Should embryo transfer always be performed ... - Wiley Online Library

Ultrasound Obstet Gynecol 2004; 24: 383–386 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.1722

Editorial Should embryo transfer always be performed under ultrasound guidance? H. N. SALLAM The University of Alexandria, Egypt (e-mail: [email protected])

Despite numerous developments in the field of assisted reproduction, the implantation rate of transferred embryos, and hence the clinical pregnancy rate, remains low. It was estimated by Robert Edwards that 85% of embryos replaced in in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) do not implant1 . In order to improve this low implantation rate, various approaches have been pursued. These include optimizing the embryo transfer technique, maximizing the implantation capacity of the embryos and improving uterine receptivity2 . In all three approaches, ultrasound plays an important if not indispensable role. Different techniques for optimizing the embryo transfer technique have been reported. These include performing a trial (mock) embryo transfer before the actual procedure, removing the cervical mucus and/or flushing the cervical canal with culture medium prior to the transfer, avoiding the use of a vulsellum, using soft rather than rigid embryo transfer catheters and depositing the embryos 2 cm away from the fundus3 . Most importantly, performing embryo transfer under ultrasound guidance has been claimed to improve both the pregnancy and the implantation rates. Ultrasound-guided embryo transfer was first described by Strickler et al. in 19854 . This group compared 16 abdominal ultrasound-guided transfers with 12 transfers guided by ‘clinical feel’ and found that ultrasoundguided transfers were easier, and there was less catheter distortion. They concluded that, with ultrasound guidance, (1) transfers can be done with the patient supine in the lithotomy position, (2) the catheter tip can be accurately positioned in the fundus of the uterine cavity, (3) the ejection of the transfer bubble into the uterus can be documented and (4) the observation of the bubble is comforting to the patient. This early work was followed by numerous publications on ultrasound-guided embryo transfer, with various claims of success. Most of these publications reported using ultrasound to confirm that the embryos were properly deposited in the uterine fundus by observing the movement of the embryo-associated air bubble. A recent randomized controlled study by Coroleu et al.5 showed that depositing the embryos 2 cm below the uterine fundus resulted in significantly higher pregnancy rates compared

Copyright  2004 ISUOG. Published by John Wiley & Sons, Ltd.

with depositing them nearer to the fundus (i.e. 1 cm). In another study, Woolcott and Stanger6 used ultrasound to track the movement of the embryo-associated air bubble after asking the patients to stand up following embryo transfer. The authors reported that after standing up, the embryo-associated air bubble did not change position in 94% of cases, moved < 1 cm in 4% of cases and > 1 cm in 2% of cases. They concluded that standing up immediately after embryo transfer does not play any part in the final position of the transferred embryos. With a slightly different aim, we have been using abdominal ultrasound to measure the uterocervical angle immediately prior to embryo transfer in order to bend the tip of the transfer catheter according to the measured angle. We had observed that the uterocervical angle was small (< 30◦ ) in 10% of patients, moderate (30–60◦ ) in 37.2% of patients and very large (> 60◦ ) in 40.6% of patients, while 12.2% of patients had no angle7 (Figure 1). We also observed that difficult transfers were more common with large angles. Lewin et al.8 had previously shown that performing embryo transfer when the patient had a full bladder to straighten the angle was associated with higher pregnancy rates, although in a subsequent study, Henne and Milki9 observed that the position of the uterus changed from anteversion to retroversion and vice versa

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Figure 1 Measuring the uterocervical angle by transabdominal sonography: (a) no angle, (b) small angle (< 30◦ ), (c) moderate angle (30–60◦ ), and (d) large angle (> 60◦ ) (modified from7 : Sallam HN, Agameya AF, Rahman AF, Ezzeldin F, Sallam AN. Ultrasound measurement of the uterocervical angle before embryo transfer: a prospective controlled study. Hum Reprod 2002; 17(7): 1767–1772.  European Society of Human Reproduction and Embryology. Reproduced by permission of Oxford University Press/Human Reproduction).

from the time of mock (trial) embryo transfer to the time of actual transfer in more than 50% of cases. With these points in mind, we have been measuring the uterocervical angle with abdominal ultrasound immediately before embryo transfer and found that the clinical pregnancy rate was significantly diminished in women with large angles (> 60◦ ) compared with those with small angles (< 30◦ ) or no angles (OR, 0.36; 95% CI, 0.16–0.52). The patients were asked to keep their bladders full during sonography and embryo transfer. By measuring the uterocervical angle and bending the catheter tip according to this angle immediately prior to transfer, we have improved our clinical pregnancy and on-going pregnancy rates significantly (OR, 1.57; 95% CI, 1.08–2.27 and OR, 1.49; 95% CI, 1.22–1.82, respectively)7 . Various workers have reported their experience with using abdominal ultrasound-guided embryo transfer but


not all of them reported improved results. Most of these studies reported the use of ultrasound-guided transfer of fresh embryos, but the technique has also been used to transfer frozen10 as well as donated11 embryos. We and others have criticized some of these studies because they lacked enough power to reach statistical significance12,13 . In order to resolve the issue, we subsequently conducted a meta-analysis of randomized controlled trials14 . We calculated that in order to reach statistical significance, the minimum number of patients included in the metaanalysis should be 786 in each arm of the study in order to improve the clinical pregnancy rate from 23% to 30%, accepting a 90% probability of finding a true difference and taking 5% as the significance level. Four studies conformed to our strict selection criteria15 – 18 and the total numbers included were 1024 and 1027 patients in each arm of the analysis14 . The results of the meta-analysis showed that abdominal ultrasound-guided

Ultrasound Obstet Gynecol 2004; 24: 383–386.

Editorial Review: Comparison: Outcome:

385 Ultrasound-guided embryo transfer 01 Ultrasound versus clinical touch 01 Clinical pregnancy rate

Study or sub-category

Ultrasound guided (n/N)

Coroleu et al.15 Tang et al.16 Garcia-Velasco18 Matorras et al.17

91/182 104/400 112/187 67/255

Clinical touch (n/N)

OR (fixed) (95% CI)

Weight (%)

OR (fixed) (95% CI)

17.74 38.52 23.89 19.85

1.95 [1.28, 2.98] 1.21 [0.88, 1.67] 1.22 [0.81, 1.84] 1.62 [1.06, 2.46]

100.00

1.42 [1.17, 1.73]

61/180 90/400 103/187 47/260

Total (95% CI) 1024 Total events: 374 (Ultrasound guided), 301 (Clinical touch) 2 Test for heterogeneity: Chi = 3.99, df = 3 (P = 0.26), I2 = 24.8% Test for overall effect: Z = 3.58 (P = 0.0003)

1027

0.1

0.2

0.5

1

2

5

10

Figure 2 A meta-analysis of randomized controlled trials showing that transabdominal ultrasound-guided embryo transfers are associated with an increased clinical pregnancy rate in in-vitro fertilization and intracytoplasmic sperm injection (modified from Sallam and Sadek14 ,  2003, with permission from the American Society for Reproductive Medicine. Review: Comparison: Outcome:

Ultrasound-guided embryo transfer 01 Ultrasound versus clinical touch 03 On-going pregnancy rate

Study or sub-category

Ultrasound guided (n/N)

Coroleu et al.15 Tang et al.16 Garcia-Velasco18 Matorras et al.17

85/182 94/400 100/187 57/255

Clinical touch (n/N)

Total (95% CI) 1024 Total events: 336 (Ultrasound guided), 259 (Clinical touch) 2 Test for heterogeneity: Chi = 5.47, df = 3 (P = 0.14), I2 = 45.1% Test for overall effect: Z = 3.89 (P < 0.0001)

OR (fixed) (95% CI)

Weight (%)

OR (fixed) (95% CI)

17.62 36.75 27.65 17.98

2.16 [1.40, 3.33] 1.31 [0.93, 1.84] 1.14 [0.76, 1.71] 1.74 [1.10, 2.74]

100.00

1.49 [1.22, 1.82]

52/180 76/400 94/187 37/260 1027

0.1

0.2

0.5

1

2

5

10

Figure 3 A meta-analysis of randomized controlled trials showing that transabdominal ultrasound-guided embryo transfers are associated with an increased on-going pregnancy rate in in-vitro fertilization and intracytoplasmic sperm injection (modified from Sallam and Sadek14 ,  2003, with permission from the American Society for Reproductive Medicine).

embryo transfer significantly improved the clinical pregnancy rate (OR, 1.42; 95% CI, 1.17–1.73) and the on-going pregnancy rate (OR, 1.49; 95% CI, 1.22–1.82) (Figures 2 and 3). These results were confirmed in another meta-analysis published by William Buckett simultaneously19 . The cause of this improvement in pregnancy and on-going pregnancy rate is probably the reduction in the incidence of difficult transfers. In a controlled study, we found that ultrasound-guided embryo transfer significantly diminished the incidence of difficult transfers (OR, 0.25; 95% CI, 0.16–0.40) as well as the incidence of bleeding during transfer (OR, 0.71; 95% CI, 0.50–0.99)20 . Both these factors have been shown to affect negatively the clinical pregnancy rate20 – 22 and Lesny et al.23 showed that difficult embryo transfers were also associated with an increased incidence of ectopic pregnancy. Abdominal ultrasound has also been used in conjunction with transabdominal transmyometrial embryo transfer. This method was first described by Suzan Lenz et al.24 , who had no pregnancies in their series of 10 patients. Transvaginal ultrasound-guided embryo transfer has also been reported25,26 as well as the use of threedimensional ultrasound27 . Transvaginal transmyometrial


ultrasound-guided embryo transfer has also been used successfully by other groups, mainly after failed difficult transfers28,29 . So far these reports have not been confirmed by large randomized studies but they certainly deserve further evaluation. At the present time, however, we believe there is enough evidence to support our conviction that embryo transfer should be performed under abdominal ultrasound guidance in order to optimize the results of IVF and ICSI.

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