1. 2 cases of congenital abnormality Lent term year 1

2. Case 1 A 27 year old woman becomes pregnant and undergoes a triple test at 14 weeks gestation The results showed: AFP 56.7 kU/l 0.6 MoM hCG 32.2 IU/ml 3.97 MoM uE 3 2.9 nmol/L 0.56 MoM i.e. Risk for Down syndrome 1:100

3. The analytes: AFP: alphafetoprotein. Produced by yolk sac and fetal liver. Excreted into amniotic fluid via fetal urine. Crosses placenta into maternal circulation hCG: human chorionic gonadotrophin. Glycoprotein produced by trophoblast. Beta sub- unit specific for pregnancy UE3: unconjugated oestriol. Synthesised in placenta

4. Then…. She undergoes amniocentesis, which confirms the baby has Down syndrome

5. Down syndrome Features of Down syndrome Screening: triple test/ultrasound Diagnosis: chromosome tests Outcome

6. What is Down syndrome? Clinical syndrome described by John Langdon Down in 1866 Trisomy 21 in 90% cases identified by Prof Lejeune in 1959

7. Clinical features Epicanthic folds Single palmar crease Flat occiput Macroglossia Cardiac murmur (1:3 congenital heart disease) Poor muscle tone/feeding/weight gain Developmental and learning delay

12. Assessing the risk for Down syndrome pregnancy Maternal age “Triple test” ultrasound

14. Maternal age at term <25 1:1500 27 1:1200 30 1:910 35 1:380 40 1:110 45 1:30

15. The “triple test” Introduced to improve sensitivity and specificity of testing Uses 3 analytes: AFP(alphafetoprotein), hCG (human chorionic gonadotrophin) and uE 3 (uncongugated Oestriol) Combines with maternal age to give risk

16. In Down syndrome: AFP lower – on average 0.7 MoM hCG higher uE3 lower Offered as part of NHS Antenatal and Newborn Screening Programme http://www.screening.nhs.uk/downs/home. htmhttp://www.screening.nhs.uk/downs/home. htm

17. Ultrasound: Nuchal translucency

18. Assessing risk Offer amniocentesis if risk >1:250 May combine triple and nuchal screening test to improve sensitivity and specificity of risk

19. Amniocentesis

20. Chromosome tests Culture and staining PCR (polymerase chain reaction) FISH (Fluorescent in situ hybridisation)

22. Normal PCR

23. FISH (offered if risk>1:30)

24. outcome In practice most parents opt for termination of pregnancy Individuals vary greatly in level of disability High incidence of congenital heart disease, duodenal atresia Some children attend mainstream school with help Increased incidence of leukaemia and Alzheimer’s disease in later life

26. Case 2 A 27 year old undergoes a triple test at 14 weeks gestation in her first pregnency The results showed: AFP 126.7 kU/l 3.20 MoM hCG 32.2 IU/ml 0.97 MoM uE 3 2.9 nmol/L 1.16 MoM She goes on to have an ultrasound at 16 weeks

27. What can cause a raised AFP?

28. Causes of a raised AFP (>2.0 MoM) Lab error/wrong gestational age Multiple pregnancy Hydatidiform mole (trophoblastic tumour) Intrauterine death Anencephaly Other open neural tube defects: spina bifida Omphalocele/gastroschisis

30. “snowstorm effect”

37. Neural tube defects Due to incomplete development of neural tube from ectoderm May present at different sites and different grades of severity Often associated with hydrocephalus Not usually linked with chromosome abnormality Evidence that folic acid supplemants reduce the incidence

38. In this case The patient was referred for ultrasound which showed a meningocele in the lumbar spine

39. What is the likely outcome in this pregnancy? Natural history difficult to predict from ultrasound Anencephaly incompatible with life after birth 50% babies with open SB survive after 5y Majority of survivors have major degree of disability: lower limb/bladder paralysis/hydrocephalus/learning disability

40. How would you manage these pregnancies? The majority of patients request termination In England, Scotland and Wales legal to 24 weeks under Abortion Act 2 doctors required to sign for clause E, which states: “there is a substantial risk that if a child were born it would suffer from such physical or mental abnormalities as to be seriously handicapped”