Conceivability_What I Learned Exploring the Frontiers of Fertility

by Elizabeth L. Katkin

  I had naively assumed that my various doctors would not have prescribed progesterone if there was insufficient evidence that it worked, so I never thought to ask. Whether the common practice of prescribing progesterone will continue in the face of this new evidence is yet to be seen.

  Progesterone aside, despite years of trial and clinical practice, the evidence is scant that hormonal therapies can help to prevent recurrent miscarriage. Since the risks of many of these timeworn therapies are low, doctors and patients alike continue to turn to them in the absence of alternatives. In addition, when women deliver healthy babies after trying Clomid, letrozole, metformin, or progesterone, they naturally become passionate advocates for the cause. Unfortunately, it is nearly impossible to know with anything approaching certainty whether a specific remedy helped, particularly in light of the fact that even veterans of multiple pregnancy losses have even odds of carrying to term on the next try.

  While many women with polycystic ovaries and PCOS go on to carry healthy babies to term, I, unfortunately, was not one of them. Although I did manage to get pregnant several times while on Clomid, I miscarried each and every time. But was the PCOS to blame? As I was to discover, I had several other obstacles in my path, and my once-intense focus on the little string of pearls on my ovaries quickly receded into the background.

  Anatomical Factors

  I had been trying to have a baby for years before I learned that there are anatomical challenges to both becoming pregnant and carrying to term—and that I, myself, might be facing one. Two of the most common anatomical abnormalities are a misshapen uterus and shortened cervix.

  UTERINE ABNORMALITIES

  I hated just about everything about my hysterosalpingogram (HSG), a test performed to discover whether all looks right in the uterus and the fallopian tubes are open and in good working order. Although Mr. P had told me the procedure was routine, for some reason I had a bad feeling about it. Richard was traveling on business again, and I had to face it alone, on an unusually gray, even by London standards, sad-looking day. My foreboding increased when I met the doctor who would perform it, which was also inexplicable, as I had subjected myself to poking and prodding for quite some time by then, as well as to uncomfortable examinations (in every sense of the word) by middle-aged, well-pedigreed men and had become quite used to it.

  Mr. C, the HSG specialist referred by Mr. P, began the procedure with something called a Cook catheter. He complained to the nurse assisting him about how difficult it was to “cannulate” my cervix, which I later learned meant basically to push the tube through it. I desperately fought to suppress my need to scream as he jabbed me in every possible direction, and I sighed with relief when he finally gave up. My respite was brief, for he came at me with a new tool, which turned out to be a device called a Leech-Wilkinson catheter.

  “I suppose you are aware that your uterus is retroverted,” he mused.

  “No, I wasn’t aware,” I squeaked. The words I needed to say, the ones that wouldn’t leave my head—What does that mean?—lay silent.

  “Well, it’s also T-shaped,” he continued. What? Silence. He didn’t choose to elaborate, and, to this day, I don’t know why I didn’t ask. I hadn’t yet found my voice. He wrapped up the procedure by telling me that my tubes looked fine and that he would send the results to my doctor.

  Mr. P shared the report with me at our next appointment. Apparently, Mr. C didn’t enjoy the procedure either: “I performed a hysterosalpingogram on this lady for you. It was not particularly easy. She has a difficult cervix to cannulate,” his letter began. “Although visualization of the cervix was easy, she has a bell-shaped endocervix with an outlet to the uterine cavity, which was difficult to negotiate with a Cook catheter,” he continued. “Accordingly after trying with a tenaculum and probe, failing to insert the Cook catheter I used a Leech-Wilkinson catheter instead. The uterine cavity did not distend very well and it was slightly T-shaped . . . .”

  Although neither doctor explained it to me at the time, uterine abnormalities are a known cause of miscarriage. If the uterus is not shaped properly, it may not be receptive to implantation. By injecting dye into the uterus and fallopian tubes, the HSG test indicates the presence of abnormalities that may present obstacles to implantation.

  It turned out that my retroverted uterus was not a big deal. Retroverted simply means that the uterus tilts backward instead of forward. One woman among four or five has a retroverted uterus, and it shouldn’t cause a problem during pregnancy. A T-shaped uterus, on the other hand, can present real problems. Most commonly seen in women whose mothers took diethylstilbestrol (DES), a synthetic hormone that acts as an endocrine disruptor, to help them conceive, I later learned that the T-shape has a high correlation with failed implantation, miscarriage, and preterm births. Of course, Mr. P didn’t mention any of this at the time. Rather, I was told that my uterus was “slightly T-shaped” and nothing to worry about.

  A few specialists and tests later, I was asked if I was ever told that I had an arcuate or septate uterus. I proudly responded that I knew I had a retroverted, slightly T-shaped uterus, but no, I had never heard those other words. The HSG test is generally used to diagnose an arcuate or septate uterus, but despite having endured the test, they did not diagnose me at the time.

  A typical uterus is often described as being shaped like an upside-down pear, providing a nice big area for a newly fertilized embryo to implant. An arcuate uterus has a slight dip at the top, rendering a less elegant, but apparently only marginally less welcoming home for the burrowing embryo. Many women with arcuate uteruses have kids without much trouble. In the case of a septate uterus, however, the dip reaches down farther, starting to form a wall between the two halves of the uterus and impeding the blood flow that is necessary for implantation. Women with septate uteruses have a lot of difficulty having kids. Many doctors advocate treating a septate uterus with surgery (a procedure called hysteroscopic metroplasty or just metroplasty) to remove the offending tissue forming the wall. While believed to be highly effective, this surgery is not without controversy, both due to risk and a lack of double-blind randomized trials proving its efficacy.

  Frustratingly, in certain women, it is hard to tell the difference. Apparently, I was one of those. In my case, I was advised that my oddly shaped uterus was likely arcuate and therefore not a problem, and that I should move on.

  When I first met Anna, the social worker who counsels teens, she visibly shuddered when she mentioned her HSG test.

  “Wasn’t it awful?” I asked.

  “Well, I had three,” she replied, “and three surgeries. Beyond awful.”

  Anna’s first HSG test revealed a suspected septum in the uterus, which she was advised to have removed before she tried to conceive. She complied, and was eager to start trying for a baby as soon as possible after the procedure. Her doctor insisted that she have a second HSG test to make sure she was ready; the test revealed lots of scar tissue, yet it did not appear that the surgeon had removed the septum. Anna had a second surgery, which she was told was successful. She then hopped on the fertility roller coaster. Nearly two years later, a new fertility specialist insisted she have another HSG test, which revealed a remaining septum that was three centimeters long. Anna went back under the knife a third time. Her septum finally vanquished, she began her IVF cycle as soon as possible after the surgery, and gave birth to a beautiful, healthy baby almost thirty-six weeks later.

  In Anna’s case, identifying and fixing the septate uterus were likely key to her success.

  CERVICAL INCOMPETENCE

  Cervical incompetence, also known as cervical insufficiency, is the second major anatomical disorder routinely treated in an effort to prevent miscarriage. The cervix is the lower part of the uterus that opens to the vagina. Normally closed, as a pregnancy progresses, the cervix gradually softens and opens in preparation for birth. An “incompetent” cervix is one that shortens too much or opens too soon, making it difficult for the uterus
to hold the baby inside. In the worst-case scenario, the baby is born far too early, before it is capable of life outside the womb.

  For nearly fifty years, doctors have treated cervical incompetence by inserting a cerclage, or surgical stitch, to literally close the door to the outside world and keep the baby inside, provided that the mother is early enough in her pregnancy—generally up to sixteen weeks, but in certain emergency cases up to the twenty-fourth week.21 It is considered too risky to perform later on in the pregnancy, and many women who are found to have shortened cervixes in their second and third trimesters find themselves instead confined to bed rest, itself not without complications, including loss of muscle strength, joint pain, and depression.

  As with so many areas surrounding infertility and miscarriage, there is no consensus on why cervical incompetence occurs, and also no agreement on whether cerclage works. There is, however, agreement on this procedure’s risks, which include infection, vaginal bleeding, a tear in the cervix, premature labor and birth, and miscarriage.

  Also in common with many other aspects of infertility and miscarriage, the verdict on success rates is inconclusive, with a few small studies indicating a benefit in the case of urgent cerclage (performed upon diagnosis of a shortened cervix)22 and numerous other studies concluding that there is no benefit to either elective (chosen because of past losses, as opposed to demonstrated physical need, and usually inserted at twelve to fourteen weeks) or urgent cerclage.23 There is no data at all on the efficacy of emergency cerclage. Performed in the event of a feared preterm labor when the cervix dilates early, emergency cerclage is, by its very nature, performed only in crises, rendering controlled studies virtually impossible.

  The success of cerclage has also been found to vary based on whether the mother is carrying one or multiple babies. Women carrying a singleton with a shortened cervix and previous preterm birth had a greater chance of making it to term and a much lower chance of miscarriage when they received a cerclage.24 But there is no evidence of similar success for women carrying multiples. To the contrary, whether the women in question actually had a shortened cervix or were just at risk by virtue of carrying multiples, five clinical trials found no improvement in preventing preterm births or deaths.25

  Yvette’s story is heartbreaking. At age thirty-two, after two years of unsuccessfully trying to have a baby, she and her husband, Karl, both Catholic, went to a renowned fertility clinic for an initial consultation. Not quite ready for intervention, they opted to first try herbs, acupuncture, and dietary changes. Yvette felt great and loved her treatments, but another year rolled by and she still was not pregnant. After considerable discussion and struggle, they eventually made the decision to move on to IVF. Concerned about the risk of multiples, her doctors transferred only two embryos to Yvette, despite having the luxury of twenty-one embryos available to them. Concerned that her blood tests revealed high HCG (the earliest indicator of both a healthy pregnancy and of multiples), Yvette and Karl awaited their first ultrasound, anxious that they might learn they were having twins. At their eight-week scan, they were startled to see not two heartbeats, as they feared, but three. One of the embryos had split, and Yvette was pregnant with triplets. At her eighteen-week checkup, she discovered that her cervix was shortening, and the doctor recommended a cerclage and bed rest.

  Optimistic that the cerclage would keep her babies safe, at least for the next few weeks, Yvette committed to bed rest. At week twenty, her cervix was still shrinking and Yvette was having contractions. Her high-risk neonatal specialist wanted her to make it at least to week twenty-one, which, with cervix stretched to the stitch, she miraculously did. Yet in the face of all their best efforts—which in addition to cerclage also included intravenous cocktails of magnesium, Celebrex, terbutaline and Procardia—to keep the babies inside, just three days after hitting the week-twenty-one milestone, Yvette gave birth to their three precious angels, who tragically left them the same day.

  Antiphospholipid Syndrome

  The blood clots that led Mr. Raj Rai to diagnose me with antiphospholipid syndrome (APS) at the Recurrent Miscarriage Clinic are believed to lead to miscarriages, premature delivery, and stillbirths, although the linkage is not yet well understood. The first commonly accepted explanation of the relationship between APS and miscarriage is that the clots, which are small enough to cross the placenta (which provides vital nutrients to the fetus), essentially starve the fetus and deprive it of vital oxygen. The second major theory holds that the hallmark antibodies may prevent the fetus from implanting properly in the womb in the first place. In either event, the correlation to pregnancy loss seems crystal clear.

  Fortunately, APS is the most significant cause of recurrent miscarriage that can be successfully remedied, which is a relief to women such as myself who are diagnosed with it. APS is the primary cause of at least 15 percent (and some believe as high as 50 percent) of recurrent miscarriages. With proper diagnosis and treatment, the pregnancy-loss rate among women with APS has fallen from 80 percent in the 1980s to only 20 to 30 percent today, an absolute miracle for many women.26

  In a study of women with APS who had at least three or more consecutive losses, it was discovered that 90 percent would miscarry again without treatment.27 The researchers established that women taking low-dose aspirin together with low-molecular-weight heparin were far more likely to have a baby (71 percent success rate) than those taking aspirin alone (42 percent success rate).28 The results were astonishing and hailed as a breakthrough worth celebrating.

  Unlike baby aspirin, which is easily swallowed daily, heparin (most commonly known by the brand names Clexane and Lovenox) must be injected subcutaneously twice a day. Definitely not ideal for a needlephobe like me, but as with acupuncture and IVF, when I want something badly enough, I get my head around it. I learned to inject myself with Clexane and even became adept at finding creative new spots to puncture myself as my once-pristine white tummy, which had rarely seen the light of day, turned purple, blue, and charcoal gray as the bruises layered upon one another.

  Additionally, in 2017, news broke about the first new drug to improve pregnancy rates in women with APS since the advent of aspirin and heparin. Though at an early stage of development, a small-scale study in London found that pravastatin, a medicine intended to lower cholesterol that has been used for almost thirty years to prevent cardiovascular disease, looks extremely promising in assisting women with APS to have healthy babies.29

  Other Immunological Problems

  First, I had been diagnosed with polycystic ovaries, and Clomid was supposed to be my answer. After that, I learned about my irregular uterus, but it was deemed to be arcuate, and therefore not a serious problem. My real trouble, we were next told, was the antiphospholipid syndrome. But that wouldn’t hold us back; I simply needed aspirin and heparin to solve that one. Yet none of the treatments seemed to make a difference. I still couldn’t manage to hang on to a single pregnancy. So by the time I first heard of natural killer cells, after four miscarriages, I was more than willing to believe that taming my rogue killer cells held the answer.

  According to the controversial theory of natural killer cells, an overactive immune system detects a newly formed fetus as a foreign and unwelcome intrusion and essentially attacks and destroys the invader. The treatment for this problem involves intravenous infusion of immunoglobulin, known as IVIG, which suppresses the immune system, some believe dangerously.

  I was blissfully unaware at the time that in a field riddled with contradictory studies and flagrant disagreements, the debates surrounding the role of natural killer cells—whether they cause miscarriage at all, let alone whether certain remedies are effective—steal the controversy crown. While there is general agreement on the impact of APS, itself an autoimmune problem, on pregnancy, the consensus on the role of immunology in miscarriage stops there. For more than fifty years, passionate supporters and equally ardent detractors have clashed over both the question of whether a mother’s immune syst
em may view her fledgling fetus as a trespasser and attack it, and if so, whether immunotherapy treatments could prevent such attacks. The conflict makes this one of the most challenging medical topics for aspiring parents to get their heads around.

  Reproductive immunology treatment, while growing in leaps and bounds, is offered in a relatively cloistered world consisting largely of specialized clinics staffed by doctors engaged in cutting-edge practice. Entering this world feels a little bit like being welcomed into a secret club. With well-respected clinics stating that immune mechanisms account for 50 percent of miscarriage and claiming a success rate of 80 percent in treating these problems,30 it is very hard to disregard the potential. On top of the success rates, the rationale is alluring and easy to understand: rogue natural killer, or NK, cells inhabiting the mother’s uterus attack the fetus, treating it as a foreign body. The treatment centers around the theory that these overly aggressive natural killer cells can be tamed, creating a hospitable environment for the fetus.

  The problem is that consistent scientific studies to back up the theory are conspicuously absent. Since the earliest forays into framing and treating the alleged immunology problem, treatments have been offered to women without sufficient evidence that they either worked or, at a minimum, would do no harm. Lymphocyte immune therapy (LIT), the first widespread treatment protocol for miscarriage deemed to be caused by the immune system, was ultimately, after decades of use, banned by the FDA. Initially considered a major theoretical breakthrough in the world of understanding miscarriage, the idea behind LIT is relatively appealing to the layperson: a woman’s immune system reacts hostilely to the baby in her womb because it contains the genes of the father, foreign to her body; injecting the mother with the father’s white blood cells will make her more accepting of the foreigner. After years of testing on mice, rats, and hamsters, the first human baby conceived following LIT was born in 1980. Under the care of Dr. Alan Beer—considered the father of reproductive immunology in the United States—the baby’s mother, who was thirty-nine and had experienced seven miscarriages, received an infusion of her husband’s blood cells, and at age forty gave birth to their healthy son.