Ultrasound versus 'clinical touch' for catheter guidance during embryo transfer in women
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine, in women undergoing embryo transfer (ET) during assisted reproductive technology (ART) cycles, whether ultrasound guidance affects treatment outcomes.
Background
Since the first pregnancy using in vitro fertilisation (IVF) was achieved nearly 30 years ago (Steptoe, 1978) many aspects of the procedure, such as ovarian stimulation, oocyte recovery and the in vitro techniques of fertilization and embryo culture have undergone major revision. In contrast, the technique of embryo transfer (ET) has remained largely unchanged. Today, approximately 80% of women undergoing IVF/ICSI will reach the embryo transfer stage with good quality embryos. However, only a small proportion will then go on to achieve a clinical pregnancy and even fewer will acheive a live birth. This makes the embryo transfer phase the final and least successful step in ART. Indeed, it is estimated that up to 85% of replaced embryos fail to implant, despite the selection of apparently normal embryos for transfer (Sallam 2002). This failure may be due to poor embryo quality, lack of uterine receptivity or the technique of embryo transfer itself.
Embryos are usually replaced into the uterine cavity, through a transcervical transfer catheter, between days two to five of development. Traditionally, the "clinical touch" method has been used to guide placement of the transfer catheter to within 5 to10 mm from the uterine fundus prior to injection of the embryos. This method is essentially "blind" and relies on the clinician's tactile senses to judge when the transfer catheter is in the correct position. Some clinicians transfer the embryos at a fixed distance from the external os (aproximately 6cm), however this may not take into account variation in cervical length or uterine size.
Assessment of the transfer catheter position is often unreliable using the "clinical touch" method. This was demonstrated by Woolcott and Stanger (Woolcott 1997) who utilised transvaginal ultrasound to observe catheter placement in relation to the endometrial surface and uterine fundus during 121 embryo transfers. They noted suboptimal catheter placement in more than half of cases, with the catheter either indenting or embedded in the endometrium. The initial position of the outer guiding cannula was also noted to abut the tubal ostia in 7.4% of cases.
It is generally accepted that an easy, atraumatic embryo transfer is essential for successful implantation (Matorras 2002). It is possible that minimizing endometrial trauma could decrease myometrial contractions, which could in turn enhance implantation. Most clinicians try to avoid the catheter tip coming into contact with the uterine fundus during embryo transfer (Kovacs 1999), as it has been suggested that this may stimulate uterine contractions (Lesny 1998), which may in turn lead to expulsion of the embryos. Indeed it has been noted that high frequency uterine contractions visualised by ultrasound are associated with a lower ongoing clinical pregnancy rate (Fanchin 1998).
Thus, the "clinical touch" method may be challenged as a potential cause of cycle failure as a result of (1) initiation of uterine contractility that may lead to immediate or delayed expulsion of the embryo/s, and (2) the inability to accurately identify the ideal location for deposition of embryos, especially in patients with acute utero‐cervical angulations, cervical stenosis or anatomical distortion of the cervical canal and uterus.
Numerous methods to improve the technique of embryo transfer have been studied to try and improve pregnancy rates, including changing the type of catheter used, performing a trial or "mock" transfer before the actual procedure, removing any cervical mucus prior to transfer, avoiding the use of a tenaculum, encouraging bed rest following embryo transfer, comparing full and empty bladder as well as performing the procedure under ultrasound guidance.
The use of ultrasound to guide embryo transfer was first discussed by Strickler et al (Strickler 1985) who postulated that this would allow accurate and atraumatic positioning of the catheter tip near the uterine fundus, along with visualization of ejection of the transfer material containing the embryos. By allowing identification of the cervical canal and endometrial cavity, ultrasound can facilitate atraumatic penetration of the catheter into the uterus, thereby minimizing endometrial trauma. Moreover, its use can confirm that the catheter tip is beyond the internal os of the cervix and placement of the embryos is at the desired level in the endometrial cavity (Lorusso 2004). This can be especially helpful in women where the uterine anatomy may be distorted by fibroids or septae (Hurley 1991). For these reasons, ultrasound guided embryo transfers have been rated as "easier" and "cleaner" by clinicians (Prapas 2001). Disadvantages are the need for a second operator, a longer time to execute and the inconvenience of filling the patient's bladder (Martins 2004). Another possible drawback is in some cases,is the necessity of moving the catheter to improve identification is required, a motion that is not needed in transfers performed by "clinical touch". This manoeuvre may potentially disrupt the endometrium, thus reducing the benefits provided by ultrasound (Garcia‐Velasco 2002). Another disadvantage with this procedure are the potential unknown side effects of early ultrasound on the pre‐implantation embryo.
Conflicting results in terms of pregnancy rates have been reported for studies comparing ultrasound guidance with the traditional clinical touch method. As a result of the lack of concurrence in the literature it was decided to review the evidence systematically to evaluate this method for successful embryo transfer.
Objectives
To determine, in women undergoing embryo transfer (ET) during assisted reproductive technology (ART) cycles, whether ultrasound guidance affects treatment outcomes.
Methods
Criteria for considering studies for this review
Types of studies
All published, unpublished and ongoing randomised trials that report data comparing outcomes of women undergoing ultrasound guided versus clinical touch Embryo Transfer (ET) through the cervical route following in‐vitro fertilisation (IVF), or intracytoplasmic sperm injection (ICSI) including frozen embryo transfers. The trials must include one of the review's outcomes.
Types of participants
Women with any form of infertility undergoing embryo transfer via the cervical route (using either fresh or cryopreserved embryos), after either IVF or ICSI and randomized to either ulrasound‐guided or clinical touch embryo transfer through the cervical route.
Types of interventions
Transcervical embryo transfer comparing ultrasound guidance with clinical touch methods.
Types of outcome measures
Primary outcome measures
(1) Live birth/ongoing pregnancy rate per woman randomised
Secondary outcome measures
(1) Implantation rate ‐ Number of implanted embryos (determined by gestational sac visible on ultrasound) per woman randomised
(2) Clinical pregnancy rate per woman randomised (as determined by detection of foetal heartbeat by ultrasound )
(3) Biochemical pregnancy rate per woman randomised (as determined by pregnancy test )
(4) Clinical pregnancy rate per embryo transferred
(5) Multiple pregnancy rate ‐ Multiple pregnancy (twins, triplets or higher order specified if possible) per clinical pregnancy, confirmed by ultrasound or delivery.
(6) Multiple birth rate per woman randomised
(7) Miscarriage rate ‐ Miscarriage (confirmed by ultrasound and pregnancy test or histology) per intrauterine pregnancy noted between biochemical pregnancy and delivery (including partial loss of multiple pregnancies).
(8) Ectopic pregnancy rate ‐Ectopic gestation per clinical pregnancy
(9) Fetal abnormalities as determined by fetal anatomy scan or after delivery per woman randomised
(10) Ongoing pregnancy rate per woman randomised
(11) Complication rate‐ Adverse effects /events associated with embryo transfer per woman randomised
(12) Ease of transfer as determined by clinician
Search methods for identification of studies
(1) We will electronically search the Menstrual Disorders and Subfertility Group's Specialised Register of Trials for any trials that have the terms: embryo transfer 'AND'/'OR', embryo transfer technique, embryo replacement, ultrasound guidance, ultrasound guided, sonography, echography, implantation rate, clinical pregnancy rate, uterine fundus randomised controlled trial(s), randomized controlled trial(s) in the title, abstract or keyword sections.
(2) The Cochrane Central Register of Controlled trials (CENTRAL; The Cochrane Library Issue 1,2006 ) will also be searched in all fields using the following search terms: embryo transfer, embryo transfer technique, embryo replacement, ultrasound guidance, sonography, echography, vaginal ultrasound, trans‐abdominal ultrasound, implantation rate, clinical pregnancy rate.
(3) We will search MEDLINE (1966 to present) and EMBASE (1980 to present) and BIO extract (1980‐present) using the following subject headings (MeSH terms) and keywords:
-
embryo transfer
-
embryo transfer technique
-
ultrasound guided embryo transfer
-
embryo replacement
-
embryo replacement technique
-
ultrasound guidance
-
ultrasound guided
-
ultrasound
-
ultrasonography
-
sonography
-
echography
-
two dimensional ultrasound
-
three dimensional ultrasound
-
four dimensional ultrasound
-
2D ultrasound
-
3D ultrasound
-
4D ultrasound
-
vaginal ultrasound
-
trans‐abdominal ultrasound
-
abdominal ultrasound
-
embryo deposition
-
randomised controlled trial (s)
-
randomized controlled trial (s)
-
controlled trial
-
random allocation
-
double ‐blind method
-
single‐blind method
-
clinical trial
-
implantation rate
-
clinical pregnancy rate
-
clinical touch
-
in‐vitro fertilisation
-
IVF
-
ICSI
-
intracytoplasmic sperm injection
-
infertility
(4) We will search The National Research Register (NRR) (a registrationof ongoing and recently completed research projects funded by, or of interest to, the United Kingdom's National Health Service); the Medical Research Council's Clinical Trial Register; and details on reviews in progress collected by the NHS Centre for Reviews and Dissemination, for trials that have any of the following keywords: embryo transfer, embryo transfer technique, embryo replacement, ultrasound guidance, ultrasound, implantation rate, clinical pregnancy rate, implantation.
(5) The citation list of relevant publications, review articles, abstracts of scientific meetings and included studies will also be handsearched. We will contact commercial entities and experts in the field to idenitify additional trials. Searches will not be restricted by language.
Data collection and analysis
Identification and description:
A standardised data extraction form will be developed and piloted for consistency and completeness. Two authors (Julie Brown and Karen Buckingham) will independently consider trials for inclusion, and evaluate their methodological quality and extract trial data independently.
Trial Characteristics:
1. Method of randomisation: Only truely randomised trials will be considered
1a. Method of randomisation will be noted: e.g computer generated, random tables, lottery methods.
Other information to be extracted from the papers
a) Age of woman and other demographic information
b) Cause and duration of infertility
c) FSH levels
d) Ovarian stimulation protocol
e) Oestradiol (E2) on day of HCG
f) Number of oocytes obtained in current IVF/ICSI cycle
g) Fertilisation rate
h) Embryo culture medium type
i) Day of embryo transfer
j) Quality of embryos
k) Number of embryos transferred
l) Fresh or frozen embryos transferred
m)Type of catheter
n) Endometrial thickness on day of transfer
o) Uterine characteristics
p) Luteal phase support
q) Type of transfer IVF/ICSI
u) Type of ultrasound scan used (2 dimensional (D), 3D, 4D)
Quality Assessment
1. Quality of allocation concealment will be noted: e.g centralised, third party, envelopes. Papers with unsatisfactory concealment will be excluded.
2. Number of women recruited, randomised, excluded, analysed or lost to follow‐up
3. Location of trial; single or multicenter
4. Whether an intention to treat analysis was done
5. Whether a power calculation was done
6. Source of funding
Statistical analyses
Differences in interpretation will be resolved by discussion and mutual agreement by referring to a third reviewer (WB ). We will conduct data management and analysis using Review Manager (RevMan 4.3).
If data from the trial reports are insufficient or missing, the authors will contact the investigators of individual trials for additional information.
The number of participants experiencing the event in each group of a trial will be recorded. Heterogeneity will be assessed using the Chi‐squared test for heterogeneity with a 10% level of statistical significance. Heterogeneity by visual inspection of the outcomes tables and by using two statistics (H and I‐squared tests) of heterogeneity will be assessed. If statistical heterogeneity is found, the reviewer authors will look for an explanation. A fixed‐effect model of analysis will be used with a random‐effects model if a sensitivity analysis is required. As the main outcomes are binary the Peto Odds ratio will be used as the summary statistic. Sensitivity analyses may be conducted on the basis of methodological quality (e.g. allocation concealment). Sub‐group analysis will be conducted on the basis of ultrasound type, method of fertilisation (IVF/ICSI), stimulation protocol, difficulty of embryo transfer, and type of catheter used. A funnel plot will be used to determine if there is the possibility of publication bias in the included studies.
