Mini-IVF: Minimal Stimulation IVF Technique

In addition to IV​F ​with conventional stimulation, we now offer a remarkable ​IVF protocol we call minimal stimulation (mini-IVF).​ This is a new, lower-cost option that provides superior results. Our Mini-IVF protocol, first conceived in Japan, is truly an amazing breakthrough. We have two somewhat different methods of Mini-IVF, both of which are very effective in the most difficult cases. Recent studies from Michigan State and Stanford University epidemiology departments have verified that high gonadotropin dosage to try to produce large numbers of egsg results in a lower, rather tan higher live baby rate with IVF.  It also prevents all the terrible sequela, which administering high gonadotropin dosage which causes a lower, rather than higher live baby rate with IVF. The least amount of hormonal stimulations has now been shown to yield the best quality eggs, better success rates, and lower cost with essentially no complications.

When patients contemplate IVF, their first reaction is often the fear of daily injections of hormones for months, the incredibly high cost of the drugs, the risk of multiple pregnancy and consequent prematurity, side effects related to high levels of estrogen resulting from large numbers of eggs, hyperstimulation syndrome, and very poor quality embryos in older women with low ovarian reserve.Mini-IVF is a very unique approach developed by our colleagues in Japan (and then perfected in our clinic) to circumvent these problems and to simplify IVF for patients, reducing the cost while maintaining the same success rates. Forolder patients, the success rate is much higher than with conventional IVF. With the refinements we have added to Mini-IVF, the pregnancy rates are startlingly high.

Mini-IVF is designed to recruit fewer (but high quality) eggs, thus avoiding the risks of hyperstimulation, reducing the number of injections and dramatically reducing the cost. In many patients who had very poor quality embryos with conventional IVF stimulation protocols, Mini-IVF dramatically improved their embryo quality and resulted in pregnancy in otherwise “hopeless cases.” This approach is not just a simple-minded reduction in hormonal stimulation. It is an ingeniously conceived and completely different approach to IVF that saves the patient much of the complexity and cost associated with more conventional IVF protocols. Here is how it works:

 

Take a look at this graph showing live baby rate per egg with mini-IVF compared to conventional ovarian stimulation. The baby rate per egg is 4 to 5 times greater with mini-IVF

The Mini-IVF Process

On Day 3 of the menstrual cycle or on day 6 of stopping birth control pills, you start on a low dose of Clomid (50mg), but you don’t stop the Clomid in five days as is usually the custom. You just keep taking the Clomid until ultrasound monitoring shows the follicles to be ready for ovulation. A very low “booster” dose of gonadotropin is added on every other day. Clomid not only stimulates your own pituitary to release FSH and LH naturally (by blocking estrogen’s suppressing effect), but also staying on the Clomid (a unique new approach) blocks estrogen’s stimulation of on ovulation, LH surge, and so prevents premature ovulation. Thus, with this simple change in protocol, the old-fashioned, cheap Clomid is able to stimulate the development of a smaller number of better quality eggs for IVF. The eggs are better quality because you get an increase of your LH as well as FSH at the very beginning of the cycle, and you only need a small amount of FSH to get good eggs as long as you start in the beginning and continue with an equivalent low level of LH to give you the best quality eggs.

Another advantage of this protocol is that you did not have to go on Lupron first to suppress the pituitary. Staying on Clomid blocks estrogen from stimulating your pituitary to release an ovulation LH surge, and this prevents premature ovulation without your having to be suppressed. This means that you can be induced to ovulate with just a simple injection or nasal sniff of Lupron. This causes a more natural LH surge.

The next step is to recognize that Clomid has a negative effect on the uterine lining (because it prevents estrogen from stimulating the endometrium). That is one reason why results in the past have been so poor with the use of Clomid for ovarian stimulation. The embryos are less likely to implant in such endometrium. But that problem is solved by using the Japanese protocol for embryo freezing, “vitrification.” Using this approach, we can now very safely freeze embryos with virtually no risk of loss. Frozen embryo transfers can then be performed in later, more natural cycles. Absolutely no damage is done to the embryos with this freezing.

For poor prognosis cases of older women with low ovarian reserve, there is a huge advantage to Mini-IVF over high dose stimulation. Such patients normally yield very few eggs even with huge megadoses of gonadotropin. Mini-IVF is just as likely to yield as many eggs (very few, of course) as giving huge megadoses of gonadotropin. But the egg quality is better and they can afford to do more cycles if that is what is required. Even in the worst-case scenario, when there are no eggs left at all, then at least the patients can discover this with less spent on drugs than with traditional IVF. In fact, it is remarkable that if a woman has a high ovarian reserve, just this simple “mini-IVF” will yield man eggs (not just a few), and these eggs will be much better quality than conventional IVF.

A Simple Parable

If you are sitting under an apple tree, and wish to eat the ripest and ready apples, you have a choice. You can chop down the tree, and look at every apple on the fallen tree to see which ones are ready. Or you can simply try to shake the lower branches and eat the one or two that have fallen. That is the idea of mini-IVF. For many patients, it will remove much of the aggravation and complexity associated with IVF, dramatically reduce the cost, and give better results. But it requires a great deal of sophisticated ability to do this well.

Poor Quality Eggs in Conventional IVF Corrected in Mini-IVF

It’s absolutely remarkable how many poor quality eggs are obtained in most conventional IVF cycles and how few of them will ever become a baby. With Mini-IVF, we get a slightly smaller number of eggs, but most of them make perfect embryos. So the pregnancy rate per egg has been shown to be fivefold higher with Mini-IVF than with conventional stimulation, and the pregnancy rates are just remarkable. For example, we have seen many patients in the older age category produce a small number of eggs and poorer quality embryos, sometimes even no embryos, with high dose ovarian stimulation. However in subsequent cycles, when we deploy minimal stimulation, paradoxically we obtain more embryos and better quality embryos. So with many patients, particularly older women, “less is more.”

Mini-IVF is tricky to perform well and many centers which try it are deficient. There is no margin for error. There are several reasons for the success we have with these much lower cost Mini-IVF techniques which we have pioneered in the U.S. Firstly, it is hard to overstate how crucial the purity of air quality in the lab as well as the operating room is. There are organic volatile toxins in the air everywhere in microscopic quantities that don’t seem to affect our well being. But they do dramatically affect the well being of these highly exposed embryos. Secondly, the very clever Japanese approach to minimal stimulation allows us to retrieve better quality eggs than the more expensive massive dosing of conventional IVF protocols, better quality eggs at a lower cost. Finally, the ability to freeze the embryos with impunity and then transfer in a later cycle where the uterine lining is more perfectly synchronized to the stage of embryo development than during a stimulated cycle, all add up to high success rates at a lower cost.

Most of all, IVF programs would have canceled such a case with only two follicles, and just recommended donor eggs. On the contrary, with us, we get two good embryos and the patient gets pregnant with her own eggs, not donor eggs.

Denmark Mini-IVF

Recently we have very successfully developed another option for Mini-IVF, which is not only good for women with low ovarian reserve, but also for young women with normal ovarian reserve. The Denmark Mini-IVF process utilizes the same principles, which is a low increase in FSH and an equal increase in LH. So we get good quality eggs in women with high ovarian reserve, resulting in more good quality embryos at the same lower cost. This new protocol was invented by Dr. Silber, using basic science principles in a brainstorming session in Denmark.

It used to be thought (and is still incorrectly thought) by most IVF doctors, that FSH is the most important drug for ovarian stimulation and that you need only a little bit of LH. This is completely incorrect.  You only need a little bit of FSH, which just recruits eggs but does nothing for egg quality. On the other hand, you need a larger amount of LH effect, in fact, in order to get better egg quality. So increasing the FSH dose, which is commonly done everywhere, simply gives you a larger number of poor quality eggs.  It is the LH effect that is necessary to give you high-quality eggs, and increasing the FSH too much is harmful. Using this basic science understanding, we were able to develop Mini IVF protocols which avoid all complications of hyperstimulation syndrome, reduce the cost dramatically, and nonetheless result in very high pregnancy rates, in older as well as in younger women. Even in women with PCOS, the Denmark Mini-IVF completely avoids hyperstimulation syndrome and gives us the best quality eggs.

 


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Our Story

I wanted to first thank Dr. Silber and staff for bringing our beautiful baby girl into this world.

My husband and I tried for years to try for a baby and was having no hope. Until one day my sister told me about Dr. Silber, she said how good he is, and how the staff is friendly and caring. She went to him and had great success. So I called Dr. Silber’s office, they gave me all the information I needed. Everyone was there for us, answering all our questions, and they were great at returning our phone calls right away.

We went through the Mini-IVF, which was much less expensive than conventional IVF, but yet gives the very same high success, and transferred 2 embryos, and 9 months later our baby girl, Gabriella Grace, was born. 8 lbs, 9 ounces. She is a miracle of God.

Thank you again to Dr. Silber and his staff,

Michelle and Lawrence Quinones
Sioux Falls, SD

 

quinones

Suzanne’s Story

Suzanne Gastineau got pregnant with her first baby so easily, it never occurred to her that a few years later, she would be trying to conceive her second for a year-and-a-half with no results.

The St. Louis-area resident and IT specialist was 38 years old when she had her son Kyle, now 6. At age 41, she was trying to get pregnant again, but nothing happened. After going to her ob/gyn and finding that the only thing affecting her was her poor quality eggs because of her age, she was put in the care of an infertility specialist and decided to undergo a special type of in vitro fertilization that works well for older women.

After two rounds of what her doctor and others refer to as “mini-IVF” — a cheaper, toned-down form of the procedure involving fewer drugs with lower dosages yielding fewer but better quality embryos, or fertilized eggs — Gastineau got pregnant with her second child despite the fact that she had only one viable embryo. Little Alex was born last August when his mom was 43 years old.

“I ended up with a gorgeous baby boy,” she told AOL Health. “He’s a little miracle patient. Personally, I’m a believer in IVF.”

 

 

 

 

Dear Dr. Silber and Staff,

Dear Dr. Silber and Staff,

I wanted to write and thank you for making Mother’s Day 2010 one of the best days of my life. We celebrated with our amazing two-month-old twin baby girls and we wanted to extend our sincerest gratitude for helping us realize our dream to become parents.

We were both well over 40 and every doctor told us there was NO CHANCE. We soon found that local doctors were not willing to ‘work with us’ because of my age 43. We changed doctors 3 times and they all prescribed the same conventional treatments and tests. This went on for a whole year while I was just getting even older. We finally figured out these doctors were trying to waste enough time to force us into using donor eggs, rather than pursue a plan that would help us try to have our OWN children. We realized that using donor eggs is a viable option for some couples but had told each doctor from the beginning that was not what we wanted. I was devastated when I realized they had basically wasted 11 precious months of our time!

Then we saw Dr. Silber. I figured if Dr. Silber was that good at thinking outside of the box, he could help a healthy 44-year-old become a mother. I ‘googled’ and found out the office was only a four and a half hour drive away.

We believe that God works through people and we had a feeling we were in the right place when we noticed a ‘promise’ displayed on the wall that said Dr. Silber would work to the best of the ability God had given him to help people. Dr. Silber explained to us the odds of conceiving because of my age, now 44, but he also had a plan to give us a chance. Things seemed to keep telling us we were on the right track.

July 6th we found out we were pregnant. July 21st we found out it was twins! WOW!! I was treated like any other ‘normal’ high-risk pregnancy because of my ‘advanced maternal age’ of 44 and carrying twins. I had a very healthy pregnancy and made it to 39 weeks with what my OB described as a pregnancy better than most of her moms carrying ‘singletons’. We had beaten the odds.

Our very healthy and alert baby girls were born after my 44th birthday on March 8th! They continue to amaze us each day as we watch them grow and change. Brielle and Lillian bring such joy to our lives and we have not stopped smiling. We are so blessed.

We cannot thank you enough for your willingness to extend your expertise to successfully treat the infertility issues which older couples face.

Forever Grateful,
Dr. Dan & Lorelei Andedo
Rock Island, Illinois

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Resources on Mini-IVF


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Mini-IVF
New form of in vitro fertilization stirs debate. St. Louis Post-Dispatch newspaper, January 26, 2012. Read More

Video- Dr. Silber performs IVF on the Today Show

Dr. Silber performed IVF live on the Today Show Watch

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Listen to Dr. Silber on KMOX Discussing Mini-IVF and Egg Freezing. September 16, 2012. (9:47 min)

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Listen to Dr. Silber on Health and Wellness with Monica Adams discussing egg freezing, male infertility, and mini-IVF on KMOX in St. Louis. January 29, 2012. (9:26 min)



Improvements in Embryo Culture

A major improvement in embryo culture was realizing that the oxygen content in the air we breathe is much too high for eggs and embryos. In fact, most cells in the body are exposed to a much lower concentration than the air we breathe. Too much oxygen delivered to these cells can, in a sense, overheat the cell. So it is much better to culture the embryos, not only in 5% CO2 but also in only 5% oxygen (not the 20% that is in air). This is difficult to do. Large amounts of pure nitrogen gas have to be blown constantly through the incubator at a carefully controlled rate to lower the oxygen concentration in the incubator. But it is worth that extra effort to get higher pregnancy rates.

Classically, most IVF labs have cultured embryos at a pH of 7.4 (the normal acid-base of blood concentration), and at an oxygen concentration of 20% (the same as in the air we breathe). However, these are not the acid or oxygen concentrations that are most favorable for embryo growth and development. In fact, the acid concentration inside the embryo is normally much greater than that, and the oxygen concentration is much lower. Conventional IVF culturing conditions, therefore, are too alkaline and too oxygen-rich. In fact, the oxygen concentration in the Fallopian tube is only about 8% (not 20% as in air), and in the uterus, it is as low as 2%.

This type of optimal culturing of embryos requires a lot of extra attention. To reduce the oxygen concentration in the incubator from 20% to 5% requires blowing through a huge amount of nitrogen (95%), and to keep the pH acid at 7.2 (but not too acid below 7.2), requires careful monitoring of the acidity of the media. This represents a lot of extra work, but it is well worth the effort. The better your pregnancy rate per cycle, the less is your eventual cost.

In a high-quality referral hospital setting such as ours, the most rigid air quality system is in place, preventing particles of volatile organic compounds from entering the environment where your embryos are growing in culture. The air around all of us is filled with these toxic compounds in low concentrations that don’t seem to affect your body’s overall health in any obvious way but do seriously affect the growth and development of your eggs and your embryos in culture. We can see the obvious negative effect of non-perfect air quality in an IVF lab on the evolution of poor quality embryos that give lower pregnancy rates than the good quality egg and embryo growth from those same women whose embryos are cultured in high air quality environments.

Only large IVF centers in high-quality hospitals that invest many millions of dollars into “clean room” air quality, can ensure the proper environment for the growth in vitro of your eggs and embryos. Even older women in their late 30’s and 40’s, whose embryos cannot tolerate the slightest stress, develop good quality embryos in a laboratory environment like ours that is free of these common toxins in the air that pervade most office-based settings.


Freezing Embryos by Vitrification

This new technique of freezing called “vitrification” avoids the damage caused by ice forming inside the cell by not trying to pull every last molecule of water out because it is impossible to do this 100%. In fact, 70% of the cell is water, and at best you can reduce that to 30%. So with the conventional controlled rate slow-freezing technique, there is always going to be some intra-cellular ice crystal formation, causing some damage to embryos, and severely damaging most eggs. Vitrification uses a super high concentration of antifreeze (DMSO and ethylene glycol), and drops the temperature so rapidly that the water inside the cell never becomes ice. It just instantaneously super-cools into a solid with no ice crystal formation at all.

We can now freeze and thaw, and even refreeze and rethaw, with impunity, using this new protocol from Dr. Masashige Kuwayama from Tokyo. With conventional “slow freezing,” the temperature of the embryo goes down at precisely 0.3°C per minute. With vitrification (using four times the concentration of antifreeze, or cryoprotectant), the temperature is dropped at 23,000 degrees C° per minute, that is 70,000 times faster. At that speed of cooling, and at that concentration of antifreeze, ice crystals simply cannot form because of severe osmotic shifts.

Of course, it is not quite as simple as it might sound. Such high concentrations of antifreeze, in a few minutes, could be toxic to cells. Therefore, the embryos (or eggs) must first be placed in lower concentrations of antifreeze (and sucrose to draw some water out) and then left in high concentrations before instantaneous freezing. Then when the time comes to thaw the embryo, it must be instantaneously warmed, immediately taken out of the high concentration of antifreeze, and then placed into a solution with a lower concentration, in order to avoid antifreeze osmotic toxicity. This requires more skill than conventional freezing, but it is faster, cheaper, and most importantly, avoids almost all freezing damage to either eggs or embryos. Such a reliable method of embryo freezing gives the IVF program much greater ability to avoid dangerous multiple pregnancy, allows ingenious new protocols like mini-IVF to work with less expense to the patient, allows the patient to have many more chances for pregnancy in subsequent cheaper frozen embryo cycles, and makes scheduling for procedures like egg donation or gestational surrogacy much simpler for the patient.

Using this vitrification technique for freezing, we can now also preserve eggs as well as embryos and sperm. This allows us to preserve the fertility of young women or cancer patients for the future in egg banks if they need to delay childbearing.


Videos On Vitrification


More Resources

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High Doses of Hormones Faulted in Fertility Care – The New York Times
Read More

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Cross-cultural Fertilization: Dr. Sherman Silber Takes His Reproductive Technology to China – St. Louis Magazine; August 2012
Read More

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Listen to Dr. Silber on Health and Wellness with Monica Adams discussing egg freezing, male infertility, and mini-IVF on KMOX in St. Louis.
January 29, 2012. (9:26 min)

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Listen to Dr. Silber and Joan Hamburg discuss male infertility, mini-IVF, fertility preservation, and infertility trends on WOR Radio in New York. February 2, 2012. (12:57 min)

 

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