Annual Research Review: Maternal antidepressant use during pregnancy and offspring neurodevelopmental problems – a critical review and recommendations for future research

Abstract

Children of women treated with antidepressants during pregnancy are more likely to develop neurodevelopmental problems than are unexposed children. Associations between prenatal antidepressant exposure and neurodevelopmental problems could reflect a causal effect or could be partially or fully explained by other factors that differ between exposed and unexposed offspring, including having mothers with conditions requiring antidepressant treatment (e.g. depression), environmental risk factors, and/or genetic risk factors shared across disorders. This translational review aims to provide a brief overview of findings from rodent experiments and critically evaluate observational studies in humans to assess the extent to which associations between prenatal antidepressant exposure and neurodevelopmental problems are due to causal mechanisms versus other influences. We focus our review on two important neurodevelopmental outcomesautism spectrum disorder (ASD) and attention-deficit/ hyperactivity disorder (ADHD). In general, rodent studies have reported adverse effects of perinatal antidepressant exposure on neurodevelopment. Between-species differences raise questions about the generalizability of these findings to humans. Indeed, converging evidence from studies using multiple designs and approaches suggest that observed associations between prenatal antidepressant exposure and neurodevelopmental problems in humans are largely due to confounding factors. We also provide specific recommendations for future research. Animal research should explicitly evaluate the impact of timing of exposure and dosage of medications, as well as better map outcome measures in rodents to human neurodevelopmental problems. Observational studies should investigate specific confounding factors, specific antidepressant drugs and classes, the potential impact of timing of exposure, and a wider range of other potential offspring outcomes. The findings summarized in this review may help women and their doctors make informed decisions about antidepressant use during pregnancy by providing reassurance that use of these medications during pregnancy is unlikely to substantially increase the risk of ASD and ADHD.

Functional dissection of prenatal drug effects on baby brain and behavioral development

“…However, the wide‐spread SSRI effects were less expected. The use of antidepressants medication during pregnancy is thought to be relatively safe (Sujan, Öberg, Quinn, & D'Onofrio, 2019), but the topic is heavily debated (Talati & Weissman, 2019), with some reports showing increased risks for speech and language disorders in childhood (Brown et al, 2016), mood disorders in early adolescence (Brown et al, 2016), and other nonpsychiatric conditions (Gingrich et al, 2017). The topic is further complicated by the fact that maternal depression, the treatment target of SSRI, itself is linked to adverse neurodevelopmental outcomes (Lebel et al, 2016; Posner et al, 2016; Qiu et al, 2015; Rifkin‐Graboi et al, 2013; Wonch et al, 2016).…”

Perinatal mental health: a review of progress and challenges

“…There is considerably less evidence on longer‐term neurodevelopmental outcomes, but an emerging consensus that findings from preclinical (animal) studies may not apply to the human population 127 . For example, an initially concerning safety signal of an association between in utero exposure to SSRIs and autism spectrum disorder 128 is not supported by more recent, better quality evidence that takes into account confounding by underlying illness and familial variables 125,129 .…”

Commentary: Studies of prenatal antidepressant exposures: what can you recommend? A reflection on Sujan et al. (2019)

“…While risk for ADHD and ASD may not be increased with fetal SSRI in utero exposure, there is other evidence that SSRI exposure may increase the risk for other problems including certain speech and language disorders in childhood (Brown et al., ), mood disorders in early adolescence (Malm et al., ), and a host of non‐psychiatric conditions (see Gingrich et al., for review) beyond the risks associated with prenatal exposure to maternal depression itself. While we applaud the Sujan et al. review and agree that the evidence for the effects of SSRI in utero exposure for ASD and ADHD is equivocal, we argue that recommendations for antidepressant use during pregnancy must take into account other potential damaging effects on the offspring or other psychiatric or non‐psychiatric complications. Effective treatment decisions require evaluation of a fuller portfolio of potential risks and benefits to the mother‐child dyad in the context of the severity of the mother's symptoms.…”

“…Sujan et al. provide an elegant summary of the value and limitation of animal studies. Their conclusion is that most rodent studies have found effects of perinatal antidepressant exposure on neuronal brain and behavior indices related to neurodevelopmental problems.…”

“…Sujan et al. are to be congratulated for completing a monumental job reviewing the literature on a critical public health question: are antidepressant medications safe to use during pregnancy from the perspective of their potential effects on the infant and growing child? They have selected a problem of great magnitude because of the high prevalence of depression in childbearing years‐ especially in pregnancy, and because of the high use of medication for treating depression in pregnant women in the U.S.…”