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. 2023 May 5;13(1):149.
doi: 10.1038/s41398-023-02441-2.

Effects of prenatal exposure to (es)citalopram and maternal depression during pregnancy on DNA methylation and child neurodevelopment

Emilie Willoch Olstad  1   2   3 , Hedvig Marie Egeland Nordeng  4   5   6   7 , Geir Kjetil Sandve  5   6   8 , Robert Lyle  5   9   10 , Kristina Gervin  4   5   6   11
Affiliations

Effects of prenatal exposure to (es)citalopram and maternal depression during pregnancy on DNA methylation and child neurodevelopment

Emilie Willoch Olstad et al. Transl Psychiatry. .

Abstract

Studies assessing associations between prenatal exposure to antidepressants, maternal depression, and offspring DNA methylation (DNAm) have been inconsistent. Here, we investigated whether prenatal exposure to citalopram or escitalopram ((es)citalopram) and maternal depression is associated with differences in DNAm. Then, we examined if there is an interaction effect of (es)citalopram exposure and DNAm on offspring neurodevelopmental outcomes. Finally, we investigated whether DNAm at birth correlates with neurodevelopmental trajectories in childhood. We analyzed DNAm in cord blood from the Norwegian Mother, Father and Child Cohort Study (MoBa) biobank. MoBa contains questionnaire data on maternal (es)citalopram use and depression during pregnancy and information about child neurodevelopmental outcomes assessed by internationally recognized psychometric tests. In addition, we retrieved ADHD diagnoses from the Norwegian Patient Registry and information on pregnancies from the Medical Birth Registry of Norway. In total, 958 newborn cord blood samples were divided into three groups: (1) prenatal (es)citalopram exposed (n = 306), (2) prenatal maternal depression exposed (n = 308), and (3) propensity score-selected controls (n = 344). Among children exposed to (es)citalopram, there were more ADHD diagnoses and symptoms and delayed communication and psychomotor development. We did not identify differential DNAm associated with (es)citalopram or depression, nor any interaction effects on neurodevelopmental outcomes throughout childhood. Trajectory modeling identified subgroups of children following similar developmental patterns. Some of these subgroups were enriched for children exposed to maternal depression, and some subgroups were associated with differences in DNAm at birth. Interestingly, several of the differentially methylated genes are involved in neuronal processes and development. These results suggest DNAm as a potential predictive molecular marker of later abnormal neurodevelopmental outcomes, but we cannot conclude whether DNAm links prenatal (es)citalopram exposure or maternal depression with child neurodevelopmental outcomes.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Overview of which questionnaires were used to assess neurodevelopmental outcomes in the children.
ADHD attention-deficit/hyperactivity disorder, ASQ Ages and Stages Questionnaire, CBCL-DSM Child Behavior Checklist DSM-oriented subscale Q- MoBa questionnaire.
Fig. 2
Fig. 2. Modified Manhattan plots of difference in DNAm between groups.
Log10 p-value against the genomic positions of the CpGs, after test statistic correction for bias and inflation using BACON [66]. Each dot represents a CpG, colored according to the DNAm difference between A (es)citalopram and depression groups, B (es)citalopram and control groups, and C depression and control groups. The red lines indicate the FDR-adjusted significance cutoff (<0.05).
Fig. 3
Fig. 3. Neurodevelopmental trajectories identified using latent class growth analysis.
Trajectories were identified for A the CBCL-DSM ADHD subscale, B the ASQ communication subscale, and C the ASQ psychomotor subscale.
Fig. 4
Fig. 4. CpGs associated with developmental trajectories and blood–brain correlation of DNAm.
A Upset plot [83, 84] shows the overlap of significant CpGs associated with communication and/or psychomotor developmental trajectories. Overlapping CpGs are indicated by filled dots for the respective outcomes. The vertical bar plot indicates the number of CpGs for the particular intersection. B Blood–brain correlation of significant CpGs associated with both communication and psychomotor trajectories. Correlation is reported as Spearman’s correlation coefficient of DNAm between blood and brain. The modified plot from the BECon web application [68].
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