Background

Gestational trophoblastic disease encompasses several disease processes that originate in the placenta. These include complete and partial moles, placental site trophoblastic tumors, choriocarcinomas, and invasive moles. Almost all women with malignant gestational trophoblastic disease can be cured with preservation of reproductive function. The following discussion is limited to hydatidiform moles (complete and partial).

Pathophysiology
A complete mole contains no fetal tissue. Ninety percent are 46,XX, and 10% are 46,XY.[1, 2] Complete moles can be divided into 2 types:

Androgenetic complete mole o Homozygous These account for 80% of complete moles. Two identical paternal chromosome complements, derived from duplication of the paternal haploid chromosomes. Always female; 46,YY has never been observed. o Heterozygous These account for 20% of complete moles. May be male or female. All chromosomes are of parental origin, most likely due to dispermy. Biparental complete mole: Maternal and paternal genes are present but failure of maternal imprinting causes only the paternal genome to be expressed.[3] o The biparental complete mole is rare. o A recurrent form of biparental mole, which is familial and appears to be inherited as an autosomal recessive trait, has been described. Al-Hussaini describes a series of 5 women with as many as 9 consecutive molar pregnancies.[4, 5] o Mutations in NLRP7 at 19q13.4 have been identified as causative in recurrent molar pregnancies.[6, 7, 8]

With a partial mole, fetal tissue is often present. Fetal erythrocytes and vessels in the villi are a common finding. The chromosomal complement is 69,XXX or 69,XXY.[9] This results from fertilization of a haploid ovum and duplication of the paternal haploid chromosomes or from dispermy. Tetraploidy may also be encountered. As in a complete mole, hyperplastic trophoblastic tissue and swelling of the chorionic villi occur.

Epidemiology
Frequency
United States

By studying elective pregnancy terminations, hydatidiform moles were determined to occur in approximately 1 in 1200 pregnancies.[10] International The reported frequency of hydatidiform mole varies greatly. Some of this variability can be explained by differences in methodology (eg, single hospital vs population studies, identification of cases). The reported frequencies range from 1 in 100 pregnancies in Indonesia to 1 in 200 pregnancies in Mexico to 1 in 5000 pregnancies in Paraguay.[11] The study of pathologic material from first- and second-trimester abortions established a frequency of complete and partial hydatidiform moles in Ireland of 1 per 1945 pregnancies and 1 per 695 pregnancies, respectively.[12]

Mortality/Morbidity
A hydatidiform mole is considered malignant if metastases or destructive invasion of the myometrium (ie, invasive mole) occurs, or when the serum hCG levels plateau or rise during the period of follow-up and an intervening pregnancy is excluded. Malignancy (see Medscape Reference's article Gestational Trophoblastic Neoplasia) is diagnosed in 15-20% of patients with a complete hydatidiform mole and 2-3% of partial moles.[13, 14] Lung metastases are found in 45% of patients with a complete hydatidiform mole and rarely in cases of partial hydatidiform moles.[15, 16]

Race
Differences in the frequency of hydatidiform moles between ethnic groups have been reported internationally.[11, 17] In the United States, comparison of frequency of hydatidiform moles in African Americans and Caucasians have yielded conflicting results.[17] If differences exist, whether they are due to genetic differences or environmental factors is not clear.

Sex
Hydatidiform mole is a disease of pregnancy and therefore a disease of women. See Medscape's Pregnancy Resource Center.

Age
Hydatidiform mole is more common at the extremes of reproductive age. Women in their early teenage or perimenopausal years are most at risk.[18, 19, 20, 11, 17] Women older than 35 years have a 2-fold increase in risk. Women older than 40 years experience a 5- to 10-fold increase in risk compared to younger women. Parity does not affect the risk.

History

Complete mole: The typical clinical presentation of complete molar pregnancies has changed with the advent of high-resolution ultrasonography. Most moles are now diagnosed in the first trimester before the onset of the classic signs and symptoms.[21, 22] o Vaginal bleeding: The most common classic symptom of a complete mole is vaginal bleeding. Molar tissue separates from the decidua, causing bleeding. The uterus may become distended by large amounts of blood, and dark fluid may leak into the vagina. This symptom occurs in 50% of cases. o Hyperemesis: Patients may also report severe nausea and vomiting. This is due to extremely high levels of human chorionic gonadotropin (hCG). o Hyperthyroidism: Signs and symptoms of hyperthyroidism can be present due to stimulation of the thyroid gland by the high levels of circulating hCG or by a thyroid stimulating substance (ie, thyrotropin) produced by the trophoblasts.[23] Partial mole: Patients with partial mole do not have the same clinical features as those with complete mole. These patients usually present with signs and symptoms consistent with an incomplete or missed abortion. o Vaginal bleeding o Absence of fetal heart tones

Physical

Complete mole (See images below.) o Size inconsistent with gestational age: A uterine enlargement greater than expected for gestational age is a classic sign of a complete mole. Unexpected enlargement is caused by excessive trophoblastic growth and retained blood. However, patients present with size-appropriate enlargement or smaller-thanexpected enlargement at a similar frequency. o Preeclampsia: Pelvic ultrasonography has resulted in the early diagnosis of most cases of hydatidiform mole and preeclampsia is seen in less than 2% of cases.[22] o Theca lutein cysts: These are ovarian cysts greater than 6 cm in diameter and accompanying ovarian enlargement. These cysts are not usually palpated on bimanual examination but are identified by ultrasonography. Patients may report pressure or pelvic pain. Because of the increased ovarian size, torsion is a risk. These cysts develop in response to high levels of beta-hCG. They spontaneously regress after the mole is evacuated, but it may take up to 12 weeks for complete regression.

Theca lutein cysts.

Complete mole.

Complete mole with an area of clot near cervix consistent with bleeding. Partial mole [24] o Uterine enlargement and preeclampsia is reported in only 5% of patients. o Theca lutein cysts, hyperemesis, and hyperthyroidism are extremely rare. Twinning (See image below.) o Twinning with a complete mole and a fetus with a normal placenta has been reported (see image below). Cases of healthy infants in these circumstances have been reported.[25, 9] o Women with coexistent molar and normal gestations are at higher risk for developing persistent disease and metastasis[26] . Termination of pregnancy is a recommended option. o The pregnancy may be continued as long as the maternal status is stable, without hemorrhage, thyrotoxicosis, or severe hypertension. The patient should be informed of the risk of severe maternal morbidity from these complications.[27] o Prenatal genetic diagnosis by chorionic villus sampling or amniocentesis is recommended to evaluate the karyotype of the fetus.

Twin gestation. Complete mole and normal twin.

Causes
A diet deficient in animal fat and carotene may be a risk factor.[17, 18]

Differential Diagnoses

Hyperemesis Gravidarum Hypertension Hypertension, Malignant Hyperthyroidism

Laboratory Studies

Quantitative beta-hCG: hCG levels greater than 100,000 mIU/mL indicate exuberant trophoblastic growth and raise suspicion for a molar pregnancy. However, a molar pregnancy may have a normal hCG level. Complete blood cell count with platelets: Anemia could be present and coagulopathy could occur. Clotting function: Test clotting function to exclude the development of a coagulopathy or to treat one if discovered. Liver function tests Blood urea nitrogen (BUN) and serum creatinine Thyroxine: Although women with molar pregnancies are usually clinically euthyroid, plasma thyroxine is usually elevated above the reference range for pregnancy. Patient may present with signs and symptoms of hyperthyroidism. Serum inhibin A and activin A: Serum inhibin A and activin A have been shown to be 7to 10-fold higher in molar pregnancies than normal pregnancies at the same gestational age. The fall in inhibin A and activin A after evacuation may prove helpful.[28] However, of the readily available markers, serum hCG levels is the standard of care.

Imaging Studies

Ultrasonography is the criterion standard for identifying both complete and partial molar pregnancies. The classic image, using older ultrasonographic technology, is of a snowstorm pattern representing the hydropic chorionic villi. High-resolution ultrasonography shows a complex intrauterine mass containing many small cysts. Once a molar pregnancy is diagnosed, a baseline chest radiograph should be taken. The lungs are a primary site of metastasis for malignant trophoblastic tumors (see Medscape Reference's article Gestational Trophoblastic Neoplasia).

Histologic Findings

Complete mole: Complete hydatidiform moles have edematous placental villi, hyperplasia of the trophoblasts, and lack or scarcity of fetal blood vessels. Their chromosomal complement is 46,XX in most cases or 46,XY in approximately 10-15% of cases. Additionally, complete moles show overexpression of several growth factors, including c-myc, epidermal growth factor, and c-erb B-2, compared with normal placenta.[29]

Partial mole: In the incomplete or partial hydatidiform mole fetal tissue is often present, as well as amnion and fetal vessels with fetal red blood cells within the mesenchyme of the villi. Like in complete hydatidiform moles, hydropic (edematous) villi and trophoblastic proliferation are present. In addition, due to tangential sectioning, scalloping of the villi results in apparent trophoblastic inclusions within the mesenchyme of the villi. Paternally imprinted gene products (eg, p57, PHLDA2) are normally expressed only by maternal chromosomes. In the absence of maternal chromosomes, as is the case in complete moles, the nuclei of the villous stroma and the cytotrophoblasts do not stain for p57 or PHLDA2 (Pleckstrin homology-like domain, family A, member 2). In contrast, these cells are positive for p57 and PHLDA2 in partial moles (which are triploid) and missed abortion with hydropic degeneration (which are diploid).[30, 31, 32]

Medical Care

Stabilize the patient. Transfuse for anemia. Correct any coagulopathy. Treat hypertension. Watch for and be prepared to treat thyroid storm, a rare complication.

Surgical Care

Evacuation of the uterus by dilation and curettage is always necessary. Prostaglandin or oxytocin induction is not recommended because of the increased risk of bleeding and malignant sequelae. Intravenous oxytocin should be started after dilation of the cervix at the initiation of suctioning and continued postoperatively to reduce the likelihood of hemorrhage. Consideration of using other uterotonic formulations (eg, Methergine, Hemabate) is also warranted. Respiratory distress can occur at the time of surgery. This may be due to trophoblastic embolization, high-output congestive heart failure caused by anemia, or iatrogenic fluid overload. Distress should be aggressively treated with assisted ventilation and monitoring, as required.[33]

Consultations
A gynecologic oncologist should be consulted if the patient is believed to be at risk for or has developed malignant disease (ie, gestational trophoblastic neoplasia).

Diet
No special diet is required.

Activity

Patients may resume activity as tolerated. Pelvic rest is recommended for 2-4 weeks after evacuation of the uterus, and the patient is instructed not to become pregnant for 6 months. Effective contraception is recommended during this period.[34] Monitor serial beta-hCG levels to identify the rare patient who develops malignant disease. If a pregnancy does occur, the elevation in beta-hCG would be confused with development of malignant disease.

Medication Summary

Prophylactic chemotherapy after evacuation of a hydatidiform mole is not routinely recommended. Only 20% of women with hydatidiform mole will develop malignant sequelae (ie, Gestational Trophoblastic Neoplasia). Prophylactic chemotherapy may be considered in patients who will not adhere to the required close follow-up.

Further Outpatient Care

Serial quantitative serum beta-hCG levels should be determined. o Serum hCG levels are obtained weekly until the levels are within reference range for 3-4 weeks. o Levels should consistently drop and should never increase. Normal levels are usually reached within 8-12 weeks after evacuation of the hydatidiform mole. As long as the hCG levels are falling intervention is not needed.[35] o Once levels have reached the reference range for 3-4 weeks, check them monthly for 6 months.[36, 37, 38] o If the serum hCG levels plateau or rise, the patient is considered to have malignant disease (ie, gestational trophoblastic neoplasia) and metastatic disease needs to be excluded. Effective contraception is recommended during the period of follow-up. To avoid uterine perforation and bleeding, if an intrauterine contraceptive device (IUD) is selected, insertion should await involution of the uterus and normalization of serum hCG levels. After a hydatidiform mole, the risk of developing a second mole is 1.2-1.4%. The risk increases to 20% after 2 moles.[39] Evaluate all future pregnancies early with ultrasonography. Human telomerase reverse transcriptase (hTERT) expression in the uterine contents of cases of complete mole has been suggested as a marker for persistent disease. The negative predictive value appears most significant. No cases of persistent disease had absence of hTERT; however, some cases in which hTERT was expressed regressed spontaneously.[40]

Complications

Perforation of the uterus during suction curettage sometimes occurs because the uterus is large and boggy. If perforation is noted, the procedure should be completed under laparoscopic guidance.

Hemorrhage is a frequent complication during the evacuation of a molar pregnancy. For this reason, intravenous oxytocin should be started at the initiation of the suctioning. Methergine and/or Hemabate should also be available. Blood for possible transfusion should be readily available. Malignant trophoblastic disease develops in 20% of molar pregnancies. For this reason, quantitative hCG should be serially monitored as described above. Factors released by the molar tissue could trigger the coagulation cascade. Patients should be monitored for disseminated intravascular coagulopathy (DIC). Trophoblastic embolism could cause acute respiratory insufficiency.[33] The greatest risk factor for this complication is a uterus larger than that expected for a gestational age of 16 weeks. The condition may be fatal.

Prognosis

Because of early diagnosis and appropriate treatment, the current mortality rate from hydatidiform mole is essentially zero. Approximately 20% of women with a complete mole develop a trophoblastic malignancy. Gestational trophoblastic malignancies (ie, gestational trophoblastic neoplasia) are almost 100% curable. Clinical factors that have been associated with risk of malignant disease are advanced maternal age, high levels of hCG (>100,000 mIU/mL), eclampsia, hyperthyroidism, and bilateral theca lutein cysts.[26] Most of these factors appear to reflect the amount of trophoblastic proliferation. Predicting who will develop gestational trophoblastic disease remains difficult, and treatment decisions should not be based on the presence of any or all of these risk factors.

Patient Education

Because of the small but real potential for development of malignant disease and because these malignancies are absolutely curable, the importance of consistent follow-up care must be emphasized. To avoid any confusion about the development of malignant disease, the patient must avoid pregnancy during the period of follow-up described above. Effective contraception should be used. If a pregnancy occurs, the elevation in beta-hCG levels cannot be differentiated from the disease process. Future pregnancies should undergo early sonographic evaluation because of the increased risk of recurrence of a molar gestation. The risk of recurrence is 1-2%. After 2 or more molar pregnancies, the risk of recurrence has been reported as 1 in 6.5 to 1 in 17.5.[41] For excellent patient education resources, visit eMedicineHealth's Pregnancy Center. Also, see eMedicineHealth's patient education articles Birth Control Overview and Birth Control Methods.