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Prenatal Diagnosis

What is prenatal diagnosis?

Prenatal diagnosis uses a variety of testing methods to determine whether a fetus has certain genetic or physical abnormalities before birth. At different stages during pregnancy, these methods are used to detect issues such as Down syndrome (trisomy 21), hemophilia, thalassemia, Turner syndrome, spina bifida and Huntington’s disease.

The International Society for Prenatal Diagnosis (ISPD) was founded in 1996 to advance the “science and practice of genetics and fetal care worldwide [and] promote the health of children, their mothers and their families.“[1]

What is prenatal screening?

Prenatal screening tests can determine the likelihood of a fetus having an abnormality. Parents at particular risk of certain problems may choose to use a variety of prenatal diagnostic tests. This decision is based on factors including their level of risk, the prenatal (before birth) or postnatal (after birth) care required to address a particular issue, and the parents’ comfort with their risk level.

Prenatal screening consists of non-invasive tests, including:

  • Ultrasound
  • Maternal serum tests
  • Prenatal cell-free DNA (cfDNA) screening (to determine the likelihood that a fetus will have a genetic disorder)

These screenings are considered together to determine a statistical probability of an issue occurring, but they cannot diagnose the existence of these issues with certainty. If a fetus is determined to have a high likelihood of a genetic abnormality, parents are encouraged to undergo diagnostic testing such as amniocentesis and chorionic villus sampling (CVS), which directly test the fetal cells. The amniocentesis and chorionic villus sampling (CVS) tests are more definitive than non-invasive screenings, but do carry risks to the fetus, such as miscarriage or congenital abnormalities.**

Purposes of prenatal diagnosis

In testing for these potential issues, prenatal diagnosis provides information to parents and doctors as early as possible, so that they can determine the best course of care for the fetus, both before and after birth. It can also detect issues that, if left unaddressed, could result in negative outcomes (including death) for the fetus or mother. This knowledge can lessen the risk for conditions requiring prenatal care or that may result in more difficult births.

Additionally, this can tell the doctors whether they should prepare to administer special care to the infant right after birth. It can also allow parents to prepare physically, emotionally and/or financially for the chance that their child will have specific medical needs. Some parents may choose to terminate the pregnancy if the information discovered during prenatal testing suggests that the fetus will not develop into a healthy baby, would not survive long outside the womb or would have an extremely poor quality of life.[2]

Prenatal diagnostic tests

Amniocentesis

Amniocentesis is an invasive prenatal diagnostic test in which a long, thin needle is passed through the mother’s abdomen (belly) and uterus into the amniotic sac to extract amniotic fluid. The fetal cells in the amniotic fluid are analyzed for irregularities in chromosomes and biochemicals. This test is usually performed in the second trimester at between 14-20 weeks of pregnancy, or as early as amniotic fluid levels will permit testing.

Amniocentesis can also be used to test for:

  • Rhesus factor: This is a very important blood factor which can cause problems when the baby’s Rh factor is different to that of the pregnant person. This can cause Rh sensitization if blood passes between the developing fetus and the mother.
  • Fetal lung development (by the third trimester)

Women may experience discomfort and cramping during this test, and should rest for the remainder of the day after it is administered. In rarer cases they may also be advised to rest for 24 or even up to 48 hours after the procedure.

Amniocentesis can detect chromosomal disorders such as Down syndrome; genetic disorders such as cystic fibrosis; and neural tube defects such as spina bifida.[3] It is not used to detect structural birth defects. Due to its ability to also determine a baby’s gender, amniocentesis is subject to legal restrictions in some countries.

The fetus is not injured during amniocentesis, though the procedure does slightly increase the risk of miscarriage.

Chorionic villus sampling (CVS)

Chorionic villus sampling (CVS) is typically carried out by passing a catheter, guided by ultrasound, from the vagina through the cervix and into the uterus, accessing the chorionic villi cells of the placenta. These cells share genetic material with the fetus. Depending on the placement of the placenta in the mother’s body, it may also be administered transabdominally (through the belly), using a long thin needle, in a procedure similar to amniocentesis.

These cells are then analyzed using a variety of methods, with the most common being chromosomal analysis. CVS detects almost all chromosomal disorders, such as Down syndrome, as well as hundreds of genetic disorders, such as sickle cell disease, cystic fibrosis and Tay-Sachs disease. It does not detect neural tube defects. Unclear results showing a discrepancy between the chromosomes of the cells in the placenta and the cells in the baby, called placental mosaicism, occur between 1-2% of the time with CVS. Amniocentesis (another test to check for chromosomal conditions) may be necessary to gain definitive results.[4]

CVS can be administered as early as 10 weeks into the pregnancy, in the first trimester. Mothers do not typically experience pronounced discomfort during the test, but some may have light bleeding (spotting) afterwards.

CVS is considered an invasive test, and carries a slightly higher risk of miscarriage than does amniocentesis, as well as other possible risks, including infection or Rh sensitization (in which the Rh positive blood cells from the baby enter the pregnant person’s bloodstream, potentially causing pregnancy complications). In rare cases, it is linked to fetal deformities of the fingers and toes, but current research suggests that this risk is smaller if the test is done after the 11th week of pregnancy.

Preimplantation genetic diagnosis

When an embryo is created for use in in-vitro fertilization (IVF), cells removed from the embryo can be used to diagnose chromosomal abnormalities and genetic disorders prior to implantation. The fetus produced by a screened embryo is extremely unlikely to have the tested disorder. Preimplantation genetic diagnosis may also be called preimplantation genetic profiling.

Prenatal screening

Ultrasound

Ultrasound is a common and non-invasive procedure that uses sound waves passing through the womb and the fetus to create an image of the fetus’s body and development. It is typically used to screen for structural birth defects at between 16-20 weeks of pregnancy. Ultrasound testing is useful for physical issues such as heart malformations or cleft palates, and to detect the fetus’s position in the womb, but it is not as effective as the invasive means mentioned above to detect genetic issues.

An ultrasound test for fetal nuchal translucency (NT) monitors the back of the fetus’s neck for signs of thickening or increased fluid, an early sign of problems such as Down syndrome, trisomy 18 or heart issues.

Prenatal cell-free DNA (cfDNA) screening

Prenatal cell-free DNA (cfDNA) screening is a relatively new, non-invasive test for the likelihood that a fetus will have some chromosomal abnormalities such as Down syndrome, trisomy 13 or trisomy 18. In some cases, it can screen for increased risk of trisomy 16, trisomy 22, triploidy, sex chromosome aneuploidy (abnormal number of sex chromosomes), Prader-Willi syndrome and other microdeletion syndromes, as well as some single-gene disorders affecting the fetus’s skeleton and bones. It can also determine the sex and rhesus blood type (Rh) of the developing fetus. As this test screens maternal blood to locate fetal DNA entering the mother’s body through the placenta, its samples are too small for some common testing procedures, so it is only useful for certain conditions, like the ones mentioned above.

CfDNA screening can be carried out after the 10th week of pregnancy, and does not increase risk of miscarriage. However, women who are obese, carrying more than one fetus or pregnant with a donor egg or as a gestational carrier (also known as a surrogate mother) may not receive accurate results from this test. It is often recommended for women with increased risk of having a baby with chromosomal abnormalities – such as older mothers or mothers who have previously given birth to a baby with these conditions – and for women with Rh negative blood types.

Screening for Rh status

A very small proportion of the population has Rh negative blood types, and if a mother with Rh negative blood is carrying a baby with Rh positive blood, meaning they are Rh incompatible, it can cause complications. If fetal blood enters the mother’s circulatory system, it triggers the production of antibodies in the mother’s system that can subsequently, most likely when the mother will be pregnant with her second Rh positive baby, attack the Rh factor in the fetus’s blood.

This will damage the babies’ red blood cells and cause anemia in the baby. This condition, which is unlikely to develop under effective prenatal care, is called Rh disease and can lead to complications including jaundice, brain damage, miscarriage or stillbirth.

The administration of a Rh immune globulin shot to the mother following any chance of exposure to fetal blood prevents these antibodies from forming. Typically, fetal blood only enters the mother’s system during birth, so these antibodies would attack the next fetus with Rh positive blood that the mother carries. In some cases, though, fetal blood can enter the mother’s body during routine testing such as amniocentesis or CVS – due to vaginal bleeding, an ectopic pregnancy or an abdominal injury – so a Rh negative mother will receive the Rh immune globulin shot within 72 hours to prevent antibody formation.

This screening is important, as once the antibodies are in the mother’s system, they cannot be removed. They increase, along with the potential for damage to the fetus, with each Rh positive fetus that the mother carries or gives birth to. There are effective treatments for Rh disease after the fetus’s birth, including blood transfusions.

Maternal serum tests and quad screen test

Numerous blood tests are a part of prenatal screening, and may be administered at various times throughout the pregnancy. These are non-invasive tests.

Pregnancy associated plasma protein screening (PAPP-A)

Usually measured in the first trimester, this test monitors the level of a protein produced by the placenta. High levels may be associated with chromosomal abnormalities such as trisomy 13, 18 and 21, while low levels can indicate that the fetus may be underweight or stillborn. High levels may also indicate an unusually large fetus.

Alpha-fetoprotein screening (AFP)

Alpha-fetoprotein screening (AFP) tests the levels of alpha-fetoprotein, a fetal liver protein that can cross into the mother’s blood. It is one of the second trimester tests referred to as quad screen test, and it is usually performed along with three other tests, for HCG, estriol and inhibin.

High levels of this protein can suggest neural tube defects such as spina bifida or anencephaly, but not with certainty, as AFP levels can be elevated for several reasons – such as if the fetus’s conception time (the moment the father’s sperm impregnates the mother’s egg) is not accurately known. Abnormal levels of AFP can also indicate chromosomal abnormalities such as Down syndrome, defects in the fetus’s abdominal wall, or the carriage of multiple fetuses.

Beta-HCG screening

High levels of this placental protein may indicate chromosomal abnormalities. Combined with maternal serum AFP (MSAFP) results, it can suggest Down syndrome.[5] This is one of the quad screen test markers.

Estriol screening

Another one of the quad screen tests, the test for estriol levels indicates whether the mother is healthy, the fetus is viable and the placenta is functioning. Low levels of estriol in the third trimester may indicate Down syndrome, adrenal hypoplasia with anencephaly or that an emergency delivery is necessary.

Inhibin-A

High levels of inhibin-A can be associated with trisomy 21, while lower levels might indicate that the baby is at risk of an early delivery. It is one of the four markers in the quad screen test.

Risks of prenatal diagnosis

Although every pregnancy carries the risk of miscarriage, non-invasive screenings like ultrasound, prenatal cell-free DNA (cfDNA) screening or maternal serum tests do not increase this risk. They are not linked to any risks for the developing fetus or pregnant person, other than the usual risks involved with drawing a blood sample from the mother’s veins, including bruising of the site and slight pain where the needle enters the vein.

Both CVS and amniocentesis carry an additional risk of miscarriage compared to other tests.[6] This is due to the nature of the procedure (an injection which passes through the wall of the womb).

  • For amniocentesis, the increased risk of miscarriage is approximately 1 percent, meaning that 1 in 100 people who undergo this test will miscarry as a result.
  • For CVS, the increased risk of miscarriage is 1-2 percent, meaning that 1-2 in 100 people who undergo the CVS test will miscarry as a result.

Although these tests are performed safely and do not result in miscarriage in the majority of cases. Doctors will recommend these tests only in cases where they feel that the information gained about possible problems which can then be treated will significantly outweigh the risk of miscarriage.

Continuous guidance by ultrasound during the procedure can minimize this risk, as it helps ensure that only one attempt will be necessary. In rare cases, CVS has been linked to fetal deformities of the fingers and toes, but current research suggests that this risk is lowered if the test is done after the 11th week of pregnancy.

Preimplantation genetic diagnosis can have major risks, including death of the embryo due to the procedure or due to thawing from cryopreservation. It can also be linked to the potential for an unsuccessful birth of the fetus.

FAQ

Q:Who should use prenatal diagnosis?
A: Prenatal diagnosis may be suggested to women older than 35 years old or who have issues such as high blood pressure, diabetes, epilepsy or lupus, as they are at higher risk to carry a fetus with certain problems. It is also recommended for women whose partners have genetic disorders, women who have previously had children with these issues or women who are pregnant with more than one fetus.

Due to the risks to the fetus associated with invasive testing, many women start with non-invasive genetic risk screenings, which can reveal their fetus’s likelihood of risk, but cannot provide a true diagnosis. Women who receive a high-risk score may then choose to undergo prenatal diagnostic testing. Women have different levels of comfort with risk, and may choose to undergo prenatal diagnostic testing at higher or lower risk levels.

Preconception genetic screening (screening the individual partners for conditions before the egg and sperm have fused and produced the embryo) is also available, which can tell parents whether they are likely to pass on certain genetic conditions but – as there is no fetus in the mother’s uterus at the time – it does not reveal a particular fetus’s risk of abnormality.

Depending on the health system, some doctors make testing for some birth defects available to all mothers regardless of their risk screenings, and allow the mother to decide.

Q: What is prenatal diagnosis for Down syndrome?
A: Two major types of prenatal testing for Down syndrome exist: prenatal screening and diagnostic testing. Prenatal screening is typically a combination of maternal serum tests, an ultrasound and statistical information about the mother’s age. These tests cannot definitively diagnose Down syndrome, but can give the likelihood that the fetus will have Down syndrome, with an accuracy of about 80%. Prenatal cell-free DNA (cfDNA) screening has recently emerged as another screening method, with higher accuracy. These screenings are offered to pregnant people in most medical contexts, regardless of age, and are often completed by 14 weeks, within the first trimester.

Amniocentesis and CVS are diagnostic tests that can diagnose Down syndrome with nearly 100% accuracy, however, they also may lead to a higher risk of miscarriage, as high as 1 or 2% higher than the general risk for miscarriage any mother has.[7] For this reason, they are often recommended only to women who have undergone a prenatal screening and found to be carrying a fetus likely to have Down syndrome.

Q: What is prenatal diagnosis for autism?
A: Right now, there is no definitive prenatal diagnosis for autism spectrum disorder (ASD) in the fetus. There is some evidence that a fetus with ASD undergoes faster growth of the brain and body during the second trimester, and these changes can be made visible by ultrasound. Some evidence also suggests abnormal development of some parts of the brain.[8] Not all babies that will develop ASD have chromosomal abnormalities, so many prenatal diagnostic tests have little to no effectiveness in that regard.


  1. "International Society for Prenatal Diagnosis." ISPD. Accessed: July 8, 2017

  2. Prenatal Genetic Screening Tests: Benefits and Risks.” LiveScience. Accessed: July 8, 2017

  3. Amniocentesis.” American Pregnancy Association. Accessed: July 8, 2017

  4. Chorionic villus sampling (CVS)” Baby Center. Accessed: July 8, 2017

  5. Prenatal Diagnosis.” Utah University of Health. Accessed: July 8, 2017

  6. Prenatal Genetic Screening Tests: Benefits and Risks.” LiveScience. Accessed: July 8, 2017

  7. Understanding a Diagnosis of Down Syndrome.” National Down Syndrome Society. Accessed: July 8, 2017

  8. “Direct Evidence that Autism Starts During Prenatal Development.](https://www.autismspeaks.org/science/science-news/direct-evidence-autism-starts-during-prenatal-development)” Autism Speaks. Accessed: July 8, 2017