Prenatal Genetic Screening and Diagnosis

Posted By SHL Librarian

Presented by: Jane Cheuh, MD
Director, Prenatal Diagnosis and Therapy
Stanford University Medical Center
March 21, 2013

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Prenatal screening, including ultrasounds and blood tests, gives pregnant women an important heads-up on possible birth defects and allow women to make decisions about their pregnancy.  The most common test is for Down syndrome (trisomy 21), a condition in which an extra chromosome causes delays in the child’s mental and physical development. It affects about 1 in every 800 babies born in the United States.

Down syndrome and other chromosomal abnormalities are tested by chorionic villus sampling (CVS), which is done when the pregnancy is at 10 to 14 weeks. CVS involves taking a small sample of cells through the cervix. The main advantage of CVS is that it can be done earlier than an amniocentesis, which is generally done between 15 and 20 weeks.

Twenty years ago, the procedure was associated with a very small risk of miscarriage (1 percent) compared to amniocentesis (.5 percent), although the risk today is minimal when performed by an experienced physician, said Jane Chueh, MD, a clinical professor of maternal fetal medicine who practices at Stanford Hospital and at Packard Children’s Hospital. Dr. Chueh spoke at a presentation sponsored by the Stanford Hospital Health Library.

Prenatal screening should be done by women over age 35, since the risk of a chromosomal anomaly tends to be higher in older mothers. However since most mothers are under age 35, the majority of Down syndrome cases occur in younger women, so she advocates that all women should be screened early in their pregnancy.

“Age is only one factor,” she said. “Age 35 is an arbitrary number and is no longer the threshold for screening.”

Dr. Chueh said the average risk of Down syndrome for women age 35 is 1 in 380,, which is considered moderate. In comparison, the risk is 1 in 11 (high) in women age 49 or older; and is 1 in 667 (low risk) in 20-year-old women. First and second trimester screening tests are available through the state of California State. If the results show high risk, the state will pay for subsequent diagnostic testing

First Trimester Tests
Several tests are offered during the first trimester. A prenatal test called a nuchal fold scan, or NT, uses ultrasound to measure the space in the tissue at the back of the developing fetus’ neck. A fetus with an abnormality tends to accumulate more fluid at the back of the neck during the first trimester, causing the space to be larger than average. The NT scan must be done between 11.5 and 14 weeks of pregnancy. The result is combined with concurrent tests for PAPP-A (pregnancy-associated plasma protein A and free beta hCG.

“Increased NT is associated with chromosomal abnormalities, cardiac problems, and other fetal anomalies,” Dr. Chueh said. “But timing is important. Being off by even one day can throw it off, and if it’s done too early we may need to redraw blood or re-measure another day”

“Screening is not the same as a diagnosis. It’s important to realize that there are certain algorithms for these tests that consider detection rates and the chance of a false positive. Testing positive means there is a possibility of Down, but the test is not definitive,” she said.

Second Trimester Tests
Second trimester screenings, which are generally integrated with the first series of tests,  include a quad marker screen, a blood test for increased risk of Down syndrome and neural tube defects such as spina bifida. The quad screen is done between 15 and 20 weeks of pregnancy and can detect about 80 percent of fetuses affected by Down syndrome.

Ultrasounds may also detect soft markers which, while not necessarily an anomaly, may increase the statistical chances of chromosomal abnormalities. These markers include an enlarged nuchal fold, echogenic bowel, and short humerus or femur bones. Often these markers have no real impact on risk if the patient has a low risk to begin with, said Dr. Chueh, and may soon become obsolete with the advent of cell free DNA screening on maternal blood.

The Future of Screenings
While current diagnostic tests such as amniocentesis and CVS are reliable and readily available, they are invasive and carry a slight risk of miscarriage. The goal, said Dr. Chueh, is to identify a technique for noninvasive and accurate diagnosis.

That goal is closer, thanks to a new finding that assesses fetal DNA circulating in the mother’s blood. Minute amounts of free-floating DNA (CfDNA) from fragments of the placenta appear to increase with gestational age and completely disappear 48 hours after birth. Physicians are able to look at the DNA sequences of certain chromosomes and match them up to determine if the fetus is normal. If the counts run less or more than normal, there is a possibility of an  anomaly. Several companies now offer cfDNA tests.

The advantages to this approach over traditional screening tests are numerous, said Dr. Chueh, including a shorter wait time for results, a single blood draw, and an earlier window of opportunity for screening. Integrated first and second trimester screening results are available after six weeks and have a 90 percent detection rate; cfDNA tests have a 99.4 percent detection rate and take one to two weeks. They are also automated, which make them more consistent and less time-consuming.

There is a downside, however, she added. These tests are still new and are more expensive than standard tests, which are covered by the state. They test for only a few conditions and have a higher failure rate in which the tests are not able to get a result.

“The success of cell free DNA has opened up renewed interest in noninvasive prenatal diagnosis. The next step is finding intact fetal cells in maternal blood with no invasive procedure to the pregnancy,” Dr. Chueh says. “We are looking for strategies that are faster, cheaper, and more comprehensive than current screening tests, but more studies are needed.”

About the Speaker
Dr. Chueh is a clinical professor of obstetrics and gynecology and the director of Prenatal Diagnosis and Therapy in the Division of Maternal Fetal Medicine. She received her MD from the University of California, San Diego, did her internship and residency at University of Washington Medical Center, and did a fellowship at University of California, San Francisco. She is Board Certified in Maternal and Fetal Medicine and in Obstetrics and Gynecology by the American Board of Obstetrics and Gynecology.

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About Dr. Chueh

Maternal Fetal Medicine

Obstetrics & Gynecology


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