- Author: Lisa E Moore, MD, FACOG; Chief Editor: Warner K Huh, MD more...
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. 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. They also noted that the mole was biparental, and there was a specific maternal loss of DNA methylation of differentially methylated regions (DMRs).
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).
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
These account for 80% of complete moles, with two identical paternal chromosome complements, derived from duplication of the paternal haploid chromosomes. Affected individuals are always female; 46,YY has never been observed.
These account for 20% of complete moles. Affected individuals may be male or female. 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.
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]
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. 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.
United States statistics
By studying elective pregnancy terminations, hydatidiform moles were determined to occur in approximately 1 in 1200 pregnancies.
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. 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.
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, comparison of frequency of hydatidiform moles in African Americans and Caucasians have yielded conflicting results. If differences exist, whether they are due to genetic differences or environmental factors is not clear.
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, 16, 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.
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. 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.
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%.
In contrast to the results of Vargas’ study, 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%.
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.[21, 22] Lung metastases are found in 4-5% of patients with a complete hydatidiform mole and rarely in cases of partial hydatidiform moles.[23, 24]
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. 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.
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.
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