Saturday, July 28, 2012
This is the fourth part in the series I have begun to help answer what In Vitro Fertilization (IVF) is and how it works with my world-wide Blog audience. What you read here is what I also provide my patients with on a daily basis. I plan on going into some detail but in a way that is understandable to the normal (lay) audience, and not the medical or scientific one. I also hope that this will not only clarify what you will go through, but explain why things are done a certain way and what the goals of each step are. I also want to convey that IVF is actually a replacement for some of the “natural” steps required to get pregnant and not some miraculous high tech fertility treatment that gets patients pregnant artificially, as many think it is. It is somewhat of a miracle that we can do as much as we can, but there are still lots of things/steps that we cannot do or influence. I hope this discussion will benefit you. This series will continue to be posted over the next few weeks in installments.
STEPS THREE AND FOUR: EGG RETRIEVAL
Thus far, we have covered the first two steps in the reproductive process. In the natural process, the brain has sent signals to the ovaries to recruit and grow the follicle and mature an egg within. The same process has been done in IVF through stimulation by the fertility medications. The follicles have grown and the eggs within have gone through their maturation process. In a natural cycle, one follicle will rupture and the fluid will rush out, taking the egg with it, and empty into the cul-de-sac. The egg will then have to find its way to the fimbriated end of one of the fallopian tubes. Follicular aspiration is the way that IVF accomplishes the ovulation step so that the egg can be retrieved. It is also the method that the egg and sperm are brought together, and therefore, a substitute for finding and being picked up by the tube.
Egg retrieval is technically known as "transvaginal ultrasound guided oocyte (egg) or follicular aspiration". It is a relatively safe procedure and simply put, just a needle poke, like drawing blood. There are some potential risks to this procedure, as with all medical procedures, such as causing bleeding, infection, organ injury or pain but these risks are very minimal and rarely occur. As with all surgeries or procedures, the experience of the physician directly influences the risks. The more experience a physician has doing the procedure, the lower the risks. In many centers, some form of conscious sedation is used so that the patient does not move or feel pain. Despite the quick duration of the procedure, the ovaries are very sensitive and can elicit a large amount of pain. There are some clinics that do not use any sedation, however, and a few that still use general anesthesia where the patient is intubated.
Some clinics will use an Anesthesiologist or Nurse anesthetist to give the conscious sedation and monitor the patient during the procedure. The safety of this set-up is that the physician doing the procedure does not have to be distracted by constantly thinking about the patient’s vital signs, and thus will be able to concentrate fully on just the aspiration part of the procedure. Also if the patient has any difficulties, such as difficulty breathing, bronchospasm, inadequate sedation or increased movement, the Anesthesiologist can attend to it without the fertility physician having to stop the aspiration procedure. The procedure takes 5-20 minutes to perform depending on the skill of the physician, the number of follicles to be aspirated and whether or not the physician uses a technique of follicular flushing (rinsing out the follicle with culture media after the initial aspiration).
The procedure proceeds as follows:
The patient is placed into an operating suite or procedure room, vital sign monitors are placed, the patient is put into the lithotomy (or pap smear type) position and the sedation medication given. In some cases, sterile drapes are put in place, but this is not absolutely necessary. In most clinics, a vaginal speculum is placed and the vagina irrigated with sterile water. Betadine or similar antiseptics are NOT used because they could be lethal to the egg if the solution contaminates the aspiration needle. Local anesthesia is not used in this procedure. Once the vagina has been thoroughly irrigated, the speculum is removed. Just as was done with a vaginal probe to view and monitor the follicular growth, a vaginal probe is used to visualize each ovary, but in this case, a needle guide has been mounted to the probe. This needle guide is so that a needle can be directed to where the probe is pointing. The vaginal ultrasound probe, with the needle guide mounted, is then placed into the vagina once the patient is sedated, and a quick inspection of the ovaries are carried out to verify position and confirm that the follicles are intact. If ovulation had occurred prematurely, the follicles would be absent. The probe is placed toward one side so that it can clearly see one ovary.
With IVF, the ovaries usually fall into the cul-de-sac, a space behind the uterus, which is located just on the other side of the vaginal wall, so the probe is actually millimeters away from the ovary and the ovary can be seen clearly. In addition, the probe is almost in direct contact with the ovary. There is only a small amount of vaginal wall between the probe and the ovary. The needle can then be easily passed through the vaginal wall, into the ovary and into the first follicle to be aspirated. Once within the ovary, it can then be moved from follicle to follicle to aspirate (or vacuum extract) the fluid within the follicle. It does not need to be removed and reinserted for each follicle. Basically the physician will move from follicle to follicle aspirating each follicle until all the fluid is removed. If the physician uses a flushing technique, the fluid will first be aspirated then culture media is injected back into the follicle and aspirated. This is done several times. Some physicians use this technique because that is how they were trained. There is no advantage of using flushing over not using flushing on pregnancy rates, but flushing may help to make sure that an egg is either retrieved or not present, especially if there are only few follicles as occurs with poor responders. The downside of this techniques is that is lengthens the retrieval procedure and so more sedation medication is required.
If the egg within the follicle has matured, and assuming that there was an egg within the follicle because not all follicles have eggs, the egg releases from the follicle wall and is floating within the follicular fluid. The exact physiologic process is more detailed than can be explained here, but suffice it to say that the egg is surrounded by a layer that is congruent with the wall of the follicle. As it matures that connection slowly gets pinched off and the egg is released from the wall. If the egg does not reach maturity, it will usually stay attached to the wall. That is why it is important for the physician to determine when is the appropriate time to trigger the follicle with HCG and schedule the aspiration/retrieval. This is another place where the “art” of IVF comes into play and experience plays an important role. Usually once the appropriate follicle size has been reached, the trigger is scheduled so that it is 34-39 hours prior to the time of the retrieval. Most clinics will schedule the retrieval to be at 36-37 hrs.
So by aspirating the follicular fluid, the egg is retrieved from that follicle. The physician will work on one ovary at a time and aspirate each follicle on that side. Once that is completed, then he or she will move to the second ovary and aspirate all the follicles on that side. The follicular fluid with the egg is aspirated, using a specialized aspiration machine with a low aspiration pressure, into a tube that has been prepared with a special culture media. A special 16 or 17 gauge aspiration needle is also used. As the needle is placed into the follicle, the end of the needle can be seen via the ultrasound as a bright echo. This allows the physician to know where the needle tip is at all times to prevent injury to other structures.
The aspirated fluid, collected in a test tube (hence the name “test tube baby” ) is then passed to the embryologist. The embryologist empties the fluid into a small plastic dish and looks for the egg using a high powered microscope. Some of the tubes will not have an egg within because either the egg did not mature and release from the follicle wall, or there was no egg within the follicle i.e. the follicle was empty. Once an egg is identified, the embryologist will move it into a special petri dish or other prepared dish with culture media. This is the dish that the eggs will stay in as it develops into an embryo. The eggs will then be placed into an incubator that has a set temperature, humidity and gas content within so that there is a stable and idealized environment for embryo growth. Fertilization is then the next step in the process.
In the meantime, the patient is awakened, most don’t remember anything that has occurred and enjoyed a short sleep, and moved to a recovery bed or returned to her recovery area. My clinic has individual rooms where the patient is prepared for the procedure and then returned to for her post-procedure care. Many clinics have an open recovery room area, and each patient is separated by a curtain. She is then closely watched by a nurse for 30 minutes to 1 hour to make sure that the sedation has cleared her system, that she remains stable and that there are no signs of any complications. She can take fluids orally at this point (we don’t allow food or drink prior to the procedure).
Once she has met criteria for discharge, she is allowed to go home. My criteria for discharge is that she will need to be able to take and keep down oral fluids, that her vital signs, especially the pulse, remain stable and within normal limits, that she is able to sit upright without getting dizzy and that she can urinate prior to leaving the recovery area. Because we place an intravenous catheter and run IV fluids in our patients, she will receive sufficient fluid to have an urge to urinate by the end of her stay. Most patients will be able to walk out of the clinic on her own after this procedure. From a pain perspective, there is some cramping that occurs immediately after the procedure, but by 30 minutes it is mostly gone. It usually does not need anything more than a warm pad on the stomach or mild nonsteroidal pain medication to relieve the pain. Most patients will not need a pain medication prescribed when they go home. Patients are directed to remain at very light activity, what I call “couch potato rest”, for the duration of the day. They do not need to remain in bed, and I do not encourage it. They should not engage in any strenuous activities, even long walks, or intercourse for 24-48 hours. I usually will prescribe antibiotics for a short course to reduce the chances of pelvic infection, but not all clinics do this. It is also at this point that patients will start their progesterone supplementation which starts the luteal phase of the endometrium in preparation for implantation.
We will continue this discussion soon with the next installment, "Step Five: "Fertilization". Thank you for joining me today! Edward J. Ramirez, M.D. F.A.C.O.G. Medical Director, Monterey Bay IVF Monterey, CA http://www.montereybayivf.com/
Sunday, July 15, 2012
This is the third part in the series I have begun to help answer what In Vitro Fertilization (IVF) is and how it works with my world-wide Blog audience. What you read here is what I also provide my patients with on a daily basis. I plan on going into some detail but in a way that is understandable to the normal (lay) audience, and not the medical or scientific one. I also hope that this will not only clarify what you will go through, but explain why things are done a certain way and what the goals of each step are. I also want to convey that IVF is actually a replacement for some of the “natural” steps required to get pregnant and not some miraculous high tech fertility treatment that gets patients pregnant artificially, as many think it is. It is somewhat of a miracle that we can do as much as we can, but there are still lots of things/steps that we cannot do or influence. I hope this discussion will benefit you. This series will be posted over the next few weeks in installments.
STEP TWO: FOLLICLE GROWTH AND EGG MATURATION
Under the influence of FSH (follicle stimulating hormone), dormant follicles within the ovary start to grow. Measurement of the dormant follicle number is called the “antral follicle count (AFC)” and also measured by the “Anti-Mullerian Hormone (AMH)”. Both these measurements are used to give one an idea of the ovarian capacity to be stimulated, also known as ovarian reserve, similar to the FSH level. They are additional indirect measurements. Many physicians and patients believe that these two measurements actually tell them how many eggs are left within the ovaries, but that is too broad an interpretation. We do not have the technology to know how many eggs are present without doing a careful dissection of the ovaries. So these are indirect measurements that serve to give warning about your fertility. Their only use is to help predict, as much as possible, whether the ovaries will yield many follicles upon the hyperstimulation that occurs with giving increased amounts of FSH.
So the real interpretation of a low AFC or AMH is that there might be a lower number of follicles produced, and consequently less eggs retrieved. As explained previously, these are additional measurements of “ovarian reserve.” They only predict success from a statistical point of view because part of how IVF enhances your chances of fertility is by increasing the number of eggs that are available for fertilization and hence the number of embryos and hence the increased chance of finding the perfect embryo that will lead to a pregnancy as explained in the previous segment. It is a total misunderstanding or misinterpretation to say that a low AFC or low AMH indicates that you are infertile, that your ovaries won’t stimulate or that you won’t have good eggs! Taken together with an elevated FSH, these measurements serve as red flags from a time point of view. It means that you may not have as much time to get pregnant using your own eggs as you might have thought. Since we cannot predict when you will run out of time, time becomes a critical consideration.
Currently, transvaginal ultrasound is used to monitor the follicular growth by simply measuring the follicles. This measurement is usually an average diameter taken from a horizontal and vertical measurement of the follicle and reported in millimeters (mms). As the ovary is stimulated with FSH, some of the follicles will grow. Follicles grow approximately 2 mms per day so there is some predictability of when the follicles will reach the appropriate size for ovulation or retrieval. As the follicle expands, Estradiol hormone is produced in increasing amounts by the growing follicle and so estradiol levels can be monitored to also help determine progress as well. With IVF, the goal is to have 15-20 total follicles and estradiol levels between 2000-4000. Each mature follicle will produce approximately 150-250 of estradiol. In IVF, we want to keep the estradiol level at less than 4000 because if there are more than 20 growing follicles and the estradiol level goes above 4000, there is an increased risk for an illness called “ovarian hyperstimulation syndrome”. That is a whole other topic so it won’t be explained here. Suffice it to say that OHSS has the potential to cause death in its worst form. A competent physician with experience doing IVF will take appropriate precautions to prevent this from occurring.
It is known that the follicle has to reach an average diameter of a minimum of 15 mms for the egg within to be mature. We cannot see the egg because it is microscopic size. Therefore, maturation is assumed by the size of the follicle, as has been shown in early IVF studies. With most IVF clinics, a follicle is deemed to be mature size and appropriate to trigger once it has reached at least 18 mms, but it can be as low as 15 mms based on previous studies. Because the follicles will grow unevenly, meaning there will be some that grow faster and some that grow slower, most physicians will trigger with HCG when the largest 2-4 follicles reach maturity size, or when the highest number are between 15-24 mms. My preference is for the larger follicles to be 20-24 mms which I have decided to use based on my long term experience. I don’t necessarily trigger when the largest ones reach that size but, rather, I want to get as many follicles into the mature stage as I can without losing the larger ones or have too many smaller ones. The problem with smaller sized follicles is the eggs within them will not have had adequate time to mature and so will be unusable. Also, follicles that grow to over 24 mms tend to have eggs that are over-mature and therefore not viable. Once the majority of the follicles reach a size of 20-24 mms, then you are ready for the “trigger” shot. The decision of when to give this shot is determined by the experience of the doctor part of the art of IVF. If given too soon, you may lose eggs because they will not be mature. Too late and you may lose them because they will be over-mature. The goal is to try to get the majority number of mature eggs as possible because only mature eggs will fertilize.
Until the trigger shot is given (or the body goes through an LH surge if allowed to occur naturally) the egg within the follicle does not go through its final phase of maturation, meiosis stage 2. Eggs within the follicle are usually in the “germinal vesicle (GV)” stage. Once stimulation occurs, they then go through meiosis phase 1 (M1) and then are mature at meiosis phase 2 (M2). In the natural reproductive process, the “trigger” occurs under the influence of a hormone called LH (luteinizing hormone) and is known as the LH surge. This is what is being checked when you use an ovulation detector kit. There is a sudden rise in the LH hormone which then signals the ovary to begin the ovulation event.
In IVF, HCG (human chorionic gonadotropin) hormone, which is chemically similar to LH, is substituted for the LH to make the eggs go through their final maturation phase and begin the process of ovulation. There are three sources for this medication:
(1) Urinary HCG extracted from human urine,
(2) Recombitant HCG (synthesized HCG) and
(3) Lupron, another drug that has a similar chemical structure to LH.
Lupron can only be used if you are on an antagonist protocol, with Ganerelix or Cetrotide, and not in a long Lupron protocol. This trigger shot will also cause the ovary to begin the ovulation process but because we don’t want the ovulation to occur, and thereby lose the eggs into the pelvis, the egg retrieval procedure is timed to occur before ovulation will take place. This is usually scheduled for 35-36 hours from the trigger shot.
We will continue this discussion soon with the next installment, "Step Three And Four: Egg Retrieval". Thank you for joining me today!
Edward J. Ramirez, M.D. F.A.C.O.G.
Medical Director, Monterey Bay IVF
Tuesday, July 3, 2012
This is the second part in the series I have begun to help answer what In Vitro Fertilization (IVF) is and how it works with my world-wide Blog audience. What you read here is what I also provide my patients with on a daily basis. I plan on going into some detail but in a way that is understandable to the normal (lay) audience, and not the medical or scientific one. I hope that this will not only clarify what you will go through, but explain why things are done a certain way and what the goals of each step are. I also want to convey that IVF is actually a replacement for some of the “natural” steps required to get pregnant and not some miraculous high tech fertility treatment that gets patients pregnant artificially, as many think it is. It is somewhat of a miracle that we can do as much as we can, but there are still lots of things/steps that we cannot do or influence. I hope this discussion will benefit you. This series will be posted over the next few weeks in installments.
STEP ONE: STIMULATION
As explained in the natural process, the first step in your body is for the hypothalamus and pituitary to send a hormone to the ovary to stimulate the growth of a follicle and maturation of the egg within.
The hypothalamus sends a hormone called GnRH or gonadotropin releasing hormone to the pituitary. This in turn, causes the pituitary to give off follicle stimulating hormone (FSH) and a little luteinizing hormone (LH). For now, I won’t go into detail regarding LH since it is not as important in this stage of the process. The FSH, or follicle stimulating hormone, stimulates the growth of a follicle, hence the name. The ovaries already have all the follicles they are going to have from birth. These follicles are in a dormant state until they are stimulated. In a natural cycle, several follicles are stimulated but only one is designated to grow to ovulation. The FSH goes through the blood stream and makes its way to the ovary. The ovary then picks up this hormone from the blood. It then processes the hormone and a follicle grows causing the production of estradiol and progesterone, and maturing the egg within. The egg is normally in an immature state in the dormant follicle.
In the IVF process, we take over the function of the hypothalamus and pituitary. In fact, we shut down the natural process so that we can control how the process goes and to help with timing. Timing is critical in IVF, as it is in the natural process. Many programs use birth control pills to shut down the ovaries and thereby shut down the hypothalamic-pituitary axis. Some clinics use leuprolide acetate or Lupron, Synarel or a similar drug, to shut down this axis. These drugs are known as GnRH (gonadotropin releasing hormone) agonists which is essentially adding GnRH but the brain monitors the levels of this hormone and if it reaches a certain threshold, shuts down production in the hypothalamus. Using Lupron from the luteal phase of the previous cycle is known as the “long protocol”. Some programs will go into IVF directly from an natural menstrual cycles and this is sometimes called “Natural cycle” IVF.
As I was explaining, in the IVF process we take over this step by giving FSH and LH hormone directly. These are known as injectable fertility drugs, but in actuality are not “fertility” drugs but merely the hormones your body would naturally produce to induce follicle growth in the ovary but at a higher dosage. So in reality, these drugs don’t increase your fertility or make you more fertile, they actually just give you more of an opportunity to become pregnant. Some of the medication used in IVF, such as Gonal-f or Follistim are now recombitant, or genetically produced FSH (in the old days, all FSH used to be natural FSH that was extracted from elderly women’s urine). These medications are pure FSH and have no LH within. There are other medications such as Pergonal, Menopur, Repronex that contain both FSH and LH. These are still derived from urine. Some clinics will use only FSH but most will use a “mixed” protocol, meaning they use both an FSH only drug in combination with an FSH/LH drug taken together.
The amount of medication given is what determines how many follicles your ovaries grow, and is dependent on how aggressive your doctor wants to be, i.e. how many follicles they want to try to get, and how well he/she thinks your ovaries are functioning or going to respond to the stimulation. We call the latter “ovarian reserve”. A younger patient will usually, but not always, have a very good ovarian reserve and therefore require less medication, whereas as a woman ages, her ovaries become more resistant or less likely to pick up the FSH from the blood, i.e. decreased ovarian reserve. Logically you can see that if the ovaries are more responsive, less medication is required and vice versa. The best way to picture this, as I explain to my patients, is to imagine a golf “wuffle” ball. If you don’t know golf, this is a practice ball with lots of holes in it so that it doesn’t fly far. Imagine that all the holes are open and you put the ball in a bowl of fluid (which is the FSH). The wuffle ball readily admits the fluid into its center. Now imagine that you block off most of the holes in the ball. You can see that less fluid gets into the ball (you also have to imagine that you have a time limit as to how long the ball gets to sit in the bowl of fluid). That is ovarian resistance. No matter how much drug you give, the ovary will only pick up as much FSH as it can and thereby only stimulate as well as it is going to stimulate. There is no technology that can change this. That leads to a lower ovarian response to the stimulation, and less follicles and eggs to work with. It is called “ovarian resistance” once stimulation has been attempted and only a few follicles grow. That is different from “ovarian reserve” which is the anticipated ovarian response or ovarian response potential before stimulation. “Ovarian resistance” is what you see once the stimulation is done and the ovary does not stimulate well.
The stimulation step is important because part of the success of IVF is an enhanced statistical chance by having lots of eggs to work with. Take for instance, if you have one dice and you want the number five. You have a 1 in 6 chance with each roll of the dice. Of course, your chances increase with rolling the dice more times, which is a different statistical chance and the statistic that changes as you attempt IVF repetitively. But taking just one roll into consideration, as in one IVF cycle, your chance is 1 in 6. Now, if you add three, four or five dices to that one roll, you can see that you have increased your chances 3, 4 or 5 fold. That is the same with each IVF cycle. In a natural cycle, you give off only one egg, so if that egg doesn’t go through each step perfectly, you don’t get pregnant. IVF increases your chances of pregnancy by accomplishing more of the steps of the process for you, but more importantly, you still need to have a perfect egg that forms a perfect embryo. If you only have one egg, the chances of having a perfect egg are significantly decreased. It increases by having more eggs to work with. That is how IVF increases your chances of pregnancy statistically. So the goal of stimulation is to try to maximize the number of eggs that you have available in order to increase your chances of getting/finding the perfect egg/embryo.
Now there is a caveat to this. You don’t necessarily want too many eggs because over stimulation can not only cause a major illness, but the egg quality may suffer. This is where the “art” of IVF lies. It is up to the doctor to try to make an educated guess as to how much stimulation would be ideal for each patient. Under-stimulate and you decrease the chances. Over-stimulate and you also decrease the chances, as well as, risk making the patient sick. Doctors get better at making this decision through experience. And this is part of what makes each doctor and each clinic different.
We will continue this discussion soon with the next installment, "Step Two: Follicle Growth and Egg Maturation". Thank you for joining me today!
Edward J. Ramirez, M.D. F.A.C.O.G.
Medical Director, Monterey Bay IVF