FERTILITY AND STERILITY
Vol. 55, No.3, March 1991
Copyright" 1991 The American Fertility Society
Printed on acid-free paper in U.S.A.
Ultrasound-guided embryo transfer: a controlled trial
Victor A. Hurley, M.D.* Jeremy C. Osborn, M.D. Maria A. Leoni, D.C.R. John Leeton, M.D. Infertility Medical Centre, Epworth Hospital, Richmond, Melbourne, Victoria, Australia
Embryo transfer (ET) was performed in 94 patients using transvaginal ultrasound guidance. Pregnancy rates were increased over a control group of 246 patients, although statistical significance was reached only in the subgroup of single ETs. Advantages over the traditional blind technique of ET were observed. Acceptance of the procedure by both clinicians and patients was high. Fertil Steril 55:559, 1991
In his review of embryo transfer (ET), Leeton 1 in 1984 observed that the step at which most failures of human in vitro fertilization (IVF) occur is after the transfer of an apparently normal embryo to the uterine fundus at the appropriate time in the early luteal phase of the menstrual cycle. Speirs2 felt failure at this stage might be ascribed to problems of either embryo quality or uterine receptivity. However, the technique of ET has not been significantly modified since its first description. The technique in our center and the majority of centers worldwide is blind, relying on the "feel" of the clinician placing the transfer catheter and embryos in the appropriate position in the upper uterine cavity. Other than the subsequent development of pregnancy, there is no absolute way of knowing that the embryo(s) have been transferred to the uterine cavity at all. Ultrasound (US) is now a key component in almost all areas of IVF-ET programs. Its use in follicle growth monitoring and egg retrieval is well established. However, it has not been widely used at the time of ET. A technique of transfundal ET under US guidance was described by Lenz et al. 3 in 1987. The only reported series was abandoned after 10
procedures failed to achieve a pregnancy. The possibility that US guidance of ET might improve the technique has been raised by Strickler et al. 4 in 1985 and Leong et al. 5 in 1986; however, no large series or controlled trials have been undertaken. The advent of high -frequency transvaginal US scanners has provided significantly improved resolution of fine details of pelvic anatomy and removed the necessity of the full bladder. The latter is a significant logistic deterrent to the use of transabdominal US in a busy IVF -ET program. A controlled trial using transvaginal US guidance of ET to assess its role in this area was mounted in our center. The objectives of the study were as follows: (1) to assess the accuracy of clinical judgement in ET; (2) to assess whether pregnancy rates (PRs) could be improved by its use; (3) to assess the feasibility of using US-guided transfer on a routine basis in our IVF-ET program; and (4) to assess the influence of US-guided ET on the incidence of ectopic pregnancy (EP). MATERIALS AND METHODS Patients
Received January 30, 1990; revised and accepted November 29,1990. * Reprint requests: Victor A. Hurley, M.D., Infertility Medical Centre, Epworth Hospital, Richmond, Melbourne, Victoria, Australia. Vol. 55, No.3, March 1991
Between October 1988 and March 1989, 94 patients on our IVF-ET treatment program had ET performed under US guidance. These patients were randomly selected in that their transfers were carHurley et al.
US-guided ET
559
ried out at a time when two of the authors (V.H. and M.L.) were available. A group of 246 similarly matched patients from the same period were selected as controls. The number of embryos transferred in each group was noted, but no further attempt was made to precisely control the two groups for all variables because this was thought to be impractical. Frozen ETs and donor embryo/donor egg patients were excluded. The standard management of patients at this time included follicle stimulation using clomiphene citrate (Clomid; Merrell-Dow, Sydney Australia), human menopausal gonadotropin (Pergonal; Serono-Aires, Melbourne, Australia), and human chorionic gonadotropin (Profasi; SeronoAires). A small number of patients during the study period were prepared using a regimen of gonadotropin-releasing hormone analogs (buserelin acetate, Suprefact Hoechst, Frankfurt, Germany).
A
Technique of Transfer
Ultrasound-guided transfer was performed according to the following regimen. Informed consent was obtained from the patient. The technique was performed with the patient unanesthetized and with no premedication. The pelvis was examined using transvaginal US assessment of the axis, degree of flexion of the uterus, and the configuration and length of the uterine cavity. The US probe was removed and a bivalve speculum inserted exposing the cervix. The outer cannula of the transfer catheter (Monash catheter, Cook, Melbourne, Australia) was inserted through the external cervical os. The inner transfer catheter was inserted to the fundus of the uterus by clinical feel in the usual way. The speculum was removed and the US probe reinserted. The transfer catheter was identified in the uterine cavity and moved to a point 1 em from the fundal limit of the uterine cavity (Fig. 1A and B). The embryo(s) were now transferred by injecting 30 JLL of culture medium containing the embryo(s) as previously described by Leeton et al. 6 in 1982. Transfer was observed on the US monitor, the embryos being clearly identified by the air bubbles inserted between them, which are seen as bright echos on the US image (Fig. 2A and B). The patient and her partner were able to observe the transfer on a nearby relay monitor. The catheter was then withdrawn and further scanning carried out to ensure the embryos remained in the transferred location. The control group underwent ET using the traditional blind technique. We did not observe the phenomenon described by Leong et al. 5 of the embryos flowing back down the 560
Hurley et al.
US-guided ET
Figure 1 Diagram (A) and ultrasonogram (B) of the longitu· dina! view of uterine body, cervix, and upper vagina. The outer cannula is positioned in the cervix. The inner transfer catheter has been inserted and withdrawn to 1 em from the fundal limit of the uterine cavity.
external surface of the catheter after transfer. In two cases, the withdrawal of the catheter led to the embryo(s) moving down into the uterine cavity. Slow withdrawal of the catheter seemed to prevent this alteration in embryo position. The catheter was checked microscopically to ensure no embryos remained within it. The US probe was removed and the patient returned to the ward. Pregnancies were diagnosed biochemically by radioimmunoassay on day 14 after transfer. Ultrasound examinations were carried out at 6 to 7 weeks to confirm normal position and viability. RESULTS
Of the 94 patients in whom US guidance was attempted, the transfer catheter and embryos could Fertility and Sterility
Figure 2 Diagram (A) and ultrasonogram (B) of the longitudinal view of uterine body, cervix, and upper vagina. Embryo transfer has occurred. The two bright echos are the bubbles of air between the embryos. The transfer catheter is being removed from the uterus.
not be visualized in 8 cases. Four of these cases occurred in the first 15 US-guided transfers. In the last 47 cases, the catheter was visualized in all transfers. Initially, the failure to visualize the catheter was ascribed to inadequacies of the vaginalscanning technique in identifying the catheter tip particularly where the axis of the uterus was parallel to the US beam as in an axial or upright uterus. However, as confidence was gained with the technique the catheter, or a part there of, was always visualized in the uterine cavity. If the catheter was not seen, we were confident that it was not appropriately sited in the uterine cavity, and the insertion of the catheter was repeated. This conclusion was strengthened by 6 cases in which the catheter was seen to curl up in the region of the internal os, despite a confident assessment by the clinician that Vol. 55, No.3, March 1991
the catheter was correctly placed in the uterine cavity. Had transfer of the embryos been carried out in these cases, the embryos would have been positioned in the cervix or upper vagina with little prospect of implantation occurring. No pregnancies occurred in the 8 patients in which neither the catheter nor the embryos could be observed. In 12 cases, the tip of the catheter was observed to be in the lower half of the uterus when it was thought to be at the fundus. These discrepancies between feel and actual position of the catheter occurred across a number of clinical operators of differing levels of experience in ET. Some specific mechanical difficulties were encountered and overcome using the US-guided technique. One patient with a distorted uterine cavity because of fibromyomata had a successful ET into the fundal portion of the uterine cavity after negotiating the distorted lower uterine cavity using US direction. Previous blind procedures had been unsuccessful. Two cases of subseptate uteri were recognized, and ET was effected into the upper portion of one horn rather than at the septum, which was found to be only 2 em from the cervix in one case. A false passage was identified in one patient into which the transfer catheter was initially introduced. It was then withdrawn and transfer effected appropriately into the cavity of the uterus. The PR achieved in the control group during the study period was 17.5% (43 of246). In the US-guided transfer group, the overall PR was 20.2% (19 of94). This increase in PR did not reach statistical significance. The PRs related to number of embryos transferred in both the US-guided transfer group and the control group are illustrated in Table 1. The most marked increase in PR was observed in the single ET group. Statistical significance was reached in this group. Eight EPs occurred in the study group of the 60 patients who had come to early pregnancy US assessment at the time of tabulation of the results. Three of these were in the US-guided group (3 of 17 or 11.1 %), and 5 were in the non-US-guided group (5 of 41, also 11.1%). No difference in the incidence of EP was thus observed. DISCUSSION
The aims of this study as outlined in the introduction were largely achieved, and we believe the results justify the introduction of transvaginal USguided ET. Although acknowledging the lack of rigorous patient randomization with respect to stimHurley et al.
US-guided ET
561
Table 1
Outcome of Transfers Performed With and Without US Guidance From October 1988 to March 1989" Control
US-guided
No. of transfers
No. of pregnancies
No. of embryos transferred 1 2 3 4
45 (18.3) 45 (18.3) 49 (19.9) 107 (43.5)
1 (2.2) 8 (17.8) 11 (22.5) 23 (21.5)
23 22 18 31
Total
246
43 (17.5)
94
No. of transfers
(24.5) (23.4) (19.4) (33.0)
No. of pregnancies
4 (17.4) 3 (13.6) 1 (5.6) 11 (35.5)
p < 0.01
19 (20.2)
• Values in parentheses are percents.
ulation regimens and US guidance, we believe the benefits demonstrated are reaL In a small but significant number of cases, clinical feel at the time of ET was shown to be an inadequate method for accurate embryo placement. This is particularly true where a congenital or an acquired uterine abnormality was present. The most marked PR improvement was noted in the single ET group. It is interesting to speculate as to the nature of this improvement. Perhaps the increased PRs because of multiple ET to some extent mask the inherent inadequacies of the transfer technique, which is only revealed where a single embryo is transferred. The other interesting groups are the three embryo groups that did significantly worse in the US-guided group. Careful analysis of these 18 patients failed to reveal any additional risk factors or reasons for the reduced PR. The PR in this category is remarkably constant, normally in our IVFET program approximately 20%. We assume that this much lower figure is a statistical aberration. Recently, in an effort to reduce drug administration and biochemical monitoring, natural ovarian cycles have been used in IVF-ET programs as described by Foulot et aL 7 The results in the single ET group suggest US-guided transfers should always be used in this group. The patients and their partners were uniformly positive about the new involvement that visualiza-
562
Hurley et al.
US-guided ET
tion of the transfer process gave them in their treatment cycle. This positive benefit subjectively led to a decreased anxiety level by the patients at the time of transfer making the procedure smoother. No significant discomfort was experienced by either group. The acceptance by clinical operators was also high, and no significant time was added when US guidance was used once the routine was established. Transvaginal US guidance of ET is now used routinely in our unit. REFERENCES 1. Leeton J: Embryo transfer. In In Vitro Fertilization and Embryo Transfer, Edited by A Trounson, C Wood. Edinburgh, Churchill Livingstone, 1984, p 197 2. Speirs AJ: The changing face of infertility. Am J Obstet Gynecol 158:1390, 1988 3. Lenz S, Leeton J, Rogers P, Trounson A: Transfundal transfer of embryos using ultrasound. J In Vitro Fert Embryo Transfer 4:13,1987 4. Strickler R, Christianson C, Crane J, Curato A, Knight A, Yang V: Ultrasound guidance for embryo transfer. Fertil Steril 43:54, 1985 5. Leong M, Leung C, Tucker M, Wong C, Chan H: Ultrasound assisted embryo transfer. J In Vitro Fert Embryo Transfer 3:383,1986 6. Leeton J, Trounson A, Jessup D, Wood C: The technique for human embryo transfer. Fertil Steril 38:156, 1982 7. Foulot H, Ranoux C, Dubuisson JB, Rambaud D, Aubriot FX, Poirot C: In vitro fertilization without ovarian stimulation: a simplified protocol applied in 80 cycles. Fertil Steril 52:617, 1989
Fertility and Sterility
Vol. 55, No.3, March 1991
Copyright" 1991 The American Fertility Society
Printed on acid-free paper in U.S.A.
Ultrasound-guided embryo transfer: a controlled trial
Victor A. Hurley, M.D.* Jeremy C. Osborn, M.D. Maria A. Leoni, D.C.R. John Leeton, M.D. Infertility Medical Centre, Epworth Hospital, Richmond, Melbourne, Victoria, Australia
Embryo transfer (ET) was performed in 94 patients using transvaginal ultrasound guidance. Pregnancy rates were increased over a control group of 246 patients, although statistical significance was reached only in the subgroup of single ETs. Advantages over the traditional blind technique of ET were observed. Acceptance of the procedure by both clinicians and patients was high. Fertil Steril 55:559, 1991
In his review of embryo transfer (ET), Leeton 1 in 1984 observed that the step at which most failures of human in vitro fertilization (IVF) occur is after the transfer of an apparently normal embryo to the uterine fundus at the appropriate time in the early luteal phase of the menstrual cycle. Speirs2 felt failure at this stage might be ascribed to problems of either embryo quality or uterine receptivity. However, the technique of ET has not been significantly modified since its first description. The technique in our center and the majority of centers worldwide is blind, relying on the "feel" of the clinician placing the transfer catheter and embryos in the appropriate position in the upper uterine cavity. Other than the subsequent development of pregnancy, there is no absolute way of knowing that the embryo(s) have been transferred to the uterine cavity at all. Ultrasound (US) is now a key component in almost all areas of IVF-ET programs. Its use in follicle growth monitoring and egg retrieval is well established. However, it has not been widely used at the time of ET. A technique of transfundal ET under US guidance was described by Lenz et al. 3 in 1987. The only reported series was abandoned after 10
procedures failed to achieve a pregnancy. The possibility that US guidance of ET might improve the technique has been raised by Strickler et al. 4 in 1985 and Leong et al. 5 in 1986; however, no large series or controlled trials have been undertaken. The advent of high -frequency transvaginal US scanners has provided significantly improved resolution of fine details of pelvic anatomy and removed the necessity of the full bladder. The latter is a significant logistic deterrent to the use of transabdominal US in a busy IVF -ET program. A controlled trial using transvaginal US guidance of ET to assess its role in this area was mounted in our center. The objectives of the study were as follows: (1) to assess the accuracy of clinical judgement in ET; (2) to assess whether pregnancy rates (PRs) could be improved by its use; (3) to assess the feasibility of using US-guided transfer on a routine basis in our IVF-ET program; and (4) to assess the influence of US-guided ET on the incidence of ectopic pregnancy (EP). MATERIALS AND METHODS Patients
Received January 30, 1990; revised and accepted November 29,1990. * Reprint requests: Victor A. Hurley, M.D., Infertility Medical Centre, Epworth Hospital, Richmond, Melbourne, Victoria, Australia. Vol. 55, No.3, March 1991
Between October 1988 and March 1989, 94 patients on our IVF-ET treatment program had ET performed under US guidance. These patients were randomly selected in that their transfers were carHurley et al.
US-guided ET
559
ried out at a time when two of the authors (V.H. and M.L.) were available. A group of 246 similarly matched patients from the same period were selected as controls. The number of embryos transferred in each group was noted, but no further attempt was made to precisely control the two groups for all variables because this was thought to be impractical. Frozen ETs and donor embryo/donor egg patients were excluded. The standard management of patients at this time included follicle stimulation using clomiphene citrate (Clomid; Merrell-Dow, Sydney Australia), human menopausal gonadotropin (Pergonal; Serono-Aires, Melbourne, Australia), and human chorionic gonadotropin (Profasi; SeronoAires). A small number of patients during the study period were prepared using a regimen of gonadotropin-releasing hormone analogs (buserelin acetate, Suprefact Hoechst, Frankfurt, Germany).
A
Technique of Transfer
Ultrasound-guided transfer was performed according to the following regimen. Informed consent was obtained from the patient. The technique was performed with the patient unanesthetized and with no premedication. The pelvis was examined using transvaginal US assessment of the axis, degree of flexion of the uterus, and the configuration and length of the uterine cavity. The US probe was removed and a bivalve speculum inserted exposing the cervix. The outer cannula of the transfer catheter (Monash catheter, Cook, Melbourne, Australia) was inserted through the external cervical os. The inner transfer catheter was inserted to the fundus of the uterus by clinical feel in the usual way. The speculum was removed and the US probe reinserted. The transfer catheter was identified in the uterine cavity and moved to a point 1 em from the fundal limit of the uterine cavity (Fig. 1A and B). The embryo(s) were now transferred by injecting 30 JLL of culture medium containing the embryo(s) as previously described by Leeton et al. 6 in 1982. Transfer was observed on the US monitor, the embryos being clearly identified by the air bubbles inserted between them, which are seen as bright echos on the US image (Fig. 2A and B). The patient and her partner were able to observe the transfer on a nearby relay monitor. The catheter was then withdrawn and further scanning carried out to ensure the embryos remained in the transferred location. The control group underwent ET using the traditional blind technique. We did not observe the phenomenon described by Leong et al. 5 of the embryos flowing back down the 560
Hurley et al.
US-guided ET
Figure 1 Diagram (A) and ultrasonogram (B) of the longitu· dina! view of uterine body, cervix, and upper vagina. The outer cannula is positioned in the cervix. The inner transfer catheter has been inserted and withdrawn to 1 em from the fundal limit of the uterine cavity.
external surface of the catheter after transfer. In two cases, the withdrawal of the catheter led to the embryo(s) moving down into the uterine cavity. Slow withdrawal of the catheter seemed to prevent this alteration in embryo position. The catheter was checked microscopically to ensure no embryos remained within it. The US probe was removed and the patient returned to the ward. Pregnancies were diagnosed biochemically by radioimmunoassay on day 14 after transfer. Ultrasound examinations were carried out at 6 to 7 weeks to confirm normal position and viability. RESULTS
Of the 94 patients in whom US guidance was attempted, the transfer catheter and embryos could Fertility and Sterility
Figure 2 Diagram (A) and ultrasonogram (B) of the longitudinal view of uterine body, cervix, and upper vagina. Embryo transfer has occurred. The two bright echos are the bubbles of air between the embryos. The transfer catheter is being removed from the uterus.
not be visualized in 8 cases. Four of these cases occurred in the first 15 US-guided transfers. In the last 47 cases, the catheter was visualized in all transfers. Initially, the failure to visualize the catheter was ascribed to inadequacies of the vaginalscanning technique in identifying the catheter tip particularly where the axis of the uterus was parallel to the US beam as in an axial or upright uterus. However, as confidence was gained with the technique the catheter, or a part there of, was always visualized in the uterine cavity. If the catheter was not seen, we were confident that it was not appropriately sited in the uterine cavity, and the insertion of the catheter was repeated. This conclusion was strengthened by 6 cases in which the catheter was seen to curl up in the region of the internal os, despite a confident assessment by the clinician that Vol. 55, No.3, March 1991
the catheter was correctly placed in the uterine cavity. Had transfer of the embryos been carried out in these cases, the embryos would have been positioned in the cervix or upper vagina with little prospect of implantation occurring. No pregnancies occurred in the 8 patients in which neither the catheter nor the embryos could be observed. In 12 cases, the tip of the catheter was observed to be in the lower half of the uterus when it was thought to be at the fundus. These discrepancies between feel and actual position of the catheter occurred across a number of clinical operators of differing levels of experience in ET. Some specific mechanical difficulties were encountered and overcome using the US-guided technique. One patient with a distorted uterine cavity because of fibromyomata had a successful ET into the fundal portion of the uterine cavity after negotiating the distorted lower uterine cavity using US direction. Previous blind procedures had been unsuccessful. Two cases of subseptate uteri were recognized, and ET was effected into the upper portion of one horn rather than at the septum, which was found to be only 2 em from the cervix in one case. A false passage was identified in one patient into which the transfer catheter was initially introduced. It was then withdrawn and transfer effected appropriately into the cavity of the uterus. The PR achieved in the control group during the study period was 17.5% (43 of246). In the US-guided transfer group, the overall PR was 20.2% (19 of94). This increase in PR did not reach statistical significance. The PRs related to number of embryos transferred in both the US-guided transfer group and the control group are illustrated in Table 1. The most marked increase in PR was observed in the single ET group. Statistical significance was reached in this group. Eight EPs occurred in the study group of the 60 patients who had come to early pregnancy US assessment at the time of tabulation of the results. Three of these were in the US-guided group (3 of 17 or 11.1 %), and 5 were in the non-US-guided group (5 of 41, also 11.1%). No difference in the incidence of EP was thus observed. DISCUSSION
The aims of this study as outlined in the introduction were largely achieved, and we believe the results justify the introduction of transvaginal USguided ET. Although acknowledging the lack of rigorous patient randomization with respect to stimHurley et al.
US-guided ET
561
Table 1
Outcome of Transfers Performed With and Without US Guidance From October 1988 to March 1989" Control
US-guided
No. of transfers
No. of pregnancies
No. of embryos transferred 1 2 3 4
45 (18.3) 45 (18.3) 49 (19.9) 107 (43.5)
1 (2.2) 8 (17.8) 11 (22.5) 23 (21.5)
23 22 18 31
Total
246
43 (17.5)
94
No. of transfers
(24.5) (23.4) (19.4) (33.0)
No. of pregnancies
4 (17.4) 3 (13.6) 1 (5.6) 11 (35.5)
p < 0.01
19 (20.2)
• Values in parentheses are percents.
ulation regimens and US guidance, we believe the benefits demonstrated are reaL In a small but significant number of cases, clinical feel at the time of ET was shown to be an inadequate method for accurate embryo placement. This is particularly true where a congenital or an acquired uterine abnormality was present. The most marked PR improvement was noted in the single ET group. It is interesting to speculate as to the nature of this improvement. Perhaps the increased PRs because of multiple ET to some extent mask the inherent inadequacies of the transfer technique, which is only revealed where a single embryo is transferred. The other interesting groups are the three embryo groups that did significantly worse in the US-guided group. Careful analysis of these 18 patients failed to reveal any additional risk factors or reasons for the reduced PR. The PR in this category is remarkably constant, normally in our IVFET program approximately 20%. We assume that this much lower figure is a statistical aberration. Recently, in an effort to reduce drug administration and biochemical monitoring, natural ovarian cycles have been used in IVF-ET programs as described by Foulot et aL 7 The results in the single ET group suggest US-guided transfers should always be used in this group. The patients and their partners were uniformly positive about the new involvement that visualiza-
562
Hurley et al.
US-guided ET
tion of the transfer process gave them in their treatment cycle. This positive benefit subjectively led to a decreased anxiety level by the patients at the time of transfer making the procedure smoother. No significant discomfort was experienced by either group. The acceptance by clinical operators was also high, and no significant time was added when US guidance was used once the routine was established. Transvaginal US guidance of ET is now used routinely in our unit. REFERENCES 1. Leeton J: Embryo transfer. In In Vitro Fertilization and Embryo Transfer, Edited by A Trounson, C Wood. Edinburgh, Churchill Livingstone, 1984, p 197 2. Speirs AJ: The changing face of infertility. Am J Obstet Gynecol 158:1390, 1988 3. Lenz S, Leeton J, Rogers P, Trounson A: Transfundal transfer of embryos using ultrasound. J In Vitro Fert Embryo Transfer 4:13,1987 4. Strickler R, Christianson C, Crane J, Curato A, Knight A, Yang V: Ultrasound guidance for embryo transfer. Fertil Steril 43:54, 1985 5. Leong M, Leung C, Tucker M, Wong C, Chan H: Ultrasound assisted embryo transfer. J In Vitro Fert Embryo Transfer 3:383,1986 6. Leeton J, Trounson A, Jessup D, Wood C: The technique for human embryo transfer. Fertil Steril 38:156, 1982 7. Foulot H, Ranoux C, Dubuisson JB, Rambaud D, Aubriot FX, Poirot C: In vitro fertilization without ovarian stimulation: a simplified protocol applied in 80 cycles. Fertil Steril 52:617, 1989
Fertility and Sterility
