A simple blood test to predict premature births can save the lives of babies

That question remained in Quake’s mind. Months before Zoe started her high school year, her father announced that he had developed a blood test with the mother that may warn women that they are going to give birth prematurely – before 37 weeks of full pregnancy. Since then, he has launched a startup to bring the technology to the market and create a cheap, simple test that women could do around the sixth month of pregnancy.

The prematurity test is not Quake’s first investigation into prenatal health. When Athina was pregnant with Zoë, she had undergone a amniotic fluid puncture, an invasive needle biopsy that was used to detect Down syndrome and other conditions. When it is performed by doctors with a lot of experience, the risk of miscarriage is low, but it exists – and that is nerve-racking for expectant parents. “I thought, oh my goodness, this is terrible – you have to risk losing the baby to ask a diagnostic question,” he says.

Convinced that there had to be a better way, Quake started developing non-invasive blood tests to assess much of the same information as amniotic puncture, but with less risk for pregnancy. He used pieces of free-floating fetal DNA found in mother blood to take a look at the genetic composition of the fetus. More than ten years later, several biotech companies are offering a version of similar tests for Down’s syndrome and other conditions for pregnant women in clinics worldwide.

“I thought, oh my God, this is terrible – that you risk losing the baby to ask a diagnostic question.”

Similarly, blood tests, often referred to as ‘liquid biopsies’, are under development for a number of applications, including early stage cancer detection and revealing whether a replacement heart fails in the body of a recipient of a transplant. In 2014, Quake identified the evidence of dying neurons in the blood circulation of Alzheimer’s patients, a step used to develop tests for neurodegenerative and autoimmune diseases.

Predicting premature birth would be another major breakthrough. More than one in ten babies worldwide are born prematurely, a public health issue that crosses socio-economic and geographical boundaries. Babies in poor countries such as Malawi are born prematurely – the country has an early birth rate of 18%, the highest in the world – but also babies in the US, such as Quake’s daughter in prosperous Southern California.

Complications from premature birth are the leading cause of death worldwide among children under the age of five. Premature babies can struggle with infections, learning disabilities and problems with seeing and hearing. In poor countries, babies who are born considerably prematurely often do not survive. In rich countries they usually do, but sometimes with long-term consequences, including behavioral problems and neurological disorders such as cerebral palsy. There is also an economic factor: babies born prematurely cost 10 times as much in the first year of life as babies whose birth had no complications.

Just ask Jen Sinconis, whose twins arrived without warning at a 24-week pregnancy in 2006. Twin pregnancies are considered a high risk, but Sinconis’ pregnancy had been calm until she began to have what she thought to be Braxton Hicks contractions which may occur weeks in advance of childbirth as the womb prepares for labor. She was wrong and her twin boys arrived within six hours.

One of the Sinconis boys in the IC.

Thanks to Jennifer Sinconis

Aidan weighed 1 pound, 14 grams (850 grams) and had to spend three months in the hospital; Ethan weighed 1 pound, 6 grams, and was worse off. He used oxygen for most of his first year of life and barely escaped a tracheotomy. Sinconis received an surfactant injection to help her sons’ lungs develop as soon as she reached the hospital, but if a test could have warned her doctor that she was at risk of having an early birth, she could have received the drug sooner when could have made a difference. “If I had known they were born prematurely, our entire lives would be different,” says Sinconis, a creative producer at Starbucks headquarters in Seattle.

The boys’ medical care cost more than $ 2 million and did not end when they left the hospital. They stayed at home for the first three and a half years of their lives; Sinconis can hardly keep up with the number of doctors and therapists that they have seen over the years. She and her husband were forced to sell their house, liquidate their retirement and savings accounts, and eventually go bankrupt to cover the nearly $ 450,000 that the insurance would not cover. Now 12, the boys have mostly caught up with developmental delays with other children their age. But their parents are just starting to get out of their financial struggle. “We are far too late for a way to predict premature birth,” Sinconis says.

The twins of Jen Sinconis arrived 24 weeks in 2006. Now 12, the boys are mostly healthy.

Thanks to Jennifer Sinconis

A new test

Zoë, now 17, “is completely mature and completely healthy,” says Quake, a professor at Stanford University for the past 14 years, but figuring out how to predict a premature birth has been in his mind since her birth. It “felt like the next big mountain to climb,” he says. “We had gained confidence through non-invasive prenatal testing. Premature birth was like Mt. Everest.”

Quake knew that there was no meaningful diagnosis that could identify which pregnant women would give birth prematurely. The biggest tip is to have a premature baby before, something that is of little use to a first mother. Moreover, premature birth can be caused by several factors: infection, twins or even maternal stress. “We have no understanding of what causes premature birth,” says Ronald Wapner, director of reproductive genetics at Columbia University Irving Medical Center. “We have shot at it.”

Quake also knew that direct DNA measurements would not help. Analyzing the DNA of a baby inherited from his or her parents is fundamental to testing for Down’s syndrome because it can reveal the presence of an extra chromosome. “It’s a genetic question,” says Quake. But research has shown that the genetic profile of the baby makes a minimal contribution to premature birth. So instead, Quake focused on the molecular cousin of DNA, RNA. These molecules are more difficult to recognize in blood (they are short-lived) but would offer a more relevant readout, Quake believed, because their levels go up and down according to what happens in a person’s body. Could it be that a pregnancy on the way to trouble sounded early alarm signals?

“Holy shit, had we perhaps found a way to determine premature birth?” He remembers thoughtfully.

Quake and his team, including Mira Moufarrej, a graduate student in his laboratory, examined blood samples from 38 African-American women who were at risk of premature birth, in some cases because they had previously had a premature baby. In general, black children in the US are born about 50% more often prematurely than whites. Thirteen of the women ended up delivering early. By analyzing RNA molecules in their blood, the researchers found seven genes whose changing activity signals, taken together, seemed to predict which babies had arrived prematurely.

Quake told me he was surprised by the result. “Holy shit, had we perhaps found a way to determine premature birth?” He remembers thoughtfully. “We are still trying to understand the biology behind these seven genes,” he adds; it is not yet clear whether the signals come from the mother, the placenta or the baby. Quake suspects that they “reflect the mother’s reaction to the pregnancy that got out of hand.” In other words, he says, “the whole thing is derailed and the mother responds.”

“The great thing about this approach is that it allows us to see a conversation between the mother, the fetus and the placenta,” says David Stevenson, co-director of Stanford’s Maternal and Child Health Research Institute and principal investigator at his premature research center. “It is just like eavesdropping. Now we have access to this during communication, which helps us to understand what is going on during pregnancy.”

Treatment Hope

Five hundred years ago, fascinated by his anatomical dissection of the womb of a deceased pregnant woman, Leonardo da Vinci wrote about his intention to unravel the secrets behind conception and premature birth. He never did that, and even today there are relatively few answers. Perhaps because so little is known, pharmaceutical companies have not seen premature birth as a promising investment area. It is indeed “one of the most neglected problems,” says Sindura Ganapathi, co-leader of the Maternal, Newborn & Child Health Discovery & Tools portfolio at the Gates Foundation, who is working with the March of Dimes and the CZ Biohub, a medical initiative funded by Mark Zuckerberg and his wife Priscilla Chan, has funded the work of Quake.

“We need many more interventions,” says Ganapathi. “We are quite limited in our armament center.”

A test can be a first step in the direction of new medicines or treatments. If you know who is at risk, women can prepare, for example, by choosing a hospital with a neonatal intensive care unit or by working with an obstetrician who can prescribe progesterone, a medicine that is sometimes given to prolong the pregnancy. “It goes back to personalized treatment,” says Wapner. “We still have not been able to figure out how progesterone works and for whom it works better. RNA can help us better understand who should receive these drugs.”

The new window on pregnancy can lead to applications that go beyond premature birth. “From the point of view where this could go, you could look at development of the placenta, development of the fetus and interaction of the fetus and the mother,” says Wapner. “Until recently, RNA was the step sister of DNA. It is a damn good clue as to how we can distinguish who is at risk of premature birth, and it could be a better way to evaluate what is going on during pregnancy. “

In line with this, Quake has formed a startup named Akna Dx with elevated goals. It has raised more than $ 10 million from investors, including Khosla Ventures from Menlo Park, California. “Our idea is to do blood-based tests to provide important insights,” said CEO and co-founder Maneesh Jain. “What is the gestational age of a fetus? Are you at risk of premature birth or severe postpartum depression? Pregnancy is still a big black box. We want to give you insights into what happens internally so that you can take action.”

Other experts say that more evidence is needed that RNA can provide those insights. That’s because so many different factors can contribute to premature birth, and it’s not clear how well Quake’s biomarkers will do in a wider population. “The difficulty is that premature birth is not caused by one thing,” says Diana Bianchi, director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and an expert in non-invasive prenatal testing. Infection, a compromised placenta, maternal stress, twin pregnancy – all these and more can cause premature birth. “In very small numbers, Steve was able to accurately distinguish women at risk of premature birth,” says Bianchi. “But the numbers were very small.”

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Quake immediately agrees that his initial findings must be validated through a large clinical trial before a test is ready for commercial use. The Quake team is busy confirming that the results of African-American women also hold in other groups. Employees, including some co-founders of Akna, now collect blood samples from 1,000 pregnant women.

“We hope this will save many lives,” says Quake. “That’s really what we’re aiming for. But this is just the beginning of the story . It’s a very fertile area, no pun intended.”

Bonnie Rochman is a health and science writer based in Seattle and the author of The Gene Machine.