Paxil pregnancy warning strengthened again.

The Food and Drug Administration has stepped up warnings that paroxetine increases the risk of congenital defects, especially cardiovascular malformations.

In September, GlaxoSmithKline, which markets paroxetine under the trade name Paxil, had updated the drug's labeling in conjunction with the FDA. The change was based on initial data from a U.S. insurance claims database indicating a slightly higher risk of fetal defects in women who had taken the drug in the first trimester.

When further information became available in December, GlaxoSmithKline and the FDA agreed that label should be changed again, and that paroxetine should be reclassified from a pregnancy category C to a D. The D designation indicates "that studies in pregnant women have demonstrated a risk to the fetus," the agency said in a statement.

The warnings apply to all formulations of paroxetine, branded and generic.

Dr. Gideon Koren, director of the Toronto-based Motherisk program, expressed concern that the FDA's newest warnings will drive many pregnant women away from antidepressants. Treating depression during pregnancy should be a top priority, said Dr. Koren, whose program conducts research and serves as a clearinghouse on potentially toxic exposures and also counsels pregnant women.

GlaxoSmithKline said that about 25% of prescriptions for paroxetine (including generics) are written for women of childbearing age.

Overall, analyses of data from two registries--one in the United States and one in Sweden--showed that women who take paroxetine during the first 3 months of pregnancy are 1.5-2 times more likely to have a baby with a heart defect than women who took other antidepressants, or women in the general population. According to the FDA, infants who were exposed to paroxetine in the first trimester had a 1.5-fold increased risk for cardiac malformations, and a 1.8-fold increased risk for congenital malformations of any kind, compared with infants exposed to any other antidepressant.

Even though the data are preliminary, the findings warrant an immediate change, said Dr. Alice Hughes, medical safety officer and safety reviewer for the division of neurology products and division of psychiatry products at the FDA. "Because of the serious nature of the potential outcome involved, we did not want to delay informing patients and prescribers of the potential risk to the fetus," she said in an interview.

But Dr. Koren maintained that the agency had acted prematurely, especially since the registries are not rigorous studies, and noted that the data had not been peer reviewed. "I don't understand how they can come to such sweeping conclusions with such poor science," said Dr. Koren, who is also a professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto.

He noted that at least two peer-reviewed, published studies have shown no increased rates of cardiac malformations with paroxetine. There has been no proven association between birth defects and any drug in the class, selective serotonin reuptake inhibitors, he added.

Dr. Hughes, however, said that the FDA did take into account all of the available evidence in deciding whether to change paroxetine's labeling.

And the data in the Swedish registry were collected prospectively, she noted.

The studies that were published before this year "had too few relevant paroxetine exposures to adequately assess paroxetine-associated birth defect risk," Dr. Hughes added.

Dr. Koren said the registry findings could be biased. Depressed women are known to seek more ultrasound and other testing, which would turn up more instances of malformations.

The primary data came from a Glaxosponsored retrospective cohort analysis of a UnitedHealthcare database. Women who were given antidepressants and who had a child between January 1995 and September 2004 were studied.

The adjusted odds ratio for congenital malformations after first-trimester exposure to paroxetine was 1.82, with a prevalence of 4%. The adjusted odds ratio for cardiovascular malformations was 1.79 and the prevalence was 2%. (Detailed methodology and findings can be accessed at http://ctr.gsk.co.uk/summary/paroxetine/studylist.asp.)

A study of Swedish national registry data found a twofold increased risk of heart defects in association with paroxetine use in the first trimester, compared with a 1% risk in the whole population. However, this study found no increased risk of overall congenital malformations, which Glaxo said is consistent with previous published analyses of the Swedish registry.

Most of the cardiac malformations were atrial or ventricular septal defects, which are among the most common of congenital defects. They only occur in the first trimester and can spontaneously resolve, but may require surgical repair. The agency said it is unclear what risk paroxetine might pose when used after the first trimester.

In its letter to health care professionals, the drug maker said, "It is not clear if the findings from these studies represent a true causal association with maternal paroxetine exposure." The company recommended that paroxetine therapy should not be initiated in women who intend to become pregnant or who are in the first trimester, unless there are no other options. Patients who become pregnant should be advised of the potential for birth defects and should either discontinue or switch to an alternative, Glaxo said.

Both FDA and the company warned that drug therapy should not be stopped abruptly, and that in individual cases, the benefits of paroxetine may outweigh the potential risk to the fetus.

Women who seek counseling from Motherisk are being told that they should not discontinue paroxetine "cold turkey," and that an ultrasound or fetal echocardiogram can detect cardiovascular malformations if that is a concern. As noted, the defects can resolve on their own, Dr. Koren said.

The December update is not likely the last word on paroxetine and birth defects. FDA's Dr. Hughes said the agency expects more data late in 2006. "It is possible that further labeling changes will be necessary," she said.

BY ALICIA AULT

Contributing Writer