Prenatal and postnatal depressive symptoms, infant white matter, and toddler behavioral problems

Highlights

• Prenatal depression was associated with diffusivity of the corpus callosum in infants.

• Postnatal depression was not related to infant limbic or corpus callosum white matter.

• Diffusivity of the corpus callosum genu predicted behavioral problems in toddlerhood.

• Treating prenatal depression may improve infants’ brain and behavioral outcomes.

Abstract

Background

Maternal depression is prevalent during and following pregnancy and is related to adverse outcomes in offspring. Perinatal depression is associated with risk for difficulties in offspring; however, the mechanisms underlying this association are not clear. We examined whether maternal prenatal and postnatal depressive symptoms were associated with infant white matter organization and with behavioral problems in toddlerhood.

Methods

37 mother–infant dyads (20 male; ages 5.95–7.66 months) participated in this study. We conducted diffusion MRI with infants during natural sleep. Mothers reported on their prenatal and postnatal depressive symptoms at six months postpartum. We calculated fractional anisotropy (FA), radial, axial, and mean diffusivity, and assessed offspring behavioral problems at age 18 months.

Results

Prenatal depressive symptoms were associated with FA of the corpus callosum; postnatal depressive symptoms were not associated with FA of limbic tracts or corpus callosum segmentations. Higher levels of prenatal depressive symptoms were associated with higher FA and lower radial diffusivity of the corpus callosum genu; FA of this region was positively associated with behavioral problems at age 18 months.

Limitations

This study had a small sample size; therefore, findings should be replicated. Further, we used retrospective reports of maternal prenatal depression, but validated them in this study.

Conclusions

Depressive symptoms during pregnancy may affect infant corpus callosum development and, in turn, offspring behaviors. These findings suggest that early maternal stress accelerates infant neurodevelopment in a manner that may increase risk for behavioral problems. Thus, efforts to reduce maternal prenatal depression should be a public health priority.

Introduction

As many as 20 percent of mothers experience clinically significant depression or depressive symptoms during pregnancy (Bennett et al., 2004; Gavin et al., 2005) and/or after childbirth (Sanger et al., 2015). These rates are even higher when including mothers with subclinical levels of depressive symptoms (Meaney, 2018). Thus, at least one in five infants is exposed to maternal depression in utero or in the year following birth (Gavin et al., 2005; O'Hara and Wisner, 2014). Maternal depressive symptoms have adverse consequences for both mothers (Gotlib, 1992;⁻Moehler et al., 2006) and offspring (Goodman and Gotlib, 1999), including increased risk for children's attentional (Zou et al., 2019), emotional (Nolvi et al., 2020), and behavioral problems (Cents et al., 2013; Hay et al., 2020; Sandman et al., 2015). The mechanisms underlying the intergenerational transmission of risk, however, are unclear (Gotlib et al., 2020). One possible mechanism involves alterations in brain structure in offspring in early life (Hay et al., 2020; Sandman et al., 2015; Zou et al., 2019). Indeed, investigators have reported findings consistent with the formulation that maternal depressive symptoms adversely affect brain structure in young children. Much of this research has been conducted with school-age and older children and adolescents. For example, investigators have reported greater cortical thinning in preschool-age (Lebel et al., 2016), adolescent (Foland-Ross et al., 2015; Peterson et al., 2009), and pre-adolescent (Sandman et al., 2015), offspring of depressed mothers. Further, Wen et al. (2017) reported that whereas prenatal depressive symptoms were associated with larger right amygdala volume, postnatal depressive symptoms were associated with higher fractional anisotropy (FA) of the right amygdala. Recently, Hay et al. (2020) found that prenatal depressive symptoms were associated with higher mean diffusivity (MD) of the cingulum and with higher MD and lower FA of the amygdala pathway in 4-year-old children and, further, that limbic-prefrontal connectivity mediated the association in boys between maternal prenatal depressive symptoms and externalizing problems.

Investigators have begun to examine neural characteristics of infants whose mothers experienced depressive symptoms in the perinatal period. Rifkin-Graboi et al. (2013) reported that neonates of mothers with higher levels of prenatal depressive symptoms had lower FA and AD of the amygdala. Similarly, Posner et al. (2016) reported that greater prenatal depressive symptoms were related in neonates to decreased structural connectivity between the right amygdala and the right ventral prefrontal cortex. Further, Dean et al. (2018) found that greater maternal prenatal depressive and anxious symptoms were associated with higher diffusivity in right frontal regions in one-month-old infants and that infant sex moderated the association between maternal symptoms and diffusion properties of the splenium (Dean et al., 2018). Finally, Nolvi et al. (2020) reported that maternal postnatal depressive symptoms predicted offspring emotional reactivity at age 6 months, but only in newborns with higher mean FA across the corpus callosum. Thus, while a small number of studies indicate that maternal prenatal depressive symptoms are associated with infant white matter organization, there is variability in the specific tracts that are implicated and in the direction of these associations. Further, moderating variables, such as offspring sex, may explain significant variance in the effects of maternal depressive symptoms on infant white matter organization (Dean et al., 2018; Hay et al., 2020; Lebel et al., 2016; Wen et al., 2017). For example, given the rapid development of the infant brain during the perinatal period (Dubois et al., 2014), maternal depressive symptoms at different peripartum timepoints (i.e., prenatal versus postnatal, broadly reflecting changes in the hormonal milieu of the intrauterine environment versus difficulties in postnatal caregiving behavior) may differentially affect neurodevelopment (Bock et al., 2015). In fact, researchers have found different associations between maternal prenatal and postnatal depressive symptoms and brain structure in youth (El Marroun et al., 2018; Lebel et al., 2016; Wen et al., 2017; Zou et al., 2019), suggesting that different mechanisms are involved in these relations. Identifying when in the perinatal period maternal depressive symptoms are most consequential for infant white matter organization may inform strategies to prevent the intergenerational transmission of risk for psychosocial difficulties in the earliest stages of life.

The goal of the current study was to examine the differential associations of maternal depressive symptoms during the prenatal period (reported retrospectively at six months postpartum) and during the postnatal period (reported contemporaneously) with white matter organization in six-month-old infants. Further, we examined the longer-term correlates of brain organization by assessing behavioral problems at 18 months.

Given the equivocal findings reviewed above, we tested two competing hypotheses: i) higher maternal depressive symptoms delay the development of infant white matter organization, reflected in lower FA in white matter tracts; and ii) higher maternal depressive symptoms accelerate the development of infant white matter organization, reflected in higher FA in white matter tracts. We examined both prenatal and postnatal depressive symptoms to assess possible differential effects on infant white matter organization of symptoms occurring in these two periods. Given that previous studies have implicated limbic regions, frontal white matter, and diffusion properties of the corpus callosum in the association between maternal depressive symptoms and infant white matter organization, in addition to alterations in these brain regions in youth with a family history of Major Depressive Disorder (Huang et al., 2011; Hung et al., 2017), we focused on limbic tracts and corpus callosum segmentations as tracts of interest.