Every pregnancy carries a small risk of fetal chromosomal abnormalities.
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 (Non-Invasive Perinatal Testing, 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 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 the country.
Before a family participates in screening during pregnancy, the parents should be given sufficient information on the purpose and content of screening by an appropriate health professional such as a public health nurse, for example, 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 http://www.eurogentest.org/index.php?id=160.
Please notice that this article was written in the Finnish context, and hence some information or examples may not be applicable in all health systems. Much of the information, however, is generic in nature. Find out also about local policies and practices concerning screening for fetal chromosomal abnormalities.
Screening methods
Early serum screening
During the first trimester (weeks 8-13), the risk of chromosomal abnormalities is estimated by measuring serum concentrations of pregnancy-associated plasma protein A (PAPP-A) and beta-human chorionic gonadotropin (β-hCG) First Trimester Serum Tests for Down's Syndrome Screening. In the case of Down's syndrome the concentration of PAPP-A is lower and that of β-hCG higher than average (0.5 and 2.3 MoM [Multiples of Medium], on an average). In trisomy 18 and trisomy 13, both levels are lower than average (below 0.5 MoM).
Increased nuchal translucency detected by ultrasound examination performed during weeks 10 to 13 signifies an increased risk of chromosomal abnormality.
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.
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.
During the second trimester (weeks 15-17), risk evaluation is usually carried out by measuring the concentrations of β-hCG and fetal alpha-1 fetoprotein (AFP).
In the case of Down's syndrome the concentration of β-hCG is higher and that of AFP lower than average.
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 Prediction of Down's Syndrome in Second Trimester by Screening.
An increased concentration of serum AFP helps to identify fetuses which might have
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, 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.
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 usually have either normal or abnormal chromosomes. Very rarely monotsygotic twins may have genomes that differ from each other, which in such cases results from a new change that occurred after fertilization. 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 can be done in twin pregnancies in some but not in all laboratories.
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.
Fetal chromosome studies
Fetal chromosome studies performed in placental or amniotic fluid samples are highly reliable: in over 99% of cases the result is definite.
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.
Chorionic villus sampling may take place after week 11 of gestation. A transabdominal sample is taken with a needle advanced under ultrasound guidance to the placenta, and a small amount of placental tissue is withdrawn into the syringe.
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 about 1-2 weeks.
Amniocentesis
Amniocentesis can be carried out after week 15 of gestation. A sample of 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 fetal cells which are cultured for chromosome studies. The results will be available after 2-3 weeks, on an average.
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 about 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.
Indications for chromosome studies
A result suggestive of increased chromosomal risk based on measurement of nuchal translucency thickness, combined ultrasound and maternal serum screening or maternal serum screening alone
Fetal abnormalities detected by ultrasound examination, on the grounds of which chromosome studies or molecular karyotyping are considered
Soft markers
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 defect
Abnormal results and further measures
If the results of fetal chromosome studies or molecular karyotyping are abnormal the parents should be offered genetic counselling to make sure that they 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 a specific week of gestation defined by the local legislation (in Finland week 24). Check local legislation and other policies.
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.
Future possibilities
Possible future alternatives to screen for chromosomal abnormalities include:
NIPT screening as the first screening method for all pregnant women wishing to have chromosomal screening
targeted screening of a maternal blood sample for gene defects or copy number variation.
References
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O'Brien JE, Dvorin E, Yaron Y, Ayoub M, Johnson MP, Hume RF Jr, Evans MI. Differential increases in AFP, hCG, and uE3 in twin pregnancies: impact on attempts to quantify Down syndrome screening calculations. Am J Med Genet 1997 Dec 12;73(2):109-12. [PubMed]
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Revello R, Sarno L, Ispas A et al. Screening for trisomies by cell-free DNA testing of maternal blood: consequences of a failed result. Ultrasound Obstet Gynecol 2016;47(6):698-704. [PubMed]
Taylor-Phillips S, Freeman K, Geppert J et al. Accuracy of non-invasive prenatal testing using cell-free DNA for detection of Down, Edwards and Patau syndromes: a systematic review and meta-analysis. BMJ Open 2016;6(1):e010002. [PubMed]
de Wit MC, Srebniak MI, Govaerts LC et al. Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature. Ultrasound Obstet Gynecol 2014;43(2):139-46. [PubMed]