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Practice of Embryo Transfer: Recommendations During and After Bulent Tıras, MD1
Pinar Ozcan Cenksoy, MD2
1 Department of Obstetrics and Gynecology, Acibadem University
School of Medicine, Istanbul, Turkey 2 Department of Obstetrics and Gynecology, Yeditepe University Medical School, Istanbul, Turkey
Address for correspondence Bulent Tıras, MD, Department of Obstetrics and Gynecology, Acibadem University School of Medicine, Istanbul, Turkey (e-mail: [email protected]).
Abstract
Keywords
► embryo transfer technique ► assisted reproductive technology ► successful embryo transfer
Many patient and embryo factors influence the outcome of assisted reproductive technology (ART) treatment. The predictors for a successful ART cycle include female age, ovarian reserve, embryo quality, endometrial receptivity, and embryo transfer (ET) technique. ET, the final step of ART, has recently been noted as a crucial step affecting ART success. Variables affecting pregnancy rates following ET include ultrasound guidance, ease of ET transfer, catheter type, transfer and catheter-loading technique, blood or mucus effects, retained embryos, trial transfer, the physician’s experience, and catheter tip placement. Despite the lack of consensus regarding the optimal ET technique, it is generally recommended that during ET, the disruption of the endometrium and the induction of uterine contractions should be avoided. The exposure of embryos to the ambient conditions should be minimized, and the embryo(s) should be placed at an optimal position within the fundal region of the uterine cavity.
Success rates with assisted reproductive technology (ART) have significantly improved over the last decades. While the average live birth rate associated with ART was reported as 28% in 1996, it had increased to 35.4% by 2006.1 Many patient and embryo factors influence the success of ART and the main predictors of pregnancy outcome include female age, ovarian reserve, embryo quality, endometrial receptivity, and embryo transfer (ET) technique.2–4 Despite great advances in ovarian stimulation protocols and embryo culture, few improvements have been noted in ET techniques because it received relatively little attention until recently.5–7 ET, the final step of ART, has recently been observed to be a crucial step in assuring ART success. Despite the lack of consensus on the optimal ET technique, most studies have recently highlighted the importance of ET procedure with various recommendations.8,9 ET is typically performed in the dorsal lithotomy position as an outpatient procedure without anesthesia and it generally starts with the insertion of speculum into the vagina for
Issue Theme Common Practices in Reproductive Endocrinology and Infertility Supported by Weak or No Evidence; Guest Editor, Orhan Bukulmez, MD
visualization of the cervix. After visualization of the cervix, the cervix is cleaned in a variety of ways avoiding embryotoxic chemicals. The transfer catheter loaded with embryo(s) is inserted through the cervical canal and advanced into the uterine cavity and then the embryo(s) is deposited by applying gentle pressure into the uterine cavity. Finally, the catheter is withdrawn. Variables affecting ET outcome consist of ultrasound (US) guidance, ease of ET, catheter type, transfer and catheterloading technique, blood or mucus effects, retained embryos, trial (mock) transfer, the physician’s experience, and proper catheter tip placement.4 To maximize embryo implantation rates, the main expectations from good ET technique include minimizing the disruption of the endometrium, avoidance of induction of uterine contractions, assuring embryo safety during the procedure, and to facilitate deposition of the embryo in an optimal position within the uterine cavity (►Table 1).
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1375181. ISSN 1526-8004.
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Table 1 Main expectations to ensure a successful embryo transfer Expectations • • • •
To avoid disruption of the endometrium by the catheter To minimize induction of the uterine contractions To protect the embryo(s) To deposit the embryo(s) in an optimal position within the uterine cavity
How Can We Minimize Disruption of the Endometrium by the Catheter and Avoid Induction of Uterine Contractions during ET? ET is generally regarded as the easiest part of the ART procedure, but ET is frankly the rate-limiting step of ART. Although it is now well known that ET is a crucial step in IVF treatment, it is difficult to standardize several variables of the ET technique such as the physician’s experience and the degree of difficulty of ET. One of the main strategies for successful ET is to atraumatically deposit the embryo(s) into the uterine cavity. Traumatic or difficult ET has been linked to a lower clinical pregnancy rate (PR) due to disruption of the endometrium and induction of uterine contractions associated with the release of prostaglandins and oxytocin. Because uterine contractions may also result from cervical trauma, the use of a tenaculum clamp, cervical stenosis requiring dilatation, or use of a firm catheter may lead to embryo expulsion. A trial transfer, gentle manipulation, use of a soft catheter, and US-guided ET have been associated with improved PR possibly by minimizing endometrial and cervical trauma during ET.10 Furthermore, progesterone frequently used for luteal phase support may also help decrease uterine contractions at the time of ET.
Difficult Transfer The transfer could be considered difficult if time spent on ET was long, and if a firmer catheter, additional maneuvers and/ or instrumentation, sounding or cervical dilatation were needed and if the resistance to the catheter advancement was encountered, and the presence of blood on the transfer catheter was noted. Difficult ET is more common in cases with severe anteflexion, retroflexion, or anteversion and retroversion of the uterus and cervical stenosis. A large retrospective study including 4,807 ETs showed that easy or intermediate transfers resulted in a 1.7-fold higher PR than difficult transfers.11 The presence of blood on the transfer catheter results from traumatic cervical passage of the catheter, subclinical infection, or endometrial bleeding due to traumatic contact with the catheter. Then, it has been suggested that difficult transfer, using additional maneuvers and/or instrumentation, and the presence of blood on the transfer catheter should be avoided during ET for the best pregnancy outcome.11–16 However, a recent review has indicated that there is some evidence that if ET Seminars in Reproductive Medicine
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was considered difficult or if there was a need for additional maneuvers and/or instrumentation, a negative effect on PR can be expected, while the presence of blood on the transfer catheter may not necessarily affect ET outcome.17 In cases with extremely difficult or even impossible transcervical ET, transmyometrial ET can be performed under transvaginal US guidance which is also known as the Towako method.18
Mock Transfer The value of mock transfer on reducing difficult ET has been controversial. Mock, dummy, or trial transfer, first reported in the early 1990s, can provide references for actual transfer regarding the selection of the appropriate transfer catheter, the direction and curve of the catheter, the length and direction of the endometrial cavity and cervical canal, and potential problems associated with the procedure. For example, encountering a severely flexed uterus requiring a tenaculum clamp or realization of a stenotic cervix needing cervical dilatation during the actual procedure may be problematic and knowing about such issues before ET may be advantageous for proper planning.19,20 Trial transfer could be performed before starting ovarian stimulation, at the time of oocyte retrieval, or just before the actual transfer. The timing of a trial transfer does not influence embryo implantation or pregnancy rates.21 In the case of severe cervical stenosis, cervical dilatation can be performed by mechanical dilation, use of osmotic dilators such as laminaria, placement of a Malecot catheter, and hysteroscopic shaving. These procedures may be performed several weeks before ET to ensure adequate recovery time of endometrium from potential injury, inflammation, or bacterial contamination inflicted by the procedure. With such approaches, an improvement in PRs has been reported in patients with cervical stenosis.22–25 The changes in length and position of uterus during ovarian stimulation should be considered when trial transfer is done before starting ovarian stimulation.26 If it is performed at the time of actual ET, to prevent disruption of the endometrium, the catheter should only be advanced to just past the internal cervical os and the transfer should be done under US guidance. Otherwise, the outer sheath of the catheter inserted into the cervical canal can be used as a guide to advance the soft inner catheter loaded with the embryo(s) also known as afterloading.5 This method provides an immediate mock transfer while minimizing manipulation of embryos.
Ultrasound Guidance The use of routine US guidance in ET rather than relying on blind clinical touch technique could be another approach to improve ET outcome because blind clinical touch technique may potentially disrupt the endometrium. US guidance in ET assists in gentle insertion of the catheter while avoiding its direct contact with the fundus, which may prevent uterine contractions during ET. The ultrasonographic visualization of newer ET catheters is made easier by the manufacturers, leading to even better live assessment of embryo replacement depth within the endometrial cavity. Therefore, US-guided ET
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Type of Catheter Many studies have been conducted to evaluate the relationship between the choice of the ET catheter and the outcomes of ART. Despite their limitations, the majority of these studies compared the outcomes of soft versus firm catheters and concluded that using the soft catheter during ET significantly increases PRs, albeit the potential effects of the catheter type is still considered controversial.34,35 It is suggested that the ideal ET catheter is soft enough to avoid trauma to the cervix and endometrium because it is known that firm catheters, which may be required in difficult transfers, can be associated with more bleeding and induction of uterine contractions. A prospective randomized trial comparing the Cook KSOFT-5100 and Frydman classical catheters concluded that variation in PRs between ET catheters is actually associated with the variation between the operators.36 Another study found that the choice of the catheter did not significantly affect the clinical PRs in IVF when it is performed under US guidance or after mock transfer.37,38 Likewise, a prospective randomized clinical trial that included 150 women undergoing fresh ET demonstrated that the type of ET catheter did not significantly influence the clinical PR because there was no significant difference in the clinical PRs between Wallace and Cook catheters.39 As a result, the choice of ET catheter may be decided by its cost and mostly by operator’s preference.
How Can We Keep Embryo(s) Safe During Embryo Transfer? Cervical Mucus Although the evidence is conflicting, the presence of macroscopic or microscopic mucus on the ET catheter may be considered as a variable affecting the ET outcome. Mucus on the transfer catheter may negatively affect ART success by causing retention of embryos with mechanical blockage of the catheter opening, also known as the “sling shot effect.”14,40,41 The presence of mucus on the ET catheter has been shown to decrease implantation and pregnancy rates.12,15,42 The cleaning of cervical mucus was shown to increase clinical PRs, although some conflicting reports exist.43 Therefore, significant cervical mucus should be routinely removed before ET in a gentle fashion in an effort to decrease the incidence of retained embryos and cervical contamination. The mucus in the cervical canal can be removed by a sterile cotton swab, with gentle irrigation
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with saline or culture media and it can also be aspirated using a sterile syringe.44 Vaginal antiseptics are not recommended at ET due to their potential toxicity to the embryos. The detection of mucus on the catheter may be associated with cervical contamination of the catheter itself while passing it through the cervical canal. The administration of antibiotics at the time of retrieval is suggested as an intervention to improve PR by reducing levels of microbial colonization during ET.45 However, the use of antibiotics for ET is still a subject of debate and is currently not recommended because of the lack of proven benefit. Furthermore, it is thought that the potential disruption of normal cervical flora induced by antibiotics may actually result in an inflammatory response.46 A Cochrane review concluded that the administration of antibiotics before ET did not affect clinical PRs, although it reduced the microbial contamination of the upper genital tract.47
Loading the Catheter An embryo is generally loaded into the ET catheter by use of the “three-drop technique” (invisible embryo(s) and visible air bubbles determining the final position of the embryo(s)) in which the air bubbles are created on both sides of the medium drop containing the embryo(s).48,49 In this technique, first an air bubble is loaded into the catheter and then 20 µL of medium is drawn up into the catheter, followed by the embryos in the smallest possible volume of medium. A second air bubble is then loaded into the catheter. Finally, enough medium is drawn up to bring the total volume to 30 µL. The excess fluid proximal to the embryo in the catheter increases the risk of embryo expulsion, while lower fluid volumes may also negatively affect embryo implantation rates.50,51
Embryo Expulsion Embryos can easily move toward the cervical canal or into the fallopian tube following their transfer into the uterine cavity and embryo expulsion is associated with a lower PR. Embryo expulsion may result from local pressure changes during ET, injection speed, negative pressure induced by the withdrawal of the catheter, and uterine contractions initiated by different factors such as touching the uterine fundus with a transfer catheter, cervical trauma, use of a tenaculum clamp, cervical stenosis, and use of a firmer catheter. A standard syringe-catheter complex used during ET can easily result in high pressure and fast fluid flow inside the catheter when there is a disproportion between the diameters of the syringe plunger and the catheter. Local pressure changes during ET are considered as a possible factor creating favorable conditions for expulsion of the embryos from the uterine cavity while impairing embryo viability.52,53 It is recommended that ET should be performed with a minimum ejection speed to protect the embryo(s) from the pressure gradient changes and to prevent embryo expulsion. A study54 presented pump-regulated ET (PRET) as a new method to standardize the injection speed during ET which may help avoid large variations in injection speed associated with manually performed ET. According to the results of that Seminars in Reproductive Medicine
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may significantly increase PRs.27–30 A Cochrane review also concluded that US guidance does appear to improve the probability of live birth/ongoing and clinical pregnancy rates as compared with the clinical touch methods, albeit most of the studies were deemed to be of limited quality.31 US-guided ET also requires a full bladder and a second operator which may cause some patient discomfort. The full bladder can allow the operator to put an appropriate curve on the catheter to accommodate the cervicouterine angle while somewhat straightening the cervicouterine angle to facilitate the proper advancement of the catheter in cases of severely anteverted and anteflexed uteri.32,33
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study, PRET may be considered as an alternative, reliable, and reproducible method to standardize injection speed.54 However, negative pressure induced after withdrawal of the catheter may still cause embryo expulsion. To minimize the effects of negative pressure, the catheter is slowly withdrawn after the deposition of the embryo into the uterine cavity, although no significant difference in ET outcome was observed between immediate and delayed withdrawal.55,56
Embryo Transfer Duration, Embryo Retention The time interval between loading the embryo and depositing it into the uterine cavity should be minimized to avoid exposure of the embryo to the ambient conditions because a longer time interval is associated with lower implantation and pregnancy rates.57 Inspection of the catheter after transfer under light microscopy is necessary for detection of retained embryos. The cervix and speculum should be routinely checked as well. If retained embryos are detected and immediately retransferred, no detrimental effects on PRs would be expected.58,59
How Can We Assure the Deposition of the Embryo in an Optimal Location within the Uterine Cavity? Another main strategy for successful ET is to deposit the embryo(s) in an optimal position within the uterine cavity (►Fig. 1). Several recent studies have focused on the potential impact of embryo replacement depth on ET outcomes.60–62 Although there is no consensus regarding optimal ET location within the uterine cavity, it seems most likely that fundal transfer is associated with the highest PRs.60–62 The air bubbles can be regarded as an identifier of the position of the embryos in regard to the fundal end of the endometrial cavity. The increased PRs have been reported when air bubbles were observed sonographically closer to the fundus. The reasons behind such an observation are not entirely clear. The fundal endometrium is suitable for implantation in terms of the expression of important factors related to implantation.
Figure 1 Locations of inner catheter and air bubble during embryo transfer. Seminars in Reproductive Medicine
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There is also lower endometrial wavelike activity in the fundus as compared with the other portions of the uterus. Endometrial tissue blood flow is also highest in the fundus, which may also play a role in increased possibility of embryo implantation in this region.63,64 A retrospective analysis of 5,055 US-guided ETs demonstrated that ongoing PRs were higher if ET was performed at a distance > 10 mm from the most distal fundal endometrial surface.65 In addition, the depth of the uterine cavity and the distance between the fundal end of the uterine cavity and the location of the catheter tip may be considered important by affecting actual ET depth. A prospective data analysis of 281 consecutive US-guided fresh ETs found that the optimal distance between the most distal fundal endometrial surface and the tip of the inner catheter should be 1.5 to 2 cm. Furthermore, in the same study, PRs were not influenced by the depth of the uterine cavity alone, but there was a trend toward increased distance between the most distal fundal endometrial surface and the air bubbles with increasing depth of uterine cavity.62 Air bubble movement shortly after the initial placement of the embryos into the uterine cavity may also influence implantation and pregnancy rates. Air bubbles moving toward the cervical canal right after ET can be associated with decreased clinical PRs, while air bubbles moving toward the uterine fundus may be associated with higher PRs albeit with higher miscarriage rates, eventually leading to similar live
Table 2 Embryo transfer practice points to optimize pregnancy rates Practice points • Use ultrasound guidance with full bladder and trial (mock) transfer to avoid ’’difficult’’ transfers, touching the fundus, using additional maneuvers and/or instrumentation, and the presence of blood on the transfer catheter • Gentle manipulation, use of a soft catheter to avoid inducing uterine contractions and to avoid trauma to the cervix and endometrium • Routine removal of cervical mucus to decrease the incidence of retained embryos and cervical and endometrial contamination • Do not use vaginal antiseptics to avoid potential toxicity to the embryos • Do not recommend the administration of antibiotics during embryo transfer • Use the “three-drop technique” for loading the embryo(s) • Use minimum ejection speed to prevent embryo expulsion • Withdraw transfer catheter slowly after the deposition of embryo • Minimize the time interval between loading the embryo and embryo transfer • Routinely check the catheter, cervix, and speculum following transfer to detect retained embryos • Perform fundal transfer • The optimal distance between the most distal fundal endometrial surface and the tip of inner catheter should be 1.5–2 cm
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12 Rhodes TL, McCoy TP, Higdon HL III, Boone WR. Factors affecting
13
What to Do After Embryo Transfer Immediate ambulation and sexual intercourse after ET do not influence PRs.67,68 Bed rest after ET is still controversial. Many fertility clinics recommend bed rest after ET for variable periods of time, but there is no insufficient evidence to support this recommendation.69
Conclusion We reviewed the commonly reported factors associated with ET outcome, although the quality of evidence regarding the most ideal ET technique is rather poor (►Table 2). It seems that every program should have its standard protocols in place for proper performance and reporting of ET while considering the best available evidence. Thereafter, ET outcomes should be closely monitored to assess the need for any additional training or improvement.
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role of uterine straightening by passive bladder distension before embryo transfer in IVF cycles. J Assist Reprod Genet 1997;14(1): 32–34 Lorusso F, Depalo R, Bettocchi S, Vacca M, Vimercati A, Selvaggi L. Outcome of in vitro fertilization after transabdominal ultrasoundassisted embryo transfer with a full or empty bladder. Fertil Steril 2005;84(4):1046–1048 Abou-Setta AM, Al-Inany HG, Mansour RT, Serour GI, Aboulghar MA. Soft versus firm embryo transfer catheters for assisted reproduction: a systematic review and meta-analysis. Hum Reprod 2005;20(11):3114–3121 Buckett WM. A review and meta-analysis of prospective trials comparing different catheters used for embryo transfer. Fertil Steril 2006;85(3):728–734 Yao Z, Vansteelandt S, Van der Elst J, Coetsier T, Dhont M, De Sutter P. The efficacy of the embryo transfer catheter in IVF and ICSI is operator-dependent: a randomized clinical trial. Hum Reprod 2009;24(4):880–887 Aboulfotouh I, Abou-Setta AM, Khattab S, Mohsen IA, Askalani A, el-Din RE. Firm versus soft embryo transfer catheters under ultrasound guidance: does catheter choice really influence the pregnancy rates? Fertil Steril 2008;89(5):1261–1262 Marconi G, Vilela M, Belló J, Diradourián M, Quintana R, Sueldo C. Endometrial lesions caused by catheters used for embryo transfers: a preliminary report. Fertil Steril 2003;80(2):363–367 McIlveen M, Lok FD, Pritchard J, Lashen H. Modern embryo transfer catheters and pregnancy outcome: a prospective randomized trial. Fertil Steril 2005;84(4):996–1000 Leeton J, Trounson A, Jessup D, Wood C. The technique for human embryo transfer. Fertil Steril 1982;38(2):156–161 Visser DS, Fourie FL, Kruger HF. Multiple attempts at embryo transfer: effect on pregnancy outcome in an in vitro fertilization and embryo transfer program. J Assist Reprod Genet 1993;10(1):37–43 Moragianni VA, Cohen JD, Smith SE, et al. Effect of macroscopic or microscopic blood and mucus on the success rates of embryo transfers. Fertil Steril 2010;93(2):570–573 Eskandar MA, Abou-Setta AM, El-Amin M, Almushait MA, Sobande AA. Removal of cervical mucus prior to embryo transfer improves pregnancy rates in women undergoing assisted reproduction. Reprod Biomed Online 2007;14(3):308–313 Michael E, Ahmady A. The use of a cytobrush in cervical canal preparation for embryo transfer procedures. Fertil Steril 2005;84: S357 Moore DE, Soules MR, Klein NA, Fujimoto VY, Agnew KJ, Eschenbach DA. Bacteria in the transfer catheter tip influence the livebirth rate after in vitro fertilization. Fertil Steril 2000;74(6): 1118–1124 Brook N, Khalaf Y, Coomarasamy A, Edgeworth J, Braude P. A randomized controlled trial of prophylactic antibiotics (co-amoxiclav) prior to embryo transfer. Hum Reprod 2006;21(11): 2911–2915 Kroon B, Hart RJ, Wong BM, Ford E, Yazdani A. Antibiotics prior to embryo transfer in ART. Cochrane Database Syst Rev 2012;3: CD008995 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(3):677–682 Eytan O, Zaretsky U, Jaffa AJ, Elad D. In vitro simulations of embryo transfer in a laboratory model of the uterus. J Biomech 2007;40(5): 1073–1080 Poindexter AN III, Thompson DJ, Gibbons WE, Findley WE, Dodson MG, Young RL. Residual embryos in failed embryo transfer. Fertil Steril 1986;46(2):262–267
ineffective loading process of the embryo transfer catheter alters implantation and pregnancy rates. Fertil Steril 2001;76(3): 630–632 Grygoruk C, Sieczynski P, Pietrewicz P, Mrugacz M, Gagan J, Mrugacz G. Pressure changes during embryo transfer. Fertil Steril 2011;95(2):538–541 Grygoruk C, Ratomski K, Kolodziejczyk M, et al. Fluid dynamics during embryo transfer. Fertil Steril 2011;96(2):324–327 Groeneveld E, de Leeuw B, Vergouw CG, et al. Standardization of catheter load speed during embryo transfer: comparison of manual and pump-regulated embryo transfer. Reprod Biomed Online 2012;24(2):163–169 Martínez F, Coroleu B, Parriego M, et al. Ultrasound-guided embryo transfer: immediate withdrawal of the catheter versus a 30 second wait. Hum Reprod 2001;16(5):871–874 Sroga JM, Montville CP, Aubuchon M, Williams DB, Thomas MA. Effect of delayed versus immediate embryo transfer catheter removal on pregnancy outcomes during fresh cycles. Fertil Steril 2010;93(6):2088–2090 Matorras R, Mendoza R, Expósito A, Rodriguez-Escudero FJ. Influence of the time interval between embryo catheter loading and discharging on the success of IVF. Hum Reprod 2004;19(9): 2027–2030 Nabi A, Awonuga A, Birch H, Barlow S, Stewart B. Multiple attempts at embryo transfer: does this affect in-vitro fertilization treatment outcome? Hum Reprod 1997;12(6):1188–1190 Goudas VT, Hammitt DG, Damario MA, Session DR, Singh AP, Dumesic DA. 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(5):878–882 Lambers MJ, Dogan E, Lens JW, Schats R, Hompes PG. The position of transferred air bubbles after embryo transfer is related to pregnancy rate. Fertil Steril 2007;88(1):68–73 Friedman BE, Lathi RB, Henne MB, Fisher SL, Milki AA. The effect of air bubble position after blastocyst transfer on pregnancy rates in IVF cycles. Fertil Steril 2011;95(3):944–947 Cenksoy PO, Fıcıcıoglu C, Yesiladali M, Akcin OA, Kaspar C. The importance of the length of uterine cavity, the position of the tip of the inner catheter and the distance between the fundal endometrial surface and the air bubbles as determinants of the pregnancy rate in IVF cycles. Eur J Obstet Gynecol Reprod Biol 2014; 172:46–50 van Gestel I, IJland MM, Hoogland HJ, Evers JL. Endometrial wavelike activity in the non-pregnant uterus. Hum Reprod Update 2003;9(2):131–138 Jinno M, Ozaki T, Iwashita M, Nakamura Y, Kudo A, Hirano H. Measurement of endometrial tissue blood flow: a novel way to assess uterine receptivity for implantation. Fertil Steril 2001; 76(6):1168–1174 Tiras B, Polat M, Korucuoglu U, Zeyneloglu HB, Yarali H. Impact of embryo replacement depth on in vitro fertilization and embryo transfer outcomes. Fertil Steril 2010;94(4):1341–1345 Tiras B, Korucuoglu U, Polat M, Saltik A, Zeyneloglu HB, Yarali H. Effect of air bubble localization after transfer on embryo transfer outcomes. Eur J Obstet Gynecol Reprod Biol 2012;164(1):52–54 Amarin ZO, Obeidat BR. Bed rest versus free mobilisation following embryo transfer: a prospective randomised study. BJOG 2004; 111(11):1273–1276 Tremellen KP, Valbuena D, Landeras J, et al. The effect of intercourse on pregnancy rates during assisted human reproduction. Hum Reprod 2000;15(12):2653–2658 Küçük M. Bed rest after embryo transfer: is it harmful? Eur J Obstet Gynecol Reprod Biol 2013;167(2):123–126
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Practice of Embryo Transfer: Recommendations During and After Bulent Tıras, MD1
Pinar Ozcan Cenksoy, MD2
1 Department of Obstetrics and Gynecology, Acibadem University
School of Medicine, Istanbul, Turkey 2 Department of Obstetrics and Gynecology, Yeditepe University Medical School, Istanbul, Turkey
Address for correspondence Bulent Tıras, MD, Department of Obstetrics and Gynecology, Acibadem University School of Medicine, Istanbul, Turkey (e-mail: [email protected]).
Abstract
Keywords
► embryo transfer technique ► assisted reproductive technology ► successful embryo transfer
Many patient and embryo factors influence the outcome of assisted reproductive technology (ART) treatment. The predictors for a successful ART cycle include female age, ovarian reserve, embryo quality, endometrial receptivity, and embryo transfer (ET) technique. ET, the final step of ART, has recently been noted as a crucial step affecting ART success. Variables affecting pregnancy rates following ET include ultrasound guidance, ease of ET transfer, catheter type, transfer and catheter-loading technique, blood or mucus effects, retained embryos, trial transfer, the physician’s experience, and catheter tip placement. Despite the lack of consensus regarding the optimal ET technique, it is generally recommended that during ET, the disruption of the endometrium and the induction of uterine contractions should be avoided. The exposure of embryos to the ambient conditions should be minimized, and the embryo(s) should be placed at an optimal position within the fundal region of the uterine cavity.
Success rates with assisted reproductive technology (ART) have significantly improved over the last decades. While the average live birth rate associated with ART was reported as 28% in 1996, it had increased to 35.4% by 2006.1 Many patient and embryo factors influence the success of ART and the main predictors of pregnancy outcome include female age, ovarian reserve, embryo quality, endometrial receptivity, and embryo transfer (ET) technique.2–4 Despite great advances in ovarian stimulation protocols and embryo culture, few improvements have been noted in ET techniques because it received relatively little attention until recently.5–7 ET, the final step of ART, has recently been observed to be a crucial step in assuring ART success. Despite the lack of consensus on the optimal ET technique, most studies have recently highlighted the importance of ET procedure with various recommendations.8,9 ET is typically performed in the dorsal lithotomy position as an outpatient procedure without anesthesia and it generally starts with the insertion of speculum into the vagina for
Issue Theme Common Practices in Reproductive Endocrinology and Infertility Supported by Weak or No Evidence; Guest Editor, Orhan Bukulmez, MD
visualization of the cervix. After visualization of the cervix, the cervix is cleaned in a variety of ways avoiding embryotoxic chemicals. The transfer catheter loaded with embryo(s) is inserted through the cervical canal and advanced into the uterine cavity and then the embryo(s) is deposited by applying gentle pressure into the uterine cavity. Finally, the catheter is withdrawn. Variables affecting ET outcome consist of ultrasound (US) guidance, ease of ET, catheter type, transfer and catheterloading technique, blood or mucus effects, retained embryos, trial (mock) transfer, the physician’s experience, and proper catheter tip placement.4 To maximize embryo implantation rates, the main expectations from good ET technique include minimizing the disruption of the endometrium, avoidance of induction of uterine contractions, assuring embryo safety during the procedure, and to facilitate deposition of the embryo in an optimal position within the uterine cavity (►Table 1).
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1375181. ISSN 1526-8004.
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Table 1 Main expectations to ensure a successful embryo transfer Expectations • • • •
To avoid disruption of the endometrium by the catheter To minimize induction of the uterine contractions To protect the embryo(s) To deposit the embryo(s) in an optimal position within the uterine cavity
How Can We Minimize Disruption of the Endometrium by the Catheter and Avoid Induction of Uterine Contractions during ET? ET is generally regarded as the easiest part of the ART procedure, but ET is frankly the rate-limiting step of ART. Although it is now well known that ET is a crucial step in IVF treatment, it is difficult to standardize several variables of the ET technique such as the physician’s experience and the degree of difficulty of ET. One of the main strategies for successful ET is to atraumatically deposit the embryo(s) into the uterine cavity. Traumatic or difficult ET has been linked to a lower clinical pregnancy rate (PR) due to disruption of the endometrium and induction of uterine contractions associated with the release of prostaglandins and oxytocin. Because uterine contractions may also result from cervical trauma, the use of a tenaculum clamp, cervical stenosis requiring dilatation, or use of a firm catheter may lead to embryo expulsion. A trial transfer, gentle manipulation, use of a soft catheter, and US-guided ET have been associated with improved PR possibly by minimizing endometrial and cervical trauma during ET.10 Furthermore, progesterone frequently used for luteal phase support may also help decrease uterine contractions at the time of ET.
Difficult Transfer The transfer could be considered difficult if time spent on ET was long, and if a firmer catheter, additional maneuvers and/ or instrumentation, sounding or cervical dilatation were needed and if the resistance to the catheter advancement was encountered, and the presence of blood on the transfer catheter was noted. Difficult ET is more common in cases with severe anteflexion, retroflexion, or anteversion and retroversion of the uterus and cervical stenosis. A large retrospective study including 4,807 ETs showed that easy or intermediate transfers resulted in a 1.7-fold higher PR than difficult transfers.11 The presence of blood on the transfer catheter results from traumatic cervical passage of the catheter, subclinical infection, or endometrial bleeding due to traumatic contact with the catheter. Then, it has been suggested that difficult transfer, using additional maneuvers and/or instrumentation, and the presence of blood on the transfer catheter should be avoided during ET for the best pregnancy outcome.11–16 However, a recent review has indicated that there is some evidence that if ET Seminars in Reproductive Medicine
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was considered difficult or if there was a need for additional maneuvers and/or instrumentation, a negative effect on PR can be expected, while the presence of blood on the transfer catheter may not necessarily affect ET outcome.17 In cases with extremely difficult or even impossible transcervical ET, transmyometrial ET can be performed under transvaginal US guidance which is also known as the Towako method.18
Mock Transfer The value of mock transfer on reducing difficult ET has been controversial. Mock, dummy, or trial transfer, first reported in the early 1990s, can provide references for actual transfer regarding the selection of the appropriate transfer catheter, the direction and curve of the catheter, the length and direction of the endometrial cavity and cervical canal, and potential problems associated with the procedure. For example, encountering a severely flexed uterus requiring a tenaculum clamp or realization of a stenotic cervix needing cervical dilatation during the actual procedure may be problematic and knowing about such issues before ET may be advantageous for proper planning.19,20 Trial transfer could be performed before starting ovarian stimulation, at the time of oocyte retrieval, or just before the actual transfer. The timing of a trial transfer does not influence embryo implantation or pregnancy rates.21 In the case of severe cervical stenosis, cervical dilatation can be performed by mechanical dilation, use of osmotic dilators such as laminaria, placement of a Malecot catheter, and hysteroscopic shaving. These procedures may be performed several weeks before ET to ensure adequate recovery time of endometrium from potential injury, inflammation, or bacterial contamination inflicted by the procedure. With such approaches, an improvement in PRs has been reported in patients with cervical stenosis.22–25 The changes in length and position of uterus during ovarian stimulation should be considered when trial transfer is done before starting ovarian stimulation.26 If it is performed at the time of actual ET, to prevent disruption of the endometrium, the catheter should only be advanced to just past the internal cervical os and the transfer should be done under US guidance. Otherwise, the outer sheath of the catheter inserted into the cervical canal can be used as a guide to advance the soft inner catheter loaded with the embryo(s) also known as afterloading.5 This method provides an immediate mock transfer while minimizing manipulation of embryos.
Ultrasound Guidance The use of routine US guidance in ET rather than relying on blind clinical touch technique could be another approach to improve ET outcome because blind clinical touch technique may potentially disrupt the endometrium. US guidance in ET assists in gentle insertion of the catheter while avoiding its direct contact with the fundus, which may prevent uterine contractions during ET. The ultrasonographic visualization of newer ET catheters is made easier by the manufacturers, leading to even better live assessment of embryo replacement depth within the endometrial cavity. Therefore, US-guided ET
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Type of Catheter Many studies have been conducted to evaluate the relationship between the choice of the ET catheter and the outcomes of ART. Despite their limitations, the majority of these studies compared the outcomes of soft versus firm catheters and concluded that using the soft catheter during ET significantly increases PRs, albeit the potential effects of the catheter type is still considered controversial.34,35 It is suggested that the ideal ET catheter is soft enough to avoid trauma to the cervix and endometrium because it is known that firm catheters, which may be required in difficult transfers, can be associated with more bleeding and induction of uterine contractions. A prospective randomized trial comparing the Cook KSOFT-5100 and Frydman classical catheters concluded that variation in PRs between ET catheters is actually associated with the variation between the operators.36 Another study found that the choice of the catheter did not significantly affect the clinical PRs in IVF when it is performed under US guidance or after mock transfer.37,38 Likewise, a prospective randomized clinical trial that included 150 women undergoing fresh ET demonstrated that the type of ET catheter did not significantly influence the clinical PR because there was no significant difference in the clinical PRs between Wallace and Cook catheters.39 As a result, the choice of ET catheter may be decided by its cost and mostly by operator’s preference.
How Can We Keep Embryo(s) Safe During Embryo Transfer? Cervical Mucus Although the evidence is conflicting, the presence of macroscopic or microscopic mucus on the ET catheter may be considered as a variable affecting the ET outcome. Mucus on the transfer catheter may negatively affect ART success by causing retention of embryos with mechanical blockage of the catheter opening, also known as the “sling shot effect.”14,40,41 The presence of mucus on the ET catheter has been shown to decrease implantation and pregnancy rates.12,15,42 The cleaning of cervical mucus was shown to increase clinical PRs, although some conflicting reports exist.43 Therefore, significant cervical mucus should be routinely removed before ET in a gentle fashion in an effort to decrease the incidence of retained embryos and cervical contamination. The mucus in the cervical canal can be removed by a sterile cotton swab, with gentle irrigation
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with saline or culture media and it can also be aspirated using a sterile syringe.44 Vaginal antiseptics are not recommended at ET due to their potential toxicity to the embryos. The detection of mucus on the catheter may be associated with cervical contamination of the catheter itself while passing it through the cervical canal. The administration of antibiotics at the time of retrieval is suggested as an intervention to improve PR by reducing levels of microbial colonization during ET.45 However, the use of antibiotics for ET is still a subject of debate and is currently not recommended because of the lack of proven benefit. Furthermore, it is thought that the potential disruption of normal cervical flora induced by antibiotics may actually result in an inflammatory response.46 A Cochrane review concluded that the administration of antibiotics before ET did not affect clinical PRs, although it reduced the microbial contamination of the upper genital tract.47
Loading the Catheter An embryo is generally loaded into the ET catheter by use of the “three-drop technique” (invisible embryo(s) and visible air bubbles determining the final position of the embryo(s)) in which the air bubbles are created on both sides of the medium drop containing the embryo(s).48,49 In this technique, first an air bubble is loaded into the catheter and then 20 µL of medium is drawn up into the catheter, followed by the embryos in the smallest possible volume of medium. A second air bubble is then loaded into the catheter. Finally, enough medium is drawn up to bring the total volume to 30 µL. The excess fluid proximal to the embryo in the catheter increases the risk of embryo expulsion, while lower fluid volumes may also negatively affect embryo implantation rates.50,51
Embryo Expulsion Embryos can easily move toward the cervical canal or into the fallopian tube following their transfer into the uterine cavity and embryo expulsion is associated with a lower PR. Embryo expulsion may result from local pressure changes during ET, injection speed, negative pressure induced by the withdrawal of the catheter, and uterine contractions initiated by different factors such as touching the uterine fundus with a transfer catheter, cervical trauma, use of a tenaculum clamp, cervical stenosis, and use of a firmer catheter. A standard syringe-catheter complex used during ET can easily result in high pressure and fast fluid flow inside the catheter when there is a disproportion between the diameters of the syringe plunger and the catheter. Local pressure changes during ET are considered as a possible factor creating favorable conditions for expulsion of the embryos from the uterine cavity while impairing embryo viability.52,53 It is recommended that ET should be performed with a minimum ejection speed to protect the embryo(s) from the pressure gradient changes and to prevent embryo expulsion. A study54 presented pump-regulated ET (PRET) as a new method to standardize the injection speed during ET which may help avoid large variations in injection speed associated with manually performed ET. According to the results of that Seminars in Reproductive Medicine
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may significantly increase PRs.27–30 A Cochrane review also concluded that US guidance does appear to improve the probability of live birth/ongoing and clinical pregnancy rates as compared with the clinical touch methods, albeit most of the studies were deemed to be of limited quality.31 US-guided ET also requires a full bladder and a second operator which may cause some patient discomfort. The full bladder can allow the operator to put an appropriate curve on the catheter to accommodate the cervicouterine angle while somewhat straightening the cervicouterine angle to facilitate the proper advancement of the catheter in cases of severely anteverted and anteflexed uteri.32,33
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study, PRET may be considered as an alternative, reliable, and reproducible method to standardize injection speed.54 However, negative pressure induced after withdrawal of the catheter may still cause embryo expulsion. To minimize the effects of negative pressure, the catheter is slowly withdrawn after the deposition of the embryo into the uterine cavity, although no significant difference in ET outcome was observed between immediate and delayed withdrawal.55,56
Embryo Transfer Duration, Embryo Retention The time interval between loading the embryo and depositing it into the uterine cavity should be minimized to avoid exposure of the embryo to the ambient conditions because a longer time interval is associated with lower implantation and pregnancy rates.57 Inspection of the catheter after transfer under light microscopy is necessary for detection of retained embryos. The cervix and speculum should be routinely checked as well. If retained embryos are detected and immediately retransferred, no detrimental effects on PRs would be expected.58,59
How Can We Assure the Deposition of the Embryo in an Optimal Location within the Uterine Cavity? Another main strategy for successful ET is to deposit the embryo(s) in an optimal position within the uterine cavity (►Fig. 1). Several recent studies have focused on the potential impact of embryo replacement depth on ET outcomes.60–62 Although there is no consensus regarding optimal ET location within the uterine cavity, it seems most likely that fundal transfer is associated with the highest PRs.60–62 The air bubbles can be regarded as an identifier of the position of the embryos in regard to the fundal end of the endometrial cavity. The increased PRs have been reported when air bubbles were observed sonographically closer to the fundus. The reasons behind such an observation are not entirely clear. The fundal endometrium is suitable for implantation in terms of the expression of important factors related to implantation.
Figure 1 Locations of inner catheter and air bubble during embryo transfer. Seminars in Reproductive Medicine
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There is also lower endometrial wavelike activity in the fundus as compared with the other portions of the uterus. Endometrial tissue blood flow is also highest in the fundus, which may also play a role in increased possibility of embryo implantation in this region.63,64 A retrospective analysis of 5,055 US-guided ETs demonstrated that ongoing PRs were higher if ET was performed at a distance > 10 mm from the most distal fundal endometrial surface.65 In addition, the depth of the uterine cavity and the distance between the fundal end of the uterine cavity and the location of the catheter tip may be considered important by affecting actual ET depth. A prospective data analysis of 281 consecutive US-guided fresh ETs found that the optimal distance between the most distal fundal endometrial surface and the tip of the inner catheter should be 1.5 to 2 cm. Furthermore, in the same study, PRs were not influenced by the depth of the uterine cavity alone, but there was a trend toward increased distance between the most distal fundal endometrial surface and the air bubbles with increasing depth of uterine cavity.62 Air bubble movement shortly after the initial placement of the embryos into the uterine cavity may also influence implantation and pregnancy rates. Air bubbles moving toward the cervical canal right after ET can be associated with decreased clinical PRs, while air bubbles moving toward the uterine fundus may be associated with higher PRs albeit with higher miscarriage rates, eventually leading to similar live
Table 2 Embryo transfer practice points to optimize pregnancy rates Practice points • Use ultrasound guidance with full bladder and trial (mock) transfer to avoid ’’difficult’’ transfers, touching the fundus, using additional maneuvers and/or instrumentation, and the presence of blood on the transfer catheter • Gentle manipulation, use of a soft catheter to avoid inducing uterine contractions and to avoid trauma to the cervix and endometrium • Routine removal of cervical mucus to decrease the incidence of retained embryos and cervical and endometrial contamination • Do not use vaginal antiseptics to avoid potential toxicity to the embryos • Do not recommend the administration of antibiotics during embryo transfer • Use the “three-drop technique” for loading the embryo(s) • Use minimum ejection speed to prevent embryo expulsion • Withdraw transfer catheter slowly after the deposition of embryo • Minimize the time interval between loading the embryo and embryo transfer • Routinely check the catheter, cervix, and speculum following transfer to detect retained embryos • Perform fundal transfer • The optimal distance between the most distal fundal endometrial surface and the tip of inner catheter should be 1.5–2 cm
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12 Rhodes TL, McCoy TP, Higdon HL III, Boone WR. Factors affecting
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What to Do After Embryo Transfer Immediate ambulation and sexual intercourse after ET do not influence PRs.67,68 Bed rest after ET is still controversial. Many fertility clinics recommend bed rest after ET for variable periods of time, but there is no insufficient evidence to support this recommendation.69
Conclusion We reviewed the commonly reported factors associated with ET outcome, although the quality of evidence regarding the most ideal ET technique is rather poor (►Table 2). It seems that every program should have its standard protocols in place for proper performance and reporting of ET while considering the best available evidence. Thereafter, ET outcomes should be closely monitored to assess the need for any additional training or improvement.
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