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Treatment of ectopic pregnancy with methotrexate
Eur. J. Obstet. Gynecol. Reprod. Biol., 24 (1987) 63-67 Elsevier
63
ET0 00406
Case report
Treatment of ectopic pregnancy with methotrexate L.C.F. Haans, P.H. van Kessel and H.C.L.V. Kock Department
of Obstetrics and Gynaecology, Maria Hospiial, Dr. Deelenlaan 5, 5042 AD Tilburg, The Netherlandr Accepted
for publication
16 September
1986
summary This is a report on the successful treatment of an unruptured tubal pregnancy with methotrexate (MTX). To our knowledge eighteen cases, including ours, have been reported in Western literature so far. The advantages and drawbacks of this therapy are discussed. Ectopic
pregnancy;
Methotrexate
(MTX);
Non-surgical
therapy;
hCG
Introduction In most cases of ectopic pregnancy surgical intervention because of life-threatening intraperitoneal bleeding is mandatory. Unruptured ectopic pregnancies, however, can be treated by operation, medical treatment, or by careful observation. The choice of therapy should depend on the results of physical examination, but also on the patient’s wishes for future fertility [1,2]. In the last two years there have been seventeen case reports on the treatment of ectopic pregnancy with methotrexate (MTX) [3-81. In only two of these cases did surgical intervention prove to be necessary during the period of MTX treatment. Case report History A 29-yr-old, gravida 3, para 1, 0 abortion, 1 ectopic pregnancy, visited the out-patient department. Her last menstrual period had been 5 weeks before. The
Correspondence: L.C.F. Haans M.D., Department Deelenlaan 5, 5042 AD Tilburg, The Netherlands.
0028-2243/87/$03.50
of Obstetrics
0 1987 Elsevier Science Publishers
and Gynaecology,
B.V. (Biomedical
Division)
Maria
Hospital,
Dr.
64
65
patient complained of vaginal bleeding and pain in the lower right abdomen, had no shoulder pain and no periods of syncope. Obstetrical history indicated a spontaneous delivery of a healthy son in 1982 and an ectopic pregnancy in 1984, treated by massage of the conceptus from the ampullary part of the right tube during laparotomy. Physical examination On physical examination we found a healthy Caucasian female having normal vital signs. The abdomen was tender in the lower right quadrant. There was a mobile, slightly enlarged, normally positioned uterus; no adnexal enlargement could be palpated and the right parametrium was tender. Laboratory findings. Hb, 7.5 mmol/l; Ht, 0.35; WBC, normal. The pregnancy test (urine) was positive (> 75 IU hCG/L). Ultrasound-examination revealed no pregnancy-ring in the uterus. There was some thickening of the uterine mucosa. A cystic mass between the right ovary and the uterus was observed, as was a small cyst in the right ovary. Laparoscopy confirmed a non-ruptured ectopic pregnancy located in the isthmic part of the intact right tube. There was some blood loss from the ampullary end. The left tube was normal. Therapy The patient was treated with five doses of 50 mg MTX, with 48-h intervals. This therapy was combined with leucovorum rescue as described by Bagshawe [9]. The patient was observed for vital signs. Blood samples were taken for daily serum hCG control and haematology control every 48 h (Table I). Results During the treatment and post-treatment period no complications appeared. The tenderness in the lower right abdomen disappeared in 5 days. Serum hCG concentration decreased progressively to less than 0.1 mIU/ml (Table I). Signs of bone-marrow depression due to chemotherapy were not evident and liver function tests remained within the normal range. Fourteen days after laparoscopy the patient was discharged from the clinic. A second laparoscopy, 4 weeks later, showed both tubes to be mobile and slim, with a normal passage of methylene blue during pertubation. Four months after discharge the patient conceived again. Ultrasound confirmed an intra-uterine pregnancy with a corpus luteum located in the right ovary. Discussion Methotrexate (MTX) reduces the activity of the dihydrofolate reductase, an enzyme that stimulates the transfer of dihydrofolic acid to tetrahydrofolic acid. As a result of this process the biosynthesis of thymine and purine, essential for DNA
66
production, is reduced. Folic acid (leucovorum) antagonizes the effect of MTX. According to Bagshawe [9] leucovorum administration, 30 h following MTX treatment, diminishes the side-effects, but not the therapeutic effects of MTX. Side-effects include bone marrow depression, stomatitis, anorexia, nausea, vomiting and diarrhea. Also liver cell necrosis, alopecia, dermatitis and prutitis are mentioned, although these symptoms are rarely seen in case of short-term therapy. Methotrexate (MTX) therapy aims to destroy the trophoblast without additional damage to the mucosal layer of the tube. This effect is difficult to evaluate, since there are only a few case reports and their follow-up is short. Pregnancy rates after conservative surgery for tubal pregnancy have been reported to be between 50 and 80% [lO,ll]. To compare the pregnancy rates after MTX therapy with those after surgery, a large-scale study is needed. The results of a totally conservative approach are described by Lund [12]. In almost half of the cases the tube ruptured or needed surgery during the observation period and in an additional 33% the end result was either a hydrosalpinx or the formation of massive peritubal adhesions. Therefore observation should not be preferred in cases where fertility has to be conserved. Preliminary results with antiprogesterones seem promising [13]. This therapy does not have the drawback of possible genetic mutation, which theoretically could be induced by chemotherapy. Van Thiel et al. [14] found in 88 pregnancies of 50 women treated with MTX for gestational trophoblastic disease (GTD) no increase in fetal wastage, congenital abnormalities or pregnancy complications. Pastorfide and Goldstein (1973) [15] reported on 118 pregnancies in 82 patients after treatment with MTX for GTD. The incidence of premature birth, congenital abnormalities and perinatal and neonatal morbidity was not increased. In this retrospective study, the abortion rate might have been somewhat higher than in the control group. Walden and Bagshawe (1976) [16] reported no higher incidence of spontaneous abortion, congenital malformation or fetal wastage after treatment with different kinds of chemotherapy for GTD in a study of 36 women. Therefore we should not consider these complications to be a major drawback of short-term MTX therapy. Summary and conclusions Up to now there have been eighteen case reports, including ours, on the treatment of an ectopic pregnancy with MTX. Only in two cases was an additional operation necessary. This therapy might lead to better preservation of tubal function and besides has the advantage of not involving surgical intervention. The patient described here conceived again, probably via the treated tube. With regard to post-treatment fertility maintenance, the totally conservative approach appears inferior to MTX therapy or surgery. A possible disadvantage of MTX therapy might be an increased number of congenital malformations in the following pregnancies. The incidence proved to be at least very low in three large series [14-161 and should therefore not be considered a major drawback.
67
References 1 Weckstein LN. Current perspective on ectopic pregnancy. Obstet Gynecol Surv 1985; 5: 259-72. 2 Dorr PJ, Vemer HM, Rolland R. De behandeling van de tubair zwangerschap. Ned T Geneeskd 1985: 21-4. 3 Tanaha T, Hyashi H, Kutsuzawa T, et al. Treatment of interstitial pregnancy with methotrexate: report of a successful case. Fertil Steril 1982; 37: 851-2. 4 Farabow WS, Futton JW, Fletcher V, et al. Cervical pregnancy treated with methotrexate. N C Med J 1983; 44: 91-3. 5 Chotiner HC. Nonsurgical management of ectopic pregnancy associated with severe hyperstimulation syndrome. Obstet Gynaecol 1985; 66: 740-3. 6 No Miyazaki Y. Nonsurgical therapy of ectopic pregnancy. Hokkaido Igahu Zasshi 1983; 58: 132-43. 7 Cowan BD, McGehee RP, Bates GW. Treatment of persistent ectopic pregnancy with methotrexate and leucovorum rescue. Obstet Gynaecol 1986; 67: 509-10. 8 Ory SJ, Villanueva AL, Sand PK, Tamura RK. Conservative treatment of ectopic pregnancy with methotrexate. Am J Obstet Gynecol 1986; 154: 1299-06. 9 Bagshawe KD. Choriocarcinoma: Clinical Biology of the trophoblast and its tumours. London, Edward Amolds; 1969: 233-57. 10 Valle JA, Lifcher AS. Reproductive outcome following conservative surgery with a single fallopian tube. Fertil Steril 1983; 39: 316-20. 11 DeChemey AH, Maheaux R, Naftolin F. Salpingostomy for ectopic pregnancy in the sole patent oviduct: reproductive outcome. Fertil Steril 1982; 37: 619-22. 12 Lund JJ. Early ectopic pregnancy. J Obstet Gynaecol Br Emp 1955; 62: 70. 13 Paris FX, Hendry-Suchet J, Tesquier, et al. Le traitement medical des grossesses extra-uterines par le Ru 486. La Presse Med 1984; 13: 1219. 14 Van Thiel DH, Ross GT, Lipsett MB. Pregnancies after chemotherapy of trophoblastic neoplasms. Science 1970; 169: 1326-7. 15 Pastorfide GB, Goldstein DP. Pregnancy after hydatiform mole. Obstet Gynaecol 1973; 42: 67-70. 16 Walden PAM, Bagshawe KD. Reproductive performance of women successfully treated for gestational trophoblastic tumours. Am J Obstet Gynaecol 1976; 125: 1108-14.
63
ET0 00406
Case report
Treatment of ectopic pregnancy with methotrexate L.C.F. Haans, P.H. van Kessel and H.C.L.V. Kock Department
of Obstetrics and Gynaecology, Maria Hospiial, Dr. Deelenlaan 5, 5042 AD Tilburg, The Netherlandr Accepted
for publication
16 September
1986
summary This is a report on the successful treatment of an unruptured tubal pregnancy with methotrexate (MTX). To our knowledge eighteen cases, including ours, have been reported in Western literature so far. The advantages and drawbacks of this therapy are discussed. Ectopic
pregnancy;
Methotrexate
(MTX);
Non-surgical
therapy;
hCG
Introduction In most cases of ectopic pregnancy surgical intervention because of life-threatening intraperitoneal bleeding is mandatory. Unruptured ectopic pregnancies, however, can be treated by operation, medical treatment, or by careful observation. The choice of therapy should depend on the results of physical examination, but also on the patient’s wishes for future fertility [1,2]. In the last two years there have been seventeen case reports on the treatment of ectopic pregnancy with methotrexate (MTX) [3-81. In only two of these cases did surgical intervention prove to be necessary during the period of MTX treatment. Case report History A 29-yr-old, gravida 3, para 1, 0 abortion, 1 ectopic pregnancy, visited the out-patient department. Her last menstrual period had been 5 weeks before. The
Correspondence: L.C.F. Haans M.D., Department Deelenlaan 5, 5042 AD Tilburg, The Netherlands.
0028-2243/87/$03.50
of Obstetrics
0 1987 Elsevier Science Publishers
and Gynaecology,
B.V. (Biomedical
Division)
Maria
Hospital,
Dr.
64
65
patient complained of vaginal bleeding and pain in the lower right abdomen, had no shoulder pain and no periods of syncope. Obstetrical history indicated a spontaneous delivery of a healthy son in 1982 and an ectopic pregnancy in 1984, treated by massage of the conceptus from the ampullary part of the right tube during laparotomy. Physical examination On physical examination we found a healthy Caucasian female having normal vital signs. The abdomen was tender in the lower right quadrant. There was a mobile, slightly enlarged, normally positioned uterus; no adnexal enlargement could be palpated and the right parametrium was tender. Laboratory findings. Hb, 7.5 mmol/l; Ht, 0.35; WBC, normal. The pregnancy test (urine) was positive (> 75 IU hCG/L). Ultrasound-examination revealed no pregnancy-ring in the uterus. There was some thickening of the uterine mucosa. A cystic mass between the right ovary and the uterus was observed, as was a small cyst in the right ovary. Laparoscopy confirmed a non-ruptured ectopic pregnancy located in the isthmic part of the intact right tube. There was some blood loss from the ampullary end. The left tube was normal. Therapy The patient was treated with five doses of 50 mg MTX, with 48-h intervals. This therapy was combined with leucovorum rescue as described by Bagshawe [9]. The patient was observed for vital signs. Blood samples were taken for daily serum hCG control and haematology control every 48 h (Table I). Results During the treatment and post-treatment period no complications appeared. The tenderness in the lower right abdomen disappeared in 5 days. Serum hCG concentration decreased progressively to less than 0.1 mIU/ml (Table I). Signs of bone-marrow depression due to chemotherapy were not evident and liver function tests remained within the normal range. Fourteen days after laparoscopy the patient was discharged from the clinic. A second laparoscopy, 4 weeks later, showed both tubes to be mobile and slim, with a normal passage of methylene blue during pertubation. Four months after discharge the patient conceived again. Ultrasound confirmed an intra-uterine pregnancy with a corpus luteum located in the right ovary. Discussion Methotrexate (MTX) reduces the activity of the dihydrofolate reductase, an enzyme that stimulates the transfer of dihydrofolic acid to tetrahydrofolic acid. As a result of this process the biosynthesis of thymine and purine, essential for DNA
66
production, is reduced. Folic acid (leucovorum) antagonizes the effect of MTX. According to Bagshawe [9] leucovorum administration, 30 h following MTX treatment, diminishes the side-effects, but not the therapeutic effects of MTX. Side-effects include bone marrow depression, stomatitis, anorexia, nausea, vomiting and diarrhea. Also liver cell necrosis, alopecia, dermatitis and prutitis are mentioned, although these symptoms are rarely seen in case of short-term therapy. Methotrexate (MTX) therapy aims to destroy the trophoblast without additional damage to the mucosal layer of the tube. This effect is difficult to evaluate, since there are only a few case reports and their follow-up is short. Pregnancy rates after conservative surgery for tubal pregnancy have been reported to be between 50 and 80% [lO,ll]. To compare the pregnancy rates after MTX therapy with those after surgery, a large-scale study is needed. The results of a totally conservative approach are described by Lund [12]. In almost half of the cases the tube ruptured or needed surgery during the observation period and in an additional 33% the end result was either a hydrosalpinx or the formation of massive peritubal adhesions. Therefore observation should not be preferred in cases where fertility has to be conserved. Preliminary results with antiprogesterones seem promising [13]. This therapy does not have the drawback of possible genetic mutation, which theoretically could be induced by chemotherapy. Van Thiel et al. [14] found in 88 pregnancies of 50 women treated with MTX for gestational trophoblastic disease (GTD) no increase in fetal wastage, congenital abnormalities or pregnancy complications. Pastorfide and Goldstein (1973) [15] reported on 118 pregnancies in 82 patients after treatment with MTX for GTD. The incidence of premature birth, congenital abnormalities and perinatal and neonatal morbidity was not increased. In this retrospective study, the abortion rate might have been somewhat higher than in the control group. Walden and Bagshawe (1976) [16] reported no higher incidence of spontaneous abortion, congenital malformation or fetal wastage after treatment with different kinds of chemotherapy for GTD in a study of 36 women. Therefore we should not consider these complications to be a major drawback of short-term MTX therapy. Summary and conclusions Up to now there have been eighteen case reports, including ours, on the treatment of an ectopic pregnancy with MTX. Only in two cases was an additional operation necessary. This therapy might lead to better preservation of tubal function and besides has the advantage of not involving surgical intervention. The patient described here conceived again, probably via the treated tube. With regard to post-treatment fertility maintenance, the totally conservative approach appears inferior to MTX therapy or surgery. A possible disadvantage of MTX therapy might be an increased number of congenital malformations in the following pregnancies. The incidence proved to be at least very low in three large series [14-161 and should therefore not be considered a major drawback.
67
References 1 Weckstein LN. Current perspective on ectopic pregnancy. Obstet Gynecol Surv 1985; 5: 259-72. 2 Dorr PJ, Vemer HM, Rolland R. De behandeling van de tubair zwangerschap. Ned T Geneeskd 1985: 21-4. 3 Tanaha T, Hyashi H, Kutsuzawa T, et al. Treatment of interstitial pregnancy with methotrexate: report of a successful case. Fertil Steril 1982; 37: 851-2. 4 Farabow WS, Futton JW, Fletcher V, et al. Cervical pregnancy treated with methotrexate. N C Med J 1983; 44: 91-3. 5 Chotiner HC. Nonsurgical management of ectopic pregnancy associated with severe hyperstimulation syndrome. Obstet Gynaecol 1985; 66: 740-3. 6 No Miyazaki Y. Nonsurgical therapy of ectopic pregnancy. Hokkaido Igahu Zasshi 1983; 58: 132-43. 7 Cowan BD, McGehee RP, Bates GW. Treatment of persistent ectopic pregnancy with methotrexate and leucovorum rescue. Obstet Gynaecol 1986; 67: 509-10. 8 Ory SJ, Villanueva AL, Sand PK, Tamura RK. Conservative treatment of ectopic pregnancy with methotrexate. Am J Obstet Gynecol 1986; 154: 1299-06. 9 Bagshawe KD. Choriocarcinoma: Clinical Biology of the trophoblast and its tumours. London, Edward Amolds; 1969: 233-57. 10 Valle JA, Lifcher AS. Reproductive outcome following conservative surgery with a single fallopian tube. Fertil Steril 1983; 39: 316-20. 11 DeChemey AH, Maheaux R, Naftolin F. Salpingostomy for ectopic pregnancy in the sole patent oviduct: reproductive outcome. Fertil Steril 1982; 37: 619-22. 12 Lund JJ. Early ectopic pregnancy. J Obstet Gynaecol Br Emp 1955; 62: 70. 13 Paris FX, Hendry-Suchet J, Tesquier, et al. Le traitement medical des grossesses extra-uterines par le Ru 486. La Presse Med 1984; 13: 1219. 14 Van Thiel DH, Ross GT, Lipsett MB. Pregnancies after chemotherapy of trophoblastic neoplasms. Science 1970; 169: 1326-7. 15 Pastorfide GB, Goldstein DP. Pregnancy after hydatiform mole. Obstet Gynaecol 1973; 42: 67-70. 16 Walden PAM, Bagshawe KD. Reproductive performance of women successfully treated for gestational trophoblastic tumours. Am J Obstet Gynaecol 1976; 125: 1108-14.