Foetal Abnormalities

Question 1

Genetic disorders in fetus

Answer 1

-Down syndrome (trisomy 21)
-Edwards syndrome (trisomy 18)
-Patau syndrome (trisomy 13)
-Triploidy
-Sex chromosome abnormalities
-XO (Turner syndrome)
-XXY (Klinefelter syndrome)
-XYY
-XXX
-Apparently balanced rearrangements (translocations or inversions)
- Unbalanced chromosomal structural abnormalities
-Gene disorders (e.g., fragile X syndrome, Huntington chorea, Tay-Sachs disease)

Question 2

Structural congenital disorders in fetus

Answer 2

-Congenital heart disease (transposition of the great arteries, atrioventricular septal defect, tetralogy of Fallot, hypoplastic left heart syndrome)
-Neural tube defects (e.g., anencephaly, encephalocele, spina bifida, cleft lip)
-Abdominal wall defects (e.g., exomphalos, gastroschisis)
-Genitourinary abnormalities (e.g., renal dysplasia, polycystic kidney disease, pyelectasis, posterior urethral valves, Potter syndrome, bilateral renal agenesis)
-Lung disorders (e.g., pulmonary hypoplasia, diaphragmatic hernia, cystic fibrosis)
-Lethal skeletal dysplasia

Question 3

Aims of prenatal diagnosis

Answer 3

-To identify congenital anomalies at early gestation that are incompatible with life, or that are likely to result in significant disability to prepare the parents, involve other specialist clinicians, and offer the option of TOP if appropriate
-To identify conditions which may influence the timing, site, or mode of delivery
-To identify fetuses who may benefit from early neonatal/paediatric intervention
-To identify fetuses who may benefit from in utero treatment.

Question 4

Risk factors for anomalies

Answer 4

-Most occur de novo
-Maternal age (increased= trisomy)
-Medical comorbidities
=Mothers with pre-existing diabetes have a higher chance of cardiac and neural tube defects, whilst women with epilepsy are at increased chance of structural anomalies, especially if taking potentially teratogenic antiepileptic drugs.
-Family history of medical conditions
=Duchenne muscular dystrophy, cystic fibrosis, and sickle cell disease. Structural anomalies are also slightly more likely to occur in those with a family history of the condition; in some instances, the chance may be higher still if the parents have had a previously affected child.

Question 5

Screening for chromosomal anomalies

Answer 5

-First-trimester combined screening test
-Second-trimester quadruple test
-Non-invasive prenatal screening test (NIPT)

Question 6

Describe the when the first-trimester combined screening test is done

Answer 6

-Offered to all eligible pregnant women to assess the chance of the baby being born with Down syndrome (trisomy 21 or T21), or Edwards syndrome (T18) or Patau syndrome (T13)

-Choices
=1 Not to have screening
=2 To have screening for T21 and T18/T13
=3 To have screening for T21 only
=4 To have screening for T18/T13 only

-Performed between 11 +2 weeks to 14 +1 weeks of gestation, which corresponds to a crown rump length (CRL) of 45.0 mm to 84.0 mm

Question 7

What does the first-trimester combined screening test include?

Answer 7

-Maternal age
-The measurement of the thickness of nuchal fluid behind the fetal neck (nuchal translucency [NT])
-Maternal biochemistry, specifically free β‐human chorionic gonadotrophin (β‐hCG) and pregnancy associated plasma protein A (PAPP-A)
-The gestational age calculated from the CRL measurement

=For absolute certainty regarding whether a fetus is affected, an invasive diagnostic test will be required (amniocentesis and chorionic villous sampling [CVS])

Question 8

Describe the second-trimester quadruple test

Answer 8

-For those in whom it is not possible to obtain a first-trimester screening test (such as when an NT measurement cannot be obtained in the first trimester due to poor fetal position or a pregnancy that is already beyond 14 weeks’ gestation), a serological test for Down syndrome may be offered (but not for T18 or T13).
-The quadruple test incorporates maternal age and four biochemical markers measured between 14 +2 weeks until 20 +0 weeks: alpha-fetoprotein (AFP), free β‐hCG, estriol, and inhibin-A.
-The detection rate is 80%, lower than for the combined screening test (85%), with an associated 4% false-positive rate.
-Down syndrome is associated with low levels of AFP and unconjugated estriol and high levels of free β‐hCG and inhibin A.
-A raised AFP should also prompt an ultrasound scan looking for a neural tube defect or gastroschisis

Question 9

What is the non-invasive prenatal screening test?

Answer 9

-NIPT is the analysis of cell-free fetal deoxyribonucleic acid (cffDNA) in maternal serum to screen for trisomies 21, 18, and 13.
-These are fragments of DNA that are released from the placenta into the maternal circulation.
-NIPT may be offered from 10 weeks of gestation, as by this stage, cffDNA makes up an average of 10% of cell-free DNA in the mother’s blood and is detectable at serum testing

Question 10

How accurate is NIPT?

Answer 10

-As cffDNA is produced by the placenta rather than the fetus, the accuracy of NIPT is influenced by a variety of factors.
-NIPT accuracy is reduced in twin pregnancies (NIPT cannot be offered to higher-order multiples), obesity, and at less than 10 weeks’ gestation (due to insufficient fetal DNA in the maternal circulation).
-False-positive results can also be caused by confined placental mosaicism or a ‘vanishing twin’ (a twin pregnancy in which demise of one twin results in a singleton pregnancy) and maternal malignancy.

Question 11

When are structural anomalies screened for?

Answer 11

-Recommended that all women should be offered a detailed ultrasound between 18 +0 and 20 +6 weeks’ gestation to screen for major fetal anomalies.
-The fetal anomaly scan screens for 11 conditions at a minimum

Question 12

Diagnosis of chromosomal and genetic anomalies

Answer 12

-If screening tests have identified a mother at ‘high chance’ of carrying a baby with a chromosomal or genetic anomaly, then she will be offered a diagnostic test, either CVS or amniocentesis, which aims to sample fetal cells.
-Both of these carry a small risk of miscarriage.
-Given the possibility of rhesus sensitization, rhesus-negative women require anti-D immunoglobulin

Question 13

Describe chorionic villus sampling (CVS)

Answer 13

-CVS is typically performed between 11 and 14 weeks’ gestation and involves passing a needle transabdominally, or occasionally transvaginally, under ultrasound guidance by an appropriately trained fetal medicine specialist to take a sample of placental tissue (villi).
-The risk of miscarriage is commonly reported to be 0.5%.
-At this early gestation, it is difficult to determine whether the miscarriage would have happened anyway due to an underlying genetic defect in the fetus or whether it is the result of the CVS.

Question 14

Describe amniocentesis

Answer 14

-Diagnostic amniocentesis may be performed from 15 weeks’ gestation. It involves passing a thin needle transabdominally into the amniotic cavity, under continuous ultrasound guidance, to extract 10 to 18 mL of amniotic fluid. The risk of miscarriage is reported to be the same as CVS, at around 0.5%.

Question 15

Describe genetic testing

Answer 15

-QF-PCR: Results are available within 48 hours and are limited to the detection of T21, T13, T18, and 45X (Turner syndrome)
-Chromosome microarray analysis (CMA) has mostly replaced traditionally karyotyping. CMA provides a more detailed assessment of alterations in the genome. It can detect small gains and losses of genetic material, known as ‘copy number variants’ (CNVs).
-Whole-genome and exome sequencing in future

Question 16

Describe non-invasive prenatal diagnosis

Answer 16

-Analysis of cffDNA circulating in the maternal plasma to identify specific monogenic disorders
-When known familial mutation for which the fetus is at risk or when prenatal ultrasound examination identifies features that are highly characteristic for a well-defined specific disorder
=achondroplasia, thanatophoric dysplasia, Apert syndrome, congenital adrenal hyperplasia, and cystic fibrosis. It can also be used for fetal sex determination when the pregnancy is at risk of a sex-linked disorder.
=most commonly employed to diagnose fetal rhesus D-antigen status for rhesus D-negative mothers. A fetus predicted to be rhesus D-negative by NIPD precludes the need for antenatal anti-D prophylaxis in the mother.
-Invasive not needed

Question 17

Overview of Down syndrome (Trisomy 21)

Answer 17

-1/1000 live births, increase with advancing maternal age
-Variable neurodevelopmental delay, hypotonia, short stature, facial features with flat nasal bridge and protruding tongue, upward slanting eyes, broad hands, single palmar crease, 50% congenital heart defect (septal), gut motility problems, hypothyroidism, increased risk of early onset dementia
-Life expectancy increased from 25 to 60
-Of all cases, 95% are due to chromosomal nondisjunction, with 4% due to translocation, and the remaining 1% to mosaicism

Question 18

Overview of Edwards syndrome (trisomy 18)

Answer 18

-1 in 3500 : nondisjunction of chromosome 18.
-Early-onset growth restriction, specific craniofacial features, including a small strawberry-shaped cranium, small facial features and low-set ears, and skeletal abnormalities, including overlapping fingers and prominent calcanei (rocker bottom feet).
-Major systemic abnormalities are common and include congenital heart disease, complex urogenital anomalies, and problems with the gastrointestinal system, such as omphalocele and oesophageal atresia.
-Approximately 68% die in utero; for those who survive to birth, the outcome is poor. Median survival is 2 weeks; up to 13.5% live to 1 year and 12.3% to 5 years.

Question 19

Overview of Patau syndrome (trisomy 13)

Answer 19

-1 in 6500 to 1 in 29,000
-Multiple severe congenital abnormalities, which result in significant physical and mental impairment.
-Approximately 80% of children will have a severe heart defect.
-Significant brain defects, clefts of the lip or palate, kidney and urogenital anomalies, extra digits, omphalocele, and spina bifida are also common features.
-The majority of babies affected are stillborn, with survivors rarely expected to live longer than 1 week. Only 11.5% will survive the first year

Question 20

Describe Triploidy

Answer 20

-Presence of an additional set of chromosomes acquired either from the mother (causing severe fetal growth restriction and fetal abnormality) or father (associated with a partial mole) during fertilization, resulting in a total of 69 as opposed to the normal 46.
-Affected fetuses usually miscarry in early pregnancy and survival to birth is rare.
-There is no expected survival past the immediate neonatal period, with the affected fetus generally severely growth restricted and affected by multiple severe abnormalities

Question 21

Overview of Turner syndrome (45,XO)

Answer 21

-1 in 2500 live-born girls: paternal chromosome, although some individuals have a mosaic pattern.
-Antenatally, Turner syndrome is associated with cystic hygroma, cardiac defects, and non-immune hydrops, which results in many affected pregnancies miscarrying.
-If not identified antenatally, the majority of girls affected are diagnosed in infancy or childhood as a result of characteristic physical features.
=These include short stature, webbed neck, widely spaced nipples, and cubitus valgus.
=Other associated problems include renal dysgenesis, coarctation of the aorta, and ovarian failure, necessitating long-term hormone replacement therapy (HRT) requirements.
=Intelligence is largely unaffected, although there may be some impairment of non-verbal skills

Question 22

Describe 47,XXX anomaly

Answer 22

-This is the most common female chromosomal abnormality, occurring in 1 in 1000 live births, although higher in pregnancies in women over 40 years.
-Those affected are phenotypically normal, with normal development of secondary sexual characteristics and fertility.
-There is often a delay in motor and speech development and an association with genitourinary problems, including premature ovarian insufficiency, requiring HRT

Question 23

Describe Klinefelter syndrome (47,XXY)

Answer 23

-This affects 1 in 1000 live births and is a frequent cause of male factor infertility.
-Those affected tend to be tall males with sparse body hair and gynaecomastia.
-Typically, the testes remain small; many cases are diagnosed during puberty as a result of this.
-There is some association with reduced intelligence quotient (IQ), hypothyroidism, cardiovascular disease, and type 2 diabetes

Question 24

Describe Jacobs syndrome (47,XYY)

Answer 24

-Incidence is around 1 in 1000 live births and is frequently undetected due to a lack of symptoms or fertility concerns.
-Characteristically, males are tall with acne. Whilst intelligence is in the normal range, there may be an association with behavioural problems, including impulsivity

Question 25

Genetic testing for haemoglobinopathies

Answer 25

-Thalassaemia and sickle cell= recessively inherited genetic conditions of haemoglobin gene
-Recommends that all pregnant women be offered a blood test by 10 +0 weeks of gestation to determine whether they carry a gene for thalassaemia and to differentiate those at high risk of being a sickle cell carrier
-Family origin questionnaire (FOQ) information is used as an initial screening tool to assess a woman’s eligibility for haemoglobin variant screening.
-All biological fathers are offered screening if the pregnant woman is a genetic carrier for sickle cell disease or thalassaemia

Question 26

Genetic testing for CF

Answer 26

NIPD (assuming that both parents are CF carriers and have DNA from an affected or unaffected child) or invasive testing if they felt that they would not continue with an affected pregnancy.

Question 27

Antenatal diagnosis of anencephaly

Answer 27

-Characterised by the absence of the cerebral hemispheres and cranial vault, giving rise to prominent orbits and a typical ‘frog-like’ appearance on ultrasound. Most of those affected will be stillborn, with the remainder dying shortly after birth.

Question 28

Diagnosis of encephalocele

Answer 28

-This describes the protrusion of the dura mater sac (with or without brain tissue) through a bony defect in the cranial vault.
-The majority are occipital.
-Prognosis depends on the presence on brain tissue within the sac and the degree of resultant herniation.

Question 29

Diagnosis of spina bifida

Answer 29

-Scalloping of the frontal bones gives rise to the typical ‘lemon’ sign seen on ultrasound, and the descent of the cerebellum, pons, and medulla through the foramen magnum results in a ‘banana’ shape to the cerebellum, also visible on ultrasound

Question 30

Diagnosis of ventriculomegaly

Answer 30

-In a normal fetus, cerebrospinal fluid (CSF) circulates around the brain and through the lateral ventricles. When an accumulation of CSF occurs, this leads to dilatation of the ventricular system. The mean size of the lateral ventricles is 7 mm
-Ventriculomegaly refers to an increase to 10.1 mm or more and is thought to affect up to 1% of pregnancies.
-Mild ventriculomegaly is considered when the lateral ventricles measure between 10.1 and 12 mm, moderate is between 13 and 15 mm, and severe ventriculomegaly is considered when the ventricles are greater than 15 mm

Question 31

Diagnosis of diaphragmatic hernia

Answer 31

-The combination of liver herniation and ultrasound measurement of the observed to expected lung-to-head ratio (O/E LHR) is now widely used to individualise prognosis and counsel parents
-Fetal endoscopic tracheal occlusion (FETO) is a minimally invasive percutaneous procedure that is being offered to women antenatally in specialised centres, largely in a research setting.

Question 32

What is exomphalos?

Answer 32

This occurs following failure of the bowel to return to the abdominal cavity at 8 weeks’ gestation, resulting in a midline defect through which the peritoneal sac protrudes

Question 33

What is gastroschisis?

Answer 33

-It is a paraumbilical defect through which the gastrointestinal organs herniate (usually bowel), allowing them to float freely in the amniotic fluid