The classic histological findings of molar pregnancy include trophoblast proliferation and villi with stromal edema (Fig. 20-1). The degree of histological changes, karyotypic differences, and the absence or presence of embryonic elements are used to classify them as either complete or partial moles. These two also vary in their associated risks for developing medical comorbidities and postevacuation GTN. Of the two, GTN more frequently follows complete hydatidiform mole.
Complete hydatidiform mole. A. Gross specimen with characteristic vesicles of variable size. (Used with permission from Dr. Brian Levenson.) B. Low-magnification photomicrograph shows generalized edema and cistern formation (black asterisks) within avascular villi. Haphazard trophoblastic hyperplasia is marked by a yellow asterisk on the right. (Used with permission from Dr. Erika Fong.)
A complete mole has abnormal chorionic villi that grossly appear as a mass of clear vesicles. These vary in size and often hang in clusters from thin pedicles. In contrast, a partial molar pregnancy has focal and less advanced hydatidiform changes and contains some fetal tissue. Both forms of moles usually fill the uterine cavity, but they rarely may be tubal or other forms of ectopic pregnancy (Hassadia, 2012; Sebire, 2005).
Epidemiology and Risk Factors
An ethnic predisposition is seen with hydatidiform mole, which has increased prevalence in Asians, Hispanics, and American Indians (Drake, 2006; Lee, 2011; Smith, 2006). The incidence in the United States and Europe has been relatively constant at 1 to 2 per 1000 deliveries (Eysbouts, 2016; Lee, 2011).
The strongest risk factors are age and a prior hydatidiform mole. Women at both extremes of reproductive age are most vulnerable. Specifically, adolescents and women aged 36 to 40 years have a twofold risk, but those older than 40 have an almost tenfold risk (Altman, 2008; Sebire, 2002a). With a prior complete mole, the risk of another mole is 0.9 percent, and with a previous partial mole, the rate is 0.3 percent. After two prior complete moles, approximately 20 percent of women have a third mole (Eagles, 2015).
Molar pregnancies typically arise from chromosomally abnormal fertilizations Figure 20-2. Complete moles most often have a diploid chromosomal composition (Table 20-1). These usually are 46,XX and result from androgenesis, meaning both sets of chromosomes are paternal in origin. The chromosomes of the ovum are either absent or inactivated. The ovum is fertilized by a haploid sperm, which then duplicates its own chromosomes after meiosis. Less commonly, the chromosomal pattern may be 46,XY or 46,XX and due to fertilization by two sperm, that is, dispermic fertilization or dispermy (Lawler, 1991; Lipata, 2010).
TABLE 20-1Features of Partial and Complete Hydatidiform Moles ||Download (.pdf) TABLE 20-1 Features of Partial and Complete Hydatidiform Moles
|Feature ||Partial Mole ||Complete Mole |
Initial hCG levels
Rate of subsequent GTN
|69,XXX or 69,XXY |
Small for dates
1–5% of cases
Large for dates
25–30% of cases
15–20% of cases
| Embryo-fetus ||Often present ||Absent |
| Amnion, fetal erythrocytes ||Often present ||Absent |
| Villous edema ||Focal ||Widespread |
| Trophoblastic proliferation ||Focal, slight to moderate ||Slight to severe |
| Trophoblast atypia |
Typical pathogenesis of complete and partial moles. A. A 46,XX complete mole may be formed if a 23,X-bearing haploid sperm penetrates a 23,X-containing haploid egg whose genes have been “inactivated.” Paternal chromosomes then duplicate to create a 46,XX diploid complement solely of paternal origin. B. A partial mole may be formed if two sperm—either 23,X- or 23,Y-bearing—both fertilize (dispermy) a 23,X-containing haploid egg whose genes have not been inactivated. The resulting fertilized egg is triploid with two chromosome sets being donated by the father. This paternal contribution is termed diandry..
Partial moles usually have a triploid karyotype—69,XXX, 69,XXY—or much less commonly, 69,XYY. These are each composed of two paternal haploid sets of chromosomes contributed by dispermy and one maternal haploid set (see Fig. 20-2B). Less frequently, a similar haploid egg may be fertilized by an unreduced diploid 46,XY sperm. These triploid zygotes result in some embryonic development, however, it ultimately is a lethal fetal condition (Joergensen, 2014; Lakovschek, 2011). Fetuses that reach advanced ages have severe growth restriction, multiple congenital anomalies, or both.
Rarely, in some twin pregnancies, one chromosomally normal fetus is paired with a complete diploid molar pregnancy. Importantly, these cases must be distinguished from a single partial molar pregnancy with its associated abnormal fetus. Amniocentesis and fetal karyotyping aid confirmation.
Several unique pregnancy problems complicate such twin pregnancies. And, many women may choose to terminate the gestation, if diagnosed early. In those with continuing pregnancy, survival of the normal fetus varies and depends on associated comorbidity from the molar component. The most worrisome are preeclampsia or hemorrhage, which frequently necessitate preterm delivery. Wee and Jauniaux (2005) reviewed outcomes in 174 women, of whom 82 chose termination. Of the remaining 92 pregnancies, 42 percent either miscarried or had a perinatal death; approximately 60 percent delivered preterm; and only 40 percent delivered at term.
Another concern for those continuing their pregnancy is the risk for developing subsequent GTN. However, most data indicate no significant difference between women who continue or terminate their pregnancy (Massardier, 2009; Sebire, 2002b). Postdelivery surveillance is conducted as for any molar pregnancy (Gestational Trophoblastic Neoplasia).
The presentation of women with a molar pregnancy has changed remarkably over the past several decades because prenatal care is sought much earlier and because sonography is virtually universal. Typically, 1 to 2 months of amenorrhea precede the diagnosis. For example, in 194 women with a complete mole, evacuation was completed at a median gestational age of 9 weeks and at 12 weeks for 172 patients with a partial mole (Sun, 2015b). As a result, most molar pregnancies are detected before complications ensue (Kerkmeijer, 2009; Mangili, 2008).
As gestation advances, symptoms tend to be more pronounced with complete compared with partial moles (Niemann, 2007). Untreated molar pregnancies will almost always cause uterine bleeding that varies from spotting to profuse hemorrhage. Bleeding may presage spontaneous molar abortion, but more often, it follows an intermittent course for weeks to months. In more advanced moles with considerable concealed uterine hemorrhage, moderate iron-deficiency anemia develops. Nausea and vomiting may be significant. Of physical findings, many women have uterine growth that is more rapid than expected, and the enlarged uterus is comparatively softer. Fetal heart motion is absent with complete moles. The ovaries can be fuller and cystic from multiple theca-lutein cysts (Fig. 20-3). These are more common with a complete mole and likely result from ovarian overstimulation by excessive hCG levels. Because theca-lutein cysts regress following pregnancy evacuation, expectant management is preferred. Occasionally a larger cyst may undergo torsion, infarction, and hemorrhage. However, oophorectomy is not performed unless extensive infarction persists after untwisting.
Sonographic image of an ovary with theca-lutein cysts in a woman with a hydatidiform mole.
The thyrotropin-like effects of hCG frequently cause serum free thyroxine (fT4) levels to be elevated and thyroid-stimulating hormone (TSH) levels to be decreased. Despite this, clinically apparent thyrotoxicosis is unusual and in our experience can be mimicked by bleeding and sepsis from infected products. Moreover, the serum free T4 levels rapidly normalize after uterine evacuation. Despite this, cases of presumed “thyroid storm” have been reported (Kofinas, 2015).
Severe preeclampsia and eclampsia are relatively common with advanced molar pregnancies. However, these are seldom seen today because of early diagnosis and evacuation. An exception is the case of a normal fetus coexisting with a complete mole, described earlier. In continuing twin gestations, severe preeclampsia frequently mandates preterm delivery.
Most women initially have irregular bleeding that almost always prompts pregnancy testing and sonography. Some women will present with spontaneous passage of molar tissue.
With a complete molar pregnancy, serum β-hCG levels are commonly elevated above those expected for gestational age. With more advanced moles, values in the millions are not unusual. Importantly, these high values can lead to erroneous false-negative urine pregnancy test results. Termed a “hook effect,” excessive β-hCG hormone levels oversaturate the assay’s targeting antibody and create a falsely low reading (Cormano, 2016). In these cases, serum β-hCG determinations with or without sample dilution will clarify the conundrum. With a partial mole, β-hCG levels may also be significantly elevated, but more commonly concentrations fall into ranges expected for gestational age.
Although this is the mainstay of trophoblastic disease diagnosis, not all cases are confirmed initially. Sonographically, a complete mole appears as an echogenic uterine mass with numerous anechoic cystic spaces but without a fetus or amnionic sac. The appearance is often described as a “snowstorm” (Fig. 20-4). A partial mole has features that include a thickened, multicystic placenta along with a fetus or at least fetal tissue. However, in early pregnancy, these sonographic characteristics are seen in fewer than half of hydatidiform moles. In the largest series of more than 1000 patients with molar pregnancy, the reported sensitivity and specificity of sonography were 44 and 74 percent, respectively (Fowler, 2006). The most common mimics are incomplete or missed abortion. Occasionally, molar pregnancy may be confused for a multifetal pregnancy or a uterine leiomyoma with cystic degeneration.
Sonograms of hydatidiform moles. A. Sagittal view of a uterus with a complete hydatidiform mole. The characteristic “snowstorm” appearance is due to an echogenic uterine mass, marked by calipers, that has numerous anechoic cystic spaces. Notably, a fetus and amnionic sac are absent. B. In this image of a partial hydatidiform mole, the fetus is seen above a multicystic placenta. (Used with permission from Dr. Elysia Moschos.)
Surveillance for subsequent neoplasia following molar pregnancy is crucial. Thus, moles must be distinguished from other types of pregnancy failure that have hydropic placental degeneration, which can mimic molar villous changes. Some distinguishing histological characteristics are shown in Table 20-1.
In pregnancies before 10 weeks, classic molar changes may not be apparent because villi may not be enlarged and molar stroma may not yet be edematous and avascular. Histopathologic evaluation can be enhanced by immunohistochemical staining for p57 expression and by molecular genotyping (Banet, 2014). p57KIP2 is a nuclear protein whose gene is paternally imprinted and maternally expressed. This means that the gene product is produced only in tissues containing a maternal allele. Because complete moles contain only paternal genes, the p57KIP2 protein is absent in complete moles, and tissues do not pick up this stain (Merchant, 2005). In contrast, this nuclear protein is strongly expressed in normal placentas, in spontaneous pregnancy losses with hydropic degeneration, and in partial hydatidiform moles (Castrillon, 2001). Accordingly, immunostaining for p57KIP2 is an effective means to isolate complete mole from the diagnostic list. For distinction of a partial mole from a nonmolar hydropic abortus, both of which express p57, molecular genotyping can be used. Molecular genotyping determines the parental source of alleles. Thereby, it can distinguish among a diploid diandric genome (complete mole), a triploid diandric-monogynic genome (partial mole), or biparental diploidy (nonmolar abortus).
Maternal deaths from molar pregnancies are rare because of early diagnosis, timely evacuation, and vigilant postevacuation surveillance for GTN. Preoperative evaluation attempts to identify known potential complications such as preeclampsia, hyperthyroidism, anemia, electrolyte depletions from hyperemesis, and metastatic disease (Table 20-2) (Lurain, 2010). Most recommend chest radiography, whereas computed tomography (CT) and magnetic resonance (MR) imaging are not routinely done unless a chest radiograph shows lung lesions or unless other extrauterine disease is suspected.
TABLE 20-2Some Considerations for Management of Hydatidiform Mole ||Download (.pdf) TABLE 20-2 Some Considerations for Management of Hydatidiform Mole
| Hemogram; serum β-hCG, creatinine, electrolyte, and hepatic aminotransferase levels |
| TSH, free T4 levels |
| Type and Rh; group and screen or crossmatch |
|Chest radiograph |
|Consider hygroscopic dilators |
|Large-bore intravenous catheter(s) |
|Regional or general anesthesia |
|Oxytocin (Pitocin): 20 units in 1000 mL Ringer lactate for continuous infusion |
|One or more other uterotonic agents may be added as needed: |
| Methylergonovine (Methergine): 0.2 mg = 1 mL = 1 ampule IM every 2 hr prn |
| Carboprost tromethamine (PGF2α) (Hemabate): 250 μg = 1 mL = 1 ampule IM every 15–90 min prn |
| Misoprostol (PGE1) (Cytotec): 200 mg tablets for rectal administration, 800–1000 mg once |
|Karman cannula—size 10 or 14 mm |
|Consider sonography machine |
|Anti-D immune globulin (Rhogam) if Rh D-negative |
|Initiate effective contraceptiona |
|Review pathology report |
|Serum hCG levels: within 48 hours of evacuation, weekly until undetectable, then monthly for 6 months |
Molar Pregnancy Termination
Regardless of uterine size, molar evacuation by suction curettage is usually the preferred treatment. Preoperative cervical dilatation with an osmotic dilator is recommended if the cervix is minimally dilated. Intraoperative bleeding can be greater with molar pregnancy than with a comparably sized uterus containing nonmolar products. Thus with large moles, adequate anesthesia, sufficient intravenous access, and blood-banking support is imperative. The cervix is mechanically dilated to preferably allow insertion of a larger suction curette. Depending on uterine size, a 10- to 14-mm diameter is typical. As evacuation is begun, oxytocin is infused to limit bleeding. Intraoperative sonography is often recommended to help ensure complete uterine cavity emptying. When the myometrium has contracted, a thorough but gentle curettage with a sharp large-loop Sims curette is performed. If bleeding continues despite uterine evacuation and oxytocin infusion, other uterotonic agents are given (see Table 20-2). In rare cases, pelvic arterial embolization or hysterectomy may be necessary (Tse, 2007). Profuse hemorrhage and surgical methods that may be useful for its management are discussed in Chapter 41 (General Considerations).
Some volume of trophoblast is deported into the pelvic venous system during molar evacuation (Hankins, 1987). With large moles, the amount of tissue may be sufficient to produce clinically apparent respiratory insufficiency, pulmonary edema, or even embolism. In our earlier experiences with substantial moles, these and their chest radiographic manifestations clear rapidly without specific treatment. However, fatalities have been described (Delmis, 2000). Because of deportation, there is concern that trophoblastic tissue will thrive within the lung parenchyma to cause persistent disease or even overt malignancy. Fortunately, no evidence suggests that this is a major problem.
Following curettage, anti-D immunoglobulin (Rhogam) is given to Rh D-negative women because fetal tissues with a partial mole may include red cells with D-antigen (Chap. 15, Prevention of Anti-D Alloimmunization). Those with suspected complete mole are similarly treated because a definitive diagnosis of complete versus partial mole may not be confirmed until histological evaluation of the evacuated products.
Following evacuation, the long-term prognosis for women with a hydatidiform mole is not improved with prophylactic chemotherapy. Moreover, chemotherapy toxicity—including death—may be significant, and thus it is not recommended routinely (Gueye, 2014; Wang, 2017).
Methods other than suction curettage can be considered for select cases. Hysterectomy with ovarian preservation may be preferable for women with complete moles who have finished childbearing. Of women aged 40 to 49 years, 30 to 50 percent will subsequently develop GTN, and hysterectomy markedly reduces this likelihood (Bandy, 1984; Elias, 2010, 2012). Theca-lutein cysts seen at the time of hysterectomy do not require removal, and they spontaneously regress following molar termination. Labor induction or hysterotomy is seldom used for molar evacuation in the United States. Both will likely increase blood loss and theoretically may increase the incidence of persistent trophoblastic disease (American College of Obstetricians and Gynecologists, 2016; Tidy, 2000).
Close biochemical surveillance for persistent gestational neoplasia follows each hydatidiform mole evacuation. This monitoring is by serial measurement of serum β-hCG to detect persistent or renewed trophoblastic proliferation. As a glycoprotein, hCG shows structural heterogeneity and exists in different isoforms. Thus for surveillance, an hCG assay that can detect all forms of hCG should be used (Harvey, 2010; Ngan, 2015). These are different from those used for routine pregnancy testing (de Medeiros, 2009). The initial β-hCG level is obtained within 48 hours after evacuation. This serves as the baseline, which is compared with β-hCG quantification done thereafter every 1 to 2 weeks until levels progressively decline to become undetectable.
The median time for such resolution is 7 weeks for partial moles and 9 weeks for complete moles. Once β-hCG is undetectable, this is confirmed with monthly determinations for another 6 months (Lurain, 2010; Sebire, 2007). Concurrently, reliable contraception is imperative to avoid confusion caused by rising β-hCG levels from a new pregnancy. Most recommend combination hormonal contraception, injectable depot medroxyprogesterone acetate, or progestin implant (Dantas, 2017). The latter two are particularly useful if poor patient compliance is anticipated. Intrauterine devices are not used until β-hCG levels are undetectable because of the risk of uterine perforation if there is an invasive mole. Although not recommended, if a woman conceives during surveillance, live-birth rates and risk for congenital anomalies appear to mirror the general population (Tuncer, 1999a,b). After these 6 months, monitoring is discontinued and pregnancy allowed.
Importantly, during β-hCG level surveillance, either increasing or persistently plateaued levels mandate evaluation for trophoblastic neoplasia. If the woman has not become pregnant, then these levels signify increasing trophoblastic proliferation that is most likely malignant. Several factors predispose a patient to trophoblastic neoplasia following molar evacuation. Most important, complete moles have a 15 to 20 percent incidence of malignant sequelae, compared with 1 to 5 percent following partial moles. Surprisingly, with much earlier recognition and evacuation of molar pregnancies, the risk for neoplasia has not been lowered (Schorge, 2000; Sun, 2015a). Other risk factors are older maternal age, β-hCG levels >100,000 mIU/mL, uterine size that is large for gestational age, theca-lutein cysts >6 cm, and slow decline in β-hCG levels (Berkowitz, 2009; Kang, 2012; Wolfberg, 2005).