May 31, 2007

Screening for Aneuploidy: What Are the New Recommendations?

By Deborah Levenson

Historically, maternal age—35 or older—has determined whether obstetricians offer their pregnant patients diagnostic testing or second trimester screening for Down syndrome, trisomy 18, and other fetal chromosomal abnormalities. But a recent practice bulletin from the American College of Obstetricians and Gynecologists (ACOG) endorses routinely offering first trimester screening diagnostic testing, regardless of age. This issue of Strategies reviews those recommendations, and what laboratorians should consider as obstetricians adopt them.

Second trimester amniocentesis and first trimester chorionic villus sampling (CVS) both offer excellent diagnostic accuracy to obstetricians and pregnant women who want to know whether a fetus has Down syndrome. But both tests carry a risk of miscarriage. In 1984, a finding that low maternal serum alpha-fetoprotein (AFP) is associated with Down syndrome ushered in the era of biochemical screening for chromosomal disorders. Since then, discovery of other screening markers including nuchal translucency measurement (NT)—an ultrasound exam that measures the thickness at the back of the neck of the fetus—and the serum markers human chorionic gonadotropin (hCG) , and pregnancy associated plasma protein (PAPP-A) have led to various screening strategies and algorithms that allow less invasive, earlier screening.

A January 2007 ACOG practice bulletin reviews these options, and rejects maternal age as a reason to offer them. “Age is all we had back in the 1970s. By itself, it has a detection rate of only about 30%. But now biochemistry by itself or combined with ultrasound gives us 80% to 90% detection, so it doesn’t make sense to use age anymore,” explained Deborah Driscoll, MD, lead author of the ACOG practice bulletin and Professor and Chair, Department of Obstetrics and Gynecology, University of Pennsylvania in Philadelphia. “Amniocentesis and CVS are safer now than in the past,” she pointed out, adding that a forthcoming document will explain ACOG’s new recommendation regarding diagnostic tests and discuss newer technology including comparative genomic hybridization and fluorescent in situ hybridization.

While ACOG does not recommend a specific protocol, research data presented in the bulletin “make clear that if a woman presents by 10–11 weeks of pregnancy, she should optimally be offered a screening strategy that encompasses both first and second trimester tests,” explained Jacob A. Canick, PhD, Professor of Pathology, Brown Medical School and Director of the Division of Prenatal and Special Testing in the Department of Pathology at Women and Infants Hospital, Providence, R.I.

Screening Approaches

The ACOG bulletin discusses the advantages and disadvantages of various screening strategies with the goal of having obstetricians offer screening tests with high detection rates and low false-positive rates, and diagnostic testing options if screening tests indicate patients have increased risk for having a child with Down’s syndrome.

The bulletin points out that combined first and second trimester screening offers better detection rates than first trimester screening alone. The integrated approach (first trimester NT and PAPP-A plus the second trimester quadruple screen including AFP, hCG, unconjugated estriol, and inhibin A) provides the highest sensitivity at 94–96%, with about a 5% false positive rate. However, NT is not available to all women. The bulletin also cites research showing that integrated screening minus NT has an 85–88% detection rate and an approximately 5% false positive rate and calls serum-only integrated testing “ideal” for patients without access to NT measurement. However, the disadvantages of the integrated approach include a long wait for results and lack opportunity to consider CVS in the first semester.

Sequential screening may diminish some of the downsides of the integrated approach. In this strategy, patients learn their first trimester screening result, and those at highest risk may opt for early diagnostic procedures and those at lower risk can still take advantage of the 95% detection rate with additional second-trimester screening.

The first trimester “combined” screening approach—incorporating NT, PAPP-A and beta hCG—has shown relatively high detection rates, ranging from 82–87% in large trials, that are comparable to the second trimester quadruple screen for women younger than 35. For women ages 35 and older, the combined approach’s detection rate is about 90%, but with higher false-positive rates of about 16–22%, the bulletin notes. First trimester NT alone has a lower detection rate—up to 76.8%—plus a false-positive rate ranging from 4.2% to 5%, and may be useful in the first trimester of multifetal gestations. That’s because serum screening isn’t as accurate for twins and is unavailable for pregnancies involving three or more fetuses, according to the bulletin.

The practice bulletin does not specifically recommend certain tests over others because some, like NT, are not widely available, Driscoll noted. “Women in Philadelphia may have access to a test that’s not available in North Dakota. For NT measurement and CVS, it’s an issue of training and a limited number of specialists who are available to perform these tests.” She also noted that the bulletin urges labs to report screening test results in terms of numerical risk rather than using an arbitrary cutoff and reporting results as positive or negative. While the fixed cutoffs are valuable in public policy discussions, Driscoll explained that an arbitrary cutoff used on the clinical level could mean that some patients with Down syndrome pregnancies are told otherwise.

Implications for Laboratorians

Lab directors should keep an eye on which tests obstetricians order and prepare for possible changes, recommended Ann Gronowski, PhD, Associate Professor at Washington University School of Medicine in St. Louis, Mo. Recommendations for first trimester PAPP-A and beta HCG tests could increase volume of these tests, while offering diagnostic testing to all women could lead to more amnioscentesis and CVS, she pointed out. In addition, a lab that normally doesn’t handle the first trimester screening tests like PAPP-A will need to decide whether to send them to a reference lab because both first and second trimester testing should be done at the same laboratory.

About two-thirds of pregnant women now get screening tests, according to Canick, but he could not predict whether the new recommendations would actually increase the volume of particular tests or aneuploidy screening in general. “But the guidelines’ discussion of more markers for Down syndrome means that labs should prepare to handle more types of screening tests,” he noted.

Recommendations regarding NT could make work much more complicated for lab staff. Labs that participate in both the integrated and first semester combined screening approaches will be responsible for using a measurement they have not made to determine a risk calculation for obstetricians, Canick pointed out. Calling this situation a “new and daunting challenge,” he noted that lab staff must normalize the NT measurement they have not made by converting it to a multiple of the median (MoM) and then use the NT MoM to calculate risk.

“Now more than ever, lab staff needs training on markers for Down syndrome and what the guidelines say about them,” Canick said. He added that although the College of American Pathologists (CAP) offers a proficiency testing survey for markers including AFP, unconjugated estriol, hCG, and inhibin A, CAP does not offer a product that assesses labs’ ability to handle first trimester serum markers or NT data and incorporate them into a risk assessment. Women and Infants Hospitals’ Interlaboratory Comparison Program for First Trimester Markers offers a survey “that complements and extends what CAP does,” Canick said.

Canick holds patents on the use of unconjugated estriol in prenatal screening and is a paid consultant to Beckman Coulter Diagnostics, which makes kits used to measure many of the markers discussed in this article.


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