Journal of Surgery and Transplantation Science

Experimental Embryo Recovery, Ex Vivo Support and Facilitated Immunosurgical Transposition for Ectopic-to-Eutopic Pregnancy Conversion

Review Article | Open Access Volume 7 | Issue 1 |

  • 1. FertiGen/Center for Advanced Genetics, San Clemente, USA
  • 2. Applied Biotechnology Research Group, University of Westminster, UK
  • 3. Department of Obstetrics & Gynecology, Palomar Medical Center; Escondido, USA
  • 4. Gen 5 Fertility Center; San Diego, USA
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Corresponding Authors
E. Scott Sills, FertiGen/Center for Advanced Genetics, San Clemente, P.O. Box 73910 San Clemente, California 92673, USA; Tel: 949-899-5686 Fax: 1858-225-3535

Prompt diagnosis of tubal ectopic pregnancy (EP) is now usually possible before rupture and catastrophic hemorrhage, yet if unrecognized, EP remains an obstetrical emergency with high maternal mortality. Long considered unsalvageable, the EP itself is incidentally terminated during treatment to save the life of the mother. Of note, the embryo ploidy error rate in EP is thought to be comparable to intrauterine gestations. As operative experience with EP has increased, rare cases have been documented where scattered trophectoderm foci occasionally escape and successfully migrate to secondary extrauterine sites following surgical removal of the primary lesion. From this sequence, the following insights are possible: 1) that trophectoderm developed well beyond the stage for in vitro culture retain the capacity to tolerate mechanical, thermal, and/or hypoxic stress of standard EP surgery, and 2) that the ectopic so dislodged is sufficiently tenacious for attachment to atypical surfaces never physiologically matched to support pregnancy (e.g., omentum, peritoneum, ovarian epithelium, etc). In this report, these features are exploited to outline an experimental surgical and laboratory protocol to facilitate ectopic-to-eutopic (E2E) pregnancy transposition. At least three relevant issues push against the limits of present technology: 1) Optimal atraumatic removal of the ectopic implant site is unsettled; 2) Once the gestational sac is exteriorized, temporary in vitro culture support will be needed with microsurgical modification to maximize subsequent graft uptake in the awaiting maternal endometrium; 3) The best method and equipment for fresh transfer of a relatively large, complex embryo is undefined. Recent progress in reviving tissue for heterologous heart transplant—even after confirmed cardiac death of the donor—suggests that estimating success with ectopic recovery, processing, and reimplantation could depend on factors besides embryo cardiac potential and gestational sac status. Parallel advances in layered tissue allografting, in utero microsurgery, and wound healing along with in vitro perfluorocarbon-based embryo oxygen support; endometrial preparation and embryo transfer techniques borrowed from IVF promote consideration for how selected EPs may be relocated to the womb. The E2E procedure thus explores the shared terrain of tissue harvest/resuscitation, organ transplant, vascular engraftment and advanced reproductive technology domains. Rescue will not be possible for every EP case, and extensive investigational work in animal models will be required to establish inclusion criteria before the concept is ready for clinical use.


Sills ES, Wood SH (2020) Experimental Embryo Recovery, Ex Vivo Support and Facilitated Immunosurgical Transposition for Ectopic-to Eutopic Pregnancy Conversion. J Surg Transplant Sci 7(1): 1072.


•    Ectopic pregnancy
•    Transplant; Embryo
•    Uterus
•    Immunosurgery


If successful implantation is but partially understood for the intrauterine pregnancy, it is an even deeper mystery for the ectopic. Indeed, reflection on fundamental biological precepts would seem to rank ectopic pregnancy (EP) as a near impossible event. It presents perhaps the most dramatic and consequential example of the “wrong place, wrong time” problem: in one urgent circumstance, two lives hang in an uncertain balance. In this transitional pregnancy phase where the classical rules of organ and fetal tissue action begin to overtake the quantum penumbra of molecular and cellular forces, the embryo here is difficult to classify. At present, EP management mandates sacrifice of the embryo so that the mother’s life might be saved. But what might be changed to give a different, better outcome? If possible, survival of the salvaged EP would depend on the sum of cell culture, anesthesiology, tissue grafting and other vectors. In this report a technical approach for microsurgical processing and EP repositioning to the uterus is theorized, with discussion of how recent developments may impact key technical bottlenecks.


For unclear reasons the EP rate has increased significantly in the United States from 11.0 to 13.7 per 1000 livebirths between 2006 and 2013 [1]. There has never been any case of EP spontaneously migrating to the uterus, reimplanting, and then continuing as a normal pregnancy. However, natural transplant of trophoblast cells to other ectopic sites in the abdomen (especially after EP surgery) does happen and this is probably an underreported event. A recent review identified 25 such cases between 1989 and 2018 involving peritoneum, omentum, bowel serosa, uterosacral ligament or uterine exterior [2]. Curiously, wound healing at laparoscopy puncture sites or C-section incisions also seem to be attractive implant sites for parasitic trophoblast [2,3].

The notable achievement of successful heart transplant from a donor following cardiac death, despite having virtually nothing in common with accepted management of EP, nevertheless recently entered the public news cycle raising wider hopes that organs and tissues once thought unfit to reclaim might still have therapeutic value [4]. Unbriefed on basic science, elected officials in the U.S. even drafted broad legislation requiring physicians to “reimplant ectopic pregnancy” (to the uterus) or risk criminal charge [4]. While that health bill failed to become law, along the way it received ridicule for mentioning a non-existent operation. The present report frames a new hypothesis to reassess EP from a fresh perspective. Respecting the limits of current technology, an ectopic-to-eutopic (E2E) conversion concept explores the shared terrain of tissue harvest/resuscitation, organ transplant, vascular engraftment and advanced reproductive technology domains. Not every EP could be salvaged even with this proposed method, and extensive animal studies will be needed to establish effectiveness and develop inclusion criteria well in advance of any clinical use.


Contemplating the E2E pregnancy transposition begins with confirmation that the patient is a proper candidate for basic laparoscopy and conventional ectopic excision. Any finding rendering minimally invasive surgery unsafe or inappropriate would a priori exclude considering E2E to supplement standard laparoscopy. As the goal of E2E is ongoing intrauterine pregnancy, if successful the patient must be apprised of and agree to prenatal assessments and interventions as recommended for high-risk first trimester care and beyond (immunizations, rhogam, etc). If unsuccessful, the patient must be counseled she will likely require a second procedure to remove the failed embryo graft from the uterus. Special parameters germane to embryo transfer (as with IVF patients) also need evaluation prior to E2E; cervical/uterine features perhaps rank among the most crucial. In particular, any cervical or uterine pathology complicating cervical os dilation, any impairment or blockage of instrument access into the endometrial space, the failure to gain full and unobstructed views of the endometrium via real-time ultrasound (USG), or history of incompetent cervix would invalidate eligibility for E2E. The endometrial cavity must be uniform as would be expected before conventional embryo transfer, with no evidence of polyp, septum, myoma or other interior contour defect. There is little agreement among IVF experts concerning upper/lower bounds for endometrial lining thickness, although if transvaginal ultrasound (TV-USG) reveals any abnormal or unsuitable characteristic which in the surgeon’s judgment represents an adverse risk, then E2E should not be attempted. For example, fluid entrapment within the endometrial cavity at time of embryo transfer can foreshadow impairments in lining receptivity [5] so this poor prognostic sign should probably be disqualifying.

The importance of USG mapping of adnexa preoperatively is difficult to overstate, as suitability for E2E is contingent on accurate assessment of gestational sac geometry, location, embryo viability, and terms of reference. Ectopic pregnancy (ICD-10-CM O00.9) is a general diagnostic classification which includes multiple extrauterine implantation variants; the E2E algorithm is intended only for a specific sub-type of tubal ectopic which is not a component of a molar, heterotopic, or compound pregnancy. EPs too early to be definitively localized, have no recognizable tubal implant site, have no discernable fetal pole or cardiac action, or are diagnosed “by exclusion” are not proper candidates for E2E. Likewise, isthmic or cornual EP will need a higher-risk resection and an unfavorable access problem; this constraint will likely limit the ability of atraumatic embryo recovery. For E2E, a best-case scenario would thus be the unruptured tubal EP situated at the central or distal fallopian tube (Figure 1).

There does exist an upper crown-rump length (CRL) limit of about 30mm above which E2E will probably fail. This guidance derives from data predicting normal karyotype from noninvasive analysis of embryos below this size range [6]. Constraints must also be acknowledged regarding the geometry of tissue extraction via laparoscopy and subsequent embryo placement into the uterus. A maximum safely recoverable EP is therefore estimated from 1) fitness, viability, and genetic normalcy pertaining to embryos up to about 30mm CRL size, and 2) transcervical placement anticipating cannula entry, access, and passage. Gestational sac and yolk sac parameters may be useful, but these measurements reflect more compressible structures and thus are less reliable than CRL data.

Pregnancies from IVF and embryo transfer enable pregnancy dating with absolute accuracy and many features vs. developmental stage have been tracked to predict outcome. At about 21d post-conception, the endothelial heart-tube of the human embryo undergoes structural folding and begins to pulse rhythmically. Yet the embryo with normal development will acquire this cardiac action long before it can be clinically verified, whether in the uterus or not. The key question is thus not how soon cardiac activity can be confirmed by TVUSG (i.e., the sonographic discrimination threshold), but rather at what developmental stage is the embryo most likely nonviable if cardiac activity is not seen using currently available imaging technology. Early pregnancy assessment after in vitro fertilization and blastocyst transfer has shown that, at least for intrauterine implantations, documentation of embryo heart rate >110/min correlates with substantially reduced miscarriage risk [7]. Multifactorial data from gestational sac size, embryo and gestational sac ratio, yolk sac size, and fetal cardiac activity has been used to forecast ongoing pregnancy viability in 100% (36 of 36 patients) and 0% of cases, depending on scores [8]. This impressively accurate assessment may be impossible to fit with EP where gestational age is not precisely known, but efforts to determine pregnancy fitness based on examiner’s experience will still play a role in patient selection.


In compliance with facility safety guidelines, written informed consent is obtained with institutional review board oversight. Patient identification is confirmed, surgical time-out is cross checked, and induction of anesthesia can begin. Following abdominopelvic prep without iodine, attention should be given to remind the theatre team of the need for close coordination needed to complete the multistage procedure ahead (Figure 2). Analogous to testis biopsy for fresh surgical sperm retrieval or oocyte aspiration during IVF, specialized staff for E2E should either attend (with satellite incubator) or be immediately available via adjacent pass-through for rapid hand-off of the tubal EP tissue block. While pelvic laparoscopies routinely include a trans-cervical manipulator inserted within the uterus to improve visualization during surgery, instrumentation of this kind cannot be used for E2E so endometrial trauma is avoided. Triple-port video laparoscopy (5/5/15mm, larger port at umbilicus) is recommended for abdominal access after buffered carboperitoneum (CO2 insufflation pressure/vol = 30mmHg/1.5L) insufflated via 120mm Veress needle.

It is important to delay extirpation of the tubal implantation site until other surgical objectives are attained first (e.g., adhesiolysis, hemoperitoneum evacuation, etc.). When necessary to clear tissue and improve visualization, intraoperative irrigation is with a modified Ontario protocol [9] with heparinized normal saline at 37°C, or equivalent. Instrument contact with adnexal tissue (especially EP implantation site and corpus luteum) should be minimized to reduce microtrauma. Once the surgical field is clear so that the implant is centrally viewed and stable in situ, the surgeon should alert the attending anesthesiologist, embryologist, and nursing team that tubal resection and EP sample separation is imminent. Patient ventilation is then adjusted up to 100% O2 x 3min, for maximum perfusion efficiency to the EP in advance of vascular disconnect.

Next, beginning distally the lateral fallopian tube margin is freed first (if necessary) followed by division of the proximal fallopian tube no closer than 3cm medial to the implantation site (i.e., wide local excision) with both procedural components achieved with bipolar current set to 40W power. With the camera temporarily relocated to a lateral 5mm port, the central 15mm site at the umbilicus is readied for en bloc tissue removal under direct video-laparoscopic guidance. Once liberated, the tubal EP specimen is quickly oriented longitudinally and held securely by atraumatic grasper at its medial margin, gently withdrawn intact at the umbilicus, and placed immediately in specimen container with designated tissue media for hand-off to embryologist. Upon completing adnexal EP excision and tissue recovery, hemostasis is confirmed and the carboperitoneum is reduced. Simultaneous closure of laparoscopic puncture sites by a secondary surgeon permits primary attention at the pelvis next, for endometrial preparation.


Despite the progress with human embryo culture, gains in technology have not moved beyond the blastocyst 7d postfertilization boundary [10]. The impasse is secondary to metabolic and nutritional demands of the rapidly growing embryo, which quickly outpace the current capacity to match these complex requirements in a fashion equivalent to that supplied by the maternal in utero microenvironment. As EP patients usually present with embryos already at a developmental stage well beyond the range which IVF embryologists can be reasonably expected to support, the difficulties of in vitro handling in this setting appear insoluble. However, this presupposes the relevant set of ongoing cell/tissue culture objectives for E2E is the same as for conventional IVF. This is not correct.

Fundamental laboratory goals for IVF include facilitating cell cleavage, ongoing assessments, and scheduled media exchange—tasks typically covering several days and often for multiple embryos. In contrast, with E2E the physiologic problem aligns more closely with post-ischemia tissue recovery. Thus it is necessary only to keep one salvaged embryo under immersive (O2 saturated) culture conditions just long enough for careful microsurgery to prepare its most peripheral tissues to meet maternal endometrial tissue. The functional duration of such a survival bridge is measured not in days but minutes, as calculated from time required for 1) degloving of gestational sac from most of the enveloping tubal adventitia, and 2) preparation of uterus/ cervix for entry of USG-guided embryo cannula transfer.

Coordinated in parallel by independent theatre teams, the first of these two tasks will likely be of greater complexity and variety, influenced by individual tissue geometry features of partial salpingectomy and EP excision unique to each case. Evaluation of the EP after laparoscopic recovery could reveal no (or indeterminate) cardiac activity, although this should not necessarily be interpreted as immediate defeat. In contrast, umbilical cord status should be determined and if disrupted this unfortunately will mark the end of rescue efforts. Yet, if intact and even if heartbeat were recently lost the planned microsurgical attempt to disaggregate redundant maternal tubal tissue and optimize chorionic exposure circumferentially should continue. Given the nature and extent of mechanical stress exerted on the surgically removed EP specimen particularly during extraction of tubal mucosa, it is likely that the gestational sac is inadvertently breached if it has not already collapsed during laparoscopic excision. Unsurprisingly, no data are available to determine if gestational sac status is predictive for post-placement pregnancy outcome. Early embryo dynamics offers only an imperfect parallel with the zona pellucida (ZP) during pre-blastocyst culture, since it was once thought that this membrane was essential for cell cohesion and embryo development. However, transfer of ZPfree blastocysts (e.g., intentional removal of ZP) can still lead to implantation and ongoing pregnancy, similar to outcomes achieved with zona intact control embryos [11,12]. Experience will show if a deformed, punctured or missing gestational sac is likewise compatible with continued embryo development. Processing the salvaged EP tissue block under immersion with buffered, oxygen-saturated media aims to provide by cellular diffusion and villi absorption the essential components needed to sustain, and if necessary revive, the embryo. Immediate ex vivo support for the retrieved EP gives the best chance for success where close attention is focused on gas exchange via tissue diffusion, under a regulated immersive environment aiming to reduce physiologic stress and metabolic demands.

Related animal research [13] anticipates the main challenge for the salvaged embryo is likely to be severe and rapidly worsening tissue acidosis, a corrosive cellular cascade starting at the moment of maternal disconnect. Since embryo hypoxia thresholds are not known and probably show wide individual variation, interventions to boost access to available free oxygen during the collection, incubation, micromanipulation, and in utero transfer sequence are appropriate. Certain differentiated cell classes have extremely poor tolerance to ischemic insult, and studies using such cells helps guide how best to support the early embryo.

For example, as with recovered EP in culture heterologous pancreatic islet cell grafts are susceptible to functional failure from hypoxia after transplant. For both classes of sensitive cells, the high O2 solubility coefficient noted with selected media can maintain elevated O2 partial pressure over extended times. Perfluorocarbon (PFC)-based culture is one way to supply a generous oxygen reservoir for tissues known to be sensitive to low ambient in vitro oxygen conditions [14]. Another media choice using perfluorohexyloctane + polydimethylsiloxane 5 (F6H8S5) also shows promise in improving isolation outcome after prolonged ischemia, a finding likely due to the enhanced lipophilicity of F6H8S5 [15]. To date no culture media has explored this system using recovered animal embryos, and collaborative investigation to develop this with laboratory colleagues is underway.

At microscopic scale, preservation of cellular functionality in the presence of oxygen saturation vs. controls has been sustained for up to 24h [14], an interval much longer than needed for E2E. At systemic scale, similar rescue effects have been proposed for extreme preterm fetal animal models where immature pulmonary gas exchange augmented with PFC with less injurious liquid ventilation (spontaneous or mechanical) was thought sufficient to support life [13]. Temporary ex vivo embryo support as proposed thus relies on an identical oxygen diffusion strategy for cells within physiologic three-dimensional tissue configurations, and research has shown the addition of PFCs can significantly increase O2 capacity of medium in this context [16]. The maternal O2 pulmonary preload administered before tubal division and EP disconnect is a more familiar ventilation strategy, proposed for subsequent embryo transfer as well. All adjustments aspire to support the recovered embryo at its most vulnerable periods.

The ex vivo culture approach proposed here for advanced embryo support during processing is admittedly unusual but represents an extension of related work in organ transplant surgery. Preservation of pancreatic cells in storage has been accomplished with oxygenated perfluorodecalin, a recovery success attributed to oxidative ATP generation during storage. Modifying incubation temperature above 20°C in one protocol accelerated the process needed to resuscitate pancreatic tissue after ischemic injury [17]. Given the limited metabolic support with brief (~15min) ex vivo culture needed for E2E, ambient tissue temperature at 37°C appears to work favorably with experimental data.

This approach envisions an E2E “jump cut” consisting of perhaps only a 15min oxygen bridge, from embryo surgical separation to repositioning into prepared endometrium. The goal is to gain passive yet adequate gas exchange for villi through transient ex vivo exposure to buffered media providing a high-O2 carry capacity. Success of the E2E recovery-culture-replace splice sequence thus must incorporate such media to provide ample access to this oxygen in vitro micromilieu, especially if cardiac action is suspended to enable cross-villi gas exchange.


Liberating the ectopic gestational sac from tubal tissue which supported it from implantation through surgical disconnect has no corollary in surgery. The aims of this procedure are clear: remove sufficient redundant tissue (peripheral to villi) so that the processed embryo will have an opportunity to liaise with awaiting maternal endometrium. With this goal in mind, it should be recognized that absolute excision of all tubal tissue vestments is neither necessary nor realistic. This method opens the fallopian tube (with magnification) longitudinally as with standard linear salpingotomy, then carefully debulks the maternal tubal tissue circumferentially to maximize exposed gestational sac surface area for villi under immersive, buffered, saturated oxygen conditions at 37°C (Figure 3). Potts-Smith 19cm dissecting scissor (Storz #792080) and 11cm atraumatic forceps (Storz #530811) are examples of blunt equipment which may assist in tissue separation, although similar instrumentation can also be evaluated.

There are at least three embryo culture protocols which, based on tissue transplant or animal models, can supply adequate O2 support during the micro-debridement procedure (Table 1). Manipulation too aggressive is balanced against insufficient clearance of intervening maternal tubal tissue—the first risks irretrievable tissue damage and the latter create a greater burden on the recovered embryo where functional, unobstructed trophectoderm is vital for gas exchange. Thus, meticulous subtraction of most tubal tissue should be considered adequate to position the embryo to avail of other interventions waiting at the endometrium. This subtractive processing of tubal vestments will invariably result in some hypoxic insult to embryo, although environmental O2 augmentation both by maternal ventilation and ex vivo culture parameters aim to reduce the negative effects of transient tissue ischemia.


The cervicovaginal field is copiously reirrigated with phosphate buffered saline or equivalent as for standard blastocyst transfer; this procedure occurs in parallel with tubal EP tissue processing by the embryology team. The urinary bladder is temporarily filled with normal saline if necessary, and the abdominal USG probe is placed anteriorly for uterine assessment. Experience at this clinic supports an endometrial micro-scratch using either 3.5Fr (TomCat®, Covidien Medical; Carlsbad Calif USA) or 3.0Fr (ESL®, Rocket Medical; Herts UK) single lumen catheter. The catheter is retained and reloaded to administer slow-push intrauterine instillation of 1.5mL autologous PRP prepared on site fresh, as previously described [18,19]. Because these factors play an important role in orchestrating local tissue remodeling and angiogenesis, the proposed use of plateletderived growth factors in utero immediately prior to embryo transfer represents a proper extension of successful PRP use for other grafts [20].

Cervical dilation occurs under transabdominal USG guidance (concurrent with 100% oxygen maternal ventilation) and the semirigid cannula selected for transfer should remain in situ just proximal to the internal os until the prepared embryo is ready for placement. There is an upper bound for cervical dilation beyond which structural tissue injury is likely to occur [21]. Accordingly, cervix dilation should be conservatively sufficient to permit insertion and guided access of a properly sized endometrial delivery cannula (Table 2). Given this upper CRL size limit, any embryo with long-axis length up to approximately 30mm should be eligible to attempt E2E. With cervix stabilized with a singletooth tenaculum applied anteriorly, maternal ventilation is adjusted to 100% O2 as the cervical os is serially dilated as per dimensions estimated for placement of the recovered embryo.

Table 2: Embryo geometry, selected anatomy & equipment guidance for E2E in utero placement.

    gestational age (weeks)
    4 5 6 7 8
CDS   10-13 14-15 16-17 18-19 20-23
CRL mm 2-6 5-9 8-14 13-18 18-31
A-P (est) - 3-6 5-9 8-11 11-19
SR cath   7 10 12 17
Fr       30 36 51
Notes: E2E = ectopic-to-eutopic pregnancy transposition, CDS = Carnegie developmental stage, CRL = crown-rump length, A-P = mean AP [perpendicular] embryo dimension, SR = cannula size for in utero embryo insertion, Fr = recommended (French) dilator.



Embryo transfer catheters now used during routine IVF usually have an outer diameter of about 6.8Fr or ~2.3mm (e.g., Soft-Pass™ G17934 K-J-SPPE-681710, Cook Medical; Bloomington, Indiana USA). While this gauge catheter is suitable for blastocyst transfers, when the conceptus is 35-50d estimated gestational age, different equipment is required. Since no medical device exists specifically designed for transcervical placement of an embryo of this size, repurposing the 16mm caliber MVA Plus® mechanism (IPAS: Chapel Hill, North Carolina USA) for this task is suggested. Of note, the redirected “off label” clinical application of this apparatus for embryo placement in E2E represents an acute departure from the manufacturer’s intended use (i.e., surgical abortion). The delivery syringe chamber of 60ml (Figure 4) has the advantage of articulating with broad gauge cannula (e.g., #906582 VAC/15mm Vacuum Aspiration Curette, McKesson Medical-Surgical; Ontario CA USA) which meets or exceeds the narrow-axis dimensional requirements of the recovered embryo for E2E (Table 2). For continuity, the same oxygenated PFC-based embryo culture media selected for microsurgical manipulation of the recovered EP/tubal tissue is used as the carrier media base for transfer.

Note that the maximum permitted volume (60ml) is more than adequate for transfer. Establishing initial transfer media volume at loading requires attention to 1) immersion or “cover” of all tissues when the embryo is placed within the delivery syringe while 2) ensuring the smallest possible culture media volume is used for transfer. As this will probably range 20-30cc, addition to the carrier (syringe) chamber of maternal PRP (diluted 10% vol/vol) will increase this total by 2-3mL and represents the final modification signaling to stimulate villi during placement. Once the IPAS device has been loaded with the prepared embryo and media, this would be passed to the surgeon to affix to the transcervical cannula in situ. Next, contents of the delivery device would be advanced slowly to enter the uterus under USG guidance. If the cervical os remained persistently patent after withdrawal of the insertion cannula, at the surgeon’s discretion a cerclage may be indicated.


Determining outcome quickly after embryo conversion is important. Because maternal serum hCG and P4 will have been measured in the immediate pre-operative period, these should be monitored 12 and 24h after surgery to estimate viability of the relocated villi and embryo graft. The procedure should be classified as unsuccessful if serum hCG declines <50% in the first day after surgery. If hCG remains static or increases in the immediate post-graft period, then pregnancy support must be extended according to the post-embryo transfer protocol discussed next.

Unlike ovarian physiology during a fresh embryo transfer IVF cycle, for E2E cases a functional corpus luteum should be present. However, the adnexal surgery and uterine manipulation required to place the recovered embryo represent stimuli likely to make the womb more sensitized to expel contents. Previous delivery success following uterine surgery for heterotopic pregnancy where one (cornual implanted) twin was excised at laparoscopy without damaging the intrauterine co-twin [22] may help guide a hormonal support regime in this circumstance. More recently, luteal support may be achieved with either exogenous P4 administered by intramuscular injection, vaginally [23], or by oral lozenge [22]. Although some data exist on benefits of hCG supplementation for IVF patients on GnRH-antagonist cycles [23] this approach for E2E patients is not ideal because of interference with early outcomes monitoring. Post-operative estrogen supplementation [23] should be considered among interventions where experience shows utility for those at risk for implantation failure [22,24].


When the processed embryo from E2E encounters the uterine interior for the first time, it will meet a decidual tissue bed developed appropriate for gestation—but vacant. What is not known is how to drive trophoblast cells to intermingle and exchange information with endometrium after the salvaged pregnancy reaches this new address. For the organ transplant, this process entails multiple vessel reanastomoses so that circulatory support can be quickly reconnected. For E2E a mechanical connection is impossible with any needle-andthread technique but could be a linkage made successful with “facilitated immunosurgery” as outlined here (Figure 5). In fact, the trophoblast–decidual dynamic relies on dozens of signaling moieties to moderate immunologic response, villi invasion, and embryo nourishment and growth. Irrespective of embryo status or implantation site, physiologic blunting of the maternal immune system is mandatory for successful acceptance of the blastocyst [25,26]. For EP before recovery, this requisite refractoriness was already established both in tubal mucosa and decidua secondary to cross-talk among trophoblast and circulating maternal cells. Failure to keep this immunotolerance has been associated with poor outcomes later (e.g., miscarriage, pre-eclampsia) [27]. Studies of endometrial microarchitecture with transcriptome mapping of ~70,000 relevant cells reveal that perivascular and stromal cells are organized in discrete strata, with differing immunomodulatory and chemokine function [28]. Interestingly, closer antigenic similarity seems preferred to immunologically unrecognized markers of foreign tissue and probably explains why oocyte donation is associated with higher preeclampsia risk in singleton pregnancies compared to conceptions from nondonor eggs [29-31].

Controlled uterine microtrauma from endometrial scratch/ mock transfer will beckon platelets to the area with release of multiple growth factors, and fresh PRP irrigation just before embryo placement further exposes the tissue field to a more concentrated signaling array. These moieties include transforming growth factor-β, vascular endothelial growth factor, epidermal growth factor, basic fibroblast growth factor, insulin-like growth factor 1, interleukin-1β, and matrix metalloproteinases, as confirmed by ELISA [32]. Macrophages are also under close cytokine control, providing an important leukocyte group in the decidua [33,34]. Such cells sustain pregnancy by promoting vascular remodeling [35], clearance of apoptotic cells [36] and by directing immunological actions particularly T-cell function and NK cell cytotoxicity [37,38], Endometrial macrophages exhibit high expression of CD206, CD209, and the scavenger receptor CD163 [34,39]. In addition, MHC class II (HLA-DR) and co-stimulatory molecules like CD86 are variably expressed throughout early gestation [40]. Interleukin (IL)-12, tumor necrosis factor (TNF) and IL-10 are among other important players in the decidual signaling concert [39,41]. IL-34 is another cytokine acting as a second ligand for the M-CSF receptor [42] which positions this interleukin as a prominent director of decidual regulation [43,44].

This model for the graft-host link in E2E builds on a wound healing “construction zone” concept, featuring responder cells at work on extracellular matrix and neovascularization tasks with high reliance on (and transmission of) multichannel chemokine mediators. Bystander trophectoderm becomes an unintended but receptive audience for this powerful cellular broadcast, drawn incidentally into a busy remodeling program to avail of an attractive anchorage opportunity. Understanding how transposed trophectoderm cells migrate through small tissue gaps in the endometrium after exposure requires a model to account for crowded environments and intricate geometries. It remains to be proven if cytokines contribute to a recently discovered cell traction mechanism [45] and additional research may yield evidence for how villi—an example of “active matter”— function and fix in early pregnancy.


For the E2E concept to succeed, transepithelial trophoblast invasion must happen despite the recovered embryo entering the uterus substantially later than would normally occur. Rare cases of superfetation suggest narrow tolerance concerning when a new embryo can move into the human womb and remain viable. Thus, a pregnancy arriving with a primordial umbilical cord and early placenta already on board is likely to find the default state of endometrium ranging from indifferent to hostile. The approach described here is the first to nominate autologous growth factors and microtrauma to assuage this antagonism with incubation methods specifically developed to sustain (temporarily) a surgically recovered embryo. The endometrial scratch for facilitated signaling is a further intervention to overcome the challenge. If effective, the embryo graft would progress with further stromal transformation, recruitment of inflammatory cells to the endometrial compartment, and apoptosis of selected uterine epithelial cells. Such multivalent cellular events directing implantation show remarkable homology with wound healing in other sites where autologous PRP already appears to show benefits.

Directed by these growth signals, programmed mRNA changes and expression of extracellular matrix receptors and matrixdegrading activities in trophoblasts may assist in shepherding villus movement at the endometrium [46]. During the earliest phases of placental growth, trophoblast cells move into any voids from phagocytosis in the mesometrial zone. Once the placenta is formed and the embryo is fully nested, further invasion is halted by decidua (as differentiated endometrium) where the trophoblast then seems to enter a dormant stage and further proliferation is halted [47,48]. Lysosomes and phagosomes of trophoblast origin also organize engulfment of necrosing endometrial epithelial and stromal cells, as well as cells of lymphopoietic origin [49]. These are complex processes, already well underway at the tubal site weeks before EP disconnection.

Some animal trophoblast cells express no MHC class I antigens before d120 of pregnancy [13] although this evolves and changes gradually during later gestation and probably helps set the stage for placental separation and subsequent parturition in all mammals. Of course, the sequence in human EP is always truncated early by surgery to remove the pregnancy and save the life of the mother. Because PRP is known to influence the immune response after tissue injury, these growth factors added to the endometrial milieu may potentiate graft uptake after transfer.

Of perhaps equal importance, our approach includes a novel tissue bed/mock transfer method, using different instruments and timing to improve upon previously published techniques [50-53]. It is hypothesized that the pre-transfer endometrial microtrauma is optimized when this occurs near time of planned embryo transfer (not during prior luteal phase, or earlier) and when smaller caliber devices are used. Others note that simple in utero IUI catheter insertion with saline injection at time of egg retrieval may impact implantation favorably [54], and the E2E method aligns with parts of this theory. Successful E2E is contingent on our ability to jump-start several sequences for the relocated embryo, following the transient ischemia from surgery required to liberate it.

This recovery and relocation of EP also finds some similarity in transplant work which requires specialized personnel, coordinated operational plans, a prepared field to receive the graft, and making a wound at the donor site [55]. For E2E, creating the donor site “wound” is not the laparoscopic tubal excision itself but rather the subsequent microsurgical removal of tubal adventitia from peripheral gestational sac tissue ex vivo under saturated O2 culture conditions, as outlined here.

Successful EP implantation on a field of tubal mucosa rebukes the axiom that a hormonally-primed endometrium is essential for implantation and pregnancy [56]. The basic premise of Perrier d’Hauterive [57] seems logical, that while implantation is possible in any human tissue (as evidenced by EP), special rules do apply for endometrium. Within the uterus, any embryo graft uptake (i.e., implantation) will fail except during a narrow permissive period or “implantation window”. Specifically, the embryo and endometrium connect under management of many local regulators influencing metabolism, cell proliferation, basement membrane and cell connectivity, and differentiation [56,58]. At present, more than 1000 regulatory proteins have been identified in this dynamic process and many of these are under hormonal or cytokine control [56]. The molecular signals controlling this phase [57,58] show considerable homology with PRP constituents.

As clinical IVF practice has shown, the instrumentation, technique, and timing for in utero embryo transfer mark this as the most challenging part of IVF. There is no reason to suspect this importance will be any different for E2E. Can the embryo survive after transfer? Even if cardiac function is temporarily lost during culture, is this recoverable as with other transplants? Will it make a link with endometrium? Will the uterus recognize the embryo, or will it be rejected? How will the embryo know where to implant? What can be safely done to modify both uterus and embryo to improve the chance of success? Questions of this kind are as relevant now for E2E as they were when IVF was first imagined nearly fifty years ago. Of note, despite millions of IVF births there is surprisingly little agreement on exact answers for most of these queries—only that the treatment does sometimes work. While it has been noted that active trophoblast proliferation is augmented secondary to platelet derived growth factor and is impacted by maternal platelet concentration [59], E2E is believed to be the first proposal to apply this experimental observation. Although EP excision unavoidably interrupts several intricate developmental cascades, this protocol aims to dampen the disruption by fostering intrauterine villus function and resuming local blood flow.


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Received : 26 Feb 2020
Accepted : 05 Mar 2020
Published : 07 Mar 2020
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