Prenatal Maternal Psychological Distress During the COVID-19 Pandemic and Newborn Brain Development

Key Points Question Is increased maternal psychological distress during the COVID-19 pandemic associated with neonatal brain development? Findings In this cross-sectional study of 159 mother-infant dyads, left amygdalar volumes were smaller in neonates born to mothers with high psychological distress during the pandemic. Meaning These findings suggest that increased maternal mental health symptoms during the COVID-19 pandemic are associated with subsequent changes in regional brain growth in newborn offspring.


Introduction
2][3] Maternal psychological distress during pregnancy, including stress, anxiety, and depression, is recognized as one such stressor on early brain development, [4][5][6][7][8][9][10][11][12] as well as psychosocial adversity such as trauma, bereavement, or poverty. 13,1419] Since 2020, several groups 4,5,7,9 have reported that alterations in offspring brain growth and metabolism in the setting of maternal psychological distress detected in utero are associated with offspring behavior at 18 months.6 During the COVID-19 pandemic, the world experienced an alarming increase in the incidence of psychological distress, [8][9][10] including among pregnant women.[20][21][22][23][24][25][26][27][28] Lu et al 4 previously demonstrated that fetal brain development during the COVID-19 pandemic was associated with decreased cerebral white matter, hippocampal, and cerebellar volumes, even in the absence of maternal COVID-19 exposure.However, the potential enduring effects of these prenatal alterations in fetal brain development in the offspring remain unclear.The magnitude and extent of maternal psychological distress experienced during the COVID-19 pandemic raise the possibility of a secondary epidemic of neurobehavioral concerns in the next generation of children born during this period. The ojective of our study was to determine the association of prenatal maternal mental health during the COVID-19 pandemic, in the absence of direct viral exposures or infection, with neonatal brain development, using the same cohort as in the previous fetal study.4 We hypothesized that elevated maternal psychological distress during pregnancy would result in smaller regional and tissue-specific brain volumes measured in the neonatal period.

Study Participants
Mother-infant dyads were prospectively recruited for longitudinal brain magnetic resonance imaging (MRI) studies, including a fetal and a neonatal scan.For this cross-sectional study, imaging performed during the neonatal period is reported. 4Acquisition protocols for MRI and maternal assessments were identical across cohorts.Exclusion criteria included multiple gestation pregnancy, known or suspected congenital infection, documented chromosomal abnormalities, or maternal contraindication to MRI.To disentangle potential effects of COVID-19 exposures, mothers with documented COVID-19 infections were excluded in this report; COVID-19 exposures were determined through serial self-reported surveys and medical records.Additionally, mothers reporting the use of medications or substances other than prenatal vitamins or supplements were excluded (eg, prescribed medications, tobacco, marijuana, or alcohol).Enrolled infants found to have structural brain abnormalities on fetal or neonatal MRIs or a postnatal confirmation of a genetic syndrome were subsequently excluded from the study.Demographic information, including maternal age, educational level, and race and ethnicity were collected via self-reported assessments by the mother.Given the relatively low numbers of participants who reported racial background

MRI Data Acquisition
Neonatal MRI studies were performed on a 3T MR scanner (Discovery MR750; GE Healthcare) and an

Image Processing
A quality assessment of each scan for signs of movement of the participant was conducted before analysis, and 3D brain images with severe motion artifacts that affected the ability to distinguish brain tissues such as the cortical gray mater, white matter, brainstem, and cerebellum were excluded from analysis.Postacquisition processing of volumetric brain measurements was performed using the DrawEM (Developing Brain Region Annotation With Expectation-Maximization [MIRTK]) software tool and 3D U-Net-based methods that have been validated in newborns. 34Regions of interest were determined based on prior reports and included the cerebral white matter, left and right hippocampus, left and right amygdala, and cerebellum, 4,5,7,34 where the cerebral white matter and cerebellum were automatically segmented by DrawEM images 35 and bilateral hippocampus and amygdala were automatically segmented by 3D U-Net images, 36,37 and all regions were manually corrected using open-source ITK-SNAP software in the coronal, sagittal, and axial fields.A representative image of this 3D reconstruction is shown in eFigure 1 in Supplement 1.

Statistical Analysis
All analyses were performed with R statistical software, version 4.

Study Population
This study prospectively enrolled 223 mother-infant dyads.One hundred three dyads were recruited

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Prenatal Maternal Psychological Distress and Newborn Brain Development

Maternal Anxiety, Stress, and Depression
Scores on the SSAI, STAI, and PSS were significantly higher in the pandemic cohort than in the prepandemic cohort (Table 2).Among women in the prepandemic cohort, 20  distress.The proportion of women who scored above the threshold for each metric was significantly greater in the pandemic cohort than in the prepandemic cohort (P < .001)(Table 2).

Association Between Pandemic and Regional Brain Volume
Neonates born during the pandemic had significantly reduced white matter volumes compared with those born before the pandemic after adjustment for gestational age at MRI, neonatal sex, and maternal age irrespective of maternal mental health status, although this was attenuated following multiple comparison corrections (−0.41 [95% CI, −0.72 to −0.10] cm 3 ; P = .01;Q = .06)(Figure 1).
Hippocampal, amygdalar, and cerebellar volumes were not significantly different between prepandemic and pandemic cohorts.a For all comparisons between the prepandemic and pandemic groups for the SSAI, STAI, and PSS measures, P < .001.For all comparisons between those with psychological distress measure scores below the threshold vs those with scores above the threshold, P < .001.
b Mothers who scored above the threshold were considered psychologically distressed.
c Unless otherwise indicated, data are expressed as No. (%) of total participants with data available.

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Prenatal Maternal Psychological Distress and Newborn Brain Development

Cumulative Associations of Pandemic and Maternal Distress With Regional Brain Volume
After adjusting for pandemic effects, elevated maternal psychological distress was inversely associated with cerebral white matter (−4.94 [95% CI, −9.76 to −0.12] cm 3 ; P = .04)and left   3).

Discussion
In this cross-sectional study, we report that neonates born during the COVID-19 pandemic demonstrated smaller cerebral white matter volumes compared with neonates in the prepandemic cohort.We also report regional decreases in cerebral white matter, right hippocampal, and left amygdalar volumes in offspring born during the pandemic to mothers with elevated prenatal maternal psychological distress.The COVID-19 pandemic negatively affected mental health globally, including pregnant women. 21,23Prior to the pandemic, maternal stress and anxiety during pregnancy were associated with decreased left hippocampal volumes in the fetus, with lasting effects on offspring behavior and development. 5,6,14Similarly, as previously reported in this cohort, 4 the increase in maternal mental distress during the COVID-19 pandemic selectively stunted fetal cerebral white matter, hippocampal, and cerebellar growth.In the present study, we found persistent decrements in newborn cerebral white matter and right hippocampal volumes, especially in the pandemic cohort with high levels of stress and anxiety.These data underscore the putative role of heightened maternal stress on vulnerable brain regions during this critical period of prenatal brain development.We also report lower volumes of the left amygdala in neonates of mothers with elevated stress and anxiety during pregnancy that has not been observed prenatally.This finding may have been previously unseen given the smaller size and limited resolution of the amygdala on fetal imaging, which prevents accurate measurement and reporting.Conversely, we did not find differences in neonatal cerebellar growth, which has been reported in fetal scans, 4 suggesting those Downloaded from jamanetwork.comby guest on 06/30/2024 differences were transient, subsequently accelerated, or subject to catch-up growth in the later part of gestation, resulting in no differences in cerebellar volumetric growth in the early postnatal period.
9][40][41] Due to the early formation of white matter in the fetal brain, specifically of the emergence and formation of limbic tracts to the cingulum and the fornix, 42 these white matter tracts may be particularly vulnerable to effects of prenatal maternal mental health. 13,15,43,44The fetal cingulum in particular has been shown to be affected by high levels of prenatal glucocorticoid exposure, such as in the case of prenatal stress.This period, specifically within the second trimester, is additionally the stage when early oligodendrocyte progenitor cells are developing and the process of myelination is beginning. 44,45sruptions in this process decrease the volume of the white matter due to the lack of myelination, but also weaken potential connections.White matter remains susceptible to changes in the mental state of the mother throughout the perinatal period, which can explain why we see significant effects of stress and anxiety on fetal and neonatal scans. 4,6,10,13,15r data show a selective vulnerability of the left amygdala in the newborn infant exposed to elevated maternal stress and anxiety during pregnancy.The amygdala is central to fear emotion processing in the brain and heavily implicated 46-48 in anxiety, particularly in threat processing and anxiety, which have been linked to the left amygdala and its projections to the prefrontal cortex. 49 also report a significant decrease in the right amygdalar volumes in newborn offspring when exposed to elevated maternal trait anxiety, which reflects more stable expression of the personality trait of anxiety, as opposed to the more transient spikes of state anxiety. 30We posit differential susceptibility between chronic and acute exposures, with the right amygdala showing an association with chronic conditions or exposures.Published work demonstrating similar reductions in right amygdalar volume in the setting of other chronic maternal conditions, such as prenatal maternal depression, support this observation. 50st, we report a differential effect between prenatal maternal state and trait anxiety and stress on neonatal brain development.Maternal mental health studies often evaluate the independent effects of stress, anxiety, depression, and trauma, 3,[9][10][11]14,16,17,32,50,51 despite the significant overlap in symptoms and high rates of mental health comorbidities. Despite these simlarities, underlying biological mechanisms of stress and anxiety are likely mediated through distinct pathways 40,47,[52][53][54] and thus may exert unique effects on the offspring brain.9,11,13,18,35,51,[55][56][57][58] Stress is thought to be predominately mediated by cortisol via the hypothalamic-pituitary-adrenal axis, whereas anxiety appears to be primarily mediated through dopamine circuits and receptors in the amygdala.46,[58][59][60][61] Additionally, differences in duration of exposure may also influence early brain development, as seen in trait anxiety, which suggests chronic exposure compared with state anxiety and shorter-term exposures.The developmental window (and timing) of exposure likely results in distinct effects on offspring brain structure.The mechanisms driving the differences we report in regional brain development are undoubtedly complex, and the long-term implications require further study.
It is important to note that while psychological distress increased significantly during the pandemic, there remained effects of the pandemic on offspring brain development, independent of maternal mental health.Additional measures of adversity, particularly trauma or bereavement, as well as shifts in societal norms and increased social isolation, 62,63 were unmeasured in this study.
Similarly, the contribution of additional factors related to job insecurity and worries over family wellbeing, along with high levels of general unrest during this period, need to be considered.However, as the current and previous work suggest, there may be cumulative effects of both the pandemic and prenatal maternal mental distress that collectively affect offspring neurodevelopment.As none of the study participants in our pandemic cohort reported a diagnosis of COVID-19 during pregnancy, these differences are unlikely to be due to effects of viral exposure or transmission.

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Prenatal Maternal Psychological Distress and Newborn Brain Development

Limitations
It is important to note the limitations of our study.First, the advent of the COVID-19 pandemic may have resulted in lifestyle changes that influenced both maternal mental health and infant development.Also, all mental health data were reported by the mothers, leading to potential selfreporting bias.Despite the rigorous screening of participants in this study to identify COVID-19 exposures, it is possible that they had unknown exposure or subclinical infection.This study included the greater Washington, DC, region and was open to pregnant women of all races, ethnicities, and resources.However, this study reported on a group of women predominantly of White race with high levels of education and employment.The experience of the participants in this study may not necessarily be representative of other communities or regions.Further, additional measures of psychosocial adversity have been shown to be associated with similar changes in brain development. 13,14,46,47These measures were beyond the scope of this work, but certainly warrant additional study.Last, there was a significant difference in gestational age at MRI; while gestational age at MRI was accounted for in our statistical models, these adjustments may not fully reflect the dynamic, and often nonlinear, nature of brain development during the neonatal developmental window.

Figure 1 .
Figure 1.Comparisons of Neonatal Brain Volumes by Cohort

Figure 2 .
Figure 2. Comparisons of Neonatal Brain Volumes by Maternal Distress Prenatal Maternal Psychological Distress and Newborn Brain Development All study procedures for the prepandemic and pandemic cohorts were reviewed and approved by the institutional review board at Children's National Hospital, Washington, DC.Written informed consent was obtained from all participants.This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines for cross-sectional studies.29 JAMA Network Open.2024;7(6):e2417924.doi:10.1001/jamanetworkopen.2024.17924(Reprinted) June 20, 2024 2/14 Downloaded from jamanetwork.comby guest on 06/30/2024 other than Black or White, additional racial and ethnic categories, including multiracial and Hispanic ethnicity, were reported as other.

Table 1 .
Demographic Characteristics Abbreviation: GA, gestational age.a Unless otherwise specified, data are expressed as No. (%) of participants.b Includes participants who reported being Asian, Hispanic, or multiracial individuals.