A Global Perspective on Newborn Screening for Cystic Fibrosis

Anil Mehta

Curr Opin Pulm Med.  2007;13(6):510-514.  ?2007 Lippincott Williams & Wilkins
Posted 11/06/2007

Abstract and Introduction

Abstract

Purpose of Review: Cystic fibrosis screening in newborns is occurring in an increasing number of countries, but protocols vary across regions, borders and continents. This review describes recent advances in the rationale for newborn screening and then suggests solutions to the hurdles that need to be overcome by clinicians to ensure long-term clinical outcomes can be measured robustly whilst retaining the confidence of the funding authorities who have many calls on limited budgets. The review is written to address the concerns of the sceptics.
Recent Findings: Beneficial evidence for screening for cystic fibrosis in newborns is accumulating and will be highlighted to aid those about to introduce screening for cystic fibrosis in competition with other diseases. Future approaches are described to minimize the amount of DNA-based information held but without compromising screening efficacy. Finally, guidelines for a pilot dataset of information that must be collected on each screened infant will be proposed.
Summary: Standardization of international programs for newborns has not yet been achieved. Progress towards this goal is being made but many differences remain. Solutions to the practical difficulties of implementation of screening for newborns are described to help cystic fibrosis clinicians convince their colleagues of the merits of this practice.

Introduction

Newborn screening (NBS) for cystic fibrosis is being implemented worldwide. The list of benefits from NBS is increasing.[1**] These benefits include opportunities to reduce complications, since it is common for unscreened cystic fibrosis to be misdiagnosed for 12-15 months; better family rapport because the pediatrician is proactive in advising on future pregnancies; significantly less stunting that correlates with lower mortality;[2] avoiding cognitive decline from prolonged vitamin E deficiency;[1**] a better quality of life as a result of less intense intravenous therapy in early childhood;[3**] and for cystic fibrosis affected women, a higher chance of achieving a successful outcome in pregnancy;[3**] Thus, the misdiagnosis risk due to imperfections in NBS[4] no longer outweighs the benefits.[5*] Sceptics remain to be convinced, however. For example, concerns exist both outside[6] but also inside the cystic fibrosis community[7] that need to be addressed urgently to maintain faith in nascent NBS programmes, particularly amongst colleagues working without the benefits of screening in other diseases that may compete for limited NBS resources. This update addresses the arguments of sceptics. NBS is examined from a government resourcing perspective to describe the impediments facing a clinician who wants to introduce NBS for cystic fibrosis.

Striving for Best Practice in Cystic Fibrosis Newborn Screening

For most cases (>90% of true cystic fibrosis positives) the NBS outcome is clear: two severe mutations are found, confirmed by an independent test - the sweat test. The inclusion of DNA tests can, however, accidentally detect potentially mild cystic fibrosis. The problem with a DNA diagnosis is that the anticipated spectrum in the resultant cystic fibrosis phenotype can still remain uncertain because various mutations affect individual organs differently with an intensity that is only partially cystic fibrosis genotype dependent. For example, there are mutations that do not affect the gut or lung, but variably damage the male (but not female) genital tract: often called organ-confined cystic fibrosis, orphan cystic fibrosis, borderline cystic fibrosis and so on. Is it ethical to screen for a disease with no symptoms that may only present as male infertility in adult life? Such concerns have already created protocol divergence, for example between England (where NBS implementation is imminent) and the rest of the UK (which already has NBS). This divergence is based on a desire not to diagnose carriers or single organ cystic fibrosis which may not otherwise ever present with any cystic fibrosis-induced illness. English screening committees point to the near five-fold excess of 'mild cystic fibrosis' cases now being followed up in NBS populations in which screening has been in place for many years and who carry adult-presenting mild alleles such as R117H mutation in CFTR.[8**] This English decision fails to answer a key question, namely, are such 'mild' patients really always asymptomatic? Are they currently being misdiagnosed in asthma clinics, other services or adult idiopathic bronchiectasis clinics? Could they benefit from smoking/alcohol avoidance advice? Nevertheless, England will adopt an initial four (rather than 30+) CFTR mutation analysis, but globally, other health schemes may follow an exact converse protocol that screens widely for many mutations.[9]

Recently, a new challenge has been posed for clinicians caring for cystic fibrosis infants and government agencies alike because the time by which a successful early diagnosis of cystic fibrosis in the newborn period must lead on to treatment has been shortened by one-third. Previously, it was thought that it was safe to wait for up to 3 months before preventive treatment was initiated. New evidence, however, suggests that extra clinical benefit accrues provided treatment initiation is in place by 2 (rather than 3) months of postnatal life.[5*] This accelerated standard requires changes in NBS practice to cope with a shortened interval from NBS to first therapy. This creates a 'treatment race' in the view of one distinguished commentator, who discusses the underlying philosophy of NBS as an instrument of government rather than from a purely clinical perspective.[10**] For example, in some places NBS is mandated either by law (as in some US states) or applied with/without parental consent to neonatal populations,[10**] which means that if the evidence base changes, practice must follow to avoid legal redress from delayed therapy. Avoidance of delay has now to be factored in during the design of NBS. Potentially, this race to prevent harm not only poses an extra budgetary burden on those delivering the NBS service at the frontline (who are not cystic fibrosis experts) but also exacerbates time constraints posed by the peculiarity of the second step in cystic fibrosis NBS when compared with many coscreened diseases. This peculiarity stems from the problem that DNA analysis, often at a remote site from the initial blood spot screening laboratory (see countermeasures below), is used to discriminate between possible cystic fibrosis (stage 1) from true cystic fibrosis (stage 2) during the first 4-6 weeks of life. Ideally, both tests should be done in the same institution to minimize delay. Given the possible harm of getting it wrong,[11*] measures must be put in place with an equally robust NBS programme,[12**] to anticipate the few, but problematic patients with wrong/ambiguous diagnoses. Otherwise, unintended harm can lead to pressure to withdraw the cystic fibrosis NBS service. No such pressure exists for its coscreened equivalents for single enzyme disorders, such as phenylketonuria, hypothyroidism or medium chain acyl-CoA dehydrogenase deficiency (for which no DNA is involved in the testing phase and phenotype matches the test result more closely).

Improving the Screening Protocol to Persuade the Sceptics

An ideal cystic fibrosis test is both suitable for mass screening and yet never picks up an uncertain cystic fibrosis diagnosis. This does not exist. Practical advances are on the horizon after the stage 1 blood test has identified a 'possible cystic fibrosis' population. Currently, stage 1 positivity only equates to a raised immunoreactive trypsinogen (IRT) above an arbitrary (typically 99.5th percentile) cutoff for that local population; unfortunately, this threshold defines 'possibles' that are not exclusively reflective of cystic fibrosis-induced pancreatic damage because IRT also rises for other reasons. Numerous false positives lie in this population and the critical goal remains to minimize the risk of either a wrong diagnosis or an ambiguous result,[11*] whilst maintaining the true goal of NBS to harvest over 90% of truly afflicted cystic fibrosis cases but without alarming the families of healthy babies.[12**] This ideal remains elusive but practical steps are being taken to minimize significant protocol variation across programmes to spread best practice.[13*]

Even when quality control is optimal, the converse problem remains for missed cases after NBS. It is often assumed by the lay public and even some healthcare professionals without direct experience of cystic fibrosis that NBS will detect all cases of cystic fibrosis at birth. In areas with NBS, this notion can create complacency with a marked fall in the numbers of sweat tests ordered based on the false belief that a child presenting with cystic fibrosis-like symptoms cannot possibly have cystic fibrosis because 'they would have been picked up' at birth (unpublished data from Scottish NBS). It is good practice to audit sweat test frequency both before and after NBS is introduced, given that many children will remain undiagnosed in the community for many years after NBS begins.

The notion of complete cystic fibrosis ascertainment at stage 1 by NBS remains aspirational but is not practical for global implementation with current technology. The key problem is that the clinical load from the potential positives that result from too low a cutoff value for the stage 1 IRT test (95-99th centile that will detect virtually all cystic fibrosis cases) creates too large a pool of unaffected babies. Thus, too low a cutoff creates more harm than good and a balance has to be struck when selecting the 'most effective' cutoff. Inevitably, this means that some cystic fibrosis babies will be missed. To overcome this impasse, two independent signatures of cystic fibrosis blood pathology reflective of severe pancreatic damage in utero are required. Excitingly, new technology using coupled pancreatic enzyme assays in a proposed new initial IRT/pancreatic associated protein (PAP) screening test may help achieve the goal of eliminating most false positives.[14] The idea is that if a second enzyme (PAP), which also enters the blood of babies with a damaged pancreas, is also elevated, then the chances of having cystic fibrosis increase geometrically. This occurs even if the IRT result hovers around the cutoff level.

This nascent technology requires urgent independent validation because it offers a second great advantage. The new IRT/PAP assay creates the potential to eliminate the need for DNA testing of populations. Such a test should address the concerns of those opposed to mass DNA testing. Crucially this new test also has the potential to overcome the delay between a repeat blood spot test required in current protocols for any ambiguous result, at stage 1 (which increases family anxiety) and any subsequent difficulties in interpretation of the genotype-phenotype at stage 2 (when healthy cystic fibrosis carriers or mild cases are detected randomly). This delay and uncertainty creates a potential for harm unless carefully managed. Cystic fibrosis is a complex disease and these 'harm-benefit' equations also manifest in daily cystic fibrosis practice given the widespread reluctance of noncystic fibrosis professionals to counsel such families.[15*] This natural reluctance is compounded by the variable availability of trained counsellors. For example, despite reassurance, the parents of healthy cystic fibrosis carriers, discovered by chance, often think that their baby really is ill. Parents are rarely told that as cystic fibrosis carriers, their baby is in some way 'super-normal' by virtue of an, albeit unknown, heterozygote advantage. This is almost never explained to carriers and can be a source of much parental comfort when applied to an accidental cystic fibrosis carrier diagnosis. This information, coupled with the advance notice for that carrier about future reproductive decisions, can be doubly beneficial to parents if explained with sensitivity.

NBS protocols also require extra vigilance in ethnically mixed populations, which are increasing in prevalence. This creates global issues for screeners across continents.[16] Encouragingly, the extra effort may be worth the cost because we found that those cystic fibrosis cases arising from such ethnic minorities may disproportionately benefit from NBS perhaps because cystic fibrosis is so difficult to diagnose in such groups.[17] Overall, to cope with this increasing trend to admixture of genes across continents,[18] a new breed of generically trained, linguistically and genetically agile counsellors will be needed, especially for those babies in which the diagnosis remains uncertain despite the best technology.

These differences in professional view across the clinical-government divide are reflected in a recent Lancet commentary on cystic fibrosis NBS from Wilcken and Gaskin,[19*] who have been screening in Australia for many years. They state that 'it remains an enigma that NBS for CF has until now been so controversial' and note that the evidence for clinical[1**] and, most recently, substantial economic benefit[20**] has been largely ignored. Recent evaluation of that evidence[21*] concludes that during early childhood, screening benefits are too numerous to ignore. Importantly, for cash-limited healthcare budgets in countries without NBS, the most recently calculated cystic fibrosis-specific additional screening costs may be substantially offset by reduced treatment burden during early childhood, given that blood is already drawn for other screened diseases after birth.[20**] Others have commented that integration of cystic fibrosis NBS programmes with other screening initiatives may ultimately reduce therapeutic costs, given that the prevalence of cystic fibrosis will inevitably decline over succeeding generations should families choose not to have a second child.[22] This multiplicity of screened diseases also has relevance to the trade off made by patients when offered more than one screening choice.[23*] Protocols for NBS in cystic fibrosis must therefore be based on a firm philosophy that clearly describes the rationale for carrying out the procedure. When cystic fibrosis outcomes are unknown (mild alleles etc. above), data collection is mandatory and must be factored into the NBS design.

Suggested Mandatory Data Collection Following Newborn Screening Diagnoses

Given the genotype-phenotype discordance, all screen-positive babies must have their clinical data aggregated at national and (increasingly) international levels to provide meaningful outcome comparisons. It should be mandatory to ensure prospective, efficient data collection after a true diagnosis, but especially after any cystic fibrosis 'diagnosis' that remains ambiguous. The underlying principle is that it is futile to screen unless the screener can measure success or otherwise; this process takes years. Success has two components: firstly, monitoring and minimizing the technological failure rate and, secondly, 100% ascertainment of entry into a treatment programme in the new 2-month window. Central to both standards is the issue of informed consent to collect long-term outcome data. A robust infrastructure to the consent process is available for Europe (see http://www.eurocarecf.eu/wp2/index.html) that is suitable for amendment to comply with country-specific laws whilst ensuring research/audit needs are met to inform future generations. This consent form thus permits the screener to collect and utilize clinical data to answer important outcome questions to which the answer is unknown. This model has been tested in the UK cystic fibrosis population for over a decade.[20**]

What Standards Could be Proposed for Data Collection After Newborn Screening?

A pilot dataset is available which addresses difficulties in NBS data collection (http://www.cystic-fibrosis.org.uk/pdfs/Scottish%20
screening/Scottish%20ScreeningData%20Form.pdf
). NBS can be broken down into three time-based and geography-based phases running in parallel with the cystic fibrosis baby's clinical journey. Data are collected in each phase by different professionals located in disparate geographical sites. Each professional reports data only on their own competency-based outputs, independently to a common database. Each must be persuaded to provide a well demarcated data-gathering role in the overall screening implementation process after a given positive diagnosis. This is essential. The dataset lies on a paper form which verifies activity in three different locations and three different times - from where the baby was born (category 1), from where the screening was done (category 2), and from where the baby was treated (category 3). Only when all three data items are returned, collated and analysed can the percentage of cases with a true positive diagnosis that received treatment in a timely fashion be ascertained. The great advantage for the funding authority is that a single centralized source of data creates a 'sum check' such that families can be reassured that they have enrolled optimally in care within the gold standard of the new 2-month window. Unless such audit and research-enabling design is planned and integrated from the outset into a screening programme, much of the evidence for NBS benefit will be dissipated. Finally, this centralized outcome data must then be fed to a national registry. The resultant publications can then inform the final debate.[20**] In the longer term, efforts are underway to unite such cystic fibrosis data held across 35 European countries and the North American CF Database (PortCF). Further practical advice is available at http://www.ich.ucl.ac.uk/newborn/cf/index.htm.

Conclusion

Ultimately, the goal must be united protocols and screening policy across the globe with transparent, audited efficacy to aid screeners such that in a few years, all cystic fibrosis-affected neonates will be followed by high-quality databases/registries such as PortCF. Only then will it be possible to measure outcomes, robustly and without ascertainment bias. A key benefit will be the easy availability of such babies for entry into clinical trials. The global application of proposed standards of data collection will hasten the day when an effective means can be proven to control the symptoms of cystic fibrosis.

References

Papers of particular interest, published within the annual period of review, havebeen highlighted as:
* of special interest
** of outstanding interest

  1. ** Grosse SD, Rosenfeld M, Devine OJ, et al. Potential impact of newborn screening for cystic fibrosis on child survival: a systematic review and analysis. J Pediatr 2006; 149:362-366.
    A good review and source material highlighting, amongst others, the cognitive benefits from NBS.
  2. Beker LT, Russek-Cohen E, Fink RJ. Stature as a prognostic factor in cystic fibrosis survival. J Am Diet Assoc 2001; 101:438-442.
  3. ** Sims EJ, Clark A, McCormick MD, et al. Cystic fibrosis diagnosed after two months of age leads to worse outcomes and requires more therapy. Pediatrics 2007; 119:19-28.
    Cited by Farrell in Ref.[5*] as the key data decreasing the interval for a NBS diagnosis from 3 to 2 months.
  4. Farrell MH, Farrell PM. Newborn screening for cystic fibrosis: ensuring more good than harm. J Pediatr 2003; 143:707-712.
  5. * Farrell PM. The meaning of an early diagnosis in a new era of cystic fibrosis care. Pediatrics 2007; 119:156-157.
    This study from the modern champion of screening at birth reviews the history of Harry Shwachmann's seminal contribution to the screening process and comments on recent advances.
  6. Twomey JG. How wise is it to screen all newborns for cystic fibrosis? Newborn and infant nursing reviews 2002; 2:214-220.
  7. Southern K. The challenge of screening newborn infants for cystic fibrosis. In: Hodson M, Geddes D, Bush A, editors. Cystic fibrosis. 3rd ed. London: Hodder Arnold Publishers; 2007.
  8. ** Scottet V, Audrezet M-P, Roussey M, et al. Immunoreactive trypsin/DNA newborn screening for cystic fibrosis: should R117H variant be included in CFTR mutation panels? Pediatrics 2006; 118:1523-1529.
    A key question that needs to be addressed by prospective data in future studies that is causing disparity of protocols across regions of a single country.
  9. Kammesheidt A, Kharrazi M, Graham S, et al. Comprehensive analysis of the cystic fibrosis transmembrane conductance regulator from dried blood spot specimens -implications for newborn screening. Genet Med 2006; 8:557-562.
  10. ** Vailly J. Genetic screening as a technique of government: the case of neonatal screening in France. Soc Sci Med 2006; 63:3092-3101.
    An excellent disposition of the context of power relations in a Foucault-based philosophy as applied by the state to its subjects.
  11. * Moran J, Quirk K, Duff JA, et al. Newborn screening for CF in a regional pediatric centre: the psychosocial effects of false positive IRT results on parents. J Cystic Fibros 2007; 6:250-254.
    This paper highlights an important but neglected aspect of the screening process when the fallibility of the screening process is exposed.
  12. ** Comeau AM, Accurso FJ, Whitew TB, et al. Guidelines for implementation of cystic fibrosis newborn screening programs: Cystic Fibrosis Foundation workshop report. Pediatrics 2007; 119:495-518.
    An outstanding review of the practice of screening.
  13. * Southern KW, Munck A, Pollitt R, et al. A survey of newborn screening for cystic fibrosis in Europe. J Cystic Fibros 2007; 6:57-65.
    Highlights the fragmented nature of the screening process and the unmet need for universal standards.
  14. Sarles J, Berthezene P, Le Louarn C, et al. Combined immunoreactive trypsinogen and pancreatitis-associated protein assays, a method of newborn screening for cystic fibrosis that avoids DNA analysis. J Pediatr 2005; 147:302-305.
  15. * Kemper AR, Uren RL, Moseley KL, Clark SJ. Primary care physicians attitudes regarding follow-up care for children with positive screening results. Pediatrics 2006; 118:1836-1841.
    An important practical paper showing what needs to be done before screening to make service provision adequate.
  16. Guisti R, Badgwell A, Iglesias AD. New York State Cystic Fibrosis Consortium. The first 2.5 years of experience with cystic fibrosis newborn screening in an ethnically diverse population. Pediatrics 2007; 119:460-467.
  17. McCormick JD, Ogston SA, Sims EJ, Mehta A. Asians with cystic fibrosis in the UK have worse disease outcomes than clinic matched white homozygous Delta F508 controls. J Cystic Fibros 2005; 4:53-58.
  18. McCormick J, Green MW, Mehta G, et al. Demographics of the UK cystic fibrosis population: implications for neonatal screening. Eur J Hum Genet 2002; 10:583-590.
  19. * Wilcken B, Gaskin K. More evidence to favour newborn screening for cystic fibrosis. Lancet 2007; 369:1146-1147.
    Reviews the relationship between screening costs and geography in relation to Ref.[20**] and other work
  20. ** Sims EJ, Mugford M, Clarke A, et al. Economic implications of newborn screening for cystic fibrosis: a cost of illness retrospective cohort study. Lancet 2007; 369:1187-1195. Cited by Ref.[19*] as an update showing how earlier diagnosis reduces costs of therapy, thus reducing screening program outlay.
  21. * US National Newborn Screening and Genetics Resource Center. National newborn screening status report. http://genes-r-us.uthscsa.edu/nbsdisorders.htm. [Accessed 27 July 2007]
    An excellent reference source (see also UK equivalent at the UK National Screening Centre for practical aspects http://www.ich.ucl.ac.uk/newborn/cf/index.htm ).
  22. Dupuis A, Hamilton D, Cole DEC, et al. Cystic fibrosis birth rates in Canada: a decreasing trend since the onset of genetic testing. J Pediatr 2005; 147:212-315.
  23. * Hall J, Fiebig DG, King MT, et al. What influences participating in genetic carrier testing? Results from a discrete choice experiment. J Health Econ 2006; 25:520-537.
    An important contribution showing that the increasing burden of screening for multiple defects creates difficulties and trade offs for parents at a stressful time.

Acknowledgements

I must thank many colleagues, too numerous to list, for stimulating debate.

Abbreviation Notes

CFTR = cystic fibrosis transmembrane conductance regulator; IRT = immunoreactive trypsinogen; NBS = newborn screening (service); PAP = pancreatic associated protein.

Reprint Address

Correspondence to: Anil Mehta, MBBS, MSc, FRCPCH, FRCP (Edin), Reader and Honorary Consultant Paediatrician, Division of Maternal and Child Health Sciences, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK Tel: +44 1382 632555/632179; e-mail: a.mehta@dundee.ac.uk


Anil Mehta, Division of Maternal and Child Health Sciences, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK