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.

The study was published online July 8 in the BMJ.

Clinical Guidance

"This paper should be helpful to healthcare providers because it combines the knowledge from the literature with data from one of the largest studies able to look at these issues, the National Birth Defects Prevention Study," first author Jennita Reefhuis, PhD, epidemiologist with the National Center on Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention, told Medscape Medical News.

"Early pregnancy is a critical time for a baby's organs to develop, so the best time to discuss the safety of medication use is before pregnancy. If healthcare providers are treating women who are already pregnant, it is important to discuss the risk and benefits of antidepressants as well as the safest options available to treat their mental health condition during pregnancy," Dr Reefhuis said.

SSRIs are widely used by women of childbearing age and during pregnancy. Reports of an association between paroxetine and heart defects prompted the US Food and Drug Administration to issue a safety alert in 2005.

"Recent meta-analyses and systematic reviews combining data from more than 20 epidemiological studies have reached conflicting conclusions and this uncertainty influences perceptions of the safety of antidepressant use in pregnancy," the investigators write.

To get a more precise estimate of the potential risk for birth defects with specific SSRIs, they used bayesian methods to combine independent study findings with those from the National Birth Defects Prevention Study (NBDPS). The final analysis included 17,952 mothers of infants with birth defects and 9857 mothers of infants without birth defects.

The analysis confirmed previously reported ties between right ventricular outflow tract obstruction (RVOTO) cardiac defects in infants and maternal use of fluoxetine or paroxetine in the month prior to conception through the first trimester, and between anencephaly or atrial septal defects and use of paroxetine.

Fluoxetine OR (95% CI) RVOTO 2.0 (1.4 - 3.1) Craniosynostosis 1.9 (1.1 - 3.0) OR, odds ratio; CI, confidence interval.

The analysis also confirmed associations between gastroschisis or omphalocele and paroxetine and between craniosynostosis and fluoxetine found in an earlier analysis of NBDPS data. However, these associations "still require corroboration in an independent data source," the researchers say.

Paroxetine OR (95% CI) Anencephaly 3.2 (1.6 - 6.2) Atrial septal defects 1.8 (1.1 - 3.0) RVOTO 2.4 (1.4 - 3.9) Gastroschisis 2.5 (1.2 - 4.8) Omphalocele 3.5 (1.3 - 8.0) OR, odds ratio; CI, confidence interval.

"Although our analysis strongly supports the validity of the associations that were observed, the increase in the absolute risks, if the associations are causal, is small," the researchers note.

For example, if the association between maternal paroxetine use and anencephaly (OR, 3.2) is causal, the absolute risk would increase from 2 to 7 per 10,000 women using paroxetine in early pregnancy; for RVOTO (OR, 2.4), the absolute risk would increase from 10 to 24 per 10,000, they point out.

Continued Scrutiny Warranted

Dr Reefhuis and colleagues say that it is "reassuring" that none of the five previously reported associations between sertraline and birth defects were confirmed in this analysis, especially because about 40% of women who reported using an SSRI during early pregnancy used sertraline. The analysis also failed to provide support for nine other previously reported associations between SSRI use during pregnancy and selected birth defects.

"This analysis confirms the need to assess the association between specific SSRIs and specific birth defects rather than combining an entire drug class or heterogeneous group of birth defects," the researchers write.

"Continued scrutiny of the association between SSRIs and birth defects is warranted, and additional studies of specific SSRI treatments during pregnancy and birth defects are needed to enable women and their healthcare providers to make more informed decisions about treatment," they conclude. "Meanwhile, the current analysis can help guide healthcare providers and women to the safest options for treatment during early pregnancy to minimize the risk of major birth defects, while providing adequate treatment of maternal depression."

Christina Chambers, PhD, MPH, from the University of California, San Diego, has studied potential risks associated with SSRI use in pregnancy but was not involved in the current study. "No matter how many papers get published in this space, because it's such a common, controversial exposure, people are going to be interested," she noted in an interview with Medscape Medical News.

Over the years, studies have been "divided" in terms of whether there is a risk for birth defects with maternal use of SSRIs or not. So the question is, "what can we add to this picture," Dr Chambers said.

"The biggest challenge with birth defects is it's unfair to say that an entire class of drugs is implicated without having looked at the specific drugs," Dr Chambers noted. "Sometimes it works out that a class of drugs all do the same thing, but that is not always the case, so you need to look at individual drugs separately. That creates a challenge in terms of getting enough people exposed to that specific drug, and that's compounded by the fact that you are looking at rare outcomes. This new study attempts to add to the body of knowledge by looking at specific drugs and risks for specific birth defects," Dr Chambers said.

"The perplexing result," she said, "was no link with sertraline, which is the most commonly used drug and yet had previously been implicated with birth defects, and they came up with none. Maybe that is reassuring in some respects, and they did continue to find associations with paroxetine and fluoxetine."

Given these data, Dr Chambers said, clinicians deciding on an SSRI will probably have two questions: "Which drug works for this woman, and all things being equal, then maybe you would choose one that works and maybe the [birth defect] data were a little bit better."

The study was funded by the Centers for Disease Control and Prevention. The authors have disclosed no relevant financial relationships.

BMJ. Published online July 15, 2015. Full text