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Prenatal testing
Definition
Prenatal diagnosis allows us to diagnose a number of diseases and abnormalities in a human being who has not yet been born. The main task of prenatal diagnosis is therefore the earliest possible diagnosis of these pathological conditions. On the basis of the diagnosis, we can:
- inform the mother (parents) about the diagnosis of the foetus, its prognosis (both during pregnancy and in the postnatal period) and possible further steps
- take specific measures for the further course of the pregnancy, for the management of the birth (birth by caesarean section) or for follow-up care (birth in a specialist centre with access to urgent surgical or other treatment)
- start prenatal therapy of the foetus (rarely - for example, treating obstructive defects of the urinary system with shunts, intrauterine transfusion for foetal anaemia)
- in the case of an unfavourable diagnosis, in the Czech Republic it is possible, in accordance with current legislation (Act No. 66/1986 Coll., on the artificial termination of pregnancy), to terminate the pregnancy for genetic reasons up to the 24th week of pregnancy. In the case of an extremely unfavourable diagnosis (a condition incompatible with life, e.g. anencephaly), the same act allows the pregnancy to be terminated at any time (even after the 24th week of pregnancy)
Systematic use of screening for genetically at-risk pregnancies and prenatal examination of their foetuses makes it possible to reduce the number of affected newborns. Organising prenatal diagnosis requires the cooperation of an obstetrician, a laboratory specialist and a geneticist.
Indications for genetic counselling
As part of comprehensive care for the pregnant woman and the foetus, genetic counselling is necessary in certain cases. The attending doctor (gynaecologist-obstetrician) refers the pregnant woman to a clinical genetics department in particular in the following cases:
- pregnant women with a history of congenital developmental defects or hereditary diseases in their family or personal history (this of course also applies to such diagnoses in the child's father or his family)
- pregnant women with a positive result of prenatal screening (combined first-trimester screening, second-trimester biochemical screening, or integrated screening)
- pregnant women with an abnormal finding on the ultrasound examination of the foetus (direct signs of congenital defects or other foetal abnormalities, abnormalities in the amount of amniotic fluid, etc.)
- pregnant women aged 35 and over (the so-called age indication); the risk of chromosomal aberrations rises continuously with the mother's age (the limit of 35 years was set artificially)
During genetic counselling, the pregnant woman may be offered more detailed prenatal diagnosis (invasive methods, detailed ultrasound examination, foetal echocardiography, foetal MRI). If a diagnosis is confirmed, the pregnant woman returns to the clinical geneticist to consider further steps.
Non-invasive prenatal diagnosis
Non-invasive methods of prenatal diagnosis are well suited to screening and are used to examine all pregnant women.
Biochemical marker tests
The mother's blood is taken for biochemical marker screening after the 16th completed week of gestation. This is the so-called triple test - the levels of the following are measured in the mother's serum:
- alpha-fetoprotein (AFP),
- chorionic gonadotropin (hCG)
- unconjugated oestriol (uE).
Elevated AFP values are a marker of congenital defects in which the foetus is not covered by skin - e.g. spina bifida; lowered AFP values and raised hCG values are characteristic of foetuses with Down's syndrome. uE reflects the overall risk of the pregnancy. For a more accurate evaluation, deviations in levels are expressed in multiples of the median (MoM), and computer programs have been developed to evaluate them that take into account not only the length of the pregnancy but also the age of the pregnant woman and her weight, and are based on the medians of the particular laboratory.
Invasive examination is recommended if the screening is positive, i.e. with risks higher than 1:350. A negative screening result means that the risk of the defects being looked for is lower than the risk that justifies an invasive examination.
In the second trimester, Rh antibodies, a blood count and an oGTT (oral glucose tolerance test) are tested.
Ultrasound examination
Ultrasound examinations in the 6th, 13th, 20th and 32nd week of pregnancy are part of standard care for pregnant women. If deviations are found, the pregnant woman should be referred for a consultant ultrasound examination and possibly also for genetic counselling.
Indirect signs indicating that the foetus is affected include growth retardation, too little or too much amniotic fluid and disproportionate development of individual parts of the foetus, and they are indications for chromosomal examination.
Targeted ultrasound examination is so far the most effective method of prenatal diagnosis. It makes it possible to diagnose in the foetus, for example, developmental disorders of the head (anencephaly), spina bifida, heart defects, kidney defects (agenesis, polycystic kidney disease), atresia of the urinary tract and Turner syndrome; with less certainty it can detect, for example, cleft lip, gastrointestinal obstruction and minor limb reduction deformities.
In the 13th–14th week of pregnancy, the nuchal fold is measured by ultrasound - nuchal translucency. Ultrasound is used to assess the thickness of the anechoic zone in the nuchal region of the foetus between the skin and the connective tissue covering the cervical spine. With a thickening of more than 3 mm there is an increased risk of chromosomal aberration, so prenatal diagnosis of the foetal karyotype (amniocentesis) is indicated.
In the 18th–20th week, the size of the foetus is measured (biparietal diameter, head circumference, femur length), along with nuchal translucency, and congenital somatic defects are detected so that a termination can be carried out by the 24th week (culture in amniocentesis takes 3 weeks).
In the 30th week, the size and position of the foetus are measured and placenta praevia is ruled out.
Invasive prenatal diagnosis
The main purpose of invasive examinations is to obtain a sample of foetal tissue for karyotype examination or for molecular genetic examination, in order to rule out chromosomal aberrations or genetically determined diseases in the foetus. Because of a certain risk associated with carrying them out (and also because of the cost of these methods), they are offered only on the basis of a special indication (see, for example, the indications for chromosomal examination).
Amniocentesis
Amniocentesis (AMC) is the taking of a sample of amniotic fluid with a needle through the abdominal wall under ultrasound guidance. It is usually carried out between the 16th and 18th week of pregnancy. It allows examination of cultured and uncultured cells of the amniotic fluid and its biochemical examination. The foetal karyotype can be examined from the amniotic fluid cells after a culture lasting 10–20 days; the biochemical examination of the amniotic fluid focuses mainly on assessing the AFP level. The risk of miscarriage after the procedure is less than 1%.
Chorionic villus sampling
Chorionic villus sampling (CVS) is carried out earlier than amniocentesis, roughly between the 10th and 13th week of gestation. The chorionic tissue is taken with a special needle under ultrasound guidance, most often transabdominally and less often transcervically (not in the Czech Republic). The advantage of chorionic villus sampling (CVS) over amniocentesis is the possibility of earlier diagnosis (for example, following first-trimester screening for developmental defects). Culture of chorionic cells (for cytogenetic examination) is also faster (trophoblast cells have a high mitotic activity and the karyotype can be examined 1–2 hours after colcemid is added) than culture of the amniocytes obtained by amniocentesis. The risk of the procedure is the same as for amniocentesis (risk of pregnancy loss 0.5–1%). A certain disadvantage of CVS is the risk of placental mosaicism, which can be a source of diagnostic uncertainty. Chromosomal abnormalities found must therefore still be confirmed by examination of the amniotic fluid, because a finding in trophoblast cells does not yet have to mean the same abnormality in the foetal tissues.
Cordocentesis
Cordocentesis (CC), or puncture of the umbilical cord, is another invasive method. The examination can only be carried out relatively later - generally from the 18th week of gestation[1]. The umbilical cord is punctured and foetal blood is taken from the umbilical vein with a special needle under ultrasound guidance. The blood elements obtained (foetal lymphocytes) can again be used for examination of the foetal karyotype or for molecular genetic examination. Karyotyping of foetal lymphocytes is very fast, with results available within 48–72 hours[1]. Cordocentesis can therefore be used successfully for repeated, rapid karyotype examination if a previous sampling with culture (amniocentesis, CVS) failed or gave ambiguous results. Foetal blood is valuable diagnostic material that can be used, among other things, to determine the foetal blood group, to diagnose foetal alloimmunisation or foetal infection, or to diagnose certain hereditary diseases and disorders (e.g. haemoglobinopathies)[1]. It also naturally allows immunological examination (detection of antibodies) and biochemical examination (ions).
In experienced hands, the risk of the procedure is comparable to that of amniocentesis (under 1% foetal losses).
Puncture of the umbilical cord is used as the access route for intrauterine transfusion, which is a therapeutic procedure (prenatal therapy) carried out, for example, in the case of foetal alloimmunisation (often incompatibility in the Rh system).
Fetoscopy
The examination consists of inserting an optical system (a fetoscope) into the amniotic cavity through a small incision in the abdominal wall. It allows the foetus to be visualised and a tissue sample (skin, muscle, liver) to be taken for further examination (suspected hereditary diseases or defects where DNA diagnosis is not possible). It is most often performed in the 18th–20th week, with a procedure risk of 3–10%. Precisely because of this high risk, it is practically no longer used today as a purely diagnostic method.