Expanding Newborn Screening: Title and subTitle BreakHow Good Is the Evidence?

State health departments have been reluctant to adopt tandem mass spectrometry for newborn screening because of its expense (start-up cost of about $400 000¹ ) and doubts about its validity and utility. However, pressure to adopt the screening technology has come from medicolegal proceedings brought by parents of infants with genetic disorders who were not screened and from the direct lobbying of hospitals and health departments by advocacy groups (http://www.savebabies.org). In addition, a private screening laboratory, Pediatrix Inc (formerly NeoGen Screening Inc), markets tandem mass spectrometry to hospitals and states. Despite the continuing lack of evidence regarding its safety and effectiveness, tandem mass spectrometry is now mandated in 24 states (http://genes-r-us.uthscsa.edu).

In this issue of THE JOURNAL, Waisbren et al² provide data that enable clinicians, policy makers, and others to begin to assess the validity and utility of tandem mass spectrometry. The authors took advantage of the adoption of tandem mass spectrometry in Massachusetts and Maine but not in the other New England states, which served as a comparison group. Infants born in Pennsylvania with positive tandem mass spectrometry results also were included. It is the first study that uses standard developmental assessment instruments to compare infants who were screened with those who were clinically detected in the same birth cohort and that uses a standard measure to compare stress levels between the parents of these 2 groups of infants. The authors also compared stress levels of parents of infants with false-positive tandem mass spectrometry results with the levels in parents of infants with true-negative results. They report that screening reduced developmental delay in infants who were clinically detected and stress levels in their parents. Stress levels were increased in parents of infants with false-positive test results.

Well-established criteria for population-wide screening include the following: the conditions being screened are important (because they occur frequently and are serious); the natural histories of the conditions (in the absence of treatment) are known; the validity of the screening test and the safety and effectiveness of treatment have been characterized; the cost-effectiveness of the screening program compares favorably with competing interventions; and screening reaches the population at risk.³ The data presented by Waisbren et al, and other recent studies can be examined against these criteria.

Importance. In the study by Waisbren et al,² tandem mass spectrometry detected 10.6 infants with 12 conditions per 100 000 births. One of these conditions, medium-chain acyl-coenzyme A (CoA) dehydrogenase deficiency (MCADD), accounted for about 40% of all infants detected. Excluding MCADD, the combined incidence of the other diagnoses was 6.4 per 100 000, or an average per other condition of about 1 per 200 000 births. To the few families whose affected infants would be protected if a program were in place, tandem mass spectrometry will appear important. Many others would argue that programs from which a greater proportion of children would benefit will be more important.

Natural History. At this juncture it is not possible to predict the natural history of some of the diseases detected by tandem mass spectrometry. Wilcken et al⁴ found that compared with clinical diagnosis, tandem mass spectrometry screening increased the rate of detection of several inborn errors of metabolism. This increase could be due to either clinical underdetection or tandem mass spectrometry overdetection, in which some screened infants might never manifest their genetic error. This seems to be the case for the increase in detection for MCADD in the study by Waisbren et al.² It may be possible to distinguish those infants at risk by determining the genotypes of infants with MCADD^{5 - 6} that was detected by tandem mass spectrometry. Another condition, 3-methylcrotonyl-CoA carboxylase deficiency (3-MCC), was detected by tandem mass spectrometry in 3 infants in the study by Waisbren et al but none of the infants were identified by clinical diagnosis. One older sibling also had 3-MCC and was healthy. Her younger sibling was not treated. At the other extreme, 5 infants identified by tandem mass spectrometry died within 5 days of birth: 2 with long-chain hydroxyacyl-CoA dehydrogenase deficiency and 1 each with carnitine palmitoyltransferase II deficiency, arginase deficiency, and very long-chain acyl-CoA dehydrogenase deficiency. Thus, almost 10% of infants detected by tandem mass spectrometry did not survive. Other infants with these conditions survived. The authors do not report whether the infants who died had different genotypes than those who survived or might have survived if the attending physicians had been informed of the screening test results earlier.

Validity of the Test. Validity is measured by the sensitivity, specificity, and predictive value of the test. During the 3.4 years of the study, 2 infants with short-chain acyl-CoA dehydrogenase deficiency were not detected by tandem mass spectrometry while 5 were clinically diagnosed, yielding a sensitivity of 71%. For all conditions the sensitivity was 50 of 52 infants, or 96%. Primarily because of the rarity of the detected disorders, the specificity and negative predictive value are both greater than 99.99%. Counting families that could not be contacted, but making no adjustment for differences in response rates, infants with true-positive results in Massachusetts, Maine, and Pennsylvania accounted for only 9.5% of all infants with positive results (positive predictive value). This result is comparable with the positive predictive value reported in other recent studies.^{4 ,7} In addition to adding to the monetary costs of screening, false-positive test results had adverse effects: more hospitalizations (P = .06) and increased maternal stress that persisted for at least 6 months according to Waisbren et al.

In considering adopting new screening tests, policy makers cannot judge them solely on their sensitivity, specificity, and predictive values; other factors, including the other criteria, should influence their decision. The values for the validity of tandem mass spectrometry are in the range of other screening tests. In this range, reasonable people will still disagree on whether they are acceptable.

Effectiveness of Treatment. The primary treatment for MCADD is avoidance of fasting. If parents of all newborns were advised to follow this regimen, and if they adhered, screening for MCADD would be unnecessary. Admittedly, adherence is a big "if." Nevertheless, other health education campaigns directed at parents have succeeded. The reduction in deaths caused by sudden infant death syndrome seems at least in part because parents are complying with advice about the sleeping position of young infants.⁸ Importantly, no child with clinically diagnosed MCADD functioned in the range of mental retardation, raising again the importance of distinguishing serious from benign forms of this condition.

The authors do not specify the disorders of the 13 children (26%) who received no treatment. Of the others, only 8 (16%) received "specific" formulas. The evidence that oral carnitine, with which 23 children (46%) were treated, improves outcome is far from convincing.^{9 - 11} Moreover, the authors do not systematically indicate the developmental outcomes by disorder or by treatment. If the best developmental outcomes in the children screened occurred among those who received no treatment, the differences in developmental outcomes between the screened and the clinically diagnosed groups because of special formulas or other treatments would be less impressive. Despite early detection and presumably early initiation of therapy, 1 infant with methylmalonic acidemia detected by tandem mass spectrometry performed in the range of mental retardation.

In judging the effectiveness of early therapy on preventing developmental delay, it would be useful to compare infants who are the same chronological age who underwent early treatment with those who underwent late treatment. The authors recognized that the different ages at which the 2 groups were administered the Bayley Scales of Infant Development (median, 9 months vs 22 months) could have influenced the discrepancy in scores, which were significantly higher in the screened group. They performed a second Bayley Scale measurement in the 22 oldest infants in the screened group at a median age of 21 months and compared it with the 19 children in the clinically identified group at a median age of 22 months. The differences in the Bayley score widened slightly, but the P value for the difference in the mental index was only .04, probably due to the smaller sample size, compared with P<.001 in the first measurement. Longer-term follow-up will be needed to resolve this critical issue.

Cost-effectiveness. Two recent analyses have demonstrated that the cost of saving 1 quality-adjusted life with newborn tandem mass spectrometry is comparable with other accepted public health strategies.^{12 - 13} These studies assumed the efficacy of early interventions and ignored the total number of lives saved. A hypothetical program with the same cost-effectiveness ratio as tandem mass spectrometry that saved 200 lives per 100 000 births instead of the maximum of 10 for tandem mass spectrometry would have a much greater impact on public health than tandem mass spectrometry. Of course, it would cost much more.

Reaches the Population at Risk. One advantage of mandated newborn screening is its universality. Throughout a state that mandates screening, hospitals and physicians that provide neonatal care have to comply. That is not the case when a private company contracts with hospitals to provide tests that are not mandated, as happens for tandem mass spectrometry in some states. Mandatory screening does not prohibit parents from refusing to have their infants screened.¹⁴ Mandatory screening does mean that parents must be offered it. When they are, very few refuse.¹⁵ The pros and cons of consent for newborn screening have been debated for many years.^{16 - 18}

Waisbren et al² have embarked on studies that may eventually answer questions about the propriety of tandem mass spectrometry for state-mandated newborn screening. They conclude (and I strongly concur) that "questions remain" regarding parental stress, developmental outcomes, and benefits vs long-term costs that must be answered before "rational decision making can occur." Nevertheless, their preliminary data could be used to bolster arguments either for or against adopting tandem mass spectrometry for mandated newborn screening. Those who favor public health interventions that benefit a larger proportion of the public will use the rarity of the disorders, the high rates and deleterious effects of false-positive results, and unresolved questions about the effectiveness of treatment to argue against mandating tandem mass spectrometry screening. Those for whom any risk should be avoided at all costs will use the apparent improvement in outcomes to argue for it. At this stage in the collection of evidence, the states that already have invested in tandem mass spectrometry are unlikely to give it up while most of the other states will probably continue to wait and see.

In the meantime, actions by the private sector may impact screening practices. Pediatrix (to which some components of the patent were transferred from NeoGen Screening Inc [US patent No. 6258605]) is now competing with health department laboratories. In Maryland, where health departments are implementing tandem mass spectrometry screening, Pediatrix is offering screening at a lower price than the public program (Susan Panny, MD, Maryland Department of Health and Mental Hygiene, oral communication, October 22, 2003). However, Pediatrix does not follow up infants with positive test results but reports them to Maryland's health department, which is responsible for finding these infants and referring them to specialists at academic medical centers (Susan Panny, MD, Maryland Department of Health and Mental Hygiene, oral communication, October 22, 2003). Eventually, Pediatrix could refer infants with positive test results to physicians in its own practice group; under existing agreements this would not be permitted in Maryland.

Because of patent protection, the entry of a private company could undermine the public health nature of newborn screening. It is possible that by charging royalties Pediatrix could force nonprofit laboratories to either raise their prices or abandon tandem mass spectrometry. By claiming patent infringement, Pediatrix could put those laboratories out of business. In the first case, disparities among infants in screening probably would increase. In both cases, the evidence needed to demonstrate the safety and effectiveness of tandem mass spectrometry is unlikely to be collected.

Until hospitals and states adopt a consistent policy, physicians caring for infants and children must be aware of the conditions for which newborns are screened in their respective states. A listing of conditions for which each state screens, including those detected by tandem mass spectrometry, is available (http://genes-r-us.uthscsa.edu/resources/newborn/screenstatus.htm).