For most women, one of the most stressful parts of giving birth is not knowing when it’s going to happen. Roughly 15 million pregnant women face life-threatening spontaneous preterm birth every year. And doctors don’t really understand why some pregnancies — nearly 10 percent of all U.S. births — end suddenly, weeks or even months before they should.
Now, a pilot study from researchers at Stanford University suggests that it may soon be possible to use a blood test to improve predictions of both healthy and too-early due dates. Such predictions could also help better explain why some births begin in crisis.
“It’s really hard to understate the potential of what these folks are proposing,” said Dr. Thomas McElrath, a maternal-fetal medicine specialist at Brigham and Women’s Hospital and an associate professor at Harvard Medical School in Boston. “The potential for how that may feed into care and into research and into furthering not just maternal but neonatal outcomes is huge. We’re just probably beginning to get a sense of what that may involve.”
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The study, published Thursday in the journal Science, shows that markers in the blood can — at least in a small group of pregnant women — predict as much as two months ahead of time when a preterm birth is likely.
The test measures levels of so-called cell-free RNA, bits of protein-coding instructions left behind when a cell dies. Every tissue in the body — including the placenta and fetus during pregnancy — contributes cell-free RNA to the bloodstream, said Stephen Quake, the paper’s senior author and a professor of bioengineering and applied physics at Stanford.
Analyzing this cell-free RNA, Quake said, “provides a very direct window into the biological processes that are happening during pregnancy. It’s really quite phenomenal.”
By measuring levels of some of these cell-free RNAs, Quake’s team was able to estimate fetal development and gestational age throughout pregnancy.
The study involved two major parts. First, the team analyzed blood samples donated weekly by 31 pregnant women in Denmark, all of whom ended up delivering at full term. From this, the team identified nine cell-free RNAs that are distinct to the placenta and appeared to be just as predictive of the timing of full-term birth as a larger panel.
Then, the team validated its model by testing it on 38 pregnant Americans who were at high risk of giving birth prematurely. Using seven types of cell-free RNA, the team was accurately able to predict preterm birth 75 percent of the time.
The group was very small, and mostly African-American, so the test needs to repeated on a much larger, more diverse cohort, Quake said, before it can be considered for general use. If it does prove out, he said, one blood test midway through pregnancy should be able to indicate whether a woman is at a high risk for delivering prematurely.
African-Americans are far more likely to deliver prematurely than white or Hispanic Americans. Experts believe that has to do with stress and socioeconomics, but don’t really know why African-American rates of prematurity are so high or what to do to prevent them, McElrath said.
“To be able to gain better insights and perhaps even better treatment modalities would be another natural outflow from this kind of work,” he said.
Quake said he and his research team have been “chipping away” at this cell-free RNA technique for the last five years, but he’s been interested in preterm birth for the last 16 — since his wife gave birth to their daughter a month early. She’s now a strong, vibrant high school junior, but he said those first anxious weeks still motivate his research.
The test will never be perfect, Quake said. “If someone told you they had a perfect test, you should be very suspicious. That’s not the way a diagnostic works.” But it’s good enough, he said, providing useful information 70 to 80 percent of the time.
Even he seemed surprised that the cell-free RNA can predict spontaneous preterm birth up to two months ahead of the potentially catastrophic event.
That predictive ability may also offer insights into the causes of prematurity, which have not been well-understood, said Dr. Yoel Sadovsky, executive director of the Magee-Womens Research Institute at the University of Pittsburgh.
Right now, he said, there are a handful of treatments that can help prevent premature delivery, but most can’t be targeted to a particular cause — because doctors don’t know what it might be.
“If their methodology of cell-free RNA can be used to predict other types of preterm birth and maybe potentially segregate different subtypes of preterm birth, it may be important not only for understanding the biology, but maybe to even come up with a precision, personalized medicine approach to therapy, which may be one of the most important steps of this field,” Sadovsky said.
McElrath said doctors have long assumed that preterm contractions force the cervix to yield, leading to preterm birth. But more recent research suggests those contractions may be the end result of a process that starts weeks or even months earlier. Analyzing the cell-free RNA might offer insights into that process, as well as into pre-eclampsia, a potentially fatal pregnancy complication.
For a healthy pregnancy, the idea of having a test that could accurately determine a due date would be so transformational that McElrath said he struggled to even imagine it.
As anyone who’s ever had a baby knows, dating a pregnancy is an imprecise art; a due date is little more than guesswork based on when the pregnancy might have started and how the baby is developing. Ultrasound dating can help early on in the pregnancy, but doesn’t work in later trimesters.
A test could also help put to rest fears in the majority of women who do not need to worry about preterm delivery, said Dr. Kelle Moley, chief scientific officer for the March of Dimes, an advocacy group that helped fund the research.
McElrath said many of his patients would appreciate more precise dates so they could plan around major work deadlines — court dates for lawyers, school terms for teachers, etc. — as well as to make sure that family members are in town for the baby’s arrival and that older children are taken care of.
“That would be huge. My patients would absolutely love that,” he said.