Ultrasound-guided soft catheter embryo transfers will improve pregnancy rates in in-vitro fertilization

Ellen G. Wood1, Frances R. Batzer, Kathryn J. Go, Jacqueline N. Gutmann and Stephen L. Corson

Thomas Jefferson University, Department of Obstetrics and Gynecology, Pennsylvania Reproductive Associates, Women's Institute for Fertility, Endocrinology and Menopause, 815 Locust Street, Philadelphia, PA 19107, USA


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Attempts to improve clinical pregnancy rates after in-vitro fertilization (IVF) and embryo transfer are constantly being made. Two changes in technique of embryo transfer of potential clinical importance were evaluated over two contiguous time periods in order to observe any corresponding change in clinical pregnancy (CP) rate per transfer: (i) embryo transfer catheter; (ii) ultrasound guidance. Catheter choices were hard: Tefcat, Tom Cat, or Norfolk; or soft: Frydman or Wallace. Ultrasound visualization was considered to be excellent/good when the catheter could be followed from the cervix to the fundus by transabdominal ultrasound with retention of the embryo-containing fluid droplet; fair/poor if visualization could not document the sequence of events. Embryo transfers were performed in 518 cycles. CP rates per transfer using soft and hard catheters was 36 and 17% (P < 0.000) respectively. CP rates per transfer for transfers performed with and without ultrasound guidance were 38 and 25% (P < 0.002) respectively. A statistically significant difference was also noted when visualization ranks were compared. CP rates per transfer in all excellent/good ultrasound-guided transfers was 41.5 versus 16.7% for fair/poor transfers (P < 0.038). In conclusion, performance of embryo transfer with a soft catheter under ultrasound guidance with good visualization resulted in a significant increase in clinical pregnancy rates.

Key words: embryo transfer/embryo transfer catheter/IVF/ultrasound guidance


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Clinical pregnancy is influenced by many critical factors: patient selection, ovulation induction protocol, oocyte retrieval technique, egg and embryo quality, uterine receptivity, laboratory protocol and embryo transfer technique. While embryo transfer is the last mechanical step in in-vitro fertilization (IVF), it represents at present the most inefficient step. The embryo transfer technique has remained relatively unexplored. Various groups have presented their techniques (Craft et al., 1981Go; Kern et al., 1981Go; Leeton et al., 1982Go; Edwards et al., 1984Go), but few IVF programmes have specifically examined variations in embryo transfer in an attempt to improve implantation. Most programmes, including our own, have relied on `feel' by the clinician placing the transfer catheter and embryos within the uterine cavity at a point `near' the fundus. Choice of catheter has remained programme-dependent. Furthermore, ultrasound, so much a part of the IVF process, seems under-used (Strickler et al., 1985Go; Hurley et al., 1991Go; Woolcott and Stanger, 1997Go). Therefore, a retrospective analysis of two factors, choice of embryo catheter and ultrasound visualization of embryo deposition into the uterine cavity, was undertaken within our programme in an attempt to improve embryo transfer technique and hence pregnancy rate.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A 2 year retrospective review from November 1, 1996, to October 31, 1998, of IVF/embryo transfer cycles was performed. All embryo transfers in IVF patients aged <=39 years/old with or without intracytoplasmic sperm injection (ICSI) were included. Critical factors identified for analysis were choice of catheter, difficulty of transfer, ultrasound guidance and the quality of transabdominal ultrasound visualization. Data on number of oocytes obtained at retrieval, number of embryos transferred, endometrial receptivity at the time of human chorionic gonadotrophin (HCG) as determined by thickness (mm) and echogenicity (grades 1, 2, and 3) (Grunfeld et al., 1991Go) were also collected. The initial hypothesis involved reviewing two contiguous 12 month periods where transabdominal ultrasound guidance was added in the latter period. Simultaneously over these time periods there was a change in transfer catheter used, from a hard to a soft catheter system.

Embryo transfer catheter
The Tefcat catheter (Cook Ob-Gyn, Spencer, IN, USA) or Tom Cat (Sherwood Medical, St Louis, MO, USA) or occasionally the Norfolk catheter (Cook Ob-Gyn) in extremely difficult transfers, were used in the initial part of the study period. These catheters have relatively stiff, hard, polyethylene or Teflon sheaths that enter the endometrial cavity to deposit the embryos. The initiation of soft catheter use began with the Frydman catheter (Laboratoire CCD, Paris, France) and evolved to almost exclusive use of the Wallace catheter (Cooper Surgical, Shelton, CT, USA). The Frydman has a soft 23 cm long inner polyurethane catheter with an external diameter of 1.53 mm with an open end. The Wallace is a soft 18 or 23 cm long inner silicon catheter with an external diameter of 1.6 mm and an open end. Both catheters possess stiffer outer sheaths that stabilize the softer inner cannula, which carries the embryos and actually enters the endometrial cavity for embryo transfer.

Embryo transfer procedure
Embryo transfer was carried out in the IVF laboratory at 72 h post oocyte retrieval in 99% of the cases. All patients were placed in the lithotomy position; no anaesthesia was used. A bivalve speculum was placed to expose the cervix. The exocervix was cleansed with sterile water. After the transfer catheter had been rinsed three times using culture medium of P-1 (Irvine Scientific, Santa Ana, CA, USA) and 10% synthetic serum (Irvine Scientific), the plunger on a tuberculin syringe was brought to 0.5 ml. Loading order was as follows: 20 µl of air space, the embryos in culture medium, a 20 µl air space and finally a small aliquot of culture medium.

In the first 12 month period analysed, the catheter was introduced into the cervical os and advanced into the uterus using clinical `feel'. If any resistance occurred, either the curve on the hard catheter was altered or with the soft catheter systems, the outer sheath could be separated and advanced to or through the internal cervical os; the inner sheath was then threaded through it. Once the catheter was felt to abut the fundus, it was retracted ~5 mm, the embryos were gently expelled and the catheter was withdrawn.

The addition of ultrasound guidance as a mandatory part of the embryo transfer was instituted on November 1, 1997. The uterus and endometrial cavity were visualized in a sagittal plane through a full bladder window using a 3 mHz mechanical sector probe (ATL Ultramark 4). A similar procedure as described above was carried out. However, efforts were made to visualize the catheter as it traversed the cervix. The soft inner catheter was then threaded through the internal cervical os under direct visualization. If resistance was met, the inner sheath was withdrawn and the outer sheath was then placed to or just through the internal os, not advanced into the uterine cavity. The inner catheter was now threaded through the outer sheath and advanced under real-time ultrasound guidance to a point approaching but not touching the fundus. The transfer volume was gently expelled as the air and fluid were visualized moving through the catheter and being deposited in the uterine fundus. Removal of the catheter was followed via ultrasound with observation of retention of the fluid droplet in its fundal position. In both groups, the catheter was then checked under the microscope and flushed for embryos retained within the lumen or adherent to the outside of the catheter.

Ultrasound visualization of embryo transfer was assessed as excellent/good if clear deposition and retention of the fluid droplet containing the embryos was noted at the fundus as well as visualization of the catheter entrance and exit from the uterine cavity. Fair/poor visualization was recorded if confirmation of catheter placement was attained but visualization of the fluid entering the uterus and retention of the fluid droplet was sub-optimal. The ease of each transfer procedure was judged subjectively by the clinician (scale: 1 = very easy; 2 = easy; 3 = some difficulty; 4 = very difficult): very easy when the catheter could be passed effortlessly into the uterine cavity; easy when the catheter required some manipulation and then passed freely; some difficulty when catheter manipulation was required plus a tenaculum; very difficult when multiple catheter changes, cervical dilatation plus the use of a tenaculum were required. The patient was then transferred to the recovery area and allowed to empty her bladder within 10–15 min of embryo transfer.

Statistical analysis
The data obtained were compared using {chi}2 analyses, Student's t-test and logistic regression for multivariate analysis using SYSTAT SPSS Inc., Chicago, IL, USA, software. P < 0.05 was considered to be statistically significant.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 518 consecutive embryo transfers in IVF patients were performed over the 2 year period. Statistical significance without and then with ultrasound guidance for embryo transfer was noted in implantation rate (IR), 14.1 and 19.9% respectively (P < 0.022) [confidence interval (CI) –0.106, –0.009] and CP rate/transfer between these two periods, 25.4% (66/260) and 38.4% (99/258) respectively (P < 0.001) (CI 1.273, 2.743) (Table IGo). No significant difference was noted in the mean age of patients, the indications for IVF treatment, endometrial thickness (mm)/ultrasound grade of the endometrium on the day of HCG (grades 1, 2, 3), mean number of eggs retrieved or mean number of embryos transferred for the two 12 month periods (Table IIGo).


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Table I. Comparison of implantation and clinical pregnancy/transfer rates with and without ultrasound guidance
 

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Table II. Patient characteristics with and without the use of ultrasound (US) guidance. There were no significant differences between the two groups
 
The transition of catheter choice was not confined to a time period and was identified as a gradual increase in the use of soft catheter transfer systems, predominantly the Wallace catheter, as shown in Figure 1Go. The choice of catheter was analysed with regard to use of hard or soft catheter transfer systems. A total of 107 embryo transfers were performed using hard catheters and 411 embryo transfers were performed using soft catheters. The choice of soft versus hard catheter was shown to significantly effect the IR, 19.1 and 8.1% respectively (P < 0.000) (CI–0.160, –0.064) and CP rate per transfer in these two groups, 36% (146/411) and 17% (18/107) respectively (P < 0.000) (CI 8.741, 26.576) (Table IIIGo). Between the hard and soft catheter transfer groups, with regard to mean patient age, indications for IVF, endometrial thickness/grade on the day of HCG, mean number of eggs retrieved or mean number of embryos were not statistically significant (data not shown).



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Figure 1. Evolution of transfer catheter use.

 

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Table III. Comparison between hard and soft catheter systems
 
In a logistic regression analysis, the choice of catheter was shown to have a significant impact on the pregnancy rate (P < 0.020) (CI 3.897–1.124) compared with the use of ultrasound guidance (P < 0.853) (CI 7.201–0.092). Further analysis of CP rate per transfer for embryo transfers using transabdominal ultrasound guidance revealed a statistically significant difference when excellent/good visualization of embryo deposition was attained irrespective of catheter type, 41.5% for excellent/good versus 16.7% for fair/poor (P < 0.038) (CI 1.010, 10.559) (Table IVGo). There was no significant difference with regard to ease or difficulty of the transfer with either catheter choice or with or without ultrasound visualization.


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Table IV. The quality of ultrasound visualization
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Embryo transfer, while critical to the IVF process, has been relatively underrated by most programmes in terms of evaluating changes that might improve clinical pregnancy rates. Most programmes still rely on clinical `feel' to determine proper placement of the transfer catheter within the uterine cavity. Various facets of embryo transfer may be pivotal in improving implantation and pregnancy clinical success: catheter position in the uterine cavity, choice of transfer catheter, volume of transfer medium, retention of the fluid droplet and endometrial receptivity.

The possible use of ultrasound guidance to facilitate embryo transfer was first reported by Strickler et al. (Strickler et al., 1985Go). A total of 16 transfers guided by ultrasound and 12 performed by clinical `feel' were compared. They reported that ultrasound-guided transfers were easier with less catheter distortion. Moreover, the retention of the fluid bubble containing the embryos was found to be reassuring to the patients, lessening anxiety that the embryos might be displaced. Leong et al. reached similar conclusions (Leong et al., 1986Go). Woolcott and Stanger recently confirmed maintenance of the embryo bubble on standing after embryo transfer in all patients using transvaginal ultrasound (Woolcott and Stanger, 1998Go), again providing reassurance to clinicians and patients alike. Hurley et al. reported on the value of transvaginal ultrasound-guided embryo transfer with improved results especially when one embryo was transferred (Hurley et al., 1991Go). Prapas et al. evaluated the adjuvant use of ultrasound guidance in 61 transfers compared with 71 blind transfers and reported a significantly higher pregnancy rate in the echoguided cases (36.6 versus 22.6%) (Prapas et al., 1995Go). Few groups describe routine use of ultrasound, transvaginal or transabdominal, as a part of their embryo transfer protocol (Leong et al., 1986Go; Rosenlund et al., 1996Go; Sieck et al., 1997Go). Others have used ultrasound only in difficult cases or during transvaginal–transmyometrial transfers (Kato et al., 1993Go; Sharif et al., 1996Go), or periurethral transvesical embryo transfers (Parsons et al., 1987Go).

We believe that the use of ultrasound clearly plays a role in embryo transfer. Tactile assessment of embryo transfer has been assessed as unreliable (Woolcott and Stanger, 1997Go). They noted sub-optimal catheter placement, from subendometrial transfers to tubal transfers and embedding of the transfer catheter within the endometrium or the fundus. Although facilitation of proper embryo placement with ultrasound seems intuitive, the use of ultrasound to minimize endometrial trauma and possibly to decrease myometrial contractions may indeed be helpful in enhancing implantation and clinical pregnancy rates (Fanchin et al., 1998Go; Lesny et al., 1998Go).

Strong fundo–cervical contractions and random uterine waves were demonstrated (Lesny et al., 1999Go) by touching the uterine fundus twice with the soft end of the catheter. Following the pathway of the catheter by ultrasound guidance should decrease the propensity for the clinician to make catheter contact with the fundus. Although the major difference reported by our study is attributed to the change from hard to soft catheter, this may contribute to the significantly higher CP rate per transfer noted when excellent/good ultrasound visualization was attained 41.5 versus 16.7% (P < 0.038). Difficulty of transfer was not significantly different in these two groups.

Kovacs recently polled 50 IVF clinicians regarding important factors for successful embryo transfer after IVF (Kovacs, 1999Go). Although ultrasound monitoring was deemed low priority, not touching the fundus was ranked particularly high on the list. Lack of clinical familiarity with performing ultrasound-guided transfers may be reflected here. Although Kovacs (1999) comments that visualizing the catheter tip via abdominal scanning is difficult, we found either excellent or good transabdominal visualization through a full bladder of the pathway of the catheter tip in >90% of our transfers.

While we used a full bladder transabdominal ultrasound technique, transvaginal guidance for transcervical uterine transfers has been reported (Hurley et al., 1991Go; Woolcott and Stanger, 1997Go). We have found no increased problems with bladder irritability or patient discomfort, or logistical problems within the context of our programme. The straightening of the utero–cervical junction by the filled bladder actually seems to favour easy entry into the endometrial cavity especially in acutely anteflexed uteri (Sundstrum et al., 1984) in contradiction of other findings (Mitchell et al., 1989Go). We noted no statistical difference in assessment of difficulty between the embryo transfers performed under abdominal ultrasound guidance with a full bladder and those performed without abdominal ultrasound guidance with an empty bladder. A straighter course through the internal os and into the uterine cavity was clearly noted by the physicians when performing embryo transfers on patients with an acutely anteflexed uterus. Our physicians felt this contributed to an easier transfer in that particular subgroup of patients.

Several reports comparing the type of catheter used for embryo transfer exist. Gonen et al. obtained significantly better efficiency in establishing pregnancy with a Frydman catheter (29 versus 16%; P = 0.03) compared to 70 transfers performed with the Tom Cat catheter (Gonen et al., 1991Go). Wisanto et al. had previously compared performance of Frydman catheters to the hard TDT catheter and the Wallace catheter and encountered more difficult transfers with the Frydman, but reported enhanced pregnancy rates when the Frydman catheter was used (Wisanto et al., 1989Go). A soft Wallace catheter yielded significantly higher pregnancy rates over the TDT catheter also in work reported by Rosenlund et al. (Rosenlund et al., 1996Go).

In early literature, Kern et al. had found the Tom Cat catheter without an introducing cannula as being `simple, painless and atraumatic to the cervical canal and the uterine cavity,' with the patient in a comfortable lithotomy position (Kern et al., 1989). However, the use of an introducing cannula was felt to be advantageous for negotiating anatomical difficulties and preventing the entry of cervical mucus into the endometrial cavity (Craft et al., 1981Go). In the early 1980s, Edwards et al. first used Wallace catheters and described them as `flexible and enclosed in a moveable outer sleeve to give support if needed' for embryo transfer (Edwards et al., 1984Go). Our CP rate per transfer was clearly better when using a soft rather than a hard catheter, 36 versus 17% (P < 0.000). Others have confirmed this (Rosenlund et al., 1996Go; McNamee et al., 1998Go). In addition, we found no significant difference in clinical pregnancy rates between the two soft catheters, Frydman or Wallace (data not shown), similar to previous findings (Al-Shawaf et al., 1993Go).

Recent work with dummy embryo transfer and methylene dye compared two catheters (Mansour et al., 1994Go). Soft Wallace catheters with complete aspiration of cervical mucus significantly reduced expulsion of dye compared to transfers performed with stiffer Craft catheters. Consequently, although we did not aspirate mucus in our study, possibly the soft catheter may be less irritating to the endometrium and induce fewer myometrial contractions, thus decreasing the expulsion rate of the transferred embryos. This may be a key factor with regard to the increased pregnancy rate noted with soft catheters in our study.

Several authors have looked at the ideal position of the catheter in the uterus. Meldrum et al. found no difference with respect to clinical pregnancy rate versus uterine depth varying from 6 to >9 cm, in 142 embryo transfers (Meldrum et al., 1987Go). However, another report found a significant difference in pregnancy rate with respect to catheter positioning (Waterstone et al., 1991Go). The transfer techniques of two physicians were compared, with one introducing the catheter tip exactly 5 cm past the external os versus the other further advancing until fundal resistance was felt and then withdrawing 5 mm before injection. A clinical pregnancy rate of 46% for the former and 24% for the latter (P < 0.01) was reported. Yovich et al. considered uterine depth to be critical, measuring it via ultrasound prior to embryo transfer (Yovich et al., 1985Go). His group performed embryo transfer blindly and relied on the length of the catheter to determine proper embryo placement, reporting an increased ectopic rate when the catheter was inserted >62.9 ± 7.9 mm from the cervical os. Nazari et al. reported similar findings (Nazari et al., 1993Go). In our 518 embryo transfers, only one ectopic pregnancy occurred and it was following an ultrasound-guided transfer with good visualization.

One report has favoured patient position as a critical factor influencing pregnancy rates (Knutzen et al., 1992Go). Mechanical issues of the exact preferred position of embryo placement within the endometrial cavity (fundal or mid-uterus) (Rosenlund et al., 1996Go), optimal volume of transfer fluid (Meldrum et al., 1987Go), time until catheter withdrawal (Knutzen et al., 1992Go) and presence of uterine contractions and their possible effects (Fanchin et al., 1998Go) were not addressed with this study. Nor were issues of endometrial receptivity evaluated (Paulson et al., 1990Go; Yaron et al., 1994Go) beyond endometrial thickness and echogenicity. Other factors, such as uterine/body positioning (Englert et al., 1986Go; Knutzen et al., 1992Go; Agarwal et al., 1994Go), the effects of a full or empty bladder (Mitchell et al., 1989Go), the presence of an air bubble within the transfer catheter (Krampl et al., 1995Go) and the length of bed rest after embryo transfer (Botta and Grudzinskas, 1997Go) have been investigated and revealed no impact on outcome.

In conclusion, performance of embryo transfer with a soft catheter system under ultrasound guidance with good visualization resulted in a significant increase in clinical pregnancy rates.


    Notes
 
1 To whom correspondence should be addressed at: 4000 Presidential Blvd, Monroe Building, Suite 100, Philadelphia, PA 19131, USA Back


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on July 5, 1999; accepted on October 5, 1999.