Partial hydatidiform molar pregnancy occurs in approximately 1 in 700 conceptions, an incidence 2–3 times higher than that of complete molar pregnancy.1–3 Like women with complete mole, those with partial molar pregnancies are at risk for developing persistent gestational trophoblastic neoplasia (GTN). However, the risk of developing a persistent malignancy is 1–3%,4,5 compared to the 15–29% risk faced by women with complete molar pregnancy.6,7
Management of both partial mole and complete mole is similar: surgical evacuation is followed by weekly gonadotropin follow-up until human chorionic gonadotropin (hCG) levels become undetectable. Human chorionic gonadotropin levels are then checked monthly for 6 months before remission is declared. An increase or a persistent plateau in the hCG level during the follow-up period is an indication for chemotherapeutic treatment.8
In recent years, investigators have questioned whether 6 months of hCG follow-up is necessary before remission can be declared in the patient with a molar pregnancy whose hCG levels fall spontaneously to undetectable levels. Our group demonstrated that the risk of GTN in 1,029 women with complete molar pregnancy whose serum hCG declined spontaneously to undetectable levels approached zero.6 Other investigators have also observed that women with complete and partial molar pregnancies whose serum hCG levels reach undetectable values do not develop GTN.9–11 The recommended 6-month follow-up regimen is expensive and time consuming, and it is a source of anxiety for patients.12 It also postpones fertility, a particularly significant issue for older women who are at higher risk for molar pregnancy.
In the only previous paper that specifically investigated this issue in women with partial mole, Lavie and colleagues13 did not find any cases where GTN developed in women who spontaneously attained gonadotropin remission. However, only 40 subjects in their study had 6 months of gonadotropin follow-up, limiting the investigators' ability to draw a definitive conclusion that GTN does not occur after undetectable hCG levels are achieved.
We sought to estimate whether women with partial mole are as unlikely to develop GTN after achieving undetectable serum hCG levels as women who have complete molar pregnancies.
MATERIALS AND METHODS
We used the Donald P. Goldstein, MD, Trophoblastic Tumor Registry of the New England Trophoblastic Disease Center, a clinical unit founded in 1965 to care for patients with molar pregnancy and GTN. There were 768 women diagnosed with 772 partial molar pregnancies on the basis of pathologic evaluation between 1973, the year the hCG radioimmunoassay became commercially available, and 2003. The database also contains data on 2,120 women with complete molar pregnancy.
We analyzed data from 284 women with partial molar pregnancies and complete clinical data. Data from 326 women for whom we had incomplete clinical data were excluded. Data from 130 women, where the patient achieved undetectable hCG levels but had less than 6 months of gonadotropin follow-up, and from 11 women who had less than 6 months of hCG data and were lost to follow-up before achieving gonadotropin remission also were excluded. None of these women returned to our center with GTN. In addition, data from 17 women who did not meet current hCG criteria for GTN but were treated with chemotherapy were excluded. Four women had two partial molar pregnancies, and data from the second pregnancy was excluded from our analysis.
Gestational trophoblastic neoplasia was diagnosed in subjects whose hCG levels increased or failed to decline by more than 10% per week for at least 2 weeks. Remission was declared if a subject's hCG level became undetectable and remained that way for 6 months. However, we evaluated all available hCG data if women had more than 6 months of testing after molar evacuation. We considered women who became pregnant within 6 months of molar evacuation (n=31) to be in remission if they had a normal pregnancy without evidence of choriocarcinoma or placental site trophoblastic tumor.
To obtain a more accurate estimate of the incidence of GTN in our population of women with partial molar pregnancy, we considered a somewhat different group than the one included in our other analyses (Fig. 1). To determine the number of GTN cases, only data from 22 women who were referred to our center before the diagnosis of GTN was made were included, and data from the 24 women referred to our institution after the diagnosed of GTN was made were excluded. This was done with the recognition that our institution serves as a regional referral center for women with trophoblastic diseases, and therefore our database is enriched with subjects who developed GTN and were referred to our institution for management. To estimate the number of women with remission, 130 women who achieved gonadotropin remission but had less than 6 months of hCG follow-up were included, in addition to the 238 women with 6 months of hCG follow-up data. This was done because we believe that these women were unlikely to have developed GTN, given their spontaneous gonadotropin remission and their failure to re-present with disease subsequently. These 130 women were excluded from the remainder of the analyses because they did not meet the current definition of remission, which requires 6 months of follow-up. All other analyses included all 46 women diagnosed with GTN and the 238 women with remission and 6 months of gonadotropin follow-up data.
Data regarding age at diagnosis, gravity, and gestational age at diagnosis were missing from some subjects. The number of subjects included in these analyses are reported in Table 1.
We used χ2 or Fisher exact tests, as appropriate, for categorical data in our analysis. Most of the subjects in our database were followed using an assay with a sensitivity of 5 milli-international units/mL, although a few patients cared for before 1990 were followed with assays sensitive to 10 milli-international units/mL. This study was approved by the Human Research Committee at our institution.
The incidence of GTN in this population was 5.6% (22 of 390, 95% confidence interval [CI] 3.4–7.9%). As noted above, this estimate excludes those subjects referred to our center after being diagnosed with GTN elsewhere and includes those subjects who achieved hCG remission but had less than 6 months of gonadotropin follow-up.
The remainder of the analyses were conducted on data from pregnancies with at least 6 months of hCG follow-up data: 238 women with spontaneous hCG remission and 46 with GTN. Women with GTN were older than women with spontaneous remission (mean 30.6 years compared with 27.5 years, P<.01). There were no significant differences between women with GTN and women with spontaneous remission in terms of gestational age at diagnosis or parity (Table 1).
None of the 238 women with complete gonadotropin follow-up and a spontaneous decline in serum hCG levels to undetectable levels subsequently developed GTN (95% CI 0–1.6%), irrespective of whether the sensitivity of the hCG assay was 5 milli-international units/mL or 10 milli-international units/mL.
The median time required for serum hCG levels to become undetectable among the 238 women with remission was 46 days. By 70 days after molar evacuation, 75% of those that would achieve spontaneous gonadotropin remission had done so. By 115 days after molar evacuation, 95% of those who would achieve spontaneous gonadotropin admission had done so (Fig. 2).
The median time required to diagnose GTN among the 46 women who developed persistent disease was 66 days. All women were diagnosed with GTN by 157 days after evacuation.
These data support the conclusion that women with partial molar pregnancy whose serum hCG level spontaneously declines to undetectable levels after molar evacuation are at exceedingly low risk of developing GTN. We conclude that it is likely that hCG monitoring for these women may be substantially abbreviated without placing the patient at sizeable risk for unrecognized malignancy. These data corroborate prior reports about partial molar pregnancy,13 and are similar to our findings for women with complete molar pregnancy.6,9–11
A truncation of the follow-up period for women with partial molar pregnancies could result in a savings of human and financial resources, particularly in countries where intensive gonadotropin follow-up is unavailable. If follow-up of the nonpersistent partial molar pregnancy were limited to two consecutive undetectable serum hCG levels measured 1 week apart, these data suggest that follow-up could be reduced to 8 weeks for 57% of women with nonpersistent disease and to 13 weeks for 86% of women with nonpersistent disease. Overall, follow-up would be shortened to at least some degree for essentially all women with nonpersistent partial molar pregnancies.
These findings are particularly meaningful for women who are attempting to become pregnant after age 35, for whom the risk of partial molar pregnancy is double that faced by younger women.14,15 These women face a time-limited window of fertility because of their age and consequently would benefit if the duration of hCG follow-up could be safely abbreviated.
The incidence of GTN reported here (5.6%) is slightly high compared with the 2–4% incidence reported elsewhere.4,5 We attempted to control for referral bias by excluding women who were referred to our center after they were diagnosed with GTN. It is possible that some women who were referred to our center before the diagnosis of GTN, in fact, were referred by their gynecologists because of concerning clinical findings. If this occurred, then the estimate of the incidence of GTN could still be elevated due to referral bias. However, we do not believe that the higher incidence of GTN in our study population would be responsible for our findings, which evaluate the hCG pattern among women who did not develop GTN.
One issue with our study arises because of the long period over which cases were accrued and the potential changes in diagnostic criteria over time. However, because none of our subjects who achieved gonadotropin remission after evacuation subsequently developed GTN, the possibility that some of our subjects originally classified as having a partial mole might have actually had another diagnosis does not affect the central finding of this paper.
We conclude that women diagnosed with complete or partial molar pregnancy whose serum hCG levels spontaneously decline to undetectable values may not be at appreciable risk for GTN. If these data are replicated by other centers that have extensive experience caring for women with molar pregnancies, it may be reasonable to shorten follow-up for the patient with either complete or partial molar pregnancy who spontaneously achieves undetectable serum hCG levels.
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