When Leigh Ann Torres was in her 29th week of pregnancy, she experienced a sudden, 14-pound weight gain along with terrible swelling in her legs and feet. At a visit to her doctor in Austin, Texas, a test showed protein in her urine—a telltale sign of a rapidly progressive disorder called preeclampsia. Characterized by symptoms including persistent high blood pressure, decreased blood platelets, headaches and visual disturbances, preeclampsia can unpredictably proceed to eclampsia (from the Greek eklampsis, or “lightning bolt”), a life-threatening complication characterized by seizures and coma.
Despite these clear warning signs, Torres was sent home with orders to buy an over-the-counter home monitor to keep a log of her blood pressure, and to rest in bed. When there were no improvements a week later, her doctor sent her to a hospital where she went into labor the same afternoon. She had a cesarian section and gave birth to identical twin girls nine weeks early. They spent 38 days in the neonatal intensive care unit, with some breathing assistance at first, before going home. Torres was lucky: “The neonatologist said the babies were boring,” she says, “and boring is good.”
Torres’ experience, though terrifying, was typical. The signs and symptoms of preeclampsia don’t show up until after the 20th week of pregnancy—at which point the only interventions are to monitor the patient closely or deliver the baby early. Some 2 to 8 percent of women will develop preeclampsia during pregnancy, including those with no known risk factors such as a previous history of high blood pressure, obesity, carrying more than one baby, or being either under 18 years old or over 40. Of the 10 million pregnant women around the world who develop preeclampsia every year, about 76,000 die. And about half a million babies die each year as a result of preeclampsia, including 10,500 in the United States.
There are new screening protocols that can detect preeclampsia early in a pregnancy, when intervention to prevent it is still possible. But they are complicated and expensive to implement. That’s why some researchers are pursuing a simple, portable and inexpensive test that can detect preeclampsia in the first trimester.
A SIMPLE BLOOD TEST
Once known as “the disease of theories,” preeclampsia is mysterious in its origins. Hypotheses abound, but the placenta and its blood supply are thought to play a key role. Currently, the only cure for preeclampsia is the delivery of the placenta, explains Inkeri Lokki, a reproductive immunologist of the University of Helsinki. This is “the single biggest indicator that placenta is at the root of the problem,” she says.
Lokki studies a preeclampsia marker, called sFlt1, that regulates growth of new blood vessels. Early on in a normal pregnancy, the spiral arteries—maternal blood vessels that feed the uterus like a twisting garden hose—open up like funnels to bathe the fetus with blood and oxygen. In preeclampsia, Lokki says, this “remodelling” process does not occur normally, and the opening of the “funnel” is too narrow to offer an adequate blood supply for the fetus.
Throughout the years, researchers have developed about 70 prediction models for preeclampsia. Many of these tests were designed to detect markers of preeclampsia in the first trimester, says genomics researcher Noam Shomron, of Tel Aviv University in Israel. But because the trials were based on a small number of samples with very few controls, “none of them were substantial.” Shomron says.
That may have changed this year. A 2018 study led by Kypros Nicolaides, a professor of fetal medicine at King’s College London, showed that detection of preeclampsia using a combination of 17 tests in the first trimester is possible. It is called the Screening Program for Preeclampsia, or SPREE.
SPREE combines maternal risk factors and medical history with testing for four predictors of preeclampsia in the 11th to 13th week of their pregnancies. The predictors are the mother’s blood pressure, blood flow in the arteries that supply the womb, and the levels of two placental hormones: plasma protein-A and placental growth factor, a protein that helps placental blood vessels grow.
The SPREE trial, which enrolled 16,747 women in the U.K. in 2016, showed that this combined screening method can detect 82 percent of all preterm preeclampsia cases. A similar trial, which included 26,941 women in the U.K., Spain, Italy, Belgium, Greece and Israel and was published in 2017, detected 76 percent of cases of preterm preeclampsia.
But the SPREE protocol isn’t a practical solution for many clinical settings. These screening methods use complicated algorithms, sophisticated sonography and other equipment often unavailable to women and doctors in low-income countries. There are doubts, too, as to whether these new screening guidelines would be cost-effective even in rich countries, according to a 2017 paper published in Drugs.
That is why Shomron and colleagues are planning to develop a cheap, portable blood test to detect preeclampsia in the first trimester based on biomolecular markers. In his lab at Tel Aviv University, Shomron holds up a handheld, mobile-phone–sized DNA sequencing device made by Oxford Nanopore Technologies. In the future, “this could be a preeclampsia test,” he says. It would only require a drop of blood from a patient’s finger.
In August 2012, Shomron and Moshe Hod, a professor of obstetrics and gynecology at Rabin Medical Center in Israel, flew to London to meet with Nicolaides, who had been following a cohort of 10,000 British women for years, sampling and storing their blood and plasma throughout their pregnancies. Nicolaides gave them frozen blood samples to take back to their lab. Next, PhD student Liron Yoffe spent a year sequencing the 20 million RNA molecules extracted from each of the 75 plasma samples. She focused on micro-RNAs—short RNAs that stick to other RNAs to stop their expression—and small, non-coding RNAs, because these molecules have many regulatory roles in the cell and are known to be involved in disorders in which the body is under physical stress. Yoffe found 25 non-coding RNAs and micro-RNAs that were expressed differently in the preeclampsia blood samples drawn in the first trimester, as compared with the controls. Notably, some were associated with obvious symptoms of the disorder, such as the development of new blood vessels to the placenta and the regulation of blood pressure.
In February 2018, Shomron and his colleagues published a paper in Scientific Reports showing that they could detect preeclampsia by sequencing small, non-coding RNA molecules extracted from plasma samples drawn early in pregnancy. One day, Shomron explains, clinicians could give mothers a simple blood test, then measure and sequence these RNA markers with readily available equipment to catch preeclampsia early.
The ability to detect preclampsia in the first trimester would give doctors a window to treat it—with an over-the-counter drug. Multiple studies and anecdotal reports going back as far as 1979 have indicated that women at high risk of preeclampsia might lower their risk by taking aspirin during pregnancy. But the results of clinical trials were contradictory, and the benefit of aspirin was sometimes small or non-existent, especially when it was introduced after the 20th week of pregnancy.
But recently, Nicolaides led a clinical trial involving 1,620 pregnant women who were at high risk of early-onset preeclampsia. The results, published in 2017, showed that those who took a daily, 150-milligram dose of aspirin beginning in the 11th to 14th week of pregnancy reduced their risk of preeclampsia by 62 percent compared to those who took a placebo. Similarly, a 2018 meta-analysis of 16 clinical trials of aspirin for preeclampsia, led by epidemiologist Stéphanie Roberge of the National Institute of Excellence in Health and Social Services (INESSS) in Quebec, found that high-risk women who took a daily dose of aspirin reduced their the risk of preeclampsia by about 70 percent—but only if the women began taking aspirin before the 16th week of pregnancy, and only if their daily aspirin dose was more than 100 milligrams.
How aspirin lowers the risk of preterm preeclampsia remains unclear, Roberge says, but the timing of efficacy suggests that it plays a role in the remodelling of spiral arteries, a process that is complete by 16 to 18 weeks of pregnancy.
CLOSING THE MORTALITY GAP
Despite these recent and promising discoveries, there is already a huge gap in preeclampsia mortality rates among the U.K., the U.S., and the rest of the world. The proportion of all maternal deaths from “hypertensive disorders of pregnancy,” the majority of them preeclampsia, is 2.8 percent in the U.K., 7.4 percent in the U.S. and 14 percent globally. Only two women died from preeclampsia and eclampsia in the U.K. during the years 2012 to 2014, compared to 200 deaths per year in the 1950s—a dramatic reduction related to improved diagnosis, timely delivery and prophylactic use of aspirin, according to obstetrics professor Lucy Chappell and her colleagues at King’s College London.
Low maternal mortality rates in the U.K. are no accident, Chappell says, citing a triannual survey called the Confidential Enquiry into Maternal Deaths. It reviews all maternal deaths, highlights areas for improvement and then issues recommendations. By contrast, there is no similar review process in the U.S., says Anupam B. Jena, a professor of health care policy at Harvard University. Most of the treatment is “very basic medical management that hasn’t really changed over a decade or two,” he says. In the U.S., the cost of treating preeclampsia is $1.03 billion for mothers and $1.15 billion for infants during the first 12 months after birth, according to a recent report by Jena and colleagues in the American Journal of Obstetrics and Gynecology.
Though the new screening algorithms for preeclampsia are promising, Chapell urges caution. “Every time somebody comes up with a new prediction model, it’s very exciting,” she says. “But what we need to see is if it is validated in other populations. Will it work for preeclampsia in Haiti, in South America, in the U.K., in Japan?” Like Hod, she notes that SPREE testing might work well in high-income countries with easy access to ultrasound and blood tests, but would likely be unavailable in poorer countries, where some prenatal clinics do not even own a blood pressure monitor. This lends support to Hod’s belief that a “one-stop shop,” first-trimester molecular test that can be done with a portable device is needed.
Any kind of first-trimester test sounds appealing to Torres, the woman with preeclampsia who gave birth to twins. Babies delivered prematurely as a result of preeclampsia often suffer lifelong problems, such as cerebral palsy, epilepsy, blindness, deafness and learning disorders. Torres’s girls, who are now 10 years old, experience minor but lingering effects of their premature birth: difficulties with fine motor skills and ongoing challenges with riding scooters and bicycles or playing softball, which emerged around their 7th birthdays. “I do still struggle with the after-effects of their prematurity,” says Torres, who is now the managing editor of Hand to Hold, a nonprofit organization that provides peer support to families with babies in the neonatal intensive care unit. “It’s very difficult to get over that, and say, ‘none of this would have happened if I hadn’t delivered early.’”