Conceivability_What I Learned Exploring the Frontiers of Fertility
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The newest technology, high-resolution next generation sequencing (NGS or hrNGS), produced its first baby in 2013, and has become more readily available in the last few years. Also known as PGS 2.0, high-resolution NGS is capable of testing 1.2 million data points, and for the first time, identifying mosaic embryos. Use of high-resolution NGS has also illuminated the size of the mosaicism problem, which may represent as many as 20 percent of all embryos produced in the lab.23 In fact, NGS can see mosaicism so precisely that genetics labs can now tell patients exactly what percent of mosaicism is present in a given embryo, with far-reaching implications for pregnancy and live birth rates. For example, an embryo judged to be normal using aCGH was transferred to a woman who became pregnant and subsequently lost the baby at seven weeks. The recovered fetal tissue was subjected to NGS, which revealed a trisomy on chromosome 4, a mutation that would have been detected with preimplantation NGS.24 As a result of this enhanced analysis, miscarriage rates are cut in half when using high-resolution NGS as opposed to aCGH.25
Hand in hand with the development of NGS technology has been the ability to test multiple cells from the outer shell of more robust day five blastocysts as opposed to a single cell from a day three embryo, largely eradicating the fear of harming the embryo. Moreover, because blastocysts are more developed, they are also less likely to be abnormal or mosaic—as abnormals are less likely to make it to day five—and are able to contribute more DNA for testing. The ability to select embryos based upon such extensive knowledge of their chromosomal makeup has important implications, including transferring fewer embryos per cycle, and in many cases a single blastocyst.
While not a first choice for embryo selection, mosaicism is not necessarily a death knell. Rather, it is a calculated risk. Many healthy babies have been born from mosaic embryos. A study in Italy in 2015 found that six out of eighteen women who had abnormal embryos transferred to their womb gave birth to healthy children.26 Dr. Santiago Munné, cofounder of Reprogenetics27—the world’s largest genetics laboratory specializing in PGD and PGS—led a multicenter study that reported 58 successful pregnancies out of 143 mosaic transfers, and Dr. Munné believes that more than one hundred babies have been born of mosaic embryos so far.28 How can this be? Scientists theorize that the embryos may have the ability to self-heal, essentially ejecting the abnormal cells while the normal cells continue to divide.29
Yet Dr. Munné and his colleague Dr. Dagan Wells of the University of Oxford emphasize that mosaic blastocysts, while capable of producing healthy babies, do not fare as well overall as normal embryos, implanting significantly less frequently and miscarrying three times more often.30 Moreover, they contend, all mosaics are not created equal; some embryos have only single or minimal aberrations, while others have complex abnormalities. Based on persuasive data made possible by hrNGS testing, Munné, Wells, and a society of experts believe it is time for a new classification system, with low-level mosaics (less than 20 percent abnormal cells) being treated as normal; high-level (greater than 80 percent abnormal cells) mosaics labeled as aneuploid; and a new, third category (those with 20 to 80 percent abnormal cells) classified as “mosaic” embryos, distinct from their normal (euploid) and abnormal (aneuploid) brethren.31 Determining what level is safe and prudent to transfer is gray, and not surprisingly, a subject of debate among fertility experts. However, recognizing the possibility that some of the lower-level mosaics may be capable of survival, in May 2017, a committee of the American Society for Reproductive Medicine declared transfer of these mosaics to be “ethically permissible.”
The bottom line: despite a risk of miscarriage, in the absence of any normal embryos, transfer of a low-level mosaic may present a woman’s best, in fact only, chance of success.
* * *
The results of preimplantation genetic screening performed using the new high-resolution NGS technology are hard to argue with, although there are, of course, still PGS detractors. There are undoubtedly those who, faced with the quandary of mosaics, sympathize with those who might believe that “perhaps the best advance now for IVF is to take a step backward” and transfer embryos without testing them.32 Yet randomized clinical trials, meta-analyses, the Centers for Disease Control and Prevention, and fertility clinics all agree: embryos subjected to PGS have demonstrably higher success rates.33,34,35 One study showed a near doubling in the live birth rate for women under thirty-four years old using hrNGS, a tripling for women aged thirty-eight to forty, and a tenfold increase for women aged forty-one to forty-two, while the overall miscarriage rate fell from 50 percent to 14 percent. Remarkably, the women in the PGS group transferred fewer embryos per cycle—in most cases only a single blastocyst—and saw an average increase of 97 percent in live birth rates per first transfer attempt.36
Additionally, of great significance for women worried about their age—an increasingly large group these days—PGS eliminates any maternal age effect on implantation rates.37 In one study, women aged forty-one and forty-two had implantation rates of more than 70 percent, higher than those of women under forty. Women without PGS, in contrast, saw implantation rates drop from 40 percent among those under thirty-five, to less than 5 percent among those over forty-two.38 On top of that, the miscarriage rate among women utilizing PGS does not increase with maternal age, in stark contrast with greatly heightened pregnancy loss—from approximately 10 percent for women under thirty-five to over 50 percent among women over forty-two—among those who do not have PGS.39
Accurate PGS is the great equalizer. If the embryo is chromosomally normal, odds are it will implant and survive.
FISH was first-generation technology; the equivalent of the dial-up telephone. And now with hrNGS we have the smartphone version. With previously unimaginable results: Fewer embryos transferred. Low risk of multiples. Reduced risk of miscarriage. Diminished impact of age. It’s a game changer, if you have the right technology and the right operator.
Unfortunately, many clinics are still using earlier generation technologies that are missing a lot of the diagnoses, particularly the mosaics. These clinics achieve the be-all-and-end-all high pregnancy rates so sought after in the field, but if they tracked their patients, experts believe they would also report high miscarriage rates.40
Yet even the dial-up version was enough to convince me. My first foray with PGS at the Lister clearly demonstrated how little could be ascertained about the viability of my embryos by just looking at them. Although my doctor warned me that testing the embryos could potentially harm them, it seemed worth the risk to me. With eleven embryos to test (and eight more in the freezer), I did not feel overly concerned about losing a few. When we received a call informing us that only one was normal, I was shocked by the result. We went from twenty-four eggs to one normal blastocyst.
I was starting to understand just how stacked the odds were against me.
All sorrows can be borne if you put them into a story or tell a story about them.
Isak Dinesen
8
The Dark Horse
The Silent Faces of Miscarriage
I dreaded calling my mother to tell her about my fifth miscarriage. I knew she would be devastated, and I feared it would be awkward as I had not yet told her that I was pregnant.
“Is there something else you’re not telling me?” my mother asked as delicately as she could after I delivered the news. I’m sure she was afraid of setting me off.
“No. Why?”
“Because you sound energized. Almost cheerful.”
I don’t think I realized, until hearing her puzzled (and undoubtedly concerned) voice on the phone, how much my reaction to my latest miscarriage differed from my earlier reactions—and from the reaction one would normally expect from a woman who had just lost her fifth baby. This time, I was beyond the grief and despair that had consumed me with each previous miscarriage; I was focusing solely on my future success.
But now the memory and the pain of my first miscarriage came back to me, as though I were
still sitting in Dr. Simona’s office at the Fetal Medicine Centre staring intently at the monitor, which looked a bit like an old-fashioned black-and-white TV. My teary eyes had tried to focus as I sought to make sense of the still image on the screen. I couldn’t look at Dr. Simona and the nurse, standing silently by my side. I knew what was happening, and I knew I would not be able to keep it together.
Lost in thought with my mother still waiting on the phone, I realized that my body had assumed my statue-like demeanor, almost bracing myself for the words that were to come. Whether she felt I’d had enough time, or wasn’t sure I understood what was happening, or simply had to move on to her next patient, Dr. Simona had broken the silence:
“Unfortunately, there is no heartbeat. The fetus is not viable.”
With her words, my world fell apart.
* * *
For as often as miscarriages happen, they often remain shrouded in mystery. What causes a miscarriage? Is it preventable? How often does it occur? Why did this happen to me? Was it the coffee? Did I exercise too much? Did we have sex too much? Could I have done something differently?
For most people who have experienced miscarriage, the questions never stop.
Frustratingly, the medical answers can be hard to come by, often because no answers exist. Yet the loss is as much an emotional experience as it is a physical one, and in this respect, there are some things I’ve come to know about miscarriage.
The Reality of Miscarriage
Miscarriage is devastating. Particularly so when it has been a challenge to conceive. Whether at four days, four weeks, or four months into a pregnancy, the life inside exists no more. It can be hard for those who have not suffered through it, my former self included, to fully comprehend that basic fact: miscarriage is the loss of a life.
A research team at Imperial College London found that nearly half of all women who suffered a miscarriage experience symptoms of post-traumatic stress disorder at the time and shortly after the loss, and that four out of ten women continue to report post-traumatic stress months later.1 Although rarely talked about, having a miscarriage is an experience most women never forget.
It is also, very often, shocking. Especially a first miscarriage. Prior to the moment that I rushed to the ladies’ room in my law firm’s office in London, nearly doubled over with cramps, desperately hoping I was wrong, and frantically discovered blood in my underwear, I, like almost every other woman I’ve met who has miscarried, rarely thought or talked about miscarriage. There is no way to prepare either physically or emotionally for miscarriage when it is not even in your field of vision.
“I had a bathroom-floor-on-hands-and-knees moment. Those moments are real,” recalls Jessica. Jessica and Ethan were fortunate to have experienced relatively smooth success when they turned to assisted reproductive technology to help them conceive their first child. They were optimistic that they would conceive again fairly easily when they decided to try for a sibling. And they did. But to their shock, they learned at the first ultrasound that the fetus didn’t look good. They were told to come back in a week. After an agonizingly slow seven days of praying for the best and fearing the worst, they returned to the clinic hand in hand, where they were informed that their baby had not survived. “It was so much harder mentally and emotionally than physically,” Jessica recounts.
That week of waiting. There are no words to describe the agony. I had been there too, as have so many others. You exist in a state in which you truly feel adrift. You realize you are at work, but have no idea how you got there. No idea how you got dressed that morning. No memory of what you ate, where you’ve been, or what you’ve said. Your only thought is of that baby in your womb, and whether it is alive.
Paula remembers this period as “hell.” Her doctor told her at her first ultrasound scan that there was a 98 percent chance of her miscarrying, and, like Jessica, that she should come back in a week. Sadly, her doctor was right. Her second pregnancy was the same. And the third. She and her husband, Derrick, saw the fetus and the heartbeat at the first ultrasound, and it was all over by the next. By the third miscarriage, they were in such despair that Derrick sank to his knees and screamed.
Sarah and Evan similarly experienced agonizing waits and terrifying ultrasounds with each of Sarah’s four miscarriages. Since they had never made it past two ultrasounds without being met by disaster, and were conditioned to expect the worst, Sarah describes her first trimesters as “brutal.” “Our hearts were palpitating at each scan,” she told me. “We had so many that our refrigerator was covered in them,” Evan added.
Jessica became so obsessed with becoming pregnant that the minute she was physically able, she started trying again. IVF stimulation drugs. Embryo transfer. Positive pregnancy test. Troubling ultrasound scan. No heartbeat. Repeat. With each miscarriage, the shock dissipated, but the sadness set in for the long term. She and her husband developed coping skills to get through the toughest times. Jessica needed time on her own to grieve, but Ethan preferred to lean in and be together. They found their balance. She would go on long walks and then return to him. “As you go through life,” Jessica reflects, “you redefine your normal.”
* * *
Of course, no time is an especially good time to lose a baby, but, in my experience, miscarriages tend to come at particularly inconvenient moments. My first began shortly after I had started working in the London office, while I was meeting with my new boss. My third started en route to a friend’s birthday dinner. To this day I don’t know why or how I did it, but I somehow managed to smile and get through the party without letting anybody know, including my husband. My fourth miscarriage happened at an ice polo tournament that should have been the treat of a lifetime. As the spectacular polo ponies in luscious shades of chocolate flew onto the blindingly white ice, impeccably framed by snow-capped mountains and a cerulean sky, I sat in the stands, praying that I wasn’t losing my future child. My fifth loss was on the day of the tragic London bombing. And my last miscarriage occurred during a nearly all-male, terribly formal board meeting when I was suddenly overcome with painful and extremely worrying cramping. By then, I knew instantly what the cramps meant and would have liked to run to the bathroom to confirm my worst fears. Instead, I forced myself to sit in the straight-backed chair, feigning interest, while wildly trying to devise a plan to get myself out of that room.
I thought I lived under a black cloud of timing. But it’s not just me.
Jessica had her first miscarriage on Christmas Day.
Paula and Derrick learned of Paula’s first miscarriage on Good Friday.
Rose, a thirty-six-year-old teacher, and her husband, Mike, learned that their precious fifteen-week-old fetus was not viable on the Fourth of July, with no experienced doctor in sight to perform a necessary medical procedure.
* * *
Miscarriage feels lonely, but it is common. Even more so among the fertility challenged. The next time you walk down a crowded street, or go to a movie, or a restaurant, or a baseball game, look at the women around you and contemplate the fact that one in four of them has likely had a miscarriage. One in four of the women in the office. One in four of the women on the train. The March of Dimes estimates that as many as half of all pregnancies may end in miscarriage, although many of these are believed to occur so early they are not even detected.2 While precise numbers are difficult to obtain, it is commonly believed that approximately 25 percent of all known pregnancies miscarry.
Miscarriage is murky. Although miscarriage is everywhere, far too many still go unexplained, largely unmentioned and unexplored.
Miscarriage is often silent. My experience of losses spanned two extremes: I either was blissfully unaware that the baby inside me had stopped growing, that its impossibly tiny heart had stopped beating; or I knew with sudden and painful certainty that my baby was gone. For whatever reason, my moments of sudden loss always occurred in situations where I was nearly powerless to act and falling to pieces publicly was neither a des
irable nor viable option.
So many women feel such pressure to appear calm and not fall apart in the face of a miscarriage. Why the shame? Why the stigma?
I have wondered if it is perhaps because to treat a miscarriage like a death is to recognize that it was a life? Or because miscarriage is regarded in some way as a failure as a woman? Or does it stem from work or other pressures? Or a perception that others don’t want to hear about it, that miscarriage somehow isn’t a socially acceptable subject to raise.
There is no societal script for reacting to miscarriage, no Hallmark card to tell someone what to say. Perhaps the inconvenience, the sheer untimeliness, of miscarriage contributes to the stoicism that often accompanies it. Women often can’t—or at least feel like they can’t—react at the time that it is happening and are forced to bottle up the most extreme emotions; yet later, when they might feel it is “appropriate,” the moment is lost. The raw immediacy is gone. We have learned, or forced ourselves, to move on in public, to keep it together. It can be hard to bring up the subject again, particularly when to do so for many is to relive the pain, and to confront the fear of being met with silence.