Maternal Blood Test May Detect Trisomy in First Trimester‏

Laurie Barclay, MD

June 07, 2013

A noninvasive blood test for fetal cell-free DNA (cfDNA) reliably detects Down's syndrome (trisomy 21) and other genetic fetal abnormalities in the first trimester with fewer false-positives than combined testing, according to findings from 2 prospective studies published online June 7 in Ultrasound in Obstetrics & Gynecology.

"Analysis of [cfDNA] in maternal blood can detect more than 99% of cases of trisomy 21 for a false-positive rate...of about 0.1%," write Kypros Nicolaides, MD, from the Harris Birthright Research Centre for Fetal Medicine at King's College London, United Kingdom, and colleagues, in the study examining contingent cfDNA testing. "This is far superior to the best of the currently available methods of screening.... Consequently, there will be widespread uptake of cfDNA testing in routine clinical practice, either as a first-line method of screening or contingent on the results of the combined test at 11–13 weeks' gestation."

Combined testing using maternal age, fetal nuchal translucency thickness on ultrasound, maternal serum free β-human chorionic gonadotropin, and pregnancy-associated plasma protein A currently has a detection rate of about 90% and a false-positive rate of 5%. Definitive testing requires chorionic villus sampling (CVS) and amniocentesis, which are invasive and increase the risk for miscarriage.

In the first prospective study of routine cfDNA testing, M.M. Gil, also from the Harris Birthright Research Centre for Fetal Medicine, and colleagues enrolled 1005 women with singleton pregnancies attending the Fetal Medicine Centre in London between October 2012 and April 2013.

They found that cfDNA testing at 10 weeks detects trisomies 21, 18, and 13, provided a lower false-positive rate and higher sensitivity than combined testing at 12 weeks. Median maternal age was 36.7 years (range, 20.4 - 48.8 years). Suspected trisomies were confirmed by karyotyping after CVS, with the exception of a single case of trisomy 18 with normal karyotype and no evidence of abnormal features at 20 weeks by ultrasound.

The screen-positive rate on cfDNA testing was 1.7% compared with 5.0% for combined testing at the recommended risk cut-off of 1:100. Both testing protocols identified all trisomies, with an estimated false-positive rate of 0.1% for cfDNA and 3.4% for combined testing. However, the authors caution, abnormal results with cfDNA still require confirmation by CVS.

"This study has shown that the main advantage of cfDNA testing, compared with the combined test, is the substantial reduction in [false-positive rate]," the study authors write. "Another major advantage of cfDNA testing is the reporting of results as very high or very low risk, which makes it easier for parents to decide in favor of or against invasive testing."

Contingent cfDNA Testing

In the study evaluating contingent cfDNA testing, the same group of researchers analyzed 984 singleton pregnancies undergoing screening at 3 UK hospitals between March 2006 and May 2012. The investigators offered cfDNA testing to approximately 36% of cases detected by first-line screening with the combined test alone, 21% of cases detected by the combined test with the addition of serum placental growth factor and alpha-fetoprotein, and 11% of the cases detected by the combined test with the addition of serum placental growth factor, alpha-fetoprotein, and ductus venosus pulsatility index for veins.

Testing for cfDNA contingent on combined testing results at 11 to 13 weeks' gestation detected 98% of Down's syndrome cases. Less than 0.5% of cases required invasive testing for confirmation.

"Screening for trisomy 21 by cfDNA testing contingent on the results of an expanded combined test would retain the advantages of the current method of screening, but with a simultaneous major increase in [detection rate] and decrease in the rate of invasive testing," the study authors write.

Study limitations include reliance on certain assumptions regarding cfDNA testing and restriction of the findings to trisomy 21, which accounts for only half of the clinically significant aneuploidies associated with increased fetal nuchal translucency thickness.

"[T]herefore, invasive testing should be considered in the presence of high [fetal nuchal translucency thickness] even if screening suggests that the risk for trisomy 21 is low," the study authors conclude.

The Fetal Medicine Foundation supported these studies. The authors have disclosed no relevant financial relationships.

Ultrasound Obstet Gynecol. Published online June 7, 2013. Nikolaides full text, Gil full text


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