1 Division for Reproductive Medicine, Department of Perinatology and Gynecology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht and 2 Department of Public Health, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, Dr. Molenwaterplein 50, 3015 GE Rotterdam, The Netherlands
3 To whom correspondence should be addressed. e-mail: F.Broekmans{at}azu.nl
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Abstract |
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Key words: embryo transfer technique/IVFembryo transfer/physician/pregnancy rate
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Introduction |
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Materials and methods |
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The IVF treatment protocol was as follows: pituitary desensitization by daily s.c. leuprolide acetate injections (Lucrin 1 mg; Abbott, The Netherlands) in a long luteal suppression protocol was followed by ovarian stimulation with hMG (Pergonal; Serono Benelux BV, The Netherlands; or Humegon; Organon, The Netherlands) or human recombinant FSH (Metrodin HP; Serono Benelux BV). Ovarian stimulation was monitored by transvaginal ultrasonography and estradiol measurements. When the two largest follicles reached a size of 18 mm, hCG (Profasi, Serono; or Pregnyl, Organon) was administered, and transvaginal oocyte collection took place 3436 h later. A maximum of two embryos was replaced in women aged <38 years. In older women three embryos were sometimes replaced. The luteal phase was supported by either hCG (Profasi; Serono) or progesterone (Progestan; Nourypharma BV, Oss, The Netherlands).
Embryo transfer procedure
Physicians were included in the study if they had performed 100 embryo transfers with both the clinical touch method as well as with the fixed distance technique (
100 with each method). In our dataset, seven out of eight providers met this criterion. The procedures for performing the embryo transfer were carefully written down in protocols, both for the practised clinical touch method, as well as for the newly applied fixed distance technique (
100 with each method). The preparation for embryo transfer was the same for both techniques. Patients were placed in the lithotomy position and the cervix was exposed using a bivalve speculum. The cervix was cleaned with embryo culture medium. The embryos were loaded in the catheter tip with
50 µl of media, fixed between air bubbles. All transfers were carried out using an Edwards Wallace Catheter (Simcare Ltd, UK). When there was difficulty passing the cervical canal or internal os with the loaded transfer catheter, it was withdrawn into the outer sheath, which was then used to facilitate the entrance into the cavity. If this made no progress a tenaculum was used to straighten the cervical canal. Ultimately, if passage could not be achieved, a switch was made to the TDT catheter (Prodimed, France). When the clinical touch method was used the catheter was advanced into the uterine cavity until its tip was felt touching the fundus. The tip was then withdrawn 0.5 cm and the embryos were expelled by advancing the plunger in the syringe, after which the catheter was gently withdrawn. When applying the fixed distance technique the catheter was advanced into the uterine cavity until 6 cm from the ostium externum. Then the embryos were expelled and the catheter was withdrawn. For both techniques the embryologist examined the catheter after the procedure to confirm that all embryos had been expelled before discharging the patient.
Variables
Primary variables, outcome variables and possible confounding variables were extracted from the database and listed in Table I. Pregnancy was defined as a positive urine pregnancy test, performed on day 14 after embryo transfer. Clinical pregnancy was defined as the presence of at least one gestational sac on ultrasonography, 23 weeks after a positive urine hCG test. Ectopic pregnancies were not counted as gestational sacs or clinical pregnancies. Implantation rate was defined as the number of gestational sacs on ultrasound, at a gestational age of 67 weeks, per 100 embryos replaced. The item duration of infertility appeared not to be completed in 699 case records. As it is considered a relevant factor in the prediction of success in IVFembryo transfer, this variable was not excluded from the analysis. The missing values were equally distributed among the two observation periods. When applying multivariate analysis this variable was omitted. Embryo quality was established according to the percentage of cytoplasmic fragmentation and the number of cells. Both items were given a score by the embryologist. For statistical comparison purposes and in order to quantify objectively the embryo quality, this score was composed as follows. Fragmentation <10% was given 5 points, 1050% 4 points and >50% 3 points. Embryos having <4 cells, 47 cells,
8 cells or a morula were given a score of 2, 3, 4 and 5 points respectively. The fragmentation and cell number score were multiplied for each transferred embryo, added up and divided by the number of embryos transferred. Hence, the mean embryo quality per patient (MEQ) was obtained. All analyses concerning MEQ score were done by dividing the dataset into groups of one specific transfer day (2, 3, 4 or 5) in order to compare embryo quality scores.
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Results |
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Discussion |
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Ultrasound-guided embryo transfer is designed to assure the correct position of the catheter in the uterine cavity, avoid touching the fundal area and thereby prevent the occurrence of bleeding and uterine contractions (Fanchin et al., 1998; Lesny et al., 1998
). Coroleu et al. (2002
) demonstrated that embryo transfer under ultrasound guidance compared with the clinical touch method improved pregnancy rates and these findings were confirmed by others (Lindheim et al., 1999
; Wood et al., 2000
; Kojima et al., 2001
; Anderson et al., 2002
). The critical role of chemical (blood) or mechanical (uterine contractions) trauma in the success rates after embryo transfer provides an explanation for the effect of the transfer technique on the differences among physicians with regard to pregnancy rates, as found in the present study. In using the clinical touch method, differences in the skill of the physician to very gently approach the fundus, never miss the touch moment and thereby creating a minimally traumatic transfer may account for the differences in pregnancy rates. In contrast, the fixed distance technique makes it possible for any provider to replace the embryos atraumatically, as the fundus need not be touched for assessing the correct position of the catheter tip in the cavity at the time of expelling the embryos.
The change in embryo transfer technique was paralleled by a significant increase in the overall pregnancy rates in our centre. As all physicians improved their pregnancy rates towards those of their best-performing collegues, it is tempting to attribute the rise in overall pregnancy rates to the change in technique. Obviously, the change in pregnancy rates after the switch may have been caused by many known or unknown factors. We analysed factors that are well known to play a role in the outcome of pregnancy after embryo transfer (Roseboom et al., 1995) and that were selected from our own data by multivariate logistic regression. We could not find clear differences in these factors before and after the switch in technique, apart from the factor embryo quality that may have contributed partly to the observed difference. Moreover, we tried to causally link the change in embryo transfer technique to the change in pregnancy rates by showing that around the time of the switch a sudden increase occurred in the pregnancy rates when using smoothing spline curves. However, we did not succeed in finding a fraction moment in the spline curve around the day of change in transfer technique. It is certainly unlikely that introducing a new technique on a given day will alter pregnancy rates immediately. Before the new technique started to be applied, a great deal of attention was paid to the role of the transfer technique in success rates. Physicians had to get used to the new technique or may have changed attitude beforehand. For these reasons the increase in pregnancy rates may show a gradual upward tendency instead of a sudden rise and may not be detectable by the technique of splining. Furthermore, another explanation may be that pregnancy rates always fluctuate with time in any centre for reproductive medicine. The fixed distance technique was introduced in a period where the trend was already upwards and this may certainly hamper the analysis of the relationship between the method and pregnancy rates. Also there may have been unknown factors which have changed between the two study periods which have not been revealed by the stepwise logistic regression analysis. Finally, proof for an overall effect on pregnancy rates can only be obtained from a prospective back-to-back comparison between the clinical touch and the fixed distance methods. To our knowledge such a study has not been performed.
With the retrospective nature of the study these arguments prevent us from drawing firm conclusions as to the question of whether overall pregnancy rates can be expected to go up if this technique is introduced in any centre for reproductive medicine.
The fixed distance technique of embryo transfer provides a simple and physician-proof method for embryo replacement. When using the fixed distance technique, embryos are being transferred at 6 cm from the external os irrespective of the individual length of the uterus. As no clear answer exists to the question in what part of the cavity the embryos need to be expelled from the catheter to obtain the best pregnancy rates, further study is needed at this point. Recently, Coroleu et al. (2002), using ultrasound controlled embryo transfer, suggested that replacement further away from the fundus will improve implantation rates. This means that assessing the sounding length of the uterus before applying the fixed distance method and using a distance
1.52 cm away from the fundus may optimize the performance of the fixed distance transfer procedure. Egbase et al. (2000
) studied the sounding length of the uterus in IVF patients by measuring the distance from the external cervical os to the fundus during a mock transfer procedure. They found that 16% of their patients appeared to have a uterine cavity length of <7 cm, meaning that in those patients a fixed distance technique at 6 cm would lead to replacing of the embryos at too short a distance from the fundus or even to touching of the fundal endometrium. In 10% of cases the cavity length was >9 cm and this may lead to replacement at a point too far away from the fundal area. To ensure that the embryos are expelled at the right distance from the uterine fundus, the sounding length of the uterus should be measured before the transfer. Pre-transfer assessment of the uterine cavity length may well be possible by using transvaginal ultrasound, although studies confirming the accuracy of this method are lacking. Mock transfer procedures will provide essential information on the depth of replacement but may be considered as a disproportionate burden for the patient as well as the doctor (Sharif et al., 1995
). The use of ultrasound-guided embryo transfer (Kan et al., 1999
; Lindheim et al., 1999
; Coroleu et al., 2000
; 2002; Wood et al., 2000
; Tang et al., 2001
; Karande et al., 2002
) offers another approach where the transfer depth can instantaneously be assessed according to the ultrasound image of the uterus. However, in transvaginal ultrasound-guided embryo transfer it may be quite difficult to simultaneously place the ultrasound probe, the speculum and the catheter. If abdominal scanning is used, the bladder needs to be filled, and the catheter may not always be easily visualized on the scan, while the need for extra staff to handle the ultrasound probe is obvious (Hurley et al., 1991
; Kovacs, 1999
). In conclusion, our study confirms that the large differences between physicians performing embryo transfers using the clinical touch method can be smoothed away by the application of the fixed distance technique. Whether the change in technique can be held responsible for an overall improvement of success rates remains difficult to prove. Future studies should be directed towards individualizing the depth of replacement and comparison with the ultrasound-guided transfer techniques.
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Submitted on November 21, 2002; accepted on January 7, 2003.