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Vol. LXVII, No. 6
March 13, 2015

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Prenatal Testing Revolutionizing Fetal Care

On the front page...

Dr. Diana Bianchi at NIH
Dr. Diana Bianchi at NIH
Recent advances in prenatal testing are transforming diagnosis and treatment of genetic conditions. A growing number of pregnant women are benefiting from a newer kind of noninvasive prenatal testing (NIPT) that analyzes cell-free fetal DNA circulating in the maternal blood. This blood test, which first became clinically available in 2011, can detect with great accuracy a range of aneuploidies (fetal chromosomal abnormalities) such as trisomy 21 (Down syndrome). These advances also are paving the way toward treating Down syndrome and other aneuploidies while the baby is still in the womb.

“We now can infer functional information about the developing brain in living fetuses,” said reproductive geneticist Dr. Diana Bianchi, whose research has had a dramatic impact on NIPT and opportunities for new fetal therapies. “That hasn’t been done before because most information about fetal gene expression is done post-mortem.”


Bianchi, executive director of the Mother Infant Research Institute at Tufts Medical Center and professor of pediatrics, obstetrics and gynecology at Tufts University School of Medicine, spoke at the NICHD Director’s Lecture in Lipsett Amphitheater recently.

NIPT is a blood test currently offered to women with high-risk pregnancies—due to advanced maternal age or previous pregnancy complications—as early as 10 weeks and up until delivery. The test screens for chromosomal disorders—primarily for trisomy 21 and trisomies 18 and 13—using massive parallel sequencing of cell-free DNA from the mother’s blood.

“One of the reasons the testing has become so rapidly incorporated into care is that the detection rate, the sensitivity, is excellent,” said Bianchi.

If the NIPT screens positive for aneuploidy, further testing is recommended to confirm the diagnosis. NIPT is so reliable that, if results are negative, it precludes the need for invasive diagnostic tests such as amniocentesis or chorionic villus sampling. In fact, there’s been a dramatic decline in such invasive testing since NIPT was introduced.

Prior to modern-day prenatal screening, Down syndrome was diagnosed by pelvic x-rays in the affected infant. In the early 1970s, it became possible to physically isolate fetal cells from the blood of pregnant women when Bianchi’s lab mentor, Dr. Leonard Herzenberg, invented a cell sorter called the flow cytometer. Herzenberg, who had a son with Down syndrome, had challenged Bianchi—then a pre-doctoral scholar—to develop a noninvasive prenatal genetic test for the syndrome. Soon after, her research revealed that fetal cells could be detected in the mother’s blood.

From 1994 to 2004, in the NIFTY trial—one of the first NIH-funded clinical trials toward developing improved NIPT—Bianchi and her co-investigators isolated intact fetal cells from maternal blood and detected a higher number of fetal cells in aneuploid pregnancies. This sparked interest from industry and, as technology improved and costs decreased, advanced prenatal sequencing became a reality.

Bianchi and her team are identifying and analyzing biomarkers for changing physiology in utero and targeting pathways for treatment.

Bianchi and her team are identifying and analyzing biomarkers for changing physiology in utero and targeting pathways for treatment.

Photos: Ernie Branson

“Though progress has been largely achieved through industry support,” said Bianchi, “the NIFTY trial and NICHD support really provided a foundation upon which a lot of the later work came.”

Current research holds great promise for developing novel fetal therapies for Down syndrome. Bianchi and her team are identifying and analyzing biomarkers for changing physiology in utero and targeting pathways for treatment.

“Down syndrome is our first target because it’s the most common of the conditions,” said Bianchi. If Down syndrome is detected at the end of the first trimester, “that would give us a 28-week window of time to treat the mother and influence fetal brain development.”

Children with Down syndrome have an observable phenotype, said Bianchi. Researchers have found a consistent pattern of gene expression in the amniotic fluid supernatant of fetuses with Down syndrome. A major abnormality present in affected fetuses is oxidative stress, which induces mitochondrial dysfunction.

“Our hypothesis is that if we treat oxidative stress in utero, we will improve neurogenesis and brain morphogenesis at a time when the brain is actively developing,” said Bianchi.

One drug already in testing is apigenin, a potent antioxidant currently used in human clinical trials for Alzheimer’s that’s been shown to inhibit oxidative stress. The drug has shown improved memory and exploratory behavior in prenatally treated adult mice and, so far, no toxic effects on human cell proliferation.

“The hope would be that treatment would improve brain growth so that there would be the opportunity for these cells to be rescued and the important normal connections could be made within the brain,” said Bianchi.

Improved prenatal screening in the first trimester has led to earlier, more reliable diagnoses of aneuploidies and has created new opportunities for developing fetal individualized therapies.

“The future vision is that a woman would have a prenatal diagnosis of Down syndrome either via ultrasound, amniocentesis or noninvasive prenatal testing and if she chooses to continue her pregnancy, she could then choose to have fetal treatment,” said Bianchi. “She herself would take a drug for fetal benefit and then ideally there’d be an improved outcome.”

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