When a woman comes in for a consultation regarding the use of medications during pregnancy, we spend most of our time reviewing the potential risks of exposure to medications during pregnancy.  However, we must also include a discussion of the effects of untreated psychiatric illness in the mother on the developing child, in utero exposure to medications, as well as exposure to untreated psychiatric symptoms in the mother, while the fetus is developing, may have effects on neurodevelopment that persist into adulthood.  

Both prenatal antidepressant exposure and maternal depressive symptoms may affect fetal  brain development.  Neuroimaging studies, though limited, have observed associations between prenatal SSRI exposure, maternal depressive symptoms, and alterations in white matter microstructure in the exposed offspring. In a recent study, researchers analyzed data from the Generation R Study, a large population-based cohort from the Netherlands following children from fetal life to adolescence.  

Prenatal  use of selective serotonin reuptake inhibitors (SSRI) was self-reported and verified using pharmacy records. During pregnancy, depressive symptoms were measured using the Brief Symptom Inventory. Using diffusion tensor imaging, the researchers focused on white matter microstructure and structural connectivity in the offspring, including whole-brain and tract-specific fractional anisotropy (FA) and mean diffusivity.  The children were scanned three times between the ages of 7 and 15 years. 

For the analysis, participants were divided into four non-overlapping groups: 

  • Prenatal SSRI exposure (n = 37 with 60 scans), 
  • Prenatal depression exposure (n = 229 with 367 scans), 
  • SSRI use before pregnancy (n = 72 with 95 scans), and 
  • A reference group with no prenatal depression, no previous or current use of SSRI (n = 2640 with 4030 scans).

At 7 years of age, prenatal exposure to SSRIs and prenatal depressive symptoms with similar changes in white matter microstructure, specifically lower FA in the whole-brain and the forceps minor at 7 years of age. In children exposed to maternal depression, there appeared to be a dose effect such that exposure to higher levels of prenatal depression was associated with lower FA in the uncinate fasciculus, cingulum bundle, superior and inferior longitudinal fasciculi, and corticospinal tracts.  There were no associations identified between postpartum depressive symptoms alone and whole-brain or tract-specific FA. 

Between the ages of 7 and 15 years, children exposed to prenatal depression showed a faster increase in FA in these white matter tracts.  Prenatal SSRI exposure was not related to white matter microstructure growth over and above exposure to depressive symptoms.

Clinical Implications

Studying the impact of prenatal medication exposures on offspring outcomes presents many challenges.  One specific methodological issue is something that we have talked a lot about, confounding by indication. We cannot use randomized controlled trials to study the safety of medications in pregnant women.  So we must gather data from studies where women decide whether or not to use a particular medication during pregnancy, and it is clear that women who use medication from pregnancy differ substantially from women who do not use medication.  The most obvious difference is that women who take medication have a specific disorder (in this study, depression and/or anxiety) and experience the symptoms associated with these disorders.  These symptoms, as well as the medications used for treatment, may have an impact on outcomes.  The current study was large enough to adjust  for multiple sociodemographic factors and confounding by indication by constructing distinct exposure groups.

The findings of this study indicate that both prenatal exposure to SSRI antidepressants and prenatal exposure to maternal depressive symptoms were associated with similar changes in white matter microstructure in children at seven years of age.  The good news is that these differences appear to diminish over time and were attenuated in scan performed at 15 years of age, suggesting an element of catch-up growth.

Most importantly, the findings of this study defined specific exposure groups (comparing outcomes in children with exposure to prenatal SSRIs versus exposure to maternal depressive symptoms) and suggest that the alterations in white matter mictoddtructure observed in children with prenatal exposure to SSRIs can be explained best by exposure to maternal depressive symptomatology rather than SSRI use itself. 

While many would like to avoid the use of antidepressants during pregnancy, the current study indicates that this may not be the best option and that untreated depression in the mother may also carry specific risks in terms of fetal development.

Ruta Nonacs, MD PhD

Koc D, El Marroun H, Stricker BH, Muetzel RL, Tiemeier H. Intrauterine Exposure to Antidepressants or Maternal Depressive Symptoms and Offspring Brain White Matter Trajectories From Late Childhood to Adolescence. Biol Psychiatry Cogn Neurosci Neuroimaging. 2024 Feb;9(2):217-226. 


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