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.

Central Autonomic Network and heart rate variability in premature neonates.

INTRODUCTION: The Central Autonomic Network (CAN) is a hierarchy of brain structures that collectively influence cardiac autonomic input, mediating the majority of brain-heart interactions, but has never been studied in premature neonates. In this study, we use heart rate variability (HRV), which has been described as the "primary output" of the CAN, and resting state functional MRI to characterize brain-heart relationships in premature neonates. METHODS: We studied premature neonates who underwent resting state functional MRI (rsfMRI) at term, (37-weeks postmenstrual age [PMA] or above) and had HRV data recorded during the same week of their MRI. HRV was derived from continuous electrocardiogram data during the week of the rsfMRI scan. For rsfMRI, a seed-based approach was used to define regions of interest (ROI) pertinent to the CAN, and blood oxygen level-dependent signal was correlated between each ROI as a measure of functional connectivity. HRV was correlated with CAN connectivity (CANconn) for each region, and sub-group analysis was performed based on sex and clinical comorbidities. RESULTS: Forty-seven premature neonates were included in this study, with a mean gestational age at birth of 28.1 +/- 2.6 weeks. Term CANconn was found to be significantly correlated with HRV in approximately one-fifth of CAN connections. Two distinct patterns emerged among these HRV-CANconn relationships. In the first, increased HRV was associated with stronger CANconn of limbic regions. In the second pattern, stronger CANconn at the precuneus was associated with impaired HRV maturation. These patterns were especially pronounced in male premature neonates. CONCLUSION: We report for the first time evidence of brain-heart relationships in premature neonates and an emerging CAN, most striking in male neonates, suggesting that the brain-heart axis may be more vulnerable in male premature neonates. Signatures in the heart rate may eventually become an important non-invasive tool to identify premature males at highest risk for neurodevelopmental impairment.

Severity of prematurity and age impact early postnatal development of GABA and glutamate systems.

Gamma-aminobutyric acid (GABA) and glutamatergic system perturbations following premature birth may explain neurodevelopmental deficits in the absence of structural brain injury. Using GABA-edited spectroscopy (MEscher-GArwood Point Resolved Spectroscopy [MEGA-PRESS] on 3 T MRI), we have described in-vivo brain GABA+ (+macromolecules) and Glx (glutamate + glutamine) concentrations in term-born infants. We report previously unavailable comparative data on in-vivo GABA+ and Glx concentrations in the cerebellum, the right basal ganglia, and the right frontal lobe of preterm-born infants without structural brain injury. Seventy-five preterm-born (gestational age 27.8 ± 2.9 weeks) and 48 term-born (39.6 ± 0.9 weeks) infants yielded reliable MEGA-PRESS spectra acquired at post-menstrual age (PMA) of 40.2 ± 2.3 and 43.0 ± 2 weeks, respectively. GABA+ (median 2.44 institutional units [i.u.]) concentrations were highest in the cerebellum and Glx higher in the cerebellum (5.73 i.u.) and basal ganglia (5.16 i.u.), with lowest concentrations in the frontal lobe. Metabolite concentrations correlated positively with advancing PMA and postnatal age at MRI (Spearman's rho 0.2-0.6). Basal ganglia Glx and NAA, and frontal GABA+ and NAA concentrations were lower in preterm compared with term infants. Moderate preterm infants had lower metabolite concentrations than term and extreme preterm infants. Our findings emphasize the impact of premature extra-uterine stimuli on GABA-glutamate system development and may serve as early biomarkers of neurodevelopmental deficits.

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.

Impaired in vivo feto-placental development is associated with neonatal neurobehavioral outcomes.

BACKGROUND: Fetal growth restriction (FGR) is a risk factor for neurodevelopmental problems, yet remains poorly understood. We sought to examine the relationship between intrauterine development and neonatal neurobehavior in pregnancies diagnosed with antenatal FGR. METHODS: We recruited women with singleton pregnancies diagnosed with FGR and measured placental and fetal brain volumes using MRI. NICU Network Neurobehavioral Scale (NNNS) assessments were performed at term equivalent age. Associations between intrauterine volumes and neurobehavioral outcomes were assessed using generalized estimating equation models. RESULTS: We enrolled 44 women diagnosed with FGR who underwent fetal MRI and 28 infants underwent NNNS assessments. Placental volumes were associated with increased self-regulation and decreased excitability; total brain, brainstem, cortical and subcortical gray matter (SCGM) volumes were positively associated with higher self-regulation; SCGM also was positively associated with higher quality of movement; increasing cerebellar volumes were positively associated with attention, decreased lethargy, non-optimal reflexes and need for special handling; brainstem volumes also were associated with decreased lethargy and non-optimal reflexes; cerebral and cortical white matter volumes were positively associated with hypotonicity. CONCLUSION: Disrupted intrauterine growth in pregnancies complicated by antenatally diagnosed FGR is associated with altered neonatal neurobehavior. Further work to determine long-term neurodevelopmental impacts is warranted. IMPACT: Fetal growth restriction is a risk factor for adverse neurodevelopment, but remains difficult to accurately identify. Intrauterine brain volumes are associated with infant neurobehavior. The antenatal diagnosis of fetal growth restriction is a risk factor for abnormal infant neurobehavior.

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.

Automatic brain segmentation in preterm infants with post-hemorrhagic hydrocephalus using 3D Bayesian U-Net.

Post-hemorrhagic hydrocephalus (PHH) is a severe complication of intraventricular hemorrhage (IVH) in very preterm infants. PHH monitoring and treatment decisions rely heavily on manual and subjective two-dimensional measurements of the ventricles. Automatic and reliable three-dimensional (3D) measurements of the ventricles may provide a more accurate assessment of PHH, and lead to improved monitoring and treatment decisions. To accurately and efficiently obtain these 3D measurements, automatic segmentation of the ventricles can be explored. However, this segmentation is challenging due to the large ventricular anatomical shape variability in preterm infants diagnosed with PHH. This study aims to (a) propose a Bayesian U-Net method using 3D spatial concrete dropout for automatic brain segmentation (with uncertainty assessment) of preterm infants with PHH; and (b) compare the Bayesian method to three reference methods: DenseNet, U-Net, and ensemble learning using DenseNets and U-Nets. A total of 41 T2 -weighted MRIs from 27 preterm infants were manually segmented into lateral ventricles, external CSF, white and cortical gray matter, brainstem, and cerebellum. These segmentations were used as ground truth for model evaluation. All methods were trained and evaluated using 4-fold cross-validation and segmentation endpoints, with additional uncertainty endpoints for the Bayesian method. In the lateral ventricles, segmentation endpoint values for the DenseNet, U-Net, ensemble learning, and Bayesian U-Net methods were mean Dice score = 0.814 ± 0.213, 0.944 ± 0.041, 0.942 ± 0.042, and 0.948 ± 0.034 respectively. Uncertainty endpoint values for the Bayesian U-Net were mean recall = 0.953 ± 0.037, mean  negative predictive value = 0.998 ± 0.005, mean accuracy = 0.906 ± 0.032, and mean AUC = 0.949 ± 0.031. To conclude, the Bayesian U-Net showed the best segmentation results across all methods and provided accurate uncertainty maps. This method may be used in clinical practice for automatic brain segmentation of preterm infants with PHH, and lead to better PHH monitoring and more informed treatment decisions.

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.

Feasibility of QSM in the human placenta.

PURPOSE: Quantitative susceptibility mapping (QSM) is an emerging tool for the precise characterization of human tissue, including regional oxygenation. A critical function of the human placenta is oxygen transfer to the developing fetus, which remains difficult to study in utero. The purpose of this study is to investigate the feasibility of performing QSM in the human placenta in utero. METHODS: In healthy pregnant women, 3D gradient echo data of the placenta were acquired with prospective respiratory gating at 1.5 Tesla and 3 Tesla. A brief period (6-7 min) of maternal hyperoxia was induced to increase placental oxygenation in a subset of women scanned at 3 Tesla, and data were acquired before and during oxygen administration. Susceptibility and T2∗ / R2∗ maps were reconstructed from gradient echo data, and mean and SD of these measures within the whole placenta were calculated. RESULTS: A total of 54 women were studied at a mean gestational age of 30.7 ± 4.2 (range: 24 5/7-38 4/7) weeks. Susceptibility and T2∗ maps demonstrated lobular contrast reflecting regional oxygenation difference at both field strengths. SD of susceptibilities, mean R2∗ , and SD of R2∗ of the placenta showed a linear relationship with gestational age (P < .01 for all). These measures were also responsive to maternal hyperoxia, and there was an increasing response with advancing gestational age (P < .01 for all). CONCLUSION: This study demonstrates the feasibility of performing placental QSM in pregnant women and supports the potential for placental QSM to provide noninvasive in vivo assessment of placental oxygenation.

Prenatal origins of neuropsychiatric diseases.

AIM: The main objective is to review the available evidence in the literature for developmental origins of neuropsychiatric diseases and their underlying mechanisms. We also probe emerging cutting-edge prenatal MR imaging tools and their future role in advancing our understanding the prenatal footprints of neuropsychiatric disorders. OBSERVATIONS: Both human and animal studies support early intrauterine origins of neuropsychiatric disease, particularly autism spectrum disorders (ASD), attention and hyperactivity disorders, schizophrenia, depression, anxiety and mood disorders. Specific mechanisms of intrauterine injury include infection, inflammation, hypoxia, hypoperfusion, ischaemia polysubstance use/abuse, maternal mental health and placental dysfunction. CONCLUSIONS AND RELEVANCE: There is ample evidence to suggest developmental vulnerability of the foetal brain to intrauterine exposures that increases and individual's risk for neuropsychiatric disease, especially the risk of ASD, depression and anxiety. Elucidating the exact timing and mechanisms of injury can be difficult and require novel, non-invasive approaches to the study emerging structural and functional brain development of the foetus. Clinical care should both emphasise maternal health during pregnancy, as well as close, continued monitoring for at risk offspring throughout young adulthood for the early identification and treatment of neuropsychiatric diseases.

Non-invasive measurement of biochemical profiles in the healthy fetal brain.

Proton magnetic resonance spectroscopy (1H-MRS) of the fetal brain can be used to study emerging metabolite profiles in the developing brain. Identifying early deviations in brain metabolic profiles in high-risk fetuses may offer important adjunct clinical information to improve surveillance and management during pregnancy. OBJECTIVE: To investigate the normative trajectory of the fetal brain metabolites during the second half of gestation, and to determine the impact of using different Cramer-Rao Lower Bounds (CRLB) threshold on metabolite measurements using magnetic resonance spectroscopy. STUDY DESIGN: We prospectively enrolled 219 pregnant women with normal fetal ultrasound and biometric measures. We performed a total of 331 fetal 1H-MRS studies with gestational age in the rage of 18-39 weeks with 112 of the enrolled participants scanned twice. All the spectra in this study were acquired on a GE 1.5 T scanner using long echo-time of 144 â€‹ms and analyzed in LCModel. RESULTS: We successfully acquired and analyzed fetal 1H-MRS with a success rate of 93%. We observed increases in total NAA, total creatine, total choline, scyllo inositol and total NAA-to-total choline ratio with advancing GA. Our results also showed faster increases in total NAA and total NAA-to-total choline ratio during the third trimester compared to the second trimester. We also observed faster increases in total choline and total NAA in female fetuses. Increasing the Cramer-Rao lower bounds threshold progressively from 100% to 40%-20% increased the mean metabolite concentrations and decreased the number of observations available for analysis. CONCLUSION: We report serial fetal brain biochemical profiles in a large cohort of health fetuses studied twice in gestation with a high success rate in the second and third trimester of pregnancy. We present normative in-vivo fetal brain metabolite trajectories over a 21-week gestational period which can be used to non-invasively measure and monitor brain biochemistry in the healthy and high-risk fetus.

Hemodynamic Responses of the Placenta and Brain to Maternal Hyperoxia in Fetuses with Congenital Heart Disease by Using Blood Oxygen-Level Dependent MRI.

Background Impaired brain development in fetuses with congenital heart disease (CHD) may result from inadequate cerebral oxygen supply in utero. Purpose To test whether fetal cerebral oxygenation can be increased by maternal oxygen administration, effects of maternal hyperoxia on blood oxygenation of the placenta and fetal brain were examined by using blood oxygenation level-dependent (BOLD) functional MRI. Materials and Methods In this prospective study, BOLD MRI was performed in 86 fetuses (56 healthy fetuses and 30 fetuses diagnosed with CHD) between 22 and 39 weeks gestational age (GA) from May 2015 to December 2017, with the following study design: phase I, 2-minute resting state at baseline (room air); phase II, 6-minute maternal hyperoxia with 100% oxygen; and phase III, 5.6-minute return to resting state. After motion correction, the signals were averaged over the placenta and fetal brain and converted to the change in R2* (ΔR2*). Fetuses with CHD were categorized into those with a single ventricle (SV) or two ventricles (TVs) and those with aortic obstruction (AO) or non-AO. Data were analyzed by using generalized linear mixed models controlling for GA and sex. Results Placental ΔR2* increased during maternal hyperoxia in healthy fetuses and fetuses with CHD, but it was higher in SV CHD (mean ΔR2*, 1.3 sec-1 ± 0.1 [standard error; P < .01], 1.9 sec-1 ± 0.2 [P < .01], and 1.0 sec-1 ± 0.3 [P < .01], respectively, for control fetuses, fetuses with SV CHD, and fetuses with TV CHD). Placental ΔR2* during maternal hyperoxia changed with GA in healthy control fetuses and fetuses with SV or AO CHD (ΔR2* per week, 0.1 sec-1 ± 0 [P < .01], 0.2 sec-1 ± 0 [P = .01], and 0.2 sec-1 ± 0 [P = .01], respectively), but not in fetuses with CHD and TV or non-AO. Fetal brain ΔR2* was constant across all phases in healthy control fetuses and fetuses with TV CHD but increased during maternal hyperoxia in fetuses with SV or AO CHD (mean ΔR2*, 0.7 sec-1 ± 0.2 [P = .01] and 0.5 sec-1 ± 0.2 [P = .02], respectively). Conclusion Six minutes of maternal hyperoxia increased placental oxygenation in healthy fetuses and fetuses with congenital heart disease, and it selectively increased cerebral blood oxygenation in fetuses with single ventricle or aortic obstruction. © RSNA, 2019 Online supplemental material is available for this article.

Nutrition and the developing brain: the road to optimizing early neurodevelopment: a systematic review.

BACKGROUND: Neonatal intensive care practices have resulted in marked improvements in the survival of premature infants; however, they remain at significant risk for adverse neurodevelopmental outcomes. The impact of current nutritional practices on brain development following early extra-uterine exposure in premature infants is not well known. METHODS: We performed a systematic review to investigate nutritional effects on postnatal brain development in healthy term and prematurely born infants utilizing advanced magnetic resonance imaging tools. RESULTS: Systematic screen yielded 595 studies for appraisal. Of these, 22 total studies were selected for inclusion in the review, with findings summarized in a qualitative, descriptive fashion. CONCLUSION: Fat and energy intake are associated with improved brain volume and development in premature infants. While breast milk intake and long-chain polyunsaturated fatty acid supplementation has been proven beneficial in term infants, the impact in preterm infants is less well understood.

Improved brain growth and microstructural development in breast milk-fed very low birth weight premature infants.

AIM: Breast milk feeding is linked to improved neurodevelopmental outcomes in very low birth weight (VLBW) infants, though the mechanisms are not well understood. This study utilised quantitative magnetic resonance imaging (qMRI) techniques to compare brain growth and white matter development in preterm infants receiving primarily breast milk versus formula feeds. METHODS: We prospectively enrolled infants born at very low birth weight (<1500 g) and <32 weeks gestational age and performed MRI at term-equivalent age. We utilised volumetric segmentation to calculate regional and total brain volumes and diffusion tensor imaging to evaluate white matter microstructural organisation. Daily nutritional data were extracted from the medical record. RESULTS: Nutritional and MRI data were obtained for 68 infants admitted within the first week of life (44 breast milk and 24 formula). Breast milk-fed infants demonstrated significantly larger total brain volumes (P = .04) as well as volumes in the amygdala-hippocampus and cerebellum (P < .01) compared with formula-fed. Infants receiving breast milk also demonstrated greater white matter microstructural organisation in the corpus callosum, posterior limb of internal capsule and cerebellum (P < .01 to .03). CONCLUSION: VLBW infants receiving primarily breast milk versus preterm formula in this small exploratory study demonstrated significantly greater regional brain volumes and white matter microstructural organisation by term-equivalent age.

In vivo textural and morphometric analysis of placental development in healthy & growth-restricted pregnancies using magnetic resonance imaging.

BACKGROUND: The objective of this study was to characterize structural changes in the healthy in vivo placenta by applying morphometric and textural analysis using magnetic resonance imaging (MRI), and to explore features that may be able to distinguish placental insufficiency in fetal growth restriction (FGR). METHODS: Women with healthy pregnancies or pregnancies complicated by FGR underwent MRI between 20 and 40 weeks gestation. Measures of placental morphometry (volume, elongation, depth) and digital texture (voxel-wise geometric and signal-intensity analysis) were calculated from T2W MR images. RESULTS: We studied 66 pregnant women (32 healthy controls, 34 FGR); during the study period, placentas undergo significant increases in size; signal intensity remains relatively constant, however there is increasing variation in spatial arrangements, suggestive of progressive microstructural heterogeneity. In FGR, placental size is smaller, with great homogeneity of signal intensity and spatial arrangements. CONCLUSION: We report quantitative textural and morphometric changes in the in vivo placenta in healthy controls over the second half of pregnancy. These MRI features demonstrate important differences in placental development in the setting of placental insufficiency that relate to onset and severity of FGR, as well as neonatal outcome.

Autonomic Dysfunction in Neonates with Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia Impairs Physiological Responses to Routine Care Events.

OBJECTIVE: To evaluate whether infants with hypoxic-ischemic encephalopathy and evidence of autonomic dysfunction have aberrant physiological responses to care events that could contribute to evolving brain injury. STUDY DESIGN: Continuous tracings of heart rate (HR), blood pressure (BP), cerebral near infrared spectroscopy, and video electroencephalogram data were recorded from newborn infants with hypoxic-ischemic encephalopathy who were treated with hypothermia. Videos between 16 and 24 hours of age identified 99 distinct care events, including stimulating events (diaper changes, painful procedures), and vagal stimuli (endotracheal tube manipulations, pupil examinations). Pre-event HR variability was used to stratify patients into groups with impaired versus intact autonomic nervous system (ANS) function. Postevent physiological responses were compared between groups with the nearest mean classification approach. RESULTS: Infants with intact ANS had increases in HR/BP after stimulating events, whereas those with impaired ANS showed no change or decreased HR/BP. With vagal stimuli, the HR decreased in infants with intact ANS but changed minimally in those with impaired ANS. A pupil examination in infants with an intact ANS led to a stable or increased BP, whereas the BP decreased in the group with an impaired ANS. Near infrared spectroscopy measures of cerebral blood flow/blood volume increased after diaper changes in infants with an impaired ANS, but were stable or decreased in those with an intact ANS. CONCLUSION: HR variability metrics identified infants with impaired ANS function at risk for maladaptive responses to care events. These data support the potential use of HR variability as a real-time, continuous physiological biomarker to guide neuroprotective care in high-risk newborns.

In vivo placental MRI shape and textural features predict fetal growth restriction and postnatal outcome.

PURPOSE: To investigate the ability of three-dimensional (3D) MRI placental shape and textural features to predict fetal growth restriction (FGR) and birth weight (BW) for both healthy and FGR fetuses. MATERIALS AND METHODS: We recruited two groups of pregnant volunteers between 18 and 39 weeks of gestation; 46 healthy subjects and 34 FGR. Both groups underwent fetal MR imaging on a 1.5 Tesla GE scanner using an eight-channel receiver coil. We acquired T2-weighted images on either the coronal or the axial plane to obtain MR volumes with a slice thickness of either 4 or 8 mm covering the full placenta. Placental shape features (volume, thickness, elongation) were combined with textural features; first order textural features (mean, variance, kurtosis, and skewness of placental gray levels), as well as, textural features computed on the gray level co-occurrence and run-length matrices characterizing placental homogeneity, symmetry, and coarseness. The features were used in two machine learning frameworks to predict FGR and BW. RESULTS: The proposed machine-learning based method using shape and textural features identified FGR pregnancies with 86% accuracy, 77% precision and 86% recall. BW estimations were 0.3 ± 13.4% (mean percentage error ± standard error) for healthy fetuses and -2.6 ± 15.9% for FGR. CONCLUSION: The proposed FGR identification and BW estimation methods using in utero placental shape and textural features computed on 3D MR images demonstrated high accuracy in our healthy and high-risk cohorts. Future studies to assess the evolution of each feature with regard to placental development are currently underway. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:449-458.

Complex Trajectories of Brain Development in the Healthy Human Fetus.

This study characterizes global and hemispheric brain growth in healthy human fetuses during the second half of pregnancy using three-dimensional MRI techniques. We studied 166 healthy fetuses that underwent MRI between 18 and 39 completed weeks gestation. We created three-dimensional high-resolution reconstructions of the brain and calculated volumes for left and right cortical gray matter (CGM), fetal white matter (FWM), deep subcortical structures (DSS), and the cerebellum. We calculated the rate of growth for each tissue class according to gestational age and described patterns of hemispheric growth. Each brain region demonstrated major increases in volume during the second half of gestation, the most pronounced being the cerebellum (34-fold), followed by FWM (22-fold), CGM (21-fold), and DSS (10-fold). The left cerebellar hemisphere, CGM, and DSS had larger volumes early in gestation, but these equalized by term. It has been increasingly recognized that brain asymmetry evolves throughout the human life span. Advanced quantitative MRI provides noninvasive measurements of early structural asymmetry between the left and right fetal brain that may inform functional and behavioral laterality differences seen in children and young adulthood.

Pattern of brain injury and depressed heart rate variability in newborns with hypoxic ischemic encephalopathy.

BackgroundDecreased heart rate variability (HRV) is a measure of autonomic dysfunction and brain injury in newborns with hypoxic ischemic encephalopathy (HIE). This study aimed to characterize the relationship between HRV and brain injury pattern using magnetic resonance imaging (MRI) in newborns with HIE undergoing therapeutic hypothermia.MethodsHRV metrics were quantified in the time domain (αS, αL, and root mean square at short (RMSS) and long (RMSL) timescales) and frequency domain (relative low-(LF) and high-frequency (HF) power) over 24-27 h of life. The brain injury pattern shown by MRI was classified as no injury, pure cortical/white matter injury, mixed watershed/mild basal ganglia injury, predominant basal ganglia or global injury, and death. HRV metrics were compared across brain injury pattern groups using a random-effects mixed model.ResultsData from 74 infants were analyzed. Brain injury pattern was significantly associated with the degree of HRV suppression. Specifically, negative associations were observed between the pattern of brain injury and RMSS (estimate -0.224, SE 0.082, P=0.006), RMSL (estimate -0.189, SE 0.082, P=0.021), and LF power (estimate -0.044, SE 0.016, P=0.006).ConclusionDegree of HRV depression is related to the pattern of brain injury. HRV monitoring may provide insights into the pattern of brain injury at the bedside.