Hydatidiform Mole 

Updated: Feb 16, 2018
Author: Lisa E Moore, MD, FACOG; Chief Editor: Warner K Huh, MD 

Overview

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. A diet deficient in animal fat and carotene may be a risk factor.[1]  More recently, Japanese investigators have identified a novel homozygous nonsense mutation in the NLRP7 gene (c.584G>A; p.W195X) in a patient that appears to associated with recurrent hydatidiform mole.[2] They also noted that the mole was biparental, and there was a specific maternal loss of DNA methylation of differentially methylated regions (DMRs).[2]

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.[3, 4] Complete moles can be divided into two types, androgenetic complete mole and biparental complete mole.

Androgenetic complete mole

Homozygous

These account for 80% of complete moles, with two identical paternal chromosome complements, derived from duplication of the paternal haploid chromosomes. They are always 46, XX; 46,YY has never been observed.

Heterozygous

These account for 20% of complete moles. The chromosome complement can be 46, XX or 46, XY. All chromosomes are of paternal origin, most likely due to dispermy.

Biparental complete mole

The biparental complete mole is rare. Maternal and paternal genes are present but failure of maternal imprinting causes only the paternal genome to be expressed.[5]

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.[6, 7]

Mutations in NLRP7 at 19q13.4 have been identified as causative in recurrent molar pregnancies.[8, 9, 10]

Partial mole

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.[11] 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

United States statistics

By studying elective pregnancy terminations, hydatidiform moles were determined to occur in approximately 1 in 1200 pregnancies.[12]

International statistics

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.[13] 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.[14]

Race-, sex-, and age-related demographics

Differences in the frequency of hydatidiform moles between ethnic groups have been reported internationally.[13, 15] In the United States, a cross-sectional study of 140 complete moles and 115 partial moles found that Asian women were more than twice as likely as white women to have a complete mole but were less likely to have a partial mole. Hispanic women were 60% less likely to have a complete mole. White women had the greatest risk of partial molar pregnancy. African-American and Hispanic women had similar risk of complete mole but when adjusted for age, African-American women had a marginally decreased risk.[16]

Hydatidiform mole is a disease of pregnancy and therefore a disease of women.

Hydatidiform mole is more common at the extremes of reproductive age. Women in their early teenage or perimenopausal years are most at risk.[1, 13, 15, 17, 18] 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.

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.[19]  Most of these factors appear to reflect the amount of trophoblastic proliferation. Predicting who will develop gestational trophoblastic neoplasia remains difficult, and treatment decisions should not be based on the presence of any or all of these risk factors.

A study by Vargas et al indicated that in women who have had molar pregnancies, the outcomes of subsequent pregnancies are similar to pregnancy outcomes in the general population. The study looked at 1388 subsequent pregnancies in women with complete hydatidiform mole, as well as 357 pregnancies following partial hydatidiform mole and 667 pregnancies after gestational trophoblastic neoplasia. Although outcomes in these cases were similar to those of women who had never had a molar pregnancy, the investigators did find that about 1.7% of women with a molar pregnancy did have another molar pregnancy later. Moreover, in women with gestational trophoblastic neoplasia who underwent successful chemotherapy for the disease, the incidence of stillbirth in subsequent pregnancies rose slightly, to 1.3%.[20]

A study by Gadducci et al indicated that women with gestational trophoblastic neoplasia have a good prognosis and that such women who conceive after chemotherapy have similar obstetric outcomes to those of the general population. In the study, 18 of 66 patients with hydatiform mole developed gestational trophoblastic neoplasia and two women were referred with a diagnosis of gestational trophoblastic neoplasia. One of the neoplasia patients died of an epithelioid trophoblastic tumor, with the rest recovering after chemotherapy. Pregnancy was achieved in seven out of eight women who attempted postchemotherapy conception, with 10 conceptions culminating in three miscarriages and seven healthy, full-term births. No molar pregnancies occurred.[21]

In contrast to the results of the above two studies, a report by Joneborg et al suggested that following a molar pregnancy, the risk of preterm birth is increased. The results also indicated that if at least one birth occurs between the molar pregnancy and the index birth, the likelihood of large-for-gestational-age birth and stillbirth is greater. However, the risk of adverse maternal outcomes was not found to be increased following molar pregnancy. The risk of having a repeat molar pregnancy in this study was found to be 0.4%.[22]

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.[23, 24]  Lung metastases are found in 4-5% of patients with a complete hydatidiform mole and rarely in cases of partial hydatidiform moles.[25, 26]

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 below (long-term monitoring).

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.[27]  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.

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 below (long-term monitoring). 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.[28]

For patient education resources, see the Pregnancy Center as well as Birth Control Overview and Birth Control Methods.

 

Presentation

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.[29, 30, 31]

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.

Hyperemesis

Patients may also report severe nausea and vomiting. This is due to extremely high levels of human chorionic gonadotropin (hCG). This is reported to occur in 4% of patients diagnosed at 5-9 weeks of gestation, and in 23% when the diagnosis is made after 10 weeks' gestation.

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.[32]  Clinical hyperthyroidism has been reported in 3.7% of women with a hydatidiform mole diagnosed after the 10th week of gestation.

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, including vaginal bleeding and absence of fetal heart tones.

In a retrospective study (1994-2013) at a Brazilian trophoblastic disease center, investigators evaluated the clinical presentations and incidence of postmolar gestational trophoblastic neoplasia (GTN) among 355 women with complete mole (n =186) or partial mole (n = 169), with the following findings[33] :

  • Risk of vaginal bleeding, biochemical hyperthyroidism, anemia, uterine size larger than dates, and hyperemesis: Reduced risk in women with partial mole
  • Preevacuation serum hCG levels: Lower in women with partial mole
  • Median gestational age at evacuation: complete mole, 9 weeks; partial mole, 12 weeks
  • Development of GTN:  women with complete mole, 17.7%; women with partial mole, 4.1%

Those with complete mole were diagnosed more commonly before evacuation than women with partial mole because they presented more often with signs/symptoms of molar disease.[33]

Physical Examination

Complete mole

Note the following:

  • 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 also present with size appropriate or smaller than expected for the gestational age.

  • 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.[30]

  • 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 are reported in 11% of cases diagnosed at  longer than10-weeks' gestational age. The cysts spontaneously regress after the mole is evacuated, but it may take up to 12 weeks for complete regression.

    Theca lutein cysts. Theca lutein cysts.
    Complete mole. Complete mole.
    Complete mole with an area of clot near cervix con Complete mole with an area of clot near cervix consistent with bleeding.

Partial mole

Uterine enlargement and preeclampsia is reported in only 5% of patients.[34]  Theca lutein cysts, hyperemesis, and hyperthyroidism are extremely rare.

Twinning

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.[11, 35]

Women with coexistent molar and normal gestations are at higher risk for developing persistent disease and metastasis.[19]  Termination of pregnancy is a recommended option.

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.[36]

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. Twin gestation. Complete mole and normal twin.
 

DDx

 

Workup

Laboratory Studies

The following laboratory studies may be used to evaluate patients with suspected hydatidiform mole:

  • Quantitative beta-hCG levels: 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 studies: 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 levels
  • Blood type and Rh factor
  • Thyroxine level: Although women with molar pregnancies are usually clinically euthyroid, biochemical hyperthyroidism has been reported in 6% of patients with hydatidiform mole diagnosed at 5-9 weeks of gestation and in 28% when the diagnosis is made after 10 weeks' gestation. Patient may present with signs and symptoms of hyperthyroidism. Clinical hyperthyroidism occurs in less than 3% of cases.
  • Serum inhibin A and activin A levels: Serum inhibin A and activin A have been shown to be 7- to 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. [37] 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 the Medscape Drugs & Disease 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.[38]

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).[39, 40, 41]

 

Treatment

Medical Care

Stabilize the patient.

Transfuse for anemia, and correct any coagulopathy.

Treat hypertension. Watch for and be prepared to treat thyroid storm, a rare complication.

Administer Rh immune globulin to nonsensitized RhD-negative women because of the possibility of a partial mole with fetal erythrocytes that express the RhD antigen. (RhD is not expressed in human trophoblast cells.)[42]

Consultation

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 and activity

No special diet is required, and 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.[43]

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.

 

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.[27]

Long-Term Monitoring

Serial quantitative serum beta-hCG levels should be determined. Note the following:

  • Serum hCG levels are obtained weekly until the levels are within reference range for 3-4 weeks.

  • 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.[44]

  • Once levels have reached the reference range for 3-4 weeks, check them monthly for 6 months.[45, 46, 47]

  • 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.[48]  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. Absence of hTERT expression was associated with a bening course (e.g.., nromalization of serum hCG). All cases of persistent disease expressed hTERT; however, some cases in which hTERT was expressed regressed spontaneously.[49]

 

Medication

Medication Summary

Prophylactic chemotherapy after evacuation of a hydatidiform mole is not routinely recommended.[50] 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.

A study by Zhao et al that included 171 patients with complete hydatidiform mole reported that prophylactic total hysterectomy had the lowest incidence of post-molar gestational trophoblastic neoplasia (11.4%) compared to expectant management (37.1%) and prophylactic chemotherapy (41.7%).[51]  

 

Questions & Answers

Overview

What is a hydatidiform mole?

What are the types of hydatidiform moles?

What are complete homozygous androgenetic hydatidiform moles?

What are complete heterozygous androgenetic hydatidiform mole?

What are complete biparental hydatidiform mole?

What is the pathophysiology of a partial hydatidiform mole?

What is the incidence of hydatidiform mole in the US?

What is the global incidence of hydatidiform mole?

Which patients are most likely to develop hydatidiform moles?

What is the prognosis of hydatidiform mole?

What is the prevalence of malignancy in hydatidiform mole?

What are the complications of hydatidiform mole?

What information about hydatidiform mole should patients be given?

Presentation

How are most hydatidiform moles diagnosed?

What is the most common classic symptom of a complete hydatidiform mole?

What causes hyperemesis in patients with hydatidiform mole?

What causes hyperthyroidism in patients with hydatidiform mole?

What are the signs and symptoms of a partial hydatidiform mole?

What is the clinical presentation characteristic of hydatidiform mole?

What are the risks of coexistent fetus and hydatidiform mole?

Which physical findings are characteristic of complete hydatidiform mole?

Which physical findings are characteristic of partial hydatidiform mole?

DDX

What are the differential diagnoses for Hydatidiform Mole?

Workup

What is the role of lab studies in the evaluation of suspected hydatidiform mole?

What is the role of imaging studies in the evaluation of suspected with hydatidiform mole?

Which histologic findings are characteristic of complete hydatidiform mole?

Which histologic findings are characteristic of a partial hydatidiform mole?

Treatment

How is hydatidiform mole treated?

Which specialist consultations are needed for the management of hydatidiform mole?

Which diet and activity modifications are used in the treatment of hydatidiform mole?

What is the role of surgery in the management of hydatidiform mole?

What is included in long-term monitoring of patients with hydatidiform mole?

Medications

Which medications are used in the management of hydatidiform mole?