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A recent randomized controlled trial (RCT) conducted at the New York State Psychiatric Institute compared the effects on gray matter and white matter development in infants exposed to selective serotonin reuptake inhibitors (SSRIs, e.g., Citalopram, Fluoxetine, Sertraline) in utero, maternal depression, and healthy controls. The researchers found an association between prenatal exposure to SSRI antidepressants and alterations in gray and white matter development.

“The prescription of selective serotonin reuptake inhibitor medications for pregnant women has accelerated over the past 30 years,” the researchers, led by Claudia Lugo-Candelas at the Columbia University Medical Center, write. “To some extent, this rise may be attributable to increased awareness of the detrimental effects of untreated prenatal maternal depression on women and children, along with early studies failing to document immediate effects of SSRI exposure in offspring.”

While prescribing of SSRIs to pregnant women increases, little research has specifically examined the effects of prenatal SSRI exposure on fetal neurodevelopment. The authors cite animal studies that have demonstrated associations between SSRI exposure and delayed motor development, reduced neuronal firing, as well as behavioral effects such as increases in anxiety and depression-like behaviors in adulthood.

In human studies, prenatal SSRI exposure has been linked to increased rates of depression in early adolescence, lower birth weight, shorter gestational period, lower Apgar score (a measure of the physical condition of the newborn infant and response to resuscitation), and neonatal abstinence syndrome (NAS). NAS is often seen in newborns exposed to addictive opiates, alcohol, benzodiazepines, and results in withdrawal symptoms in the newborn.

Lugo-Candelas et al. hypothesized that infant exposed to SSRI’s in the womb would show alterations in grey matter and white matter connectivity. They recruited three groups. 16 infants with in utero exposure to SSRI’s, 21 with exposure to in utero untreated maternal depression, and 61 healthy controls. They then conducted MRI scans of infants at about three weeks.

Gray Matter Volume

Compared to infants not exposed to SSRIs, those exposed to SSRIs showed significant differences in the right amygdala and insula, superior frontal gyrus and left occipital gyrus. When compared to infants exposed to maternal depression, those exposed to SSRI’s experienced significant increase in volume in the right amygdala, right insula, and right superior frontal gyrus. Of note, no significant differences were found between infants exposed to maternal depression and the healthy control group, suggesting an alteration in gray matter volume can be attributed to SSRI use.

White Matter Connectivity

Infants exposed to SSRIs had significantly greater connectivity than both healthy controls and infants exposed to maternal depression in the right amygdala-right insula, left anterior cingulate cortex-left thalamus, right precentral gyrus-right cuneus, and left insula-right precuneus.

These findings, the authors write, suggest “an association between prenatal SSRI exposure, likely via aberrant serotonin signaling, and the development of the amygdala-insula circuit in the fetal brain.”

This finding is of importance as “abnormalities in the amygdala-insula circuitry may be associated with anxiety and depression” and “MRI studies show increased functional connectivity between the amygdala and insula in generalized anxiety and posttraumatic stress disorder.”

Overall, this study presents evidence that prenatal exposure to SSRI’s can affect infant neurodevelopment and may be associated with increased susceptibility to anxiety disorders, hyperactivity and maladaptive processing.

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Lugo-Candelas, C., Cha, J., Hong, S., Bastidas, V., Weissman, M., Fifer, W. P., … & Monk, C. (2018). Associations Between Brain Structure and Connectivity in Infants and Exposure to Selective Serotonin Reuptake Inhibitors During Pregnancy. JAMA Pediatrics, 172(6), 525-533. (Link)