Genetic Testing in Pregnancy
Prenatal fetal genetic testing is not performed for every pregnancy, but may be recommended for women who have a high risk profile or for those who have abnormal early screening test results. Many women prefer having accurate information to make healthcare decisions for their pregnancy. Reasons for having the testing performed include:
- Ensuring the health of the mother
- Ensuring the health of the baby
- Making decisions based on definitive information
- Preparing interventions (educational and/or medical) in the event a baby does have a genetic condition
- Having time to understand a genetic condition prior to the baby's arrival
Screening Tests vs. Diagnostic Tests
Screening tests are generally performed early in pregnancy (first or second trimester) and give information about the risk of specific genetic or anatomic anomalies. Diagnostic tests are generally performed when a screening test indicates a risk and give specific information for genetic diseases and chromosomal disorders.
Carrier Status Screening
Carrier status testing is performed on the mother or father’s genetic material, not the baby’s. This testing will identify the likelihood of a parent carrying one copy of a mutation for a disease prevalent within a high risk population. In this case, the parent does not have the disease, but if both parents carry a single copy, the baby might inherit a genetic disease. Some genetic diseases are more prevalent among certain populations. Cystic Fibrosis carrier testing, for example, might be offered to a mother with European heritage as this disorder has a higher prevalence among this population. The parental DNA is gathered via a blood test or cheek swab.
First Trimester Screening
The initial blood tests and ultrasound tests in the first trimester are not capable of diagnosing any condition. A level of risk is assigned from these tests, and a recommendation to carry out diagnostic testing is made from this information. The first-line testing in early pregnancy includes an ultrasound to evaluate the thickness of the back of the baby's neck and two blood hormone tests. Elevated nuchal fold thickness and blood test results often cause a lot of distress, but these results are not diagnostic of any condition.
Nuchal Translucency Screening
Nuchal Translucency (NT) Screening is performed when a woman’s pregnancy is between 11-13 weeks. This test involves an ultrasound to measure the amount of fluid at the back of the baby’s neck. This thickness is then measured as a percentage of the baby’s length from crown to rump. The nasal bone is also measured during this test. This test is done in conjunction with two blood tests, which measure the levels of PAPP-A and hCG in the mother’s blood. In general, a NT thickness of >2 mm is considered to be high risk. This test, however, is not diagnostic and babies may have a “risky” NT measurement when they are perfectly healthy. Diagnostic testing is advised for those who fall into the “high risk” category
The accuracy of the NT test is dependent upon the precision of the ultrasound machine-probe combination. Trisomic babies will have a thick NT score 65-85% of the time. This means that 15-35% of the time, a baby with a trisomy will have a normal NT score and not be detected with this measurement alone. In addition, up to 13% of completely healthy babies demonstrate a nuchal thickness >2.5 mm.
Conditions Associated with a High NT measurement include:
- Trisomies, such as Down Syndrome and Edwards Syndrome
- Congenital Lymphadema
- Cardiac Defects
- Diaphragmatic Hernia
- Congenital Adrenal Hyperplasia
Pregnancy Associated Plasma Protein-A Blood Test
- PAPP-A is a screening test for pregnancy associated plasma protein-A. A large glycoprotein produced by the fetus, PAPP-A is responsible for protecting the baby from the mother’s immune system, mineralizing the fetal matrix, and forming blood vessels. The quantity of PAPP-A in the mother’s blood is used in conjunction with hCG and the nuchal translucency ultrasound to determine the likelihood for certain fetal anomalies.
Low PAPP-A levels at 11-13 weeks of gestation are associated with stillbirth, pre-eclampsia, and intra-uterine growth restriction for fetuses without trisomies. Low PAPP-A levels combined with a high nuchal translucency measurement are often indicative of a trisomy.
The sensitivity and positive predictive value of low PAPP-A levels are extremely poor, however, when used in isolation. The risk of pregnancy loss before 20 weeks is only 1-4% when a low value is observed. Even with levels in the first percentile of normal only predict 24% of intra-uterine growth retardation.
This test is only a screening method and must be used in conjunction with other tests to determine risk. If a high risk pregnancy is suggested, further diagnostic testing will be suggested.
Human Chorionic Gonadotropin Blood Test
hCG is a screening test for human chorionic gonadotropin, the “pregnancy hormone.” The amount of beta hCG is often monitored in early pregnancy to ensure the pregnancy is developing appropriately. In the case of Down Syndrome (trisomy 21), the free beta-hCG level is elevated. The free beta-hCG levels are reduced for trisomy 18 and trisomy 13. The use of serum free beta-hCG levels is not meant to be used in isolation, but alongside the PAPP-A levels in the mother’s blood and nuchal fold translucency evaluation as part of the first trimester “triple screen.”
First Trimester Evaluations
Second Trimester Screening
The Quadruple Screen (or Quad Screen) is performed in the second trimester, and is most accurate between weeks 16-18 of the pregnancy. This screening test evaluates four different markers to determine the risk level for trisomies and other disorders, including anencephaly and spina bifida. As with the first trimester screen, this test does not diagnose any condition, but relays a relative risk. Further diagnostic testing is required to ascertain the health of the pregnancy. Many different factors can influence the hormone levels, including the gestational age of the baby and the number of babies being carried (twins will have a higher AFP level than single babies). The most common reason for an elevated AFP level is an inaccurate dating of the pregnancy.
Second Trimester Evaluation
Disorders Associated with Low Levels
Disorders Associated with Elevated Levels
Human Chorionic Gonadotropin
A hormone produced by the placenta
Down Syndrome (T21) Edwards Syndrome (T18)
A hormone produced by the placenta and ovaries
Down Syndrome (T21) Edwards Syndrome (T18)
A form of estrogen produced by the baby and the placenta
Impending labor Congenital adrenal hyperplasia
Down Syndrome (T21) Edwards Syndrome (T18) Pregnancy Loss Smith-Lemli-Opitz Syndrome
Protein produced by the baby
Neural tube defects Turner Syndrome Other birth defects
Down Syndrome (T21) Edwards Syndrome (T18)
Combining the information obtained from the first trimester (Nuchal Translucency) and the second trimester quadruple screen often give a more accurate risk assessment in early pregnancy. None of these tests offers a diagnosis and will only give a relative risk, which may be further investigated through diagnostic testing.
Cell-Free DNA Testing
Cell-Free DNA Testing is a screening test possible as early as 10 weeks of gestation. This blood test evaluates the mother’s blood for fetal chromosomal anomalies, including trisomies and sex chromosome disorders. A sample of blood is taken from the mother, and the relative quantity of DNA from chromosomes 13, 18, 21, and the sex chromosomes (X,Y) are evaluated. This test is more accurate than the first and second trimester screening methods listed below, but is not considered diagnostic. 99% of all cases of trisomy 21 (Down Syndrome) will be identified using this method, but 1% will be missed. The sensitivity is lower for trisomy 13 (~87% identified) and trisomy 18 (~97% identified). The accuracy is reduced for women carrying twins, and this test cannot be performed for women carrying triplets. If the cell-free DNA testing indicates an elevated risk, the mother will be referred on to diagnostic testing (including chorionic villus sampling). Test results are generally available approximately two weeks after the blood is drawn.
If initial screening tests indicate an elevated risk, the physician will offer diagnostic tests to the mother. Obtaining an accurate diagnosis will allow the mother to make informed healthcare decisions. The genetic analysis methods include the following:
Fluorescence in situ Hybridization (FISH): A method of observing chromosomes to determine if there is an abnormal number for chromosomes 13, 18, 21, X, and Y. This test is faster than a traditional karyotype and results will be available in 1-2 days.
Karyotype: Chromosomes are arranged and photographed to obtain a detailed view of each set. An abnormal number of chromosomes is verified using this method. Results take approximately 1-2 weeks from the time of sampling.
Microarray: This test is able to identify more detailed problems (such as specific deletions within a chromosome) that a karyotype may be unable to observe. This test is performed by using a normal reference sample and the test sample. Complementary DNA is coated onto a microarray plate and the DNA from the sample will bind to the strands on the plate. The amount of genetic expression from each genetic fragment is recorded and compared to the reference. A higher than normal amount of genetic expression will turn red, indicating a genetic duplication or over-expression of that particular genetic fragment. A lower than normal amount will turn green, indicating a genetic deletion or loss-of-function. An equal amount of expression with the normal reference will turn yellow, indicating normal results. Results are usually available in approximately 1 week.
DNA Analysis: This testing is the most detailed and looks for mutations in specific genes. If both parents are carriers for cystic fibrosis or sickle cell, a genetic test to identify the specific mutations associated with this disorder will be carried out. Panels specific to identified risks will be ordered if a particular genetic disease is suspected.
Cell Free DNA Testing vs. Amniocentesis
For women undergoing in-vitro fertilization procedures, an option to evaluate the genetic health of an embryo prior to implantation is available. This testing allows embryos to be screened for genetic diseases prior to implantation.
Chorionic Villus Sampling
Chorionic Villus Sampling (CVS) is able to detect and diagnose chromosomal disorders and specific genetic diseases. The test is performed by obtaining a small part of the placenta. The sample is either taken using a catheter through the cervix or by a needle through the abdomen. Ultrasound is used to ensure the proper placement of the retrieval device, and the procedure takes approximately 10 minutes. The tissue then undergoes a karyotype analysis, which allows the doctor to see the baby’s chromosomes. A positive CVS test indicates a chromosomal or other genetic abnormality. Results should be available within approximately two weeks of the procedure. There is a small risk of miscarriage that accompanies CVS testing, which varies by hospital. Selecting a hospital with experience performing this procedure is vital. The benefit of CVS over amniocentesis is that CVS may be performed as early as 10 weeks, while amniocentesis is not typically performed until 15-20 weeks of pregnancy.
Amniocentesis is the evaluation of the baby’s genetic material obtained by needle aspiration of the amniotic fluid. There is a slight risk of miscarriage with amniocentesis (~0.6%). The rate of miscarriage is higher the earlier in pregnancy the procedure is performed, which is why the test is not done until at least 15 weeks of pregnancy.
The fetal DNA is evaluated for the presence of chromosomal disorders and many genetic diseases. Tay-Sachs, Cystic Fibrosis, Sickle Cell Anemia, and other disorders may be diagnosed prior to birth using this test.
Amniocentesis may also be performed later in pregnancy to assess the infant’s lung maturity for those at risk of pre-term birth, determine Rh factor status of the baby, and to remove excess amniotic fluid from women with polyhydramnios.
- Axel, R.G., Gillett, A. et. al. (2014). Accuracy of Nuchal Translucency Measurement Depends on Equipment Used and Its Calibration. Ultrasound in Obstetrics and Gynecology, 44(1): 31-7.
- Sharifzadeh, M., Adibi, A. et. .al. (2015). Normal Reference Range of Fetal Nuchal Translucency Thickness in Pregnant Women in the First Trimester, One Center Study. Journal of Research in Medical Sciences, 20(10): 969–973.
- Patil, M., Panchanadikar, T. M., & Wagh, G. (2014). Variation of Papp-A Level in the First Trimester of Pregnancy and Its Clinical Outcome. The Journal of Obstetrics and Gynecology of India, 64(2): 116–119.
- Yazdani, S., Rouholahnejad, R., et. al. (2015). Correlation of Pregnancy Outcome With Quadruple Screening Test at Second Trimester. Medical Journal of the Islamic Republic of Iran, 29: 281
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