Mock embryo transfer does not affect uterine contractility Antoine Torre, M.D.,a,b,c Juliano Brum Scheffer, M.D.,a,b,c Luca Maria Sch€ onauer, M.D.,a,b,c b,c,d a,b,c Nelly Frydman, Pharm.D., and Renato Fanchin, M.D., PhD. a Assistance Publique–H^opitaux de Paris (AP-HP), Department of Obstetrics and Gynecology and Reproductive Medicine, H^ opital Antoine Beclere, Paris, France; b Universite Paris-Sud, UMR-S0782, Clamart, France; c Institut National de la Sante et de la Recherche Medicale U782, Clamart, France; and d AP-HP, Department of Reproductive Biology, H^opital Antoine Beclere, Paris, France
Objective: To assess the degree of utero-stimulation induced by transcervical introduction of a catheter as in mock ET. Design: Prospective study. Setting: Reproductive medicine unit. Patient(s): Eighty volunteers undergoing mild ovarian stimulation and IUI. Intervention(s): Just before IUI, women had uterine contraction (UC) frequency assessed with 2-minute sagittal ultrasound scans of the uterus (precatheter measurement). Thereafter, one of three types of catheters, each with a different stiffness level (low, n ¼ 25; medium, n ¼ 30; or high, n ¼ 25) was introduced into the cervix up to the inner cervical os, then immediately withdrawn, and the UC frequency reassessed (postcatheter measurement). Main Outcome Measure(s): Percentage change in UC frequency. Result(s): Median (range) UC frequency was not significantly different at pre- and postcatheter measurements: 2.0 (0.0–4.5) UC per minute and 2.2 (0.0–5.5) UC per minute. In addition, the stiffness of the catheter (low, medium, or high) did not influence the UC frequency, with median (range) percentage of change from pre- to postcatheter measurement at 0 (–100% to þ75%), 0 (–100% to þ100%), and 0 (–40% to þ100%), respectively. Conclusion(s): The introduction of a catheter up to the inner cervical os, as usually performed in mock ET, does not stimulate uterine contraction frequency, irrespective of catheter stiffness. (Fertil Steril 2010;93:1343–6. 2010 by American Society for Reproductive Medicine.) Key Words: Intrauterine insemination, mock embryo transfer, uterine contraction frequency, catheter
Embryo transfer is possibly the most sensitive clinical step for the establishment of a pregnancy after IVF. Among the factors that are likely to influence the effectiveness of such a procedure ranks the utero-stimulation that is potentially generated by the introduction of a catheter into the intrauterine milieu (1), in particular, under traumatic conditions (2). Indeed, all evidence indicates that the hyperactivity of the muscle fibers surrounding the endometrium is detrimental at the time of ET because it may increase the risk of embryo expulsion. In agreement with this hypothesis, our group has observed that high-frequency uterine contractions (UC) at the time of ET negatively influence the outcome of IVF-ET (3). Other investigators have observed that the choice of less-traumatic catheters positively influences the outcome of IVF-ET (4, 5). In an effort to decrease uterine trauma and the resulting stimulation of uterine contractility at the time of ET, some investigators have proposed ruling out the presence of cerviReceived July 19, 2008; revised October 24, 2008; accepted October 29, 2008; published January 7, 2009. A.T. has nothing to disclose. J.B.S. has nothing to disclose. L.M.S. has nothing to disclose. N.F. has nothing to disclose. R.F. has nothing to disclose. Reprint requests: Renato Fanchin, M.D., Department of Obstetrics and ^ pital Antoine Be cle re, 157 Gynecology and Reproductive Medicine, Ho rue de la Porte de Trivaux, 92141 Clamart, France (FAX: 0033 1 4537 49 80; E-mail:
[email protected]).
0015-0282/10/$36.00 doi:10.1016/j.fertnstert.2008.10.054
cal obstacles by the gentle introduction of an empty catheter through the cervix up to the inner cervical os immediately before ET (6). However, it remains unclear whether such a ‘‘mock ET’’ can itself generate UC and whether its possible stimulatory effect depends on the type of catheter used. Hence, the present investigation was conducted to quantify the possible utero-stimulation generated by mock ET performed using three ET catheters with different characteristics. MATERIALS AND METHODS Patient Characteristics We prospectively studied 80 infertile volunteers undergoing mild ovarian stimulation and IUI. The choice of IUI as a clinical model to study the impact of mock ET on uterine contractility was based on the fact that, unlike IVF-ET, utero-stimulation during IUI has been shown to increase IUI effectiveness (7); therefore, this experimental model could be considered acceptable for patients. All patients enrolled in the present study met the following criteria: [1] aged 18–41 years, [2] patent fallopian tubes confirmed by hysterosalpingography and/or laparoscopy, [3] normal uterine cavity on hysterosalpingography and/or laparoscopy and/or ultrasonography, [4] adequate uterine visualization on transvaginal ultrasound scans, and [5] a partner with at
Fertility and Sterility Vol. 93, No. 4, March 1, 2010 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc.
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least 1 106 spermatozoa showing progressive mobility after sperm preparation. Mild controlled ovarian hyperstimulation (COH) and IUI were indicated because of unexplained infertility (48%), ovulatory abnormalities (20%), mild sperm abnormalities (12%), mild pelvic endometriosis (10%), or mild tubal abnormalities (10%). Because the present study analyzed only clinical procedures that are routinely performed at our center, informed consent was obtained from each participant, but previous submission to our institutional review board was not required. COH Protocol All patients underwent mild COH using three different protocols: recombinant FSH (rFSH) (Gonal-F; Merck-Serono, Lyon, France) alone (68% of cases), a combination of clomiphene citrate (Clomid; Aventis, Paris, France) and rFSH (14% of cases), or a combination of GnRH agonist (Decapeptyl 0.1 mg; Beaufour-Ipsen Pharma, Boulogne-Billancourt, France) and rFSH (18% of cases), as described elsewhere (8). The choice of one protocol over another was strictly arbitrary and determined by individual preferences of the physicians belonging to our ovulation induction program. Administration of hCG (Gonadotrophine Chorionique Endo; Organon, Puscau, France; 5,000 IU, IM) was performed when one to four follicles simultaneously exceeded 15 mm in diameter. Intrauterine insemination was performed 36 hours after hCG administration. The luteal phase was supported with micronized P (Estima; Effik Pharmaceuticals, Bievres, France; 600 mg/d) administered daily through the vaginal route starting on the evening of IUI. Uterine Contractility Assessment and Catheter Introduction Just before insemination (precatheter assessment), women underwent an ultrasonographic assessment of UC, as described elsewhere (3). In brief, 2-minute ultrasound scans of a sagittal plane of the uterus were performed using a 7.5-MHz transvaginal probe (Siemens Elegra; Siemens SAS, Saint-Denis, France). Environmental conditions were standardized throughout ultrasound examinations. Images were digitized on line using a two-image-per-second rate, and UC frequency was assessed on time–mode graphs generated electronically using three-dimensional (3D) reconstruction software (I^ oTEC 3.1.2; I^ oDP, Paris, France). Uterine contraction frequency was identified by the number of major vertical displacements of the myometrial–endometrial interface and of the uterine cavity line over time. This 3D approach for the measurement of UC frequency showed results equivalent to those from visual UC counting on accelerated ultrasound sequences (9). The precision of uterine contraction frequency measurements, expressed as interassay coefficient of variation, was 8% (3). Immediately after UC recording, an ET catheter was introduced into the cervix up to the inner cervical os, then immediately withdrawn. This procedure, which mimics mock ET in IVF-ET (6), is done routinely at our center to rule out cer1344
Torre et al.
Mock ET and uterine contractions
vical obstacles. Three types of catheters (C.C.D Laboratories, Paris, France), of different stiffness, were alternately used in blocks strictly respecting the random order of arrival of patients at our institution for IUI: a low-rigidity group (Ultra-soft catheter; n ¼ 25), medium-rigidity group (Classic catheter; n ¼ 30), or high-rigidity group (Memory catheter; n ¼ 25). External diameters were, respectively, 1.6 mm, 1.6 mm, and 2.2 mm. Only one type of catheter was used for each patient. Just after catheter removal, another 2-minute recording of UC was performed using similar methodology as at baseline (postcatheter assessment). For all patients, IUI was performed with another Classic catheter. No difficulty in cervical catheterization was noted, and no cervix tenaculum was used. Hormonal Measurements Serum E2 and P levels were determined by an automated multianalysis system using a chemiluminescence technique (Advia-Centaur; Bayer Diagnostics, Puteaux, France). For E2, the lower detection limit was 15 pg/mL, linearity up to 1,000 pg/mL, and intra- and interassay coefficients of variation 8% and 9%, respectively. For P, the lower detection limit was 0.1 ng/mL, linearity up to 60 ng/mL, and intra- and interassay coefficients of variation 8% and 9%, respectively. Statistics Medians were used as the measure of central tendency, and minimum and maximum values were used as measures of variability. Changes in UC frequency were assessed using the Wilcoxon signed rank test. The catheter effect on UC frequency was assessed using the Kruskal-Wallis test. A P value of < .05 was considered statistically significant. RESULTS Patient characteristics and COH data in the low-, medium-, and high-rigidity catheter groups are summarized in Table 1. As shown, women included in the three groups were comparable with regard to age, etiology and duration of infertility, prevalence of COH protocols, and cycle day of hCG administration, as well as number of preovulatory follicles (>15 mm in diameter) and serum E2 and P levels on the day of hCG administration. Overall, pre- and postcatheter UC frequency remained unchanged at 2.0 UC per minute (range, 0–4.5 UC per minute). Detailed data on uterine contractility in the low-, medium-, and high-rigidity catheter groups are shown in Table 2. No noticeable stimulatory effect of mock ET was noted, regardless of the characteristics of the catheter used. DISCUSSION Mock ET and others practices, such as ultrasound-guided transfer or pretreatment hysteroscopy, have been proposed to prevent traumatic transfer that could negatively affect the implantation rate (10). Indeed, hysteroscopy could rule out Vol. 93, No. 4, March 1, 2010
TABLE 1 Patient characteristics and COH data in the low-, medium-, and high-rigidity catheter groups. Characteristic Female age (y) Etiology of infertility Unexplained Ovulatory Mild male Mild endometriosis Mild tubal Duration of infertility (y) COH protocol FSH CC–FSH GnRH agonist–FSH Day of hCG administration No. of follicles >15 mm Serum E2 level (pg/mL) Serum P level (ng/mL)
Low rigidity (n [ 25)
Medium rigidity (n [ 30)
High rigidity (n [ 25)
35 (27–41)
35 (20–44)
32 (27–39)
NS
38 13 21 8 20 4 (1–12)
51 25 9 10 5 4 (1–10)
54 22 8 12 4 4 (1–11)
NS NS NS NS NS NS
70 13 17 11 (8–19) 1 (1–4) 329 (141–1636) 0.24 (0.10–1.69)
76 6 18 11 (8–25) 2 (1–4) 675 (208–1045) 0.15 (0.10–0.76)
P value
60 20 20 10.5 (8–24) 2 (1–4) 533 (133–1514) 0.45 (0.10–0.99)
NS NS NS NS NS NS NS
Note: Values are percentages or median (range). NS ¼ not statistically significant; CC ¼ clomiphene citrate. Torre. Mock ET and uterine contractions. Fertil Steril 2010.
potential intracervical or intrauterine obstacles (11). Because ultrasound performed at the time of the transfer estimates hysterometry more accurately than pretreatment mock ET (12, 13), it more efficiently prevents uterine fundus stimulation, leading to improved IVF outcomes (14). However, difficult cervix passage attested to by bleeding (15) or long (16) ET can also negatively affect implantation rate and should be prevented by previous intracervical insertion of a catheter. This mock ET, which can be performed before any treatment (pretreatment mock ET), at the time of oocyte retrieval or just before ET, directly allows the best shape and stiffness of the catheter to be selected for each endocervical canal (10), which appears otherwise inaccessible to ultrasound (17). Although evidence supporting mock ET is only available when performed before treatment (18), its timing may not be as helpful as when it takes place just before ET, because of uterine mobility (19, 20). Some investigators,
including us, now recommend this last practice (6), with, in our case, a comforting implantation rate of 33.4% (for patients aged
