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Mothers who took certain antidepressants in early pregnancy had an elevated risk of having children with birth defects, a case-control study found.

Compared with other selective serotonin reuptake inhibitors (SSRIs), paroxetine (Paxil) and fluoxetine (Prozac) had the highest number of associations with specific birth defects, reported Kayla Anderson, PhD, of the CDC's National Center on Birth Defects and Developmental Disabilities in Atlanta, and colleagues in .

For example, fluoxetine use in early pregnancy was linked to more than double the risk of anomalous pulmonary venous return in infants when compared to unexposed pregnancies (aOR 2.56, 95% CI 1.10-5.93), though the risk was attenuated by accounting for underlying mental health disorders (aOR 1.89, 95% CI 0.56-6.42).

Venlafaxine (Effexor), a selective norepinephrine reuptake inhibitor (SNRI), had the highest proportion of elevated birth defect risks, and was associated with heart and neural tube defects, gastroschisis, and defects to the oral cleft.

Between 6-8% of pregnant women in the U.S. reported being prescribed or using an antidepressant, according to the study, and the risk of antidepressant use in pregnancy is not well defined, with limited evidence on specific medications.

In an email to 乌鸦传媒, co-author Jennita Reefhuis, PhD, said that this research clarified previous findings, showing that SSRIs like sertraline (Zoloft), fluoxetine, paroxetine, and citalopram (Celexa), were each associated with a small number of birth defects.

"We were surprised to find that the small number of associations between specific SSRIs and non-heart birth defects remained even after partially accounting for the underlying mental health condition," said Reefhuis. She added that this may suggest defects are due to the medications themselves, but further research is needed.

In an accompanying , Katherine Wisner, MD, of Northwestern University School of Medicine in Chicago, and colleagues pointed out that distinguishing between the adverse effects of psychiatric illness and effects of medications on risk of birth defects is a major challenge in observational research.

Missing information on psychiatric diagnosis, unaccounted residual confounders, and recall bias are all possibilities that may skew these results, the editorialists wrote. They added that the multiple risks with venlafaxine affect a small proportion of this patient population, as it's not a first-line drug for pregnant women.

"The evidence accumulated over the past 2 decades points to the risk (if any) for birth defects associated with antidepressants to be acceptable compared with the risks of untreated or undertreated maternal depression," Wisner and colleagues wrote. "Only when we effectively define and communicate scientific evidence of benefit-risk tradeoffs to pregnant women and clinicians will we improve outcomes for this vulnerable population."

Reefhuis said that this study may inform larger conversations around antidepressant use during pregnancy.

"Healthcare providers play an important role in reviewing safety information and making shared decisions with women about treatments before, during, and after pregnancy," she said. "Fully informed, shared decision-making requires balancing the risks and benefits of medical treatment with the potential risks to women, and their developing babies, of untreated depression or anxiety."

Study Details

Anderson and colleagues obtained data from the , a population-based, multisite case-control study in the U.S., and included pregnancies from 1997 to 2011.

The researchers compared mothers of infants with a birth defect to those whose infants had none. Mothers were interviewed via computer-assisted technology, anywhere from 6 weeks to 2 years after their estimated delivery date. Participants self-reported start and stop dates, frequency and duration of antidepressant use in the 3 months leading up to conception and during pregnancy.

All infants with known genetic disorders or chromosomal abnormalities were excluded from the study, as were mothers with incomplete medication histories, diabetes during pregnancy, or teratogenic medication use before or during pregnancy.

Researchers conducted two birth defect analyses. The first compared women exposed to antidepressants in early pregnancy to those who were not exposed at all. This analysis was adjusted for maternal race and ethnicity, prepregnancy body mass index (BMI), education, and early pregnancy smoking and alcohol use.

After this, the group compared women exposed to antidepressants in early pregnancy to those who were exposed outside of this time period, to account for the underlying conditions that indicated medication use. They adjusted this model for maternal education.

There were 30,630 mothers of infants who had a birth defect, and 11,478 in the control group. Around 5% of those whose infant had a birth defect and 4% of control mothers reported antidepressant use in early pregnancy. The most common antidepressants used by the control group were sertraline, fluoxetine, paroxetine, citalopram, escitalopram, venlafaxine and bupropion.

Mothers exposed to antidepressants in early pregnancy were more likely to be older, non-Hispanic white, have a previous live birth, and report alcohol or smoking use during pregnancy. They also had higher education levels and prepregnancy BMI.

Risks were attenuated when underlying conditions were accounted for, and no elevated birth defect risk was observed with the use of escitalopram.

Anderson and colleagues did not confirm mental health diagnoses associated with specific drug treatment, which limited their ability to completely account for underlying conditions. They also did not account for the differences in half-life of antidepressants, which may have resulted in periods of use classified as non-exposures.

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