by Melanie Padgett Powers, writer
Four-year-old Fitz Kettler pulls his stepstool up to the kitchen counter, eager to help his mom stir the cupcake batter.
“He really likes to help with the baking because he knows there will be a blueberry muffin or a cupcake that he can eat afterward,” mom Christina Kettler said. One day she came into the kitchen to find her sweet boy using his cutting board and toddler-safe knife to cut up watermelon into tiny cubes for his baby sister, Zoe. Fitz is a healthy and happy child, but these family scenes were not a given four years ago.
When Fitz was born in June 2019 via donor egg in vitro fertilization (IVF), his newborn screening (NBS) results were indicative of an immune deficiency, which would make him highly vulnerable to infection and illness. He was placed in a sterile room at Rady Children’s Hospital in San Diego, and whole genome sequencing confirmed he had a form of severe combined immunodeficiency (SCID), a rare disease more commonly known as “bubble boy disease.” Specifically, Fitz had Artemis SCID, a severe form of primary immunodeficiency caused by mutations in the DCLRE1C gene. The Kettlers were told their baby likely wouldn’t live to see his first birthday.
Then Fitz was able to get into a gene therapy trial at University of California, San Francisco, that was accepting kids with Artemis SCID. His stem cells were harvested, and a healthy copy of the DCLRE1C gene was introduced. In the laboratory, his stem cells began making healthy new cells. At two months old, Fitz was given the healthy cells via an infusion into his port in just 15 minutes. It worked. Fitz is now a regular preschooler with a strong immune system. He’s been sick a few times, including with asymptomatic COVID-19, but he recovered like any healthy kid. He’s up to date on his vaccines, including live vaccines for chickenpox, COVID-19, and measles, mumps and rubella.
The Start of NBS
The United States NBS program—which has improved and saved countless lives—celebrates its 60th anniversary in 2023. All 50 US states, as well as Puerto Rico and Washington, DC, have NBS programs.
“Newborn screening has impacted hundreds of thousands of families in the developed world,” said Dianne Webster, PhD, vice president of the International Society for Newborn Screening. “It’s saving money and time and grief and giving people better lives. There’s absolutely no question about that.”
In the US, NBS starts in the hospital with a simple heel prick to gather a few drops of blood when a baby is one to two days old. (A hearing test and heart screening are also conducted.) Public health laboratory professionals are typically the next step in this critical public health program, screening almost four million babies in the US each year to uncover rare but serious, treatable disorders.
“I want to say it changed our life,” Kettler said, “but it’s actually the very first thing that gave Fitz his life. … I’m just forever grateful to everyone involved over the decades to have newborn screening.”
NBS was created in 1963, after Robert Guthrie, MD, PhD, developed a blood test to screen for phenylketonuria (PKU) in New York. His successful pilot studies led other states to begin screening newborns. By the mid-1960s, almost every state was screening for PKU. Screening soon followed for congenital hypothyroidism, other inborn errors of metabolism, and hemoglobinopathies, including sickle cell disease. Now, each US NBS program screens for at least 31 disorders, according to the APHL Newborn Screening Technical assistance and Evaluation Program (NewSTEPs). The federal Recommended Uniform Screening Panel (RUSP) recommends that all newborns be screened for 37 core disorders and 26 secondary disorders. APHL plays an important role in the nationwide program, hosting both hands-on trainings in the laboratory and didactic webinars and conference sessions. APHL hosts a Newborn Screening Symposium every fall, provides resources online, monitors state and federal legislation, and supports global initiatives to expand NBS.
Over the past 60 years, the technology behind NBS has advanced tremendously. Public health laboratory professionals and NBS experts point to several milestones that launched the program forward. But, among all the successes, there have been challenges—many of which remain today.
NBS Leaps Forward
Bradford L. Therrell, MS, PhD, MD (hon), remembers screening for only PKU in the mid-1970s and keeping manual records. Therrell is director of the US National Newborn Screening and Global Resource Center and professor (ret.) at the University of Texas Health Science Center at San Antonio. He credits the invention of the punch index machine for improving NBS efficiency in the 1970s. He vividly remembers inventor Robert Phillips demonstrating his punch index machine at a conference in 1975. The machine could punch four holes—with the right size and number needed for consistent, quality testing—in the filter paper used in the screening test.
Before that, for each test, laboratory workers had “to do the same thing over and over and over with a simple hand punch, like what’s used to punch holes in notebook paper, so preparing samples for testing was very expensive and time consuming,” Therrell said. But the punch machine allowed “you to punch four samples, or multiples of four, for the same amount of energy that you needed to prepare a single sample,” he explained. “That was a very important accomplishment in newborn screening, and it really moved things along.”
As for the data itself, microcomputers became available at about the same time. It can be easy today to underestimate the massive advancement and ubiquitousness of computers. Before the late-1970s, laboratories were forced to collect data by hand. Then, thanks to powerful microprocessors that shrunk the size of computers, microcomputers became available. Before that, computers were huge, expensive machines that few could afford.
“We were able to utilize micro computerization, and computerization in general, to handle the data in the newborn screening laboratory program and to handle the follow-up information,” Therrell said. “So, we went from hand-recording all of this information to computer-recording it, and it changed everything, especially in the larger screening programs.”
The next leap forward came with the invention of tandem mass spectrometry for chemical analysis. “It was a major shift in the science and technology of newborn screening because it allowed a laboratory to screen for an entire group of disorders from a single specimen punch,” said Guisou Zarbalian, MS, MPH, manager of Newborn Screening and Genetics at APHL.
Tandem mass spectrometry “revolutionized” NBS, said Susan Berry, MD, professor of genetics and metabolism in the Department of Pediatrics at University of Minnesota. “That was a big, big change, and newborn screening went from many states doing five or six tests to most states, with time, doing … in the 20s to 30s, or sometimes even more testing.”
After tandem mass spectrometry allowed for more efficient screening, there was a call for a uniform screening panel. “Prior to the initiation of the RUSP, it was a terrible Wild, Wild West,” Berry said. “Some states did lots of screening and some did little. The general sense of the Recommended Uniform Screening Panel was that we wanted to try to be as fair as we could for everybody so that all kids could be screened uniformly.”
In 2002, the federal Health Resources and Services Administration’s (HRSA) Maternal and Child Health Bureau asked the American College of Medical Genetics (ACMG) to develop guidelines for newborn screening. According to NIH, ACMG considered 81 conditions, ultimately placing 29 of them in a core screening panel. This became the RUSP. In 2003, the Advisory Committee on Heritable Disorders in Newborns and Children was formed to advise the secretary of the US Department of Health and Human Services (HHS). In 2005, that committee recommended a panel of conditions to the HHS secretary as the nation’s RUSP. It was adopted in May 2010 with the addition of SCID, according to NIH.
Ongoing NBS Challenges
Diseases and conditions are added to the RUSP based on evidence that supports the potential net benefit of screening, the ability of states to screen for the disorder and the availability of effective treatments, according to HRSA. That third part—the availability of effective treatments—has become one of the challenges of NBS, leading to passionate arguments and both philosophical and real-world debates among parents, disease advocacy groups, researchers and public health professionals.
Berry points to the example of Krabbe disease, a rare genetic condition with no direct treatment and no cure. Babies diagnosed with Krabbe disease progressively get worse and often die before age 2. However, some states have included Krabbe disease as part of their NBS panel. Usually, the argument for adding it to a panel, Berry said, is that you can do a bone marrow transplant, if you start that transplant very early in life.
“The problem is it’s very difficult to accomplish that,” she said. “And there’s very poor evidence that it really makes a big difference other than prolonging life. So, it’s very, very controversial among the newborn screening community.”
At its February 2023 meeting, the Advisory Committee on Heritable Disorders in Newborns and Children decided not to recommend adding Krabbe disease to the RUSP. It was a tie vote, and the committee requested a scientific review of the evidence and more discussion with the nominating group, Hunter’s Hope Foundation, which aims to support research and increase awareness of Krabbe disease and related leukodystrophies.
As a part of these debates, Berry said the community needs to ask, and think back, to the purpose of NBS. Is the purpose to detect all disorders in children? “That’s very different than the original objective of newborn screening, which was to do early detection so you could change outcomes because of early treatment,” she said.
Berry said some argue that NBS is the best—and perhaps only time—to find out this genetic information so we should screen for more diseases, which can help the scientific community learn more about these rare diseases. Others worry that that will dilute the original purpose of NBS, which could make parents reluctant to screen their baby.
“There’s a lot of philosophic debate about where NBS should go, and there are reasonable arguments on both sides,” Berry said.
How different programs count tests also invites reflection and scrutiny. When screening for hemoglobinopathies, for example, one state might count hemoglobinopathies as a single test, while another might count possible detection of each individual hemoglobin variant as a test, which leads to a larger number depending on how the analysis is run. A third state might count hemoglobinopathies as three tests because the RUSP lists three hemoglobin conditions or the state determines there to be only three clinically significant sickle hemoglobinopathies, Therrell explained.
The lack of standardization among how the states count the tests in their panel affects public perception, he said. States already have discrepancies in the number of actual tests included in their panels, but the counting issue confuses the matter even more. Both the general public and legislators “perceive that because you’ve got a larger number out there, you’re doing better than everybody else,” he said. An APHL task force is studying this issue.
A Look at Outcomes and Privacy
A gap in the NBS system is the lack of data about long-term outcomes, Berry said. In short, does NBS work? “We know bits and pieces of it, and we know a lot of anecdotes, but no one has ever gone back for almost any disorder … to study long-term outcomes.”
Her state of Minnesota has been using tandem mass spectrometry since 2001, which means there are young adults who were diagnosed with a rare genetic disease because of NBS. “No one’s systematically going back to those adults and saying, ‘how you doing?’ I think that’s a shame. The promise of newborn screening was that we’d have improved outcomes and people would live better lives, and we honestly don’t know if they do.”
A large ongoing discussion is about privacy. Some states store dried blood spots for years, using them for quality control, research and implementation of new screening tests. However, lawsuits have challenged the storage and use of dried blood spots, primarily because DNA can be extracted from them. In one New Jersey case, law enforcement used an infant’s dried blood spots to identify a criminal suspect related to that child. In a Michigan lawsuit, lawyers argued that the existing consent form—which is required from parents before their baby’s blood can be used for research—was vague and that parents were not sure what they actually signed.
“There’s a tug of war between advocates who have interest in a specific disorder and advocates who are pushing for genetic privacy and have concerns about security of data and sometimes even how newborn screening is conducted,” Zarbalian said. “Some families feel really uncomfortable with the state obtaining a child’s blood and storing it and using it for different processes that are necessary to operate a newborn screening program.”
Furthermore, there has been increased public scrutiny of public health programs in recent years. “Building the public’s trust and support for newborn screening is key to the success of the program,” said Richard Olney, MD, MPH, Genetic Disease Screening Program division chief for the California Department of Public Health. “The newborn screening community must be vigilant in continuing to educate providers and new parents about the value of this important public health screening program. This education includes challenging discussions about newborn screening research that incorporates ethical principles while remaining equitable and representative of the entire state’s population.”
Education of NBS in general is an ongoing issue. Do parents really know what the heel prick is for and what the results mean? Although most parents won’t think twice about it, for those 12,000 families who get a phone call informing them their baby needs follow-up testing, it can be a confusing process. Parents who took part in the Parent/Patient Panel during APHL’s 2021 Newborn Screening Symposium said it didn’t help that it was often a stranger calling them, not a physician they had an existing relationship with.
Natalie and Eric Lamb received a phone call in September 2020 informing them their daughter, Etta, tested positive for spinal muscular atrophy. The Lambs are both nurses, but they didn’t know the neuromuscular doctor on the phone and didn’t understand what she was talking about. “She basically just started spitting a bunch of genetic information at us, and all we heard was complete gibberish,” Eric said during the conference session.
Other families shared similar stories: When Diane and John Pytel received a call in 2006 that their newborn, Mia, had PKU, John thought it was the “state” calling. He assumed it was a Pennsylvania bureaucratic mistake because it was just some stranger on the phone. The parents on the panel all agreed that better education is needed, perhaps during pre-pregnancy planning—and it shouldn’t be just a pamphlet handed to them by a nurse. Because of lack of proper communication and education about the importance of NBS, the parents said they’ve heard of resistance from other parents. Reasons given include thinking the government is going to have their baby’s DNA stored in a database, that there are no genetic diseases in their family so it’s unnecessary, and for home birth families, that it’ll disrupt their bonding and they’ll “do it later.”
“Many parents are not aware that their newborn is going to get screened shortly after birth,” Olney said. “Ideally, parents should be informed about newborn screening while they are pregnant, and getting this message out through the cooperation of prenatal care providers is an ongoing challenge.”
Incorporating Next-generation Sequencing
An area that fits into both the success and challenge columns is next-generation sequencing, which includes whole exome sequencing and whole genome sequencing (WGS). Laboratories now have the ability to sequence large amounts of a person’s DNA in a much shorter time, although it is not a routine part of NBS. WGS can be a life-saver when used to discover the cause of a child’s severe illness. But should it be done routinely on seemingly healthy babies? And what to do with that information?
“You’re going to find a lot of stuff you can’t do anything about if you do that,” Berry said. “Is that right, to be done as part of newborn screening? That’s a big challenge and a big area of controversy.”
A genome sequence is a lot of data and it’s “still pretty mysterious,” Berry said. “Even when we get a gene sequence back using just the coding sequence for the proteins, we don’t always know if the genetic error that we see is something that causes a problem, that is it’s pathogenic, or if it’s just something that’s a variation from person to person that is benign.”
Webster quoted her colleague, who said: “We need to define what we mean by early detection.” As Webster explains, “There are patients who presented in adulthood who think it would be good if they’d have known about their disease earlier. But if you were to ask a number of families if they want to know if their newborn baby was going to develop late-onset Pompe disease when they were in their 30s or 40s, the family may not want to know.” Furthermore, one must consider the autonomy of the child—should they be told about a disease early in their childhood that may develop when they are an adult?
Like her older brother, Zoe Kettler, now 16 months old, was born via donor egg IVF. She was the Kettler’s “Hail Mary baby” as their last remaining embryo to transfer. The couple knew Zoe would be an Artemis SCID carrier but not have the disease. Nevertheless, the Kettlers nervously awaited the NBS results after Zoe was born. “It was a much different experience waiting for that newborn screening test than the first time when I didn’t think there was anything to be concerned about,” Christina Kettler said.
She choked up as she reflected back on that day: “I remember when the doctor came in and told me that it was fine, it was negative. I was crying and I felt so relieved.”
Despite the challenges, complexities and ongoing questions, newborn screening is one of the leading public health success stories.
“It’s still one of the most important things we’ve ever done. It’s a little-recognized, tremendous public health advance,” Berry said. “I just hope that by continuing to help people understand it better, they’ll realize how much public health has done to improve the lives of children through newborn screening.”