Prenatal Antidepressant SSRIs Linked to Offspring Brain Development Changes

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Prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) may be linked to changes in the development trajectories of emotional regulation in the brain among offspring, according to new research.

Data from a team of Holland and US investigators showed parameters of brain morhopmetry—including significant changes in amygdala volume, cerebral white matter and fusiform gyrus through early adolescent age among children exposed to SSRIs in utero versus those who were not. Though the findings also showed a “catch-up growth” stage of compensation among those affected, the team believes more follow-up analysis into the impact of the antidepressant drug class on offspring brain development is necessary.

Investigators led by Henning Tiemeier, MD, PhD, of the department of social and behavioral sciences at Harvard T.H. Chan School of Public Health, sought to assess the associations between intrauterine SSRI exposure, maternal depressive symptoms and structural brain development in offspring from childhood through early puberty.

Up to 1 in 5 women experience symptoms of depression and anxiety during pregnancy, investigators noted; another 1 in 10 receive antidepressant treatments including SSRIs, generally as a maintenance therapy for the prevention of relapsing psychiatric symptoms.

Currently, prescribing SSRIs to pregnant individuals is generally considered safe,” investigators wrote. “However, methodologic limitations complicate understanding of potential direct consequences of prenatal SSRI exposure for offspring.”

Tiemeier and colleagues conducted the prospective, population-based cohort analysis using data from the Generation R Study held in Rotterdam; the trial included pregnant participants with an expected delivery date between April 2002 and January 2006. As the team noted, prenatal SSRI uptake in northern Europe is generally lower than among US women. The team analyzed cohort data from February – September 2022.

Investigators sought a primary outcome of offspring brain morphometry, including global and cortical brain volumes, measured at 3 magnetic resonance imaging (MRI) assessments from ages 7 – 15 years old, based on maternal SSRI uptake.

Pharmacy records were used to verify maternally-reported SSRI use; participants reported depressive symptoms via Brief Symptom Inventory assessment at mid-pregnancy, then 2 and 6 months post-delivery. Participants and their offspring were stratified into 5 cohorts:

• SSRI use during pregnancy (n = 41; 80 scans)
• SSRI use only prior to pregnancy (n = 77; 126 scans)
• Prenatal depressive symptoms without prenatal SSRI use (n = 257; 477 scans)
• Postnatal depressive symptoms only (n = 74; 128 scans)
• Nonexposed control individuals (n = 2749; 4813 scans)

The final analysis included 3198 mother-child dyads and 5624 total offspring scans from ages 7 – 15 years; mean maternal age at intake was 31.1 years old. A majority (52.2%) of offspring were female.

A majority of brain gray matter volumes showed an inverted U-shaped trajectory in offspring. Children prenatally exposed to SSRIs reported less cerebral gray matter—particularly within the corticolimbic circuit—compared to nonexposed children at up to 15 years old. Exposed children additionally showed a significantly greater mean increase in amygdala volume and fusiform gyrus from 7 to 15 years old. However, the volumetric differences did not persist until early adolescence.

Investigators additionally observed an association between prenatal depression and smaller volume of the rostral anterior cingulate gyrus, as well as with postnatal depression and reduced fusiform gyrus. They did not, however, identify a link between SSRI use prior to pregnancy and changes in offspring brain outcomes.

In an editorial accompanying the research, Ardesheer Talati, PhD, of the department of psychiatry at Columbia University and division of translational epidemiology at New York State Psychiatric Institute, praised the research as helping to provide “inroads to our understanding of how brain development through adolescences may be associated with prenatal SSRI exposure.”

“However, the clinical significance was unclear, especially as key limbic regions, including the amygdala, normalized over time,” Talati wrote. “If future evidence links brain anomalies to adverse youth outcomes, this will need to be calibrated into the risk-benefit profile. Until then, it seems unwise to overinterpret studies like that of Koc et al to either promote or discourage antidepressant medication use during the critical period of pregnancy.”

Investigators concluded similarly, noting that the findings may elucidate a greater understanding of the link between exposure to antidepressants in utero and offspring brain growth—if further explored.

“Well-designed replication studies in diverse settings are needed before evidence-based recommendations can be derived, as the prevalence of SSRI use during pregnancy varies across populations,” they wrote.

References

1. ^{Koc D, Tiemeier H, Stricker BH, Muetzel RL, Hillegers M, El Marroun H. Prenatal Antidepressant Exposure and Offspring Brain Morphologic Trajectory. JAMA Psychiatry. Published online August 30, 2023. doi:10.1001/jamapsychiatry.2023.3161}
2. ^{Talati A. Maternal Depression, Prenatal SSRI Exposure, and Brain Trajectories in Childhood. JAMA Psychiatry. Published online August 30, 2023. doi:10.1001/jamapsychiatry.2023.2664}