Maternal Blood Screening for Birth Defects

It's important for pregnant women to understand the difference between a screening test and a diagnostic test. Screening tests are offered to all pregnant women to help evaluate their risk for certain birth defects, but they cannot diagnose a birth defect.

Diagnostic tests, such as amniocentesis and chorionic villus sampling (CVS), are generally offered to women considered at increased risk of a birth defect, and are highly accurate at diagnosing or ruling out a birth defect. Women who have an abnormal screening test result are offered follow-up diagnostic tests.

ACOG recommends that pregnant women of all ages have the option of choosing a diagnostic test for chromosomal birth defects, instead of a screening test (1). Until recently, only women over age 35 and others considered at increased risk for having a baby with birth defects were offered diagnostic testing, rather than a screening test.

Some women now have a choice of screening tests. These may include a new first-trimester screening test, a second-trimester screening test or both of these tests. The first-trimester test, however, is not yet available everywhere.

What is the first-trimester screening test?
Some providers offer a first-trimester screening test for Down syndrome and trisomy 18. This test also may show if a baby is at increased risk for heart defects.

This test is done between 11 and 13 weeks after a woman's last menstrual period. It is called the combined test because the test has two parts: a blood test and an ultrasound examination (a test that uses sound waves to take a picture of the fetus). The provider sends the blood sample to the lab, which measures the levels of two substances in the mother's blood: free-beta hCG (a specific form of the pregnancy hormone human chorionic gonadotropin) and pregnancy-associated protein A (PAPP-A). Levels of PAPP-A tend to be decreased, and hCG increased, with Down syndrome.

The woman also will have a special ultrasound exam to measure the thickness at the back of the baby's neck (called nuchal translucency). Increased thickness is associated with Down syndrome, other chromosomal abnormalities and heart defects. The ultrasound exam should be done by a health professional who is specifically certified, for example by the Nuchal Translucency Quality Review Program, because special training is required to do this test accurately (2). A woman's provider can refer her to an appropriate facility.

The lab will calculate a woman's risk of chromosomal birth defects, using the combined results of her blood test and ultrasound exam. Studies show that this test can detect about 82 to 87 percent of pregnancies affected by Down syndrome and up to 95 percent of those affected by trisomy 18 (1, 3, 4).

What is the second-trimester screening test?
Most women are offered a second-trimester screening test, which is done 15 to 20 weeks after a woman's last menstrual period. This test has a number of names, including maternal serum (blood) screening test, multiple marker screening test, triple screen and quad screen. This test screens for NTDs, chromosomal birth defects and certain uncommon abdominal birth defects.  

This test currently measures the levels of three or four substances in the mother's blood. When maternal blood testing first began in the early 1980s, the test measured only alpha-fetoprotein (AFP), a substance produced by the liver of the fetus. Some of this protein passes into the amniotic fluid surrounding the fetus and into the mother's bloodstream, where its concentration rises gradually until late in pregnancy. Levels of AFP are used to screen for NTDs.

Along with maternal serum alpha-fetoprotein (MSAFP) levels, the test now measures the levels of hCG and another pregnancy hormone called estriol. When the test measures these three substances, it's called the triple screen.

Most laboratories in the United States measure the level of a fourth hormone called inhibin A. When this substance is included, the test is called a quadruple (quad) screen. Studies show that adding inhibin A to the test make it more accurate than the triple screen in detecting Down syndrome (about 80 percent vs. about 70 percent) (1). Both the triple and quad screen can detect about 75 to 80 percent of pregnancies affected by spina bifida, and nearly 95 percent of those affected by a related NTD called anencephaly (5).

Researchers continue to study other substances in the mother's blood, which eventually may be added to the blood test to improve its ability to detect birth defects.

The laboratory calculates a woman's individual risk for NTDs, Down syndrome and trisomy 18 based on the levels of the three or four substances plus the woman's age, weight, race, number of fetuses (e.g., twins) and whether she has diabetes requiring insulin treatment. These last four factors influence MSAFP levels.

Do some women have both a first- and second-trimester screening test?
Women who have the first-trimester screening test for Down syndrome should be screened for NTDs in the second trimester by checking MSAFP levels or having an ultrasound exam (1).

Providers may offer women the option of taking both the first- and second-trimester screening tests. This is called integrated screening if a woman does not receive her results until after the second-trimester test, or sequential screening if she receives results after both parts of the test. Studies show that these tests together can detect about 95 percent of cases of Down syndrome (1, 3).

Does an abnormal result on the first- or second-trimester screening test mean the baby has a birth defect?
No. These tests cannot diagnose a birth defect; they only can indicate increased risk. An abnormal screening test result simply means that additional testing is recommended. Out of every 100 women who take a screening test, about 5 will have an abnormal result. However, only about 2 to 3 percent of women whose test results show an increased risk for Down syndrome will actually have a baby with Down syndrome (6). Similarly, only a very small number of women whose test results show an increased risk for spina bifida and related birth defects will actually have an affected baby. A woman's provider can give her a better estimate of the risk to her baby, based on her test results.

For many women, an abnormal result on the second-trimester screening test simply indicates that the fetus is either a few weeks older or younger than the woman and her provider thought. This can account for an abnormal result because what is considered a normal amount of AFP varies depending on a woman's stage of pregnancy. An ultrasound exam can show the correct gestational age of the fetus. Another common cause of an abnormal second-trimester test result is a multiple pregnancy (twins, triplets, etc.).

What are neural tube defects, Down syndrome and the other disorders detected by screening tests?
Neural tube defects: The neural tube is the embryonic structure that develops into the brain and spinal cord. If the neural tube does not close properly during the fourth week after conception, the baby will have an NTD, such as spina bifida or anencephaly. About 1 in 1,000 pregnancies are affected by these birth defects each year in this country (7).

Spina bifida, often called open spine, affects the backbone and sometimes the spinal cord. Children with the severe form of spina bifida have varying degrees of leg paralysis and bladder and bowel control problems. Anencephaly is a fatal condition in which a baby is born with a severely underdeveloped brain and skull.

Studies show that, if all women consumed the recommended amount of the B vitamin folic acid before and during early pregnancy, up to 70 percent of NTDs could be prevented (8). The March of Dimes recommends that all women of childbearing age take a multivitamin containing 400 micrograms of folic acid daily, and eat a healthy diet.

Abdominal wall defects: Abdominal wall defects called gastroschisis and omphalocele each affect about 1 in 5,000 births (9). Affected babies have intestines that protrude outside the body through an opening in the abdominal wall or through a hernia in the umbilical area. Surgery can help correct these defects.

Heart defects: Between 1 in 100 and 1 in 200 babies is born with a heart defect (7). The effects can range from mild to life-threatening. Many babies require surgery to help correct the defect.

Down syndrome: About 1 in 800 babies is born with Down syndrome, which is caused by an extra copy of chromosome 21 (7). Affected children have mental retardation, characteristic facial features, and often, heart defects and other physical problems.

Trisomy 18 (Edward syndrome): About 1 in 6,000 babies is born with trisomy 18, which is caused by an extra copy of chromosome 18 (10). Affected babies have severe mental retardation, heart defects and numerous other birth defects. Most die in the first year of life.

The risk of Down syndrome, trisomy 18 and other chromosomal problems increases with a woman's age. Until recently, ACOG recommended that providers offer women who are 35 years of age and older prenatal diagnostic testing (see below) with amniocentesis or chorionic villus sampling (CVS) to diagnose or, far more likely, rule out these disorders.

However, ACOG now recommends that providers offer these women the option of having a screening test to assess their risk before deciding whether or not to go ahead with amniocentesis or CVS (1). Both diagnostic tests pose a very small risk of miscarriage. It's important to keep in mind, however, that screening tests cannot definitively diagnose or rule out Down syndrome or other chromosomal birth defects, as amniocentesis and CVS can.

What diagnostic tests are recommended following an abnormal screening test result?
Women who have abnormal results on a first-trimester screening test should be offered genetic counseling and the option of CVS or second-trimester amniocentesis. CVS is usually done between 10 and 12 weeks of pregnancy.

During CVS, the provider obtains a small tissue sample from the placenta by placing a slim tube in the vagina or by inserting a needle into the woman's abdomen. The tissue sample is tested for Down syndrome and other chromosomal abnormalities. Some women with an abnormal first-trimester screen test result may be offered a special ultrasound examination called an echocardiogram to look for fetal heart defects.

For women with abnormal results on a second-trimester screening test, the next step often is an ultrasound examination. This test can check the gestational age of the fetus and show if a woman is carrying twins. If either of these factors accounts for the abnormal test result, no further testing is needed. If ultrasound does not explain the abnormal test result, the provider will recommend further diagnostic tests.

If the second-trimester screening test suggests an increased risk for Down syndrome or trisomy 18, the provider will offer a woman amniocentesis. This test is done at 15 to 20 weeks of pregnancy. The provider inserts a thin needle through the abdominal wall and into the uterus to withdraw a few teaspoons of amniotic fluid. Fetal cells in the fluid are tested for chromosomal abnormalities.

If second-trimester screening shows that a woman is at increased risk for having a baby with an NTD, her provider may recommend a detailed ultrasound examination (sometimes called a targeted, comprehensive or level II exam), amniocentesis or both.

A targeted ultrasound examination of the fetal skull, spine and other organs can quite accurately detect or rule out serious NTDs. It also may help predict the severity of NTDs. If this type of ultrasound is not available, or if more information is needed after an ultrasound examination, the provider often recommends amniocentesis to measure the level of AFP and another substance called acetylcholinesterase in the amniotic fluid.

When amniocentesis is done to help detect NTDs, cells from the fetus usually are tested for chromosomal abnormalities because they sometimes can accompany an NTD or an abdominal wall defect.

What are the benefits of maternal screening tests?
For most women, a screening test provides reassurance that their fetus does not appear to have certain serious birth defects. Test results also can help a woman manage her pregnancy more effectively. For example, finding the correct gestational age helps determine whether the fetus is growing at a normal rate. And detecting a multiple pregnancy allows for special care.

When an NTD or other problems are diagnosed or suspected, a woman can discuss all her options with her health care provider. She can plan for delivery in a specially equipped medical center so that the baby can have any surgery or treatment required soon after birth.
 
In some cases, there is no clear-cut explanation for an abnormal screening test result. Some abnormal results have been linked with pregnancy problems such as preterm labor, low birthweight and stillbirth (11).

If a woman has an unexplained abnormal screening test result, her provider may monitor her carefully in the last trimester of pregnancy. She may need more frequent prenatal visits and various tests of fetal well-being, such as ultrasound.

References

1. American College of Obstetricians and Gynecologists (ACOG). Screening for Fetal Chromosomal Abnormalities. ACOG Practice Bulletin, number 77, January 2007.

2. The Nuchal Translucency Education and Quality Review Program. Accessed 1/30/07, www.ntqr.org/.

3. Malone, F.D., et al. First-Trimester or Second-Trimester Screening, or Both, for Down's Syndrome. New England Journal of Medicine, volume 353, number 19, November 10, 2005, pages 2001-2011.

4. Reddy, U.M. and Mennuti, M.T. Incorporating First-Trimester Down Syndrome Studies into Prenatal Screening. Obstetrics and Gynecology, volume 107, number 1, January 2006, pages 167-173.

5. Norem, C.T., et al. Routine Ultrasonography Compared with Maternal Serum Alpha-Fetoprotein for Neural Tube Defect Screening. Obstetrics and Gynecology, volume 106, number 4, October 2005, pages 747-752.

6. American College of Obstetricians and Gynecologists (ACOG). Screening Tests for Birth Defects. ACOG Patient Education Pamphlet, April 2005.

7. Centers for Disease Control and Prevention (CDC). Birth Defects: Frequently Asked Questions. Updated 12/12/06.

8. Centers for Disease Control and Prevention (CDC). Folic Acid: PHS Recommendations. Updated 7/26/05.

9. Children's Hospital of Philadelphia. Your Child's Health. Accessed 12/14/06..

10. National Institutes of Health (NIH). Genetics Home Reference. Published 12/8/06.

11. Smith, G.C.S. Pregnancy-Associated Plasma Protein A and Alpha-Fetoprotein and Prediction of Adverse Perinatal Outcome. Obstetrics and Gynecology, volume 107, number 1, January 2006, pages 161-166.

January 2007