Diseases of the placenta and membranes

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Chapter 18 Diseases of the placenta and membranes

ABNORMAL PLACENTATION

The shape of the definitive placenta is determined at the time the placenta forms, the variations found (Fig. 18.1) mostly having no clinical significance.

Fig. 18.1 Abnormal placentation.

The umbilical cord may enter the placenta at its midpoint, may join it at an edge (marginal insertion of the cord), or the umbilical vessels may run some distance along the membranes (velamentous insertion of the cord). Should the vessels run across the cervix they may be compressed by the fetal head during labour, or bleed causing fetal anaemia. In some cases the placenta is smaller than the chorionic plate and the trophoblast invades the decidua laterally more deeply, giving a ridged appearance on the placental surface (placenta circumvallata). In most cases this has no clinical significance, but occasionally may be found in women who have antepartum or intrapartum haemorrhage. In other cases the placenta has an accessory lobe separated by membranes from the main placenta (placenta succenturiata).

In a few cases the trophoblastic invasion is not regulated by maternal immune defences and the myometrium is invaded, causing placenta accreta, increta or percreta. Haemangiomata occur in 1% of placentae. In most cases they are small and of no clinical significance, but larger haemangiomata may be associated with polyhydramnios, antepartum haemorrhage or preterm labour.

GESTATIONAL TROPHOBLASTIC DISEASE

Gestational trophoblastic disease is uncommon affecting 1/750 pregnancies of women of non-Asian ethnicity but 1/380 of those from Asia. It is potentially lethal, but with treatment a 98% cure rate is attainable. The disease occurs in two forms (Box 18.1).

Hydatidiform mole

The tumour may have completely or partially replaced the placenta (Fig. 18.2). In the complete form, hydropic swelling and vesicle formation is associated with trophoblastic proliferation and a paucity or absence of blood vessels within the villi (Fig. 18.3). No fetus can be found. Five per cent of complete moles undergo malignant change.

Fig. 18.2 Benign trophoblastic tumour (hydatidiform mole): gross specimen. Note the grape-like masses.

Fig. 18.3 Microphotograph of a benign trophoblastic tumour (hydatidiform mole), showing the distended villi and irregular trophoblastic proliferation.

In the partial form a fetus is present but areas of the placenta show the changes described for the complete mole. Partial moles become malignant less frequently (0.05%).

Malignant trophoblastic disease

The tumour may be confined to the uterus (invasive mole) or spread via the bloodstream to distant organs (choriocarcinoma).

In the invasive mole the trophoblast-covered villi penetrate the myometrial fibres and may extend to other organs, the appearance of the villi remaining that of the benign tumour.

In choriocarcinoma (Fig. 18.4) the tumour is characterized by sheets of trophoblastic cells, both syncytio- and cytotrophoblasts, with few or no villi formed.

Fig. 18.4 Choriocarcinoma.

Aetiology

Gestational trophoblastic disease is caused by a genetic disorder in which a spermatozoon enters an ovum that has lost its nucleus, or in which two sperms enter the ovum. In over 90% of complete moles only paternal genes are found, and in 10% the mole is heterozygous. In contrast, partial moles usually have a triploid chromosomal constitution, with two sets of paternal haploid genes and one set of maternal haploid genes.

The development of gestational trophoblastic tumours is thought to be due to a defective maternal immune response to the invasion by the trophoblast. In consequence, the villi become distended with nutrients. The primitive vasculature within each villus does not form properly, with the result that the embryo starves, dies and is absorbed, whereas the trophoblast continues to thrive and, in certain circumstances, invades the maternal tissues.

The increased syncytiotrophoblast activity leads to an increased production of human chorionic gonadotrophin (hCG), chorionic thyrotrophin and progesterone. A fall in oestradiol secretion occurs, as oestradiol synthesis requires enzymes from the fetus, which does not exist. The raised hCG levels may induce the development of theca lutein cysts of the ovary.

Diagnosis of benign gestational trophoblastic disease

The first sign is bleeding per vaginam, which tends to persist. The bleeding may be followed fairly soon by uterine contractions and the expulsion of grape-like material. In other cases the tumour grows without symptoms. During this time examination will show the following features:

• The uterus is usually larger than expected from the gestational dates and is ‘doughy’ to the touch.

• Fetal heart sounds cannot be heard.

• Ultrasonic scanning shows a distinct speckled appearance (Fig. 18.5).

• If serum hCG is measured it is found to be unexpectedly high (Fig. 18.6).

Fig. 18.5 Twin gestation at 16 weeks with a hydatidiform mole on the right and a fetus and normal placenta on the left.

Fig. 18.6 Chorionic gonadotrophin excretion in trophoblastic disease. The normal range is shown in pink; levels found in trophoblastic disease are shown in the blue area.

Treatment

If the patient is admitted expelling the tumour, no immediate treatment is needed unless the expulsion slows down, at which time a digital evacuation of the uterus is carried out. Blood is obtained for possible transfusion, as the expulsion is often accompanied by marked blood loss.

If the diagnosis is reached before the expulsion of any vesicles, the uterus may be evacuated using a suction curette. The administration of prostaglandins or oxytocics to induce contractions should be avoided as these may lead to the intravascular dissemination of trophoblast. Gentle curettage may be performed later to remove any residual trophoblast. Some authorities give a single course of chemotherapy if they think that the woman presents with increased risk factors. If bleeding persists for more than 21 days a further curettage may be indicated.

Women over the age of 40, or women who have completed their family, may prefer to have a hysterectomy, to avoid potential malignancy.

Follow-up

Follow-up is important as the disease persists in between 5 and 10% of cases, often developing a malignant form. Follow-up is primarily by serial β-hCG assays as outlined in Box 18.2 and Figure 18.7. Many countries have a molar register so compliance with follow-up can be monitored.

Box 18.2 Follow-up of benign trophoblastic disease using a specific radioimmunoassay

1. Radioimmunoassay of serum β-hCG at 7–10-day intervals. If the level falls serially no drug treatment is needed. Complete disappearance of β-hCG takes 12–14 weeks on average.

2. When β-hCG level has been normal for 3 consecutive weeks, test monthly for 6 months.

3. If the assay shows normal β-hCG levels for 6 consecutive months, follow-up can be discontinued.

4. During the follow-up period pregnancy should be avoided. Oral contraceptives may be prescribed.

5. If the serum β-hCG level plateaus for more than 3 consecutive weeks, or rises, or if metastases are detected, treat with methotrexate or actinomycin D.

Fig. 18.7 Hormone follow-up of benign trophoblastic disease (mean and 95% confidence limits).

Malignant gestational trophoblastic disease

Malignancy follows a complete mole in 15% of cases and 0.5% after a partial mole. It follows a spontaneous abortion in 1 in 5000 cases, and a viable pregnancy in 1 in 50 000 cases.

Women who have had a benign gestational trophoblastic tumour are at greater risk of developing a malignancy if the woman:

• Is over the age of 40

• Secretes large amounts of β-hCG (>100 000 IU/mL)

• Has theca lutein cyst(s) more than 6 cm in diameter.

Malignant gestational trophoblastic disease is best managed at special centres, where meticulous follow-up is conducted. Treatment is by chemotherapy (Table 18.1) and follow-up is shown in Box 18.3.

Table 18.1 Chemotherapy in malignant trophoblastic disease

	Non-Metastatic mg/kg IM	Metastatic mg/kg IM
Initial course
Methotrexate at 48-hour intervals for 4 doses	1	1.5
Folic acid (citrovorum factor) on alternate days, 24 hours after the injection of methotrexate	0.1	0.15
Subsequent courses
1. If response, i.e. a fall in the β-hCG level <20%, repeat the regimen 2. Without response, increase methotrexate by 0.5 mg/kg and folic acid by 0.05 mg/kg 3. If no response after two consecutive courses change to actinomycin D 4. If no response to actinomycin D after two courses change to three chemotherapeutic drugs used in combination. Currently etoposide + methotrexate + cyclophosphamide (or vincristine) are recommended

Laboratory tests Full blood count, platelet count, SGOT (serum glutamic oxaloacetic transaminase) on day 1 (before starting therapy) and days 3, 5, 7, 11, 15, 18, 21

Box 18.3 Principles of the management of malignant trophoblastic disease

1. During treatment the serum levels of the β-hCG are assayed each week.

2. Provided that the β-hCG level continues to fall after a course of chemotherapy, withhold further courses.

3. When the β-hCG level is normal for 3 consecutive weeks, assay each month for 6 months.

4. If the β-hCG level remains normal for 12 months, discontinue follow-up. Patients should avoid pregnancy throughout this period.

5. Repeat the course of chemotherapy if the β-hCG level plateaus for more than 3 consecutive weeks, or rises, or if new metastases are detected.

6. If the β-hCG level plateaus after 3 consecutive courses of chemotherapeutic agent, or if it rises during a course, change to another chemotherapeutic regimen.

Following a molar pregnancy and after their β-hCG have returned to normal, women should be offered contraceptive therapy and advised not to conceive for a further 6 months. The risk of a further mole in a subsequent pregnancy is 1 in 55.