Prenatal diagnosis

Congenital Abnormalities
Definition: Abnormalities of the neonate, evident at birth. (With the use of antenatal diagnostic tests, these same defects may be detected before birth, and are still classified as congenital defects)

Congenital Abnormalities
Incidence Major: 2-3% Minor: 14%
cause of 20% of deaths in first week of life.

Congenital Abnormalities
Suspected cause Unknown Genetic Environmental
Maternal conditions Infectious agents Mechanical problems Chemicals, radiation etc

% of total 65-75 10-25 10

4 3 1-2 <1

Congenital Abnormalities
Chromosomal defects (numerical defects)
Down syndrome (trisomy 21)
1 in 600-700 livebirths

Edwards syndrome (trisomy 18) Patous syndrome (trisomy 13) Sex-chromosome aneuploidies
Turners syndrome (45,X) Klinefelters syndrome (47,XXY) 47,XXX; 47,XYY

Congenital Abnormalities
Gene defects - inheritance
Autosomal recessive Autosomal dominant chance mutation

Causes
base substitution, deletion or addition

Congenital Abnormalities
Gene defects - examples
Cystic fibrosis thalassemia Fragile-X Prader- Willi
etc etc

Congenital Abnormalities
Maternal conditions
Diabetes PKU alcoholism smoking

Infectious causes (see later lecture)

Congenital Abnormalities
Mechanical problems
amniotic bands / early amnion rupture sequence umbilical cord constraint lack of liquor

Chemicals, drugs, radiation etc

notes)

(see later lecture

Antenatal Diagnosis
Methods available
ultrasound amniocentesis chorionic villous sampling cordocentesis

Antenatal Diagnosis

SCREENING DIAGNOSIS

Antenatal Diagnosis
Diagnostic tests
ultrasound amniocentesis CVS cordocentesis

Screening tests
ultrasound
nuchal translucency (NT)

maternal serum
2nd trimester 1st trimester

? fetal cells in maternal circulation (in the future)

Antenatal Diagnosis
Diagnostic tests - amniocentesis
performed between 15-20 weeks 22G needle passed into amniotic sac 20 mls of fluid obtained
karyotype Alpha-fetoprotein (AFP) level (rarely other biochemical tests) PCR and FISH for rapid cytogenetic result

Risk of miscarriage: % Result: 2 weeks

Antenatal Diagnosis
Diagnostic tests - CVS
Performed between 10+ and 12 weeks, (although placental biopsy can be used until early 3rd trimester) Trans abdominal or trans cervical approach Placental tissue obtained
karyotype genetic testing (known gene defects)

Risk of miscarriage: 1%

CVS vs amniocentesis
CVS
10-12 weeks miscarriage: 1 in 100 NTD diagnosis: no DNA analysis: easier results: 2+ weeks; direct prep: 48 hrs mosaicism:1-2% ToP: D&C

Amniocentesis
15-20 weeks 1 in 200 (Open NTD): yes more difficult 2 weeks (FISH: 24-48 hrs) rare usually induction of labour

Antenatal Diagnosis
Diagnostic tests - cordocentesis
(aka PUBS or funicentesis)

22G needle into the umbilical vein 2-3 mls of fetal blood extracted can be examined for karyotype Hb concentration (useful in fetal hydrops and Rh disease) blood gases and pH (used mainly experimentally) virtually any test done on human blood (but normal values not always available) miscarriage rate :1-2%

Antenatal Diagnosis
Diagnostic &/or Screening tests Ultrasound (US)
No known risk to fetus can be performed at any stage of pregnancy(although embryo not visible until 5 weeks
gestation)

requires expensive equipment and good training of personnel Cannot diagnose all congenital abnormalities (due to nature of abnormality, timing of US, size of mother,

Antenatal Diagnosis ultrasound

Diagnostic test: 18-20 week US
offered to all pregnant women in most studies detects 50-60% of major abnormalities Detects structural abnormalities, rarely functional abnormalities is additionally useful in determining gestational age (1 week), number of fetuses and placental site

Antenatal Diagnosis ultrasound

Screening test: Nuchal translucency (NT)
performed between 10 and 14 weeks will detect 54-72% of Down Syndrome (DS) fetuses 35+ invasive tests to detect 1 DS fetus enlarged NT measurement more common in fetuses with heart defects

Antenatal Diagnosis ultrasound

Screening test - 2nd trimester
soft markers
thickened nuchal fold short middle phalanx of little finger sandal gap echogenic bowel short femur/ humerus, etc, etc

soft markers detection rate of malformations, but false-positive rate

Antenatal Diagnosis screening

Biochemistry
2nd trimester [1st trimester]

Antenatal Diagnosis screening

2nd trimester biochemistry - maternal
serum screening, triple test, quadruple test, etc Maternal age Alpha-fetoprotein (AFP) hCG (total, , free-, free-) estriol (uE3)* inhibin*
*optional

Antenatal Diagnosis screening

2nd trimester biochemical
performed at 15-20 weeks gestation 60-70% detection rate for DS 5%-8% false-positive rate (depending on maternal-age distribution) 40-50 amniocenteses to detect 1 DS fetus

Antenatal Diagnosis screening

1st trimester biochemical screening
Maternal age free -hCG Pregnancy associated plasma protein-A (PAPP-A)

not yet in general usage

Antenatal Diagnosis in Victoria

Who makes use of invasive antenatal diagnostic tests?
Women at ed risk of an abnormal fetus (test depends on abnormality being looked for) eg
women 37 years of age at delivery previous child with abnormality parent with abnormality women at risk on the basis of a biochemical or screening test result

Antenatal Diagnosis
What is available in Cork?
MSS at 15-20 weeks US at 18-20 weeks Amnio, but may choose another form of screening Women at risk for other reasons usually need referral to genetic counsellor

Congenital Abnormalities
Suspected cause Unknown Genetic Environmental
Maternal conditions Infectious agents Mechanical problems Chemicals, radiation etc

% of total 65-75 10-25 10

4 3 1-2 <1