Paroxetine, Fluoxetine in Early Pregnancy Linked to Heart Defects in Offspring

Findings Do Not Warrant Cessation of Antidepressant Treatment With These Agents

Caroline Cassels

December 03, 2008

December 3, 2008 — Fluoxetine and paroxetine, 2 of the most commonly used selective serotonin reuptake inhibitors (SSRIs), have been linked to an increased risk for congenital cardiac abnormalities in the offspring of women who took these medications in early pregnancy, new research suggests.

However, say investigators, the findings do not warrant cessation of antidepressant therapy with these agents in this patient population.

"We did find an increased risk of cardiac anomalies, but the vast majority were not severe, and most were treatable, so we do not recommend women stop their treatment," principal investigator Asher Ornoy, MD, from Israeli Teratology Information Service, in Jerusalem, Israel, told Medscape Psychiatry.

Of much greater concern, said Dr. Ornoy, is the finding that smoking while taking either of these agents has a synergistic effect. The researchers found women taking these medications who smoked more than 10 cigarettes per day while pregnant had a significantly increased risk of giving birth to a child with a major cardiac malformation.

"Pregnant women who take these medications and who smoke should stop smoking immediately," said Dr. Ornoy.

The study is published in the November issue of the British Journal of Clinical Pharmacology.

Need for Prospective Data

It is estimated that 9% to 14% of all pregnant women display signs of depression and/or meet diagnostic criteria for depression. In the United States SSRI use during pregnancy increased from 1.5% in 1996 to 6.4% in 2004.

In recent years, there has been concern about the use of SSRIs in pregnancy and that paroxetine, in particular, may increase the risk for fetal malformations, mainly cardiac.

In September 2005, GlaxoSmithKline, a manufacturer of paroxetine, revised the drug's label, adding a warning that the drug's use in pregnancy may increase the risk for cardiac defects.

In December 2005, the label was further revised and the pregnancy warning was revised again to indicate there is positive evidence of human fetal risk, but despite this risk, the benefits from use in pregnancy may be acceptable.

According to Dr. Ornoy, some of the previous research into SSRIs during pregnancy has been retrospective and burdened with recall and selection bias, highlighting the need for prospective data.

The current prospective, controlled, observational study from 3 Teratogen Information Centers in Israel, Italy, and Germany followed up 2191 pregnant women — 410 who had taken paroxetine and 314 who had taken fluoxetine in the first trimester of pregnancy and 1467 control patients who had not taken either drug.

The study's primary outcome was the rate of major congenital abnormalities, defined as structural abnormalities in the offspring that have serious medical, surgical, or cosmetic consequences, in the 3 groups.

Significant neurodevelopmental or functional problems were also categorized as major anomalies, even in the absence of a structural abnormality, when they required special education or interventions.

Secondary end points included pregnancy outcome, birth weight, gestational age at delivery and neonatal complications.

The researchers found an approximate 2-fold increased risk in the overall rate of congenital anomalies in the SSRI groups compared with control groups, and of these, cardiovascular anomalies were the most common.

No Increase in Other Congenital Anomalies

The prevalence of heart anomalies was 2.8% in the fluoxetine group, 2% in the paroxetine group, and 0.6% in the control group. However, there was no increase in other major congenital anomalies.

Among 665 women who took 1 of the 2 SSRIs in the first trimester of pregnancy, 88 (13.2%) — 52 in the paroxetine group and 36 in the fluoxetine group — smoked more than 10 cigarettes per day, and this was associated with a 5.4-fold increased risk of having a child with a cardiac anomaly.

Previous pregnancy terminations were also higher in the fluoxetine and paroxetine groups compared with controls, with rates of 7.8%, 4.8%, and 2.8%, respectively. Birth weights were slightly lower in the fluoxetine and paroxetine groups than the control group.

In addition, women taking SSRIs were much more likely to smoke — approximately 20% vs 7.5% for control patients. In addition, those on fluoxetine and paroxetine were more likely to smoke more than 10 cigarettes a day, with rates of 12.3%, 14%, and 4.4% respectively.

"Generally these 2 medications are safe in pregnancy. There may be an increase in cardiac anomalies, but in general these are not severe and most are treatable. In addition, these medications do not increase the rate of other major anomalies and do not increase the rate of perinatal complications, including prematurity," Dr. Ornoy said.

"Based on these results, we believe pregnant women should continue to take these medications. However, if they smoke, they should be encouraged to stop as soon as possible and perhaps undergo fetal echocardiography for early detection," he added.

No relevant conflicts of interest reported.

Br J Clin Pharmacol. 2008;65:695-705. Abstract

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