Hysteroscopic Embryo Transfer or Implantation-Experience of a Decade: An Alternative Objective and Reliable Method for Embryo Transfer (HEED) and Implantation (SEED)

Aims: Here we present early experience using HEED and SEED along with a description of these procedures in more detail. There is also a new look at the endometrial cavity and the placement of embryo transfer or implantation while under direct visualization. Methodology: Embryo transfer was done using a mini flexible hysteroscope with an articulating tip. This was accomplished by either placing the embryo gently on the surface of the endometrium (HEED) in 35 patients undergoing IVF, or embedding the embryo just beneath the endometrial surface (SEED) in 24 patient starts using egg donation. Once pregnancy was confirmed with a positive serum hCG, they were followed up with transvaginal ultrasounds and serial serum hCG’s in the first trimester. They were then referred to their local obstetricians and final outcomes were recorded after deliveries. Results: There were a total of 35 patients in the early (days 2 or 3) embryo transfer group (HEED) which resulted in 16(46%) total pregnancies, which included 2 biochemical pregnancies, 2 ectopics, 5 spontaneous miscarriages, and 3 multiple pregnancies. There were 7 (20%) live births. In the second group of patients with day 5 or 6 embryo implantations (SEED), there were a total of 24 patient starts, with 16(67%), 4, 0, 5, and 4 total, biochemical, ectopic and multiple pregnancies respectively. There were 7(29%) live births. Conclusion: Hysteroscopic embryo transfer or implantation may increase successful pregnancies and decrease risks and side effects from IVF procedures. Further prospective, controlled and randomized studies are needed to determine effectiveness of these procedures.


INTRODUCTION
Over the last 35 years since the birth of the first human IVF pregnancy, major progress has been made in different components of IVF procedures [1-6]. However, there is a great difference of approximately 85% between normal embryo development and pregnancy rate [7]. This failure rate suggests that the embryo transfer stage is a key step to successful live pregnancy rates in assisted reproductive technology (ART) [8].
Traditionally, embryo transfer is done by using a catheter that is introduced into the uterus guided by a feeling of touch that is dependent on the individual operator's past experience. Although routine use of ultrasound to increase pregnancies remains controversial [9-13], a fixed distance from uterine fundus and varying lengths of insertion into the uterine cavity have been suggested with or without the use of ultrasound. Other factors implicated in the low pregnancies from IVF include: Non-tactile uterine contractions, embryos falling out of the uterine cavity into the cervix, bloody or mucus plugs on the catheter tip, bacterial contamination of the catheter, and embryos that were not expelled out of the transfer catheter [14]. Furthermore, other yet undiscovered factors responsible for embryo attachment and implantation are also of utmost importance in achieving pregnancies from healthy embryos [15][16][17][18]. Since the initial success with endoscopic embryo implantation (SEED) [19][20][21], endoscopic embryo transfers were subsequently extended to the earlier stages of embryo development especially in patients with advanced age or poor responders, for direct transfers onto the endometrium (HEED).

MATERIALS AND METHODS
Prior to the procedures, informed consent regarding traditional embryo transfer versus hysteroscopic embryo transfer or implantation were obtained from all patients. The techniques for the two procedures, HEED and SEED (Hysteroscopic Endometrial Embryo Deposition) have been previously described [19][20][21].
Uterine distention was achieved using nitrogen gas via a hysteroscopy insufflator. The catheter used in these procedures were initially made by Cook OB/GYN™, Spencer, Indiana USA and subsequently made by IVF Scientific, Beverly Hills, CA 90212 USA (Fig. 1). The loading catheter is shown in Fig. 1. Endometrial placement of embryos is shown in Figs. 2, 3 and 4.

DISCUSSION
There has been little change in embryo transfer technique using a catheter to blindly guide by feel and touch into the uterine cavity and then ejecting the embryo(s). Gamete intra-fallopian transfer (GIFT), zygote intra-fallopian transfer (ZIFT), pronuclear stage transfer and Embryo Intrafallopian Transfer (EIFT) [22][23][24][25][26][27][28][29] require invasive surgical procedures done under general anesthesia. Although ultrasound guided ET was desired to improve successful pregnancy outcomes and reduce side effects, it has been received with mixed results [30][31][32][33][34][35][36][37][38][39][40][41][42]. It also requires simultaneous coordination of two professionals, the clinician who performs the transfer and the ultrasound technician [37]. Furthermore, with the transmyometrial technique, the needle has to go through the myometrium first and then be inserted into the endometrium or released onto the endometrial surface. The procedure is more invasive than going through the natural opening of the cervix. Consistent and accurate positioning of the catheter would be difficult with the mobile uterus and hyperstimulated ovaries. In addition, myometrial invasion would be more likely to produce involuntary uterine contractions and bleeding that although cannot be seen nor verified with high accuracy by ultrasound, could have deleterious effects on final pregnancy outcome [43,44]. In order to compensate in part for luteal phase defects and other yet undiscovered factors that may interfere with embryo adherence, penetration or implantation clinicians transfer more embryos. By mechanically inserting the embryo into the endometrium using SEED technique, problems associated with the maternal receptivity may become a moot point [18].  After the initial success with SEED [19], attention was focused on a better prognostic group of patients, i.e. egg donors [20]. Hysteroscopic SEED virtually eliminated ectopic pregnancies (tubal, placenta previa, cervical, or heterotopic) from embryo transfers that occurred in approximately 8-10% of high risk pregnancies [11, 45,46]. Lost embryos were also minimized as the embryo(s) was implanted into the endometrium and not left to float within the uterine cavity. Using the flexible minihysteroscope affords an objective and accurate confirmation of the placement of the embryo that is reliable and should make the procedure replicable with more consistent and improved results. In patients with advanced age, low ovarian reserve or poor responders, a day 2 or 3 embryo transfer using HEED technique is more desirable as the in vitro conditions may not be optimal for the extended culture survival of the embryos. In situations where there are many high quality embryos to choose from, allowing the embryos to reach the blastocyst stage prior to transfer has gained more acceptance [45,46]. This natural selection of the healthier embryos would make the final embryo selection for transfer easier and allow for a less number of embryos to be transferred [47,48]. This is compatible with the results in this report showing no multiple pregnancies from day 6 implantations (SEED) ( Table 1).
Hysteroscopic embryo transfer, whether by HEED or SEED, is objective and reproducible. Since involuntary uterine contractions are known to decrease embryo retention and implantation [43,44,49,50], using the endoscopic approach would be invaluable at detection of contractions prior to actual release of the embryo(s). In these situations, embryo transfer is aborted and the embryo(s) are frozen and stored for future replacement under more favorable conditions. In addition, embryo transfer under direct visualization allows for visual confirmation of release of the very low volume of transfer fluid [8, 51,52] and a more precise placement of embryo(s). The ability to visualize the uterine cavity through an endoscope at time of embryo transfer is particularly important in patients with uterine fibroids, adenomyosis and intrauterine adhesions as the flexible and articulating tip of the scope can be easily maneuvered in the gaseous space. In addition, multiple suitable areas for implantation can be identified (Fig. 4).
The disadvantage and risk of this technique is possible endometrial injury with the scope. Since the uterine cavity is distended prior to scope entry, the risk is less than blind and ultrasound guided transfers [53]. Additionally, direct visualization allows one to place the embryo at a different and non-traumatized location if endometrial injury is noted. The major drawback to its acceptance is that hysteroscopy will increase the total cost of the procedure. However, the small increase in cost is well worth the despair, agony, and further additional cost of repeat IVF's to achieve a successful pregnancy.

CONCLUSION
Hysteroscopic embryo delivery provides a visually confirmed technique for embryo placement. It allows for a targeted positioning of the embryo(s), which may increase live delivery rate and decrease untoward side effects from embryo transfer. Hence, reductions in multiple pregnancies can be focused on selecting the healthiest single embryo for transfer. Attention to detail in loading the embryo(s) [21] and direct visual placement of embryo(s) away from both internal cervical os and the junction of endometrium with endosalpingeal epithelium (Fig. 4), will minimize ectopic pregnancies in various anatomical locations. SEED is especially appealing in patients with prior tubal pregnancies and failed IVF. Additionally, patients will feel more at ease because they can simultaneously see the procedure on a live video monitor while undergoing treatment. A quicker successful pregnancy outcome will also decrease the cost to the patient because it will decrease the number of attempts necessary using IVF procedures in order to achieve a successful singleton pregnancy [54].

ETHICAL APPROVAL
Both authors hereby declare that all experiments have been examined and approved by the appropriate ethics committees and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.