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A review and meta-analysis of prospective trials comparing different catheters used for embryo transfer
TECHNIQUES AND INSTRUMENTATION A review and meta-analysis of prospective trials comparing different catheters used for embryo transfer William M. Buckett, M.D. Department of Obstetrics and Gynecology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada
Objective: To determine the relative efficacy of different types of embryo transfer (ET) catheters. Design: Systematic review and meta-analysis of prospective randomized, controlled trials comparing at least two different ET catheters. Setting: Infertility centers providing treatment with in vitro fertilization/embryo transfer (IVF-ET). Patient(s): Women undergoing ET. Intervention(s): Embryo transfer with soft or hard catheters. Main Outcome Measure(s): Clinical pregnancy rate. Result(s): A total of seven prospective trials were identified that compared soft (Cook or Wallace) catheters with hard (TDT, Frydman, Tomcat, Rocket) catheters. The meta-analysis demonstrated an increased chance of clinical pregnancy when soft ET catheters were used. The TDT catheter was compared against both soft catheters and other hard catheters, showing decreased chance of clinical pregnancy when the TDT catheter was used. Six more prospective trials were identified comparing the Cook and Wallace soft catheters, and the meta-analysis of these data showed no demonstrable difference in clinical pregnancy rates. Conclusion(s): An increased chance of clinical pregnancy is achieved when soft ET catheters are used. There appears to be little difference between the Cook and Wallace soft catheters. (Fertil Steril威 2006;85:728 –34. © 2006 by American Society for Reproductive Medicine.) Key Words: Embryo transfer catheter, IVF-ET, catheter type, meta-analysis
Embryo transfer remains the most inefficient step in in vitro fertilization/embryo transfer (IVF-ET) treatment cycles, and a great deal of research effort has been directed at ET technique. Although undoubtedly much of the embryo attrition has been due to aneuploidies, other abnormalities, or degenerative changes in the embryo (1, 2), several studies have shown increases in clinical pregnancy rates resulting from improvements in various aspects of the ET technique, including cervical cleaning (3, 4), a full bladder (5, 6), a dummy or mock transfer either before starting ovarian stimulation or immediately before ET (7–9), pretreatment cervical dilatation in difficult cases (10), and ultrasound guidance (11–13). The use of different ET catheters has also been studied. Many large retrospective studies (14 –18) have reported higher clinical pregnancy rates with “soft” embryo transReceived April 4, 2005; revised and accepted August 14, 2005. Presented at the 50th Annual Meeting of the Canadian Fertility and Andrology Society, Jasper, Alberta, Canada; November 24 –27, 2004. Reprint requests: William M. Buckett, M.D., Assistant Professor, Department of Obstetrics and Gynecology, McGill University, Royal Victoria Hospital, 687, Avenue des Pins Ouest, Montréal, Québec, Canada H3A 1A1 (FAX: 1-514-843-1496; E-mail: [email protected]).
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fer catheters such as the Cook catheter (Cook Ob/Gyn, Inc., Bloomington, IN) and the Wallace catheter (Marlow Technologies, Willoughby, OH) compared with “hard” embryo catheters such as the TDT (Laboratoire CCD, Paris, France), Frydman (Laboratoire CCD), Tomcat (Kendell Health Care, Hampshire, MA), Tefcat (Kendell Health Care), and Rocket ET catheters (Rocket Medical, Watford, UK). However, in technically difficult ET, particularly where difficulties are encountered negotiating the internal cervical os, there is often a need for the stiffer hard catheters. The change from soft to hard catheters for these transfers as well as the inherent difficulties of the transfer itself could account for any difference in pregnancy rate (14). However, the evidence from prospective trials has been conflicting, and sample sizes are often too small to identify small changes in clinical pregnancy rate. Thus, the objective of this systemic review and meta-analysis was to identify prospective randomized controlled trials comparing at least two different ET catheters and to determine the relative risk of clinical pregnancy with different ET catheters.
Fertility and Sterility姞 Vol. 85, No. 3, March 2006 Copyright ©2006 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/06/$32.00 doi:10.1016/j.fertnstert.2005.08.031
MATERIALS AND METHODS Study Identification and Selection Publications, in all languages, describing prospective randomized controlled trials comparing at least two different ET catheters were sought by searching online databases (MEDLINE, EMBASE, CINAHL, the Science Citation Index, and OVID Healthstar), using the headings “embryo transfer,” “embryo transfer catheter,” “catheter type,” and “embryo transfer technique.” Bibliographies of relevant publications and review articles were also scanned, and journals and abstracts from major infertility meetings from 1990 to 2004 were also hand-searched in an effort to identify any unpublished trials. Inclusion criteria for selection were a prospective randomized trial comparing at least two different types of ET catheters. All retrospective studies including case controlled and historical case controlled studies were excluded. Institutional ethics board approval was not required for a systemic review and meta-analysis of previously published clinical trials. Outcome Measures Outcome measures were the rate of clinical pregnancy per ET, where a clinical pregnancy was identified by the
presence of a gestational sac at ultrasound at least 4 weeks following the ET. Validity Assessment and Data Analysis Each study was assessed for methodologic quality to confirm that the trials were genuinely randomized and that there were no differences in the two groups after randomization. All prospective controlled randomized trials were included. The data were extracted into 2 ⫻ 2 tables and checked for accuracy. The data were checked for homogeneity using the Q statistic, and the fixed-effects model for relative risk was used. Funnel plot analysis was used to detect any publication bias. RESULTS The search strategy identified a total of 168 articles in which different ET catheters used for human ET were studied. Nearly half of these (75) concerned other aspects of ET (such as ultrasound guidance, embryo deposition, catheter loading, fluid dynamics, and cervical preparation). Of the remaining articles, 22 were reviews, 21 were retrospective case series, 18 were case reports, 11 were prospective nonrandomized comparative studies, 6 were case-controlled studies, and 15 were prospective randomized controlled trials (RCTs).
TABLE 1 Studies analyzed comparing hard embryo transfer catheters (TDT, Frydman, Tomcat, Rocket, Erlangen) with soft embryo transfer catheters (Wallace, Cook). Study profile
Sample size
Wisanto et al. (19) ● Randomized RCT
TDT: 100 Wallace: 100 Frydman: 100 Wallace: 162 Frydman: 62
Al Shawaf et al. (20) ● Propspective trial of ET techniques ● Randomized RCT Foutouh et al. (21) ● Randomized RCT Weering et al. (22) ● Randomized RCT McDonald & Norman (23) ● Randomized RCT ● Stratified for frozen embryo transfers Mortimer et al. (24) ● Randomized RCT Ghazzawi et al. (25) ● Randomized RCT ● Study excluded as cervix grasped and sounded in Wallace group
Wallace: 114 Rocket: 91 TDT: 657 Cook: 639 Cook: 324 Tomcat: 326
Cook: 60 Tomcat: 58 Wallace: 160 Erlangen: 160
Randomization Number table
Randomized by laboratory staff
Not given Computer-generated random blocks Numbered sealed envelopes
Not given Alternate cases
Pregnancy rate (%) TDT: 9.2% (9/98) Wallace: 19.2% (19/99) Frydman: 32.3% (31/96) Wallace: 30.3% (49/162) Frydman: 30.7% (19/62)
Wallace: 28.1% (32/114) Rocket: 14.3% (13/91) TDT: 20.5% (135/657) Cook: 27.1% (173/639) Cook: 29.6% (96/324) Tomcat: 20.5% (67/326)
Cook: 51.7% (31/60) Tomcat: 27.6% (16/58) Wallace: 19.4% (31/160) Erlangen: 30.0% (48/160)
Buckett. Meta-analysis of ET catheters. Fertil Steril 2006.
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FIGURE 1 Funnel plot to detect any publication bias in trials comparing hard with soft embryo transfer catheters.
Buckett. Meta-analysis of ET catheters. Fertil Steril 2006.
Of the RCTs, a total of 7 prospective trials compared soft with hard ET catheters (Table 1). One compared three catheter types: the TDT and Frydman hard catheters with the Wallace soft catheter (19). The other trials compared the Frydman cath-
eter with the Wallace catheter (20), the Rocket hard catheter with the Wallace catheter (21), and the TDT catheter with the K-soft 5000 Cook soft catheter (22); two trials compared the Tomcat hard catheter with the Cook soft catheters (23, 24)
FIGURE 2 Relative risk for clinical pregnancy per embryo transfer in trials comparing soft with hard embryo transfer catheters (over unity in favor of soft catheters).
Buckett. Meta-analysis of ET catheters. Fertil Steril 2006.
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FIGURE 3 Relative risk for clinical pregnancy per embryo transfer in trials comparing the TDT catheter with both hard and soft embryo transfer catheters (over unity in favor of TDT catheters).
Buckett. Meta-analysis of ET catheters. Fertil Steril 2006.
using the Cook SIVF 7019 and SIVF 6019 soft models, respectively. One study was excluded (25), which compared a metal Erlangen ET hard catheter with the Wallace catheter. The reason for exclusion was because, in the Wallace arm, the cervix was usually grasped and the cavity was sounded before ET.
A funnel plot (Fig. 4) indicated that publication bias was unlikely. A total number of 1277 ETs were performed. The meta-analysis of the data from these studies demonstrated little difference in clinical pregnancy between the two soft ET catheters (RR ⫽ 1.06; 95% CI, 0.93–1.19) (Fig. 5).
The Q statistic for noncombinability was 7.4 (df ⫽ 5, P⫽.2), indicating that these studies were relatively homogenous. A funnel plot (Fig. 1) indicates that publication bias was unlikely. Among these studies, a total of 3063 ETs were performed. Meta-analysis of the data from these studies demonstrated an increased chance of clinical pregnancy when soft ET catheters were used (RR ⫽ 1.34; 95% CI, 1.18 –1.54) (Fig. 2).
DISCUSSION Although many factors—particularly training and personal experience—lead to the choice of catheter, and these preferences inevitably affect any study, the overall conclusion from this systemic review and meta-analysis is that planned use of soft ET catheters (such as the Cook or Wallace ET catheters) leads to a higher chance of clinical pregnancy when compared with first use of hard or stiff catheters.
The TDT hard catheter has been compared against both soft catheters and other hard catheters in three studies: with the Frydman hard catheter and the Wallace soft catheter (19), with the Tomcat hard catheter (26), and with the Cook soft catheter (22). The meta-analysis demonstrated a decreased chance of clinical pregnancy when the TDT hard catheter was used (RR ⫽ 0.54; 95% CI, 0.31– 0.92) (Fig. 3). However, these studies were less homogenous (Q statistic ⫽ 7.6; df ⫽ 2; P⫽.02); thus, the random effects model was used.
This analysis represents a robust evaluation of the available evidence. The sample size required to detect an absolute difference in clinical pregnancy rate of 5% with 80% power in a two-tailed analysis is 2500 (assuming a clinical pregnancy rate of 25% and a significance level of 0.05). None of the individualized prospective randomized controlled trials comparing soft with hard ET catheters had sufficient power to detect a difference at this level.
A further 6 prospective trials were identified comparing the Cook and Wallace soft catheters (27–32) (Table 2). The Q statistic for noncombinability was 5.1 (df ⫽ 4, P⫽.9), indicating that these studies were relatively homogenous. Fertility and Sterility姞
The largest individual prospective randomized study (n ⫽ 1296) has enough power to detect only an 8% difference in clinical pregnancy rate (18). The combination of these data in this systemic review and meta-analysis comparing hard with soft catheters (n ⫽ 3063) has a power of 97% to detect a difference of 4.8% in clinical pregnancy rate. 731
TABLE 2 Studies analyzed comparing Wallace and Cook soft embryo transfer catheters. Study profile
Sample size
Boone et al. (27) ● Randomized RCT Grunert et al. (28) ● Randomized RCT Mayer et al. (29) ● Randomized RCT Karande et al. (30) ● Randomized RCT Levi-Setti et al. (31) ● Randomized RCT Saldeen et al. (32) ● Randomized RCT
Wallace: 53 Cook: 60 Wallace: 49 Cook: 50 Wallace: 106 Cook: 107 Wallace: 141 Cook: 110 Wallace: 100 Cook: 100 Wallace: 198 Cook: 202
Randomization Computer-generated random blocks Not given Not given Alternate cases starting with Wallace each day Not given Not given
Pregnancy rate (%) Wallace: 52.8% (28/53) Cook: 50.0% (30/60) Wallace: 38.8% (19/49) Cook: 32.0% (16/50) Wallace: 39.6% (42/106) Rocket: 36.4% (39/107) Wallace: 57.4% (81/141) Cook: 55.4% (61/110) Wallace: 43.0% (43/100) Cook: 37.0% (37/100) Wallace: 39.9% (79/198) Cook: 40.1% (81/202)
Buckett. Meta-analysis of ET catheters. Fertil Steril 2006.
There was no demonstrable difference between the two soft catheters (Wallace or Cook); the combination of these data comparing the two soft catheters (n ⫽ 1276) had power to detect only an 8% difference. Publication bias may confound the results of all systemic reviews and meta-analyses, as studies showing positive re-
sults are more likely to be published (33, 34). In our systematic review, every effort was made to avoid bias by searching a wide variety of databases and by including abstracts from major meetings and non-English-language publications. The use of funnel plots can detect publication bias or bias as a result of location and selection of studies
FIGURE 4 Funnel plot to detect any publication bias in trials comparing Cook with Wallace soft embryo transfer catheters.
Buckett. Meta-analysis of ET catheters. Fertil Steril 2006.
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FIGURE 5 Relative risk for clinical pregnancy per embryo transfer in trials comparing Cook with Wallace soft embryo transfer catheters (over unity in favor of Wallace catheters).
Buckett. Meta-analysis of ET catheters. Fertil Steril 2006.
(35). However, our funnel plot analyses confirmed that selective bias was unlikely. No study reported any adverse effects of either hard or soft ET catheters. The main disadvantage of using a soft ET catheter for the first attempt would appear to be the increased time needed for the ET if it is difficult to negotiate the angle at the cervical-uterine junction, particularly if the embryos need to be transferred to a different catheter. This problem can be overcome by a mock or trial ET immediately before the “real” ET (7–9), a full bladder, and ultrasound-guidance to determine the cervical-uterine angle during the ET (36). The exact mechanism whereby soft ET catheters improve clinical pregnancy rates is unclear. Less trauma as the soft tip enters the uterine cavity causing less direct damage to the endometrium may lead to improved clinical pregnancy rates. Hysteroscopy studies have suggested that there is less trauma after mock transfer when soft catheters are used, although trauma to the endometrium still occurs with the soft Wallace transfer catheter (37) and Cook catheter (38). Soft ET catheters may reduce the incidence and nature of any uterine contractions, which may also affect implantation and thus pregnancy rates (39). Fertility and Sterility姞
Our systemic review and meta-analysis has demonstrated that use of soft ET catheters does lead to a higher chance of clinical pregnancy when compared with the use of hard or stiff catheters; soft catheters should, therefore, be considered as the first-choice ET catheter. REFERENCES 1. Angell RR. Aneuploidy in older women. Higher rates of aneuploidy in oocytes from older women. Hum Reprod 1994;9:1199 –2000. 2. Lim AS, Tsakok MF. Age-related decline in fertility: a link to degenerated oocytes? Fertil Steril 1997;68:265–71. 3. Awonuga A, Nabi A, Govindbhai J, Birch H, Stewart B. Contamination of embryo transfer catheter and treatment outcome in in vitro fertilization. J Assist Reprod Genet 1998;15:198 –201. 4. Mansour RT, Aboulghar MA, Serour GI, Amin YM. Dummy embryo transfer using methylene blue dye. Hum Reprod 1994;9:1257–9. 5. Sundstrom P, Wramsby H, Persson P, Liedholm P. Filled bladder simplifies human embryo transfer. Br J Obstet Gynaecol 1984;91: 506 –7. 6. Lewin A, Schenker JG, Avrech O, Shapira S, Safran A, Friedler S. The role of uterine straightening by passive bladder distension before embryo transfer in IVF cycles. J Assist Reprod Genet 1997; 14:32– 4. 7. Urman B, Aksoy S, Alatas C, Mercan R, Nuhoglu A, Isiklar A, Balaban
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B. Comparing two embryo transfer catheters. Use of a trial transfer to determine the catheter applied. J Reprod Med 2000;45:135– 8. Sharif K, Afnan M, Lenton W. Mock embryo transfer with a full bladder immediately before the real transfer for in-vitro fertilization treatment: the Birmingham experience of 113 cases. Hum Reprod 1995;10:1715– 8. Mansour R, Aboulghar M, Serour G. Dummy embryo transfer: a technique that minimizes the problems of embryo transfer and improves the pregnancy rate in human in vitro fertilization. Fertil Steril 1990;54: 678 – 81. Prapas N, Prapas Y, Panagiotidis Y, Prapas S, Vanderzwalmen P, Makedos G. Cervical dilatation has a positive impact on the outcome of IVF in randomly assigned cases having two previous difficult embryo transfers. Hum Reprod 2004;19:1791–5. Strickler RC, Christianson C, Crane JP, Curato A, Knight AB, Yang V. Ultrasound guidance for human embryo transfer. Fertil Steril 1985;43: 54 – 61. Sallam HN, Sadek SS. Ultrasound-guided embryo transfer: a metaanalysis of randomized controlled trials. Fertil Steril 2003;80:1042– 6. Buckett WM. A meta-analysis of ultrasound-guided versus clinical touch embryo transfer. Fertil Steril 2003;80:1037– 41. Burke LM, Davenport AT, Russell GB, Deaton JL. Predictors of success after embryo transfer: experience from a single provider. Am J Obstet Gynecol 2000;182:1001– 4. Choe JK, Nazari A, Check JH, Summers-Chase D, Swenson K. Marked improvement in clinical pregnancy rates following in vitro fertilizationembryo transfer seen when transfer technique and catheter were changed. Clin Exp Obstet Gynecol 2001;28:223– 4. Wood EG, Batzer FR, Go KJ, Gutmann JN, Corson SL. Ultrasound guided soft embryo catheters will improve pregnancy rates in in vitro fertilization. Hum Reprod 2002;15:107–12. De Placido G, Wilding M, Stina I, Mollo A, Alviggi E, Tolino A, et al. The effect of ease of transfer and type of catheter used on pregnancy and implantation rates in an IVF program. J Assist Reprod Genet 2002;19:14 –18. Sallam HN, Agameya AF, Rahman AF, Ezzeldin F, Sallam AN. Impact of technical difficulties, choice of catheter, and the presence of blood on the success of embryo transfer— experience from a single provider. J Assist Reprod Genet 2003;20:135– 42. Wisanto A, Janssens R, Deschacht J, Camus M, Devroey P, Van Steirteghem AC. Performance of different embryo transfer catheters in a human in vitro fertilization program. Fertil Steril 1989;52:79 – 84. Al-Shawaf T, Dave R, Harper J, Linehan D, Riley P, Craft I. Transfer of embryos into the uterus: how much do technical factors affect pregnancy rates? J Assist Reprod Genet 1993;10:31– 6. Foutouh IA, Youssef M, Tolba M, Rushdi M, Nakieb A, Meguid WA. Does embryo transfer catheter type affect pregnancy rate? Mid East Fertil Soc J 2003;8:154 – 8. Weering HG, Schats R, McDonnel J, Vink JM, Vermeiden JP, Hompes PG. The impact of embryo transfer catheter on the pregnancy rate in IVF. Hum Reprod 2002;17:666 –70.
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23. McDonald JA, Norman RJ. A randomised controlled trial of a soft double lumen embryo transfer catheter versus a form single lumen catheter: significant improvements in pregnancy rates. Hum Reprod 2002;17:1502– 6. 24. Mortimer ST, Fluker M, Yuzpe A. Effects of embryo transfer catheter on implantation rates. Fertil Steril 2002;78(Suppl 1):S17– 8. 25. Ghazzawi IM, Al-Hasani S, Karaki R, Souso S. Transfer technique and catheter choice influence the incidence of transcervical embryo expulsion and the outcome of IVF. Hum Reprod 1999;14:677– 82. 26. Meriano J, Weissman A, Greenblatt EM, Ward S, Caspar RF. The choice of embryo transfer catheter affects embryo implantation after IVF. Fertil Steril 2000;74:678 – 82. 27. Boone WR, Johnson JE, Blackhurst DM, Crane MM. Cook versus Edwards-Wallace: are there differences in flexible catheters? J Assist Reprod Genet 2001;18:15–17. 28. Grunert GM, Dunn RC, Valdes CT, Wan CC, Wun WS. Comparison of Wallace, Frydman DT, and Cook embryo transfer catheters for IVF: a prospective randomized study. Fertil Steril 1998;70(Suppl 1):S120. 29. Mayer JF, Nehchiri F, Jones EC, Weedon VM, Kalin HL, Lanzendorf SE, et al. Prospective randomized analysis of the impact of two different transfer catheters on clinical pregnancy rates. Fertil Steril 1999; 72(Suppl 1):S144. 30. Karande VA, Hazlett D, Vietzke M, Gleicher N. A prospective randomized comparison of the Wallace catheter and the Cook Echo-Tip catheter for ultrasound-guided embryo transfer. Fertil Steril 2002;77: 826 –30. 31. Levi-Setti PE, Albani E, Baggiani AM, Zannoni E, Colombo G, Liprandi V. Prospective randomized study comparing two soft catheters for embryo transfer. Fertil Steril 2002;78(Suppl 1):S234 –5. 32. Saldeen P, Bergh T, Sundstrom P, Holte J. A prospective randomized controlled trial comparing two embryo transfer catheters in an ART programme. Hum Reprod 2003;18(Suppl 1):P384. 33. Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet 1991;337:867–72. 34. Dickerson K, Min YL, Meinert CL. Factors influencing publication of research results. J Am Med Assoc 1992;267:374 – 8. 35. Egger M, Davy-Smith G, Sneider M, Minder CE. Bias in meta-analysis detected bias a simple, graphical test. Br Med J 1997;315:629 –34. 36. Sallam HN, Agameya AF, Rahman AF, Ezzeldin F, Sallam AN. Ultrasound measurement of the uterocervical angle before embryo transfer: a prospective controlled study. Hum Reprod 2002;17:1767–72. 37. Marconi G, Vilela M, Bello J, Diradourian M, Quintana R, Sueldo C. Endometrial lesions caused by catheters used for embryo transfers: a preliminary report. Fertil Steril 2003;80:363–7. 38. Murray AS, Healy DS, Rombauts L. Embryo transfer: hysteroscopic assessment of transfer catheter effects on the endometrium. Reprod Biomed Online 2003;7:583– 6. 39. Fanchin R, Righini C, de Ziegler D, Olivennes F, Ledee N, Frydman R. Effects of vaginal progesterone administration on uterine contractility at the time of embryo transfer. Fertil Steril 2001;75:1136 – 40.
Vol. 85, No. 3, March 2006
Objective: To determine the relative efficacy of different types of embryo transfer (ET) catheters. Design: Systematic review and meta-analysis of prospective randomized, controlled trials comparing at least two different ET catheters. Setting: Infertility centers providing treatment with in vitro fertilization/embryo transfer (IVF-ET). Patient(s): Women undergoing ET. Intervention(s): Embryo transfer with soft or hard catheters. Main Outcome Measure(s): Clinical pregnancy rate. Result(s): A total of seven prospective trials were identified that compared soft (Cook or Wallace) catheters with hard (TDT, Frydman, Tomcat, Rocket) catheters. The meta-analysis demonstrated an increased chance of clinical pregnancy when soft ET catheters were used. The TDT catheter was compared against both soft catheters and other hard catheters, showing decreased chance of clinical pregnancy when the TDT catheter was used. Six more prospective trials were identified comparing the Cook and Wallace soft catheters, and the meta-analysis of these data showed no demonstrable difference in clinical pregnancy rates. Conclusion(s): An increased chance of clinical pregnancy is achieved when soft ET catheters are used. There appears to be little difference between the Cook and Wallace soft catheters. (Fertil Steril威 2006;85:728 –34. © 2006 by American Society for Reproductive Medicine.) Key Words: Embryo transfer catheter, IVF-ET, catheter type, meta-analysis
Embryo transfer remains the most inefficient step in in vitro fertilization/embryo transfer (IVF-ET) treatment cycles, and a great deal of research effort has been directed at ET technique. Although undoubtedly much of the embryo attrition has been due to aneuploidies, other abnormalities, or degenerative changes in the embryo (1, 2), several studies have shown increases in clinical pregnancy rates resulting from improvements in various aspects of the ET technique, including cervical cleaning (3, 4), a full bladder (5, 6), a dummy or mock transfer either before starting ovarian stimulation or immediately before ET (7–9), pretreatment cervical dilatation in difficult cases (10), and ultrasound guidance (11–13). The use of different ET catheters has also been studied. Many large retrospective studies (14 –18) have reported higher clinical pregnancy rates with “soft” embryo transReceived April 4, 2005; revised and accepted August 14, 2005. Presented at the 50th Annual Meeting of the Canadian Fertility and Andrology Society, Jasper, Alberta, Canada; November 24 –27, 2004. Reprint requests: William M. Buckett, M.D., Assistant Professor, Department of Obstetrics and Gynecology, McGill University, Royal Victoria Hospital, 687, Avenue des Pins Ouest, Montréal, Québec, Canada H3A 1A1 (FAX: 1-514-843-1496; E-mail: [email protected]).
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fer catheters such as the Cook catheter (Cook Ob/Gyn, Inc., Bloomington, IN) and the Wallace catheter (Marlow Technologies, Willoughby, OH) compared with “hard” embryo catheters such as the TDT (Laboratoire CCD, Paris, France), Frydman (Laboratoire CCD), Tomcat (Kendell Health Care, Hampshire, MA), Tefcat (Kendell Health Care), and Rocket ET catheters (Rocket Medical, Watford, UK). However, in technically difficult ET, particularly where difficulties are encountered negotiating the internal cervical os, there is often a need for the stiffer hard catheters. The change from soft to hard catheters for these transfers as well as the inherent difficulties of the transfer itself could account for any difference in pregnancy rate (14). However, the evidence from prospective trials has been conflicting, and sample sizes are often too small to identify small changes in clinical pregnancy rate. Thus, the objective of this systemic review and meta-analysis was to identify prospective randomized controlled trials comparing at least two different ET catheters and to determine the relative risk of clinical pregnancy with different ET catheters.
Fertility and Sterility姞 Vol. 85, No. 3, March 2006 Copyright ©2006 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/06/$32.00 doi:10.1016/j.fertnstert.2005.08.031
MATERIALS AND METHODS Study Identification and Selection Publications, in all languages, describing prospective randomized controlled trials comparing at least two different ET catheters were sought by searching online databases (MEDLINE, EMBASE, CINAHL, the Science Citation Index, and OVID Healthstar), using the headings “embryo transfer,” “embryo transfer catheter,” “catheter type,” and “embryo transfer technique.” Bibliographies of relevant publications and review articles were also scanned, and journals and abstracts from major infertility meetings from 1990 to 2004 were also hand-searched in an effort to identify any unpublished trials. Inclusion criteria for selection were a prospective randomized trial comparing at least two different types of ET catheters. All retrospective studies including case controlled and historical case controlled studies were excluded. Institutional ethics board approval was not required for a systemic review and meta-analysis of previously published clinical trials. Outcome Measures Outcome measures were the rate of clinical pregnancy per ET, where a clinical pregnancy was identified by the
presence of a gestational sac at ultrasound at least 4 weeks following the ET. Validity Assessment and Data Analysis Each study was assessed for methodologic quality to confirm that the trials were genuinely randomized and that there were no differences in the two groups after randomization. All prospective controlled randomized trials were included. The data were extracted into 2 ⫻ 2 tables and checked for accuracy. The data were checked for homogeneity using the Q statistic, and the fixed-effects model for relative risk was used. Funnel plot analysis was used to detect any publication bias. RESULTS The search strategy identified a total of 168 articles in which different ET catheters used for human ET were studied. Nearly half of these (75) concerned other aspects of ET (such as ultrasound guidance, embryo deposition, catheter loading, fluid dynamics, and cervical preparation). Of the remaining articles, 22 were reviews, 21 were retrospective case series, 18 were case reports, 11 were prospective nonrandomized comparative studies, 6 were case-controlled studies, and 15 were prospective randomized controlled trials (RCTs).
TABLE 1 Studies analyzed comparing hard embryo transfer catheters (TDT, Frydman, Tomcat, Rocket, Erlangen) with soft embryo transfer catheters (Wallace, Cook). Study profile
Sample size
Wisanto et al. (19) ● Randomized RCT
TDT: 100 Wallace: 100 Frydman: 100 Wallace: 162 Frydman: 62
Al Shawaf et al. (20) ● Propspective trial of ET techniques ● Randomized RCT Foutouh et al. (21) ● Randomized RCT Weering et al. (22) ● Randomized RCT McDonald & Norman (23) ● Randomized RCT ● Stratified for frozen embryo transfers Mortimer et al. (24) ● Randomized RCT Ghazzawi et al. (25) ● Randomized RCT ● Study excluded as cervix grasped and sounded in Wallace group
Wallace: 114 Rocket: 91 TDT: 657 Cook: 639 Cook: 324 Tomcat: 326
Cook: 60 Tomcat: 58 Wallace: 160 Erlangen: 160
Randomization Number table
Randomized by laboratory staff
Not given Computer-generated random blocks Numbered sealed envelopes
Not given Alternate cases
Pregnancy rate (%) TDT: 9.2% (9/98) Wallace: 19.2% (19/99) Frydman: 32.3% (31/96) Wallace: 30.3% (49/162) Frydman: 30.7% (19/62)
Wallace: 28.1% (32/114) Rocket: 14.3% (13/91) TDT: 20.5% (135/657) Cook: 27.1% (173/639) Cook: 29.6% (96/324) Tomcat: 20.5% (67/326)
Cook: 51.7% (31/60) Tomcat: 27.6% (16/58) Wallace: 19.4% (31/160) Erlangen: 30.0% (48/160)
Buckett. Meta-analysis of ET catheters. Fertil Steril 2006.
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FIGURE 1 Funnel plot to detect any publication bias in trials comparing hard with soft embryo transfer catheters.
Buckett. Meta-analysis of ET catheters. Fertil Steril 2006.
Of the RCTs, a total of 7 prospective trials compared soft with hard ET catheters (Table 1). One compared three catheter types: the TDT and Frydman hard catheters with the Wallace soft catheter (19). The other trials compared the Frydman cath-
eter with the Wallace catheter (20), the Rocket hard catheter with the Wallace catheter (21), and the TDT catheter with the K-soft 5000 Cook soft catheter (22); two trials compared the Tomcat hard catheter with the Cook soft catheters (23, 24)
FIGURE 2 Relative risk for clinical pregnancy per embryo transfer in trials comparing soft with hard embryo transfer catheters (over unity in favor of soft catheters).
Buckett. Meta-analysis of ET catheters. Fertil Steril 2006.
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FIGURE 3 Relative risk for clinical pregnancy per embryo transfer in trials comparing the TDT catheter with both hard and soft embryo transfer catheters (over unity in favor of TDT catheters).
Buckett. Meta-analysis of ET catheters. Fertil Steril 2006.
using the Cook SIVF 7019 and SIVF 6019 soft models, respectively. One study was excluded (25), which compared a metal Erlangen ET hard catheter with the Wallace catheter. The reason for exclusion was because, in the Wallace arm, the cervix was usually grasped and the cavity was sounded before ET.
A funnel plot (Fig. 4) indicated that publication bias was unlikely. A total number of 1277 ETs were performed. The meta-analysis of the data from these studies demonstrated little difference in clinical pregnancy between the two soft ET catheters (RR ⫽ 1.06; 95% CI, 0.93–1.19) (Fig. 5).
The Q statistic for noncombinability was 7.4 (df ⫽ 5, P⫽.2), indicating that these studies were relatively homogenous. A funnel plot (Fig. 1) indicates that publication bias was unlikely. Among these studies, a total of 3063 ETs were performed. Meta-analysis of the data from these studies demonstrated an increased chance of clinical pregnancy when soft ET catheters were used (RR ⫽ 1.34; 95% CI, 1.18 –1.54) (Fig. 2).
DISCUSSION Although many factors—particularly training and personal experience—lead to the choice of catheter, and these preferences inevitably affect any study, the overall conclusion from this systemic review and meta-analysis is that planned use of soft ET catheters (such as the Cook or Wallace ET catheters) leads to a higher chance of clinical pregnancy when compared with first use of hard or stiff catheters.
The TDT hard catheter has been compared against both soft catheters and other hard catheters in three studies: with the Frydman hard catheter and the Wallace soft catheter (19), with the Tomcat hard catheter (26), and with the Cook soft catheter (22). The meta-analysis demonstrated a decreased chance of clinical pregnancy when the TDT hard catheter was used (RR ⫽ 0.54; 95% CI, 0.31– 0.92) (Fig. 3). However, these studies were less homogenous (Q statistic ⫽ 7.6; df ⫽ 2; P⫽.02); thus, the random effects model was used.
This analysis represents a robust evaluation of the available evidence. The sample size required to detect an absolute difference in clinical pregnancy rate of 5% with 80% power in a two-tailed analysis is 2500 (assuming a clinical pregnancy rate of 25% and a significance level of 0.05). None of the individualized prospective randomized controlled trials comparing soft with hard ET catheters had sufficient power to detect a difference at this level.
A further 6 prospective trials were identified comparing the Cook and Wallace soft catheters (27–32) (Table 2). The Q statistic for noncombinability was 5.1 (df ⫽ 4, P⫽.9), indicating that these studies were relatively homogenous. Fertility and Sterility姞
The largest individual prospective randomized study (n ⫽ 1296) has enough power to detect only an 8% difference in clinical pregnancy rate (18). The combination of these data in this systemic review and meta-analysis comparing hard with soft catheters (n ⫽ 3063) has a power of 97% to detect a difference of 4.8% in clinical pregnancy rate. 731
TABLE 2 Studies analyzed comparing Wallace and Cook soft embryo transfer catheters. Study profile
Sample size
Boone et al. (27) ● Randomized RCT Grunert et al. (28) ● Randomized RCT Mayer et al. (29) ● Randomized RCT Karande et al. (30) ● Randomized RCT Levi-Setti et al. (31) ● Randomized RCT Saldeen et al. (32) ● Randomized RCT
Wallace: 53 Cook: 60 Wallace: 49 Cook: 50 Wallace: 106 Cook: 107 Wallace: 141 Cook: 110 Wallace: 100 Cook: 100 Wallace: 198 Cook: 202
Randomization Computer-generated random blocks Not given Not given Alternate cases starting with Wallace each day Not given Not given
Pregnancy rate (%) Wallace: 52.8% (28/53) Cook: 50.0% (30/60) Wallace: 38.8% (19/49) Cook: 32.0% (16/50) Wallace: 39.6% (42/106) Rocket: 36.4% (39/107) Wallace: 57.4% (81/141) Cook: 55.4% (61/110) Wallace: 43.0% (43/100) Cook: 37.0% (37/100) Wallace: 39.9% (79/198) Cook: 40.1% (81/202)
Buckett. Meta-analysis of ET catheters. Fertil Steril 2006.
There was no demonstrable difference between the two soft catheters (Wallace or Cook); the combination of these data comparing the two soft catheters (n ⫽ 1276) had power to detect only an 8% difference. Publication bias may confound the results of all systemic reviews and meta-analyses, as studies showing positive re-
sults are more likely to be published (33, 34). In our systematic review, every effort was made to avoid bias by searching a wide variety of databases and by including abstracts from major meetings and non-English-language publications. The use of funnel plots can detect publication bias or bias as a result of location and selection of studies
FIGURE 4 Funnel plot to detect any publication bias in trials comparing Cook with Wallace soft embryo transfer catheters.
Buckett. Meta-analysis of ET catheters. Fertil Steril 2006.
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FIGURE 5 Relative risk for clinical pregnancy per embryo transfer in trials comparing Cook with Wallace soft embryo transfer catheters (over unity in favor of Wallace catheters).
Buckett. Meta-analysis of ET catheters. Fertil Steril 2006.
(35). However, our funnel plot analyses confirmed that selective bias was unlikely. No study reported any adverse effects of either hard or soft ET catheters. The main disadvantage of using a soft ET catheter for the first attempt would appear to be the increased time needed for the ET if it is difficult to negotiate the angle at the cervical-uterine junction, particularly if the embryos need to be transferred to a different catheter. This problem can be overcome by a mock or trial ET immediately before the “real” ET (7–9), a full bladder, and ultrasound-guidance to determine the cervical-uterine angle during the ET (36). The exact mechanism whereby soft ET catheters improve clinical pregnancy rates is unclear. Less trauma as the soft tip enters the uterine cavity causing less direct damage to the endometrium may lead to improved clinical pregnancy rates. Hysteroscopy studies have suggested that there is less trauma after mock transfer when soft catheters are used, although trauma to the endometrium still occurs with the soft Wallace transfer catheter (37) and Cook catheter (38). Soft ET catheters may reduce the incidence and nature of any uterine contractions, which may also affect implantation and thus pregnancy rates (39). Fertility and Sterility姞
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