surface of the chorionic disc, forming a rim delimiting the branching of the chorionic vasculature. It is believed to occur following any situation that decreases intra-amniotic pressure, allowing collapse of the membranes at the margin. Re-establishment of normal intra-amniotic pressure allows re-expansion at the angle where the chorionic disc and the membranes meet, with crumpled membranes trapped in the margin. Often the local decidua becomes necrotic and turns tan/yellow, making the delimitation of circumvallate membranes easy to identify. This finding is associated with clinical complications of pregnancy.

  E. Accessory lobes
Whenever the placental sphere is able to acquire sufficient oxygen and nutrients to allow villous proliferation, an accessory placental lobe may develop in the area which should be undergoing physiological atrophy to form the bald chorion. These can be problematic to the fetus, since they require velamentous blood vessels running from any detached lobes to the main body of the placenta (which may be compressed or lacerated). Predisposing factors for accessory lobes include any anatomical anomalies of the uterus that might constrain normal expansion of the fundus, or implantation in the lower uterine segment.

III. Multifetal Gestations

 A. Zygosity

 B. Chorionicity
Chorionicity does not equal zygosity.

Monochorionic siblings develop within the same chorion "shell", and are obligatorily monozygous (identical) siblings.

Dichorionic siblings develop each within their own chorion "shell". Of dichorionic twin pregnancies, 80% are fraternal twins, and 20% are identical twins. Identical twins can be dichorionic if splitting of the conceptus occurs prior to the formation of the chorion (most commonly pre-implantation).

    C. Twin-Twin Transfusion Syndrome
Whenever twins develop within a single chorion, it is generally assumed that vascular anastomoses are present. Blood vessel development occurs in situ within the placenta, with isolated segments of blood vessels forming, and only secondarily becoming attached end-to-end and connected to the fetal circulation and the beating fetal heart. Normally it is considered that the pressure and direction of blood flow determines whether a blood vessel will become an artery or a vein. When blood vessels are forming within a single chorion, and there are two beating fetal hearts, some shared circulation is almost inevitable. Whether such a shared circulation develops into a functionally significant transfusion syndrome depends on the nature of the circulatory communications, as well as other factors such as velamentous umbilical cord insertions and placental implantation which may influence hemodynamics and/or placental growth and development.

Twin transfusion becomes clinically relevant in two circumstances:
1) When a chronic donor becomes sufficiently nutrient-, oxygen-, and volume depleted as to be unable to maintain normal growth, the donor will demonstrate fetal growth restriction, and often decreased amniotic fluid volume (due to decreased feel urine output due to hypovolemia or brain-sparing circulatory shunting). The recipient will be of normal size until chronic circulatory overload due to hypervolemia leads to congestive heart failure and fetal hydrops. Often the chronic recipients will have polyhydramnios (elevated amniotic fluid volume). Either the donor or the recipient, or both, may die.
2) Following fetal death, balanced or unbalanced circulatory anastomosis may acutely become uni-directional, due to the drop in blood pressure on the side of the demised sibling's circulation. If this happens, the living twin may lose significant blood volume into the sink of its sibling's circulation causing acute hypotension, cerebral injury or death. A chronic twin transfusion syndrome is not required for the development of an acute transfusion following death of a sibling.

III. Pathophysiology

 A. Acute ascending infection
Bacterial invasion via the cervix of the uterine space, extra placental membranes, or amniotic fluid falls in the category of acute ascending infection. Clinically relevant infections are generally confined to either the extra placental membranes (predisposing to membrane rupture and potential preterm delivery), or the amniotic fluid space. The latter, termed intra-amniotic infection, is important because the fetus breathes and swallows amniotic fluid. In these cases, the fetal lung and GI tract may be the portals of entry for fetal or neonatal infection or sepsis.

When an infection is sufficiently severe, the membranes grossly are tan-yellow and cloudy, due to the tissue neutrophil infiltration. The maternal response to intra-amniotic infection is found in the extra placental membranes and the chorionic plate, from which maternal PMNs are recruited by intra-amniotic cytokines. The same chemicals recruit fetal PMN's from the umbilical cord blood vessels and from blood vessels on the chorionic plate.

Some degree of intra-amniotic bacterial contamination may occur simply in the process of cervical dilatation for normal labor and delivery. Even more extensive processes are most commonly clinically silent. Some mothers may develop a fever, tachycardia, uterine tenderness, purulent discharge, foul smelling amniotic fluid, or a left shift in the complete blood count. Fetal manifestations may include heart rate abnormalities including tachycardia, variable decelerations or decreased beat-to-beat variability, changes in fetal behavior, but acidosis is uncommon. Clinical presentations include incompetent cervix, preterm labor, premature membrane rupture, dysfunctional labor, or fetal intolerance to labor.

  B. Oligohydramnios
Desquamated amnion epithelium and fetal keratinocytes normally accumulate within the amniotic fluid, but remain in solution when there is adequate amniotic fluid volume. If there is a severe, prolonged decrease in amniotic fluid volume, keratinaceous intra-amniotic debris may be ground into and under the viable amnion epithelium, forming amnion nodosum. When oligohydramnios is severe and prolonged, pulmonary hypoplasia and mechanical deformity of the limbs are common.

   C. Polyhydramnios
Abnormal increase in amniotic fluid volume is more rare, but is generally associated with either fetal hypervolemia, or abnormalities of fetal swallowing. The latter may be due to interruptions of the trachea (e.g., tracheo-esophageal fistula) or conditions which cause increased intra-thoracic pressure, which limit pulmonary expansion and fluid exchange.

  D. Amnion bands
The amnion epithelium presents a smooth and slippery surface protecting the delicate fetal skin. The amnion may be mechanically ruptured by trauma or amniocentesis, or may rupture spontaneously. Following rupture, bands of amnion may form. These may wrap around extremities and result in amputations. If amnion rupture occurs before the skin is well keratinized, fetal skin may become adherent to the connective tissue of the chorion. This may cause unusual patterns of fetal external anomalies including asymmetric encephalocele or gastroschisis.

  E. Preterm labor
Preterm labor indicates the premature onset of uterine contractions sufficient to cause cervical dilatation and effacement. A variety of causes that contribute to uterine irritation are associated with labor, for example, acute mechanical distention (from abruption or polyhydramnios) and prostaglandin production (from infection or tissue injury). Fetal consequences are related both to consequences of neonatal visceral immaturity, and to the causes underlying preterm birth.

  F. Abruption
The placenta normally does not separate from the uterine lining until after the delivery of the newborn. If the placenta begins to separate before the baby exits the intervillous blood flow and fetal oxygenation will be compromised. From the mother's viewpoint, the placenta provides powerful anticoagulants, and significant maternal blood loss may follow partial or complete abruption. Abruption most commonly follows a maternal "uteroplacental vascular accident", with retroplacental hemorrhage traumatically detaching the placenta, compressing and distorting its tissue, and affecting fetoplacental hemodynamics in addition to changes in oxygen and nutrient availability. Such vascular accidents are most commonly due to vessel thrombosis or abnormal conversion. Tissue injury from a severe acute infection may also undermine the placental margin and lead to marginal abruption.

  G. Placenta previa
Placental implantation preferentially occurs in the fundus, where the spiral arterial/uteroplacental vascular density (and oxygen/nutrient availability) is greatest. Therefore, it is not advantageous for implantation to occur in the lower uterine segment or over the least well vascularized uterine cervix. It is not possible for the baby to be delivered through the placenta without risking fetal hemorrhage from the damaged placenta, so cesarean delivery is obligatory with a complete previa. Since the lower uterine segment basalis is thinner, and absent over the cervix proper, abnormal placental invasion may lead to abnormally deep implantation (accreta, increta or percreta), each of which is potentially lethal to the mother.

  H. Accreta, increta & percreta
Abnormally deep placental implantation (through the decidua and into the myometrium proper) can be classified as accreta, increta or percreta depending on the depth of invasion. Its absolute pathologic diagnosis requires villi to be in direct contact with the myometrium without intervening decidua. Deeply implanted placentas do not separate normally from the uterine lining, since Nitabuch's fibrin results in an incomplete placental separation at parturition with delivery. It is classified as accreta, increta or percreta depending on the depth of invasion. Percreta can lead to uterine rupture.

  I. Meconium
Slimy green membranes suggest meconium staining, especially at term. When a preterm placenta has green membranes, however, the differential diagnosis includes intraamniotic infection with the green pigment representing bacterial by-product. When fecal material is discharged prior to delivery, which is more likely as it becomes functionally "easier" late in the third trimester, the fetus and placenta may be meconium stained. Meconium can be seen in the amnion and chorion after several hours, but it commonly takes longer for the cord to become meconium stained. Old meconium may be yellow.

IV. The Placenta in Maternal Disease

       A. Chronic hypertension is hypertension identified either before conception or before 20 weeks gestation, or if the blood pressure elevation persists more than 6 weeks postpartum. Chronic hypertension without superimposed PIH is generally not associated with significant placental lesions.

       B. Pregnancy induced hypertension (PIH) is hypertension which develops in pregnancy, not associated with proteinuria or pathological edema (edema which usually involves the face and hands). It is closely related to pre-eclampsia, and patients with PIH may evolve into pre-eclampsia.

       C. Pre-eclampsia is a clinical triad of 1) PIH, 2) pathological edema and 3) proteinuria. It most common in a first pregnancy after 20 weeks gestation. Its most classic intrauterine pathologic anatomy is related to failure of normal maternal vascular conversion. Fetal risks include acute and chronic uteroplacental insufficiency, which may result in IUGR or stillbirth.

       D. Eclampsia is pre-eclampsia accompanied by grand-mal seizures before, during or after labor.

       E. HELLP syndrome (Hemolytic anemia, Elevated Liver enzymes and Low Platelet count) is closely related to pre-eclampsia and probably reflects a differential maternal target organ/end organ sensitivity (liver versus kidney).

       F. Erthroblastosis Fetalis due to Rh-incompatibility between mother and father, with an Rh- mother carrying an Rh+ fetus. The placenta is large, pale and edematous, typical of any circumstance of chronic fetal anemia.

       G. Autoimmune diseases such as systemic lupus erythematosus (SLE) are associated with a greater frequency of complications of pregnancy. Autoantibodies produced within the context of SLE can interfere with uteroplacental and fetoplacental blood flow and cause platelet aggregation. Whether it is primarily an aberrant immune system function, or a cumulative vascular injury which more commonly underlies obstetric complications is not clear.

       H. Diabetes Mellitus Glucose readily passes through the placenta causing fetal hyperglycemia. This results in hyperplasia of the fetal islets of Langerhans, and fetal hyper-insulemia. The fetus and newborn in this condition are commonly large, hyper-volemic and may have severe hypoglycemia in the early newborn period. The placenta is large (over-grown), congested and edematous. Many placentas can show "diabetic type features," with normal blood sugars. Certain subsets of such patients can be shown to have insulin resistance but not frank gestational diabetes even on rigorous glucose testing.

       I. Maternal Infections are most commonly ascending (transcervical), but can be hematogenous (most commonly viral). Acute inflammation of tissues around or in the amniotic fluid space are characteristic of ascending infection; chronic villitis is a hallmark lesion, but is not generally diagnostic of hematogenous (congenital viral) infection. Maternal cervical, rectal or vaginal colonization of group B streptococcus (GBS) may infect the placenta. It is thought that GBS infection causes hypoxic conditions leading to fetal distress.

V. Gestational Trophoblastic Disease
Lesions arising from pregnancy associated trophoblastic cells with malignant potential. The diagnosis is made based upon persistent chorionic gonadotropin (hCG)serum levels. Invasive moles are characterized by villi that invade the myometrium.
     A. Hydatidiform mole
       1. Complete mole
Villi are edematous
No fetal tissues
Trophoblastic hyperplasia
46 chromosomes - all paternal -> androgenic diploid
       2. Partial mole
Focal edematous villi admixed with normal villi
Trophoblastic hyperplasia
Fetal tissues
Triploid - two sets paternal and one maternal

     B. Choriocarcinoma results from a malignant transformation of persistent,
residual trophoblastic cells of a previous normal or abnormal pregnancy.
No chorionic villi are present. Symptoms depend on location. This tumor
is aggressive and widely metastatic, but responds to chemotherapy.

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