Performing Embryo Transfer: The “Process”

Embryo transfer (ET) is undoubtedly a rate limiting factor in IVF. Unquestionably, the IVF doctor’s expertise in performing ET as one of the most important factors that will determine IVF outcome. It takes confidence, dexterity, skill, gentility and above all, experience to do a good transfer. This having been said, of all the procedures in IVF this is the most difficult to teach. It is a true “art” and there is little doubt that many women will fail to conceive following IVF simply because their doctor could not perform this procedure optimally.

Good quality embryos are those whose cells (blastomeres) continue to divide at a regular and predictable rate, such that within 72 hours of fertilization they contain 5-9 cells and within 5-6 days, they will have developed into  expanded blastocysts with >100 cells. Such embryos are the ones that are most likely to be “competent” (i.e., able to propagate a pregnancy upon being transferred to a receptive uterus). Conversely, embryos that fail to develop into expanded blastocysts within 5-6 days of being fertilized, are almost invariably chromosomally abnormal (aneuploid), “incompetent” and are unworthy of transfer.

The addition of preimplantation genetic screening (PGS) with full embryo karyotyping (which assesses all the embryo’s chromosomes), markedly improves the ability to select truly “competent” embryos for transfer. The select transfer of such PGS-normal blastocysts, vastly increases the baby rate per embryo transferred, markedly reduces the likelihood of miscarriage, and minimizes the occurrence of chromosomal birth defects such as Down’s syndrome.

Shortly before performing ET, the embryos are put together in a single laboratory dish containing growth medium. The laboratory staff informs the clinic coordinator that the embryos are ready for transfer, and the coordinator prepares the patient and informs the physician that a transfer is imminent.

Ultrasound Guided Embryo Transfer: A Must!

Today all embryo transfers should in my opinion be performed under direct ultrasound guidance to ensure proper placement in the uterine cavity. All other factors being equal, such practice, properly conducted, will significantly enhanced embryo implantation and pregnancy rates.

Optimal Bladder filling to promote visualization:

I prefer to perform all embryo transfers with the patient having a full bladder. This tends to facilitate clear into visualization of the uterus by abdominal ultrasound and the bladder distention causes reflex nervous suppression of uterine contractility, reducing the chance of embryo expulsion. The patient is allowed to empty her bladder 10 minutes following the embryo transfer. In cases where at the time of ET, the bladder is found to be over-full or insufficiently distended this can be readily corrected. In cases of an over-full bladder the patient partially empty her bladder or it can be achieved through deliberate controlled catheterization and drainage. An under-filled bladder can be addressed by increasing fluid intake and monitoring bladder filling ultrasonographically or by catheterization followed by controlled bladder filling with sterile isotonic saline solution.

Adequate relaxation:

  It is important that the woman be as relaxed as possible during the embryo transfer because many of the hormones that are released during times of stress, such as adrenalin, can cause the uterus to contract. Accordingly, we offer our patients, an oral tranquilizer (usually 5mg of oral diazepam or Valium) taken about a half hour prior to the embryo transfer, to relax the woman and reduce apprehension

Some IVF programs believe that imagery helps the woman relax and feel positive about the process and in the process reduce the stress level. In such a program a counselor and/or clinical coordinator may help the woman focus on visual imagery for a few minutes immediately prior to embryo transfer so as to enhance her relaxation.

How Many Embryos should be transferred?

There is an overriding need to minimize the occurrence of multiple gestations, especially high order multiples (triplets or greater). This is because of the risk of prematurity-related complications increase proportionate to the number of babies in the uterus. Unfortunately, there are several confounding considerations in determining how many embryos to transfer at a time:

  1. The stage of development that the embryos have reached by the time of the ET must also be taken into account in deciding how many to transfer. The reason for this is that blastocysts are far more likely to propagate pregnancies than are cleaved (day 2-3) embryos. So fewer blastocysts need be transferred at a time.
  2. The older the woman who produced the eggs, the greater the likelihood that upon being fertilized, the resulting embryo(s) would be “incompetent:”. It follows that the number of embryos that might safely be transferred per IVF procedure (without resulting in a high-order multiple) should be governed by the age of the egg provider. So, while it would be reasonable to restrict the number of “high grade” embryos transferred to a younger woman to one (1) or two (2), the same restriction would be inappropriate and unreasonable in the case of  a  woman in her 40’s receiving embryos derived from the fertilization of their own eggs.
  3. Microscopic grade of the embryos. When a decision on how many embryos to transfer is often based upon the microscopic appearance of such embryos than their microscopic “grade” should be taken into consideration. Since it is less likely that a “lower grade” embryo would propagate a baby than would be the case for one that was of “high grade”, it follows that when it comes to older women, it would be both appropriate and acceptable to transfer more low-grade embryos at a time than were the embryos to be of “high grade”
  4. Embryo genetic “competency”. Since an embryo’s “competence” can largely be determined through PGS.). It is thus is feasible in the case of PGS-normal blastocysts to conduct single embryo transfers

As a rule of thumb however, I tend to transfer one (2) PGS-untested blastocysts to women under 40years and, up to three (3) PGS-untested embryos to the uteri of women > 40 years I support a policy where single PGS-normal blastocysts are transferred to women of any age.

 The Embryo Transfer Process:

When the woman is in the proper position, and her bladder is adequately filled, the physician first inserts a speculum into the vagina to expose and rigorously clean the outer cervix with a sterile, isotonic saline solution to remove any mucus or other secretions, followed by a gentle lavage of the outer cervical canal with Human Tubal Fluid (HTF)  An abdominal ultrasound transducer is placed suprapubically on the lower abdomen to allow clear visualization of the uterus is clearly visualized. Thereupon, using sterile technique, I introduce a sonically activated embryo transfer cannula (with an empty internal catheter through the entire length of the cervical canal until the sonically activated tip reaches the junction of the cervical canal and uterine cavity. The laboratory is then notified to load a catheter with the embryo (s) to be transferred and deliver them to me in the procedure room. At this point the empty catheter is removed from the positioned cannula and the embryo-loaded catheter is passed via the perfectly positioned cannula, to within approximately one (1) centimeter of the top of the uterine cavity, whereupon the embryologist is directed to slowly inject the embryo(s) into the uterus. The passage of the embryos into the uterine cavity can be tracked by ultrasound visualization. A period of about 30 seconds is allowed to elapse, whereupon the catheter and cannula are simultaneously withdrawn slowly. Thereupon, the catheter is immediately returned to the laboratory where it is examined under the microscope to make sure that all the embryos have been released. Any residual embryos would be promptly re-transferred using the same technique.

Frozen Embryo Transfers:

Available evidence suggests that FET (of previously cryopreserved embryos) is at least as successful as is the transfer of “fresh” embryos and might even have the edge. The probably explanation is certainly unlikely to have anything to do with the freezing process itself. The reason likely has to do with being able to better able to prepare the uterus optimally for embryo implantation by using targeted hormone replacement therapy that when a “fresh” transfer is performed immediately following ovarian stimulation with fertility drugs.

 I prefer for my patients to initiate FET cycles with oral contraceptive (OC) starting within 5-6 days of the start of menses to the recipient. This is later overlapped with an “agonist such as Lupron  daily for 5-6 days. The OC is then withdrawn, but the daily Lupron injections are continued until the onset of menstruation. Next, the Lupron dosage is reduced and intramuscular (IM) estradiol valuate (Delestrogen) is administered every 3 days. The objective of the estradiol is to achieve and sustain an optimal plasma E2 concentration of 500pg/ml-1,000pg/ml and a 9mm endometrial lining as assessed by ultrasound examination. Intramuscular (preferably) and/or intravaginal progesterone is administered daily starting about 6 days prior to the FET and continued along with twice weekly IM Delestrogen until the 10th week of pregnancy or until it has been confirmed that the patient is not pregnant. Daily oral dexamethasone commences with the Lupron start and continues until a negative pregnancy test or until the completion of the 8th week of pregnancy. Then it is tapered down and discontinued. The recipient also receives prophylactic oral antibiotics starting with the initiation of Progesterone therapy, until the day after ET. Usually we would thaw vitrified blastocysts with the objective of having 1, 2 or 3 for transfer; depending on a couple’s stated preference. Commencing on the day following the ET, the patient inserts a vaginal progesterone suppository daily and this is continued until the completion of the 8th week of pregnancy or until a negative pregnancy test. An alternative regimen for women who cannot tolerate intramuscular Progesterone (PIO), is to supplant this with daily vaginal Crinone 8% or Endometrin inserts.

Blood hCG pregnancy tests are performed 13days and 15 days after the first progesterone administration is commenced. The beta-hCG level should more-or-less double every 2 days for the pregnancy to be viable. An ultrasound is thereupon performed 2 weeks later to confirm the existence of a viable pregnancy.

4 Comments

Jessica Amos

Hello Dr. Sher,

I had a day 2 IVF transfer on March 30. I had Two fertilized embryos (grade AA and grade B). The doctor said the transfer went very smoothly and I have trying to take it easy. I did acupuncture that afternoon and bed rest the remainder of the day. Unfortunately, the morning after the transfer there was a stressful event that was out of my control. I’m concerned in the wake of the stress and wonder if there is anything I can do to bolster the implanting process. I am taking it easy now – though still running occasional errands and walking my dog – mostly reading and watching movies with my love nearby. I feel optimistic but I am open to anything that could help. Please let me know. Thank you!

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Dr. Geoffrey Sher

It is highly unlikely that the stressful event will determine outcome!

Good luck!

___________________________________________________________
ADDENDUM:
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Hitherto I have personally performed the actual hands-on treatment of all patients who, seeking my involvement, elected to travel to Las Vegas for my care. However, with the launching of Sher-Fertility Solutions (SFS), I will as of March 31st take on a new and expanded consultation role. Rather than having hands-on involvement with IVF procedures I will, through SFS, instead provide fertility consultations (via SKYPE) to the growing number of patients (from >40 countries) with complex Reproductive Dysfunction (RD) who seek access to my input , advice and guidance. In this way I will be able to be involved in overseeing the care, of numerous patients who previously, because they were unable to travel long distances to be treated by me, were unable to gain access to my input.

Anyone wishing to schedule a Skype consultation with me, can do so by: Calling my concierge (Patti Converse) at 1-800-780-7437 for an appointment,enrolling online on my website, http://www.SherIVF.com, or 702-533-2691; or emailing Patti at concierge@SherIVF.com or . sher@sherivf.com .
I was very recently greatly honored in receiving an award by the prestigious; International Association of Top Professionals (IAOTP). For more information, go to the press release on my website, http://www.sherIVF.com .

PLEASE HELP SPREAD THE WORD ABOUT SFS!

Geoff Sher

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Ghezal Levi

Hi Dr. Sher,
I have all my immunological test completed since I had endometriosis and adenomyosis. All came back negative except for slightly high APA’s……would you recommend endometrial receptivity testing., why so or why not? I just have ONE viable embryo and want to transfer it, want to make sure I proceed cautiously and check everything before my transfer.

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Dr. Geoffrey Sher

Others may disagree but I personally am not a believer in ERA. As far as immune testing is concerned, all I can say is it is only helpful if the correct tests were done in the right setting. However, if they are all negative and inn addition your uterine lining reaches at least 8mm by the day of the “trigger” or the day that progesterone therapy is initiated, then yes, I personally would go ahead with transferring that one blastocyst.

Unless tests for immunologic implantation dysfunction (IID) are performed correctly and conducted by a one of the few reliable reproductive immunology reference laboratory in the United States, treatment will likely be unsuccessful. . In this regard it is most important that the right tests be ordered and that these be performed by a competent laboratory. There are in my opinion only a handful of reliable Reproductive Immunology Laboratories in the world and most are in the U.S.A. Also, it is my opinion that far too often, testing is inappropriate with the many redundant and incorrect tests being requested from and conducted by suboptimal laboratories. Finally for treatment to have the best chance of being successful, it is vital that the underlying type of IID (autoimmune IID versus alloimmune) be identified correctly and that the type, dosage, concentration and timing of treatments be carefully devised and implemented.
Who Should Undergo IID testing?
When it comes to who should be evaluated, the following conditions should in always raise a suspicion of an underlying IID, and trigger prompt testing:
• A diagnosis of endometriosis or the existence of symptoms suggestive of endometriosis (heavy/painful menstruation and pain with ovulation or with deep penetration during intercourse) I would however emphasize that a definitive diagnosis of endometriosis requires visualization of the lesions at laparoscopy or laparotomy)
• A personal or family history of autoimmune disease such as hyper/hypothyroidism (as those with elevated or depressed TSH blood levels, regardless of thyroid hormonal dysfunction), Lupus erythematosus, Rheumatoid arthritis, dermatomyositis, scleroderma etc.)
• “Unexplained” infertility
• Recurrent pregnancy loss (RPL)
• A history of having miscarried a conceptus that, upon testing of products of conception, was found to have a normal numerical chromosomal configuration (euploid).
• Unexplained IVF failure
• “Unexplained” intrauterine growth retardation due to placental insufficiency or late pregnancy loss of a chromosomally normal baby
What Parameters should be tested?
In my opinion, too many Reproductive Immunologists unnecessarily unload a barrage of costly IID tests on unsuspecting patients. In most cases the initial test should be for NK cell activation, and only if this is positive, is it necessary to expand the testing.
The parameters that require measurement include:
o For Autoimmune Implantation Dysfunction: Autoimmune implantation dysfunction, most commonly presents with presumed “infertility” due to such early pregnancy losses that the woman did not even know she was pregnant in the first place. Sometimes there as an early miscarriage. Tests required are: a) blood levels of all IgA, IgG and IgM-related antiphospholipid antibodies (APA’s) directed against six or seven specific phospholipids, b) both antithyroid antibodies (antithyroid and antimicrosomal antibodies), c) a comprehensive reproductive immunophenotype (RIP) and, c) most importantly, assessment of Natural Killer (NK) cell activity (rather than concentration) by measuring by their killing, using the K-562 target cell test and/or uterine cytokine measurement. As far as the ideal environment for performing such tests, it is important to recognize that currently there are only about 5 or 6, Reproductive Immunology Reference Laboratories in the U.S capable of reliably analyzing the required elements with a sufficient degree of sensitivity and specificity (in my opinion).
o For Alloimmune implantation Dysfunction: While alloimmune Implantation usually presents with a history of unexplained (usually repeated) miscarriages or secondary infertility (where the woman conceived initially and thereupon was either unable to conceive started having repeated miscarriages it can also present as “presumed” primary infertility. Alloimmune dysfunction is diagnosed by testing the blood of both the male and female partners for matching DQ alpha genes and NK/CTL activation. It is important to note that any DQ alpha match (partial or complete) will only result in IID when there is concomitant NK/CTL activation (see elsewhere on this blog).
How should results be interpreted?
Central to making a diagnosis of an immunologic implantation dysfunction is the appropriate interpretation of natural killer cell activity (NKa) .In this regard, one of the commonest and most serious errors, is to regard the blood concentration of natural killer cells as being significant. Rather it is the activity (toxicity) of NK cells that matters as mentioned. Then there is the interpretation of reported results. The most important consideration is the percentage of target cells “killed” in the “native state”. In most cases a level of >10% killing should be regarded with suspicion and >12% overtly abnormal. In my opinion, trying to interpret the effect of adding IVIG or Intralipid to the sample in order assess whether and to what degree the use of these products would have a therapeutic benefit is seriously flawed and of little benefit. Clinically relevant NK cell deactivation can only be significantly effected in vivo and takes more than a week following infusion to occur. Thus what happens in the laboratory by adding these products to the sample prior to K-562 target cell testing is in my opinion likely irrelevant.
There exists a pervasive but blatant misconception on the part of many, that the addition of Intralipid (IL) /immunoglobulin-G IVIG) can have an immediate down-regulatory effect on NK cell activity. This has established a demand that Reproductive Immunology Reference Laboratories report on NK cell activity before and following exposure to IVIG and/or IL. However, the fact is that activated “functional” NK cells (NKa) cannot be deactivated in the laboratory. Effective down-regulation of activated NK cells can only be adequately accomplished if their activated “progenitor/parental” NK cells are first down-regulated. Thereupon once these down-regulated “precursor” NK cells are exposed to progesterone, they will begin spawning normal and functional NK cells, which takes about 10-14 days. It follows that to assess for a therapeutic response to IVIG/IL therapy would require that the patient first be treated (10-14 days prior to embryo transfer) and thereupon, about 2 weeks later, be retested. While at 1st glance this might seem to be a reasonable approach, in reality it would be of little clinical benefit because even if blood were to be drawn 10 -14 days after IL/IVIG treatment it would require an additional 10 days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.
Neither IVIG nor IL is capable of significantly suppressing already activated “functional NK cells”. For this to happen, the IL/IVIG would have to down-regulate progenitor (parent) NK cell” activity. Thus, it should be infused 10-14 several prior to ovulation or progesterone administration so that the down-regulated “progenitor/precursor” NK cells” can propagate a sufficient number of normally regulated “functional NK cell” to be present at the implantation site 7 days later. In addition, to be effective, IL/IVIG therapy needs to be combined with steroid (dexamethasone/prednisone/prednisolone) therapy to down-regulates (often) concomitantly activated T-cells.
I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation (COS)
• The Fundamental Requirements for Achieving Optimal IVF Success
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management 🙁 Case Report)
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; how it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!

I urge you to set up a Skype or an in-person consultation with me. To do so, simply call 1-800-780-7437 (if you reside in the U.S.A or Canada) or 702-533-2691 (if you reside elsewhere). Alternatively you can enroll online by going to the home page of the Sher-IVF website, http://www.SherIVF.com where, upon completing an enrollment form), you will immediately be eligible to download my new book, “Recurrent Pregnancy Loss (RPL) and unexplained IVF Failure: The Immunologic Link”, free of charge.

Geoffrey Sher MD

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