Risk of recurrent hydatidiform mole and subsequent pregnancy outcome following complete or partial hydatidiform molar pregnancy
* Dr N. J. Sebire, Trophoblastic Disease Unit, Department of Cancer Medicine, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Charing Cross Campus, Fulham Palace Road, London W6 8RF, UK.
Objective To determine pregnancy outcome, including the rate of repeat molar pregnancy, following histologically confirmed complete or partial hydatidiform mole.
Design Retrospective review of a large supraregional database of registrations for gestational trophoblastic disease.
Setting Supraregional Trophoblastic Disease Unit, London.
Sample Women with pregnancies affected by complete or partial hydatidiform mole registered between 1992 and 1998.
Methods All patients with a diagnosis of histologically confirmed complete or partial hydatidiform mole were identified and data on subsequent pregnancies compared between groups using comparison of proportion test.
Main outcome measures Pregnancy outcome by partial or complete mole subtype, with particular regard to risk of subsequent molar pregnancy.
Results Of 2578 complete moles, the subsequent pregnancy was affected by hydatidiform mole in 27 (1.9%) cases, including 22 (81%) complete moles and 5 (19%) partial moles. Of 2627 partial moles, the subsequent pregnancy was also molar in 25 (1.7%) cases, including 17 (68%) partial moles and 8 (32%) complete moles. Overall recurrence risk for molar pregnancy was 1.8% (1 in 55), or a 20-fold increase compared with the background risk. Of 27 cases with repeat complete moles, three had further complete moles, suggesting the recurrence risk following two previous complete moles is approximately 10%. There were no other significant differences in pregnancy outcome between cases with previous complete or partial hydatidiform mole and that expected in an unselected obstetric population.
Conclusions Women having a pregnancy affected by a histologically confirmed complete or partial hydatidiform mole may be counselled that the risk of repeat mole in a subsequent pregnancy is about 1 in 60 and if this were to occur, the majority of cases will be of the same type of mole as the preceding pregnancy. However, >98% of women who become pregnant following a molar conception will not have a further hydatidiform mole and these pregnancies are at no increased risk of other obstetric complications.
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Hydatidiform moles are abnormal conceptions, which occur in about 1 in 500–1000 pregnancies1,2. Pathological and cytogenetic studies have demonstrated that molar pregnancies may be either of two distinct subtypes, complete or partial hydatidiform mole. Complete moles are usually diploid and androgenetic, demonstrating minimal embryonal development with hydropic chorionic villi and trophoblastic hyperplasia. Partial moles are usually paternally derived triploid conceptions in which embryonal development occurs in association with trophoblastic hyperplasia3,4. Several epidemiological risk factors for the development of molar pregnancy are recognised, the most important of which appear to be geographical factors and extremes of maternal age1. It is also recognised that previous hydatidiform moles increase the risk of hydatidiform moles in future pregnancies1. Many epidemiological research findings are based on data derived prior to the accurate recognition of the distinctive pathological features of complete moles and partial moles at different stages of pregnancy. Although there are some data available regarding the specific risk of subsequent hydatidiform moles after complete moles or partial moles5–7, the aim of this study was to examine a large number of cases of histologically confirmed molar pregnancies reviewed at a single referral centre, to provide data on pregnancy outcome following the previous molar pregnancy and, in particular, accurate data on the specific risk of hydatidiform moles in the subsequent pregnancy following complete moles or partial moles.
In the United Kingdom, all cases of hydatidiform moles since 1973 must be registered in a system jointly set up by the Royal College of Obstetricians and Gynecologists and the Department of Health8,9. The aims of registration are to facilitate monitoring of hCG levels following surgical evacuation, to provide optimal management of persistent trophoblastic disease and to provide information for patients and medical staff. The Trophoblastic Disease Surveillance Centre, Charing Cross Hospital, London, is the largest of the United Kingdom trophoblastic disease registration centres. Following registration, patients undergo hCG monitoring and all women are requested to notify the centre in any subsequent pregnancies for further hCG monitoring. The database therefore includes all registered cases of suspected or proven complete moles or partial moles, invasive mole, placental site tumour and choriocarcinoma. In all cases referred with a diagnosis of partial moles, and many with a pathological diagnosis of complete moles, the histological slides were reviewed by a specialist pathologist at the referral centre. This is the policy of the Trophoblastic Disease Unit as it has been previously reported that in many cases with a referral diagnosis of partial moles, histological review may result in modification of the diagnosis and follow up subsequently adjusted4,10. Pathological features of complete moles and partial moles are well documented but, in summary, complete moles demonstrate hydropic villi, some with a ‘budding’ outline, focal cistern formation and villous stromal karryorhectic debris, with circumferential villous trophoblast proliferation, with or without significant nuclear atypia. Partial moles exhibit focally hydropic villi, some with an irregular ‘scalloped’ outline, stromal fibrosis, round or oval stromal pseudoinclusions and focal circumferential trophoblast hyperplasia4.
A computer search of the database at Charing Cross Hospital was carried out to identify all cases of women with a molar pregnancy registered between 1992 and 1998 (inclusive) in which a diagnosis of complete mole or partial mole was confirmed on histological examination. For each case, data on the subsequent pregnancy were examined with particular regard to the presence of a further molar pregnancy. The prevalence of various pregnancy outcomes, including repeat molar pregnancies, was calculated and the frequencies were compared between cases with a preceding complete mole or partial mole using comparison of proportions test [Arcus ProStat BioMedical (1.1), Research Solutions, UK].
A total of 5205 confirmed molar pregnancies were included between 1992 and 1998, comprising 2578 complete moles and 2627 partial moles. The median maternal age was 29 (range 14–59) years and 30 (range 13–55) years, respectively. A summary of subsequent pregnancy outcome overall and by histological group is provided in Table 1.
Table 1. Summary details of subsequent pregnancy outcome in 5205 women with an index pregnancy affected by complete or partial hydatidiform mole registered at the Trophoblastic Disease Surveillance Centre, London, UK. Values are expressed as n or n (%).
|Further pregnancy||1417||1512|| |
|Live birth||1076 (75.9)||1185 (78.4)||Z=−1.6, P= 0.12|
|ToP||64 (4.5)||41 (2.7)||Z= 2.6, P= 0.007|
|Miscarriage||240 (17)||245 (16.2)||Z= 0.5, P= 0.60|
|Ectopic pregnancy||5 (0.4)||10 (0.7)||Z=−1.2, P= 0.21|
|Stillbirth*||5 (0.4)||6 (0.4)||Z=−0.2, P= 0.85|
|Repeat mole||27 (1.9)||25 (1.7)||Z= 0.5, P= 0.58|
In the complete mole group, no further pregnancies were recorded in 1161 cases (45%). In 1417 cases (55%), a subsequent pregnancy was recorded during the follow up period (range 2–8 years). In this group, there were 1076 (75.9%) live births, 5 (0.4%) ectopic pregnancies, 5 (0.4%) stillbirths, 240 (16.9%) miscarriages and 64 (4.5%) non-molar terminations of pregnancy. The subsequent pregnancy was affected by a further hydatidiform mole in 27 (1.9%) cases; there were 22 (81%) cases in which the further mole was also a complete mole, and 5 (19%) in which it was a partial mole. Three (11%) patients with a second complete mole had a third complete mole in the next pregnancy.
In the partial mole group, no further pregnancies were recorded in 1115 (42.4%) cases, leaving 1512 (57.6%) cases in which a subsequent pregnancy occurred. In this group, there were 1185 (78.4%) live births, 10 (0.7%) ectopic pregnancies, 6 (0.4%) stillbirths, 245 (16.2%) miscarriages and 41 (2.7%) terminations of pregnancy. The subsequent pregnancy was affected by hydatidiform mole in 25 (1.7%) cases; there were 17 (68%) cases in which the further mole was also a partial mole and 8 (32%) in which it was a complete mole.
Overall, there were 2929 cases in which subsequent pregnancies occurred, including 52 (1.8%) complicated by a further complete mole or partial mole (prevalence 1 in 55 pregnancies). Because the overall prevalence of hydatidiform moles is about 1 in 1000 pregnancies, the occurrence of a conception complicated by complete moles or partial moles is associated with a 20-fold increase in risk of molar disease in a subsequent pregnancy. Three of the 27 cases with a repeat mole following a complete mole had at least one further pregnancy complicated by another complete mole during the study period. This suggests that the risk of a third complete mole following two previous complete moles is about 10%. In addition, there were three cases, two complete moles and one partial mole, in which the women had experienced a molar pregnancy prior to the index pregnancy. However, in these cases, no further pregnancies were recorded during the study period and therefore they were non-contributory to the calculation of recurrence risk.
There was no significant difference in gestational age distribution of the cases resulting in live birth between the groups with preceding complete moles or partial moles [median 40 (range 24–42) weeks and median 40 (range 29–42) weeks, respectively; T−0.70, P= 0.48]. The proportion of cases delivering preterm (<37/40) or severely preterm (≤32/40) for live births following complete mole and partial mole were 4.0% and 0.7% and 5.5% and 0.8%, respectively, which were not significantly different from those expected in an unselected population delivered in London during the same period (6.2% and 1.1%)11. The frequency of development of pregnancy-induced hypertension/pre-eclampsia was 1.5% and 1.9% for subsequent pregnancies following complete mole and partial mole, respectively.
The findings of this study have demonstrated that the overall recurrence risk for hydatidiform moles in the subsequent pregnancy following a pregnancy affected by complete mole or partial mole is about 2%. This is in accordance with previous results from studies which have examined recurrence risk following hydatidiform moles1,5–7. In the present study, we have also provided data regarding risks of recurrence after histologically confirmed complete moles or partial moles independently. Both complete mole and partial mole are associated with similar recurrence risks although the pathological type of molar pregnancy differs between the groups should a repeat mole occur. In both complete mole and partial mole, the subsequent pregnancy, if molar, is most likely to be of the same type as the index pregnancy. However, as in previous studies5,12, we have demonstrated that any combination of complete mole and partial mole can occur in repeat hydatidiform moles. In the current study, about 25% of repeat moles in both groups were found to be of a different type to the index pregnancy. Our overall recurrence risk of about 1.5–2.0% is similar to that reported in a smaller study of histologically confirmed complete moles and partial moles in Japan7, but is higher than the 0.7% reported from another study in the UK5. Because the actual numbers of repeat molar pregnancies occurring are relatively small, this may simply be a consequence of chance. Alternatively, as we only included cases in which histological confirmation of the diagnosis was available, rather than all cases registered with the trophoblastic disease unit, we may have included less ‘possible’ partial moles and hydropic abortions in our denominator data.
Because the risk of complete mole and partial mole is strongly associated with extremes of maternal age13, our calculated overall recurrence risk of about 2% will only be an approximation for any individual patient. However, most women with a pregnancy affected by hydatidiform moles are within the age range 20–40, where the relationship with maternal age is insignificant, and the recurrence rate of 1.5–2.0% is likely to be accurate. Nevertheless, in women with a complete mole or partial mole at age >40, the background rate increases semi-exponentially with age and therefore, the recurrence risk for such women may be greater. Much larger numbers are, however, required in order to statistically examine such a model, which could incorporate likelihood ratios for recurrence in combination with the relation to maternal age.
The increased risk of subsequent hydatidiform mole in patients having a pregnancy affected by a complete mole or a partial mole suggests that in some women, there is a predisposition to the development of molar conceptions. Complete moles are diploid and may be monospermic, arising by fertilisation of an anucleate egg by a single sperm, which then doubles to provide a diploid chromosome complement14, or dispermic, arising from fertilisation of an anucleate egg by two sperms15. Partial moles are usually dispermic triploids16–18. The genetic origin of complete moles in this study was not examined. However, we speculate that in those cases where both complete moles and partial moles occurred, dispermy may be the underlying mechanism in both the complete and partial moles.
Patients with two or more consecutive complete moles are of particular interest. This group of patients has been previously reported to have a further increased risk of repeat hydatidiform moles of between 1 in 6.58 and 1 in 17.55. In the present study, the lower limit of recurrence risk following two complete moles would be about 10%, which will be an under-estimate as not all women with a repeat hydatidiform mole have had another further pregnancy during this time interval. Within this group, the risk of subsequent complete moles may vary greatly and may depend upon the genetic origin of the complete mole. It has been shown that recurrent hydatidiform mole may occasionally be familial19–22. In women with familial recurrent hydatidiform moles, and at least some women with recurrent hydatidiform moles and no family history23, the hydatidiform moles are diploid, but biparental, rather than androgenetic in origin22–25. These patients appear to have an autosomal recessive condition predisposing them to molar pregnancies and very little chance of a successful pregnancy23–25. However, women with two consecutive complete moles do go on to have normal live births6,12,26. Because biparental complete moles are rare, most women with repeat complete moles are likely to have androgenetic complete moles. We propose that patients with recurrent hydatidiform moles fall into two groups: patients with biparental complete moles who are most likely to have another hydatidiform mole and patients with androgenetic complete moles for whom the risk of a subsequent hydatidiform mole will be much lower. In these patients, the risk of a hydatidiform mole after a second molar pregnancy may be no greater than that after the first hydatidiform mole, the increased risk for patients with two complete moles resulting from inclusion of patients with biparental complete moles and a much higher recurrence risk. Further studies of patients with recurrent hydatidiform moles of defined genetic origin are needed to determine the relative risk in each group. For women with two or more complete moles, concerned about the risk of further molar pregnancies, genetic testing may enable a more accurate assessment of their risk.
This study has demonstrated that in women conceiving following a pregnancy affected by complete or partial mole, there is an increased risk of repeat hydatidiform mole. The majority, however, will have a non-molar pregnancy, in which the outcome is not significantly different from that of an unselected population. This suggests that a molar pregnancy does not have any direct adverse or residual effects for subsequent obstetric health1,6,7. However, only 50% of women became pregnant again during the study period, and so it is not possible to exclude an effect of molar pregnancy on fertility. The present study primarily assessed the risk of a repeat hydatidiform mole and did not determine the effects of chemotherapy on fertility and subsequent pregnancy outcome. However, previous reports have shown that chemotherapy does not appear to significantly impair fertility, although it can bring forward the onset of menopause6,27–29.
Women having a pregnancy affected by a histologically confirmed complete mole or partial mole may be counselled that the risk of a repeat hydatidiform mole in a subsequent pregnancy is about 1 in 60 and if this were to occur, the majority of cases will be of the same type of mole as the preceding pregnancy. However, it should be stressed that more than 98% of women who become pregnant following a molar conception will not have another hydatidiform mole and furthermore, they are at no increased risk of obstetric complications in this pregnancy.