Noninvasive Prenatal Testing Excels at Finding Abnormalities

Neil Osterweil

March 07, 2015

LA JOLLA, California — Noninvasive prenatal testing is so good at ruling out certain fetal abnormalities that rates of more invasive procedures have plummeted.

This "is the biggest clinical implementation of genomic medicine to date," Diana Bianchi, MD, executive director of the Mother Infant Research Institute at Tufts Medical Center in Boston, said here at the Future of Genomic Medicine VIII.

"We're in the middle of a real-time revolution in prenatal care that affects not only clinical care, but training as well. I have fellows at my hospital who tell me, 'I never get to do an amniocentesis, and it's your fault!' " she said.

Since October 2011, when noninvasive testing first became available, more than 1 million screens have been performed around the world. At the same time, there has been a 79% decline in the use of amniocentesis and a 69% decline in the use of chorionic villus sampling.

The sequencing of cell-free DNA in maternal plasma, in addition to being noninvasive, apart from a needle stick, has a high level of sensitivity and a remarkably low rate of false-positive results.

Circulating cell-free DNA comes primarily from bone marrow, but it can also come from a malignant tumor. And, in pregnant women, circulating cell-free DNA from the fetus comes from the placenta, said Dr Bianchi.

"When we take a sample from a pregnant woman, which ideally is not before 9 or 10 weeks of gestation, it is 90% maternal cell-free DNA and 10% fetal cell-free DNA," she explained. As gestation progresses, the proportion of fetal cell-free DNA increases, "so the test actually gets better as you get closer to delivery."

As a result, massive parallel sequencing can be performed on the sample without isolating fetal from maternal DNA.

Just a Screen

Although noninvasive prenatal testing is a very good screen, it is not diagnostic. When chromosomal duplication or aneuploidy is detected in a sample, a diagnostic workup is still required, Dr Bianchi explained.

"It can't be diagnostic for the fetus. We're not really assaying the fetal nucleic acids; we're assaying a mix of placenta and mother," she said.

Nonetheless, the screen has a high detection rate for common fetal abnormalities such as trisomy 21 in Down's syndrome; trisomy 18 in Edwards syndrome, which is characterized by low birth weight and congenital heart defects; and trisomy 13 in Patau syndrome, which is associated with heart defects, microphthalmia, polydactyly, cleft lip, hypotonia, death in the first days or weeks of life, and abnormalities of the central nervous system, brain, or spinal cord.

Table. Accuracy of Noninvasive Prenatal Testing

Chromosomal Abnormality Detection Rate, % False-Positive Rate, %
Trisomy 21 99.2 0.90
Trisomy 18 91.0 0.13
Trisomy 13 90.3 0.23


In its guidelines for noninvasive prenatal testing, the American Congress of Obstetricians and Gynecologists (ACOG) recommends offering cell-free DNA testing as a routine alternative to invasive procedures for women at high risk because of advanced maternal age, family history, or other known risk factors.

Although the benefits of noninvasive testing have been established for women at high risk, the picture is less clear for the general population, Dr Bianchi pointed out.

The false-positive rate of 0.2% has led to some concern that a woman with a positive result might choose to terminate her pregnancy without confirming the result with an invasive diagnostic test.

"That's actually a very, very small fraction of cases," said Dr Bianchi. "I think most of the women, if they meet with a geneticist or genetic counselor, are advised that the tests are not diagnostic." She said she prefers to look at it from a different perspective: the testing provides accurate information on maternal and fetoplacental biology in most cases.

Differential diagnoses for false-positive results include confined placental mosaicism, co-twin demise, mosaic maternal chromosome abnormality, a maternal medical condition, maternal organ or bone marrow transplant, and laboratory error.

Dr Bianchi and colleagues analyzed 35 false-positive results in assays for sex chromosomes. The majority were related to maternal sex chromosome abnormalities, she reported. In the case of monosomy X for Turner syndrome, 34 of the false-positive results were related to the age-related loss of an X chromosome in the blood cells of older mothers. In 12 cases of a false-positive result for the 47,XXX abnormality, the fetus turned out to have a normal 46,XX karyotype.

"This is teaching us about new biology, and giving us an appreciation that women with 47,XXX can actually have normal fertility, she said.

Optimizing Baby's Brain Development

The goal for the future, Dr Bianchi said, will be to treat the fetus. For example, for the 40% of American women who opt to carry their pregnancies to term after a diagnosis of trisomy 21, a drug might be able to influence and optimize fetal brain development.

The ACOG recommends providing the patient with incidental findings on 56 genes detected during genomic sequencing, although similar recommendations do not necessarily apply to noninvasive testing, said session moderator Ali Torkamani, PhD, from the Scripps Translational Science Institute in La Jolla, California.

But "where do you draw the line in terms of what's an incidental finding and what's a finding that should be returned in a noninvasive screen?" he asked. "We know that the resolution of these assays is going to get down to the point where you're looking at single-gene events."

Dr Bianchi explained that testing cannot drill down to the DNA base-pair level and is not ready for primetime as a full genomic sequencing tool. And she pointed out that consent forms currently required for testing do not mention findings other than fetal aneuploidy.

"How to handle incidental findings related to testing is a pressing issue. To my knowledge, it hasn't been handled at all by any of the professional societies yet, because this has all been happening in real time," she said.

Dr Bianchi reports receiving honoraria and research funding from Illumina. Dr Torkamani reports financial ties to Cypher Genomics and Sorrento Therapeutics.

Future of Genomic Medicine (FoGM) VIII. Presented March 5, 2015.


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