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 which persist into adulthood.  Two recent articles — one from Posner and colleagues, the other from Lebel and colleagues — look at the effects of antenatal depression on the development of the child’s brain.  

Prenatal Depression Associated with Amygdala-Prefrontal Cortex Connectivity

In the first study, maternal mood was assessed in pregnant women between 34 and 37 weeks of gestation. In addition, fetal behavior was assessed at the same time, measuring fetal heart rate (FHR) reactivity to in utero stimuli, elicited through the mother’s autonomic nervous system response to acute stress. Previous studies have demonstrated that heightened FHR responses are associated with exposure to depression in utero and more reactive infant temperament.

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 prenatal maternal depression (PMD). One of the things that distinguishes this study from others is that the infants were assessed very early (mean age=5.8±1.7 weeks) in order to limit the effects of postpartum maternal mood and other postpartum factors on the findings.  

Resting fMRI and diffusion MRI both indicated atypical amygdala–prefrontal cortex (PFC) connectivity in infants exposed to maternal depression.  This finding may have clinical relevance in that the amygdala is the part of the brain that helps to modulate stress reactivity and vulnerability to mood and anxiety disorders.  Older studies using structural MRI have demonstrated that the amygdala is increased in size in adolescents and adults diagnosed with major depressive disorder.  In addition, functional MRI studies have demonstrated hyperactivation of the amygdala in subjects with major depression.  In the context of fetal programming, the amygdala has received special attention because the amygdala develops at an early embryonic stage and its development appears to be particularly sensitive to elevated levels of the stress hormone cortisol, which is produced by the mother who is experiencing depression, anxiety, and/or stress.

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 conclude 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.

Cortical Thickness and Diffusivity in Children Exposed to Prenatal and Postpartum Depression

In the second study, 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 study 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 explain these findings in the context of life history theory:

“… wherein the timing of key developmental achievements is altered by exposure to early adversity, a theory supported by evidence that childhood stress can lead to earlier reproductive development. Limited brain data also support this theory: early weaning can lead to premature myelination in mice ( 45 ), and early life adversity in children is associated with a more adult-like arrangement of amygdala connectivity. Maternal perinatal depression, acting as an early adverse experience, may lead to earlier brain development in children via premature myelination and synaptic pruning. This early development occurs at the expense of extended brain plasticity, as underused neural connections that could ultimately have been useful may be prematurely pruned, affecting cognitive and behavioral outcomes throughout life.”

Understanding the Clinical Relevance of These Findings

These findings suggest 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.  Other studies have yielded similar findings in children with prenatal exposure to maternal depression.

  • Exposure to PMD was associated with cortical thinning, particularly over the frontal lobes, in school age children (Sandman 2015)
  • The microstructure of the amygdala was altered in newborns exposed to PMD (Rifkin-Graboi et al, 2013)
  • 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)

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, this study indicates 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

 

Gee DG, Gabard-Durnam LJ, Flannery J, Goff B, Humphreys KL, Telzer EH et al. Early developmental emergence of human amygdala–prefrontal connectivity after maternal deprivation. Proc Natl Acad Sci USA 2013; 110: 15638–15643.

 

Lebel C, Walton M, Letourneau N, Giesbrecht GF, Kaplan BJ, Dewey D. Prepartum and Postpartum Maternal Depressive Symptoms Are Related to Children’s Brain Structure in Preschool. Biol Psychiatry. 2016: 80(11):  859–868.

 

Luking KR, Repovs G, Belden AC, Gaffrey MS, Botteron KN, Luby JL et al. Functional connectivity of the amygdala in early-childhood-onset depression. J Am Acad Child Adolesc Psychiatry 2011; 50: 1027–41. e3.

 

Pannekoek JN, Werff S, Meens PH, Bulk BG, Jolles DD, Veer IM et al. Aberrant resting?state functional connectivity in limbic and salience networks in treatment?naive clinically depressed adolescents. J Child Psychol Psychiatry 2014; 55: 1317–1327.

 

Posner J, Cha J, Roy AK, Peterson BS, Bansal R, Gustafsson HC, Raffanello E, Gingrich J, Monk C. Alterations in amygdala-prefrontal circuits in infants exposed to prenatal maternal depression. Transl Psychiatry. 2016 Nov 1;6(11):e935.

 

Qiu A , Anh TT, Li Y, Chen H, Rifkin-Graboi A,  Broekman BFP,  Kwek K,  Saw S-M,  Chong Y-S, Gluckman PD, Fortier MV, Meaney MJ. Prenatal maternal depression alters amygdala functional connectivity in 6-month-old infants.  Transl Psychiatry. 2015 Feb; 5(2): e508. Published online 2015 Feb 17.

 

Rifkin-Graboi A, Bai J, Chen H, et al.  Prenatal maternal depression associates with microstructure of right amygdala in neonates at birth.  Biol Psychiatry. 2013 Dec 1; 74(11):837-44.

 

Sandman CA, Buss C, Head K, Davis EP. Fetal exposure to maternal depressive symptoms is associated with cortical thickness in late childhood. Biol Psychiatry 2015; 77: 324–334.