Intrauterine exposure to SARS-CoV-2 infection and early newborn brain development.

Epidemiologic studies suggest that prenatal exposures to certain viruses may influence early neurodevelopment, predisposing offspring to neuropsychiatric conditions later in life. The long-term effects of maternal COVID-19 infection in pregnancy on early brain development, however, remain largely unknown. We prospectively enrolled infants in an observational cohort study for a single-site study in the Washington, DC Metropolitan Area from June 2020 to November 2021 and compared these infants to pre-pandemic controls (studied March 2014-February 2020). The primary outcomes are measures of cortical morphometry (tissue-specific volumes), along with global and regional measures of local gyrification index, and sulcal depth. We studied 210 infants (55 infants of COVID-19 unexposed mothers, 47 infants of COVID-19-positive mothers, and 108 pre-pandemic healthy controls). We found increased cortical gray matter volume (182.45 ± 4.81 vs. 167.29 ± 2.92) and accelerated sulcal depth of the frontal lobe (5.01 ± 0.19 vs. 4.40 ± 0.13) in infants of COVID-19-positive mothers compared to controls. We found additional differences in infants of COVID-19 unexposed mothers, suggesting both maternal viral exposures, as well as non-viral stressors associated with the pandemic, may influence early development and warrant ongoing follow-up.

Experience of early-life pain in premature infants is associated with atypical cerebellar development and later neurodevelopmental deficits.

BACKGROUND: Infants born very and extremely premature (V/EPT) are at a significantly elevated risk for neurodevelopmental disorders and delays even in the absence of structural brain injuries. These risks may be due to earlier-than-typical exposure to the extrauterine environment, and its bright lights, loud noises, and exposures to painful procedures. Given the relative underdeveloped pain modulatory responses in these infants, frequent pain exposures may confer risk for later deficits. METHODS: Resting-state fMRI scans were collected at term equivalent age from 148 (45% male) infants born V/EPT and 99 infants (56% male) born at term age. Functional connectivity analyses were performed between functional regions correlating connectivity to the number of painful skin break procedures in the NICU, including heel lances, venipunctures, and IV placements. Subsequently, preterm infants returned at 18 months, for neurodevelopmental follow-up and completed assessments for autism risk and general neurodevelopment. RESULTS: We observed that V/EPT infants exhibit pronounced hyperconnectivity within the cerebellum and between the cerebellum and both limbic and paralimbic regions correlating with the number of skin break procedures. Moreover, skin breaks were strongly associated with autism risk, motor, and language scores at 18 months. Subsample analyses revealed that the same cerebellar connections strongly correlating with breaks at term age were associated with language dysfunction at 18 months. CONCLUSIONS: These results have significant implications for the clinical care of preterm infants undergoing painful exposures during routine NICU care, which typically occurs without anesthesia. Repeated pain exposures appear to have an increasingly detrimental effect on brain development during a critical period, and effects continue to be seen even 18 months later.

Magnetic Resonance Spectroscopy of Brain Metabolism in Fetuses With Congenital Heart Disease.

BACKGROUND: Congenital heart disease (CHD) remains a significant risk factor for neurologic injury because altered fetal hemodynamics may be unable to support typical brain development during critical periods of growth and maturation. OBJECTIVES: The primary objective was to assess differences in the cerebral biochemical profile between healthy fetuses and fetuses with complex CHD and to relate these with infant outcomes. METHODS: Pregnant participants underwent fetal magnetic resonance imaging with cerebral proton magnetic resonance spectroscopy acquisitions as part of a prospective observational study. Cerebral metabolites of N-acetyl aspartate, creatine, choline, myo-inositol, scyllo-inositol, lactate, and relevant ratios were quantified using LCModel. RESULTS: We acquired 503 proton magnetic resonance spectroscopy images (controls = 333; CHD = 170) from 333 participants (controls = 221; CHD = 112). Mean choline levels were higher in CHD compared with controls (CHD 2.47 IU [Institutional Units] ± 0.44 and Controls 2.35 IU ± 0.45; P = 0.02), whereas N-acetyl aspartate:choline ratios were lower among CHD fetuses compared with controls (CHD 1.34 ± 0.40 IU vs controls 1.44 ± 0.48 IU; P = 0.001). Cerebral lactate was detected in all cohorts but increased in fetuses with transposition of the great arteries and single-ventricle CHD (median: 1.63 [IQR: 0.56-3.27] in transposition of the great arteries and median: 1.28 [IQR: 0-2.42] in single-ventricle CHD) compared with 2-ventricle CHD (median: 0.79 [IQR: 0-1.45]). Cerebral lactate also was associated with increased odds of death before discharge (OR: 1.75; P = 0.04). CONCLUSIONS: CHD is associated with altered cerebral metabolites in utero, particularly in the third trimester period of pregnancy, which is characterized by exponential brain growth and maturation, and is associated with survival to hospital discharge. The long-term neurodevelopmental consequences of these findings warrant further study.

Impact of bronchopulmonary dysplasia on brain GABA concentrations in preterm infants: Prospective cohort study.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is associated with cognitive-behavioral deficits in very preterm (VPT) infants, often in the absence of structural brain injury. Advanced GABA-editing techniques like Mescher-Garwood point resolved spectroscopy (MEGA-PRESS) can quantify in-vivo gamma-aminobutyric acid (GABA+, with macromolecules) and glutamate (Glx, with glutamine) concentrations to investigate for neurophysiologic perturbations in the developing brain of VPT infants. OBJECTIVE: To investigate the relationship between the severity of BPD and basal-ganglia GABA+ and Glx concentrations in VPT infants. METHODS: MRI studies were performed on a 3 T scanner in a cohort of VPT infants [born ≤32 weeks gestational age (GA)] without major structural brain injury and healthy-term infants (>37 weeks GA) at term-equivalent age. MEGA-PRESS (TE68ms, TR2000ms, 256averages) sequence was acquired from the right basal-ganglia voxel (∼3cm3) and metabolite concentrations were quantified in institutional units (i.u.). We stratified VPT infants into no/mild (grade 0/1) and moderate-severe (grade 2/3) BPD. RESULTS: Reliable MEGA-PRESS data was available from 63 subjects: 29 healthy-term and 34 VPT infants without major structural brain injury. VPT infants with moderate-severe BPD (n = 20) had the lowest right basal-ganglia GABA+ (median 1.88 vs. 2.28 vs. 2.12 i.u., p = 0.025) and GABA+/choline (0.73 vs. 0.99 vs. 0.88, p = 0.004) in comparison to infants with no/mild BPD and healthy-term infants. The GABA+/Glx ratio was lower (0.34 vs. 0.44, p = 0.034) in VPT infants with moderate-severe BPD than in infants with no/mild BPD. CONCLUSIONS: Reduced GABA+ and GABA+/Glx in VPT infants with moderate-severe BPD indicate neurophysiologic perturbations which could serve as early biomarkers of future cognitive deficits.

Ex-utero third trimester developmental changes in functional brain network organization in infants born very and extremely preterm.

Introduction: The latter half of gestation is a period of rapid brain development, including the formation of fundamental functional brain network architecture. Unlike in-utero fetuses, infants born very and extremely preterm undergo these critical maturational changes in the extrauterine environment, with growing evidence suggesting this may result in altered brain networks. To date, however, the development of functional brain architecture has been unexplored. Methods: From a prospective cohort of preterm infants, graph parameters were calculated for fMRI scans acquired prior to reaching term equivalent age. Eight graph properties were calculated, Clustering Coefficient (C), Characteristic Path Length (L), Modularity (Q), Local Efficiency (LE), Global Efficiency (GE), Normalized Clustering (λ), Normalized Path Length (γ), and Small-Worldness (σ). Properties were first compared to values generated from random and lattice networks and cost efficiency was evaluated. Subsequently, linear mixed effect models were used to assess relationship with postmenstrual age and infant sex. Results: A total of 111 fMRI scans were acquired from 85 preterm infants born at a mean GA 28.93 ± 2.8. Infants displayed robust small world properties as well as both locally and globally efficient networks. Regression models found that GE increased while L, Q, λ, γ, and σ decreased with increasing postmenstrual age following multiple comparison correction (r2Adj range 0.143-0.401, p < 0048), with C and LE exhibited trending increases with age. Discussion: This is the first direct investigation on the extra-uterine formation of functional brain architecture in preterm infants. Importantly, our results suggest that changes in functional architecture with increasing age exhibit a different trajectory relative to in utero fetus. Instead, they exhibit developmental changes more similar to the early postnatal period in term born infants.

Hippocampal rotation is associated with ventricular atrial size.

BACKGROUND: Fetal ventriculomegaly is a source of apprehension for expectant parents and may present prognostic uncertainty for physicians. Accurate prenatal counseling requires knowledge of its cause and associated findings as the differential diagnosis is broad. We have observed an association between ventriculomegaly and incomplete hippocampal inversion. OBJECTIVE: To determine whether ventricular size is related to incomplete hippocampal inversion. MATERIALS AND METHODS: We retrospectively evaluated pre- and postnatal brain MRIs in normal subjects (mean GA, 31 weeks; mean postnatal age, 27 days) and patients with isolated ventriculomegaly (mean GA, 31 weeks; mean postnatal age, 68 days) at a single academic medical center. Lateral ventricular diameter, multiple qualitative and quantitative markers of hippocampal inversion, and evidence of intraventricular hemorrhage were documented. RESULTS: Incomplete hippocampal inversion and ventricular size were associated in both normal subjects (n=51) and patients with ventriculomegaly (n=32) (P<0.05). Severe ventriculomegaly was significantly associated with adverse clinical outcome in postnatal (P=0.02) but not prenatal (P=0.43) groups. In all additional cases of isolated ventriculomegaly, clinical outcome was normal over the time of assessment (mean 1±1.9 years; range 0.01 to 10 years). CONCLUSION: Lateral ventricular atrial diameter and incomplete hippocampal inversion are associated. Less hippocampal inversion correlates with larger atria. For every 1-mm increase in fetal ventricular size, the odds of incomplete hippocampal inversion occurring increases by a factor of 1.6 in normal controls and 1.4 in patients with ventriculomegaly.

Pregnancy and Child Outcomes Following Fetal Intracranial Hemorrhage.

BACKGROUND: The prenatal and early postnatal outcomes of fetal intracranial hemorrhage (ICH) prenatally diagnosed by fetal magnetic resonance imaging (MRI) have not been well described. METHODS: A retrospective study of cases with fetal ICH diagnosed by fetal MRI at Children's National Hospital, Washington, DC, from 2012 to 2020 was conducted. Maternal characteristics, prenatal imaging, pregnancy outcome, and child developmental outcomes were recorded. Abnormal outcomes were categorized as mild for required physical/occupational therapy without other delays, moderate for intermediate multidomain developmental delays, and severe if nonambulatory, nonverbal, or intellectual disability. RESULTS: Fifty-seven cases with fetal ICH were included. The mean (S.D.) maternal age was 31.1 (6.9) years, gestational age at fetal evaluation was 28.1 (5.3) weeks, and gestational age at birth was 38.2 (1.3) weeks. Pregnancy outcomes were 75% (n = 43) live birth, 14% (n = 8) termination of pregnancy, and 11% (n = 6) intrauterine demise (IUD). Live births decreased from 90% to 33% and IUD increased 10% to 22% when comparing unilateral intraventricular hemorrhage with more extensive hemorrhages. Among the 37 live-born infants with clinical follow-up to age 1.8 (1.6) years, neurodevelopmental outcome was normal in 57%, mildly abnormal in 24%, moderately abnormal in 14%, and severely abnormal in 5%. In five cases, an etiology was identified: two had placental pathologies, two had genetic findings (fetal neonatal alloimmune thrombocytopenia and COL4A1 mutation), and one had congenital cytomegalovirus infection. CONCLUSION: Perinatal and early child outcomes following fetal ICH have a wide spectrum of outcomes. Fetal MRI description of ICH location may aid in pregnancy and postnatal outcome prediction.

Preschool neurodevelopment in Zika virus-exposed children without congenital Zika syndrome.

BACKGROUND: Children with in utero Zika virus (ZIKV) exposure without congenital Zika syndrome (CZS) are at risk for abnormal neurodevelopment. Preschool-age outcomes for children with antenatal ZIKV exposure have not yet been established. METHODS: Children with in utero ZIKV exposure and non-exposed controls had neurodevelopmental evaluations at age 3-5 years in Sabanalarga, Colombia. Cases did not have CZS and were previously evaluated prenatally through age 18 months. Controls were born before ZIKV arrival to Colombia. Neurodevelopmental assessments included Pediatric Evaluation of Disability Inventory (PEDI-CAT), Behavior Rating Inventory of Executive Function (BRIEF-P), Bracken School Readiness Assessment (BSRA), and Movement Assessment Battery for Children (MABC). Family demographics and child medical history were recorded. RESULTS: Fifty-five ZIKV-exposed children were evaluated at mean age 3.6 years and 70 controls were evaluated at 5.2 years. Family demographics were similar between groups. BRIEF-P t-scores were higher for cases than controls in shift and flexibility domains. Cases had lower PEDI-CAT mobility t-scores compared to controls. There was no difference in MABC between groups. In 11% of cases and 1% of controls, parents reported child mood problems. CONCLUSIONS: Children with in utero ZIKV exposure without CZS may demonstrate emerging differences in executive function, mood, and adaptive mobility that require continued evaluation. IMPACT: Preschool neurodevelopmental outcome in children with in utero Zika virus exposure is not yet known, since the Zika virus epidemic occurred in 2015-2017 and these children are only now entering school age. This study finds that Colombian children with in utero Zika virus exposure without congenital Zika syndrome are overall developing well but may have emerging differences in executive function, behavior and mood, and adaptive mobility compared to children without in utero Zika virus exposure. Children with in utero Zika virus exposure require continued multi-domain longitudinal neurodevelopmental evaluation through school age.

Autonomic markers of extubation readiness in premature infants.

BACKGROUND: In premature infants, extubation failure is common and difficult to predict. Heart rate variability (HRV) is a marker of autonomic tone. Our aim is to test the hypothesis that autonomic impairment is associated with extubation readiness. METHODS: Retrospective study of 89 infants <28 weeks. HRV metrics 24 h prior to extubation were compared for those with and without extubation success within 72 h. Receiver-operating curve analysis was conducted to determine the predictive ability of each metric, and a predictive model was created. RESULTS: Seventy-three percent were successfully extubated. The success group had significantly lower oxygen requirement, higher sympathetic HRV metrics, and a lower parasympathetic HRV metric. α1 (measure of autocorrelation, related to sympathetic tone) was the best predictor of success-area under the curve (AUC) of .73 (p = 0.001), and incorporated into a predictive model had an AUC of 0.81 (p < 0.0001)-sensitivity of 81% and specificity of 78%. CONCLUSIONS: Extubation success is associated with HRV. We show an autonomic imbalance with low sympathetic and elevated parasympathetic tone in those who failed. α1, a marker of sympathetic tone, was noted to be the best predictor of extubation success especially when incorporated into a clinical model. IMPACT: This article depicts autonomic markers predictive of extubation success. We depict an autonomic imbalance in those who fail extubation with heightened parasympathetic and blunted sympathetic signal. We describe a predictive model for extubation success with a sensitivity of 81% and specificity of 78%.

Isolated Absent Septum Pellucidum: A Retrospective Study of Fetal Diagnosis and Postnatal Outcomes.

BACKGROUND: Absent septum pellucidum (ASP) is a brain abnormality often associated with neuroanatomic abnormalities including septo-optic dysplasia (SOD). We aimed to determine how frequently prenatally diagnosed isolated ASP is confirmed by postnatal imaging and to examine clinical outcomes for ASP. METHODS: This was a retrospective study of maternal-fetal dyads referred to Children's National Hospital from January 1, 2012, to June 30, 2019. We included cases with fetal diagnosis of isolated or complex ASP. Diagnosis was based on ASP and the presence or absence of additional neuroanatomic findings. Data included obstetric and birth history, genetic testing, imaging, and neurodevelopmental outcomes. RESULTS: ASP was diagnosed in 35 fetuses. Of 17 fetuses with isolated ASP, 10 had postnatal evaluation. In five (50%) isolated ASP cases, postnatal imaging revealed additional brain abnormalities. The five children with postnatally confirmed isolated ASP had lower rates of hydrocephalus (0% vs 54%) and abnormal feeding (0% vs 20%), hearing (0% vs 14%), and vision (0% vs 14%) than those with complex ASP (n = 17). Children with isolated ASP had lower rates of developmental delay (33% vs 50%) and seizures (11% vs 30%) than children with complex ASP. One child with prenatal isolated ASP was diagnosed with SOD (10%). CONCLUSIONS: Few children with prenatally diagnosed isolated ASP had SOD diagnosed postnatally. Overall, children with isolated ASP demonstrate better outcomes than children with complex ASP. Fetal magnetic resonance imaging is a useful tool to evaluate the septum pellucidum and may reveal additional abnormalities that can impact prognosis and affect prenatal counseling.

Outcome of Agenesis of the Corpus Callosum Diagnosed by Fetal MRI.

BACKGROUND: Fetal magnetic resonance imaging (MRI) is increasingly utilized for prenatal diagnosis of agenesis of the corpus callosum (ACC). This study aimed to (1) describe cases of ACC diagnosed by fetal MRI, (2) determine the frequency of postnatal confirmation by MRI, and (3) understand postnatal outcomes of infants with ACC. METHODS: Maternal records from Children's National Hospital between January 2012 and June 2019 with a prenatal neurological consultation, fetal MRI, and ACC on imaging were included. Maternal, prenatal, and postnatal infant data were collected. Each case was categorized as complete or partial ACC and isolated or complex ACC by fetal MRI and group comparisons of outcomes were analyzed. RESULTS: A total of 127 maternal-fetal dyads with ACC were categorized into 45 isolated-complete, 17 isolated-partial, 46 complex-complete, and 19 complex-partial ACC. Of 75 live births, 72 had postnatal evaluations. In 43 of 59 (73%) cases with postnatal neuroimaging, prenatal ACC subcategory was confirmed. Children with isolated or complex and with partial or complete ACC had similar rates of developmental delays and epilepsy. Complex ACC cases had worse outcomes than isolated ACC, with complex ACC having more postnatal dysmorphisms and abnormal feeding and vision compared with isolated ACC. Similar neurodevelopmental outcomes were seen for partial and complete ACC. CONCLUSIONS: Children with isolated or complex ACC and with partial or complete ACC have a range of neurodevelopmental outcomes. Fetal and postnatal brain MRI is a valuable tool to understand differences of the corpus callosum that can guide genetic testing, prenatal counseling, and postnatal care.

Defining Objective Measures of Physician Stress in Simulated Critical Communication Encounters.

This study had three aims: 1) quantify the difference in stress levels between low and high stress roles during simulated critical communication encounters using objective physiologic data (heart rate variability [HRV]) and subjective measures (State-Trait Anxiety Inventory [STAI]), 2) define the relationship between subjective and objective measures of stress, and 3) define the impact of trainee preparedness and reported self-efficacy on stress levels. DESIGN: Mixed methods simulation-based study. SETTING: Single center. PATIENTS: Pediatric critical care fellows and faculty (n = 12). INTERVENTIONS: Subjects participated in six simulated scenarios in both high stress "hot seat" and low stress "observer" roles. MEASUREMENTS AND MAIN RESULTS: Subjective stress was measured using the STAI at baseline and after each scenario. Objective stress was measured continuously using a wearable biometric device measuring HRV. Previous residency communication training and self-confidence surrounding various communication topics were collected via questionnaire. Significant changes in subjective (STAI) and objective stress (HRV) measurements in the low- versus high-stress roles were observed. STAI scores increased 8 points during low stress and 12 points during high stress role (p = 0.021) compared with baseline. Two specific HRV markers, root mean square of successive differences between normal heartbeats, a marker of parasympathetic tone, and the low frequency/high frequency (LF/HF) ratio, a marker of sympathetic activation, were significantly correlated with STAI levels (-0.032, p = 0.001; 1.030, p = 0.002, respectively). Participants who reported increased confidence in discussing code status had a significant decrease in stress response (measured via LF/HF ratio) during both the observer (p = 0.033) and hot seat roles (p = <0.001). CONCLUSIONS: Communicating life-altering news in a simulated environment is a stressful experience. This stress results in physiologic changes that can be measured continuously using HRV. HRV measurement may serve as a novel method in evaluating the effectiveness of communication training programs and measuring future stress-reduction interventions.

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.

Autonomic development in preterm infants is associated with morbidity of prematurity.

BACKGROUND: Previous studies have described an association between preterm birth and maturation of the autonomic nervous system (ANS); however, this may be impacted by multiple factors, including prematurity-related complications. Our aim was to evaluate for the effect of prematurity-related morbidity on ANS development in preterm infants in the NICU. METHODS: We compared time and frequency domains of heart rate variability (HRV) as a measure of ANS tone in 56 preterm infants from 2 NICUs (28 from each). One cohort was from a high-morbidity regional referral NICU, the other from a community-based inborn NICU with low prematurity-related morbidity. Propensity score matching was used to balance the groups by a 1:1 nearest neighbor design. ANS tone was analyzed. RESULTS: The two cohorts showed parallel maturational trajectory of the alpha 1 time-domain metric, with the cohort from the high-morbidity NICU having lower autonomic tone. The maturational trajectories between the two cohorts differed in all other time-domain metrics (alpha 2, RMS1, RMS2). There was no difference between groups by frequency-domain metrics. CONCLUSIONS: Prematurity-associated morbidities correlate with autonomic development in premature infants and may have a greater impact on the extrauterine maturation of this system than birth gestational age. IMPACT: Autonomic nervous system development measured by time-domain metrics of heart rate variability correlate with morbidities associated with premature birth. This study builds upon our previously published work that showed that development of autonomic tone was not impacted by gestational age at birth. This study adds to our understanding of autonomic nervous system development in a preterm extrauterine environment. Our study suggests that gestational age at birth may have less impact on autonomic nervous system development than previously thought.

Maternal mental distress and cortisol levels in pregnancies with congenital heart disease.

OBJECTIVES: Prenatal maternal stress is associated with adverse offspring outcomes, which may be mediated by maternal stress hormones. However, evidence supporting the association between maternal stress and cortisol levels in high-risk pregnancies is limited. This study aims to determine the relationship between self-reported maternal mental distress and maternal salivary cortisol levels in pregnancies complicated by foetal CHD compared with healthy pregnancies. METHODS: We recruited women with pregnancies complicated by foetal CHD and healthy pregnancies. Maternal saliva was collected between 22 and 40 gestational weeks. Standardized questionnaires measuring stress, depression, and anxiety were completed by patients. Generalized estimating equation was used to evaluate associations between maternal mental distress scales and cortisol levels. RESULTS: We studied 165 women (55 CHD, 110 controls) and collected 504 cortisol samples (160 CHD, 344 controls). Women carrying CHD foetuses had higher stress, anxiety, and depression scores compared to women carrying healthy foetuses. However, maternal cortisol levels did not significantly differ in CHD and controls. Cortisol levels were higher in women carrying foetuses with functionally single-ventricle versus two-ventricle CHD. In both CHD and controls, there was no significant association between maternal stress, depression or anxiety scores and cortisol levels. CONCLUSION: Our data suggest that self-reported maternal stress, anxiety, and depression are not associated with maternal salivary cortisol levels in CHD and healthy pregnancies. The impact of maternal mental distress on foetal health may be through other mediating pathways other than maternal cortisol concentrations.

In Utero MRI Identifies Impaired Second Trimester Subplate Growth in Fetuses with Congenital Heart Disease.

The subplate is a transient brain structure which plays a key role in the maturation of the cerebral cortex. Altered brain growth and cortical development have been suggested in fetuses with complex congenital heart disease (CHD) in the third trimester. However, at an earlier gestation, the putative role of the subplate in altered brain development in CHD fetuses is poorly understood. This study aims to examine subplate growth (i.e., volume and thickness) and its relationship to cortical sulcal development in CHD fetuses compared with healthy fetuses by using 3D reconstructed fetal magnetic resonance imaging. We studied 260 fetuses, including 100 CHD fetuses (22.3-32 gestational weeks) and 160 healthy fetuses (19.6-31.9 gestational weeks). Compared with healthy fetuses, CHD fetuses had 1) decreased global and regional subplate volumes and 2) decreased subplate thickness in the right hemisphere overall, in frontal and temporal lobes, and insula. Compared with fetuses with two-ventricle CHD, those with single-ventricle CHD had reduced subplate volume and thickness in right occipital and temporal lobes. Finally, impaired subplate growth was associated with disturbances in cortical sulcal development in CHD fetuses. These findings suggested a potential mechanistic pathway and early biomarker for the third-trimester failure of brain development in fetuses with complex CHD. SIGNIFICANCE STATEMENT: Our findings provide an early biomarker for brain maturational failure in fetuses with congenital heart disease, which may guide the development of future prenatal interventions aimed at reducing neurological compromise of prenatal origin in this high-risk population.

In infants with congenital heart disease autonomic dysfunction is associated with pre-operative brain injury.

BACKGROUND: Brain injury is a serious and common complication of critical congenital heart disease (CHD). Impaired autonomic development (assessed by heart rate variability (HRV)) is associated with brain injury in other high-risk neonatal populations. OBJECTIVE: To determine whether impaired early neonatal HRV is associated with pre-operative brain injury in CHD. METHODS: In infants with critical CHD, we evaluated HRV during the first 24 h of cardiac ICU (CICU) admission using time-domain (RMS 1, RMS 2, and alpha 1) and frequency-domain metrics (LF, nLF, HF, nHF). Pre-operative brain magnetic resonance imaging (MRI) was scored for injury using an established system. Spearman's correlation coefficient was used to determine the association between HRV and pre-operative brain injury. RESULTS: We enrolled 34 infants with median birth gestational age of 38.8 weeks (IQR 38.1-39.1). Median postnatal age at pre-operative brain MRI was 2 days (IQR 1-3 days). Thirteen infants had MRI evidence of brain injury. RMS 1 and RMS 2 were inversely correlated with pre-operative brain injury. CONCLUSIONS: Time-domain metrics of autonomic function measured within the first 24 h of admission to the CICU are associated with pre-operative brain injury, and may perform better than frequency-domain metrics under non-stationary conditions such as critical illness. IMPACT: Autonomic dysfunction, measured by heart rate variability (HRV), in early transition is associated with pre-operative brain injury in neonates with critical congenital heart disease. These data extend our earlier findings by providing further evidence for (i) autonomic dysfunction in infants with CHD, and (ii) an association between autonomic dysfunction and brain injury in critically ill neonates. These data support the notion that further investigation of HRV as a biomarker for brain injury risk is warranted in infants with critical CHD.

GABA and glutamate in the preterm neonatal brain: In-vivo measurement by magnetic resonance spectroscopy.

Cognitive and behavioral disabilities in preterm infants, even without obvious brain injury on conventional neuroimaging, underscores a critical need to identify the subtle underlying microstructural and biochemical derangements. The gamma-aminobutyric acid (GABA) and glutamatergic neurotransmitter systems undergo rapid maturation during the crucial late gestation and early postnatal life, and are at-risk of disruption after preterm birth. Animal and human autopsy studies provide the bulk of current understanding since non-invasive specialized proton magnetic resonance spectroscopy (1H-MRS) to measure GABA and glutamate are not routinely available for this vulnerable population due to logistical and technical challenges. We review the specialized 1H-MRS techniques including MEscher-GArwood Point Resolved Spectroscopy (MEGA-PRESS), special challenges and considerations needed for interpretation of acquired data from the developing brain of preterm infants. We summarize the limited in-vivo preterm data, highlight the gaps in knowledge, and discuss future directions for optimal integration of available in-vivo approaches to understand the influence of GABA and glutamate on neurodevelopmental outcomes after preterm birth.