Is what we clearly see really so obvious? Ultrasonography and transcervical embryo transfer—a review
2006; Elsevier BV; Volume: 87; Issue: 1 Linguagem: Inglês
10.1016/j.fertnstert.2006.06.017
ISSN1556-5653
Autores Tópico(s)Reproductive Health and Technologies
ResumoObjectiveTo critically review the role of ultrasound-guided embryo transfer (ET) and its influence on the outcome of in vitro fertilization (IVF).DesignMedline review of published manuscripts.Result(s)Studies evaluating the role of ultrasound-assisted ET have had mixed results, and although meta-analysis of prospective trials suggests an improvement in outcome, limitations in study design may overstate the effect of ultrasonography. Other ET techniques may eliminate the advantages provided by ultrasonography, limiting its benefit to specific clinical scenarios. However, because no trial has demonstrated an adverse effect and because cases that may benefit from its use often cannot be predicted reliably, the routine application of ultrasonography can be justified. To critically review the role of ultrasound-guided embryo transfer (ET) and its influence on the outcome of in vitro fertilization (IVF). Medline review of published manuscripts. Studies evaluating the role of ultrasound-assisted ET have had mixed results, and although meta-analysis of prospective trials suggests an improvement in outcome, limitations in study design may overstate the effect of ultrasonography. Other ET techniques may eliminate the advantages provided by ultrasonography, limiting its benefit to specific clinical scenarios. However, because no trial has demonstrated an adverse effect and because cases that may benefit from its use often cannot be predicted reliably, the routine application of ultrasonography can be justified. Improvements in in vitro fertilization (IVF) and embryo transfer (ET) have resulted from evaluating each step of the process, analyzing effects of different techniques, then assessing outcomes to select the best method, whether related to preparation of the patient, choice of stimulation protocol, culture technique, embryo selection, mechanics of transfer, or posttransfer management. Although seemingly simple by comparison with the process of controlled ovarian hyperstimulation, oocyte retrieval or embryo culture, ET has been recognized more recently as carrying a disproportionate degree of influence on cycle outcome relative to the task’s complexity. Embryo transfer was originally performed by advancing the transfer catheter until contact was made with the uterine fundus, then withdrawing the catheter 5–10 mm and expelling the embryos into the uterine cavity. This “blind” technique, so called because definitive localization of the catheter’s position is not known, relied on the ability of the operator to “feel” proper catheter placement. An ultrasound study, however, showed that this subjective sense frequently failed: in nearly one fifth of transfers examined, the operator was unaware that the catheter was poorly positioned (1Strickler R.C. Christianson C. Crane J.P. Curato A. Knight A.B. Yang V. Ultrasound guidance for human embryo transfer.Fertil Steril. 1985; 43: 54-61Abstract Full Text PDF PubMed Scopus (100) Google Scholar). When performed with ultrasonography, transfers were subjectively easier, but no proof of their superiority was demonstrated. Despite lack of confirmatory studies, ultrasound-assisted techniques found immediate advocates (1Strickler R.C. Christianson C. Crane J.P. Curato A. Knight A.B. Yang V. Ultrasound guidance for human embryo transfer.Fertil Steril. 1985; 43: 54-61Abstract Full Text PDF PubMed Scopus (100) Google Scholar, 2Leong M. Leung C. Tucker M. Wong C. Chan H. Ultrasound-assisted embryo transfer [letter].J In Vitro Fert Embryo Transf. 1986; 3: 383-385Crossref PubMed Scopus (47) Google Scholar). Interest in this aspect of IVF was low, and studies comparing ultrasonography with blind transfers were not performed or published until many years later. As atraumatic techniques developed and have since been shown to be superior to contact techniques, emphasis has been placed on avoiding the uterine fundus. In addition to provoking bleeding, contact with the fundus can stimulate uterine contractions (3Lesny P. Killick S.R. Tetlow R.L. Robinson J. Maguiness S.D. Embryo transfer—can we learn anything new from the observation of junctional zone contractions?.Hum Reprod. 1998; 13: 1540-1546Crossref PubMed Scopus (164) Google Scholar), which can expel transferred embryos out of the uterine cavity, resulting in IVF failure or ectopic pregnancy. Now “clinical touch” transfer refers to techniques in which imaging is not concurrently performed, but contact with the fundus is avoided. Advances in the quality and resolution of ultrasonography, including the development of multiple frequency transducers and transvaginal instruments, have made increased scrutiny of the ET possible. As with transabdominal imaging, transvaginal ultrasonography after catheter placement has similarly been shown to reveal suboptimal placement of the catheter tip near the opening of the fallopian tube (7.4%), abutting the fundus (17.4%), or below the endometrial surface (24.8%) after the catheter was threaded into the uterus by clinical touch (4Woolcott R. Stanger J. Potentially important variables identified by transvaginal ultrasound-guided embryo transfer.Hum Reprod. 1997; 12: 963-966Crossref PubMed Scopus (123) Google Scholar). Conflicting studies evaluating transabdominal ultrasound-assisted ET have been performed, some showing an improvement in outcome (5Coroleu B. Carreras O. Veiga A. Martell A. Martinez F. Belil I. et al.Embryo transfer under ultrasound guidance improves pregnancy rates after in-vitro fertilization.Hum Reprod. 2000; 15: 616-620Crossref PubMed Scopus (151) Google Scholar, 6Matorras R. Urquijo E. Mendoza R. Corcóstegui B. Exposito A. Rodríguez-Escudero F.J. Ultrasound-guided embryo transfer improves pregnancy rates and increases the frequency of easy transfers.Hum Reprod. 2002; 17: 1762-1766Crossref PubMed Scopus (104) Google Scholar, 7Lindheim S.R. Cohen M.A. Sauer M.V. Ultrasound guided embryo transfer significantly improves pregnancy rates in women undergoing oocyte donation.Int J Gynecol Obstet. 1999; 66: 281-284Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 8Li R. Lu L. Hao G. Zhong K. Cai Z. Wang W. Abdominal ultrasound-guided embryo transfer improves clinical pregnancy rates after in vitro fertilization: experiences from 330 clinical investigations.J Assist Reprod Genet. 2005; 22: 3-8Crossref PubMed Scopus (18) Google Scholar, 9Prapas Y. Prapas N. Hatziparasidou A. Prapa S. Nijs M. Vanderzwalmen P. et al.The echoguide embryo transfer maximizes the IVF results.Acta Eur Fertil. 1995; 26: 113-115PubMed Google Scholar), others demonstrating no difference (10al-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: 31-36Crossref PubMed Scopus (96) Google Scholar, 11Kan A.K.S. Abdalla H.I. Gafar A.H. Nappi L. Ogunyemi B.O. Thomas A. et al.Embryo transfer: ultrasound-guided versus clinical touch.Hum Reprod. 1999; 14: 1259-1261Crossref PubMed Scopus (77) Google Scholar, 12Coroleu B. Barri P.N. Carreras O. Martínez F. Veiga A. Balasch J. The usefulness of ultrasound guidance in frozen-thawed embryo transfer: a prospective randomized clinical trial.Hum Reprod. 2002; 17: 2885-2890Crossref PubMed Scopus (36) Google Scholar, 13García-Velasco J.A. Isaza V. Martinez-Salazar J. Landazábal A. Requena A. Remhoí J. et al.Transabdominal ultrasound-guided embryo transfer does not increase pregnancy rates in oocyte recipients.Fertil Steril. 2002; 78: 534-539Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 14Mirkin S. Jones E.L. Mayer J.F. Stadtmauer L. Gibbons W.E. Oehninger S. Impact of transabdominal ultrasound guidance on performance and outcome of transcervical uterine embryo transfer.J Assist Reprod Genet. 2003; 20: 318-322Crossref PubMed Scopus (31) Google Scholar, 15de Camargo Martins A.M.V. Baruffi R.L.R. Mauri A.L. Peteresen C. Oliveira J.B.A. Contart P. et al.Ultrasound guidance is not necessary during easy transfers.J Assist Reprod Genet. 2004; 21: 421-425Crossref PubMed Scopus (21) Google Scholar, 16Flisser E. Grifo J.A. Krey L.C. Noyes N. Transabdominal ultrasound-assisted embryo transfer and pregnancy outcome.Fertil Steril. 2006; 85: 353-357Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar), and others with mixed results (17Prapas Y. Prapas N. Hatziparasidou A. Vanderzwalmen P. Nijs M. Prapa S. et al.Ultrasound-guided embryo transfer maximizes the IVF results on day 3 and day 4 embryo transfer but has no impact on day 5.Hum Reprod. 2001; 16: 1904-1908Crossref PubMed Scopus (54) Google Scholar, 18Hurley V.A. Osborn J.C. Leoni M.A. Leeton J. Ultrasound-guided embryo transfer: a controlled trial.Fertil Steril. 1991; 55: 559-562Abstract Full Text PDF PubMed Scopus (76) Google Scholar, 19Tang O.S. Ng E.H.Y. So W.W.K. Ho P.C. Ultrasound-guided embryo transfer: a prospective randomized control trial.Hum Reprod. 2001; 16: 2310-2315Crossref PubMed Scopus (65) Google Scholar). No study has shown a worsening of outcome when ultrasonography is used. Though transvaginal ultrasonography is technically more challenging to perform, reports exist evaluating its use (7Lindheim S.R. Cohen M.A. Sauer M.V. Ultrasound guided embryo transfer significantly improves pregnancy rates in women undergoing oocyte donation.Int J Gynecol Obstet. 1999; 66: 281-284Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 18Hurley V.A. Osborn J.C. Leoni M.A. Leeton J. Ultrasound-guided embryo transfer: a controlled trial.Fertil Steril. 1991; 55: 559-562Abstract Full Text PDF PubMed Scopus (76) Google Scholar, 20Anderson R.E. Nugent N.L. Gregg A.T. Nunn S.L. Behr B.R. Transvaginal ultrasound-guided embryo transfer improves outcome in patients with previous failed in vitro fertilization cycles.Fertil Steril. 2002; 77: 769-775Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 21Kojima K. Nomiyama M. Kumamoto T. Matsumoto Y. Iwasaka T. Transvaginal ultrasound-guided embryo transfer improves pregnancy and implantation rates after IVF.Hum Reprod. 2001; 16: 2578-2582Crossref PubMed Scopus (51) Google Scholar). Studies in which true clinical touch transfers were performed and contact with the uterine fundus was deliberately made introduce a confounding variable (21Kojima K. Nomiyama M. Kumamoto T. Matsumoto Y. Iwasaka T. Transvaginal ultrasound-guided embryo transfer improves pregnancy and implantation rates after IVF.Hum Reprod. 2001; 16: 2578-2582Crossref PubMed Scopus (51) Google Scholar), as do studies in which uterine sounding was performed immediately before ET (7Lindheim S.R. Cohen M.A. Sauer M.V. Ultrasound guided embryo transfer significantly improves pregnancy rates in women undergoing oocyte donation.Int J Gynecol Obstet. 1999; 66: 281-284Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 14Mirkin S. Jones E.L. Mayer J.F. Stadtmauer L. Gibbons W.E. Oehninger S. Impact of transabdominal ultrasound guidance on performance and outcome of transcervical uterine embryo transfer.J Assist Reprod Genet. 2003; 20: 318-322Crossref PubMed Scopus (31) Google Scholar), because contact with the fundus has been shown to be a complicating factor by promoting uterine contractions and possibly by traumatizing the endometrium. Inadvertent contact with the fundus may confound studies in which mock transfer was performed immediately before transfer to determine the best catheter choice (14Mirkin S. Jones E.L. Mayer J.F. Stadtmauer L. Gibbons W.E. Oehninger S. Impact of transabdominal ultrasound guidance on performance and outcome of transcervical uterine embryo transfer.J Assist Reprod Genet. 2003; 20: 318-322Crossref PubMed Scopus (31) Google Scholar). When mock transfer was performed in all patients immediately before ET to determine the catheter best suited to the patient, differences in the background characteristics of the patients become evident when second- or third-choice catheters are disproportionately used, undermining the validity of the study outcome (14Mirkin S. Jones E.L. Mayer J.F. Stadtmauer L. Gibbons W.E. Oehninger S. Impact of transabdominal ultrasound guidance on performance and outcome of transcervical uterine embryo transfer.J Assist Reprod Genet. 2003; 20: 318-322Crossref PubMed Scopus (31) Google Scholar). When catheter position is viewed only after placement, doubt can be cast on the original placement and whether contact with the fundus might have been made (18Hurley V.A. Osborn J.C. Leoni M.A. Leeton J. Ultrasound-guided embryo transfer: a controlled trial.Fertil Steril. 1991; 55: 559-562Abstract Full Text PDF PubMed Scopus (76) Google Scholar). Studies demonstrating the utility in ultrasonography only for single ET (18Hurley V.A. Osborn J.C. Leoni M.A. Leeton J. Ultrasound-guided embryo transfer: a controlled trial.Fertil Steril. 1991; 55: 559-562Abstract Full Text PDF PubMed Scopus (76) Google Scholar) or on certain transfer days (17Prapas Y. Prapas N. Hatziparasidou A. Vanderzwalmen P. Nijs M. Prapa S. et al.Ultrasound-guided embryo transfer maximizes the IVF results on day 3 and day 4 embryo transfer but has no impact on day 5.Hum Reprod. 2001; 16: 1904-1908Crossref PubMed Scopus (54) Google Scholar) call into question the validity of the conclusion, either because of the power of the statistical study or the applicability of conclusions drawn from the raw data. Although the value of ultrasonography appears certain by meta-analysis of prospective, randomized comparisons (22Sallam H.N. Sadek S.S. Ultrasound-guided embryo transfer: a meta-analysis of randomized controlled trials.Fertil Steril. 2003; 80: 1042-1046Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 23Buckett W.M. A meta-analysis of ultrasound-guided versus clinical touch embryo transfer.Fertil Steril. 2003; 80: 1037-1041Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar), differences in individual study design and execution may limit the statistical value by overstating the effect of ultrasonography and deemphasizing important differences in study design. For example, in one study, clinical touch transfer was performed without prior sounding reported (5Coroleu B. Carreras O. Veiga A. Martell A. Martinez F. Belil I. et al.Embryo transfer under ultrasound guidance improves pregnancy rates after in-vitro fertilization.Hum Reprod. 2000; 15: 616-620Crossref PubMed Scopus (151) Google Scholar). In another, transfer was performed to a fixed depth in the control group, not individualized to the patient (19Tang O.S. Ng E.H.Y. So W.W.K. Ho P.C. Ultrasound-guided embryo transfer: a prospective randomized control trial.Hum Reprod. 2001; 16: 2310-2315Crossref PubMed Scopus (65) Google Scholar). In these studies, systemic bias in technique may have resulted in discrimination against the control group. In cases where prior uterine sounding has been performed and transfer performed relative to this measure, ultrasonography may not produce a statistically significant result. Unfortunately, more recent randomized, control trials that might be used to update the meta-analysis have similar technical problems in the control group (8Li R. Lu L. Hao G. Zhong K. Cai Z. Wang W. Abdominal ultrasound-guided embryo transfer improves clinical pregnancy rates after in vitro fertilization: experiences from 330 clinical investigations.J Assist Reprod Genet. 2005; 22: 3-8Crossref PubMed Scopus (18) Google Scholar). Ultrasound guidance may improve outcome when uterine depth has not been previously accurately assessed, but when it has been reliably performed, ultrasound guidance may have no effect. In programs with high success rates, ultrasonography has not been shown to have a significant effect on outcome measures (16Flisser E. Grifo J.A. Krey L.C. Noyes N. Transabdominal ultrasound-assisted embryo transfer and pregnancy outcome.Fertil Steril. 2006; 85: 353-357Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). No study examining the frequency of ectopic pregnancy has demonstrated a difference in its occurrence (6Matorras R. Urquijo E. Mendoza R. Corcóstegui B. Exposito A. Rodríguez-Escudero F.J. Ultrasound-guided embryo transfer improves pregnancy rates and increases the frequency of easy transfers.Hum Reprod. 2002; 17: 1762-1766Crossref PubMed Scopus (104) Google Scholar, 13García-Velasco J.A. Isaza V. Martinez-Salazar J. Landazábal A. Requena A. Remhoí J. et al.Transabdominal ultrasound-guided embryo transfer does not increase pregnancy rates in oocyte recipients.Fertil Steril. 2002; 78: 534-539Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 14Mirkin S. Jones E.L. Mayer J.F. Stadtmauer L. Gibbons W.E. Oehninger S. Impact of transabdominal ultrasound guidance on performance and outcome of transcervical uterine embryo transfer.J Assist Reprod Genet. 2003; 20: 318-322Crossref PubMed Scopus (31) Google Scholar, 18Hurley V.A. Osborn J.C. Leoni M.A. Leeton J. Ultrasound-guided embryo transfer: a controlled trial.Fertil Steril. 1991; 55: 559-562Abstract Full Text PDF PubMed Scopus (76) Google Scholar, 19Tang O.S. Ng E.H.Y. So W.W.K. Ho P.C. Ultrasound-guided embryo transfer: a prospective randomized control trial.Hum Reprod. 2001; 16: 2310-2315Crossref PubMed Scopus (65) Google Scholar), an outcome that would seem less likely if ultrasound guidance to a specific point enhanced implantation at that site; however, the relative infrequency of ectopic pregnancy, even in high-risk patients such as patients with infertility, means that most studies are unlikely to have enough power to demonstrate a difference, if one exists. Although ultrasonography may confirm the position of the catheter within the uterus, it may not improve the ease of entry into the uterine cavity when negotiating a tortuous endocervical canal. The speculum may also interfere with visualizing the initial catheter placement by scattering or interfering with the acoustic signal. Visualizing the entire catheter track may not always be possible; aligning the canal and endometrial stripe within the narrow acoustic window of the transducer may be technically difficult if the route traversed by the catheter falls wide of this path. In some studies, ease of transfer has been associated with improved outcomes over difficult transfer (24Mansour 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. 1999; 54: 678-681Google Scholar, 25Sharif 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: 1715-1718Crossref PubMed Scopus (31) Google Scholar). Some authors have demonstrated improved ease of transfer when ultrasonography is performed concomitantly (6Matorras R. Urquijo E. Mendoza R. Corcóstegui B. Exposito A. Rodríguez-Escudero F.J. Ultrasound-guided embryo transfer improves pregnancy rates and increases the frequency of easy transfers.Hum Reprod. 2002; 17: 1762-1766Crossref PubMed Scopus (104) Google Scholar, 14Mirkin S. Jones E.L. Mayer J.F. Stadtmauer L. Gibbons W.E. Oehninger S. Impact of transabdominal ultrasound guidance on performance and outcome of transcervical uterine embryo transfer.J Assist Reprod Genet. 2003; 20: 318-322Crossref PubMed Scopus (31) Google Scholar, 26Sallam H.N. Agameya A.F. Rahman A.F. Ezzeldin F. Sallam A.N. Ultrasound measurement of the uterocervical angle before embryo transfer: a prospective controlled study.Hum Reprod. 2002; 17: 1767-1772Crossref PubMed Scopus (69) Google Scholar), but this finding has not been consistently observed (16Flisser E. Grifo J.A. Krey L.C. Noyes N. Transabdominal ultrasound-assisted embryo transfer and pregnancy outcome.Fertil Steril. 2006; 85: 353-357Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 19Tang O.S. Ng E.H.Y. So W.W.K. Ho P.C. Ultrasound-guided embryo transfer: a prospective randomized control trial.Hum Reprod. 2001; 16: 2310-2315Crossref PubMed Scopus (65) Google Scholar). Systems for grading difficulty of transfer, though, vary by study. When ultrasound estimate of the acuity of the uterocervical angle was used to mold the transfer catheter, improved ease of transfer and improved outcome were seen (26Sallam H.N. Agameya A.F. Rahman A.F. Ezzeldin F. Sallam A.N. Ultrasound measurement of the uterocervical angle before embryo transfer: a prospective controlled study.Hum Reprod. 2002; 17: 1767-1772Crossref PubMed Scopus (69) Google Scholar). In this study, the ultrasound group was noted to have a ≥30° arc in deflection of the uterocervical angle in 77.8% of the patients. Assuming an equal distribution of patient characteristics, because the uterocervical angle was not measured in the control group, it is possible that molding the catheter facilitated its movement along a path of least resistance, contributing to the outcome effect, a technique not performed in the control group. Given that the vast majority of patients in the ultrasound group had nonzero uterocervical angles, it may be preferential to bend all transfer catheters when estimate of this angle is not performed. Significantly more catheters contaminated with blood were observed in the control group, a characteristic known to be associated with lower pregnancy rates (27Goudas V.T. Hammit D.G. Damario M.A. Session D.R. Singh A.P. Dumesic D.A. Blood on the embryo transfer catheter is associated with decreased rates of embryo implantation and clinical pregnancy with the use of in vitro fertilization-embryo transfer.Fertil Steril. 1998; 70: 878-882Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). Other studies have shown decreased presence of blood when ultrasonography is performed (14Mirkin S. Jones E.L. Mayer J.F. Stadtmauer L. Gibbons W.E. Oehninger S. Impact of transabdominal ultrasound guidance on performance and outcome of transcervical uterine embryo transfer.J Assist Reprod Genet. 2003; 20: 318-322Crossref PubMed Scopus (31) Google Scholar), but this effect has not been consistently observed. When difficult transfer requires greater cervical manipulation, the resulting increase in uterine contraction frequency may hinder implantation (28Lesny P. Killick S.R. Robinson J. Raven G. Maguiness S.D. Junctional zone contractions and embryo transfer: is it safe to use a tenaculum?.Hum Reprod. 1999; 14: 2367-2370Crossref PubMed Scopus (90) Google Scholar); pretransfer assessment of the uterocervical angle may permit the use of simple interventions, such as molding the catheter, and thereby avoid the noxious stimuli associated with tenaculum use. Presumably, the value of ultrasonography lies in correctly identifying the distal position of the catheter. Because not all clinical situations permit optimal visualization, catheters designed for enhanced detection by ultrasonography may have particular merit over standard catheters when ultrasonographic guidance is used. In a randomized trial comparing transfer catheters, when the TDT catheter (Prodimed, Neuily-en-Thelle, France) was used, applying ultrasonography was associated with a significant improvement in pregnancy rate (19.4% vs. 9.2%, P<.05) (29Wisanto A. Janssens R. Deschacht J. Camus M. Devroey P. Van Steirteghem A.C. Performance of different embryo transfer catheters in a human in vitro fertilization program.Fertil Steril. 1989; 52: 79-84Crossref PubMed Scopus (97) Google Scholar). The metal insert improved the ability to visualize this catheter and was thought to contribute to the enhanced pregnancy rate, but the improved success rate was still significantly lower than in cases where the soft catheters were used. Although soft catheters outperform hard catheters (30Buckett W.M. A review and meta-analysis of prospective trials comparing different embryo catheters used for embryo transfer.Fertil Steril. 2003; 85: 728-734Abstract Full Text Full Text PDF Scopus (67) Google Scholar), whether specially designed soft catheters with improved echogenicity enhance utility and further contribute to IVF success is undetermined, because no randomized trials using these catheters have yet been published. Using ultrasound assistance in all cases, a comparison of 141 transfers performed with the Wallace catheter (SIMS Portex Ltd, Hythe, Kent, UK) and 110 with the Cook Echo-tip catheter (Cook Ob/Gyn, Spencer, IN) showed no differences in implantation rate (30% vs. 35%), clinical pregnancy rate (57% vs. 55%), or catheter visualization (100% vs. 95%) when patients were assigned to treatment and control groups (31Karande V. 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: 826-830Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). Subjective improvement in catheter identification with obese patients or patients who had insufficiently filled bladders suggests that this special type of catheter may improve technical aspects of transfer in specific scenarios, even if superior results are not demonstrated under all conditions (31Karande V. 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: 826-830Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 32Letterie G.S. Marshall L. Angle M. A new coaxial catheter system with an echodense tip for ultrasonographically guided embryo transfer.Fertil Steril. 1999; 72: 266-268Abstract Full Text PDF PubMed Scopus (28) Google Scholar). The advantages of these new catheters may be subtle and difficult to demonstrate given the current success of IVF. Easily visualized catheters may require less manipulation to identify ultrasonographically, and because the to-and-fro sawing movement occasionally used to visualize standard catheters could traumatize the endometrium, this hazard may be avoided. Excessive manipulation could otherwise nullify gains achieved by improved embryo placement. However, because repeated transfers for retained embryos have not been demonstrated to reduce pregnancy rates (33Nabi A. Awonuga A. Birch H. Barlow S. Stewart B. Multiple attempts at embryo transfer: does this affect in-vitro fertilization outcome?.Hum Reprod. 1997; 12: 1188-1190Crossref PubMed Scopus (84) Google Scholar, 34Tur-Kaspa I. Yuval Y. Bider D. Levron J. Shulman A. Dor J. Difficult or repeated sequential embryo transfers do not adversely affect in-vitro fertilization pregnancy rates or outcome.Hum Reprod. 1998; 13: 2452-2455Crossref PubMed Scopus (75) Google Scholar), atraumatic manipulation of the standard catheters may not pose any additional risks. It is possible that adjunct techniques associated with the use of ultrasound contribute in part to its success. Distension of the bladder may straighten the uterocervical angle when the uterus is anteflexed (35Sundström P. Wrambsy H. Persson P.-H. Liedhom P. Filled bladder simplifies human embryo transfer.Br J Obstet Gynaecol. 1984; 91: 506-507Crossref PubMed Scopus (36) Google Scholar), as might pressure applied to the anterior abdominal wall exerted by the ultrasonographer via the transducer. A distended bladder alters the uterocervical angle and may improve IVF outcome in the absence of ultrasound guidance, although this effect has not been consistently observed. In one randomized trial, no difference was seen after transfer with a full or an empty bladder (36Mitchell J.D. Wardle P.G. Foster P.A. Hull M.G.R. Effect of bladder filling on embryo transfer.J In Vitro Fert Embryo Transf. 1989; 6: 263-265Crossref PubMed Scopus (12) Google Scholar), though after voiding, the volume imbibed before transfer was small (250 mL). In a larger, pseudorandomized trial, a higher pregnancy rate was observed in two similar groups of patients when transfer was performed with a distended versus an empty bladder (26.8% vs. 16.6%, P<.01), which was believed to be a result of increased ease of transfer (37Lewin A. Schenker J.G. 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: 32-34Crossref PubMed Scopus (47) Google Scholar). Patients in this study had a higher pretransfer fluid intake (1000 mL). Bladder distension, however, does not appear to be a criterion required to improve outcome when ultrasonography is performed. A randomized trial of 171 patients comparing ultrasound guided transfer with or without a full bladder with traditional transfer without ultrasonography and bladder distension failed to demonstrate a significant difference in outcome for any group (38Lorusso F. Depalo R. Bettocchi S. Vacca M. Vimercati A. Selvaggi L. Outcome of in vitro fertilization after transabdominal ultrasound-assisted embryo transfer with a full or empty bladder.Fertil Steril. 2005; 84: 1046-1048Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). Though no difference in outcomes was observed, additional manipulation of the cervix with use of a hysterometer (P<.002), tenaculum (P<.002), or obturator (P<.02) was less frequently performed in the full bladder group. Undoubtedly, there are cases when ultrasonography has prevented transfer of embryos to a suboptimal location, but prospectively determining which cases will benefit from its use is difficult. In a study in 100 patients with a history of easy mock ET performed before the start of ovarian hyperstimulation, no advantages were observed in the ultrasound group compared with controls for implantation (19.6% vs. 16.3%) or pregnancy rates (42.0% vs. 30.0%) (15de Camargo Martins A.M.V. Baruffi R.L.R. Mauri A.L. Peteresen C. Oliveira J.B.A. Contart P. et al.Ultrasound guidance is not necessary during easy transfers.J Assist Reprod Genet. 2004; 21: 421-425Crossref PubMed Scopus (21) Google Scholar). When done without confirmatory imaging, sounding done in a previous cycle or before the onset of ovarian hyperstimulation may be inaccurate, leading to the few cases where transfer depth at retrieval is clearly deeper when observed by ultrasonography than had been previously suspected by prior sounding. Without concurrent imaging, the difference would likely have led to loss of embryos by transfer into the cervical canal. Transvaginal ultrasonography alone appears an insufficient substitute for physical sounding (39Sher G. Fisch J.D. Measuring uterine depth with colpohydrosonography.J Reprod Med. 2003; 48: 325-329PubMed Google Scholar). A comparison study of uterine sounding depth and depth measured with a combination of catheter placement and ultrasound measurement found that in 29.9% of cases initial sounding depth was >1 cm different from transfer catheter placement and ≥1.5 cm in 19.4%, when the transfer catheter was deliberately placed 1 cm less than the uterine sounding depth based on a prior measurement (40Shamonki M.I. Spandorfer S.D. Rosenwaks Z. Ultrasound-guided embryo transfer and the accuracy of trial embryo transfer.Hum Reprod. 2005; 20: 709-716Crossref PubMed Scopus (18) Google Scholar). The difference detected by ultrasonography, however, had no influence on pregnancy outcome. The errors detected always underestimated the true uterine depth, but in no cases was the catheter reported to be in the cervical canal. Because there is still much debate on the optimal site of ET, the value of this difference is uncertain. Initial evidence suggesting that transfer to sites lower in the uterine cavity improved pregnancy rates is confounded by use of the true clinical touch transfer technique, in which contact with the uterine fundus was made to direct catheter placement 5 mm from the fundus, whereas the comparison group had embryos deposited 5 cm from the external os (41Waterstone J. Curson R. Parsons J. Embryo transfer to low uterine cavity [letter].Lancet. 1991; 337: 1413Abstract PubMed Scopus (67) Google Scholar). Transfer of the embryos too far into the cavity can have a profoundly negative influence on outcome. When the depth of catheter insertion was equal to or exceeded the ultrasound-estimated length of the uterine cavity, a significant decrease in implantation and pregnancy rates was observed (P<.05), though ectopic pregnancy rates were not increased (42Pope C.S. Cook E.K.D. Arny M. Novak A. Grow D.R. Influence of embryo transfer depth on in vitro fertilization and embryo transfer outcomes.Fertil Steril. 2004; 81: 51-58Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). However, as has been shown, ultrasound-derived estimates of uterine depth can be unreliable (39Sher G. Fisch J.D. Measuring uterine depth with colpohydrosonography.J Reprod Med. 2003; 48: 325-329PubMed Google Scholar). When transfer was aided by ultrasonography, implantation rates were significantly higher when ET was performed approximately 15–20 mm from the fundus compared with 10 mm, and no implantation was observed when transfer occurred >20 mm from the fundus (43Coroleu B. Barri P.N. Carreras O. Martínez F. Parriego M. Hereter L. et al.The influence of the depth of embryo replacement into the uterine cavity on implantation rates after IVF: a controlled, ultrasound guided study.Hum Reprod. 2002; 17: 341-346Crossref PubMed Scopus (154) Google Scholar). The optimal site of transfer, which likely represents an area rather than a single point, is still unclear. By ultrasound estimate, regression analysis revealed a pregnancy rate proportionally increasing with distance from the intracavity fundus by odds ratio of 1.11 (95% confidence interval 1.07–1.14, P<.001) to a maximum distance of 27 mm from the fundus, an increase of 11% per millimeter. When sounding depth to the intracavitary fundus was measured ultrasonographically, implantation improved with increasing distance from the fundus; however, when compared with physical measurement, no correlation was seen (42Pope C.S. Cook E.K.D. Arny M. Novak A. Grow D.R. Influence of embryo transfer depth on in vitro fertilization and embryo transfer outcomes.Fertil Steril. 2004; 81: 51-58Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). When controlling for differences in uterine cavity size, increased implantation rates were observed when transfer was performed in the midpoint to lower third of the endometrial cavity, rather than a fixed distance from the uterine fundus, though the study was not randomized (44Frankfurter D. Trimarchi J.B. Silva C.P. Keefe D.L. Middle to lower uterine segment embryo transfer improves implantation and pregnancy rates compared with fundal embryo transfer.Fertil Steril. 2004; 81: 1273-1277Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). By contrast, no difference was observed in pregnancy rates when transfer distance from the external cervical os was analyzed from 5.5 to 8 cm by 0.5 cm intervals (10al-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: 31-36Crossref PubMed Scopus (96) Google Scholar). In an observational study, no difference was seen in outcome based on the location of the transfer droplet or catheter tip (45Rosenlund B. Sjöblom P. Hillensjö T. Pregnancy outcome related to the site of deposition in the uterus.J Assist Reprod Genet. 1996; 13: 511-513Crossref PubMed Scopus (41) Google Scholar). No statistical difference was seen when randomly transferring embryos to either the lower or upper half of the endometrial cavity as observed by ultrasonography, and no difference in ectopic pregnancy rates was observed (46Franco Jr, J.G. Martins A.M.V.C. Baruffi R.L.R. Mauri A.L. Petersen C.G. Felipe V. et al.Best site for embryo transfer: the upper or lower half of endometrial cavity?.Hum Reprod. 2004; 19: 1785-1790Crossref PubMed Scopus (42) Google Scholar). A limit to the utility of ultrasound guidance is embryo migration after transfer, motivated by uterine activity (47Ijland M.M. Evers J.L.H. Dunselman G.A.J. van Katwijk C. Lo C.R. Hoogland H.J. Endometrial wavelike movements during the menstrual cycle.Fertil Steril. 1996; 65: 746-749Abstract Full Text PDF PubMed Scopus (128) Google Scholar, 48Fanchin R. Righini C. Olivennes F. Taylor S. de Ziegler D. Frydman R. Uterine contractions at the time of embryo transfer alter pregnancy rates after in-vitro fertilization.Hum Reprod. 1998; 13: 1968-1974Crossref PubMed Scopus (407) Google Scholar). When tracked by 3-dimensional ultrasonography, 19% of implanting embryos were observed to have implanted at sites other than where transferred (49Baba K. Ishihara O. Hayashi N. Saitoh M. Taya J. Kinoshita K. Where does the embryo implant after embryo transfer in humans?.Fertil Steril. 2000; 73: 123-125Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). After transfer, embryos may be propelled by uterine contractions to other locations, including out of the cavity, confounding attempts to deposit them at optimal implantation sites. Competence with ET technique can be achieved only through experience, yet the requisite number of procedures is unknown, and success is undoubtedly dependent on individual dexterity (50Karande V.C. Morris R. Chapman C. Rinehart J. Gleicher N. Impact of the “physician factor” on pregnancy rates in a large assisted reproductive technology program: do too many cooks spoil the broth?.Fertil Steril. 1999; 71: 1001-1009Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 51Hearns-Stokes R.M. Miller B.T. Scott L. Creuss D. Chakraborty P.K. Segars J.H. Pregnancy rates after embryo transfer depend on the provider at embryo transfer.Fertil Steril. 2000; 74: 80-86Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). The teaching of ET is fraught with concern because of the crucial nature of this step. Embryo transfer can be learned (52Barber D. Egan D. Ross C. Evans B. Barlow D. Nurses performing embryo transfer: successful outcome of in-vitro fertilization.Hum Reprod. 1996; 11: 105-108Crossref PubMed Scopus (39) Google Scholar, 53Sinclair L. Morgan C. Lashen H. Afnan M. Sharif K. Nurses performing embryo transfer: the development and results of the Birmingham experience.Hum Reprod. 1998; 13: 699-702Crossref PubMed Scopus (28) Google Scholar), and ultrasonography may provide reassurance to the trainee (as well as patient and mentor) that the transfer is being performed correctly (54Papageorgiou T.C. Hearns-Stokes R.M. Leondires M.P. Miller B.T. Chakraborty P. Cruess D. et al.Training of providers in embryo transfer: what is the minimum number of transfers required for proficiency?.Hum Reprod. 2001; 16: 1415-1419Crossref PubMed Scopus (47) Google Scholar). A logical next step is the application of 3-dimensional, or “4-D” (“real-time” 3-dimensional) ultrasonography to ET. Three-dimensional ultrasonography has not yet proved a critical factor to optimizing success and is hampered, as is conventional 2-dimensional ultrasonography, by limited knowledge of the true ideal transfer site, though the ability to observe deflection of the catheter in a third dimension may ultimately prove valuable (55Letterie G.S. Three-dimensional ultrasound-guided embryo transfer: a preliminary study.Am J Obstet Gynecol. 2005; 192: 1983-1988Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). This newer, exciting technology has not been shown to improve catheter placement or to improve pregnancy rates, and it is not yet widely available or employed, though its routine use has been reported (56Gergely R.Z. de Ugarte C.M. Danzer H. Surrey M. Hill D. DeCherney A.H. Three dimensional/four dimensional ultrasound-guided embryo transfer using the maximal implantation potential point.Fertil Steril. 2005; 84: 500-503Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). The value of ultrasound-guided ET may lie in reassuring the patient and operator that the catheter is in the optimal location, because prospective selection of cases likely to benefit from ultrasound guidance is nearly impossible. Ultrasonography may be particularly useful for training purposes and when performing transfer for patients with prior failed cycles, history of difficult transfer or sounding, obesity, or congenital müllerian malformation. Given the ease of use, minimal discomfort, and lack of side effects, and because no study has shown a worsening of outcomes when ultrasound is utilized, ultrasound-assisted ET is widely employed, though it may not be critically necessary to achieve IVF success. Improvements in catheter design that increase visibility may be particularly useful as a teaching technique and may provide reassurance to the patient and to the operator, even if outcomes are not significantly changed.
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