Part Two What is Down’s syndrome? The classification of Down’s syndrome was made in 1866 by Dr John Langdon Down who made ‘Observations on an ethnic classification of idiots’. In 1956 46 chromosomes were described and in 1959 Professor Jerome Lejeune described the extra copy of chromosome 21 Regular Down’s syndrome

Recurrence risk Following a regular trisomy 21, the recurrence risk is 0.75% at 12 weeks (Nicolaides et al 1999) 0.42% mid trimester and 0.34% at term (Noble 1998) plus the background age chance • Following a trisomy due to a translocation the recurrence chance is dependent on type of tranlocation and which partner carries the translocation • Affected persons rarely reproduce and there is no evidence of paternal offspring. Of maternal offspring less than half are affected Clinical features •

Aetiology • • • • • •

Incidence of 1 in 600 – 800 births 95% are regular Trisomy 21 due to nondysjunction 85% maternally derived 15% paternally derived 4% due to translocation usually Robertsonian 1% mosaicism

• • • • • • • • • •

Brachycephaly excess neck folds, small nose, flattened broad bridge of nose, flat facial profile Low set simple ears Epicanthic folds Upslanting palpebral fissures Small carp-shaped mouth, protruding tongue Brushfield spots Single palmar crease Clinodactyly Sandal gap toes Hypotonia and poor feeding Developmental delay

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Part Two What is Down’s syndrome? Gastrointestinal Tract

Cardiac Anomalies • •

40 – 50% have Congenital Heart Defect - 30 – 40% have complete AVSD - Common others include VSD and PDA All babies should have a clinical examination and an echocardiogram

•

• •

10 – 12% have abnormalities of the gastrointestinal tract. Most prevalent are TOF (Tracheo-oesophageal fistula), duodenal obstruction with or without pyloric stenosis, imperforate anus and Hirschsprungs disease Constipation is very common at all ages Coeliac Disease

Atrial septal defect Other Associated Problems

Ventricular septal defect

Epilepsy 10% in late fifties, 1 -2% in children Leukaemia 1% in first 2 -3 years Alzheimer’s disease is common affecting 45% from age 45 Dentition hypoplasia – less caries, more gum disease Skin is dry, some hyperkeratotic areas, less elastic, prone to chapping. Fine and sparse hair with some balding

Hearing and Opthalmic • • • • •

Over 50% have significant impairment, sensorineural and/or conductive loss Need lifelong audiological surveillance High incidence of visual problems, 5 times more likely to wear glasses Cataracts and/or glaucoma may occur in infancy Neonatal testing for cataracts and continued opthalmological screening is required Thyroid Disorder

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• •

At all ages more frequent than in general population, usually hypothyroidism. Around 10% of school age children with Down’s have uncompensated hypothyroidism, but prevalence increases with age Biochemical screening essential throughout life Hyperthyroidism rare Musculoskeletal

• • • 2

Joint laxity – knee problems, patella-femoral instability, genu valgus, pes planus High BMI – feet problems, vertical talus, spinal problems, genu valgum Cervical spine instability – atlantoaxial joint. There is a small chance for acute or chronic neurological problems

Down’s syndrome •

• •

One of the most common cause of learning difficulties – some will cope with extra help in mainstream schools, others will need to attend special schools Some adults will live semi-independent lives, others will always be dependent Life expectancy is 50 -55 years with 44% of live births surviving to age 60

It is therefore difficult to generalise since there are more difference between people with Down’s syndrome than there are similarities... Most children with Down’s syndrome will walk and talk. Many will read and write. Many go to ordinary schools, and look forward to a semi-independent life, away from the family home... Just as there is a wide spread of abilities in the general population, the ability range of people with Down’s syndrome is very wide. Extracts from leaflet by the DSA See Down’s syndrome Scotland for further information: http://www.dsscotland.org.uk/

Part Two First Trimester Screening for Down’s Syndrome

Screening Tests

Diagnostic Tests

Screening tests identify individuals as broadly ‘high’ or ‘low’ chance. High chance results do not indicate that the baby definitely has Down’s syndrome, but should prompt the health care professional to offer further screening or diagnostic tests.

Diagnostic tests for Down’s syndrome give definite information on fetal chromosomes by confirming the presence of a third copy of chromosome 21.

Historical Milestones

1933

Association between maternal age and Down’s syndrome reported

1959

Trisomy 21 identified as cause of Down’s syndrome

1966

First chromosome analysis from amniotic fluid

1968

Prenatal diagnosis of Down’s syndrome

1974

1983-8

1988

Raised AFP associated with open neural tube defects

Maternal serum markers for Down’s syndrome

Triple test introduced

1990

Nuchal translucency test introduced

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Part Two First Trimester Screening for Down’s Syndrome Terminology Detection Rate (DR) The proportion of women who will be identified by the screening test with an affected pregnancy

False Negative Rate (FNR) The proportion of women who are given a lower chance result but have an affected pregnancy

False Positive Rate (FPR) The proportion of women with a higher chance/ screen positive result but have an unaffected pregnancy

Multiples of the median The serum marker concentration for a pregnant woman, divided by the median concentration value for unaffected pregnancies of the same gestational age.

Communicating Chance Reframing Chance Chances of an affected pregnancy

Chances of an unaffected pregnancy

1 in 4

25%

3 in 4

75%

1 in 5

20%

4 in 5

80%

1 in 10

10%

9 in 10

90%

1 in 20

5%

19 in 20

95%

1 in 30

3%

29 in 30

97%

1 in 50

2%

49 in 50

98%

1 in 100

1%

99 in 100

99%

1 in 200

0.5%

199 in 200

99.5%

First Trimester Serum Markers Pregnancy Associated Plasma Protein – A (PAPP – A)

Free beta Human Chorionic Gonadotrophin (FßhCG)

•

• • • • •

• • • •

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Originates mainly from placental syncytiotrophoblast Concentration increases with gestation Screening sensitivity decreases with gestation Optimal sensitivity at 8 – 9 weeks gestation Levels reduced in pregnancies affected by Down’s syndrome

Beta subunit of hCG/intact hCG Produced by the syncytiotrophoblast cells Decreases with gestational age Sensitivity maintained in second trimester Raised levels in pregnancies affected by Down’s syndrome

Part Two First Trimester Screening for Down’s Syndrome Nuchal Translucency Chitty describes nuchal tranlucency (NT) the ‘swelling’ just under the skin at the back of the fetal neck’, recognised to be a collection of lymphatic fluid under the skin. The measurement is defined as a saggital (front to back) measurement between the muscles of the cervical spine and the inner layer of echogenic skin. An increased NT measurement is associated with chromosomal abnormalities, an increasing risk of structural anomalies (including cardiac defects), neuromuscular problems and a wide range of syndromic problems. The risk of all these increases as the NT increases from about 2.5mm upwards. Screening for Down’s syndrome Women should have a pre-test discussion regarding the screening programme available in Scotland and its benefits. A copy of the national information leaflet to support the pregnancy screening programmes should be given at least 48 hrs prior to collection of the blood sample, unless precluded by late presentation however these women still need to give informed choice and appropriate support to facilitate this should be given. The woman should be asked to sign the consent section in their Scottish Woman Held Maternity Record (SWHMR) accepting or declining screening stating that they have received sufficient information to understand the reasons for testing, the consequences of the results and the significance of not having these tests performed. The form should be countersigned by the midwife/ health professional taking the blood sample or ultrasound examination. It should be noted and parents should be made aware that other conditions such as Edwards’s syndrome may also be identified through either the screening test or any subsequent diagnostic procedure. First trimester combined screen for Down’s syndrome consists of an ultrasound scan to measure the nuchal fold of the fetus and the result of this will be combined with the results of a blood test and also the woman’s age to calculate the woman’s individual chance of their baby having Down’s syndrome. The first trimester markers free beta subunit of hCG (FßhCG) and pregnancy associated plasma protein A (PAPP-A)

are measured in serum by specific immunoassay. Results are converted to MoM and corrected for co-variables including maternal weight, smoking status, and if applicable, previous affected pregnancy and assisted conception. NT measurements (in mm) are averaged and converted to MoM. This test is carried out between 11 – 13+ 6 weeks gestation and the blood samples should be collected on the same day that the NT measurement is performed. The first trimester screening test should give a detection rate of 90% at a 5% false positive rate (Stenhouse et al 2004). It should be noted that this test no longer screens for neural tube defects and the 18 – 21 week fetal anomaly scan is now the screening test of choice for these conditions. Median MoMs in Down’s syndrome pregnancies: AFP

0.75

hCG

2.07

UE3

0.72

Inhibin-A

1.99

Second trimester screening for Down’s syndrome There will always be a percentage of women who will present too late to be offered a first trimester combined screen for Down’s syndrome (estimated to be around 15-20%) and the new policy is for these women to be offered a second trimester screen using four serum markers [alphafetoprotein (aFP); total human chorionic gonadotrophin

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Part Two Screening for Down’s Syndrome (HCG); unconjugated eostriol (UE3) and Inhibin-A (Inhibin)] to make it closer to the sensitivity and specificity of the first trimester combined screen. The quadruple test should give a detection rate of 75%. Second Trimester Screening Markers Alpha-fetoprotein (AFP) • Produced by fetal yolk sac and liver • Increases with gestational age • Levels reduced in pregnancies affected by Down’s syndrome • Levels increased in pregnancies affected by open spina bifida or abdominal wall defects e.g. gastroschisis Human Chorionic Gonadotrophin (Intact hCG) • Produced by the syncytiotrophoblast cells • Decreases with gestational age Unconjugated estriol (uE3) • Produced by placenta, fetal liver and fetal adrenals • Increases with gestation • Levels reduced in pregnancies affected by Down’s syndrome Inhibin-A • Produced by placenta • Decreases with gestational age between 14 and 17 weeks whereupon it begins to increase again • Levels increased in pregnancies affected by Down’s syndrome It should be noted that women who have second trimester screening will have AFP measured as part of the screening test and an interpretation of the result for neural tube defects will be provided. Clinical Follow-up If the screening test result indicates the woman is in the “higher chance” group she will be offered counselling and a diagnostic test. If the pregnancy is beyond 15 weeks’ gestation, the follow-on diagnostic procedure for Down’s syndrome is amniocentesis. If the pregnancy is of less than 13 weeks’ gestation, the follow-on diagnostic procedure is chorionic villus sampling (CVS). 6

Amniocentesis This test is performed usually between 15 and 20 weeks of pregnancy, although this may vary. Amniocentesis is quite a common procedure and is undertaken for many reasons. Normally it is performed to establish the structure and number of the chromosomes or to establish any genetic problems that may affect the baby. A needle is inserted through the abdomen. It is recommended that this is performed under the guidance of ultrasound. A small amount of fluid is removed and sent to the genetic laboratory for investigation. Chorionic villus sampling (CVS) This is normally performed between 11 and 13 weeks of pregnancy. It is known that performing this test before 9 weeks will increase the possibility of limb abnormalities. Again it is recommended that this procedure is performed under ultrasound guidance. A needle is inserted through the abdomen or, rarely, through the cervix. The aim is to remove a small piece of placenta. The placenta originates alongside the same cells as the baby and consequently should have the same type of chromosomal and genetic makeup. Both of these diagnostic procedures carry a risk of miscarriage, quoted as 2% for CVS and 1% for amniocentesis by most hospitals. Information Information needs to be given in a way that helps make it clear to the parents that the health professional recognises the impact the diagnosis will have on the parents. The diagnosis of abnormalities which are perceived by health professionals as ‘less severe’ than others still cause significant distress for parents. (Statham, Solomou & Green, 2003) For parents, the quality of the care they receive is crucial. Few forget their experience of loss. Most have vivid memories of what happened, what was done and what was said and these memories may stay with them for months, years and often a lifetime to come. For further information go to: www.fetalanomaly.screening.nhs.uk/ fetalanomalyfolder

Part Two Laboratory Perspectives Screening for Down’s syndrome Drivers for change in Scotland • CUBS screening for Down’s Syndrome in the 1st trimester: a Scottish multicentre study. JA Crossley et al 2002 BJOG 109 p 667 • Health Technology Assessment Report 5 March 2004 Routine ultrasound scanning before 24 weeks of pregnancy • Quality Improvement Scotland ‘Clinical Standards’ October 2005 Pregnancy and Newborn Screening • CEL 31(2008) Changes to Pregnancy and Newborn Screening Programmes UK Screening Committee Benchmarks • >75% detection rate for a 90% detection rate for a