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, for there is a growing body of literature which demonstrates that what happens in utero, while the fetus is developing, may have effects on the child that persist into adulthood.
In a recent study from Borchers and colleagues at Stanford University, 37 mother–infant dyads, including 20 male and 17 female infants between the ages of 5.95 and 7.66 months were examined using diffusion MRI while sleeping. Fractional anisotropy (FA), radial, axial, and mean diffusivity were assessed.
Mothers reported on their depressive symptoms during pregnancy and the postpartum period. using the Edinburgh Postnatal Depression Scale. Offspring behavioral problems at age 18 months were assessed using the Early Childhood Screening Assessment (ECSA) completed by mothers.
Fractional anisotropy (FA) and diffusivity were used as measures of white matter connectivity and integrity. Depressive symptoms during pregnancy were associated with changes in the fractional anisotropy (FA) of the corpus callosum. Postpartum depressive symptoms were not associated with any changes in the FA of limbic tracts or corpus callosum segmentations.
There was a dose response effect, such that higher levels of prenatal depressive symptoms were associated with higher FA and lower radial diffusivity (RD) of the corpus callosum. an interhemispheric white matter tract that connects the right and left frontal lobes.
Six-month-old infants with higher FA of the corpus callosum had higher levels of behavioral problems, as measured using the ECSA at 18 months of age. This association persisted after excluding mothers who took antidepressants during pregnancy.
The observed association between depressive symptoms during pregnancy and higher FA coupled with lower RD suggests that the brains of infants exposed to maternal depression during pregnancy have lower diffusivity. This finding of lower diffusivity is consistent with the hypothesis that exposure to maternal depression in utero may actually accelerate development, as demonstrated by accelerated myelination, increased fiber density and axonal packing, or more uniform fiber orientation.
Borchers and colleagues note that these findings support the stress acceleration hypothesis proposed by Callaghan and Tottenham in 2016. They hypothesized that early life adversity, including insults that occur during pregnancy, affect the circuitry of the brain and typically accelerate maturation. In a sense, this is an adaptive response, allowing the individual to prepare and to compensate for inadequate parental care or other stressors in the environment.
Antenatal Depression Associated with Alterations in Amygdala-Prefrontal Cortex Connectivity
Other studies have looked at the effects of antenatal depression on the development of the child’s brain and connectivity using MRI. While all of these studies have demonstrated microstructural changes in the infants of depressed mothers, the findings have varied across the studies.
In a study from Posner and colleagues, maternal mood was assessed in pregnant women between 34 and 37 weeks of gestation. Using resting-state functional magnetic resonance imaging (fMRI) and diffusion MRI, the researchers examined functional and structural connectivity within amygdala–prefrontal circuits in 64 infants with (n=20) and without (n=44) exposure to antenatal depression. Resting fMRI and diffusion MRI assessed at a mean age of 5.8 ± 1.7 weeks both indicated atypical amygdala–prefrontal cortex (PFC) connectivity in infants exposed to maternal depression.
In addition, they observed that these alterations in amygdala–PFC connectivity were associated with an increase in fetal heart rate reactivity. Based on these findings, the authors concluded that exposure to maternal depression during pregnancy alters the maturation and connectivity of the amygdala and prefrontal cortex, and that these changes are associated with increased autonomic reactivity in the infant. They speculate that later on these alterations in autonomic reactivity may increase the child’s vulnerability to stress and mood and anxiety disorders.
Similarly Rifkin-Graboi and colleagues (2013) observed that 6- to 14-day-old infants born to mothers with higher levels of antenatal depressive symptoms had lower fractional anisotropy and axial diffusivity but no changes in volume of the right amygdala compared to infants born to non-depressed mothers.
In one-month old infants, Dean and colleagues (2018) found that greater maternal depressive symptoms and anxiety were associated with higher diffusivity in right frontal regions. This study also observed differences in male vs. female offspring, suggesting that white matter development may be differentially sensitive to maternal depression and anxiety symptoms in males and females during the prenatal period.
These studies clearly demonstrate that prenatal depressive symptoms impact white matter organization in the infant brain; however, there is variability in the specific findings. Moderating variables, such as offspring sex or age at the time of assessment, may explain some of this variability. In addition, exposure to maternal depressive symptoms at different times may have different effects. Nonetheless, there is a large body of research to indicate that maternal depression and anxiety impact the microarchitecture of the developing brain.
Cortical Thickness and Diffusivity in Children Exposed to Prenatal and Postpartum Depression
Other studies have examined the impact of antenatal depression by assessing the brains of older children. In a study from Lebel and colleagues, 52 pregnant women were assessed for depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) during each trimester of pregnancy and at 3 months postpartum. Their children were assessed using MRI between the ages of 2.6 to 5.1 years. Note that this is different from the previous studies in that the children were much older. Thus, in the analysis they had to account for exposure to prenatal, as well as, postpartum depression.
In the children, higher levels of depressive symptoms during the second trimester were associated with decreased cortical thickness in right inferior frontal and middle temporal regions and with decreased radial and mean diffusivity in white matter emanating from the inferior frontal area.
When they accounted for postpartum depressive symptoms, the association between prenatal depressive symptoms and cortical thickness (but not diffusivity) persisted. Postpartum symptoms negatively correlated with children’s right superior frontal cortical thickness and with diffusivity in white matter originating from that region, even after correcting for depressive symptoms during pregnancy.
The cortical thinning and lower diffusivity observed here suggests that exposure to both prenatal and postpartum depression alter fetal brain development in children. Cortical thinning and decreased diffusivity are actually part of normal brain development, but typically they take place later in a child’s life. So what we see here is earlier brain maturation in the children exposed to higher levels of maternal depressive symptoms.
The authors note that this accelerated maturation has been associated with cognitive deficits and behavioral problems. They speculate that maternal depression, acting as an early adverse experience, may lead to accelerated brain development in children via premature myelination and synaptic pruning. While accelerated development may have certain benefits, it occurs at the expense of extended brain plasticity. Specifically, certain, potentially useful, neural connections may have been prematurely pruned, affecting cognitive and behavioral outcomes across the child’s lifespan.
Other studies have yielded similar findings in children with prenatal exposure to maternal depression.
- Exposure to antenatal depression was associated with cortical thinning, particularly over the frontal lobes, in school age children (Sandman 2015)
- Exposure to prenatal maternal depression was associated with a thinner superior frontal cortex in the left hemisphere of 8-year-old children (El Maroun, 2016)
- Another study showed that PMD-exposed infants had increased functional connectivity between the amygdala and several frontal regions in 6-month old infants (Qiu et al, 2015)
- Wen et al. (2017) reported that prenatal depressive symptoms were associated with larger right amygdala volume
These findings indicate that the mother’s depression may affect the structure and organization of the fetal brain, particularly the development of the amygdala and its connections to the cortex, regions of the brain which modulate vulnerability to mood and anxiety disorders. Furthermore, these changes which take place during fetal development continue to be evident in older children.
Understanding the Clinical Relevance of These Findings
While this type of research is still in its infancy, it provides us with another mechanism for the transgenerational transmission of depression. Many other research studies have focused on genetic contributions and the quality of parenting and the mother-child relationship; however, these studies indicate that the fetal environment is vitally important and that risk may be transmitted from mother to child during fetal life. Together these results suggest that exposure to maternal depression in utero — independent of the medications we use to treat it — influences the development of the frontal cortex, and the amygdala–prefrontal circuits, a finding that has implications for future affect regulation. Specifically, altered amygdala–prefrontal connectivity has been implicated in pediatric depression (Pannekoek et al, 2014; Gee et al, 2013; Luking et al, 2011).
Taking these findings back into the exam room is not always easy. We must consider the potential risks of exposure to medications during pregnancy, but at the same time take into account the effects of untreated psychiatric illness in the mother on the developing child. Avoidance of all medications is not necessarily the safest option. Women planning a pregnancy must be properly counseled regarding the risks of treatment versus the risks associated with the untreated psychiatric illness in the mother, and the woman’s health care provider plays an important role in weighing these individual risks and selecting the best options for treatment.
Ruta Nonacs, MD PhD
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