Screening for Birth Defects During Pregnancy

(Must read before attending genetic counseling clinic day)

What is prenatal diagnosis?
Some structural birth defects can be diagnosed by targeted ultrasound. Chromosomal defects (and some other genetic diseases) can be diagnosed by invasive tests, such as chorionic villus sampling (CVS) usually at 10-13 weeks gestation, or amniocentesis (at > 15 weeks gestation). Invasive testing carries some risk for pregnancy loss or complications and is optional.

What is prenatal screening?
Prenatal screening tests are non-invasive tests that calculate the risk for a birth defect to be present in a pregnancy based on a variety of factors, including maternal age, analyte levels in maternal blood, and sometimes specialized ultrasound measurements.
Most women choose to begin with screening tests to further evaluate their personal level of risk for birth defects, before deciding whether or not to pursue diagnostic testing.

Why is it important to be familiar with these screening tests?
In 2007, the American College of Obstetricians and Gynecologists (ACOG) stated that all pregnant women who present for prenatal care prior to 20 weeks gestation should be offered prenatal screening for Down syndrome. Therefore, physicians who work with pregnant women or women of reproductive age should have a basic level of knowledge regarding these tests.

What are the conditions that screening tests are calculating a risk for?
Prenatal screening is currently available for trisomy 21 (Down syndrome), trisomy 18 (Edward's syndrome), trisomy 13 (Patau syndrome) and open neural tube defects (spina bifida).

What are the different screening tests that are currently available?
There are a number of new screening tests that have become clinically available over the past few years, making a complete list of screening options difficult to summarize. The most widely available and commonly performed tests will be reviewed here, the quad (quadruple) screen and first trimester screening.

Quad screen:

The quad screen is performed in the second trimester of pregnancy, typically between 15-20 weeks gestation. The quad screen analyzes four analytes in maternal blood: alpha-fetal protein (AFP), human chorionic gonadotropin (hCG), unconjugated estriol (μE3), and inhibin-A.
Using different factors including gestational age and maternal weight, the levels of each of these analytes is converted into a multiple of the median (MOM), with 1.0 MOM being the normal level. For example, if the AFP level was 0.5 MOM, then the level of AFP present in the woman's blood was half of the expected level.
The MOM values are used to calculate a risk for Down syndrome, trisomy 18 and open neural tube defects based in the pattern present (see chart).
If the risk for a pregnancy to have one of these conditions is elevated above a lab determined cut-off, then the test is considered a “screen positive” result, meaning that an increased risk for the condition to be present in the pregnancy was calculated by the quad screen.

Increased Risk For:	AFP	hCG	uE3	Inhibin A
ONTD	↑	-—	——	——
Down Syndrome	↓	↑	↓	↑
Trisomy 18	↓	↓	↓	——

First trimester screen

First trimester screening is performed in the first trimester of pregnancy, typically between 11-13 weeks gestation. First trimester screening analyzes two analytes in maternal blood, free beta human chorionic gonadotropin (free bhCG) and pregnancy associated plasma protein A (PAPP-A). It also uses an ultrasound measurement of the fluid on the back of the fetal neck called a nuchal translucency. (A nuchal translucency measurement is a technically difficult measurement to obtain, therefore can only be performed by those technicians who have obtained nuchal translucency measurement certification.)
Using different factors including gestational age and maternal weight, the levels of each of these analytes is converted into a multiple of the median (MOM), with 1.0 MOM being the normal level.
The MOM values along with the nuchal translucency measurement are used to calculate a risk for Down syndrome and trisomy 18 and trisomy 13 (see chart).
If the risk for a pregnancy to have one of these conditions is elevated above a lab determined cut-off, then the test is considered a “screen positive” result, meaning that an increased risk for a condition to be present in the pregnancy was calculated by the first trimester screen.

Increased Risk For:	β hCG	PAPP-A	NT
Down Syndrome	↑	↓	↑
Trisomy 18/13	↓	↓	↑

What is the detection rate and screen positive rate for these tests?
Both the quad screen and the first trimester screen have a 5% screen positive rate. The quad screen detects 85% of pregnancies with spina bifida, 75-80% of pregnancies with Down syndrome and 60% of pregnancies with trisomy 18. The first trimester screen detects 85-90% of pregnancies with Down syndrome and 90% of pregnancies with trisomy 18 and 13.
In addition, a significantly increased NT measurement may also signify other chromosome abnormalities or structural defects such as congenital heart disease.

What should patients know about screening tests in order to make a decision about whether or not to pursue screening?
Patients should be informed that screening is optional, and available if they would like to know if they are at an increased risk to have a baby with Down syndrome or another chromosome abnormality. They should also be informed that having a negative test result does not exclude the possibility of Down syndrome. Also, a positive result does not mean that the baby has Down syndrome, but they would be offered further testing. If they are sure they would not want further (invasive) testing in the event of a positive screen, they may not want to have the screening test, as it can induce stress during the pregnancy and is not diagnostic. However, some patients who state they would continue an abnormal pregnancy may still wish to know the genetic status of their baby prenatally and would use the screening test to help them decide about invasive testing. Although there is no cure for a chromosome abnormality, some patients benefit from some time to prepare emotionally or medically for the birth of a child with special needs. Women who will be over 35 years of age at the time of delivery or who have a family history of birth defects or chromosome abnormalities may benefit from speaking with a genetic counselor regarding options for testing during pregnancy.

If a patient has a normal first trimester screen, should a quad screen be ordered? Or if a quad screen is positive, can it be repeated?
Screening should only be performed once in a pregnancy. A positive screening test should be followed by a diagnostic test (like an amniocentesis or a chorionic villus sampling), but not by another screening test. If a woman has a first trimester screen, she should be offered an AFP only (MSAFP) level in the second trimester to screen for open neural tube defects.

Is one screening test better than another?
Both the quad screen and the first trimester screen have been studied extensively, and their validity has been proven. First trimester screening has a slightly better detection rate than quad screening, and patients with a positive result may have the option of earlier diagnosis testing such as a chorionic villus sampling. However, not all insurance companies cover the cost of first trimester screening. Also, there are some instances where a suitable nuchal translucency measurement cannot be obtained or a woman will present to prenatal care after 13 weeks gestation, in which case a quad screen would be appropriate.

What about women over 35? Are these tests valid or helpful for them?
Women over 35yo should be offered diagnostic testing first. If they decline, they should be offered screening testing, in order to better evaluate their personal risk.

While it is true that women over 35 are predisposed to have a positive result, it should be explained to them that the patient is considered “positive” (or high-risk) before they take the test. Adding additional data points (in addition to her age) to further delineate her personal risk for aneuploidy is often helpful as she considers diagnostic testing. In addition, targeted ultrasound alone is limited (especially in detecting Down syndrome) when evaluating for aneuploidies. Most laboratories provide pre-and post- test risk estimates in order to put the results into context.

OTHER NOTES:

These tests depend greatly on accurate demographic information. Results can be recalculated using the original blood sample, if changing a data point such as gestational age at the time of the blood draw.
Other variations to these screening tests: There are other permutations to the above-described screening tests available at other centers, including the “integrated screen” which combines the dates from first trimester screening and quad screening but does not provide results until after both are performed; and the “sequential screen,” which provides a result after each test is performed. There is some data to suggest these may help increase detection rate above the first trimester screen alone. However, there is currently no national consensus regarding this issue. In addition, variations on the analytes described in this paper have been used by different laboratories, such as total beta hCG instead of free-beta hCG (which is currently patented).
All diagnostic and screening tests for birth defects are optional. The correct way to think about this process is that the patient is offered any may elect to pursue or decline testing, rather than the traditional concept of recommending and refusing. Of course, benefits, risks, and limitations of test options should be discussed thoroughly with the patient before she makes her decision.

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