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Fibrin glue improves pregnancy rates in women of advanced reproductive age and in patients in whom in vitro fertilization attempts repeatedly fail
FERTILITY AND STERILITYt VOL. 71, NO. 5, MAY 1999 Copyright ©1999 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.
Fibrin glue improves pregnancy rates in women of advanced reproductive age and in patients in whom in vitro fertilization attempts repeatedly fail Itai Bar-Hava, M.D., Haim Krissi, M.D., Jacob Ashkenazi, M.D., Raoul Orvieto, M.D., Michal Shelef, M.Sc., and Zion Ben-Rafael, M.D. Department of Obstetrics and Gynecology, Rabin Medical Center, Golda Campus, Petah Tiqva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Objective: To evaluate the possible contribution of fibrin sealant to the ET stage of IVF. Design: Case-control study. Setting: An assisted reproductive technology unit that performed 2,535 treatment cycles from 1996 –1997. Patient(s): All consecutively seen patients who underwent ET from January 1996 to September 1997. Intervention(s): All women who underwent ET with the aid of fibrin sealant during the study period were compared with those who underwent standard ET (controls). Thereafter, a case-control study was conducted on the first consecutively seen 174 women who underwent ET with fibrin sealant and a control group that was matched for age and number of previous unsuccessful cycles. Main Outcome Measure(s): Patient age, number of previous unsuccessful IVF attempts, number of embryos transferred, and pregnancy rates. Result(s): During the study period, ET was performed with fibrin sealant in 265 women and by the standard procedure in 1,402 women. Women in the fibrin sealant group were significantly older. The pregnancy rate was not significantly different between the groups in the whole-cohort study (20.4% versus 23.1%), but it was significantly higher in the fibrin sealant group in the case-control study (25.3% versus 14.9%). This also was true when the older women (.35 years) and the women with $4 previous failed IVF attempts were analyzed separately (23.2% versus 9.8% and 26.1% versus 13.4%, respectively). Conclusion(s): The use of fibrin sealant in ET appears to be beneficial in women of advanced reproductive age and in patients in whom IVF attempts repeatedly fail. (Fertil Sterilt 1999;71:821– 4. ©1999 by American Society for Reproductive Medicine.) Key Words: Fibrin glue, age, IVF, recurrent failure
Received June 10, 1998; revised and accepted December 8, 1998. Reprint requests: Itai BarHava, M.D., Department of Obstetrics and Gynecology, Rabin Medical Center, Golda Campus, Petah Tiqva 49 372, Israel (FAX: 972-3-937-2512; Email: [email protected] .il). 0015-0282/99/$20.00 PII S0015-0282(99)00066-7
Embryo transfer is a crucial stage in all assisted reproductive technology modalities. Extensive research has been conducted into methods to improve implantation rates (1), such as modifications of ET catheters, changes in patient position, and the use of general anesthesia, but these have had little effect. One major unsolved problem is embryo expulsion immediately after the ET procedure, which occurs in a significant percentage of cases (2).
of note that patients .39 years of age were excluded from their studies. On the basis of our preliminary experience with the use of fibrin sealant in IVF (7), our team sought to evaluate further its possible contribution to the success of ET in certain populations that have a poor prognosis.
The use of fibrin glue is widely recommended in many surgical procedures to promote hemostasis and serve as a biologic adhesive (3, 4). Feichtinger et al. (5, 6) were the first to use fibrin sealant in IVF, although it is
Fibrin Sealant
MATERIALS AND METHODS The components of fibrin sealant (Tisseel Kit; Immuno AG, Vienna, Austria), a blood product derivative, have been described in detail (8). All products used in the manufacture of 821
fibrin sealant are carefully screened for human immunodeficiency virus and other potential contaminants (5). The glue has no known embryotoxic effects (9). The preparation of fibrin sealant, described by Feichtinger et al. (6), involves preheating all components to 37°C. The first component consists of lyophilized fibrinogen combined with plasma fibronectin, factor XIII, and plasminogen, which are reconstituted in aprotinin solution. The osmolarity is adjusted meticulously to the physiologic range (280 –300 mOsm/kg) using aprotinin solution (120 Kallidinogenase inactivator units [KIU]/mL). For the second component, the lyophilized thrombin is reconstituted in calcium chloride solution, and the osmolarity is adjusted to the physiologic range by dilution in sterile water. Both diluting solutions contain garamycin (50 mg/L) and are handled under sterile conditions. In our unit, a new solution is prepared each day to prevent contamination.
Patients and Procedure The study was divided into two phases. In phase 1, all women in our IVF unit who reached the ET stage between January 1996 and September 1997 were recruited for the study with the use of our computerized (prospectively created) data base. Exclusion criteria were the use of donor oocytes or the transfer of frozen-thawed embryos. The IVF and intracytoplasmic sperm injection methodologies used in our unit have been described in detail previously (10). The ovarian stimulation protocol, ultrasound and hormonal surveillance methods, timing of hCG administration, oocyte retrieval techniques, and sperm processing and embryo culture methods used were similar for both IVF and intracytoplasmic sperm injection cycles. Cleaving embryos were selected for transfer or freezing on the basis of their morphologic score. All embryos were left in culture until the day of ET and then transferred with fibrin sealant or our usual medium (IVF-Medium; Medicult, Copenhagen, Denmark). Patients in the fibrin sealant group were allowed to walk immediately after ET, and those in the standard process (control) group were kept recumbent for 1 hour before discharge. A Wallace catheter (Sincate Ltd., Colchester, England) was used in both groups. In the fibrin sealant group, the catheter was loaded by the one-step method, as previously described (6). Briefly, the medium that contained the embryos was surrounded by air-filled spaces and both components of the fibrin from both sides, presumably enabling the embryos enclosed within the glue to be attached to the endometrium. We regularly use a low transfer approach, taking special care to prevent contact between the catheter tip and the uterine fundus. The catheter was withdrawn immediately from the uterine cavity in the fibrin sealant group and after 5–10 seconds in the control group. The patients in whom fibrin sealant was used were compared with those who underwent standard ET for age and 822
Bar-Hava et al.
Fibrin sealant in IVF
TABLE 1 Characteristics and outcomes of the fibrin sealant group and the control group. Study group (no. of cycles) Fibrin sealant (n 5 265)
Control (n 5 1,402)
P value
38.20 6 0.5
35.20 6 0.30
.0005*
3.30 6 0.04 23.1
NS* NS†
Variable Mean (6SE) patient age (y) Mean (6SE) no. of embryos transferred Pregnancy rate (%)
3.30 6 0.10 20.4
Note: NS 5 not significant. * Determined by Student’s t-test. † Determined by the x2 test.
pregnancy rate (PR; defined as the presence of a gestational sac on transvaginal ultrasound examination in association with rising b-hCG levels). In phase 2, the first consecutively seen 174 women who underwent ET with fibrin sealant were entered into a casecontrol study. The women were matched with the next consecutively seen patients in our chart file (controls) by age (63 years) and number of previous unsuccessful IVF cycles. The main outcome measures of the case-control study were patient age, number of embryos transferred, and PR. These groups also were subdivided further by age (#35 years and .35 years) and number of previous IVF failures (4 or $4), and were analyzed for the same outcome measures. Before the ET procedure, each patient attended a counseling session in which the theoretic advantages of fibrin sealant were explained. On the basis of the findings of an earlier prospective, controlled, randomized study performed by our team (7), we tended to recommend fibrin sealant to women who were .35 years old and to those in whom more than four previous IVF attempts had failed. The final decision was made by the patient. All study participants signed an informed consent form. The use of fibrin sealant in our unit and for the present study was approved by our center’s institutional review board.
RESULTS During phase 1 of the study, ET was performed in 1,667 treatment cycles, 265 with fibrin sealant (study group) and 1,402 with standard medium (control group). The mean (6SD) patient age differed significantly between the groups (38.2 6 0.5 years versus 35.2 6 0.3 years, P,.0005), but the PR did not (20.4% versus 23.1%) (Table 1). Separate analysis of the intracytoplasmic sperm injection cycles (n 5 878) in the study and control groups yielded similar PRs (20.7% versus 21.5%). In a reference population that was not Vol. 71, No. 5, May 1999
TABLE 2
TABLE 3
Characteristics and outcomes in the case-control study (phase 2).
Characteristics and outcomes of patients in whom IVF attempts repeatedly ($4 times) had failed.
Study group (no. of patients)
Variable Age (y) No. of months of treatment Total no. of treatment cycles No. of embryos transferred Pregnancy rate (%) Overall Patients .35 y Patients #35 y
Study group (no. of patients)
Fibrin sealant (n 5 174)
Control (n 5 174)
P value
37.40 6 0.35 19.70 6 1.60 4.10 6 0.17 3.40 6 0.13
37.70 6 0.36 22.50 6 1.72 4.20 6 0.19 3.50 6 0.17
NS* NS* NS* NS*
25.3 23.2 (n 5 112) 29.3 (n 5 62)
14.9 9.8 (n 5 112) 24.2 (n 5 62)
,.05† ,.01† NS†
Note: All values are means 6 SE unless otherwise indicated. NS 5 not significant. * Determined by Student’s t-test. † Determined by the x2 test.
treated with fibrin sealant for ET during the same period, the PRs for the corresponding age groups (38 and 35 years) were 17.3% and 28%, respectively (P,.05, confidence interval 1.03–3.34). In phase 2, the case-control study, there was no difference in the mean (6SD) number of embryos transferred between the study and control groups (3.4 6 0.13 versus 3.5 6 0.17), but the fibrin sealant group had a significantly higher PR (25.3% versus 14.9%), P,.05, confidence interval 1.0 –3.4). This difference was even more pronounced when the older women (.35 years) were analyzed separately (23.2% versus 9.8%, P,.01, confidence interval 1.2– 6.3) (Table 2). Analysis of the patients in whom IVF attempts repeatedly ($4 times) failed also yielded a significantly higher PR in the fibrin sealant group than in the control group (26.1% versus 13.4%, P,.05, confidence interval 0.18 – 0.96). This time, however, the difference was more pronounced in the younger subgroup (34.4% versus 12.5%, P,.05, confidence interval 0.23–1.23) (Table 3).
DISCUSSION The findings of the present study support those of our earlier preliminary work (7) and demonstrate that ET with fibrin sealant is beneficial for IVF candidates who are .35 years old as well as for women in whom IVF attempts repeatedly ($4 times) have failed. Several mechanisms may explain these findings. First, embryos that are surrounded by the glue are compelled to stay in place at least for a few days until the clot dissolves and, therefore, cannot be expelled. Second, the enhanced FERTILITY & STERILITYt
Variable Age (y) No. of months of treatment Total no. of treatment cycles No. of embryos transferred Pregnancy rate (%) Overall Patients #35 y Patients .35 y
Fibrin sealant (n 5 92)
Control (n 5 92)
P value
37.50 6 0.52 31.50 6 2.32 6.20 6 0.20 3.60 6 0.18
37.80 6 0.49 36.70 6 2.31 6.20 6 0.18 3.70 6 2.58
NS* NS* NS* NS*
26.1 34.4 (n 5 32) 21.7 (n 5 60)
13.4 12.5 (n 5 32) 13.3 (n 5 60)
,.05† ,.05‡ NS†
Note: All values are means 6 SE unless otherwise indicated. NS 5 not significant. * Determined by Student’s t-test. † Determined by the x2 test. ‡ Determined by Fisher’s exact test.
adhesive quality of the embryo surface facilitates the initial implantation process. Third, the fibrinolytic process that is provoked by the fibrin component of the sealant may assist in the chemical absorption of the zona pellucida membrane, resulting in better embryonic hatching. Finally, the increased dimensions of the embryo/medium complex achieved by the glue may increase the likelihood of retention of the embryo inside the uterine cavity (similar to the expanded blastocyst stage of development). Because we are the only IVF unit in Israel that uses fibrin sealant, many women approach us (after multiple failures in other units) for this particular therapy. This makes our results even more impressive, given that a portion of the patients actually underwent more IVF cycles than stated (we have no way of accurately determining how many cycles a woman has undergone in another unit). From the physiological point of view, we believe that women who knew that their embryos were “glued” to the endometrium had a sense of security. The procedure also has the advantage that patients can resume walking immediately afterward. We believe that the use of fibrin sealant for ET can improve the PRs in certain populations that have a poor prognosis. Our findings need further verification in a large, multicenter, randomized, prospective study. References 1. Diedrich K, van der Ven H, Al-Hasani S, Krebs D. Establishment of pregnancy related to embryo transfer techniques after in vitro fertilization. Hum Reprod 1989;4:111– 4. 2. Schulman JD. Delayed expulsion of transfer fluid after IVF/ET. Lancet 1986;1:44.
823
3. Jackson MR, MacPhee MJ, Drohan WN, Alving BM. Fibrin sealant: current and potential clinical applications. Blood Coagul Fibrinolysis 1996;7:737– 46. 4. Rutgeerts P, Rauws E, Wara P, Swain P, Hoos A, Solleder E, et al. Randomised trial of single and repeated fibrin glue compared with injection of polidocanol in treatment of bleeding peptic ulcer. Lancet 1997;350:692– 6. 5. Feichtinger W, Barad D, Feinman M, Barg P. The use of twocomponent fibrin sealant for embryo transfer. Fertil Steril 1990;54: 733– 4. 6. Feichtinger W, Strohmer H, Radner KM, Goldin M. The use of fibrin sealant for embryo transfer: development and clinical studies. Hum Reprod 1992;7:890 –3.
824
Bar-Hava et al.
Fibrin sealant in IVF
7. Ben-Rafael Z, Ashkenazi J, Shelef M, Farhi J, Voliovich I, Feldberg D, et al. The use of fibrin sealant in in vitro fertilization and embryo transfer. Int J Fertil 1995;40:303– 6. 8. Redl H, Schlag G. Fibrin sealant and its modes of application. In: Schlag G, Redl H, eds. Fibrin sealant in operative medicine, gynecology and obstetrics-urology. Berlin: Springer Verlag, 1986:180 –5. 9. Rodrigues FA, Van Rensburg JHJ, De Vries J, Sonnendecker EWW. The effect of fibrin sealant on mouse embryos. J In Vitro Fert Embryo Transfer 1989;5:158 – 60. 10. Bar-Hava I, Ashkenazi J, Shelef M, Schwartz A, Brengauz M, Feldberg D, et al. Morphology and clinical outcome of embryos after in vitro fertilization are superior to those after intracytoplasmic sperm injection. Fertil Steril 1997;68:653–7.
Vol. 71, No. 5, May 1999
Fibrin glue improves pregnancy rates in women of advanced reproductive age and in patients in whom in vitro fertilization attempts repeatedly fail Itai Bar-Hava, M.D., Haim Krissi, M.D., Jacob Ashkenazi, M.D., Raoul Orvieto, M.D., Michal Shelef, M.Sc., and Zion Ben-Rafael, M.D. Department of Obstetrics and Gynecology, Rabin Medical Center, Golda Campus, Petah Tiqva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Objective: To evaluate the possible contribution of fibrin sealant to the ET stage of IVF. Design: Case-control study. Setting: An assisted reproductive technology unit that performed 2,535 treatment cycles from 1996 –1997. Patient(s): All consecutively seen patients who underwent ET from January 1996 to September 1997. Intervention(s): All women who underwent ET with the aid of fibrin sealant during the study period were compared with those who underwent standard ET (controls). Thereafter, a case-control study was conducted on the first consecutively seen 174 women who underwent ET with fibrin sealant and a control group that was matched for age and number of previous unsuccessful cycles. Main Outcome Measure(s): Patient age, number of previous unsuccessful IVF attempts, number of embryos transferred, and pregnancy rates. Result(s): During the study period, ET was performed with fibrin sealant in 265 women and by the standard procedure in 1,402 women. Women in the fibrin sealant group were significantly older. The pregnancy rate was not significantly different between the groups in the whole-cohort study (20.4% versus 23.1%), but it was significantly higher in the fibrin sealant group in the case-control study (25.3% versus 14.9%). This also was true when the older women (.35 years) and the women with $4 previous failed IVF attempts were analyzed separately (23.2% versus 9.8% and 26.1% versus 13.4%, respectively). Conclusion(s): The use of fibrin sealant in ET appears to be beneficial in women of advanced reproductive age and in patients in whom IVF attempts repeatedly fail. (Fertil Sterilt 1999;71:821– 4. ©1999 by American Society for Reproductive Medicine.) Key Words: Fibrin glue, age, IVF, recurrent failure
Received June 10, 1998; revised and accepted December 8, 1998. Reprint requests: Itai BarHava, M.D., Department of Obstetrics and Gynecology, Rabin Medical Center, Golda Campus, Petah Tiqva 49 372, Israel (FAX: 972-3-937-2512; Email: [email protected] .il). 0015-0282/99/$20.00 PII S0015-0282(99)00066-7
Embryo transfer is a crucial stage in all assisted reproductive technology modalities. Extensive research has been conducted into methods to improve implantation rates (1), such as modifications of ET catheters, changes in patient position, and the use of general anesthesia, but these have had little effect. One major unsolved problem is embryo expulsion immediately after the ET procedure, which occurs in a significant percentage of cases (2).
of note that patients .39 years of age were excluded from their studies. On the basis of our preliminary experience with the use of fibrin sealant in IVF (7), our team sought to evaluate further its possible contribution to the success of ET in certain populations that have a poor prognosis.
The use of fibrin glue is widely recommended in many surgical procedures to promote hemostasis and serve as a biologic adhesive (3, 4). Feichtinger et al. (5, 6) were the first to use fibrin sealant in IVF, although it is
Fibrin Sealant
MATERIALS AND METHODS The components of fibrin sealant (Tisseel Kit; Immuno AG, Vienna, Austria), a blood product derivative, have been described in detail (8). All products used in the manufacture of 821
fibrin sealant are carefully screened for human immunodeficiency virus and other potential contaminants (5). The glue has no known embryotoxic effects (9). The preparation of fibrin sealant, described by Feichtinger et al. (6), involves preheating all components to 37°C. The first component consists of lyophilized fibrinogen combined with plasma fibronectin, factor XIII, and plasminogen, which are reconstituted in aprotinin solution. The osmolarity is adjusted meticulously to the physiologic range (280 –300 mOsm/kg) using aprotinin solution (120 Kallidinogenase inactivator units [KIU]/mL). For the second component, the lyophilized thrombin is reconstituted in calcium chloride solution, and the osmolarity is adjusted to the physiologic range by dilution in sterile water. Both diluting solutions contain garamycin (50 mg/L) and are handled under sterile conditions. In our unit, a new solution is prepared each day to prevent contamination.
Patients and Procedure The study was divided into two phases. In phase 1, all women in our IVF unit who reached the ET stage between January 1996 and September 1997 were recruited for the study with the use of our computerized (prospectively created) data base. Exclusion criteria were the use of donor oocytes or the transfer of frozen-thawed embryos. The IVF and intracytoplasmic sperm injection methodologies used in our unit have been described in detail previously (10). The ovarian stimulation protocol, ultrasound and hormonal surveillance methods, timing of hCG administration, oocyte retrieval techniques, and sperm processing and embryo culture methods used were similar for both IVF and intracytoplasmic sperm injection cycles. Cleaving embryos were selected for transfer or freezing on the basis of their morphologic score. All embryos were left in culture until the day of ET and then transferred with fibrin sealant or our usual medium (IVF-Medium; Medicult, Copenhagen, Denmark). Patients in the fibrin sealant group were allowed to walk immediately after ET, and those in the standard process (control) group were kept recumbent for 1 hour before discharge. A Wallace catheter (Sincate Ltd., Colchester, England) was used in both groups. In the fibrin sealant group, the catheter was loaded by the one-step method, as previously described (6). Briefly, the medium that contained the embryos was surrounded by air-filled spaces and both components of the fibrin from both sides, presumably enabling the embryos enclosed within the glue to be attached to the endometrium. We regularly use a low transfer approach, taking special care to prevent contact between the catheter tip and the uterine fundus. The catheter was withdrawn immediately from the uterine cavity in the fibrin sealant group and after 5–10 seconds in the control group. The patients in whom fibrin sealant was used were compared with those who underwent standard ET for age and 822
Bar-Hava et al.
Fibrin sealant in IVF
TABLE 1 Characteristics and outcomes of the fibrin sealant group and the control group. Study group (no. of cycles) Fibrin sealant (n 5 265)
Control (n 5 1,402)
P value
38.20 6 0.5
35.20 6 0.30
.0005*
3.30 6 0.04 23.1
NS* NS†
Variable Mean (6SE) patient age (y) Mean (6SE) no. of embryos transferred Pregnancy rate (%)
3.30 6 0.10 20.4
Note: NS 5 not significant. * Determined by Student’s t-test. † Determined by the x2 test.
pregnancy rate (PR; defined as the presence of a gestational sac on transvaginal ultrasound examination in association with rising b-hCG levels). In phase 2, the first consecutively seen 174 women who underwent ET with fibrin sealant were entered into a casecontrol study. The women were matched with the next consecutively seen patients in our chart file (controls) by age (63 years) and number of previous unsuccessful IVF cycles. The main outcome measures of the case-control study were patient age, number of embryos transferred, and PR. These groups also were subdivided further by age (#35 years and .35 years) and number of previous IVF failures (4 or $4), and were analyzed for the same outcome measures. Before the ET procedure, each patient attended a counseling session in which the theoretic advantages of fibrin sealant were explained. On the basis of the findings of an earlier prospective, controlled, randomized study performed by our team (7), we tended to recommend fibrin sealant to women who were .35 years old and to those in whom more than four previous IVF attempts had failed. The final decision was made by the patient. All study participants signed an informed consent form. The use of fibrin sealant in our unit and for the present study was approved by our center’s institutional review board.
RESULTS During phase 1 of the study, ET was performed in 1,667 treatment cycles, 265 with fibrin sealant (study group) and 1,402 with standard medium (control group). The mean (6SD) patient age differed significantly between the groups (38.2 6 0.5 years versus 35.2 6 0.3 years, P,.0005), but the PR did not (20.4% versus 23.1%) (Table 1). Separate analysis of the intracytoplasmic sperm injection cycles (n 5 878) in the study and control groups yielded similar PRs (20.7% versus 21.5%). In a reference population that was not Vol. 71, No. 5, May 1999
TABLE 2
TABLE 3
Characteristics and outcomes in the case-control study (phase 2).
Characteristics and outcomes of patients in whom IVF attempts repeatedly ($4 times) had failed.
Study group (no. of patients)
Variable Age (y) No. of months of treatment Total no. of treatment cycles No. of embryos transferred Pregnancy rate (%) Overall Patients .35 y Patients #35 y
Study group (no. of patients)
Fibrin sealant (n 5 174)
Control (n 5 174)
P value
37.40 6 0.35 19.70 6 1.60 4.10 6 0.17 3.40 6 0.13
37.70 6 0.36 22.50 6 1.72 4.20 6 0.19 3.50 6 0.17
NS* NS* NS* NS*
25.3 23.2 (n 5 112) 29.3 (n 5 62)
14.9 9.8 (n 5 112) 24.2 (n 5 62)
,.05† ,.01† NS†
Note: All values are means 6 SE unless otherwise indicated. NS 5 not significant. * Determined by Student’s t-test. † Determined by the x2 test.
treated with fibrin sealant for ET during the same period, the PRs for the corresponding age groups (38 and 35 years) were 17.3% and 28%, respectively (P,.05, confidence interval 1.03–3.34). In phase 2, the case-control study, there was no difference in the mean (6SD) number of embryos transferred between the study and control groups (3.4 6 0.13 versus 3.5 6 0.17), but the fibrin sealant group had a significantly higher PR (25.3% versus 14.9%), P,.05, confidence interval 1.0 –3.4). This difference was even more pronounced when the older women (.35 years) were analyzed separately (23.2% versus 9.8%, P,.01, confidence interval 1.2– 6.3) (Table 2). Analysis of the patients in whom IVF attempts repeatedly ($4 times) failed also yielded a significantly higher PR in the fibrin sealant group than in the control group (26.1% versus 13.4%, P,.05, confidence interval 0.18 – 0.96). This time, however, the difference was more pronounced in the younger subgroup (34.4% versus 12.5%, P,.05, confidence interval 0.23–1.23) (Table 3).
DISCUSSION The findings of the present study support those of our earlier preliminary work (7) and demonstrate that ET with fibrin sealant is beneficial for IVF candidates who are .35 years old as well as for women in whom IVF attempts repeatedly ($4 times) have failed. Several mechanisms may explain these findings. First, embryos that are surrounded by the glue are compelled to stay in place at least for a few days until the clot dissolves and, therefore, cannot be expelled. Second, the enhanced FERTILITY & STERILITYt
Variable Age (y) No. of months of treatment Total no. of treatment cycles No. of embryos transferred Pregnancy rate (%) Overall Patients #35 y Patients .35 y
Fibrin sealant (n 5 92)
Control (n 5 92)
P value
37.50 6 0.52 31.50 6 2.32 6.20 6 0.20 3.60 6 0.18
37.80 6 0.49 36.70 6 2.31 6.20 6 0.18 3.70 6 2.58
NS* NS* NS* NS*
26.1 34.4 (n 5 32) 21.7 (n 5 60)
13.4 12.5 (n 5 32) 13.3 (n 5 60)
,.05† ,.05‡ NS†
Note: All values are means 6 SE unless otherwise indicated. NS 5 not significant. * Determined by Student’s t-test. † Determined by the x2 test. ‡ Determined by Fisher’s exact test.
adhesive quality of the embryo surface facilitates the initial implantation process. Third, the fibrinolytic process that is provoked by the fibrin component of the sealant may assist in the chemical absorption of the zona pellucida membrane, resulting in better embryonic hatching. Finally, the increased dimensions of the embryo/medium complex achieved by the glue may increase the likelihood of retention of the embryo inside the uterine cavity (similar to the expanded blastocyst stage of development). Because we are the only IVF unit in Israel that uses fibrin sealant, many women approach us (after multiple failures in other units) for this particular therapy. This makes our results even more impressive, given that a portion of the patients actually underwent more IVF cycles than stated (we have no way of accurately determining how many cycles a woman has undergone in another unit). From the physiological point of view, we believe that women who knew that their embryos were “glued” to the endometrium had a sense of security. The procedure also has the advantage that patients can resume walking immediately afterward. We believe that the use of fibrin sealant for ET can improve the PRs in certain populations that have a poor prognosis. Our findings need further verification in a large, multicenter, randomized, prospective study. References 1. Diedrich K, van der Ven H, Al-Hasani S, Krebs D. Establishment of pregnancy related to embryo transfer techniques after in vitro fertilization. Hum Reprod 1989;4:111– 4. 2. Schulman JD. Delayed expulsion of transfer fluid after IVF/ET. Lancet 1986;1:44.
823
3. Jackson MR, MacPhee MJ, Drohan WN, Alving BM. Fibrin sealant: current and potential clinical applications. Blood Coagul Fibrinolysis 1996;7:737– 46. 4. Rutgeerts P, Rauws E, Wara P, Swain P, Hoos A, Solleder E, et al. Randomised trial of single and repeated fibrin glue compared with injection of polidocanol in treatment of bleeding peptic ulcer. Lancet 1997;350:692– 6. 5. Feichtinger W, Barad D, Feinman M, Barg P. The use of twocomponent fibrin sealant for embryo transfer. Fertil Steril 1990;54: 733– 4. 6. Feichtinger W, Strohmer H, Radner KM, Goldin M. The use of fibrin sealant for embryo transfer: development and clinical studies. Hum Reprod 1992;7:890 –3.
824
Bar-Hava et al.
Fibrin sealant in IVF
7. Ben-Rafael Z, Ashkenazi J, Shelef M, Farhi J, Voliovich I, Feldberg D, et al. The use of fibrin sealant in in vitro fertilization and embryo transfer. Int J Fertil 1995;40:303– 6. 8. Redl H, Schlag G. Fibrin sealant and its modes of application. In: Schlag G, Redl H, eds. Fibrin sealant in operative medicine, gynecology and obstetrics-urology. Berlin: Springer Verlag, 1986:180 –5. 9. Rodrigues FA, Van Rensburg JHJ, De Vries J, Sonnendecker EWW. The effect of fibrin sealant on mouse embryos. J In Vitro Fert Embryo Transfer 1989;5:158 – 60. 10. Bar-Hava I, Ashkenazi J, Shelef M, Schwartz A, Brengauz M, Feldberg D, et al. Morphology and clinical outcome of embryos after in vitro fertilization are superior to those after intracytoplasmic sperm injection. Fertil Steril 1997;68:653–7.
Vol. 71, No. 5, May 1999