Assisted Reproduction Linked to Rare Genetic Disorder

Salynn Boyles

January 15, 2003

Jan. 15, 2003 -- Preliminary findings from two recent studies indicate that the process of assisted reproduction can cause the genetic disruption associated with the disorder Beckwith-Wiedemann syndrome (BWS).

New research from the U.K., published in the January issue of the Journal of Medical Genetics, found that children with the syndrome were four times more likely than the general population to have been conceived by assisted reproduction technology (ART). A similar study of BWS from Johns Hopkins University researchers and reported in the January issue of the American Journal of Medical Genetics found that patients were six times as likely to have been conceived through in vitro fertilization (IVF).

Although the numbers are small -- with six identified BWS cases out of roughly 40,000 ART births during the time of the U.K. study -- they offer some of the strongest evidence yet that ART such as IVF and intracytoplasmic sperm injection (ICSI) carry a risk of genetic imprinting disorders.

"The theory is that assisted reproduction could change the normal process by which an imprint or a gene pattern expresses itself at a very early stage in the process of cell division," UK study author Trevor R. Cole, MD, of the University of Birmingham, tells Medscape. Imprinting is when one copy of a gene is switched off. Cole explains that this takes place at the two, four, or eight cell stages when the embryo is implanting into the womb. This is also when AR techniques may influence the process.

"We first recognized this association association four years ago, but we didn't have enough cases. We actually designed a protocol to ask families specifically about IVF two years ago, and we have collected the data over the last two years," Michael R. DeBaum, MD, second author of the Johns Hopkins study, told Medscape.

BWS normally occurs in about 0.13 per 10,000 births, and is characterized classically by macroglossia, pre- and/or postnatal overgrowth, anterior abdominal wall defects, and with variable features including hemihypertrophy, neonatal hypoglycemia, facial nevus flammeus, ear pits and creases, and renal anomalies. Children born with BWS are at high risk for developing embryonal tumors.

Suspecting a link between BWS and ART, U.S. researchers recently assessed conception history for a registry of 64 BWS patients, and found that three, or 4.6%, were conceived through IVF. Roughly 0.8% of total births in the U.S. are due to assisted reproduction. The findings by researchers at Baltimore's Johns Hopkins Medical Institutions and St. Louis' Washington University School of Medicine, were first reported last November.

"Our study is certainly not conclusive," says Cole, "but there are more cases than you would expect to see coincidentally."

Dr. Cole and colleagues found that three of the 149 babies with BWS in their registry were conceived through IVF and another three were conceived using ICSI.

Lead author in the American Journal of Medical Genetics study, Andrew Feinberg, MD, from Johns Hopkins University, also conducted molecular testing to look for characteristic patterns associated with BWS. Abnormal imprinting of the genes LIT1 and H19 normally accounts for about half of BWS cases, and Dr. Feinberg found these changes in five of seven patients conceived through IVF.

Dr. Feinberg told Medscape that more study is needed to clarify the link between BWS and ART, but he is disappointed with the response within assisted reproduction circles.

"I am a big advocate of ART, I think it is a miracle for families. I am not against it any means," Dr. Feinberg said. "But you still want to know what the effects are. This may well be a function of the culture condition or some other part of the process."

He theorized that culture conditions during assisted reproduction or the method of combining the sperm and egg could cause the genetic disruption that leads to the disorder.

"It is possible that this is preventable, but we will never know until this is studied further," Dr. Feinberg said. "We were hoping that our study would prompt the IVF community to look at this issue, but that has not been the reaction. The message to fertility doctors is loud and clear."

Obstetrician/gynecologist and geneticist Joe Leigh Simpson, MD, agrees that more research is needed to determine the true incidence of BWS in children conceived through ART. But he says the number of cases is likely to be so small that they will not dissuade infertile couples who are considering IVF or ICSI. Dr. Simpson is chairman of the OB/GYN department at Baylor College of Medicine in Texas and is past president of the American Society for Reproductive Medicine.

"There have been a million IVF babies born now, and there has not been a scintilla of concern that the overall frequency of anomalies with standard IVF is any different than the population as a whole," Dr. Simpson told Medscape. "That is not to say the community would be shocked if there were problems with a limited subset of the 40,000 genes that we have. But that remains to be proven."

What is needed, suggested Dr. DeBaum, is to determine the incidence of BWS in a large cohort of IVF babies. "Pediatricians should look for this in IVF babies at birth," he said. "BWS can be diagnosed at birth, but it is often not spotted until childhood or even later."

J Med Genet. 2003;40:62-64
Am J Hum Genet. 2003;72:156-160

Reviewed by Gary D. Vogin, MD


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