Newborn screening programs are public health services aimed at ensuring that the close to 4 million infants born each year in the United States are screened for certain serious disorders at birth. These disorders, albeit rare, are detected in roughly 12,500 newborn babies every year.
Newborn screening isn’t new, although it has expanded and transformed over the decades. The first newborn screening test was developed in the 1960s to detect phenylketonuria (PKU).1 Since then, the number of conditions screened for has increased, with programs in every US state and territory. “Newborn screening is well established now, not experimental or newfangled,” Wendy Chung, MD, PhD, professor of pediatrics, Harvard Medical School, Boston, Massachusetts, told Neurology Reviews.
In newborn screening, blood drawn from the baby’s heel is applied to specialized filter paper, which is then subjected to several analytical methods, including tandem mass spectrometry and molecular analyses to detect biomarkers for the diseases.2 More recently, genomic sequencing is being piloted as part of consented research studies.3
Newborn screening includes not only biochemical and genetic testing, but also includes noninvasive screening for hearing loss or for critical congenital heart disease using pulse oximetry. And newborn screening goes beyond analysis of a single drop of blood. Rather, “it’s an entire system, with the goal of identifying babies with genetic disorders who otherwise have no obvious symptoms,” said Dr. Chung. Left undetected and untreated, these conditions can be associated with serious adverse outcomes and even death.
Dr. Chung described newborn screening as a “one of the most successful public health programs, supporting health equity by screening almost every US baby after birth and then bringing timely treatments when relevant even before the baby develops symptoms of a disorder.” In this way, newborn screening has “saved lives and decreased disease burdens.”
There are at present 38 core conditions that the Department of Health and Human Services (HHS) regards as the most critical to screen for and 26 secondary conditions associated with these core disorders. This is called the Recommended Uniform Screening Panel (RUSP). Guidance regarding the most appropriate application of newborn screening tests, technologies and standards are provided by the Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC).
Each state “independently determines which screening tests are performed and what follow-up is provided.”4 Information about which tests are provided by which states can be found on the “Report Card” of the National Organization for Rare Diseases (NORD).
Challenges in Expanding the Current Newborn Screening
One of the major drawbacks in the current system is that “we don’t screen for enough diseases,” according to Zhanzhi Hu, PhD, of the Department of Systems Biology and the Department of Biomedical Information, Columbia University, New York City. “There are over 10,000 rare genetic diseases, but we’re currently screening for fewer than 100,” he told Neurology Reviews. Although in the United States, there are about 700-800 drugs approved for genetic diseases, “we can’t identify patients with these diseases early enough for the ideal window when treatments are most effective.”
Moreover, it’s a “lengthy process” to add new diseases to RUSP. “New conditions are added at the pace of less than one per year, on average — even for the hundreds of diseases for which there are treatments,” he said. “If we keep going at the current pace, we won’t be able to screen for those diseases for another few hundred years.”
Speeding up the pace of including new diseases in newborn screening is challenging because “we have more diseases than we have development dollars for,” Dr. Hu said. “Big pharmaceutical companies are reluctant to invest in rare diseases because the population is so small and it’s hard and expensive to develop such drugs. So if we can identify patients first, there will be more interest in developing treatments down the road.”
On the other hand, for trials to take place, these babies have to be identified in a timely manner — which requires testing. “Right now, we have a deadlock,” Dr. Hu said. “To nominate a disease, you need an approved treatment. But to get a treatment developed, you need to identify patients suitable for a clinical trial. If you have to wait for the symptoms to show up, the damage has already manifested and is irreversible. Our chance is to recognize the disease before symptom onset and then start treatment. I would call this a ‘chicken-and-egg’ problem.”
Dr. Hu is passionate about expanding newborn screening, and he has a very personal reason. Two of his children have a rare genetic disease. “My younger son, now 13 years old, was diagnosed at a much earlier age than my older son, although he had very few symptoms at the time, because his older brother was known to have the disease. As a result of this, his outcome was much better.” By contrast, Dr. Hu’s oldest son — now age 16 — wasn’t diagnosed until he became symptomatic.
His quest led him to join forces with Dr. Chung in conducting the Genomic Uniform-screening Against Rare Disease in All Newborns (Guardian) study, which screens newborns for more than 450 genetic conditions not currently screened as part of the standard newborn screening. To date, the study — which focuses on babies born in New York City — has screened about 11,000 infants.
“To accumulate enough evidence requires screening at least 100,000 babies because one requirement for nominating a disease for national inclusion in RUSP is an ‘N of 1’ study — meaning, to identify at least one positive patient using the proposed screening method in a prospective study,” Dr. Hu explained. “Most are rare diseases with an incidence rate of around one in 100,000. So getting to that magic number of 100,000 participants should enable us to hit that ‘N of 1’ for most diseases.”
The most challenging part, according to Dr. Hu, is the requirement of a prospective study, which means that you have to conduct a large-scale study enrolling tens of thousands of families and babies. If done for individual diseases (as has been the case in the past), “this is a huge cost and very inefficient.”
In reality, he added, the true incidence of these diseases is unclear. “Incidence rates are based on historical data rather than prospective studies. We’ve already seen some diseases show up more frequently than previously recorded, while others have shown up less frequently.”
For example, in the 11,000 babies screened to date, at least three girls with Rett syndrome have been identified, which is “quite a bit higher” than what has previously been identified in the literature (ie, one in 10,000-12,000 births). “This is a highly unmet need for these families because if you can initiate early treatment — at age 1, or even younger — the outcome will be better.”
He noted that there is at least one clinical trial underway for treating Rett syndrome, which has yielded “promising” data.5 “We’re hoping that by screening for diseases like Rett and identifying patients early, this will go hand-in-hand with clinical drug development. It can speed both the approval of the treatment and the addition to the newborn screening list,” Dr. Hu stated.