Tubal Transfer Techniques for Assisted Reproduction
Table Of Contents
Edmond Confino, MD
TUBAL TRANSFER TECHNIQUES
TRANSVAGINAL GAMETE AND EMBRYO TRANSFER INTO THE FALLOPIAN TUBES
ARE INTRATUBAL GAMETE DEPOSITION PROCEDURES INDICATED?
Gamete intrafallopian transfer (GIFT) was performed for the first time in 1984,1 when in vitro fertilization (IVF) was in its inception. At that time pregnancy rates were very low, oocyte aspiration required laparoscopy, and laboratory embryo culture was in its early learning stages. It is therefore understandable that the transfer of sperm and oocytes into the fallopian tube, with its relatively high pregnancy rates, was received enthusiastically.2,3,4 Earlier attempts to transfer oocytes and sperm into the fallopian tubes via minilaparotomy were quickly replaced by laparoscopy, and the laparoscopic technique of elevating the fimbriated end of the fallopian tube and performing transabdominal cannulation of the fallopian tube using a catheter was perfected (Fig. 1). Although GIFT could not be performed in patients with damaged fallopian tubes, this procedure could be successful in patients with oligozoospermia, idiopathic infertility, and other indications.
The remarkable GIFT pregnancy rates, two to three times higher than IVF pregnancy rates, prompted many IVF centers to start GIFT programs in the 1980s.5,6,7 Performing GIFT required basic laboratory skills, including oocyte identification, sperm washing and concentration, adequate insemination, and short incubation of the oocytes in culture media. Therefore, many beginning IVF programs opted to perform GIFT first; only when they achieved pregnancies using GIFT did they switch to the more elaborate and demanding IVF setting.
In the late 1980s, vaginal probe real-time sonography became available, with improved gray scale images and better resolution. Transvaginal oocyte aspiration was less invasive and more efficient than laparoscopic oocyte aspiration (Fig. 2). Therefore, the GIFT technique was modified again. Vaginal aspiration of oocytes was followed by laparoscopy, tubal cannulation, and sperm and oocyte deposition into the ampulla. Minilaparotomy for GIFT was almost completely abandoned in the late 1980s. The superiority of laparoscopy was recognized by most GIFT programs, and this technique became the standard approach to GIFT.8
The attractive pregnancy rates of GIFT prompted early investigators to replace zygotes laparoscopically in the pronuclear stage into patients with normal fallopian tubes.9 The placement of zygotes inside the fallopian tube was more reassuring than GIFT because it documented fertilization. The pronuclear stage embryo transfer was labeled PROST.10 The tubal transfer of cleaved-for-the-first-time zygotes was named zygote intrafallopian transfer (ZIFT). The most recent development in tubal transfer occurred when embryo culture techniques improved and embryos were replaced into the fallopian tube at the two-cell to four-cell stage.11 The acronym for this procedure was TEST (tubal embryo-stage transfer) and was shortened to TET (tubal embryo transfer).
Once GIFT, ZIFT, and TET became well accepted in the medical community, additional applications were proposed for tubal gamete transfer. GIFT oocyte donation was successfully performed in patients with premature ovarian failure.12,13 GIFT was also extended to patients who repeatedly failed donor insemination.14
|TUBAL TRANSFER TECHNIQUES|
Patient preparation for GIFT, ZIFT, or TET is similar to that for any IVF procedure. Patients who undergo tubal procedures must have at least a hysterosalpingogram to determine the normality of their fallopian tubes. Recent studies have suggested that hysterosalpingography may not be sufficient, and additional evaluation of the fallopian tube may be necessary. Recent reports from Australia have suggested that falloposcopy performed before a GIFT procedure may improve the pregnancy rate.15 The underlying premise is that falloposcopy can be used to select only patients with normal endotubal folds; patients with subtle endotubal damage (e.g., microagglutination of mucosal folds and flattened endotubal epithelium) are rerouted to IVF-embryo transfer (IVF-ET) procedures.
Because laparoscopy is required during the conventional performance of GIFT, adding pre-GIFT laparoscopy to assess peritubal damage in the presence of a normal hysterosalpingogram has not received wide acceptance. The notion that GIFT could be combined with diagnostic laparoscopy to exclude peritubal damage was never widely accepted because of limited ability to visualize the stimulated ovaries and the peritoneal surfaces and to intervene and correct newly discovered pathology.
It is routine practice before tubal transfer procedures to evaluate semen parameters at least twice. It is also prudent to evaluate ovarian function based on the patient's history, age, and preexisting problems. Many programs reculture the patient's cervix for sexually transmitted agents and search for the presence of antibodies to Chlamydia trachomatis or other potential infectious agents, either in all patients or only in some.
Post-GIFT treatment may include progesterone support during the luteal phase. Some centers prefer repeat injections of low-dose human chorionic gonadotropin (hCG); others use progesterone supplementation only. There was concern that progesterone support in the luteal phase may compromise tubal mobility and result in higher ectopic pregnancy rates. However, this was never corroborated by any data, and ectopic pregnancy rates during tubal transfer procedures were comparable to those during uterine embryo transfer.11
Access into the abdominal cavity during GIFT, ZIFT, and TET requires two-puncture laparoscopy. One trocar in the umbilical region is used to gain access to the abdominal cavity and introduce a light source and a video laparoscope. The second entry port, in the suprapubic area, is used to introduce a nontraumatic fimbria-grasping instrument. The gamete catheter is introduced through a third and smaller port hole, typically in the selected site for gamete transfer.
The selection of either the right or left fallopian tube may be made intraoperatively at the time of the laparoscopy. Sometimes one fallopian tube is easier to reach; the other one may be more difficult to cannulate because of the patient's anatomic configuration or her hyperstimulated ovaries. The tube of choice is usually the easier one to cannulate. If the patient has only one normal fallopian tube, the gamete transfer catheter port of entry may be selected based on the shortest route and the ease of access into the fimbriae.
Multiple-catheter transfer systems have been evaluated for tubal transfer procedures. Most of these catheter systems involve a rigid straight trocar with a secondary curved catheter and a tertiary embryo or gamete transfer catheter (see Fig. 1). Most laparoscopic tubal transfer procedures can be performed with various simple coaxial catheter systems; they do not require the more elaborate steerable catheter systems introduced in the mid-1980s.16
The embryo transfer catheter is protested using the mouse embryo model to confirm that embryo toxicity is not present. Before the procedure, the catheter is rinsed with culture media, and the oocytes and sperm mixture or media-suspended embryos are loaded under a stereo microscope into the transfer catheter into a fluid bubble chamber. During GIFT procedures, three or four oocytes are inseminated with 100,000 motile spermatozoa. If male factor infertility is the underlying condition, the number of spermatozoa may be increased many fold.
Once the laparoscopic trocars are in place, the fallopian tube is visualized and the ampullary portion is elevated above the pelvic floor. A curved plastic or metal catheter is introduced gently into the ampullary portion of the fallopian tube. Gentle grasping of the fimbriated end of the fallopian tube is mandatory to avoid fimbrial damage and bleeding. The preferable location of the tubal grasper is at the antimesenteric portion of the fallopian tube, thus avoiding the fimbria ovarica. Careful observation will eliminate false catheterization of the fallopian tube. Once the curved catheter is placed inside the isthmoampullary junction of the fallopian tube, the embryologist loads the gametes into the transfer catheter. Within seconds, the catheter is introduced gently through the guiding catheter and the gametes are flushed out using 5 to 10 μL of culture medium. During the transfer procedure, the ampullary portion should be suspended in a vertical position to avoid leakage. The transfer catheter is flushed under a stereo microscope to verify complete expulsion of the gametes. The tube is gently placed in a horizontal position and the fimbriae are checked carefully to detect any leakage of fluid. If small amounts of transfer medium are used, reflux from the fallopian tube is unlikely to occur.
Recovery after a tubal transfer procedure is similar to that for diagnostic laparoscopy performed for other indications. The follow-up of early pregnancy is performed similar to that of any IVF gestation. Early β-hCG level detection and early sonographic monitoring of the pregnancy are directed toward early identification of abnormal pregnancies, including the detection of ectopic pregnancies.
|TRANSVAGINAL GAMETE AND EMBRYO TRANSFER INTO THE FALLOPIAN TUBES|
Once oocyte retrieval could be accomplished via outpatient transvaginal sonographically guided needle aspiration, the laparoscopy performed to accomplish tubal transfer became an obvious disadvantage compared to transcervical uterine embryo transfer.17 Noninvasive transvaginal catheterization of the fallopian tubes was reported for the first time under sonographic guidance in the late 1980s.18,19 Multiple attempts were made to establish a successful transvaginal gamete deposition technique. The development of a transcervical noninvasive technique required a reliable means of access into the fallopian tubes, under tactile impression or ultrasound or hysteroscopically. The ultrasound-guided approach was attractive because it was less invasive.20 Tubal catheterization under tactile impression required significant skills. Failure to catheterize the fallopian tubes occurred in about 12% of patients.19 This report was one of the few reports that documented pregnancy rates above 20% using the transcervical approach. Tubal gamete-embryo deposition performed under ultrasound guidance initially had only a 2% pregnancy rate, probably reflecting an early learning curve.21
Table 1 shows the variability in pregnancy rates with different transcervical procedures. This inconsistency is probably related to the various catheterization techniques, variable operator skills in transcervical cannulation, different patient selection, different sample sizes, and other unpredictable factors.19,20,21,22,23,24,25,26,27,28
US, ultrasound; GIFT, gamete intrafallopian transfer.
Although the higher pregnancy rates in Table 1 seem to be in a good range, consistently higher rates were reported during laparoscopic gamete tubal transfers, and the transcervical approach has not received wide acceptance to date. Transcervical GIFT, ZIFT, and TET will become accepted only if consistency is demonstrated, laparoscopic results are matched, and clear superiority is established over IVF-ET. Transcervical tubal deposition of gametes remains a technique that requires technological and medical refinements.
|ARE INTRATUBAL GAMETE DEPOSITION PROCEDURES INDICATED?|
Evaluating the efficacy of procedures such as GIFT, ZIFT, and TET depends largely on the comparison of their pregnancy rates to that of IVF-ET in patients with different medical indications. Laparoscopy is more invasive, riskier, and more costly than transcervical uterine embryo transfer; therefore, tubal transfer procedures must demonstrate unequivocal superiority over IVF-ET.
Most assisted reproduction programs in the United States and Canada prefer IVF-ET treatments, and fewer patients undergo laparoscopic tubal procedures.29,30 Table 2 shows the number of IVF and GIFT cycles and pregnancy and delivery rates in the United States. Interpreting Table 2 is quite complicated. Undoubtedly, between 1988 and 1993 both IVF and GIFT pregnancy rates have improved. Although the number of IVF cycles reported has almost doubled, the number of GIFT cycles has increased less than expected. This observation is intriguing because GIFT pregnancy rates were higher than IVF-ET pregnancy rates. The unaware observer may conclude that GIFT is superior to IVF. However, biases introduced by dropout rates after the first and subsequent cycles, life table analysis, and bias introduced from higher fecundity in the first 3 to 6 months of observation may affect the final pregnancy rates. Indications for GIFT may differ from the indications for IVF, resulting in the selection of GIFT patients who are more likely to conceive.31 Comparison of GIFT to conventional treatments among women with unexplained infertility generates an initial calculation of a sevenfold improvement when GIFT is applied. However, taking into consideration only three months or less of observation for GIFT, compared to longer periods of observation for patients without any treatment, reduces the apparent superiority of GIFT to an odds ratio of only 1.79 with a wide confidence interval, making it statistically insignificant compared to no treatment.31,32 If GIFT is compared to superovulation combined with intrauterine insemination (IUI) in patients with unexplained infertility, and only prospective studies are evaluated, the cycle fecundity of GIFT ranges between 0.12 to 0.28, and the cycle fecundity of patients who underwent IUI and superovulation ranges between 0.01 and 0.36.32 The very large overlapping pregnancy odds ratio does not support the superiority of GIFT over less invasive and less expensive interventions such as superovulation and IUI.
IVF, in vitro fertilization; GIFT, gamete intrafallopian transfer.
In a prospective randomized study comparing IVF, GIFT, and TET in 150 couples with unexplained infertility, male factor infertility, and minimal endometriosis, the pregnancy rates per transfer were 46% for IVF, 38% for TET, and 26% for GIFT. If the number of eggs and embryos transferred were controlled for, GIFT had a significantly lower implantation rate of 7% compared to IVF with 13%.33 This report concluded that implantation rates per embryo transferred are not superior in tubal procedures compared to IVF.34 A prospective single-cycle IVF-ET nonrandomized study with patients who underwent a previous IVF cycle demonstrated a higher pregnancy rate with GIFT than with IVF.35 If one accepts that patients with unexplained infertility demonstrate higher fertilization rates during IVF but lower implantation rates than patients with tubal disease, then it would be preferable to perform IVF rather than GIFT.31
The costs of tubal procedures also determine the final selection in patients with normal fallopian tubes. If one to four cycles of superovulation and IUI are as effective as one cycle of IVF in producing a pregnancy, three non-IVF cycles are superior to IVF or ZIFT and comparable to GIFT. Using the same assumptions, four cycles of superovulation and IUI are superior to IVF or GIFT. If the average costs of one cycle of superovulation with human menopausal gonadotropins (hMG) and IUI are compared to one cycle of IVF, one would prefer four cycles of hMG combined with IUI over IVF, GIFT, or ZIFT.36,37 The absence of the expected rise in the use of GIFT procedures over time (see Table 2) reflects a similar understanding of practitioners. Other considerations, such as IVF's high costs and lack of insurance coverage for GIFT procedures, may have also resulted in the preferential use of superovulation with IUI over IVF, GIFT, or TET. Therefore, IVF or GIFT is performed only in patients who can either afford this procedure or have insurance coverage.37
The percentage of IVF-related ectopic pregnancies is higher than in the general population. However, there is no indication that tubal transfer procedures result in an ectopic rate higher than that of IVF-ET. This observation was confirmed in several reports.29,30
Both IVF and GIFT pregnancies demonstrate a relatively high proportion of preterm births and low-birthweight infants.38,39 Some of those preterm deliveries are induced because of multiple gestations. However, even singleton term intrauterine gestations obtained either by IVF-ET or GIFT have higher prematurity rates than in the general population.39 This finding raises major concerns about the use of both IVF and tubal transfer procedures, because the use of assisted reproductive technologies increases significantly the medical expenses per live-born “take-home” baby. The increased percentage of twins and triplets is associated with the obvious risks of prematurity, neonatal morbidity and mortality, and increased risks of cardiovascular disease, diabetes mellitus, and subsequent obstructive lung disease in adult life. Therefore, not only pregnancy rates but also cost-effectiveness and the well-being of the offspring must be included in the final assessment of the role of tubal transfer procedures in the treatment of nontubal infertility.
Only a few studies have tested prospectively the hypothesis that tubal transfer of gametes and embryos is superior to uterine transfer in patients with nontubal factor infertility.40,41 Prospective randomization of patients did not demonstrate any superiority of either procedure when standard outcome parameters were used in relatively small studies. It can be argued that increasing the sample sizes of those prospective randomized studies would have brought statistical significance, and large studies would have demonstrated the superiority of tubal transfer procedures. However, if power analysis requires very large studies to demonstrate statistically significant differences in pregnancy rates, then the magnitude of the difference is probably of minor or no clinical importance.
Until the superiority of tubal transfer procedures is unequivocally established, they cannot be advocated without considering the IVF-ET alternative. Only a few patients who demonstrate cervical stenosis or uterine cavities inaccessible to catheters are unequivocal candidates for GIFT, ZIFT, and TET. Even those patients may achieve an IVF-ET pregnancy using a transmyometrial embryo transfer system42 (Fig. 3).
The added cost of laparoscopy during tubal transfer procedures mandates a careful consideration of health-care resources. Laboratory improvements and the delivery of high-quality embryos into the uterine cavity may eventually render tubal transfer procedures obsolete. The final role of tubal transfer procedures in clinical practice remains unclear. The early need to compensate for inferior laboratory skills is decreasing. Like many other procedures, tubal transfer procedures will eventually find their role in patients with nontubal factor infertility.
2. Noss U, Weideman R, Hepp H: Gamete intra-fallopian transfer (GIFT): Results of 219 treatment cycles in idiopathic sterility, andrological subinfertility and selected forms of genital pathology. Geburtshilfe Frauenheilkd 47: 797, 1987
7. Asch RH, Balmaceda JP, Wong PC et al: Gamete intrafallopian transfer (GIFT): Use of mini-laparotomy and an individualized regimen of induction of follicular development. Acta Eur Fertil 17: 187, 1986
13. Asch RH, Balmaceda JP, Ord T et al: Gamete intrafallopian transfer (GIFT) and oocyte donation: A novel treatment for infertility in premature ovarian failure: Case report. Gynecol Endocrinol 1: 99, 1987
14. Cefalu E, Cittadini E, Balmaceda JP et al: Successful gamete intrafallopian transfer following failed artificial insemination by a donor: Evidence for a defect in gamete transport? Fertil Steril 50: 2, 1988
21. Jansen RPS, Anderson JA: Transvaginal gamete and embryo transfer to the fallopian tubes. In Capitanio GL, Asch RL, De Cecco L, Croce S (eds): GIFTS: From Basics to Clinics, p 383. New York, Raven, 1989
23. Lucena E, Ruiz JA, Mendoza JC et al: Vaginal intratubal insemination (VITI) and vaginal GIFT endosonographic technique: Early experience. Presented at the VI World Congress of In Vitro Fertilization, Jerusalem, April 2–7, 1989
24. Bustillo M, Munabi AK, Bender S et al: Transcervical ultrasound-guided intrafallopian placement of gametes, zygotes, and embryos. Presented at the VI World Congress of In Vitro Fertilization, Jerusalem, April 2–7, 1989
26. Sholtes MCW, Roozenburg BJ, Alberda TH, Zeilmaker GH: Transcervical intrafallopian transfer (TIFT): A randomized study between TIFT and IVF-ET. Presented at the 7th World Congress on In Vitro Fertilization and Assisted Procreations, Paris, June 30-July 3, 1991
29. The American Fertility Society/Society for Reproductive Technology: Assisted reproductive technology in the United States and Canada: 1992 results generated from The American Fertility Society/Society for Assisted Reproductive Technology Registry. Fertil Steril 62:1121, 1994
30. Society for Reproductive Technology/American Society for Reproductive Medicine: Assisted reproductive technology in the United States and Canada: 1993 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril 64:13, 1995
31. Dawood MY: In vitro fertilization, gamete intrafallopian transfer, and superovulation with intrauterine insemination: Efficacy and potential hazards on babies delivered. Am J Obstet Gynecol 174: 1208, 1996
32. Murdoch AP, Harris M, Mahroo M et al: Gamete intrafallopian transfer (GIFT) compared with intrauterine insemination in the treatment of unexplained infertility. Br J Obstet Gynaecol 98: 1107, 1991
33. Tanbo T, Dale PO, Abyholm T: Assisted fertilization in infertile women with patent fallopian tubes: A comparison for in-vitro fertilization, gamete intra-fallopian transfer and tubal embryo stage transfer. Hum Reprod 5: 266, 1990
34. Leeton J, Roger P, Caro C et al: A controlled study between the use of gamete intrafallopian transfer (GIFT) and in vitro fertilization and embryo transfer in the management of idiopathic and male infertility. Fertil Steril 48: 605, 1987
35. Mills MS, Eddowes HA, Cahill HJ et al: A prospective controlled study of in-vitro fertilization, gamete intra-fallopian transfer and intrauterine insemination, combined with superovulation. Hum Reprod 7: 490, 1992
36. Petersen CM, Hatasaka HH, Jones KP et al: Ovulation induction with gonadotropins and intrauterine insemination compared with in vitro fertilization and no therapy: A prospective, nonrandomized, cohort study and meta-analysis. Fertil Steril 62: 535, 1994
37. Grobler S, Hamlett DK: Cost-effectiveness of gamete intrafallopian transfer in comparison with induction of ovulation with gonadotropins in the treatment of female infertility: A clinical trial. Fertil Steril 57: 163, 1992
41. Fluker MR, Zouves CG, Begginton MW: A prospective randomized comparison of zygote intrafallopian transfer and in vitro fertilization—embryo transfer for nontubal factor infertility. Fertil Steril 60: 515, 1993