Screening for fetal chromosomal abnormalities

EBM Klinik protokolları

02.05.2017 • Sonuncu dəyişiklik 02.05.2017

CarolaSaloranta

Background of screening

The incidence of trisomy 21, which causes Down's syndrome, is about 1/700. The incidence increases with increasing maternal age, being less than 1/1 000 if the mother is below 30 years of age and more than 1/100 if the mother is over 40 years of age. The incidences of trisomy 18 and 13 are about 1/8 000 and 1/20 000 neonates, respectively.
Trisomy 21, 18 and 13 can be screened for based on serum markers, nuchal translucency thickness detected by ultrasound examination and small signs seen on ultrasound. In addition, fetal chromosomal abnormalities can be screened for based on fetal DNA in maternal blood (NIPT).
In Finland, screening for chromosomal abnormalities is primarily done through first-trimester combined screening (serum markers in week 9+0 – 11+6 of the pregnancy and the measurement of neck oedema in connection with a general ultrasound scan in week 11+0 – 13+6 of the pregnancy) or, alternatively, through a second-trimester serum screening test in week 15+0 – 16+6 of the pregnancy.
In Finland, each hospital district offers mothers belonging to a risk group an alternative to invasive further examinations, i.e. participating in more accurate screening based on fetal DNA in maternal blood (NIPT). Such more accurate screening reduces the number of invasive further examinations.
- NIPT will detect more than 99% of all cases of trisomy 21 and about 95% and 80–90% of all cases of trisomy 18 and 13, respectively.
- The more accurate NIPT can also be used as the primary screening method but in that case its positive predictive value is slightly worse and, at least for the time being, it is too expensive to be used as the primary screening method throughout Finland.
Before a family participates in screening during pregnancy, the parents should be given sufficient information on the purpose and content of screening. In Finland, the information is provided by a public health nurse at a maternal health centre. It should be emphasized that screening is voluntary, so that people do not participate routinely but only after due consideration. Unconsidered participation in screening may lead to unwanted situations for which the family is not prepared.
If screening shows that the woman belongs to a risk group, after having been informed about the reliability of invasive further examinations of the placenta or amniotic fluid, about the risk of miscarriage involved and about the time of sampling, she should decide herself whether she wants to have such examinations. Guides concerning fetal examinations and chromosomal abnormalities are available in over 30 languages at the EuroGentest website .Each pregnancy carries a small risk of foetal chromosomal abnormalities. The incidence of trisomy 21, which causes Down's syndrome, is less than 1/1000 if the mother is below 30 years of age, and more than 1/100 if the mother is over 40 years of age. Older pregnant women (35–40 years of age) should be offered chorionic villus sampling or amniocentesis to screen for chromosomal abnormalities. Down’s syndrome and other chromosomal abnormalities can be screened in women in any age based on age, serum markers or minor abnormalities of the foetus discovered by ultrasonography. One possible strategy for screening of chromosomal abnormalities is to use combined screening in early pregnancy (serum markers at 8–11 weeks of gestation and measurement of nuchal translucency as a part of routine ultrasound examination at week 10–12) or alternatively with maternal serum triple screening at week 14 or 15. Remember that screening is voluntary and a pregnant woman can choose whether she wants foetal diagnostic studies after she has been given information on the reliability, risks, timing of the studies and the reporting methods.

Screening methods

Early serum screening

Measurement of nuchal translucency

It has been noted that increased nuchal translucency increases the fetal risk of other abnormalities, as well, such as congenital heart defects (the risk being about 5 to 10%).
Nuchal translucency is usually transient but in some cases the swelling increases and leads to spontaneous miscarriage regardless of the chromosomal state of the fetus.
Increased nuchal translucency may be transient regardless of whether the fetus has normal or abnormal chromosomes. If the fetal chromosomes are normal, nuchal translucency is transient, and the result of ultrasound screening for structural abnormalities is normal, the child born is usually healthy.Increased nuchal translucency detected by ultrasound examination performed during the weeks 10 to 13 signifies an increased risk of chromosomal abnormality. Nuchal translucency is usually transient but in some cases the swelling increases and leads to spontaneous miscarriage regardless of the chromosomal state of the foetus. It has also been noted that in these pregnancies the risk of congenital heart defects is slightly increased (5 to 10%) .

Combined ultrasound and maternal serum screening in early pregnancy

The risk evaluation takes into account nuchal translucency thickness (mm), the size of the fetus (crown-rump length) and maternal age.
Based on these data, computer software is used to calculate the statistical probability of trisomy 21 and trisomy 18 in that pregnancy.
In first-trimester combined screening, slightly less than 5% of all participating mothers are classified as belonging to a risk group. A chromosomal abnormality is detected in further examinations in only a small share of the fetuses. First-trimester combined screening will detect about 85% of all trisomies.Combined ultrasound and maternal serum screening consists of the measurement of PAPP-A and β-hCG during the first trimester. The risk evaluation also takes into account nuchal translucency (mm), the size of the foetus (crown-rump length) and maternal age. Based on the above data, a computer will calculate the statistical probability of trisomy 21 .

Serum screening in mid-pregnancy

In the case of Down's syndrome the concentration of β-hCG is higher and that of AFP lower than average.During the second trimester (weeks 15–17) risk evaluation is usually carried out by measuring the concentration of β-hCG and foetal alpha fetoprotein (AFP). In cases of Down's syndrome the concentration of β-hCG is higher than normal and that of AFP lower.
When maternal age is taken into consideration this screening programme will identify the group of mothers (5% of all pregnant women) with an increased risk of fetal trisomy 21. Further chromosome studies within the group will identify approximately 60% of all trisomy 21 cases .
An increased concentration of serum AFP helps to identify fetuses which might have
- a neural tube defect or gastroschisis
- congenital nephrosis or
- certain other structural abnormalities.

Ultrasound screening for structural anomalies

If the fetus is found to have structural abnormalities, the family should be offered chromosomal tests or molecular karyotyping since even the slightest abnormality may be the only sign of a chromosomal defect.
So-called soft markers, or minor findings not showing structural abnormality but suggestive of increased risk of chromosomal defects include shorter than average femur or humerus, dilated renal pelvis, hyperechogenic fetal bowel, hyperechogenic foci in the heart, choroid plexus cysts or increased nuchal fold thickness found in ultrasound screening for structural anomalies. Invisible nasal bone in the first trimester also increases the risk of chromosomal defect. The risk of chromosomal defect is significantly increased only if two or more soft markers are detected.If structural abnormalities are detected in the foetus, chromosomal studies and molecular karyotyping are warranted since even the slightest abnormality may signify a chromosomal defect. Slight findings that are suggestive of chromosomal defects include choroid plexus cysts, pyelectasis, hyperechogenic foetal bowel, hygroma in the nuchal region, foetal hydrops, nuchal translucency and the absence of nasal bone during the first trimester.

Twin pregnancy

In a twin pregnancy an ultrasound examination is carried out to determine whether the pregnancy is monochorionic or dichorionic.
It is important to determine chorionicity because a monochorionic pregnancy will always also be monozygotic whereas 90% of all dichorionic pregnancies are dizygotic.
In monozygotic pregnancies, both fetuses have either normal or abnormal chromosomes. In dizygotic pregnancies, the chromosomes of the fetuses are independent of each other.
The measurement of nuchal translucency thickness is an effective screening method in twin pregnancies but risk calculation by first-trimester combined screening cannot be done in twin pregnancies.
The concentrations of screening markers in tests performed during mid-pregnancy will be doubled. A twin pregnancy must therefore be taken into account in risk assessment calculations. In practice, definite risk stratification is not possible but twin pregnancies can be screened into positive and negative groups.
So far, we do not have as comprehensive data about the validity of NIPT screening in twin pregnancies as in single pregnancies. In single pregnancies the use of NIPT screening is also so far limited to second degree screening, i.e. the screening of women already included in a risk group. In a dizygotic pregnancy the twinning naturally doubles the risk of trisomy, whereas in a monozygotic pregnancy the maternal age related risk is the same as in a singleton pregnancy but both foetuses either have normal or abnormal chromosomes. The concentrations of blood tests, taken for screening during mid-pregnancy, will be doubled. A twin pregnancy must therefore be taken into account in risk assessment calculations. In practice, definite risk stratification is not possible, but twin pregnancies can be screened into positive and negative groups . The measurement of nuchal translucency can be carried out during a twin pregnancy.

Fetal chromosome studies

Discrepancy can be caused by a so-called mosaic finding, where the sample shows both cells with normal chromosomes and cells with abnormal chromosomes.
If only trisomies and sex chromosomes are investigated using the trisomy PCR test instead of full chromosomal analysis (karyotype), this should be taken into account in counselling.Foetal chromosome studies are very reliable; in over 99% of cases the result is definite. Discrepancy can be caused by a so-called mosaic finding, where the sample shows cells with both normal and abnormal chromosomes. If only trisomies and sex chromosome abnormalities are investigated instead of full chromosomal analysis, this should be particularly taken into account in counselling.

Chorionic villus sampling

In most cases the sampling will yield dividing cells quickly, within about one week, and the stained chromosomes can be examined under a microscope.
If this is unsuccessful the sample can be cultured, and the result will be available within 3–4 weeks.
The result of the trisomy PCR test that is used instead of chromosomal analysis can be obtained in about one week. The result of molecular karyotyping can be obtained in 1–2 weeks.Chorionic villus sampling may take place after week 10 of gestation. A transabdominal sample is taken with a needle. The needle is advanced under ultrasound guidance to the chorion and a small amount of the placental tissue is withdrawn into the syringe. In most cases the sampling will yield dividing cells, within about one week, and the stained chromosomes can be examined under a microscope. If this is unsuccessful the sample will be cultured, and the result will be available within 3–4 weeks.The result of trisomy PCR that is used instead of chromosomal analysis can be obtained in about one week.

Amniocentesis

The result of the trisomy PCR test that is used instead of chromosomal analysis can be obtained in about one week. The result of molecular karyotyping can be obtained in 1–2 weeks.
In addition to defining chromosomes, the concentration of alpha fetoprotein (AFP) can be measured from an amniotic fluid sample, as necessary. The concentration may be increased if the fetus has certain structural abnormalities (e.g. various closure defects, such as the neural tube defect) or congenital nephrosis, a disease that causes massive proteinuria but does not give any ultrasound findings.Amniocentesis is usually carried out between weeks 15 and 16 of gestation. A sample of the amniotic fluid is withdrawn transabdominally using a needle. The procedure is carried out under ultrasound guidance to follow the advance of the needle into the uterine cavity. Amniotic fluid always contains some foetal cells which are cultured for chromosome studies. The results will be available, on average, after 2–3 weeks. In addition to chromosome studies, the concentration of AFP is usually measured from the sample. The AFP concentration may be increased if the foetus has a structural abnormality (e.g. various closure defects, such as a neural tube defect) or congenital nephrosis.

Indications for chromosome studies

Fetal abnormalities detected by ultrasound examination, on the grounds of which chromosome studies or molecular karyotyping are considered
- Two or more soft markers (a hyperechogenic focus in the heart, short femur or humerus, dilated renal pelvis, hyperechogenic fetal bowel, choroid plexus cyst, increased nuchal fold thickness)
- A structural defect identified during ultrasound examination that is associated with an increased risk of chromosomal defect, such as umbilical or diaphragmatic hernia or heart defect
- Delayed fetal growth
One of the parents, or a previous child, has a diagnosed chromosome defectThe age of the pregnant mother > 40 years. Slight foetal abnormalities detected during ultrasound examination on the grounds of which chromosome studies are considered: Nuchal translucency over 95th percentile Choroid plexus cyst Pyelectasis Hyperechogenic foetal bowel Increasingly retarded foetal growth A result suggestive of increased risk during maternal serum screening or during combined ultrasound and maternal serum screening. A structural defect identified during ultrasound examination, e.g. umbilical hernia, clubfoot or cardiac anomalies. One of the parents, or a previous child, has a diagnosed chromosome defect.

Abnormal results and further measures

If the parents so wish they may ask for the pregnancy to be terminated due to a developmental disorder or injury up to week 24 of gestation.
If the parents decide to continue with the pregnancy, subsequent monitoring of the pregnancy, the delivery and any care required by the neonate should be optimally organized.
In association with termination and if the pregnancy continues but the fetus has been diagnosed with a disease, the patient should be offered psychological support from a psychologist or psychiatric nurse.
If the pregnancy is terminated due to a developmental defect the exact nature of the defect should be established by examining the fetus (visual inspection, photographs, chromosomal studies, post mortem). This way the parents may be given information in future genetic counselling regarding both the risk of recurrence and appropriate fetal testing during any subsequent pregnancies.If the results of the chromosome studies are abnormal the parents should be offered genetic counselling. This ensures that the parents fully understand the significance of the results and are well equipped to plan further measures. If the parents so wish they may ask for the pregnancy to be terminated, due to a developmental disorder or injury, up to week 24 of gestation. If the parents decide to continue with the pregnancy, the subsequent monitoring of the pregnancy, the delivery itself and any care required by the neonate should be optimally organized. If the pregnancy is terminated due to a developmental defect the exact nature of the defect should be established by examining the foetus (visual inspection, photographs, chromosomal studies, post mortem). This way the parents may be given information during future genetic counselling regarding both the risk of recurrence and appropriate foetal testing during any subsequent pregnancies.

Future possibilities

Possible future alternatives to screen for chromosomal abnormalities include:

Related resources

Other Internet resources

Literature

Ədəbiyyat

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