Scientists from Johns Hopkins and Washington University School of Medicine in St. Louis have discovered that in vitro fertilization (IVF) appears to be associated with a rare combination of birth defects characterized by excessive growth of various tissues.
After studying data from a national registry of patients with Beckwith-Wiedemann syndrome (BWS), the researchers found that IVF-initiated conception was six times more common than in the general population. The findings are slated for the January issue of the American Journal of Human Genetics, and should be online by the end of November.
Children born with BWS, which may predispose them to Wilms' tumor, hepatoblastoma, neuroblastoma and other cancers, would likely represent only a tiny fraction of babies conceived via IVF if the findings are confirmed, the researchers emphasize. The results should stimulate further investigation, not change parents' decisions, they say.
"This analysis should not affect people's decisions about whether to have IVF, because our findings still need to be validated," says Andrew Feinberg, M.D., King Fahd Professor of Medicine at Johns Hopkins and a member of the school's McKusick-Nathans Institute for Genetic Medicine. "What is learned might improve the health of all children."
"At this point, we simply have a strong association between BWS and IVF," adds Michael R. DeBaun, M.D., M.P.H., assistant professor of pediatrics at Washington University School of Medicine and a staff physician at St. Louis Children's Hospital. "We need additional data to verify our findings, and if confirmed, to understand why there is an association."
BWS occurs in about 1 in 15,000 births overall. Currently, IVF is not thought to result in birth defects at a higher rate than natural conception, according to the Society for Assisted Reproductive Technology. "While our study has its limitations, we believe it's time to begin looking at these issues more formally," says Feinberg, who has been studying imprinting's role in disease, particularly cancer, for some time.
DeBaun started the Beckwith-Wiedemann Syndrome Registry in 1994 as part of an effort with Feinberg to find links between altered genes and different versions of BWS. Prior to June 2001, four of the BWS patients in the registry were known to have been conceived by IVF (out of 279). Suspecting an association, DeBaun began collecting details about conception methods for new patients entering the registry. Subsequently, three of 65 BWS patients added to the registry were conceived through IVF.
In the United States, roughly 0.8 percent of births are due to assisted reproductive technology, including IVF. The incidence is 4.6 percent among BWS patients entered into the registry since June 2001. The researchers note that they did not specifically recruit parents who had used IVF in order to have a child, but they can't exclude the possibility that such parents may have been more likely to participate.
BWS and other syndromes characterized by excessive growth are frequently due to so-called epigenetic changes - alterations to the gene other than to the DNA sequence itself. BWS is often caused by abnormal "imprinting" - biochemical marks on DNA that tell the cell whether the gene copy came from the father or mother. For imprinted genes, the cell uses only the copy from a particular parent (the mother or the father, depending on the gene) to make proteins.
If imprinting marks are lost, the cell may make proteins using both copies, or neither, causing abnormal growth, such as in BWS or cancer. Abnormal imprinting of two genes, LIT1 and H19, normally accounts for about half of BWS cases. At least five of the seven known registry patients conceived through IVF had such changes, says Feinberg.
While the association still needs to be confirmed, Feinberg suggests that some aspect of culture conditions or the method of combining the sperm and egg could possibly affect the epigenetics of embryos, based on reports of others' experience with animals.