Conceivability_What I Learned Exploring the Frontiers of Fertility
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Danielle left her local British clinic after three failed attempts and sought out a famously controversial doctor with the highest success rates in London after her husband found him through his research. My good friend Susan in London left the Lister, where she had once had great confidence, opting to try a famous doctor in New York.
Everyone is going every which way.
Is there rhyme or reason to it?
Certain clinics, often with high success rates, are lightning rods. As in every industry, there are outliers—those who achieve success far greater than the norm. In the case of fertility, their approaches and practices are routinely called into question. Are they turning away difficult cases? Taking unnecessary risks, such as implanting high numbers of embryos? Throwing “the kitchen sink” at patients, regardless of clear need or even of the health of the patient? Or are they genuinely superior? These questions are very hard to answer, and it seems that for each patient running to a famous doctor, there is another running away at equal speed. Ironically, in the same week, one woman I interviewed called her doctor a god, and another told me that she had just run into that very same doctor at a restaurant and the sight of him made her so upset and angry that she couldn’t eat her meal.
Scientific and technological advances have given doctors—and patients—a bigger tool kit with which to treat previously insurmountable problems. But with great advances in medicine comes a great mass of information to sort through. What works? What doesn’t? How does a patient decide? How much does the practitioner matter? How does a patient choose a clinic? As I learned during my journey, this new world of fertility is complex and changing, and patients must be educated and involved in order to successfully navigate through it.
In my view, when deciding whether and where to do IVF, it is wise to evaluate certain key treatment elements that are critical, if not essential, differentiators among clinics, apart from the (often obscure) measure of their success rates. These elements are: tailored drug protocols, blastocyst capabilities, and availability and sophistication of genetic screening.
Protocols
The first stage in any IVF cycle involves preparing a woman’s ovaries to produce one or more eggs to be retrieved and then fertilized before being placed back into the womb. In all but a natural cycle (the rarest form of IVF), a woman takes a series of drugs intended to stimulate, in most cases, the greatest number of eggs for removal. While traditional IVF has different regimen options (for example, the GnRH agonist, also known as Lupron downregulation, protocol; the GnRH antagonist, or ganirelix, protocol; the microflare protocol), the general goal of each phase remains consistent: women take hormones to stimulate the growth of eggs, control the timing of ovulation, and prepare the uterus for implantation. Since its inception, there has been remarkably little variation in the protocols. “For nearly thirty years we’ve been doing the same thing,” lamented Dr. Laura Rienzi, senior clinical embryologist and laboratory director of the GENERA Centres for Reproductive Medicine in Italy. “We’re just doing what they did at the beginning of IVF, but the physical and chemical environment is so important.”7
Because no two women are alike, a fertility expert should ideally tailor the cocktail to suit the individual medical situation. There are reasons that one hormone may be preferable to another at any given stage of the process. For example, for the stimulation phase of my cycle, I was first prescribed Puregon (FSH) but switched in subsequent cycles to Menopur (FSH and LH). I later learned that adding LH to the mix was not advisable for patients with PCOS, who already often have abnormally high LH levels. The additional LH placed me at greater risk of hyperstimulation (which, in fact, occurred). Similarly, while the agonist and antagonist protocols are used in fairly equal numbers among fertility clinics, women with repeat implantation failure, poor ovarian response to stimulation, and PCOS have been found to experience improved embryo quality and higher implantation and pregnancy rates using the more recently developed antagonist protocol.8
In the same vein, most IVF protocols rely on an injection of HCG thirty-six hours prior to egg collection to trigger ovulation. Like the vast majority of IVF patients, I took the HCG trigger shot in all my IVF cycles. But the HCG shot lingers in the body for ten days, continuing to support hormone production in the ovaries, risking hyperstimulation. Moreover, the standard dosage of ten thousand units originally came from veterinary medicine, and may in fact be too high for most women, or at least higher than they need to be effective. Experts believe that a dosage of only half that amount does the trick at less risk to the growing eggs of the patient. Although far less commonly prescribed, some specialists are now swapping out the HCG altogether in favor of Lupron, or using Lupron in combination with lower amounts of HCG, which they believe can get the ovulation job done with virtually no risk of OHSS.9 While the ten-thousand-unit trigger has been the gold standard for decades, it is important to look at the pros and cons of the newer options for each particular patient.
These choices matter, and can make the difference between having a baby and not having a baby. Danielle and her husband credit their beautiful four-year-old twins, born after years of failure, to the famously obsessive daily tweaking of her protocol by a doctor who she felt “was on top of every single aspect of [her] health and care.” IVF protocols are constantly evolving, and the ever-increasing knowledge is resulting in greater and greater success. But not all clinics are keeping up, and not all doctors are cognizant of the changes, as well as the important impact of subtle tweaking of protocols. It is critically important to ask your doctor detailed questions about your protocol and why he or she believes it is the best for you.
Blastocysts
A blastocyst is to an embryo kind of like a teenager is to an infant. That is, you can tell a lot more about what kind of being it will grow up to be as it matures. An embryo starts out as a single-cell organism inside a protective shell. The cell separates into two cells within the first twenty-four hours, then the two into four, and ideally, four into eight. Although the rate of cell division varies, typically, on day three, a healthy embryo will have around eight cells. Up to this point, the embryo’s growth is fueled by its mother’s egg, much as an infant is dependent on its mother’s milk. But in order to survive past this stage, the embryo must activate its own genes to propel its development. By day four, a thriving embryo will have between sixteen and thirty-two cells, at which point it is called a morula. In the next one to two days, the morula undergoes a huge growth spurt in which a fluid-filled cavity forms in its center, the cells keep dividing into two hundred to three hundred cells, and differentiation of the embryo begins. This far more complex version of the embryo is called a blastocyst. Not all embryos are capable of making this difficult transition to independence. In fact, only about one-third of all normal-looking embryos successfully evolve into blastocysts. Yet these survivors are healthier, stronger, and more highly developed than the rest of the pack. As a result, they have a greater chance of growing into fetuses, and eventually, healthy children.
From the early days of IVF (including my first two cycles with Mr. P), nascent four-cell embryos were transferred on the second day after their creation in the lab (day two). The procedure then evolved into doing transfers at day three, at which stage the clinicians had more observable information about the embryos, as they could see which had developed into eight-cell embryos, and speculate from their appearance as to which of those would be more likely to continue healthy growth. The practice evolved this way due to both technological limitations (early laboratory culture media could only sustain life in the petri dish for two to three days) and a belief, now dispelled, that the embryos were more likely to thrive in the womb than in the lab.10 Because it is difficult at best to predict with accuracy on day two or day three which embryos are more likely to produce a viable pregnancy, multiple embryos are often transferred.
Yet, biologically, transferring an embryo to the uterus on day two or day three is earlier than what occurs in a natural
conception, in which an embryo at this stage would still be growing in the fallopian tube. A naturally created embryo would typically arrive in the uterus five or six days after conception, precisely when it would be ready to hatch and the endometrium would be ready to receive it. Improvements in the culture medium now enable embryos to grow to the blastocyst stage, leading not only to a more informed selection of healthy embryos but also facilitating the transfer of these embryos at the optimal time for implantation in the womb. Importantly, improved selection of viable embryos with a greater chance of success means that far fewer, and ideally only one embryo can be transferred to the mother, reducing the risk of pregnancy complications and multiple births.
The success rates certainly bear out the theory, with some clinics reporting pregnancy and live birth rates of day five blastocyst transfers that more than double the rates of day three embryo transfers. Notably, the differential tends to increase with age, with women aged forty-one and forty-two experiencing an almost 150 percent increase in live birth rates when transferring blastocysts.11
Challengingly, blastocysts can be hard to come by. By the time Sarah and Evan learned of her clotting disorder, they had experienced four losses and wanted to do everything in their power to avoid another nightmarish Groundhog Day. For their next cycle, in addition to Sarah’s immune therapies, they were planning to try a blastocyst transfer. Accustomed to bountiful egg harvests, they weren’t particularly concerned about their numbers, but it was nerve-racking to see Sarah’s fifteen eggs dwindle down to just four blastocysts, only one of which was ultimately viable.
Anna, the social worker who underwent immune treatments for her lupus, had a nail-biter as well. Anna produced five eggs, three of which fertilized, and she knew that with those odds her chances were slim. As it turned out, her three embryos resulted in exactly one normal blastocyst, as bookies would predict.
During my first two IVF cycles, I had produced not only copious amounts of eggs but also enjoyed a large number of beautiful (round, nonfragmented) grade I and II embryos. Sixteen eggs obtained in the first cycle yielded twelve embryos, seven of which were deemed to be high quality on day two, while twenty-six eggs obtained in the second cycle led to nineteen embryos, twelve of which were deemed to be of similarly high quality. Mr. P frequently commented about my being a great producer of gorgeous embryos, focusing his efforts on making the embryos stick.
My cycle at the Lister started out much like the others. I had twenty-four eggs, nineteen of which developed into embryos. Given the large pool, the clinic immediately froze eight embryos for a potential future frozen embryo transfer—for a sibling, they explained, optimistic of success. We kept the remaining fertilized batch of embryos in the lab for four more days, planning to transfer two blastocysts on day five. Each doctor we spoke with warned us about the risk of multiples, especially as blastocysts had a far higher rate of implantation, but we weren’t daunted. After our failures and frustration, two seemed like a good deal. We never had to make that final decision though. When we arrived at the clinic bright and early for the much-anticipated transfer, we learned that only one normal blastocyst had made it that far. But it was absolutely flawless, the doctor and embryologist assured us. A winner.
Sadly, this picture-perfect blastocyst did not successfully take up residence in my womb.
Preimplantation Genetic Diagnosis (PGD) and Screening (PGS)
The reality is that we just can’t learn very much about the health and viability of an embryo by simply looking at it. If only I had a dollar for every woman I spoke with who told me about her amazing A / A+ / A++ / grade I / grade II embryos that unfortunately did not bring the dearly hoped-for baby. Fortunately, although many embryos are still selected that way throughout the IVF world, doctors and patients no longer need be dependent on the human eye alone.
Progress in the field of genetic testing of embryos formed in vitro is perhaps one of the most exciting and promising developments in the field of treating infertility, and it has been a long time coming. Dr. John Rock, who fertilized the first human egg in a glass test tube in his lab at Harvard in 1944, predicted back in 1937 not only that human babies would be born of embryos created in labs but also that one day science would enable parents to choose to have a son or daughter.12 More than fifty years after Dr. Rock’s prediction, in 1990, the first baby girls were born as a result of IVF performed using preimplantation genetic diagnosis (PGD), testing the pair of sex chromosomes in a single cell removed from the embryo in order to select females, XX, rather than males, XY. The genetic testing enabled the parents to eliminate the risk of their children being born with adrenoleukodystrophy and mental retardation, genetic diseases typically affecting only males.13
PGD, which tests one chromosome for a specific genetic disease, grew from gender testing to include a wide array of abnormalities linked to single genes, such as cystic fibrosis, and inherited blood disorders, like sickle cell disease.14 Just under two years after the first successful PGD birth, the same team helped a couple who were genetic carriers of cystic fibrosis to have a normal girl unaffected by cystic fibrosis and free of both parents’ genetic mutation.15 Detection of a mutation in an embryo’s DNA enabled clinicians to weed them out. The early technology was relatively slow, requiring weeks or months of work by highly skilled scientists, with a typical waiting period of three to six months to obtain results. Within the last five years, however, rapid progress has led to a new process called karyomapping, capable of accurately identifying all single-gene disorders, generally in as little as two to four weeks. As a result of karyomapping, according to Dr. Mark Hughes, a molecular biochemist who was one of the founding fathers of PGD, “there are no technical limitations anymore for inherited disorders.”16 Just think about that. Genetic mutations like those that cause cystic fibrosis and Tay-Sachs can now—given the directive and resources—be completely eliminated. A mother with breast cancer can prevent her offspring from inheriting her BRCA1 mutation.17
PGD’s success in detecting specific disorders led scientists on a quest to test more chromosomes, looking not to identify a specific inherited disease but rather to identify embryos with too few or too many chromosomes, which would render them impaired or incapable of survival—and which is the most common cause of failed pregnancies. To their surprise, they found that lethal chromosome defects were detected in the lab in seemingly normal chromosomes.18 Simply put, we cannot see chromosomal abnormalities with the human eye. As a result, in an effort to help doctors and patients select chromosomally normal embryos most capable of progressing through a healthy pregnancy, preimplantation genetic screening (PGS), also known as aneuploidy screening, was born.
While it took fifty-three years for Dr. Rock’s prediction of sex selection to come true, scientific advances in the last five to ten years are moving at breakneck speed. When I first tried PGS, in 2005, my clinic used a technique called fluorescence in situ hybridization, or FISH, testing. The first available technology for PGS, and for nearly two decades the gold standard, FISH typically screened the seven chromosomes most frequently seen in miscarriage specimens (chromosomes 13, 16, 18, 21, 22, X, and Y). The embryologist would remove one cell from each day three embryo (having ideally eight cells, but embryos with five to nine cells might be tested), analyze the specified chromosomes in the selected cells, and within forty-eight hours, transfer the embryos deemed to be normal, if any, back to the mother.
Although theoretically an unequivocal improvement, PGS has been highly controversial, primarily for two reasons. First, given the relative youth and instability of the three-day-old embryos, doctors legitimately feared that healthy embryos could be lost or destabilized during the biopsy process—a concern that was reinforced by early studies revealing lower pregnancy rates and live birth rates among women who used PGS.19 In addition, both critics and supporters alike discovered another challenge to successful genetic testing—a phenomenon called mosaicism.
In a perfect embryo, the genetic makeup of all cell
s in the embryo is identical. A mosaic embryo is one in which not all of its cells are genetically the same; some cells might be chromosomally normal and others abnormal. Although all derived from a single cell, errors can occur during the repeated cell divisions, leaving an intended pairing with too many or too few chromosomes. A single-cell biopsy renders only one set of data points and might not be reflective of the whole embryo. Mosaicism, therefore, could lead to both false positives and false negatives; that is, the tested cell could be normal, while others in the embryo were abnormal, meaning a “bad egg” could be transferred, or conversely, the tested specimen might be the sole, or one of the few abnormal cells, and an otherwise healthy egg might be inadvertently discarded.
Perhaps surprisingly, unlike chromosomal abnormalities, mosaicism is not at all correlated to maternal age. Women over forty-two do not have higher rates of mosaics than women under thirty-five.20 Experts believe that this is likely explained by the fact that mosaicism results from a mitotic cell division after the embryo is formed, as opposed to meiotic errors present in the egg of the mother, known to be correlated with age.21
It is literally jaw-dropping how far the technology has developed in the decade since I first tried PGS. A single cell of a human embryo has twenty-three pairs of chromosomes (twenty-two pairs of nonsex chromosomes, plus the X and Y pairing). The FISH method was capable of testing eleven data points, essentially one cell on each of eleven chromosomes, although many clinics tested only five, seven, or nine chromosomes. The next “gold standard” of testing, array comparative genomic hybridization (aCGH), which came on the IVF scene in the mid to late 2000s and is still used in many clinics today, tested twenty-seven hundred data points on all twenty-four chromosomes, detecting far more abnormalities than FISH had been capable of detecting.22 Yet despite its remarkable improvements in detecting abnormalities, like its predecessor, aCGH could not detect mosaic embryos.