CLN - Feature
Preeclampsia is a serious hypertensive disorder in pregnancy that affects an estimated 3.4% of pregnant individuals in the United States. It’s one of the leading causes of maternal and neonatal morbidity and mortality — the cause of about 14% of deaths in pregnant patients and between 10% and 25% of perinatal deaths. Although the underlying cause is still poorly understood, it’s thought to potentially arise because of the placenta not developing properly. Left untreated, the patient can die.
Despite the danger of the condition, determining who is at risk of developing a severe form of preeclampsia has historically proven tricky. The traditional method involves testing a patient for high blood pressure, checking urine protein levels, and looking for neurological problems or signs of kidney dysfunction. “That paradigm has existed for the last hundred years,” said Ananth Karumanchi, MD, professor of medicine at Cedars-Sinai Medical Center. “The problem is that those are fairly nonspecific.” Headaches could be explained away by migraine disorder; high blood pressure could be from kidney disease.
The broadness of the clinical criteria means that some cases may be classified as preeclampsia unnecessarily. “It is clear that we need additional methods of prevention, monitoring, and treatment for patients experiencing serious hypertensive disorders like preeclampsia,” said Christopher Zahn, MD, chief of clinical practice and health equity and quality at the American College of Obstetricians and Gynecologists (ACOG).
Now, guidelines on how to use a new blood test that aims to help streamline the clinical decision-making process have been published by the organization; in June 2024, ACOG released a new clinical practice update on sFlt-1:PlGF ratio testing for preeclampsia.
According to clinical research outside of ACOG's guidance, 9 times out of 10, the test can correctly determine which pregnant individuals hospitalized for hypertensive disorders are at risk for progression to a severe form of preeclampsia. A positive result may indicate that severe preeclampsia could develop within the next 2 weeks, and that those patients need to be monitored closely in case their babies need to be delivered early. Those who test negative can be expectantly managed, which means the pregnancy can be prolonged safely and the baby delivered at a later point in pregnancy when the complications related to prematurity are lower. Altogether, this means that use of the test could enable hospitals to better prioritize treatment for those most in need.
However, some laboratory medicine experts still harbor doubts about the clinical utility of sFlt-1:PlGF ratio testing, and challenges remain that must be overcome before the test can be widely implemented across the U.S.
Is it really ready for prime time?
The biomarker assay works by measuring the ratio of two placental proteins in maternal serum: soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF). This is based on the idea that, when placentation is abnormal, levels of sFlt-1 and PlGF are altered.
In 2023, Thermo Fisher Scientific became the first company to receive Food and Drug Administration (FDA) marketing approval for the test in the U.S. ACOG’s new guidelines recommend the use of the ratio be limited only to patients who meet the inclusion criteria that were described in the PRAECIS trial; that is, the test should not be used in asymptomatic, nonhospitalized individuals at less than 23 weeks or more than 35 weeks of gestation and in postpartum individuals. The PRAECIS clinical trial, for which Karumanchi was a co-author, included more than 1,000 pregnant women who were between 23 and 35 weeks along at 18 U.S. medical centers from 2019 to 2021. The aim was to identify and validate a sFlt-1:PlGF ratio that could be used to stratify the short-term risk of developing preeclampsia with severe features in pregnant individuals with hypertension who were hospitalized in late pregnancy.
Not everyone is convinced of the efficacy and utility of the test, however. For Ann Gronowski, PhD, a professor of pathology and immunology, and obstetrics and gynecology at Washington University School of Medicine in St. Louis, the test doesn’t have the positive predictive value — the measure of how often someone who tests positive for disease actually has disease — that it needs to be useful. “There’s insufficient data to recommend management strategies after a positive or negative,” she said. “So why do we do a test where it’s not going to change our management?”
Indeed, Zahn said that the organization recommends that “the sFlT-1:PlGF ratio alone should not replace current clinical criteria for diagnosing or excluding a diagnosis of preeclampsia with severe features.” Instead, it should serve as a complementary risk-stratification test that will add to the diagnostic work-up.
For other lab professionals, Gronowski urges her peers to exercise caution. “I certainly hope that other laboratorians have the same reservations, because I feel like it is our job to think critically about test utility.” What Gronowski would like to see are studies that investigate how the use of the test affects outcomes. She admits that in certain populations, it could turn out to be really high-performing. “Then the proof will be in the pudding,” she said. “In my personal opinion, I don’t think this is ready for prime time, but I would be delighted if I’m proven wrong.”
“I would use caution and think about, for this population, what do we need? What is the ideal test? What kind of positive predictive value do we need? And I would argue that I don’t think this test is delivering the positive predictive value that we need for the population in which its use is currently recommended,” she said.
Also, there is still no effective treatment for preeclampsia other than delivering the baby. However, Karumanchi said that this test may help to develop therapeutics down the line by enabling clinical trials to focus on patients at the greatest risk for adverse outcomes. Gronowski agreed that it perhaps “could be used to stratify patients when we’re going to test treatments for preeclampsia.”
Expanding the test’s usage
The need for the test — and better therapeutic interventions — is reinforced by the fact that rates of preterm birth are on the rise in the U.S. Preterm birth can have long-term negative developmental effects for the baby, and experts believe preeclampsia is one of many factors contributing to its uptick. Driven by a rise in obesity, the incidence of preeclampsia almost doubled in the U.S. from 2007 to 2019. Even more concerning is the fact that preeclampsia disproportionately affects Black pregnant patients and is the top cause of maternal mortality among Black people, who are three times more likely to die from pregnancy-related causes than White people.
The sFlT-1:PlGF ratio could potentially help with all of this, but despite having FDA approval for over a year, the test is still not as widely used as it could be, Karumanchi said. This may be because the instrument that the FDA-approved test runs on is not available in all hospitals. The assay is designed to run on Thermo Fisher’s Brahms Kryptor Compact Plus clinical analyzer; however, many labs do not possess this technology as of yet. In Karumanchi’s hospital, where they do have this platform, they can turn around the test results in an hour. However, some hospitals are sending the test to a reference lab, which takes as long as 48 hours to get a result. “It might still be useful in many of the cases, but if a patient was really sick, 48 hours is too late,” he said.
It’s worth noting that sFlT-1:PlGF ratio testing is already widely used in the U.K. and Europe, and has been for many years. Karumanchi said that the U.S. should look across the Atlantic to see how the use of the test has evolved in the past decade or so.
Sofia Cerdeira, MD, PhD, an academic clinical lecturer in women’s health at the University of Oxford who researches preeclampsia, has seen firsthand how the test is being used in the U.K. and Europe. She thinks the test is a “game-changer” for preeclampsia, though she does echo others’ words of caution that it is important that clinical decisions aren’t based on the test alone. Rather, the test’s results should be incorporated with the rest of the patient’s clinical signs and symptoms.
But in her opinion, it’s the negative predictive value — the likelihood that a person who has a negative test result does not have preeclampsia — that is where the real benefit lies. “For the first time, we have a biomarker that can help you to tell who is not going to develop the disease with a negative predictive value of 99.3%.” That means you can reassure that patient in the next week with over 99% accuracy they are not going to develop the condition. "We have witnessed an exponential adoption of this test in maternity centers and most of our clinicians are now familiar with its use."
Grace Browne is a freelance journalist who lives in London. She currently has a fellowship funded by the International Center for Journalists through the Health Innovation call. +Email: [email protected]
Read the full November/December 2024 CLN issue here.