Prenatal diagnosis Flashcards
What are the most common chromosomal abnormalities?
95% are Trisomy 21, 18, 13, or changes in X and Y
Most of these are Down syndrome
what is a major risk factor for chromosomal abnormalities?
maternal age
at 20 the risk is 1/530
at 45 the risk is 1/19
what are the benefits of prenatal screening and diagnosis?
parental reassurance
it may allow woman to undertake a pregnancy they may not have otherwise undertaken
if an abnormality is detected in prenatal screening what are the options?
further testing referral counselling regarding planned birth or termination preparation for special needs child altered obstetric management facilitated neonatal management.
what are the risks associated with prenatal screening and diagnosis?
parental anxiety (false positive, true positive)
pregnancy complication s
pregnancy loss
who is prenatal screening offered to ?
all pregnant woman at >90% of structural and chromosomal abnormalities are born to low risk woman.
what are the current screening methods?
all have detection >75% with <3% false positive rate
Integrated Prenatal Screening (IPS)
First trimester screening
Quadruple maternal serum screening
what is the nuchal translucency?
subcutaneous fluid-filled space located between back of metal neck and skin
measured on USS 6/7 weeks
NT increases with gestational age
what is done if the Nuchal Translucency is greater than >3mm
greater than 3 or 3.5 (depending on centre) is said to be elevated.
- -> diagnostic testing is indicated
- -> fetal echo indicated at 20 weeks in NT>3mm
- -> detailed anatomy scan at 18-20 weeks
- ->genetic counselling
What is increased Nuchal Translucency associated with?
- Trisomies 21, 18, 13, triploidy and Turner syndrome
- Spontaneous fetal loss
- With normal chromosomes: cardiac defects, diaphragmatic hernia, pulmonary defects, skeletal dysplasias, congenital infection, metabolic/haem disorders, rare single gene disorders
- Normal pregnancy – chance of a normal birth varies with size of NT measurement
what is done for combined screening???
Nuchal Translucency measurement 11 to 13 weeks
T1 serum markers (PAPP-A, free beta hCG
NTD screening with MS-AFP and/or USS is still recommend in T2
what are non-invasive methods of chromosomal evaluation?
Fetal cells from maternal blood preimplantation embryos (PGD)
what are invasive methods of chromosomal evaluation?
amniotic fluid (amniocentesis)
placenta (chorionic villus tissue)
Fetal blood
what is considered as late and early amniocentesis?
Late – second trimester after 15 weeks
Early – earlier than 15 weeks
Three types of chorionic villus sampling?
Abdominal
Trans cervical
Trans vaginal
what can be evaluated on genetic screening/diagnosis?
Chromosomal aberrations: Trisomy, Monosomy, Polyploidy, Marker chromosome, Deletion, duplication, inversion, translocation, ring chromosome . Genetic aberrations (DNA) Infectious disease Biochemical markers (AFP)
what are the complications of amniocentesis?
pregnancy loss 0.3 - 1%
Leakage of amniotic fluid (better prognosis than spontaneous leakage) Amnionitis Vaginal bleeding Needle puncture of the fetus Long term complications: Respiratory distress?? Isoimmunization??
what increases the risk of amniocentesis?
Needle larger than 18g
Multiple needle insertion
Discoloration of the fluid
High AFP, multiple late miscarriages, previous vaginal bleeding
what are risk with amniocentesis and HIV what is done to prevent risk?
Increased rate of vertical transmission
Chemoprophylaxis previous to amniocentesis appears to be beneficial in preventing vertical transmission
Chorionic Villus sampling
what does the direct and cultured analysis show?
Direct analysis examines the trophoblast cells of the placenta (very rapidly dividing cells)
Results in few hours
greater vulnerability to mitotic error
Cultured analysis examines the fibroblast like cells of the villus stroma or mesenchymal core.
Approximately 10-14 days
Accurately reflect the chromosomes of the fetus.
how safe is trans abdominal CVS
Transabdominal CVS as safe as second trimester amniocentesis
Trans abdominal and transcervical CVS are equally safe and efficacious, provided that centers have expertise with both approaches
what is true mosaicism?
True chromosomal mosaicism is when two or more abnormal cells lines are detected in two or more cultures from the same individual.
what is pseudomosacisim?
Pseudomosaicism is a term used to describe two abnormal cell lines that are found in only one culture
what is the clinical outcome of mosaicism?
Most often involving trisomic cell and normal cells
Clinical outcome of chromosomal mosaicism is strongly dependent on the specific chromosome involved and the number of trisomic cells in both the placenta and the fetus
what are the four possible conditions is there is mosaicism (trisomy cells) in CVS?
Mosaicism only in the placenta not affecting the fetus or placental function.
Mosaicism only in the placenta not affecting the fetus but alter placental function (IUGR)
Trisomy cells are both in the placenta and in the fetus
Trisomy cells in the placenta and uniparental disomy in the fetus
what does it mean if there is Mosaicism (triatomic cells) in amniotic fluid?
Probably there are trisomic cells in the fetus
The true level and distribution of trisomic cells cannot be accurately assessed with any prenatal procedure
Ultrasound is often the best judge of how a baby is developing
what is uniparental Disomy?
Arises when an individual inherits two copies of a chromosome pair from one parent and no copy from the other parent
Maternal UPD – two copies from the mother
Paternal UPD – two copies from the father
how does uniparental disomy happen?
Loss of a chromosome from a trisomic zygote, “trisomic rescue”
Duplication of a chromosome from a monosomic zygote, “monosomic rescue”
Fertilization of a gamete with two copies of a chromosome by a gamete with no copies of the same chromosome, called gamete complementation.
molecular uniparental testing should be considered for which chromosomes? and why?
molecular UPD testing should be considered for certain chromosomes (including 6, 7, 11, 14, 15) that are known to have adverse phenotypic imprinting effects.
what factors should be considered when trying to predict the outcome of mosaicism?
the chromosomes involved
(A mosaic finding 18 or 21 is likely to have worse implications
mosaic finding for trisomy 15 or 16 is likely to have less implications (trisomy 15 or 16 cells cannot survive )
The tissues affected and the level of trisomy in those tissues
methods of ascertainment
(CVS shows that the placenta is affected
Amniotic fluid suggests that at least one fetal tissue may be affected
Fetal blood sampling confirms the diagnosis of chromosomal mosaicism)
USS findings
presence or nascence of uniparental disomy
what is non-invasive prenatal testing (NIPT)?
it is new technology
it is a single blood test that uses cutting-edge technology to screen pregnant women for chromosome problems, as early as 10-weeks in pregnancy.
who can be offered NIPT?
Maternal age-related risks
Positive results on maternal serum screening
Abnormal ultrasound finding(s)
Prior pregnancy with aneuploidy
Parental Robertsonian translocation involving one of the tested chromosomes
what are the aims of NIPT??
reduce exposure of fetes to risk
reduce false positives
enable a high detection rate
testing that can be offered to all pregnant woman
what are the two sources of fatal DNA
Fetal cells
1 in a billion of total cell population
Require isolation via mechanical and/or biochemical means
Cell-free DNA (cfDNA)
Maternal blood contains both maternal and fetal cfDNA
2–20% of total cfDNA is fetal
what is fatal cell-free DNA?
it is maternal blood
Released through apoptosis
Fetal cfDNA likely arises from cytotrophoblastic cells of placenta
Released into bloodstream as small DNA fragments (150-200bp)
Reliably detected after 7+ weeks gestation
Undetectable within hours postpartum
what are the methods of analysing cfDNA?
Direct analysis
Massive parallel sequencing
Many companies/papers professing that their technique is the best
Unclear at present which gives best and most reliable results
what are the advantages of NIPT?
Reduces unnecessary procedures in borderline high risk women
Can give more equivocal risk assessment than any of the options offered on NHS
i.e. < 1 in 10,000 (0.1%) or > 99%
what are the disadvantages of NIPT?
Currently not available on NHS
Costly
Still classified as screening – NOT diagnostic
Takes 7-10 working days.
