key: cord-0976200-dxcdcv5s authors: Manning, Kathryn Y.; Long, Xiangyu; Watts, Dana; Tomfohr-Madsen, Lianne; Giesbrecht, Gerald F.; Lebel, Catherine title: Prenatal maternal distress during the COVID-19 pandemic and associations with infant brain connectivity date: 2022-05-16 journal: Biol Psychiatry DOI: 10.1016/j.biopsych.2022.05.011 sha: e72e7b2f6e3792d2b7ca32bf9f8a40f52c3f6851 doc_id: 976200 cord_uid: dxcdcv5s BACKGROUND: The COVID-19 pandemic has caused substantially elevated distress in pregnant individuals, which has the potential to impact the developing infant brain. Our main objective was to understand how prenatal distress was related to infant brain structure and function, and whether social support moderated the associations. METHODS: This Pregnancy during the COVID-19 Pandemic cohort study collected Patient Reported Outcomes Measurement Information System anxiety, Edinburgh Depression Scale, and Social Support Effectiveness Questionnaire from a population-based sample of pregnant individuals living in Canada (N=8602). For a sub-sample of participants, their infants (N=75) underwent MRI at 3-months of age to examine whether prenatal maternal distress was associated with infant brain architecture, including the role of social support as a potential protective factor. RESULTS: 33.4% participants demonstrating clinically elevated depression symptoms and 47.1% of participants demonstrating clinically elevated anxiety symptoms. Importantly, we identified lower social support significantly predicts clinically elevated prenatal maternal distress (T=-22.3, p<0.001). After image quality control, we retained 63 image datasets (40M/23F, 92+/-14 days old). We found significant relationships between prenatal maternal distress and infant amygdala-prefrontal microstructural and functional connectivity measures, and demonstrate for the first time that social support moderates these relationships. CONCLUSIONS: Our findings suggest a potentially long-lasting impact of the COVID-19 pandemic on children and show that social support acts as a possible mediator not just for pregnant individuals, but also developing infants. These findings provide timely evidence to inform clinical practice and policy surrounding the care of pregnant individuals and highlight the importance of social support. Prenatal maternal distress, defined as elevated symptoms of anxiety and/or depression, can have immediate negative effects on pregnant individuals as well as the rapidly developing and vulnerable fetus. Prenatal maternal distress is associated with preterm birth as well as long-term risks for behavioural and mental health problems in children (1) (2) (3) . Alterations to the developing infant brain, especially within the limbic system, likely underlie compromised behavioural development (4) (5) (6) (7) . In particular, infants exposed to higher prenatal stress have larger amygdala volumes, disrupted white matter connectivity between the amygdala and prefrontal cortex (including the uncinate fasciculus), and functional connectivity changes between the amygdala and prefrontal regions (8) (9) (10) . Further, amygdala-prefrontal pathways mediate the relationship between maternal prenatal depression and externalizing behaviours (hyperactivity, aggression) in children (11) , showing that brain structure is a mechanism via which prenatal maternal distress can impact children's behavioural development. The COVID-19 pandemic has had a profound and prolonged effect on the mental health of pregnant individuals. Pregnant individuals have faced fear for themselves and their developing babies, disruptions to prenatal care (including lack of partner support) (12) , reduced access to services, and loss of support from friends and family. Rates of psychological distress in pregnant individuals have more than tripled during the pandemic (13) (14) (15) ), compared to rates pre-pandemic (16, 17) . Previous studies of children born during natural disasters demonstrate the long-term consequences of prenatal distress on brain development (18, 19) and behaviour (20) , raising significant concerns about how the generation of children born during the COVID-19 pandemic J o u r n a l P r e -p r o o f 4 will be affected. Data are emerging that demonstrates deficits in early infant and child cognitive development (21) . Social support can moderate the effects of prenatal distress on maternal HPA axis activity (22) and has been shown to reduce psychological distress during pregnancy (16, 23, 24) . Evidence is overall highly consistent and supports the notion that social support is an important protective factor against depression (25) . However, it is unclear whether social support can disrupt the transmission of prenatal maternal distress to infant brain development. Understanding how prenatal maternal distress affects brain development, including potential modifiable risk and protective factors such as social support, will aid in identifying children most at risk and inform policy recommendations to rapidly benefit families. Here, we measured prenatal depression, anxiety, and social support in a very large sample of pregnant individuals across Canada during the COVID-19 pandemic. We hypothesized that higher prenatal maternal distress measures reported during the pandemic would demonstrate a negative relationship with measures of social support, while controlling for maternal education, household income and ethnicity. In a subset of infants who provided imaging data, we examined how prenatal maternal distress was related to infant amygdala structural and functional connectivity at 3-months of age, while controlling for maternal education, household income, postnatal maternal distress, child age and sex. Furthermore, an interaction term between prenatal maternal distress and social support was included to test the hypothesis that social support moderates associations between prenatal maternal distress and the infant brain. J o u r n a l P r e -p r o o f 6 to assess the amount and quality of social support provided by a partner or close friend/family member. Clinically elevated depression symptoms were defined as a score of >12 on the EPDS (27) and clinically elevated anxiety was defined as PROMIS scores > 59 (28) . We also obtained postpartum mental health measures through our online survey at 3-months postpartum. We acquired brain imaging data from 75 infants (92 +/-14 days old; Table S1) using the GE 3T MR750w MRI using a 32-channel head coil at the Alberta Children's Hospital. Infants were ExploreDTI (30) was used to process the diffusion data, including signal drift, Gibbs ringing, eddy currents and head motion corrections. Participants who awoke early during the scanning protocol and were removed from the scanner before completing the diffusion portion of the protocol or those with excessive motion and compromised diffusion data determined with manual visual check were not included in data analyses. Whole brain whiter matter tractography J o u r n a l P r e -p r o o f was performed using semi-automated deterministic streamline tractography with fractional anisotropy (FA) > 0.1 and angle < 30 degrees. We focused our analysis on the bilateral uncinate fasciculus and fiber bundles connecting the amygdala to the prefrontal cortex given previous findings (6, 11) and these two tracts were generated using our previous methods (11) . Mean FA and mean diffusivity (MD) were calculated within each tract for each participant. Rs-fMRI preprocessing was conducted using FSL (31) and included brain extraction, motion correction, 5mm smoothing, and high pass temporal filtering. Participants were excluded if they awoke too early during the scanning protocol and were removed from the scan before completing the functional portion of the protocol or if they had excessive motion (> 0.25mm relative mean displacement for > 120 volumes). Volumes with excessive motion (> 1mm) within individual datasets (N = 19) were truncated. As the infants were scanned during natural sleep, motion only occurred at the beginning of the scan (when the noise changes sometimes startled the infant) or at the end of the scan (if the infant awoke), so we were able to retain a subset of continuous data for each of these 19 participants. Independent component analysis (ICA) denoising was used to regress non-neuronal components from the data and clean images were registered to an infant atlas template for neonates (32) . FEAT (33) higher-level analysis was used to create an average amygdala connectivity map ( Figure 3A ). From this, the infant Automated Anatomical Labeling (AAL) atlas (32) was used to identify regions (superior orbitofrontal cortex and inferior frontal gyrus) with significant functional connectivity (z > 2.3) with the amygdala. We tested intrahemispheric functional connectivity between these two prefrontal regions (left and right) and the amygdala (left and right) using Pearson correlation in MATLAB. Standard scores from the EPDS and PROMIS Anxiety measures were highly correlated (R = 0.78) and combined using a factor analysis in SPSS into a single factor to quantify prenatal maternal distress, similar to what has been done previously (5) . This was done to determine overall prenatal maternal distress and also decrease the number of hypotheses tested. A general linear model was used to investigate the relationship between prenatal maternal distress and social support (SSEQ), while controlling for maternal education, household income and ethnicity. We also conducted a logistic regression analysis in MATLAB to determine if SSEQ score predicts clinically significant prenatal psychological distress defined as > 0. 25 where the relationship between MRI measures and prenatal maternal distress were tested for significance at p < 0.05. Results were corrected for multiple comparisons using false-discovery rate (FDR) correction based on 12 general linear models (4 FA measures, 4 MD measures and 4 functional connectivity measures). The interaction term between SSEQ and prenatal maternal distress was included to examine whether social support moderates the relationship between J o u r n a l P r e -p r o o f prenatal maternal distress and the developing infant brain. If the interaction was significant, posthoc tests between high and low social support groups (based on the median i.e. above and below SSEQ=60) were used to further understand the relationships. If the interaction term was not significant, the model was re-run without it included. The mean EPDS score was 10.4 +/-5. A total of 75 infants participated in imaging at the Alberta Children's Hospital between August 2020 and May 2021. Mean EPDS and PROMIS Anxiety scores in this sub-sample were 8.6 +/-5.3 and 54.7 +/-12.4, respectively, and were normally distributed ( Figure S1 ). These scores are J o u r n a l P r e -p r o o f significantly lower than the full survey sample (p < 0.01), but still elevated compared to prepandemic anxiety and depression levels. After image quality control (described in the methods section), we retained 58 DTI datasets for diffusion analysis (38M/20F, 92 +/-14 days old); 6 infants awoke early and were unable to complete the protocol, 6 infants had excessive motion during the scan, and 5 infants' mothers did not provide 3-month postpartum maternal distress measures. For the functional imaging analysis, we retained 41 rs-fMRI datasets (28M/13F, 92 +/-14 days old); 14 infants had excessive motion, 14 awoke before the rs-fMRI acquisition and did not complete the protocol, 2 had a field of view error, and 4 infants' mothers did not provide 3month postpartum maternal distress measures. The SSEQ x prenatal maternal distress interaction terms were not significant for diffusion measures, so the model was run with this term removed (Table S2) Both of these functional imaging relationships also had a significant main effect of sex (Table S2 ) where males had significantly higher functional connectivity between the amygdala and inferior frontal gyrus (T = -2.2, p = 0.04, 95% CI: [-0.3, -0.01]). Furthermore, we explored these models including an interaction term between infant sex and prenatal maternal distress, and amygdala-inferior frontal gyrus connectivity also had a significant interaction (T = 2.7, p = 0.01,  = 0.2, 95% CI: [0.04, 0.3]) where males tended to have a more negative relationship between functional connectivity prenatal maternal distress compared to females that demonstrated a slightly positive relationship. However, post-hoc correlation analyses between amygdala-inferior frontal gyrus connectivity and prenatal distress were not significant when grouped by sex. Here, in a very large cross-Canada sample of pregnant individuals, we show substantially elevated prenatal maternal distress during the pandemic that was associated with social support measures. In a subset of participants who provided infant imaging data, prenatal maternal J o u r n a l P r e -p r o o f distress was associated with structural and functional brain connectivity alterations. One third and nearly half of pregnant individuals demonstrated clinically significant depression and anxiety symptoms, respectively. This is consistent with other studies around the world and demonstrates how substantially affected pregnant people have been during this pandemic (17) . The prevalence of clinically elevated depression and anxiety symptoms among this cohort has increased substantially in comparison to pre-pandemic distress levels among pregnant individuals (38) and US population norms (28, 35) (Figure 1) . Importantly, prenatal psychological distress was moderated by social support where individuals with better quality and/or quantity of perceived social support reported lower symptoms of anxiety and depression. In a subsample of participants who provided imaging data, we found prenatal distress was associated with white matter microstructure and functional connectivity in the infant brain. Furthermore, we demonstrate for the first time that the relationship between prenatal distress and functional brain connectivity is moderated by social support, suggesting that social support in pregnancy may not only support mothers, but may also mitigate the intergenerational transmission of prenatal stress to their infants. In the largest sample to date of pregnant individuals during the COVID-19 pandemic, our findings affirm previous research showing that a high level of perceived social support from a partner or another supportive person may buffer the severity of psychological symptoms among pregnant individuals (39, 40) . Our results reflect the importance of strong social support for pregnant individuals, and the role of partners and others in maintaining healthy prenatal mental health, where we identified that social support was a protective factor for clinically elevated prenatal maternal distress. Partner support may have been especially important during the J o u r n a l P r e -p r o o f the general community, due to public health measures and fears of exposure to the virus. Partners may have had limited access to attend appointments, and some prenatal appointments were virtual instead of in-person. Changes in a support person attending the birth specifically have been related to elevated symptoms of prenatal anxiety and depression in this cohort (12) . In infants born during the pandemic, we showed both structural and functional alterations in amygdala-prefrontal connectivity associated with prenatal distress. Infants exposed to higher prenatal maternal distress had higher FA and lower MD. Because FA generally increases and MD generally decreases across childhood (41), our findings may reflect a more mature pattern of brain structure of the right uncinate fasciculus and amygdala-prefrontal white matter connections involved in emotion regulation. Previous studies of infant brain microstructure and maternal prenatal depression have demonstrated mixed findings, with some reporting higher FA and lower MD in infants and young children associated with higher maternal distress (42) (43) (44) while others report higher prenatal depressive symptoms related to lower neurite density (5) and lower FA (9) in 1-month and two-week old infants, respectively. The tracts identified in these studies vary; for example, higher pre and postnatal depression symptoms were associated with higher FA in the genu of the corpus callosum (supporting prefrontal connections) but not in the uncinate fasciculus when averaged across both hemispheres. Our right-lateralized functional and structural results are consistent with prior findings showing that prenatal maternal depressive symptoms are associated with prefrontal white matter connections in the right hemisphere (9) . Previous studies have identified right cortex structural variations in children and adolescents with or at risk of depression (45, 46) , and EEG studies have demonstrated functional brain activity in infants and children using right frontal electrodes that relate to prenatal anxiety and depression (47) . The right hemisphere is also more implicated in mental health in children (48) and adolescents (49) , suggesting that functional and structural brain alterations may be an underlying mechanism via which maternal prenatal distress can lead to increased risk for mental health difficulties in adolescence. Importantly, our results also show, for the first time, that social support plays a role not only on the impact of prenatal distress on pregnant individuals, but also on the developing infant brain. Prenatal distress was negatively related to infant brain functional connectivity in mothers with low social support, but this relationship was not present in individuals with high social support. We found reduced functional connectivity between the right amygdala and superior orbitofrontal cortex as well as the inferior frontal gyrus was related to higher prenatal distress, suggesting an alteration in the development of the functional connectome that supports emotional regulation and decision making. Previous research in 6-month-old infants demonstrated a positive relationship between amygdala functional connectivity and prenatal depression (50); negative associations have also been observed in young children (8) . Our data in infants is consistent with the latter finding and demonstrates a similar pattern in infants born to mothers with low social support. Including social support measures and other important covariates may improve the reproducibility of the complex relationship between prenatal distress and the developing infant brain. These findings suggest that social support may disrupt the transmission of prenatal stress to altered functional connectivity in the developing infant brain. Maternal education significantly correlated with survey measures of prenatal distress and social support. It also played a role in the infant amygdala and orbitofrontal cortex functional connectivity model, where relatively less education was related to higher functional connectivity. Structural connectivity showed alterations associated with prenatal distress, but these were not moderated by social support. It is possible that these relationships may change in later stages of development as the functional and structural connectome of the infant brain continues to develop and refine (41, 51, 52) . In general, stronger structural connectivity measures and weaker functional connectivity were related to higher prenatal maternal distress. Additionally, functional connectivity, but not structural connectivity, relationships were moderated by social support. At this early stage of development, structural and functional brain connectivity appear to have distinct relationships with prenatal maternal distress. Longitudinal imaging data throughout childhood will help better understand the developmental trajectories of the structural and functional connectome and how this relates to perinatal maternal distress. Potential mechanisms linking prenatal maternal distress to infant brain alterations include epigenetic changes such as increased glucocorticoid receptor methylation in children in order to silence stress responses (53) . Invasive animal studies often attribute heightened and sustained cortisol concentrations to changes in infant cognition and behaviour, however the human literature is inconsistent and an indirect mechanism such as regulation of enzymes may be responsible for cortisol metabolism (54). Prior research has also shown that social support can mitigate the impacts of prenatal stress on this underlying neurophysiology through normalizing the dysregulation of the HPA-axis and consequent cortisol levels (22) , providing further evidence for the importance of social support for pregnant individuals and the developing infant. While our study demonstrates the important role of social support and its relationship with prenatal maternal distress during the pandemic, as well as the relationship with infant functional and structural connectivity measures, there are limitations and opportunities to extend our findings. Our imaging sample had slightly different educational and racial demographic profiles compared to the larger survey sample and reaching a wider population at multiple sites could be useful to replicate our findings. The infant brain images were acquired at 3-months of age. By this time, postnatal factors may influence the relationships between infant brain and prenatal distress. We controlled for postnatal maternal distress, but infant feeding, sleep, family structure, and infection may also have influenced early brain development in this population. Infants were scanned while asleep without the use of sedatives, however functional connectivity profiles may differ in awake states. Future studies with higher resolution measures of white matter will be able to further elucidate the nature of these relationships. In conclusion, we show that pregnant individual's mental health has been especially impacted during the COVID-19 pandemic and that social support plays an important role. Furthermore, we observed a relationship between prenatal maternal distress and the developing infant brain. There may be long-lasting impacts of this pandemic-related stress on infants, and our findings will help inform health policies and identify families who may benefit from early interventions (55). The brain shows developmental plasticity in infancy and early childhood, and evidence-based interventions exist to improve children's behaviours and mental health risk (56). Importantly, our findings provide evidence that social support may disrupt the intergenerational transmission of stress. This highlights the pressing need for prenatal mental health screening as well as policies that target improving social support (56), as we have demonstrated that this may also support healthy infant brain development in early life. (35)). (B) There was a negative relationship between Social Support Effectiveness Questionnaire (SSEQ) total score and prenatal maternal distress, while controlling for maternal education, household income and ethnicity. Higher social support was associated with lower prenatal maternal distress. 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