Two key biomarkers could signal early risk for ‘two-person disease’ of preeclampsia
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Key takeaways:
- A new initiative will test novel biomarkers that could predict early-onset preeclampsia.
- The study could lead to qualified FDA biomarkers that could be used for clinical trials.
Preeclampsia remains a leading cause of maternal death and a significant cause of maternal and offspring morbidity, yet effective methods to diagnose preeclampsia early in pregnancy and potentially prevent those outcomes are lacking.
Biomarkers that can detect preeclampsia early could enable interventions that delay the onset of disease, especially its most damaging form, early-onset preeclampsia. The Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium recently announced the launch of a new initiative to identify biomarkers that predict when women are at high risk for developing early-onset preeclampsia. The 3-year project, a collaboration with the NIH and eight other partners including life sciences companies, academia, and nonprofit and patient advocacy organizations, will evaluate the predictive value of two circulating biomarkers — placental growth factors (PGIF) and pregnancy-associated plasma protein-A (PAPP-A) — during the first trimester of pregnancy.
If the program meets its goals, mothers and their newborns will have better outcomes and researchers will have greater opportunities to study preeclampsia and develop new therapies, according to Tania Kamphaus, PhD, MSc, director of metabolic disorders at the FNIH.
Kamphaus said the FNIH project marks the first public-private partnership in the United States to detect biomarkers of early-onset preeclampsia. Despite the availability of point-of-care testing of these two biomarkers in Europe, they have never been tested on populations reflective of the U.S.
Healio spoke with Kamphaus about the risks for preeclampsia, the need for early diagnosis, and how new biomarkers could lead to more clinical trials that include pregnant participants.
Healio: What is the prevalence of preeclampsia, and what are the consequences of preeclampsia?
Kamphaus: More than 70,000 women and 500,000 newborns die each year from preeclampsia worldwide. In the United States, preeclampsia can only be diagnosed clinically, often late in the process after organ damage has already occurred and premature delivery may be required. Currently, preeclampsia risk is determined early in pregnancy using a combination of maternal medical history and clinical risk factors.
Preeclampsia in many circles is thought of as a rare disease, especially early-onset preeclampsia. Preeclampsia occurs in about one in 25 pregnancies in the United States, according to the CDC, and frequently during a first pregnancy. If a person develops preeclampsia during the first pregnancy, the likelihood of it occurring in subsequent pregnancies is much higher.
Preeclampsia in general is difficult because it is a metabolic issue. Both the mother and fetus are dealing with the effects of increased blood pressure, so it is a two-person disease. Once a child is delivered, those effects continue to linger for the first year of a child’s life. Extra care and support may be needed if the baby was delivered prematurely or experienced intrauterine growth restriction.
What we do not talk about often is the routine strain on the mother’s body and her high risk for conditions like stroke. If a person knows they have preeclampsia, there is education about the long-term CV and metabolic challenges, and there may be more ways we can tend to and address those. But you would not, for example, prescribe a young woman of childbearing age a statin for a long time, because that is not how we typically treat. Knowledge and understanding of what preeclampsia can do during and after pregnancy and birth is critical.
Healio: How does preeclampsia impact people of different racial backgrounds?
Kamphaus: As with many conditions in the U.S. and globally, preeclampsia disproportionately kills people of color. This could be a health care access issue, but also because the disease does not present with symptoms early on. At least three times as many women of color die of preeclampsia than white women. The actual incidence and mortality from preeclampsia is high globally. Our hope is that if we can look at a racially and ethnically diverse population in the United States and establish a way to help with early detection as well as spur innovation in clinical trials for pregnant people, those things will have long-reaching impacts downstream on a global scale.
Healio: When is preeclampsia typically identified in a pregnancy, and what are the advantages of earlier detection?
Kamphaus: For most people, preeclampsia is detected at an OB visit during the second or third trimester of pregnancy. The woman might report symptoms such as swelling or have high BP. The clinician may decide to check their urine for proteinuria, a sign of kidney malfunction. If the patient has hypertension plus proteinuria and some other clinical factors, the clinician may admit the person for observation.
There are a few nuances. First, preeclampsia is always detected during the second or third trimester, which is almost always after the organ damage has happened. A person can have hypertension without preeclampsia. Differentiating those two is another challenge for physicians. The care of that person and the quality of care for that person becomes critically important.
This new biomarkers initiative will study the predictive value of two circulating biomarkers — PIGF and PAPP-A — during the first trimester of pregnancy. The two proteins we are looking at are detected only in pregnant people. If a person has them, and we know the healthy threshold and you can detect them as early as first trimester, that is an early detection module we can now deploy. We still have to confirm this, but it has been confirmed in some European countries, that a lower threshold of the PIGF and PAPP-A are correlated with early-onset preeclampsia.
I will repeat this because we use the word “early “ twice, and that can be confusing. We want early detection of early-onset preeclampsia. It would be great to have early detection of late-onset preeclampsia as well, but early-onset preeclampsia has more serious consequences and is defined as less than 34 weeks gestation. We are also trying in the same study to see if we can use early detection for term preeclampsia or late-onset preeclampsia.
There are other ways to measure preeclampsia. The goal is to get these two biomarkers qualified by FDA. If they are qualified by FDA, then those data can be used for a risk-benefit assessment in a clinical trial. During the 12th or 13th week of pregnancy, a person undergoes the test. If they have a high risk for developing early-onset preeclampsia, they may opt to enroll in a trial for a drug that can treat it. That was the other key goal of this project.
Healio: Can you briefly describe how this new biomarkers initiative will work?
Kamphaus: The project will use patient data and banked samples from more than 25,000 pregnancies representative of the ethnic and racial diversity found within the North American population.
At the Foundation for NIH, we build public-private partnerships. We partner with NIH and FDA when warranted and partner with companies invested in the space. This can be companies with assets they are trying to bring forward and biomarker developers. This is a core group of people who come together along with key opinion leaders in the space. Early detection has the enormous value of leading to better care that can improve a person’s gestation window significantly. Even something like aspirin, which is inexpensive and easily available, can improve pregnancy outcomes for people at risk of preeclampsia.
We were troubled by how little innovation is happening in medicine that will take care of diseases of maternity. Most clinical trials exclude pregnant and lactating people. We are trying to find a way that trials can be more inclusive. There are ethical issues, of course, when there is a developing fetus. How do you manage the risk-benefit ratio? If there is a way to detect whether there is a high chance that you will develop this disease, the likelihood that one can have a small study to see the effect of a therapy or an intervention improve. We hope that spurs innovation in the field. We need strategies for how to bring innovations to people.
Through our NIH partner, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD),we had access to several cohorts of people with preeclampsia. We have banked first-trimester blood samples from all of the patients and we know whether they have early- or late-onset preeclampsia or a healthy birth.
All blood samples will go to a lab at Cedars-Sinai where we will run the tests across the two platforms that our partners have donated in kind. We are going to combine the biomarker information from those tests.
Healio: What are the next steps in this research?
Kamphaus: We have a small pilot study underway that will take about 4 to 6 months. After that, all the data will go to a data coordinating center and all samples will go to Cedars-Sinai. We expect a 1-year run time for everything. This is about a 2-to-3-year project. Because we already have the samples, it is a matter of how much time it takes to go through all of the data and conduct the analyses.
At the conclusion of the study, the project team will submit a letter of intent to the FDA biomarker qualification program, an important step toward obtaining regulatory approval from the FDA for further use of these biomarkers. With FDA approval, the biomarkers may help identify pregnant individuals at risk for developing early-onset preeclampsia, and potentially inform decision-making about the use of therapeutic interventions and facilitate enrollment in clinical trials for future treatments.
Because this is a fast-moving project, results should be coming quickly. We could use help getting the world to understand that things need to happen in this space.
Reference:
FNIH. Biomarkers consortium — Biomarkers for risk stratification and early detection of preeclampsia. Available at: https://fnih.org/our-programs/biomarkers-for-risk-stratification-and-detection-of-early-onset-preeclampsia/. Accessed March 20, 2024.
For more information:
Tania Kamphaus, PhD, MSc, can be reached at tkamphaus@fnih.org; X (Twitter): @FNIH_Org.
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