Newborn Screening: The Spigot is Open and Threatens to Become a Flood
Article Outline
Abbreviations: MCAD, Medium-chain acyl CoA dehydrogenase, MS/MS, Tandem mass spectrometry technology, PKU, Phenylketonuria
The principles of newborn screening for inherited metabolic disorders were established beginning in 1961 and in the years following. The only substantial addition to a very limited repertoire of tests for amino acid disorders and galactosemia, until recently, was testing for hypothyroidism and for hemoglobinopathies, instituted in the 1980s and 1990s. Enormous economic savings, very easily demonstrated with unsophisticated tools and without elaborate economic modeling, were generated by the screening for phenylketonuria (PKU) and hypothyroidism. In each of these disorders, a severe intellectual impairment rate of nearly 100% and 75%, respectively, in patients with clinically diagnosed disease assured the economic viability of the model and protected disorders like galactosemia and the hemoglobinopathies, economic benefits of which were less easily demonstrable.
See related articles, p 115 and p 121
The early 1990s witnessed the advent of technological advances that allowed the menu of screened disorders to expand greatly. This expansion, powered by tandem mass spectrometry technology (MS/MS), began to diffuse substantially at the turn of the 21st century and is now in full swing. Virtually every developed country, both East and West, either had instituted expanded newborn screening with MS/MS or is about to do so. Critics argue that this expansion is premature and that the intellectual basis and the cost benefit basis have not been established. The arguments are not entirely wrong, but they are certainly quixotic, and the bases for them are insufficient to reverse this very powerful trend. Like a snowball rolling downhill, it not only is unstoppable, but it grows bigger as it descends with time. In reality, MS/MS may merely be the tip of the iceberg, with screening for lysosomal storage disorders, adrenoleukodystrophy, immunodeficiencies, Smith-Lemli-Opitz Syndrome, and possibly others being not far behind. Surely these are technology driven, but there is a rational argument that can be made for many of the proposals now on the table. Each is driven by a disease-focused group of parents and patient advocates and a committed group of physicians and professionals who believe that their disorder belongs on a higher plain of societal attention and to see the patients receive earlier and more effective therapy. All are promoted with the promise of earlier and better treatments. All are compared with PKU in frequency and societal impact, and, for virtually all, no prospective cost benefit study has been done.
A unique aspect of the American society and political process is the extent to which a group of individuals who are press-savvy and politically connected can influence the introduction of new programs into the national and state health mandates in the absence of careful prospective consideration of the impact. To an extent this has occurred for Krabbe disease in New York State and MS/MS, augmenting the obvious attraction of preventing some of the serious consequences of these disorders when diagnosed after clinical presentation.
The western European countries have often had a wiser approach, attempting to moderate the rate at which new tests are introduced and to delay them until their effectiveness has been assessed. This assessment takes diverse forms. Great Britain has been running a controlled pilot program aimed at determining the effectiveness of the test for medium-chain acyl CoA dehydrogenase (MCAD) deficiency, the most common of the disorders ascertained uniquely by MS/MS technology1, although at a time when the prospective results from other venues were already available. When the study is complete, and assuming that the results are favorable by predetermined end points and criteria, only then will the test be introduced into routine clinical care. Germany has taken an approach somewhere in between the United States and Great Britain. After open, uncontrolled pilot studies done independently in different regions, they relied on an expert panel to make reasoned judgments about the cost-effectiveness of the tests, much like the American College of Medical Genetics/Maternal and Child, Health Resources and Services Administration panel in the United States. Unlike the United States, in which the recommendations of a very broadly representative panel are binding on no one, the recommendations of this panel of experts were binding on all German screening programs and results of other studies that may derive from the MS/MS run are forbidden to be reported.1 There exist variations in between. In all events, judgments have been largely ad hoc, without really adequate data.
Two studies published in The Journal this month from Australia and the Netherlands look at their screening experience for MCAD deficiency and attempt to assess its cost benefit and standard terms of health economics. Haas et al2 assess the cost per patient ascertained by newborn screening as compared with the cost engendered by those patients ascertained through clinical symptoms. They do not report any patients who may have died and thus cannot factor in the costs in patients in whom the diagnosis was never made. Similarly, they do not specifically report any patients who may be intellectually damaged and institutionalized as a result of the diagnosis. Despite this, the calculated cost per patient of those ascertained through screening is comparable with that in patients ascertained clinically, and the benefit of screening is clearly justified by the the absence of the tragedy of an unexpected death and certainly the absence of any brain damage that is known to occur as a consequence of delayed diagnosis. Their costs include the cost of following and of the preemptive hospitalization of those patients who might never have had a clinical episode and might not ever have been at risk of sudden death or brain damage. The study did not attempt to quantitate any element of the psychological dimension of false positive tests.
The study by van der Hilst et al3 from the Netherlands is more sophisticated, uses complex health economic modalities, and is more arcane, but arrives at a similar conclusion. The very nature of the healthcare system in the Netherlands and the commitment to study MCAD deficiency from a multi-faceted perspective allowed them to ascertain patients with the condition in whom the diagnosis had been made clinically and who had sustained some of the ravages of the disorder and to ascertain any other patients who may have died from MCAD deficiency. Thus, the study had a more complete data set and was able to calculate costs per patient and the cost of quality of life year gained effectively. The costs of screening were higher than those calculated by Haas et al, as were the institutionalization costs for those patients who had sustained cognitive impairment during an acute episode of hypoglycemia. They concluded, as did the Haas group, that screening for MCAD deficiency is reasonable in its costs and reasonable in the cost of quality years gained. The outcome was favorable even though future economic productivity was not considered. These studies confirm other studies done by US groups that arrive at the same conclusion.4, 5, 6 None of them depend on using the substantial amounts of dollars saved by PKU and hypothyroid screening to justify the inclusion of MS/MS technology as part of the screening program. They feel, and I concur, that MS/MS expanded screening is justified on its own.
The problem becomes more tricky and sticky when one considers the other conditions that can be ascertained by MS/MS technology. These conditions are less frequent, and the screening may generate a much higher proportion of false positive results in most screening programs. Although the positive predictive value of MCAD deficiency screening is approximately 50%, the positive predictive values for the myriad of other conditions may be as low as 10%. In addition, many of the true positive results may be destined to be asymptomatic, as is the case for MCAD deficiency. This raises the cost for each prevented death or disability to far higher levels and fails to factor in the intangible psychological impact of positive test results on families whose child was never destined to have these disorders. However, the screening costs for the additional MS/MS tests are marginal.
On top of MS/MS, there is very strong advocacy, in the United States and Australia especially, for the introduction of new tests for entirely new families of disorders.7 It is not difficult to imagine or anticipate that the same issues will arise for them as for the disorders ascertained by the use of MS/MS technology. Each is likely to be proposed before the existence of any objective and effective cost-benefit information and perhaps even the ascertainment of false positive and false negative result rates. It is important to remember, too, that similar issues and objections arose in screening for PKU, and in time each was, if not solved completely, reduced to a manageable level of concern. The great controversies that currently surround the more negative aspects of expanded newborn screening probably do not give sufficient weight to the successes of the past and the great capacity of man to solve its problems. As an eternal optimist, I believe we will solve these dilemmas, that we will have the courage to remove disorders for which screening is not beneficial from testing panels, and that we will justify the power and the compassion of expanded newborn screening. I believe it was Churchill who said, “Nothing significant will ever be accomplished if all possible objections must be dealt with beforehand”. I strongly agree.
References
- . International perspectives on newborn screening. J Inherit Metab Dis. 2006;29:390–396
- . Healthcare use and costs of MCAD deficiency in Australia: screening versus no screening. J Pediatr. 2007;151:121–126
- . Cost-effectiveness of neonatal screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: the homogeneous population of the Netherlands. J Pediatr. 2007;151:115–120
- Newborn screening by tandem mass spectrometryfor medium-chain acyl-CoA dehydrogenase deficiency: accost effectiveness analysis. Pediatrics. 2003;112:1005–1015
- . Newborn screening with tandem mass spectrometry:examining its cost-effectiveness in the Wisconsin newborn screening panel. J.Pediatr. 2002;141:524–531
- . Cost-benefit analysis of universal tandem mass spectrometry for newborn screening. Pediatrics. 2002;110:781–786
- Newborn screening for lysosomal storage disorders. Mol Genet Metab. 2006;88:307–314
PII: S0022-3476(07)00365-4
doi:10.1016/j.jpeds.2007.04.035
© 2007 Mosby, Inc. All rights reserved.
Refers to article:
- Cost-Effectiveness of Neonatal Screening for Medium Chain acyl-CoA Dehydrogenase Deficiency: The Homogeneous Population of the Netherlands
- Healthcare Use and Costs of Medium-chain Acyl-Coa Dehydrogenase Deficiency in Australia: Screening Versus No Screening , 16 June 2007
