Key Points
Question To what extent is the persistent association of poor prenatal family functioning with preadolescent problem behavior mediated by subcortical brain development?
Findings In this population-based cohort study of 2583 children with neuroimaging data, smaller hippocampal volumes were found in preadolescents exposed to prenatal maternal-reported poor family functioning. Smaller hippocampal volumes partially mediated the association of prenatal maternal-reported poor family functioning with preadolescent problem behavior.
Meaning Subcortical brain characteristics found after more than 10 years of follow-up may help clinicians understand why poor family functioning is associated with child neurodevelopment and well-being.
Abstract
Importance The association of poor family functioning, a potent stressor, with child behavior is potentially long term and relevant for a person’s well-being later in life. Whether changes in brain development underlie the associations with preadolescent behavior and help identify periods of vulnerability is unclear.
Objective To assess the associations of poor family functioning from pregnancy onward with cortical, white matter, and subcortical volumes, and to examine the extent to which, in particular, hippocampal volume mediates the association of prenatal parental environmental exposures with child problem behavior in preadolescence.
Design, Setting, and Participants This population-based cohort study, conducted from April 2002 to January 2006, was embedded in Generation R, a multiethnic population-based cohort from fetal life onward. All pregnant women living in Rotterdam, the Netherlands, with an expected delivery date between April 2002 and January 2006 were invited to participate. Of the 8879 pregnant women enrolled during pregnancy, 1266 mothers with no partner data and 490 with missing family functioning data were excluded, as well as 1 sibling of 32 twin pairs. After excluding an additional 657 children with poor imaging data quality or incidental findings, the final sample consisted of 2583 mother-child pairs. Data analysis was performed from March 1, 2019, to June 28, 2019.
Exposures Mother- and father-rated poor family functioning was repeatedly measured by the General Functioning subscale of the Family Assessment Device.
Main Outcomes and Measures Our primary hypothesis, formulated after data collection but before analysis, was that poor prenatal family functioning would be associated with smaller hippocampal and amygdala volumes in late childhood. High-resolution structural neuroimaging data of children aged 10 years were collected with a single 3-T magnetic resonance imaging system. Child emotional and behavioral problems were assessed with the Child Behavior Checklist.
Results Data were available for 2583 children (mean [SD] age, 10.1 [0.6] years; 1315 girls [50.9%]). Data for parents included 2583 mothers (mean [SD] age, 31.1 [4.7] years; 1617 Dutch race/ethnicity [62.6%]) and 1788 fathers (mean [SD] age, 33.5 [5.3] years; 1239 Dutch race/ethnicity [69.3%]). Children exposed to prenatal maternal-reported poor family functioning had smaller hippocampal (B = −0.08; 95% CI, −0.13 to −0.02) and occipital lobe (B = −0.70; 95% CI, −1.19 to −0.21) volumes in preadolescence. There was no evidence for an association of exposure to poor family functioning at mid- or late childhood with brain morphology. Hippocampal volumes partially mediated the association of prenatal maternal-reported poor family functioning with preadolescent problem behavior (B = 0.08; 95% CI, 0.03-0.13), even after adjusting for prior child problems at age 1.5 years. Analyses of combined maternal and paternal family functioning ratings showed similar results, but associations were largely driven by maternal family functioning reports.
Conclusions and Relevance In this population-based cohort study, prenatal maternal-reported poor family functioning was associated with a smaller hippocampus in preadolescents. This difference in brain structure may underlie behavioral problems and is a possible neurodevelopmental manifestation of the long-term consequences of poor family functioning for the child.
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Discussion
This cohort study of children from fetal life onward suggests that poor maternal-reported prenatal family functioning is associated with brain development in late childhood. In particular, we observed smaller hippocampal volumes in children exposed to poor family functioning occurring prenatally but not in mid- or late childhood. The association remained when we accounted for parental psychopathology and harsh parenting, indicating a unique association of poor prenatal family functioning with differences in preadolescent brain development. The contribution of prenatal maternal-reported poor family functioning to preadolescent problem behavior was partially mediated by hippocampal volumes. Interestingly, prenatal maternal-reported poor family functioning was associated with smaller occipital lobe volumes. Associations between poor family functioning and brain outcomes did not differ by child sex.
The vulnerability of the hippocampus to prenatal family functioning is consistent with previous studies reporting that the hippocampus matures rapidly and is functional very early in childhood.41,42 That the association between poor family functioning and hippocampal volumes was observed only from prenatal maternal-reported family functioning and not from mid- or late-childhood family functioning may reflect a sensitive period, which occurs early in life.43 Other research supports this inference. For example, higher levels of early-life maternal support have been linked to increased volume of the hippocampus.44,45 Our key finding, namely the interaction of poor family functioning with child age, suggests that pregnancy is a vulnerable period when development in response to parental care disruptions is maximally dynamic.46
In contrast to our hypothesis, we were not able to demonstrate an association between poor family functioning and amygdala volumes. The lack of a discernible sensitive period to family functioning for amygdala development is consistent with previous studies of children exposed to adversity, which have found no difference in amygdala volume in adults.47
The present findings provide evidence for a smaller occipital lobe in children exposed to prenatal maternal-reported poor family functioning. This observation, which was not expected a priori, should be interpreted with caution until it is replicated. However, the face-processing systems relating to occipital regions, in particular the lateral occipital lobe, were found to be particularly vulnerable to early-life adversities.48-50
Furthermore, we found that the association between prenatal maternal-reported poor family functioning and preadolescent problem behavior was partially mediated by hippocampal volumes. This may suggest that brain morphologic changes precede or may even contribute to behavioral changes. Our results are consistent with the extant literature, showing that smaller hippocampal volumes partially mediated the contribution of early-life stress to higher levels of behavioral problems.21 However, it is likely that the associations in the mediation model are more complex, and they may well be bidirectional. A sample with multiple repeated measures of imaging data starting early in childhood would be necessary to test the directionality between behavior and brain development. Indeed, a twin study in veterans with PTSD showed that a smaller hippocampus may reflect a preexisting vulnerability to stress and thus reverse causality.20 Alternatively, the difference in hippocampal volume could be explained by genetic variation. Recently, a genome-wide association meta-analysis identified a few genetic loci associated with hippocampal volume,51 which could be (indirectly) associated with poor family functioning.
In addition, associations between paternal-reported family functioning and brain structural measures did not remain after adjustment for sociodemographic factors and paternal psychopathology. Although prenatal parental family functioning factors reflect a common variance across mother- and father-reported family functioning, their association with brain structural measures was largely driven by the maternal report. Thus, the clear association found using maternal-reported functioning during pregnancy suggests that direct maternal physiological changes may underlie the findings. This is consistent with the developmental origins hypothesis that the prenatal or early postnatal environment can be associated with negative health outcomes later in life. Maternal psychological distress may lead to a suboptimal intrauterine environment with long-term consequences for the growth and health of the child.52-54 Intrauterine stress exposure may affect child development via dysregulation of the hypothalamic-pituitary-adrenal axis, but it may also affect brain development through inflammatory responses and changes in the balance of the autonomic nervous system.55 Another potential mechanism is dietary behavior and poor nutrition by which a variation in maternal nutrition (either a surplus or paucity of maternal nutrition) plays multiple roles in the health outcomes of children.56 However, postnatal experiences cannot be ruled out as a mechanism underlying our findings, because the prenatal period could be a marker of exposures in the early postnatal period, such as poor parenting.57 Thus, children of parents with poor family functioning may be more likely to experience a less optimal environment, which underlies the relation with brain developmental differences.
Parental psychopathology remains another important mechanism potentially underlying our observations. However, when we adjusted for parental psychopathology, we found that the association between poor prenatal family functioning and hippocampal volumes was, if anything, stronger. Thus, our results suggest that poor family functioning and parental psychopathology are closely associated and may predispose each other,13 but higher levels of parental psychopathology did not account for the association of poor family functioning with hippocampal volume.
Limitations and Strengths
The current study has several limitations. First, this study has a population-based design, but the relative homogeneity of the population limits its generalizability. Second, we found an association between poor prenatal family functioning and preadolescent brain morphology among children aged 10 years. Although we assessed prenatal family functioning, we cannot establish whether these associations result from strictly prenatal exposures or whether our measure indexes childhood exposure during the period up to age 6 years when parents were reassessed. Third, because poor family functioning was associated with brain findings in children aged 10 years, it is possible that the associations of family functioning reported prenatally had their effects in utero. However, because no scans were obtained before age 10, this cannot be determined. Furthermore, we were unable to examine whether the parental hippocampus is a marker of vulnerability that increases the likelihood of poor family adjustment and whether this propensity is transmitted genetically to the children. Strengths of the present study are the large number of participants and broad spectrum of measured covariates, which enabled us to adjust for multiple confounders. Because of our longitudinal design, we were able to look at possible sensitive periods by leveraging baseline and repeated assessments of poor family functioning reported by both mothers and fathers.
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