IVF In Vitro Fertilization
If you have any questions, you may call us at (314) 576-1400.
“Infertile couples from all over the world come to St. Louis, Missouri, to chase their dream, because Dr. Sherman Silber and his team are simply the best there is.” – Discovery Health Channel Documentary
Video: Dr. Silber explains all the modern Assisted Reproductive Technologies (ART), including IVF
Video: Dr. Silber discusses Egg and Ovary Banking to Preserve Fertility
Unfortunately IVF has become so popular as a treatment for infertile couples, that sometimes without adequate supervision or serious regulation, some small "IVF" centers are opening up in little doctors' office buildings, and non-experts or newly self-proclaimed "fertility doctors" are delivering the IVF care.
It is best to look for IVF in a setting of a major quality medical center that is more concerned about the practice of good medicine than about your pocketbook and which has invested heavily in high standards "clean room" air purification systems. So you are going to need to do your research.
Audio: Dr. Silber and Joan Hamburg discuss how 20 years of studies clearly show ICSI babies are normal (WOR Radio in New York, April 26, 2012)
Will My Baby Be Normal?
IVF (in vitro fertilization) is the most common form of ART (Assisted Reproductive Technology). If the fallopian tubes are damaged or the sperm is poor, it is obviously the only acceptable treatment. It is also usually the most effective treatment for most other types of infertility as well. The eggs are fertilized in our laboratory, and the resulting embryos then are placed into the uterus 2 to 5 days later. This procedure achieves remarkable pregnancies even in women with hopelessly damaged fallopian tubes, seemingly sterile husbands, and even “unexplained” infertility. Problems with the husband’s sperm are never a serious issue, since we can fertilize the eggs with ICSI. In fact, in our program we routinely use ICSI in all cases to guarantee against any risk of failed fertilization. Our IVF pregnancy rate is over 50% per attempt, regardless of diagnosis, and we accept all of the most difficult cases.
Extra embryos are frozen and saved for a later, much less expensive future pregnancy. Our very special Japanese freezing technique essentially assures no damage to viable embryos. Therefore, the success rate for frozen embryo transfers in our program is just as high as for “fresh” IVF. The cost for subsequent frozen IVF cycles is one quarter the cost of the original cycle, thus easing the economic burden to some degree.
With IVF, the eggs are fertilized in the laboratory, as opposed to GIFT, which simply leaves fertilization up to nature in the fallopian tubes.
How Does IVF Work?
Eggs are retrieved by ultrasound guided needle aspiration under light sedation (in the operating room). This involves no surgical incision, and virtually no pain afterward. You just leave the hospital directly from the operating room, with no pain, and come back three days later to have the embryo (or embryos) placed very simply into the uterus through the cervix with a tiny catheter. No incision and no anesthetic are needed. An hour later you are able to go home. There is no pain from the procedure.
In order to retrieve these multiple eggs for IVF, the woman must undergo injections with hormones and careful monitoring of her ovaries by ultrasound and her hormone levels by blood tests every day or every other day until she is ready for the egg retrieval. This can at first seem very intimidating, but we will "hold your hand" throughout the whole time and guide you gently through this. There are several methods of hormonal stimulation for IVF, that basically can be divided into what we call "conventional stimulation" and "minimal stimulation," or "mini-IVF." We will explain which approach is most suited for your particular situation. Meanwhile you can find out more about this by reading our pamphlet, by watching our ART teaching DVD, or in more depth by ready my book, How to Get Pregnant [links to Amazon.com].
Intra-Cytoplasmic Sperm Injection (ICSI)
If there is a question of the sperm’s ability to fertilize the egg, due to either a low sperm count or poor quality of the sperm, that poses no problem whatsoever. Intra-Cytoplasmic Sperm Injection (ICSI) would be performed instead of regular IVF. We actually were part of the original Belgian team that developed ICSI, and first introduced it to the U.S. With ICSI, the eggs are retrieved the same as if you were doing conventional IVF. However, the eggs and the sperm are then fertilized in the laboratory, by direct injection of a single sperm into each egg. Two to five days later the resulting embryos are simply placed into your uterus with no surgery, just as with IVF. Extra embryos are frozen for later, much less expensive, attempts at pregnancy, using the Japanese vitrification freezing technique.
The availability of this Intra-Cytoplasmic Sperm Injection, “ICSI” technique (which was developed and perfected by the Brussels University and our institution in St. Louis) means that men whose sperm previously were too weak or too few to fertilize in vitro (IVF), now have no problem fertilizing their wife’s eggs. The fertilization rate per egg using ICSI is about 70% despite the sperm being terrible. The fertilization rate per infertile couple is over 99% if the wife has adequate eggs, and the pregnancy rate per treatment cycle is over 50%. This is no different from regular IVF with normal sperm. This technique is very cost-effective, and will give you the same high chance for getting pregnant as any couple with normal sperm. In fact, we perform ICSI at no extra charge for all of our IVF cycles to obtain better fertilization rates and better results even when the husband's sperm count is not impaired.
How Does ICSI Work?
My colleagues, Drs. Van Steirteghem and Devroey from the Free University in Brussels, and I showed how we can take a single, almost non-moving “dead” appearing sperm and inject it into a woman’s egg, getting a normal embryo and a completely normal baby. So far, over 100,000 babies have been born with this new technique, from men who were otherwise considered hopelessly sterile. The babies are physically, mentally, and genetically normal, no matter how poor or miserable the sperm of the father.
We can take a man who would otherwise have to resort to donor sperm, and if we can find just a few weak sperm in his otherwise sterile appearing ejaculate, it is more than enough to microsurgically inject these few sperm into his wife’s eggs, fertilize them normally, and get her pregnant.
If there is absolutely no sperm in the ejaculate, we can perform a testicle biopsy, remove the few non-moving sperm that we find through a highly refined ultra micropipette, inject it into the wife’s egg and still get her pregnant. Even in testicles where allegedly there is no sperm production, we can usually (but not always) find a few sperm, which is enough for successful ICSI. Even in cases where we find no sperm, we can safely freeze the wife's eggs and save them for a future date when further breakthroughs will allow us to find sperm.
Immobilizing the sperm's tail before picking it up.
Injection of sperm into the egg.
Fertilized egg demonstrating the two nuclei – one from the father, one from the mother.
Since infertility treatment is expensive, we try to soften its impact by achieving the highest possible pregnancy rates, and thus reduce the number of treatment attempts and the overall expense. We also make sure not to charge extra for unnecessary testing or ineffective preliminary treatment approaches. We only recommend what we feel is necessary to help you achieve a pregnancy as soon as possible. Furthermore, we have no hidden extra charges added on which in some clinics might result in much higher costs.
For example, there is no additional charge for office visits, semen analysis and/or sperm freezing, embryo freezing, assisted hatching, blastocyst culture, or ICSI, which we always do in every case to give you the greatest chance for pregnancy. Also, we will not order an expensive list of purely remunerative tests with procedures that just delay the most cost effective treatment.
Couples often ask if there is a discount for subsequent cycles if they don't get pregnant with the first cycle. With our remarkable vitrification technique [video] for embryo freezing, the pregnancy rate for subsequent frozen embryo transfers is just as high as for fresh IVF, but the cost is only one quarter the cost of a regular IVF cycle. So if we can get high pregnancy rates with the normal IVF cycle, and then even higher pregnancy rates with cheap subsequent frozen embryo cycles, your overall cost is dramatically lowered. Furthermore, our "mini-IVF" technology dramatically reduces your cost as well.
"For women who are told IVF isn't an option, mini-IVF could be a more successful path to parenthood…" Fertility Road magazine, May/June 2011. Read More
Listen to Dr. Silber on KMOX Discussing Mini-IVF and Egg Freezing. September 16, 2012. (9:47 min)
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)
Mini-IVF: Minimal Stimulation IVF Technique
In addition to IVF with conventional stimulation, we also offer IVF with minimal stimulation (mini-IVF), which is a new, dramatically lower cost option with comparable results. Our mini-IVF protocol, first conceived in Japan, is truly an amazing breakthrough.
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 the prospect of painful daily progesterone injections for a full ten weeks even after the IVF procedure. 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. For older patients, the success rate is even 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 only a few (but high quality) eggs, thus avoiding the risks of hyperstimulation, reducing the number of injections and dramatically reducing the cost of medications. 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 "useless 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:
On Day 3 of the menstrual cycle, 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 (just 150 iµ of FSH), is added on Days 8, 10, and 12. Clomid not only stimulates your own pituitary to release FSH naturally (by blocking estrogen’s suppressing effect), but also staying on the Clomid (a unique new approach) blocks estrogen’s stimulation of LH release, and so also prevents premature ovulation. Thus, with this simple change in protocol, the old-fashioned, cheap Clomid is able to stimulate the development of smaller number of better quality eggs for IVF.
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 LH, 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, and avoids the luteal phase defect caused by HCG that would otherwise require months of progesterone injections.
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 natural cycles.
Even for poor prognosis cases of older women with low ovarian reserve, there is an 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 only $300 spent on drugs instead of $7,000 (cost of maximum dosage).
Think of this simple parable: If you are sitting under an apple tree, and wish to eat the most ripe 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 were 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, and also dramatically reduce the cost. But it requires a great deal of sophisticated ability to do well.
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 smaller numbers of eggs, but most of them make perfect embryos. So the pregnancy rate per egg has been shown to be five fold higher with mini-IVF than with conventional stimulation, and the pregnancy rates are just remarkable. Nonetheless for some patients conventional stimulation is preferable in order to get more embryos, and we can explain that to you for your particular case.
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 smaller numbers of better quality eggs than the more expensive massive dosing of conventional IVF protocols, better quality eggs at 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 lower cost.
Here's an interesting example:
I wanted to first thank Dr. Silber and staff for bringing our beauitful 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. Silbers 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 transfered 2 embryos, and 9 months later our baby girl, Gabriella Grace, was born. 8 lbs, 9 ounches. She is a miracle of God.
Thank you again to Dr. Silber and his staff,
Michelle and Lawrence Quinones
Sioux Falls, SD
Minimal ovarian stimulation (mini-IVF) for IVF utilizing vitrification and cryopreserved embryo transfer Reproductive BioMedicine Online; September 2010
Strong ovarian stimulation linked to egg abnormalities and poor pregnancy rates in older women BioNews.org.uk; July 4, 2011
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, 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 insure 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 the Kato Clinic in 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.
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 only for less than a minute 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 lower concentration, in order to avoid antifreeze 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.
Summary of IVF Cost Reduction
There are several ways in which to lower the costs for IVF and improve quality in which we are leaders. There are some clinics that simply charge less by doing slipshod work, and we abhor that. There are many relatively poor quality OB-GYN doctors who have been kicked off of hospital staffs who are opening cheap IVF clinics with the idea or making an easy dollar by cutting quality, and who have little depth of knowledge. We recently performed a successful low cost IVF on a patient who had gone through eleven previous IVF cycle failures at such a bargain rate clinic. She wound up spending a fortune on all these failures before we finally achieved her goal in just one properly performed cycle. We have also seen many patients come from such office IVF settings to our hospital with life threatening hyperstimulation syndrome from poorly managed IVF stimulation and of course they endured a huge hospital bill for the intensive care required to save her life. To avoid such charlatans, you will need to understand and research IVF carefully.
The first requirement is to have the most perfect industrial-grade laboratory conditions. This results in better quality embryos with high pregnancy rates even in patients with otherwise lower prognosis. The second is that with our remarkable freezing technology, considered the best in the U.S., subsequent frozen embryo transfers, which cost very little, will give you even higher pregnancy rates because your endometrial uterine lining is more perfectly synchronized to the stage of embryo development than in a fresh stimulated cycle. Thus you have more chances per retrieval of eggs for pregnancy. The third is that we have developed a novel method of ovarian stimulation that is very mild and less drug intensive called mini-IVF.
Mini-IVF is not suitable for all cases, but it is clearly the least expensive and most comfortable way to undergo IVF. Its only disadvantage is less frozen embryos for future babies, but for many couples that is preferable anyway. But even when conventional stimulation IVF is required or preferred (because of the greater number of embryos), overall cost is reduced because of the technical perfection of our freezing protocol, which results in many more embryos transfer opportunities at dramatically lower cost than a fresh IVF cycle.
The American College of Pathologists (CAP) inspects American IVF labs every two years and issues reports on the IVF laboratory's quality. Our lab has been rated as one of the very best in the U.S. It is our compulsive attention to quality and detail that produces our great results in some of the most difficult cases, and is why our CAP inspection reports are at the highest possible level. Ultimately these better results are the best method for cost saving.
More details of costs for these different approaches can be discussed with our office personnel after your initial consultation, which is completely complimentary.
Blastocyst Culture — Dr. Silber’s comments
Whenever IVF or ICSI is performed, embryos may be cultured for either one day, two days, or even five days, before transferring them back into the woman. In order to culture the embryos for five days, i.e. to what we call the "blastocyst" stage, you need to use "sequential" culture media systems. We have used such a system since the summer of 1997 because it gives us the option of culturing the embryos for as long as is clinically appropriate for each particular patient's situation.
However, there is a great deal of debate, and some considerable commercial hype, centering around whether to culture for two days, three days, or five or six days. The media we use, and which many other of the best programs use, allows us to culture the embryos to whatever number of days is appropriate for the particular patient. Since this media is commonly available, it should not be used to hype any particular program.
For some patients with poor quality embryo development (a condition which is programmed into the genome of many infertile women), even with the best culture media, the embryos may be better off going directly into the fallopian tube immediately. For the average patient, day two or day three transfer either to the fallopian tube or to the uterus may be best. For some patients, day 5 transfer to the uterus may be a good option. The problem with extended culture to day 5 is that there may be a loss of some embryos that might have "made it" if they had been transferred earlier.
The major advantage (despite the already mentioned disadvantage) of day 5 transfer is embryo selection. The implantation rate per day 5 blastocyst transfer is greater than for transfer of day 2 or 3 embryos. But only 20 percent to 50 percent of day 2 embryos can develop in vitro to day five no matter how perfect the in vitro culture system. There is a potential loss therefore of what could have been viable embryos. So selection is the only advantage of blastocyst culture, and this selection has nothing to do with the "quality" of the baby, but rather just whether the embryo "makes it" or not to becoming a baby.
Either way, because our system of embryo freezing is so good, we do not lose anything if we transfer less embryos to reduce your risk of triplets or quadruplets, and just save the extra embryos for a later pregnancy. We can even transfer just one embryo at a time (if that is your wish) without at all reducing your chance of pregnancy.
Therefore, hype should be removed from this issue, and decisions should be made that are in the best interest of the particular patient's situation.
Nonetheless we believe that use of sequential culture media, as we routinely do, is an advantage, in that patients can have the option of prolonged embryo culture if that is in their best interest.
Assisted Hatching: Excerpt from "How to Get Pregnant With the New Technology, Updated and Revised"
Another attempt at improving the pregnancy rate is the idea of "assisted hatching". The concept of this procedure is that based on the fact that the embryo normally sits around in the uterus without any effort to implant until around day six. Until day six, the embryo keeps growing within its very tough zona pellucida (outer shell). But on day six, that zona pellucida begins to thin out, and the embryo then eventually "hatches," just like a chicken out of an egg. It is at this moment of hatching that the embryo, now called a "blastocyst," actually implants into the uterine lining, the endometrium. It is at this moment, around day seven after fertilization, that pregnancy actually occurs, and this free floating ball of cells finally becomes a part of the mother. One theory to explain the perplexing phenomenon that many IVF embryos do not result in a pregnancy has been that this thinning of the zona and hatching of the embryo may be defective and in some way impeded in embryos that have been cultured in vitro.
The solution to this problem would be to microsurgically thin out the wall of the zona pellucida of these embryos on day three, just prior to transfer. It was hoped that this micromanipulative process to the embryos might provide a necessary extra bit of help to improve the implantation rate. This proposition is very difficult to prove with certainty, but in many centers, including ours, assisted hatching is performed on most embryos, and the results have thereby improved. It is a beautiful procedure and a wonderful rationale, and in women who have failed to get pregnant through the transfer of perfectly good embryos, the standard approach at the present should be to give them the benefit of the doubt, and to do assisted hatching.
A healthy blastocyst hatching.
IVF for Older Women
"For women who are told IVF isn't an option, mini-IVF could be a more successful path to parenthood…" Fertility Road magazine, May/June 2011. Read More
Mini-IVF - Fox News St. Louis
We are willing to take on the most difficult cases with lower prognosis, so long as we feel there is a chance for pregnancy. Women over 38 years of age often have very few eggs, respond poorly to conventional ovarian stimulation, and because of lower pregnancy rates, are often just cancelled by IVF clinics for fear that such cases will lower their reportable statistics. Also, such patients usually require huge doses of expensive drugs that can add another $6,000 or $7,000 to the already high cost of conventional IVF, bringing total costs to as much as $18,000 or more per cycle.
Of course, one option for such women is donor eggs, but many women would prefer getting pregnant with their own eggs. The best solution for such patients is the Japanese mini-IVF protocol using a very highly specialized pure air environment of the highest industrial "clean room" grade, and an absolutely safe and reliable system for embryo freezing.
Mini-IVF, first developed by the Kato Ladies Clinic in Japan and then perfected and popularized at St. Luke's Hospital in St. Louis, is just the right approach for older women or women with low ovarian reserve who still want to use their own rather than donor eggs. It takes advantage of your own natural FSH elevation with an ingeniously simple protocol that strives for smaller numbers of better quality eggs. Instead of massive doses of expensive hormones to try to blast out a few poor quality eggs, it more naturally teases out of the older ovaries their best quality eggs with a carefully devised protocol of minimal stimulation. There are no symptoms of huge hormonal swings or hyperstimulation. It is easier on the patient and much cheaper than conventional IVF.
The success of this approach depends not only on a novel endocrine stimulation protocol, but also upon a flawless method of embryo freezing such as our vitrification system, and the highest level laboratory air purification system to give the eggs from older women the best possible environment in which to develop.
Let's give a few examples:
A 43 year old woman who married relatively late in life was told by numerous doctors and infertility clinics that she could only get pregnant if she used donor eggs, and some also recommended donor sperm because of the husband's age (which was silly). However this couple was only interested in having a child from their own sperm and eggs. We placed her on a program of mini-IVF back to back cycles to store up embryos by vitrification over the next year. We were only able to attain one egg (and one embryo, therefore) with each cycle. After four embryos were finally stored up, we transferred two thawed embryos at a time in subsequent months, and with the second embryo transfer, at age 44, she became pregnant with her own eggs and delivered a healthy baby boy.
Another example: A 43 year old woman married, at age 38, to a 34 year old man, already had conceived naturally and delivered a healthy son four years earlier. Now the couple wanted a second child and had been told that donor eggs was her only option because of her age and low ovarian reserve. But they were definitely not interested in their son's sibling having a different maternal DNA origin than his. So we put her through two cycles of mini-IVF back to back, and stored up three embryos retrieved from her own eggs, only one of which looked viable. One half year later we thawed that single embryo and transferred it to her uterus. She became pregnant and delivered a healthy baby at age 44 without having to resort to donor eggs.
Another example: A 41 year old nurse married to a 39 year old physician had already gone through three conventional IVF cycles elsewhere with PGD and no success. So they were recommended to use donor eggs for her next (fourth) cycle, but they were just not ready for this option. In desperation they underwent three back to back cycles of mini-IVF with us (at about one fifth of what she spent in her previous IVF's), obtaining two eggs each time, resulting in six stored up frozen embryos [video]. We transferred two at a time the next year, and she finally got pregnant with her final embryo transfer, with her own eggs, and delivered her own healthy baby.
Some women lose most of their eggs earlier in life, like in their early 30's or late 20's, just as though their ovaries were that of a 40 year old. For them the news is even harsher when an IVF clinic tells them they will need to use donor eggs. One such couple we treated with back-to-back mini-IVF cycles had immigrated to the U.S. 12 years ago. Both were physicians, only 34 years old, and had been told by several IVF centers they had visited that she had only a few follicles left, was about to go into early premature menopause, and was not a candidate for IVF with her own eggs. They had started expensive stimulation protocols for IVF at several clinics and each time the cycle was cancelled because "there were too few follicles."
When they came to us, we initiated several relatively inexpensive cycles of mini-IVF, and retrieved 3 eggs in one cycle, and one egg in each of two more cycles, resulting in a total of three blastocysts which were frozen by vitrification and stored for later transfer. All three of these cycles cost less than they had spent for just one standard cancelled cycle elsewhere. Her first embryo transfer here resulted in no pregnancy, but with her second single blastocyst transfer she became pregnant and delivered a healthy baby boy, with her own eggs, never having to resort to donor eggs.
A great example of the superiority of mini-IVF for older women is a 43 year old who had gone through 5 previous conventional high dose stimulation IVF cycles since she was 40 years old. Each cycle produced only one or two poor quality embryos and no pregnancy. Now at age 43, we put her through one cycle of mini-IVF, and she produced 5 high quality embryos and is pregnant. Too much FSH stimulation produces poorer quality eggs, especially in older women.
A very determined 45 year old woman underwent four cycles of mini-IVF stimulation for IVF resulting on a total of 14 frozen stored embryos, because she knew how low her chance was for pregnancy per embryo with her own 45 year old eggs. Finally, we transferred 4 embryos (because her eggs were so old, and as expected, she did not become pregnant. However, six months later we thawed and transferred 4 more embryos, but this time she became pregnant and delivered a healthy baby with her own eggs at the age of 46. She still has 6 more frozen embryos remaining, and so it is possible she could even have a second child in a few years, before she is 50, to be a sibling for this miracle baby she had from mini-IVF with her own eggs at age 46.
A dramatic example of mini-IVF for older women is a typical case of what we call secondary infertility, where the couple was able to conceive and deliver a healthy baby when they were younger, but now find themselves infertile in their attempt to have another child a few years later. Secondary infertility is almost always caused just by the declining number and quality of eggs as the wife gets older.
For example, a physician patient with a zero sperm count because of pituitary deficiency (a rare condition in males), had his sperm count return with the proper hormone treatment, but because the count was still low, they needed ICSI-IVF. However, by the time they saw us, the wife was already 40 years old, and she only had a few eggs retrievable and would have been cancelled at most centers and just told to use donor eggs, which they were opposed to. With mini-IVF and ICSI we managed to get 3 eggs, all good quality, inject them with his few sperm, obtain 3 good quality embryos resulting in a healthy baby boy nine months later.
But that was not enough of a miracle. Now at age 43, with such a low ovarian reserve, three years later, they wanted to try for another child. This is about as serious a case of “secondary” infertility as one could ever imagine. Their local IVF center laughed at them; but because they were physicians, they knew not to give up hope. So this time, again with mini-IVF, we actually got 6 eggs and 5 good quality embryos, giving them two more children, even at age 43, when every other center would automatically turn them down because the results are normally so poor with conventional IVF in women over 40. As though this was not enough of a family, they decided at 45 to try once again with her remaining 3 frozen embryos to enlarge her family further and now again has a healthy pregnancy due to deliver when she is 46 years old, all from her own few remaining eggs, and his near zero sperm count.
A 45 year old single woman had to go through 4 cycles of mini-IVF with embryo banking, and was thereby able to store up 6 good quality embryos derived from her own eggs. But she was obviously not certain that even this would result in a pregnancy because of her age, and so she decided in her 5th cycle to use donor eggs as well. We transferred one thawed embryo of her 6 that were frozen from her own eggs, and one embryo derived from her donor eggs (at her request). She wound up delivering healthy twins, one from the donor eggs, but clearly one also from one of her 6 frozen embryos that had resulted from her own eggs. This case exemplifies dramatically that if you can get good quality embryos using mini-IVF from your own eggs, even for patients in their mid-forties, pregnancy is still possible without the need necessarily of donor eggs.
An interesting 38 year old couple saw us in whom the husband was deemed to be azoospermic (no sperm) and the wife’s testing revealed premature ovarian failure with only a few antral follicles and a high day 3 FSH. But despite these clear negatives, which no other clinic would take on (and would only recommend donor sperm and donor eggs), we gave it a try. Indeed we found a few sperm in him with TESE that were quite good quality, and with mini-IVF, obtained 3 eggs from her very deficient ovaries. This resulted in 3 great quality embryos, which we froze. After saving up several more embryos, with another cycle of mini-IVF, and another TESE for him, they now had 5 good quality embryos frozen using our advanced vitrification technique. As a result, this unlikely couple now has two healthy babies using the husband’s sperm and the wife’s eggs, and never had to resort to either donor sperm or donor eggs.
I would like the emphasize that we are not against donor eggs or donor sperm. We are enthusiasts for this, and we have literally no “waiting list” problems for donor eggs. We have a ready supply, and patients who choose that route are very happy with the result. It is just that most people would prefer their own DNA, and for that goal, properly administered mini-IVF with embryo banking is the best alternative for the older woman or for even for the younger woman who suffers from low ovarian reserve.
In fact the remarkable successes with some of these older women resulting from the mini-IVF protocol are causing us to be cautious about how many embryos we transfer at one time even when older eggs are involved. One 44 year old woman who was turned down by many IVF centers unless she agreed to use donor eggs, underwent two mini-IVF cycles at our center in which we were able to retrieve 4 eggs each time, resulting remarkably in 4 embryos each time, which were frozen by vitrification and stored for eventual transfer. So at age 44, we thawed and transferred just two embryos (to be safe) and she did not get pregnant. Two months later we thawed and transferred two more embryos, and again she did not get pregnant. So five months later, at almost 46 years of age, she asked to thaw and transfer all four of her remaining frozen embryos, thinking that from such old eggs, there was very little risk of multiple pregnancy. Yet at age 46. she now became pregnant with triplets, all from her own 44 year old eggs. Fortunately, and as expected, her triplet pregnancy spontaneously reduced to twins, and she delivered healthy term twins, with her own eggs. Thus, with our new mini-IVF technology, we have to still be cautious not to transfer too many embryos at one time, even with older eggs.
This 43 year old couple was told by every clinic they would have to use donor eggs, but they did not want donor eggs and were able to get pregnant using mini-IVF with her own eggs, and they now have two healthy babies (twins) and want to tell their story:
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 (42 at the time we first sought help). 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 43 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 43, 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 43 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 one week 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.
Dr. Dan & Lorelei Andedo
Rock Island, Illinois
Reasons for our remarkable success in older women using mini-IVF
There are several reasons for the remarkable success in our cases of older women using this approach. Firstly, it is hard to overstate how crucial is the purity of air quality in the lab as well as in the operating room. 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 just as many (or few) eggs from older women as more expensive massive dosing conventional stimulation protocols, but better quality eggs and 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 adds up to better success rates in challenging cases.
We can sometimes even achieve pregnancies in women 46 years of age and older with this approach (although donor eggs is a much more sure technique for achieving a successful result for such cases).
A striking example of how mini-IVF with back-to-back cycles to store up vitrified embryos can allow older women to get pregnant and have babies with their own eggs is a couple from the north central area of the U.S. who first saw us a year earlier, both 47 years old. He had had a vasectomy 20 years earlier as a young man, and had not decided till this late age finally, after 12 years of happy marriage, that they both really wanted a child. I told them we could easily restore his fertility with a vasectomy reversal or just retrieve his sperm microsurgically, but the problem was her age. Although I brought up donor eggs as the surest solution, they insisted on trying with her own eggs. So we reluctantly agreed to give it a try at age 47.
Her first mini-IVF cycle (using his retrieved sperm, of course) yielded just one egg, which resulted in a perfect looking embryo, which we froze. The next month another mini-IVF cycle yielded 3 eggs, which resulted in two more beautiful embryos which we also froze. The following month, the next mini-IVF cycle resulted in just one empty follicle and no further embryos to freeze. She was completely out of eggs and we had managed to retrieve her last remaining eggs in the nick of time. A half a year later, at age 48, and completely devoid of eggs, we transferred these three beautiful frozen embryos, and she has a healthy pregnancy at age 48.
Another beautiful example is a 47 year old woman who went so far as to store up 14 embryos with mini-IVF. She already now has two babies (with her own eggs) and still has four more frozen embryos with which she can try for a third baby despite now being almost 50 years old. These cases of women over 46 getting pregnant with their own eggs are unusual, but it is nonetheless quite possible if donor eggs are not an option for them.
Of course we always suggest donor eggs to older women as a much surer way of having a baby, and we are strong advocates for accepting donor eggs once a woman has run out of her own eggs. But with this mini-IVF approach of storing up vitrified embryos month by month in older women, we have a remarkable pregnancy rate even in women over 42 years of age of over 50%, and this year thus far 67%. But it takes a great deal of patience on the part of the patient to retrieve just a few eggs at a time every month until enough embryos are banked to warrant thawing and transfer.
This principle can also apply to younger women who have very few remaining eggs who are suffering from premature ovarian failure. Most IVF centers will turn these women down if they do not agree to donor eggs, or else string them along with tests and meager treatments that are doomed to fail, until they finally agree to donor eggs.
We recently took care of such a case, a young woman I had known since she was a little girl, who had undergone multiple surgeries at various clinics for other health problems, but the result of her cure was just one remaining ovary with hardly any eggs left. In fact she did not just want one baby, she dreamed of having a big family. The misery this brave and beautiful young woman had to go through, being told by everyone that she could never have her own children, and her determination not to be swayed by the naysayers was truly inspirational. She went through a total of 6 cycles of IVF just to store up embryos, retrieving only a few eggs at a time, and eventually storing up 10 embryos. This resulted in a healthy pregnancy and enough frozen embryos to eventually have the big family she always dreamed about.
There are many more such examples where persistence and mini-IVF can be successful with older couples or women with very few eggs. The advantage of mini-IVF is that we can get better quality embryos at a much lower cost per cycle, store them up safely with vitrification, and spend less than the conventional IVF cycles would cost. Nonetheless, some women simply will not have any viable eggs of her own, and then donor eggs becomes the only remaining option.
If a woman absolutely cannot get pregnant with her own eggs, then donor eggs is her only remaining option. Actually, although not her first choice, it is nonetheless a very good option. We have been offering donor egg IVF for over 24 years, and therefore have had a chance to follow these children and their parents for a almost a quarter century. Both the children and the parents are well adjusted and completely happy with their lives as a result of the donor egg IVF. In fact, these wonderful outcomes convince me that in the controversial nature vs. nurture debate, nurture is the clear winner. The reason it is so often misunderstood is that what appears to be ingrained character in a child is in truth, a subtle result of early interaction with parents in the first two or three years of life. The character, personality, intelligence, and even coordination motor skills of the child are dependent on that emotional bonding and complex interaction with parents in the first few months and years. So couples who have to take their second choice, donor eggs, because they have run out of their own eggs, should not be forlorn. Donor eggs are a great option for them.
How does it work and how do you select an egg donor? Many IVF programs just have a small local pool of egg donors, which we feel is not a favorable approach. We work with a variety of specialized donor agencies all around the U.S. encompassing every geographic region and every ethnic and racial group so as to give the couple with ovarian failure the largest possible choice. We do all the medical work and screening, but the infertile couple does the choosing based on detailed characteristics and appearance of the donor. However, for psychological reasons, we feel it is best for both the donor and recipient to remain anonymous to each other, although an occasional couple will prefer a known donor. In either event, if you are forced by complete lack of any fertile eggs of your own, to use donor eggs instead, in the end you can feel quite comfortable that you can still have a very happy and fulfilling family.
Many women have irregular menstrual cycles, varying from 25 days to 60 or 90 days apart, and they do not ovulate. There is tremendous confusion amongst some physicians as to the cause of this problem and how to treat it. It is sometimes referred to vaguely as "the metabolic syndrome," which is meaningless, and such women are put on diabetes-type drugs even though they don't remotely have diabetes. Physicians struggle for years with such patients, trying drugs like clomid or metformin with absolutely no improvement, and even at medical meetings they often scratch their heads because of the failure of most of these drug therapies. But actually the answer to both these questions are very clear and straight forward.
Women with PCOS ("polycystic ovary syndrome") were born with an excessive number of eggs. If anything they are too richly endowed. They will go through a late menopause and when they get older, into their mid-forties, their cycles will begin to become regular. The reason is they simply and ironically have too many eggs. This overabundance of eggs suppresses their pituitary gland's secretion of FSH, and thus inhibits the prime starter of the ovulatory cycle, resulting in an elevated LH/FSH ratio, and an accumulation of non-ovulated, mid size, non-atretic follicles in the ovary.
Just recently we saw a typical example of a 40 year old woman and her husband who had been trying for 13 years to get pregnant unsuccessfully. Her periods had always been irregular varying from 20 days to over 90 days but in the last few years as she approached 40, they finally became regular, as her number of eggs declined to more normal levels, but they were now older eggs, and so she still needed IVF to get pregnant. Her egg count was still high for a 40 year old woman, but when she was younger, it was so high that her FSH was severely suppressed, and so she didn't ovulate.
If you try to stimulate with clomid, you usually cannot push the FSH level up enough to normalize the cycles fully, and certainly metformin (glucophage) which increases insulin receptivity and forces the glucose and potassium to go inside the cells, does nothing to solve the primary problem of too many eggs suppressing FSH secretion. So often an effort is made to stimulate ovulation using injectable FSH combined with intra-uterine insemination (IUI). The IUI is absolutely inferior to natural intercourse for insemination, and the injectable FSH often causes the formation of way too many follicles and thus risking a dangerous high order multiple pregnancy, because there are so many eggs.
The correct approach for PCOS patients therefore should be remarkably clear cut. Go on birth control pills when you are not trying to get pregnant, and do IVF when you want to get pregnant. Birth control pills for these patients will regulate her periods, and thus prevent the future likelihood of uterine cancer and "woman's heart disease." IVF for such patients will allow the safe transfer of one or two embryos only, and freezing of any "extra" embryos for future babies, thus eliminating the risk of a dangerous multiple pregnancy.
The biggest risk for treating these patients is OHSS (ovarian hyperstimulation syndrome). The most effective, and the safest stimulation protocol for patients with PCOS (who otherwise are at great risk for hyperstimulation syndrome which can be very dangerous) is the "Filicori protocol" which unfortunately many IVF clinics do not know how to perform, and yet it is so simple. After the first 5-6 days of stimulation with FSH to recruit follicles, you discontinue FSH completely and only take low dose HCG (200 units). This allows the developed follicles to mature into great quality eggs, while the thousands of dangerous small follicles decline. This provides great quality eggs but avoid dangerous overstimulation.
WHAT IS PREIMPLANTATION GENETIC DIAGNOSIS (PGD)?
Most of the twenty-five thousand or so genes in the human genome have now been identified and their DNA sequenced. Molecular analysis of genes is becoming simpler and more efficient. As a consequence, PGD with IVF, can now prevent couples from having to face the horror of giving birth to children with almost any of the genetic defects such as Down syndrome, cystic fibrosis, muscular dystrophy, sickle cell anemia, Tay-Sachs, Gaucher’s disease, mental retardation, etc., that terrify every woman who ever gets pregnant. With PGD, we can also better understand the problem of recurrent, early miscarriage and the genetic errors that arise in pregnancies of older mothers.
PGD should not be construed as creating “designer babies,” an incorrect term used only by the press and not by physicians. We could not manipulate (even if we wanted to) the features or characteristics of an offspring. That is just pure fiction. All we can do is eliminate heartbreaking and devastating genetic disease.
Figure 1: 8 Cell Embryo Ready for Biopsy (i.e. Remove One Cell)
WHAT IS EMBRYO BIOPSY?
When an embryo reaches the third day of development, it normally has eight cells. One or two of these cells, called “blastomeres,” can be removed from the embryo with micromanipulation technique. The embryo is usually unharmed, and can go on to develop just as though this one cell were never removed. You can then subject those one or two cells to genetic analysis, and know the chromosomal composition of the embryos, and if they carry a specific disease-producing mutation.
Figure 2: Removing One Cell for DNA Analysis
BASIC GENETIC LESSONS
DNA Testing and Single Gene Disease
Everything we are physically is determined by approximately 25,000 genes located in our DNA. Your entire body is made up of many thousands of different proteins whose structure and orientation determine the incredible machinery of your body and brain. However, these many thousands of different proteins are in turn composed of just twenty amino acids. The variety of amino acids that theoretically could be expected to exist is unlimited. Chemists can synthesize many thousands of them. However, living nature is composed of only twenty specific amino acids, which are absolutely the same for all living things on earth. The differences between living creatures lie in the differences in the sequences of these twenty amino acids, which make up all the different proteins of which they are composed. In turn, this sequence of amino acids has been determined by the sequence of the 4 basic letters that comprise our DNA. The entire human genome represents 3 billion base pairs, or letters, of DNA. A specific set of combinations of three DNA letters are codes for each one of the twenty amino acids. Therefore, the order in which the DNA letters occurs on the chromosome determines the sequence of amino acids, and this, in turn, determines the proteins, which determine everything in our body. A single error in an amino acid sequence in any protein can cause a dramatic change in its structure, and a severe genetic disease like cystic fibrosis or Tay Sachs. These errors in DNA sequence can be diagnosed by a process (carried out in a test tube) called PCR, and that is the basis of PGD for single gene genetic disease.
Chromosome Testing and Aneuploidy Screening
All of our 6 billion DNA “letters” are located on forty-six chromosomes, which are coiled up inside the nucleus of every single cell in your body and are divided into twenty-three pairs, twenty-two “autosomal” pairs and one “sex” chromosome pair, the “X” and the “Y”. The child who has two X chromosomes will be a girl, and one with one Y chromosome and one X chromosome will be a boy.
For conception to occur, twenty-three chromosomes from the husband’s set of forty-six, and twenty-three chromosomes from the wife’s set of forty-six, must meet at the moment of fertilization and become an embryo with a new normal set of forty-six chromosomes. The process whereby primitive sperm cells and primitive eggs lose half of their chromosome number as they become sperm and mature eggs ready for fertilization is called “meiosis.” The aging process of eggs makes it harder for them to undergo the meiosis process than sperm. That is why the eggs from older women are less likely to result in a viable embryo, and that is also why older women are more infertile than younger women, and why older women have higher rates of miscarriage and of babies with abnormalities such as Down’s syndrome.
If there is an error in division of the egg’s chromosomes and one of the pairs of chromosomes fails to separate, then the egg will have twenty-four chromosomes instead of twenty-three. In Down’s syndrome, for example, the embryo has a total of forty-seven chromosomes instead of forty-six because it has three sets of chromosome 21 instead of the normal two sets. This kind of a chromosome error, in which one of the chromosomes has three copies instead of the proper two copies, is called “trisomy.” All of these chromosomal errors, including trisomies, monosomies, and various combinations can occur in virtually any of the chromosomes, and these errors, as a group, are called “aneuploidy.” These numerical chromosomal errors in a cell can be diagnosed by counting color signals on a slide by a process called FISH.
Most of these chromosomal defects that occur in human embryos are lethal and result in either failure of the embryo to implant, or result in a miscarriage. Only occasional chromosomal defects such as trisomy 21, or Down syndrome result in the actual birth of an abnormal baby, and even in that event (trisomy 21), only 20% of the time. Nothing about in vitro fertilization (IVF) or ICSI, increases the risk of these chromosomal abnormalities.
Criticisms and Limitations of PGD
Single gene defects are the rare genetic diseases like cystic fibrosis or Tay Sachs (there are thousands of them), which occur in the offspring of otherwise fertile couples who are carriers, and which are diagnosed by PCR. PGD for such couples is extremely accurate today because for verification, multiple DNA sequences near the defective gene (linked markers) can be tested for, as well as the mutation itself. PGD is also very accurate for recurrent miscarriage caused by chromosomal translocations for which about 1.5% of infertile couples are carriers.
However, PGD (referred to as PGS in Europe) for routine aneuploidy screening during IVF for infertile couples has recently come under severe criticism in Europe owing to several prospective, randomized control studies in Holland and Belgium. PGS has failed to show any improvement in IVF clinical outcome per initiated cycle for advanced maternal age, nor for recurrent implantation failure.
In European studies of even younger, infertile couples, only 36% of embryos subject to PGD were found to be chromosomally normal (where two embryos are removed and tested rather than one). When embryos diagnosed as chromosomally abnormal on Day 3 (and, therefore, not transferred to the patient) were re-examined on Day 5, only 54% turned out to have that abnormality. The error rate for the FISH technique has been clearly shown to be as low as 5%. Therefore, this 50% discordance appears to be mostly due to the wide prevalence of embryo mosaicism. This means that some of the cells in many embryos are normal and some are abnormal. About 50% of embryos in the European studies have thus been found to be mosaic. Therefore, the use of PGS may result in good embryos being discarded (diagnosed as abnormal) and abnormal embryos (diagnosed as normal) being transferred.
However, there is still some benefit to PGS in certain cases. Firstly, if two cells are tested instead of one, and both reveal chromosomal errors, the diagnosis of abnormal embryo is very likely to be correct. Likewise, the diagnosis of normal embryo using two cells also is likely to be correct. (However, the problem is that removing two cells is more likely to hurt the embryo than removing one cell.)
Secondly, for recurrent miscarriage in younger women, even with removing and testing only one cell, PGS is likely to reduce the miscarriage rate. (However, unfortunately, with PGS there are certain to be some normal embryos that are discarded as abnormal.) PGS can also vastly reduce the risk of a Downs Syndrome conception.
Thirdly, it may be useful in counseling for cases who consistently produce all chromosomally abnormal embryos in order to understand their problem better.
Our experience with PGS and PGD is extensive, and we can counsel you on whether it is a good idea or not for your particular IVF cycle. In general it is best reserved for carriers of single gene disease who do not want an offspring to have such disease, and for recurrent miscarriage.
"Fertility: stop all the clocks" from The London Daily Telegraph Sunday Magazine
Cover story on The Riverfront Times: The Egg Man - Dr. Sherman Silber says he can extend a woman's fertility by decades. He just needs to freeze her eggs or even a piece of her ovarian tissue; October 4, 2007
- Fertility expert Dr. Sherman Silber gives hope to infertile men and women
- "IVF Worked For Them" - AOL Health
- Minimal ovarian stimulation (mini-IVF) for IVF utilizing vitrification and cryopreserved embryo transfer (PDF, 406K)
- Pre-implantation Genetic Diagnosis (PGD)
- Intra-Cytoplasmic Sperm Injection (ICSI)
- Vasectomy Reversal
- Tubal Ligation Reversal
- Egg Donation
- A Special Message From Dr. Silber About Your Biological Clock and Preserving Your Fertility
- Preserving Your Fertility
- Egg, Ovarian Tissue, Embryo, and Sperm Freezing
- Sperm Aspiration
- News Coverage of Ovary Transplantation
- Read Q&A article about mini-IVF
- Hokey ideas about raising sperm count
Also listen to Dr. Silber's radio commentaries:
Listen to Dr. Silber's internet radio chat on msnbc.com. (47:26 min.)
Listen to Dr. Silber and Joan Hamburg discuss the exciting new procedure for determining exactly how long a woman has left on her biological clock. (25:52 min.)
If you have any questions, you may call us at (314) 576-1400.