Hindsight CGH: A Valuable, New Diagnostic/Therapeutic Tool in IVF

Whenever a patient fails to achieve a successful outcome following IVF, the question arises as to why. Clearly, if the embryos had appeared to be of poor quality microscopically, arrested in their development or failed to achieve appropriate developmental milestones over time, the answer would be clear. Similarly, if the uterine lining was thin, having failed to thicken appropriately in response to hormonal stimulation or there was an intractable immunologic implantation dysfunction, the cause of the failure would be clearly apparent. These are all examples of cause and effect relationships between response-to-treatment and outcome.

In the vast majority of cases - especially when the quality of the embryos transferred is deemed to be adequate, the uterine lining well developed, and the embryo transfer technique satisfactory - the reason for failure is not that cut and dried. In fact, in such cases the explanation given by the treating physician, albeit well intended, usually amounts to nothing more than educated speculation. The reason for this is that when it comes to evaluating embryo competence, microscopic assessment has significant limitations, as does the assessment of uterine receptivity. In addition, we have no control of what happens to embryos after they have been transferred to the uterus (albeit under ultrasound guidance).

While poor uterine receptivity and inadequate technique with regard to embryo transfer do indeed contribute to poor IVF outcome, there can be little doubt that in more than 70% of cases where IVF fails, it is due to the embryo being abnormal and thus incapable of propagating a viable pregnancy. Such embryo "incompetence" is almost invariably the consequence of there being an abnormal quota of chromosomes (aneuploidy) in its cells. Such aneuploid embryos will fail to develop normally, fail to gain attachment to the uterus, miscarry, or result in abnormal offspring (e.g., Down’s syndrome).

It is important to recognize that in spite of looking normal microscopically, an embryo can still be aneuploid. In fact, on average,under one half of normal looking embryos are chromosomally normal (euploid), even in younger women. In women in their early to mid 40’s, less than 1 in 10 are normal. It is thus “disingenuous” to discount poor embryo quality as the reason for failure simply because the embryos that were transferred appeared to have a “good” microscopic grade. The truth is that without a genetic assessment to confirm the presence of all 23 chromosome pairs, it is impossible to reliably affirm embryo "competence".

We at SIRM were the first to introduce CGH embryo testing into the clinical IVF realm... a few years back. This method does permit relatively accurate assessment of embryo “ploidy”. We have reported on the fact that when a healthy euploid embryo (one that has the correct number of chromosomes in their respective places) is transferred, it affords about a 60-70% chance of a viable pregnancy (several times better than for an untested embryo).

The problem with CGH testing is that it takes so long to get the result back from the laboratory that it becomes necessary to vitrify (freeze and bank) the embryos while awaiting the results of the genetic evaluation, and then perform a subsequent frozen/thawed embryo transfer. While IVF outcome is unaffected by the process of vitrification, the delay in receiving the CGH report nevertheless introduces an additional waiting period which is inconvenient, and introduces an element of apprehension into what already represents a very stressful process.

Hitherto, the inability to reliably assess embryo "competence" through the use of microscopic evaluation led to uncertainty in being able to identify the cause of IVF failure. The fact that embryo aneuploidy (regardless of embryo microscopic appearance) is responsible for more than 70% of poor IVF outcomes, serves to explain why prior to the CGH era it was virtually impossible to reliably pinpoint the cause. It follows that the transfer of chromosomally normal (CGH tested) embryos to the uterus would permit the IVF physician to focus on the remaining 20-30% of causes (i.e., implantation failure and poor embryo transfer technique). This would vastly enhance the ability to define the exact cause of IVF failure and so modify future treatment.

About Hindsight CGH: Many couples, once made to understand the benefits associated with selectively transferring CGH normal embryos rapidly come to terms with the inconvenience and stress related to delaying their embryo transfers. What really discourages people from doing CGH is the cost, which can be $3000-$4000. This is where a new approach we have referred to as “Hindsight CGH” comes in. Here we perform an egg retrieval, fertilize the woman’s eggs and on the third day biopsy her embryos. The biopsied DNA specimens are frozen and stored rather than being sent off for CGH testing. The embryos are then transferred fresh to the uterus (without requiring vitrification and storage). Thereupon once the result of the IVF procedure is known, a decision can be made whether or not to dispatch the biopsied material for CGH analysis. If the woman/couple achieves a viable pregnancy following the fresh embryo transfer, she/they might decide to forgo CGH testing and so save the cost of the genetic analysis. On the other hand, if a viable pregnancy does not ensue, the decision might be made to perform CGH testing in the hope of reaching a diagnosis as to why the procedure had failed in the first place. The latter information might play a pivotal role in helping the patient(s) decide whether they wish to try again, how any future treatment cycle should be modified to address the underlying cause of failure, whether to disengage altogether or move on to third party parenting (egg donation or gestational surrogacy).

A large number of IVF patients who fail to conceive from a fresh cycle of treatment end up having several vitrified (cryostored) embryos remaining. Many of these patients would benefit from knowing whether those embryos are chromosomally normal before embarking on the frozen embryo transfer. The prior performance of embryo biopsy (during the fresh cycle) and storage of the DNA material would afford such couples the opportunity to gain insight into the quality of their remaining embryos. For this reason, it is probably advisable for most couples undergoing IVF to consider hindsight CGH as an approach that would leave them with options should their initial fresh cycle fail.

There is nothing worse for an IVF patient than to undergo repeated attempts and to fail and to not know why. "Hindsight CGH", through its diagnostic benefits and through the opportunity it provides to modify future treatment in the hope of ultimately succeeding, is an invaluable addition to the IVF diagnostic and therapeutic armamentarium.

The Ultimate Standard of Infertility Care

It is impossible for those of us who have been able to have children at the drop of a hat to put ourselves in the position of couples who so yearn to become parents that they are willing to risk depleting themselves emotionally, spiritually, physically and financially in the process.

I’ve often asked myself what drives infertile couples to be willing to sacrifice so much in an attempt to achieve parenthood. The conclusion that I have come to is that while for many, having a child is the ultimate consummation of a loving relationship, the basic driving force behind procreation is the fact that that we as humans all yearn to leave some tangible evidence of our existence behind when we depart this world. We can’t take our possessions with us, and our fame and personal achievements rapidly fade from memory when we are gone. All that remains as proof that we were here is the genetic thumbprint we leave behind in the form of our offspring. I believe that is the fear of being denied the opportunity to gain some degree of immortality through our progeny that motivates infertile couples to go to virtually any length to have children.

Wouldn’t it be wonderful if we as physicians could help every infertile couples achieve their goal. But alas, the truth is that no matter how good we are at providing reproductive medical services, this is not possible. There will always be some couples who, in spite of availing themselves of all infertility treatment options and state of the art therapies, will remain childless. For these couples, adoption is an excellent option because it solves both infertility and a social problem at the same time.

When it comes to fertility treatment it is as well to remember that while doctors can improve circumstances that favor fertility, we are unable to create life. That is way above our pay grade. When we understand that the “creation of life” requires a divine spark, it makes it much easier to understand why best effort is not always rewarded with a successful outcome. The realization of this sobering reality will help ground us and inject much needed humility in the way we treat human beings who entrust us with their care. It is about having the right intent, the proper application of tried and tested methodologies, coupled with the realization that ultimate success comes through the grace of a supreme being that ultimately provides all parties (i.e., patients, physicians, families and society) with the best possible medical service.

I firmly believe that to be both successful and rewarding at all levels, the treatment of infertility mandates that from the very get-go, patients and medical providers interact at the basic human level - one person to the other - and thereby establish a clear understanding of one another’s motivations and intent before proceeding to the intricacies of therapy. It is only through dialogue at such a grass roots level that patients and physicians can come to recognize each other as human beings that, while they might differ with regard to their areas of expertise, share a common humanity. Only once this has been established, and suspicion of intent has been cast aside, can medical care be optimized and the relationship between physician and patient become fulfilling. Any physician who has avoided the indignity of patient-driven litigation will tell you that it was because they interacted with their patients, keeping them informed at all times, and did so with deference and respect.

So, it is as well for consumers of IVF care and physicians to understand that failure to achieve a pregnancy does not mean failure of treatment, provided that such treatment was medically appropriate and administered in a spirit of good intent and humility.

IVF: Planning The Trip Before Embarking on the Journey

While it is true that it will often take more than one IVF attempt to achieve a successful outcome, it is not good enough to simply offer this argument as a reason to just “keep on trying.” Ninety percent of my personal IVF practice involves treating patients who have experienced two or more prior IVF failures. Some had experienced more than 10 failures and believe it or not, in one case the couple had failed more than twenty prior attempts. A common thread often underlying such heartbreaks is the failure to thoroughly plan the IVF journey before embarking on it.

Preparing for IVF requires a very individualized approach. It is important to understand that each patient/couple is different and that a “one size fits all” or “cookbook” approach is inappropriate. Here are the steps that I follow to assure that patients are prepared for the IVF journey:

1. Evaluation of medical suitability for IVF: The Hippocratic doctrine declares “do no harm”. This means that every patient /couple must be carefully assessed medically and psychologically in advance of undergoing IVF in order to identify potential health hazards that could be revealed in the course of a cycle of treatment or during an ensuing pregnancy. The following are examples:
   

   a. Very young women, and those that don’t menstruate or ovulate regularly on
   their own are at inordinate risk of developing life endangering complications
   associated with severe ovarian hyperstimulation syndrome (OHSS) following
   administration of fertility drugs and require modified treatment regimes
   b. Women with certain hereditary blood clotting disorders (thrombophilia) are at much greater risk of early and late pregnancy complications and require specific treatments as soon as pregnancy is diagnosed.
   c. Women with cardiovascular disease or hypertension are at greater risk of developing pregnancy related complications that can compromise their well being as well as that of their baby(ies).
   d. Some women have hidden bleeding disorders due to blood platelet
   disorders or abnormalities in certain blood clotting defects which if
   undiagnosed can lead to serious complications during egg retrieval.
   e. The presence of active viral and bacterial sexually transmittable diseases should be identified and if possible treated in advance. In some cases where the risk of transmission to partner of baby cannot be avoided, detailed advance disclosure and counseling is essential. These are but a few examples to illustrate the point; there are many potential others.

2. Defining the cause of the infertility: About one third of infertility is due to female causes, one third due to male sperm dysfunction and the remaining third is due to a combination of both male and female factors. In addition, there is very often more than a single female (or male) factor contributing to the problem. To ignore this important factor can be detrimental to the success of IVF treatment. Here are a few examples:
   

   a. One third of women who have endometriosis also have a concomitant immunologic implantation problem. In such cases, the performance of IVF without appropriate selective immunotherapy will usually lead to failure.
   b. Tubal damage necessitating IVF is sometimes associated with internal uterine scarring and a poor endometrial thickening. Bypassing the tubal issue through IVF will usually not achieve a viable pregnancy unless the uterine lining can be improved concurrently.

3. Timing of treatment: With a few exceptions (very poor responders to fertility drugs), women undergoing repeated cycles of IVF need at least one full resting cycle after an unsuccessful cycle before undergoing another attempt.
4. Selecting the ideal protocol for ovarian stimulation: Most IVF failure is attributable to “poor embryo quality.” True, in many cases, unavoidable factors such as advanced maternal age or severe intractable male infertility lie at the root of this problem. However, poor embryo quality mostly stems from poor egg quality, which in turn is due to poor egg development in advance of administering the hCG trigger. This boils down to the selection of suboptimal protocols for ovarian stimulation and inappropriate timing of the administration of the hCG “trigger” shot.
5. Moving to third party parenting: There comes a time when it is necessary to decide whether to solicit the assistance of an egg donor or a gestational surrogate or whether to stop trying. I generally advise menopausal and premenopausal women of any age, and women over 43 (for whom the chance of successful IVF using own eggs is very small) to move to egg donation. Women with serious health conditions that contraindicate pregnancy, those who do not have a functional uterus and those who have an intractable immunologic or anatomical implantation dysfunction should consider using a gestational carrier. Likewise, there should be a timely recommendation for sperm donation made to men who have incurable absence of sperm production and those with intractable severe sperm dysfunction.

The objective with In Vitro Fertilization is to transfer “competent” embryos into an optimal uterine environment. This requires a very individualized and meticulous approach to evaluating and addressing those factors that can influence IVF outcome. All patients/couples should learn what they can reasonably expect before committing to IVF and to “plan the trip before embarking on the IVF journey.”

Testosterone’s Role in Infertility Treatment: The “Root of Both Good and Evil!”

The hormone testosterone is undoubtedly a major driving force when it comes to human function and endeavor. On the one hand it has led to bold initiatives that have resulted in human prosperity and achievement. On the other hand however, it has also prompted many ill-conceived and even foolish urges and actions that have ended in misfortune, heartache and even in disater.Similarly, when it comes to reproductive function testosterone effects have likewise been a mixed bag. Consider the following:

1. Both male and female libido is in large part driven by testosterone. In the man, hypotestosteronism causes impotence and a lack of sex drive, while in the female, the production and the local release of testosterone by the ovaries also profoundly influences female libido.


2. Neither ovarian follicle growth and development nor the production of estrogen could occur without the availability of the body’s own testosterone. The hormone is produced by the connective tissue (stroma) surrounding follicles from which it is delivered in a “bucket brigade” fashion to cells that line the inside of the follicle (granulosa cells). There, enzymatic digestion triggered by follicle stimulating hormone (FSH) converts testosterone to estrogen (mainly estradiol). This causes granulosa cells to proliferate, follicles to grow in size, and eggs housed in such follicles to undergo development and differentiation. At the same time, blood estrogen levels rise progressively. Thus, without access to ovarian testosterone, human reproduction would come to a halt.
   However, it is also true that too much testosterone delivered to follicles (as commonly occurs in older women who have diminished ovarian reserve and women with polycystic ovarian syndrome or PCOS), can lead to exhaustion of granulosa cells, compromised egg development and poor egg and embryo quality. It is all about a delicate balance that involves regulation of ovarian testosterone production. Since this is regulated by luteinizing hormone (LH), it follows that when it comes to ovarian stimulation with fertility drugs, it is important to properly control (down regulate) the amount of LH administered and or produced immediately prior to and during stimulation.


3. Everyone knows that male hormones (predominantly testosterone) act peripherally to increase muscle mass. Such peripheral activity is dependant upon the conversion of testosterone to a more active form known as dihydrotestosterone. This is why body builders use androgen type hormones (anabolic steroids) in order to maximize muscle growth, bulk and definition. But testosterone also suppresses body’s own pituitary LH which is necessary for adequate testicular sperm production which in turn results in reduced sperm production (spermatogenesis) and serves to explain why overuse of such synthetic, commercial products can lead to a reduction in sperm production and even to testicular atrophy. It is come as no surprise therefore, that many bodybuilders and other athletes who overindulge in the use of such synthetic hormones often end up with male infertility.

Another point of interest is that testosterone also works centrally at the level of brain synapses where it promotes libido (in both men and women) by being converted enzymatically to estrogen. Unfortunately, many synthetic commercially available androgen products (e.g. Dianabol) inhibit this conversion, thereby explaining why many athletes that use such products experience decreased libido.

Clearly, when it comes to treating women undergoing IVF (especially those with ovarian stromal overgrowth) it is important to maintain body’s own LH at a low level prior to and throughout the stimulation cycle. To do so it is necessary administer fertility drugs that are low in LH-like activity. Clomiphene citrate (Serophene) and letrozole (Femara) tend to cause the pituitary gland to release much LH while injectable gonadotropin fertility drugs such as Menopur and Repronex contain about as much LH-like activity as they do FSH.

Also, drugs like Lupron, Buserelin, Nafarelin and Synarel (agonists), elicit a profound increase of the body’s own (pituitary) LH. Thus when agonists are used they need to be administered several days before initiating stimulation so as to exhaust the woman’s own LH and allow the levels of this hormone to drop and thereupon be sustained at negligible concentrations before beginning stimulation. When the administration of agonists is initiated at the start of ovarian stimulation (microflare protocols), the LH levels rise rapidly, causing increased ovarian testosterone production at the very time that follicle and egg development starts. This has the potential of adversely affecting the quality of eggs in that cycle.

Also, since women with stromal overgrowth commonly have high LH activity, the use of protocols where an antagonist (Cetrotide, Ganirelix, Orgalutron) that blocks LH release is first administered 6-7 days after ovarian stimulation has been initiated, should in my opinion also be used with caution (especially in women with stromal overgrowth). The reason is that by the time LH release is controlled through their use, some degree of irreversible egg damage for that cycle might have already occurred.

One of the great travesties still being perpetuated by some doctors, is the indiscriminate administration of testosterone to infertile men in the erroneous belief that it will improve sperm production. Nothing could be further from the truth.

When it comes to reproduction, testosterone can truly be regarded as being the “root of both good and evil”. Its role in promoting reproductive objectives is indisputable but its therapeutic role can be fraught with hazard. It is as well that those desiring to conceive understand the dynamics involved in this delicate balance.

Is IVF Safe?

Hardly a month goes by without reading or hearing a media report of some or other catastrophe that a woman undergoing IVF has experienced. It was not long ago following the tragic death of the Saturday Night Live star Gilda Radner from ovarian cancer and the concern that it was her use of fertility drugs that caused or contributed to the disease. Then there were the numerous reports suggesting that babies born following IVF are at an increased risk of birth defects and of developing autism. Other reports have suggested that women receiving fertility drugs as part of an IVF procedure are invariably at serious risk of ovarian hyperstimulation with its sometimes life endangering complications. Most recently there was a report suggesting that the performance of intracytoplasmic sperm injection (ICSI) causes an increased risk of birth defects. Patients/couples seeking IVF treatment are highly vulnerable to alarmist reports, which in many cases, turn out to be “much ado about nothing.” Nevertheless, it is well to recognize that almost all patients/couples destined to undergo IVF will pose the question as to whether the process itself is safe for them and for their prospective offspring.

To start with, it is important to recognize that no medical intervention is totally devoid of risk. IVF is no exception to this rule. However, any decision regarding whether to proceed with a medical treatment must take the risk/benefit ratio into account. When it comes to IVF, the risks are not the same for all cases. Some patients/couples are at very low risk while others may be at higher risk. As with all medical procedures, it is essential to provide patients/couples with sufficient information with which to make an informed decision. Consider the following:

On average, women trying to conceive through IVF tend to be older. Accordingly, these women are thus more likely to have diseases such as hypertension and diabetes mellitus when they conceive. Both of these conditions can add a significant risk in any ensuing pregnancy. In addition, older women are more likely to have an anatomical reproductive disease such as uterine fibroids and/or endometriosis. Obviously, the greater the anatomical distortion, the more difficult it would be to access the ovaries or perform an embryo transfer, and accordingly, the greater the likelihood of causing bleeding and infection. Finally, there is the fact that babies born to older women are more at risk of chromosomal birth defects such as Down’s syndrome and of autism.

There is no doubt that the proliferation of IVF has been accompanied by a significant increase in the incidence of IVF multiple births, especially high-order multiples (triplets or greater) which in turn, leads to a much higher rate of premature births. These often have serious risks and consequences to the offspring as well as for the families.

Very young women and women who do not ovulate or who ovulate irregularly, are at a much greater risk of developing severe ovarian hyperstimulation syndrome following the administration of fertility drugs in preparation for IVF. Such complications can be life endangering if not managed expeditiously and properly.

Certain women are at an increased risk of developing blood clots during pregnancy as a result of an underlying condition known as thrombophilia. These clots can affect the placenta and so compromise growth and development of the baby. Sometimes clotting occurs in the deep veins of the lower limbs or pelvis. Such clots, should they become dislodged, can travel to the lung or brain with serious or even lethal consequences.

One important risk associated with IVF that is often overlooked is the fact that in some women, it causes such a degree of emotional destabilization as to unmask serious and often persistent psychological problems.

The question of course is whether such risks can be mitigated through preemptive prevention, evaluation, and management.

The performance of preimplantation genetic diagnosis can be used to assess the chromosomal genetic integrity of the woman’s eggs/embryos and can allow for the selective transfer of embryos that are free of chromosomal abnormalities. Once pregnant, timely performance of prenatal genetic testing through chorionic villus sampling (CVS) in the first trimester and amniocentesis early in the second trimester can detect chromosomal abnormalities that would warrant consideration of pregnancy termination. Unfortunately there is no prenatal test that can predict the subsequent occurrence of autism in the offspring, but this risk is small. It should, however, be discussed with older women who contemplate IVF.

Pregnancy induced complications such as preeclampsia and gestational diabetes are often predictable. Women that are markedly overweight, have a family history of diabetes, have polycystic ovarian syndrome (PCOS), etc., are more at risk of developing such complications during pregnancy. The performance of certain tests will go a long way towards identifying those women most at risk for developing such conditions. These include but are not limited to EKG, blood chemistry and a glucose tolerance test. The absence of any such predisposition in older woman significantly reduces there level of risk during pregnancy. In some cases, preemptive treatment, while not totally eliminating the risk of pregnancy-induced complications, can minimize it.

There is no doubt that IVF has caused a virtual explosion in the incidence of multiple births and that this represents the biggest risk associated with undergoing the procedure. Multiple births, especially high order multiples (triplets or greater) often times result in preterm deliveries. Premature babies in turn have a much higher mortality rate, and a large percentage of those that do survive arduous, prolonged and expensive treatment in neonatal intensive care units are left with long-term health problems that impact the quality of their lives, the lives of their caregivers, and society as a whole.

The main reason for high-order multiple IVF births is the transfer of multiple embryos at one time. Such practice (as evidenced by the recent “Octomom” experience) is irresponsible and inexcusable, given newer methods for identifying “competent” embryos. Newer genetic techniques such as the use of comparative genomic hybridization (CGH) to identify those embryos that are most likely to make a baby, now allow for fewer embryos to be transferred without compromising the chance of success. BUT it will take a long time for this new technology to gain a strong foothold - especially since it involves the additional cost associated with sophisticated genetic testing.

Severe ovarian hyperstimulation can be avoided through the use of a procedure known as “prolonged coasting” (see elsewhere) which completely eliminates the associated life-endangering risks.

Thrombophilia can be diagnosed through blood testing prior to the initiation of IVF. Appropriate treatment with high dosage folic acid and/or heparin (e.g. Lovenox, Clexane) starting as soon as pregnancy is diagnosed and continuing throughout gestation, will go a long way towards preventing related complications.

Finally, it is important not to ignore the emotional/psychological risks associated with IVF. It is my opinion that all patients need psychological support prior to and during IVF. While in most cases such support can be provided by a seasoned and well trained medical team of physicians and nurses, it is essential at all times to be on the lookout for those patients whose demeanor and behavior suggests severe emotional vulnerability. They should be referred for appropriate psychological counseling (and in some cases psychiatric treatment) prior to proceeding with IVF.

I wish to re-emphasize that IVF will never be a totally risk-free procedure. However, it is important to recognize that not all reports by sensationalistic media are necessarily valid. Often times the risks and complications that occur with IVF are related to the woman’s underlying health rather than to the process of IVF itself. As an example, after the Gilda Radner debacle, a large retrospective study undertaken and reported on in a highly prestigious medical journal concluded that fertility drugs increased the risk of ovarian cancer. This evoked such a degree of alarm that subsequently and for at least a decade, virtually every patient undergoing IVF required detailed advanced counseling and many IVF physicians even required that their patients sign a release form, exonerating them from any risk should ovarian cancer develop in the future.

Ultimately, after a few well conducted prospective studies showed that there was no association between the use of injectable fertility drugs and the subsequent development of ovarian cancer, things returned to normal. More recently, a similar alarmist publication suggested there was a link between the performance of ICSI and birth defects. Subsequent multicenter studies showed that it was not the performance of ICSI itself that caused the problem, but rather the underlying sperm dysfunction that mandated the treatment in the first place. These are but two of numerous examples that demonstrate how and why it is so important not to overreact when there is a media report of an adverse consequence associated with IVF.

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.