Most women with gestational trophoblastic disease are of reproductive age. Because the disease is readily treatable with favourable prognosis, fertility becomes an important issue. Hydatidiform mole is a relatively benign disease, and most women do not require chemotherapy after uterine evacuation. A single uterine evacuation has no significant effect on future fertility, and pregnancy outcomes in subsequent pregnancies are comparable to that of the general population, despite a slight increased risk of developing molar pregnancy again. If women develop persistent trophoblastic disease, single or combined chemotherapy will be needed. Although ovarian dysfunction after chemotherapy is a theoretical risk, a term live birth rate of higher than 70% has been reported without increased risk of fetal abnormalities. Successful pregnancies have also been reported after choriocarcinoma. Only a few case reports have been published on fertility-sparing treatment in placental-site trophoblastic tumour, and the successful rate is about 67%. Women are advised to refrain from pregnancy for at least 6 months after a molar pregnancy, and at least 12 months after a gestational trophoblastic neoplasia. Most of the contraceptive methods do not have an adverse effect on the return of fertility. Finally, at least one-half of these women suffer from some form of psychological or sexual problems. Careful counselling and involvement of a multi-disciplinary team are mandated.
Introduction
Gestational trophoblastic disease (GTD) is a pregnancy-related disorder, consisting of hydatidiform mole, invasive mole and metastatic mole, choriocarcinoma, placental-site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour. Gestational trophoblastic neoplasia (GTN) is diagnosed when a woman’s human chorionic gonadotropin (hCG) level fails to return to normal after a pregnancy. In order to diagnose GTN, using the recommendation from the International Federation of Obstetrics and Gynecology (FIGO), hCG should either plateau, with at least four persistently elevated hCG values on days 1, 7, 14 and 21, or rise sequentially for 2 weeks on days 1, 7 and 14 or longer; lung metastases should be diagnosed by chest X-ray. Gestational trophoblastic disease also includes invasive mole, choriocarcinoma and PSTT. In FIGO’s 26th report, most women with GTN are between 25 and 29 years of age, and 82.7% are younger than 40 years. It is therefore important to preserve the fertility of this group of women. For this chapter, we conducted a literature search from PubMed, and reviewed references of articles on fertility and GTD. These will be discussed below.
Fertility after gestational trophoblastic disease
Hydatidiform mole
Hydatidiform mole includes partial mole and complete mole. Both conditions are regarded as benign, and most women do not require additional treatment after uterine evacuation. Several studies from different centres have investigated the pregnancy outcomes after a molar pregnancy; all showed no difference from the general population. In particular, the rate of subsequent term live pregnancy was in the range of 68–83% for both partial and complete moles, whereas the rates of stillbirth rate, spontaneous miscarriage and congenital abnormalities were 0.3–1.3%, 9–20%, and 1.8–3.9%, respectively.
The treatment of choice for molar pregnancy is uterine evacuation, curettage, or both. Although most women with hydatidiform mole can retain their fertility, it is essential to pay extra caution in carrying out uterine evacuation, as it may lead to torrential bleeding, necessitating hysterectomy. First, it is advised to avoid using misoprostol for cervical priming because of a small risk of uterine contraction, which may result in tumour embolism into the venous system. Second, the procedure should be conducted by an experienced gynaecologist because the uterus tends to be bigger and more vascular and than the usual uteri. Third, it is usually not necessary to give an oxytocic agent. If heavy bleeding occurs, this can be given after the evacuation is completed. In the USA, some centres advocate using intravenous oxytocin infusion starting at the onset of the uterine evacuation until several hours after the operation to increase uterine contractility. Medical abortion is not recommended because of risks of bleeding, incomplete abortion, and tumour embolisation, which may, in turn, increase the need of subsequent chemotherapy. Nevertheless, medical abortion may be considered in partial mole at second trimester because the fetal parts may obstruct the evacuation, and the risk of persistent trophoblastic disease is low.
Some investigators have evaluated the effectiveness and safety of prophylactic chemotherapy with either methotrexate or actinomycin-D for high-risk molar pregnancy. Prophylactic chemotherapy is considered on the basis of age, uterine size, presence of intra-uterine mass and ovarian cysts. A woman’s history and presentation, during or shortly after uterine evacuation, is taken into account in order to decrease the chance of post-molar GTN and the potential side-effects of chemotherapy, which may affect the ovarian function. Although most studies have shown a reduction in the incidence from 18–50% to 7–18%, with occasional tolerable side-effects, only two were randomised-controlled trials with about 30 women in each arm. The criteria of high-risk molar pregnancy, however, differed in different centres. Currently, chemo-prophylaxis is usually considered in countries with limited resources for follow up, or in women with poor compliance to follow up.
Hysterectomy is rarely carried out for women who have completed their families or with life-threatening haemorrhage. Hysterectomy can provide permanent sterilisation and prevent local myometrial invasion, but it cannot obviate the risk of metastasis and the need of chemotherapy.
As there is a small risk of developing persistent trophoblastic neoplasia, women should be counselled to refrain from pregnancy for at least 6 months (see below). If women happen to conceive before completing the 6-month follow-up period, the overall viable pregnancy rate increases to 75% (33 out of 44 women; 83% for partial mole and 65% for complete mole), with no detectable fetal abnormalities.
After a molar pregnancy, the reported risk of repeated molar pregnancy is about 0.6–2% ; however, one study in Korea reported a rate up to 3.1% (two out of 65 women who became pregnant). This is 10–20 times higher than the background risk of the general population, which is 0.1–0.2% depending on different regions. After two or more molar pregnancies, the risk increases to 5–28%. It is, therefore, important to remind women to have their hCG measurement 6 and10 weeks after completing their pregnancies.
Fertility after gestational trophoblastic disease
Hydatidiform mole
Hydatidiform mole includes partial mole and complete mole. Both conditions are regarded as benign, and most women do not require additional treatment after uterine evacuation. Several studies from different centres have investigated the pregnancy outcomes after a molar pregnancy; all showed no difference from the general population. In particular, the rate of subsequent term live pregnancy was in the range of 68–83% for both partial and complete moles, whereas the rates of stillbirth rate, spontaneous miscarriage and congenital abnormalities were 0.3–1.3%, 9–20%, and 1.8–3.9%, respectively.
The treatment of choice for molar pregnancy is uterine evacuation, curettage, or both. Although most women with hydatidiform mole can retain their fertility, it is essential to pay extra caution in carrying out uterine evacuation, as it may lead to torrential bleeding, necessitating hysterectomy. First, it is advised to avoid using misoprostol for cervical priming because of a small risk of uterine contraction, which may result in tumour embolism into the venous system. Second, the procedure should be conducted by an experienced gynaecologist because the uterus tends to be bigger and more vascular and than the usual uteri. Third, it is usually not necessary to give an oxytocic agent. If heavy bleeding occurs, this can be given after the evacuation is completed. In the USA, some centres advocate using intravenous oxytocin infusion starting at the onset of the uterine evacuation until several hours after the operation to increase uterine contractility. Medical abortion is not recommended because of risks of bleeding, incomplete abortion, and tumour embolisation, which may, in turn, increase the need of subsequent chemotherapy. Nevertheless, medical abortion may be considered in partial mole at second trimester because the fetal parts may obstruct the evacuation, and the risk of persistent trophoblastic disease is low.
Some investigators have evaluated the effectiveness and safety of prophylactic chemotherapy with either methotrexate or actinomycin-D for high-risk molar pregnancy. Prophylactic chemotherapy is considered on the basis of age, uterine size, presence of intra-uterine mass and ovarian cysts. A woman’s history and presentation, during or shortly after uterine evacuation, is taken into account in order to decrease the chance of post-molar GTN and the potential side-effects of chemotherapy, which may affect the ovarian function. Although most studies have shown a reduction in the incidence from 18–50% to 7–18%, with occasional tolerable side-effects, only two were randomised-controlled trials with about 30 women in each arm. The criteria of high-risk molar pregnancy, however, differed in different centres. Currently, chemo-prophylaxis is usually considered in countries with limited resources for follow up, or in women with poor compliance to follow up.
Hysterectomy is rarely carried out for women who have completed their families or with life-threatening haemorrhage. Hysterectomy can provide permanent sterilisation and prevent local myometrial invasion, but it cannot obviate the risk of metastasis and the need of chemotherapy.
As there is a small risk of developing persistent trophoblastic neoplasia, women should be counselled to refrain from pregnancy for at least 6 months (see below). If women happen to conceive before completing the 6-month follow-up period, the overall viable pregnancy rate increases to 75% (33 out of 44 women; 83% for partial mole and 65% for complete mole), with no detectable fetal abnormalities.
After a molar pregnancy, the reported risk of repeated molar pregnancy is about 0.6–2% ; however, one study in Korea reported a rate up to 3.1% (two out of 65 women who became pregnant). This is 10–20 times higher than the background risk of the general population, which is 0.1–0.2% depending on different regions. After two or more molar pregnancies, the risk increases to 5–28%. It is, therefore, important to remind women to have their hCG measurement 6 and10 weeks after completing their pregnancies.
Gestational trophoblastic neoplasia
About 0.5–1% of partial mole and 15–29% complete mole may progress to GTN requiring chemotherapy. The variation in reported rates can be explained by the inconsistent definition of persistent trophoblastic neoplasia and criteria for chemotherapy used in different centres. The role of repeating uterine evacuation is controversial. Pezeshki et al. reported their 10-year experience with second evacuation in 282 women with persistent GTD who had plateau or elevation of hCG level with or without symptoms or ultrasound abnormalities. Among them, 171 (60%) women did not require subsequent chemotherapy, and chemotherapy was likely to be required when a histological diagnosis was made of persistent trophoblastic disease or when the hCG was greater than 1500 IU/L at the second evacuation. Despite the apparent benefit of repeating uterine evacuation reported in that study, another Dutch cohort study showed that only eight out of 85 women with persistent GTD (9.4%) were cured by second evacuation alone. In addition, the procedure may potentially lead to uterine perforation, bleeding, uterine infection, Asherman’s syndrome and cervical incompetence; four out of 85 (4.8%) women experienced uterine perforation and bleeding over 1000 ml in the Dutch cohort. With the high effectiveness of chemotherapy, repeating evacuation is not widely practised in the USA, where vigilant follow up is readily available.
The mainstay treatment for GTN is chemotherapy. As previously mentioned, different centres have different criteria for chemotherapy. One example used by the Charing Cross Hospital, London, UK, is shown in Table 1 . The staging system and regimens used also vary. The FIGO staging system with a risk score system from the World Health Organization is commonly used ( Tables 2 and 3 ). In general, low-risk GTN, usually with risk score less than 6, is treated by a single agent, such as methotrexate or actinomycin-D, whereas high-risk GTN, usually scoring 7 or above, is treated by multi-agent such as EMA-CO (etoposide, methotrexate, actinomycin-D, cyclophosphamide and vincristine with folinic acid rescue).
| Brain, liver, gastrointestinal or lung metastases greater than 2 cm on chest X-ray. |
| Histological evidence of choriocarcinoma. |
| Heavy vaginal bleeding, gastrointestinal or intraperitoneal bleeding. |
| Pulmonary, vulval or vaginal metastases, unless the hCG level is falling. |
| Rising hCG in two consecutive serum samples of greater than 10% over at least 2 weeks. |
| hCG plateau in four consecutive serum samples over 3 weeks after evacuation. |
| Serum hCG greater than 20,000 IU/l more than 4 weeks after evacuation. |
| Raised hCG level 6 months after evacuation even if it is falling. |
| International Federation of Obstetrics and Gynecology staging and classification | |
|---|---|
| Stage I | Disease confined to the uterus. |
| Stage II | Gestational trophoblastic neoplasia extends outside of the uterus, but is limited to the genital structures (e.g. adnexal, vagina, broad ligament). |
| Stage III | Gestational trophoblastic neoplasia extends to the lungs, with or without known genital tract involvement |
| Stage IV | All other metastatic sites. |
| Scores | 0 | 1 | 2 | 4 |
| Age (years) | <40 | ≥40 | – | – a |
| Antecedent pregnancy | Mole | Abortion | Term | – |
| Interval from index pregnancy (months) | <4 | 4 to <7 | 7 to <13 | ≥13 |
| Pre-treatment serum human chorionic gonadotropin (IU/l) | <10 3 | 10 3 to <10 4 | 10 4 to <10 5 | ≥10 5 |
| Largest tumour size (including uterus) | – | 3 to <5 cm | ≥5 cm | – |
| Site of metastases | Lung | Spleen, kidney | Gastro- intestinal | Liver, brain |
| Number of metastases | – | 1–4 | 5–8 | >8 |
| Previous failed chemotherapy | – | – | Single drug | ≥two drugs |
The toxic effect of chemotherapy agents on ovarian function has raised concern. A recent review by Oktem and Urman summarised the gonadotoxicity by different kinds of chemotherapy drugs and those commonly used to treat GTN ( Table 4 ). In fact, a retrospective controlled survey attempted to compare the age of menopause between women treated with chemotherapy and those who were not. The former group (median 50, range 25–56 years) had menopause 3 years earlier than the latter group (median 53, range 40–57 years) (Log-rank χ 2 test = 12.6, P = 0.0004). In addition, those who received combination chemotherapy (median 49, range 25–56 years) also had earlier menopause than those receiving single methotrexate (median 51, range 25–56 years) (Log-rank χ 2 test = 8.3, P = 0.004). The difference, however, was small and the investigators concluded that it was not of clinical significance.
| Groups | Drugs | Gonadotoxicity |
|---|---|---|
| Antimetabolites | Methotrexate | Mild toxicity; mainly on growing follicles |
| Alkylating agents | Cyclophosphamide, ifosfamide, cisplatin | High toxicity; mainly on primordial follicles |
| Spindle poison mitotic inhibitors | Vincristine | Moderate toxicity |
| Cytotoxic anti-tumour antibiotics | Actinomycin-D, bleomycin, hydroxyurea | Mild to moderate toxicity |
| Topoisomerase inhibitors | Etoposide | Unknown |
Women can be further reassured that their pregnancy outcomes are comparable to those of the general population. In a recent review, data from 10 different international centres were summarised. Women with persistent GTN, regardless of the risk scores and the chemotherapy regimens used, had favourable pregnancy outcomes. The live birth rate was 76.4% and the term delivery rate was 71.5%, whereas the rates of premature deliveries, stillbirth, miscarriage and congenital abnormalities were only 5.0%, 1.3%, 14.0% and 1.3%, respectively. Khan et al. focused their investigation on a low-risk group composed of 141 women who became pregnant. They found that 90.8% had live birth, 14.9% ended with miscarriage, and only two women (0.8%) developed repeated moles. Using etoposide alone for the treatment of low-risk GTN, the investigators of a Japanese study showed that 92.3% (36 out of 39 women who wished to conceive) became pregnant and 91.7% had at least one live birth. Out of the 56 pregnancies, 75% of women had a term live birth, 12.5% had first-trimester miscarriage, 1.8% had second-trimester miscarriage, none had fetal anomalies, and 3.6% had repeated moles. For women with high-risk GTN, a questionnaire survey involving 33 women treated with EMA-CO in the Netherlands showed a conception rate of 86%, term delivery rate of 76.2% (16 out of 21 pregnancies), miscarriage rate of 9.5%, and two (9.5%) fetal anomalies, which the authors thought were difficult to explain because of the small sample size. In another report by Bower et al., 56% of the 272 women receiving EMA-CO conceived, resulting in 112 (73%) live births and three (2.0%) congenital abnormalities. Although some investigators have found no relationship between the type of chemotherapy regimens and pregnancy outcomes, Rustin et al. showed that women receiving a combination of three or more drugs were less likely to conceive or have a live birth than those receiving methotrexate alone or in combination with one more drug ( P < 0.001). Those who received actinomycin D or vincristine were also less likely to have a live birth than those who did not ( P < 001 and P < 0005, respectively). All these studies were retrospective and limited to a single institution. More prospective studies are needed to determine the influence of the type of chemotherapy regimen on the reproductive performances.
Women are advised not to become pregnant for at least 1 year after completing chemotherapy because it may be difficult to recognise a relapse if they happen to conceive. Also, the growth of primordial Graafian follicles is estimated to take more than 6 months. By waiting for 1 year, this may allow damaged DNA to be repaired. Nonetheless, if women conceive during the mandated follow-up period, it is not necessary to terminate the pregnancy, as most studies have shown fair outcomes, with an overall 67.2% live birth rate and 2% fetal abnormality rate ( Table 5 ) ; however, women conceiving within 6 months after chemotherapy might have a higher incidence of abnormal pregnancies, including miscarriage, stillbirth and repeated moles, than those who conceive more than 12 months later (37.5% v 10.5%; P = 0.14).
| Reference | Years | Chemotherapy | Total pregnancies | Live births | Term deliveries | Preterm deliveries | Stillbirth | Miscarriage | Termination | Fetal anomalies | New moles | Relapse |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Rustin et al. | 1984 | Mixed | 45 | 31 | NA | NA | 1 | 7 | 6 | 1 | 0 | NA |
| Tuncer et al. | 1999 | Mixed | 39 a | 25 | 22 | 3 | 0 | 3 | 10 | 2 | 1 | 1 |
| Blagden et al. | 2002 | Single | 153 | NA | 120 | NA | 2 | 12 | 17 | 1 | 2 | 3 |
| Blagden et al. | 2002 | Multiple | 77 | NA | 44 | NA | 0 | 14 | 18 | 2 | 1 | 2 |
| Matsui et al. | 2004 | Mixed | 38 | 26 | NA | NA | 1 | 7 | 4 | 1 | 0 | NA |
| Total | 352 | 82 | 186 | 3 | 4 | 43 | 55 | 7 | 5 | 6 | ||
| 67.2% (82/122) | 69.1% (186/269) | 7.7% (3/39) | 1.7% (4/236) | 12.2% (43/352) | 15.6% (61/352) | 2.0% (7/352) | 1.4% (5/352) | 2.2% (6/269) | ||||
The relapse rate is about 3% in low-risk GTN and 7–10% in high-risk GTN. The New England Trophoblastic Disease Center has also observed that relapse after initial remission occurred in 2.9% of women with stage I disease, 8.3% of women with stage II disease, 4.2% of women with stage III disease, and 9.1% of women with stage IV disease. In another review, Lurain reported that about 20% of women with low-risk GTN and 30% of women with high-risk GTN would either relapse or become refractory to first-line chemotherapy. Multiple chemotherapy regimens, such as EP-EMA (etoposide, cisplatin, etoposide, methotrexate and actinomycin-D), MBE (methotrexate, bleomycin and etoposide), TP/TE (paclitaxel, cisplatin / paclitaxel, etoposide), BEP (bleomycin, etoposide and cisplatin), VIP or ICE (etoposide, ifosfamide and cisplatin or carboplatin), floxuridine, dactinomycin, etoposide, and vincristine (FAEV), have been reported, with response rates varying from 50– 85%. The overall 5-year survival for women with relapsed GTN was more than 90%, which is nearly 100% for women with low-risk GTN and around 85% for women with high-risk GTN. Hysterectomy is only rarely carried out for refractory diseases with single focus in the uterus. Despite the relative favourable prognosis, pregnancy after remission of relapse is seldom described, which may be because of the rarity of the disease and the possible poor ovarian function and psycho-sexual problems after multiple courses of chemotherapy.
Choriocarcinoma
Owing to the chemosensitivity of the tumour, choriocarcinoma is now mainly managed with combined chemotherapy. In fact, several studies have shown that the recurrence rate and survival rate are similar between those who have had and those who have not had hysterectomy, with a trend favouring fertility-sparing treatment. These studies have also reported a 77–79% term delivery rate and a 7–9% miscarriage rate. Song et al. reported two intrauterine deaths, three stillbirths, six neo-natal deaths and two infancy deaths among 355 total pregnancies. Goto et al. also reported an 8.8% (three out of 34 term births) incidence rate of congenital heart abnormalities, which was higher than the background risk (0.7–1%) in the Japanese population. The total dosage of methotrexate received by these mothers was also significantly higher compared with the rest, whose children did not have cardiac abnormalities ( P < 0.02). Another small study by Lan et al., included 22 women with choriocarcinoma and invasive moles who conceived within 1 year after completing chemotherapy. One suspected recurrence of GTN and another repeated hydatidiform mole were reported, and the fetal loss rate was 27.1% (6 out of 22). These included one repeated hydatidiform mole, one intrauterine death, one inevitable miscarriage and three threatened miscarriages, reiterating the need to wait for 1 year before contemplating the next pregnancy.
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