24 January 2003
Studies See Ills for In Vitro Children
Rosie Mestel, Times Staff Writer
vitro fertilization has birthed a million babies worldwide, but
now there are glimmerings of concern that the 25-year-old technology
and other methods known collectively as assisted reproductive technology
are causing several rare medical abnormalities.
pair of studies in the last three months have linked in vitro fertilization
and a related method called intracytoplasmic sperm injection, to
a fourfold to sixfold increased risk for a condition known as Beckwith-Wiedemann
syndrome, an overgrowth disorder typified by children with enlarged
tongues and other organs. Other reports within the last year have
spotted a possible increase in Angelman syndrome, in which children
have a spectrum of problems including speech impairment and mental
2002, an Australian study published in the New England Journal of
Medicine reported that rates of birth defects were twice as high
in children conceived in vitro. And a U.S. study in the journal
found that such children were more likely to have a low birth weight.
today, in the journal the Lancet, Dutch researchers report a fourfold
to sevenfold increase in the rate of retinoblastoma, a rare cancer
of the eye, in children conceived via assisted reproductive technology.
studies are few, their findings tentative, and the increased risks
they point to are in most cases quite slight. Disorders such as
retinoblastoma and Beckwith-Wiedemann syndrome are very rare to
syndrome normally occurs in 1 in 15,000 births; retinoblastoma affects
1 in 17,000.
a growing number of scientists and doctors think the reports are
a cause for unease.
not saying to families that at this point this ought to affect their
decision for in vitro fertilization -- assisted reproductive technology
is a miracle for families," said Dr. Andrew Feinberg, professor
of medicine at Johns Hopkins University School of Medicine and co-author
of one of the Beckwith-Wiedemann studies. "However, we are
saying to the in vitro fertilization community that this needs to
be studied in detail."
than 99,000 assisted reproductive procedures took place in the United
States in 2000, the most recent year for which data are available.
As a result, about 35,000 babies were born. Since the advent of
the technology in the late 1970s, it has become a common, albeit
procedure has been a boon to couples who could not conceive a child
another way. It involves harvesting eggs from a woman using hormones,
fertilizing the egg in a dish with sperm from a man and then growing
the embryo for a few days in a culture that provides the necessary
nutrients -- and finally returning it to a woman's body.
the connection between in vitro fertilization and disorders such
as Beckwith-Wiedemann syndrome is only now entering the medical
literature, parents of children with some of these diseases have
suspected a link for several years.
a 33-year-old Baltimore resident who asked that her last name not
be used, has a child with Beckwith-Wiedemann. The child was conceived
using intracytoplasmic sperm injection. Seeking support online,
Melissa said she quickly noticed how many of the Beckwith-Wiedemann
parents online had also gone through assisted reproductive technology.
were all thinking: 'Wow, that's really kind of strange, why are
all of us on this message board?' " she said.
list of possible causes is varied, but scientists suspect that culturing
eggs and embryos in the lab may be behind the heightened risks.
studies already have raised a number of red flags. For instance,
researchers working with mice have found that embryos cultured in
laboratories are different in several ways from embryos that are
grown inside the body of an animal.
Richard Schultz and Marisa Bartolomei at the University of Pennsylvania
have found that small differences in the amount of salt or amino
acids used in the culture can cause certain genes in the embryo
to behave aberrantly -- turning on when they should be off, or off
when they should be on.
errors Schultz and Bartolomei have detected crop up in a small collection
of genes known as "imprinted" genes. In contrast to the
usual way in which genetic information is passed on to a child,
these genes retain a chemical mark of their heritage -- an "imprint"
-- depending on whether they come from the mother or the father.
The imprinting ensures that only one copy of a gene -- from the
mother or father -- is turned on.
syndrome and Beckwith-Wiedemann syndrome are caused by mistakes
in such imprinted genes.
and Bartolomei found in their in vitro animal studies that a gene
named H19 -- linked in humans to Beckwith-Wiedemann syndrome --
is improperly imprinted in the parts of the embryo that will later
form a placenta. They think this is caused by some abnormal reaction
by the embryos to being cultured in the lab.
recent trend within the in vitro fertilization community may be
exacerbating potential problems caused by this embryo culture. Traditionally,
embryos are implanted into the mother after a day or so in culture,
when the embryo has divided only a few times. In the last few years,
more clinics have been growing eggs for about five days to produce
an embryo known as a blastocyst -- in an effort to select the best
and sturdiest embryos and increase the chances of a successful pregnancy.
could potentially be exposing the embryos even more to conditions
that could have a long-term health impact," said John Eppig,
senior staff scientist at the Jackson Laboratory in Bar Harbor,
suspect abnormalities may be more likely in cases of intracytoplasmic
sperm injection, in which sperm cells are injected into the egg.
The procedure, pioneered in the 1990s, is used in cases of male
studies have suggested that rates of abnormalities may be higher
in children conceived by this method. This could be because the
mechanics of the procedure, or the immaturity of the injected sperm
that are sometimes used, disrupt the delicate regulation of genes
that takes place in a developing embryo.
said disorders such as Beckwith-Wiedemann syndrome can be tested
for and avoided. They are more concerned about subtler errors involving
complex traits and genes for which there are no tests.
raises the principle that we could have things happening that might
take longer to be manifested -- and which might involve behavior,"
said Dr. Arthur Beaudet, professor and chair of molecular and human
genetics at Baylor College of Medicine in Houston.
link between in vitro fertilization and birth abnormalities may
still turn out to be spurious. Dr. Sandra Carson, president of the
American Society for Reproductive Medicine and professor of obstetrics
and gynecology at Baylor, said the findings, while unsettling, must
be verified in better studies.
fertility experts pointed out that other studies have found no heightened
addition, the recent in vitro studies have their limitations. Registries
of children with birth defects and syndromes may overly represent
people who have had in vitro fertilization. In vitro children are
more likely to be tested for birth defects, and parents who can
afford in vitro fertilization may be more likely to participate
in studies because of their education level.
is also possible that infertile people have genetic problems that
make birth defects more likely in their children.
not debunking it -- I'm just saying we need bigger studies to verify
it," said Dr. Alan DeCherney, professor of obstetrics and gynecology
at UCLA Medical Center.
studies would have to be large, national enterprises that tracked
the health of in vitro children not at birth, but for years to come.
the same time, scientists said, more research must be conducted
in animals. Only that way will they come to understand what happens
during the complex, multistep procedure.
even if the risks are confirmed, DeCherney thinks it unlikely that
infertile couples seeking a child will be deterred. "They really
want children -- they'll do almost anything," he said.