IVF - 32 Years Since the Birth of Louise Brown: What a Journey!

I can hardly believe that it has been 32 years since the 1st successful IVF conception, (initiated by Patrick Steptoe, the father of human IVF) resulted in the birth of Louise Brown. Time has certainly flown.

I first met Patrick Steptoe in the very early 70’s when he was a visiting professor at the University of Cape Town, South Africa where I was a young professor. I was assigned the responsibility of chaperoning Dr. Steptoe around Cape peninsula and I got to know him quite well. When Dr. Steptoe, a passionate musician, met my wife Charlene, a professional stage actress, they immediately clicked. A friendship soon developed.

So, why am I mentioning this and what does it have to do with IVF? To me…everything because it literally opened the door for me, when 8 years later, he and Robert Edwards introduced human IVF. In fact, I vividly recall the day that Dr. Steptoe called my home to speak to my wife. He and Charlene were talking and at the tail end of the conversation when I got a few minutes to talk to him, he shared with me that he and Robert Edwards had after more than 100 unsuccessful attempts, succeeded in initiating the world’s 1st human IVF pregnancy. He suggested that I visit him in England, learn the technology and then set up an IVF program in the US where, at the time, there were only a handful of existing programs (today…almost 400).

So, off I went with Cliff Stratton PhD (a professor of embryology at the University of Nevada), to England. A few weeks later we returned and established the first private (non-university based) IVF program in the US. (Our 1st IVF babies were born less than 1 year later).

To be quite honest, establishing a “private” IVF program did not sit well with those of our colleagues who operated the other 3 (university-based) IVF programs in the US. The general feeling was that procedure was still in the research stage of development and did not belong in the “private setting.” But we were lucky because we were able to turn to Dr. Steptoe and Robert Edwards who were very forthcoming and eager to help when we hit the inevitable bumps.

Dr. Steptoe went even further in assisting me getting my career in IVF launched. Often times when he was lecturing in the US, Canada and Asia, he would invite me along and introduce me to the powers that be, thereby affording me an opportunity to make scientific presentations. In this way, I was able to establish myself quite rapidly in what represented an emerging and exciting new field of medicine.

When I look back to where I started in 1982 and where we are today, I can hardly believe my good fortune in having known Drs. Steptoe and Edwards. I am in awe of how the field of assisted reproduction has evolved over a mere three decades.

Consider the following: When I started doing IVF and through most of the early 80’s, we had to harvest eggs from the woman’s ovaries by a surgical process known as laparoscopy. This required the introducing a “telescope”-like instrument through the belly button into the woman’s pelvis to visualize her ovaries and the follicles in them. Then through a separate puncture site, a needle was introduced into each follicle in turn, in order to aspirate the eggs that they contained. It was truly a cumbersome process – taking about an hour to perform – and it had to be conducted under deep general anesthesia. Moreover, post operative recovery was not a “picnic”. It was often a bumpy road. (By comparison, today when we do an IVF egg retrieval we aspirate eggs from the follicles via a needle passed alongside a vaginally introduced ultrasound probe which allows clear visualization of the ovaries.)

This was also a time when most women received an oral medication, clomiphene citrate to stimulate the development of follicles and eggs in their ovaries. This yielded a low number of eggs and also created a less than ideal uterine environment for embryo implantation. I recall being one of the first in the world to switch from clomiphene to injectible fertility drugs (Pergonal and Humegon at that time). Our results immediately improved dramatically, allowing us to differentiate ourselves from the competition. It also heralded a major advance in the IVF arena, since injectible fertility drugs were found to be much more effective than clomiphene. As a foot note, it was around this time that I remember getting the idea that it might be possible by washing and preparing semen and then inseminating the enhanced sperm directly into the uterus and so improve results with artificial insemination (hitherto very poor). And so….the now common procedure known as Intrauterine Insemination (IUI) was born.

In the 80’s and early 90’s few people were performing in vitro fertilization in women over the age of 40 or for non tubal causes of infertility. The results were simply too poor, and with most IVF practitioners competing for business it was important to report the best possible outcome statistics. But the IVF field was growing as more and more physicians, both in the private and academic sectors, became captivated by the new technology and the promise it offered. Yet at that time IVF success rates were dismal, ranging from 5-10% per procedure, even in young women.

Then, in the mid 90’s, clinical researchers in Europe began reporting on a technique referred to as Intracytoplasmic Sperm Injection (ICSI) in cases of IVF of male infertility where results using conventional fertilization in the Petri dish had been dismal. With ICSI, a single sperm was injected into an egg to force fertilization. The success rate with IVF for male infertility shot up, to the point where they were comparable to cases of non-male factor.

I knew the researchers who had developed ICSI and contacted them. Within weeks I sent a team of embryologist to Europe to learn ICSI and upon their return, became among the first in the US to apply the technology in cases of male infertility. Today, we at SIRM, rather than fertilizing eggs conventionally in a Petri dish, prefer to perform ICSI across the board (for male factor and non-male factor cases alike). We (and other IVF programs) have found that routine ICSI improves fertilization rates as well as pregnancy rates without posing any significant risks to the offspring (read on ICSI elsewhere in this blog).

It was also in the latter part of the 90’s that everyone in the IVF field started moving away from using clomiphene to stimulate a woman’s ovaries for IVF, to injectable fertility drugs. Originally, these injectible fertility drugs (gonadotropins) were all derived from the urine of menopausal women which is rich in gonadotropins (active ingredients). Then, around the turn of the century came the widespread introduction of recombinant DNA, purified gonadotropin products such as Gonal F, Puregon and Follistim which have since all but replaced urinary-derived fertility drugs since they apear to be more effective ....to the great benefit of patients worldwide.

By the year 2000, the number of IVF programs in North America had risen to above 200in number and the quality of service had improved dramatically. Birth rates were now ranging between 20-30% per procedure with some programs reporting even higher results.

Unfortunately, the level of accountability in reporting IVF statistics did not keep pace with the evolution of the science and the technology. In fact, our governing body, the Society for Assisted Reproductive Technology (SART), that had been charged by central government with the responsibility of ensuring accurate reporting of success rates was unable to do so. This was largely because member programs were non-compliant and because SART lacked the will and the means to enforce compliance. This meant that, often unbeknownst to IVF patients, they could not rely on IVF outcome statistics reported by SART. Sadly even now , in this regard things have not changed . Yes, even mow in 2010 the so called “SART Report” that is supposed to accurately portray annual IVF outcome statistics on a dedicated website simply, regurgitates the IVF success rates reported to them anually by member programs without any audit or other verification of authenticity. Clearly this is something that must change... Consumers derserve more.

The most recent paradigm shift in the field of IVF occured with the emergence of genetic testing of eggs and embryos to identify those that are the most “competent” (i.e. the ones that have by far the greatest potential to propagate healthy pregnancies). Technologies such as comparative genomic hybridization (CGH) and polymerase chain reaction (PCR) now allow us to identify genetically “competent" embryos. The same technology also affords an opportunity to selectively freeze only the most competent eggs, opening the door to fertility preservation and egg banking.

Perhaps one of the most important benefits of CGH egg/embryo testing its use to select the most competent embryo for transfer, thereby promising a reduction in the risk of multiple pregnancies that cause much of the morbidity and mortality associated with IVF babies.

The changes that have occurred in the field of IVF over the last 32 years since Louise Brown was born would have been almost unimaginable to Dr Steptoe when he initiated all of this. For me, the 28 years that I have been involved in this medical field have been nothing short of a spectacular ride.

Yes indeed, things have come along way. Just consider the fact that IVF success rates which were under 5% in the early 80’s are now better than 50% per procedure in certain categories of patients. Then consider the introduction and the potential impact of CGH egg and embryo selection where the birth rate per single embryo transferred is now almost 70%. Now consider where we are likely to be headed with the emergence of applied genetic techniques that could have the potential to identify horrific life threatening diseases in advance.

No doubt, to Patrick Steptoe the consummate musician, this would have been “music to his ears”.

IVF for the Fertile Population: Fast Becoming a Justifiable Option

Ask virtually anyone about the indications for in vitro fertilization (IVF) and you will receive the answer hear that it is a procedure performed for the treatment of resistant infertility. While this is true for the vast majority of cases, it is not true for all. In fact, an ever growing number of women/couples are electing to undergo IVF for reasons other than infertility. Let us examine some of these reasons:

Fertility Preservation: The fast pace of the 21st century has catapulted women into the career building arena. Justifiably women of today often aspire to compete with men at the professional level. One of the disadvantages that they confront is the fact that in initiating having a family, it will often require interrupting their career path for a protracted period of time to give birth and then nurture their child(ren) through much of the formative years of childhood. Then, when they attempt to re-enter the workforce, they usually will find themselves having to play catch-up. While some can overcome this hurdle, the majority will find themselves severely disadvantaged by the interruption. Many will simply not be able to make up the lost ground. In the past, this factor has compelled many such women to delay having a family until they are older and have established themselves firmly in their career paths. However, the obvious problem in delaying having children is that advancing age inevitably decreases the ability to conceive, increases the risks of miscarriage and birth defects, and is associated with a growing risk of life-endangering pregnancy complications that can affect both mother and child.

The recent introduction of egg freezing, especially when genetic testing such as Comparative Genomic Hybridization (CGH) is used to select the best quality eggs for cryopreservation (vitrification) and storage (banking), now offers promise that women will be able to safely freeze their eggs and store them for use when they are ready to embark on having a family. By resorting to egg banking they are able to “stop the clock” and are afforded the opportunity to defer child bearing to a time of their choosing and with the man of their choice. Banking frozen eggs does however mandate that when the decision is made to have a baby, they will have to be thawed and fertilized before being transferred to the uterus........ In other words, IVF will be needed. The emerging ability to freeze eggs has the potential of profoundly expanding the reproductive choices of women. It puts them back in the driver’s seat where they belong.

Fertility Rescue: In the past, women requiring surgery and/or chemotherapy for treatment of cancer often found themselves being propelled into a premature menopause with no hope of having a baby with their own eggs. The introduction of egg banking now affords such women the option of preserving their eggs before undergoing such treatment. In this way, once they have been cured, they have the opportunity to conceive using their own eggs. As with fertility preservation, the introduction of selectively banking CGH-tested eggs has vastly improved the efficiency of this process.

Embryo Banking: In this day and age, many couples who decide upon having a family find that they are not quite ready early on. Pressures in the workplace, financial considerations and even uncertainly regarding the stability of their relationship with their partner might justifiably drive them towards delaying building a family. Unfortunately, the biological clock cannot be reset, and for many such couples, the quality of their eggs will have declined by the time they decide to embark on family building…making it much more difficult for them to succeed. For such couples, the option of undergoing an egg retrieval, fertilizing their eggs, and then freezing (vitrifying) and banking the resulting embryos will provide a safe way to plan and time having babies. Again, the process would require IVF in spite of there being no fertility issue.

Same Sex Relationships: For same-sex male monogamous couples, IVF using donated eggs is one way to have a family. The use of a gestational surrogate and an egg donor is required in such cases. While this is of course a complex arrangement, it is far safer than the alternative, where a gestational surrogate is inseminated with a male partner’s sperm and ends up contributing her genetic package (in the egg) to the offspring. The latter situation is fraught with legal concerns regarding custody. One need only go back a few decades to recall the Baby M saga where the surrogate demanded custody of the child and a horrendous legal battle ensued.

For female same-sex couples, the options of undergoing artificial insemination using donated sperm is usually the first choice because it is less costly and is not likely to be subject to legal custody conflicts. However, for a growing number of these couples, there is a desire on the part of both that they contribute equally to the creation of the baby. In such cases, IVF is required because the process will of necessity require the harvesting of eggs from one partner and transferring the resulting embryos into the other.

Embryonic Stem Cell Technology: This is probably the most controversial of all applications of IVF. Here, in some cases of childhood disease, the use of embryonic stem cells might be the only hope of a cure. It is conceivable in such circumstances that the parents might elect to undergo IVF to gain access to embryos from which cells can be harvested for stem cell propagation and therapy to the afflicted child. It is also possible, subject to resolution of serious ethical, moral, religious and societal hurdles, that in the future, embryos might be generated specifically for the purpose of propagating stem cells for therapeutic use.

Clearly in the past, IVF was largely performed in reaction to a fertility problem but things are changing as the above article suggests. We are fast approaching a time where individuals/couples will choose proactively to undergo In Vitro Fertilization so as to secure their future child bearing potential, resolve lifestyle and career issues and/or address serious life threatening ailments.

IVF and Age: Assessing the Options

An ever increasing number of women are deferring having babies until they have fulfilled career aspirations. Advancing age is associated with a progressive increase in the number of chromosomally abnormal (aneuploid) eggs and consequently a decline in egg “competence” (i.e., the ability to propagate embryos that can produce babies). Since it is predominantly the egg (rather than the sperm) that determines embryo “competence” it follows that as women get older, they experience an inevitable decline in reproductive performance which manifests in reduced fertility, as well as increased miscarriages and birth defects such as Down’s syndrome. Both are attributable to egg aneuploidy. It is therefore not surprising that the mean age of women seeking IVF services is also on the rise.

The woman’s age, largely through the effect it has on her eggs, determines both her natural fertility potential as well as her ability to achieve success following In Vitro Fertilization. But age can also impact on the woman’s ability to successfully complete a pregnancy as well as the health of the baby she gives birth to.

Older women (reproductively speaking) - especially those over the age of 39 - are much more likely to have underlying medical conditions such as diabetes, hypertension, coronary and cerebral vascular disease as well as an increased potential to develop thromboembolism. For this reason it is advisable that such women routinely undergo detailed screening before embarking on a journey to achieve a pregnancy. A full physical examination as well as pap smears, pelvic ultrasound and tests such as EKG, chest X ray, blood urea/electrolytes/creatinine/lipid profile/thrombophilia panel/liver enzymes as well as a glucose tolerance test should be done. Women who pass such testing often are not that much more at risk at developing pregnancy-induced complications such as preeclampsia, placental abruption, gestational diabetes, and pre-term delivery than are their untested counterparts. Their babies are also far less likely to be low birth weight and/or to suffer maternal age-related complications such as autism and intrauterine growth retardation.

It is unfortunate that older women only come to realize their predicament when they are already confronted with the ravages of the biological clock. At that point, most will be faced with only two options. The first is to attempt to have a baby using their own eggs; the second, to consider In Vitro Fertilization with eggs derived from young donors and which are less likely to be chromosomally abnormal. Consider the fact that at age 35, about 2 in 3 eggs are aneuploid, at 40 the chances are about 6 in 7, and at 45 years, more than 9 in 10 are “incompetent.”

Obviously, most women would far prefer to have a baby using their own eggs than those of an egg donor. In fact, in my experience, most couples will push to at least have one attempt with their own eggs before going to IVF-egg donation -- even those who also have severely diminished ovarian reserve and have little chance of achieving a pregnancy with their own eggs, whether or not IVF is used. They simply have a need to reach “closure” before moving on. Not only is this understandable, but it is their right to make such a decision, which their IVF doctor should not deny them simply on the grounds that it will lower his or her statistics. It should be the patient’s choice to make, provided that there is no medical reason to believe that either the IVF process or an ensuing pregnancy will place the patient in harm’s way. It is our responsibility as IVF physicians to disclose all information necessary to patients that will enable them to make informed choices, not to dictate those choices to them.

Egg donation is the preferred treatment for all women with depleted ovarian reserve (regardless of their age) as well as for women over the age of 43 years (regardless of their ovarian reserve). The chance of a woman of 43 years or beyond having an IVF baby with her own eggs is well under 10% per attempt. Thus, any such woman desiring to use her own eggs should be informed of this fact. If, in spite of this information, she still chooses to proceed, and is physically and mentally healthy enough to do so, she should be afforded the opportunity to try. I will never forget a patient who came to me at the age of 47 years demanding to do IVF with her own eggs. In spite of my protestations, she ultimately prevailed and we embarked upon what I then considered to be an exercise in futility rather than fertility. It took several attempts but she did conceive and her healthy little boy that she delivered (my Godson) at age 48, currently bears my name. While this serves to remind us that no matter how clever we think we are.... "man proposes while G-d disposes” it should not and does not suggest a change in policy with regard to the age beyond which a woman should preferably choose to use an egg donor.

I’m often told by older women that the reason they are reluctant to use an egg donor is that this would deny them the ability to have their own biological child. My routine answer in such cases is that the woman who gives birth is by definition the biological parent. No man can bear a child and thus he can only be a genetic contributor….never a biological parent under the former definition. Under normal circumstances the woman is both a genetic contributor and a biological parent. Thus, giving up the genetic component by using donated eggs still enables the woman to share her biological contribution with her partner as a genetic parent and together with him to create a nuclear family.

There have been several important recent advances in the field of advanced assisted reproduction that provide attractive options to women who anticipate to, or find themselves already in a situation where they seek to have a child at a later age. These are the following:

1. Customizing ovarian stimulation: As women get older, so do their ovaries. In the process, they respond differently to standard, “recipe” protocols of ovarian stimulation. What works in the younger woman does not necessarily work in an older woman or in a woman with diminished ovarian reserve. In such cases, protocols of stimulation need to be customized to meet individual needs. To the developing follicle and egg in such women, the biggest enemy is overexposure to LH-induced testosterone, which compromises egg development and increases the risk of egg aneuploidy. In such women, it is important to avoid protocols that either deliver too much LH (fertility drugs such as Repronex and Menopur have too much LH-like activity) or that cause the release of too much LH (“flare” protocols or the administration of Clomiphene and/or Letrozole). Ideally, in such women who undergo ovarian stimulation, LH concentrations should be kept low prior to and during the stimulation. My preference is to prescribe what we call agonist/antagonist conversion protocol (A/ACP) with or without estrogen priming. Having said this, it is important to note that even the ideal protocol cannot counter the inevitable increase in egg aneuploidy that occurs with advancing age. All it can do is avoid compromising the ovarian environment during ovarian stimulation and further prejudice egg quality.
2. Blastocyst transfers: A blastocyst is an advanced embryo that contains more than 100 cells. It takes 5-6 days for healthy embryos to reach this stage. Those that do not make it are almost invariably aneuploid and not worthy of transfer. Those that do make it are more likely to be (but certainly not always) chromosomally normal. Thus, other than convenience, there is little reason to transfer earlier cleaved (day 2-3) embryos. Furthermore, by taking embryos to the blastocyst stage it is possible to improve the “efficiency” of the IVF process. With few exceptions, I recommend this to my patients.
3. Vitrification (ultra rapid egg/embryo freezing): Conventional (slow freezing) causes ice crystals to form in the cells and so damages them. That is why in the past, IVF success rates using frozen eggs or embryos have been much lower. With vitrification, the rate of freezing occurs 600 times faster, thus avoiding ice crystal formation. As a result, eggs and embryos so frozen are virtually as viable as are their fresh (unfrozen) counterparts. In addition, more than 95% of embryos and eggs will survive thawing following vitrification.
4. Embryo banking: Since older women often produce few eggs/embryos per cycle and a small percentage of these are likely to be “competent” there is often an advantage in performing several egg retrieval procedures sequentially (over several months) in order to stockpile as many embryos as possible. In this way, the woman can prolong her own reproductive potential by subsequently transferring 1 or more embryos to her uterus at a time.
5. Genetic embryo selection: We recently introduced Comparative Genomic Hybridization (CGH) as a method for identifying chromosomally normal eggs and embryos. This process now allows us to selectively transfer only embryos that are chromosomally normal or are derived from CGH normal eggs. When we transfer such embryos, the baby rate per embryo is dramatically improved, and when we vitrify eggs that are CGH normal, the baby rate per frozen egg is at least 7-fold greater than when non-genetically tested eggs are used. CGH may well turn out to be a “game changer” in IVF, but in the case of the older women considering embryo banking, it has a special significance. In such cases, it is possible to provide the older women with more confidence that her vitrified, CGH tested, banked embryos have a high potential to propagate viable babies regardless of her age.
   
   In cases of IVF with egg donation, CGH affords the opportunity to store only “competent” embryos and then to transfer only 1 or 2 at a time (at a later date). This avoids the risk of high order multiples (triplets or greater) and at the same time facilitates convenience in that the woman does not need to synchronize her cycle with that of her chosen donor.
   
   Another advantage of this method is that it allows younger women to bank their eggs for future dispensation. This is especially advantageous for young women embarking on a career and who know that by interrupting their career path through having a baby, they might fall behind in the opportunities otherwise available. In other words, women who intend to delay child bearing can stop the biological clock by selectively banking their genetically tested eggs. We call this Fertility Preservation (FP). It has been estimated that the demand for FP is probably 7 or 8 times larger than for IVF.
   
   Egg freezing also opens the door to donor egg banking. We hope soon so establish the world’s first genetically tested egg bank – wherein we will compile a large selection of CGH tested donor eggs. What this will do is allow women/couples to choose one or more eggs (based upon their need and preference) for thawing and transfer without having to embark in a detailed complex and tedious donor selection process. It will shorten the time involved in an ovum donor cycle, will improve success rates per embryo transferred (and thus reduce multiple birth rates) while drastically reducing the cost of service in the US.

Older women face two opposing situations. The first is that as they get closer to the menopause, diminishing ovarian reserve will inevitably lead to a reduction in the availability of their eggs. The second is that as they get older, the quality of their eggs will decline at an ever increasing rate. Thus, time becomes their enemy. On the other hand, once a decision is made to go to egg donation, the issues of both egg quality and ovarian reserve fall away. The only area of concern that remains is their ability to safely complete a pregnancy. It is this grappling with the decision as to whether they should use their own eggs or go to egg donation that often creates the greatest amount of torment. It is our responsibility to help them navigate this journey, and in doing so, it is often necessary to seek the assistance of qualified counselors, psychologists and sometimes even psychiatrists. As advising IVF physicians it is also important to avoid allowing personal preferences and prejudices to cloud our judgment.

As physicians who have taken the Hippocratic Oath, it is our responsibility to try our best to “avoid doing harm”. Thus, it is essential to fully evaluate all patients we treat. When it comes to IVF where we actively induce a condition that if misdirected can indeed cause harm it becomes even more important to thoroughly evaluate our patients in advance of treatment. And in the case of older women who, when it comes to pregnancy, are even more vulnerable and at potential risk this becomes even more of an imperative.

IVF Affordability: An Urgent Need for Insurance Reimbursement

Fewer than 150,000 IVF procedures (out of a pool of more than 1.5 million women/couples that are believed to be in need of IVF) are currently performed yearly in the United States. In other words, fewer than 10% of patients who need IVF gain access to this treatment. The number of procedures performed barely scratches the surface of the demand. At the same time most of the more than 360 programs in this country are grossly underutilized.

One half of all the IVF procedures in the United States are probably performed in fewer than 40 programs, with the remainder divided among the rest of the clinics. Since some larger programs are doing more than 1,000 procedures a year that means that others are performing far fewer than 100. Yet no one can gain optimal expertise doing so few procedures per year. Nor can smaller programs afford to incorporate many important technologic advances in the field. It is also impossible to develop meaningful statistics, let alone confidently report them, when they are based on such small numbers of cases per clinic.

The fact that only about one in ten women who need IVF actually undergo the treatment bears is largely due to two factors: First, most women/couples who are in need of IVF often find themselves being prescribed other lesser such as reproductive surgery and intrauterine insemination that do not offer them a reasonable prospect of success. Second, since only about 20% of American women/couples have insurance that covers IVF, such expensive treatment often represents an out of pocket expense that is unaffordable to most.

The fact that even in this the “era of Viagra” many insurance companies still reimburse for procedures such as penile implants done in cases of male impotence, and yet the same providers refuse to cover infertility, is an embarrassment. Perhaps, the predominantly older male executives of these insurance companies view male impotence as a life‑endangering condition and a couple’s desire to have a baby, as a vanity....Talk about a "double standard!" Also, many insurance companies cover relatively ineffectual surgeries to unblock Fallopian tubes, and in some cases for fertility hormone therapy and intrauterine insemination, but not IVF procedures. They do so either through ignorance, naivety or in the hope of avoiding or deferring IVF, probably as a cost-cutting strategy …yet another example of a "double standard". After all, if they recognize the need for infertility treatment and are willing to pay for some forms of therapy, the only plausible explanation for denying coverage for IVF which is far more likely to be successful, is to cut their expenses and bolster profit. Americans deserve better.

Insurance companies would no doubt argue that they are reluctant to pay for IVF treatment for two basic reasons. The first is the unacceptably high cost associated with caring for mothers and babies compromised as a result of the very high incidence of IVF-multiple pregnancies (especially triplets or greater). The second is that IVF statistics currently reported annually by the Society for Assisted Reproductive Technology are delivered unaudited and unaccredited. While most IVF programs are honest in the reporting of there statistics, this not true for all, giving some credence to the claim by insurance providers that without access to valid outcome statistics they are unable to determine the cost of doing business.

So should Federal or State government mandate that insurance companies pay for all IVF? Some states already do, but this has led to internal cost-cutting trends that can prejudice standards of care. So, I personally do not favor mandatory regulation. I do, however, strongly advocate independent accreditation of all IVF programs. All United States IVF programs should submit their statistics on quality of service for review by an impartial accrediting agency. There are strong incentives for IVF programs to participate in such accreditation, including the argument that, (provided accreditation is accompanied by a forced limitation in the number of embryos transferred so as to reduce the incidence of multiple births), insurance companies should start stepping up to the plate when it cones to covering IVF .

I believe that until IVF programs become accountable and submit to a full and transparent accreditation process that verifies their IVF success rates, we will not achieve universal insurance reimbursement for IVF. As a result, the remaining 90% of couples who need this treatment will continue to be left out in the cold. And why should the size of the pocket book determine the ability to have a family?

I firmly believe that accountability and legislation should go hand in hand. Neither approach would be entirely successful alone. But it will not be easy to accomplish these changes. Convincing insurance companies that it is in their own best interests to fund IVF performed by accredited programs will be a long, slow process. And until there is more accountability by individual IVF programs, insurance companies forced to fund procedures with widely varying outcomes might be expected to lobby for repeal of mandatory reimbursement laws.
Under such a system, IVF programs might submit to an ongoing process of peer review. Participating programs would register each prospective patient with the accrediting body prior to initiation of treatment. A patient code number could ensure confidentiality, and registration of the patient with the society would guarantee proper data interpretation. New programs that initially submit themselves for accreditation could have 12 months to demonstrate an ability to meet "acceptable” operational and outcome standards. Programs wishing to apply for accreditation after the first year could submit to a similar prospective evaluation or may elect to undergo a detailed retrospective audit according to the standards set forth by the accrediting body's peer‑review committee. Instead of eliminating marginal IVF programs (which might otherwise occur under government‑mandated regulation), such an accrediting body would set an example and would even help struggling programs upgrade their standards and performance in the area of high‑tech infertility treatments. Each accredited program would undergo an annual peer review to become re-accredited. This would provide an ongoing assurance of proficiency to the consumer and to the referring doctor, and would also give each program important feedback regarding its own performance.

I further anticipate that participation in such an accrediting process would snowball as IVF programs become convinced that accreditation would be in their own best interest for the sake of insurance reimbursement, and to forestall mandatory regulation by federal or state governments.

Ultimately, consumers can control the debate. They may have to band together to make their voices heard against the forces of the marketplace, but they can bring about change. Now is the time for IVF consumers to be outspoken. If they don't participate in the campaign to put the IVF house in order, they will have only themselves to blame if progress towards insurance reimbursement comes slowly. One of the most promising lobbying avenues would be to join one of the infertility support groups, both to become more informed, and to speak with a louder voice before the medical profession, legislative groups, and the insurance industry.

It is time for consumers to marshal their buying power to demand that these "Four A's" in the field of high‑tech infertility management are met:

Accreditation of IVF programs

Accountability by the medical profession with regard to providing validated statistics or a track record, and instilling rational expectations in infertile couples who seek their advice.

Availability and access to the consumer of state‑of‑the‑art standards of care.

Affordability of services to all those in whom they are indicated.

Embryo Banking in IVF: An Approach That Arrests the Adverse Effects of the Biological Clock

An ever increasing number of American women first seek IVF treatment in their late 30’s or early 40’s.This trend is in large part due to the fact that more and more women are choosing to defer childbearing until they have fulfilled their career aspirations. While such deliberate deferment is understandable, it nevertheless poses significant problems, because women in their late 30’s and early 40’s have about one half the chance of having a baby following IVF than do women in their early to mid 30’s. There are two primary reasons for this:

First is the fact that advancing age beyond 35 years is accompanied by an inevitable and progressive increase in chromosomal egg abnormalities (aneuploidy) which lead to “incompetent” embryos that cannot propagate viable pregnancies. That is why we see a profound and steady decline in IVF success rates as well as an increase in chromosomal miscarriages and birth defects such as Down’s syndrome with advancing maternal age.

Second, as women get older, there occurs a progressive decline in their ovarian egg supply. This so-called “diminished ovarian reserve” (DOR) results in less eggs being accessible via egg retrieval and consequentially, fewer “competent” embryos available for transfer to the uterus.

Most women/couples would like to have more than one child. This desire is no less prevalent in older women. However, by the time the older woman decides to do IVF, goes through the process successfully, has a baby, completes breastfeeding, and thereupon re-establishes regular menstruation in order to try for another IVF baby, a period of 2-3 years will have elapsed. While such a hiatus would usually be of little consequence to a young woman, for an older woman such a delay could seriously impact her “biological clock” so as to drastically reduce her chance of having another baby with her own eggs.

Egg/embryo banking offers a potential solution for older women and those with DOR who wish to minimize the relentless effect of the biological clock. The process involves undergoing several IVF stimulation/egg retrieval procedures in relatively quick succession, and then freezing/banking all viable embryos for future dispensation, rather than having them transferred to the uterus immediately. Such embryo “stockpiling” would literally stop the biological clock in its tracks, allowing for the subsequent elective thawing of one or two frozen embryos at a time in future frozen embryo transfer (FET) cycles. This process would avert the risk of progressive declining egg/embryo “competency” over time.

The concept of embryo banking/stockpiling would not have been feasible even 5 years ago, since it was not until quite recently that we became able to reliably identify chromosomally normal (“competent”) embryos for selective banking. Embryo freezing technology has also evolved dramatically over that time. Just a few years ago, the freezing process took a serious toll on embryos, severely damaging up to 50% of them in the freeze/thaw process. But that was then…Today, through the adaptation of comparative genomic hybridization (CGH) technology to egg and/or embryo selection we are able to much better identify “competent” embryos for banking and stockpiling. In addition, the recent introduction of much improved egg/embryo freezing through ultra-rapid cryopreservation (i.e. vitrification) eliminates most of the potential damage incurred to “competent” embryos during the freezing and thawing process. In fact, in IVF centers of excellence, the frozen embryo transfer (FET) process using vitrified/thawed embryos now yields the same IVF success rate as when fresh embryos are transferred!
These innovations (CGH and Vitrification) have not only made embryo banking/stockpiling feasible, but have rendered the approach a most appealing option for older women and women with DOR who seek to undergo IVF using their own eggs.

This having been said, CGH is not an indispensable part of embryo banking. The process can be done without it. But, given the inevitability of an age-related increase in the incidence of chromosomal abnormalities in the egg/embryo, it would be impossible for patients to know whether they have stored “competent” embryos and which ones to transfer to the uterus for the best chance of success when the time comes.

I want to emphasize that CGH does not improve embryo quality. It is an efficiency tool that allows us to select “competent” embryos for transfer and thereby dramatically improve the baby rate per embryo transferred. It is also well to bear in mind that aneuploidy not only reduces the chance of a successful pregnancy but it is also the cause of miscarriages and many birth defects (e.g. Down’s syndrome). Thus CGH embryo selection not only improves IVF success (per embryo transferred), but it also reduces the incentive to transfer multiple embryos at a time, thereby virtually eliminating the occurrence of high-order multiple pregnancies (triplets or greater).

Proudly, we at SIRM were the first to introduce CGH embryo selection into the clinical IVF arena. Since then, we have reported hundreds of successes using this approach, which is finally starting to gain wide acceptance in the IVF field. We were also among the first in the United States to supplant conventional egg/embryo freezing with “vitrification.” It is against this background that we now provide selective embryo banking/stockpiling to an ever increasing number of older women and women with DOR. We have already witnessed the profound benefits of such an approach.

Finally, embryo banking/stockpiling would also have appeal to younger women who plan on deferring having children until later in life – or who want to at least have the option available, should their life/career path so dictate. Even some fertile women for whom IVF would otherwise not be necessary could fall into this category.

Through our technology and package pricing, we at SIRM have attempted to make this approach relatively accessible to those that need or desire access to this advantage.

Preserving Fertility in Cancer Patients

It is only through propagation of our biological offspring that we as humans can leave a lasting legacy of our existence. Perhaps this explains why the desire to have children is a basic human instinct and why an inability to achieve this goal (infertility) often leads to considerable psychological and social strain. Infertility evokes a strong sense of failure, loss and helpless leading to one of life’s most distressing crises.

According to an article published a few years ago in the Journal of Philosophy, Science and Law: "Seven out of ten children and young adults with cancer can be cured. Accordingly, by the end of this decade, an estimated one in two hundred and fifty adults will be survivors of childhood cancer." Unfortunately for many of them, one of the long-term risks of treatment is infertility

Many cancer chemotherapy and/or radiation regimens that are directed at the reproductive organs will render the patients infertile. It is argued by some that cancer survivors should be so grateful as to ignore the “inconvenience” of having been rendered infertile by the treatment they underwent -- that the burden of post-treatment infertility pales in significance when compared to the long term and often life-endangering complications associated with radiation and chemotherapy. Moreover, those who make this argument often take the position that such patients could always have a baby through using donated eggs or sperm. But this dispassionate attitude ignores the fact that most people crave having their own biological children.

In the last decade, the advances in Reproductive Technology have made it possible for cancer patients to have their sperm or eggs collected and cryopreserved (frozen) for post-recovery dispensation. For males, the collection and cryopreservation of sperm specimens is quite uncomplicated and efficient, while for females gaining access to eggs for cryopreservation is significantly more involved and costly. It requires the prior administration of fertility hormones for more than a week followed by a surgical procedure (egg retrieval), performed under local or general anesthesia.

The recent introduction of a procedure known as in vitro maturation (IVM), where the woman has her eggs harvested without having to undergo prior hormonal stimulation, would simplify the procedure of egg collection for cryopreservation. It would shorten the delay in starting cancer therapy and would reduce the cost associated with egg banking. The bad news is that as yet, the efficacy of the IVM process in securing viable eggs for banking is by no means established.

Another troublesome problem is the fact that conventional egg banking has until recently been much of a hit-and-miss proposition. The baby rate per frozen egg has hovered around 3-4%....hardly sufficient to give a woman confidence that that her banked eggs will ultimately produce a baby for her. This low yield per frozen egg is the reason that most egg banks advise women to freeze a large numbers of eggs (15-20) in advance of undergoing cancer therapy in order to provide reasonable level of confidence that banked eggs will ultimately produce a baby. Sadly, ignorance of this reality has led many women to freeze eggs with only a false sense of expectation that by doing so, they will ultimately be able to be mothers.

A recent major advance promises to change all this. It involves a genetic test [comparative genomic hybridization (CGH)] that selectively identifies those eggs that are most likely to make a baby. In fact, a CGH selected frozen egg yields a baby rate of 27%, which is eight-fold higher than previously attainable. As such, the selective banking of 4-6 such “competent” eggs should provide a far greater level of confidence and offer particular promise for young female cancer victims scheduled to undergo chemotherapy/radiotherapy.

Another obstacle to fertility preservation via egg freezing is that cancer patients rarely have the luxury of time to undergo these procedures. Additionally, some patients (e.g. young women with estrogen-receptor-positive breast cancer), the use of fertility hormones might be contraindicated for medical reasons, due to the potential for increasing the rate of cancer cell growth. This is perhaps where IVM, once the technology matures, could provide a significant advantage.

Then there is the issue of financial cost of fertility preservation. Insurance companies and government payers rarely cover the costs. While the freezing and storage of eggs is not that much more expensive than the analogous service for sperm, the costs associated with the ovarian stimulation, egg retrieval, and anesthesia can be considerable - and in the current economic environment must be totally borne by the patient and/or her family.

The bottom line is that technology is indeed available to help cancer patients preserve the option of having biological children. Since we now have the know-how to preserve human gametes (eggs and sperm), the preservation of fertility for cancer patients should become a standard service available to all those in need of it, rather than a “luxury” reserved only for those who can afford it. Unfortunately, major challenges remain that prevent this from becoming a reality.

Sher Institute Blog

I'm pleased to announce that in addition to my blog, we have created a forum for the other Sher Institute physicians, embryologists and clinical staff to post their articles and insights. You can find it at:

www.haveababy.com/infertilityblog

Dr. Tortoriello has written the inaugural post on Minimal Stimulation IVF. Please feel free to visit and post your comments and suggestions on what topics you would like to see addressed.

- Geoff Sher