Polygenic Risk Scores: New Frontier in IVF or Just a Hype?

Couples undergoing in vitro fertilization (IVF) are presented with a dizzying number of choices as they navigate the process — from selecting a retrieval method to selecting the sex of their fetus. Now, add one more choice: Using polygenic risk scores (PRS) to screen embryos for potential health risks like diabetes, cardiovascular disease, and certain cancers.

Choosing to undergo the genetic screening reflects growing interest among future parents interested in the possibility of giving their future child the healthiest start in life. Indeed, nearly three quarters of US adults support using PRS to screen embryos during IVF, according to a study published recently in JAMA Network Open.

However, mounting research suggests this test does not offer consistently accurate predictions, raising concerns about the clinical and ethical implications of the emerging reproductive technology.

Scientists calculate PRS by analyzing the number of risk increasing and decreasing variants in an embryo biopsy to measure the chance of developing a particular disease. The scores are presented as a percentile comparing the embryo to an average person’s risk of developing conditions such as schizophrenia, asthma, and inflammatory bowel disease.

The technology has shown some predictive power for assessing risk for similar conditions among adults. Commercial labs in the United States have offered PRS since 2019.

But the screening has shown limited clinical benefit for preimplanted embryos, according to multiple studies, including research presented at the annual conference of the European Society of Human Genetics in Berlin.

Shinichi Namba, PhD, an assistant professor in the Department of Genomic Information at the University of Tokyo in Tokyo, and his colleagues used large-scale simulations and data to construct a screening tool for predicting adult height and the risk of developing type 2 diabetes.

“Our results were so conclusive that we can confidently say PRS scores in embryos are currently worthless,” Namba told Medscape Medical News. “There is no point in further research until the technology improves significantly.”

Many US-based physician groups recommend against the screening.

“At this time, there is insufficient evidence for the clinical utility of PRS testing for embryo selection,” reads a February 2024 position statement from the American College of Medical Genetics (ACMG). “It should not be offered as a clinical service.”

But companies that offer the screening say that the data acquired from the screenings can offer valuable and validated insights to help patients select healthy embryos.

In response to criticism of PRS, Jennifer Eccles, director of clinical genetics at LifeView, which offers genetic testing, said the technology is not designed to determine whether an embryo has a particular disease.

Instead, the screening tool measures which embryo has the lowest risk of developing a chronic condition relative to the other embryos and relative to the average risk for a person, Eccles said. LifeView partners with over 100 fertility clinics in the United States to provide PRS services.

“[Risk reduction is] a measurable number, and that is something we can calculate, validate, and publish,” Eccles, who is also a genetic counselor, said. “This is a screening tool, not a diagnostic test. We’re still exploring how it’s used clinically, but we know mathematically this test works.”

Still, a significant concern of using PRS is that parents might overlook healthy, viable embryos due to predicted risks, even if those risks are minimal, according to Jason Flanagan, a spokesperson for the National Society of Genetic Counselors (NSGC), which is not affiliated with LifeView.

“For example, if one embryo has a 0.5% increased risk for diabetes, is that a reason not to use the embryo?” he said.

Flanagan, who is also a genetic counselor at Sanford Fertility & Reproductive Medicine in Sioux Falls, South Dakota, said the technology “isn’t ready for prime time; so until it becomes more standard and accessible, our clinic won’t be offering it to patients.”

NSGC maintains that the “evidence gaps” and “critical limitations of this technology” may not make it appropriate yet for widespread use, according to the group’s practice resource guide.

Namba from the University of Japan said private companies that market embryo screenings to prospective parents “should clearly state the limitations and acknowledge the inaccuracy and inconsistency of the results. Even if the technology improves, a society-wide debate is needed before making it widely available.”

Still a Niche Service

Still, most IVF patients are focused on overcoming infertility and are not concerned with genetic predictions, Flanagan said. For instance, many patients do not want to conduct other, more reliable testing “for known genetic diseases that we can prevent,” he said.

IVF patients also may not know about PRS.

“In my busy clinical practice, which includes a lot of patients undergoing IVF, I have not had one patient ask for PRS,” said Susan D. Klugman, MD, president of the ACMG and director of Reproductive and Medical Genetics in the Department of Obstetrics & Gynecology and Women’s Health at Albert Einstein College of Medicine in New York City. “Its use is limited in that it only accounts for the possible heritability of disease and not environmental or other lifestyle factors.”

However, Nathan Treff, PhD, co-founder and chief science officer of Genomic Prediction, the parent company of LifeView, said patients may not know about the test because many clinicians are reluctant to introduce the option.

“It’s a problem that many patients aren’t aware of it,” Treff said. “There is a risk with all of these negative opinions with patients who may benefit from the test not even being informed about the availability of testing.”

Eccles said the scrutiny of PRS is similar to other genetic screenings during early iterations, such as Preimplantation Genetic Testing for Aneuploidy. This test, which is now routinely offered, looks at the number of chromosomes of an embryo to detect abnormalities in a fetus.

“These tests are always introduced before the medical community knows what to do about it,” Eccles said. “We’re in that period now with PRS.”

If clinicians do offer the service, they should work with genetic counselors to communicate with patients the reliability and risks for the test, “given the absence of regulation and the recent commercial availability of the test,” Namba and his colleagues wrote.

LifeView requires pretest genetic counseling for anyone considering screening, Eccles said. Genetic counselors discuss how the test works, its limitations, and how to understand the results, she said.

After undergoing the test, the clinician and patient ultimately decide how the results might influence their embryo choice, Eccles said. LifeView does not provide a genetic counselor to discuss results afterward.

However, Flanagan said PRS information should be accompanied by thorough genetic counseling before and after receiving the results to help couples make informed decisions.

“Information by itself isn’t harmful; it is how we interpret or respond to it that can cause harm or anxiety,” he said. “With appropriate counseling, this information could inform a couple in such a way that they transfer the embryo with the healthiest potential.”

Lara Salahi is a freelance reporter living in the Boston area.

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