Screening newborn infants for cystic fibrosis
The Leeds Method of Management. April, 2008. Screening newborn infants for Cystic Fibrosis [online]. Leeds Regional Adult and Paediatric Cystic Fibrosis Units, St James's University Hospital, Leeds, UK. Available from http://www.cysticfibrosismedicine.com
We began neonatal screening (NS) for CF in Leeds in 1975 and a total of 62 affected children have been identified. Since implementing an IRT (immunoreactive trypsin)-DNA–IRT protocol in 1995, 88,382 newborns have been screened. Twenty-four children with CF and 17 carriers of a CF causing mutation have been identified. We adopted the UK national screening program in August 2006. This is due to be gradually introduced to the rest of the country over the next three years.
The purpose of NS for CF is to limit morbidity and mortality. The benefit of early diagnosis must outweigh any potential disadvantage from screening to both the affected and unaffected. With NS programmes for CF (CF NS) existing for more than 30 years, there is now consistent evidence emphasising the benefits of, and minimal risk from, such programmes (Young et al, 2001). Clinical outcome studies have reported decreases in hospital admissions during first year of life (Doull et al, 2001) and early improved nutrition for screened infants (Farrell et al, 1997; Farrell et al, 2001). Furthermore, a systematic review concluded CF NS may result in improved child survival (Grosse et al, 2006).
Cumulative world-wide experience of CF NS has tipped “the balance of opinion” towards initiating programmes where none exist (Murray et al, 1999; Young et al, 2001; Doring & Hoiby, 2004; Farrell et al, 2005; Sims et al, 2005; Sims et al, 2007). Current debate does not focus on “Should we screen?” but on “How should we screen?” (Farrell et al, 2004). However, as yet, there is no consensus on the optimal CF NS protocol or process, with different procedures being introduced throughout the world.
Under ideal circumstances a blood spot taken from a newborn in the first week could be tested for CF and the answer would be a definitive and accurate yes or no. Unfortunately the IRT screening test does not give such clear cut answers as are obtained for phenylketonuria and neonatal hypothyroid disease. The distinction between a normal and abnormal IRT screening test for CF may be blurred. For every 10 abnormal IRT tests there will be one case of CF identified. As a consequence screening programmes are designed to identify the maximum number of cases that would benefit from early diagnosis whilst avoiding causing anxiety to parents of children who subsequently turn out not to have CF. It is also argued that screening tests should avoid detecting unaffected carriers of CFTR mutations. The proposed national screening program involves an IRT-DNA protocol (figure 1).
|Figure 1: National standard protocol for neonatal screening for cystic fibrosis - algorithm|
If the initial IRT is greater than the 99.5th centile the same sample is examined for the four commonest CF causing mutations in the UK. If only one mutation is detected then a further 27 mutations are looked for. The purpose of limiting the initial search to four mutations is to minimise the number of carriers detected. If no mutation is detected and the initial IRT is greater than the 99.9th centile or if only one CF mutation is detected, a second sample and repeat IRT test is requested.
On the basis of these results, for every 10,000 newborns screened, 3.5 will be categorised as “presumptive diagnosis of CF”, 0.5 as “high likelihood”, 5 as “low likelihood” but a carrier of one CFTR mutation requiring counselling, and 9,991 as “CF not suspected”.
Of the 9,991 categorised as “CF not suspected” 9,950 will have a negative initial IRT; 38 will have an initial positive IRT below the 99.9th centile with none of the four commonest mutations identified; 2.9 will have an initial positive IRT with a value above the 99.9th centile and none of the commonest four mutations, followed by a repeat negative IRT. The three with an initial very high IRT (>99.9th centile) and none of the common four mutations together with 5.5 newborns identified as having a single mutation, when tested for 31 common mutations, will have a second IRT. There will therefore be a contact made with parents as a result of the initial screen in 3.5 cases per 10,000 with a screening outcome of “presumed to have CF”, and in 8.5 cases per 10,000 for a repeat IRT. Of the 8.5 children who need a repeat IRT, the risk of having CF depends on why they need a repeat IRT and varies from 1:11 (initial IRT >99.5th centile and one identified mutation) to 1:30 (initial IRT >99.9th centile and no mutations identified).
It is recommended that all cases of CF, including those known to carry two CF mutations, are confirmed as early as possible with a sweat test, allowing that there are technical difficulties in performing sweat tests in babies. Failure rates of 53% and 20% in newborns using the nanoduct and macroduct methods respectively (Desax et al, 2006; Jayaraj et al, 2006), and 10% in children less than six weeks using the Gibson Cooke technique (Gibson & Cooke, 1959) are reported.
Potential disadvantages of screening
It is anticipated that some infants with CF will not be identified by the screening programme. This is likely to be between 1:25 to 1:50 children with CF. It is important that all clinicians managing children and adults continue to consider CF as a potential diagnosis and perform sweat tests to exclude the diagnosis in suspected cases.
The protocol will inevitably create some uncertainty and anxiety. For example, some children categorised as “low likelihood” or “CF not suspected” after a second blood sample and IRT test will develop symptoms. It is probable that some of these parents will be anxious and want CF as a possible diagnosis excluding. These patients and families will require intensive investigation. Unfortunately, it is difficult to exclude CF in some patients. For those individuals identified as being carriers of CF it is essential that appropriate, reassuring and consistent information is given. The implications of the result need to be discussed thoroughly and genetic counselling offered.
It may be more difficult for a family to come to terms with their child having a serious life threatening disease that requires lifelong daily treatment when they are informed about this diagnosis as a result of a screening test rather than after experiencing worrying and recurrent symptoms. Screening for CF provides the opportunity to start treatment before significant damage has occurred.
It is important that the CF team establishes a close working relationship with the family without causing undue anxiety or allowing the necessary medical care to interfere with the bonding process between the parents and the newborn baby. The importance of good nutrition needs to be emphasised but it is essential that parental anxiety about weight does not encourage the development of feeding behaviour problems. Fathers often find it difficult to attend frequent outpatient appointments because of work commitments. Steps should be taken to ensure that they do not feel excluded and both parents should be involved in the normal and extra medical care of the child. Families and individuals inevitably develop their own coping strategies. The CF team should be sensitive to these and aim to work in partnership with the parents and child to maintain normal function and good health.
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