Transmyometrial embryo transfer and junctional zone contractions

F.P. Biervliet1,3,4, P. Lesny3, S.D. Maguiness1,3, J. Robinson2,3 and S.R. Killick1,3

1 Academic Department of Obstetrics and Gynaecology, 2 Department of Biological Sciences, University of Hull, Cottingham Road, Kingston Upon Hull HU6 7RX and 3 The Hull IVF Unit, Princess Royal Hospital, Saltshouse Road, Kingston Upon Hull HU8 9HE, UK


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: Embryo transfer is a crucial step in IVF–embryo transfer cycles. Several studies have explored transmyometrial embryo transfer, but although this procedure has several favourable characteristics, its role in assisted reproduction has not yet been established. Junctional zone (JZ) contractions during embryo transfer are associated with a negative outcome and factors which increase JZ contractions should be avoided. METHODS: In this study, we have investigated the effect of transmyometrial embryo transfer on JZ contractions. Ten patients with a previously difficult embryo transfer, or a difficult mock embryo transfer, underwent transmyometrial embryo transfer. Before and after this procedure a transvaginal ultrasound scan was performed and this was recorded on videotape for 5 min. The recordings were digitized and then analysed for JZ contractions. RESULTS: Transmyometrial embryo transfer causes a significant increase in JZ contractions. CONCLUSION: The increase in JZ contractions after transmyometrial embryo transfer forms a theoretical objection to this procedure. However, its alternative, a difficult transcervical embryo transfer, is also associated with an increase in JZ contractions. We therefore suggest a large prospective study to investigate the most effective method of embryo transfer in cases where a difficult transcervical embryo transfer is anticipated due to cervical factors.

Key words: difficult embryo transfer/junctional zone contractions/transmyometrial embryo transfer


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Despite the considerable importance of embryo transfer in the IVF–embryo transfer process, the procedure has not changed significantly since its introduction and relatively little research has been directed towards it. In most cases the procedure is performed blindly without any apparent problems. However, several studies have shown that in some cases it can be difficult or even impossible to perform a transcervical embryo transfer (Wood et al., 1985Go; Noyes et al., 1999Go). In these cases, embryo transfer can be performed by introducing a needle into the uterine cavity through the myometrium, referred to as a transmyometrial embryo transfer (TMET). In a study by the Towako Maternity Clinic group (Kato et al., 1993Go) and in a subsequent smaller study (Sharif et al., 1997), the clinical pregnancy rates were 36.5 and 23% respectively. The procedure of TMET is technically not difficult and is usually performed without anaesthetic. It is performed under transvaginal ultrasound scan guidance and therefore would prevent problems associated with a blind transcervical procedure, such as intra-tubal transfer or curling up of the embryo transfer catheter in the region of the internal os, as identified in studies (Hurley et al., 1991Go; Woolcott and Stanger, 1997Go). Despite these favourable characteristics, the role of TMET in assisted conception procedures has not been clearly established.

Several studies have investigated the role of junctional zone (JZ) contractions in IVF–embryo transfer cycles. It has been shown that these contractions can interfere with the success rate of IVF (Fanchin et al., 1998Go), possibly by expelling embryos from the uterine cavity. Our unit has recently shown that difficult transcervical embryo transfers, and the use of a tenaculum, could stimulate JZ contractions (Lesny et al., 1998Go, 1999aGo). The following study was therefore designed to assess the effect of TMET on JZ contractions.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Patients characteristics
Ten patients in whom a difficult transcervical embryo transfer was anticipated were offered a TMET. Difficulties were anticipated if there had been a difficult transcervical embryo transfer in a previous, unsuccessful IVF cycle (n = 8) or a difficult mock embryo transfer (n = 2). All patients were counselled and participated on a voluntary basis after having given written consent. The research project was approved by the Hull and East Riding Local Research Ethics Committee.

The age of the patients varied from 27–37 years (median = 31). Male factor was responsible for subfertility in five cases, two patients suffered from unexplained subfertility, one from severe endometriosis and two from tubal factor subfertility.

Medication
Ovulation induction prior to IVF was achieved with a standard regimen of pituitary down-regulation with 800 µg of GnRH agonist (Nafarelin; Searle Pharmaceuticals, High Wycombe, UK) administered daily from the mid-luteal phase, followed by appropriate doses of urofollitrophin (Metrodin High Purity; Serono Laboratories UK Ltd, Welwyn Garden City, UK). When the lead follicle reached a diameter of 20 mm, 10 000 IU HCG (Profasi; Serono) was given. Luteal support was provided by vaginal micronized progesterone (Utrogestan; Basins Iscovesco Laboratories, Paris, France) in a dosage of 600 mg/night from the day of oocyte retrieval for 80 days. All patients received 600 mg of Ibuprofen (Brufen; Knoll Ltd, Nottingham, UK) 2 h before oocyte retrieval. Midazolam (Hypnovel; Roche products, Welwyn Garden City) was used for sedation and Alfentanil (Rapifen; Janssen-Cilag Ltd, High Wycombe) was given for analgesia during oocyte retrieval and embryo transfer.

Transmyometrial embryo transfer
The patient was placed in lithotomy position with an empty bladder. The procedure was performed under transvaginal ultrasound scan guidance (ATL Ultramark 4, 5MHz transducer; Advanced Technology Laboratories, Seattle, USA).

A Towako needle (Cook Ltd, Letchworth, Herts, UK) with its stylet was passed through the anterior vaginal fornix, through the myometrium of the anterior uterine wall with its adjacent endometrium and into the endometrium of the posterior wall. In cases of a retroverted uterus, the Towako needle was passed through the posterior vaginal fornix and through the myometrium and endometrium of the posterior uterine wall into the endometrium of the anterior uterine wall. The needle was then gently pulled back into the uterine cavity and the stylet was removed. To shorten the procedure, the embryologist had begun to load the 2.0 French polyethylene transfer catheter with embryos suspended in 20 µl of culture medium (Medi-Cult IVF Culture Medium; Medi-Cult Ltd, Redhill, UK) when the clinician started to insert the needle. The catheter was passed through the needle by the embryologist who performed the transfer of the embryos. Their correct placement was confirmed by a flow of fluid seen inside the uterine cavity. The needle and the catheter were removed and checked for retention of embryos.

Imaging techniques
A transvaginal ultrasound scan of the mid-sagittal plane of the uterus was performed for 2 min before and for 3 min after TMET. The images were videotaped (VHS P4341: Goldstar, South Korea), digitized by computer and converted to x5 normal speed using Speed Razor Mach III (Synch Corporation, 1993, Bethesda, USA). A frame time-coding system allowed us to evaluate timing of events with an accuracy of ±0.04 s. Contraction pattern and frequency were assessed and agreed by two independent observers. The wave classification system introduced by IJland was used (IJland et al., 1996). This system subdivides five types of endometrial movements: no activity; waves from the cervix to the fundus; waves from the fundus to the cervix; opposing waves, starting simultaneously at the fundus and the cervix; and random waves, originating at various foci.

These observations were evaluated on Statistics Package for Social Sciences for Windows (SPSS UK Ltd, St. Andrews House, Woking, Surrey, UK) using Wilcoxon's matched-pairs test.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The TMET was technically successful in all patients and the procedure was well tolerated. In all 10 patients, three embryos were transferred (Table IGo). The quality of the embryos was average to good (median score = 3.6 on a 5 points scale, with 5 being the highest quality). Three patients had a positive urine pregnancy test; one patient had a missed abortion at 8 weeks, one patient had a tubal pregnancy and one delivered spontaneously at term.


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Table I. Characteristics of patients undergoing transmyometrial embryo transfer
 
The effect of TMET on JZ contractions is shown in Table IIGo (individual patients) and Table IIIGo (all patients). Before the TMET, minimal JZ activity was seen, predominantly of the random and opposing subtypes. No patient exhibited cervico–fundal contractions and four patients fundo–cervical contractions. After transmyometrial transfer there was an increase in all contractions, which was statistically significant except for the fundo–cervical subtype. This increase did not only involve patients who exhibited JZ contractions before the TMET; four patients exhibited cervico–fundal, three fundo–cervical, three random and three opposing contractions de novo. No difference could be seen in the pattern between patients who achieved a pregnancy as compared with those who did not.


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Table II. Amount of junctional zone contractions per minute in individual patients before and after transmyometrial embryo transfer. The contractions are subdivided according the wave classification system introduced by IJland
 

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Table III. Total amount of junctional zone (JZ) contractions per minute in the group of 10 patients before and after transmyometrial embryo transfer. The contractions are subdivided according the wave classification system introduced by IJland
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Recently it has been realised that embryo transfer might be a major success-limiting step in the process of IVF–embryo transfer. Although this treatment has been available for >20 years, the technique of embryo transfer has changed little, which might reflect the fact that the majority of embryo transfers are performed without apparent problems. However, there are widespread opinions as to what might be important factors for a successful embryo transfer, and the need to further validate basic elements, such as type of catheter used and the role of sonographic guidance, has been addressed (Kovacs, 1999Go). It is therefore remarkable that so little research has been directed towards establishing the optimal method of embryo transfer for various clinical circumstances. For instance, under specific circumstances transcervical embryo transfer might not be the most effective route.

TMET has been used as an alternative to transcervical embryo transfer. The Towako Maternity Clinic group used this method when a difficult transcervical embryo transfer occurred in a previous cycle (Kato et al., 1993Go), whilst Sharif used the method after a difficult or impossible transcervical mock embryo transfer immediately before the real transfer (Sharif et al., 1996Go). However, in addition to an impossible or difficult transcervical embryo transfer, it has been suggested that a TMET should be performed for other indications such as `fragile' embryos (Kato et al., 1993Go) or multiple implantation failure (Asaad and Carver-Ward, 1997Go; Groutz et al., 1997Go).

In this study, we have investigated the occurrence of JZ contractions after TMET. We have demonstrated that TMET is a powerful stimulus to JZ contractility; a significantly increased number of random, opposing and cervico–fundal contractions after the insertion of the Towako needle were noted. Only three out of the 10 patients developed fundo–cervical contractions and although a statistically significant difference in the frequency of this type of contraction could not be demonstrated, there appeared to be an increasing trend after TMET. These findings resembled the pattern of JZ contractions observed in our study, where stimulation of JZ contractions was caused by the application of a tenaculum to the cervix (Lesny et al., 1999aGo). The negative effect of increased JZ contractility on pregnancy rate has been documented in an elegant study (Fanchin et al., 1998Go) and is now well accepted. Thus, the increased JZ contractility in all our patients after insertion of a Towako needle must be treated with great caution, as one would expect a rather quiescent endometrium at the time of embryo transfer. Three patients achieved a clinical pregnancy but, due to the small numbers involved in this study, no conclusion can be made regarding the frequency of contractions and success of the cycle. The occurrence of an ectopic pregnancy despite the transfer of the embryos in the midcavity is remarkable and has been reported previously (Lesny et al., 1999bGo); this further demonstrates that JZ contractions are able to relocate embryos from the uterine cavity.

Based on this study, TMET should be avoided if possible. However, the main indications for TMET are cervical factors such as cervical stenosis or an acute angle of the cervical canal and in these cases the alternative would be a difficult transcervical embryo transfer, possibly after cervical dilatation. It has been shown previously that these difficult embryo transfers are associated with an increase in JZ contractions (Lesny et al., 1998Go). These two methods of embryo transfer have been compared in one study, but no advantage in either method could be found (Groutz et al., 1997Go). However, this study was performed on a small number of patients and the indication to either method was not only a difficult transcervical embryo transfer, but also multiple implantation failure in previous cycles.

An alternative to dilatation directly prior to embryo transfer could be cervical dilatation after pituitary suppression prior to gonadotrophin stimulation, which would facilitate transcervical embryo transfer. This method has been described by the Bourn Hall group and resulted in a decreased incidence of difficult embryo transfer (Abusheikha et al., 1999Go).

The question, `Which is the most successful method of embryo transfer in cases of complicating cervical factors?' remains unanswered at present. TMET seems an attractive alternative, although the increase in JZ contractions, as demonstrated in our study, forms a theoretical objection. Although this study has shown a significant physical response to TMET, we are reluctant to draw any conclusions regarding the effect of this response on the pregnancy rate, due to the small number of patients involved. We therefore suggest a large prospective study to establish the most effective method of embryo transfer for this small, but important, subgroup of patients.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Elaine Gurney, Department of Mathematics, University of Hull is kindly thanked for her help with the statistical analysis.


    Notes
 
4 To whom correspondence should be addressed at: The Hull IVF Unit, Princess Royal Hospital, Saltshouse Road, Kingston Upon Hull HU8 9HE, UK. E-mail: f.p.biervliet{at}hull.ac.uk Back

Submitted on June 22, 2001


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Asaad, M. and Carver-Ward, J.A. (1997) Twin pregnancy following transmyometrial–subendometrial embryo transfer for repeated implantation failure. Hum. Reprod., 12, 2824–2825.[Abstract]

Abusheikha, N., Lass, A., Akagbosu, F. and Brinsden, P. (1999) How useful is cervical dilatation in patients with cervical stenosis who are participating in an in vitro fertilization–embryo transfer program? The Bourn Hall experience. Fertil. Steril., 72, 610–612.[ISI][Medline]

Fanchin, R., Righini, C., Olivennes, F., Taylor, S., de Ziegler, D. and Frydman, R. (1998) Uterine contractions at the time of embryo transfer alter pregnancy rates after in-vitro fertilization. Hum. Reprod., 13, 1968–1974.[Abstract]

Groutz, A., Lessing, J.B., Wolf, Y., Azem, F., Yovel, I. and Amit, A. (1997) Comparison of transmyometrial and transcervical embryo transfer in patients with previously failed in vitro fertilization–embryo transfer cycles and/or cervical stenosis. Fertil. Steril., 67, 1073–1076.[ISI][Medline]

Hurley, V.A., Osborn, J.C., Leoni, M.A. and Leeton, J. (1991) Ultrasound-guided embryo transfer: a controlled trial. Fertil. Steril., 55, 559–562.[ISI][Medline]

IJland, M.M., Evers, J.L., Dunselman, G.A., van Katwijk, C., Lo, C.R. and Hoogland, H.J. (1996) Endometrial wavelike movements during the menstrual cycle. Fertil. Steril., 65, 746–749.[ISI][Medline]

Kato, O., Kataksuka, R and Asch, R.H. (1993) Transvaginal–transmyometrial embryo transfer: the Towako method; experience of 104 cases. Fertil. Steril., 59, 51–53.[ISI][Medline]

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

Lesny, P., Killick, S.R., Tetlow, R.L., Robinson, J. and Maguiness, S.D. (1998) Embryo transfer—can we learn anything new from the observation of junctional zone contractions? Hum. Reprod., 13, 1540–1546.[Abstract]

Lesny, P., Killick, S.R., Robinson, J., Raven, G. and Maguiness, S.D. (1999a) Junctional zone contractions and embryo transfer: is it safe to use a tenaculum? Hum. Reprod., 14, 2367–2370.[Abstract/Free Full Text]

Lesny, P., Killick, S.R., Robinson, J., Titterington, J. and Maguiness, S.D. (1999b) Ectopic pregnancy after transmyomerial embryo transfer: case report. Fertil. Steril., 72, 357–359.[ISI][Medline]

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Sharif, K., Afnan, M., Lenton, W., Bilalis, D., Hunjan, M. and Khalaf, Y. (1996) Transmyometrial embryo transfer after difficult immediate mock transcervical transfer. Fertil. Steril., 65, 1071–1074.[ISI][Medline]

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accepted on October 19, 2001.





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