Faculty Bibliography

Altered fetal brain function is proposed as a mechanism underlying the relationship between prenatal maternal depression (PMD) and neurodevelopmental outcomes in offspring. This study investigated the association between PMD symptoms and fetal brain functional connectivity (FC) using graph theory. A total of 123 pregnant women participated in the study, completed the Center for Epidemiologic Studies Depression Scale (CES-D), and underwent fetal MRI scans. Results revealed a significant relationship between elevated PMD symptoms and reduced global efficiency in the right insular region of the fetal brain. However, because fetal age was not associated with local or global efficiency in the insular brain region, we cannot determine if the PMD-related reduction in insula global efficiency is indicative of an accelerated or delayed developmental pattern. This study is one of the few to examine fetal brain connectivity in relation to prenatal maternal depression, providing valuable insights into early neurodevelopmental risks and potential targets for early intervention.

BACKGROUND:Maternal infections are linked to neurodevelopmental impairments, highlighting the need to investigate SARS-CoV-2-induced immune activation. OBJECTIVE:This study aimed to evaluate the impact of maternal infection on neurodevelopment and investigate whether cytokine and chemokine profiles predict delays at 24 months. METHODS:Conducted in Brazil (January 2021-March 2022), this follow-up study included 18 SARS-CoV-2 positive pregnant women at 35-37 weeks' gestation, 15 umbilical cord blood samples, and blood samples from 15 children at 6 months and 14 at 24 months. Developmental delay was defined using the Bayley Scales of Infant and Toddler Development, Third Edition, with scores below 90 in cognitive, communication, or motor domains. RESULTS:At 6 months, 33.3% of infants exhibited cognitive delays, 20% communication delays, and 40% motor delays, increasing to 35.71%, 64.29%, and 57.14% at 24 months, respectively. Elevated interferon-gamma and tumor necrosis factor-alpha in cord blood correlated with cognitive delays, while interleukin (IL)-6, IL-8, IL-17, and IL-1β were associated with motor delays. Increased C-X-C motif chemokine ligand 10 and other cytokines were associated with communication delays. CONCLUSION/CONCLUSIONS:Maternal SARS-CoV-2 may impact infant neurodevelopment, as early cytokine elevations correlate with delays, highlighting the importance of early monitoring and interventions to reduce long-term effects. IMPACT/CONCLUSIONS:Prenatal SARS-COV-2 infection in pregnant women is linked to developmental delays in toddlers, with cytokine and chemokine changes associated with neurodevelopmental outcomes at 24 months. This study shows the long-term impact of maternal SARS-COV-2 infection on child development, highlighting inflammatory markers like IFN-γ, TNFα, IL-6, IL-8, IL-17, IL-1β, and CXCL10. Identifying specific cytokines correlating with cognitive, communication, and motor delays suggests potential biomarkers for early intervention. Conducted in Fortaleza, Brazil, the study emphasizes understanding local epidemiological impacts on child development, especially in regions with high infection rates. Graphical depiction of the SARS-CoV-2-induced maternal immune activation and its impact on the child's neurological development. Maternal immune activation from SARS-CoV-2 infection can affect a baby's neurological development, leading to motor, communication, and cognitive delays, assessed at 6 and 24 months old. Alterations in cytokine and chemokine levels in cord blood at six months may help predict these adverse outcomes observed at 24 months.

Parental reflective functioning (PRF) refers to a parent's ability to understand their own and their child's mental states and connect them to behaviors. This longitudinal study evaluated (1) associations among prenatal PRF, using the Pregnancy Interview, demographics, prenatal maternal depressive symptoms, and maternal-fetal attachment and (2) whether prenatal PRF predicted parenting quality assessed during unstructured and challenging mother-child interaction tasks beyond infancy, after controlling for cumulative risk. Data were collected in an urban community sample of women in the midwestern US. Prenatal PRF was positively associated with maternal educational attainment and negatively associated with cumulative demographic risk, but not with depressive symptoms or maternal-fetal attachment. Controlling for cumulative risk, hierarchical regressions showed that prenatal PRF was the sole significant predictor of positive parenting at 36 months, observed during a challenging teaching task but not during free play. Prenatal PRF did not predict negative parenting. These patterns persisted when analyses were repeated within a subsample of Black mothers, with PRF again being the sole significant predictor of positive parenting. Further attention to cultural variations in PRF and parenting in future research is warranted.

INTRODUCTION/BACKGROUND:Foundational preacademic skills are crucial for academic success and serve as predictors of socioeconomic status, income and access to healthcare. However, there is a gap in our understanding of neurodevelopmental patterns underlying preacademic skills in children across low-income and middle-income countries (LMICs). It is essential to identify primary global and regional factors that drive children's neurodevelopment in LMICs. This study aims to characterise the typical development of healthy children and factors that influence child development in Bahir Dar, Ethiopia. METHODS AND ANALYSIS/METHODS:The Bahir Dar Child Development Study is a cross-sectional study implemented in two health centres, Shimbit and Abaymado and in Felege Hiwot Comprehensive Specialized Hospital (FHCSH) in Bahir Dar, Amhara, Ethiopia. Healthy children between 6 and 60 months of age will be recruited from the health centres during vaccination visits or via community outreach. Young children aged 6-36 months will complete the Global Scale for Early Development. A battery of paper and tablet-based assessments of neurocognitive outcomes including visual and verbal reasoning, executive functions and school readiness will be completed for children aged 48-60 months. Caregivers will respond to surveys covering sociodemographic information, the child's medical history and nutrition, and psychosocial experiences including parental stress and mental health. During a second visit, participants will undergo a low-field MRI scan using the ultra-low-field point-of-care Hyperfine MRI machine at FHCSH. Analyses will examine relationships between risk and protective factors, brain volumes and neurocognitive/developmental outcomes. ETHICS AND DISSEMINATION/BACKGROUND:The study is approved by the Institutional Review Boards of Addis Continental Institute of Public Health (ACIPH/lRERC/004/2023/Al/05-2024), Mass General Brigham Hospital (2022P002539) and Brown University (STUDY00000474). Findings will be disseminated via local dissemination events, international conferences and publications. TRIAL REGISTERATION NUMBER/BACKGROUND:NCT06648863.

IMPORTANCE/UNASSIGNED:General trauma is the leading cause of nonobstetric maternal morbidity and mortality, affecting approximately 8% of all pregnancies. Pregnant women with traumatic brain injury (TBI) face high morbidity and mortality rates, requiring complex management due to physiological changes, teratogenic risks of treatments, and the need for fetal monitoring. OBJECTIVES/UNASSIGNED:To assess the consequences of TBI during pregnancy on maternal and fetal outcomes and to evaluate management strategies to inform clinical decision-making. EVIDENCE REVIEW/UNASSIGNED:A systematic literature search was conducted on January 12, 2024, in PubMed, Web of Science, and PsycInfo to identify articles published in English, German, or Spanish between January 1, 1990, and December 31, 2023, that included at least 1 pregnant individual with TBI. Peer-reviewed, human-based studies with original data on maternal and fetal outcomes were included. Reviews, meta-analyses, and nonhuman studies were excluded. Two independent reviewers screened abstracts and full-text articles. Study characteristics, pregnancy outcomes (maternal and fetal), management methods, and authors' conclusions were extracted. Risk of bias was assessed by 2 reviewers, with interrater agreement measured using Cohen κ. Disagreements were resolved through discussion. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was followed. FINDINGS/UNASSIGNED:This systematic review included 16 articles involving a total of 4112 individuals (mean maternal age, 26.9 years; range, 16-47 years) who experienced TBI during pregnancy (mean gestational age at injury, 24 weeks; range, 3-38 weeks). The articles comprised 10 case reports, 2 case series, and 4 cohort studies. Motor vehicle crashes were the most common cause of injury, reported in 12 articles. The average Glasgow Coma Scale score ranged from 3 to 15 across all individuals. Conservative management was reported in 7 case patients, whereas surgery was performed in 6 case patients. Maternal outcomes ranged from functional recovery to severe cognitive impairment, and fetal outcomes varied from stable to severe adverse outcomes, including stillbirth and death. Risk of bias assessment indicated moderate to good methodological validity overall, but most articles demonstrated poor quality of evidence. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this review, no definitive association between TBI during pregnancy and maternal or fetal outcomes was found owing to conflicting findings, poor to moderate study quality, and limited evidence. Although some articles suggested increased risks such as placental abruption and cesarean delivery, the findings remained inconclusive. The findings of this review underscore the need for high-quality research, standardized reporting, and rigorous methodology to improve data reliability. Future research should focus on developing consensus-driven, multidisciplinary management strategies to improve maternal and fetal outcomes.

Iron in the brain is essential to neurodevelopmental processes, as it supports neural functions, including processes of oxygen delivery, electron transport, and enzymatic activity. However, the development of brain iron before birth is scarcely understood. By estimating R2* (1/T2*) relaxometry from a sizable sample of fetal multiecho echo-planar imaging (EPI) scans, which is the standard sequence for functional magnetic resonance imaging (fMRI), across gestation, this study investigates age and sex-related changes in iron, across regions and tissue segments. Our findings reveal that brain R2* levels significantly increase throughout gestation spanning many different regions, except the frontal lobe. Furthermore, females exhibit a faster rate of R2* increase compared to males, in both gray matter and white matter. This sex effect is particularly notable within the left insula. This work represents the first MRI examination of iron accumulation and sex differences in developing fetal brains. This is also the first study to establish R2* estimation methodology in fetal multiecho functional MRI.

Preterm birth poses a major public health challenge, with significant and heterogeneous developmental impacts. Latent profile analysis was applied to the National Institutes of Health Toolbox performance of 1891 healthy prematurely born children from the Adolescent Brain and Cognitive Development study (970 boys, 921 girls; 10.00 ± 0.61 years; 1.3% Asian, 13.7% Black, 17.5% Hispanic, 57.0% White, 10.4% Other). Three distinct neurocognitive profiles emerged: consistently performing above the norm (19.7%), mixed scores (41.0%), and consistently performing below the norm (39.3%). These profiles were associated with lasting cognitive, neural, behavioral, and academic differences. These findings underscore the importance of recognizing diverse developmental trajectories in prematurely born children, advocating for personalized diagnosis and intervention to enhance care strategies and long-term outcomes for this heterogeneous population.

INTRODUCTION/BACKGROUND:Maternal undernutrition and inflammation in utero may significantly impact the neurodevelopmental potential of offspring. However, few studies have investigated the effects of pregnancy interventions on long-term child growth and development. This study will examine the effects of prenatal nutrition and infection management interventions on long-term growth and neurodevelopmental outcomes of offspring. METHODS:The Enhancing Nutrition and Antenatal Infection Treatment ('ENAT') study (ISRCTN15116516) was a pragmatic, open-label, 2×2 factorial, randomised clinical effectiveness study implemented in 12 rural health centres in Amhara, Ethiopia. The study enrolled 2399 pregnant women who were randomised to receive routine care, an enhanced nutrition package (iron and folic acid, monthly household supply of iodised salt, and micronutrient-fortified balanced energy protein supplement for undernourished women), an enhanced infection management package (genitourinary tract infection screening and treatment, and enhanced deworming), or both packages. In the present Longitudinal Infant Development and Growth study, a subset of 480 children of mothers from ENAT will be recruited equally from each of the four study arms and visited at 12, 18, and 24 months of postnatal age. We will evaluate a range of domains and deploy multiple measures to assess child neurodevelopment, including resting electroencephalography and visual evoked potentials, Hammersmith Infant Neurological Examination, eye-tracking, Bayley Scales of Infant and Toddler Development (Bayley-III), and Magnetic Resonance Imaging (MRI). DISCUSSION/CONCLUSIONS:This study will advance understanding of the impact of nutrition and inflammation in pregnancy on long-term offspring neurodevelopment. This study aims to fill a critical knowledge gap on the benefits of prenatal interventions to promote the health of mothers and their offspring. ETHICS AND DISSEMINATION/BACKGROUND:This study was approved by the Institutional Review Boards of Addis Continental Institute of Public Health (ACIPH/IRB/002/2022) and Mass General Brigham (2023P000461). Results will be disseminated to local and international stakeholders. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT06296238.

This review summarizes recent findings on stress-related programming of brain development in utero, with an emphasis on situating findings within the mothers' broader psychosocial experiences. Meta-analyses of observational studies on prenatal stress exposure indicate the direction and size of effects on child neurodevelopment are heterogeneous across studies. Inspired by lifespan and topological frameworks of adversity, we conceptualize individual variation in mothers' lived experience during and prior to pregnancy as a key determinant of these heterogeneous effects across populations. We structure our review to discuss experiential categories that may uniquely shape the psychological and biological influence of stress on pregnant mothers and their developing children, including current socioeconomic resources, exposure to chronic and traumatic stressors, culture and historical trauma, and the contours of prenatal stress itself. We conclude by identifying next steps that hold potential to meaningfully advance the field of fetal programming.