Review
Newborn screening for cystic fibrosis

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Summary

Since the late 1970s when the potential of the immunoreactive trypsinogen assay for early identification of infants with cystic fibrosis was first recognised, the performance of newborn blood spot screening (NBS) has been continually assessed and its use has gradually expanded. NBS for cystic fibrosis is a cost-effective strategy and, if standards of care are fully implemented and robust management pathways are in place, has a positive effect on clinical outcomes. In the past decade, NBS has undergone rapid expansion and an unprecedented number of infants with cystic fibrosis have access to early diagnosis and care. Cystic fibrosis NBS has now moved on from the development phase and is entering an era of consolidation. In the future, research should focus on the rationalisation and optimisation of existing programmes, with particular attention to bioethical implications such as unwanted detection of carriers and inconclusive diagnoses.

Introduction

A proactive multidisciplinary approach has long been promoted for the care of people with cystic fibrosis.1, 2 In the past three decades, increasing evidence that well-nourished and active patients enjoy a better quality of life, respiratory function, and survival has emerged to support this strategy.3, 4 Early researchers in cystic fibrosis believed newborn blood spot screening (NBS) was a valid strategy to help achieve these goals. The characterisation of the immunoreactive trypsinogen (IRT) assay in 1979 provided laboratories with a potential screening test to identify infants with cystic fibrosis in the first weeks of life, often before they presented with clinical signs.5 The IRT assay seemed to have better sensitivity than other screening tests that had previously been used to identify infants with cystic fibrosis (eg, measuring meconium albumin or lactase levels)6, 7 and was included in the NBS schedule already established for other diseases such as phenylketonuria. However, concerns were raised that screening of infants for cystic fibrosis might not have sufficient effect on clinical outcomes to meet the criteria required to advocate universal screening. This concern prompted a call for evidence to show that NBS was beneficial for children with cystic fibrosis.

Section snippets

Clinical trials and epidemiological studies

Two pseudo-randomised clinical trials were initiated in the 1980s. A trial in the UK screened newborn babies for cystic fibrosis on alternate weeks.8 After 4 years, no substantial differences were reported in the nutritional or respiratory outcomes of 58 infants with cystic fibrosis identified by screening compared with 44 children diagnosed clinically.8 Simultaneously, in a trial in Wisconsin, a substantial nutritional benefit was noted in the cohort of 56 infants who were diagnosed early

The IRT assay

The IRT assay provides the framework on which all NBS for cystic fibrosis is currently based.19 Elevated IRT is thought to be related to the pancreatic damage often present in infants with cystic fibrosis, but it can also identify infants with a milder, pancreatic sufficient phenotype and some carriers.20 Automated immunoassays enable large numbers of samples to be processed as part of a NBS programme.21 A better quality of dried blood spot sample is needed for the IRT assay compared with other

Strategies to reduce false-negative and false-positive rates

Similar to most public health interventions, a flawless cystic fibrosis NBS programme is unrealistic if not unachievable. Accurate strategic choices might optimise the effectiveness of cystic fibrosis NBS, however, some false negatives and false positives and infants in whom cystic fibrosis cannot be confirmed or excluded are inherent in screening programmes. Tolerance of a few missed cases might be instrumental in limiting unwanted effects of NBS, such as inconclusive cases. Table 1 shows how

Carriers

Genetic analysis is considered inappropriate in children, unless it has health advantages. This is the case for cystic fibrosis NBS, in which the inclusion of mutation analysis usually improves the performance of the protocol. Inevitably, some infants who have a normal sweat test will have one CFTR mutation detected. These children are carriers, a widely recognised incidental finding for programmes that include mutation analysis. Reports suggest that the rate of carrier recognition is higher

Population carrier screening and NBS

Early diagnosis might be possible through antenatal cystic fibrosis carrier screening. Couples are offered testing for common CFTR mutations and those identified to be carriers might choose prenatal diagnosis. If parents opt not to terminate an affected fetus, the opportunity for very early care is available. Although formal cystic fibrosis carrier screening programmes are less widely available than NBS, many couples of reproductive age are offered the carrier test in the USA and in some areas

NBS in the context of CFTR modulator therapies

The development of therapeutic options that target the underlying defect in cystic fibrosis has put the potential for early disease control into sharp perspective. These therapies, which target the basic pathophysiology of cystic fibrosis, could substantially reduce morbidity and mortality in individuals with specific mutations. The use of ivacaftor in patients carrying class III mutations has become the model of a personalised medicine approach to cystic fibrosis care, and more compounds

The future: consolidation of a complex system

Cystic fibrosis NBS has been through three phases: discovery, assessment, and expansion. After a slow start, cystic fibrosis NBS has expanded rapidly over the past decade. Data from a European Cystic Fibrosis Society Neonatal Screening Working Group survey showed that over 5 million European newborn babies and 4 million US newborn babies were screened for CF in 2012.11 Furthermore, it has been estimated that worldwide over 12 million newborn infants were screened in 2014.11 The use of cystic

Search strategy and selection criteria

We searched PubMed for reports published in English between Jan 1, 1979, and July 31, 2015, with the search terms “newborn screening” AND “cystic fibrosis”. We also identified relevant trials and studies through hand searches of relevant journals (from 2000 to 2015) and abstract books of conference proceedings (from 1990 to 2015), including the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference between 1990 and 2015. Selection for inclusion was on the basis of

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