28 Rachel Cutting Since the advent of in vitro fertilization (IVF) there have been many advances in ovarian stimulation regimens and laboratory conditions which have led to the complex process of IVF employed worldwide today. Although technological advances in the laboratory have improved embryo viability and increased knowledge of endometrial receptivity has been gained, embryo transfer is still a critical limiting technique in an IVF cycle. Meldrum et al. as early as 1987, highlighted that a meticulous embryo transfer technique is essential for a successful programme. However, despite its clear importance, the technique itself remains relatively unchanged and although millions of babies have been born worldwide, across Europe pregnancy rates per embryo transfer still remain around 32% (Ferraretti et al. 2013), with lack of implantation attributed to poor uterine receptivity, poor quality embryos, or the embryo transfer technique (Brown et al. 2010). In recent years, in an attempt to improve implantation rates, focus has been on adjuncts to treatment around the time of embryo transfer, either through patient medication or modifications to procedures in the laboratory. This chapter aims to review the technique of embryo transfer and discuss the additional factors which can influence implantation rates. The paucity of published material on embryo transfer techniques should not detract from the importance of the procedure and it is clear that to maximize implantation rates, embryos should be transferred back to the uterus in a gentle and atraumatic manner (Schoolcraft et al. 2001), minimizing the chance of inducing uterine contractions (Frydman, 2004). Reviewing the literature, it is reported that technically challenging embryo transfers reduce the chance of pregnancy (Englert et al. 1986; Tomas et al. 1998) with use of a tenaculum, touching the fundus, and blood on the catheter being ranked highly as factors affecting successful outcomes (Kovacs 1999). Other factors, such as the presence of mucus on the catheter, are thought to reduce implantation rates by either plugging the end of the catheter or introducing contamination into the endometrial cavity. Therefore, removal of cervical mucus prior to the catheter being inserted is recommended (Schoolcraft et al. 2001). Two meta‐analyses/systematic reviews show that higher pregnancy rates are achieved using soft catheters compared with hard catheters (Abou‐Setta et al. 2005; Buckett 2006). Figures 28.1 and 28.2 show a two‐part catheter, with an inner and outer part. The outer introducer can be placed in position before the embryos are loaded into the inner catheter. Figure 28.1 Guardia access catheter with inner and outer catheter. Reproduced with permission of Cook Medical, Bloomington, Indiana, USA. Figure 28.2 The two‐part catheter. Reproduced with permission of Cook Medical, Bloomington, Indiana, USA. Christianson et al. (2014) conducted a worldwide survey focused on how the embryo catheter was loaded and different embryo transfer techniques, which included responses from 265 centres in 71 countries. Common practices amongst clinics included prewashing the embryo transfer catheter (82%), preference for the use of a catheter marked for ultrasound view (42%), and use of a different embryo transfer media (42%). A wide variation of transfer medium was used. The most commonly reported method for loading the catheter was medium–air–embryo–air–medium (42%) with the final volume of the catheter up to 0.3 mL in 68% of centres (Figure 28.3). The use of air bubbles aids visualization under ultrasound guidance and may protect the embryos from trauma (Christianson et al. 2014). However, some reports are contradictory and postulate that air bubbles can be detrimental. Ebner et al. (2001) reported that low transfer volume (<10 μL) and air bubbles have a negative effect on outcome. Embryos were retained in the catheter for longer than 60 seconds in only 9% of centres and 100% of centres checked the catheter for retained embryos after the procedure. Figure 28.3 Embryo transfer loading. Where embryos are deposited in the uterus can affect outcome (Figure 28.4). Touching the fundus reduces pregnancy rates (Schoolcraft et al. 2001) and if embryos are deposited less than 5 mm from the fundus, this can increase the risk of ectopic pregnancy (Nazari et al. 1993). The use of ultrasound to visualize the embryo transfer catheter as it traverses the cervical canal, internal os, and enters the uterine cavity allows the embryos to be deposited accurately at a defined distance from the fundus allowing for variations in cervical length, uterine size, and position to be taken into account. Many IVF centres routinely perform ultrasound‐guided embryo transfers, as evidence suggests improvement in clinical pregnancy rates using ultrasound rather than just ‘clinical touch’ (Abou‐Setta 2012). The update of the 2007 Cochrane review in 2010 included 17 randomized trials and demonstrated significantly higher pregnancy rates with ultrasound guidance, but no difference in live birth rates (Brown et al. 2010). However, the authors did note that this finding should be interpreted with caution due to heterogeneity of the trials. Visualization of the catheter tip rather than introducing the catheter blindly into the uterine cavity has several benefits. Not only does it allow the catheter tip to be accurately positioned, it also minimizes endometrial trauma by preventing the catheter either indenting or embedding in the endometrium (Woolcott and Stanger 1997). Avoiding trauma to the endometrium is thought to decrease myometrial contractions, which are associated with reduced implantation rates (Fanchin et al. 1998). Several catheters are now echogenic, which enhances ultrasound visualization (Figure 28.5). Figure 28.4 Uterine embryo transfer. Source: © 2013 Lisa Clarke courtesy of Cook Medical, Bloomington, Indiana, USA. Figure 28.5 Catheter with echogenic tip. Reproduced with permission of Cook Medical, Bloomington, Indiana, USA. Measurement of the thickness of endometrium in the midsagittal plane via transvaginal ultrasound is a standard method used as an indicator for endometrial receptivity (Wu et al. 2014). A 2014 systematic review and meta‐analysis showed that although endometrial thickness cannot be used to predict IVF outcome in terms of occurrence (pregnant versus not pregnant), it could be used to indicate the probability of implantation occurring (Kasius et al. 2014). The analysis found that the probability of pregnancy was significantly lower in the group with thin endometrium (≤7 mm), although it is difficult to explain the reason for this finding due to limited research. It has, however, been suggested that in thin endometrium, oxygen concentrations are increased in basal layer endometrium, which negatively impacts on implantation (Casper 2011). Further research, however, is required using molecular tools to provide more information on the link between thin endometrium and endometrial receptivity. Endometrial pattern is also currently used as a measure of endometrial receptivity and although this could not be included in the meta‐analysis due to a lack of consistency in the classification systems for endometrial patterns, several studies have found a relationship between pattern and outcome (Dechaud et al. 2008; Chen 2010; Kuc et al. 2011). Although some studies contradict this (Detti et al. 2011), a study including 1933 women undergoing IVF treatment found a significantly reduced implantation and pregnancy rate in cycles where a triple‐line endometrial pattern (Figure 28.6) was not observed on the day of human chorionic gonadotropin (hCG) administration (Zhao 2012). The group concluded that combined endometrial thickness and pattern could not predict the outcome of IVF‐embryo transfer when endometrial thickness was <7 mm or >14 mm, while a triple‐line pattern with a moderate endometrial thickness appeared to be associated with higher pregnancy rates. Figure 28.6 A triple line endometrium. The findings that lower pregnancy rates are achieved in stimulated IVF cycles compared with natural cycles in ovum donation cycles have led to further studies looking at the effect of controlled ovarian stimulation on endometrial receptivity. Investigations using microarray technology have compared endometrial gene expression profiles during the implantation window in a woman’s stimulated and preceding natural cycle. The study found more than 200 genes showed a differential expression of more than threefold when the stimulated and natural cycles were compared (Horcajasdas et al. 2005). Haouzi et al. (2012) also described how different gene and protein‐expression profiles may play a critical role in endometrial receptivity in natural and stimulated cycles. Recently, there has been much interest in the effect of elevated progesterone on cycle outcome. Studies have shown that elevated progesterone levels on the day of hCG administration negatively affect pregnancy rates (Bosch et al. 2010; Xu et al. 2012). A systematic review and meta‐analysis of more than 60 000 cycles concluded that elevated levels of progesterone on the day of hCG administration was associated with reduced pregnancy rates in fresh cycles (Venetis et al. 2013). However, the effect seems to be linked with endometrial receptivity rather than an effect on embryo quality, as live birth rates from frozen embryo cycles with elevated progesterone in the associated stimulation cycle (in which the embryos are created) are not affected (Lahoud et al. 2012). Further studies have shown that in patients with elevated progesterone levels (>1.5 ng/mL) on the day of hCG administration there is a shift in endometrial gene expression from the prereceptive to the receptive stage, which suggests accelerated endometrium maturation (Haouzi 2014). However, it is unclear whether this advancement in maturation reduces endometrial receptivity, as study of receptivity biomarkers did not show a change. Further research is therefore required to determine if it is the receptivity which is affected, or a desynchronized cross‐talk between the embryo and endometrium due to the acceleration of endometrial maturation (Haouzi et al. 2014).
Embryo Transfer Techniques and Improving Embryo Implantation Rates
Introduction
Embryo Transfer Technique
Endometrial Thickness and Pattern
Endometrium Receptivity
Embryo Transfer Media
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