Retrospective analysis of stored dried blood spots from children with cystic fibrosis and matched controls to assess the performance of a proposed newborn screening protocol in Switzerland

BackgroundNewborn screening (NBS) for Cystic Fibrosis (CF) has been introduced in many countries, but there is no ideal protocol suitable for all countries. This retrospective study was conducted to evaluate whether the planned two step CF NBS with immunoreactive trypsinogen (IRT) and 7 CFTR mutations would have detected all clinically diagnosed children with CF in Switzerland.MethodsIRT was measured using AutoDELFIA Neonatal IRT-Kit in stored NBS cards.ResultsBetween 2006 and 2009, 66 children with CF were reported, 4 of which were excluded for various reasons (born in another country, NBS at 6 months, no informed consent). 98% (61/62) had significantly higher IRT compared to matched control group. There was one false negative IRT result in an asymptomatic child with atypical CF (normal pancreatic function and sweat test).ConclusionsAll children but one with atypical CF would have been detected with the planned two step protocol.     

Cost effectiveness of newborn screening for cystic fibrosis: A simulation study

BackgroundEarly detection of cystic fibrosis (CF) by newborn screening (NBS) reduces the rate of avoidable complications. NBS protocols vary by jurisdiction and the cost effectiveness of these different protocols is debated.ObjectiveTo compare the cost effectiveness of various CF NBS options.MethodsA Markov model was built to simulate the cost effectiveness of various CF-NBS options for a hypothetical CF-NBS program over a 5-year time horizon assuming its integration into an existing universal NBS program. NBS simulated options were based on a combination of tests between the two commonly used immunoreactive trypsinogen (IRT) cutoffs (96th percentile and 99.5th percentile) as first tier tests, and, as a second tier test, either a second IRT, pancreatic-associated protein (PAP) or CFTR mutation panels. CFTR mutation panels were also considered as an eventual third tier test. Data input parameters used were retrieved from a thorough literature search. Outcomes considered were the direct costs borne by the Quebec public health care system and the number of cases of CF detected through each strategy, including the absence of screening option.ResultsIRT–PAP with an IRT cutoff at the 96th percentile is the most favorable option with a ratio of CAD$28,432 per CF case detected. The next most favorable alternative is the IRT1–IRT2 option with an IRT1 cutoff at the 96th percentile. The no-screening option is dominated by all NBS screening protocols considered. Results were robust in sensitivity analyses.ConclusionThis study suggests that NBS for cystic fibrosis is a cost-effective strategy compared to the absence of NBS. The IRT–PAP newborn screening algorithm with an IRT cutoff at the 96th percentile is the most cost effective NBS approach for Quebec.     

A survey of newborn screening for cystic fibrosis in Europe.

BACKGROUND: Cystic fibrosis (CF) is a recessively inherited condition caused by mutation of the CFTR gene. Newborn infants with CF have raised levels of immuno-reactive trypsinogen (IRT) in their serum. Measurement of IRT in the first week of life has enabled CF to be incorporated into existing newborn screening (NBS) blood spot protocols. However, IRT is not a specific test for CF and NBS therefore requires a further tier of tests to avoid unnecessary referral for diagnostic testing. Following identification of the CFTR gene, DNA analysis for common CF-associated mutations has been increasingly used as a second tier test. The aim of this study was to survey the current practice of CF NBS programmes in Europe. METHOD: A questionnaire was sent to 26 regional and national CF NBS programmes in Europe. RESULTS: All programmes responded. The programmes varied in number of infants screened and in the protocols employed, ranging from sweat testing all infants with a raised first IRT to protocols with up to four tiers of testing. Three different assays for IRT were used; in the majority (24) this was a commercially available kit (Delfia). A number of programmes employed a second IRT measurement in the 4th week of life (as the IRT is more specific at this point). Nineteen programmes used DNA analysis for common CFTR mutations on samples with a raised first IRT. Three programmes used a second IRT measurement on infants with just one recognised mutation to reduce the number of infants referred for sweat testing. Referral to clinical services was prompt and diagnosis was confirmed by sweat testing, even in infants with two recognised mutations in most programmes. Subsequent clinical pathways were less uniform. Multivariate analysis demonstrated a relationship between the age of diagnosis and the timing of the first IRT. More sweat tests were undertaken if the first IRT was earlier and the diagnosis was later. CONCLUSIONS: Annually these programmes screen approximately 1,600,000 newborns for CF and over 400 affected infants are recognised. The findings of this survey will guide the development of European evidence based guidelines and may help new regions or nations in the development and implementation of NBS for cystic fibrosis.     

European best practice guidelines for cystic fibrosis neonatal screening

There is wide agreement on the benefits of NBS for CF in terms of lowered disease severity, decreased burden of care, and reduced costs. Risks are mainly associated with disclosure of carrier status and diagnostic uncertainty. When starting a NBS programme for CF it is important to take precautions in order to minimise avoidable risks and maximise benefits.In Europe more than 25 screening programmes have been developed, with quite marked variation in protocol design. However, given the wide geographic, ethnic, and economic variations, complete harmonisation of protocols is not appropriate. There is little evidence to support the use of IRT alone as a second tier, without involving DNA mutation analysis. However, if IRT/DNA testing does not lead to the desired specificity/sensitivity ratio in a population, a screening programme based on IRT/IRT may be used.Sweat chloride concentration remains the gold standard for discriminating between NBS false and true positives, but age-related changes in sweat chloride should be taken into account. CF phenotypes associated with less severe disease often have intermediate or normal sweat chloride concentrations. Programmes should include arrangements for counselling and management of infants where the diagnosis is not clear-cut.All newborns identified by NBS should be managed according to internationally accepted guidelines. CF centre care and the availability of necessary medication are essential prerequisites before the introduction of NBS programmes.Clear explanation to families of the process of screening and of implications of normal and abnormal results is central to the success of CF NBS programmes. Effective communication is especially important when parents are told that their child is affected or is a carrier. When establishing a NBS programme for CF, attention should be given to ensuring timely and appropriate processing of results, to minimise potential stress for families.     

Pilot newborn screening project for cystic fibrosis in the Czech Republic: Defining role of the delay in its symptomatic diagnosis and influence of ultrasound-based prenatal diagnosis on the incidence of the disease

The objective need for cystic fibrosis (CF) newborn screening (NBS) in the Czech Republic has recently been substantiated by a significant delay of its symptomatic diagnosis. This trend most likely resulted from the process of decentralisation of health care which led to the deterioration of care for patients who need specialised approaches. Applied newborn screening model (IRT/DNA/IRT) was efficacious enough to detect CF cases with median age at diagnosis of 37 days. The incidence of CF (1 in 6946 live births) ascertained in this project was lower than that established previously by epidemiological studies (1 in 2700–1 in 3300). However, adjustment for broadly applied ultrasound-based prenatal diagnosis (PND) in the 2nd trimester of pregnancy, that was performed within the period of the project (1/2/2005–2/11/2006), rendered an incidence estimate of 1 in 4023. This value is closer to that observed in other CF NBS programmes and reflects influence of PND on the incidence of CF.     

Final results of the southwest German pilot study on cystic fibrosis newborn screening – Evaluation of an IRT/PAP protocol with IRT-dependent safety net

BackgroundPrevious studies suggest that PAP-based CF protocols are suitable for newborn screening (NBS) for cystic fibrosis (CF) when newborns designated as CFSPID should not be detected. However, there are still discussions about the performance of IRT/PAP algorithms. We present the final results of a pilot study evaluating a IRT/PAP protocol with an IRT-dependent safety net (SN) conducted from 2008 to 2016 in southwestern Germany on nearly 500,000 newborns.MethodsTo achieve reliable data, all newborns were screened using both the PAP-based and a DNA-based CFNBS algorithm. PAP quantification and genetic analysis of the four most common CFTR mutations in Germany were performed in all newborns with IRT≥99.0 percentile. NBS was rated positive if either PAP was ≥1.6 µg/l and/or at least one CFTR mutation was detected. In addition, an IRT-dependent SN resulted in positive rating for both protocols if IRT was ≥99.9 percentile. To evaluate the IRT/PAP protocol, its performance was compared to that of the IRT/DNA protocol.ResultsThe IRT/PAP protocol with IRT-based SN used in the study achieved a sensitivity of 94%, if false-negative detected neonates with meconium ileus and those designated as CFSPID were excluded from analysis. CF/CFSPID ratio was 92. However, PPV of the IRT/PAP+SN protocol was with 10.3% very low.ConclusionsPAP-based CFNBS protocols can be used, if less detection of CFSPID is desired. The IRT/PAP protocol with IRT-dependent SN evaluated here achieved adequate sensitivity but should probably be used in combination with a third-tier test to also achieve an acceptable PPV.     

Comparing age of cystic fibrosis diagnosis and treatment initiation after newborn screening with two common strategies

BackgroundNewborn screening (NBS) for CF has become widespread, although there are multiple strategies. Little is known about outcomes such as age of diagnosis after different NBS methods.MethodsWe used the U.S. Cystic Fibrosis Foundation Patient Registry to identify infants with CF born between 2001 and 2008 in states that utilized NBS. We compared ages at diagnosis, genotyping, sweat test, and first visit to a CF Centre between states that used serial immunoreactive trypsinogen (IRT/IRT) levels and states that used IRT and DNA analysis (IRT/DNA).ResultsWe identified 1288 infants with CF. Compared to infants born in IRT/IRT states, infants born in IRT/DNA states were younger at the time of diagnosis (median 2.3 weeks versus 4.0 weeks in IRT/IRT states, p < 0.001), genotyping (0.7 weeks versus 5.3 weeks, p < 0.001), and initial CF Centre visit (5.9 weeks versus 7.7 weeks, p = 0.008).ConclusionsAlthough there is room to improve outcomes with both strategies, infants born in IRT/DNA states have treatment initiated at a younger age than infants born in IRT/IRT states.     

A high frequency of the Cystic Fibrosis 2184insA mutation in Western Ukraine: Genotype–phenotype correlations,relevance for newborn screening and genetic testing

We present the first comprehensive report on the distribution and genotype–phenotype correlations of CF-causing mutations in Western Ukraine (former Galicia). The 2184insA mutation was identified in 17 unrelated CF patients, 2 of whom are homozygotes for this allele. This mutation is associated with the classical form of CF. The high frequency of 2184insA mutation (7.20% of all mutated CF chromosomes) suggests that it is likely of Galician origin, from where it has spread throughout Europe and beyond. The achieved 83.71% mutation detection rate fulfills the minimal pre-requisite for introduction of the “two-tier” (IRT/DNA) newborn screening program.     

Cystic fibrosis screen positive inconclusive diagnosis (CFSPID): Experience in Tuscany,Italy

ObjectiveThe implementation of cystic fibrosis (CF) newborn screening (NBS) has led to identification of infants with a positive NBS test but inconclusive diagnosis classified as “CF screen positive, inconclusive diagnosis” (CFSPID). We retrospectively evaluated the prevalence and clinical outcome of CFSPID infants diagnosed by 2 NBS algorithms in the period from 2011 to 2016 in the Tuscany region of Italy.MethodsIn 2011–2016, we assessed the diagnostic impact of DNA analysis on the NBS 4-tier algorithm [immunoreactive trypsin (IRT) – meconium lactase – IRT2 – sweat chloride (SC)]. All CFSPID patients repeated SC testing every 6 months, and CFTR gene analysis was performed (detection rate 98%). We reclassified children as: CF diagnosis in presence of at least 2 pathological SC results; healthy carrier or healthy in presence of at least 2 normal SC results for age and either 1 or 0 CF-causing mutations, respectively.ResultsWe identified 32 CF and 50 CFSPID cases: 20/50 (40%) were diagnosed only by the IRT-DNA-SC algorithm and 16/50 (32%) only by IRT-meconium lactase-IRT2-SC. Both protocols identified the remaining 14 cases (28%). Thirty-seven of 50 (74%) CFSPID patients had a conclusive diagnosis on December 31, 2017:5 (10%) CF, 17 (34%) healthy and 15 (30%) healthy carriers; 13/50 (26%) cases were asymptomatic with persistent intermediate SC and followed as CFSPID (CF:CFSPID ratio 2.85:1).ConclusionsIn 6 years, the CF:CFSPID ratio modified from 0.64:1 to 2.85:1, and 10% of CFSPID cases progressed to CF. Genetic analysis improved positive predictive value and identified a higher number of CFSPID infants progressing to CF.     

High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France

In this report, we present updated spectrum and frequency of mutations of the CFTR gene that are responsible for cystic fibrosis (CF) in Languedoc-Roussillon (L-R), the southwestern part of France. A total of 75 different mutations were identified by DGGE in 215 families, accounting for 97.6% of CF genes and generating 88 different mutational genotypes. The frequency of p.F508del was 60.23% in L-R versus 67.18% in the whole country and only five other mutations (p.G542X, p.N1303K, p.R334W, c.1717-1G>A, c.711+1G>T) had a frequency higher than 1%. The mutations were scattered over 20 exons or their border. This sample representing only 5.7% of French CF patients contributed to 24% of CFTR mutations reported in France. This is one of the highest molecular allelic heterogeneity reported so far in CF. We also present the result of a neonatal screening program based on a two-tiered approach "IRT/20 mutations/IRT" analysis on blood spots, implemented in France with the aim to improve survival and quality of life of patients diagnosed before clinical onset. This 18-month pilot project showed an unexpected low incidence of CF (1/8885) in South of France, with only six CF children detected among 43,489 neonates born in L-R, and 13 among 125,339 neonates born in Provence-Alpes-C?te-d'Azur (PACA).     

Evidence for a Causal Relationship Between Early Exocrine Pancreatic Disease and Cystic Fibrosis–Related Diabetes: A Mendelian Randomization Study

Circulating immunoreactive trypsinogen (IRT), a biomarker of exocrine pancreatic disease in cystic fibrosis (CF), is elevated in most CF newborns. In those with severe CF transmembrane conductance regulator (CFTR) genotypes, IRT declines rapidly in the first years of life, reflecting progressive pancreatic damage. Consistent with this progression, a less elevated newborn IRT measure would reflect more severe pancreatic disease, including compromised islet compartments, and potentially increased risk of CF-related diabetes (CFRD). We show in two independent CF populations that a lower newborn IRT estimate is associated with higher CFRD risk among individuals with severe CFTR genotypes, and we provide evidence to support a causal relationship. Increased log_e(IRT) at birth was associated with decreased CFRD risk in Canadian and Colorado samples (hazard ratio 0.30 [95% CI 0.15–0.61] and 0.39 [0.18–0.81], respectively). Using Mendelian randomization with the SLC26A9 rs7512462 genotype as an instrumental variable since it is known to be associated with IRT birth levels in the CF population, we provide evidence to support a causal contribution of exocrine pancreatic status on CFRD risk. Our findings suggest CFRD risk could be predicted in early life and that maintained ductal fluid flow in the exocrine pancreas could delay the onset of CFRD.     

Newborn screening for cystic fibrosis in Switzerland — Consequences after analysis of a 4 months pilot study

BackgroundSwitzerland introduced newborn screening (NBS) for CF in 2011, using an IRT/DNA/IRT protocol. This paper describes the results of the first year and compares two versions of the protocol with different IRT cut-offs, particularly effects on recall rate, sensitivity and specificity.MethodsIRT cut-offs were > 45 ng/ml (99.0th percentile) in period 1 (months 1–4) and > 50 ng/ml (99.2nd percentile) in period 2 (months 5–12). In period 2 we abstained from recalls when none of the 7 most common CF mutations were detected and IRT was < 60 ng/ml.ResultsIn periods 1 and 2, 26,535 and 56,663 tests were performed. Recall rates were 0.94% and 0.48%, respectively (p < 0.001), PPV increased from 23% to 47% (p = 0.024) and sensitivity was 90% and 100%.ConclusionsRaising initial IRT cut-off from the 99.0th to the 99.2nd percentile and abstaining from recalls for children with an IRT < 60 ng/ml and carrying no major CFTR mutation significantly reduced the recall rate without affecting sensitivity.     

Utility of thermal image scanning in screening for febrile patients in cold climates

BackgroundInfrared thermography (IRT) for fever screening systems was introduced in not only general hospitals, but also orthopedic hospitals as a countermeasure against the spread of coronavirus disease 2019 (COVID-19). Despite the widespread use of IRT, various results have shown low and high efficacies, so the utility of IRT is controversial, especially in cold climates. The aims of this study were to investigate the utility of IRT in screening for fever in a cold climate and to devise suitable fever screening in orthopedic surgery for COVID-19.MethodsA total of 390 orthopedic surgery patients were enrolled to the outdoor group and 210 hospital staff members were enrolled to the indoor group. Thermographic temperature at the front of the face in the outdoor group was immediately measured after entering our hospital from a cold outdoor environment. Measurements for the indoor group were made after staying in the hospital (environmental temperature, 28 °C) for at least 5 h. Body temperature was then measured using an axillary thermometer >15 min later in both groups.ResultsIn the outdoor group, mean thermographic temperature was significantly lower than axillary temperature and IRT could not detect febrile patients with axillary temperatures >37.0 °C. Mean thermographic temperature was significantly lower in the outdoor group than in the indoor group. Sensitivity was 11.5% for the outdoor group, lower than that for the indoor group.ConclusionsWe verified that IRT was not accurate in a cold climate. IRT is inadequate as a screening method to accurately detect febrile individuals, so we believe that stricter countermeasures for second screening need to be employed to prevent nosocomial infections and disease clusters of COVID-19, even in orthopedic hospitals.     

Neonatal screening for cystic fibrosis: Comparing the performances of IRT/DNA and IRT/PAP

BackgroundFrench health authorities promoted a study on 553,167 newborns comparing the performances of IRT/DNA and IRT/PAP for CF newborn screening.MethodsIn parallel to IRT/DNA, PAP was assayed in newborns with IRT > 50 μg/L. Provisional PAP cutoffs at 3.0 μg/L when 50 < IRT < 100 μg/L and 1.7 μg/L when IRT > 100 were used. Positive newborns were subjected to sweat test. Optimal cutoffs were established by a non-inferiority method.Results95 CF newborns were identified (83 classical forms (ClF), including 9 meconium ileus (MI), and 12 atypical (mild) forms (AF) Of them, IRT/DNA identified 85 (73 ClF including 5 MI and 12 AF). PAP cutoffs at 1.8 μg/L when 50< IRT<100 μg/L and 0.6 μg/L when IRT>100 μg/L would identify 82 CF: 77 ClF, including 8 MI, and 5 AF. The number of sweat tests was 314 and 1039 in the IRT/DNA and IRT/PAP strategies, respectively.ConclusionsUsing the optimal cutoffs, the sensitivity of the IRT/PAP strategy would not be inferior to that of IRT/DNA if identification of MF is not required.     

Comparison of different IRT-PAP protocols to screen newborns for cystic fibrosis in three central European populations

BackgroundIn recent years different IRT/PAP protocols have been evaluated, but the individual performance remains unclear. To optimize the IRT/PAP strategy we compared protocols from three regional CF newborn screening centers (Heidelberg, Dresden, and Prague).MethodsWe evaluated the effect of elevating the IRT-cut-off from 50 to 65 μg/l (~ 97.5th to ~ 99.0th percentile), the need of a failsafe protocol (FS, IRT ≥ 99.9th percentile) and the relative performance using either two IRT-dependent PAP-cut-offs or one PAP-cut-off.FindingsElevation of the IRT cut-off to 65 μg/l (~ 99.0th percentile) increased the PPV significantly (Dresden: 0.065 vs. 0.080, p < 0.0001, Prague: 0.052 vs. 0.074, p < 0.0001) without reducing sensitivity. All three IRT/PAP protocols showed a trend towards a higher sensitivity with FS than without and when using one PAP-cut-off instead of two IRT-dependent PAP-cut-offs.ConclusionsFor best performance we suggest an IRT/PAP protocol with an IRT-cut-off close to the 99.0th percentile, FS, and a single PAP-cut-off.     

Screening practices for nontuberculous mycobacteria at US cystic fibrosis centers

BackgroundCurrent guidelines recommend at least once yearly screening for nontuberculous mycobacteria (NTM) in Cystic Fibrosis (CF), however screening practices remain widely variable. This study evaluates current practices among United States CF centers with specific focus on clinical predictive factors for NTM screening.MethodsThe CF Patient Registry (CFFPR) was queried for CF patients ages 10 and older with NTM cultures completed between 2010–2014. Predictors for screening were assessed using univariate and multivariate logistic regression. Centers were evaluated by groups based on screening rates for analysis of clinical drivers of screening.ResultsFrom 2010–2014 a total of 22,739 patients were identified with 17,177 (75.5%) tested for NTM during this time. In the overall cohort, those who were tested for NTM had lower pulmonary function (70.7% vs 83.9%), higher annual average of visits with pulmonary exacerbations (1.0 vs 0.3), and higher rate of coinfection with Pseudomonas aeruginosa (PA) as well as Methicillin resistant Staphylococcus aureus (MRSA). Among CF centers, pulmonary function, exacerbations, and coinfections with PA and MRSA were predictive of NTM screening in the lower screening cohort while pulmonary function was not predictive of screening in the highest screening cohort. Those programs who screened at a higher rate were successful in identifying NTM in more CF patients.ConclusionNTM screening practices vary widely among United States CF centers with many centers testing only on clinical changes. With higher rates of testing shown as successful in identifying more patients with NTM, routine screening should be emphasized in CF care going forward.     

A survey of the prevalence,management and outcome of infants with an inconclusive diagnosis following newborn bloodspot screening for cystic fibrosis (CRMS/CFSPID) in six Italian centres

ObjectiveWe evaluated the prevalence, Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene profile, clinical data, management and outcome for infants with a CFTR-related metabolic syndrome/CF Screen Positive, Inconclusive Diagnosis (CRMS/CFSPID) designation from six Italian centres.MethodsAll newborn bloodspot screening (NBS) positive infants born from January 2011 to August 2018 with a CF diagnosis or a CRMS/CFSPID designation were enrolled. Data on sweat testing, genetics, clinical course and management were collected.ResultsWe enrolled 257 CF patientsand 336 infants with a CRMS/CFSPID designation (CF: CRMS/CFSPID ratio of 1:1.30).Blood immuno-reactive trypsinogen (IRT) was significantly lower in CRMS/CFSPID infants and the F508del variant accounted for only 20% of alleles. Children with CRMS/CFSPID showed a milder clinical course, pancreatic sufficiency compared to CF infants. Varied practice across centres was identified regarding sweat testing, chest radiograph (8-100%) and salt supplementation (11-90%). Eighteen (5.3%) CRMS/CFSPID infants converted or were reclassified to diagnosis of CF. Four infants (1.3%) developed a clinical feature consistent with a CFTR-related disorder (1.2%). Twenty-seven were re-classified as healthy carriers (8.0%) and 16 as healthy infants (4.8%).ConclusionsWe have identified considerable variability in the evaluation and management of infants with an inconclusive diagnosis following NBS across six Italian centres. CRMS/CFSPID is more regularly seen in this population compared to countries with higher prevalence of F508del.Conversion to a CF diagnosis was recorded in 18 (5.3%) of CRMS/CFSPID infants and in 16 was as a result of increasing sweat chloride concentration.     

Newborn blood spot screening for cystic fibrosis with a four-step screening strategy in the Netherlands

Background

Newborn screening for cystic fibrosis (NBSCF) was introduced in the Dutch NBS program in 2011 with a novel strategy.

Cascade testing in families of carriers identified through newborn screening in Western Brittany (France)

BackgroundNewborn screening (NBS) for cystic fibrosis (CF) can lead to the detection of healthy carriers. We report a unique assessment of family testing following the identification of carriers by NBS for over 20 years, in an area where CF is frequent.MethodsWe reviewed all of the carriers identified by NBS between 1991 and 2010 and registered the tests done in those families.ResultsNBS identified 0.1% of the newborns as carriers, which correspond only to 2.6% of the expected carriers born within the period, and 1/3 of those with an increased IRT level. Of the 195 families, 75.9% requested testing (2.5 tests per family).We identified 183 carriers and five 1-in-4 risk couples. Reassurance about genetic status was provided to 96% of the couples.ConclusionsCarriers detected by NBS appeared to be well managed in our area, and cascade testing that informs on genetic status seems relatively active.     

Cost-effectiveness of carrier screening for cystic fibrosis in Australia

BackgroundCarrier screening for cystic fibrosis is not widely available in Australia, partly due to concerns regarding its cost-effectiveness. The benefit of information from pregnancy to pregnancy has not been widely considered in existing cost-effectiveness analyses.MethodsA decision tree was constructed estimating costs and outcomes from screening, including both initial and subsequent pregnancies. Effectiveness was expressed in terms of CF births averted. Costs were collected using a health service perspective. All costs and outcomes were discounted at 5% per annum.ResultsScreening reduced the annual incidence of CF births from 34 to 14/100,000 births (an aggregate number of CF births of 100.9 and 41.9 respectively). In initial pregnancies, costs in the screening arm (A$16.6 million/100,000 births) exceed those in the non-screening arm (A$13.4 million/100,000 births). The incremental cost per CF birth in initial pregnancies is therefore approximately A$150,000. However, this was reversed for subsequent pregnancies, in that the pre-collected information reduces the incidence of CF in subsequent pregnancies at low additional costs. When aggregated, the results suggest screening is likely to be cost-saving.ConclusionsThe introduction of national carrier screening for cystic fibrosis should be considered, as it is likely to reduce CF incidence at an acceptable (potentially negative) cost.