Research probes problems among test-tube offspring

Miscommunication in genes, multiple births called anomalies

  • 10-24-04-fertilization-primer

  • Mice do not yearn for wide open spaces.

    They would make bad cowpokes, even if you developed mouse-size cows.

    What mice want are cozy, dark tunnels. That sense of shelter. A comfy assurance that nothing can swoop down from the sky and turn them into appetizers.

    Then there are Richard Schultz's mice. The males among them exhibit an uncommon comfort in the great outdoors. Such boldness is utterly unmouselike.

    Mr. Schultz, a researcher at the University of Pennsylvania in Philadelphia, developed these mice in an unusual manner. He allowed their embryos to live outside the womb for a few days. The little embryos grew in a brew of nutrients similar to what a human embryo might experience during in vitro fertilization. Then he put the embryos into mom, and let nature proceed.

    In most ways, these mice were like any others. They grew normally, grasped objects normally, they balanced on sticks with relative ease -- anything an average mouse might do, they did too.

    READ MORE: Harnessing the Power of Creation

    Then they were tested for anxiety levels in open spaces. There, the differences arose. Further tests revealed another problem: while all the mice were good learners, the petri-dish-raised mice had poor spatial memory.

    Of course, it's impossible to say whether Mr. Schultz's mice are adequate stand-ins for humans. But his work feeds into a growing body of research that suggests a small but significant increased risk for certain kinds of genetic defects among infants conceived through in vitro fertilization. They are called gene imprinting disorders.

    How imprinting works

    An embryo has two copies of every gene, one from mother and one from father. In imprinting, only one of those genes is allowed to "talk." Whether the active gene is the mother's or the father's depends on the gene, but which gene is active is very specific, and very consistent from one person to the next, explains Judith Hall, a professor at the University of British Columbia and an expert on genetic imprinting.

    In imprinting disorders, both gene copies are left on or turned off.

    "If you have two turned on, you have a problem. If you have none turned on, you have a problem," she said.

    Researchers worry that the nutrients in which embryos bathe in a petri dish, or the way a sperm and egg meet in a laboratory, could make IVF embryos particularly vulnerable to these types of defects.

    But does it? It's hard to say.

    The scientific literature about the risks of test-tube reproduction often is a befuddling storm of conflicting results, uncertainty, and inadequate data, said many who have attempted to sort it out.

    What's emerging from this research may be a conclusion of a different sort: There is not enough information about the more than quarter-million children conceived through IVF in the United States. There ought to be more and better statistics gathered on IVF children. And the number of studies contain inadequate data to support the reported results.

    "The papers are shoddy," said Dr. Hall, who is a member of a committee for the Genetics and Public Policy Center that spent the last year reviewing in vitro fertilization research.

    Studies often compare IVF infant health to infant health in the general population without distinguishing what kind of procedure was used to create the IVF embryo.

    "You would never publish a paper on mice where you didn't describe" research methods in detail, Dr. Hall said. "There's something kind of mystical about assisted reproduction technology. People say, 'we won't discuss that.' "

    Despite the blur in the literature, most observers agree that some IVF problems are unquestionably evident:

    • IVF pregnancies result in a higher number of twin, triplet, and quadruplet births than natural conception. Such children face an increased risk of birth defects.
    • Even IVF babies who do not share the womb with a twin are more likely to be premature than naturally conceived children and suffer the complications that may engender.
    • IVF single births often are underweight, even when they are full-term.

    Fertility experts seem to agree that the number of multiple births is one problem that demands urgent attention. In fact, there has been progress. Recent statistics show a decline in these births.

    But the problem is far from solved and there still are many clinics where multiple births make up more than half of the successful IVF procedures.

    Nationwide, multiple births occurred in 40 percent of all successful IVF procedures among women younger than 35. Eight percent were triplets or more.

    Although a triplet pregnancy generally is acknowledged to pose a significant health risk, twins often are thought to be a fairly safe bet. But the risks that can accompany twin births are not trivial. Twins have a fetal death rate three to five times higher than single babies. Their newborn death rate is five to seven times higher. Twin births cost four times what single births cost. If the twin is severely underweight, medical costs for that first year of life can be as high as 44 times the cost of caring for a single infant.

    Reducing multiple births

    Fertility specialists are looking at a number of ways to reduce multiple births.

    For instance, many clinics in Europe return only a single embryo to the womb among patients with the best prospects for a successful pregnancy. But the trend has no evident following in the United States, where patients often pay for fertility treatment out of their own pockets, and an IVF attempt can run to $10,000 to $12,000. At that price, people want to get it right the first time. In Europe, fertility treatment often is part of government-supplied health coverage. In the United States, insurance coverage for such treatment is rare.

    In the United States, many clinics are choosing to grow embryos outside the womb for an extra day or two. Additional growing days could reveal which embryos are most likely to succeed. Thus, fewer embryos can be returned to the womb. Ironically, some research shows that this technique may increase the likelihood of identical twins.

    Others raise questions about the health consequences of a longer time outside the womb.

    Mr. Schultz, of the bold-mice experiment, conducted genetic studies on embryos growing outside the womb. These showed severe genetic errors. Specifically, the genes were not properly imprinted. Genes that were supposed to be shut off were turned on. Those genes gave bad instructions to other genes. More than 100 genes failed to behave the way they were supposed to.

    That's why Mr. Schultz decided to test the behavior of in vitro mice. Sure, embryos make genetic mistakes, but did it really make a difference in the adult mouse? His study of mouse behavior at least suggests that yes, it may.

    The issue is of rising importance as some clinics choose to grow embryos outside the body for longer periods.

    One troubling statistic that may relate to the shortcomings of raising embryos in a laboratory is an apparent slight but significant increase among IVF kids for diseases caused by imprinting errors.

    Because of the unique nature of the genetic failures in the mouse embryos, and this assortment of these diseases, Mr. Schultz said a critical next step would be a study that assigned one group of IVF patients to use embryos grown outside the womb for a short time, and another group to use embryos grown outside the womb for a longer time. The children of these practices should then be followed for life.

    As it stands, the United States doesn't track any IVF child, making it impossible to know if children born of these procedures are experiencing any problems as they get older.

    "These practices that [fertility doctors] do are very aggressively implemented,'' Mr. Schultz said. "The implementation has fairly outpaced the underlying science.''

    He said IVF practices are often introduced into patient care without much long-term research, which "is a real anomaly in the practice of Western medicine."

    What's needed, many say, is a method to follow the health of children conceived from assisted reproductive technology in a systematic way.

    Canada recently passed legislation that requires more tracking of these children. Scandinavian countries already do this. But in the United States, record-keeping extends not much further than a fertility clinic's report that a birth was achieved and how many times a particular method was used to achieve a pregnancy.

    Often, a child's pediatrician will not even know a child was conceived with assisted reproduction, said Dr. Hall, the genetic imprinting expert from British Columbia. If they did know, there is no central database to report any problems that might arise for these children, she said.

    As a result, prospective parents can't know what risks their IVF child may face. The risks are probably statistically small, Dr. Hall said, but important.

    For instance, if there was a higher risk for a very rare cancer "wouldn't you want to know that? It seems to me these are highly highly valued children. If that's the risk, even though it's small, you'd monitor [the child] differently. But we don't know. We absolutely don't know, because they are not followed. They don't tell the pediatrician. We don't know the outcomes for these people,'' she said.

    "That's the whole frustration."