The New York Times, March 12, 2006
A Wrongful Birth?
By ELIZABETH WEIL
Like most American women who give birth to a severely handicapped child, Donna Branca
became pregnant with A.J. well before the age of 35. Had she been older, her doctors would
almost certainly have recommended amniocentesis to screen for genetic disorders. But she was
31, so they did not, despite the fact that she had an unusual pregnancy. Branca bled during her
first trimester, a possible indication of birth defects, and at her midterm sonogram, when she was
20 weeks pregnant, her fetus looked smaller than it should have based on when her doctors
originally presumed she conceived. Branca had not gained much weight, either, but her doctors - whom she is barred from identifying, by a legal settlement -- saw no cause for alarm. ''Looking
back now, of course, it's easy to say I should have asked more questions or maybe been a little
more concerned,'' she told me last fall, sitting in her grassy backyard in Orangeburg, 20 miles
north of Manhattan. Branca is a pretty woman, dark and compact, with a winning suburban New
York accent. She glanced at A.J., a 6-year-old with a head of dark curls and the mental capacity
of a 6-month-old. Her 3-year-old twins from a subsequent pregnancy ran around collecting
acorns.
On April 22, 1999, when Branca was 28 weeks pregnant -- four weeks past the legal window for
terminating a pregnancy in New York -- she saw her regular doctor (for what would be the last
time) and was reassured that her baby was fine. But three weeks later, while on vacation on the
Jersey Shore, Branca began to bleed again. Her husband, Anthony, drove her to the emergency
room at Southern Ocean County Hospital in Manahawkin, N.J. Anthony Branca, like his wife, is
compact and mild-mannered. When the obstetrician arrived, the doctor got out a tape and
measured Donna's belly, a standard procedure to gauge a fetus's size. Although such
measurements are a routine part of prenatal medicine and require only a few seconds, Donna had
never had her belly measured. The obstetrician on duty that day asked Donna if she had had any
prenatal care at all. Then he told her, based on his calculations, her fetus appeared to be only 24
weeks old, not 31.
An emergency sonogram confirmed that the fetus was indeed abnormally small, and an
amniocentesis later performed at Westchester Medical Center in Valhalla, N.Y., revealed much
worse news: Donna Branca's fetus had both a gene duplication and a gene deletion on his fourth
chromosome. (It was not until after birth that it would became clear that her baby had WolfHirschhorn syndrome, which commonly includes mental retardation, physical disfigurement,
inability to speak, seizures and respiratory and digestive problems.) After two weeks of bed rest,
during which doctors tried to delay labor, Donna delivered A.J. Branca on June 11, 1999, about
six weeks before her due date. He was 15 inches long and weighed two and a half pounds, and he
didn't cry when he came out. ''One of the first things the attending doctor said to me,'' Donna told
me, ''was, 'It's not hereditary, so you should just have another child right away.'''
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What happened next -- the years in which the Brancas came to love A.J. deeply and also to file a
multimillion-dollar lawsuit claiming that Donna Branca's obstetrician's poor care deprived her of
the right to abort him -- sheds an uncomfortable light on contemporary expectations about
childbearing and on how much control we believe we should have over the babies we give birth
to. The technology of prenatal care has been shifting rapidly: sonograms became standard in the
80's; many new genetic tests became standard in the 90's. Our ethical responses to the
information provided has been shifting as well. As in many other realms, from marriage and its
definition to end-of-life issues, those ethics and standards are being hashed out in the courts, in
one lawsuit after another. And what those cases are exposing is the relatively new belief that we
should have a right to choose which babies come into the world. This belief is built upon two
assumptions, both of which have emerged in the past 40 years. The first is the assumption that if
we choose to take advantage of contemporary technology, major flaws in our fetus's health will
be detected before birth. The second assumption, more controversial, is that we will be able to do
something -- namely, end the pregnancy -- if those flaws suggest a parenting project we would
rather not undertake.
The practice of terminating specific pregnancies, as opposed to aborting pregnancies so as not to
have a child at all, is seldom discussed in its baldest terms. It is also poised to rise. Just this past
November, scientists at Columbia University published a major paper in The New England
Journal of Medicine on the effectiveness of new, noninvasive techniques for screening for Down
syndrome in the first trimester, when the decision to terminate will most likely be more common
and, some argue, more humane. In in vitro settings, a new technology called P.G.D. -preimplantation genetic diagnosis -- allows doctors to test for genetic defects days after
fertilizing an egg in a petri dish. Perhaps most important, the number of prenatal genetic tests is
increasing exponentially -- it jumped from 100 to 1,000 between 1993 and 2003 -- and no
regulations yet guide parents and doctors about fair reasons for terminating or going forward
with particular births. Should it be O.K. to terminate a deaf child? What about a blind one? How
mentally retarded is too mentally retarded? What if the child will develop a serious disease, like
Huntington's, later in life? According to one reproductive legal scholar, Susan Crockin in
Newton, Mass., ''As reproductive genetics opens up new possibilities, we should expect to see
more of these cases, and we should expect to see more novel issues.''
At present, courts in about half the states recognize wrongful birth as a subset of medical
negligence or allow lawsuits under the more general malpractice umbrella if a doctor's poor care
leads to the delivery of a child the parents claim they would have chosen to terminate in utero
had they known in time of its impaired health. In some of these states, like New York, where the
Brancas' case was tried, emotional damages -- compensation for the distress incurred by having
an impaired child -- cannot be recovered. No matter the legal context, terminating a wanted
pregnancy is no one's first choice, but for the time being at least, when faced with a fetus that
will become a severely handicapped child, all the choices are bad. At this moment, we are fairly
adept at finding chromosomal flaws and horribly inept at fixing them. There is no chemical or
surgical remedy if you find out your child-to-be has cystic fibrosis, fragile X, Down syndrome,
Tay-Sachs, anencephaly -- the list goes on and on. As Leon Kass, former chairman of the
President's Council on Bioethics, has noted, in prenatal cases, often the only way to cure the
illness is to prevent the patient.
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The first significant wrongful-birth lawsuit involving a disabled child, Gleitman v. Cosgrove,
reached the New Jersey Supreme Court in 1966. One plaintiff was the child's mother, who had
contracted rubella early in her pregnancy in 1959. Worried, she consulted her doctor and was
assured that her unborn baby would be fine, despite the common understanding that rubella early
in pregnancy can lead to birth defects. The baby in question was born with ''substantial defects. .
.in sight, hearing and speech.'' Interestingly, the court recognized the physicians' failure as well
as the parents' anguish and attendant financial burdens although it still decided in favor of the
defendants, in part, it seems, because it did not want to enter the ethical thicket inherent in
finding for the parents. ''A court cannot say what defects should prevent an embryo from being
allowed life.. . .'' the opinion reads. ''Examples of famous persons who have had great
achievement despite physical defects come readily to mind, and many of us can think of
examples close to home.. . .The sanctity of the single human life is the decisive factor in this suit
in tort. Eugenic considerations are not controlling. We are not talking here about the breeding of
prize cattle.''
By 1978, however, when the next significant wrongful-birth case was decided by a higher court,
the 1973 Roe v. Wade decision had established a woman's right to choose -- that is, to terminate
a pregnancy. The new case, Becker v. Schwartz, involved a geriatric mother (a medical term for
a pregnant woman over 35) who was not advised by her doctor that her advanced age put her
unborn child at greater risk for birth defects. Her child was born with Down syndrome, and
shortly thereafter the mother sued. This time, the New York State Court of Appeals found in
favor of the family, declaring it had the right to seek financial damages for the added cost of
raising a child with a disability. The court, however, refused to allow the claim of emotional
damages. It did recognize the family's suffering, but reasoned it ''may experience a love [for their
child] that even an abnormality cannot fully dampen.''
This paradigm -- awarding financial but not emotional damages -- has become the standard in
contemporary wrongful-birth lawsuits. Only a few states -- including Georgia, Kentucky,
Minnesota, Michigan and Utah -- have barred wrongful-birth cases through legislation or case
law. (Conversely, wrongful-life lawsuits in which disabled children sue doctors for the suffering
they are incurring by being alive have generally been rejected. These arguments come down to
''better off dead,'' and courts have claimed it is impossible to weigh suffering versus
nonexistence.) Yet the ethical thicket that the first court feared is as thorny as ever. We may not
want to give birth to disabled children, but at the same time we do not want to see ourselves as
reproducing in a way that calls to mind prize cattle.
The moral quandary we find ourselves in pits the ideal of unconditional love of a child against
the reality that most of us would prefer not to have that unconditional-love relationship with a
certain subset of kids. ''I think the reason that this topic is as loaded and painful as it is,'' says
Adrienne Asch, a professor of bioethics at Yeshiva University in New York, ''is that prospective
parents want to think that they are open to loving whomever comes into their families, and they
don't want to think that they aren't.'' Asch is one of this country's most outspoken advocates for
disability rights and against the ''automatic assumption'' that prenatal testing that reveals
disability should lead to abortion. It is her observation, shared by many on both the left and right,
that prenatal testing ''is not a medical procedure to promote the health of the fetus. It is a
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procedure to give prospective parents information to decide whether or not to eliminate a
possible future life.''
The reasons to oppose termination are both obvious and subtle and not necessarily tied to
abortion views in general. (The question of abortion rests on a single issue: is it O.K. to destroy a
potential life? Termination involves an infinite number of heartbreaking queries that boil down
to this: what about this life in particular?) Some argue that our desire not to raise impaired
children is based on prejudice. Others claim that a choosy attitude toward fetuses brings a
consumerist attitude toward childbearing and undermines the moral stature of the family. Still
others maintain that the act of terminating impaired children drags us into a moral abyss -- or its
opposite, that raising children with impairments increases our humanity.
I had to face these very questions in my own pregnancy two years ago. I was 23 weeks pregnant
with our second child when my husband and I were told that our unborn son had contracted
cytyomegalovirius, or CMV, a virus that if contracted by the mother for the first time while she
is pregnant and is passed along to her fetus can lead to serious birth defects. Most likely our child
would be deaf, blind and have serious mental retardation -- a doctor friend told me that this
prognosis could make a child with Down look like a walk in the park -- but no one could tell us
for sure what our unborn son's health would be like. What is more, no good studies existed
because most of the women in the samples terminated before birth. The uncertainty was awful:
weren't we supposed to be given solid information on which to base a decision? In lieu of that,
we were offered a sonogram riddled with anomalies, a 20-something genetics counselor and
terrible odds. We tried to take solace in the fact that our older daughter had never picked up on
the fact that there was a baby in her mother's belly. We did what seemed right at the time: we
aborted.
David Wasserman, a bioethicist at the University of Maryland, wrote a paper with Asch titled
''Where Is the Sin in Synecdoche?'' in which the two argue that prenatal testing is morally suspect
because the system leads people to reduce fetuses to a single trait, their impairment. ''Since time
immemorial people have felt fear and aversion toward people with impairments, but these tests
legitimize those fears,'' Wasserman says. Parenthood, according to Wasserman, is and should
remain a gamble.
Opposing this, of course, is the plain fact that a healthy newborn is the best outcome -- what
every parent wants. No reasonable person would choose sickness over health, and we seem to
have the ability to choose. So how to proceed? Much hand wringing goes on about a sci-fi
''Gattaca''-like future in which terminating kids with Down syndrome leads to selecting for only
highly intelligent, physically powerful blue-eyed children. Yet in truth we are not at risk of
creating a society of such supposedly perfect human beings any time soon. ''There's enough evil
and caprice to always assure there will be disabilities,'' says Laurie Zoloth, director of the Center
for Bioethics, Science and Society at Northwestern University. ''But could there be fewer? When
people worry about curing too many things, I'm always glad that bioethics wasn't around when
people were thinking about infectious diseases or polio or yellow fever.''
The Brancas have little way of making sense of how Donna's primary doctors failed to
apprehend that her pregnancy was not going well except to assume that they saw too many
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patients, believed her baby would be fine because she was relatively young or jumped to
conclusions about the Brancas' ideas about abortion based on the gold cross that Anthony wore
around his neck. Whatever the case, A.J.'s first days and weeks were a horrendous roller coaster.
One of the earliest, hardest moments was when a doctor approached the Brancas with a D.N.R.,
or Do Not Resuscitate, order. They struggled with the choice, but decided to sign.
During A.J.'s first few months, he was hooked up to oxygen tubes to help him breath and to
feeding tubes to help him eat, and he lived in an incubator to regulate his temperature. He
remained hospitalized for 17 weeks. Donna spent every day by his bedside, usually returning
home to eat a takeout dinner with Anthony and then driving back to the hospital again with her
husband. During this time, the Brancas had to decide whether to institutionalize A.J. or raise him
at home. Wolf-Hirschhorn syndrome is so rare that virtually every doctor who counseled the
Brancas could tell them no more than what the Brancas gleaned from a single study they found
on the Internet. The Brancas were also cautioned that severely disabled children are often easiest
on parents both emotionally and physically when they are infants, as all infants are wholly
dependent on their parents.
When A.J. was discharged in October 1999, four months after his birth, he was still ''medically
fragile,'' he needed round-the-clock care and he spent nearly as many calories trying to eat and
regurgitating his food as he managed to keep down in his stomach. The Brancas feared that if
they took A.J. home, he might not make it through his first year. With the encouragement of their
families and A.J.'s doctors, the Brancas placed him at St. Margaret's Center for Children in
Albany.
''It was just awful,'' Donna told me, tears streaming down her otherwise composed face as she
recently described the experience of dropping him off years ago. ''Anthony and I just sat in the
car and cried for hours. I was a mother, and yet I didn't feel like a mother. It didn't seem natural.
As a mother, you have this feeling: no matter what, you're supposed to care for your child.''
Back home in Orangeburg, Anthony and Donna tried but failed to find solace in the Catholic
Church. (Neither had been churchgoers before, though both were raised in religious families;
both identify with Catholicism culturally but say that families at times need more leeway than
the church allows on family-planning issues.) They also started hanging around their single
friends because they couldn't bear hearing about children. When A.J. was 5 months, Donna
returned to work in marketing for I.B.M. part time because, she says, ''I just needed to think
about something else, or I was going to have a nervous breakdown.'' Around this time, too, the
Brancas started considering legal action. Anthony's mother, a court stenographer, encouraged
Donna to requisition her medical records, and when Donna showed them to Dennis Donnelly, a
medical malpractice lawyer in New Jersey, he immediately took the case.
Donnelly cautioned the Brancas that her doctors probably wouldn't settle -- about 75 percent of
medical malpractice cases are found in favor of the defendant -- though he also told the Brancas
that if they won, they should expect a settlement in the millions. For the trial, he prepared a video
called ''A Day in the Life of A.J.,'' since Donna and Anthony did not want A.J. to take the stand.
The trial started in June 2004 and lasted three weeks. By then, Anthony and Donna had 2-yearold twins. In court, Donnelly asked the Brancas' doctors why they had never measured Donna's
5
fundal height, particularly in light of her low weight gain, why they had been unconcerned with
her first-trimester bleeding (a possible indication of chromosomal damage) and why they had not
done any follow-up testing after her 20-week sonogram suggested the fetus was small. He also
showed the video in which the jurors could see A.J. hooked up to a feeding tube and taking
endless meds.
The defense, for its part, tried to insinuate that Donna herself had declined to seek follow-up
testing and that even if she had sought such testing, the results might not have arrived in time for
her to abort. Furthermore, they argued that the Brancas would not have terminated. (Donnelly
used the signed Do Not Resuscitate order to argue that the Brancas would, in fact, have
terminated.) The doctors conceded that the falloff in Donna's due dates should have raised a ''red
flag'' and that a follow-up sonogram after her 20-week sonogram would have showed a further
deterioration in fetal size and weight. Donna's doctors also had little recollection of Donna as a
patient, so they could speak only about their practice in general and of her case based on her
records.
Separately, both Donna and Anthony told me that they believed they might not have sued had
Donna's doctors just called to apologize. ''They never felt any remorse,'' Donna said, ''never
called me after my son was born to say, 'I'm sorry this happened.'''
The jury deliberated for two hours and found the doctors guilty of medical negligence.
Ultimately, all parties agreed to a multimillion-dollar settlement -- its exact amount is
confidential -- which remains in a trust for A.J.'s care.
Some people argue against the idea that we should have a right to terminate unwanted
genetically flawed children on scientific, not moral, grounds. Bill Hurlbut, a Stanford professor
and a member of the President's Council on Bioethics, asserts that a lot of genetic testing is
hyped. ''Genes are not like Legos,'' he says, mocking the idea that the results of an amniocentisis,
often delivered to parents as a neat picture of 23 chromosome pairs, can tell you who a child will
be. ''Our genes mix with whole societies of molecular interactions, including our environment.
It's not just nature-nurture; it's cycles of momentum that get going. A lot of very sophisticated
people believe there is a straight line from a gene to an expressed trait, and that is just wrong.
We're going to regret we had this phrase, 'It's in our genetics.'''
Serious questions have been raised by preimplantation genetic diagnosis. P.G.D. is available to
families undergoing in vitro fertilization, and it works like this: an egg is fertilized and starts
dividing. When the embryo reaches the eight-cell stage, a single cell is removed and tested for
genetic abnormalities. If the cell's DNA looks normal, the embryo is implanted in the mother. If
the DNA does not, the embryo is frozen or tossed out. But it is not so simple. In 2005, a team
from Reprogenetics in West Orange, N.J., continued growing 55 embryos that previously tested
as abnormal and found that a surprising number of the cells, when tested later, were genetically
normal. After a few more days, an average of 48 percent of the cells were normal. After 12 days,
one embryo contained 76 percent normal cells. This raises some interesting questions: do
embryos containing some genetically flawed cells tend to heal themselves? How do you know if
the cells selected for P.G.D. are representative? Is basing termination decisions on genetic
6
information as solid a footing as we have thought? If not, how can we conscience the decision to
abort?
Susan Crockin, the legal scholar, says she believes that P.G.D., as well as other types of
prepregnancy testing, like screening donor eggs and sperm for genetic disorders, will very likely
be the causes of all sorts of new lawsuits. For instance, a sperm bank in California has already
found itself facing a wrongful-conception lawsuit, brought by parents who argue that their
genetically impaired child would not have been conceived at all had the donated sperm been
vetted properly. Egg-donor programs may soon be in the same position.
An unintended and particularly disconcerting consequence of all these new reproductive lawsuits
is that they may bias the medical establishment toward termination, and some argue that such a
bias already exists. This is alarming for many reasons, not least of which is the fact that several
studies have shown that the raising of children with impairments is on the whole a lot less
difficult and a lot less different from raising so-called normal kids than we imagine it will be.
''Families with severely impaired children do not differ significantly in stresses and burdens from
families with normal children,'' Wasserman, the bioethicist, maintains, citing articles like ''The
Experience of Disability in Families: A Synthesis of Research and Parent Narratives.'' The idea
that a handicapped child will destroy a marriage is exaggerated, he told me: ''A child prodigy can
have just as large an impact on a family as a child with cystic fibrosis or Down.''
The ways in which genetic counseling is biased toward termination are both systemic and subtle.
Research suggests that counselors may steer patients toward, as one counselor said to me,
''starting again with a clean slate.'' As another expert, Barbara Biesecker, director of the geneticcounseling training program at Johns Hopkins University, explains, ''There's kind of a trend out
there to call people at home and then just refer them back to the hospital'' -- meaning that the
family who has learned that a fetus has a genetic disease is quickly referred to someone who will
help get rid of it. This, according to Biesecker, is ''a cop-out.'' Delivering the news on the phone,
often without a spouse present, is, she says, ''filled with assumptions about what's right for
people -- it assumes that they'll act,'' meaning terminate. ''When I ask counselors why they're
doing so much work on the phone, they say, 'That's what people want.' But people are in crisis;
they need to slow down. I believe we're capable of making good decisions for ourselves in hard
circumstances, but I think we should be putting up roadblocks to quick answers. I don't think it
should be easy.''
Compounding the problem, most of the news that genetic counselors provide to prospective
parents about disabilities is negative and clinical. Face-to-face meetings, which often occur
before amniocentesis, tend to be filled with mini-science lectures about how chromosomes
replicate or how trisomies occur, not the swirling emotions that surround the news that the baby
in your belly may not be the baby you dreamed of having. In an attempt to rectify the situation,
Senators Sam Brownback, Republican of Kansas, and Edward Kennedy, Democrat of
Massachusetts, last March sponsored the Prenatally Diagnosed Conditions Awareness Act, a bill
designed to mandate that more positive information be given to parents about the life of a
disabled child. At a news conference to announce the bill was Brian Skotko, a Harvard Medical
School student. Skotko published a paper in The American Journal of Obstetrics and Gynecology
last spring based on his study, the largest and most comprehensive on prenatally diagnosed
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Down syndrome. It showed that obstetricians and genetic counselors failed to give expectant
mothers who received a prenatal diagnosis of Down encouraging data about raising a Down
child. One mother in Skotko's study reported that her genetic counselor ''showed a really pitiful
video first of people with Down syndrome who were very low tone and lethargic-looking and
then proceeded to tell us that our child would never be able to read, write or count change.''
Few would be against parents getting a complete and accurate picture of raising an impaired
child, but how, exactly, does that picture look? Different families' experiences with similar
impairments are wildly disparate, and Skotko's study has been criticized for having sample bias,
because he collected his surveys through Down-syndrome family associations, groups
presumably filled with people having relatively good experiences with the disease. (Skotko has a
sister with Down.) Not included in his sample, for instance, was a 66-year-old woman named
Wendolyn Markcrow of Buckinghamshire, England, who last year on Easter Monday gave her
36-year-old son, Patrick, 14 sleeping pills and suffocated him with a plastic bag and then
attempted suicide. Patrick had Down syndrome, rarely slept at night and hit himself in the face so
regularly and forcefully that he detached his retina. When arrested, Markcrow told the police that
she had ''snapped.''
Why does A.J. have to get on the bus?'' Julia Branca, one of Donna and Anthony's 3-year-old
twins, paused to ask her mother, referring to the shuttle that was taking A.J. back to St.
Margaret's on a Sunday afternoon. (A.J. has since moved to the Center for Discovery, in Harris,
N.Y., closer to the Brancas' home.) The sun dappled the lawn through the tall oak trees. A.J.,
three years older than his siblings, but about the same size, played with a LeapFrog infant piano
in his wheelchair in the shade.
Julia is extremely engaged with the world of disability. At ''A.J.'s house,'' what she used to call
St. Margaret's and now calls the Center for Discovery, she says hello to all the kids, whether they
respond or not, while her brother Johnny hugs Donna's leg. Julia ran off for a few minutes and
returned with a cup full of acorns and set them on A.J.'s wheelchair tray. A.J. raised his head, as
if to acknowledge Julia's gift, then sank back into the looping riffs of his musical toy. Nobody
knows how much A.J. comprehends. He turns his head toward his family, sometimes reaches out
an arm. ''One time,'' says Anthony, ''up in Albany, he started to cry when we left. He started to
moan.''
In A.J.'s infancy, when his son visited home, Anthony slept in the same room with A.J., often in
the same bed, dispensing food and meds at one- and two-hour intervals and making sure A.J.,
who weighed only nine pounds at 1 year, didn't vomit and choke. When he found out Donna was
pregnant with twins, he felt guilty because he ''knew it was really going to take away from A.J.
When the twins were born, it was like having triplets.'' Now, thanks to the settlement, when A.J.
is home, a nurse comes at night. In some ways, being A.J.'s parents has grown harder as he has
grown older. Yet despite the direst predictions from some of his doctors, A.J. is progressing, if
slowly. No one expects that A.J. will ever talk, but last summer he learned to belly crawl, and his
father was intensely proud. ''Everyone talks about when their child says his first word,'' Anthony
says. ''With A.J., we don't have that. But I think Donna and I have more satisfaction.'' Anthony
sounds calm but surprised, like a man long accustomed to unexpected and unsettling news. ''A.J.
was voted Most Improved Mobility last year at school,'' he told me. ''I was more proud of that.
8
Every kid who has what he's got doesn't learn to belly crawl. I felt like he'd hit a home run in the
Little League World Series.''
The Brancas love the son they wish they hadn't had. My family continues to mourn the child we
don't regret terminating. ''Anything you might say about the wrongfulness or the rightness of a
birth,'' Laurie Zoloth, the bioethicist, says, ''the particularity of that choice is only, and always,
experienced by a particular set of parents in a particular family with certain grandparents, certain
aunts and uncles, in a certain religion on a certain block in a certain neighborhood. These are
circumstances that as professionals, and certainly as bioethicists, it's nearly impossible to fully
understand. And then, of course, we have the luxury of walking away.''
Elizabeth Weil lives in San Francisco. Her last article for the magazine was about childhood
obesity in southern Texas.
9
NEWS FEATURE
GLASSHOUSE IMAGES/ALAMY
NATURE|Vol 438|8 December 2005
Screen
test
IMAGE
UNAVAILABLE
FOR COPYRIGHT
REASONS
A new technique could allow
doctors to spot hundreds of
potential genetic problems in
unborn babies. But is it too
soon to put it to use? Erika
Check finds out.
hree years ago, a doctor told Debbie
Sukin that her son had a rare and serious genetic disease called Angelman’s
syndrome. The diagnosis meant that
her son, then just one year old, would face
tremendous physical and mental challenges
for the rest of his life. After the diagnosis,
Sukin went to see Arthur Beaudet, a leading
expert on the syndrome. Beaudet tested Sukin
and her husband, and found that neither of
them was carrying the genetic fault that had
caused her son’s disease — the condition had
arisen spontaneously in the unborn child.
Because there was no reason to suspect a problem, Sukin did not have any genetic tests
performed during her pregnancy.
Beaudet, a geneticist at the Baylor College of
Medicine in Houston, Texas, felt that Sukin’s
story represented a broader problem in medicine. He could see a widening gap between
geneticists’ growing understanding of the
roots of disease and their inability to detect
those diseases in the womb. The main problem is that prenatal tests can only catch genetic
problems if doctors know to look for them. For
Beaudet, this was simply not good enough.
To tackle the problem, Beaudet’s lab has
developed a way to test for more than 150 chromosomal abnormalities using a single package
that costs just under US$2,000 a go. Over the
past year, Beaudet has tested the technique in
an unpublished clinical trial in 98 women who
were at high risk of having babies with genetic
problems. He was so convinced by the results
that this August his clinic became the first in
the world to offer the prenatal test. Beaudet
predicts that the test will change the face of
medicine. “This is going to cause a world revolution in prenatal and perinatal care,” he claims.
Beaudet’s claims are perhaps optimistic — for
now, the test will only be used by women who
can already afford genetic screening.
Other doctors and scientists agree that the
technique has huge potential, but they worry
that it is too soon to use it in unborn children.
They say it could pick up genetic features that
are difficult to interpret, causing extra anxiety
T
Hard to spot: current tests for genetic defects in fetuses rely on doctors anticipating what they might find.
for parents-to-be. In some cases, the results
mean that additional tests must be done to
examine DNA from both parents, which could
reveal instances of what geneticists delicately
call ‘non-paternity’. And others fear that the
test will give parents more opportunities to
terminate fetuses with undesirable traits.
Beaudet’s technique is the latest development in a long line of tests that examine chromosomes in the fetus. Until recently, doctors
could detect only large deletions, copies or
rearrangements of chromosomes, such as an
extra copy of chromosome 21, which causes
Down’s syndrome. Now, modern techniques
such as fluorescence in situ hybridization, or
FISH, can pick up much smaller changes.
A wider net
Beaudet’s test has two powerful advantages. It
picks up even smaller changes than the FISH
test, and unlike FISH it simultaneously screens
hundreds of chromosome areas that have been
linked to disease. Doctors don’t usually check for
mutations in all of these areas because most of
the mutations are extremely rare accidents that
occur during development. Any abnormalities
that show up can then be investigated further.
“Our system allows you to do every known
“The big question is, where are we
going to go with all of this?”
— Dorothy Mitchell-Leef
©2005 Nature Publishing Group
FISH test in the world at once,” says Beaudet.
The new test uses microarray-based comparative genomic hybridization, or array
CGH. This is based on the principle that every
cell should have two full copies of its DNA —
one from the mother and one from the father.
The test scans for regions of fetal DNA that
deviate from this pattern because they contain
too much or too little DNA. These aberrant
patterns correspond to regions of the genome
that are either copied or deleted, and could
therefore cause disease.
Although array CGH is still very new, a few
labs in Europe and the United States are
already using it in the clinic. But in most
instances, they use it only to look for genetic
problems in children or adults who have unexplained mental retardation1–3. And, unlike
Baylor, these labs believe that it is too early to
use the test as a prenatal screening tool.
Their hesitation stems from a new understanding of human genetic diversity4.
Researchers are finding that individuals who
seem perfectly healthy often carry deletions
and duplications of certain genes. The Baylor
test looks for mutations across long stretches of
DNA, and it could be difficult to predict the
consequences of deletions and duplications of
these regions in a fetus. “Until we have a much
better understanding of what normal variation
is, it is dangerous to launch into clinical testing
in the prenatal context,” says Martin Bobrow, a
medical geneticist who is working with a group
at the Wellcome Trust Sanger Institute near
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NATURE|Vol 438|8 December 2005
Cambridge, UK, on developing pre- and postnatal diagnostic tests based on array CGH.
Bobrow and others are also concerned about
the test’s power to uncover ever more detailed
information about a developing baby. For
instance, an old version of one genetic testing
device scanned regions of the Y chromosome
that allow a man to make sperm. If found in a
fetus, defects in this part of the chromosome
might signal that a baby boy is destined to grow
into an infertile adult, perhaps leading some
parents to think twice about keeping the baby.
But, as Bobrow says: “Very few doctors would
want to be involved in terminating a pregnancy
on the basis of male infertility.”
“The big question is, where are we going to
go with all of this?” asks Dorothy MitchellLeef, a fertility doctor at Reproductive Biology
Associates in Atlanta, Georgia. “I doubt if
there’s anyone alive today who is a perfect
example of a healthy individual and has
absolutely no disease.” That makes it difficult
to know what genetic changes really mark a
fetus as abnormal, she notes.
the test uncovered obvious abnormalities —
four were the tell-tale signature of Down’s syndrome. In nine other cases, the test detected a
genetic hiccough that wasn’t known to be associated with any disease, but the variation was
also found in one of the baby’s healthy parents,
so doctors assumed it was not dangerous.
Only once did the test turn up a variant that
was not associated with disease and was also
not found in either of the baby’s parents. In
future cases, Beaudet says, the group would like
to perform a paternity test in these situations,
to be sure it is looking at the right parental
DNA. He admits that this raises issues of its
own. “It’s relatively new territory for prenatal
diagnostics to have to look at data from both
parents to interpret data on the fetus,” he says.
But, he adds, the Baylor group will refine its
methods as it learns which DNA variations are
harmless to the fetus. And both Beaudet’s team
and other groups have performed studies to
prove that the technology actually detects
genetic changes that lead to disease5,6.
Beaudet’s prenatal work has followed strict
ethical guidelines. But there is a legitimate
Baby steps
Beaudet is aware of these pitfalls. But he argues
that genetic counsellors have been dealing
with these issues since the 1970s, when prenatal testing began. “We have always faced
findings of uncertain significance in prenatal
diagnosis,” he says.
He adds that the results of Baylor’s year-long
preliminary study, described at the American
Society of Human Genetics meeting on 26
October in Salt Lake City, Utah, have been
reassuring. The test turned up no abnormal
findings in the vast majority of pregnancies. In
five of the 98 women taking part in the trial,
734
worry that less scrupulous operators could
develop the test to screen for genetic variations
associated with desirable traits, such as height
or IQ. Although more rigorous than in most
other parts of the world, US regulation of
genetic tests is still somewhat patchy. So some
doctors are calling for self-regulation. MitchellLeef believes that medical societies should set
policies now on what sorts of conditions
should be tested in embryos and fetuses.
Beaudet and his group agree that such issues
are important. But just as important, they say,
are the voices of the pregnant women who
have requested the test so far. This January, for
instance, Anca Segall, a biologist at San Diego
State University, had her unborn child tested.
At 44, she was anxious to know upfront if her
child had any major problems. “You really
have to think about whether this knowledge is
important for you, and it was for us,” Segall
says. Her test raised no red flags, and she gave
birth this October to a healthy baby girl.
Sukin is not sure what she would have done
had she found out five years ago that she was
carrying a child who might have Angelman’s
syndrome. But she is sure she would have
wanted to know. “We have a responsibility to
share whatever knowledge is available,” Sukin
says. “The majority of people will have a
healthy child. But when you’re the statistic,
your one kid is the most important thing.” ■
Erika Check is Nature’s Washington
biomedical correspondent.
For Anca Segall, taking a full prenatal screening
test was important for her pregnancy.
©2005 Nature Publishing Group
de Vries, B. B. et al. Am. J. Hum. Genet. 77, 606–616 (2005).
Shaw-Smith, C. et al. J. Med. Genet. 41, 241–248 (2004).
Bejjani, B. A. et al. Am. J. Med. Genet. A 134, 259–267 (2005).
Check, E. Nature 437, 1084–1086 (2005).
Rickman, L. et al. J. Med. Genet.
doi:10.1136/jmg.2005.037648 (2005).
6. Le Caignec, C. et al. J. Med. Genet. 42, 121–128 (2005).
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A. SEGALL & F. ROHWER
Informed choice: Arthur Beaudet discusses his prenatal genetic screening test with an expectant mother.
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