Implementation of the French Nationwide Cystic Fibrosis Newborn Screening Program

doi:10.1016/j.jpeds.2008.02.028

The Journal of Pediatrics

Volume 153, Issue 2, August 2008, Pages 228-233.e1

https://doi.org/10.1016/j.jpeds.2008.02.028 Get rights and content

Objectives

To describe optimization of a nationwide newborn screening program for cystic fibrosis (CF) that combines an immunoreactive trypsinogen (IRT) assay and DNA mutation analysis in dried blood samples at day 3.

Study design

Data from regional screening laboratories and CF care centers were centralized and periodically analyzed to allow adaptation, thus limiting the number of false-positive cases.

Results

A total of 2 717 905 infants were screened between 2002 and 2005. Flow chart protocol was modified twice. First, the IRT d3 cutoff value increased from 60 to 65 μg/L, thus decreasing the percentage of samples requiring mutation analysis from 0.82% to 0.64%. Second, for infants with no mutations using the screening panel, a recall for IRT was performed only if IRT d3 was > 100 μg/L; the percentage of recalls decreased from 0.51% to 0.12%, and the percentage of infants requiring a sweat test decreased from 0.14% to 0.01%. No significant change in the CF detection rate was observed after these 2 modifications. A total of 625 CF cases were detected, and 22 false-negative findings (3.4%) were observed, most of them inevitable, with a low initial IRT.

Conclusions

The centralized data analysis led to changes in the screening strategy to optimise the newborn screening program.

Section snippets

Patients

All neonates born in France and La Reunion Island between the time of implementation of systematic CF newborn screening (region by region from mid-2002 to early 2003) and December 31, 2005 were included in this study.

Screening Strategy

The main lines of the organization have been described previously.¹¹ Dried blood samples (on Whatman 903 filter paper) were obtained at age 3 days. To fulfil requirements of French bioethical legislation for genetic analysis, written informed parental consent for DNA testing was

Overall Results

Among the 2 717 905 screened newborns, 18 610 (0.7%) had an elevated IRT value; CFTR gene analysis was performed in 18 177 of these newborns (97.7%). Three periods can be identified according to changes in cutoff values introduced after a review of screening data (Table I). The first period, starting on initiation of the program, used 60 μg/L as the IRT cutoff at day 3 and 30 μg/L as the cutoff at day 21, taking into account the known decrease in IRT with age in CF patients. Data analysis revealed

Discussion

Evidence that newborn CF screening provides nutritional and also likely pulmonary4, 5, 7, 18 benefits related to early follow-up care led the Centers for Disease Control and Prevention to conclude that “on the basis of evidence of moderate benefits and low risk of harm, newborn screening for CF is justified.”¹⁹ France is one of the first countries in Europe to have set up a free nationwide program that includes genetic analysis.²⁰

Early screening methodology used a 2-stage IRT-based screen, in

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Cited by (58)

Cystic fibrosis and pregnancy: Outcome, prognostic factors and obstetrical management
2020, Gynecologie Obstetrique Fertilite et Senologie
La survenue d’une grossesse chez une patiente atteinte de mucoviscidose est une éventualité de plus en plus fréquente compte tenu des avancées thérapeutiques et de l’augmentation de la proportion de patientes en âge de procréer. Les premières publications étaient très pessimistes sur le devenir d’une patiente enceinte lorsqu’elle en est atteinte. Elles ont rapporté une diminution des capacités respiratoires et de la survie maternelle à la suite de la grossesse, ainsi qu’une augmentation importante de la morbidité fœtale. Actuellement, les études récentes sont plutôt encourageantes. L’objectif de cette mise au point est d’évaluer, à travers une revue de la littérature récente, les conséquences de la grossesse sur les différents aspects de la maladie et inversement le retentissement de la mucoviscidose sur le déroulement de la grossesse ce afin d’apporter un conseil médical approprié à ces patientes et d’adapter leur prise en charge obstétricale.
As a result of improvements in life expectancy and therapies, increasing numbers of patients with cystic fibrosis become pregnant. The first studies were pessimistic and report adverse outcomes on the fetus and the mother. In the recent publications, long-term outcome for women with cystic fibrosis does not appear to be negatively impacted by pregnancy. Furthermore, the number of women successfully completing pregnancy continues to rise. The aim of this review is to assess the outcome of pregnancy in women with cystic fibrosis and the impact of pregnancy on the disease. It is hoped it will improve the counseling for pregnant women with cystic fibrosis and their obstetrical management.
Newborn screening for CF in France: An exemplary national experience
2020, Archives de Pediatrie
Newborn screening (NBS) for cystic fibrosis (CF) was implemented throughout France since 2002, with a 3-tiered strategy consisting in an immunoreactive trypsinogen (IRT) measurement at day-3, a search for the most common mutations responsible for CF when the IRT value is above the cut-off level, and, if necessary, a safetynet retesting of IRT at day-21. Coordination and follow-up are ensured at the national level and NBS is carried out through a regional organization involving NBS centers, biochemical and molecular genetics laboratories. Sweat testing and comprehensive mutation gene analysis are then performed according to a defined algorithm. Between 2002 and 2014, screening for the 30 most common mutations identified 87% of the alleles and comprehensive mutation gene analysis performed when applicable identified more than 300 additional mutations and resulted in a detection rate of 99.8% of the mutated alleles. Program surveillance ensured at a national level allowed to carry out adaptation of cut-off levels and removal of the p.Arg117His mutation. Thanks to these modifications, the performance of the French NBS program for CF meets the European guideline standards regarding positive predictive values, sensitivity and time to initial visit at the CF center, thus making the strategy effective.
© 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.
Preface
2020, Archives de Pediatrie
Diagnosis of Cystic Fibrosis in Screened Populations
2017, Journal of Pediatrics
Citation Excerpt :
In all cases, sensitivity and specificity of algorithms using VHIRT must be evaluated, as has been done in New York.42 The use of VHIRT as a safety net also has been used elsewhere, including France45 and the United Kingdom.46 In the United Kingdom, the national NBS program uses a safety net for infants with a VHIRT value but no mutations identified on a limited mutation panel.
Cystic fibrosis (CF) can be difficult to diagnose, even when newborn screening (NBS) tests yield positive results. This challenge is exacerbated by the multitude of NBS protocols, misunderstandings about screening vs diagnostic tests, and the lack of guidelines for presumptive diagnoses. There is also confusion regarding the designation of age at diagnosis.
To improve diagnosis and achieve standardization in definitions worldwide, the CF Foundation convened a committee of 32 experts with a mission to develop clear and actionable consensus guidelines on diagnosis of CF with an emphasis on screened populations, especially the newborn population. A comprehensive literature review was performed with emphasis on relevant articles published during the past decade.
After reviewing the common screening protocols and outcome scenarios, 14 of 27 consensus statements were drafted that apply to screened populations. These were approved by 80% or more of the participants.
It is recommended that all diagnoses be established by demonstrating dysfunction of the CF transmembrane conductance regulator (CFTR) channel, initially with a sweat chloride test and, when needed, potentially with newer methods assessing membrane transport directly, such as intestinal current measurements. Even in babies with 2 CF-causing mutations detected via NBS, diagnosis must be confirmed by demonstrating CFTR dysfunction. The committee also recommends that the latest classifications identified in the Clinical and Functional Translation of CFTR project [http://www.cftr2.org/index.php] should be used to aid with CF diagnosis. Finally, to avoid delays in treatment, we provide guidelines for presumptive diagnoses and recommend how to determine the age of diagnosis.
Newborn screening for cystic fibrosis
2016, The Lancet Respiratory Medicine
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.
A false positive newborn screening result due to a complex allele carrying two frequent CF-causing variants
2016, Journal of Cystic Fibrosis
The detection of two frequent CFTR disease-causing variations in the context of a newborn screening program (NBS) usually leads to the diagnosis of cystic fibrosis (CF) and a relevant genetic counseling in the family. In the present study, CF-causing variants p.Phe508del (F508del) and c.3140-26 A > G (3272-26 A > G) were identified on a neonate with positive ImmunoReactive Trypsinogen test by the Elucigene™ CF30 kit. The CF diagnosis initially suggested, despite three inconclusive Sweat Chloride Tests (SCT), was finally ruled out after the familial segregation study combined with a negative SCT. Haplotype studies, based on the comparison of 80 p.Phe508del haplotypes, suggested a probable de novo occurrence of c.3140-26 A > G on the p.Phe508del ancestral allele in this family.
This false positive case emphasizes the importance of SCT in the NBS strategy. Moreover, it raises the need for familial segregation studies in CF and in overall molecular diagnosis strategy of autosomal recessive diseases.

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Original articleImplementation of the French Nationwide Cystic Fibrosis Newborn Screening Program

Objectives

Study design

Results

Conclusions

Section snippets

Patients

Screening Strategy

Overall Results

Discussion

J Pediatr

J Pediatr

J Pediatr

Lancet

Arch Pediatr

Mol Cell Probes

J Pediatr

J Pediatr

J Pediatr

J Cyst Fibros

J Pediatr

J Pediatr

J Pediatr

Cystic fibrosis: what is the incidence?

Arch Fr Pediatr

Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growthWisconsin Cystic Fibrosis Neonatal Screening Study Group

Pediatrics

Comparing the clinical evolution of cystic fibrosis screened neonatally to that of cystic fibrosis diagnosed from clinical symptoms: a 10-year retrospective study in a French region (Brittany)

Pediatr Pulmonol

Long-term prognosis of patients with cystic fibrosis in relation to early detection by neonatal screening and treatment in a cystic fibrosis centre

Thorax

Original article
Implementation of the French Nationwide Cystic Fibrosis Newborn Screening Program