Prenatal Diagnosis

Prenatal diagnosis needs to be differentiated from routine antenatal screening. NICE and the UK National Screening Committee have laid down standards for antenatal care including the routine screening tests that should be offered to all pregnant women.^1,2 These screening tests do not always give a definitive prenatal diagnosis and may just show the probability of a problem with the fetus. In most cases, further diagnostic tests are required to confirm and diagnose the fetal abnormality.

Prenatal diagnosis is therefore offered to all pregnant women if they have positive antenatal screening results. However, some women may be offered definitive prenatal diagnosis from the outset without any preceding screening tests, for example:

• If there is a family history of an inherited condition
• If they have had a previous pregnancy with fetal abnormality
• If they have been exposed to viral illness such as toxoplasmosis or rubella during the pregnancy
• If they have been exposed to teratogens, such as certain drugs or radiation, during the pregnancy
• If the woman has type 1 diabetes mellitus, epilepsy or myotonic dystrophy

The primary aim of a prenatal diagnosis is to provide an accurate diagnosis that will allow the widest possible range of informed choice to those at increased risk of having children with genetic disorders or with congenital abnormalities.³

Informed consent should always be obtained before antenatal screening and prenatal diagnostic testing.

In all cases of antenatal screening, the woman must be fully informed and understand the implications of the test, be promptly advised of their test result and be referred for further management and definitive diagnosis if their screening test is positive or high risk.

A positive prenatal diagnosis poses many ethical issues and challenging decisions for parents and clinicians. In those at increased risk of having a baby with a genetic condition, the risk should be identified and discussed fully before pregnancy and options for prenatal diagnosis discussed. Genetic counselling should be provided.³

The following antenatal screening tests are offered:

• Screening for potential for neonatal infection: Testing for hepatitis B, HIV, syphilis is offered to all women at antenatal booking. This means that effective postnatal intervention can be offered to infected women to decrease the risk of mother-to-child-transmission.
• Screening for haemolytic disease of the newborn: Maternal blood group and RhD status are checked at antenatal booking. Assessment for atypical red cell alloantibodies is also carried out at booking and again at 28 weeks to screen for the possibility of the development of haemolytic disease of the newborn. All non-sensitized pregnant women who are RhD negative are offered routine antenatal anti-D prophylaxis.
• Screening for sickle cell and thalassaemia: Maternal blood testing for disease and carrier status is carried out and, if necessary, paternal blood testing is undertaken so that the probability of the fetus being affected can be assessed.
• Down's Syndrome screening: NICE guidelines state that all pregnant women should be offered this screening. This is done using nuchal transluncency, serum screening or both combined, depending on the gestation of pregnancy. Please refer to the separate article on Antenatal Screening for Down's Syndrome.
• Fetal anomaly screening: An ultrasound scan is performed between 18-20 weeks to screen for structural anomalies including skeletal, genitourinary, gastrointestinal, central nervous system and other organ defects. There is no evidence that ultrasound causes harm to the fetus or the mother.
• Abdominal palpation and measurement of symphysis-fundal distance: This is a screening test to help detect babies that are small- or large-for-gestational-age and to help detect poly or oligohydramnios which may suggest an underlying problem with the fetus that requires further investigation and definitive prenatal diagnosis.

If an antenatal screening test is deemed to be positive or high risk, a definitive diagnostic test will be offered to the woman. Women who have had a previous fetal abnormality or who have a family history of an inherited condition may be offered these diagnostic tests from the outset. The tests that are carried out include:

• Amniocentesis: This is the most common invasive prenatal diagnostic procedure carried out in the UK.⁴ This is normally carried out from 15 weeks gestation. A needle is inserted into the amniotic cavity and amniotic fluid is sampled allowing culture and assessment of fetal cells in the fluid. Fetal cells in the amniotic fluid can then be analysed.
  • Cytogenetic analysis: Analysis for chromosomal abnormalities such as Down's Syndrome can be carried out using cell culture and karyotyping. More recently, rapid aneuploidy techniques using PCR have been used to detect Down's Syndrome which provide results much more quickly than karyotype analysis from cultured cells which usually takes 13-14 days.^5,6
  • Molecular genetic tests: If a disease-causing mutation has been identified in a family, molecular genetic tests can be performed to detect genetic diseases such as cystic fibrosis.
  • Biochemical analysis: Enzyme levels can be assayed to detect inborn errors of metabolism. Alpha-fetoprotein and acetylcholinesterase levels can be measured to help identify and distinguish between neural tube defects, anencephaly and ventral wall defects, such as gastroschisis and omphalocoele, that may have been suspected during anomaly scanning. Hormone levels can be assessed to diagnose adrenogenital syndrome. Please refer to the separate article on amniocentesis.
• Chorionic villus sampling: This can be carried out earlier usually between 10-13 weeks. It involves sampling of the developing placenta and again the same type of analysis of fetal cells to detect chromosomal, genetically inherited and endocrine or metabolic conditions. Please refer to the separate article on chorionic villus sampling.
• Fetoscopy: This allows visualization of the fetus using endoscopic techniques. It is usually carried out between 18-20 weeks gestation. It allows fetal inspection for structural abnormalities, fetal blood sampling to detect, and possibly allow intervention in, conditions such as haemophilias, thalassaemia and sickle cell disease, as well as fetal skin and liver biopsy.
• Cordocentesis/percutaneous umbilical blood sampling: This technique uses ultrasound guidance to obtain fetal blood cells from the umbilical cord. It enables karyotyping/chromosome analysis as well as being used for the assessment and treatment of rhesus iso-immunisation. Intrauterine blood transfusions may be performed using this technique. Fetal viral infection can be confirmed by immunoglobulin assessment of fetal blood and some haematological and metabolic abnormalities can be detected. The fetal loss rate is 1-3%.³
• Fetal radiology: In suspected skeletal dysplasia, x-rays can be taken around the same time as the routine anomaly ultrasound scan. Prenatal MRI is also used to assess fetuses with spina bifida, look for associated malformations, and along with ultrasound scanning help to predict neurological deficit and ambulatory potential.^7,8 Fetal echocardiography can also be carried out if cardiac defects are suspected, for example if there is a family history or in maternal diseases with an increased risk if fetal heart defects such as diabetes.
• Maternal blood tests: Maternal serum alpha-fetoprotein levels can be measured to aid the diagnosis of neural tube defects between 15-22 weeks. They are also raised in abdominal wall defects but amniotic fluid analysis of acetylcholinesterase can help to differentiate between these conditions.
• Ultrasound guided percutaneous skin and organ biopsy: This can also be carried out to allow skin, muscle, liver and other fetal organ analysis.

If a prenatal diagnosis is made, the woman may choose to have a termination of the pregnancy. If a potentially lethal fetal abnormality is detected, most parents do opt for termination, which may include feticide.⁹ They may, however, choose to continue with the pregnancy and opt for perinatal palliative care. Any woman seeking a termination for whatever reason must have grounds under the Abortion Act 1967. This area becomes very grey when considering relatively "minor" abnormalities detected by prenatal diagnosis, such as cleft lip and palate, limb abnormalities etc. Please refer to the separate article on termination of pregnancy.

Other women prefer to have confirmation of an abnormality using prenatal diagnosis to allow them to prepare peri and postnatally. Prenatal diagnosis may allow potential in utero fetal treatment of the condition in some cases, for example in rhesus iso-immunisation.

This is a technique that allows the analysis of blastocysts conceived through in vitro fertilization. Embryos that are affected by a specific genetic disorder are in this way not transferred back to the mother.

At present, in most cases, accurate prenatal diagnosis requires invasive testing. There is current research into non-invasive prenatal diagnosis using PCR and molecular genetic techniques to examine fetal DNA obtained from maternal blood.^10,11,12

Prenatal diagnostic accuracy is improving but as one UK study showed, may be lower than many clinicians assume and the public expects for some important conditions such as diaphragmatic hernia, bladder outlet obstruction and major skeletal defects in which detection rates prenatally were still less than 70%.¹³