Gamete intrafallopian transfer by hysteroscopy as an alternative treatment for infertility

FERTILITY AND STERILITY Copyright

©

Vol. 56, No. 3, September 1991

1991 The American Fertility Society

Printed on acid· free paper in U.S.A.

Gamete intrafallopian transfer by hysteroscopy as an alternative treatment for infertility

Giovanna Possati, M.D.* Renata Seracchioli, M.D. Corrado Melega, M.D.

Anna Pareschi, M.D. Andrea Maccolini, M.D. Carlo Flamigni, M.D.

Department of Obstetrics and Gynecology, Reproductive Medicine Unit, University of Bologna, Italy

Objective: To evaluate efficacy and safety of the hysteroscopic cannulation by flexible catheter of the fallopian tubes for gamete intrafallopian transfer (GIFT). Design: We studied the pregnancy rate (PR) and the safety of this new technique. Setting: All patients were enlisted for GIFT at our Reproductive Medicine Unit. Patients: We treated 26 patients whose infertility causes were terminal tubal damage, male factors, unexplained factors, and endometriosis. Patients with uterine tubal ostia unsuitable for gamete transfer or cervical incontinence were not included in the group. Interventions: The patients underwent ovulation induction and oocyte retrieval by transvaginal ultrasonically guided puncture. The gamete transfers were carried out by hysteroscopic procedure using a flexible catheter put through the operating channel. Main Outcome Measure: The efficacy was evaluated by the PR (25.9%). Results: Seven clinical pregnancies were obtained, but two patients aborted during the first weeks of pregnancy. No ectopic pregnancies were observed. Conclusions: Our results indicate that hysteroscopic GIFT is an alternative, safe, effective, and not invasive technique for fertility problems. Fertil Steril 56:496, 1991

Gamete intrafallopian transfer (GIFT) is a technique of reproductive assistance that was first reported by Asch et al. 1 in 1984. Gamete intrafallopian transfer is currently used to deal with fertility problems when the fallopian tubes are patent. Laparoscopy or minilaparotomy to retrieve the oocytes and reach the tube for transfer are used. 1- 3 Therefore, these procedures require hospitalization and general anesthesia. Dellenbach et al. 4 first introduced oocyte retrieval through ultrasonically guided transvaginal puncture. Some authors5 suggested transferring the gametes by hysteroscopy, performing all procedures without general anesthesia.

Received September 4, 1990; revised and accepted May 17, 1991. *Reprint requests: Giovanna Possati, M.D., Department of Obstetrics and Gynecology, Reproductive Medicine Unit, University of Bologna, Via Massarenti no. 13, 40128 Bologna, Italy. 496

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To assess the clinical importance of this technique, a group of patients who underwent hysteroscopic GIFT were treated. The purpose of this study was to evaluate the pregnancy rate (PR) and the safety of this new technique (occurrence of pregnancy loss and intratubal pregnancy). MATERIALS AND METHODS

Twenty-six female patients (mean age of 31 + 4.7; range 21 to 41 years) were treated in this study during a 6-month period (June 1989 to December 1989). Every couple underwent complete infertility evaluation before scheduling GIFT. 6 •7 Semen analysis (count, motility, morphology), postcoital test, hormonal levels (prolactin = 12.8 + 2.5 ng/mL, progesterone [P] = 0.5 + 0.1 ng/mL), hysterosalpingogram, and laparoscopy were performed. The causes of infertility were terminal tubal damage (patient no. 10; 38.5%), male factor (patient no. 5; 19.2%) with sperm count < 20 X 106 and Fertility and Sterility

Table 1

Cause and Duration of Infertility

No. of patients Duration of infertility (y)

Tubal

Male

10 (38.5)" 5.9 + 2.6b

5 (19.2) 5 + 2.1

• Values in parentheses are percents.

motility < 30%, and unexplained factors (patient no. 7; 26.9% ), and endometriosis (patient no. 4; 15.4%) stage I and II, according to revised American Fertility Society classification.8 The mean duration of infertility for each cause is shown in Table 1. The risk of ectopic pregnancy (EP) in the patients with terminal tube damage is known, so the procedure was limited to the cases in which tubes seemed to be less impaired, and the better one was chosen by laparoscopy. The aspects of terminal tube damage were perifallopian tube filmy adhesion, filmy adhesion of the fimbriated end of the tube, and phimosis. The semen was also studied by a swim-up test according to those patients entering the study who had at least 1 X 106 spermatozoa/mL with motility superior to 35%. Otherwise, the patients underwent an in vitro fertilization/embryo transfer procedure to test fertilization capacity. To complete the infertility evaluation,9 hysteroscopy was carried out in the surgery on all patients to confirm the hysterosalpingogram results and to check and choose the tubal ostia for gamete transfer. During hysteroscopy, no paracervical block was used, but atropine (0.5 mg intramuscularly [IM]) was administered 30 minutes before the procedure. The patients with uterine tubal ostia unsuitable (no. 3; 9.1%) for gamete transfer or cervical incontinence (no. 4; 12.1%), which did not allow uterine distention, were not included in this group.

Vol. 56, No.3, September 1991

Endometriosis

7 (26.9) + 3.2

4 (15.4) 8.3 + 4.7

5.4

bValues are means± SD.

two or more follicles exceeded the mean size of 16 mm and E 2 levels were 600 pg/mL. Three days after transfer of gametes, all patients received a dose of 25 mg/d IM of pure P (Gestone; AMSA, Florence, Italy) for 2 weeks to support the luteal phase until the pregnancy test was positive or menses onset. If pregnant, the patient continued P supplementation for an additional 4 weeks. Oocyte Retrieval and Gamete Transfer

Oocyte retrieval was performed 34 to 36 hours after hCG administration by transvaginal ultrasonically guided puncture. The patients underwent sedation with diazepam 10 mg IM administered 15 minutes before all procedures. Atropine (0.5 mg IM) was administered 30 minutes before oocytes retrieval and gamete transfer. Once the oocytes were retrieved, they were placed in culture medium (human Table 2

Stimulation Protocol

Day of therapy 1st to 14th" 15th 16th 17th

Induction of Ovulation

Gonadotropin-releasing hormone analog (300 f.Lg Suprefact; Hoechst, Amsterdam, The Netherlands), was administered subcutaneously (SC) twice a day starting from the midluteal phase of the cycle preceding the one chosen for the treatment. After obtaining pituitary suppression, a routine stimulation protocol was used up to day 6 (Table 2). Ovulation induction was monitored by daily pelvic ultrasound (US) and serum estradiol (E 2 ) levels starting on day 7 until the day of human chorionic gonadotropin (hCG, Profasi; Serono, Rome, Italy) administration. Gonadotropin-releasing hormone analog was continued until10,000 IU hCG administration if at least

Unexplained

Hour

Dosage

8A.M. 8P.M. 8A.M. 8P.M. 8A.M. 8P.M. 8A.M.

Suprefact 300 JLg, SC Suprefact 300 JLg, SC Suprefactb + 300 IU FSHc Suprefact Suprefact + 300 IU FSH Suprefact Suprefact + 75 IU FSH + 75 IUhMGd Suprefact + 75 IU FSH + 75 IUhMG Suprefact + 75 IU FSH + 75 IUhMG Suprefact + 75 IU FSH + 75 IUhMG Suprefact + 75 IU hMG Suprefact + 75 IU hMG Suprefact Suprefact + 150 IU hMG Suprefact Start of monitoring and individually adjusted therapy

8P.M. 18th

8A.M. 8P.M.

19th 20th 21st

8A.M. 8P.M. 8A.M. 8P.M. 8A.M.

• The 1st day of treatment corresponds to day 21 of cycle. b Suprefact dosage is the same (300 JLg SC) for all the super· ovulation protocol duration. c FSH, follicle-stimulating hormone. d HMG, human menopausal gonadotropin.

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tubal fluid [GIBCO Ltd./ 0 Paisley, Scotland] plus 10% of patient serum) and graded for maturity. Then the transfer was carried out into the fallopian tube under C0 2 hysteroscopic visualization. A 30° chorionhysteroscope with 4 mm of outer diameter sheath (Storz, Tuttlingen, Germany) was used. An operating sheath with two stopcocks and an operating channel feeding into a common channel was employed. Sperm and oocytes were placed in the transfer catheter as follows: spermatozoa, oocytes, spermatozoa, and human tubal fluid. The gametes were loaded in the endoscopic catheter, and no medium or air bubbles separated the gametes. The flexible endoscopic catheter (Teflon-Katheter 1.15 X 1.60 mm; Wisap, Sauerlach, Germany) was put through the operating channel and was advanced 2 to 4 em into the tubal lumen. The C0 2 distention medium of uterine cavity was stopped, and after 1 minute, the gametes were gently injected into the tube, using a 1-ml syringe. The catheter then was checked to ensure that it was completely emptied of gametes. The number of mature oocytes transferred into one tube was 2 to 5, and the motile sperm was generally 100,000 to 200,000. The total volume placed into the tube was 60 to 100 mL. Sperm Preparation

Sperm was collected by masturbation 1.5 up to 2 hours before follicular aspiration. The semen specimen, after liquefaction, was washed, centrifugated at 270 to 300 X g for 10 minutes, and allowed to swim-up using Ham's F-10 medium (Gibco Ltd.) containing streptomycin and penicillin. The final pool was therefore incubated at 37° in an atmosphere of 5% C0 2 and 95% air until gamete transfer. RESULTS

From June 1989 to December 1989, twenty-seven hysteroscopic G 1FT procedures were carried out. Twenty-nine cycles were started, but two were stopped because patients did not respond to induction of ovulation. No cycle was discontinued because of technical reasons or ovarian inaccessibility. One hundred twenty-eight oocytes were retrieved by transvaginal ultrasonically guided puncture. The mean number of oocytes retrieved per cycle was 4.8 ± 2.8. The mean number of mature oocyte transferred per hysteroscopic GIFT was 3.7 ± 1.3. Only one tube was used for hysteroscopic GIFT. Seven clinical pregnancies were established (25.9% percycle), and the pregnancy outcome within each diagnostic group is shown in Table 3. Two pregnancies 498

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Table 3

Cause of Infertility and Occurrence of Pregnancy Male

Unexplained

Tubal

Endometriosis

5

7

10

4

2

2

1

2"

Study group (n = 26) Pregnant women " Miscarriage.

are ongoing. One patient gave birth to a healthy infant, whereas two patients gave birth to twins. Two patients aborted between the 5th and 6th weeks after transfer. No EP was observed. All procedures were performed without hospitalization and general anesthesia. No US and hysteroscopic G1FT were discontinued because of excessive pain or stress. Thus, patients who underwent hysteroscopic G 1FT procedures reported low distress. DISCUSSION

In our study, the retrograde cannulation of the fallopian tube 11 •12 was performed by flexible catheter for gamete transfer through the operating channel of the hysteroscope. This new technique for GIFT involved using the chorionhysteroscope and C0 2 to visualize uterine cavity and tubal ostia. To avoid the adverse effects of C0 2 on oocyte fertilization, C0 2 was stopped for at least 60 seconds before the injection. Certain authors 13 •14 demonstrated that C0 2 has adverse effects on mouse and human oocytes (low rate of cleavage and fertilization). Boyers et aU 5 found that the last recovered oocytes fertilized less than the first recovered eggs when the time interval between recovery of first and last eggs was >5 minutes. Seven pregnancies were established and no EP occurred. The good PR (25.9%) was not influenced by employing only one tube. Haines and O'Shea, 16 in fact, have reported that unilateral laparoscopic GIFT may be at least as successful as the bilateral approach. Our data on the PR confirm their results by employing only one tube, even if the technique for gamete transfer is different. Pregnancies were obtained in all infertility groups. Our data, though, are still too few to allow clinical conclusions as to pregnancies in group of patients more suitable for this technique. The new technique for hysteroscopic G 1FT procedure, allowing the use of sedation and no hospitalization or general anesthesia, was well accepted by all patients and the grading of distress was low. Fertility and Sterility

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Thanks to these new procedures and to their tolerability, the treatment of infertility is easily repeatable and allows good occurrence of pregnancy. The criteria used for patient selection in hysteroscopic GIFT were the same as patient selection in laparoscopic GIFT. Moreover, hysteroscopic procedures were used when the patients could not tolerate general anesthesia, when there were pelvic adhesions that did not allow to reach tubes, and when, because of organizational reasons, the operating room was not available. On the other hand, patients with tubal ostia imperfections or cervical incontinence, diagnosed before infertility treatment, were not scheduled for hysteroscopic GIFT. This new technique also involves considerably lower costs. There are still some questions requiring an answer, such as the usefulness of hysteroscopic GIFT in damaged tubes in distal area or which is optimum insertion length. It must also be found out whether a rigid, a semirigid, or a flexible hysteroscope may be preferable and whether there are better catheters available. In spite of these problems, though, our results showed that hysteroscopic transfer of gametes into the fallopian tube is a new, safe, and effective technique for fertility problems. REFERENCES 1. Asch RH, Ellsworth LR, Balmaceda JP, Wong PC: Pregnancy after translaparoscopic gamete intrafallopian transfer. Lancet, 2:1034, 1984 2. Asch RH, Balmaceda JP, Ellsworth LR, Wong PC: Preliminary experiences with gamete intrafallopian transfer (GIFT). Fertil Steril 45:366, 1986 3. Molloy D, Speirs A, du Plessis Y, Mcbain J, Johnston 1: A laparoscopic approach to a program of gamete intrafallopian transfer. Fertil Steril 4 7:289, 1987

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4. Dellenbach P, Nisand I, Moreau L, Feger B, Plumere C, Gerlinger P, Brun B, Rumpler Y: Transvaginal sonographically controlled ovarian follicle puncture for egg retrieval. Lancet 1:1467, 1984 5. Wurfel W, Krusmann G, Rothenaicher M, Hirsch P, Krusmann W: Pregnancy following intratubal gamete transfer by hysteroscopy. Geburtshilfe Frauenheilkd 48:401, 1988 6. The American Fertility Society: Minimal standards for gamete intrafallopian transfer (GIFT). Fertil Steril50:20, 1988 7. The American Fertility Society: Revised minimum standards for in vitro fertilization, gamete intrafallopian transfer, and related procedures. Fertil Steril 53:225, 1990 8. The American Fertility Society: Revised American Fertility Society classification of endometriosis: 1985. Fertil Steril43: 351, 1985 9. Seinera P, Maccario S, Visentini L, Digregorio A: Hysteroscopy in IVF-ET program. Acta Obstet Gynecol Scand 67: 135, 1988 10. Quinn P, Kerin JF, Warnes GM: Improved pregnancy rate in human in vitro fertilization with the use of a medium based on the composition of human tubal fluid. Fertil Steril 44:493, 1985 11. Jansen RPS, Anderson JC: Catheterization of the fallopian tube from the vagina. Lancet 2:309, 1987 12. Risquez F, Boyer P, Rolet F, Magnani M, Guichard A, Cedard L, Zorn JR: Retrograde tubal transfer of human embryos. Human Reprod 5:185, 1990 13. Pabon JE, Jr, Findley WE, Gibbons WE: The toxic effect of short exposures to the atmospheric oxygen concentration on early mouse embryonic development. Fertil Steril51:896, 1989 14. Hayes MF, Sacco AG, Savoy-Moore RT, Magyar DM, Endler GC, Moghissi KS: Effect of general anesthesia on fertilization and cleavage of human oocytes in vitro. Fertil Steril 48:975, 1987 15. Boyers SP, Lavy G, Russell JB, De Cherney AH: A paired analysis of in vitro fertilization and cleavage rates of firstversus last-recovered preovulatory human oocytes exposed to varying intervals of 100% C0 2 pneumoperitoneum and general anesthesia. Fertil Steril 48:969, 1987 16. Haines CJ, O'Shea RT: Unilateral gamete intrafallopian transfer: the preferred method? Fertil Steril 51:518, 1989

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