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Multicenter Study
, 172 (6), 525-533

Associations Between Brain Structure and Connectivity in Infants and Exposure to Selective Serotonin Reuptake Inhibitors During Pregnancy

Affiliations
Multicenter Study

Associations Between Brain Structure and Connectivity in Infants and Exposure to Selective Serotonin Reuptake Inhibitors During Pregnancy

Claudia Lugo-Candelas et al. JAMA Pediatr.

Abstract

Importance: Selective serotonin reuptake inhibitor (SSRI) use among pregnant women is increasing, yet the association between prenatal SSRI exposure and fetal neurodevelopment is poorly understood. Animal studies show that perinatal SSRI exposure alters limbic circuitry and produces anxiety and depressive-like behaviors after adolescence, but literature on prenatal SSRI exposure in humans is limited and mixed.

Objective: To examine associations between prenatal SSRI exposure and brain development using structural and diffusion magnetic resonance imaging (MRI).

Design, setting, and participants: A cohort study conducted at Columbia University Medical Center and New York State Psychiatric Institute included 98 infants: 16 with in utero SSRI exposure, 21 with in utero untreated maternal depression exposure, and 61 healthy controls. Data were collected between January 6, 2011, and October 25, 2016.

Exposures: Selective serotonin reuptake inhibitors and untreated maternal depression.

Main outcomes and measures: Gray matter volume estimates using structural MRI with voxel-based morphometry and white matter structural connectivity (connectome) using diffusion MRI with probabilistic tractography.

Results: The sample included 98 mother (31 [32%] white, 26 [27%] Hispanic/Latina, 26 [27%] black/African American, 15 [15%] other) and infant (46 [47%] boys, 52 [53%] girls) dyads. Mean (SD) age of the infants at the time of the scan was 3.43 (1.50) weeks. Voxel-based morphometry showed significant gray matter volume expansion in the right amygdala (Cohen d = 0.65; 95% CI, 0.06-1.23) and right insula (Cohen d = 0.86; 95% CI, 0.26-1.14) in SSRI-exposed infants compared with both healthy controls and infants exposed to untreated maternal depression (P < .05; whole-brain correction). In connectome-level analysis of white matter structural connectivity, the SSRI group showed a significant increase in connectivity between the right amygdala and the right insula with a large effect size (Cohen d = 0.99; 95% CI, 0.40-1.57) compared with healthy controls and untreated depression (P < .05; whole connectome correction).

Conclusions and relevance: Our findings suggest that prenatal SSRI exposure has an association with fetal brain development, particularly in brain regions critical to emotional processing. The study highlights the need for further research on the potential long-term behavioral and psychological outcomes of these neurodevelopmental changes.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.
Figure 1.. Brain Region Volumes in Infants With Prenatal Selective Serotonin Reuptake Inhibitor (SSRI) Exposure
A, Significant group volume differences in infant brains (mean, 4 weeks). Regression analyses were conducted on gray matter (GM) volume maps, estimated from T2-weighted magnetic resonance imaging and through voxel-based morphometry, using a whole-brain corrected P < .05 (randomization permutation; cluster-extent based correction). The colored areas show an increase in volume in SSRI-exposed infants relative to prenatal maternal depression (PMD) without SSRI exposure (green), healthy controls (HC) (blue), and both groups combined (orange) (SSRI, n = 14; PMD, n = 19; HC, n = 47). Compared with the PMD, HC, and both groups combined, the SSRI group showed significant expansion in volume in the right amygdala and insula compared with the PMD group and combined groups only in the superior frontal gyrus, and compared with combined groups only, the occipital gyrus. B, Distribution (colored area), quartiles (thick bar), 95% CIs (thin line), and medians (white dots). Open triangles represent individual infant values. The significance of group differences was based on voxelwise analysis (whole-brain corrected using randomization permutation) from the 2 separate clusters in the right amygdala and the anterior insula. au indicates arbitrary unit; c, cortex; g, gyrus. aP = .03 compared with both the PMD group, P = .02 compared with the HC group, and P = .01 compared with the PMD and HC groups combined, all significant results. bP = .34 compared with the HC group.
Figure 2.
Figure 2.. White Matter (WM) Structural Connections in Infants With Prenatal Exposure to Selective Serotonin Reuptake Inhibitors (SSRIs)
A, White matter structural connectomes (90 regions) estimated using diffusion tractography; across both hemispheres, similar connectome organization was evident in each study group: healthy control (HC) infants, SSRI-exposed infants, and prenatal maternal depression (PMD)-exposed infants without SSRI exposure (permutation tests against 1000 randomized connections; P < .05; SSRI, n = 14; PMD, n = 20; HC, n = 58). B, Upper row shows a map of significant group differences in WM connectivity. Regression analyses were conducted on the connectivity matrix using a whole-brain-corrected P < .05 (randomization permutation; false discovery rate control). Lower row shows a representative WM pathway connecting the right amygdala (red) and the right insula (yellow) color-coded by direction. C, Distributions (colored area), quartiles (thick bar), 95% CIs (thin line), and medians (white dots). Open triangles represent infants. The significance of the group differences was based on a regression model performed on the right amygdala-right amygdala connectivity (exhaustive permutations). aP < .001 compared with the PMD group, P < .001 compared with the HC group, and P = .001 compared with the PMD and HC groups combined. bP = .80 compared with the HC group.
Figure 3.
Figure 3.. Selected Gray Matter (GM) and White Matter (WM) Measures Associated With Brain Changes After Prenatal Exposure to Selective Serotonin Reuptake Inhibitors (SSRIs)
Receiver operating characteristics analysis curve showing cross-validated diagnostic accuracy of a linear regression model predicting SSRI exposure (leave-1-out cross validation). We tested 3 logistic regression models with different sets of the selected brain measures as predictors: GM+WM (orange), WM (gray), and GM (blue) models (predictors: for GM, right amygdala volume and right insula volume; for WM, amygdala-insula connectivity). Shaded areas are confidence bounds (estimated in 5000 bootstrap samples).

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