Screening for Trisomies 18 & 21

First Trimester Screening for Trisomies 21 (Down's Syndrome) and 18

What is the problem, and what is known about it so far? 
Trisomy occurs when an embryo is formed with three of a particular chromosome (Chromosomes are long pieces of DNA contained in the nucleus of cells) instead of the usual two or occasionally, with two of the chromosomes and an extra piece of the same chromosome.  Trisomy 21 is also known as Down's syndrome. Children with Down's syndrome typically have characteristic facial features and mental retardation, about one-third of them will be born with a heart defect and all have an increased risk for leukemia.  Trisomy 18 results in characteristic facial features, heart defects, and distinctive deformities of the hands and feet but it is unusual for these infants to survive for more than a few months after birth.  Approximately 1 in 800 live-born infants will have Down's syndrome and 1 in 7500 will have Trisomy 18.  Both of these disorders are more common in infants born to women older than 35 years of age.  Currently, screening for Down's syndrome and Trisomy 18 is done after 15 weeks of pregnancy.  The risk that Down's syndrome or Trisomy 18 will affect an individual woman's pregnancy can be estimated by screening.  At present, risk estimates are made using the age of the woman and the results from a blood test that measures the levels of three substances found during pregnancy (alpha-fetoprotein, human chorionic gonadotropin (hCG), and unconjugated estriol). However the blood tests are not useful until the second trimester of pregnancy.

Why did the researchers do this particular study?
The investigators wanted to see if blood tests for other substances (pregnancy-associated plasma protein A and beta-hCG) that can be found in the first trimester, along with the measurement of the neck-thickness of the fetus using an ultrasound machine, would allow Down's syndrome and Trisomy 18 to be determined in the first-trimester.

Who was studied?
Screening was done on 8,514 women whose average age at time of expected delivery was 34.5 years. Each woman had a single fetus with a gestational age of 74 and 97 days at the time of screening. 102 of the women had previously had a pregnancy affected by Down's syndrome or Trisomy 18.  8,216 (96%) patients were used in the main analysis.

How was the study done?
Patients were given blood tests and had an ultrasound test. The statistical risk for each woman in the study was calculated using a series of mathematical formulas from her age and the results of her blood test and ultrasound.  The women were then followed to the end of their pregnancies, whether they ended by miscarriage, induced abortion, or the birth of an infant to see if the pregnancy produced a fetus affected by Down's syndrome or Trisomy 18.  A screening test was considered to be positive for Down's syndrome if the calculated risk was at least 1 in 270 and for Trisomy 18 if the risk was 1 in 150.

What did the researchers find?
Using the combination of blood tests and ultrasound, screening identified about 85% of the cases of Down's syndrome in the group of women studied.  Approximately 9% of the time, women who had a positive screening result with this approach actually did not  have a pregnancy affected by Down's syndrome.  This is known as the false-positive rate of the test. Screening of women 35 years or older, identified about 90% of the pregnancies affected by Down's syndrome but there was a 15% false positive rate in this group. This approach also identified about 91% of the cases of Trisomy 18 that occurred in the study group with only 2% having a false positive result. Among women 35 years or older, this approach identified 100% of pregnancies affected by Trisomy 18.

What were the limitations of the study?
The accuracy of ultrasound measurements varies with the body shape of a given patient and the magnification, resolution and contrast in the images formed, all of which affect the clarity of the image. In addition to these factors, the varied interpretations of the images by different ultrasonographers (the person who reads the ultrasound) and the fact that the difference between a positive test and a negative test is very small will make it difficult to get results as reliable as those obtained in this study in other settings. Additionally, greater neck-thickness of fetuses has been associated with other genetic abnormalities, irregularities of chromosome number, and heart defects. 

What are the implications of the study?
First trimester screening based on the mother's age and the results of a blood test and ultrasound can identify a large percentage of pregnancies affected by Down's syndrome or Trisomy 18, and has a reasonably low rate of incorrectly identifying unaffected pregnancies as being affected.  Effective first-trimester screening could allow women more privacy, could provide earlier reassurance about the health of a fetus, and the option of termination of pregnancy would be available at an earlier, safer point.  However the results of this study alone do not provide enough evidence that first-trimester screening is significantly better than second trimester screening or that changes to the present practice should be introduced at this time.  Other studies currently in progress should help to shed more light on this issue.

Summarized by Shine Gentler, College of Medicine, University of Vermont.
Summarized from "First-Trimester Screening for Trisomies 21 and 18."  Wapner, R. et al.  New England Journal of Medicine, October 9, 2003, Volume 349, Number 15, Pages 1405 -1413.