Version May 2024
INTRODUCTION — Hydatidiform mole (HM) is one of a group of diseases that develop from abnormal proliferation of trophoblasts and are classified as gestational trophoblastic disease (GTD). The two distinct types of HM, complete mole and partial mole, have different karyotypes, gross and microscopic histopathology, clinical presentations, and prognoses [1-3]. Management is similar but with some differences.
Treatment involves surgical removal of the molar pregnancy followed by surveillance of serial human chorionic gonadotropin (hCG) levels to confirm resolution of disease or to identify development of gestational trophoblastic neoplasia (GTN), which includes invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. Although GTN is the invasive or metastatic form of GTD, it has an excellent cure rate with chemotherapy [1-4].
The treatment and follow-up of HM will be discussed here. The clinical findings, pathology, and diagnostic evaluation of HM and issues related to GTN are reviewed separately:
●(See "Hydatidiform mole: Epidemiology, clinical features, and diagnosis".)
●(See "Gestational trophoblastic disease: Pathology".)
●(See "Initial management of low-risk gestational trophoblastic neoplasia".)
●(See "Initial management of high-risk gestational trophoblastic neoplasia".)
●(See "Management of resistant or recurrent gestational trophoblastic neoplasia".)
CHOICE OF PROCEDURE FOR REMOVAL OF MOLAR TISSUE — Surgical removal of the HM is the central component of treatment and can be accomplished by either uterine evacuation or hysterectomy. We suggest surgical uterine evacuation for most patients because it is effective, preserves childbearing capacity, and is less morbid.
Hysterectomy is a reasonable alternative for patients who have completed childbearing, particularly those with a known or presumptive complete mole and the following risk factors for gestational trophoblastic neoplasia (GTN) (see 'Frequency of gestational trophoblastic neoplasia after molar pregnancy' below):
●Signs of excessive trophoblastic proliferation (eg, uterine size greater than gestational age, serum human chorionic gonadotropin [hCG] levels >100,000 milli-international units/mL, ovarian theca lutein cysts >6 cm in diameter).
●Evidence of myometrial invasion on diagnostic imaging studies [5]. (See "Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification", section on 'Imaging studies'.)
●Age >40 years [6,7].
Hysterectomy eliminates any locally invasive disease at the time of initial treatment of HM and reduces the chance of developing GTN, but does not prevent all cases of metastatic disease because some patients have occult metastases before the procedure [8]. In a meta-analysis including six retrospective studies (291 patients) evaluating the incidence of postmolar GTN in patients >40 years, patients undergoing total hysterectomy compared with uterine evacuation had lower rates of postmolar GTN (odds ratio [OR] 0.19, 95% CI 0.08-0.48) [9].
Medication-only methods of uterine evacuation (misoprostol, mifepristone, oxytocin) should not be used, although data are limited. The only study that evaluated this approach reported that 20 of 77 cases (26 percent) subsequently required surgical evacuation (suction or sharp curettage) for persisting symptoms, persistently raised hCG levels, or a combination of symptoms and raised hCG [10]. In addition, medical evacuation was associated with a higher rate of subsequent need for chemotherapy than was surgical evacuation (9.1 versus 3.8 to 5.9 percent).
PATIENT PREPARATION
●RhD-negative patients – Patients who are RhD-negative should receive anti-D immune globulin at the time of treatment. A complete mole does not contain fetal red cells, but prophylaxis after evacuation is suggested because fetal red cells are present in partial molar pregnancies. In addition, sometimes it is initially difficult to determine whether the patient had a molar pregnancy, a missed abortion, or a partial mole with fetal absorption. (See "RhD alloimmunization: Prevention in pregnant and postpartum patients".)
●Hyperthyroidism and preeclampsia – Hyperthyroidism and preeclampsia may occur in patients with HM. However, as complete mole is usually detected in the first trimester, and these conditions do not usually present until the second trimester, they are infrequently seen.
•Symptomatic hyperthyroidism – Although hyperthyroidism due to gestational trophoblastic disease resolves with treatment of the HM and subsequent normalization of human chorionic gonadotropin (hCG) levels, symptomatic patients require treatment with a beta blocker prior to surgery [11]. The longer acting beta blockers (eg, atenolol) are preferred because an oral dose taken one hour before surgery will usually maintain adequate beta blockade until the patient is able to take oral medications postoperatively. We typically start with atenolol 25 to 50 mg daily and increase the dose, as needed, to maintain the pulse rate below 80 beats/minute; up to 200 mg daily may be needed for the symptomatic treatment of hyperthyroidism and control of tachycardia.
Intravenous propranolol (0.5 to 1 mg over 10 minutes followed by 1 to 2 mg over 10 minutes every few hours) can be used to control fever, hypertension, and tachycardia intraoperatively. However, patients with possible thyroid storm are at risk for acute respiratory distress syndrome and pulmonary hypertension and procedures should only be performed with a secure airway in place [12].
Beta blockers should be continued until the patient's thyroid disease is under control. (See "Nonthyroid surgery in the patient with thyroid disease", section on 'Beta blockers'.)
Some patients may require thionamides. (See "Hyperthyroidism during pregnancy: Treatment", section on 'Therapeutic options'.)
•Preeclampsia – Preeclampsia associated with HM resolves promptly after molar evacuation and usually does not require medical management, unless severe features of the disease are present. For example, severe hypertension, if present, should be treated to reduce the risk of stroke. Eclampsia is rare; the decision to administer magnesium sulfate for seizure prophylaxis should be individualized [13,14]. (See "Treatment of hypertension in pregnant and postpartum patients", section on 'Acute therapy of severe hypertension' and "Preeclampsia: Intrapartum and postpartum management and long-term prognosis", section on 'Candidates for seizure prophylaxis'.)
PROCEDURES
Uterine evacuation — Uterine evacuation consists of mechanical dilation of the cervix, followed by suction aspiration (regardless of uterine size), and then sharp curettage to help assure complete evacuation of molar tissue. Electric and manual suction evacuation are comparable in terms of their effectiveness for complete evacuation and in side effects [15,16]. The technique is the same as for pregnancy termination. Use of ultrasound guidance is recommended to ensure complete evacuation of uterine contents [17]. (See "First-trimester pregnancy termination: Uterine aspiration" and "Second-trimester pregnancy termination: Dilation and evacuation".)
We do not use osmotic dilators, but some clinicians insert them in nulliparas on the day before the procedure to facilitate dilation (see "Pregnancy termination: Cervical preparation for procedural abortion"). Medications (eg, prostaglandins) are not used for cervical ripening because their use delays the procedure, they are associated with side effects, they may increase the risk of complications, and they do not confer proven benefit [10].
At the time of anesthesia induction, an oxytocin infusion (10 units in 1 L Lactated Ringer solution at 50 drops/minute) is begun to promote myometrial contraction and thus decrease blood loss.
Mechanical dilation of the cervix is performed gradually until a cannula diameter appropriate for the uterine size can be inserted. Most clinicians choose a diameter equal to or 1 mm smaller than the number of weeks of gestation of a similarly sized normal intrauterine pregnancy.
Disruption of the HM can cause brisk bleeding. Although the uterus generally shrinks rapidly as the contents are aspirated and oxytocin is infused, which diminishes blood loss, bleeding is typically substantially more than that encountered during evacuation of a pregnancy. Transabdominal fundal massage can facilitate uterine contraction if the uterus is sufficiently above the pelvic brim (≥14 week size). However, hysterectomy or uterine artery embolization may be needed for emergency management of acute hemorrhage [18]. As the risk of bleeding increases with uterine size, blood for transfusion should be available when the uterus is larger than a first trimester gestation.
When suction evacuation is believed to be complete, gentle sharp curettage should be performed to remove any residual molar tissue [19]. Intraoperative sonography can be used to monitor the procedure and help determine when evacuation is complete.
The evacuated tissue should be inspected at the end of the procedure. Complete molar tissue usually will have markedly dilated villi that appear like grape clusters. The changes in partial mole are usually more subtle, and partial mole may only be suspected or diagnosed based upon the microscopic findings. In select cases when clinical or sonographic findings suggest the initial uterine curettage was incomplete, a second uterine curettage may be performed to remove retained molar tissue. However, second curettage may not lower the risk of developing gestational trophoblastic neoplasia (GTN). In a retrospective study including 173 patients with HM in Japan, patients undergoing routine second curettage compared with second curettage only for molar remnants had similar rates of GTN [20].
Hysterectomy — Hysterectomy can be safely performed by either an abdominal or laparoscopic approach; the choice is influenced by technical issues such as uterine size and the clinician's familiarity with the techniques [21]. Uterine artery embolization prior to hysterectomy (to reduce intraoperative blood loss) and laparoscopic hysterectomy in combination with dilation and evacuation (to reduce uterine size and avoid laparotomy) have also been described [22,23]. (See "Hysterectomy (benign indications): Selection of surgical route".)
Preoperative issues (eg, thromboprophylaxis, prophylactic antibiotics, elective oophorectomy) are similar to those before any abdominal or laparoscopic hysterectomy for benign uterine disease, except for administration of anti-D immune globulin in D-negative patients. Due to the highly vascular nature of the gravid uterus, supracervical hysterectomy may be performed to reduce blood loss and avoid ureteral injury. (See "Hysterectomy: Abdominal (open) route" and "Hysterectomy: Laparoscopic".)
If prominent ovarian theca lutein cysts are present and symptomatic (large cysts can cause troublesome pressure symptoms), they can be aspirated to reduce the volume and patient discomfort.
The ovaries may be left in situ since ovarian metastases are rarely encountered.
POSTEVACUATION COMPLICATIONS
Cardiopulmonary symptoms — In patients treated in the first trimester, postoperative cardiopulmonary symptoms are rare [24,25]. In the second trimester, approximately 2 percent of patients treated by evacuation develop cardiopulmonary symptoms, including chest pain, dyspnea, tachypnea, and tachycardia [24]. Respiratory distress after uterine evacuation is usually attributed to trophoblastic embolization. Respiratory problems can also be due to massive fluid replacement, complications of thyroid storm, or preeclampsia and can develop in patients who undergo hysterectomy.
Auscultation of the chest usually reveals diffuse rales, and the chest radiograph often demonstrates bilateral pulmonary infiltrates, which have been misinterpreted as metastases. With standard cardiopulmonary support, the infiltrates resolve in most cases over 48 to 72 hours as the human chorionic gonadotropin (hCG) level decreases since complications of complete mole (eg, hyperthyroidism, preeclampsia) are strongly associated with marked trophoblastic proliferation and high hCG values [26].
Ovarian theca lutein cysts — Theca lutein cysts usually regress slowly over two to four months following evacuation as hCG levels decline. Large cysts causing troublesome pressure symptoms can be aspirated transabdominally under ultrasound guidance.
Theca lutein cysts may cause adnexal torsion or, rarely, they rupture spontaneously. In such cases, they can be managed laparoscopically [27]. (See "Ovarian and fallopian tube torsion" and "Evaluation and management of ruptured ovarian cyst".)
USE OF PROPHYLACTIC CHEMOTHERAPY — We rarely administer prophylactic chemotherapy around the time of molar evacuation. Prophylactic chemotherapy has been evaluated as a method to reduce the risk of development of gestational trophoblastic neoplasia (GTN), but supporting data are weak, and prophylactic chemotherapy may increase drug resistance and is associated with toxicities (see 'Frequency of gestational trophoblastic neoplasia after molar pregnancy' below). We only consider it in patients who have a complete mole and all of the following:
●Treated by evacuation rather than hysterectomy.
●High risk of developing GTN (ie, they have signs of trophoblastic proliferation, uterine size greater than gestational age, serum human chorionic gonadotropin [hCG] levels >100,000 milli-international units/mL, and ovarian theca lutein cysts >6 cm in diameter, and are age >40 years).
●hCG follow-up is either unavailable or unreliable, which is a particular consideration in global areas that are resource-limited.
In a 2017 meta-analysis of patients with complete moles (three randomized trials, 613 patients), use of prophylactic chemotherapy resulted in a 63 percent reduction in GTN (relative risk [RR] 0.37, 95% CI 0.24-0.57) [28]. Two trials were of poor methodologic quality. When only the small, well-conducted trial in 59 high-risk patients was analyzed, the reduction remained statistically significant but with a wide confidence interval (RR 0.28, 95% CI 0.1-0.73). However, the overall benefit of prophylactic chemotherapy was not clear because, among patients who were subsequently diagnosed with GTN, those who had received prior prophylactic chemotherapy experienced a one-month delay in subsequent diagnosis and required an additional cycle of chemotherapy to achieve remission of GTN relative to those who had not received prophylactic chemotherapy. In a subsequent randomized trial of 76 patients with complete moles, those treated with methotrexate (100 mg as a single intramuscular injection; 34 patients) compared with standard of care had normalization of hCG five weeks earlier (9.7 versus 14.7 weeks); all patients achieved hCG normalization [29]. The authors suggested that the reduced surveillance time was an advantage in areas with limited resources.
Both methotrexate and actinomycin D have been used for chemoprophylaxis; no data are available to suggest whether one is superior to the other. At our center, we generally administer actinomycin D when prophylaxis is indicated. Chemoprophylaxis does not appear to impact future fertility potential [30,31]. Dosing and side effects are reviewed separately. (See "Initial management of low-risk gestational trophoblastic neoplasia", section on 'Methotrexate as the preferred option' and "Initial management of low-risk gestational trophoblastic neoplasia", section on 'Alternatives including dactinomycin and other agents'.)
POSTOPERATIVE MONITORING — Postoperative human chorionic gonadotropin (hCG) monitoring is performed to detect development of gestational trophoblastic neoplasia (GTN), which is indicated by an hCG level that does not return to undetectable. Persistent hCG elevation is usually due to molar tissue that invaded the myometrium (ie, invasive mole) and thus was not completely removed by aspiration and curettage, but a small proportion are due to metastatic invasive mole. Occasionally, persistent hCG elevation is due to development of choriocarcinoma and, very rarely, to development of placental site trophoblastic tumor or epithelioid trophoblastic tumor.
Poor compliance with postevacuation surveillance and treatment protocols is associated with poorer outcomes due to advanced disease. In the United States, indigent patients treated at urban, public hospitals are the group most likely to fail to comply with standard protocols for a number of reasons, including cost, transportation issues, and childcare requirements [32]. Patient education is crucial to help patients understand and comply with surveillance protocols. Internet resources can substantially contribute to a patient's understanding of gestational trophoblastic disease (GTD) and support compliance with treatment recommendations [33].
Contraception during monitoring — Patients with HM must be advised to use reliable contraception during the entire period of postoperative hCG monitoring. A new pregnancy during this time would make it difficult or impossible to interpret hCG results and would complicate management. Options include hormonal contraception (progestin-only or combined estrogen-progestin) or barrier methods [34,35]. Oral contraceptives after molar evacuation as compared with barrier methods do not increase the risk for or clinical aggressiveness of GTN when adjusted for risk factors.
For patients with confirmed intrauterine disease and persistently elevated hCG levels, the Centers for Disease Control and Prevention recommends not inserting an intrauterine device (IUD) because of theoretical risk for perforation, infection, and hemorrhage [34]. An IUD may be used in patients with confirmed GTD and undetectable or decreasing hCG levels. For patients with suspected intrauterine disease, an IUD should be used with caution, and in our practice, we suggest that other forms of contraception (eg, combined estrogen-progestin, barrier methods) be more strongly considered.
Protocol for serial hCG measurements — After surgical treatment of HM (evacuation or hysterectomy), measurements of serum hCG levels are obtained weekly in all patients until either the level remains undetectable or criteria are met for an increasing or plateaued level, as described below. Our approach is shown in the algorithm (algorithm 1). (See 'Interpretation and management of hCG levels during monitoring' below.)
The hCG assay should measure the intact hCG dimer as well as its various subunits and fragments, which are increased in GTD compared with normal pregnancy. (See "Human chorionic gonadotropin: Biochemistry and measurement in pregnancy and disease".)
Interpretation and management of hCG levels during monitoring
Decreasing and undetectable hCG levels — A decreasing hCG level is defined as a level that progressively decreases >10 percent across four values during a three-week period (eg, on days 1, 7, 14, and 21).
When the hCG level becomes undetectable, the risk of developing GTN in patients with a partial mole or complete mole is much less than 1 percent and is lower for partial mole than complete mole [36-45]. Therefore, in patients with complete mole, after one normal hCG, we obtain monthly hCG values for three additional months and then discontinue monitoring if the level remains undetectable. In patients with partial mole, after hCG normalizes, we obtain a single additional hCG measurement one month later and then discontinue monitoring if the level remains undetectable (algorithm 1).
The International Federation of Gynecology and Obstetrics (FIGO) recommends following patients with molar pregnancies with hCG levels every one to two weeks until hCG normalization and then monthly [46]. In patients with a partial mole, if a normal hCG is confirmed one month after the hCG normalized, then hCG monitoring can be discontinued; in patients with a complete mole, confirmatory normal hCG levels are needed for six months before discontinuing hCG monitoring. National Comprehensive Cancer Network (NCCN) guidelines also suggest following hCG levels every one to two weeks [47]. When three consecutive hCG levels are normal, two additional hCG assays should be obtained every three months, with discontinuation of hCG monitoring if the hCG remains normal.
These approaches are based, in part, on data from a study of molar pregnancy from Charing Cross Hospital in England that showed in patients with a complete mole (8400 patients), the risk of GTN at zero, four, and seven months from the point of hCG normalization was 1 in 406, 1 in 839, and 1 in 932, respectively [45]. For patients with a partial mole (9586 patients), the risk was 1 in 3195, 1 in 4793, and 1 in 9584, respectively. The rapidity of hCG normalization was predictive of the likelihood of resolution versus development of GTN. In patients with a complete mole, normalization within 56 days of evacuation reduced the risk of GTN to approximately 1 in 1159 versus 1 in 308 when normalization occurred after 56 days. A trend in reduction with rapid normalization was also observed in patients with a partial mole: 1 in 4002 versus 1 in 2792. In another study of patients with a complete mole, hCG levels <200 milli-international units/mL in the fourth week after evacuation or <100 milli-international units/mL in the sixth week after evacuation had a risk of persistence <9 percent, whereas an hCG level >2000 milli-international units/mL in the fourth week was associated with a 64 percent risk [36]. In a study of patients with a partial mole, an hCG level >199 milli-international units/mL in the third through eighth weeks following evacuation was associated with at least a 35 percent risk of GTN [48]. hCG regression after molar evacuation does not appear to be influenced by patient’s age, race, ethnicity, body mass index, or hormonal contraception use [49].
In a meta-analysis dominated by data from Charing Cross Hospital described above [45], the overall risk of GTN after normalization of the hCG was 0.35 percent after a complete mole and 0.03 percent after a partial mole [50]. Among GTN cases after normalization of hCG level following complete mole, 90 percent occurred when the time from evacuation to normalization was ≥56 days, and 61 percent occurred beyond FIGO's six-month surveillance period. These data support the safety of reducing the duration of hCG follow-up of molar pregnancies after hCG levels become undetectable and have prompted us to consider shortening our approach to surveillance of complete moles from three months to one monthly confirmatory hCG [51].
In some patients, the decrease in hCG level is slow, such that hCG levels remain detectable six months or more after postmolar evacuation. Although this pattern (decreasing hCG but still detectable at six months) used to be considered diagnostic of GTN, FIGO removed this criterion in 2018 due to findings in the following studies conducted in the United Kingdom and Brazil [52,53]. These patients can be managed conservatively (ie, continued hCG monitoring until levels meet criteria for undetectable, rising, or plateaued).
●In one study in which 76 of nearly 14,000 patients with an HM (complete 58 percent, partial 36 percent, unclassified 6 percent) had detectable hCG concentrations (range 5 to 887 international units/L) at 6 months after evacuation, 64 of 66 patients managed expectantly spontaneously achieved undetectable levels within 18 months of evacuation [52]. Of the remaining two patients managed expectantly, one was lost to follow-up but subsequently had a successful pregnancy and a normal hCG level, and the other had slightly raised hCG concentrations that were attributed to impaired renal clearance from end-stage kidney disease.
●In another study in which 81 of over 12,000 patients with HM had persistent but falling hCG six months after evacuation (range 6 to 1750 international units/L), 80 percent managed expectantly spontaneously achieved undetectable levels [53].
Increasing hCG levels — An increasing hCG is defined as a level that progressively increases >10 percent across three values during at least a two-week period (eg, on days 1, 7, and 14) [54,55]. Patients with this pattern meet criteria for postmolar GTN and typically require chemotherapy to achieve remission. The diagnostic evaluation, classification, staging, and treatment of postmolar GTN are discussed in detail separately. (See "Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification" and "Initial management of low-risk gestational trophoblastic neoplasia" and "Initial management of high-risk gestational trophoblastic neoplasia".)
Plateaued hCG levels — A plateaued hCG level is defined as four measurements that remain within ±10 percent over at least a three-week period (eg, days 1, 7, 14, and 21) [54,55]. Patients with this pattern meet criteria for postmolar GTN and typically require chemotherapy to achieve remission. The diagnostic evaluation, classification, staging, and treatment of postmolar GTN are discussed in detail separately. (See "Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification" and "Initial management of low-risk gestational trophoblastic neoplasia" and "Initial management of high-risk gestational trophoblastic neoplasia".)
●Low-level plateaued hCG (quiescent GTN) – On very rare occasions following molar evacuation, plateauing is due to quiescent GTN, which is defined as a low level (<200 milli-international units/mL) of hCG that persists for at least three months after evacuation of an HM in the absence of any clinical or radiologic evidence of GTN. This condition is thought to be due to the presence of a small focus of highly differentiated, noninvasive syncytiotrophoblast cells that produce small amounts of hCG and usually do not progress to invasive disease as long as cytotrophoblast or intermediate cells are absent [56].
Patients with quiescent GTN do not require therapy but do require close follow-up because 6 to 10 percent will eventually develop active GTN, requiring treatment [57-59]. They should be monitored with monthly hCG testing and advised to avoid pregnancy [56,60,61].
Because quiescent GTN is far less common than active GTN after a molar pregnancy, patients who develop a persistent plateau or elevation of hCG at low levels during HM follow-up may reasonably be diagnosed with active GTN and treated. Evidence of chemotherapy resistance (hCG level unresponsive to therapy presumably because the growth cycle of these cells is long and comparable to normal cells) combined with absence of any clinical or radiologic evidence of GTN supports the diagnosis of quiescent GTN and should prompt discontinuation of chemotherapy unless active GTN is documented by increasing hCG levels. Measurement of hyperglycosylated hCG (hCG-h) has been proposed for surveillance in patients with quiescent GTN [58,60]. Levels of hCG-h below 10 percent of total hCG would be consistent with quiescent GTN.
There are several other etiologies of a persistent low-level hCG, including pituitary gland hCG production particularly in perimenopausal patients. The differential diagnosis of persistent low hCG is discussed in detail separately. (See "Human chorionic gonadotropin: Biochemistry and measurement in pregnancy and disease".)
OUTCOME
Frequency of gestational trophoblastic neoplasia after molar pregnancy
After a complete mole — After a complete mole, approximately 15 to 20 percent of patients develop gestational trophoblastic neoplasia (GTN) [50]. Invasive disease is several-fold more common than metastatic disease [50].
As discussed above, signs of trophoblastic proliferation (uterine size greater than gestational age, serum human chorionic gonadotropin [hCG] levels >100,000 milli-international units/mL, and ovarian theca lutein cysts >6 cm in diameter) are a marker for high risk of development of GTN. In a study of 858 patients with complete HM from our center, the New England Trophoblastic Disease Center (NETDC), the presence versus absence of these signs was associated with higher rates of both uterine invasion (31 versus 3.4 percent) and metastases (8.8 versus 0.6 percent) [62].
Older age (>40 years) is another high-risk factor for development of GTN. In patients over age 40, the risk may be 30 to 60 percent [6,63,64]. In patients over age 50, risks of 53 and 56 percent have been reported [7,65]. The reason that older age is a risk factor may be because complete moles are more commonly aneuploid in older patients, and aneuploidy may be a risk factor for GTN [66,67]. In comparison, adolescents (<20 years of age) appear to have a low risk of developing GTN [68].
The combination of markedly elevated hCG levels >175,000 milli-international units/mL and older age appears to constitute an "ultra high-risk" group: 11 of 13 patients (85 percent) ages 40 to 49 years with pre-evacuation hCG levels >175,000 milli-international units/mL developed GTN in one study [6].
First-trimester versus second-trimester diagnosis does not impact the incidence of postmolar GTN [24,25].
After a partial mole — After a partial mole, 1 to 5 percent of patients develop GTN [50]. Almost all patients with GTN have invasive disease; metastatic disease is rare. In 11 studies, including 7579 patients with partial mole, only 76 (1 percent) developed persistent tumor, and only nine (0.1 percent) had metastases [1,2,69-77].
While risk factors for GTN after partial molar pregnancy are less well defined, a study of 111 patients with partial molar pregnancy suggested an approximately twofold risk of developing GTN if the partial mole was the patient's first gestational event [78].
Obstetric outcomes of subsequent pregnancies — In general, patients with either a complete or partial mole can anticipate normal future reproductive outcomes.
At the NETDC between 1965 and 2013, obstetric outcomes included the following [79]:
●In patients with a complete mole, there were 1388 subsequent pregnancies: 949 (68.4 percent) term live births, 103 (7.4 percent) premature deliveries, 7 (0.5 percent) stillbirths, 256 (18.4 percent) spontaneous abortions, and 11 (0.8 percent) ectopic pregnancies. Major and minor congenital anomalies were detected in 40 (3.8 percent) infants.
●In patients with partial mole, there were 357 subsequent pregnancies: 260 (72.8 percent) term live births, 8 (2.2 percent) premature deliveries, 1 (0.3 percent) stillbirth, 64 (17.9 percent) spontaneous abortions, and 2 (0.6 percent) ectopic pregnancies. Major and minor congenital anomalies were diagnosed in only 4 (1.5 percent) infants.
Others have reported similar results [80,81].
Frequency of repeat molar pregnancy — Patients with a prior HM are at increased risk of developing subsequent HM compared with the general population [82].
Estimates of the risk of subsequent HM are:
●After one molar pregnancy: 1 to 1.9 percent [80,81,83].
●After two molar pregnancies: 15 to 17.5 percent [79,80].
A single-institution series reported that, among 2578 patients with complete mole, the subsequent pregnancy was molar in 27 (1.9 percent), including 22 (81 percent) complete moles and 5 (19 percent) partial moles [81]. Among 2627 patients with a partial mole, the subsequent pregnancy was molar in 25 (1.7 percent), including 17 (68 percent) partial moles and 8 (32 percent) complete moles. The overall risk of molar pregnancy was 1.8 percent, which represented a 20-fold increase compared with the general population. Among 27 cases with repeat complete mole, 3 had later molar pregnancies, indicating a recurrence rate after two previous complete moles of 11 percent.
At the NETDC between 1965 and 2013, following two molar pregnancies, 25 patients had 40 subsequent pregnancies: 7 (17.5 percent) molar pregnancies (6 complete, 1 partial), 25 (62.5 percent) term live births, 1 intrauterine fetal demise (2.5 percent), 3 spontaneous abortions (7.5 percent), 3 induced abortions (7.5 percent), and 1 ectopic pregnancy (2.5 percent) [79].
Patients with repeat molar pregnancy are at an increased risk of developing GTN. One study reported a threefold increased risk of postmolar tumor in patients with a repeat molar pregnancy [84]. Among 39 patients with two molar pregnancies managed at the NETDC from 1965 to 2013, persistent tumor developed following the first mole in 4 of 20 (20 percent) complete moles and following the second mole, in 8 of 20 (40 percent) complete moles, and in 2 of 17 (11.7 percent) partial moles [79].
Rare patients with molar pregnancy have mutations primarily in the NLRP7 gene and, in some cases, the KHDC3L or PADI6 genes. These mutations can lead to a diploid biparental rather than the usual androgenetic molar pregnancy and predispose affected patients to recurrence. (See "Gestational trophoblastic disease: Pathology", section on 'Genetics of molar pregnancy' and "Hydatidiform mole: Epidemiology, clinical features, and diagnosis", section on 'Familial recurrent molar pregnancy'.)
Patients with a prior molar pregnancy should also be counseled that in vitro fertilization by intracytoplasmic sperm injection (ICSI) does not completely prevent recurrence. In a retrospective study of over 5400 patients with HM, 31 cases (0.6 percent) occurred after ICSI (26 singleton and 5 twin gestations) [85]. Those with HM following ICSI compared with spontaneous conception were diagnosed earlier (7 versus 10 weeks) and had a lower risk of GTN (adjusted odds ratio 0.22, 95% CI 0.05–0.93). This study also supports other data that GTN is higher in heterozygous compared with homozygous HM [85-87] .
OBSTETRIC MANAGEMENT OF SUBSEQUENT PREGNANCIES — Due to the risk of recurrent HM, in our practice, we do the following in patients with a prior HM who become pregnant:
●First-trimester ultrasound to confirm normal gestational development.
●After delivery, carefully examine the placenta and send to pathology for histologic examination if any gross abnormalities are present.
●Measure serum human chorionic gonadotropin (hCG) six weeks after the completion of any type of future pregnancy (eg, term delivery, miscarriage, pregnancy termination) to exclude choriocarcinoma.
●Send all products of conception from miscarriages and pregnancy terminations for examination by a pathologist.
SPECIAL CIRCUMSTANCES
Multiple gestation — In rare situations, molar gestations can arise as a multiple gestation, either a complete or partial mole and a viable fetus. These cases are challenging but, with expectant management, can lead to delivery of a live infant; the risk of GTN in these cases is approximately 50 percent [88,89]. This is discussed in detail separately. (See "Hydatidiform mole: Epidemiology, clinical features, and diagnosis".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gestational trophoblastic disease".)
SUMMARY AND RECOMMENDATIONS
●Clinical significance – Hydatidiform mole (HM) is part of a group of diseases classified as gestational trophoblastic disease (GTD), which originate from abnormal proliferation of trophoblast. The two distinct types of HM, complete mole and partial mole, have different karyotypes, gross and microscopic histopathology, clinical presentations, and prognoses. Gestational trophoblastic neoplasia (GTN) is the subtype of GTD that is invasive or metastatic and includes invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. (See 'Introduction' above.)
●Treatment
•Choice of surgical procedure – Surgical removal of the HM is the central component of treatment and can be accomplished by either uterine evacuation or hysterectomy. For most patients, surgical uterine evacuation is preferred because it is effective, preserves childbearing capacity, and is less morbid. Hysterectomy is a reasonable alternative for patients who have completed childbearing, particularly those with risk factors for developing GTN. (See 'Choice of procedure for removal of molar tissue' above.)
•Role of prophylactic chemotherapy – Prophylactic chemotherapy may reduce the risk of development of GTN, but supporting data are weak, and prophylactic chemotherapy may increase drug resistance and is associated with toxicities. We only consider it in patients with complete moles in whom follow-up with human chorionic gonadotropin (hCG) is either unavailable or unreliable, those being treated by evacuation rather than hysterectomy, and at high risk of developing GTN (ie, they have signs of trophoblastic proliferation, uterine size greater than gestational age, serum hCG levels >100,000 milli-international units/mL, ovarian theca lutein cysts >6 cm in diameter, and are age >40 years). (See 'Use of prophylactic chemotherapy' above.)
●Postoperative monitoring
•Serial hCG measurements – Following surgical treatment of HM, hCG levels are obtained until undetectable, plateaued, or rising levels are documented, as described in the algorithm (algorithm 1). A plateaued or rising level indicates GTN, which is treated with chemotherapy. (See 'Protocol for serial hCG measurements' above and 'Interpretation and management of hCG levels during monitoring' above.)
•Contraception during monitoring – Patients with molar pregnancy should be advised to use reliable contraception during the entire interval of hCG monitoring. A new pregnancy during this period would make it difficult or impossible to interpret hCG results and would complicate management. Options include hormonal contraception (progestin-only or combined estrogen-progestin) or barrier methods. (See 'Contraception during monitoring' above.)
●Outcomes
•Frequency of GTN – After a complete mole, 15 to 20 percent of patients develop GTN; invasive disease is several-fold more common than metastatic disease. After a partial mole, 1 to 5 percent of patients develop GTN. Almost all of these patients have invasive disease; metastatic disease is rare. (See 'Frequency of gestational trophoblastic neoplasia after molar pregnancy' above.)
•Future pregnancies and recurrence – In general, patients with either a complete or partial mole can anticipate normal future reproductive outcomes. Estimates of the risk of recurrent HM are 1 to 1.9 percent after one molar pregnancy and 15 to 17.5 percent after two molar pregnancies. (See 'Obstetric outcomes of subsequent pregnancies' above and 'Frequency of repeat molar pregnancy' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Donald Peter Goldstein, MD, who contributed to an earlier version of this topic review.
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