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

Importance: Elevated maternal psychological distress during pregnancy is associated with altered fetal brain development. During the COVID-19 pandemic, prenatal maternal psychological distress more than doubled. Objective: To examine the association of the pandemic and rising maternal psychological distress with brain growth in newborns using quantitative 3-dimensional volumetric magnetic resonance imaging (MRI). Design, Setting, and Participants: This prospective cross-sectional study recruited mother-infant dyads at Children's National Hospital, Washington, DC, during the COVID-19 pandemic (June 1, 2020, to June 30, 2022) into a longitudinal infant brain development study and compared them with an existing normative healthy cohort (recruited March 1, 2014, to December 31, 2019). Exclusion criteria included multiple gestation pregnancy, known or suspected congenital infection, documented chromosomal abnormalities, or any maternal contraindication to MRI, as well as prenatal COVID-19 exposure. Infants with structural brain abnormalities or a postnatal confirmation of a genetic syndrome were excluded. Exposure: Psychological distress during COVID-19 pandemic. Main Outcomes and Measures: Prenatal maternal mental health was evaluated using the Spielberger State-Trait Anxiety Inventory and the Perceived Stress Scale. Neonates underwent nonsedated brain MRI. An ordinary least squares linear regression model was used to measure the differences in regional brain volumes of neonates born before vs during the pandemic with and without exposure to elevated prenatal maternal psychological distress after adjustment for neonatal sex and gestational age at MRI and maternal age and educational level. Results: A total of 159 mother-infant dyads were included in the analysis: 103 before and 56 during the pandemic (median gestational age of infants, 39.6 [IQR, 38.4-40.4] weeks; median maternal age, 34.5 [IQR, 31.0-37.0] years). Eighty-three infants (52.2%) were female. Among the mothers, 130 (81.8%) had a college degree and 87 (54.7%) had a graduate degree. Forty-four mothers (27.7%) identified as Asian, Hispanic, or multiracial; 27 (17.0%), as Black; and 88 (55.3%), as White. Scores on anxiety and stress measures were significantly increased in the pandemic cohort. Infants of mothers with elevated maternal distress showed median reductions in white matter (-0.36 [95% CI, -0.61 to -0.11] cm3; Q < .001), right hippocampal (-0.35 [95% CI, -0.65 to -0.06] cm3; Q = .04), and left amygdala (-0.49 [95% CI, -0.84 to -0.13] cm3; Q = .03) volumes compared with infants of mothers with low distress levels. After adjusting for the cohort effect of the pandemic, elevated trait anxiety remained significantly associated with decreased left amygdalar volumes (-0.71 [95% CI, -1.12 to -0.29]; Q < .001). Conclusions and Relevance: In this cross-sectional study of maternal-infant dyads prior to and during the COVID-19 pandemic, regional neonatal brain volumes were associated with elevated maternal psychological distress.

Genome-wide neonatal epigenetic changes associated with maternal exposure to the COVID-19 pandemic.

BACKGROUND: During gestation, stressors to the fetus, including viral exposure or maternal psychological distress, can fundamentally alter the neonatal epigenome, and may be associated with long-term impaired developmental outcomes. The impact of in utero exposure to the COVID-19 pandemic on the newborn epigenome has yet to be described. METHODS: This study aimed to determine whether there are unique epigenetic signatures in newborns who experienced otherwise healthy pregnancies that occurred during the COVID-19 pandemic (Project RESCUE). The pre-pandemic control and pandemic cohorts (Project RESCUE) included in this study are part of a prospective observational and longitudinal cohort study that evaluates the impact of elevated prenatal maternal stress during the COVID-19 pandemic on early childhood neurodevelopment. Using buccal swabs collected at birth, differential DNA methylation analysis was performed using the Infinium MethylationEPIC arrays and linear regression analysis. Pathway analysis and gene ontology enrichment were performed on resultant gene lists. RESULTS: Widespread differential methylation was found between neonates exposed in utero to the pandemic and pre-pandemic neonates. In contrast, there were no apparent epigenetic differences associated with maternal COVID-19 infection during pregnancy. Differential methylation was observed among genomic sites that underpin important neurological pathways that have been previously reported in the literature to be differentially methylated because of prenatal stress, such as NR3C1. CONCLUSIONS: The present study reveals potential associations between exposure to the COVID-19 pandemic during pregnancy and subsequent changes in the newborn epigenome. While this finding warrants further investigation, it is a point that should be considered in any study assessing newborn DNA methylation studies obtained during this period, even in otherwise healthy pregnancies.

Influence of maternal psychological distress during COVID-19 pandemic on placental morphometry and texture.

The Coronavirus Disease 2019 (COVID-19) pandemic has been accompanied by increased prenatal maternal distress (PMD). PMD is associated with adverse pregnancy outcomes which may be mediated by the placenta. However, the potential impact of the pandemic on in vivo placental development remains unknown. To examine the impact of the pandemic and PMD on in vivo structural placental development using advanced magnetic resonance imaging (MRI), acquired anatomic images of the placenta from 63 pregnant women without known COVID-19 exposure during the pandemic and 165 pre-pandemic controls. Measures of placental morphometry and texture were extracted. PMD was determined from validated questionnaires. Generalized estimating equations were utilized to compare differences in PMD placental features between COVID-era and pre-pandemic cohorts. Maternal stress and depression scores were significantly higher in the pandemic cohort. Placental volume, thickness, gray level kurtosis, skewness and run length non-uniformity were increased in the pandemic cohort, while placental elongation, mean gray level and long run emphasis were decreased. PMD was a mediator of the association between pandemic status and placental features. Altered in vivo placental structure during the pandemic suggests an underappreciated link between disturbances in maternal environment and perturbed placental development. The long-term impact on offspring is currently under investigation.

Maternal psychological distress during the COVID-19 pandemic and structural changes of the human fetal brain.

Background: Elevated maternal psychological distress during pregnancy is linked to adverse outcomes in offspring. The potential effects of intensified levels of maternal distress during the COVID-19 pandemic on the developing fetal brain are currently unknown. Methods: We prospectively enrolled 202 pregnant women: 65 without known COVID-19 exposures during the pandemic who underwent 92 fetal MRI scans, and 137 pre-pandemic controls who had 182 MRI scans. Multi-plane, multi-phase single shot fast spin echo T2-weighted images were acquired on a GE 1.5 T MRI Scanner. Volumes of six brain tissue types were calculated. Cortical folding measures, including brain surface area, local gyrification index, and sulcal depth were determined. At each MRI scan, maternal distress was assessed using validated stress, anxiety, and depression scales. Generalized estimating equations were utilized to compare maternal distress measures, brain volume and cortical folding differences between pandemic and pre-pandemic cohorts. Results: Stress and depression scores are significantly higher in the pandemic cohort, compared to the pre-pandemic cohort. Fetal white matter, hippocampal, and cerebellar volumes are decreased in the pandemic cohort. Cortical surface area and local gyrification index are also decreased in all four lobes, while sulcal depth is lower in the frontal, parietal, and occipital lobes in the pandemic cohort, indicating delayed brain gyrification. Conclusions: We report impaired fetal brain growth and delayed cerebral cortical gyrification in COVID-19 pandemic era pregnancies, in the setting of heightened maternal psychological distress. The potential long-term neurodevelopmental consequences of altered fetal brain development in COVID-era pregnancies merit further study.

Association of Elevated Maternal Psychological Distress, Altered Fetal Brain, and Offspring Cognitive and Social-Emotional Outcomes at 18 Months.

Importance: Prenatal maternal psychological distress is associated with disturbances in fetal brain development. However, the association between altered fetal brain development, prenatal maternal psychological distress, and long-term neurodevelopmental outcomes is unknown. Objective: To determine the association of fetal brain development using 3-dimensional magnetic resonance imaging (MRI) volumes, cortical folding, and metabolites in the setting of maternal psychological distress with infant 18-month neurodevelopment. Design, Setting, and Participants: Healthy mother-infant dyads were prospectively recruited into a longitudinal observational cohort study from January 2016 to October 2020 at Children's National Hospital in Washington, DC. Data analysis was performed from January 2016 to July 2021. Exposures: Prenatal maternal stress, anxiety, and depression. Main Outcomes and Measures: Prenatal maternal stress, anxiety, and depression were measured using validated self-report questionnaires. Fetal brain volumes and cortical folding were measured from 3-dimensional, reconstructed T2-weighted MRI scans. Fetal brain creatine and choline were quantified using proton magnetic resonance spectroscopy. Infant neurodevelopment at 18 months was measured using Bayley Scales of Infant and Toddler Development III and Infant-Toddler Social and Emotional Assessment. The parenting stress in the parent-child dyad was measured using the Parenting Stress Index-Short Form at 18-month testing. Results: The cohort consisted of 97 mother-infant dyads (mean [SD] maternal age, 34.79 [5.64] years) who underwent 184 fetal MRI visits (87 participants with 2 fetal studies each) with maternal psychological distress measures between 24 and 40 gestational weeks and completed follow-up infant neurodevelopmental testing. Prenatal maternal stress was negatively associated with infant cognitive performance (ß = -0.51; 95% CI, -0.92 to -0.09; P = .01), and this association was mediated by fetal left hippocampal volume. In addition, prenatal maternal anxiety, stress, and depression were positively associated with all parenting stress measures at 18-month testing. Finally, fetal cortical local gyrification index and sulcal depth were negatively associated with infant social-emotional performance (local gyrification index: ß = -54.62; 95% CI, -85.05 to -24.19; P < .001; sulcal depth: ß = -14.22; 95% CI, -23.59 to -4.85; P = .002) and competence scores (local gyrification index: ß = -24.01; 95% CI, -40.34 to -7.69; P = .003; sulcal depth: ß = -7.53; 95% CI, -11.73 to -3.32; P < .001). Conclusions and Relevance: In this cohort study of 97 mother-infant dyads, fetal cortical local gyrification index and sulcal depth were associated with infant 18-month social-emotional and competence outcomes, and fetal left hippocampal volume mediated the association between prenatal maternal stress and infant cognitive outcome. These findings suggest that altered prenatal brain development in the setting of elevated maternal distress has adverse infant sociocognitive outcomes, and identifying early biomarkers associated with long-term neurodevelopment may assist in early targeted interventions.