While we have data to support the use of antidepressants, including the selective serotonin reuptake inhibitors (SSRIs) and the serotonin norepinephrine reuptake inhibitors (SNRIs), during pregnancy, most studies have focused on risk of congenital malformations, and we have less information on longer term neurodevelopmental outcomes.  In a recent study, Singal and colleagues look at neurodevelopmental outcomes in kindergartners with prenatal exposure to antidepressants.  

Researchers utilized administrative databases to identify a population-based cohort of 266,479 children born in Manitoba, Canada between 1996 and 2014, with follow-up of the children through 2015.  This analysis was restricted to a subset of children whose mothers had a documented diagnosis of a mood or anxiety disorder during the 90 days before conception (N = 13,818). Exposure was defined as the dispensation of 2 or more SSRI or SNRI prescriptions during pregnancy (n = 2055).  A control group of unexposed mothers did not have any dispensation of an SSRI or SNRI during pregnancy (n = 10,017). 

The Early Development Instrument (EDI) was used to assess developmental health in kindergarten children. The EDI is a 104-component teacher-administered questionnaire, encompassing five developmental domains: physical health and well-being, social competence, emotional maturity, language and cognitive development, and communication skills and general knowledge.  

Of the 3048 children included in the analysis who met inclusion criteria and had an assessment with the EDI, 21.43% of the children in the exposed group were assessed as vulnerable on 2 or more domains versus 16.16% of the children in the unexposed group (adjusted odds ratio = 1.43; 95% confidence interval 1.08-1.90). Children in the exposed group also had a significant risk of being vulnerable in language and/or cognition (adjusted odds ratio = 1.40; 95% confidence interval 1.03-1.90).

One of the strengths of this study is that it attempted to control for confounding by indication. In contrast to previous studies which have used unexposed children born to healthy mothers with no history of psychiatric illness as a comparison group, this study included only women with a history of a mood or anxiety disorder.  While this strategy is likely to decrease potential confounding variables, it cannot completely eliminate confounding because it is likely that the women who elect to remain on antidepressant treatment during pregnancy differ from the women who elect to discontinue medication during pregnancy.  For example, women who decide to maintain treatment may have more chronic or severe depression or may be managing significant life stressors, factors which may ultimately affect the outcomes of their children independent of medication exposure. 

While this study suggests that children exposed to antidepressants during pregnancy may have worse developmental outcomes, it is important to note that measuring the impact of prenatal antidepressant exposures on neurodevelopmental outcomes presents significant challenges, as outcomes may evolve over the course of many years and are influenced by a myriad of external factors including nutritional status, education level, quality of child care, and adverse childhood experiences.  The studies using large medical databases cannot possibly take all of these variables into consideration.

Over the last few decades we have seen some studies indicating worse long term outcomes in children; however, a recent study encompassing data from 18 studies revealed no impact of antidepressant exposure on neurodevelopmental outcomes.  When researchers controlled for potential confounding variables, they found no consistent associations between antidepressant exposure and neurodevelopmental outcomes, including cognition, behavior, IQ, motor development, speech, language, and scholastic outcomes.  

Given that we will never be able to conduct large randomized controlled trials in pregnant women, this is as good as it gets.  (There are several excellent articles from Chittaranjan Andrade on this topic, see below.)  While we cannot say (and will never be able to say) that there is zero risk associated with prenatal exposure to SSRI and SNRI antidepressants, we can say that the risk is low, when we take all of the studies into consideration, rather than focusing only on a single or the most recent study.  

Ruta Nonacs, MD PhD

Singal D, Chateau D, Struck S, Lee JB, Dahl M, Derksen S, Katz LY, Ruth C, Hanlon-Dearman A, Brownell M.  In Utero Antidepressants and Neurodevelopmental Outcomes in Kindergarteners.  Pediatrics. 2020 May;145(5). 

Andrade C.  Genes as Unmeasured and Unknown Confounds in Studies of Neurodevelopmental Outcomes After Antidepressant Prescription During Pregnancy.  J Clin Psychiatry. 2020 May 26;81(3):20f13463. Free Article

Rommel AS, Bergink V, Liu X, Munk-Olsen T, Molenaar NM.    Long-Term Effects of Intrauterine Exposure to Antidepressants on Physical, Neurodevelopmental, and Psychiatric Outcomes: A Systematic Review.  J Clin Psychiatry. 2020 May 12;81(3):19r12965.

Andrade C.  Offspring Outcomes in Studies of Antidepressant-Treated Pregnancies Depend on the Choice of Control Group.  J Clin Psychiatry. 2017 Mar;78(3):e294-e297. Free Article