Human Reproduction vol.7 no.10 pp. 1457-1460, 1992
Transvaginal intratubal insemination, ectopic pregnancy and treatment by single-dose parenteral methotrexate
Department of Obstetrics and Gynaecology and 2Hormonal Laboratory, Faculty of Medicine, Hospital Clinic i Provincial, C/Casanova 143, 08036-Barcelona, Spain 'To whom correspondence should be addressed
We report a case of a woman with ectopic pregnancy with fetal cardiac activity after ovulation induction and transvaginal intratubal insemination by tactile sensation. The patient was successfully treated by single-dose methotrexate (MTX) (77 mg or 50 mg/m2 given intramuscularly). Control hysterosalpingograms showed no tuba! patency on the involved side. Potential advantages and hazards of transvaginal intratubal insemination and single-dose MTX for ectopic pregnancy are discussed. Key words: ectopic pregnancy/intratubal insemination/single-dose methotrexate
Introduction Assisted reproductive technology (ART), which has become the mainstay in the treatment of infertility in the last decade, includes in-vitro fertilization and embryo transfer (TVF — ET), gamete intra-Fallopian transfer (GIFT), zygote intra-Fallopian transfer (ZIFT), and other modalities of zygote or gamete transfer. Since the first report on transvaginal tubal catheterization for medically assisted procreation (Jansen and Anderson, 1987; Risquez et al., 1990a), transvaginal catheterization of the Fallopian tube for the purpose of transferring embryos and gametes has been gaining popularity in the treatment of infertile couples when the female partner has at least one patent Fallopian tube (Pratt et al., 1991). However, ectopic pregnancy has been associated with the use of ART (Russell, 1987; Lucena etal., 1989). Traditionally, surgical removal of tuba! pregnancy has been the treatment of choice, but in the past decade different conservative treatment methods have been reported (Shapiro, 1987; Vermesh, 1989). Nonsurgical treatment includes expectant management, RU486, prostaglandins and methotrexate (MTX) (Vermesh, 1989). Chemotherapy with MTX for ectopic pregnancy has shown significant promise as an alternative to surgical management (Cannon and Jesionowska, 1991). Early studies which have included multiple MTX doses with or without citrovorum rescue indicated that this treatment should not be undertaken if tubal pregnancy with fetal heart motion is noted © Oxford University Press
on ultrasound (Sauer etal., 1987; Cannon and Jesionowska, 1991). However, a very recent study of 30 patients with ectopic pregnancy including six cases with cardiac activity, suggests that single-dose i.m. MTX could be effective medical treatment for the unruptured tubal pregnancy of ^3.5 cm in greatest dimension with or without cardiac activity (Stovall etal., 1991). We report here a case of a woman with ectopic pregnancy and fetal heart motion after ovulation induction and transvaginal intratubal insemination, who was successfully treated by singledose, parenteral administration of methotrexate.
Case report A 31-year-old woman was referred to our care because of 6 years primary infertility. Past medical histories of the patient and her husband were unremarkable. A normal female infertility evaluation included basal body temperature charts, hysterosalpingography, midluteal plasma progesterone, oestradiol and prolactin, late luteal phase endometrial biopsy and cultures, and laparoscopy. The postcoital test was repeatedly negative (spermatozoa absent or immotile) in spite of good cervical mucus (thin, clear, acellular, high spinnbarkeit) and different semen examinations revealed persistent asthenozoospermia (>20 X 106 spermatozoa/ml, motility 50% (Cannon and Jesionowska, 1991). MTX has been applied by several different methods, either via parenteral or oral therapy or via local injections. Effort has been directed toward attaining maximal efficacy while minimizing or eliminating adverse complications. This has resulted in a progression from systemic to local MTX treatment (Cannon and Jesionowska, 1991). However, several important issues concern local MTX treatment. Firstly, a very recent study on its systemic
pharmacokinetics after local injection intratubally showed that its peak serum level and the area under the curve are similar to those observed after i.m. injection of the drug (Schiff et al., 1992). Therefore, in regard to serum drug level and exposure to systemic toxicity, there is no advantage to the local tubal-guided injection over that of a single-dose i.m. treatment. Secondly, there remains the question whether local MTX injection is directly toxic to the Fallopian tube and would result in significant changes leading to a decrease in reproductive function (Cannon and Jesionowska, 1991). Although in a pregnant rat model no toxicity on the genital tract mucosa has been observed with local MTX injection (Menard et al., 1990), clinical studies emphasize that a potential disadvantage of high local concentrations might be the negative influence on the recovery of the tubal mucosa and the muscular layer (Kooi and Kock, 1990; Menard et al., 1990; Risquez etal, 1990b). Finally, a recently published series including an analysis of previous literature on the subject concludes that, in fact, there is a truly increased risk for additional surgical or medical treatment among patients with ectopic pregnancy managed using intratubal MTX injection (Mottla etal, 1992). Taking into account the above-mentioned facts and the preliminary report by Stovall et al. (1991), which is indicative of consistent success from single-dose MTX for treatment of ectopic pregnancy of < 3.5 cm in larger dimension, single i.m. treatment is likely to be favoured. In early parenteral trials 'fetal heart motion' was a contraindication to MTX treatment (Sauer et al., 1987; Cannon and Jesionowska, 1991) and only six cases with cardiac activity were included in the series by Stovall et al. (1991); five of the six cases were successfully treated. The case presented here adds further evidence to the usefulness of this treatment modality, but further studies are necessary to establish tuba! patency rates after single-dose parenteral MTX for treatment of ectopic pregnancy. References Allen,N., Herbert.C.M., Maxson,W.S., Rogers,B.J., Diamond,M.P. and Wentz,A.C. (1985) Intrauterine insemination: a critical review. Fenil. Sterii, 44, 569-580. Bauer,O., Van der Ven.H., Diedrich.K., Al-Hasani,S., Krebs.D. and Gembruch.U. (1990) Preliminary results on transvaginal tubal embryo stage transfer (TV-TEST) without ultrasound guidance. Hum Reprod., 5, 553-556. Cannon,L. and Jesionowska,H. (1991) Methotrexate treatment of tubal pregnancy. Fenil Sterii., 55, 1033-1038. Confino,E., Friberg.J., Dudkiewicz,A.B. and Gleicher.N. (1986) Intrauterine insemination with washed human spermatozoa. Fenil. Sterii., 46, 55-60. Jansen,R.P.S. and Anderson J.C. (1987) Catheterization of the fallopian tube from the vagina. Lancet, II, 309-310. Kooi,S. and Kock,H. (1990) Treatment of tubal pregnancy by local injection of methotrexate after adrenaline injection into the mesosalpinx: a report of 25 patients. Fenil. Sterii., 54, 580-584. Li.M.C, Hertz.R. and Spencer.D.B. (1956) Effect of methotrexate therapy upon chonocarcinoma and chorioadenoma. Proc. Soc. Exp. Biol. Med.. 93, 361-365. Lucena,E., RuizJ.A., MendozaJ.C, OrtizJ.A., Lucena.C, Gdmez.M. and Arango,A. (1989) Vaginal intratubal insemination (VTTl) and vaginal GIFT, endosonographic technique: early experience. Hum. Reprod.. 4, 658-662. 1459
Downloaded from https://academic.oup.com/humrep/article-abstract/7/10/1457/664786 by Western Sydney University Library user on 11 January 2019
insemination with husband's semen can be related not only to the selection of patients but also to other technical factors, such as sperm preparation or site of insemination. The methodology of intrauterine insemination has evolved considerably as a result of developments in assisted reproductive technology. Thus, semen characteristics can be improved with the use of washing and capacitation techniques, clomiphene citrate and gonadotrophins are used to 'time' ovulation, and intratubal insemination can place the spermatozoa in the Fallopian tube nearest the ovary with the dominant follicle (Confino et al., 1986; Melis et al., 1987; Pratt et al., 1991). Transvaginal tubal transfer via tactile sensation is easily performed and can result in pregnancy rates comparable to those obtained using a transvaginal approach with ultrasound guidance (Lucena et al., 1989; Pratt et al., 1991). However, like other invasive procedures, these techniques are not without hazard. A case of severe pelvic infection requiring laparotomy has been reported (Pratt et al., 1991) and the other main complication is ectopic pregnancy (Lucena et al., 1989) as observed in the case report of the patient presented here. Tubal catheterization and the use of clomiphene citrate may account for ectopic pregnancy (Russell, 1987; Lucena et al., 1989; Risquez et al., 1990a). As previously stated by Pratt et al. (1991), further controlled studies with large numbers of patients are needed comprehensively to evaluate the overall success and complication rates of this procedure. Also as further stressed by Risquez et al. (1990a), while it seems clear that tubal cannulation via the cervix may contribute to the non-invasive exploration of the Fallopian tube, larger studies will help to define the role of transcervical cannulation in assisted reproduction.
J.BaJasch el al.
Received on June 17, 1992; accepted on My 24, 1992
1460
Downloaded from https://academic.oup.com/humrep/article-abstract/7/10/1457/664786 by Western Sydney University Library user on 11 January 2019
Melis.G.B., Paoletti,A.M., Strigini.F., Fabris.F.M., Canale.D. and Fioretti.P. (1987) Pharmacologic induction of multiple follicular development improves the success rate of artificial insemination with husband's semen in couples with male-related or unexplained infertility. FertiL Steril., 47, 441-445. Menard.A., CrequatJ., Mandelbrot,L., HauuyJ.P. and Mandelenat.P. (1990) Treatment of unruptured tubal pregnancy by local injection of methotrexate under transvaginal sonographic control. Fertil. Steril., 54, 4 7 - 5 0 . Moghissi,K.S. (1986) Some reflections on intrauterine insemination. Fertil. Steril., 46, 13-15. Mottla.G.L., Rulin.M.C. and Guzick.D.S. (1992) Lack of resolution of ectopic pregnancy by intratubal injection of methotrexate. Fertil. Steril., 57, 685-687. Ory.S.J., Villanueva.A.L., Sand.P.K. and Tamura,R.K. (1986) Conservative treatment of ectopic pregnancy with methotrexate. Am. J. Obstet. Gynecol, 154, 1299-1306. Pratt.D.E., Bieber.E., Barnes,R., Shangold,G., Vignovic.E. and Schreiber.J. (1991) Transvaginal intratubal insemination by tactile sensation: a preliminary report. Fertil. Steril, 56, 984—986. Risquez.F., MathiesonJ. and Zorn.J.R. (1990a) Tubal cannulation via the cervix: A passing fency—or here to stay? J. In Vitro Fertil. Embryo Transfer, 7, 301-303. Risquez.F., Mathieson.J., Pariente.D., Foulot.H., Dubuisson.J.B., Bonnin,A., Cedard.L. and ZomJ.R. (1990b) Diagnosis and treatment of ectopic pregnancy by retrograde selective salpingography and intraluminal methotrexate injection: work in progress. Hum. Reprod., 5, 759-762. Russell.J.B. (1987) The etiology of ectopic pregnancy. Clin. Obstet. Gynecol, 30, 181-190. Sauer.M.V., Gorrill.M.J., Rodi,I.A., Yeko.T.R., Greenberg.L.H., Bustillo.M., Gunning.J.E. and BusterJ.E. (1987) Nonsurgical management of unruptured ectopic pregnancy: an extended clinical trial. Fertil. Steril, 48, 752-755. Schiff.E., Shalev.E., Bustan.M., Tsabari.A., Mashiach.S. and Weiner.E. (1992) Pharmacokinetics of methotrexate after local tubal injection for conservative treatment of ectopic pregnancy. Fertil. Steril, 57, 688-690. Shapiro,B.S. (1987) The nonsurgical management of ectopic pregnancy. Clin. Obstet. Gynecol, 30, 230-235. Stovall.G., Ling.F.W. and Gray.L.A. (1991) Single-dose methotrexate for treatment of ectopic pregnancy. Obstet. Gynecol., 77, 754—757. Tanaka.T., Hayashi.H., Kutsuzawa.T., Fujimoto.S. and Ichinoe.K. (1982) Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case. Fertil. Steril, 37, 851-852. Vermesh.M. (1989) Conservative management of ectopic gestation. Fertil. Steril, 51, 559-567.
Transvaginal intratubal insemination, ectopic pregnancy and treatment by single-dose parenteral methotrexate
Department of Obstetrics and Gynaecology and 2Hormonal Laboratory, Faculty of Medicine, Hospital Clinic i Provincial, C/Casanova 143, 08036-Barcelona, Spain 'To whom correspondence should be addressed
We report a case of a woman with ectopic pregnancy with fetal cardiac activity after ovulation induction and transvaginal intratubal insemination by tactile sensation. The patient was successfully treated by single-dose methotrexate (MTX) (77 mg or 50 mg/m2 given intramuscularly). Control hysterosalpingograms showed no tuba! patency on the involved side. Potential advantages and hazards of transvaginal intratubal insemination and single-dose MTX for ectopic pregnancy are discussed. Key words: ectopic pregnancy/intratubal insemination/single-dose methotrexate
Introduction Assisted reproductive technology (ART), which has become the mainstay in the treatment of infertility in the last decade, includes in-vitro fertilization and embryo transfer (TVF — ET), gamete intra-Fallopian transfer (GIFT), zygote intra-Fallopian transfer (ZIFT), and other modalities of zygote or gamete transfer. Since the first report on transvaginal tubal catheterization for medically assisted procreation (Jansen and Anderson, 1987; Risquez et al., 1990a), transvaginal catheterization of the Fallopian tube for the purpose of transferring embryos and gametes has been gaining popularity in the treatment of infertile couples when the female partner has at least one patent Fallopian tube (Pratt et al., 1991). However, ectopic pregnancy has been associated with the use of ART (Russell, 1987; Lucena etal., 1989). Traditionally, surgical removal of tuba! pregnancy has been the treatment of choice, but in the past decade different conservative treatment methods have been reported (Shapiro, 1987; Vermesh, 1989). Nonsurgical treatment includes expectant management, RU486, prostaglandins and methotrexate (MTX) (Vermesh, 1989). Chemotherapy with MTX for ectopic pregnancy has shown significant promise as an alternative to surgical management (Cannon and Jesionowska, 1991). Early studies which have included multiple MTX doses with or without citrovorum rescue indicated that this treatment should not be undertaken if tubal pregnancy with fetal heart motion is noted © Oxford University Press
on ultrasound (Sauer etal., 1987; Cannon and Jesionowska, 1991). However, a very recent study of 30 patients with ectopic pregnancy including six cases with cardiac activity, suggests that single-dose i.m. MTX could be effective medical treatment for the unruptured tubal pregnancy of ^3.5 cm in greatest dimension with or without cardiac activity (Stovall etal., 1991). We report here a case of a woman with ectopic pregnancy and fetal heart motion after ovulation induction and transvaginal intratubal insemination, who was successfully treated by singledose, parenteral administration of methotrexate.
Case report A 31-year-old woman was referred to our care because of 6 years primary infertility. Past medical histories of the patient and her husband were unremarkable. A normal female infertility evaluation included basal body temperature charts, hysterosalpingography, midluteal plasma progesterone, oestradiol and prolactin, late luteal phase endometrial biopsy and cultures, and laparoscopy. The postcoital test was repeatedly negative (spermatozoa absent or immotile) in spite of good cervical mucus (thin, clear, acellular, high spinnbarkeit) and different semen examinations revealed persistent asthenozoospermia (>20 X 106 spermatozoa/ml, motility 50% (Cannon and Jesionowska, 1991). MTX has been applied by several different methods, either via parenteral or oral therapy or via local injections. Effort has been directed toward attaining maximal efficacy while minimizing or eliminating adverse complications. This has resulted in a progression from systemic to local MTX treatment (Cannon and Jesionowska, 1991). However, several important issues concern local MTX treatment. Firstly, a very recent study on its systemic
pharmacokinetics after local injection intratubally showed that its peak serum level and the area under the curve are similar to those observed after i.m. injection of the drug (Schiff et al., 1992). Therefore, in regard to serum drug level and exposure to systemic toxicity, there is no advantage to the local tubal-guided injection over that of a single-dose i.m. treatment. Secondly, there remains the question whether local MTX injection is directly toxic to the Fallopian tube and would result in significant changes leading to a decrease in reproductive function (Cannon and Jesionowska, 1991). Although in a pregnant rat model no toxicity on the genital tract mucosa has been observed with local MTX injection (Menard et al., 1990), clinical studies emphasize that a potential disadvantage of high local concentrations might be the negative influence on the recovery of the tubal mucosa and the muscular layer (Kooi and Kock, 1990; Menard et al., 1990; Risquez etal, 1990b). Finally, a recently published series including an analysis of previous literature on the subject concludes that, in fact, there is a truly increased risk for additional surgical or medical treatment among patients with ectopic pregnancy managed using intratubal MTX injection (Mottla etal, 1992). Taking into account the above-mentioned facts and the preliminary report by Stovall et al. (1991), which is indicative of consistent success from single-dose MTX for treatment of ectopic pregnancy of < 3.5 cm in larger dimension, single i.m. treatment is likely to be favoured. In early parenteral trials 'fetal heart motion' was a contraindication to MTX treatment (Sauer et al., 1987; Cannon and Jesionowska, 1991) and only six cases with cardiac activity were included in the series by Stovall et al. (1991); five of the six cases were successfully treated. The case presented here adds further evidence to the usefulness of this treatment modality, but further studies are necessary to establish tuba! patency rates after single-dose parenteral MTX for treatment of ectopic pregnancy. References Allen,N., Herbert.C.M., Maxson,W.S., Rogers,B.J., Diamond,M.P. and Wentz,A.C. (1985) Intrauterine insemination: a critical review. Fenil. Sterii, 44, 569-580. Bauer,O., Van der Ven.H., Diedrich.K., Al-Hasani,S., Krebs.D. and Gembruch.U. (1990) Preliminary results on transvaginal tubal embryo stage transfer (TV-TEST) without ultrasound guidance. Hum Reprod., 5, 553-556. Cannon,L. and Jesionowska,H. (1991) Methotrexate treatment of tubal pregnancy. Fenil Sterii., 55, 1033-1038. Confino,E., Friberg.J., Dudkiewicz,A.B. and Gleicher.N. (1986) Intrauterine insemination with washed human spermatozoa. Fenil. Sterii., 46, 55-60. Jansen,R.P.S. and Anderson J.C. (1987) Catheterization of the fallopian tube from the vagina. Lancet, II, 309-310. Kooi,S. and Kock,H. (1990) Treatment of tubal pregnancy by local injection of methotrexate after adrenaline injection into the mesosalpinx: a report of 25 patients. Fenil. Sterii., 54, 580-584. Li.M.C, Hertz.R. and Spencer.D.B. (1956) Effect of methotrexate therapy upon chonocarcinoma and chorioadenoma. Proc. Soc. Exp. Biol. Med.. 93, 361-365. Lucena,E., RuizJ.A., MendozaJ.C, OrtizJ.A., Lucena.C, Gdmez.M. and Arango,A. (1989) Vaginal intratubal insemination (VTTl) and vaginal GIFT, endosonographic technique: early experience. Hum. Reprod.. 4, 658-662. 1459
Downloaded from https://academic.oup.com/humrep/article-abstract/7/10/1457/664786 by Western Sydney University Library user on 11 January 2019
insemination with husband's semen can be related not only to the selection of patients but also to other technical factors, such as sperm preparation or site of insemination. The methodology of intrauterine insemination has evolved considerably as a result of developments in assisted reproductive technology. Thus, semen characteristics can be improved with the use of washing and capacitation techniques, clomiphene citrate and gonadotrophins are used to 'time' ovulation, and intratubal insemination can place the spermatozoa in the Fallopian tube nearest the ovary with the dominant follicle (Confino et al., 1986; Melis et al., 1987; Pratt et al., 1991). Transvaginal tubal transfer via tactile sensation is easily performed and can result in pregnancy rates comparable to those obtained using a transvaginal approach with ultrasound guidance (Lucena et al., 1989; Pratt et al., 1991). However, like other invasive procedures, these techniques are not without hazard. A case of severe pelvic infection requiring laparotomy has been reported (Pratt et al., 1991) and the other main complication is ectopic pregnancy (Lucena et al., 1989) as observed in the case report of the patient presented here. Tubal catheterization and the use of clomiphene citrate may account for ectopic pregnancy (Russell, 1987; Lucena et al., 1989; Risquez et al., 1990a). As previously stated by Pratt et al. (1991), further controlled studies with large numbers of patients are needed comprehensively to evaluate the overall success and complication rates of this procedure. Also as further stressed by Risquez et al. (1990a), while it seems clear that tubal cannulation via the cervix may contribute to the non-invasive exploration of the Fallopian tube, larger studies will help to define the role of transcervical cannulation in assisted reproduction.
J.BaJasch el al.
Received on June 17, 1992; accepted on My 24, 1992
1460
Downloaded from https://academic.oup.com/humrep/article-abstract/7/10/1457/664786 by Western Sydney University Library user on 11 January 2019
Melis.G.B., Paoletti,A.M., Strigini.F., Fabris.F.M., Canale.D. and Fioretti.P. (1987) Pharmacologic induction of multiple follicular development improves the success rate of artificial insemination with husband's semen in couples with male-related or unexplained infertility. FertiL Steril., 47, 441-445. Menard.A., CrequatJ., Mandelbrot,L., HauuyJ.P. and Mandelenat.P. (1990) Treatment of unruptured tubal pregnancy by local injection of methotrexate under transvaginal sonographic control. Fertil. Steril., 54, 4 7 - 5 0 . Moghissi,K.S. (1986) Some reflections on intrauterine insemination. Fertil. Steril., 46, 13-15. Mottla.G.L., Rulin.M.C. and Guzick.D.S. (1992) Lack of resolution of ectopic pregnancy by intratubal injection of methotrexate. Fertil. Steril., 57, 685-687. Ory.S.J., Villanueva.A.L., Sand.P.K. and Tamura,R.K. (1986) Conservative treatment of ectopic pregnancy with methotrexate. Am. J. Obstet. Gynecol, 154, 1299-1306. Pratt.D.E., Bieber.E., Barnes,R., Shangold,G., Vignovic.E. and Schreiber.J. (1991) Transvaginal intratubal insemination by tactile sensation: a preliminary report. Fertil. Steril, 56, 984—986. Risquez.F., MathiesonJ. and Zorn.J.R. (1990a) Tubal cannulation via the cervix: A passing fency—or here to stay? J. In Vitro Fertil. Embryo Transfer, 7, 301-303. Risquez.F., Mathieson.J., Pariente.D., Foulot.H., Dubuisson.J.B., Bonnin,A., Cedard.L. and ZomJ.R. (1990b) Diagnosis and treatment of ectopic pregnancy by retrograde selective salpingography and intraluminal methotrexate injection: work in progress. Hum. Reprod., 5, 759-762. Russell.J.B. (1987) The etiology of ectopic pregnancy. Clin. Obstet. Gynecol, 30, 181-190. Sauer.M.V., Gorrill.M.J., Rodi,I.A., Yeko.T.R., Greenberg.L.H., Bustillo.M., Gunning.J.E. and BusterJ.E. (1987) Nonsurgical management of unruptured ectopic pregnancy: an extended clinical trial. Fertil. Steril, 48, 752-755. Schiff.E., Shalev.E., Bustan.M., Tsabari.A., Mashiach.S. and Weiner.E. (1992) Pharmacokinetics of methotrexate after local tubal injection for conservative treatment of ectopic pregnancy. Fertil. Steril, 57, 688-690. Shapiro,B.S. (1987) The nonsurgical management of ectopic pregnancy. Clin. Obstet. Gynecol, 30, 230-235. Stovall.G., Ling.F.W. and Gray.L.A. (1991) Single-dose methotrexate for treatment of ectopic pregnancy. Obstet. Gynecol., 77, 754—757. Tanaka.T., Hayashi.H., Kutsuzawa.T., Fujimoto.S. and Ichinoe.K. (1982) Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case. Fertil. Steril, 37, 851-852. Vermesh.M. (1989) Conservative management of ectopic gestation. Fertil. Steril, 51, 559-567.
