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Newborn screening report sparks debate in USA

2005; Elsevier BV; Volume: 365; Issue: 9469 Linguagem: Inglês

10.1016/s0140-6736(05)66401-x

1474-547X

Harvey Black,

Ethics in Clinical Research

New technology now makes it possible to screen newborn infants for scores of disorders from a single drop of blood. A US expert panel is recommending that all children be screened for 29 disorders, but critics say some tests may cause more harm than good. Harvey Black reports. For Dean Jerrehian, whose 11-year-old son Matt has phenylketonuria (PKU), there is absolutely no doubt of the value of screening newborns for PKU and other relatively rare conditions. “Institutions in this country are full of adults born before 1960 that weren't tested for PKU. They can't care for themselves; they have low IQs, I'm afraid that's where my son would have been if he weren't tested early”, says Jerrehian, a 44-year-old businessman from Philadelphia, PA. Children with PKU lack an enzyme called phenylalanine hydroxylase, which is needed for the metabolism of the aminoacid phenylalanine. Without this enzyme, phenylalanine and its derivatives can build up to toxic amounts and cause brain damage. But because Matt was screened for PKU shortly after birth, he was put on a diet low in phenylalanine protecting him from its toxic effects and severe mental retardation. Phenylketonuria is one of 29 rare inherited disorders that an expert group is now recommending all US states include in newborn screening programmes. Currently, screening panels vary from state to state. The group, from the American College of Medical Genetics (ACMG), drew up its recommendations under a contract from Health Resources and Services Administration of the US Department of Health and Human Services (HHS) and has received endorsement from the HHS Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children. But the proposals are drawing fire from critics who say the group has not based its findings on sound science, and is ignoring ethical problems posed by screening for conditions that may never cause disease or for which there is no proven treatment. One critic, Norman Fost, professor of paediatrics and bioethics at the University of Wisconsin in Madison notes that when PKU screening was put into place more than 40 years ago it was assumed that if a child had high blood phenylalanine they had PKU and should be fed a strict diet. But there were few data to support that assumption, says Fost. “It turned out that 95% of people with an abnormal screening test had no disease, and it turned out the diet was lethal. It caused brain damage in we don't know how many kids, and killed we don't know how many kids”, he explains. Fost and a number of other medical ethicists are concerned, if not alarmed, that the ACMG group's recommendations will lead to a tremendous waste of money and cause unnecessary anxiety among many parents because, in the critics' view, there is simply not enough information about many of the disorders in the panel. In many cases, it is not clear that the disorder will ever cause disease or if recommended therapies provide significant benefit, they argue.PanelAMCG-recommended disorders for newborn screeningOrganic acid metabolism disordersBeta-ketothiolase deficiencyGlutaric acidaemia type IHydroxymethylglutaric aciduriaIsovaleric acidaemia3-Methylcrotonyl-CoA Carboxylase deficiencyMethylmalonic acidaemia, Cbl A and Cbl B FormsMethylmalonic acidaemia, mutase deficiency formMultiple carboxylase deficiencyProprionic acidaemiaFatty acid oxidation disordersCarnitine uptake defectLong-chain hydroxyacyl-CoA dehydrogenase deficiencyMedium-chain acyl-CoA dehydrogenase deficiencyTrifunctional protein deficiencyVery-long-chain acyl-CoA dehydrogenase deficiencyAminoacid metabolism disordersArgininosuccinic acidaemiaCitrullinaemiaHomocystinuriaMaple syrup urine diseasePhenylketonuriaTyrosinaemia type IHaemoglobin disordersHb S/Beta-thalassaemiaHB S/C diseaseSickle cell anaemiaOthersBiotinidase deficiencyCongenital adrenal hyperplasiaCongenital hypothyroidismCystic fibrosisGalactosemiaHearing deficiency Organic acid metabolism disorders Beta-ketothiolase deficiency Glutaric acidaemia type I Hydroxymethylglutaric aciduria Isovaleric acidaemia 3-Methylcrotonyl-CoA Carboxylase deficiency Methylmalonic acidaemia, Cbl A and Cbl B Forms Methylmalonic acidaemia, mutase deficiency form Multiple carboxylase deficiency Proprionic acidaemia Fatty acid oxidation disorders Carnitine uptake defect Long-chain hydroxyacyl-CoA dehydrogenase deficiency Medium-chain acyl-CoA dehydrogenase deficiency Trifunctional protein deficiency Very-long-chain acyl-CoA dehydrogenase deficiency Aminoacid metabolism disorders Argininosuccinic acidaemia Citrullinaemia Homocystinuria Maple syrup urine disease Phenylketonuria Tyrosinaemia type I Haemoglobin disorders Hb S/Beta-thalassaemia HB S/C disease Sickle cell anaemia Others Biotinidase deficiency Congenital adrenal hyperplasia Congenital hypothyroidism Cystic fibrosis Galactosemia Hearing deficiency The screening technique that would be used is tandem mass spectrometry (MS/MS), a highly sensitive technique that can detect biochemical markers for dozens of metabolic disorders from a single blood dot. A child who tests positive for one of these disorders with this technique would require additional testing to confirm the diagnosis and rule out a false-positive result. But critics of the recommendations sharply question the scientific approach taken by the ACMG working group, saying the group based much of its decisions on opinion surveys of experts and patient advocacy groups—an approach one critic dismisses as a “popularity contest”—and used a scoring system that arbitrarily ranked diseases on the basis of incidence, severity, the sensitivity and specificity of screening tests, and the cost of treatment. “They did not develop their arguments based on a careful analysis of the literature. The methodology is not strong”, says Jeffrey Botkin, professor of paediatrics and medical ethics at the University of Utah in Salt Lake City, Utah. To be justified, newborn screening needs to make possible an early intervention that can prevent morbidity or mortality, he says. The ACMG working group, he argues, did not provide data to show that kids will do better as a result of early intervention based on newborn screening. As one example, Botkin points to one of the conditions the panel included in its list: arginosuccinic acidemia, a rare urea cycle abnormality, which can lead to mental retardation. Treatment for this condition, Botkin says, is “complex” requiring a low protein diet with an arginine supplement, but is “of uncertain benefit”. But Michael Watson, project director of the ACMG expert group, says Botkin is incorrect. Watson says there is evidence that all 29 disorders on the recommended uniform panel can be treated. “I think the information that's in the report is as good as you can get”, concurs Rodney Howell, a professor of paediatrics at the University of Miami in Miami, Florida, and chair of the ACMG working group. “There is not a body of literature about how to treat some of these conditions; you can't go to the literature and look up what the facts really are, and so the only way to get information is to ask the four or five experts what their experience has been”, says Peter Van Dyck, who heads the HHS Maternal and Child Health Bureau, and is a member of the advisory committee that endorsed the ACMG report. In contrast to the recommendations of the ACMG working group, UK experts have proposed a far more cautious approach. A British study published last year examined the clinical and cost-effectiveness of MS/MS for screening inborn errors of metabolism. That study, a health technology assessment report prepared for the UK national health service's research and development programme, concluded that while replacing existing technologies for PKU screening with MS/MS was not economically justified, adding medium-chain acyl-CoA dehydrogenase deficiency (MCADD; a disorder in fatty acid oxidation that puts a child at risk for profound hypoglycaemia during fasting or illness that can cause severe encephalopathy, mental retardation, and death) to the panel made tandem MS economical. Although MS/MS can identify scores of disorders, says James Chilcott, technical director of the Health Technology Assessment Group at the University of Sheffield, one of the report's authors, that does not automatically mean they should be included in screening panels. There is just too little evidence to show that screening for these disorders improves outcomes, he says. In the case of maple syrup urine disease (MSUD)—in which individuals cannot metabolise the aminoacids leucine, isoleucine, and valine—the group did not find convincing evidence that MS/MS screening, as implemented in the UK, would improve outcomes. Screening for MCADD is moving ahead in the UK, but on a pilot basis, says Carol Dezateux of the Institute of Child Health in London. She is leading a government-funded 5-year study to assess a pilot programme of newborn screening for MCADD. The study will measure the clinical, psychosocial, and economic outcomes of early detection through screening of MCADD. Treatment includes the avoidance fasting and caloric support during times of stress. “We've screened over 300 000 babies so far and are working with clinicians, laboratory and social scientists, and parent support groups to evaluate the impact on children and families of early diagnosis through screening”, she says. The intention is “to set out a stronger evidence base for policy making by the UK National Screening Committee.” The children will be followed to 2 years of age to determine if the screening programme reduces the risk of death and major neurological episodes, but systems to allow longer term follow up are being set up. In the USA, the ACMG working group's report will be open for public comment through the first week of May. HHS Secretary Leavitt will then be presented with those comments, the report, and the advisory committee's comments on the report. “One would hope that the secretary would heed to some degree the advice of the [advisory] committee”, says Howell.