Prenatal Diagnostic Testing

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, tests to analyze the genetic material of the fetus may be done.
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 neural tube defects) or a chromosomal abnormality (particularly when the woman is 35 or older). 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, would they still want to know of an abnormality before birth (for example, to prepare psychologically) or would knowing 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. These tests are available only in specialized centers and are used primarily for couples with a high risk of certain genetic disorders (such as cystic fibrosis) or chromosomal abnormalities.




Some Genetic Disorders That Can Be Detected Before Birth
Disorder
Incidence
Inheritance Pattern

Cystic fibrosis
1 of 3,300 white people
Autosomal recessive

Congenital adrenal hyperplasia
1 of 10,000
Autosomal recessive

Duchenne's muscular dystrophy
1 of 3,500 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 2000 male births

1 of 4000 female births
X-linked dominant

Polycystic kidney disease (adult type)
1 of 3,000
Autosomal dominant

Sickle cell anemia
1 of 400 black people in the United States
Autosomal recessive

Tay-Sachs disease
1 of 3,600 Ashkenazi Jews and French Canadians

1 of 400,000 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, and some rarer genetic disorders. Knowing the woman's individual risk as precisely as possible can help the couple better assess the benefits of having invasive prenatal genetic testing. Doctors usually offer to measure these markers as part of routine prenatal care, although women can choose not to have these tests. For example, if couples can decide whether to have prenatal genetic testing without knowing the precise risk of a genetic or chromosomal abnormality, most parts of screening are unnecessary.

Markers are usually measured at 16 to 18 weeks of pregnancy (during the 2nd trimester), when these measurements are fairly accurate. Other markers can be measured during the 1st trimester.

First-Trimester Screening

Sometimes blood tests to estimate the risk of Down syndrome are done at about 11 to 14 weeks of pregnancy. These tests involve measuring levels of pregnancy-associated placental protein A (produced by the placenta) and beta-human chorionic gonadotropin in a pregnant woman's blood.

Also, ultrasonography is done to measure a fluid-filled space near the back of the fetus's neck (called fetal nuchal translucency). Abnormal ultrasound measurements indicate an increased risk of Down syndrome or another chromosomal abnormality in the fetus.

First-trimester blood tests plus ultrasonography provide 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.

First-trimester tests give results earlier than 2nd-trimester screening, which has been the traditional approach for over two decades. Abortion, if desired, is safer when done earlier.

Second-Trimester Screening

During the 2nd trimester, markers in the pregnant woman's blood are measured and sometimes ultrasonography is done to identify women at increased risk of certain problems.

Important markers include the following:

Alpha-fetoprotein: A protein produced by the fetus
Estriol: This hormone's precursors are produced by the fetus
Human chorionic gonadotropin: A hormone produced by the placenta
Inhibin A: A hormone produced by the placenta

Alpha-fetoprotein levels: Alpha-fetoprotein 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
More than one fetus
Pregnancy complications, such as miscarriage, slowed growth or death of the fetus, and premature detachment of the placenta (placental abruption)

If blood tests detect an abnormal alpha-fetoprotein level in a pregnant woman, ultrasonography is done. 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, amniocentesis to measure the alpha-fetoprotein level in the fluid that surrounds the fetus (amniotic fluid) is recommended by many doctors. Also, the fetus's chromosomes may be analyzed and the amniotic fluid may be tested to determine whether it contains an enzyme called acetylcholinesterase. Levels of alpha-fetoprotein and acetylcholinesterase help doctors better assess risk:

A high alpha-fetoprotein level plus acetylcholinesterase in the amniotic fluid indicates an increased risk of a neural tube defect, such as anencephaly or spina bifida.
A high alpha-fetoprotein level with or without acetylcholinesterase may indicate an increased risk of a neural tube defect and of abnormalities in other organs, such as the esophagus and the abdominal wall

Sometimes the amniotic fluid sample is contaminated with blood from the fetus, resulting in an abnormal alpha-fetoprotein level. In such cases, the fetus may not have any abnormalities.

Triple and Quad Screening: Measuring 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. If risk is high, amniocentesis is considered. Quad screening results are abnormal (positive) in almost 80% of Down syndrome cases. Triple screening detects almost as many cases.

At some medical centers, targeted ultrasonography (a genetic sonogram) 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 the risk of a chromosomal abnormality is reduced.

Combining 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 Symptoms and Diagnosis of Gynecologic Disorders: 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 findings that tend to indicate a higher-than-normal chance of a chromosomal abnormality in the fetus (targeted ultrasonography)

Fetal Ultrasound Scanning


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, which means careful assessment of fetal anatomy is performed by experts at such testing. 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 (see Normal Pregnancy:Stages of Development). This procedure is used to diagnose some disorders in the fetus, usually between 10 and 12 weeks of pregnancy. Chorionic villus sampling may be used instead of amniocentesis unless a sample of amniotic fluid is needed, as when the alpha-fetoprotein level in amniotic fluid must be measured.

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 enable doctors to treat the fetus appropriately before birth. For example, a pregnant woman may be given a corticosteroid to prevent male characteristics from developing in a female fetus that has congenital adrenal hyperplasia. In this hereditary disorder, the adrenal glands are enlarged and produce excessive amounts of male hormones (androgens).

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). With both methods, ultrasonography is used for guidance and the tissue sample is suctioned through a needle or catheter with a syringe and then sent for laboratory analysis. Many women have light spotting for a day or two afterward.

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), chronic inflammation of the cervix, or a placenta that covers the passage between the cervix and uterus.
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.

After chorionic villus sampling, most women who have Rh-negative blood and who do not have antibodies to Rh factor are given an injection of Rh0(D) immune globulin to prevent them from producing antibodies to Rh factor (see Pregnancy Complications: 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, with the most common risk being that of miscarriage. In experienced centers, the risk of miscarriage is 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.




Did You Know...

All pregnancies have a 2 to 3 % risk of miscarriage, and amniocentesis or CVS increase that by about 0.2%.


Amniocentesis

One of the most common procedures for detecting abnormalities before birth is amniocentesis. It is often offered to women over 35 to estimate their risk of having a baby with Down syndrome. However, it can be done for any woman who chooses, 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 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. Results are usually available in about 1 to 2 weeks.

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

Women who have Rh-negative blood are given Rh0(D) immune globulin after the procedure to prevent them from producing antibodies to Rh factor, which can cause problems in a fetus with Rh-positive blood (see Pregnancy Complications: Rh Incompatibility).

Amniocentesis rarely causes any problems for the woman or the fetus.

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

Percutaneous umbilical blood sampling is used when rapid chromosome analysis is needed, particularly toward the end of pregnancy when ultrasonography has detected abnormalities in the fetus. Often, results can be available within 48 hours. It is occasionally done for other reasons?for example, when doctors suspect that a fetus has anemia. If the fetus has severe anemia, blood can be transfused to the fetus during percutaneous 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 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 and has risks for the woman and fetus. Loss of the pregnancy as a result of this test occurs in about 1 in 100 procedures.