Diagnostics & Imaging Week Washington Editor

WASHINGTON – Newborn screening for genetic diseases has been around since President John Kennedy occupied the White House.

It seems intuitive that in the last 40 years, screening babies for potentially life-threatening conditions would have become commonplace and uniform across the U.S.

That is not the case.

According to Peter van Dyck, MD, associate administrator for the Maternal and Child Health Bureau of the Health Resources and Services Administration (HRSA), older screening tests did not vary much from state to state between the 1970s and early 1990s.

States would test for roughly the same four to six conditions, van Dyck told Diagnostics & Imaging Week.

New technology has greatly expanded that number. Tandem mass spectrometry can screen for up to 40 conditions at once using just a few drops of blood taken by a heel stick. The results for dozens of molecular disease markers are available in a matter of minutes.

Because mandated testing is up to individual states, adoption of new technology has begun to vary as states evaluate the cost and medical evidence used to determine the effectiveness and validity of each test.

“But with the advent of mass spectrometry, the potential for being able to test for so many more conditions was made possible and states haven’t even decided to move ahead in the realm of increased testing,” van Dyck said. “In the last five years, the unevenness among states has really developed. Now we have a variability of three or four tests performed in some states to up to 40 in others.”

But as with many technological advances in medicine, tandem mass spectrometry has been a breakthrough, but also has raised questions as well.

For example, some critics question that just because you can screen for a congenital abnormality doesn’t mean you should. There also are no effective treatments for some of the disorders it can detect. Some experts have estimated that hundreds more metabolic genetic defects that fall into this gray area may be identified.

Another problem is that machines can cost as much as $500,000 in addition to the trained staff to run them.

Advocates of expanded screening say early detection and treatment means the difference between life and death, between profound disability and normal mental and physical development.

The first newborn screening test was developed in 1961 for phenylketonuria, or PKU, an enzyme abnormality that, without dietary management, causes mental retardation, dangerous blood clots and liver failure.

Babies with PKU aren’t able to process part of a protein called phenylalanine. Babies who screen positive for the disorder immediately are put on a phenylalanine-free formula, followed by a special low-phenylalanine diet, which means no high-protein foods. Carefully monitored diets through adolescence will allow most children to mature with normal intelligence.

PKU remains the only metabolic disorder for which every state mandates newborn screening. Congenital hypothyroidism, sickle cell disease, beta thalassemia and glactosemia are the only other conditions for which every U.S. newborn is screened.

But by the early 1990s, screening was becoming a complex issue and more disorders were identified as scientists found subtler defects in genes that regulate the body’s metabolism of proteins and enzymes.

Typically, screening tests get new parents’ attention only in the rare case of an abnormal result, which, because of the false positives common with such tests, may not necessarily mean their baby has a problem. Further testing then is required for a more definitive answer.

According to figures from the March of Dimes (White Plains, New York), about 15,000 to 19,000 of the 4 million babies born each year in the U.S. have a treatable condition for which a screening test is available.

“All medical screening programs, by their very nature, must cast a wide enough net to identify all affected individuals, even at the cost of some initial false positives,” a March of Dimes spokesperson told D&IW. “But the family of any newborn who screens positive for a disorder, along with the pediatrician, would receive a notice to bring the baby in for further testing to confirm the diagnosis before any treatment would begin.”

The American College of Medical Genetics (Bethesda, Maryland), the March of Dimes and the American Academy of Pediatrics (Elk Grove Village, Illinois) recommend that all U.S. newborns be screened for hearing loss and 28 other conditions using the heel stick (see sidebar, p. 5).

At present, only Mississippi screens for all 29, according to the March of Dimes, although other states provide testing for other diseases. New York, for example, screens for HIV – not a genetic condition, but part of a larger panel of tests the state conducts.

Twenty of the conditions are rare metabolic disorders, such as maple syrup urine disease in which the urine of affected children has a sweet odor resembling maple syrup. Untreated, these children can die or have severe neurological damage.

The others include a variety of inherited conditions, such as cystic fibrosis and sickle cell disease. They were selected because they can be detected in newborns with an accurate screening test and treated. Tandem mass spectrometry can screen for about two dozen other disorders for which no treatment is available, according to the March of Dimes.

The cost of screening varies per state. Some programs – such as New York’s – are completely tax supported, and there is no fee. Testing in other states can range anywhere from $15 to $150.

In most cases, if a parent insists upon it, testing may still be obtained at healthcare facilities thought it may not be mandated by a particular state.

The March of Dimes and HRSA, which falls under the umbrella of the Department of Health and Human Services (HHS), has developed educational pamphlets for states to deliver to expectant mothers, outlining what is mandated by each state, and what other screening may be available through supplemental screening by a private provider.

A recent report from the American College of Medical Genetics recommends, however, that newborn screening should not solely be left up to private laboratories. “Newborn screening is more than testing,” the report said. “It is a coordinated and comprehensive system consisting of education, screening, follow-up, diagnosis, treatment and management.”

Mike Leavitt, secretary of HHS, currently is evaluating a recent report commissioned by HRSA that makes recommendations for more systematic screening nationwide. Public comment period ended last month, and an expert panel has been convened to examine the feedback and advise HHS.

Though the government cannot mandate testing, van Dyck hopes HHS’ proposal would serve as a basis for states to follow. A final decision is expected in late summer or early fall.

As the use of the tandem mass spectrometry increases and the technology improves, the tests will become more sensitive, cutting down on false positive results, says Brad Therrell, PhD, director of the National Newborn Screening and Genetics Resource Center (Austin, Texas) and professor of pediatrics at the University of Texas Health Science Center at San Antonio.

“The whole purpose of screening is to find those that are at increased risk,” he told D&IW. “It is not diagnostic; it’s screening. You can then take it to the next step, just to make sure.”

Therrell responds to testing critics by saying even if there is no cure for a particular condition flagged by screening, the information – though traumatic – is still important for parents to have. He acknowledges the ethical problems some results cause, but argues that parents should be as informed as possible.

“There are strong arguments on both side, but I think it allows parents to make some family and life decisions – decisions about future births,” he said. “If you were to have a second child, you could have double the deaths or disability. There are strong arguments on both sides.”

Therrell said the impact on parents depends on how the information is presented to them. “There is concern, but it goes away with time. Most people feel it was better to know.”

(Next week: The parent perspective on neonatal testing, plus more on the upcoming recommendations from HHS.)