Department of Gynecology and Obstetrics, University Hospitals of Geneva, Geneva, Switzerland
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Abstract |
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Key words: hydatidiform mole/metastasis/ovulation induction/persistent trophoblastic tumour
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Introduction |
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HM after fertility therapy seems to be a rare complication despite the widespread use of these treatments. The true incidence is however not known due to the lack of sufficient information regarding the number of treatments performed and the number of HMs avoided by current policies in reproductive medicine. These policies imply that only embryos derived from normally fertilized oocytes are selected for replacement. The normal fertilization process is usually considered to have occurred when two pronuclei (2PN) and two polar bodies are observed. If the number of pronuclei is different, as for monopronuclear (1PN) or tripronuclear (3PN), the embryos are generally not transferred as it is presumed that some of them could be an origin for HM. An incidence of 1/659 pregnancies has been disclosed by Merril-National Labs., Cincinnati, Ohio, USA, and reported by Schneidermann and Waxman in a group of 2 369 clomiphene-induced pregnancies (natural incidence estimated as 0.51.1/1000 in USA) (Schneiderman and Waxman, 1972). In another report Kurachi reported a rate of 1/1034 pregnancies in Japan (natural incidence estimated as 1.92.8/1000 in Japan) (Kurachi, 1982
; Bracken, 1987
).
New treatments in assisted reproductive medicine represent a major step forward but a careful evaluation is necessary to identify potential harmful effects on the mother. Molar pregnancy after exposure to fertility drugs is a rare condition that precludes an appropriate prospective study. Currently, the only available information is on the basis of case reports. These data do not permit an assessment of the real rate of PTT due to reporting bias but only allow the discussion of the potential association between the exposure to this treatment and the subsequent development of PTT.
Our study aim was to identify all published reports of molar pregnancies after ovulation induction and to evaluate if there could be an association between this therapy and the development of PTT or metastatic disease.
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Materials and methods |
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All reports were reviewed with regards to (i) pre-evacuation clinical features: type of fertility therapy used, maternal age at diagnosis, estimated gestational age at diagnosis, gravidity, parity, presenting symptoms, ultrasound findings, pre-evacuation HCG; and (ii) post-evacuation clinical features: type of HM, molar karyotype, PTT, and presence of metastasis. For pregnancies combining an HM and coexistent fetus(es) (HM-and-CF), the additional following features were extracted: presence before the transfer of two pronuclei, estimated gestational age at termination, indication for termination/delivery, fetal karyotype, and fetal outcome.
Patients with HM-and-CF were divided into two groups: (i) pregnancy with a delivery 24 weeks gestation; and (ii) pregnancy with a delivery at
24 weeks gestation. The percentage of patients was calculated only for those with available data. Missing or incomplete clinical data of reported patients were considered as a not-available (NA) category. We have considered that patients with a mention of one negative ß-HCG or other mention attesting an absence of PTT, as having no PTT. Differences in continuous variables were evaluated using the Mann-Whitney U-test and differences in proportion by the two-tailed Fisher's exact test. Statistical significance was defined as a P-value <0.05.
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Results |
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Comparison between singleton HM and HM-and-CF
Table I summarizes the clinical and laboratory parameters of the reported cases and compares patients with singleton HM and those with an HM and CF. A total of 15% of patients with singleton HM developed a PTT but none had metastasis. In patients with HM-and-CF, 42% developed a PTT with 15% developing metastasis. All patients with metastatic disease had lung metastasis and all achieved a complete remission after chemotherapy. Among the cases of HM-and-CF, 17 were twin, and there were eight triplet or quadruplet pregnancies. In these two groups, PTT was 41% (7/17) and 50% (4/8) respectively.
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Discussion |
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CHM may be considered as a precancerous condition which can transform into an invasive tumour. The aim of our study was to identify potential carcinogenic effects of ovulation-inducers and to analyse the clinical outcome of singleton HM and HM-and-CF pregnancies occurring after fertility therapy. This information could provide a basis for decision-making and the counselling of patients when an HM is diagnosed in early or late pregnancy. The present series is comprised exclusively of patients with an HM after having undergone fertility treatment and, to the best of our knowledge, no previous study has evaluated this issue, apart from isolated case reports.
Patients with singleton HM have an incidence of PTT after evacuation of the mole of 14%. This rate is similar to those with pregnancy occurring naturally. Compared with HM-and-CF, singleton HM are diagnosed earlier in the pregnancy (11.5 versus 16 weeks gestation; P < 0.05) probably because the presence of fetal heartbeat falsely reassured the clinician and is responsible for the delayed diagnosis. A statistically significant difference in age between the two groups was observed (31 versus 27.5 years; P < 0.05), but we have no immediate explanation for this finding.
Patients with an HM-and-CF have a pregnancy composed of two different conceptus; one is a normal fetus and placenta and the other is a molar pregnancy. This type of pregnancy has a more aggressive post-evacuation behaviour with a risk of PTT significantly higher than a singleton HM. Steller et al. reported 12/22 (55%) PTT in patients with HM-and-CF compared with only 10/71 (14%) in patients with single HM (Steller et al., 1994). Other reports have confirmed this observation with a risk of PTT which has been estimated as between 4057% (Vejerslev, 1991
; Miller et al., 1993
; Bristow et al., 1996
; Fishman et al., 1998
; Bruchim et al., 2000
; Matsui et al., 2000
). We found similar results in our series with a risk of PTT occurring of 42%, suggesting that the course of CHM-and-CF after ovulation induction has a similar evolution to a natural one. It is still unclear if the greater risk of PTT is associated with a more aggressive behaviour of the molar tissue or because of delayed delivery. However, recent reports have observed that an advancement of the gestational age does not appear to increase the risk of developing a PTT (Bristow et al., 1996
; Matsui et al., 2000
). Our report concurs with the existing literature in that the rate of PTT in pregnancy of <24 weeks and
24 weeks gestation is similar.
At present, it is possible to distinguish between a prenatal diagnosis of a triploid non-viable fetus and a chromosomally-normal and viable infant. The latter condition presents the patient and the physician with a critical dilemma between a therapeutic abortion or an expectant management until fetal viability. The conservative approach is supported by the fact that there have now been several reported cases of HM-and-CF after natural conception that have been carried to viability and delivery of a live infant. In a review of the literature, Bristow et al. have found 26 cases of HM-and-CF with seven cases of surviving infants (Bristow et al., 1996).
Once a diagnosis of gestation consisting of an HM and co-existing chromosomally-normal fetus(es) has been made, and if the clinical course is stable, the decision to allow such a pregnancy to continue should be taken with the couple. The women should be aware of the increased risk of pregnancy complications such as severe antepartum haemorrhage, pre-eclampsia or hyperemesis gravidarum that may require prompt uterine evacuation. As previously mentioned, if the gestation shows a benign clinical course, an expectant observation until infant viability must be considered. Such a management may be encouraged in those patients having undergone fertility therapy, sometimes at an advanced age and after many attempts of assisted conception, which implies a profound desire to continue the pregnancy until viability of the fetus. According to our series and that of Bristow et al., ~25% of patients will have the possibility of having a viable live birth (Bristow et al., 1996).
Results from the present study must be interpreted within the context and limitations of our data as they include reports from the literature only and, with meta-analyses, are subject to reporting bias. It is well known that cases with complications are documented more frequently than uneventful observations. Another limitation is that some observations have been included despite the fact that no cytogenetic analysis was carried out. However, at present, the only way to have some insight into the course of HM after ovulation-inducers, and to acquire knowledge about the optimal management of this type of pregnancy, is to retrieve from the literature all the well-documented cases.
In conclusion, our study suggests that women having a singleton or multiple pregnancy after exposure to ovulation-inducers seem to have no additional risk of PTT than those who conceive naturally. However, as this therapy is more likely to result in multiple pregnancy than spontaneously conceived singleton pregnancy, patients are at greater risk of developing PTT. In clinical practice, the overall rate of PTT after ovulation-inducing drug treatment is probably increased.
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Acknowledgements |
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Notes |
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References |
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Submitted on October 18, 2001; accepted on January 17, 2002.