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Screening for Fetal Chromosomal Abnormalities

Essentials

  • Every pregnancy carries a small risk of fetal chromosomal abnormalities.
  • The possibility of screening is offered at antenatal clinics.
  • Screening is voluntary. Each family decides for themselves whether they want to participate.
  • Due to variation in national legislation and policies in different countries, some information in this article may not be applicable in all health systems. Find out also about local legislation, policies and practices..

Background of screening

  • The incidence of trisomy 21, which causes Down's syndrome, is about 1/600 Down's Syndrome. 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 http://www.orpha.net/en/disease/detail/3380 and 13 http://www.orpha.net/en/disease/detail/3378 are about 1/8 000 and 1/8 000-1/22 000 neonates, respectively.
  • Check local legislation as well as policies and practices concerning the screening for chromosomal abnormalities. As an example, the screening offered to expectant mothers in Finland includes the following:
    • Early pregnancy general ultrasound scan in pregnancy week 10+0 - 13+6
    • Examination for chromosomal anomalies after pregnancy week 10+0
    • An ultrasound scan to detect severe structural anomalies in pregnancy week 18+0 - 21+6 or after week 24+0
  • Participation in screening is voluntary.
  • 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 an antenatal clinic. 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.
  • Chromosomal abnormalities are often screened by combined screening in early pregnancy (serum markers in pregnancy weeks 9+0 - 11+6 and measurement of nuchal translucency during a general ultrasound scan in pregnancy weeks 11+0 - 13+6) or, alternatively, by serum screening in mid-pregnancy in pregnancy weeks 15+0 - 16+6. Screening for fetal chromosomal abnormalities is also possible using non-invasive prenatal testing (NIPT) of fetal DNA in the blood of the expectant mother.
  • For pregnant women belonging in a risk group, the possibility of further testing is offered: NIPT or directly invasive sampling for chromosome analysis. The use of NIPT reduces the number of invasive follow-up examinations.
  • If screening shows that an expectant mother 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. Check local availability of patient education materials and information for professionals. See also EuroGEMS information http://www.eurogems.org/for-patients--families.html (for patients and families) http://www.eurogems.org/non-genetics-specialists--primary-care.html (for professionals).

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).

Measurement of nuchal translucency First Trimester Ultrasound Tests in Combination with First Trimester Serum Tests for Down's Syndrome Screening

  • Increased nuchal translucency detected by ultrasound examination performed during weeks 10 to 13 signifies an increased risk of chromosomal abnormality.
  • 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.
  • If a family does not want to have chromosomal abnormalities screened, the first trimester ultrasound scan can be performed without measuring nuchal translucency.

Combined ultrasound and maternal serum screening in early pregnancy First Trimester Serum Tests for Down's Syndrome Screening, First Trimester Ultrasound Tests in Combination with First Trimester Serum Tests for Down's Syndrome Screening, First and Second Trimester Serum Tests with and Without First Trimester Ultrasound Tests for Down's Syndrome Screening

  • Combined ultrasound and maternal serum screening during the first trimester consists of measuring maternal serum concentrations of pregnancy-associated plasma protein A (PAPP-A) and beta-human chorionic gonadotropin (hCG-β) First Trimester Ultrasound Tests in Combination with First Trimester Serum Tests for Down's Syndrome Screening.
  • 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.

Serum screening in mid-pregnancy First and Second Trimester Serum Tests with and Without First Trimester Ultrasound Tests for Down's Syndrome Screening, Prediction of Down's Syndrome in Second Trimester by Screening

NIPT

  • More specific screening based on the determination of fetal DNA in a blood sample from the expectant mother
    • NIPT is generally estimated to detect more than 99% of all trisomy 21 cases.
    • For trisomies 18 and 13, the sensitivity may be slightly lower; the exact figure varies depending on the testing method used.
  • Can usually be performed after the 10th week of pregnancy.
  • Non-invasive screening test not associated with increased risk of miscarriage
  • A positive result is generally confirmed by a diagnostic test on a placental or amniotic fluid sample.
  • Usually used for screening for the most common trisomies or for sex determination. NIPT can also screen for copy number alterations in smaller chromosomal regions, but the sensitivity is not as good.

Ultrasound screening for structural anomalies

  • See also Ultrasound Scanning during Pregnancy.
  • If the fetus is found to have structural abnormalities that are known to be possibly associated with chromosomal abnormalities, the family is offered the possibility of chromosomal examinations (trisomy PCR and molecular karyotyping).

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. It is usually possible to use NIPT as a screening test also 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.

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.
  • Trisomy PCR is used to determine the number of chromosomes 13, 18 and 21 in the foetus, as well as the number of sex chromosomes. If this is normal, molecular karyotyping is usually performed to look for minor copy number alterations, deletions, duplications or multiple copies of all chromosomes.
  • The risk of miscarriage after chorionic villus sampling and amniocentesis is about 1% Amniocentesis and Chorionic Villus Sampling for Prenatal Diagnosis.

Chorionic villus sampling

  • 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.
  • The result of the trisomy PCR test can be obtained in about one week and of molecular karyotyping often in 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.
  • The result of the trisomy PCR test can be obtained in about one week and of molecular karyotyping usually in about 1-2 weeks.
  • Also 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 a neural tube defect or congenital nephrosis, for example.

Indications for chromosome studies

  • A result suggesting an increased risk of chromosomal abnormality based on measurement of nuchal translucency, combined ultrasound and maternal serum screening, or maternal serum screening alone
  • Fetal abnormalities detected by ultrasound examination, on the grounds of which trisomy PCR and molecular karyotyping are considered
    • A structural abnormality identified during ultrasound examination that is associated with an increased risk of chromosomal abnormality, such as umbilical or diaphragmatic hernia or heart defect
    • Delayed fetal growth
  • One of the parents, or a previous child, has a diagnosed chromosome abnormality

Abnormal results and further measures

  • If the result of fetal chromosomal analysis is 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, for example). 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 of pregnancy and if the pregnancy continues and the fetus has been diagnosed with a disease, the parents should be offered the possibility of psychological support, for example in the form of counselling by a psychologist or psychiatric nurse.
  • If the pregnancy is terminated due to a structural abnormality, it is important to perform the necessary examinations to establish the exact type of the structural abnormality (e.g. visual inspection of the fetus, photographs, trisomy PCR, molecular karyotyping or sometimes a gene test, autopsy). This way, in the genetic counselling following the pregnancy termination, the parents may be given information on both the risk of recurrence and the possibility of carrying out investigations during any subsequent pregnancies.

    References

    • Flöck A, Tu NC, Rüland A, ym. Non-invasive prenatal testing (NIPT): Europe's first multicenter post-market clinical follow-up study validating the quality in clinical routine. Arch Gynecol Obstet 2017;296(5):923-928. [PubMed]
    • Äyräs O, Eronen M, Tikkanen M, ym. Long-term outcome in apparently healthy children with increased nuchal translucency in the first trimester screening. Acta Obstet Gynecol Scand 2016;95(5):541-6.[PubMed]
    • Sarno L, Revello R, Hanson E et al. Prospective first-trimester screening for trisomies by cell-free DNA testing of maternal blood in twin pregnancy. Ultrasound Obstet Gynecol 2016;47(6):705-11. [PubMed]
    • 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]
    • Norton ME, Jacobsson B, Swamy GK, ym. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med 2015;372(17):1589-97.[PubMed]
    • Äyräs O, Eronen M, Tikkanen M, ym. Long-term neurodevelopmental outcome of children from euploid pregnancies with increased nuchal translucency in the first trimester screening. Prenat Diagn 2015;35(4):362-9. [PubMed]
    • Ayräs O, Tikkanen M, Eronen M, ym. Increased nuchal translucency and pregnancy outcome: a retrospective study of 1063 consecutive singleton pregnancies in a single referral institution. Prenat Diagn 2013;33(9):856-62.[PubMed]
    • Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM, SURUSS Research Group. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technol Assess 2003;7(11):1-77. [PubMed]