STEP SEVEN: EMBRYO TRANSFER
In my previous entries, I have been discussing each of the steps involved in In Vitro Fertilization (IVF). By this point, the ovaries have been stimulated with fertility drugs to recruit and grow follicles, where the eggs are located, these follicles have been aspirated to retrieve the eggs, the eggs have been put with the sperm and allowed to fertilize and the fertilized eggs, now embryos, have been cultured and allowed to grow. We are now at the step where the embryos have to be returned into the womb (uterus) for the final stages to occur so that a pregnancy can result. Embryo transfer is essentially the last step for IVF and the farthest this technology can take us to influence whether or not a pregnancy can occur. This is the step that replicates the natural step where the embryo enters the uterus. From that point, the embryo has to hatch out of its shell and attach to the uterine lining, and then the lining has to grow around the embryo, which is implantation. At that point, beta HCG hormone will be produced and testing for this hormone will be detectable by blood testing. This is a positive pregnancy test. So, as you can now understand, IVF is NOT a perfect technology and, in reality, cannot get make you pregnant. It can help you to become pregnant or expedite the natural process. It still requires your body or nature or God to influence the final steps so that a pregnancy can ensue. Because of the limits of current technology, we cannot yet attain 100% pregnancy rates.
Failure after the embryo transfer of good embryos is often referred to as "implantation failure" but this is not necessarily the cause of the failure. There are many little steps in this final process, which I will explain, that influence whether or not actual implantation will occur. If you fail an IVF cycle, it may not necessarily indicate that there is something wrong with you. It could be the embryo’s fault, the doctor’s fault, the uterine lining’s fault or your body’s fault. Unfortunately, there is no testing that can be done at this step to help with the specific identification of what did not occur and so it is lumped into one big category, “implantation failure.”
The exact protocols and procedures done at the embryo transfer step can vary widely among clinics. They can vary even among doctors in the same clinic. I’m sure that I will not be able to explain all or cover all variations, because many are clinic, country and physician specific, but I will mostly cover the protocol that I use, and of course, think is the best way. But don’t fault your doctor if they don’t do it the same as I do. I’ll try to generalize as much as possible.
In most clinics, the doctor doing the transfer will meet with the patient to go over the findings of the embryo culturing and reveal how many embryos are available to transfer, what they look like and give some type of recommendation as to how many to transfer. The number to transfer will likely depend on the patient’s age, the quality of the embryos (based on their appearance) and specific regulations or laws governing the clinic. An example of the latter is that many European countries with a large Catholic base disallow transferring more than one embryo. In the U.S., we don’t have a specific law or regulation that restricts the number of embryos to transfer, but most clinics are members of the Society for Assisted Reproductive Technology (SART), a division of the American Society for Reproductive Medicine (ASRM), which over sees IVF, and the society has specific recommendations for the number of embryos to transfer for each age group and based on embryo quality. This was put into place because of the desire and need to reduce the incident of multiples (twins or higher) that occur with IVF. When evaluating clinics and their pregnancy rates, that is something you may want to look at. Studies have shown a near equivalent pregnancy rate with single embryo/blastocyst transfer but all those studies don’t look at per cycle rates but cumulative rates. That is, it may take two to three cycles to get the same pregnancy rate as a clinic that transfers two to three embryos in a single cycle. But it seems that those single embryo transfer rates are getting better and closer to multi-embryo transfer rates per cycle. Eventually we will probably have the technology to identify the perfect embryo in its entirety so that we can just choose one to transfer and not have to hedge our bet by transferring more than one. At this point in time, we don’t have that ability. So this is one aspect of IVF that you might want to check on when choosing an IVF clinic, that is, do they have a policy that restricts you to single embryo transfer (SET) and what is their per cycle pregnancy rate.
Prior to the embryo transfer, my procedure is to meet with the couple and do a review of the cycle up to that point, explaining each step and the results. I then show them a chart that indicates where each embryo is in terms of the number of cells they have attained to that point, and the quality based on how they look (grading). I also show them a chart that has tracked their development each day so that we can see how each embryo has evolved and to verify that they are dividing at a good rate. This latter chart or evaluation is important because it is one way to help determine which embryos are behaving as healthy embryos versus ones that are not dividing well, or unhealthy. This also helps to eliminate embryos from being transferred and that are eligible for freezing. I will then provide them with a counseling sheet, that they sign, that shows what the SART recommendations are and what category they fit into based on their age. I also give them my personal recommendations and share my multiple gestation rate based on how many embryos were transferred (this is based on cumulative data over the 18 years I have had my clinic and when we were transferring a lot more embryos than we do now). I am not yet personally confident about single embryo transfer and so do not encourage it unless a patient does not want to take the risk of a twin pregnancy at all. I average transferring two embryos now and try to follow the SART guidelines. I rarely do single embryo transfers but again, keep in mind that this is a personal preference and I don’t like to risk a failed cycle with my patients. There are many clinics that now only do single embryo transfers and, as long as their pregnancy rates support that decision on a per cycle basis, then that is fine. If their per cycle pregnancy rates suffer because of this policy then I feel they are not taking the patient’s emotional and financial risks into consideration.
Because I usually transfer two to three embryos, I make sure to explain the risks associated with a multiple gestation, especially the risk of loss of the pregnancy due preterm delivery, as well as, the complications that can cause the pregnancy to be a hardship for the patient. Ultimately I believe the patient has the right to make the decision, since they are paying for the procedure, but, at the same time, I will not allow them to go overboard on how many to transfer and make a poor decision, so the ultimate decision is a combination of their choice, as well as, my endorsement of that decision. Once we have had this discussion, we then decide which specific embryos to transfer. Due to the lack of any other technology to help us decide which embryos are the best embryos, we will choose the two embryos that look the best (highest grade) and have been developing appropriately. In my consultation sheet, I indicate which two embryos this will be so that the embryologist knows what we chose. I then also recommend what to do with the remaining embryos as to whether to freeze, culture further or discard them. I then indicate those specific choices as well on our transfer form. Finally, the patient signs this transfer form to verify their choices since, after all, the embryos belong to them and we need their permission to do anything with their embryos.
PRE-TRANSFER PATIENT PREPARATION
In this step, clinics will vary highly so this is only a guideline based on what I do. It may not be the only way or the way your doctor proceeds. I put on sterile gloves and then measure the embryo transfer catheter and mark how far the catheter should be inserted. This measurement is based on the MET (mock embryo transfer) that I did prior to the start of the IVF cycle. Before the ultrasound was used to verify the position of the catheter (ultrasound guided embryo transfer), this measurement was the only way that we knew where to put the embryos. Fortunately, someone was smart and astute enough to think to use the ultrasound to help identify the position of the catheter within the uterus, which I think immensely helped increase pregnancy rates. Since doing ultrasound guided transfers, I have had many situations where I changed the position of the catheter beyond the original measurement based on the ultrasound visualized position. In any case, I still mark the position on the catheter just in case I am unable to visualize the catheter by ultrasound, which can happen in heavier patients, patients with retroflexed uteri and patients without sufficient urine in their bladder. It’s my back-up.
The embryologist will then come to the transfer room and I will give her (it’s a her in my clinic and this is not intended to be sexist), and recite the name of the patient and the number of embryos to be transferred. The embryologist then repeats that information back to me. This is my protocol for verifying the identity of the patient and to make sure the embryologist knows who the patient is as well. From this point, the embryologist returns to the laboratory to load the appropriate embryos into the catheter. Some clinics with multiple embryologists might have an additional identity verification step in the lab when the embryos are being drawn into the catheter where a second embryologist recites the name of the patient and confirms that the identifying information for the embryos is the same as the name they’ve recited. Our embryos are strictly identified as to which incubator they are in and where in the incubator they are placed, as well as, identifying information on the Petri dish. The petri dishes are placed apart and in unique positions i.e. different incubators, different racks and different positions on the rack, so that they don’t get mixed up. All that information is noted in the embryologist’s log. Verification of all this information is part of the embryo identification protocol.
In the meantime, I then prepare the patient for the procedure. The patient is placed into the lithotomy position, the same position as doing a pap smear. In the center where I trained, the patient was placed either on her tummy with the bottom up or on her back in the lithotomy position based on whether the uterus was angled up or toward the back. That type of positioning has not been shown to make any difference in pregnancy rates so I just use the one lithotomy position. In patients with a uterus that is angled up (anteverted or anteflexed), I will tilt the bed a little more so that the patient’s head is lower than her bottom but not so steeply that she is uncomfortable. Again, using sterile gloves and sterile technique, a sterile speculum is placed into the vagina. I will then irrigate the cervix and surrounding area with culture media using a forceful but gentle squirting technique. No antiseptics are used because this can kill the embryos. Next, I remove my first set of gloves and help position the abdominal ultrasound transducer to find the uterus, and make any adjustments I need to make to the ultrasound machine. My assistant has been trained to do this as well and holds the transducer in the proper position. That frees me up to do the transfer procedure. Because the ultrasound sound waves have to pass through the abdominal tissues of fat and muscle to reach the uterus, there has to be adequate filling of the bladder for the sound waves to pass through and get deep enough to see the uterus. Too much filling is just as bad as not enough because it pushes the uterus further back and farther away from the ultrasound transducer. A bladder that is uncomfortably full can also cause bladder spasm, causing pain, and uterine contractions which will adversely affect the chances of pregnancy. Inevitably there are cases where we can’t proceed with the transfer because the bladder is not full enough and therefore have to allow the patient to drink and fill her bladder, or have to have the patient go to the bathroom to let out some urine or sometimes use a bladder catheter to drain some. But if the bladder is filled properly, we can see the uterus and, more importantly, the endometrial lining so that we can see the catheter pass within. We are then ready to proceed with the transfer procedure.
By now, the embryologist returns to the transfer room with the loaded catheter. As she enters the room, she again recites the name of the patient for verification. Both I and the patient acknowledge that she is correct. I then put on new sterile gloves, since I will be handling the catheter with the embryos. Since most uteri are angled, and since I already know the specific direction of the patient’s canal based on the previously performed MET that I have documented on an MET form, as well as, what I know from her previous ultrasounds, I will usually need to put a curve in the introducer. I use an embryo transfer catheter that has an outer sheath (introducer) through which the catheter passes. The embryo transfer catheter is very very soft and without an introducer, would get stuck in the crevices of the cervical canal. The introducer helps it to pass through the canal and get into the endometrial cavity. I put the curve in the introducer after the catheter has been pulled back a bit so as not to squeeze the catheter inadvertently (that would be very bad because the embryos could be pushed out from that pressure). Sometimes in doing the transfer it can take several attempts to place the introducer because it can take several attempts to get the right angle, or the introducer doesn’t hold the angle long enough. I then advance the introducer into the cervix to the point of the internal cervical os but not farther. I do not advance the catheter with the embryos through the introducer until I know that the introducer is in the proper place, just beyond the internal os. I don’t want any resistance or difficulty advancing the catheter, which could influence pregnancy rates.
The technique of the embryo transfer is one of the most important steps in IVF. I cannot emphasize that enough. It is this technique that usually causes varying pregnancy rates among doctors. This step is important because even if you have the most beautiful and healthy appearing embryos, if the transfer is not done properly and with utmost gentleness, pregnancy will not occur. Many studies have been done comparing transfer techniques among Physicians and even among Physicians in the same group and found wide variations in pregnancy rates. This is attributed to the technique of and gentleness of the embryo transfer. It is absolutely critical that no bleeding is induced, because blood is toxic to the embryo, and that the back of the uterus is not touched, which can cause uterine contractions leading to failure. For this reason, I consider it very important that the Physician doing the transfer knows your uterus because he/she has done the MET before and practiced the transfer, and is not learning your cervical canal and uterine cavity for the first time. This point is especially important if you have a very deviated, curving or abnormal cervical canal. This is a problem with many, if not most, large IVF clinics because you may have the transfer done by a doctor that has never met you due to their cross-coverage schedule.
I also think that this is where experience is very important. You want to choose a doctor that has done a lot of embryo transfers. A recent study in the U.S. found that a Fellow (an Ob/Gyn doctor undergoing specialty training) graduating from an infertility fellowship (advanced training) in the U.S., has only done an average of three embryo transfers. That would be like a new doctor that has only done three cases in a specific surgery. Essentially, they are not yet expert in that technique or surgery and therefore still need to “practice”. I agree that all doctors need to gain experience when they are just starting out, and most fellowship programs are unable to allow an untrained doctor to learn on their cash paying patients, but if you have a choice and since you are spending $10,000 or more for this treatment, just like with surgery, wouldn’t you want the doctor with the most experience so that you have the best chance of success?
To continue: so now, the introducer is in place and the catheter is very gently fed through the introducer into the endometrial cavity to a point that had been pre-measured. The ultrasound also helps to see the catheter tip to verify its location and make sure that it is in the proper place. If the catheter is seen as not in the proper place, then the position is adjusted to put it in the correct position. Technically the catheter is not placed all the way to the end of the endometrial cavity. Studies have shown that the optimal placement is 0.5 to 1 cm from the top of the endometrium. The embryos are then very slowly injected into the cavity. The embryos are within a bubble of culture media so that fluid injected can be seen but the embryos cannot because they are too small. I then allow the embryos to settle for 30 seconds but that is how I was trained. Other doctors may just quickly remove the catheter which is okay as well. Studies show no difference. From this point, I tell my patients not to move, cough, sneeze, laugh or talk above a whisper in order to minimize abdominal pressure on the uterus. Again, this is a precaution I take but probably is not an absolute necessity. I then return the catheter to the embryologist and she returns to the lab to verify that the embryos have been expelled. Sometimes embryos will reflux back into the catheter. Studies have shown that if the refluxed embryo is returned to the uterus immediately, pregnancy rates will drop because of the likelihood of disturbing the embryo that remained. In some cases, the previous placed embryo can be aspirated with the second procedure and be injured. For this reason, my recommendation is not to do a second procedure to replace the refluxed embryo. It is left out and allowed to be frozen. I have already counseled my patients about this possibility in the pre-transfer counseling so the plan is already set. The only situation where I would repeat the procedure is (1) if all the embryos refluxed and there are none left inside, which can occur when mucus plugs up the catheter opening, or (2) if the best embryo refluxes in a group where several embryos are being placed and the other embryos are poor quality (as in a patient that has a low number of embryos to transfer).
Once the embryologist informs me that there were no refluxed or retained embryos, we then place the patient in position to rest for 30 minutes. It is my protocol to have the patient rest after the transfer, more for psychological reasons than medical reasons. In fact, studies have shown no differences in pregnancy rates if the patient rests or gets up right away. Since the patient is in lithotomy (pap smear) position, and we don’t want the patient to use any muscles to move into place, I put the table into a head down or trendelenberg position (this is where the patient is tilted to be head down). In this position, I and my assistant have the assistance of gravity to easily slide the patient up to the top of the bed without the patient pushing. I then return the bed to a flat position so that she can rest.
From this point in the overall IVF treatment, the patient continues the medications that were started at the time of the egg retrieval to support the luteal phase and prepare the endometrium for implantation. Again, these medications and hormones are to help with the implantation step but cannot make implantation take place.
So now the IVF procedure is essentially done. There are no other techniques or procedure to be done because this is the extent of the technology. The process is again a natural process from this point. The embryo needs to continue developing to a blastocyst, if it was a day #3 transfer, needs to hatch out of its shell, attach to the endometrium and then the endometrium needs to engulf or grow around the embryo (implantation). Failure at any one of these remaining steps can cause failure in the cycle. As mentioned previously, if the transfer is not done well, then despite having the very best embryos, failure will occur. Also, if the embryo does not continue its development to the blastocyst stage then that is the end of the process; or if the embryo does not exit (hatch) from its shell, then it will not be able to attach to the endometrium and that is the end of the process; or if the endometrium does not engulf the embryo because it is not in the correct anatomical form, timing is not correct, or other possible factors that we don’t completely understand, then the process is at an end. Any of these factors can lead to what we refer to as “implantation failure” and is the reason why we often don’t have solutions for failure at this step. Some people might ask about “assisted hatching” which I have not explained yet. Assisted hatching is where a small hole is placed into the shell of the embryo. All it does is give the shell a defect where the inner embryo can emerge from, but the process of emerging or hatching is still dependent on factors within the embryo. So having assisted hatching does not guarantee that the embryo will in fact hatch out of the shell. However, in older eggs, where we know the shell is often too thick or if the embryologist measures the zona (shell) and finds that it is too thick, it may be a good idea to have assisted hatching done.
I would also like to mention some technologies that have been advertised that are not yet verified and accepted universally. One of those is laser drilling of the endometrium, where a small laser is introduced into the endometrial cavity to make a hole where the embryo can be placed. You need to understand that implantation is NOT the embryo making a hole and burying itself into the endometrium, rather, it is the process by which the endometrium grows around the embryo. As logic dictates, making a hole probably does nothing to help the process. A second technique that I have heard of is using “embryo glue”. I don’t have detailed information about this “glue” since it is proprietary, but again, this may help the embryo to stabilize itself in a certain point in the endometrium, but it does nothing to help the embryo hatch out of the shell or help the endometrium to grow around the embryo. So, again logic dictates that it doesn’t make sense for this to help with implantation. As a result, and expectedly, neither of these techniques have been shown to be of benefit in any legitimate studies.
THE TEN DAY WAIT
So we have now come to the end of the IVF procedure and the maximum that our technology can help a person to achieve a pregnancy. We are at the point where we have to wait to see if the next steps happen on their own. If a day #3 transfer was done, it will take approximately 7 days for the remainder of the process to be completed and for the pregnancy test to be positive. For that reason, I do my pregnancy tests at 8 or 9 days post transfer. For a blastocyst transfer, you only need three more days to get a positive pregnancy test. I know that some clinics want to be absolutely sure so they wait for 14 days but the problem with that protocol is that an early chemical pregnancy will be missed, and in my opinion, it is important to know if a chemical pregnancy occurred or not. This event is important to know because it verifies that the patient can become pregnant with IVF and that the last steps actually occurred. With that knowledge the patient can be reassured that this treatment can work, that her body can do what it needs to do, and it is just a matter of getting a perfect embryo into her womb for her to be successful. The majority of chemical pregnancies occur because the embryo is genetically abnormal. It would be good to know that those last steps, those steps that are beyond our technology, can occur on their own.
Before I leave the patient to rest after the embryo transfer, I say a little prayer because I know that this is the point where God takes over, and so I will leave this prayer for you to use if you wish to pray to whichever God you believe in: “Dearest Lord God, Bless this couple with fruit of the womb and Grant their wish for a Child. We ask this through your Son, Jesus Christ. Amen”. I hope that this series has been valuable to your understanding of the process that you will be or are going through, and I wish you the best of luck and blessings to eventually realize the wonderful dream of having a child. It may seem very expensive, arduous, stressful and emotionally draining but when you are successful and hold that baby in your hands, you will realize that it was more than worth what you went through.
My mother used to always tell me that “if you want something bad enough and it is something very valuable, there will be no easy way to get there and you will have to work harder for it.” She was referring to careers and my desire to become a doctor, but as a former IVF patient, I know that this same advice applies to doing IVF as well. It is neither an easy path nor a guaranteed path. With the technology that is now available in fertility treatments, the only thing that can cause you to ultimately fail is yourself, when you give up trying. Otherwise, if you are open to all the options available and want a baby bad enough, you only have to choose to keep trying, consider all your options, revise your strategy and not forget to look forward to your goal, the success in the end; holding that new baby, and not the failures of the past or the path you had to go through.
God Bless you on your journey.
Edward J. Ramirez, M.D. F.A.C.O.G.
Medical Director, Monterey Bay IVF