Which Antidepressants May Cause Birth Defects?

While associations have been found between antidepressant use during gestation and an increased risk of major congenital malformations, variations in study results still remain, and may be confounded by the mother’s depression, class effect, or a lack of statistical power. 

Anick Bérard, PhD, from the University of Montreal in Quebec, Canada and colleagues investigated this topic further and found that in a large study of pregnant, depressed women, antidepressants that affected serotonin reuptake during embryogenesis increased the risk of some organ malformations in the baby.¹

The researchers included data from 18 487 women from the Quebec Pregnancy Cohort (QPC). Pregnancies were included if mothers had a diagnosis of depression or anxiety, if they were exposed to antidepressants within 12 months before pregnancy, or if they delivered a single, live-born baby.

The researchers compared different classes of antidepressants (selective serotonin reuptake inhibitors (SSRI), serotonin–norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants, (TCA) and other antidepressants) during the first trimester with non-exposure to antidepressants during the first trimester (depressed untreated), and identified major congenital malformations and organ-specific malformations in the first year of life.

Out of the 18 487 women, 3640 were exposed to antidepressants during the first trimester; 2327 (63.9%) were exposed to SSRIs (1132 were exposed to paroxetine, 365 to sertraline, 584 to citalopram, 191 to fluoxetine, and 55 to fluvoxamine), 738 (20.3%) to SNRIs (all users of venlafaxine), 382 (10.5%) to TCA (318 of TCA users were on amitriptyline), and 193 (5.3%) to other antidepressants.

Major Congenital Malformations

The researchers found that when comparing specific antidepressants’ effects during the first trimester, only citalopram significantly increased the risk of major congenital malformations (adjusted OR, (aOR) 1.36, 95% CI 1.08 to 1.73; 88 exposed cases). The other antidepressants increased risk as follows: paroxetine (aOR 1.24, 95% CI 0.99 to 1.55), sertraline (aOR 1.09, 95% CI 0.80 to 1.50), fluoxetine (aOR 0.80, 95% CI 0.49 to 1.31), fluvoxamine (aOR 0.63, 95% CI 0.23 to 1.77), venlafaxine (aOR 1.10 95% CI 0.87 to 1.38), tricyclic antidepressants (aOR 1.16, 95% CI 0.86 to 1.56), and other antidepressants (aOR 0.93, 95% CI 0.59 to 1.47).

Organ-Specific Defects

Antidepressants with a serotonin reuptake inhibition effect (SSRI, SNRI, amitriptyline (the most used TCA)) increased the risk of certain organ-specific defects. Paroxetine increased the risk of cardiac defects (aOR 1.45, 95% CI 1.12 to 1.88) and ventricular/atrial septal defects (aOR 1.39, 95% CI 1.00 to 1.93); citalopram increased the risk of musculoskeletal defects (aOR 1.92, 95% CI 1.40 to 2.62) and craniosynostosis (aOR 3.95, 95% CI 2.08 to 7.52); TCA was associated with eye, ear, face and neck defects (aOR 2.45, 95% CI 1.05 to 5.72) and digestive defects (aOR 2.55, 95% CI 1.40 to 4.66); and venlafaxine was associated with respiratory defects (aOR 2.17, 95% CI 1.07 to 4.38).

“Given that the majority of antidepressant use during the first trimester of pregnancy is from inadvertent exposure when women are not aware that they are pregnant, exposure occurs during the early phase of gestation,” the authors wrote. “Serotonin during early organogenesis is essential for the development of all embryonic cells, and thus any insult that has the potential to disturb the serotonin signaling process has the potential to result in a wide variety of malformations.”²

Clinical Applicability

The researchers concluded that infants were at an increased risk of cardiac, musculoskeletal, craniofacial, digestive, and respiratory defects, as well as craniosynostosis, from in utero exposure to serotonin inhibitor drugs (SSRI, SNRIs, and some TCAs).

This has direct implications for managing the increasing numbers of women diagnosed with depression during pregnancy, especially given that the effectiveness of antidepressants during pregnancy has been shown to be marginal.³

“Hence, the need for caution with antidepressant use during pregnancy is warranted and alternative non-drug options should be considered,” the authors concluded.

Limitations 

• Only single, live births were considered. Because spontaneous abortions were not included, which are indicative of severe birth defects, these study results likely underestimate the true risk of antidepressants to the fetus.
• Analyses of some organ-groups had lower statistical power (post hoc statistical power ranged from 28% to 86%.) 

References 

1. Bérard A, Zhao J-P, Sheehy O. Antidepressant use during pregnancy and the risk of major congenital malformations in a cohort of depressed pregnant women: an updated analysis of the Quebec Pregnancy Cohort. BMJ Open. 2017;7(1):e013372. doi:10.1136/bmjopen-2016-013372
2. Sadler TW. Selective serotonin reuptake inhibitors (SSRIs) and heart defects: potential mechanisms for the observed associations. Reprod Toxicol. 2011;32:484–9. doi:10.1016/j.reprotox.2011.09.004
3. Swanson SA, Hernandez-Diaz S, Palmsten K, et al. Methodological considerations in assessing the effectiveness of antidepressant medication continuation during pregnancy using administrative data. Pharmacoepidemiol Drug Saf. 2015;24:934–42. doi:10.1002/pds.3798