Seeing a fetus' future ills

Barbara Bernhardt led a Penn study of women's reactions to abnormal results from a new test.
Barbara Bernhardt led a Penn study of women's reactions to abnormal results from a new test.
Posted: November 21, 2012

The ability to find genetic problems before birth is undergoing a revolution that could expand prenatal testing while reducing the number of babies born with serious defects.

But it is also increasing the ranks of expectant parents who are left in limbo, their joy turning to dread, because their offspring has a DNA variant that is not yet understood.

"I started getting really panicky that the child I was carrying was going to be severely autistic with seizures and schizophrenia," said one such parent, interviewed for a University of Pennsylvania study of reactions to abnormal results. "I would look online and I met with a geneticist and talked to an autism specialist. And frankly, nobody could really tell me" how the child would be affected.

In less than five years, experts say, such dilemmas will be more common and complex because current obstacles to obtaining and analyzing fetal DNA will be overcome. Commercial tests now in development will be able to sequence the entire genetic blueprint of a fetus no bigger than a cranberry, using a mere blood sample from the pregnant woman, for $1,000.

This "noninvasive prenatal testing" will be able to find a growing list of potentially harmful genetic variants - few of them treatable. It will also detect susceptibilities to treatable problems such as cancer and diabetes, and propensities for devastating late-life diseases such as Alzheimer's, not to mention the unborn's sex and physical traits.

How will such genetic fortune-telling be regulated and used in medical practice? Will expectant parents receive counseling? What are the implications for privacy, disability rights, abortion?

No one really knows.

"There is an urgent need," University of California reproductive law expert Jamie S. King and colleagues wrote in a recent journal article, "for policymakers, regulators, and professional societies to provide guidance on the most efficient and ethical manner for such tests to be introduced."

Although prenatal testing goes back 40 years, technology has limited its scope.

Conventional blood tests and ultrasound imaging can screen for markers of Down syndrome and several other chromosomal disorders. But a definitive diagnosis requires an invasive procedure - amniocentesis or placental sampling - in which a needle or tube is put into the womb to extract fetal DNA. The DNA is then analyzed, or "karyotyped," under a microscope.

Less than 2 percent of American pregnancies - about 80,000 out of four million a year - undergo invasive prenatal diagnosis, which carries a small risk of miscarriage. Most of these women are older or have had a worrisome ultrasound.

A newer technology called chromosomal microarray analysis is making invasive testing more informative, if not more common.

Once a research tool, microarrays are now the basis of commercial tests that doctors can order and many insurers cover.

Microarrays identify deleted or extra fetal DNA that is far too tiny to be seen under a microscope. The DNA still has to be extracted from the womb, but it can be screened for more than 100 disorders - many so rare and obscure that their names are their genetic location, such as "2q35 microdeletion."

In February, the results of a national validation study of more than 4,000 fetal DNA samples confirmed that microarray sensitivity surpasses karyotyping. Microarrays identified all 371 abnormalities found by karyotyping - and many that the conventional test missed.

Of fetal samples from older women, about 2 percent had a flaw not found with the older technology. Of DNA from fetuses with physical defects seen on ultrasound, about 6 percent had genetic errors revealed by microarrays but not karyotyping.

Study leader Ronald Wapner, a maternal-fetal medicine specialist at Columbia University, declined an interview pending publication of the full study. But in a February news release, he said: "Why would anyone want to continue to use the standard method, which gives only part of the answer?"

Anyone with a choice probably would not want to, judging from the Penn study, led by genetic counselor Barbara A. Bernhardt. It interviewed 23 women who got abnormal microarray results in the national study.

All 23 originally agreed to the newer test because they could "get more information about their baby's health at no additional cost or risk," Bernhardt wrote.

Some, however, later regretted their decision. Those who got a normal karyotype followed by an abnormal microarray felt blindsided, despite having been counseled that it could happen.

Worse, about 1.6 percent of women with conflicting test results in the national study were told that the microarray finding was of "potential" but "uncertain clinical significance."

This information - Bernhardt called it "toxic knowledge" - led to anxiety, confusion, frustration, depression, and, in some cases, abortion. Eight women who opted to give birth admitted to ongoing worries, even after the baby appeared normal.

"The public expects that more certainty will accompany more technology," Bernhardt said. "But the opposite is true, particularly in genetics."

For all their power, microarrays scan only a tiny amount of the genetic code, or genome.

Experts are concerned about what will happen in three to five years, when the whole fetal genome - all three billion chemical pairs of DNA - can be analyzed affordably, rapidly, early in pregnancy, just by drawing blood from the pregnant woman.

Such a feat used to be unimaginable.

Consider that the Human Genome Project, completed in 2003, took 13 years and cost $3 billion. Now, whole genome analysis can be done in 10 days for about $5,000.

Over the last two years, leading academic labs have also proved that pieces of fetal DNA floating in the mother's blood can be used to reconstruct an entire fetal genome. (The discovery that maternal blood contains fetal DNA fragments is only 15 years old.)

Based on this advance, Sequenom Inc. and three other California companies recently began marketing noninvasive tests that screen for Down syndrome and a few other disorders.

Experts see these limited tests as a prologue to a growing portfolio of noninvasive prenatal prediction options with vexing ethical, legal, and clinical implications. Among them:

Genetic tests are being launched, with little oversight, under Medicare regulations that cover laboratory quality. The Food and Drug Administration has criticized this and said it would propose new rules, but after two years, it still has not.

People who reject prenatal testing, and people born with genetic conditions, may be stigmatized and devalued. "Is the unstated intention to promote the termination of affected fetuses?" asked Barbara Bowles Biesecker, a researcher at the National Institutes of Health.

Current privacy protections are inadequate. And some bioethicists point out that children may have an interest in not knowing results that could negatively affect their self-perception or goals.

The worst scenarios, while perhaps far-fetched, are as frightening as the movie Gattaca, about a world in which people are controlled according to their DNA.

"We could start to see pregnancy being thought of as being predicated on the results of prenatal testing," said King at the University of California. "The eugenics potential is quite high."

At a May conference, Stanford University bioethicist Hank Greely suggested that the revolution might even trump evolution:

"The world is changing in ways that may really, honestly change our species."

Contact Marie McCullough at 215-854-2720 or

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