Ultrasound-guided embryo transfer and the accuracy of trial embryo transfer

Mousa I. Shamonki1, Steven D. Spandorfer1,2 and Zev Rosenwaks1

1 Cornell Center for Reproductive Medicine, 505 East 70th Street, 3rd floor, New York, NY 10021, USA

2 To whom correspondence should be addressed. Email: sdspando{at}med.cornell.edu


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: Studies have suggested that ultrasound-guided embryo transfer (UG-ET) may improve the outcome in IVF; however, several factors may account for the improvement in pregnancy rate. This study examines the use of ultrasound to determine the accuracy of trial transfer (TT) in preparation for ET. METHODS: Sixty-seven consecutive patients prospectively underwent UG-ET over a 2 month period. Total cavity length by US was compared with the length noted by TT. A difference of ≥1 cm was considered significant. All embryos were placed within 1–2 cm of the fundus by US. RESULTS: Twenty patients (29.9%) had a difference of ≥1 cm and 13 patients (19.4%) had a difference of ≤1.5 cm. Patients with a difference of ≥1 or ≥1.5 cm had a significantly greater depth at transfer (P<0.001) and uterine cavity length (P<0.001) when compared with patients without a difference. Clinical pregnancy, implantation, delivery and overall miscarriage rates did not differ between patients with a difference of ≥1 or ≥1.5 cm versus no difference. There were no ectopic pregnancies. CONCLUSIONS: Nineteen percent of patients had a discrepancy of ≥1.5 cm and ~30% had a difference of ≥1 cm from TT at UG-ET, suggesting a benefit to UG-ET. A large prospective randomized trial comparing UG-ET with blind transfer is required to assess further if UG-ET should be used in all cases of ET.

Key words: embryo transfer/IVF/pregnancy/trial transfer/ultrasound


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The utility of ultrasound-guided embryo transfer (UG-ET) with IVF was first reported in the mid-1980s (Strickler et al., 1985Go; Leong et al., 1986Go), and its application was further described by case reports (Sieck et al., 1997aGo), case series (Prapas et al., 1995Go), retrospective studies (Hurley et al., 1991Go; Woolcott and Stanger, 1997Go; Sieck et al., 1997bGo; Lindheim et al., 1999Go; Wood et al., 2000Go; Kojima et al., 2001Go; Anderson et al., 2002Go) and prospective studies (Al-Shawaf et al., 1993Go; Kan et al., 1999Go; Coroleu et al., 2000Go; Prapas et al., 2001Go; Tang et al., 2001Go; Sallam et al., 2002Go; Garcia-Velasco et al., 2002Go; Coroleu et al., 2002aGo,bGo; Matorras et al., 2002Go). The eight large prospective trials published to date comparing ultrasound-guided with clinical touch embryo transfer (a blind transfer performed by clinical feel with the knowledge of a prior trial transfer to a position beyond the internal os) have shown conflicting results; five studies have shown a benefit (Coroleu et al., 2000Go; Prapas et al., 2001Go; Tang et al., 2001Go; Sallam et al., 2002Go; Matorras et al., 2002Go; Coroleu et al., 2002bGo) while three have not (Al-Shawaf et al., 1993Go; Kan et al., 1999Go; Garcia-Velasco et al., 2002Go).

Recently, two meta-analyses have been published evaluating the existing data on UG-ET (Buckett, 2003Go; Sallam and Sadek, 2003Go). Out of the eight prospective studies identified, four were deemed to be properly randomized (Coroleu et al., 2000Go; Tang et al., 2001Go; Garcia-Velasco et al., 2002Go; Matorras et al., 2002Go) versus quasi- or non-randomized. The meta-analyses showed a significant difference in favour of UG-ET for clinical pregnancy, ongoing pregnancy and implantation rates.

Several factors have been hypothesized for why ultrasound guidance may better improve embryo transfer. The potential benefits result from minimization of the following factors: improper placement of embryos within the uterine cavity (Rosenlund et al., 1996Go; Coroleu et al., 2002aGo), placement of embryos outside the uterine cavity (Woolcott and Stanger, 1997Go), indentation of the endometrium (Woolcott and Stanger, 1997Go), difficult transfers (Leeton et al., 1982Go; Nabi et al., 1997Go; Hearns-Stokes et al., 2000Go; Sallam et al., 2002Go) that may cause greater endometrial trauma (Woolcott and Stanger, 1997Go; Letterie et al., 1999Go) or bleeding (Nabi et al., 1997Go; Goudas et al., 1998Go; Sallam et al., 2002Go), or other variables that may otherwise not be identified without the use of ultrasound.

We have postulated that clinical experience supercedes the potential benefit accrued with routine use of ultrasound guidance. Furthermore, the main disadvantage of using ultrasound guidance for embryo transfer may be the additional time and personnel required (Buckett, 2003Go). The goal of this study is to use abdominal ultrasound guidance to determine the accurary of trial embryo transfer in preparation for actual transfer in a highly experienced IVF centre. Futhermore, we review how abdominal ultrasound guidance may improve outcome based on the results of this study and a review of the literature.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients
Patients at a university-based IVF centre undergoing traditional IVF transfer were offered to participate in this prospective study to undergo embryo transfer under abdominal ultrasound guidance. Institutional Review Board approval was obtained. Sixty-nine consecutive patients were recruited for UG-ET from January 2003 to March 2003. At the time of abdominal UG-ET, two patients were excluded from the study because of a complete inability to visualize the endometrium and trial transfer catheter secondary to a combination of an empty bladder, uterine position and body habitus. Sixty-seven remaining patients were analysed further. These patients had all undergone an initial office trial transfer within 6 months of the actual embryo transfer. Just before the UG-ET, patients underwent a second trial transfer, where catheter placement was confirmed by ultrasound, and uterine cavity measurements were performed. Finally, UG-ET was performed with any catheter depth adjustments made as a result of findings accrued from the second trial transfer. Trial and embryo transfer techniques are described below. Patient characteristics evaluated included age, height, weight, body mass index (BMI), pregnancy history, IVF history including any difficulty with embryo transfer, reason for and duration of infertility, uterine position and measurement differences, IVF cycle characteristics and response, the presense of myomas, and pregnancy outcome. Primary outcome measures included differences between the findings at initial trial transfer versus the second ultrasound-measured trial transfer and UG-ET, as well as any characteristic differences between these groups. Secondary outcome measures include pregnancy and implantation rates.

Patient stimulation protocols
The majority of study patients underwent a fresh IVF cycle. The most common protocol utilized luteal phase downregulation with leuprolide acetate (Lupron; TAP Pharmaceuticals, Deerfield, IL) 1 mg/day decreased to 0.5 mg/day once gonadotrophin stimulation was initiated on day 3 or later in the lupron-induced menses. Patients at risk for ovarian hyperstimulation syndrome had protocols utilizing oral contraceptive (OCP) suppression initiated on day 5 of the prior menstrual cycle and given for 21 days with lupron overlapping the last 5 days. Patients with predicted lower responses were placed on an antagonist protocol. These patients had gonadotrophin stimulation initiated on day 2 of a natural or OCP-induced menses with the daily GnRH antagonist ganerelix acetate 250 µcg/0.5 ml (Antagon; Organon, Inc, Roseland, NJ) initiated when the lead follicle reached 12–14 mm or the estradiol level rose above 400 pg/ml. The step-down protocol was utilized for all patients undergoing a fresh IVF cycle. HCG at a dose range of 3300–10 000 IU was administered i.m. when the lead follicle was 17–18 mm. Oocyte aspiration was performed 35–36 h after HCG administration. One patient underwent a lupron microflare protocol with lupron 40 µg twice daily initiated on day 2 of menses with gonadotrophin stimulation initiated 2 days later. Some patients underwent frozen embryo transfers during either a natural cycle or a hormonally programmed cycle utilizing estradiol patching and i.m. progesterone in oil. Programmed cycles utilized estradiol patches initiated on day 2 of a spontaneous or induced menses with a dose of 0.1 mg (Climara, Berlex, Inc, Montville, NJ) changed every other day with doses increasing 0.4 mg every other day. Overlapping progesterone in oil at 50 mg/ml was started after 14 days of estradiol patching, with eventual embryo transfer occuring on the fourth (day 3 embryos) or sixth day (blastocysts) of progesterone supplementation. Donor egg recipients also underwent exogenous hormone stimulation in a similar fashion while being sychronized with a young egg donor (age 21–35 years) undergoing a fresh IVF cycle.

Typical preparation for embryo transfer
In the study centre, the vast majority of patients undergo an initial mid-cycle trial transfer in the office within 1–6 months of the actual embryo transfer. Uterine cavity depth by initial trial transfer is the measurement that guides the physician to place the embryos at a depth 1–2 cm less than the depth noted at the initial trial transfer. On the day of the embryo transfer, a second trial embryo transfer is performed without ultrasound guidance in preparation for actual embryo transfer. This second trial transfer is performed to mimic the actual embryo transfer, utilizing a soft catheter positioned to a depth at 1–2 cm less than the initial trial transfer, with care to avoid fundal contact or endometrial trauma. This second trial transfer is performed routinely just prior to the actual embryo transfer in order to ascertain the position of the cervical canal, and to note any difficulties. This routine procedure helps correct for the vast majority of unforeseen problems that may otherwise occur during the actual embryo transfer. Patients then undergo clinical touch embryo transfer unless there is an indication for abdominal ultrasound assistance, such as a previous difficult trial transfer or difficult embryo transfer.

In addition, the study centre performs ~2000 embryo transfers annually, with each of five clinicians performing an average of 400 embryo transfers annually and each having a minimum of 6 years experience. These clinicians perform the initial trial transfer on their patients in the office. However, all of the second trial transfers and embryo transfers in this study were performed by one of those clinicians (S.S.) in order to minimize potential differences in embryo transfer technique that otherwise may affect the study findings.

Initial trial transfer
Patients underwent an intial trial transfer in the office 1–6 months prior to the actual embryo transfer. This trial transfer was usually performed just prior to mid-cycle, typically on menstrual cycle days 10–12. Each patient was placed in the dorsal lithotomy position and a bivalve speculum was placed to visualize the cervix. The cervix was cleansed with betadine-soaked guaze. An Insemicath catheter (Cook Ob/Gyn, Spencer, IN) was used to navigate the cervical canal into the uterine cavity until the tip touched the uterine fundus in order to ascertain the depth and direction of the uterine cavity. The catheter was then removed and the length of the catheter that was within the uterine cavity and cervical canal was measured.

Clinical touch embryo transfer technique
The typical ‘clinical touch’ embryo transfer is performed in the following manner at the study centre. Each patient is placed in the dorsal lithotomy position without anaesthesia or sedation. A bivalve speculum is used to expose the cervix. The cervical mucous is removed using a 1 ml syringe and the cervix is cleansed using a gauze moistened with a small amount of embryo culture medium. A Wallace catheter (SIMS Portex Ltd. Hythe, Kent, UK) loaded with the embryos is used to navigate the cervical canal and, after the tip within the uterine cavity is pulled back then pushed gently forward to make sure the catheter is not kinked, the tip is placed at a depth of 1–2 cm from the presumed fundus as measured by the office trial transfer. Care is taken to avoid catheter contact with the fundus, and the outer sheath does not extend past the internal os at any time. The embryos are gently expelled and, after ~20 s, the catheter is slowly removed.

Ultrasound-guided trial and embryo transfer techniques
In the study, embryo transfers were all performed 3–5 days after oocyte retrieval for fresh IVF cycles in the same gynaecological operating room, or as timed by frozen embryo or donor egg recipient cycles. Patients were instructed to have a full bladder, which would provide an acoustic window for visualization of the uterus, in preparation for the cavity measurements and UG-ET. Each patient was placed in the dorsal lithotomy position without anaesthesia or sedation. The same physician (S.S.) performed every embryo transfer with a Wallace catheter, while another physician (M.S.) performed every abdominal ultrasound using a 5 MHz probe (GE Logiq 400 Pro Series, General Electric Company, Pewaukee, WI).

Embryos were graded according to the scoring criteria of Veeck (1998)Go. The number of embryos replaced depended primarily on the age of the patient or egg donor if applicable. Other variables which impacted the number of embryos replaced included the number of embryos available for transfer, the quality of those embryos and the number of previous IVF failures at the study centre.

All embryo transfers were performed in the same fashion. After the patient was placed in the dorsal lithotomy position, a bivalve speculum was used to expose the cervix. The cervical mucous was removed using a 1 ml syringe to minimize the risk of retained embryos in the transfer catheter (Nabi et al., 1997Go) and the cervix was cleansed using a gauze moistened with a small amount of embryo culture medium.

Prior to embryo transfer, a trial transfer was performed using an unloaded Wallace catheter within its Teflon open-ended guiding sheath to ascertain the ease and angle of the transfer. The trial transfer was performed in the identical manner to a clinical touch embryo transfer as previously described. Once the tip of the catheter was placed to the appropriate depth (1–2 cm less than the cavity length obtained from the initial trial transfer), a transabdominal ultrasound probe (3.5 MHz) was placed on the abdomen to visualize the endometrium and catheter tip. Measurements were then performed as described below. Most trial and embryo transfers were performed without difficulty or the need to adjust the outer sheath. Where necessary, the outer sheath was angled manually to approximate the angle of the cervix to help navigate the cervical canal. At no point did the outer sheath extend past the internal cervical os into the uterine cavity, and care was taken to avoid contact of the transfer catheter with the uterine fundus.

At the time of the embryo transfer, the Wallace catheter tip loaded with the embryos was placed at 1–2 cm from the uterine fundus as measured by abdominal ultrasound (Figure 1). The transfer was performed in the identical fashion to the clinical touch transfer as described, with the added benefit of ultrasound guidance. The embryos were transferred subsequently under ultrasound visualization, and the catheter was held in place for ~20 s before slow removal from the uterine cavity. The transfer catheter was then carefully examined under the microscope by the embryologist to ensure that no embryos were retained.



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Figure 1. Ultrasound-guided embryo transfer just prior to placement of the embryos. The catheter and uterus are outlined. A straight line demonstrates the distance from the catheter tip to the apex of the uterine cavity.

 
Ultrasonographic uterine measurements
Total cavity length by ultrasound, i.e. the length of the catheter within the uterus and cervix plus the length from the tip of the second trial transfer catheter to the fundus by ultrasound, was compared with the length of the cavity as noted by the initial office trial transfer. A difference of ≥1 cm was considered an important difference. Patients were grouped as having a difference of ≥1 or ≥1.5 cm from the initial trial transfer versus having no difference. All embryos were placed within 1–2 cm from the fundus as measured by ultrasound in all patients. Therefore, any difference of ≥1 cm from the initial trial transfer was corrected for using ultrasound guidance prior to the embryo transfer. Patients were also segregated by transfer between 1 to <1.5 cm from the fundus versus 1.5–2 cm from the fundus.

Definitions
We define a successful IVF cycle as resulting in a term or preterm delivery. An unsuccessful IVF cycle is defined as one resulting in no pregnancy, a biochemical pregnancy or clinical miscarriage. Overall miscarriage rate is defined as the percentage of total first trimester pregnancy losses which includes biochemical pregnancy and clinical miscarriages. Biochemical pregnancy is defined as a serum-positive {beta}HCG which eventually drops back down to zero without intervention and does not result in a clinical pregnancy. Clinical miscarriage is the first trimester loss of a clincal pregnancy. A clinical pregnancy is defined as a pregnancy which results in the visualization of an intra-uterine gestational sac on ultrasound by 6 weeks gestation, or results in an ectopic pregnancy. Ectopic pregnancy is defined as a pregnancy diagnosed outside the uterine cavity at laparoscopy or laparotomy, or a pregnancy with a serum {beta}HCG >1500 mIU/ml with no visible intra-uterine gestational sac requiring treatment with methotrexate therapy. With regard to protocols, ‘other’ defines either a frozen embryo preparation cycle transfer or a donor egg recipient preparation cycle and transfer. For the frozen embryo transfer patients, the IVF response refers to the previous fresh IVF cycle. For the donor egg recipients, IVF response refers to that of the donor.

Statistical analysis
Statistical analysis was performed using the Statview software package, Abacus Concepts, Inc. Quantitative variables were evaluated using the Student's t-test and and qualitative variables were evaluated using the {chi}2 test. Statistical significance was set at P≤0.05.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Twenty patients (29.9%) had a difference of ≥1 cm from the initial trial transfer (group A) and 13 patients (19.4%) had a difference of ≥1.5 cm from the initial trial transfer (group B). Between groups A or B versus no difference, there was no significant difference in age, duration of infertility prior to treatment, BMI, mean number of failed IVF cycles, history of previous difficult transfers, percentage of transfers with blood at the catheter tip, percentage of transfers with suboptimal visualization or percentage of difficult transfers. When compared with patients without a difference from initial trial transfer, patients from group A (but not group B) had significant differences in pregnancy history and previous successful IVF cycles. There were no patients with submucosal myomas (within the uterine cavity); however, versus no difference from trial transfer, group B had a significantly higher percentage of intramural or subserosal myomas, 23.1 versus 3.7%, respectively, P≤0.025. When compared with patients without a difference, patients in groups A and B had significantly longer uterine cavities and larger catheter depths at embryo transfer, P<0.001 for both categories in each group (Tables I and II). When comparing group A versus no difference, there were no differences in percentage of lupron protocols (most common), antagonist protocols or protocols defined as ‘other’. One patient in groups A and B utilized a lupron flare protocol. The three most common infertility diagnoses included diminished or absent ovarian reserve (secondary to advancing maternal age or ovarian failure), tubal factor and male factor, and were consistently distributed among the patient groups (Tables III and IV). The overall pregnancy rate was 61.2% (41 out of 67). The overall pregnancy rate for group A was 65% (13 out of 20 patients) versus 59.6% (28 out of 47) in the patient group with no difference, while the overall pregnancy rate for group B was 61.5% (eight out of 13 patients) versus 61.1% (33 out of 54) in the patient group with no difference; all percentages not significantly different. When compared with patients without a difference, patients in groups A and B had no difference in biochemical pregnancy or overall miscarriage rates, mean number of oocytes retrieved, mature, fertilized or transferred, quality of day 3 embryos transferred, or percentage of blastocyst transfers (Tables V and VI). There were no ectopic pregnancies. When the patients were segregated by transfer <1.5 cm from the fundus by ultrasound versus ≥1.5 cm by ultrasound, the pregnancy rates were 53.3% (16 out of 30 patients) and 67.6% (25 out of 37 patients), respectively, P not significant.


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Table I. Patient characteristics between group A (difference ≥1 cm) versus patients without a difference of ≥1 cm

 

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Table II. Patient characteristics between group B (difference ≥1.5 cm) versus patients without a difference of ≥1.5 cm

 

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Table III. The number and percentage (in parentheses) of patients with each specific infertility diagnosis: group A (difference ≥1 cm) is compared with the group of patients without a difference of ≥1 cm

 

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Table IV. The number and percentage (in parentheses) of patients with each specific infertility diagnosis: group B (difference ≥1.5 cm) is compared with the group of patients without a difference of ≥1.5 cm

 

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Table V. Patient characteristics between group A (difference ≥1 cm) versus patients without a difference of ≥1 cm

 

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Table VI. Patient characteristics between group B (difference ≥1.5 cm) versus patients without a difference of ≥1.5 cm

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Since the introduction of UG-ET during the mid-1980s (Strickler et al., 1985Go; Leong et al., 1986Go), this technique has evolved into a more routine part of IVF practices around the world. Now that two meta-analyses have established an improvement in IVF success using UG-ET (Buckett, 2003Go; Sallam and Sadek, 2003Go), this best evidence to date will further encourage practitioners to make this technique a more ubiquitous part of their practices. As described by numerous authors, UG-ET may offer some distinct advantages over the traditional ‘blind’ or ‘clinical touch’ method which can explain why routine ultrasound guidance may improve pregnancy outcome.

The ease of embryo transfer has been demonstrated by several authors to improve outcome in IVF (Leeton et al., 1982Go; Wood et al., 1985Go; Englert et al., 1986Go; Diedrich et al., 1989Go; Goudas et al., 1998Go; Ghazzawi et al., 1999Go; Hearns-Stokes et al., 2000Go). The use of ultrasound guidance has been shown to decrease the incidence of difficult transfers (Sallam et al., 2002Go; Matorras et al., 2002Go), but this finding is not consistent in all prospective studies (Tang et al., 2001Go). Furthermore, the reduction of difficult transfers by the use of ultrasound does not always translate to a better outcome. Sallam et al. (2002)Go demonstrated a significant reduction in difficult embryo transfers with the use of ultrasound guidance; however, they found no difference in pregnancy rates when comparing patients who had a difficult versus an easy transfer. In addition, other studies have demonstrated no difference in pregnancy rates between easy and difficult transfers (Tur-Kaspa et al., 1998Go; Burke et al., 2000Go).

The use of ultrasound may reduce the incidence of endometrial trauma which may be more likely to occur with a traditional blind transfer where multiple movements of the catheter are done to help locate the position of the catheter tip (Woolcott and Stanger, 1997Go; Letterie et al., 1999Go). Endometrial stimuli have been demonstrated to cause early endometrial decidualization (De Feo, 1963Go). Woolcott and Stanger used transvaginal ultrasound in 121 embryo transfers to observe the position of the transfer catheter. They found that the outer guiding catheter touched the fundus in 17.4% and indented the endometrium in 24.8%, while the transfer catheter embedded the endometrium in 33.1% (Woolcott and Stanger, 1997Go). The impact of these findings on the pregnancy rate was not known. Furthermore, endometrial trauma may cause bleeding. In IVF, blood in the catheter tip has been shown to increase the rate of embryo retention within the catheter and coincides with the difficulty of the transfer (Nabi et al., 1997Go). The presence of blood in the catheter has also been correlated with a worsening in the pregnancy rate with traditional embryo transfer (Goudas et al., 1998Go) and UG-ET (Sallam et al., 2002Go). Endometrial trauma may also lead to uterine contractions (Fanchin et al., 1998Go; Lesny et al., 1998Go, 1999Go) which may conceivably lead to extrusion of the embyos from the uterine cavity. The use of a soft transfer catheter instead of a firm catheter may minimize uterine trauma and has been shown to improve pregnancy rates (Wood et al., 2000Go).

Undoubtedly, the use of ultrasound guidance will assist in the more precise placement of embryos with the hope that those embryos will implant at or near to where deposited. This study showed that even at a highly experienced centre, if the practitioner relies on the measurements accrued from the office trial transfer for placement during actual embryo transfer, >19% of embryos would be placed ≥1.5 cm from where initially intended and ~30% would be placed ≥1 cm from where intended. In a recent retrospective study by Pope et al. (2004)Go where trial transfer was performed 1 month prior to UG-ET, cavity depth by ultrasound differed from cavity depth by mock transfer by at least 1 cm in >30% of cases. Studies have shown that most embryos stay and implant at or close to where extruded from the transfer catheter. A study by Woolcott and Stanger utilizing transvaginal UG-ET performed with a second ultrasound in the standing position immediately after transfer assessed the movement of embryo-associated air bubbles with the patient standing, then sitting after embryo transfer. No air bubble movement occurred in 94.1% of transfers, movement of <1 cm in 4.0% of transfers and movement of 1–5 cm in 2.0% transfers. No movement of embryo-associated air out of the uterine cavity, either into the cervix or into the intramural portion of the Fallopian tube, was seen (Woolcott and Stanger, 1998Go). Although embryo-associated air bubble movement may not directly correlate with actual embryo movement, there may be no better method to assess this variable. A recent study utilizing 3-dimensional ultrasound demonstrated that in pregnancies resulting from embryo transfer, ~80% of embryos implant in areas to which they initially are transferred and ~20% implant in other areas (Baba et al., 2000aGo). Since current evidence suggests that most embryos implant at or near to where placed, this further emphasizes the importance of confirming catheter tip position before deposition of embryos.

The best location to place the embryos continues to be a topic of debate. This study suggested an increased pregnancy rate when the embryos were transferred from 1.5–2.0 cm from the uterine fundus, although not statistically significant. Unfortunately, this study lacks statistical power and would require a much larger number of patients to assess this finding more accurately. Pope et al. (2004)Go found that increasing the embryo transfer distance from the fundus as seen by ultrasound resulted in a significantly increased pregnancy rate as well as a lower ectopic pregnancy rate. Other studies confirmed an improved pregnancy rate when embryos are placed lower in the uterine cavity and thus farther from the fundus (Waterstone et al., 1991Go; Naaktgeboren et al., 1997Go). Furthermore, Coroleu et al. (2002a)Go), in a prospective randomized trial of women undergoing abdominal UG-ET, found a significantly higher pregnancy rate when the embryos were transferred at ~1.5 and 2.0 cm instead of at 1.0 cm from the intracavitary fundus. Embryo transfer in the lower part of the uterine cavity confirmed with ultrasound visualization may also avoid catheter contact with the uterine fundus. Catheter contact with the fundus has been suggested to cause strong fundo-cervical contractions which may negatively affect the pregnancy rate (Lesny et al., 1999Go). However, studies have also demonstrated no association between pregnancy rate and the location of embryo deposition in the uterine cavity (Rosenlund et al., 1996Go). The use of 3-dimensional ultrasound may most accurately locate the position of the transfer catheter (Baba et al., 2000aGo,bGo), but this technology is not yet widely available.

Another unresolved question is if ultrasound guidance would lessen the chance of an ectopic pregnancy after embryo transfer. Woolcott and Stanger (1997)Go using transvaginal ultrasound detected that accidental tubal embryo transfer occurred in 7.4% of blind embryo transfers. However, the use of ultrasound guidance does not eliminate the risk of ectopic pregnancies (Sieck et al., 1997aGo,bGo) and even a case of a cervical pregnancy after an UG-ET was reported (Sieck et al., 1997aGo). Large studies comparing traditional embryo transfer versus UG-ET found no statistical difference in the ectopic pregnancy rate (Coroleu et al., 2000Go; Garcia-Velasco et al., 2002Go; Matorras et al., 2002Go). This finding of no statistical significance was confirmed by one meta-analysis (Sallam and Sadek, 2003Go), although a trend for a lower ectopic pregnancy rate was noted in the ultrasound-guided group. In fact, the study of a very large number of patients would be needed to truly evaluate if there is a difference, as the rate of ectopic pregnancy after embryo transfer is low.

Several variables exist which may impact pregnancy results whether or not ultrasound guidance is used, including the utility of a ‘mock’ or trial transfer prior to the actual embryo transfer. Mansour et al. (1990)Go, in a randomized trial, demonstrated an improvement in the pregnancy rate when a mock transfer was performed prior to the actual embryo transfer. In addition, it has been postulated that mock transfer may lessen the benefit accrued with ultrasound guidance during embryo transfer (Tang et al., 2001Go). Mock transfer was performed prior to all embryo transfers in the current study which demonstrates an inaccuracy of ≥1 cm in ~30% of patients.

Another variable which may confound the pregnancy results when comparing abdominal ultrasound-guided versus traditional transfer is the need for a full bladder in the abdominal ultrasound group. Several studies have noted that a full bladder may straighten the cavity in relation to the cervial canal which may decrease the difficulty of embryo transfer (Sundstrom et al., 1984Go; Sharif et al., 1995Go; Wood et al., 2000Go). However, some groups which compared the effect of a full bladder without the use of ultrasound guidance on the pregnancy rate showed conflicting results (Mitchell et al., 1989Go; Lewin et al., 1997Go), and the use of transvaginal ultrasound which relies on an empty bladder for better visualization has been shown retrospectively to improve the pregnancy rate (Lindheim et al., 1999Go). Furthermore, Sallam et al. who measured uterocervical angles at the time of UG-ET noted that despite a relatively full bladder, almost 80% of patients still had a moderate to large uterocervical angle (Sallam et al., 2002Go). The use of transvaginal ultrasound guidance would minimize the problem of poor endometrial visualization, although all studies with this method to date comparing tranvaginal ultrasound-guided versus traditional embryo transfer have been retrospective (Hurley et al., 1991Go; Woolcott and Stanger, 1997Go; Kojima et al., 2001Go; Anderson et al., 2002Go).

The type of catheter used for the initial trial transfer (Cook Insemicath, semi-rigid) differed from that used for the second trial transfer and embryo transfer in this study (Wallace, soft, very flexible). The Cook catheter is used in the study centre for the initial trial transfer because it is generally felt by the clinicians to predict the uterine cavity length accurately in the vast majority of cases, it is simple to use, and this catheter is relatively inexpensive when compared with a softer embryo transfer catheter. The Cook catheter is tapered (thinner at the tip), so that one could argue that the wider base may get stuck at the external os of the cervix and thus underestimate the cavity length of a longer uterus. Pope et al. use a similarly tapered Tomcat catheter for the trial transfer and showed a discrepancy of ≥1 cm at the actual transfer in >30% of patients (Pope et al., 2004Go). This argument, however, may not be the only explaination. The ‘blindness’ of the trial transfer may also lead to an inaccurate uterine sounding but, in order to assess this variable, one would need to study the accuracy of using an untapered embryo transfer catheter for trial transfer.

In this analysis, even in highly experienced hands, 19.4% of patients had a discrepancy of ≥1.5 cm and 29.9% had a discrepancy of ≥1 cm noted at the time of ultrasound-guided trial and embryo transfer when compared with the cavity length at initial trial transfer. This suggests a major benefit to UG-ET over traditional blind transfer, in that ultrasound allows for a more accurate placement of embryos in those patients where there is a significant discrepancy between actual and blindly perceived uterine cavity length. Patients with a discrepancy from the trial transfer had a significantly longer uterine cavity and greater catheter depth at embryo transfer. These patients also had a history of a larger number of pregnancies and deliveries, suggesting that these patients may benefit most from having ultrasound confirmation of uterine cavity depth. A large prospective randomized trial with at least 700–800 patients in each arm comparing UG-ET with the traditional blind transfer is required to assess further if UG-ET should be utilized for all cases of embryo transfer.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on June 24, 2004; accepted on September 10, 2004.