Cell-Free Fetal DNA Testing Warrants Caution, Committee Says

Ricki Lewis, PhD

July 03, 2015

The Committee on Genetics of the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine has released an opinion on the "advantages and limitations" of cell-free DNA screening for fetal aneuploidy in the general obstetric population, published online June 26.

"We have tried to produce guidelines for reasonable application of the screen, underscoring that more information can be gained from conventional screening," Nancy C. Rose, MD, director, Reproductive Genetics, Intermountain Healthcare; professor of obstetrics and gynecology at the University of Utah, Salt Lake City; and a member of the committee that drafted the opinion, told Medscape Medical News.

The new opinion extends one from 2011 that targeted fetuses at elevated risk for aneuploidy. Risk factors are maternal age 35 years or older, ultrasound findings consistent with aneuploidy, family history of trisomy or balanced Robertsonian translocation of chromosome 13 or 21 that could generate a trisomy, and positive maternal serum marker screening results.

From 3% to 13% of cell-free DNA in the circulation of a pregnant woman comes from the fetus. Sequencing DNA fragments can reveal the extra representation of DNA from a trisomy.

Studies conducted since 2012 indicate that the sensitivity and specificity of cell-free fetal DNA screening are similar in the high-risk and general obstetric populations. However, positive predictive value is lower in the general group because the prevalence of aneuploidy is so much lower. The American Congress of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine has encouraged laboratories to report results with positive predictive values (probability that a positive is a true positive) as well as residual risk values (probability that a negative is truly negative) for each result that indicates increased risk for aneuploidy.

False-positives can arise from placental mosaicism; maternal malignancy; maternal chromosomal duplication; multiple gestation, including a vanishing twin; use of a donor egg; consanguinity; and bone marrow transplant. False-negatives are much rarer than false-positives, but can arise for a triploid fetus.

Another issue with cell-free fetal DNA screening is the fetal fraction, which should exceed 4% to generate accurate results, according to most laboratories. "Screen failures" occur in 1% to 8% of samples and may also be reported as "no call," "indeterminate," or "uninterpretable." Up to 23% of women who receive these questionable results carried aneuploid fetuses. Repeating the screen yields results in only 50% to 60% of cases.

"Patients must realize that if they do not get a result — a 'no call' — this may be an indication that they are at higher risk for a chromosomal abnormality, and they may opt for invasive testing," Susan Klugman, MD, director, reproductive genetics, and professor of clinical obstetrics and gynecology and women's health at Montefiore Medical Center/Albert Einstein College of Medicine told Medscape Medical News. Montefiore offers the screen to all obstetric patients, who can opt to see a genetic counselor, a geneticist, or a maternal fetal medicine specialist. Obstetric providers are trained to counsel patients about the risks, benefits, and alternatives of all genetic screening options, Dr Klugman added.

Cell-free fetal DNA analysis has other limitations: It cannot reliably detect microdeletions, and for multiple gestations, it provides an overall reading, not results corresponding to individual fetuses.

The technology also does not distinguish between sporadic nondisjunction and an unbalanced rearrangement as the source of a trisomy. Because these scenarios carry different recurrence risks, the distinction is crucial for genetic counseling. "Only a diagnostic test can tell if the aneuploidy is due to an inherited condition such as a translocation," Dr Rose said.

Not for Neural Tube Defect Screening

Cell-free fetal DNA is not an appropriate screen for neural tube defects. Therefore the committee opinion advises concomitant maternal serum alpha-fetoprotein screening or ultrasound evaluation for risk assessment.

All abnormal ultrasound findings should be followed up with diagnostic (invasive) testing. "An 11- to 13-week ultrasound, done to look for nuchal translucency as part of first trimester screening, is incredibly valuable and can often pick up anomalies," Dr Klugman said.

The opinion advises against parallel testing with multiple screening techniques for aneuploidy, which would not be cost-effective. It also advises genetic counselors to inform patients that cell-free fetal DNA analysis at present only returns results for trisomies 13, 18, and 21, and with some companies' products, the X and Y. To avoid the use of sex selection screening for nonclinical reasons, the opinion advises withdrawing the offer to screen if the patient claims to want information only on the sex chromosomes.

The decision to terminate a pregnancy for medical reasons should not rely solely on cell-free fetal DNA analysis, the opinion cautions. Instead, positive findings must be followed up with a confirmatory diagnostic procedure, preferably amniocentesis. This echoes a recent statement from the American Society of Human Genetics and the European Society of Human Genetics.

The opinion continues, "Given the performance of conventional screening methods and the limitations of cell-free DNA, conventional screening methods remain the most appropriate choice for first-line screening for most women in the general obstetric population."

It concludes, "A discussion of the risks, benefits, and alternatives of various methods of prenatal screening and diagnostic testing, including the option of no testing, should occur with all patients."

A major benefit of cell-free fetal DNA screening is that it can identify women whose risk of having an aneuploid fetus is too low to justify invasive procedures. However, those approaches may be around for some time. "We have had a decrease in the number of invasive procedures, but I do not believe it will replace invasive testing just yet, as it does not provide coverage for all chromosomes," said Dr Klugman.

The authors and commentators have disclosed no relevant financial relationships.

"Cell-free DNA Screening for Fetal Aneuploidy." American Congress of Obstetricians and Gynecologists/Society for Maternal-Fetal Medicine. Published online June 26, 2015. Full text

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