However, the investigators, led by Henning Tiemeier, MD, PhD, professor of social and behavioral sciences at Harvard School of Public Health in Boston, note that the findings should be interpreted cautiously because the size of the study population who received brain MRI was relatively small.
Dr. Tiemeier said in an interview that the associations detected were small and could not show causality between prenatal SSRI use and a decrease in gray and white matter across certain areas of the brain.
“Women who are pregnant and on maintenance therapy should consult their therapist if preventive therapy is still needed and if there are alternatives. This choice must be carefully considered, and women should be carefully advised,” he said.
The study was published online in JAMA Psychiatry.
An important decision
The investigators note that the decision to prescribe antidepressants, particularly SSRIs, during pregnancy is challenging. Though SSRI use during pregnancy is generally considered safe, some previous research suggests an association with negative outcomes in offspring, including adverse effects on neurodevelopment.
However, the researchers also note that it’s possible that pregnant women who use SSRIs may have other factors, including more severe depressive symptoms, which may be independently associated with adverse outcomes in offspring.
To investigate the link between intrauterine SSRI exposure and brain development, the researchers conducted a prospective, population-based study that included 3,198 pregnant individuals with an expected delivery date between April 2002 and January 2006. Study participants were divided into five groups: 41 who used SSRIs during pregnancy, 257 who did not use the medications but had depressive symptoms during pregnancy, 77 who used SSRIs prenatally, 74 who developed depressive symptoms after giving birth, and 2,749 controls with no SSRI use or depressive symptoms. Participants had a mean age of 31 years, and all identified as women.
Of those who took SSRIs during pregnancy, 20 used them during the first trimester only, and 21 used them the first or in one or two additional trimesters. The SSRIs used included paroxetine, fluoxetine, sertraline, fluvoxamine, and citalopram.
Offspring of the women enrolled in the study received MRIs at three different times between the ages 7 and 15 years.
The 41 children born to the women who took SSRIs prenatally had 80 scans in total, the 257 with mothers who did not use SSRIs yet had depressive symptoms while pregnant had 477 MRIs, the 77 children born to the mothers who took SSRIs before pregnancy had 126 MRIs, the 74 born to mothers with postnatal depression only had 128 MRIs, and the 2,749 children born to the mothers with no SSRI use or depression had 4,813 MRIs.
The study’s primary outcome was brain morphometry in offspring including global and cortical brain volumes, measured by three MRI assessments from ages 7 to 15 years.
Reduced brain volume
Compared with children with no in utero SSRI exposure, those who were exposed had reduced gray and white matter volume that persisted up to 15 years of age (P = .006), particularly in the corticolimbic circuit.
Investigators observed a “persistent association between prenatal SSRI exposure and less cortical volumes across the 10-year follow-up period, including in the superior frontal cortex, medial orbitofrontal cortex, parahippocampal gyrus, rostral anterior cingulate cortex, and posterior cingulate.”
Investigators noted that prenatal SSRI exposure was consistently associated with 5%-10% lower brain volume in the frontal, cingulate, and temporal cortex throughout the age range studied.
In a couple of areas of the brain, however, the brain volume gradually increased back to levels seen in non-SSRI exposed children. For instance, smaller amygdala volumes had increased by age 15 years, so children who were exposed to SSRIs were not any different from control children.
Among the group of women with postnatal depression using an SSRI before or during pregnancy who had depressive symptoms post natally, neonates had a reduced fusiform gyrus (P = .002)
Dr. Tiemeier could not speculate on the effects of the volume differences on children’s development, although the parts of the brain found to be reduced are primarily responsible for emotion regulation.
Investigators noted there was limited ability to investigate trimester-specific outcomes of SSRI use and assess associations with specific SSRIs due to low prevalence of SSRI use.
In addition, research on the long-term behavioral and psychological outcomes associated with demonstrated brain changes is needed, investigators noted.
Clinical significance ‘unclear’
In an accompanying editorial, Ardesheer Talati, PhD, Columbia University, New York, noted that though the research enhances understanding of how brain development through adolescence may be associated with SSRI exposure, “the clinical significance was unclear, especially as key limbic regions, including the amygdala, normalized over time.”
If future evidence links brain anomalies to adverse youth outcomes, Dr. Talati writes, this will need to be “calibrated into the risk-benefit profile.” Until then, he said, the findings must not be overinterpreted “to either promote or discourage antidepressant medication use during the critical period of pregnancy.”
The study was funded by the Netherlands Organization for Scientific Research, European Union’s Horizon Research and Innovation Program, the Netherlands Organization for Health Research and Development, the Sophia Foundation for Neuroimaging, and the European Union’s Horizon Research and Innovation 5 Program. Dr. Talati reported receiving grants from the National Institutes of Health outside of the submitted work.
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