Conceivability_What I Learned Exploring the Frontiers of Fertility
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Given how common miscarriage is, the enormity of the lost communication is tragic, especially in light of how much it can help to discuss the loss—to share, to learn, to regain hope. Sarah, who describes herself as a very private person, was unsure at first about whether she wanted to share her story with me. But as we talked, she became increasingly enthusiastic. “If no one is talking about it, you’re just suffering,” she concluded. “Alone. For no reason really.”
Medical Aspects of Miscarriage
The history of the medical study of miscarriage is peppered with erroneous assumptions that have led to decades of false understandings and ineffective therapies. Surprisingly, even the number of women who experience miscarriage has not been well understood. But scientific understanding of miscarriage is constantly evolving, and while much remains unknown, there are more answers today than ever before.
For example, miscarriage, we now know, occurs as frequently as childbirth. Modern detection techniques have led to a new understanding of miscarriage rates, indicating not only that half of all pregnancies fail, but also that 25 percent of women who try to become pregnant likely will have two miscarriages, and that another 12.5 percent will have three.3 This latter figure is in stark contrast to the oft-cited figure that a mere 1 to 2 percent of women will experience multiple, or recurrent, miscarriages. For the women out there, like myself, who suffer recurrent miscarriage loss, these statistics are of huge significance: You are not alone. Not even in the 1 percent. There are others like you, and most will go on to have healthy children.
Miscarriages broadly fall into two categories: sporadic miscarriages and recurrent miscarriages. Sporadic miscarriages, by far the more common and experienced by a quarter of all women, are believed to result from an isolated occurrence, in most cases a chromosomal abnormality, or occasionally, an aggressive infection or virus. At least half of all miscarriages, in fact, result from one or more chromosomal abnormalities in the fetus, a fact borne out by numerous scientific studies, but itself not yet well understood. If half of all pregnancies end in miscarriage, and half of all miscarriages are a result of chromosomal abnormalities, that means that one in four embryos conceived has a chromosomal abnormality.
Recurrent miscarriages, by contrast, are generally defined to be three (or, more recently by some clinicians, two) miscarriages in a row, and are thought to result from chronic, underlying causes, such as hormone imbalances, abnormalities in the shape of the uterus, cervical insufficiency, and immune problems.
Traditional thinking on miscarriage holds that while nothing can be done to prevent sporadic miscarriages, action can be taken to remedy certain causes of recurrent miscarriage. Recent scientific research and new thinking on egg quality, however, may lead to innovative views on both. For example, enhanced PGS techniques enabling those undergoing IVF with PGS to select chromosomally normal embryos dramatically reduce sporadic miscarriage rates, as does improving egg quality. At the same time, but tending toward the opposite direction, newer studies reveal that some common treatment protocols for recurrent miscarriage actually have no demonstrable effect on success.
Sporadic Miscarriage
“There is actually something a lot worse than not getting pregnant, and that’s getting pregnant and having a loss,” said Dr. Mark Hughes, MD, PhD, to a rapt audience including some of the world’s leading fertility specialists at the 2016 ART World Congress in New York City.4 One of the founding fathers of PGD,5 Dr. Hughes, a molecular biochemist and head of the Genesis Genetics Institute, has devoted much of his career to helping families elude these avoidable losses. In light of the fact that aneuploidy is the number one cause of miscarriage and failed IVF implantations, the allure of eliminating aneuploidy is easy to see. Emphasizing its promise and directly addressing its earlier limitations, Dr. Hughes proceeded to present research on current PGS methods that demonstrably lower a woman’s risk of miscarriage to that of only one-third of their non-PGS peers. The evidence showed that when “normal” embryos implanted, they tended to stick around, and for women and couples with repeated miscarriages, like myself, the promise of transferring chromosomally healthy embryos, less likely to result in loss, is extremely persuasive.6
Sitting quietly in the back of the ballroom, I felt myself nodding in violent agreement, gratified to hear a doctor say these words. This was exciting news for a field in which chromosomal abnormalities—which cannot be corrected postconception—eclipse all other forms of miscarriage. Screening out abnormal embryos could prevent so much heartache and pain. Nina, the physician in Boston, certainly shared this view. After three miscarriages and a protracted battle with her insurance company (disappointingly, in one of the most insurance friendly states in the country), she and her husband turned to genetic testing at their own expense for their last IVF cycle. To their overwhelming disappointment, they were told that their only two blastocysts were both abnormal. Despite the heartbreak, Nina told me that “it was so much better than having a miscarriage . . . think of all the time wasted on top of the emotional devastation.”
Perhaps because it is considered random and occurs so frequently, sporadic miscarriage is perceived by some in the medical field as both uncorrectable and medically trivial. This perception sadly leads some doctors to treat their patients with a level of care that is not commensurate to the great emotional distress patients feel. Jessica, for example, still gets angry when recalling the callousness of the doctor and nurses at her very expensive clinic, who treated her loss as a statistic and focused immediately on her next cycle. Paula, similarly, remembers that minutes after her miscarriage occurred, while she was still in the depths of despair, she was blithely told such loss was to be expected with older eggs and that she needed an egg donor.
Jane, herself in the medical field, recounts in painful detail her conversation with the nurse who confirmed her miscarriage. When she arrived at the hospital emergency room both in great pain and severe distress, her husband informed the nurse that his wife was twelve weeks pregnant. The nurse replied, without a detectable hint of empathy, “Well, is she twelve weeks pregnant or was she twelve weeks pregnant?” Later, during that same visit, Jane went to the bathroom and discovered that she was already passing the fetus, in the form of plum-size clots. Cognizant that the fetal tissue could be useful for diagnostic purposes, she mentioned it at the nurses’ station on her way back to the examination room. A few minutes later, she heard them joking about who on that shift would have to fish out the contents of the toilet bowl.
Speaking with these and other women about the moments following their miscarriages prompted me to reflect on my own vastly different miscarriage experiences. After my first miscarriage, I had little communication from my doctor, who made no attempt to explain to me why it may have occurred or assuage my fears. When I finally went for my belated D&C, I was sent to the delivery floor of a maternity hospital. The pale yellow walls proudly displayed baby art—infant handprints and footprints, photos of beatific babies—while newborn cries provided the soundtrack to my hospital stay. In contrast, when helping me through a later miscarriage, Mr. Braithwaite kindly scheduled me for a D&C the very next day and booked me into the cardiac ward at a different hospital far from sights and sounds of happy new families. Although in both instances the physical procedure was virtually identical, their emotional impact was decidedly different, a distinction worth noting given that most women who have experienced miscarriage describe the emotional trauma as far more difficult than the physical.
While raising the standard for compassionate care seems like a fairly achievable goal, changing the perception that sporadic miscarriage cannot be prevented may be more challenging. Yet there is reason for optimism, as researchers continue to study aspects of miscarriage in order to understand and address underlying factors. Going one step further than the genetic screening that identifies abnormal embryos, scientists are now starting to focus on egg quality and whether and how it might be improved, leading to the creation of a greater proport
ion of normal embryos.7 Although the research is in its early days, improving egg quality is a potential game changer. Since abnormal embryos are the number one cause of sporadic miscarriage, addressing poor egg quality—to date viewed as “incurable”—may be nothing short of miraculous.
Recurrent Miscarriage
Recurrent miscarriage veterans tend to speak their own language.
“Seven: six early, one late, five silent, three D&Cs.”
That translates to seven miscarriages, six of which were early, generally meaning before a heartbeat was detected, or perhaps simply meaning first trimester; one was later, indicating that it was both more unusual and more surprising, after the heartbeat was seen and the odds of loss declined severely; five were silent miscarriages, an expression invoked when there has been no actual bleed or loss of the fetus, rather the baby’s heart has stopped beating inside the womb and was only detected by ultrasound; and three D&Cs signifies three dilation and curettage procedures to evacuate the products of conception, often performed after a silent miscarriage.
The language continues, ripe with acronyms. “PCOS, APS, high FSH, low AMH . . .” Women who fall through the rabbit hole into the world of recurrent miscarriage often rapidly acquire fluency in this new language as they arm themselves to conquer the obstacles nature has placed in their way.
In contrast with their approach to sporadic miscarriage, fertility specialists have long believed in their ability to combat certain causes of recurrent miscarriage. Fortunately for many, some recurrent miscarriage treatments do in fact have a demonstrable record of success, such as taking aspirin or heparin to thin blood clots, or having surgery to repair an ill-formed uterus. But the various remedies, often offered to couples so desperate to have a healthy pregnancy that they will try almost anything (myself and Richard included), range from the scientifically sound to the speculative to practices that have been proven to be bunk.
Balancing the statistical odds of a treatment working against the hope that you may be one of the lucky ones, no matter how low the odds, is an excruciating task. Presented with any prospect of having a child, many patients opt for treatments with no proven record of success. But what if those treatments may actually be harmful, or expose a mother-to-be to unnecessary risk, or actually lower the odds of success? For example, DES, a synthetic hormone widely prescribed to women in the 1950s and 1960s to prevent miscarriage, was later shown to both increase the risk of miscarriage and to cause devastating health effects in both the mothers who took it and their daughters.8 Doctors and their patients must look critically at the demonstrable upside versus the real-world costs and risks of experimental treatments. Evaluating the efficacy of any of the treatments, however, can be vexing, as many, if not most, pregnant women who have experienced multiple miscarriages will go on to carry to term with no intervention at all, and the majority of treatment protocols have not been validated with randomized, double-blind studies.
The known and suspected causes of recurrent miscarriage that are generally understood to be susceptible to treatment can be grouped into four major categories: hormone imbalances, including polycystic ovarian syndrome (PCOS); anatomical problems, such as an abnormally shaped uterus or an incompetent cervix; antiphospholipid syndrome and other blood-clotting disorders; and immune problems, most commonly referred to as elevated “natural killer” cells.9 I had the dubious distinction of falling into every one of the four categories, undergoing treatments for all of them.
Hormone Imbalances / Polycystic Ovarian Syndrome
When I learned from my first doctor in DC that I had polycystic ovaries, not only did I not comprehend the impact that it would have on my efforts to get pregnant, the idea of miscarriage could not have been further from my mind. The doctor never said the word miscarriage or connected it to PCOS, nor did the many doctors whom I saw over the next several years.
This omission is startling in light of the fact that the most common abnormality found among women with recurrent miscarriage is the telltale string of pearls along the ovaries—the many tiny cysts rendering the namesake polycystic ovaries.10 While the cysts present the most visible manifestation, polycystic ovaries and PCOS, the syndrome associated with it, are actually an endocrine disorder. Women with polycystic ovaries often have high levels of testosterone and/or insulin, as well as abnormally high levels of LH in relation to FSH (hormones that are key to ovulation, responsible for triggering the release of a mature egg from its follicle), leading, among other problems, to irregular or absent periods. In addition to conspiring to make pregnancy more difficult to achieve, these hormone imbalances pose a challenge to maintaining a pregnancy. In fact, Professor Lesley Regan, director of the Recurrent Miscarriage Clinic and one of the world’s leading miscarriage experts, found a miscarriage rate in women with elevated LH levels that was five times the rate of women with normal levels.11 Further large-scale studies of women with PCOS estimate miscarriage rates of up to 60 percent.12
Yet despite uncovering the correlation between PCOS and miscarriage, clinicians and researchers alike have struggled to understand the exact mechanism by which they are connected. Treating women with hormone imbalances is a tricky business, and while drugs like clomiphene citrate (Clomid) and letrozole (Femara) have been effective in varying degrees in helping women with PCOS get pregnant, it is not clear that they have the same impact on helping women stay pregnant. In the absence of a clear cure, doctors have frequently turned to two additional well-traveled paths to prevent hormonally based recurrent miscarriage: metformin (marketed as Glucophage) and progesterone.
The idea behind using metformin, a drug developed for diabetes, is that it will combat the insulin resistance that often accompanies PCOS. It has been prescribed by doctors for many years to help treat women with PCOS, as well as those with unexplained infertility and recurrent miscarriage, whether or not they were diagnosed with glucose intolerance, despite the fact that large-scale studies indicate that, except for certain cases of women with glucose intolerance, metformin is not effective in ovulation induction and combatting infertility.13,14 As for combatting miscarriage, however, the results, albeit mixed, are more promising. While some studies have failed to demonstrate any improvement in reducing loss and complications of pregnancy,15 a number of contradictory trials have in fact shown a marked reduction in early pregnancy loss and preterm labor.16 In the absence of a prohibition, or any clear guideline at all, many doctors opt to throw metformin into the mix and hope it works. My doctors recommended that I try it throughout many cycles while attempting to conceive, and through two (failed) pregnancies. It didn’t work for me, but hopefully it didn’t hurt either.
Progesterone, a natural hormone that is essential to maintaining a healthy pregnancy, has long been a go-to in the fertility industry—for PCOS, for unexplained miscarriage, and for a condition called luteal phase deficiency (LPD), itself a point of great controversy in the fertility world. Not only is there wide disagreement about whether luteal phase deficiency exists, there are also similar disagreements on how to diagnose and treat it.17
A woman’s menstrual cycle is divided into two phases: the follicular phase, which occurs prior to ovulation, and the luteal phase, which begins when the egg is released from the follicle. During the critical luteal phase, the follicle develops into a corpus luteum and releases progesterone, which is necessary to develop the uterine lining. Advocates of LPD believe that in some women the luteal phase is too short to produce enough progesterone to sufficiently develop the endometrium. Their remedy for this seemingly simple problem is to support the body with supplementary progesterone to help the endometrium grow, generally in the form of suppositories or intramuscular injections. Skeptics are, well, skeptical—both that the condition exists at all and that progesterone can help it.
Dozens of studies have sought to answer the question of whether progesterone can prevent miscarriages, and, while a handful of small trials from the 1950s and 1960s have shown some positive effects for women who have
experienced three or more miscarriages, the evidence is increasingly falling on the side of the naysayers.18 Yet puzzlingly, the data has not had a perceptible impact on clinical practice. Despite the fact that a landmark large-scale evaluation of fourteen research studies found no significant difference in birth rates between women who received progesterone and those who did not,19 doctors have continued to prescribe it, and women have continued to ask for it, in hopes that it might help.
The very first, and long overdue, double-blind randomized comprehensive assessment of whether progesterone therapy reduces the risk of miscarriage in women with a history of recurrent miscarriage was finally completed and its findings published in 2016. Known as the PROMISE trial, this groundbreaking international study, the largest clinical trial ever conducted on the subject of recurrent pregnancy loss, involved forty-five clinics treating women ranging in age from eighteen to thirty-nine, all of whom had suffered at least three or more losses. Its major finding can be summed up in one sentence: “[P]rogesterone therapy in the first trimester of pregnancy in women with recurrent miscarriage is of no benefit and, therefore, should not be used in clinical settings.”20
I suspect that the majority of women who take it have no idea that there is little evidence that progesterone helps maintain a pregnancy. I was prescribed progesterone suppositories with three of my IVF cycles in the United Kingdom and the United States, and (painful) progesterone shots with an additional two. The progesterone shots are so nasty that women lament them daily: “It gets more and more painful each night. It hurts so bad that I literally had tears,” commented one woman in the midst of her cycle. “Of all the injections and things that have gone on with this IVF—these progesterone shots are by far the worst. I have lumps on both sides and sometimes itch like crazy at the site afterward,” remarked another. Women and their partners develop tactics for coping with the difficult shots and readily share successful tips with others: “I used a heating pad for about ten minutes on my rear end before doing the injections. After applying the heat, I’d rub an ice cube inside a sandwich baggie, wrapped in a washcloth, to numb the skin. Then the heating pad went back on my tush afterward to relax the muscle again.”