While newborn screening for cystic fibrosis (CF) has been feasible since 1979 using the IRT (immunoreactive trypsinogen test), and there have been slowly accumulating observational data regarding the potential benefits of such testing, it is not routinely performed in most states. In part, this is because CF is different from the classic model of PKU newborn screening in which a relatively simple intervention must be initiated within a short time frame (weeks) in order to avoid a significant complication (severe mental retardation). In contrast, cystic fibrosis is a chronic and gradually progressive disease and the potential benefit of newborn screening may be harder to discern.
There have also been concerns regarding the potential harms of newborn screening such as adverse effects on parental bonding in children diagnosed with cystic fibrosis, increased acquisition of pulmonary pathogens, and confusion and anxiety in families of children identified with false positive tests. In the early 1980's there were particular concerns about the sensitivity and positive predictive values of the IRT. At that time, two clinical research programs on neonatal screening were developed in the United States: an observational study in Colorado; and a randomized controlled trial in Wisconsin.
The data from the Wisconsin trial continues to be analyzed and there is yet no published information regarding changes in pulmonary outcome during nine years of screening in Wisconsin (1985-1994). Both the Colorado and Wisconsin trials have generated data suggesting that there is a short-term (less than five years) improvement in nutritional parameters, including height and weight, among individuals identified by newborn screening. While the pulmonary data from Wisconsin have not yet been analyzed, a number of observational studies in Europe and Australia suggest some pulmonary improvement compared to controls; certainly newborn screening does not result in worse, lower pulmonary function compared to patients not screened.
Additionally, qualitative studies in Wisconsin and Australia suggested that there are no significant negative psychosocial problems in children identified with CF through screening. There may also be a reduction in the parental anxiety since the time to diagnosis is less with newborn screening, but this is difficult to assess for methodological reasons.
The most significant risk of cystic fibrosis screening has been adverse effects in false positive patients. With either the repeat IRT approach (Colorado) or a single IRT approach (Wisconsin) there is some anxiety, stress, and anger in parents due to the sensitivity and specificity of the test. However, after more than ten years of screening in both Colorado and Wisconsin, these problems, while present, have been observed in only a small number of families. In the single IRT approach (Wisconsin), the positive predictive value was only 15%. For this reason, in 1991 a combined screening using the IRT and molecular mutation analysis of the CF gene was developed using a second tier test for DeltaF508 (the most common CF gene mutation). This offered the benefit of improved positive predictive value. However, this has meant that many individuals identified as false positives are CF carriers. Thus this approach needs to include careful genetic counseling for all at-risk family members.
In January 1997, a conference sponsored by the NIH, CDC, and the CF Foundation was held to review the data from the Colorado and Wisconsin programs as well as information from Europe and Australia. The consensus of the meeting was that there was accumulating evidence of short-term nutritional benefits of cystic fibrosis newborn screening and lack of clear evidence of significant harms. The data were not sufficiently compelling to recommend neonatal screening for all infants, because of continued unanswered questions about the ideal approach to the implementation of statewide newborn screening programs, the appropriate handling of carrier families, and the value of early interventions. There was a consensus that these questions could not be answered by waiting for additional data from the Wisconsin trial, but it would be necessary to move to a further phase of observational research in the context of a statewide newborn screening program to answer these questions.
There was discussion about the reasonableness of additional states adopting the statewide newborn screening programs. Ideally, hypothesis-driven research questions would be incorporated regarding the role of early interventions in cystic fibrosis. Such interventions could include use of anti-inflammatory drugs, antibiotics, or deoxyribonuclease. Other possible research questions could deal with the ideal approach to genetic counseling for the IRT/DNA method, and the logistics of statewide implementation. Additionally it was emphasized that newborn screening programs must be linked to the provision of standard of care treatment for cystic fibrosis. This would mean that patients identified would need to have access to cystic fibrosis centers and that such centers might require additional support in the current managed care environment to maintain the same quality of care provided previously. Finally, there was acknowledgment of the need to develop better approaches to informed consent for newborn screening.
In summary, the accumulating data worldwide regarding newborn screening for cystic fibrosis suggest a potential benefit. Before CF screening can be fully implemented, however, new programs need to be developed to address the unanswered questions regarding ideal approaches to screening design and the opportunity for the enrollment of identified children into clinical trials.
The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131
