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IVM: in vitro maturation
IVM is a variation of IVF which uses immature eggs removed from the ovaries without having to perform an ovulation induction to make those eggs mature in the body. The eggs are instead matured in the laboratory. They are then fertilized, cultured and transferred as in routine IVF. Injectible medications to stimulate the ovaries are not used, which eliminates many side effects for the patient as well as decreasing the expense. IVM also eliminates the need for most of the ultrasound monitoring which is routine for IVF procedures. Blood tests to assess the progress of the ovulation induction are similarly eliminated, making the procedure more convenient and comfortable for the patient.
In the normal menstrual cycle, an egg develops inside of a cyst or follicle over a two week period in response to gonadotrophin hormones that a woman produces. The follicle increases in diameter from about 2 mm to about 20 mm. The cells around the egg multiply over this time period and produce estrogen. The egg is firmly attached to the follicle wall until increased amounts of the hormone LH (or in medical cycles, HCG) induce enzymes that free the egg from the wall so that it is free floating in the fluid in the follicle. It can then leave the follicle after LH also induces enzymes to create a hole in the follicle. During this time, the egg increases very slightly in size and all of the chromosomes are contained in a membrane in the cytoplasm. With the increase in LH as a trigger, this membrane breaks down and the egg divides the chromosomes into two equal groups and moves one of these groups outside the egg (polar body). An egg that has done this is referred to as a mature egg (or MII). In the natural cycle, the egg, which has been freed from the follicle, is then picked up by the end of one of the fallopian tubes. If the egg is lucky enough to be fertilized, it again divides the chromosomes into two equal groups and pushes one of them outside the egg (the second polar body).
In 1935, it was observed that if rabbit eggs were removed from their follicles, some of them would spontaneously mature. In 1965, Edwards (one of the original scientists responsible for the first baby born from IVF) showed that the same thing occurred for human eggs. The first baby born from IVF, Louise Brown, was not born until 1978. The first baby born through IVM was reported in 1991. The first baby born through IVM in North America was through McGill University in 1999. The process of IVM was never as efficient as IVF. A commercial media for egg maturation is now available and the details that enable pregnancies to occur at a reasonable rate in appropriately selected patients have also been worked out. The exact limits of IVM are far from agreed upon, but IVM is clearly another tool that can be used to help some patients achieve pregnancy.
The use of IVF technology in humans developed after this technique was perfected commercially for cows (bovines). IVF for bovines was a major agricultural advance enabling the production of better cows for both beef and milk production. IVM has since been perfected for bovines and the use of IVF in bovines has now largely been abandoned. In cows, it is more cost efficient to obtain immature eggs rather than cause them to become mature within the cow. The technology used for IVM in humans is based in part on the experience obtained from agriculture as was IVF.
In the United States, IVM is not widely available. However, IVM is available in counties throughout the world. There are many excellent centers for IVM in Europe, Asia, and Canada. We can only speculate as to why IVM is not widely available in the United States. Its advantages over conventional IVM are its lower cost, its simplicity and its lower invasiveness for the patient. Although IVM is more cost efficient than conventional IVF, in most programs, its success rate is lower. There is no separate registry in the US which provides information about IVM success rates. IVM results are reported separately from IVF in some countries. The accumulated world experience with IVM is substantially less than with conventional IVF. For these reasons, IVM has recently been labelled experimental in the United States. However, large prominent programs in Canada (McGill), England (Oxford), Italy, Hong Kong, and Korea have been providing IVM for years.
We started our IVM program in 2009. We have used multiple approaches to IVM. One initial approach was based on the programmed cycle approach popularized by Dr. Jared Robbins at Brown University in Rhode Island. This approach is a pure IVM approach and maximizes patient convenience. The date of retrieval and transfer can be chosen months in advance. Egg quality is as uniform as it can be since the eggs receive no exogenous stimulation prior to aspiration and it offers the best opportunity to control the development of the uterine lining.
Our current approach grew out of the long established program at McGill University. The approach starts with natural cycle IVF and adds IVM to it. Some call such an approach natural cycle IVM. We use limited injectible medications to increase the quantity of medium and large antral follicles based in part on data from Fadini in Italy. (We stop medication before follicles leave the antral follicle stage and and thus before they are capable of being stimulated.) This type of cycle can be varied to adjust to differences in patients and appears to have a better quality egg collection yield than other approaches to IVM.
Our patients are evaluated during their initial visit with an ovarian antral follicle count (small follicles between 3 and 10 mm in diameter). The best patients for this therapy will be under age 35 and have a total antral follicle count of at least 20. For such patients, we expect our clinical pregnancy rate to be about 2/3rds of the success rate for our regular IVF patients. Our results over the last several years are reviewed elsewhere on this site.
IVM or IVF are never the first therapies to be considered for a patient who has not been evaluated, but are certainly indicated in couples where the sperm count is low (e.g., less than 10 million/ml), in a woman with missing or very damaged tubes, or in the woman who does not ovulate in response to oral medications. The work-up for IVM focuses on the semen analysis, the uterine cavity, and the cervix. It thus can be completed very quickly.
Once a couple has decided to start an IVM cycle, the woman is usually placed on birth control pills for timing. Prior to an egg retrieval, the woman will require one or two ultrasound exams. A nurse anesthetist will provide in office anesthesia so the patient will not feel or remember the egg retrieval. Eggs will be removed and matured in the laboratory. We begin the process of fertilizing eggs once they are mature. About 20% of the eggs are mature on the day they are removed (despite their coming from small follicles). These are often the best eggs to work with and they may be identical so some of the eggs obtained during a conventional IVF cycle. The technique used for fertilization is ISCI, which can compensate for almost any male factor problem. Embryos are usually transferred back into the patient three days after the retrieval. A pregnancy test is obtained two weeks after the retrieval.
We are one of very few programs in the United States to offer IVM. We are certainly the first program in the Lehigh Valley and in NE Pennsylvania to offer IVM. We also have the first pregnancies using IVM in Pennsylvania.
The procedure does not require any medications to stimulate the ovaries. The IVM procedure eliminates the need for injectable medications to suppress a patient's endogenous (own) gonadotropin production such as Lupron, Ganirelix. or Cetrotide. It also eliminates the need for the gonadotropin medications to stimulate large follicle development to obtain mature eggs. These medications include Follistim, Gonal F, Bravelle, Menopur, and Repronex. For most patients, this is the most complex part of IVF. Patients find the process of injecting themselves with multiple different medications several times a day to be highly stressful. For the process to work well, they need to take the correct medication in the correct amount (which may change daily). By not using these medications, the complex monitoring required for IVF is no longer needed. Ovarian produced hormone levels are in the same range as a normal menstrual cycle. Office visits are reduced by more than 50% as are ultrasound exams. Blood tests are eliminated. Medication use and injections are decreased by 90%
2. Time Saving
In IVF, the patient is frequently monitored with ultrasound exams and blood tests to optimize the development of follicles (containing eggs) in the ovaries. This monitoring process usually takes 10 to 14 days and requires a number of office visits that are necessary to guide the ovulation induction. For the patient, this requires missed time from work or school. For IVM, in our program, we use an average of 2.7 ultrasound vaginal exams and no blood tests. The patient obviously needs to be there for the egg retrieval and the embryo transfer three days later, but dates of these procedures can be estimated to within a few days.
3. Less Painful and less risk
Eliminating most medication injections and eliminating all blood tests clearly decreases patient discomfort with IVM compared to IVF. Almost all patients handle these discomforts with IVF as a necessary component of the process, but they are still unpleasant. We counted the number of injections taken by 20 of our conventional IVF patients and compared it to 20 of our IVM patients. IVF patients (about half using lupron and half using ganirelix) averaged 54.3 injections in each cycle compared to 5.6 injections for IVM.
Generally, the patients who have the most discomfort after an egg retrieval are those with a large number of eggs, a PCO (polycystic ovary) pattern in their ovaries, or a PCOS (polycystic ovarian syndrome) diagnosis. (These types of patients also have the most success with IVM.) Because the medications we use in IVF hyperstimulate the ovaries, these patients may have swelling of pelvic tissues and loss of fluid into their abdomen (ascites). Some experience this for a day or two, but rare patients may experience it for several weeks. Some require hospitalization since there is a risk of death. There is NO risk of ovarian hyperstimulation syndrome with IVM. It is the only therapy which completely eliminates the risk of ovarian hyperstimulation. (See my chapter "Avoidance of Severe Ovarian Hyperstimulation with IVM Treatment" in DEVELOPMENT OF IN VITRO MATURATION FOR HUMAN OOCYTES: Natural and Mild Approaches to Clinical Infertility Treatment, edited by Ri-Cheng Chian, MSc., PhD, Geeta Nargund, MD, Jack YJ. Huang, MD, PhD., Springer)
Even patients without potential for ovarian hyperstimulation, are likely to experience less recovery pain after the egg retrieval procedure. Because the cysts from which we obtain the eggs IVM are much smaller than for IVF, a smaller needle has to be used. This usually results in less discomfort after the procedure.
4. Lower Cost
IVM patients should have significant savings by not using many injectable medications and eliminating most of the monitoring of a normal IVF cycle. In our program, we estimate that most self-pay patients will save about 50% of the total cost of a traditional IVF cycle. For some patients, IVM will offer them the opportunity to do an IVF variant cycle when they could not afford a traditional IVF cycle. Specific cost for IVF are presented in detail on another web page. Patients may realize additional savings if they choose to use our IVM multi-cycle discount program.
IVM is clearly safer than IVF for patients with significant PCO for whom the IVF ovulation inductions entails the risk of severe ovarian hyperstimulation. All IVF involves some degree of ovarian hyperstimulation, but for some patients, the side effect of ovarian hyperstimulation is dangerous as well as uncomfortable. Some patients get severely dehydrated and loose fluid into their abdomens. Abdominal distension may be severe enough to cause abdominal pain and difficultly breathing. The patients most severely effected can not be determined ahead of time, but anyone with PCO is at an increased risk. IVM eliminates this risk.
There is also the theoretical risk associated with the ovaries producing high levels of female hormones (breast or ovarian cancer, etc.). This potential risk is also eliminated with IVM.
6. More Natural
Although details for the best approach to IVM are not completely agreed upon, it appears that the best results are obtained if egg harvesting is done before there is follicle stimulation occurring in the ovary. Thus any medications used should be stop before they stimulate the ovaries. We view the use of medications that may effect the ovary during an IVM cycle as nutritional for the eggs developing in the ovary. Since there is no stimulation, there is no risk of ovarian hyperstimulation from the medications. Many women worry about how they will feel if they use the medications routinely used for IVF and cause very high estrogen production in the ovary. This is not an issue with IVM.
7. Theoretical Egg Advantages
Eggs produced in IVM cycles are more similar to each other in appearance than eggs produced in IVF cycles. For example, eggs from older patients sometimes have a dark cytoplasm after the ovulation which requires high doses of medications with routine IVF. With IVM, eggs from such patients generally have a normal appearing cytoplasm. There is limited and contradictory information in the medical literature comparing quality of eggs obtained from IVF compared to IVM in the same patient. One especially provocative study, suggests that chromosomal abnormalities (which are created at the time of HCG or at the time of fertilization) of eggs is reduced with IVM. Earlier studies using different approaches to IVM suggested that chromosomal abnormalities were increased.
1. Limited Use
Perhaps 3000-4000 babies have been born world-wide from IVM. This compares to more than one million born with IVF (57 thousand in the United States alone in 2007). There are only a few programs in the United States which offer IVM. There are over 430 IVF programs in the United States. In terms of safety and knowledge about the long term impact of the getting pregnant process on the resulting children, we can be more assured about the safety of IVF than IVM. There are a number of small studies that compare the safety of IVM to IVF within programs and find no safety problems. McGill University in Canada has an informal registry of babies born through IVM and they have found no problems. Another reassuring aspect to IVM is that there is extensive experience with IVM in commercial large mammals. More than 100,000 cows are produced each year utilizing IVM. IVF had been an important part of cattle breeding, but has been replaced by IVM over the last fifteen years. Although we believe that IVM is safe since most of what we do isn't much different than IVF, one can never prove safety in any absolute way, and the greater our experience with a procedure the more comfortable we are with it and have a greater basis for reassuring patients about its safety.
Most practitioners consider IVM to be a minor variant of IVF since once the eggs have matured in the laboratory, all the same things are done with them as with IVF. By this reasoning, the same safety data should apply to both IVF and IVM. However, there are clearly differences in the eggs produced by this procedure. Because of the minimal use of gonadotopins with all versions of IVM, some would view IVM as theoretically safer than IVF.
2. Limited Clinical Data
Because of the widespread use of IVF and the limited use of IVM, the medical literature about these procedures is not comparable. Most management decisions for IVM are taken from what we know from IVF. Protocols for IVM are still at an early stage of evolution and it is easy to ask clinical questions that have no answers in the medical literature. Current approaches are very dependent on the clinician in charge, their understanding of the IVM and IVF literature, and their clinical experience. Although IVM has been offered at major programs in other countries for some years (Canada (McGill), England (Oxford), Italy, Hong Kong, Korea). the American Society for Reproductive Medicine has recently labelled IVM as experimental. One consequence of this is that insurance is unlikely to pay for any aspect of IVM.
3. Pregnancy Rates
The best IVM literature suggests a pregnancy rate slightly below that for routine IVF to a rate about that of IVF (25-35% clinical pregnancy rate per transfer). An important variable in the IVM literature that predicts success is the number of eggs retrieved. The best candidates for IVM are those young patients with a PCO pattern in their ovaries. For these patients our clinical pregnancy rate with IVM is similar to our success with conventional IVF. These patients are also the best candidates for IVF and have the highest pregnancy rates as a subgroup of all patients undertaking IVF.
Age is a key predictor of success with IVF and is also likely to be one for IVM. There is limited data on IVM in older patients or in non-PCO patients. Unfortunately, the SART national data collection of IVF success rates of programs in the United States does not distinguish between conventional IVF and IVM in its data collection. (CDC removed them from data collection.) This means that the SART generated data on pregnancy rates from different programs is a mixture of the pregnancy rates for conventional IVF and IVM (if they have IVM). IVM is reported separately in some national registries, but most countries also include results with IVF.
4. Cycle Cancellation
Although IVM can clearly result in babies, it takes a lot of eggs to get there. Eggs are harder to get during the retrieval that with IVF. In IVF, the eggs are free floating in the follicle. In IVM, they are attached to the follicle wall and have to be dislodged during the retrieval (which takes longer). It there are not many antral follicles, few eggs are likely to be retrieved. A good maturation rate is 40-50%, so you need a good number of eggs to have many to work with. A good fertilization rate is 70% (similar to routine IVF). These factors lead to an increased frequency of cycle cancellation in patients who do not have a PCO pattern in their ovaries. (However, cycle cancellation is much lower than it is for procedures such as natural cycle IVF. IT is also lower than the cancellation rate of many conventional IVF programs.)
At this point in our experience, it appears that fewer embryos need to be created to achieve pregnancy with IVM than with IVF. This may reflect our particular selection of patients for IVM or it may mean that mature eggs obtained with IVM are more likely to be normal than mature eggs created through IVF (using high dose gonadotropins).
5. Program Selection
Although there are important differences between IVF programs in patient management, these differences are much smaller than the different variants of IVM. Over the years, a network of information on IVF programs has evolved. The CDC/SART database serves as a tool that patients can use to begin evaluating programs. There is little similar information to help patients select programs for IVM. In terms of physician management and laboratory management, IVM is different from IVF. There is a learning curve involved in transitioning from one to the other. (Some of our interactions with other programs has been described.)
Other Opportunities and Considerations
Managing the development of endometrial lining is more of an issue for IVM than it is for IVF. The ovaries produce many hormones in addition to estrogen and progesterone. In large amounts, some of these hormones may impair the ability of the lining to accept an implantation. We actively manage the endometrial lining of all of our patients with estrogen and progesterone.
Managing the lining for IVM is also difficult because embryos may be produced on up to four different days. Different programs optimize outcomes in different ways with respect to this issue and management is likely to undergo changes as more research is done on the issue.
Related Egg Donors
From a practical viewpoint, IVM is likely the best procedure to use for a related egg donor. Many patients find that they need to use donor eggs and have a younger relative who could be a potential donor. However, asking the donor to give up so much time and undergo the discomfort and stress of multiple shots and frequent monitoring is just too much to ask. This is especially true when the donor has small children to care for, which is often the case. IVM really requires only one day of the donor's time for a significant procedure done under IV sedation. It can also be scheduled months in advance. Ideally the donor should have a PCO pattern in her ovaries to present the best chance of success. However, the donation process is easy enough that is is reasonable to do it with donors who are likely to produce relatively few eggs and repeat egg harvesting at another time if necessary.
The treatment of some cancers may result in sterilization. Patients often wish to preserve their fertility using advanced reproductive technologies. However, a traditional IVF cycle requires some time. An IVM retrieval can be done anytime after an induced period. Eggs can then be matured in vitro and cryopreserved. There are IVM pregnancies from both traditional slow freezing cryopreservation of embryos and from vitrified oocytes. Egg vitrification is still viewed as experimental, but does not differ much from embryo vitrification (our preferred method of embryo cryopreservation). Unfortunately, data on this approach to fertility preservation is extremely limited.
New or Expanded Indications to do IVM (Cheaper or Quicker)
Infertility differs from many areas of medicine. For the vast majority of of patients, the only important issue is getting pregnant quickly (as opposed to why infertility exists). For some patients, the higher probability of getting pregnant quickly may be a reason to omit a traditional work-up or less aggressive therapies and going directly to IVM.
Many patients have no insurance coverage for infertility therapy. Some have no insurance coverage to pay for an infertility work-up. Patients who are good candidates for IVM (which can be determined with a very minimal work-up), may find it cost effective to do IVM as opposed to completing a traditional infertility workup or trying more traditional lower probability infertility therapies such as gonadotropins with IUI.