Thursday, August 6, 2015

Antidepressants and birth defects

The latest study on the risk for birth defects in women taking selective serotonin reuptake inhibitors (SSRIs) early in pregnancy provides "reassuring" evidence for some antidepressants in this class but not others.
The study of nearly 28,000 women found no increased risk for birth defects linked to citalopram (Celexa, Forest Laboratories, Inc), escitalopram (Lexapro, Forest Laboratories, Inc), and sertraline (Zoloft, Pfizer Inc) but confirmed two previously reported birth defects associated with fluoxetine (multiple brands) ― heart wall defects and craniosynostosis ― and five previously reported birth defects associated with paroxetine (multiple brands), including heart defects, anencephaly, and abdominal wall defects. 

Although these birth defects occurred 2 to 3.5 times more frequently among infants of women taking paroxetine or fluoxetine early in pregnancy, the absolute risk is low, the researchers note.
Jennita Reefhuis, Owen Devine, Jan M Friedman, Carol Louik, Margaret A Honein, on behalf of the National Birth Defects Prevention Study.  Specific SSRIs and birth defects: bayesian analysis to interpret new data in the context of previous reports.  BMJ 2015;351:h3190. 


Objective To follow up on previously reported associations between periconceptional use of selective serotonin reuptake inhibitors (SSRIs) and specific birth defects using an expanded dataset from the National Birth Defects Prevention Study. 

Design Bayesian analysis combining results from independent published analyses with data from a multicenter population based case-control study of birth defects. 

Setting 10 centers in the United States. 

Participants 17 952 mothers of infants with birth defects and 9857 mothers of infants without birth defects, identified through birth certificates or birth hospitals, with estimated dates of delivery between 1997 and 2009. 

Exposures Citalopram, escitalopram, fluoxetine, paroxetine, or sertraline use in the month before through the third month of pregnancy. Posterior odds ratio estimates were adjusted to account for maternal race/ethnicity, education, smoking, and prepregnancy obesity. 

Main outcome measure 14 birth defects categories that had associations with SSRIs reported in the literature. 

Results Sertraline was the most commonly reported SSRI, but none of the five previously reported birth defects associations with sertraline was confirmed. For nine previously reported associations between maternal SSRI use and birth defect in infants, findings were consistent with no association. High posterior odds ratios excluding the null value were observed for five birth defects with paroxetine (anencephaly 3.2, 95% credible interval 1.6 to 6.2; atrial septal defects 1.8, 1.1 to 3.0; right ventricular outflow tract obstruction defects 2.4, 1.4 to 3.9; gastroschisis 2.5, 1.2 to 4.8; and omphalocele 3.5, 1.3 to 8.0) and for two defects with fluoxetine (right ventricular outflow tract obstruction defects 2.0, 1.4 to 3.1 and craniosynostosis 1.9, 1.1 to 3.0). 

Conclusions These data provide reassuring evidence for some SSRIs but suggest that some birth defects occur 2-3.5 times more frequently among the infants of women treated with paroxetine or fluoxetine early in pregnancy.


  1. Today, I will be talking about our study published in the British Medical Journal titled, "Specific SSRIs and Birth Defects: Bayesian Analysis to Interpret New Data in the Context of Previous Reports." This study reassessed several previously reported links between birth defects and the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy.

    In this study, we looked at pregnant women who took one of five SSRIs during pregnancy and who received care between 1997 and 2009 at 10 sites in the United States. We compared women who took an SSRI and had a baby with a birth defect vs women taking the same SSRI whose live-born babies did not have a major birth defect. We used a Bayesian analysis, which allowed us to combine results from the published literature with over 12 years of data from the National Birth Defects Prevention Study, which is one of the largest collaborative, case-control studies aimed at understanding factors that increase the risk for major birth defects in the United States. This approach allowed us to demonstrate and refine linkages between use of SSRIs during pregnancy and certain birth defects.

    Overall, our study did not see some earlier reported links but confirmed other links previously observed between birth defects and some SSRIs when taken during early pregnancy. We found that some birth defects occur two to three times more frequently among babies born to women who took certain types of SSRI medications, like paroxetine and fluoxetine, early in pregnancy.

    Previous studies have reported links between fluoxetine use and four types of birth defects. Our study confirmed two of these links—heart defects that obstruct the right ventricular outflow tract and craniosynostosis. Our study also confirmed five of seven previous links between paroxetine use and certain birth defects. Paroxetine use appeared to be linked to anencephaly, atrial septal defects, heart defects that have obstruction of the right ventricular outflow tract, gastroschisis, and omphalocele.

    Reassuringly, we did not confirm links between sertraline, the SSRI used most often, and any of the birth defects observed in previous studies. Additionally, previous studies had shown links between the use of citalopram and escitalopram and certain birth defects, but our study did not definitively confirm any of those findings. However, citalopram and escitalopram were the least commonly used SSRIs by pregnant women in our study population.

    It is important to note that although our study found increased risks for a few types of birth defects among women using certain types of SSRIs, the absolute risk for a birth defect in an infant born to a mother taking one of these medications is small. For example, a woman's chance of having a child with a heart defect that obstructs the right ventricular outflow tract is about 10 per 10,000 births. Our results suggest that if she took paroxetine in early pregnancy, that risk could increase to about 24 per 10,000 births.

    If you are a healthcare provider treating women of reproductive age for depression or another mental health condition, you know that these conditions can be serious. Many women need to take medication during pregnancy for appropriate management of their symptoms.

  2. 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.(continued)

  3. (continued)"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...

    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...

    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)...

    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...

    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.

  4. Anick Bérard, Noha Iessa, Sonia Chaabane, Flory T. Muanda, Takoua Boukhris, Jin-Ping Zhao. The risk of major cardiac malformations associated with paroxetine use during the first trimester of pregnancy: A systematic review and meta-analysis. British Journal of Clinical Pharmacology published online doi: 10.1111/bcp.12849.


    The aim of this study was to perform an up-to-date meta-analysis on the risk of cardiac malformations associated with gestational exposure to paroxetine, taking into account indication, study design, and reference category.


    A systematic review of studies published between 1966 and November 2015 was conducted using EMBASE and MEDLINE. Studies reporting major malformations with first trimester exposure to paroxetine were included. Potentially relevant articles were assessed and relevant data extracted to calculate risk estimates. Outcomes included any major malformations, and major cardiac malformations. Pooled odds ratios and 95% confidence intervals were calculated using random-effects models.


    Twenty-three studies were included. Compared to non-exposure to paroxetine, first trimester use of paroxetine was associated with an increased risk of any major congenital malformations combined (pooled OR 1.23, 95% CI 1.10, 1.38; n=15 studies); major cardiac malformations (pooled OR 1.28, 95% CI 1.11, 1.47; n=18 studies), specifically bulbus cordis anomalies and anomalies of cardiac septal closure (pooled OR 1.42, 95% CI 1.07, 1.89; n=8 studies), atrial septal defects (pooled OR 2.38, 95% CI 1.14, 4.97; n=4 studies), and right ventricular outflow track defect (pooled OR 2.29, 95% CI 1.06, 4.93; n=4 studies). Although the estimates varied depending on the comparator group, study design and malformation detection period, a trend towards increased risk was observed.


    Paroxetine use during the first trimester of pregnancy is associated with an increased risk of any major congenital malformations and cardiac malformations. The increase in risk is not dependent on the study method or population.

  5. Huybrechts KF, Palmsten K, Avorn J, Cohen LS, Holmes LB, Franklin JM, Mogun H, Levin R, Kowal M, Setoguchi S, Hernández-Díaz S. Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med. 2014 Jun 19;370(25):2397-407.



    Whether the use of selective serotonin-reuptake inhibitors (SSRIs) and other antidepressants during pregnancy is associated with an increased risk of congenital cardiac defects is uncertain. In particular, there are concerns about a possible association between paroxetine use and right ventricular outflow tract obstruction and between sertraline use and ventricular septal defects.


    We performed a cohort study nested in the nationwide Medicaid Analytic eXtract for the period 2000 through 2007. The study included 949,504 pregnant women who were enrolled in Medicaid during the period from 3 months before the last menstrual period through 1 month after delivery and their liveborn infants. We compared the risk of major cardiac defects among infants born to women who took antidepressants during the first trimester with the risk among infants born to women who did not use antidepressants, with an unadjusted analysis and analyses that restricted the cohort to women with depression and that used propensity-score adjustment to control for depression severity and other potential confounders.


    A total of 64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6403 infants who were not exposed to antidepressants were born with a cardiac defect (72.3 infants with a cardiac defect per 10,000 infants), as compared with 580 infants with exposure (90.1 per 10,000 infants). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. The relative risks of any cardiac defect with the use of SSRIs were 1.25 (95% confidence interval [CI], 1.13 to 1.38) in the unadjusted analysis, 1.12 (95% CI, 1.00 to 1.26) in the analysis restricted to women with depression, and 1.06 (95% CI, 0.93 to 1.22) in the fully adjusted analysis restricted to women with depression. We found no significant association between the use of paroxetine and right ventricular outflow tract obstruction (relative risk, 1.07; 95% CI, 0.59 to 1.93) or between the use of sertraline and ventricular septal defects (relative risk, 1.04; 95% CI, 0.76 to 1.41).


    The results of this large, population-based cohort study suggested no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester. (Funded by the Agency for Healthcare Research and Quality and the National Institutes of Health.).