Widely Prescribed Antidepressant Linked to Birth Defects

Liam Davenport

January 14, 2016

Taking a widely used antidepressant during the first trimester of pregnancy is associated with an increased risk for congenital and cardiac malformations, concludes a systematic review and meta-analysis by Canadian researchers.

Anick Bérard, PhD, Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada, and colleagues found that use of the selective serotonin reuptake inhibitor (SSRI) paroxetine (multiple brands) during the first trimester of pregnancy is associated with a 23% increased risk for major congenital malformations and a 28% increased risk for major cardiac malformations.

Although noting that the absolute risk for congenital and cardiac malformations is low, the team writes: "Regardless of the size of the risk, it is essential to disseminate these findings given that it should be used to change practice, and impact appropriate antidepressant use during pregnancy."

The findings should not be considered to be proof of a link between use of SSRIs and birth defects, warned Katherine L. Wisner, MD, Norman and Helen Asher Professor in psychiatry and behavioral sciences and obstetrics and gynecology at Northwestern University Feinberg School of Medicine, Chicago, Illinois.

"Berard et al's meta-analytic results do not confirm that paroxetine causes birth defects. The observational studies included in this meta-analysis explore associations, not causality," Dr Wisner, who was not involved in the research, told Medscape Medical News.

"Meta-analyses are useful tools, but they are not conclusive. The quality of the meta-analysis is dependent upon the quality of the studies used to compose it," she added.

The study was published online November 27 in the British Journal of Clinical Pharmacology.

Consistent Increase in Risk

Dr Bérard explained that paroextine is one of the most widely used SSRIs and is "the most widely studied antidepressant in pregnancy." These studies indicated that, overall, there appeared to be an increased risk for congenital malformations and cardiac malformations with taking the drugs.

"There were mixed results between studies, but there was a consistent increase in risk demonstrated within studies, and of course some were statistically significant, some were not, and some showed no effect," she said.

The team undertook the current study because there were questions as to whether the differences in the size and significance of the risk was due to differences in study designs or populations or whether maternal depression was appropriately taken into account or adjusted for.

They conducted a systematic review of the EMBASE and MEDLINE databases for studies published between 1966 and 2015 on the risk for cardiac malformations associated with gestational exposure to paroxetine during the first trimester.

In all, 23 studies from Europe, the United States, Australia, Canada, and Israel met the inclusion criteria. Four were case-control studies; 15 were cohort studies. The study populations ranged from 534 to 949,504 individuals.

First-trimester exposure to paroxetine, in comparison with nonexposure, was associated with an increased risk for any major congenital malformations, at a pooled odds ratio (OR) of 1.23 across 15 studies.

Paroxetine exposure was associated with an increased risk for major cardiac malformations (pooled OR, 1.28 across 18 studies), specifically, bulbus cordis anomalies and anomalies of cardiac septal closure (pooled OR, 1.42; n = 8 studies), atrial septal defects (pooled OR, 2.38; n = 4 studies), and right ventricular outflow track defect (pooled OR, 2.29; n = 4 studies).

"There are differences [between studies] in outcome depending on study design, whether it's a cohort study, a case-controlled design, whether studies were performed on groups of women with maternal depression, or whether the maternal depression was taken into account in various ways in multivariate statistical models," Dr Bérard noted.

"But, overall, this could not explain, really, the increase in risk, because when we stratified on all these characteristics, we could see a consistent increase in risk. Sometimes it wasn't statistically significant because the sample size was decreasing the more you stratified, but, overall, there was an increase in risk," she added.

Class Effect?

Dr Bérard said that she believes that the effects seen with paroxetine represent a class effect, although she noted that the team did not study this specifically.

She pointed that that paroxetine inhibits fetal reuptake of serotonin during the first trimester, which is common to all SSRIs.

"Basically, serotonin is essential for embryogenesis, for heart development and the CNS and musculosketelal system and so forth, and the fact of inhibiting serotonin during that critical period can result in multiple birth defects. Here we were only looking at heart defects, but you can also see it in other types of birth defects," she said.

Dr Bérard believes that the findings contain a number of take-home messages for pregnant women.

"Basically, any women who have chronic conditions ― here we're taking about anxiety and depression, but we can talk about any chronic condition (asthma, hypertension, type 2 diabetes, and so forth) ― should really, really plan their pregnancy. I think this is essential," she said.

"Although we know that 50% of pregnancies are unplanned, it doesn't mean that they're not wanted. It's just that at 5 to 6 weeks of gestation, women find out that they're pregnant, and this is where most inadvertent exposures occur."

Dr Bérard highlighted the point that depression is a "very, very serious condition" that should be treated appropriately. "Antidepressants are one treatment option," she said, adding: "There are other treatment options.

"You have to remember that the majority, 80% to 85%, of our pregnant population that suffer from depression and anxiety are actually mildly to moderately depressed. Very few are severely depressed.

"In this subgroup, there're other options. Antidepressants is one of them, but there're very, very good randomized controlled trials [RCTs] in this subpopulation ― of course, not in the pregnant population because RCTs are not performed in the pregnant population ― showing that exercise or psychotherapy work very, very well in that subgroup, which is the majority of our pregnant population," she added.

In a message to pregnant women, Dr Bérard said: "If you find out you are pregnant, you've been taking paroxetine, and you're 5, 6 weeks into your pregnancy, do not stop your medication overnight. This is probably the worst thing to do when it comes to antidepressants.

"Depression is a very debilitating condition. It's associated with a lot of comorbidities and lifestyles that are not very good during pregnancy, so do not stop your medication but have a clear discussion with your healthcare provider at this point," she added.

Confounding a Major Issue

Commenting, Dr Wisner said that a "major methodological challenge" in interpreting studies such as these is that of confounding, and that the confounding factors "inherent in individual studies are not removed by inclusion in meta-analyses.

"Health factors associated with depression that affect pregnancy outcome (including risk for birth defects) include high levels of stress, poor diet, obesity, diabetes, and alcohol and other drug use," she added.

"Psychiatrically ill women who take SSRI medications during pregnancy differ from women who do not take them, often on severity of the disorder and other sociodemographic factors."

Dr Wisner pointed to a recent study by Krista F. Huybrechts, PhD, and colleagues, that involved almost 950,000 pregnant women, as reported by Medscape Medical News. In that study, no significant associations between the use of antidepressants during the first trimester and the risk for specific cardiac defects were found.

"A critical finding was that associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding," said Dr Wisner.

"This is the most methodologically sophisticated study conducted to date, and therefore it has had a major impact on the field of perinatal mental health," she added.

Returning to the current study, Dr Wisner took issue with the claim by Dr Bérard and colleagues that, "given that the benefit of using these medications during pregnancy is debatable, any increase in risk is significant."

Noting that no reference is provided to support the "debate" and that the data provided do not address the efficacy of maternal antidepressant treatment, she said: "The statement appears to be the authors' opinion rather than a balanced interpretation of this complex clinical issue.

"The choice to continue antidepressants in pregnancy must be an individualized decision with information from the prescriber and weighing of benefits and risks by the patient."

This study was funded by the Fonds de la Recherche du Québec–Santé (FRQ-S) and the Réseau Québécois de Recherche sur les Médicaments. Dr Bérard is the holder of a research chair on medications and pregnancy from the FRQ-S and is a consultant for plaintiffs in litigation involving antidepressants and birth defects. A coauthor is the recipient of a postdoctoral fellowship from the Canadian Institutes of Health Research.

Br J Clin Pharmacol. Published online November 27, 2015. Abstract

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