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Three-Year FNIH-Led Study Could Clear a Path for Earlier Preeclampsia Tests in the US


NEW YORK – Rising numbers of preeclampsia cases are contributing to an already alarming rate of maternal deaths in the US, and a public-private coalition will study biomarkers that could be used to help determine earlier who is at high risk of the pregnancy-related hypertensive condition as well as support research into new treatments.

The Foundation for the National Institutes of Health (FNIH) said earlier this month it was partnering with eight other organizations on a three-year project to evaluate the prognostic value of placental growth factor (PlGF) and pregnancy-associated plasma protein-A (PAPP-A) as biomarkers of preeclampsia risk during the first trimester of pregnancy. The organizations will evaluate in the project more than 25,000 banked blood samples and patient data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, which will provide samples from patients who are representative of the ethnic and racial diversity of North America.

Tania Kamphaus, director of metabolic disorders for the FNIH, said that the FNIH-led project is intended to generate evidence to support use of the biomarkers in the US for earlier detection and management of preeclampsia as well as to help secure US Food and Drug Administration biomarker qualification, which would allow use of those tests in clinical trials for preeclampsia treatments. Tests sold in the EU already measure for PlGF and PAPP-A to aid the detection and management of preeclampsia, she noted.

If the biomarkers gain FDA qualification or the study at least generates evidence supporting their use, the hope is that "companies that have assets to treat preeclampsia can start thinking about designing clinical trials."

She also hopes the evidence will be used to develop policies and protocols that could improve management of patients who are at elevated risk. Those considered to be at high risk today often are prescribed daily low-dose aspirin to delay or prevent the onset of preeclampsia.

One project participant is Cedars-Sinai in Los Angeles, whose researchers will be testing patient samples. Its chair of the department of obstetrics and gynecology, Sarah Kilpatrick, said the study could give healthcare providers the tools to identify months earlier which patients are at high risk of developing preeclampsia.

"We really don't have anything that we use now in the US to predict with a high degree of accuracy whether someone will go on to develop preeclampsia," she said.

In the near term, identifying those high-risk patients could aid in patient management through biomarker-based testing. Longer term, it could identify patients who may benefit from treatments to reduce or eliminate the effects of the disease, Kilpatrick said. That management can include hospitalization and decisions when to deliver the baby to avoid progression of the condition and worse outcomes.

Preeclampsia is one of the top three causes of maternal death globally, and the only cure is delivery of the baby and removal of the placenta, Kilpatrick said.

She added that supporting the development of diagnostic tests is the quicker and easier of the project's two goals, although supporting therapy development is the primary goal. She said a first-trimester prognostic test could help healthcare providers focus their attention on a smaller group of patients who are the most likely to develop the disease compared to the broader number today who are identified by risk factors such as advanced maternal age, patient history, and reported race or ethnicity.

According to the US Centers for Disease Control and Prevention, preeclampsia occurs in about 5 percent to 7 percent of all pregnancies. However, the rate of preeclampsia is about 60 percent higher among Black women than in white women, and Black women are more likely to have preeclampsia that results in kidney damage or death.

Telle Ukonaho, global business development manager for Revvity, a participant in the FNIH study, said that since 2009, the company has sold CE-IVD marked PlGF assays that are used outside the US to aid the identification of preeclampsia.

The firm, then called PerkinElmer, launched its Delfia Xpress PlGF Assay in 2010 outside the US and Canada to stratify patients by risk of preeclampsia during the first trimester of pregnancy. The automated immunoassay is designed for use with the company's Delfia Xpress tabletop instrument.

Those tests are often used to screen women who are considered at elevated risk based on demographic or clinical information, Ukonaho said. Applying in the US the tests that are available in Europe could lead to healthier pregnancies and more babies delivered at full term, which would have immediate and long-term consequences for both the mother and the fetus. Even treatment using the current standard of daily low-dose aspirin can reduce high-risk preeclampsia cases by 80 percent, she said.

Thermo Fisher Scientific, which is also taking part in the project, received FDA clearance in May 2023 for a pair of immunoassays for PlGF and soluble fms-like tyrosine kinase 1 (SFlt-1) that are used in combination to assess the risk of developing preeclampsia. Those assays are used with other lab tests and clinical assessments to determine whether pregnant patients who have been hospitalized for hypertensive disorders of pregnancy are at risk of progressing to preeclampsia within the following two weeks.

Kamphaus said that test is useful for differentiating in pregnant patients between hypertension and preeclampsia, typically during the second trimester, but it is not an early detection test.

"As you can imagine, that's already a population that has gone to the hospital, has been treated," she said.

Thermo Fisher also offers a pair of blood-based assays for the PlGF and PAPP-A biomarkers, and those assays have been available for preeclampsia screening in Europe for about a decade. According to Sascha Johannes, director of US medical affairs for the company, the test results help to improve the management of preeclampsia through screening during the first trimester in weeks 11 to 14 of gestation, although how widely the tests are used varies by country. The firm also sells in the EU biomarker-based tests that are used to differentiate chronic hypertension from preeclampsia.

The PlGF and PAPP-A tests are for use with Thermo Fisher's Brahms Kryptor analyzers, and results are used along with clinical risk factors such as the blood pressure, age, and weight of the patient to calculate the risk of developing preeclampsia.

"At the moment, there is no cure for preeclampsia, so whenever it does happen, the physicians are usually fighting to keep the mother pregnant as long as possible," Johannes said.

Clinicians decide how early to deliver the baby to prevent further organ damage to the mother that results from high blood pressure, he said. However, earlier delivery raises the risk of adverse outcomes for the fetus.

The FNIH-led project could generate the evidence needed to help bring those tests to the US, although they would be backed by algorithms specific to US demographics. Whether Thermo Fisher will be able to support qualification using its evidence gathered in Europe remains under discussion with FDA officials, Johannes said, but he thinks the current three-year retrospective study will generate data that will demonstrate the safety and effectiveness of the biomarker-based testing.

"If you ask me, 'Is there already sufficient data to say it would work in the US?' My answer is 'yes,' but we know we live in a world where we have to prove it," he said. "That's why this FNIH project is going to be very helpful, to make sure we are providing the necessary proof in general to providers, to the medical community, as well as to regulators."