A randomized controlled trial of a soft double lumen embryo transfer catheter versus a firm single lumen catheter: significant improvements in pregnancy rates

Janelle A. McDonald1,3 and Robert J. Norman1

1 Suite 14, John James Medical Centre, 175 Strickland Crescent, Deakin, ACT 2600 and 2 The Reproductive Medicine Unit, The Queen Elizabeth Hospital and Wakefield Clinic, Department of Obstetrics and Gynaecology, University of Adelaide, Australia


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
BACKGROUND: Embryo transfer has changed little since originally described in 1978. Clinicians rate the type of catheter used as the third most important variable in embryo transfer, but there are no adequately powered randomized trials. We compared the clinical pregnancy rates with the single lumen catheter (TCC) and the double lumen catheter (CC) in a randomized single blind trial. METHODS: A total of 650 cycles of women from the Adelaide University reproductive medicine units in Australia were included in this trial. Patients were <40 years of age undertaking IVF and embryo transfer. Exclusion criteria were: known uterine abnormality, day 3 FSH >10 IU/l, previous difficult embryo transfer and pre-implantation genetic diagnosis. Cycles were randomized from numbered sealed envelopes immediately prior to embryo transfer with stratification for fresh or frozen cycles. RESULTS: There was a significantly higher pregnancy rate in the group treated with the CC compared with the TCC catheter [29.6 versus 20.5% per embryo transfer, odds ratio (OR) = 1.63 (95% confidence interval: 1.14–2.30), P = 0.0076]. The point estimate for the OR was similar for fresh and frozen cycles. CONCLUSIONS: The pregnancy rate was increased by 50% and this justifies the increased cost of the soft double lumen catheter and the training of clinical staff required.

Key words: catheter/embryo transfer/IVF/pregnancy rates/randomized controlled trial


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Embryo transfer is an important step in the IVF cycle but has changed little since originally described (Steptoe and Edwards, 1978Go). A survey of Australian clinicians found they rated the type of catheter used as the third most important variable in embryo transfer (Kovacs, 1999Go) and a postal survey in the UK found that the type of catheter used was believed to be the fourth most important variable (Salha et al., 2001Go). However, there is no conclusive evidence for the preferred use of any particular catheter and previous randomized trials have been too small to show significant differences in pregnancy rates (Wisanto et al., 1989Go; al-Shawaf et al., 1993Go; Ghazzawi et al., 1999Go; Meriano et al., 2000Go; Boone et al., 2001Go).

At the time of planning the trial our pregnancy rates in fresh IVF cycles were relatively disappointing in spite of excellent embryology services and very experienced clinical staff. We hypothesized that a higher pregnancy rate could be achieved by changing the embryo transfer protocol. Prior to the trial we had routinely used the Tom Cat catheter for embryo transfer. Our aim was to compare pregnancy rates in IVF with the single lumen Tom Cat catheter (TCC) and the double lumen Cook catheter (CC).


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Six hundred and fifty cycles of women from the reproductive medicine units at Queen Elizabeth Hospital Adelaide, Wakefield Clinic Adelaide and Darwin Private Hospital were included in this prospective randomized trial. Inclusion criteria were all patients aged <40 years who were undertaking IVF and embryo transfer. The exclusion criteria were: known uterine abnormality, day 3 FSH >10 IU/l, previous difficult embryo transfer and pre-implantation genetic diagnosis. Cycles were randomized immediately prior to embryo transfer with stratification for fresh or frozen cycles. The trial was approved by the area health service ethics committee. Informed consent was obtained from all patients. An interim analysis was planned for approximately halfway through with cessation of the trial if significance was <1%. Following the interim analysis no further patients were recruited. The results presented are those of all randomized patients (see flow chart, Figure 1Go). A pregnancy was defined as positive serum beta HCG with a sustained rise in the initial weeks of pregnancy, plus absence of menstruation. Biochemical pregnancies or cases where the initial HCG was borderline or the HCG fell or failed to rise appropriately in early gestation were excluded.



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Figure 1. Flow chart of randomized controlled trial of Cook versus Tom Cat embryo transfer catheters.

 
Statistical analysis
A power calculation estimated that a sample size of 695 would show a 10% difference in pregnancy rates with 80% power (alpha = 0.05) and a sample of 1132 would show a 7% difference. We therefore aimed for a total sample of 1150 cycles. A computer generated randomization schedule was obtained using STATA (version 4.0, 1995, Stata Corp., TX, USA) with stratification for fresh and frozen embryo transfer. Concealment of treatment allocation was by use of opaque envelopes. Data were entered directly onto a case record form and were transferred to a spreadsheet. Statistical analysis was performed using STATA. The study was terminated following the interim analysis.

The catheters
The Tom Cat catheter (Kendell Health Care, Hampshire, MA, USA) is 11.5 mm long and is made of polyethylene. The external and internal diameters of the tip are 1 mm and 0.3 mm respectively. The base is 6 mm in diameter and fits onto a 1 ml disposable syringe. The Tom Cat catheters used were all from one batch and were subject to mouse embryo testing by an external observer (Dr Patrick Quinn, SAGE BioPharma, CA, USA). A bend was placed on the end of the catheter whilst maintaining a sterile technique.

The Cook Catheter (K-JETS-7019-SIVF; Cook IVF, Eight Miles Plains, Queensland, Australia) is a double lumen catheter set. The guiding (outer) catheter is 19 cm long, has a polcarbonate hub, a bulb tip and the distal end is angled. The transfer (inner) catheter is 23 cm long and the tip is 2.8 French size. The base of the transfer catheter fits onto a 1.0 ml plastic syringe. All catheters used in the trial were from the same batch, and the batches are mouse embryo tested during manufacture.

The embryo transfer
The catheters were prepared by the embryologist prior to transfer. Embryo transfer procedures were carried out in a treatment room 48–72 h after oocyte retrieval or at corresponding times following ovulation in frozen cycles. A maximum of three embryos was transferred. The clinician performing the transfer was not aware of the catheter allocated prior to the procedure. It was not possible to be certain that the patient was blind to the catheter used as it may have been visualized by the woman at embryo transfer. We did however avoid discussion regarding the catheter used during and following the transfer. All women were placed in the lithotomy position and no sedation was required. A bivalve speculum was inserted to visualize the cervix. The cervix was cleaned with a cotton wool swab soaked in culture media. The embryos were loaded by the embryologist into the allocated catheter in 10 µl of culture media. The loaded CC set was handed to the clinician with the tip of the transfer catheter situated inside the guiding catheter. The guiding catheter was passed through the cervical canal until the bulb tip was located just beyond the internal os of the cervix. The transfer catheter was then advanced 2 cm and the embryos were deposited. The loaded TCC was introduced to 60 mm, aiming to deposit the embryos just short of the uterine fundus. The respective catheter was kept in the uterus for 30–60 s and was then slowly withdrawn. The CC set was withdrawn without moving the transfer catheter back inside the guiding catheter. The tip of the TCC and the tip of the Cook transfer catheter were immediately inspected by the embryologist for the presence of a retained embryo. It was thought to be unnecessary to inspect the Cook guiding catheter for a retained embryo.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
A total of 650 cycles were studied, 324 randomized to the CC and 326 to the TCC. There were no significant differences in the baseline characteristics for women treated with the CC and TCC (Table IGo). There were significantly more pregnancies in the CC cycles than in the TCC cycles [96/324 (29.6%) versus 67/326 (20.5%), P = 0.0076, odds ratio (OR): 1.63 (95% CI 1.14–2.3)]. The OR were similar for those undergoing fresh and frozen embryo transfer and at both of the two larger sites (Table IIGo). The age of the patients ranged from 20 to 39 years. Interestingly the age bracket 30–34 years had a higher pregnancy rate (28.3%) than women aged <30 years (24.5%) as well as women aged 35–39 years (21.7%). There was a slightly better prognosis for cycle 1 or 2 (26.9 versus 21.7% in others). If only one embryo was transferred the pregnancy rate was lower (14.5%), but there was no difference between those who had two or three embryos transferred (26.9 and 26.2%). No women had elective single embryo transfer.


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Table I. Baseline characteristics, site, clinician and procedural factors according to randomized group
 

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Table II. Pregnancy rates with the Cook (CC) versus the Tom Cat catheter, examining for an effect of site, clinician or fresh/frozen cycles
 
The clinicians rated approximately the same number of transfer in each group as difficult and there was no significant difference in the number of embryos retained in the catheter in the two groups or the incidence of blood contaminating the tip of the catheter. The pregnancy rates were no worse in those embryo transfers rated as difficult (25.8%) or those with blood on the catheter tip (22.5%).

Analysis of individual clinicians' results found that embryo transfer was, to some extent, operator dependent (Table IIGo). There was substantial variability in pregnancy rates with the CC. However, experience was not a factor, with inexperienced clinicians achieving results as good or better than experienced clinicians. In contrast, pregnancy rates in all clinicians were remarkably similar when the TCC was used (Table IIGo). Eight clinicians participated in the study but one (I) ceased working for the clinic shortly after the trial commenced. The other clinicians had worked in IVF for variable times at the commencement of the trial (1 month to 20 years) and all participated fully for the duration of the trial. They included two registrars in subspecialty training, one nurse practitioner and four specialists in reproductive medicine. The four clinicians (B, C, D and G) with the highest pregnancy rates using the CC and with the greatest differences between the two catheters included both registrars and two very senior clinicians with many years experience in IVF. The results for all clinicians were as good or better with the CC compared with the TCC (Table IIGo).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
This is the largest prospective multicentre randomized clinical trial that has shown a major difference in outcomes based on the type of catheter used. The numbers were not sufficiently large to have statistical power to determine whether differences existed between subgroups, although our results suggest that all subgroups benefited from a change to CC. The major limitation of our study is that we studied two catheters only and we can only speculate on the reason for this difference and the implications for other catheters.

There are a number of plausible theories to explain why the CC is associated with higher pregnancy rates. The tip of the TCC is harder than the tip of the CC and may cause more trauma to the endometrium. The soft transfer catheter of the CC may follow the natural curvature of the uterine cavity better than the TCC, possibly reducing the risk of burrowing into the posterior endometrium in the anteflexed uterus. This is supported by the ultrasound detected endometrial changes following intrauterine insemination which differ between hard and soft catheters (Lavie et al., 1997Go). In this study the TCC was associated with loss of the endometrial three layer pattern after 50% of treatments with the hard TCC and 12.5% with the soft Wallace catheter. The guiding catheter of the CC is firmer than the TCC and may protect the embryos from physical trauma during the passage through the cervical canal. The tip of the transfer catheter of the CC is protected within the guiding catheter when contact is made with the cervix, potentially reducing contamination of the embryos by cervical flora.

Embryo transfer may be operator dependent to some degree. We were encouraged to find that inexperienced IVF clinicians were able to achieve excellent pregnancy rates with the CC. This suggests that the CC is user friendly with a short learning curve. All but one clinician in our study had not used the CC regularly prior to the study period. A recent audit on training in embryo transfer found that trainees using the Wallace catheter achieved equivalent results to experienced staff by the time they had done 50 transfers (Papageorgiou et al., 2001Go). In our study clinicians B, C and G achieved improved pregnancy rates with only a small amount of experience with the CC (Table IIGo). The results varied substantially according to clinician (Table IIGo) but the numbers treated by each clinician are not sufficient to give an indication as to whether this was due to other factors. It is possible that expectations played a role in this difference. Unfortunately, it is impossible to blind clinicians performing the transfer and difficult to blind patients to the catheter used.

There have been many publications over the years discussing ways of improving embryo transfer and hopefully pregnancy rates. Most data have been descriptive and collected retrospectively. Factors that have been studied include the use of soft versus hard catheters (Meriano et al., 2000Go; Wood et al., 2000Go), ultrasound guidance for embryo transfer (Letterie et al., 1999Go; Wood et al., 2000Go), use of cervical introducers or obturators (Ghazzawi et al., 1999Go), the value of resting after transfer (Woolcott and Stanger, 1998Go), the position of embryo insertion in the uterus (Yovich et al., 1985Go; Waterstone et al., 1991Go), flushing of the cervical canal to remove mucus (Sallam et al., 2000Go) and microbiological factors in terms of the local flora (Ralph et al., 1999Go) and contamination of the catheter tip. The live birth rate after IVF is influenced by the presence of bacteria in the catheter tip (Moore et al., 2000Go). Lactobacillus and S. viridans were associated with increased and decreased live births respectively.

Previous studies of catheters have been predominantly observational studies with only five small randomized controlled trials, none of which have directly compared the CC with the TCC (Wisanto et al., 1989Go; al-Shawaf et al., 1993Go; Ghazzawi et al., 1999Go; Meriano et al., 2000Go; Boone et al., 2001Go). These have been often contradictory and have not led to a consensus on the preferred catheter. Other than two studies comparing the Frydman and Wallace catheters, there are no trials that compare the same catheters. This precludes meta analysis. A retrospective analysis of 518 embryo transfer, comparing five catheters [hard (Tefcat, Tom Cat, Norfolk) and soft (Frydman, Wallace)] found that a soft catheter was associated with higher pregnancy rates than a hard catheter (Wood et al., 2000Go). Wood also found that ultrasound guidance, when good visualization was obtained, led to better pregnancy results than those cycles where there was poor visualization. There was no significant difference in pregnancy rates when the degree of difficulty of embryo transfer was considered in both catheter groups.

Combined data from three small prospective randomized trials totalling 429 embryo transfer with an average of 3.2 embryos transferred per embryo transfer compared the Cook soft-pass catheter with the Edwards–Wallace catheter and found no significant difference in pregnancy rates (39% versus 43%) (Boone et al., 2001Go) (Table IIIGo).


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Table III. Pregnancy rates (%) in randomized controlled trials comparing two or more catheters
 
Another prospective randomized trial compared the performance of the TDT, Frydman and Wallace catheters. Large differences were found between catheters in pregnancy rates (9.2, 32.3 and 19.2% respectively). The Frydman, a soft single lumen catheter, had the highest pregnancy rate but was associated with more difficulty in the transfer (Wisanto et al., 1989Go). A retrospective study found higher pregnancy rates with the Wallace catheter (42%, n = 91) than the TDT catheter (20%, n = 39) (Rosenlund et al., 1996Go).

On the whole (including this study) soft catheters have been associated with better outcomes. Data suggesting that hard catheters are better than soft catheters is limited to two questionable studies. A small (n = 66) prospective randomized trial compared the TCC with the TDT catheter and concluded that the TCC achieved higher pregnancy rates than the TDT catheter (47 versus 15%) (Meriano et al., 2000Go). The sample size was, however, very small and results for both groups were extreme, suggesting that no sample size calculation had been performed and that the study was prematurely terminated. Also, the authors mention that the TDT catheters were from more that one batch and do not state that embryo toxicity testing was carried out. A retrospective comparison of the TCC and the Frydman catheter evaluated 193 embryo transfer and found that the TCC performed significantly better than the Frydman (29 versus 16%) (Gonen et al., 1991Go).


    Conclusions
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Pregnancy rates in an IVF programme can be improved by changing the type of catheter and the technique employed. The almost 50% improvement in pregnancy rates in IVF cycles justifies the increased cost of the Cook catheter and the training of clinical staff required. Further studies comparing other catheters with the Cook should be done to see whether any further improvement in pregnancy rates can be achieved.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
The authors would like to thank Reina Flynn in Darwin, Sally Wuttke at Queen Elizabeth Hospital, all the nurses for recruiting patients, Regan Jeffery for co-ordinating the laboratory, Lou Warne for providing pregnancy results, Reina Flynn, Christine Kirby, John Kerin, Rogan Draper, Fong Lok and Trish Davies for performing the embryo transfer and Nick Buckley for the statistical analysis and for advice on the manuscript.


    Notes
 
3 To whom correspondence should be addressed. E-mail: buckdonald{at}netspeed.com.au Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
al-Shawaf, T., Dave, R., Harper, J., Linehan, D., Riley, P. and Craft, I. (1993) Transfer of embryos into the uterus: how much do technical factors affect pregnancy rates? J. Assist. Reprod. Genet., 10, 31–36.[ISI][Medline]

Boone, W.R., Johnson, J.E., Blackhurst, D.M. and Crane, M.M. (2001) Cook versus Edwards–Wallace: are there differences in flexible catheters? J. Assist. Reprod. Genet., 18, 15–17.[ISI][Medline]

Ghazzawi, I.M., Al-Hasani, S., Karaki, R. and Souso, S. (1999) Transfer technique and catheter choice influence the incidence of transcervical embryo expulsion and the outcome of IVF. Hum. Reprod., 14, 677–682.[Abstract/Free Full Text]

Gonen, Y., Dirnfeld, M., Goldman, S., Koifman, M. and Abramovici, H. (1991) Does the choice of catheter for embryo transfer influence the success rate of in-vitro fertilization? Hum. Reprod., 6, 1092–1094.[Abstract]

Kovacs, G.T. (1999) What factors are important for successful embryo transfer after in-vitro fertilization? Hum. Reprod., 14, 590–592.[Free Full Text]

Lavie, O., Margalioth, E.J., Geva-Eldar, T. and Ben-Chetrit, A. (1997) Ultrasonographic endometrial changes after intrauterine insemination: a comparison of two catheters. Fertil. Steril., 68, 731–734.[ISI][Medline]

Letterie, G.S., Marshall, L. and Angle, M. (1999) A new coaxial catheter system with an echodense tip for ultrasonographically guided embryo transfer. Fertil. Steril., 72, 266–268.[ISI][Medline]

Meriano, J., Weissman, A., Greenblatt, E.M., Ward, S. and Casper, R.F. (2000) The choice of embryo transfer catheter affects embryo implantation after IVF. Fertil. Steril., 74, 678–682.[ISI][Medline]

Moore, D.E., Soules, M.R., Klein, N.A., Fujimoto, V.Y., Agnew, K.J. and Eschenbach, D.A. (2000) Bacteria in the transfer catheter tip influence the live-birth rate after in vitro fertilization. Fertil. Steril., 74, 1118–1124.[ISI][Medline]

Papageorgiou, T.C., Hearns-Stokes, R.M., Leondires, M.P., Miller, B.T., Chakraborty, P., Cruess, D. and Segars, J. (2001) Training of providers in embryo transfer: what is the minimum number of transfers required for proficiency? Hum. Reprod., 16, 1415–1419.[Abstract/Free Full Text]

Ralph, S.G., Rutherford, A.J. and Wilson, J.D. (1999) Influence of bacterial vaginosis on conception and miscarriage in the first trimester: cohort study. Br. Med. J., 319, 220–223.[Abstract/Free Full Text]

Rosenlund, B., Sjoblom, P. and Hillensjo, T. (1996) Pregnancy outcome related to the site of embryo deposition in the uterus. J. Assist. Reprod. Genet., 13, 511–513.[ISI][Medline]

Salha, O.H., Lamb, V.K. and Balen, A.H. (2001) A postal survey of embryo transfer practice in the UK. Hum. Reprod., 16, 686–690.[Abstract/Free Full Text]

Sallam, H.N., Farrag, F. and Ezzeldin, A. (2000) Vigorous flushing of the cervical canal prior to embryo transfer, a prospective randomised study. Fertil. Steril., 74S, 203.[ISI][Medline]

Steptoe, P.C. and Edwards, R.G. (1978) Birth after the reimplantation of a human embryo. Lancet, ii, 366.

Waterstone, J., Curson, R., and Parsons, J. (1991) Embryo transfer to low uterine cavity. Lancet, 337, 1413.[ISI][Medline]

Wisanto, A., Janssens, R., Deschacht, J., Camus, M., Devroey, P. and Van Steirteghem, A.C. (1989) Performance of different embryo transfer catheters in a human in vitro fertilization program. Fertil. Steril., 52, 79–84.[ISI][Medline]

Wood, E.G., Batzer, F.R., Go, K.J., Gutmann, J.N. and Corson, S.L. (2000) Ultrasound-guided soft catheter embryo transfers will improve pregnancy rates in in-vitro fertilization. Hum. Reprod., 15, 107–112.[Abstract/Free Full Text]

Woolcott, R. and Stanger, J. (1998) Ultrasound tracking of the movement of embryo-associated air bubbles on standing after transfer. Hum. Reprod., 13, 2107–2109.[Abstract]

Yovich, J.L., Turner, S.R. and Murphy, A.J. (1985) Embryo transfer technique as a cause of ectopic pregnancies in in vitro fertilization. Fertil. Steril., 44, 318–321.[ISI][Medline]

Submitted on September 20, 2001; accepted on January 16, 2002.