Some birth-defects specialists say they are concerned about the possibility of a cholesterol-lowering statin drug going over the counter, a move to be considered today and Friday by a Food and Drug Administration advisory committee.
In a joint venture with Johnson & Johnson, drugmaker Merck has asked the FDA for permission to make Mevacor, the brand name for lovastatin, available without a prescription. The companies hope to market a 20-milligram daily dose to men 45 and older and women 55 and older, the ages at which cardiovascular disease risk begins to rise. Over-the-counter Mevacor would widen access to cholesterol treatment, thereby helping to reduce the number of Americans who have heart attacks, Merck argues.
The FDA classifies Mevacor and other statins as pregnancy category X, which means they are not supposed to be taken by pregnant women. Not only have category X drugs been linked to fetal abnormalities in animal or human studies, but the FDA also has declared that the benefits of taking them do not outweigh potential risks.
“Of course, there will be women who take it off-label,” acknowledges Merck executive Edwin Hemwall, referring to the use of non-prescription Mevacor by women under 55.
That worries the March of Dimes, which will distribute a statement at the FDA meeting expressing its opposition to Merck’s plan. “Increasing maternal ages and widespread public recognition of statins may increase the likelihood of pregnancy and statin use,” the statement says.
“There is a hypothesized link between the use of statins during pregnancy and a set of birth defects,” says Siobhan Dolan of the March of Dimes. “Until we have research that really tests this hypothesis it is very concerning to us to consider making more widely available a medication that could cause birth defects.”
Although it is extremely unlikely that a doctor would prescribe a statin to a pregnant patient, a woman might unknowingly become pregnant while taking a statin, says Stephen Braddock, director of Missouri’s Teratogen (drugs, chemicals or infections that could cause birth defects) Information Service. After all, Braddock notes, half of all pregnancies are unplanned.
Braddock surveyed 11 of the 20 North American teratology information services and found they had had a total of 188 calls from January 2001 to September 2004 from pregnant women who took statins.
Importance of cholesterol
Cholesterol is essential for development of the brain, heart and limbs, and statin researchers have long been aware of the need to avoid interfering with its production in a fetus, says Hemwall, vice president of worldwide regulatory and scientific affairs for Johnson & Johnson/Merck.
“There are hundreds of healthy babies that have been born to women who have been exposed to statins,” he says, adding that there have been reports of fetal abnormalities. “We’re very concerned that this not be taken indiscriminately by women of childbearing potential.” The proposed label for OTC Mevacor warns pregnant or breastfeeding women not to use it.
About 3% or 4% of all babies have a birth defect, says John Carey, founder of Utah’s Pregnancy Risk/Line, a teratogen information service. In two out of three cases, doctors are never able to pinpoint a cause, although they probably are not due to medicine the mother took, says Carey, a University of Utah pediatrician.
A possible link studied
Though it is not known whether any birth defects in babies born to women who took statins were caused by the drugs, a study published last month in the American Journal of Medical Genetics raises the possibility.
“This work has definitely pressed the issue that there should be some concern about statin use in pregnancy,” editor in chief Carey says.
Robin Edison and Maximilian Muenke of the National Human Genome Research Institute obtained reports from the FDA, manufacturers and the medical literature about pregnant women who took statins during their first trimester. Reporting problems related to medication use is voluntary, so the cases are thought to represent only a fraction of the total.
Edison and Muenke, chief of medical genetics, were looking for patterns of defects that might suggest a link to statin use. Of the 70 reports that contained enough information to assess, there were 22 cases of babies born with anatomical defects. Of those 22 cases, a handful stood out. They were extremely rare defects consistent with those seen in experimental animals with low cholesterol and in humans with a genetic mutation that prevents proper use of cholesterol.
Two babies whose mothers took Zocor had legs of unequal lengths and foot abnormalities. One of those babies, as well as a baby whose mother took Mevacor, also had a constellation of other birth defects that affected the heart, kidneys, skeleton and other organs. In addition, one baby whose mother took Mevacor and one whose mother took Baycol had a severe brain defect. (Baycol came off the market in 2001 because it had been linked to a life-threatening muscle condition.)
Anthony Scialli, director of the National Institute of Environmental Health Sciences’ Center for the Evaluation of Risks to Human Reproduction, says he is skeptical about the findings’ significance. In his view, Scialli says, the noted birth defects are too dissimilar to suggest a pattern related to statin use. “The whole question is are these just incidental?” he says.
Edison and Muenke acknowledged that their small study of case reports, which lacks a comparison group of babies whose mothers did not take statins, does not rule out other causes. But, they write, their findings represent “a meaningful signal that deserves further attention.” Edison says she will discuss the results with the FDA panel.
Difficulty showing a connection
Determining whether statins cause birth defects will be difficult, says Lewis Holmes, director of the Antiepileptic Drugs Pregnancy Registry at Massachusetts General Hospital. Relatively few women take statins during pregnancy, and if only a small percentage of their babies are affected, “it’s going to take a long time to nail it down,” he says. One way to get answers, Holmes says: Have the FDA require makers to track OTC statin use by pregnant women, Holmes says.
Braddock, a University of Missouri pediatrician, has asked the National Institutes of Health to finance research he thinks could answer the pregnancy question. The study would enroll 90 pregnant women who had taken statins. For comparison purposes, the study also would enroll pregnant women who did not take statins.
Once their babies were born, doctors would examine them for even the subtlest of abnormalities that might or might not track with statin use.
Meanwhile, Sonja Rasmussen, a medical geneticist at the Centers for Disease Control and Prevention, says the CDC’s National Birth Defects Prevention Study plans to investigate the possible connection between statin use in pregnancy and birth defects.
Researchers with the project, one of the largest birth-defects studies ever done, have interviewed more than 18,000 mothers of babies with and without birth defects, Rasmussen says. But, she says, the study does not yet include enough women who took statins while pregnant “to provide a meaningful analysis of the risks.”