Neonatal bloodspot screening
MRC Research Fellow and General Practitioner University of Southampton, UK
E-mail: caes{at}soton.ac.uk
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 TOP Abstract The objectives of screeningNeonatal bloodspot screeningPhenylketonuriaCongenital hypothyroidismCystic fibrosisSickle cell diseaseMedium chain acyl-CoA...Duchenne's muscular dystrophyReferences |
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Neonatal bloodspot screening involves taking a small blood sample obtained by pricking a baby's heel. The blood is placed on special filter paper (formerly called the Guthrie card) and sent for analysis. The test is offered to all newborn babies in the UK and is usually carried out by the midwife when the baby is 5–8 days old. It is part of the national child health promotion programme. This article introduces the neonatal bloodspot screening test and describes the features of the important diseases that are currently screened for.
| The GP curriculum and neonatal bloodspot screening With respect to screening programmes, the GP curriculum requires GPs in training to:
Several of the conditions covered by the neonatal bloodspot screening programme are genetic conditions. This is covered in curriculum statement 6 of the GP curriculum. GPs in training must be aware that a significant minority of any practice population will include patients who have a genetic condition; have a knowledge of common and important genetic conditions such as haemoglobinopathies and cystic fibrosis; demonstrate an awareness of the genetic aspects of newborn screening programmes; demonstrate an awareness of the emotional impact of a genetic diagnosis on a patient and his or her family, particularly associated with guilt about ‘passing on’ a condition; and describe the support services available for those with a genetic condition.
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The objectives of screening |
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TOPAbstractThe objectives of screeningNeonatal bloodspot screeningPhenylketonuriaCongenital hypothyroidismCystic fibrosisSickle cell diseaseMedium chain acyl-CoA...Duchenne's muscular dystrophyReferences |
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The idea of screening is attractive – the ability to diagnose and treat a potentially serious condition at an early stage when it is still treatable. An ideal screening test should pick up all those who have the disease (have high sensitivity) and must exclude those who do not (high specificity). It must detect only those who have a disease (high positive predictive value) and should exclude only those who do not have the disease (high negative predictive value). Table 1 shows how sensitivity, specificity, and positive and negative predictive value can be calculated.
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Apart from the obvious benefit of picking up conditions at early stages when treatment is more effective, screening may also provide reassurance for those receiving negative results, and gives increased information to society on the natural history of disease. However, screening is not without risks. There are risks inherent to the screening test – for example infections from a neonatal heel prick. Where prognosis is unaltered, screening may result in longer morbidity for patients and their families. There may also be false reassurance for those with false negative results and unnecessary anxiety, and possibly intervention, for those with false positive results. Finally, screening costs money and uses resources. It is important that the cost implications of screening tests are explored before screening programmes are instigated.
The World Health Organization recommends that screening should only be introduced to the target population if the following (Wilson–Jungner) criteria are met:
- The condition being screened for is an important health problem
- The natural history of the condition is well understood
- There is a detectable early stage
- Treatment at early stage is of more benefit than at late stage
- There is a suitable test to detect early stage disease
- The test is acceptable to the target population
- Intervals for repeating the test have been determined
- Adequate health service provision has been made made for the extra clinical workload resulting from screening
- Risks, both physical and psychological, are less than the benefits of screening
- The costs of screening are worthwhile in relation to the benefits gained
There is no ideal screening test. For any screening test, always explain:
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Neonatal bloodspot screening |
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TOPAbstractThe objectives of screeningNeonatal bloodspot screeningPhenylketonuriaCongenital hypothyroidismCystic fibrosisSickle cell diseaseMedium chain acyl-CoA...Duchenne's muscular dystrophyReferences |
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The aim of bloodspot screening is to identify babies at high risk of having conditions for which early diagnosis and treatment improves outcome. At present, throughout the UK babies are screened for phenylketonuria (PKU), cystic fibrosis (CF) and congenital hypothyroidism (CHT). In England babies are additionally screened for sickle cell disease and will all be screened for medium chain acyl-CoA dehydrogenase deficiency (MCADD) by the end of 2009. A pilot study of screening boys for Duchenne muscular dystrophy was undertaken in the 1990s in Wales and screening has continued there. There are currently no plans to extend the muscular dystrophy neonatal screening programme elsewhere in the UK. In all cases, screening is not diagnostic and further tests are necessary to confirm diagnosis. When screening tests are positive it is essential that babies are referred quickly for further diagnostic tests and/or treatment.
As bloodspot screening is performed so soon after birth, it is important that parents have a chance to think about whether they wish their child to be screened for all or any of the conditions covered by the bloodspot screening programme, before the child is born. Where possible, ensure parents are given the national pre-screening leaflet during pregnancy at around 28 weeks gestation.
Parents are entitled to decline screening for all or any one of the conditions being screened for. Whilst screening is strongly recommended, parents’ decisions must be respected. Discussions with parents and their consent (or decline) to screening should be recorded in the mother's health record. If a parent declines screening, explore the reasons why consent has not been given.
| If screening is declined, it is important to flag in the child's notes that the child has not been screened in case the child becomes ill later on.
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Phenylketonuria |
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TOPAbstractThe objectives of screeningNeonatal bloodspot screeningPhenylketonuriaCongenital hypothyroidismCystic fibrosisSickle cell diseaseMedium chain acyl-CoA...Duchenne's muscular dystrophyReferences |
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In the UK 1 in every 10,000 babies is born with phenylketonuria (PKU), so it is very unlikely that you will ever see a child with PKU as a GP. It is inherited as an autosomal dominant trait and has highest incidence in Northern Ireland. Children with PKU are unable to break down phenylalanine, an amino acid present in many foods. The baby appears normal at birth but develops severe developmental delay, learning difficulty and seizures in infancy. The neonatal blood spot test detects high levels of blood phenylalanine in newborn babies. Prenatal diagnosis is also possible if there is a family history. Treatment is with lifelong dietary restriction of phenylalanine. With treatment, growth and development are normal. Although PKU is rare, early disease can be detected by screening and actions preventing later deterioration are effective and cheap.
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Congenital hypothyroidism |
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TOPAbstractThe objectives of screeningNeonatal bloodspot screeningPhenylketonuriaCongenital hypothyroidismCystic fibrosisSickle cell diseaseMedium chain acyl-CoA...Duchenne's muscular dystrophyReferences |
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One in 4000 babies in the UK is born with congenital hypothyroidism. The condition affects twice as many female as male infants and can be associated with Down's syndrome. Untreated, children with abnormally low levels of thyroid hormone fail to grow properly and have varying degrees of mental disability. The neonatal bloodspot test detects low levels of blood thyroxine. Treatment is with thyroxine replacement and results in normal growth and development. Usually thyroxine replacement is needed lifelong. Again, although a relatively rare condition, the argument for screening is strong. Early stage disease is easily detectable with a simple and acceptable screening test and treatment at this stage is highly effective for preventing later complications.
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Cystic fibrosis |
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TOPAbstractThe objectives of screeningNeonatal bloodspot screeningPhenylketonuriaCongenital hypothyroidismCystic fibrosisSickle cell diseaseMedium chain acyl-CoA...Duchenne's muscular dystrophyReferences |
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Cystic fibrosis (CF) is the most common inherited disorder in the UK with a prevalence of 1 in 2500 births. It results from mutation of a single gene on chromosome 7 (cystic fibrosis transmembrane conductance regulator) that is essential for salt and water movement across cell membranes. This leads to thickened secretions. More than 1200 different mutations have been described. Cystic fibrosis is passed on through autosomal recessive inheritance and is much more common amongst Causasians than those of Afro-Caribbean origin. Around 1 in 25 adults in the UK carries the cystic fibrosis gene (72.3 million adults) and there is a 1 in 4 chance of having a child with cystic fibrosis if both parents are carriers (Figure 1). Clinical features of cystic fibrosis are summarized in Figure 2.
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The cystic fibrosis neonatal bloodspot screening test
Cystic fibrosis is a common and important health problem. Early treatment of cystic fibrosis improves outcome and prolongs both quality and quantity of life, so a strong argument can be made for a cystic fibrosis screening programme.
Screening detects immunoreactive trypsin (IRT) which is increased in children with CF. If IRT is raised, the blood is then DNA tested for the most common gene alterations (Figure 3). As there are many more mutations described than tested for, not all gene mutations will be detected and some affected babies will be missed by newborn screening. Continue to watch for later presentations such as failure to thrive or malabsorption, and/or recurrent respiratory infections.
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If a child tests positive, it is vital that parents and siblings receive genetic counselling and are offered genetic testing for the condition. If both parents are carriers of a CF gene, there is a 1 in 4 chance of any subsequent children that they have together being affected. Antenatal screening with chorionic villus sampling at around 10 weeks gestation is possible for parents with an affected child already or where both parents are positive on karyotyping. It is important to note that genetic tests of parents may bring up issues about paternity. For example, if a couple has a child affected by CF, then the child must have a CF gene from the mother and another from the father. If testing of the parents shows that only the mother is a carrier, then the child's father cannot be the biological father.
Screening will also detect healthy carriers. This has implications not only for the child but also the parents. Healthy children who are carriers may be treated as if they have the disease or be stigmatized because they are carriers. Carrier status may become an issue when they reach reproductive age themselves. Parents should be offered karyotyping as, if both are carriers, they have a risk of having an affected child in future and can be offered early antenatal diagnosis for future pregnancies. Ensure parents have a full explanation of results and understand their meaning.
Treatment of children found to have cystic fibrosis
Once diagnosed with cystic fibrosis, children are usually referred to specialist paediatric CF teams and have direct access to care. CF is a multisystem disease requiring a holistic approach to care which aims to maintain patients’ independence, improve quality of life and extend life expectancy. Care broadly divides into:
- Treatment of lung disease: This aims to prevent chronic infection as long as possible and later stabilize respiratory infection through exercise, physiotherapy and postural drainage, and drugs (bronchodilators, antibiotics and mucolytics)
- Maintaining a good nutritional state: Patients with pancreatic insufficiency require pre-meal oral pancreatic enzymes (e.g. Creon®) and a high calorie diet supplemented with fat soluble vitamins (A,D and E) – advice from a dietician is essential
- Treatment of complications: Patients with CF may develop diabetes mellitus and/or osteoporosis. Their major cause of death is cor pulmonale and/or respiratory failure. Cadaveric heart–lung transplant or partial lung transplant from a related donor is a last resort and has 50% 5 year survival
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Sickle cell disease |
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TOPAbstractThe objectives of screeningNeonatal bloodspot screeningPhenylketonuriaCongenital hypothyroidismCystic fibrosisSickle cell diseaseMedium chain acyl-CoA...Duchenne's muscular dystrophyReferences |
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In the UK, 1 in every 2400 babies is born with a sickle cell disorder. These disorders are most common among people of Afro-Caribbean or sub-Saharan origin. Sickle cell disease is a genetically transmitted (autosomal recessive – Figure 1) disorder of haemoglobin production. Sickle haemoglobin (HbS) is a haemoglobin in which the sixth amino acid on the β-globin chain, glutamic acid, is replaced by valine. HbS undergoes liquid crystal formation as it becomes deoxygenated causing ‘sickling’ of the affected blood cells (Figure 4). The effect of sickling is to shorten survival of red blood cells (resulting in haemolytic anaemia) and to cause aggregation of the sickled cells. Aggregation in turn leads to tissue infarction resulting in pain and/or tissue damage (e.g. stroke affects 10% of children with sickle cell anaemia) and sequestration in the liver spleen or lungs producing sudden and profound anaemia.
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Sickle cell disease affects individuals who have inherited two HbS genes (Hb SS sickle cell anaemia) or a sickle cell gene together with an interacting gene (Table 1). Infants with sickle cell disease are at risk of presenting for the first time with severe overwhelming infections and splenic sequestration crises. Early diagnosis allows prophylaxis with penicillin and vaccines, and parent training to identify children with complications and educate them to present early for treatment. This reduces complications and deaths in young infants.
The sickle cell neonatal bloodspot test
Again, the argument for screening for sickle cell disease is strong. Sickle cell disease is relatively common, especially in areas with a high proportion of patients of Afro-Caribbean origin. There is an acceptable screening test and treatment at early stage can improve prognosis and save on healthcare costs.
Abnormal haemoglobin on the neonatal blood spot is screened for using either high-performance liquid chromatography (HPLC), or iso-electric focusing (IEF). If detected, a confirmatory test is performed on the original spot using a different technique to the initial screening test. This test detects sickle cell disease and its variants. If a child tests positive, it is important that parents and siblings receive genetic counselling and are offered genetic testing for the condition.
The carrier state for HbS (sickle cell trait) is also detected by this test. Patients with less than 40% haemoglobin S have no symptoms unless they are subjected to anoxia (e.g. during anaesthesia). It is important that parents of these children understand what sickle cell trait is and how it can affect their child. It is also important that parents and siblings are offered counselling and genetic testing for the sickle cell genes.
The neonatal bloodspot screen also identifies other clinically significant haemoglobinopathies (Table 2) and some clinically benign haemoglobinopathies (Table 2). Even if these have no clinical consequences for the child the current policy is to inform parents of the results. It is essential that parents receive accurate information about what these results mean and the likely implications for the child and other family members to avoid confusion and misunderstanding of the child's likely health problems in future.
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Medium chain acyl-CoA dehydrogenase deficiency |
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TOPAbstractThe objectives of screeningNeonatal bloodspot screeningPhenylketonuriaCongenital hypothyroidismCystic fibrosisSickle cell diseaseMedium chain acyl-CoA...Duchenne's muscular dystrophyReferences |
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MCADD is an autosomal recessive disorder (Figure 1) of fatty acid oxidation that is estimated to have an occurance rate of 1 in 13,000–20,000 births. Infants who suffer from this enzyme deficiency are unable to metabolize fats effectively, and if their systems are stressed by fasting or infection, will build-up toxic levels of fatty acids that may result in metabolic crises and serious health outcomes such as seizures, coma or even death. If untreated, MCADD can result in permanent brain damage.
The MCADD neonatal bloodspot test
The argument for MCADD screening is weaker than for CF or sickle cell screening as MCADD is rare. However, as with both these other conditions, treatment is cheap, simple and can prevent death and serious disability.
Testing for MCADD from the neonatal blood spot involves testing for a fatty acid of medium length called Octanoyl carnitine or C8 carnitine (C8). When the C8 level is elevated, a diagnosis of MCADD is likely. Rarely other metabolic disorders may be detected through the screening process. If a child tests positive, it is important that parents and siblings receive genetic counselling and are offered genetic testing for the condition. Some children remain asymptomatic from MCADD and it is possible for older siblings to be homozygous for the condition and be unaware of their diagnosis.
Treatment of MCADD
Treatment is required lifelong and involves ensuring that the child does not go without food for more than 4-6 h (this period can be extended when the child reaches adolescence); having a low fat, high carbohydrate diet; taking L-carnitine supplements; and seeking early medical attention if the child is unwell. Prompt treatment prevents any long-term consequences.
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Duchenne's muscular dystrophy |
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TOPAbstractThe objectives of screeningNeonatal bloodspot screeningPhenylketonuriaCongenital hypothyroidismCystic fibrosisSickle cell diseaseMedium chain acyl-CoA...Duchenne's muscular dystrophyReferences |
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Duchenne's muscular dystrophy is an X-linked recessive disorder caused by a defect in the gene coding for a muscle protein known as dystrophin. Due to its X-linked recessive inheritance, it is a condition almost exclusively confined to males and has an incidence of 1 in 3500–4500 male children, though mild signs can be found in around 8% of female carriers. One in three cases is due to a new mutation.
Presentation is usually at around 4 years of age with progressive loss of muscle strength, affecting the legs first. The ability to walk unaided is usually lost by 9–10 years of age. Progression continues and patients usually die in their early twenties.
The neonatal bloodspot test for Duchenne's muscular dystrophy
Although Duchenne's muscular dystrophy is a devastating condition for suffers, the benefits of a screening programme are debatable. There is no treatable early stage of this disease and whether or not the disease is found, the child will progressively become more disabled and die prematurely. Screening will just increase the length of time that the family are aware of the child's diagnosis, which may increase length of morbidity. It does not therefore meet the Wilson–Jungner criteria and, for this reason, a decision has been made not to extend this screening programme beyond the piloting area in Wales. However, there are are some advantages to screening. Benefits of early diagnosis relate mainly to the family as a whole rather than to the child. Given advance warning, parents can make appropriate plans to cope with an increasingly disabled child and, as antenatal diagnosis is possible, early diagnosis may also prevent the birth of further affected children before the diagnosis is known in the first child.
The primary screen is creatine kinase (CK) activity, which is usually measured by a bioluminescence test or a fluorescence assay on bloodspots taken from male infants. In the Welsh programme, transient increase in CK is found in 0.02% of male babies tested. Positive tests are followed up with repeat CK testing and DNA analysis to confirm diagnosis.
| Further information for parents: UK Newborn Screening Programme Centre Leaflets about screening for parents www.newbornscreening-bloodspot.org.uk National society for phenylketonuria (NSPKU) Tel: 0845 603 9136 www.nspku.org Cystic Fibrosis Trust www.cftrust.org.uk UK Thalassaemia Society www.ukts.org Sickle Cell Society Tel: 0800 001 5660 www.sicklecellsociety.org Muscular dystrophy campaign Tel: 020 7720 8055 www.muscular-dystrophy.org
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References |
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TOPAbstractThe objectives of screeningNeonatal bloodspot screeningPhenylketonuriaCongenital hypothyroidismCystic fibrosisSickle cell diseaseMedium chain acyl-CoA...Duchenne's muscular dystrophyReferences |
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RCGP Curriculum. Accessed via www.rcgp.org.uk [date last accessed 29.11.07].
UK Newborn Screening Programme Centre. www.newbornscreening-bloodspot.org.uk [date last accessed 29.11.07].
Wilson, Jungner. Principles and practice of screening for disease. (1968) Geneva. Public Health Paper Number 34.
CF Trust Standards for the clinical care of children and adults with CF in the UK. (2001).
NHS. Haemoglobinopathy Screening Programme. Sickle cell and thalassaemia: Handbook for laboratories (2006) Accessed via: www.kcl-phs.org.uk/haemscreening/documents/LabHandbook2006.pdf [date last accessed 29.11.07].
Zeuner D, Ades AE, Karnon J, et al. Antenatal and neonatal haemoglobinopathy screening in the UK: review and economic analysis (1999) 3((11): i–v):1–186. Health Technology Assessment.
MCADD Laboratory Screening Protocol. www.newbornscreening-bloodspot.org.uk: [date last accessed 29.11.07].
Seymour CA, Thomason MJ, Chalmers RA. Newborn screening for inborn errors of metabolism: a systematic review. Health Technology Assessment (1997) 1((11): i–iv):1–95.[Medline]
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