Antenatal diagnosis of fetal and chromosomal abnormalities

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Chapter 27 Antenatal diagnosis of fetal and chromosomal abnormalities

Jackie Chua

In all, 2%–3% of children are born with a significant physical/mental handicap, and a further 3% have mild retardation.

Major malformations are present in 10%–15% of abortions, 50% of stillbirths and 3% of newborns. One-third of malformations are associated with genetic abnormalities. Table 27.1 lists causes of malformation. Multifactorial causes of malformation include neural tube defects, congenital heart defects or cleft lip/palate. The recurrence rate is about 2%–4%.

Table 27.1 Causes of malformation

Cause Incidence
Single gene defect 9%
Chromosomal defect 6%
Multifactorial 20%
Environmental 5%
Unknown 60%

Indications for prenatal diagnosis

• chromosomal abnormalities: suspected parental carriers, maternal age, previously affected pregnancy, known abnormality in either parent
• metabolic disease
• neural tube defect
• isoimmunisation
• skeletal dysplasia
• all women with a high risk
• fetus with a diagnosable defect

Tests available for antenatal diagnosis

Screening

• maternal age
• first trimester: combined nuchal translucency
• second trimester: triple/quadruple test, morphology test

Diagnosis

• first trimester: chorionic villus sampling
• second trimester: amniocentesis
• other: fetal blood sampling

Genetic counselling

All women who choose to have an antenatal screening test should have access to adequate counselling. Specialist genetic counselling clinics should be available for:

• discussion of abnormal screening tests
• discussion of abnormal ultrasound and karyotype findings
• patients with a family history of genetic disorders
• a specific medical condition of the mother with possible fetal transmission (e.g. human immunodeficiency virus (HIV))
• three or more miscarriages
• consanguinity
• chemical or radiation exposure in pregnancy

Indications for genetic counselling

• previously affected child
• history of genetic condition in family
• consanguinity
• advanced maternal age
• prenatal diagnosis
• physically or mentally handicapped parent

Aims of genetic counselling

• make accurate diagnosis
• provide adequate pedigree information
• explain risks to family
• identify methods of avoiding or decreasing risks
• arrange follow-up
• explain options available: ignore risks, have no more children, adoption, sperm or ovum donation, prenatal diagnosis and selective termination

Indications for chromosome studies

• recurrent abortion
• fetus or infant suggestive of malformation
• fetus or infant with one or more malformations
• fetus over 13 weeks gestation with ambiguous genitalia
• macerated fetus/stillbirth
• severe intrauterine growth restriction
• advanced maternal age

Distribution of chromosomal abnormalities

• first-trimester abortion: 50%–60%
• second-trimester abortion: 35%
• stillbirths: 5%
• live births: 0.5%

After two or more abortions, there is a 5% chance of chromosomal abnormalities in the parents. This rises to 10% with four or more abortions.

Screening

Risk assessment

• low or high risk for aneuploidy
• maternal age: >35 years high risk for aneuploidy

Combined nuchal translucency and biochemical screening

• combined nuchal translucency (ultrasound assessment performed between 11 weeks and 1 day and 13 weeks and 6 days) and biochemical screening (free beta-human chorionic gonadotrophin (HCG) and pregnancy-associated plasma protein A (PAPP-A) combined with maternal age)
• detection rate of 90%, with a false-positive of 5%
• other markers used to increase sensitivity (but not currently used in the Australian risk assessment program) include:

• presence or absence of nasal bone
• presence or absence of tricuspid regurgitation
• presence or absence of ductus venosus A-wave
• fetal maxillary facial angle
• biochemical markers may also be used to screen for pre-eclampsia, intrauterine growth restriction and fetal demise

Second-trimester screening

• Screening is performed using alpha-fetoprotein (AFP), unconjugated estriol, free beta-hCG and inhibin A combined with maternal age. Sensitivity is 70%.
• AFP is the principal plasma protein of the fetus in early gestation. It is initially produced in the yolk sac, and then the fetal liver and gut:

• Fetal AFP: plasma levels peak at 12–13 weeks gestation and fall throughout pregnancy.
• Maternal serum AFP rises in the second trimester, reaches maximum levels at approximately 30 weeks and then falls.
• Amniotic fluid AFP parallels levels in the fetal plasma, but in a ratio of 1:200.
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