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Prenatal Diagnostic Testing

by Jeffrey S. Dungan, MD

  • Measurement of certain substances in the pregnant woman’s blood plus ultrasonography can help estimate the risk of genetic abnormalities in the fetus.

  • These blood tests and ultrasonography may be done as part of routine care during pregnancy.

  • If results of these tests suggest an increased risk, doctors may do tests to analyze the genetic material of the fetus, such as amniocentesis and chorionic villus sampling.

  • These genetic tests are invasive and have certain risks for the fetus.

Prenatal diagnostic testing involves testing the fetus before birth (prenatally) to determine whether the fetus has certain abnormalities, including certain hereditary or spontaneous genetic disorders. Some of these tests, such as ultrasonography and certain blood tests, are often part of routine prenatal care. Ultrasonography and blood tests are safe and sometimes help determine whether more invasive prenatal genetic tests (chorionic villus sampling, amniocentesis, and percutaneous umbilical blood sampling) are needed. Usually, these more invasive tests are done when couples have an increased risk of having a baby with a genetic abnormality (such as a neural tube defect) or a chromosomal abnormality (particularly when the woman is 35 or older). However, many doctors offer this type of testing to all pregnant women, and any pregnant woman can request it. These tests have risks, although very small, particularly for the fetus.

Couples should discuss the risks with their health care practitioner and weigh the risks against their need to know. For example, they should think about whether not knowing the results of testing would cause anxiety and whether knowing that an abnormality was not found would be reassuring. They should think about whether they would pursue an abortion if an abnormality was found. If they would not, they should consider whether they still want to know of an abnormality before birth (for example, to prepare psychologically) or whether knowing would only cause distress. For some couples, the risks outweigh the benefits of knowing whether their baby has a chromosomal abnormality, so they choose not to be tested.

If in vitro fertilization is done, genetic disorders can sometimes be diagnosed before the fertilized egg is transferred from the culture dish to the uterus (called preimplantation genetic diagnosis).

Some Genetic Disorders That Can Be Detected Before Birth

Disorder

Incidence

Inheritance Pattern

Cystic fibrosis

1 of 3,300 white births

1 of 15,300 black births

1 of 32,000 Asian-American births

Autosomal recessive

Congenital adrenal hyperplasia

1 of 9,000 to 14,000 births

Autosomal recessive

Duchenne muscular dystrophy

1 of 4,700 male births

X-linked recessive

Hemophilia A

1 of 8,500 male births

X-linked recessive

Alpha- and beta-thalassemia

Varies widely by ethnic and racial group

Autosomal recessive

Fragile X syndrome

1 of 4,000 male births

1 of 8,000 female births

X-linked dominant

Polycystic kidney disease (adult type)

1 of 1,000 births

Autosomal dominant

Sickle cell anemia

1 of 400 black births in the United States

Autosomal recessive

Tay-Sachs disease

1 of 3,600 births to Ashkenazi Jews and French Canadians

1 of 400,000 births in other groups

Autosomal recessive

Screening of the Pregnant Woman

Measuring levels of certain substances (called markers) in blood can help identify women with an increased risk of problems, such as having a baby with a brain or spinal cord defect (neural tube defect), Down syndrome, other chromosomal abnormalities, or some rarer genetic disorders. These blood tests have no risks for the fetus. They can help determine the woman’s individual risk of having a baby with an abnormality more precisely and thus can help the couple better assess the benefits of having invasive prenatal genetic testing. Doctors usually offer to do blood tests to measure these markers as part of routine prenatal care. However, some couples decide not to have any testing done. Other couples, such as those with a high risk of certain disorders, may skip these blood tests and proceed directly to invasive prenatal genetic testing (such as chorionic villus sampling or amniocentesis). If women decide to have chorionic villus sampling, doctors usually advise them to have a blood test to measure the level of a marker called alpha-fetoprotein (a protein produced by the fetus). Measuring the alpha-fetoprotein level helps doctors determine the risk of brain or spinal cord birth defects (neural tube defects), such as spina bifida (see Second-Trimester Screening). Chorionic villus sampling does not give this information.

Markers are usually measured at 10 to 13 weeks of pregnancy (first-trimester screening). Other markers are measured at 16 to 18 weeks of pregnancy (2nd-trimester screening).

First-Trimester Screening

Screening during the first trimester usually consists of

  • Blood tests to measure levels of pregnancy-associated placental protein A (produced by the placenta) and beta-human chorionic gonadotropin in the pregnant woman’s blood

  • Ultrasonography to measure a fluid-filled space near the back of the fetus’s neck (called fetal nuchal translucency)

The blood tests are done to estimate the risk of Down syndrome. They may be done at about 11 to 14 weeks of pregnancy.

Ultrasonography can help estimate the risk of Down syndrome and certain other chromosomal abnormalities. It can show whether the space at the back of the fetus's neck is enlarged. If it is, risk of these abnormalities is increased.

Alternatively, a new blood test (called cell-free fetal nucleic acid testing) may be done. For this test, small fragments of the fetus's DNA, which are present in the pregnant woman's blood in tiny amounts, are analyzed. This test can accurately determine the risk of Down syndrome and some other chromosomal abnormalities in couples with a high risk of having a fetus with a chromosomal abnormality. The test can be done as early as 10 weeks of pregnancy but can also be done later.

First-trimester screening provides results early. If results are abnormal and the couple wishes, chorionic villus sampling can then be done early to determine whether Down syndrome is present. Amniocentesis can also detect Down syndrome, but it is usually done later in pregnancy.

One advantage of 1st-trimester screening is that with earlier results, abortion, if desired, can be done earlier, when it is safer.


Second-Trimester Screening

During the 2nd trimester, markers in the pregnant woman’s blood are measured and sometimes ultrasonography is done to evaluate the risk that the fetus will have certain abnormalities.

Important markers include the following:

  • Alpha-fetoprotein: A protein produced by the fetus

  • Estriol: A hormone formed from substances produced by the fetus

  • Human chorionic gonadotropin: A hormone produced by the placenta

  • Inhibin A: A hormone produced by the placenta

The alpha-fetoprotein level in blood is usually measured in all women, even those who have had 1st-trimester screening or chorionic villus sampling. A high level may indicate an increased risk of having any of the following:

  • A baby with a neural tube defect of the brain (anencephaly) or spinal cord (spina bifida)

  • A baby with a birth defect of the abdominal wall

  • Later pregnancy complications, such as miscarriage or slowed growth or death of the fetus

Ultrasonography (see Procedures : Ultrasonography) is done if blood tests detect an abnormal alpha-fetoprotein level in a pregnant woman. It can help by doing the following:

  • Confirming the length of the pregnancy

  • Determining whether more than one fetus is present

  • Determining whether the fetus has died

  • Detecting many birth defects

High-resolution or targeted ultrasonography, which can be done at some specialized centers, provides more detail and may be more accurate than standard ultrasonography, particularly for small birth defects.

If ultrasonography results are normal, a fetal problem is less likely, but certain conditions, such as neural tube defects, are still possible. Thus, whether ultrasonography results are normal or not, many doctors offer amniocentesis to all women.

Amniocentesis (see Procedures : Amniocentesis) enables doctors to measure the alpha-fetoprotein level in the fluid that surrounds the fetus (amniotic fluid), to analyze the fetus’s chromosomes, and to determine whether the amniotic fluid contains an enzyme called acetylcholinesterase. Knowing what the alpha-fetoprotein level is and whether acetylcholinesterase is present helps doctors better assess risk.

A high alpha-fetoprotein level or the presence of acetylcholinesterase in the amniotic fluid suggests

  • A neural tube defect

  • An abnormality in another structure, such as the esophagus, kidneys, or abdominal wall

A high alpha-fetoprotein level plus acetylcholinesterase in the amniotic fluid indicates a high risk of

  • A neural tube defect, such as anencephaly or spina bifida

Sometimes the amniotic fluid sample is contaminated with blood from the fetus. This blood may increase the alpha-fetoprotein level even when the fetus does not have an abnormality, making the results hard to interpret. In such cases, the fetus may not have any abnormalities.


Triple and quad screening

Blood tests to measure other markers (estriol and beta-human chorionic gonadotropin) can help estimate the risk of Down syndrome and other chromosomal abnormalities. This testing may not be necessary for women who have had 1st-trimester screening. Measuring estriol and beta-human chorionic gonadotropin plus alpha-fetoprotein is called triple screening. Inhibin A may also be measured. Measuring these four markers is called quad screening.

Triple or quad screening is done around 15 to 20 weeks of pregnancy. It can help estimate the risk of Down syndrome in the fetus. Quad screening results are abnormal (positive) in almost 80% of Down syndrome cases. Triple screening detects almost as many cases. If the risk of Down syndrome is high, amniocentesis is considered.

At some medical centers, targeted ultrasonography is done during the 2nd trimester to help estimate the risk of a chromosomal abnormality. Targeted ultrasonography aims to identify certain structural birth defects that indicate an increased risk of a chromosomal abnormality. This test can also detect certain variations in organs that do not affect function but may indicate an increased risk of a chromosomal abnormality. However, normal results do not necessarily mean that there is no risk of a chromosomal abnormality.


Combined 1st- and 2nd-trimester screening

For the most accurate results, both groups of tests—1st-trimester tests and 2nd-trimester tests—are done, and results from both are analyzed together. However, if couples want information sooner, they can request a type of screening that provides results during the 1st trimester. Then screening is done in the 2nd trimester only if results of 1st-trimester screening did not require chorionic villus sampling or amniocentesis.

Couples should remember that screening tests are not always accurate. They may miss abnormalities, or they may indicate abnormalities when none are present.


Procedures

Several procedures can be used to detect genetic and chromosomal abnormalities. All, except ultrasonography, are invasive (that is, they require insertion of an instrument into the body) and have a slight risk for the fetus.

Ultrasonography

Ultrasonography is commonly done during pregnancy (see Diagnostic Procedures : Ultrasonography). It has no known risks for the woman or fetus. Ultrasonography can do the following:

  • Confirm the length of the pregnancy

  • Locate the placenta

  • Indicate whether the fetus is alive

  • After the third month, detect certain obvious structural birth defects, including those of the brain, spinal cord, heart, kidneys, stomach, abdominal wall, and bones

  • In the 2nd trimester, detect structural defects that tend to indicate an increased risk of a chromosomal abnormality in the fetus (targeted ultrasonography)

Ultrasonography is often used to check for abnormalities in the fetus when a pregnant woman has abnormal results on a prenatal blood test or a family history of birth defects. However, normal results do not guarantee a normal baby because no test is completely accurate. Results of ultrasonography may suggest chromosomal abnormalities in the fetus, but ultrasonography cannot identify the specific problem. In such cases, amniocentesis may be recommended.

Ultrasonography is done before chorionic villus sampling and amniocentesis to confirm the length of the pregnancy so that these procedures can be done at the appropriate time during the pregnancy. During these procedures, ultrasonography is used to monitor the fetus and to guide placement of instruments.

At some specialized medical centers, targeted ultrasonography can be done. For this test, experts carefully assess the fetus to check for structural defects that indicate an increased risk of a chromosomal abnormality. This test can provide greater detail than conventional ultrasonography. Thus, this test may detect smaller abnormalities, and abnormalities can be seen earlier, more accurately, or both.


Chorionic Villus Sampling

In chorionic villus sampling, a doctor removes a small sample of the chorionic villi, which are tiny projections that make up part of the placenta. This procedure is used to diagnose some disorders in the fetus, usually between 10 and 12 weeks of pregnancy. Unlike amniocentesis, chorionic villus sampling does not enable doctors to obtain a sample of amniotic fluid. Consequently, doctors cannot measure the alpha-fetoprotein level in amniotic fluid to check for brain and spinal cord defects (neural tube defects). Doctors may suggest that amniocentesis be done later in the pregnancy to check for these defects.

The main advantage of chorionic villus sampling is that its results are available much earlier in the pregnancy than those of amniocentesis. Thus, if no abnormality is detected, the couple’s anxiety can be relieved earlier. If an abnormality is detected earlier and if the couple decides to terminate the pregnancy, simpler, safer methods can be used. Also, early detection of an abnormality may give the couple more time to prepare for the birth of a child with special medical needs.

Before the chorionic villus sampling, ultrasonography is done to determine whether the fetus is alive, to confirm the length of the pregnancy, to check for obvious abnormalities, and to locate the placenta.

A sample of the chorionic villi can be removed through the cervix (transcervically) or the abdominal wall (transabdominally).

  • Through the cervix: The woman lies on her back with her hips and knees bent, usually supported by heel or knee stirrups, as for a pelvic examination. The doctor inserts a thin, flexible tube (catheter) through the vagina and cervix into the placenta. For most women, the procedure feels very similar to a Papanicolaou (Pap) test, but a few women find it more uncomfortable. This method cannot be used in women who have an active genital infection (such as genital herpes or gonorrhea).

  • Through the abdominal wall: The doctor anesthetizes an area of skin over the abdomen and inserts a needle through the abdominal wall into the placenta. Most women do not find this procedure painful. But for some women, the area over the abdomen feels slightly sore for an hour or two afterward.

For both procedures, doctors use ultrasonography to guide them as they insert the catheter or needle and suction out the tissue sample with a syringe. The sample is then sent for analysis. Many women have light spotting for a day or two after either of these procedures.

After chorionic villus sampling, women who have Rh-negative blood and who do not have antibodies to Rh factor are given an injection of Rh 0 (D) immune globulin to prevent them from producing antibodies to Rh factor (see Rh Incompatibility). A woman with Rh-negative blood may produce these antibodies if the fetus has Rh-positive blood and it comes into contact with her blood, as it may during chorionic villus sampling. These antibodies can cause problems in the fetus. The injection is not needed if the father also has Rh-negative blood because in such cases, the fetus always has Rh-negative blood.

The risks of chorionic villus sampling are comparable to those of amniocentesis. The most common risk is that of miscarriage, which occurs in about 1 in 500 procedures.

Rarely, the genetic diagnosis is unclear after chorionic villus sampling, and amniocentesis may be necessary. In general, the accuracy of the two procedures is comparable.


Amniocentesis

One of the most common procedures for detecting abnormalities before birth is amniocentesis. It is often offered to women over 35 because they have a higher risk of having a fetus with chromosomal abnormalities than younger women. However, many doctors offer this test to all pregnant women, and any pregnant woman can request it, even if her risk is not higher than normal.

In this procedure, a sample of the fluid that surrounds the fetus (amniotic fluid) is removed and analyzed. Amniocentesis is usually done at 15 weeks of pregnancy or later. The fluid contains cells that have been shed by the fetus. These cells are grown in a laboratory so that the chromosomes in them can be analyzed. Amniocentesis enables doctors to measure the alpha-fetoprotein level in the amniotic fluid. This measurement more reliably indicates whether the fetus has a brain or spinal cord defect than does measurement of this level in the woman’s blood.

Detecting Abnormalities Before Birth

Chorionic villus sampling and amniocentesis are used to detect abnormalities in a fetus. During both procedures, ultrasonography is used for guidance.

In chorionic villus sampling, a sample of chorionic villi (part of the placenta) is removed by one of two methods. In the transcervical method, a doctor inserts a thin, flexible tube (catheter) through the vagina and cervix into the placenta. In the transabdominal method, a doctor inserts a needle through the abdominal wall into the placenta. In both methods, a sample of the placenta is suctioned out with a syringe and analyzed.

In amniocentesis, a doctor inserts a needle through the abdominal wall into the amniotic fluid. A sample of fluid is withdrawn for analysis.

Before the procedure, ultrasonography is done to evaluate the heart of the fetus, to confirm the length of the pregnancy, to locate the placenta and amniotic fluid, and to determine how many fetuses are present.

A doctor inserts a needle through the abdominal wall into the amniotic fluid. Sometimes a local anesthetic is first used to numb the site. During the procedure, ultrasonography is done so that the fetus can be monitored and the needle can be guided into place. Fluid is withdrawn, and the needle is removed.

Occasionally, the amniotic fluid contains blood from the fetus. Such blood may increase the alpha-fetoprotein level, making the results hard to interpret.

If women have Rh-negative blood, they are given Rh 0 (D) immune globulin after the procedure to prevent them from producing antibodies to Rh factor. Women with Rh-negative blood may produce these antibodies if the fetus has Rh-positive blood and the blood comes into contact with her blood, as it may during amniocentesis. These antibodies can cause problems in a fetus with Rh-positive blood (see Rh Incompatibility). The injection is not needed if the father also has Rh-negative blood because in such cases, the fetus always has Rh-negative blood.

Amniocentesis rarely causes any problems for the woman or the fetus. The following may occur:

  • Soreness: Some women feel slightly sore for an hour or two afterward.

  • Spotting of blood or leakage of amniotic fluid from the vagina: About 1 to 2% of the women have these problems, but the problems do not last long and usually stop without treatment.

  • Miscarriage: The chance of miscarriage due to amniocentesis is about 1 in 500 to 1,000.

  • Needle injuries to the fetus: These injuries are very rare.

Amniocentesis can usually be done when a woman is pregnant with twins or even more fetuses.


Percutaneous Umbilical Blood Sampling

In percutaneous (through the skin) umbilical blood sampling, the doctor first anesthetizes an area of skin over the abdomen. Guided by ultrasonography, the doctor then inserts a needle through the abdominal wall and uterus into the umbilical cord. A sample of the fetus’s blood is withdrawn and analyzed, and the needle is removed. Percutaneous umbilical blood sampling is an invasive procedure. It may cause miscarriage in about 1 in 100 procedures.

In the past, percutaneous umbilical blood sampling was used when rapid chromosome analysis was needed, particularly toward the end of pregnancy when ultrasonography detected abnormalities in the fetus. However, this procedure is now rarely used for this purpose. Instead, doctors analyze the genes in amniotic fluid cells (obtained during amniocentesis), or they analyze part of the placenta (obtained during chorionic villus sampling). These tests are less dangerous and provide results more quickly.

Currently, percutaneous umbilical blood sampling is occasionally done when doctors suspect that a fetus has anemia. If the fetus has severe anemia, blood can be transfused to the fetus through the needle while it is still inserted in the umbilical cord.


Preimplantation Genetic Diagnosis

When in vitro (test tube) fertilization (see Infertility:In vitro (test tube) fertilization (IVF)) is done, doctors can sometimes diagnose genetic disorders in the embryo before it is transferred to the woman’s uterus. The procedure requires technical expertise and is expensive. These tests are used mainly for couples with a high risk of certain genetic disorders (such as cystic fibrosis) or chromosomal abnormalities. However, newer techniques may reduce costs and make the tests more widely available.

For older women, preimplantation genetic diagnosis to screen embryos for chromosomal abnormalities does not appear to increase the chance of successful pregnancy.


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