**4. Discussion**

Various techniques and technologies for ET have been proposed since the introduction of IVF. This list includes ultrasound-controlled transcervical intrauterine transfer or transmyometrial transfer and more invasive procedures, often referred to as surgical ET, which include: gamete intra-fallopian transfer (GIFT), zygote intra-fallopian transfer (ZIFT), pronuclear stage transfer and embryo intrafallopian transfer (EIFT) (14-17). Although ultrasound guided ET was desired to improve successful pregnancy outcomes and reduce side effects, it has been received with mixed results (18-32). It also requires simultaneous coordination of two professionals, the physician who performs the transfer and the ultrasonographer (29). Furthermore, all transcervical and transmyometrial techniques involve "blind" introduction of the embryo(s) via transfer catheters with no real time flexibility of the tip of the transfer catheter and subsequent release of embryo(s) onto the surface of the endometrium. As a result if the embryo fails to adhere, due to some luteal phase defect or other, undefined "implantation window" problem, there is a significant risk that the embryo might be washed out of the cervix or become lodged in the fallopian tubes. In part, to compensate for this potential conceptus loss, physicians have adopted the practice of transferring higher numbers of embryos back to the uterus. Here we reinvestigate the potential of surgical implantation of embryos developed to the blastocyst stage *in vitro* by day 5 or 6 post insemination. It does appear that this procedure may enable circumvention of those problems associated with the maternal receptivity aspect of the so called "window of implantation"(4). Under normal, non-assisted, circumstances, implantation begins six to seven days post ovulation. It involves multiple steps which can be summarized as pre-attachment, attachment-invasion, and decidualization - early placentation (33, 34). The reader is referred to a recent paper by Dominguez et al. (2) for a comprehensive review. Thus far, mechanisms for repairing defects in this process or clinically relevant markers of uterine receptivity have proven elusive. Similarly to the now well-accepted procedure of ICSI (35), where a single sperm is mechanically injected into an oocyte, with the development of this project we aim to develop an instrument and procedure whereby "mechanical" implantation of the embryo is achieved.

148 Enhancing Success of Assisted Reproduction

Spotaneous Abortions 2

In this series, 24 IVF cycles in 21 patients were completed. Endometrial thicknesses varied between 7 and 16mm by transvaginal ultrasound. There were sixteen positive hCG's at levels greater than 5 IU/ml. There were five biochemical pregnancies, and eleven clinical pregnancies as evidenced by the presence of a gestational sac (Fig 1E) visualized by ultrasound examination at five weeks of gestation and heart beat at six weeks of gestation (Fig 1F). There were 5 spotaneous abortions. Healthy babies were delivered by seven patients. No ectopic pregnancies (tubal, placenta previa, cervical, or heterotopic ) were seen

Day 5 Implantation Day 6 Implantation Combined

D5 and D6

3 5

(Table 1). There were 4 twins from day five and none from day 6 implantations.

Patient starts 14 10 24 Total Pregnancy/Start 8(57%) 8(80%) 16(67%) Biochemical Pregnancy 2 2 4 Ectopic Pregnancy **0 0 0** 

4

Multiple Pregnancy 0 4 Live/Start 4 (29%) 3 (30%) **7 (29%)** 

Various techniques and technologies for ET have been proposed since the introduction of IVF. This list includes ultrasound-controlled transcervical intrauterine transfer or transmyometrial transfer and more invasive procedures, often referred to as surgical ET, which include: gamete intra-fallopian transfer (GIFT), zygote intra-fallopian transfer (ZIFT), pronuclear stage transfer and embryo intrafallopian transfer (EIFT) (14-17). Although ultrasound guided ET was desired to improve successful pregnancy outcomes and reduce side effects, it has been received with mixed results (18-32). It also requires simultaneous coordination of two professionals, the physician who performs the transfer and the ultrasonographer (29). Furthermore, all transcervical and transmyometrial techniques involve "blind" introduction of the embryo(s) via transfer catheters with no real time flexibility of the tip of the transfer catheter and subsequent release of embryo(s) onto the surface of the endometrium. As a result if the embryo fails to adhere, due to some luteal phase defect or other, undefined "implantation window" problem, there is a significant risk that the embryo might be washed out of the cervix or become lodged in the fallopian tubes. In part, to compensate for this potential conceptus loss, physicians have adopted the practice of transferring higher numbers of embryos back to the uterus. Here we reinvestigate the potential of surgical implantation of embryos developed to the blastocyst stage *in vitro* by day 5 or 6 post insemination. It does appear that this procedure may enable

**3. Results** 

**Table 1.**

**4. Discussion** 

Ectopic Pregnancies after IVF specially for tubal disease account for approximately 8-10% of pregnancies (7, 48). Hysteroscopic SEED minimizes the chances of "losing" the embryo, and virtually eliminates ectopic pregnancies (tubal, placenta previa, cervical, or heterotopic) from embryo transfer, as the embryo(s) is embedded into the endometrium and not floating in the uterus. Using the flexible mini-hysteroscope affords an objective and accurate confirmation of the placement of the embryo that should make the procedure replicable, and thus more reliable with more consistent and improved results. Allowing the embryos to reach the blastocyst stage prior to transfer is gaining more acceptance (37-39). It allows both for more normal embryos to be naturally selected and for a more accurate selection of more viable, healthier embryo(s) (40-42). Thus a less number of embryos can be selected for transfer with more certainty for a successful singleton pregnancy (43, 44). This is congruent with the results in this study where there were no multiple pregnancies from day 6 implantations (Table 1).

A previous report on the use of SEED technique documented a promising set of results in patients with a variety of reasons for IVF (36). In this report we wanted to focus on a specific group of patients to better define the role of SEED technique. An overall pregnancy rate of 67% with a live birth rate of 29% was achieved. This is consistent with treating a better prognostic group of patients, i.e. egg donors in contrast with a non selective group of patients (36).

A possible drawback with the transcervical hysteroscopic embryo implantation (SEED) is the potential to scratch the endometrium and trigger some deleterious effect. Yet this is a potential hazard of "blind" procedures as well. The risk of disruption of the uterine lining, however is postulated to be less than "blind" and ultrasound guided transfers due to the advantage of direct visualization of the uterine lining and not requiring movement of the catheter to facilitate identification during ultrasound (32). As opposed to rigid endoscopes which may cause trauma to the uterus, the hysteroscope used in this study is a minihysteroscope with a 3mm diameter and flexible tip that allows one to easily follow the curvature of the uterus. With this protocol, though, the physician may then choose a nonscratched portion of the endometrium for implantation. Having said that, a growing number of literature suggests that mild inflammation may very well facilitate, if not be required for implantation and placentation (45-47).

Likewise, visualizing implantation allows for the physician to avoid losing embryos due to intrinsic uterine contractions or those brought on by the transfer, enabling the physician to defer the procedure until the enhanced activity has subsided. Furthermore, visualization allows one to place the embryo at a different location if trauma ensues. Also, the catheter used is semi-rigid to prevent kinking as it passes through the endoscope yet with enough flexibility to bend with the endoscope however bend and become kinked to prevent inadvertent passage into the myometrium. In addition, the uterine cavity is allowed to be distended during introduction of the hysteroscope into the uterus by slow passage through the endocervical canal. This would allow the hysteroscope to move in a gaseous space and not in direct contact with the endometrium as is the case with the blind procedure. In our study, no disruption to the uterine lining or uterine bleeding occurred. Increased cost is another drawback, however utilizing a hysteroscope with an objective replicable procedure that improves results will decrease the costs from multiple failed IVF-ET attempts and improve patient satisfaction.

SubEndometrial Embryo Delivery (SEED) with Egg Donation – Mechanical Embryo Implantation 151

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