Prenatal Diagnosis Flashcards
What percentage of neonates have a significant congenital abnormality?
2-3%
When do you carry out prenatal diagnosis tests?
High risk i.e. family history of genetic disease, maternal illness (DM), previous history of an abnormal pregnancy
Or abnormal screening test
What is screened for in a low risk pregnancy?
Major:
Congenital anomalies e.g. neural tube defects, congenital heart disease, brain malformations
Chromosome abnormalities
What are the common neural tube defects?
Anencephaly and spina bifida (90%)
Open defects –> neural tissue and meninges exposed
Closed = 15-20%
What is the test for neural tube defects?
Open: increased maternal serum alpha-fetoprotein
Closed: undetectable
Why has there been a decline in neural tube defects?
Better nutrition and dietary folic acid
What are the different types of chromosomal abnormality?
Aneuploidy = addition or loss of whole chromosome Addition or loss of part of a chromosome Chromosome rearrangement (translocation or inversion)
How do you detect chromosome aneuploidies?
Cytogenetic analysis
Microarray analysis for addition or loss of part of a chromosome
What are the common trisomies?
13, 18, 21, X 13 = Patau 18 = Edwards 21 = Down XXY = Klinefelter
What is Trisomy 21? Describe the symptoms
Down Syndrome
Intellectual disability - mild to moderate
Dysmorphic - nasal flat bridge, up slanting palpebral fissures, epicanthic folds (fold of skin on medial upper eyelid), single palmar crease, protruding tongue, clinodactyly (curvature of 5th finger towards adjacent 4th finger)
Cardiac defects - 40% of cases
What is the incidence change of trisomy 21 with maternal age?
1:700 to 1:50 at maternal age 43
60% sponataneously abort
What is Trisomy 18? Describe the symptoms.
Edward's syndrome Severe learning disability Dysmorphic - micrognathia, prominent occiput Clenched overlapping fingers Prominent heels and rocker-bottom feet Cardiac defects
What is the incidence change of trisomy 18 with maternal age?
1:3000 to 1:500 at age 43
30% die within 1 month, 90% one year
What is Trisomy 13? Describe the symptoms
Patau Syndrome
Severe mental disability
Dysmorphic - cleft lip, cleft palate, holoprosencephaly, postaxial polydactyly, renal abnormalities, cardiac defects
What is the prevalence change of trisomy 13 with maternal age?
1:5000 to 1:1100 at 43
45% die within 1 month, 85% within 1 year
What is Turner Syndrome? What is the incidence?
1/5000
XO
What is Klinefelter Syndrome? What is the incidence?
1/1000
XXY
Describe the progression of prenatal ultrasound scanning?
Booking scan 1 trimester less than 15w
Foetal anomaly scan 18-20w second trimester. Most abnormalities pciked up here
Fetal MRI for brain imaging
What is the early pregnancy scan for?
- Establish gestational age accurately (essential for trisomy 21 screening)
- Fetal crown-rump length <12 weeks or
- Biparietal diameter >12 weeks.
- Nuchal translucency measurements. Between 11-13w gestatation. Non-specific
V few abnormalities picked up here
Test of viability, foetal number and in multiple pregnancies the chorionicity/amnionicity
Detection of gross fetal abnormalities.
Which conditions is increased nuchal translucency thickness seen with?
Trisomy 21
Cardiac failure associated with congenital heart disease
Venous congestion in head and neck caused by constriction of foetal body (amniotic band, superior mediastinal compression caused by diaphragmatic hernia, narrow chest in skeletal dysplasia)
Abnormal development of the lymphatic system
Impaired fetal movement due to neuromuscular disorder
Foetal anaemia/hypoproteinaemia
Congenital infection through anemia or cardiac dysfunction
Some rare single gene disorders
What is the normal nuchal thickness?
2.5mm
>5.5 = 80% risk adverse outcome (abnormality/fetal or postnatal death)
From when are neural tube defects detectable by antenatal ultrasound? What are the signs?
Anencephaly 10-14 weeks
Spina bifida 16-22 weeks
Indirect cranial or cerebellar markers are Lemon + Banana signs - tonsils of the cerebellum come down onto spinal canal
Most detected by 20 week anomaly scan
What is Meckel-Gruber syndrome?
Example of an abnormality that leads to specific diagnosis
Encephalocoele
6 digits
Single gene disorder
What are the modes of screening?
Maternal age
Serum screening
Combined screening using information from ultrasound and maternal serum tests
Describe alphafetoprotein
Reaches maternal serum directly across placenta or indirectly from amniotic fluid across chorion and amnion and then uptake by maternal vasculature in the decidua.
Measure by immunoassay
Levels change with gestation (lower trimester 2 than 1)
Used to screen for NTDs and trisomy 21.
Need accurate estimate of gestation at which sample is obtained to interpret
Made by yolk sac and fetal liver
What is the false positive problem in AFP serum tests?
Unaffected and spina bifida overlaps
At 5% false + rate around 75% open spina bifida cases detected. Balance between specificity and sensitivity.
Why can you not use maternal age alone to screen for trisomy?
Because although risk rises, the majority of cases still occur in younger women
What are the prenatal markers for Down Syndrome?
Maternal age
Nuchal scan
Brackets = multiple of median
Serum screening for AFP (0.75), unconjugated estriol (0.73), hCG (2/05)
If greater than 1 in 250 threshold risk, i.e. 5% false positive rate, give women amniocentesis
Give examples of tests used in high risk pregnancies
Invasive CVS chorionic villus sampling Amniocentesis Fetal blood sampling Non-invasive Ultrasound Free fetal DNA
Describe CVS
Chorionic villus sampling
Enables samples to be taken in first trimester after 11 weeks
Fetally derived cells (trophoblast)
Maternal material must be discarded
Gives good preparations of DNA without culture
Chromosome analysis can be done rapidly within 24h, but best quality analysis after 2 weeks culture.
1-2% miscarriage risk.
Possible of surgical termination in 1 trimester.
Problem: testing placenta not fetus - some abnormalities are seen in the placenta but not the fetus so diagnositclaly difficult
Describe amniocentesis
10-20 mls of amniotic fluid sampled transabdominally under US
16w gestation or later
Cells from amnion, fetal skin and urinary tract pelleted
Culture 2 weeks
Longer culture may be needed for DNA or biochemical studies - nb rapid trisomy screen results by PCR bypass this time requirement
0.5% risk miscarriage
Medical/late termination of pregnancy.
What are the pros and cons of CVS?
Pro Earlier Diagnosis Cons Higher risk miscarriage Extraembronic tissue Possibility of confined placental mosaicism
What are the pros and cons of amniocentesis?
Pros Fetal material Lower risk miscarriage Cons Later diagnosis
How do you investigate fetal structural anomaly?
Karyotype - misses inversions and translocations
Chromosomal microarrays +5%
DNA sequencing + ??%
What is a foetoscopy and what is it used for
Foetal skin biopsy
Used for hereditary skin disorders e.g. epidermolysis bullosa
What is cordocentesis and what is it used for?
Foetal blood sampling for chromosomal disorders, haematological disorders and congenital infection
What is the total schema of Pre-implantanation genetic diagnosis?
- Genetically examine couple
- Genetic conclusion
- Fertilisation IVF or ICSI
- Blastomer biopsy
- PCR FISH
- Embryo transfer (not more than 2)
What are the pros and cons of cell free foetal DNA?
No increased risk miscarriage
Easier sample collection
Earlier diagnoses (from 7 weeks)
Describe cell free fetal DNA testing cffDNA
Originates from placenta
Represents whole fetal genome
Detectable from 4 weeks
% increases with gestation
10-20% total cfDNA
Cleared from circulation within 30 mins delivery
Shorter than maternal cfDNA 166bp cw 143 bp
What is NIPD NIPT NIPS?
Non invasive prenatal diagnosis/testing/screening
NIPD for high risk cases - doesn’t require invasive test for confirmation ie single gene disorders, sex determination
NIPT NIPS for low risk cases. Aneuploidy. Requires invasive testing for confirmation.
Give examples of use of NIPD
Fetal sex determination genes on Y chromosome - don’t need to test female.
