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

• all women with a high risk

• fetus with a diagnosable defect

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

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

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.

• Raised AFP (>2.0 multiples of the median (MoM)) may be due to neural tube defects, gastrointestinal defects (omphalocele, gastroschisis, oesophageal and duodenal atresia), cystic hygroma, threatened abortion or antepartum haemorrhage, fetal death in utero, multiple pregnancy and advanced gestation.

Ultrasound screening

• There is 50% sensitivity for babies with Down syndrome.

• Nearly all trisomy 13/18 have ultrasound findings.

• Previous soft markers of echogenic focus in the heart, choroid plexus cysts and hypoplasia of the middle phalanx of the fifth finger are not generally used anymore.

Definitive diagnosis tests

• Fluorescent in situ hybridisation (FISH) analysis for trisomy and specific marker genes may give rapid diagnosis.

• Confirmation is from long-term culture karyotypes.

• Free fetal DNA for Rhesus (Rh) cases in the future.

Amniocentesis

• It is usually performed after 16 weeks gestation when the amnion has fused with the chorion.

• Information gained includes chromosomes and DNA analysis, AFP and enzymology.

• Fetal loss is 1 in 200 procedures.

• False-positive results occur in 0.3%, inadequate cell collection in up to 2% of samples, and maternal contamination in 1 of 1000 samples.

• Anti-D prophylaxis is required if the woman is RhD-negative.

Chorionic villus sampling

• It is usually performed at 11–14 weeks gestation. As the sample is directly from the chorion, there is a 1% risk of mosaicism (i.e. the presence of a genetic cell line that is not fetal, but purely placental in origin and therefore a false-positive result). If this occurs, amniocentesis is required for fetal karyotyping.

• An earlier test has the advantage that termination of pregnancy may be performed earlier, possibly operatively rather than induction in comparison with amniocentesis.

• The tissue may be collected transabdominally or transcervically. The risk of fetal loss from the procedure is 1%–2%.

• It has a false-positive rate of 2%, inadequate specimen collection in up to 8%, and maternal contamination in 1%–2%. Up to 4% of cases require follow-up by amniocentesis.

• The oromandibular limb hypogenesis syndrome has been reported with procedures performed at 56–66 days gestation and is probably due to vascular insult in early pregnancy.

Cordocentesis/fetal blood sampling

• collection of fetal blood sample from cord; performed in second and third trimester

• use: fetal karyotype, viral serology, full blood count, blood group, blood gases, metabolic abnormalities and DNA analysis, as well as treatment such as transfusion

• fetal loss of 1%–2%

Chromosomal abnormalities

Translocations

• If the mother has a translocation, there is a 10% recurrence risk.

• If the father has a translocation, there is a 2% recurrence risk.

Reciprocal translocation

If this is demonstrated through an unbalanced translocation in the offspring, the risk of unbalanced translocation in another offspring is 10%–20% for female carriers and 5%–10% for male carriers. If amniocentesis shows a balanced translocation and the parents have normal chromosomes, the child will look normal, but there is a 1 in 8 risk of intellectual handicap, as some genes may be lost during the translocation.

Robertsonian translocation

This involves acrocentric chromosomes (13, 14, 15 21 and 22). The carrier has 45 chromosomes. Be aware of the risk of uniparental disomy with the imprinted chromosomes (i.e. 14 and 15). Of people with Down syndrome, 4% have a parent with a Robertsonian translocation. When the translocation occurs on the same chromosome, the risk of another affected child is 100%.

Trisomies

After one affected fetus, the recurrence risk is 1% plus the risk for maternal age.

Trisomy 21

• Incidence is 1 in 800 live births.

• The only factor related to trisomy 21 is maternal age (see Table 27.2).

Table 27.2 Risk of trisomy 21

Maternal age	Risk
20	1 in 2000
25	1 in 1200
30	1 in 700
35	1 in 400
37	1 in 250
40	1 in 100
43	1 in 50

The incidence of all chromosomal abnormalities is about twice that of trisomy 21. Women affected by trisomy 21 are often infertile. However, if the woman becomes pregnant, the risk of trisomy 21 to her offspring is 33%, which is less than the expected 50% because of an increased trisomic loss in early pregnancy.

Other genetic syndromes

Fragile X syndrome

• incidence of 1 in 1000 male births; responsible for 25% of male intellectual handicap

• second only to trisomy 21 as a chromosomal cause of mental impairment; 35% of heterozygote females are mentally impaired

• prenatal testing available, though parental karyotype comparison important

• diagnosis by presence of nucleotide triplet repeat and expansion of >220 repeats in males.

Cystic fibrosis

This is an autosomal recessive disorder, with an incidence in Caucasians of 1 in 2500 and a carrier frequency of 1 in 25.

Genetics. The mutant gene is the cystic fibrosis transmembrane conductance regulator, situated on the long arm of chromosome 7 (CFTR gene). In 75% of cases, cystic fibrosis is due to the deletion of a single codon (delta F508 is the most common).

Screening. If one parent has a close relative with cystic fibrosis, then the carrier risk is reduced to a 1 in 99 chance by a negative result in tests for F508 and other common gene deletions. Prenatal diagnosis may be necessary if ultrasound abnormalities are discovered, such as hyperechogenic bowel. Prenatal diagnosis is possible by 12–19 mutation panel, which detects 80% of the most common mutations. The whole CFTR gene can be sequenced (sent to New Zealand).

Muscular dystrophies

Duchenne muscular dystrophy has an incidence of 0.3 in 1000 male births. It is an X-linked recessive disorder with the mutant gene at Xp21. Presentation is one of progressive muscle wasting, with death in the second or third decade of life. Diagnosis is based on the absence of dystrophins on immunoblotting muscle biopsy.

Myotonic dystrophy is an autosomal dominant inheritance with associated abnormalities of mental retardation, cataracts, diabetes, cardiomyopathy and infertility. Pregnancy in an affected woman can increase the severity of disease, causing prolonged labour, uterine atony, postpartum haemorrhage and polyhydramnios.

Phenylketonuria

• Phenylketonuria has an incidence of 1 in 12,000 births. It is an autosomal recessive disorder.

• The pathology is that of an inborn error of metabolism with a deficiency of the enzyme phenylalanine hydroxylase. This enzyme converts phenylalanine to tyrosine. In phenylalanine hydroxylase deficiency, there is a rise in serum phenylalanine levels in children, leading to impaired myelination of the brain and subsequent mental retardation.

• The concentration gradient across the placenta produces fetal levels that are twice maternal levels.

Marfan’s syndrome

Marfan’s syndrome is an autosomal dominant connective tissue disorder.

Neurofibromatosis

Neurofibromatosis is an autosomal dominant disorder.

Thalassaemia

Alpha-thalassaemia is due to gene deletion. Beta-thalassaemia has more than 40 gene mutations. Both have lethal forms.

Incidence in ethnic and racial groups

Genetic disorders are more common in certain ethnic and racial groups. For example:

• Ashkenazi Jews: Tay-Sachs disease

• African Americans: sickle cell anaemia

• South-East Asians, Greeks, Italians: thalassaemia

Morphology ultrasound assessment

Under defined protocol, assessments are performed typically between 18 and 20 weeks gestation. Common anomalies screened include the following.

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