Prenatal diagnosis needs to be differentiated from routine antenatal screening. The National Institute for Health and Care Excellence (NICE) and the UK National Screening Committee (UK NSC) have laid down standards for antenatal care, including the screening tests that should be offered to all pregnant women.These screening tests do not give a definitive prenatal diagnosis but give a risk/probability of a problem with the fetus - for example, Down's syndrome. 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 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.
Informed consent should always be obtained before antenatal screening and prenatal diagnostic testing.
Antenatal screening for fetal abnormality offered to all women
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.Information about antenatal screening should be given in a setting where discussion can take place, and information given should be balanced and accurate.
A positive prenatal diagnosis poses many ethical issues and challenging decisions for society as a whole as well as 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.
The following subsections cover the antenatal screening tests that are routinely offered.
Screening for potential for neonatal infection
Testing for hepatitis B, HIV and syphilis, and susceptibility to rubella, is offered to all women, in each pregnancy, at antenatal booking. This means that effective antenatal intrapartum and 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-sensitised pregnant women who are RhD negative are offered routine antenatal anti-D prophylaxis.
Screening for sickle cell disease and thalassaemia
Maternal blood testing for disease and carrier status is offered and, if necessary, paternal blood testing is undertaken so that the probability of the fetus being affected can be assessed.If both parents are found to be carriers of a haemoglobinopathy then prenatal diagnosis will be offered.
Down's syndrome screening
NICE guidelines state that all pregnant women should be offered this screening. In England and Scotland this is done using the combined test (nuchal translucency measurement combined with serum markers beta-human chorionic gonadotrophin and pregnancy-associated plasma protein A). This should be offered between 11 weeks 0 days and 13 weeks 6 days. For women who book too late for the combined test a quadruple serum screening test should be offered up until 20 weeks of gestation.
In Wales at present the quadruple test is offered for women choosing Down's syndrome screening.
Northern Ireland does not have a Down's syndrome screening programme but a second trimester fetal anomaly scan is offered.
See separate article Antenatal Screening for Down's Syndrome.
Fetal anomaly scanning by ultrasound is offered to all pregnant women in the UK between 18 weeks and 20 weeks 6 days of gestation. Although this can uncover a large number of structural anomalies, the UK NSC has agreed that only those conditions that have sufficiently high detection rates should be formally assessed as part of the programme's pathway standards and quality assurance system.
The following fulfil that criterion and are part of the current programme: anencephaly, open spina bifida, gastroschisis, Edwards' syndrome and Patau's syndrome all have detection rates over 90%; cleft lip, exomphalos and bilateral renal agenesis have detection rates between 70% and 80%; diaphragmatic hernia, serious cardiac abnormalities and lethal skeletal dysplasias have detection rates between 50% and 60%.
Identification of anomalies in utero allows:
- Choice of termination of pregnancy.
- Parents to prepare for disability, treatment, palliative care or termination.
- Managed birth in a specialist unit.
- Intrauterine treatment.
Measurement of fundal height
Abdominal palpation and measurement of symphysis-fundal distance (fundal height) are used to screen for babies that are small- or large-for-gestational-age and to help detect polyhydramnios or oligohydramnios. These findings may suggest an underlying problem with the fetus that requires further investigation and definitive prenatal diagnosis.
Definitive prenatal diagnostic tests
If an antenatal screening test result suggests the pregnancy is at a high risk of a condition, 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 following types of tests are available depending on the condition being tested for:
- 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 omphalocele, that may have been suspected during anomaly scanning. Hormone levels can be assessed to diagnose adrenogenital syndrome.
- 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 polymerase chain reaction (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.[6, 7]
- 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.
The following techniques are used:
This is the most common invasive prenatal diagnostic procedure carried out in the UK. This is normally carried out from 15 weeks of 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. Additional risk of miscarriage is approximately 1%. See separate article Amniocentesis.
Chorionic villus sampling (CVS)
This can be carried out earlier - usually between 11-13 weeks. Risk of miscarriage may be slightly higher than for amniocentesis. CVS 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, can be performed. See separate article Chorionic Villus Sampling.
This allows visualisation of the fetus, using endoscopic techniques. It is usually carried out between 18-20 weeks of 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. It has also been used therapeutically for severe congenital diaphragmatic hernia, division of amniotic bands, laser coagulation of placental vessels in twin-to-twin transfusion syndrome or in twin pregnancies where one twin has a severe abnormality.The risk is preterm rupture of membranes.
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. This is usually done from 18 weeks of pregnancy onwards. Miscarriage rate is variable depending on the condition and the gestational age of the fetus.
In suspected skeletal dysplasia, ultrasound (2D and 3D) and MRI are now the investigations of choice.[10, 11]There are huge numbers of potential skeletal dysplasias, and many are rare, so prenatal diagnosis can be a challenge, but guidelines help establish severity and likely lethality of the condition.
Fetal echocardiography, involving a four-chamber view of the fetal heart and outflow vessels, is now recommended as part of the routine anomaly scan.
Ultrasound-guided percutaneous skin and organ biopsy
This can also be carried out to allow skin, muscle, liver and other fetal organ analysis.
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.
There is increasing interest in, and use of, the detection of fetal DNA in maternal blood. Recent developments have allowed separation of fetal from maternal DNA, allowing the potential for more non-invasive prenatal diagnostic opportunities.Cell-free fetal DNA (cffDNA) in the maternal DNA has been used for some years to determine fetal blood group status in at-risk rhesus negative women. Male fetal sex can be determined by the presence of Y chromosome sequences in maternal plasma, aiding in diagnoses of X-linked genetic diseases. Confirmation of a female fetus in pregnancies known to be at risk of congenital adrenal hyperplasia (CAH) allows prenatal treatment with dexamethasone, thus reducing the risk of virilisation of the external genitalia in female babies, and avoiding unnecessary treatment with its attached risks.
Use of maternal plasma massively parallel sequencing (MPS) has increased accuracy of non-invasive diagnosis of chromosomal abnormalities such as trisomies 21, 18 and, more recently, 13. Factors which make the test less reliable include low gestational age, maternal obesity, multiple pregnancy and placental mosaicism. The UK is still considering future policy for the role of this technique in antenatal screening and diagnosis, but in the USA and Canada it is recommended for women at increased risk of trisomy.This is also the current position of the International Society for Prenatal Diagnosis. This technology is likely to become the screening method of choice in the future, and have big implications for the way antenatal screening is delivered in the UK.
What happens if a prenatal diagnosis of a fetal problem is made?
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. 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. The Royal College of Obstetricians and Gynaecologists (RCOG) guidelines does not advise on the ethics of these decisions, and recommends that clinicians adopt a "non-directive, non-judgemental and supportive" approach when helping couples to reach a decision.Termination of pregnancy for fetal abnormality may only be considered if there is a substantial risk that the child, if born, would suffer physical or mental abnormalities that would result in serious handicap. Termination for fetal abnormality requires in law two practitioners to testify by signing the certificate of opinion form, that they believe that the grounds for termination of pregnancy are met. (See separate article Termination of Pregnancy.) There is no legal definition of substantial risk. Whether a risk will be regarded as substantial may vary with the seriousness and consequences of the likely disability. Neither is there a legal definition of serious handicap. An assessment of the seriousness of a fetal abnormality should be considered on a case-by-case basis. Decisions about whether to terminate a pregnancy for fetal abnormalities are devastatingly difficult for couples on an individual level, and a source of debate for society as a whole.
Other women prefer to have confirmation of an abnormality using prenatal diagnosis to allow them to prepare perinatally and postnatally. Prenatal diagnosis may allow potential in utero fetal treatment of the condition in some cases - for example, in rhesus iso-immunisation.
Pre-implantation prenatal diagnosis
This is a technique that allows the analysis of oocytes or embryos conceived through in vitro fertilisation (IVF). This information then informs the choice of optimal embryos to be transferred back to the mother. This is an accepted technique for avoiding the birth of affected children from parents with a known genetic abnormality. Its use as a routine screening tool in IVF is more controversial. This is an evolving area.
Further reading and references
Antenatal care - uncomplicated pregnancy; NICE CKS, March 2011 (UK access only)
Antenatal care for uncomplicated pregnancies; NICE Clinical Guideline (March 2008, updated 2018)
Reynolds TM; The ethics of antenatal screening: lessons from Canute. Clin Biochem Rev. 2009 Nov30(4):187-96.
NHS Sickle Cell and Thalassaemia Screening Programme; Public Health England
Langlois S, Duncan A; Use of a DNA method, QF-PCR, in the prenatal diagnosis of fetal aneuploidies. J Obstet Gynaecol Can. 2011 Sep33(9):955-60.
Chitty LS, Kagan KO, Molina FS, et al; Fetal nuchal translucency scan and early prenatal diagnosis of chromosomal abnormalities by rapid aneuploidy screening: observational study. BMJ. 2006 Feb 25332(7539):452-5. Epub 2006 Feb 13.
Amniocentesis and Chorionic Villus Sampling; Royal College of Obstetricians and Gynaecologists (June 2010)
Peiro JL, Carreras E, Guillen G, et al; Therapeutic indications of fetoscopy: a 5-year institutional experience. J Laparoendosc Adv Surg Tech A. 2009 Apr19(2):229-36. doi: 10.1089/lap.2007.0149.
Noel AE, Brown RN; Advances in evaluating the fetal skeleton. Int J Womens Health. 2014 May 136:489-500. eCollection 2014.
Krakow D, Lachman RS, Rimoin DL; Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Genet Med. 2009 Feb11(2):127-33. doi: 10.1097/GIM.0b013e3181971ccb.
Non-invasive Prenatal Testing for Chromosomal Abnormality using Maternal Plasma DNA. Scientific Impact Paper No. 15 March 2014; Royal College of Obstetricians and Gynaecologists
Breeze AC, Lees CC, Kumar A, et al; Palliative care for prenatally diagnosed lethal fetal abnormality. Arch Dis Child Fetal Neonatal Ed. 2007 Jan92(1):F56-8. Epub 2006 May 16.
Termination of pregnancy for fetal abnormality in England, Scotland and Wales; Royal College of Obstetricians and Gynaecologists, May 2010
Spence D; Bad medicine: antenatal screening. BMJ. 2013 Feb 26346:f1226. doi: 10.1136/bmj.f1226.
Brezina PR, Brezina DS, Kearns WG; Preimplantation genetic testing. BMJ. 2012 Sep 18345:e5908. doi: 10.1136/bmj.e5908.