In a recent commentary, Dr. Lee Cohen, notes that over the last 15-20 years, we have collected an enormous amount of data on the use of antidepressants during pregnancy. Data from multiple studies and meta-analyses have demonstrated no increased risk of major malformations in children exposed to antidepressants during pregnancy, including the SSRIs, SNRIs, tricyclic antidepressants and bupropion.
While previous studies have focused primarily on the risk of major malformations in children with prenatal exposure to antidepressants, more recent studies have attempted to measure more subtle outcomes, specifically the impact of prenatal antidepressant exposure on brain development and function. A recent prospective, population-based cohort study conducted in the Netherlands as part of the Generation R Study investigates the association between intrauterine SSRI exposure and maternal depressive symptoms and structural brain development in offspring 7 to 15 years of age.
In this study, all pregnant individuals with an expected delivery date between April 1, 2002, and January 31, 2006, were invited to participate. Maternal reports of SSRI use were verified using pharmacy records. To estimate the impact of depressive symptoms during and after pregnancy on brain development, mothers were assessed during pregnancy and at 2 and 6 months after delivery using the Brief Symptom Inventory.
Brain morphology was assessed in the offspring, including global and cortical brain volumes, measured at three different time points between the ages of 7 and 15 using magnetic resonance imaging (MRI).
What Did the Study Show?
The study included 3198 mother-child dyads. The mean (SD) age at intake was 31.1 (4.7) years. Children (1670 [52.2%] female) underwent brain imaging assessment between the ages of 7 and 15 years of age, with a total of 5624 scans.
Outcomes were assessed in five distinct groups of mother-infant dyads with different exposures:
- Maternal SSRI use during pregnancy (n = 41; 80 scans),
- Maternal SSRI use only before pregnancy (n = 77; 126 scans),
- Prenatal depressive symptoms without prenatal SSRI use (n = 257; 477 scans),
- Postpartum depressive symptoms only (n = 74; 128 scans), and
- Non-exposed control individuals (n = 2749; 4813 scans).
In terms of measurements of brain volumes, the researchers observed the following:
- Compared to non-exposed controls, children prenatally exposed to SSRIs had lower cerebral gray matter volumes, particularly within the corticolimbic circuit. These changes persisted up to 15 years of age.
- Children prenatally exposed to SSRIs during pregnancy also had lower cerebral white matter volumes; however, these volume differences diminished with age.
- Children exposed to SSRIs prenatally showed a steeper increase in volumes of the amygdala from 7 to 15 years of age. These volumetric differences in the amygdala and fusiform seen in childhood did not persist until early adolescence
- Prenatal SSRI exposure was not associated with changes in the volume or growth trajectory of the hippocampus.
They also noted that exposure to maternal depression was associated with changes in brain morphology:
- Children exposed to prenatal depressive symptoms had reduced rostral anterior cingulate gyrus volumes.
- Children exposed to postpartum depressive symptoms had reduced fusiform gyrus volumes.
SSRI use before conception was not associated with any brain differences.
Strengths and Limitations of the Study
Overall this is a well done and carefully constructed study. The prospective nature of the study and the fact that it is embedded within a larger study of child development reduces the risk of selection bias. Participation in the Generation R study is offered to all pregnant mothers and is not specifically targeted to women with histories of psychiatric illness.
While older studies have often compared outcomes in antidepressant-exposed children to outcomes in healthy children born to mothers without psychiatric illness, this study selected more appropriate comparison groups to better control for genetic and environmental factors that may be more commonly associated with the use of antidepressants and/or psychiatric illness. More specifically, they compared outcomes in antidepressant-exposed children to children born to women previously treated with SSRIs who elected to stop antidepressant treatment prior to conception. In addition, antidepressant-exposed children were compared to non-exposed children born to mothers who experienced either prenatal or postpartum depression.
This approach helps to minimize the contribution of some confounding factors, but it is unlikely to fully account for all confounding variables. More specifically, we cannot conclude that the mother who elects to stop antidepressants during pregnancy is clinically or genetically comparable to women who elect to maintain treatment. Notably, in this study, the researchers observed that women using SSRIs during pregnancy had higher levels of depressive symptoms and were more likely to also be taking benzodiazepines compared with the reference group, a finding that suggests a more severe depression or comorbidity in women who elect to maintain treatment with antidepressants during pregnancy.
Furthermore, other factors that may potentially have adverse developmental outcomes in the child, such as increased BMI and smoking, are more common in women with psychiatric illness. Although the study was able to control for educational level and socioeconomic status, other important variables, including BMI, smoking, comorbid psychiatric diagnoses, were not taken into consideration.
Because it is not possible to do a randomized controlled trial where identical groups of women are treated with antidepressants or placebo, there is no such thing as a perfect study.
What Does This Study Tell Us? How Can We Use This Information?
The findings of the current study suggest that SSRI exposure during pregnancy may be associated with changes in brain morphology. Specifically, the authors observed altered developmental trajectories in brain regions associated with emotional regulation in the offspring. In the comparison group — women who stopped SSRIs prior to pregnancy — did not exhibit any differences in brain morphology compared to non-exposed controls.
Of note, they also observed that maternal depression (without exposure to SSRIs) was also associated with changes in brain morphology, although the specific changes were distinct from those associated with antidepressant exposure.
One explanation of these findings is that SSRIs (as opposed to associated genetic or environmental factors) may alter brain development and/or morphology. However, we cannot exclude the possibility that the women who elect to take antidepressants during pregnancy have more severe psychiatric illness or comorbidity and it is the underlying illness (as opposed to the treatment itself) that affects brain development.
It is interesting to note that while some changes persisted into adolescence, others (reduced white matter volumes) did not, suggesting a developmental delay rather than a permanent structural change. Further studies are required to follow these findings into adulthood.
Most importantly, the current study measured structural changes but did not assess function or evidence of psychopathology. We must consider this study along with other studies exploring clinical outcomes. For example, a recent study from Suarez and colleagues analyzed data from nearly 150,000 children with prenatal antidepressant exposure in two healthcare databases and found no association between prenatal exposure to antidepressants and risk for neurodevelopmental disorders. This is the largest study to date examining neurodevelopmental outcomes in children exposed to antidepressants during pregnancy. Antidepressant use in pregnancy itself does not increase the risk of neurodevelopmental disorders in children. There are, however, other factors more common in women who take antidepressants during pregnancy that may increase the risk of having a child with a neurodevelopmental disorder.
Does This Study Change What We Recommend?
Concerns regarding the effects of fetal exposure to antidepressants is appropriate given that about 15% of women experience depression during pregnancy. For some women, psychotherapy may be an effective treatment option in this setting. However, a substantial number of women do not respond to psychotherapy alone or have severe depressive symptoms and may require treatment with an antidepressant.
While this study suggests the possibility that SSRIs may affect fetal brain development, the study also clearly shows that maternal depression — whether it during pregnancy or the postpartum period — also alters brain development. The decision to use antidepressants during pregnancy involves weighing the risks associated with exposure to a particular medication against the risks associated with untreated depression in the mother.
The current study adds to our understanding of the effects of antidepressant exposure on fetal brain development; however, the information is still incomplete. At this point, it would be premature to limit antidepressant treatment during pregnancy based on this study. Further research on the functional implications of these findings is warranted.
Ruta Nonacs, MD PhD
Koc D, Tiemeier H, Stricker BH, Muetzel RL, Hillegers M, El Marroun H. Prenatal Antidepressant Exposure and Offspring Brain Morphologic Trajectory. JAMA Psychiatry. 2023 Aug 30:e233161.
Talati A. Maternal Depression, Prenatal SSRI Exposure, and Brain Trajectories in Childhood. JAMA Psychiatry. 2023 Aug 30.