Newswire

IVF Babies: Trouble In The Making

IVF Babies: Trouble In The Making

Fears grow over potential for long-term health issues

After 27 years and 2 million in vitro babies, scientists still can't say for sure that those children will grow old with normal health.

The 1978 birth of Louise Brown, the world's first "test-tube" baby, raised moral concerns about doctors playing God. And many doctors had their own concerns: that in vitro babies might exhibit chromosome abnormalities or physical deformities. When Louise and the hundreds of babies that followed – including her sister, Natalie – appeared healthy, anxieties faded.

Today, there are new worries about the procedure known as in vitro fertilization, or IVF – more subtle, but still troubling. Genetic disturbances may occur while the embryo incubates in the clinic, researchers say, affecting genes in ways that scientists didn't know to even look for three decades ago.

While fertility technology has become widely used – 45,000 in vitro babies are born each year in the U.S. – only now have scientists begun to understand how even the smallest environmental changes may have a profound effect on an embryo.

There is no indisputable evidence that IVF procedures cause harm, but that may be because researchers aren't examining the children in a systematic or immediate way.

"This is a procedure that seems to be very safe," said Dr. Maruzio Macaluso, branch chief of women's health and fertility in the division of reproductive health at the Centers for Disease Control and Prevention in Atlanta. "But from our data, we can't tell whether there are long-term effects."

IVF techniques are prime candidates for causing errors in genetic programming, altering which genes are actively producing important biological chemicals. Such alterations – known as epigenetic effects – have been linked to cancer and are suspected in many chronic health problems that strike later in life.

And that means such problems may not have had a chance to appear in the in vitro baby population. In the U.S., more than half of IVF babies haven't even celebrated their fifth birthdays yet. Researchers will have to wait years to see whether health problems appear as the babies age.

Studying the effects of IVF is complicated, but the procedure itself is straightforward. Sperm and egg unite in a lab dish instead of a woman's body.

Even with so simple a procedure, though, there are opportunities for problems.

Ovarian stimulation

In 2003, scientists reported in the journal Biology of Reproduction that mice treated with several rounds of ovulation medication produced eggs with some deficiencies such as low levels of an important cellular energy source. Fetal weight also was affected, although ultimately, development was normal. Long-term health wasn't charted, and the scientists said they don't know if ovulation drugs have the same effect on humans.

Other researchers worry that triggering ovulation in women may cause eggs to mature faster than normal. Before the egg is ever released, a special type of genetic programming (known as imprinting) readies the egg for development of a new individual.

Most of the imprinting occurs early in life, but there may be some residual programming that occurs just before ovulation, scientists say. Ovulation medications could alter that programming and have a ripple effect on the health or development of the baby.

"There could be genes in the human that get imprinted relatively late and could be altered," said Dr. Wolf Reik, a developmental geneticist at the Babraham Institute in Cambridge, England. "It's something that should be looked at."

In the lab dish

Inside a woman's body, naturally fertilized eggs are bathed in fluid produced by the oviduct, the tube that leads from the ovary to the uterus. This fluid is optimized for the cell divisions that mark the first few days of an embryo's development.

Embryos conceived in lab dishes are bathed in manmade fluid, called culture medium. Researchers say the fluid, even from a single manufacturer, can vary from batch to batch.

The embryo spends only three to five days in this culture medium, but they are crucial days. Just after fertilization, both mother's and father's genetic contributions are reworked to prepare for the coming cell divisions. In these early days, the pattern of cell divisions determines the proportion of fetal to placental cells, a ratio important for proper development.

A 2004 study from the Proceedings of the National Academy of Sciences showed that mouse embryos grown in culture medium show slight, but measurable, behavioral problems as adults compared with mice that never left the womb.

Other studies have shown that for some animal species, growing embryos in culture medium can yield offspring that are larger than normal; several studies have shown that altering lab dish conditions can change the behavior of critical genes.

For a long time, said Richard Schultz, a biologist from the University of Pennsylvania in Philadelphia who conducted the 2004 study, scientists assumed that if an embryo could survive life in a lab dish and beyond, it was healthy.

"There's been a sense," he said, "that if something bad happens, it doesn't implant or it aborts."

Scientists are now questioning that assumption but also concede that the animal studies may not apply directly to humans. And even though there's no evidence that the culture medium is harming human babies, there's also little opportunity to check.

The recipes for many of the commercially made media are secret – each manufacturer's proprietary information – so determining whether an ingredient has any consequences for long-term health is impossible.

"A doctor should know exactly what he's doing to a patient," said John Biggers, the Harvard Medical School biologist whose work on culture medium decades ago allowed scientists to grow embryos in lab dishes. "It's impeding scientific progress."

Since the beginning, scientists have tweaked the culture medium to improve embryo viability. Paradoxically, those improvements in the culture media may actually help increase the survival chances of less-hardy embryos.

On the other hand, scientists point out that for some women, the manmade media may be better than what is produced naturally.

"The couples using IVF may not have healthy media themselves in their tubes," said Dr. Alistair Sutcliffe, a pediatrician at the Royal Free and University College Medical School in London.

Low birth weights

Like Louise Brown, the majority of babies conceived through IVF appear normal at birth. Studies that track children as far as five years suggest that mental development and general physical condition are normal.

But a 2002 study from the CDC suggested that babies conceived through IVF are more likely to have low birth weights, even if the woman is carrying just one baby.

Low birth weight has been connected to heart disease, diabetes and other conditions later in life among naturally conceived babies, although it's not known whether these risks apply to low birth weight IVF babies, too. Other research has also suggested that birth defects, while still rare, are perhaps as much as 40 percent more common in babies conceived through IVF.

In addition to low birth weight and birth defects, scientists have also found a connection between IVF and Beckwith-Wiedemann syndrome. In natural conception, abnormal genetic programming of particular genes can cause the syndrome, which results in growth defects and a predisposition to certain cancers.

It's unclear whether the connection between Beckwith-Wiedemann syndrome and IVF is real, and not just a chance association. The syndrome is rare to begin with, and even if IVF does increase the risk, odds of getting it are still extremely low. But, scientists say, if IVF does cause the syndrome, it could be a sign the procedure causes other epigenetic problems.

Even with the links between IVF babies and birth abnormalities, scientists warn that you cannot presume that IVF itself is to blame. Any abnormalities could be due to a couple's underlying infertility, rather than the IVF techniques. And low birth weight could occur if a woman starts out carrying twins and one of the fetuses dies. The remaining baby might still be born weighing less than normal.

Actually, researchers say, the biggest known risk of IVF is implanting multiple embryos. Twin and triplet pregnancies present risks to both baby and mother.

More surveillance

More recently, scientists have called for greater scrutiny of IVF, also referred to as ART, for assisted reproductive technology. In 2004, scientists from the CDC and the National Institutes of Health wrote that "research on the safety of ART treatments has seemed to lag behind the continued progress in achieving higher pregnancy and live-birth rates."

In the U.S., the CDC helps maintain a registry of IVF births, but this system, the authors noted, "was designed to measure ART success and has insufficient information about many important infant and child outcomes."

Despite the scientific concerns about its safety, many researchers are reluctant to be too critical. Compared with all the assaults engendered by modern life, IVF doesn't seem excessively risky, they say.

Also, the level of concern in the medical literature may be misleading, noted Tom Mayo, an SMU bioethicist. Scientists have a duty and incentives to research potential risks.

"The papers that get published say there might be a problem," he said. "We don't publish the good news."

And while there may be health risks with IVF, there is also uncertainty in natural conceptions – they may be unplanned or occur in women with poor health habits.

It's impossible to be absolutely certain about safety, said Mark Gibson, professor of obstetrics and gynecology at the University of Utah School of Medicine in Salt Lake City and a member of the editorial board for the journal Obstetrics & Gynecology.

"You can make an argument that we don't know enough about it and that we should stop IVF," he said. "But we could never start it again, because there'd never be an end to the uncertainties."

For now, clinicians must decide what to tell patients about these scientific discussions, said Dr. Carmen Williams, an obstetrician/gynecologist at the University of Pennsylvania Medical Center.

"There's the reality of speaking to a patient," she said. "Is it incumbent to tell them every last risk when the risks aren't known, or they're extremely small?"

Mr. Mayo, the SMU bioethicist, believes so.

"I think that people contemplating these procedures are entitled to know that there are issues," he said. "And that answers are few and far between."

The reality is that it could take several decades to see any ill effects of IVF, scientists say. And creating the kind of study necessary to rule out most problems is deeply problematic.

To assess the effects of culture media, scientists would want to compare an IVF embryo to one conceived naturally. Practically and ethically, this is virtually impossible, said Penn's Dr. Schultz.

To find out whether problems are caused by IVF rather than infertility, researchers could attempt to enroll fertile women – say those who have had their tubes tied – in an IVF study.

"You'd need to do probably thousands and then you'd need to follow them for decades," said Utah's Dr. Gibson. That, he said, is simply impractical.

Even with these limitations, scientists say there is more research that could be done. In 2004, the President's Council on Bioethics recommended a long-term, federally funded study of children born through ART.

In response, the federal government's upcoming National Children's Study will have a special focus on children conceived with assisted reproductive technologies (assuming the funding is granted). And the National Institute for Child Health and Development is funding laboratory research to better assess the vulnerability of the developing egg and early embryo.

Scientists also say that the media used for each round of IVF should be recorded and that infertility treatments should be listed on the certificates of live birth. Some scientists advocate research on human embryos, although in the U.S., this is illegal with federal funds.

And, says Dr. Andrew Feinberg, a professor of genetic medicine at Johns Hopkins School of Medicine in Baltimore, "the direct evidence that would be most helpful hasn't been collected – asking about cancer late in life. And in children, collecting blood and checking their epigenetic status."

The future

In IVF, scientific ingenuity and human desire have joined to create a powerful force. Researchers are hesitant to stand in the way of the birth of babies who are so carefully planned and desperately yearned for.

For all the concerns in the scientific literature, researchers say they don't foresee – and can't justify – any slowdown. But they say more research is warranted.

"It's probably safe, but we don't know," said Penn's Dr. Williams. "Are we just going to shut our eyes and not check?"


http://www.dallasnews.com/sharedcontent/dws/news/healthsc
ience/stories/DN-ivf_06nat.ART.North.Edition2.d866295.html

Posted by Editor at November 9, 2005 07:24 AM