Yale Medicine physician develops a test that detects miscarriage quickly, and genomic testing looks for answers to recurrent miscarriage.
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As a woman and a mother, there’s a part of medical history questionnaires I always dread filling out at doctors’ appointments:
Number of pregnancies: Nine
Number of live births: Two
Number of miscarriages: Seven
I keep this part of my history tucked away in a side-table drawer where I still keep all their positive pink pregnancy tests and ultrasound pictures. But, the experience of losing babies I so desperately wanted tends to resurface in moments like these.
People who’ve not had this experience may not realize how much uncertainty there is surrounding miscarriage—why a pregnancy ends this way and if a miscarriage has even occurred. It would have helped my husband and me through these difficult losses if a doctor could have quickly confirmed I was, in fact, miscarrying—and then, after each one, be able to tell us why it happened.
“Often testing for miscarriage can take days or weeks,” explains Hugh Taylor, MD, Yale Medicine’s chief of Obstetrics, Gynecology & Reproductive Sciences. “It can be really troubling during the time when the diagnosis is underway. It is almost better to know—one way or the other—than to be on the precipice of not knowing for days or weeks.”
That’s why Dr. Taylor is working to bring clarity to the diagnosis of miscarriage with a new test he helped develop. With technology soon to be available in labs (during the next phase of a research trial), women may soon be able to know—the same day—if a miscarriage is happening. At the same time, Yale Medicine geneticists are conducting an extensive research study using whole-genome sequencing to understand why multiple miscarriages happen.
Detecting miscarriage is not always straightforward
“Many people come in with bleeding and are justifiably nervous,” says Dr. Taylor, acknowledging that bleeding and cramping can be signs of a loss. But, bleeding during pregnancy can also be normal. Implantation bleeding, or light spotting, can occur in the early months. Bleeding can also occur when the uterus or cervix stretches, common during pregnancy.
To determine if a miscarriage is happening, blood tests to measure a hormone produced by the placenta, human chorionic gonadotropin (hCG), are needed. Women who may be miscarrying are tested for hCG levels twice within 48 hours, but the results aren’t always precise—in which case, still more blood work is needed over the following week or weeks.
During the first trimester of a healthy pregnancy, hCG levels will multiply quickly into the thousands and will continue to climb steadily. “If the placenta grows well, hCG rises,” Dr. Taylor says. Conversely, hCG values rise more slowly, stall, or plummet when a woman is miscarrying.
Waiting days or weeks to know if a pregnancy had ended was absolute agony for my husband and me. It required repeat trips to the Ob/Gyn’s office for blood work, sitting in a waiting room with women whose pregnancies might not have been hanging in the balance, and then receiving a phone call with results that often were unclear.
What are called early miscarriages are those that happen before 20 weeks. This is when 80% of miscarriages occur, according to the American College of Obstetrics & Gynecology (ACOG), a professional association of physicians specializing in obstetrics and gynecology. After seven weeks, an ultrasound can be used to determine if there’s still a heartbeat. But in miscarriages that occur earlier, blood tests and time are the only diagnostic tools currently available.
“You have to wait and see,” says Dr. Taylor. “It can go on for a week or more. It can be a tense, heartbreaking time. If the tissue hasn’t passed, waiting to see the growth of the fetus using ultrasound or for a rise in hCG levels is not an expedient way to know if your baby is safe or not.”
A faster way to detect early losses on the way
Dr. Taylor is working on a new hormonal test with colleagues at GENESIS Fertility and Reproductive Medicine in New York. Yale offered the test last summer as a self-pay, lab-developed test, and it is still in the research phase.
The technology pinpoints the source of a particular pregnant woman’s bleeding. “This is a new test that will give you a same-day answer,” Dr. Taylor explains, noting that it relies on a different pregnancy-related hormone, not hCG.
“There is a protein made by the fetus that the mother doesn’t make. It’s called alpha-fetoprotein [AFP],” he says. Levels of AFP are high within fetal blood and amniotic fluid. “The lack or presence of AFP will tell you if bleeding is coming from the mother or the baby,” Dr. Taylor says.
If the test detects high levels of AFP, then the bleeding is from a fetal loss. Low levels of AFP mean the mother is experiencing bleeding, which occurs in about a quarter of pregnant women.
Another concerning reason for bleeding early in pregnancy is an ectopic pregnancy, in which the fetus implants in a Fallopian tube or an ovary, resulting in a fetal loss.
Without this new technology, if an ectopic pregnancy is suspected, physicians will usually first treat the patient with methotrexate. This can be problematic for women undergoing fertility treatment because they will need to temporarily delay further fertility treatment until the medication is no longer in the body, which can take a few months. This can be an unnecessary—and frustrating—delay for those who aren’t experiencing an ectopic pregnancy and want to try again soon.
“As an infertility doctor, when people have struggled for months or years to become pregnant, seeing them go from great joy to devastation is heartbreaking,” says Dr. Taylor. “It’s almost harder being pregnant for a little while than never being pregnant.”
Recurrent miscarriage is often a mystery
According to Dr. Taylor, about 15% of pregnancies end in miscarriage. And when a couple has two or more losses, it is considered recurrent miscarriage (or recurrent pregnancy loss), the causes of which can be particularly challenging to unravel.
“There are thousands of reasons why pregnancies can fail,” explains Dr. Taylor, offering three examples: endometriosis, thyroid issues, and low progesterone. Because human development is intricate, “many things can go wrong with something so complex,” he says. “Some of them are likely to be genetic.”
Since half of all recorded miscarriages are thought to stem from genetic causes, Dr. Taylor is working with Yong-Hui Jiang, MD, Ph.D., chief of Medical Genetics at Yale Medicine, Uma Reddy, MD, and Ira Hall, Ph.D., finding answers.
A $7.5 million National Institutes of Health (NIH) grant allows them to conduct detailed phenotyping and whole-genome sequencing for parents and miscarried fetal tissue to identify reasons for recurrent losses. This knowledge will guide the clinical evaluation and counseling for couples with infertility and reproductive health issues, says Dr. Jiang.
According to ACOG, repeated miscarriage is uncommon—it occurs in only 1% of women. “Currently, little is known about the cause of recurrent loss,” says Dr. Jiang. “This creates confusion and frustration for couples who want to seek help and intervention. Our study and cutting-edge technology could offer real hope for these couples to understand the cause and to choose effective interventions.”
Dr. Jiang says that those who’ve experienced more than two miscarriages of an unknown cause will be eligible for the study, which will start recruitment at Yale, along with 13 other collaborative sites in different states. The Yale Fertility Center will evaluate patients with recurrent pregnancy loss, offering infertility and reproductive genetics services to make participation easier.
Thanks to these innovations, individuals experiencing miscarriage may find answers to some of their painful questions. A simple lab test may help them know sooner if they’re miscarrying, saving them days of worry and false hope.
And those who have been through multiple miscarriages, like my husband and I, may understand why they’re experiencing so many heart-wrenching losses.
Written by Colleen Moriarty
Source: Yale University