The classic histological findings of molar pregnancy include villous stromal edema and trophoblast proliferation (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 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. (Image contributed by 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. (Image contributed by 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. Although both forms of moles usually fill the uterine cavity, they rarely may be tubal or other forms of ectopic pregnancy (Sebire, 2005).
Epidemiology and Risk Factors
There is an ethnic predisposition to 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 (Lee, 2011; Lybol, 2011; Salehi, 2011).
The strongest risk factors are age and a history of 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). For those with a prior complete mole, the risk of another mole is 1.5 percent. With a previous partial mole, the rate is 2.7 percent (Garrett, 2008). After two prior molar pregnancies, Berkowitz and associates (1998) reported that 23 percent of women had a third mole.
With rare exceptions, molar pregnancies arise from chromosomally abnormal fertilizations. 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. As shown in Figure 20-2A, an ovum is fertilized by a haploid sperm, which then duplicates its own chromosomes after meiosis. The chromosomes of the ovum are either absent or inactivated. 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 |
|Karyotypea ||69,XXX or 69,XXY ||46,XX |
|Clinical Presentation || || |
|Diagnosis ||Missed abortion ||Molar gestation |
|Uterine size ||Small for dates ||Large for dates |
|Theca-lutein cysts ||Rare ||25–30% of cases |
|Initial hCG levels ||< 100,000 mIU/mL ||> 100,000 mIU/mL |
|Medical complicationsb ||Rare ||Uncommon |
|Rate of subsequent GTN ||1–5% of cases ||15–20% of cases |
|Pathology || || |
|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 ||Mild ||Marked |
|p57KIP2 immunostaining ||Positive ||Negative |
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 (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. Fetuses that reach advanced ages have severe growth restriction, multiple congenital anomalies, or both.
Twin Pregnancy Comprised of a Normal Fetus and Coexistent Complete Mole
Rarely, in some twin pregnancies, one chromosomally normal fetus is paired with a complete diploid molar pregnancy. These are recognized in only 1 in 22,000 to 100,000 pregnancies (Steller, 1994). It is important that these cases be distinguished from a single partial molar pregnancy with its abnormal associated fetus. Amniocentesis done for fetal karyotyping is used to confirm the diagnosis.
There are a number of unique pregnancy complications with this twin pregnancy. And, many women may choose to terminate the pregnancy, if diagnosed early. In those with continuing pregnancy, survival of the normal fetus is variable and dependent on complications that commonly develop 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 possible risk for developing subsequent GTN. Sebire and colleagues (2002b) reviewed such twin pregnancies and reported that in those not terminated, 21 percent of mothers subsequently required chemotherapy. But, this was not significantly different from a rate of 16 percent among women who chose termination. Others have reported rates up to 50 percent following continuation (Massardier, 2009). At this time, most data indicate that women with these twin pregnancies are not at greater risk for subsequent neoplasia than those with a singleton complete mole (Niemann, 2007b). Postdelivery surveillance is conducted as for any molar pregnancy and is discussed on Gestational Trophoblastic Neoplasia.
The clinical 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. As a result, most molar pregnancies are detected when they are small and before complications ensue (Kerkmeijer, 2009; Mangili, 2008).
Typically, there are usually 1 to 2 months of amenorrhea before discovery. In 41 women with a complete mole diagnosed at a mean of 10 weeks, Gemer and colleagues (2000) reported that 41 percent were asymptomatic and 58 percent had vaginal bleeding. Moreover, only 2 percent had anemia or hyperemesis, and none had other manifestations that in the past were common in these women.
As gestation advances, symptoms generally tend to be more pronounced with complete compared with partial moles (Niemann, 2007a). 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. Many women have uterine growth that is more rapid than expected. The enlarged uterus has a soft consistency, but typically no fetal heart motion is detected. Nausea and vomiting may become significant. The ovaries contain multiple theca-lutein cysts in 25 to 60 percent of women with a complete mole (Fig. 20-3). These likely result from overstimulation of lutein elements by sometimes massive amounts of hCG. 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 there is extensive infarction that 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, a case of presumed “thyroid storm” has been reported (Moskovitz, 2010).
Severe preeclampsia and eclampsia are relatively common with large molar pregnancies. However, these are seldom seen today because of early diagnosis and evacuation. An exception is in the case of a normal fetus coexisting with a complete mole, described earlier. In those cases in which pregnancy is not terminated, severe preeclampsia frequently mandates preterm delivery. The predilection for preeclampsia is explained by the hypoxic trophoblastic mass, which releases antiangiogenic factors that activate endothelial damage (Chap. 40, Immunological Factors).
Most women initially have amenorrhea that is followed by 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 because of oversaturation of the test assay by excessive β-hCG hormone (Chap. 9, Breast and Skin Changes). 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 sonographic imaging 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” (Figure 20-4). A partial mole has features that include a thickened, multicystic placenta along with a fetus or at least fetal tissue. In early pregnancy, however, these sonographic characteristics are seen in fewer than half of hydatidiform moles (Fowler, 2006). The most common misdiagnosis is 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 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. (Image contributed by Dr. Elysia Moschos.)
Surveillance for subsequent neoplasia following molar pregnancy is crucial. Thus, moles must be histologically 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 (Paradinas, 1996). In such situations, other techniques are used to differentiate. One takes advantage of the differing ploidy to distinguish partial (triploid) moles from diploid entities. Complete moles and nonmolar pregnancies with hydropic placental degeneration are both diploid.
Another technique involves histological immunostaining to identify the p57KIP2 nuclear protein. Because the gene that expresses p57KIP2 is paternally imprinted, only maternally donated genes are expressed. Because complete moles contain only paternal genetic material, they cannot express this gene; do not produce p57KIP2; and thus, do not pick up this immunostain. In contrast, this nuclear protein is strongly expressed in partial moles and in nonmolar pregnancies with hydropic change (Castrillon, 2001). As a result, the combined use of ploidy analysis and p57KIP2 immunostaining can be used to differentiate: (1) a complete mole (diploid/p57KIP2-negative), (2) a partial mole (triploid/p57KIP2-positive), and spontaneous abortion with hydropic placental degeneration (diploid/p57KIP2-positive) (Merchant, 2005).
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 x-ray, whereas computed tomography (CT) and magnetic resonance (MR) imaging are not routinely done unless the chest radiograph shows lung lesions or unless there is evidence of other extrauterine disease such as in the brain or liver.
TABLE 20-2Some Considerations for Management of Hydatidiform Mole ||Download (.pdf) TABLE 20-2 Some Considerations for Management of Hydatidiform Mole
Large-bore intravenous catheter(s)
Regional or general anesthesia
Oxytocin (Pitocin): 20 units in 1000 mL RL 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 12
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
Termination of Molar Pregnancy
Regardless of uterine size, molar evacuation by suction curettage is usually the preferred treatment. Preoperative cervical dilatation with an osmotic agent 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 allow insertion of a 10- to 14-mm suction curette. As evacuation is begun, oxytocin is infused to limit bleeding. Intraoperative sonography is recommended to help ensure that the uterine cavity has been emptied. When the myometrium has contracted, 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 shown in Table 20-2 are given. In some 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 (Red Cell Substitutes).
It is invariable that some degree of trophoblastic deportation into the pelvic venous system takes place during molar evacuation (Hankins, 1987). With large molar pregnancies, the volume of tissue may be sufficient to produce clinically apparent respiratory insufficiency, pulmonary edema, or even embolism. In our earlier experiences with very large moles, these and their chest x-ray 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, there is no evidence 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 Rh D Alloimmunization). Those with suspected complete mole are similarly treated because a definitive diagnosis of complete versus partial mole may not be confirmed until pathological evaluation of the evacuated products.
Following evacuation, the long-term prognosis for women with a hydatidiform mole is not improved with prophylactic chemotherapy (Goldstein, 1995). Moreover, chemotherapy toxicity—including death—may be significant, and thus it is not recommended routinely by the American College of Obstetricians and Gynecologists (2012).
Methods other than suction curettage may be considered for select cases. Hysterectomy with ovarian preservation may be preferable for women who have completed childbearing. Of women aged 40 and older, approximately a third will subsequently develop GTN, and hysterectomy markedly reduces this likelihood (Hanna, 2010). Theca-lutein cysts seen at the time of hysterectomy do not require removal, and they spontaneously regress following molar termination. Some recommend aspiration of larger cysts to minimize pain and torsion risk. In contrast, 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, 2012).
Close biochemical surveillance for persistent gestational neoplasia should follow hydatidiform mole evacuation. Concurrently, reliable contraception is imperative to avoid confusion caused by rising β-hCG levels from a new pregnancy. Most recommend either combination hormonal contraception or injectable medroxyprogesterone acetate. The latter is particularly useful if there is poor compliance. Intrauterine devices are not used until β-hCG levels are undetectable because of the risk of uterine perforation if there is an invasive mole. Finally, barrier and other methods are not recommended because of their relatively high failure rates.
Biochemical surveillance is by serial measurements of serum β-hCG to detect persistent or renewed trophoblastic proliferation. 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. After this, surveillance is discontinued and pregnancy allowed. Because such intensive monitoring has a high noncompliance rate, a truncated approach has been studied, and it may be unnecessary to verify undetectable β-hCG levels for 6 months. Specifically, it was shown that no woman with a partial or complete mole whose serum β-hCG level became undetectable subsequently developed neoplasia (Lavie, 2005; Wolfberg, 2004). Importantly, during the time during which β-hCG levels are monitored, 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.
There are a number of risk factors for developing 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). Other risk factors are older 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). Although not routine, postevacuation uterine sonographic surveillance showing myometrial nodules or hypervascularity may be a predictor of subsequent neoplasia (Garavaglia, 2009).