Chapter 55. Diseases of Pregnancy; Trophoblastic Neoplasms

Under normal circumstances, the ovum is fertilized by the sperm in the ampullary portion of the uterine tube, whence it passes into the uterine cavity prior to implantation.

The ovum divides rapidly, differentiating into (1) the embryo, which develops over the next 40 weeks into the full-term fetus; and (2) the trophoblast, which invades the progestational endometrium to form the placenta. The developing fetus becomes enclosed in an amniotic cavity that contains amniotic fluid. The amniotic cavity is lined by amnion and chorion (fetal membranes). The amnion also covers the fetal surface of the placenta and umbilical cord. The chorion is accentuated at one pole of the uterus to form the placenta, which is usually located in the fundus of the uterus. The fetus is connected to the placenta by the umbilical cord.

An ectopic pregnancy is one in which implantation of the fertilized ovum occurs at a site other than the uterine cavity (Figure 55-1).

Tubal Pregnancy

Tubal pregnancies are common, representing about 0.5% of all pregnancies. The incidence is believed to be increasing, possibly as a consequence of the general increase in the incidence of pelvic inflammatory disease, which causes tubal narrowing and adhesions that interfere with passage of the fertilized ovum. Endometriosis involving the uterine tube is also associated with an increased risk of tubal pregnancy. In many cases of tubal pregnancy, however, no etiologic factor is identified.

Pathology

In spite of the abnormal implantation site, the ovum develops normally in the first few weeks, forming a placenta, an embryo, and an amniotic sac. Later development is greatly impeded by the lack of space, poor vascular supply, and limited placental size.

Rupture of the tube containing the pregnancy frequently occurs 2–6 weeks after fertilization, causing massive, potentially fatal intraperitoneal hemorrhage (Figure 55-2). This may occur so early in the course of the pregnancy that the patient may not have missed a menstrual period. The embryo may still be alive (in which case the pregnancy test for serum or urinary human chorionic gonadotropin (hCG) will still be positive). In most cases, the released embryo dies soon after tubal rupture. When rupture of a tubal pregnancy releases a live embryo into the peritoneal cavity, it can move to a secondary implantation site on the peritoneal surface (secondary abdominal pregnancy). Very rarely, such a pregnancy progresses to term, although of course normal delivery cannot occur.

If the tubal pregnancy does not rupture, death of the embryo occurs at about 10 weeks, with one of several consequences: (1) absorption of the products of conception; (2) calcification of the fetus to form a lithopedion (Gk lithos, stone, paidion, child); or (3) extrusion of the dead fetus into the peritoneum through the fimbrial end of the tube—again associated with severe intraperitoneal hemorrhage.

Clinical Features

Patients with tubal pregnancy present with evidence of early pregnancy such as a missed menstrual period, vomiting of pregnancy, or a positive pregnancy test. This is associated with an absence of appropriate uterine enlargement and the presence of a tender mass in the adnexa, representing the expanded uterine tube.

Rupture of a tubal pregnancy produces severe abdominal pain and intraperitoneal bleeding, often rapid and severe. The presence of blood in the peritoneal cavity can be confirmed by aspiration or laparoscopy. Many patients are in a state of hypovolemic shock at the time of presentation.

Death of the fetus in a tubal pregnancy results in rapid decline in the serum level of chorionic gonadotropin, leading to a negative pregnancy test. Decline in hCG levels causes the corpus luteum to degenerate. This leads to decreased estrogen and progesterone levels, which causes the endometrium to break down. Uterine bleeding results.

The diagnosis of tubal pregnancy is established by clinical examination. The absence of chorionic villi in endometrial curettings from a woman who appears to be pregnant requires exclusion of the presence of tubal pregnancy. Endometrial curettage is performed in a patient who shows evidence of pregnancy only when there is persistent severe vaginal bleeding. In such patients, the differential diagnosis includes spontaneous abortion and ectopic pregnancy.

Treatment

The diagnosis and treatment of tubal pregnancy is urgent. Traditionally, the treatment of choice has been to remove the uterine tube on the affected side (salpingectomy). Recently, attempts have been made to save the tube (salpingostomy), particularly if bilateral tubal disease is present, in order to preserve maximal fertility. In such patients, there is a high risk of recurrence of tubal pregnancy.

The developing pregnancy is called an embryo for the first 8 weeks and a fetus thereafter. Most of the major organs have formed at 12 weeks (at which time the fetal crown-rump length is 7–10 cm and the genitalia are recognizably male or female). In most countries, the fetus is considered viable at 20 weeks, although as a practical matter the proportion of fetuses that survive after delivery at 20–28 weeks is small.

Delivery of the embryo or fetus before 20 weeks is termed abortion; after 20 weeks and up to term at 40 weeks, premature delivery. Spontaneous abortion is common, and the causes are many (Table 55-1). It has been estimated that 25% of fertilized ova abort—many so early that the pregnancy is never recognized and others during the eighth to twelfth weeks. Spontaneous abortion is characterized clinically (1) by vaginal bleeding, which may be rapid and severe, leading to hypovolemia and shock; or (2) by lower abdominal pain due to uterine contraction. Pregnancy tests become negative. It is not uncommon for products of conception to be retained in the uterus (incomplete abortion; Figure 55-3). This may cause continued irregular bleeding over the next several weeks. For this reason, most patients with spontaneous abortion require surgical evacuation of the uterus (dilation and curettage).

Placenta Previa

The fertilized ovum normally implants in the fundus, and the placenta forms in that location. Abnormally low implantation may lead to formation of the placenta in the lower uterine segment. When the placenta is formed over the internal os (Figure 55-4A), it is called placenta previa.

Placenta previa causes problems only in late pregnancy, chiefly at the onset of labor. Uterine contractions in the first stage of labor cause effacement, stretching, and dilation of the cervix, leading to premature separation of the placenta previa, which results in bleeding, often severe, at the onset of labor (antepartum hemorrhage).

The availability of ultrasonography for placental localization permits early detection of placenta previa. Treatment is elective cesarean section before the onset of labor.

Abruptio Placentae

Abruptio placentae is premature separation of a normally situated placenta after 20 weeks of gestation, leading to antepartum hemorrhage due to rupture of vessels between the myometrium and separated placenta. In 20% of cases, blood is retained in the placental bed (Figure 55-4B) as concealed hemorrhage, and extensive loss may result in shock and disseminated intravascular coagulation (Chapter 9: Abnormalities of Blood Supply). In the remainder, severe bleeding occurs vaginally due to opening of the retroplacental hematoma into the cervical os (Figure 55-4C) (revealed hemorrhage). In both instances, fetal death and premature labor are likely.

Placenta Accreta

The normal placental villi are separated from the myometrium by a plate of decidual tissue (modified endometrial stroma). This decidual plate is the plane of normal separation of the placenta in the third stage of labor after the fetus has been delivered. Placental separation and expulsion (as afterbirth) must occur to permit sustained contraction of the uterine muscle at the end of labor, the principal mechanism whereby bleeding from the raw placental site is controlled.

Placenta accreta is absence of a plane of separation between the placental villi and myometrium. The placenta fails to separate in labor, leading to severe postpartum hemorrhage (Figure 55-4D). Placenta increta is a further stage of this abnormality in which the villi actually penetrate the myometrium. Placenta percreta is the most severe degree, with penetration of villi through the full thickness of the myometrium to reach the serosa.

In this group of placental abnormalities, hysterectomy is frequently necessary to arrest bleeding.

Placental Infection

Placental infection may be classified into two types, as follows:

1. Infection of the fetal membranes (chorioamnionitis), which represents ascending infection from the vagina and cervix. Escherichia coli, β-hemolytic streptococci, and anaerobes are the usual organisms. Rupture of the membranes not followed by delivery of the fetus within 24–48 hours almost always leads to chorioamnionitis.

2. Maternal hematogenous infections involving the placenta, which include syphilis, tuberculosis, cytomegalovirus infection, toxoplasmosis, listeriosis, rubella, and herpes simplex. These organisms cause villitis, characterized by focal abscesses, granulomas, and necrosis of the placenta; rarely, the organism can be identified in the inflamed villi.

Amniotic Fluid Embolism

Amniotic fluid and debris may gain entry to uterine veins at the time of placental separation in labor and travel in the maternal circulation as emboli. Although amniotic fluid embolism is rare, it accounts for a significant percentage of maternal deaths in developed countries, where maternal mortality rates are very low. Predisposing factors include premature placental separation and a dead fetus.

Amniotic debris, which consists mainly of fetal squames, may be found in the lungs. The identification of squamous epithelial cells in pulmonary capillaries at autopsy is a reliable method of diagnosis (see Chapter 9: Abnormalities of Blood Supply). The amniotic fluid contains thromboplastic substances that cause disseminated intravascular coagulation, which is responsible for the main clinical manifestations.

A normal uterus in normal labor “never” ruptures. Factors that predispose to rupture during labor include fibroids, placenta increta or percreta, the presence of a fibrous scar from a previous cesarean section, prolonged labor due to malposition (eg, breech presentation), instrumentation (forceps), and extensive uterine stimulants (oxytocin, prostaglandins, ergot infusions). Rupture not associated with labor may be associated with choriocarcinoma, invasive hydatidiform mole, or endometrial carcinoma.

The term eclampsia (Gk eklampo, shine, flash, forth) was initially applied to convulsions occurring in pregnancy, which were commonly accompanied by visual symptoms of flashing lights. The condition has been recognized for over 2000 years, and a prodromal condition, thought to be due to a toxin, was described—thus the term preeclamptic toxemia. Today, while the cause is still unclear, it is universally accepted that blood-borne toxins are not involved, and the term preeclampsia is used.

Preeclampsia is a syndrome consisting of three principal signs: hypertension, proteinuria (albuminuria), and generalized edema. The term gestational edema with proteinuria and hypertension (GEPH) is sometimes used for preeclampsia. The condition is distinct from pregnancy occurring in a patient with preexisting hypertension.

Incidence

Preeclampsia complicates about 5% of pregnancies in the United States, and 10% of patients with preeclampsia develop seizure symptoms (eclampsia). Presentation is usually in the third trimester.

Predisposing factors include (1) primigravida status—two thirds of cases of preeclampsia occur in first pregnancies; (2) multiple pregnancies and hydramnios (excess amniotic fluid); (3) preexisting diabetes or hypertension; (4) hydatidiform mole; and (5) malnutrition and familial factors.

Etiology

The cause of preeclampsia-eclampsia is unknown. Theories include (1) placental ischemia; (2) immunologic reaction against placental vessels; (3) deficient production of prostaglandin E by the placenta, resulting in increased sensitivity to the hypertensive effects of renin and angiotensin, and (4) disseminated intravascular coagulation (DIC), which certainly occurs in established eclampsia due to substances with thromboplastic activity released by the placenta. DIC is probably a complication rather than an etiologic factor in preeclampsia-eclampsia.

Pathology

The placenta shows degeneration, hyaline deposition, calcification, and congestion (premature aging). The maternal decidua shows hemorrhage and necrosis with thrombosis of spiral arteries. Accumulation of foamy macrophages in the necrotic vessel wall (acute atherosis) is a typical histologic feature. Placental infarcts may occur.

In eclampsia, the maternal kidneys show swelling of glomerular endothelial cells, mesangial proliferation, and marked narrowing of glomerular capillary lumens. Significant cortical ischemia with renal cortical necrosis may follow. The liver typically shows periportal necrosis and congestion in severe cases. Endothelial thickening, hemorrhages, and edema also occur in other tissues, including the brain, heart, lungs, and pituitary.

Clinical Findings

Edema is common in pregnancy and does not of itself warrant a diagnosis of preeclampsia. Hypertension is the most critical feature, together with proteinuria, which usually is last to appear. Fetal growth may be less than expected because of placental insufficiency (small-for-gestational-age fetus).

Eclampsia is preceded by increasing hypertension. Individual twitchings of muscles are followed by generalized clonic contractions. Eclampsia may occur before or during labor and carries a high mortality rate.

Treatment

Treatment of preeclampsia is aimed at reducing the blood pressure and preventing eclampsia. Diet and sedatives are used widely, and antihypertensive drugs in severe cases. Induction of labor or cesarean section when the fetus is judged sufficiently mature is dramatically effective.

Hydatidiform Mole (Molar Pregnancy)

The incidence of hydatidiform mole varies greatly in different parts of the world. It occurs in one in every 2000 pregnancies in the United States but has a much higher frequency (1:150) in India and the Far Eastern countries.

Etiology

Two distinct types of hydatidiform mole are recognized:

Complete Mole

This results from fertilization by one or two sperms of an ovum that has lost all its chromosomes. In complete moles, all the chromosomal material is derived from sperms. In 90% of cases, a single sperm is involved, and the molar karyotype is 46,XX. In 10%, the karyotype includes Y chromosomes. In complete mole, early embryonic death is the rule, and no fetal parts are seen.

Partial Mole

This results from fertilization of an ovum by two sperms: one 23,X and the other 23,Y. Partial moles are therefore triploid (69,XXY). The embryo may develop for a few weeks, and fetal parts may be present when the mole is evacuated.

Pathology

Complete Mole

The uterus is usually enlarged. The uterine cavity is filled with a mass of grape-like structures—thin-walled, translucent, cystic, and grayish-white. This represents the hydatidiform mole. The weight of this evacuated mass is usually in excess of 200 g. No normal fetal parts are identified.

Microscopically, the cysts are composed of dilated chorionic villi, the interior being filled with an avascular, loose myxoid stroma. Trophoblastic proliferation produces sheets of cytotrophoblastic and syncytiotrophoblastic cells (Figure 55-5). Cytologic atypia may be present.

Complete mole is associated with greatly elevated levels of chorionic gonadotropin. The high gonadotropin level causes multiple bilateral theca lutein cysts in the ovary in about 30% of cases (see Chapter 52: The Ovaries & Uterine Tubes). These regress after removal of the mole.

Partial Mole

The uterus may not be enlarged. The enlargement and edema involves only a proportion of villi, and many normal villi coexist. Fetal parts may be present. The degree of trophoblastic proliferation is mild, and the serum level of chorionic gonadotropin is often only slightly elevated.

Clinical Features

The initial features are those of early pregnancy, including amenorrhea, vomiting of pregnancy—often severe—and a positive pregnancy test. Uterine enlargement is usually greater than in the case of normal pregnancy. Vaginal bleeding usually begins in the third to fourth month. Passage of grape-like clusters admixed with blood may also be observed. Ultrasound examination is usually diagnostic, showing the enlarged, multicystic placenta and the absence of a fetus. Diagnosis is confirmed by the greatly elevated levels of βhCG in the serum.

Hydatidiform mole is treated surgically, with evacuation of the mole from the uterine cavity by curettage. This is curative in the great majority of cases. After evacuation, the serum βhCG level falls rapidly to normal; failure to do so indicates residual mole.

Complications

About 2.5% of complete moles are complicated by choriocarcinoma; 10% develop into invasive moles. Partial moles have a minimal risk. The presence of marked cytologic atypia in a hydatidiform mole shows some correlation with later development of choriocarcinoma, although not to the extent that would permit reliable prediction. The most precise method of detecting complications after molar pregnancy is by follow-up determination of serum βhCG. In patients who develop invasive mole, the βhCG level does not return to normal after the mole is evacuated. If the βhCG level returns to normal after the mole is evacuated and becomes elevated at a later time, choriocarcinoma should be considered.

Chorioadenoma Destruens (Invasive Mole)

Chorioadenoma destruens is a hydatidiform mole that shows extensive penetration of the villi and trophoblast into the myometrium. Some extension into superficial myometrium is usually present in hydatidiform mole. In invasive mole, extension often reaches the serosal surface.

Invasive mole is associated with necrosis and hemorrhage in the myometrium (Figure 55-6), and uterine rupture may occur. Villi may embolize to distant sites—commonly the lungs—but regress spontaneously. Invasive mole is associated with persistent elevation of βhCG levels after evacuation of the uterine cavity. Without treatment, the mortality rate from hemorrhage or uterine rupture is about 10%. Treatment with chemotherapy is effective.

Gestational Choriocarcinoma

Gestational choriocarcinoma of the uterus is a malignant neoplasm of trophoblast. It is rare, complicating about one in 40,000 pregnancies. About half follow a hydatidiform mole; others occur after abortion (25%), normal pregnancy (23%), or ectopic pregnancy (2%).

Choriocarcinoma, like hydatidiform mole, has a relatively high incidence in some parts of Asia and Africa. Histologically, gestational choriocarcinoma arising from a pregnancy is identical to ovarian (or testicular) choriocarcinoma having a germ cell origin.

Pathology

Choriocarcinoma presents grossly as a friable hemorrhagic mass in the uterine cavity. It infiltrates the myometrium extensively, and vascular invasion occurs early, with widespread metastases in lungs, brain, liver, and bone marrow. Microscopically, choriocarcinoma is composed of cytologically malignant sheets of cytotrophoblastic and syncytiotrophoblastic cells associated with necrosis and hemorrhage (Figure 55-7). Formed chorionic villi are absent. βhCG can often be demonstrated in the tumor cells.

Clinical Features & Treatment

Patients with choriocarcinoma present with abnormal uterine bleeding, commonly occurring within a few months after normal pregnancy, abortion, or hydatidiform mole. Many patients have metastatic lesions at the time of diagnosis.

Serum βhCG is markedly elevated. The diagnosis is made by histologic examination of an endometrial biopsy specimen, which shows malignant trophoblastic cells and an absence of chorionic villi. Many tumors (most commonly lung carcinomas) other than choriocarcinoma secrete βhCG, although at lower levels.

The prognosis of gestational choriocarcinoma was hopeless fewer than 20 years ago. With aggressive combined chemotherapy using methotrexate and dactinomycin, the 5-year survival rate has improved to over 90% even in patients with widespread metastases at presentation. Serum βhCG levels are extremely useful in monitoring treatment. Elevated βhCG levels in serum indicate persistence of viable trophoblastic tissue and the need for further chemotherapy.

Placental Site Trophoblastic Tumor (PSTT)

This is a rare lesion characterized by the diffuse proliferation in the uterus of sheets of intermediate trophoblastic cells resembling cytotrophoblast, most commonly after abortion or normal pregnancy. No chorionic villi or fetal parts are identified. The proliferating cells may show considerable cytologic abnormalities, which results in a resemblance of this lesion to choriocarcinoma. The neoplastic cells contain human placental lactogen, demonstrable by immunoperoxidase techniques. Unlike choriocarcinoma, PSTT shows only a slight elevation of βhCG and no syncytiotrophoblastic cells. The biologic behavior of PSTT is usually benign. Most cases are cured by curettage. A few cases have demonstrated a more aggressive biologic behavior, and rare cases with metastases have been reported.