Latest Research Findings
by Irene Daria
My second child, Eric Carl, is a miracle baby for two reasons. First, because he was born thanks to a brand new treatment for recurrent miscarriage and, second, because of the way I learned of this treatment--through sheer luck.
"Luck" is a word you hear often when you miscarry. Like most women, I was assured that my first miscarriage was a matter of "bad luck," meaning a random chromosomal error--thought to cause 50 to 60 percent of all miscarriages--that wouldn't be repeated. This seemed to be borne out when I gave birth to a perfectly healthy baby the following year. Then I had two more miscarriages. Again, my ob-gyn assured me those losses were simply a matter of "bad luck" but he agreed to send miscarried tissue from my last loss out for chromosomal analysis. I was stunned and heartbroken when my ob-gyn called to tell me the chromosomal analysis had come back normal. Those results indicated that a problem within my own body--not with the babies' chromosomes--was causing me to lose my pregnancies. Unfortunately, no one knew what that problem was, since the tests screening for possible causes had come back fine.
According to the American College of Obstetricians and Gynecologists (ACOG), 50 to 75 percent of the 50,000 women who experience recurrent pregnancy loss each year--defined as two or more consecutive early losses--will not be able to find out what caused them. That's not surprising since only four conditions have been definitely proven to cause recurrent loss: random chromosomal errors; hereditary chromosomal abnormalities passed on to the embryo from the mother, the father, or both; an abnormally shaped uterus; and Antiphospholipid Syndrome (APS), an auto-immune disorder that causes blood clots in the placenta. With no definite diagnosis, many women are venturing into the land of the unproven in order to save their pregnancies.
A TWIST OF FATE
My own journey into the land of the unproven began when my ob-gyn advised me to see a reproductive endocrinologist. He in turn instructed me to have the hospital send the pathology slides from my last miscarriage (hospitals routinely keep these slides in their records) to Larchmont, New York-based reproductive pathologist Carolyn Salafia, M.D., Ph.D. She specializes in identifying exactly what went wrong in failed pregnancies. Her examination of my slides revealed rigid blood vessels. This indicated that something had been wrong with the blood flow to my uterus while I was pregnant. (Blood vessels need to be as malleable as clay so that they can shape themselves into a healthy placenta that will be capable of supporting a pregnancy. My placental blood vessels were as rigid as cement and would have been incapable of forming a well-functioning placenta). Dr. Salafia recommended that I be screened for constricted uterine arteries. My endocrinologist assured me that there was no need because blood thinners would take care of any blood-flow problem I might have once I conceived.
When I got pregnant again, I began a treatment regimen of heparin and baby aspirin, both of which thin the blood. I started spotting and cramping in my seventh week, just as I had with the pregnancies I'd lost. I knew I was about to miscarry again but my RE told me not to worry. "Your hormone levels are fine," he said. "Lots of women spot in early pregnancy. Everything looks good." Everything had "looked good" in the pregnancies I'd lost too. A heartbeat had been established in all of them and my pregnancy hormone levels had risen beautifully. Then I'd spotted and cramped in the seventh week...and miscarried. As Eric's seventh week of gestation progressed, the spotting and cramping got worse. This was such an ominous sign that, instead of telling my parents and in-laws I was pregnant again, I announced my pregnancy by telling them I was miscarrying again.
Then the miracle happened: Dr. Salafia returned a phone call I had made to her two weeks earlier, asking to interview her for an article I was writing. When I told her I was about to miscarry again she said, 'You should be on hCG too" (hCG stands for human chorionic gonadotrophin, a hormone you secrete only when you're pregnant. Home pregnancy tests screen for it, as does the blood test your doctor sends you for to confirm pregnancy.) Like many conservative doctors, the RE who had referred me to Dr. Salafia for a diagnosis was not willing to treat me with hCG since it is not a definitively proven treatment.
Immediately, I switched to a new RE. After an ultrasound confirmed abnormal blood flow to my uterus, my new doctor started me on hCG injections. By the following week, my uterine blood flow had normalized. I gave birth to perfectly healthy Eric Carl (the "Carl" is in honor of Carolyn Salafia) on July 31, 2000.
THE LATEST TREATMENTS
The infertility grapevine--on the internet and in various support groups and organizations--buzzes with stories like mine, tales of women who are convinced they had their babies due to a treatment that is either new or not definitely proven to be effective. There is a great need for this grapevine since so much about recurrent miscarriage is not yet understood and many doctors haven't even heard of some of the conditions that are, or seem to be, linked to pregnancy loss. Also, many doctors are treating patients according to what makes sense to the doctor intellectually, or by what seems to have worked for their patients in the past. The field is so muddled that a recent statement by the ACOG refers to an inundation of widely varying studies and guidelines in the field of recurrent pregnancy loss that is causing patients and physicians to turn to alternative therapies. Because many causes are unknown, it is quite common to have one doctor tell you that a progesterone defect can definitely cause miscarriage, while another one will tell you that it definitely can't. That leaves many women confused and uncertain of which way to proceed.
To help allay some of this confusion--and in the hope that you won't have to rely on luck, the way that I did, in order to have your next baby, we've pulled together the latest news on conditions that have either been proven to cause--or are believed to cause--recurrent pregnancy loss:
Although APS was discovered and linked with recurrent miscarriage in 1983, it wasn't until 2001 that research results were indisputable enough for ACOG to call it a definite cause of recurrent loss and some doctors may still be unaware of it. Women with APS have immune systems that destroy phospholipids, molecules that prevent blood clots. That causes blood clots to form in the placenta, which damages it and leads to miscarriage. You can develop APS at any point in your life, which explains why women experiencing secondary miscarriage may not have had a problem with earlier pregnancies.
* Warning signs: The main symptom in women is recurrent pregnancy loss.
* Diagnosis: A blood test screening for antiphospholipid antibodies and lupus anticoagulant. If positive, another blood test should be performed in 6 to 8 weeks.
* Treatment: Heparin and baby aspirin, both of which are blood thinners.
These inherited, genetic mutations have only recently been linked to recurrent pregnancy loss. "Even obstetricians who graduated from medical school as recently as 10 years ago probably don't know what they are," says Sandra Carson, M.D., a professor of obstetrics and gynecology at Baylor College of Medicine in Houston and co-author of ACOG's most recent practice bulletin on recurrent pregnancy loss.
* Warning signs: Early cardio-vascular disease (before age 55 for women; 65 for men) that runs in the family; early strokes; blood clots anywhere in the body; recurrent early or late pregnancy loss; late pregnancy complications such as intra-uterine growth retardation, preeclampsia, or placental abrution.
"Keep in mind that hereditary thrombophilias from the father can complicate a pregnancy," says Dr. Salafia. "Too many physicians will ask the mother for her medical history but will leave the father out of the screening process."
* Diagnosis: A blood test of both the mother and the father screening for abnormal levels of Protein C, Protein S and Factor V Leiden
* Treatment: Heparin and baby aspirin.
ABNORMAL BLOOD FLOW TO THE UTERUS
This is that happened to me. It occurs when one, or both, of the uterine arteries constrict, robbing the fetus of oxygen and vital nutrients.
* Warning signs: The main symptom is recurrent pregnancy loss. Women with diabetes or high blood pressure may have a higher risk, as do women over 35 since problems with arteries are common as people age. It is very important to keep in mind that your hCG levels do not need to be abnormal for you to have abnormal blood flow. Some doctors believe that something may be molecularly wrong with the structure of hCG in women who miscarry. So "even though your hCG levels may be fine, the hCG may not be functioning properly," says Dr. Salafia.
* Diagnosis: Rigid blood vessels on a pathology report of any previous losses and/or color doppler ultrasound.
* Treatment: Very few doctors are aware of this condition. Most of those who are have been prescribing hCG because researcher C.V. Rao, Ph.D., and his colleagues at the University of Louisville School of Medicine found that hCG relaxes the uterine arteries. Also, doctors at the Sher Institute for Reproductive Medicine, in Las Vegas, have seen promising results with Viagra suppositories, which can increase blood flow to the uterus.
LUTEAL PHASE DEFECT
This is a progesterone defect in the second half (or "luteal" phase) of your menstrual cycle. It keeps the uterine lining from developing properly, which prevents the uterus from supporting a pregnancy. It is an accepted cause of infertility and, for decades, was considered a well-established cause of miscarriage. Now, ACOG calls it "controversial" since women with normal pregnancies will have LPD in up to 50 percent of any given menstrual cycles and in up to 25 percent of sequential cycles.
So why do so many doctors test, and treat, for LPD in relation to early pregnancy loss? "Two meta-analysis were done, reviewing many studies done on LPD," says Charles J. Lockwood, chairman of the department and of obstetrics and gynecology at New York University School of Medicine and chairman of the committee on obstetric practice at ACOG. "One meta-analysis showed no benefit of progesterone treatment and one showed a 25 percent improvement in pregnancy outcome. Because of that last statistic, most of us, including me, continue to treat women with unexplained losses of chromosomally normal fetuses for LPD just in case it is an issue."
* Warning signs: recurrent, very early pregnancy losses, at four to six weeks.
* Diagnosis: It used to be standard for doctors to perform two consecutive biopsies during two consecutive menstrual periods or to measure the levels of progesterone in your blood for two consecutive months. "Those approaches have now gone by the wayside because they are totally unreliable," says Lockwood. "You progesterone levels can be normal one cycle and then you can still have LPD when you get pregnant, or they can be abnormal and then you'll be normal when you get pregnant. Many doctors, including myself, don't do any testing for this condition. Based on the symptoms, and normal results of a chromosomal analysis, we go ahead and treat women with unexplained losses for LPD."
* Treatment: Progesterone, beginning a day or two after ovulation. If you wait until you know you're pregnant, it will be too late to correct LPD.
NATURAL KILLER CELLS AND CYTOKINES
Over the past two decades researchers have theorized that a problem with how the mother's immune system interacts with the father's genetic contribution to the pregnancy can cause recurrent pregnancy loss. This theory was--and remains--extremely controversial. The researchers used to believe that if the mother's cells were too similar to the father's, the mother would not make the antibodies needed to block her immune system from recognizing the fetus as a foreign body and destroying it. Although a few researchers and obstetricians still strongly believe in these blocking antibodies, most who once thought they might play a role in pregnancy loss, no longer believe they do. "I was among the first to publish about that theory and I was the first to refute it," says Carolyn B. Coulam, M.D., medical director at the Sher Institute for Reproductive Medicine and a prominent researcher in the field of immunology. "We've found that women who have normal pregnancies don't have blocking antibodies either."
Although blocking antibodies are no longer believed to be involved in pregnancy loss, researchers do still believe that some women may be losing their pregnancies because their cells are too similar to the fathers. "In the last two years we've realized that a similarity in the parents' cells triggers the formation of blood clots in the placenta," says Dr. Coulam, as opposed to causing the mother to reject her own fetus as a foreign body. "It's very exciting that we've identified the mechanism of loss and that we've identified the substances that trigger the formation of those blood clots." These substances are called natural killer cells and cytokines. Everyone has natural killer cells but some women with recurrent pregnancy loss have higher levels of them.
Natural killer cells are white blood cells that make cytokines, various forms of protein. "Some cytokines are good and some are bad with regard to pregnancy success," says Coulam. "Bad cytokines have been termed TH1 cytokines." It is the "bad" cytokines that stimulate clotting in the placenta.
* Warning signs: Recurrent, otherwise unexplained pregnancy loss.
* Diagnosis: Your blood will be screened for an oversupply of natural killer cells and for TH1 cytokines.
* Treatment. Some doctors will immunize you with the father's white blood cells. This treatment has been shown to be effective in 10 percent of women with unexplained recurrent loss. However, there have been some indications it can actually cause a negative immune response to a pregnancy in women who had no prior immune problem. As one physician said, "I am no longer convinced that this is a do-no-harm kind of treatment."
Dr. Coulam treats patients with injections of intravenous immunoglobulin (IVIg) and reports an increased success rate of 30 percent. This is a very controversial treatment since it is a blood product from many donors. "There are some real risks to it," says Dr. Carson. "You can have a severe allergic reaction, you run the risk of developing autoimmune diseases, there's some evidence that it might cause intrauterine growth retardation and there are risks we don't even know since a new virus could be discovered and it might be contained in those blood products." Make sure to discuss all these risks with your doctor before deciding on a course of treatment.