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Natural cycle IVF

Mini-IVF or Micro-IVF


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Home : Minimal Stimulation IVF Options

Mini-stim IVF (minimal stimulation IVF), Micro-IVF, natural cycle IVF, IVM and its variants

The recent popularity of Mini-IVF (minimal stimulation IVF), Micro-IVF, natural cycle IVF, IVM attests to the changes taking place in the practice of advanced reproductive technologies.  The differences between these technologies are not easy for most people to understand.  Because these terms are used differently between different groups and because some of these procedures have significantly evolved over time, it can be confusing to understand exactly what is meant by these terms.  Our objective here is to try to make them more understandable.  We will also try to point out some of the strengths and weakness of the above procedures in terms of our understanding of them.

A common feature all of these procedures share is the use of less infertility medications.  The reduction in medication use compared to a normal IVF cycle ranges from a 50% to a 100% reduction.  If less medication is used, then less monitoring is required (blood test and ultrasounds).  The amount of reduction in monitoring depends on the procedure being done and the philosophy of the practice.  For most of these approaches, fewer eggs are involved, which may mean there is less work for the laboratory to do.  Some programs will discount their routine laboratory charges compared to regular IVF; others may not.   Generally, IVM involves more laboratory work than routine IVF.  (We discount our IVM charges as a package price in part because we feel that overall patient management with IVM is easier than it is with IVF.)

The process of IVF can be difficult for some patients.  Monitoring requires missed work or the disruption of a woman’s schedule.  Blood tests are unpleasant.  Medications cause major changes in hormone levels and result in bloating and discomfort.  The most significant risk of IVF, severe ovarian hyperstimulation syndrome, is decreased in all of these procedures and completely eliminated in some (pure natural cycle IVF and programmed IVM).  This can be very important for some women with severe PCOS who are at increased risk for significant discomfort or even (rarely) hospitalization with routine IVF approaches.

The biggest “ variable” in assessing the effectiveness of IVF technologies is the patient.  The same approach can yield vastly different results depending on the subset of patients it is applied to.  Some programs are gentler in their use of IVF medications than other programs; some physicians are more effective than others.  All IVF variations work better on a younger patient population.  This makes comparing these IVF variation procedures difficult since the number of patients reported on in the medical literature is unlikely to large enough to smooth over the variables likely to cause some differences in results.  The IVF cycle data reporting program managed by the CDC does not distinguish between different approaches to IVF.  It considers them all to be IVF, which diminishes the value of this data reporting in comparing programs or better understanding the efficacy of these procedures.

Natural cycle IVF

Natural cycle IVF generally refers to a process in which patients are monitored during their regular menstrual cycles, and in mid-cycle, one or two mature eggs are harvested from their ovaries from large developing follicles.   Eggs are harvested as they are in routine IVF and the laboratory process is the same as with routine IVF (except fewer eggs are involved).   One of the bigger problems with natural cycle IVF (and it variants) is its high cancellation rate (estimated at 40% due to inadequate response, premature LH surge (20% by itself), no embryos to transfer).

Natural cycle IVF has been an appealing idea to many physicians and there are a number of publications over the years which have documented the results.  A generally accepted on-going success rate for natural IVF is 7% per cycle with a range of 0 to 14%.  This compares to an overall IVF success rate of 30.5% take home baby rate per started cycle (US CDC data).  It is estimated that total natural cycle IVF costs are ¼ that of a routine IVF cycle.  One paper suggests that four cycles of natural IVF have a pregnancy rate similar to routine IVF.  Advocates feel that since natural IVF is so much easier for patients than routine IVF, this pregnancy rate is reasonable since patients can do more cycles.

Natural cycle IVF had been modified in many ways with the use of clomiphene citrate, antagonists (like ganirelix) and gonadotropins (75-300 units/day).  Published pregnancy rates with these approaches differ widely, for example, 8.3% for good prognosis patients in one study, 13.3% for patients with severe male factor in another, 0% in poor prognosis patients in a third.  Some of these cycles are not distinguishable from what some physicians have more recently been calling minimal stimulation cycles.

We feel that natural cycle IVF can best be combined with IVM.  (This is one of the approaches that we take.)  Because we then have both mature and immature eggs to work with, the pregnancy rate is higher and the patient does not have “more” to go through.  In some programs, the pregnancy rate with natural cycle IVF/IVM is the same as for routine IVF (for patients under 38) and it has a very low cancellation rate.

Mini-IVF or minimal stimulation IVF

Minimal stimulation IVF, mini-IVF, Mini-stim IVF, or micro-IVF is the advanced technology procedure that is used to describe the widest range of procedures and is potentially the most misleading terminology.  The IVF consumer should be aware that most IVF practitioners want to use the lowest amount of medications that will achieve their objectives with routine IVF.  Generally, patients who are given higher doses of medications are patients with poor responses in prior cycles, decreased antral follicle counts on ultrasound, or advanced age (>37 years old).  None of these lower dose IVF technologies have been shown to work well in any of these groups, but for some of these groups there is little difference in the effectiveness of IVF compared to mini-IVF (for example women > 40 years old). Roughly, in groups for whom IVF is very effective, mini-IVF is about half as effective.  For groups in whom IVF is not very effective, mini-IVF does almost as well.

The definition of “minimal stimulation IVF” appears to mean using a slightly different ovulation induction protocol from routine IVF and attempting to produce follicles likely to contain mature eggs.  The harvest, fertilization, culture and transfer of those eggs/embryos does not differ from routine IVF.  Generally these cycles are cancelled if a minimal number of reasonable sized follicles are not produced or if there are not embryos growing well enough for transfer after 3 to 5 days of culture.  A high cancelation rate is common with this type of cycle.

One of the best established practitioners of minimal stimulation is Fauser from Utrecht in the Netherlands.   His approach should best be termed a “late start mild stimulation IVF cycle.”  With his protocol the patient waits until day 5 before starting gonadotropins and he uses an antagonist (like ganirelix) once the follicle begins to grow to avoid a premature LH surge.  His usual gonadotropin starting dose is 150 units. Simply starting gonadotropins on day 5 instead of day 1 reduces gonadotropin use by 30-50%.  His pregnancy rate is approximately the same as for a higher dose regimen in his program and his cancellation rate (40%) is higher than for a higher dose regimen (25% one study).  (The higher dose regimen in his program is gentler than what is commonly used in the US.  Ongoing pregnancy rates of 16-25% are lower than the average in the US and the cycle cancellation rates (25%) are much higher than in the US for routine IVF in good prognosis patients.)

Another type of minimal stimulation cycle is popular in Japan. Teromoto published his experience involving more that 40,000 cycles (about the number of IVF cycles done in Canada in four years).  His objective was to design a minimal stimulation IVF cycle that was easier for patients to do than IVF in part because of differences between the practice of medicine in the United States and Japan (patients must go to a physician's office for each injection of infertility medications).  By not using injectible medications, these cycles were cheaper and easier than routine IVF.  Because of the large number of cycle reported and broken down by age, one can estimate success based on age.  Roughly, in age groups for whom IVF is very effective, mini-IVF is about half as effective.  For age groups in whom IVF is not very effective, mini-IVF does almost as well.

Our approach to mini-IVF is called Mini-stim IVF and is based on Teramoto's approach with changes reflecting differences in medical practice in the United States compared to Japan.  We also utilize ideas supported by Fauser's research as well as our experience with minimal stimulation for IUIs.

IVM cycles

IVM involves in vitro maturation of immature eggs in the laboratory.  Much of the literature looks at the maturation of immature eggs that were obtained during a stimulated IVF retrieval.  These eggs mature at a low rate and are usually chromosomally abnormal.  Some babies have been born by this technique, but the current view is that most eggs that don’t mature after a routine IVF ovulation induction are likely abnormal to begin with.  Current IVM uses eggs that have not received stimulation or have received minimal stimulation.  Elsewhere on this web site, we describe multiple variations of IVM that we perform.  All of these use no to minimal fertility medications.  All require minimal monitoring and all are easier for the patient than routine IVF.  The cancellation rate for these cycles is very low.  The risk of hyperstimulation for patients with PCO varies for no risk to a theoretical risk. 

Pregnancy rates with these techniques have been reported in several programs and they range from slightly lower than routine IVF in that program to the same as routine IVF (25-50%/cycle) in that program.   Reports of any substantial size restrict IVM to good prognosis patients (younger and with adequate ovarian reserve).   However, there are small reports of success with IVM in more difficult to work with groups.  Our view is that older patients and patients with ovarian reserve problems are best served with traditional IVF approaches, but there is currently no data to support this approach.  Such patients may prefer to “try” IVM variant cycles for cost reasons.

Male factor

Some of the data on minimal stimulation IVF cycles demonstrate the high effectiveness of IVF (with ICSI) in completely overcoming sperm issues.  Even if only a few eggs are obtained, injecting them with sperm results a high rate of pregnancy for whatever techniques used.  ICSI is simply the most targeted effective therapy for male factor.  If the cost of a minimal stimulation therapy is low enough, this is the most cost effective way to achieve pregnancy when male factor is present.  (We look at this for IVM in more detail elsewhere on this website.)