Everett Olson was found to have galactosemia through newborn screening. The 11-month-old is now thriving.

Photo by Steve Wewerka

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March 2009 | Back to Table of Contents

Cover Story

Living Proof

Minnesota’s newborn screening program is considered one of the best in the nation. What’s important to parents, however, is that it is detecting rare-but-treatable conditions.

By Kate Ledger

Few physicians get to experience in a lifetime the kind of medical progress that pediatrician Susan Berry, M.D., has seen in her office in the last eight years. Only a decade ago, Berry, director of the department of pediatrics’ genetics and metabolism division at the University of Minnesota, went through an elaborate sleuthing process in order to diagnose infants who turned up with mysterious symptoms. Typically, by the time she was called onto a case to consider whether nonspecific signs of illness such as vomiting, lethargy, and seizures might be caused by an inborn error of metabolism, a sick child had been seen by numerous doctors, undergone multiple diagnostic tests, and endured several hospital stays. Then, in 2001, Berry says, “everything changed.” Along with several other states, Minnesota began screening newborns for a much larger number of metabolic and genetic conditions. Until then, newborns in Minnesota were screened for only five conditions—phenylketonuria, congenital hypothyroidism, galactosemia, hemoglobinopathies, and congenital adrenal hyperplasia. Using only a few drops of blood collected from a simple heel prick, an additional 41 disorders could be detected. All of a sudden, Berry had an amazing new tool at her disposal.

Although each of the conditions that concerned her tended to be rare, as a group they affected about 140 of the 73,000 children born in the state each year. Catching them early meant staving off brain damage, organ failure, and even sudden death in a newborn. With the new screen, Berry was able to see children who had a presumptive diagnosis within days of being born, most before they experienced the onset of symptoms. Instead of trying to solve mysteries as best she could, newborn screening quickly told her which children were at risk so she could confirm the diagnosis, meet with their families, and establish a treatment plan. “It completely changed my practice,” she attests, “a hundred percent.”

What’s happened in the state since then has awed her even more. Over the years, Minnesota has built what’s now one of the premier newborn screening programs in the nation. In 2007, with a mandate from the Legislature to screen all newborns for hearing, Minnesota became one of the first states to screen for all 54 primary and secondary conditions recommended by the American College of Medical Genetics (ACMG). In December of 2007, the March of Dimes presented a National Award of Excellence in Newborn Screening to Gov. Tim Pawlenty in recognition of the fact that Minnesota was part of that elite group.

No Turf Battles
But implementing the ACMG’s recommended panel was only the beginning. A unique working relationship involving the Minnesota Department of Health, Mayo Clinic, Children’s Hospitals and Clinics of Minnesota, and Berry’s group at the University of Minnesota has since developed. Together, they have refined testing, reduced the occurrence rate of false-positive results to one of the lowest in the United States, and found a way to assemble information for physicians so that babies can begin treatment as soon as possible.

The venture, which is coming to be known as the Minnesota model, took shape five years ago. “We’ve tried to export it,” Berry says, although she acknowledges that other states have found it challenging to adopt the model. Berry suggests that turf struggles between departments of health and academic institutions may have prevented other states from forging similar public-private partnerships.

Mark McCann, director of Minnesota’s Newborn Screening Program, agrees with Berry that what’s happened here “is almost magical.” Starting in 2003, in a concerted drive to refine testing practices and reduce the time to clinical intervention, the Department of Health began working with Mayo Clinic, where sophisticated lab techniques were already being used to diagnose a broad spectrum of metabolic disorders. Department of Health officials also reached out to Berry’s group at the University of Minnesota, which, because of its central location and its team of experts, sees 90 percent of children in the state who have metabolic disorders. “We needed to leverage the best,” McCann says.

The process they’ve developed works like this: When a child is born anywhere in the state, the hospital or birthing center collects a tiny amount of blood to create five spots on a two-part filter-paper card. (Hospitals purchase the cards from the Department of Health and wrap the cost of the card and lab work into the charges for the infant’s delivery.) A courier whisks the card to the Department of Health in St. Paul, where it is carefully registered and bar-coded to ensure that the specimen is tracked to the newborn from whom it came. Then, the two parts of the card are separated: One section remains at the health department, where the lab tests for 11 disorders; the other is sent to Mayo Clinic in Rochester, where laboratory medicine and pathology staff use tandem mass spectrometry to identify biochemical markers for other disorders.

Although Mayo experts had extensive experience with the technology, applying it to newborn screening has been a challenge. “It’s a little bit of a finicky technology,” says Dietrich Matern, M.D., director of Mayo’s biochemical genetics laboratory.

Yet Mayo’s experience has been valuable, particularly in reducing the incidence of false-positive test results, says Piero Rinaldo, M.D., Ph.D., a colleague of Matern. A Mayo pediatrician and biochemical geneticist who has spent 25 years characterizing metabolic disorders and advancing the clinical applications of tandem mass spectrometry, Rinaldo says a baby who receives parenteral nutrition after birth, for example, might appear to have elevated levels of the amino acids that are markers for the metabolic disorder known as maple syrup urine disease. In less-experienced hands, results that exceed the “arbitrary value that people define as a cut-off” may set wheels in motion. “The end result of that decision is that the parents will get a phone call that there is something abnormal,” he says. “We look at it and say, ‘That’s a nutritional artifact. No need to create unnecessary anxiety.’”

Although the false-positive rate of newborn screening using tandem mass spectrometry is between 0.5 and 1 percent nationwide, in Minnesota, this statistic has been reduced to a mere 0.06 percent since the collaboration formally began in 2004. Rinaldo knows of states where false positives can occur in as many as 3 percent of cases. He points out that false positives not only emotionally drain families but cost the health care system and frustrate primary care practitioners, who typically must deliver the news. Ultimately, they can undermine the credibility of the screening program.

In Minnesota, when positive results come along for certain markers, a second-tier test is used to corroborate and further describe the finding. A careful protocol is in place to make sure information about the case is coordinated, up-to-date, and properly disbursed. For example, a positive test that turns up at Mayo Clinic gets reported back to the Department of Health. Details about the test and information about the health of the child get entered on a secure, private, password-protected website to which only professionals involved in the provision of care for the child can gain access. Genetic counselors at the Department of Health and specialists at Mayo contact the baby’s primary care physician about the positive result. During this call, the physician learns of the test result, the condition, and the recommendations for further follow-up. Then, email notifications go out to the specialists (including Berry’s group) to let them know that a positive test result was found, that the physician was notified, and that they should expect to hear from the baby’s physician. The emails contain no sensitive or personal information, nor do they include test results; they simply alert the recipient that new information has been entered on the website, keeping all physicians and test coordinators in the loop.

What’s perhaps most remarkable is that, while inborn errors of metabolism can be devastating, early intervention—with drugs, supplementary nutrients, or a simple change of diet—can often mean the difference between life and death for a child. One mother, who asked that she not be named, was naturally concerned when her son was born prematurely three years ago. But along with pediatricians, she was surprised when he didn’t seem to be learning to eat. The difficulty he had breathing was chalked up to “water in his lungs,” she recalls, and he was kept in the NICU another day. Even before the parents took their son home from the hospital, they received word that he had a positive screen for the condition known as very long-chain acyl CoA dehydrogenase deficiency, an inability to break down fatty acids that prevents his body from metabolizing fat to produce energy. The condition can quickly cause heart failure and even death.

“We were very lucky,” she says, “because it took only three days to get the results. He was diagnosed right away, and we didn’t have to take him home and find out that he can’t have regular [formula] or breast milk.” The family was referred immediately to Lisa Schimmenti, M.D., who works with Berry and is familiar with the disease that affects only one in 50,000 newborns. In this case, the boy’s condition was caught before any permanent damage was done to his heart. With specialized formula, he was soon able to eat normally, and now, with a fat-restricted diet, he’s grown into a typical, rambunctious preschooler.

A Small-But-Vocal Opposition
The success of the Minnesota model has not come without strife. The state also happens to have, according to McCann, “a small-but-vocal and well-organized opposition” that’s not only found philosophical fault with the newborn screening program and the way it’s conducted, but has also appealed to the state Legislature to restrict screening practices. Twila Brase, R.N., is co-founder of the Citizens Council on Health Care (CCHC), an organization concerned with maintaining genetic privacy and ensuring informed consent for patients in all health matters. She views the testing as a violation of the state’s Genetic Privacy Law, which went into effect in 2006 and which, she says, “prohibits government from collecting, storing, using, and disseminating [test results and blood specimens] without informed written consent.” Brase is concerned that screening is often presented to parents when they’re in the “fog” of having just delivered a baby. She’s even more disturbed that the Department of Health keeps the remaining blood spots on file after the screening is completed.

The practice of keeping leftover samples is not new. In Minnesota, the samples, which have been stored since July 1, 1997, are kept securely at the health department and an off-site protected center. McCann notes that the cards are stored under privacy protections “stricter than HIPAA.” No one has direct access to them, he says. Any specimens used to help develop new screening tests have all identifying information removed, unless parents have given consent to keep names attached. Informed consent must be obtained in order for any specimen that contains identifying information to be used for research.

Investigators consider the specimens to be a valuable resource for developing new screening tests. For Rinaldo, who sits on several national committees dedicated to improving and standardizing screening practices and whose laboratory work has focused on expanding the diseases that can be detected, the CCHC’s charges against the program are personally crushing. His first reaction when he learned of the degree of suspicion from the CCHC was disbelief, he says, “then you actually get mad.” He points to a recent breakthrough at Mayo that resulted in a screen for Wilson’s disease, a rare liver condition that doesn’t turn up until adolescence but now has an effective treatment that can save patients’ lives. Researchers went to the state of California, which over the last 20 years has kept millions of leftover samples under lock and key. Among those stored samples, they were able to locate two cases of Wilson’s disease to confirm the effectiveness of the newly developed screen. Matern, who develops new tests for devastating lysosomal storage disorders that now have FDA-approved treatments, also depends on those stored samples.

Over the last three years, much wrangling on the topics of screening and sample storage has gone on in hearings before the state Legislature. In 2007, the Department of Health agreed to do a better job of informing parents about screening and about the retention of samples. Recently, a judge issued an opinion that screening did not fall under the Genetic Privacy Law but that the practice of storing blood specimens was another issue altogether. This year, a new piece of legislation put forward by the Department of Health proposes that the leftover samples, of which there are nearly a million in Minnesota, be destroyed and filter-paper cards be kept on file in the future for only two years.

Ultimately, the CCHC would prefer to see screening, blood storage, and genetic research as “opt-in” programs instead of programs with “opt-out” provisions. There’s no guarantee, Brase says, what the leftover blood samples will be used for, whether they could be used to brand people with diagnoses they didn’t want to know about, create hierarchies of people based on their genes, affect people’s employment or insurance options, or be given to law enforcement agencies. She calls the storage of the cards an “open door to research [that] could mean anything in the future.” What’s more, there’s no guarantee of privacy.

Currently, more than a hundred families opt out of newborn screening each year, while more request destruction of stored samples. From a public health point of view, McCann says changing to an opt-in program would not be nearly as effective at catching potentially devastating illnesses. “It’s a slippery slope to losing children and putting babies at risk,” he says. Rinaldo says that for every 700 newborns who are not tested in a given year, at least one child would be missed and suffer irreversible damage or early death.

The Department of Health has been working hard to broaden its education initiatives. It has expanded outreach to birth educators, hospital nurses and other staff, and organizations such as the Minnesota Hospital Association to communicate the benefits of the newborn screening program. McCann is hoping to further its outreach to physicians, too. By talking about newborn screening during prenatal visits, for instance, physicians can make the topic less intimidating for expectant parents. “It’s about saving lives and improving medical outcomes for children,” he says.

Korissa Olson of Brooklyn Park is one mother who’s grateful for the nurses at North Memorial Medical Center who came back to her maternity room three times (“lovingly,” Olson says) to see if she’d reconsider screening for her newborn son, Everett. “That test saved my son’s life,” she says.

Olson, who prefers natural medicines and has delayed vaccines for her older son, had seen people going around with petitions against newborn screening, describing the test as “an invasion of privacy.” Also, she could point to no known genetic conditions in her or her husband’s families, so she didn’t think it was likely that Everett needed the screen. (Many families believe that without a family history of any of the disorders, their baby doesn’t need the screen. But, in fact, most babies affected with one of the disorders do not come from families that have a known history.)

After the nurses’ third request, however, Olson decided that the simple heel prick wasn’t invasive or “putting anything into his body,” and she agreed. Then, four days later, at Everett’s first check-up with his pediatrician, she learned his screen had come back positive for the rare metabolic disorder galactosemia, an autosomal recessive disorder that makes him unable to digest the main sugar in any kind of milk product, including breast milk, and leaves too much galactose in his blood, which becomes toxic. Untreated, it could result in mental retardation, learning disabilities, cataracts, and liver failure.

Although he seemed fine those first few days, Everett became suddenly lethargic a few hours after his check-up. He was sent to North Memorial to have his bilirubin levels checked. When they were found to be sky-high, the Olsons were sent immediately to the University of Minnesota Children’s Hospital, where Everett was placed in the NICU. “It was very terrifying,” Olson recalls. Two weeks later, the results of a second blood test confirmed classic galactosemia. (By this time, because of the initial screening test results, treatment had already begun.)

When Everett was put on a restrictive diet with special formula, his liver enzymes went down, and he began to gain weight like any other baby. Today, his liver function and galactose levels are tested every few months, and he has to avoid milk products and some vegetables. “He’s proof-positive the test works,” says Olson, who has become an advocate of screening. Of her bubbly, sparking 11-month-old child, she adds, “He’s brought so much joy into our lives.”

There’s no doubt that newborn screening will continue to evolve and that ethical concerns will continue to crop up. As Rinaldo points out, it has long been the case that the availability of an effective treatment for a condition presenting early in life was the tenant for considering large-scale population screening. That is starting to change, he says, as we are now able to detect conditions that may not manifest for years such as Wilson’s disease. It would make sense, he notes, to begin the process of collecting the evidence to justify nationwide screening for those conditions, as well as the ones that show up in childhood.

At this stage, few would deny that the Minnesota model has made important strides toward assuring the well-being of the state’s youngest residents. For Sue Berry, the benefits are visible every day at work. Thinking back to the days before screening, she says, “I’d never want to go back to the way it was before.” MM

Kate Ledger is a Twin Cities freelance writer and frequent contributor to Minnesota Medicine.

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