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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.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.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.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.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.

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.

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 T

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.

Congenital heart disease (CHD) remains the most common birth defect in infants, and critical CHD is associated with significant rates of morbidity and mortality. With the advent of powerful yet noninvasive advanced fetal imaging, it is becoming increasingly evident that the presence of CHD in utero disrupts typical development and contributes to the lifelong morbidity in this population. Across healthy and high-risk populations, intrauterine influences can permanently alter fetal development that may manifest in complex morbidities later in life, the so-called fetal-onset-of-adult-disease (FOAD) phenomenon. The placenta plays a critical role in not only supporting fetal development, but also by adapting to specific intrauterine conditions. The role of placental health, adaptation and dysfunction, however, in CHD is not well understood. In this article, we will review current evidence relating placental health in CHD, appraise existing knowledge-gaps in the field and highlight promising new avenues to better understand the impact of placental function on fetal well-being. We will review evidence of ex vivo human placental studies that describe abnormal placental findings in pregnancies complicated by CHD, as well evidence for in vivo assessments of the human placenta. While overall clinical in vivo assessments of placental development are rather limited, we will also review emerging evidence from advanced quantitative and functional magnetic resonance imaging that are bringing new insights into placental structure and function throughout gestation. By providing novel information about placental development, we can now explore the maternal-fetal-placental connection in greater detail, and better understand the multi-factorial mechanisms that may contribute to adverse outcomes seen in survivors of CHD.

Preterm infants are born before the critical period of lipid accretion and brain development that occurs during the third trimester of pregnancy. Dietary lipids serve as an important source of energy and are involved in complex processes that are essential for normal central nervous system development. In addition to traditional neurodevelopmental testing, novel quantitative magnetic resonance imaging (MRI) techniques are now available to evaluate the impact of nutritional interventions on early preterm brain development. Trials of long-chain polyunsaturated fatty acid supplementation have yielded inconsistent effects on neurodevelopmental outcomes and quantitative MRI findings. Recent studies using quantitative MRI suggest a positive impact of early lipid intake on brain volumes and white matter microstructural organization by term-equivalent age.

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, attention and hyperactivity disorders, schizophrenia, depression, anxiety and mood disorders. Specific mechanisms of intrauterine injury include infection, inflammation, hypoxia, hypo-perfusion, ischemia polysubstance use/abuse, maternal mental health and placental dysfunction. Conclusions and Relevance: There is ample evidence to suggest developmental vulnerability of the fetal brain to intrauterine exposures that increases and individual's risk for neuropsychiatric disease, especially the risk of autism spectrum disorders, 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 fetus. Clinical care should both emphasize 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.

BACKGROUND: Despite recent advances in nutrition practice in the neonatal intensive care unit, infants remain at high risk for growth restriction following preterm birth. Additionally, optimal values for macronutrient administration, especially lipid intake, have yet to be established for preterm infants in the extrauterine environment. METHODS: We studied preterm infants born at very low-birth weight (VLBW

Introduction Gross and microstructural changes in placental development can influence placental function and adversely impact fetal growth and well-being; however, there is a paucity of invivo tools available to reliably interrogate in vivo placental microstructural development. The objective of this study is to characterize invivo placental microstructural diffusion and perfusion in healthy and growth-restricted pregnancies (FGR) using non-invasive diffusion-weighted imaging (DWI). Methods We prospectively enrolled healthy pregnant women and women whose pregnancies were complicated by FGR. Each woman underwent DWI-MRI between 18 and 40 weeks gestation. Placental measures of small (D) and large (D*) scale diffusion and perfusion (f) were estimated using the intra-voxel incoherent motion (IVIM) model. Results We studied 137 pregnant women (101 healthy; 36 FGR). D and D* are increased in late-onset FGR, and the placental perfusion fraction, f, is decreased (p Discussion Placental DWI revealed microstructural alterations of the invivo placenta in FGR, particularly in late-onset FGR. Early and reliable identification of placental pathology in vivo may better guide future interventions.

To determine whether ventilator-related fluctuations in cerebral blood volume (CBV) are associated with cerebral pressure passivity. In a prospective study of newborns undergoing positive-pressure ventilation, we calculated coherence between continuous mean arterial pressure (MAP) and cerebral near-infrared spectroscopy hemoglobin difference (HbD). Significant HbD–MAP coherence indicated cerebral pressure passivity. CBV changes were measured as the spectral power of total hemoglobin (SHbT) at the ventilator frequency. A regression model tested whether SHbT predicts cerebral pressure passivity and/or death/brain injury, controlling for birth gestational age and other factors. We studied 68 subjects with prematurity (n = 19), congenital heart disease (n = 11), and hypoxic–ischemic encephalopathy (n = 38). SHbT, sedative use, and pCO2 were positively associated, and circulating hemoglobin negatively associated, with cerebral pressure passivity (p

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 (

ispartof: J Neonatal Perinatal Med vol:15 issue:2 pages:411-426 ispartof: location:Netherlands status: published

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.

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.

Converging evidence from clinical and preclinical studies suggests that fetal vulnerability to adverse prenatal exposures increases the risk for neuropsychiatric diseases such as autism spectrum disorder, schizophrenia, and depression. Recent advances in fetal magnetic resonance imaging have allowed us to characterize typical fetal brain growth trajectories in vivo and to interrogate structural and functional alterations associated with intrauterine exposures, such as maternal stress, environmental toxins, drugs, and obesity. Here, we review proposed mechanisms for how prenatal influences disrupt neurodevelopment, including the role played by maternal and fetal inflammatory responses. We summarize insights from magnetic resonance imaging research in fetuses, highlight recent discoveries in normative fetal development using quantitative magnetic resonance imaging techniques (i.e., three-dimensional volumetry, proton magnetic resonance spectroscopy, placental diffusion imaging, and functional imaging), and discuss how baseline trajectories are shaped by prenatal exposures.

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). 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. 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. 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

Background: Elevated maternal psychological distress during pregnancy is linked to adverse short- and long-term outcomes in the offspring. The potential deleterious 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 with negative COVID-19 diagnoses 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 1.5T MRI Scanner. High-resolution 3D models of the fetal brains were reconstructed, and volumes of six brain tissue types were calculated: cortical gray matter (CGM), white matter (WM), cerebellum, deep gray matter (DGM), brainstem, and hippocampus. Cortical folding measures, including brain surface area, local gyrification index (LGI), and sulcal depth were determined. At each MRI scan, maternal distress was assessed using validated stress, anxiety and depression scales. Generalized estimating equations (GEEs) were utilized to compare maternal distress measures, brain volume and cortical folding differences between pandemic and pre-pandemic cohorts. Findings: Stress and depression scores were significantly higher in the pandemic cohort (14.2 vs. 10.4 for stress; 5.9 vs. 4.2 for depression; p

Introduction: Studies have shown that maternal stress and anxiety during pregnancy have been associated with a higher incidence of preterm birth and low birth weight. However, the relationship between prenatal maternal mental distress and placental development in fetuses with congenital heart disease (CHD) is unknown. Hypothesis: We tested the hypothesis that elevated maternal anxiety is associated with altered placental morphology in fetuses with CHD. Methods: A total of 141 pregnant women were recruited prospectively (control: 91; two-ventricle/2V CHD: 29; single-ventricle/SV CHD: 21), in which 228 fetal MR scans were performed (gestational age: 31.8±4.5 weeks). Single shot fast spin echo T2-weighted images were acquired on a 1.5 Tesla GE MRI scanner. Placenta tissue was manually segmented, and slice-to-volume registration was used for motion correction and 3D reconstruction. Six placental features were calculated: volume, thickness, elongation, surface area, mean diameter, and umbilical cord centricity. We completed the Spielberger State (SSAI) and Trait (SSAI) Anxiety Inventory at each study visit. Linear mixed models were utilized to analyze the placental features predicted by maternal anxiety. Results: Placental volume, surface area, and mean diameter were decreased with elevated SSAI in 2V CHD fetuses, while volume and cord centricity were increased with higher SSAI in SV CHD fetuses. Lower cord centricity was associated with elevated STAI in 2V CHD fetuses, and elongation was positively associated with STAI in SV CHD fetuses. There were no associations between anxiety measures and placental features in control fetuses. Conclusions: We report for the first time that elevated prenatal maternal anxiety is associated with altered in vivo placental structures in pregnancies complicated by fetal CHD. Our data suggest that disturbances in placental structure vary based on the type of fetal CHD (SV vs. 2V) in the setting of elevated prenatal maternal anxiety.

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.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.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.Prenatal maternal stress, anxiety, and depression.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.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 (β = -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: β = -54.62; 95% CI, -85.05 to -24.19; P .001; sulcal depth: β = -14.22; 95% CI, -23.59 to -4.85; P = .002) and competence scores (local gyrification index: β = -24.01; 95% CI, -40.34 to -7.69; P = .003; sulcal depth: β = -7.53; 95% CI, -11.73 to -3.32; P .001).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.

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.

Placental dysfunction is a major cause of fetal demise, fetal growth restriction, and preterm birth, as well as significant maternal morbidity and mortality. Infant survivors of placental dysfunction are at elevatedrisk for lifelong neuropsychiatric morbidity. However, despite the significant consequences of placental disease, there are no clinical tools to directly and non-invasively assess and measure placental function in pregnancy. In this work, we will review advanced MRI techniques applied to the study of the in vivo human placenta in order to better detail placental structure, architecture, and function. We will discuss the potential of these measures to serve as optimal biomarkers of placental dysfunction and review the evidence of these tools in the discrimination of health and disease in pregnancy. Efforts to advance our understanding of in vivo placental development are necessary if we are to optimize healthy pregnancy outcomes and prevent brain injury in successive generations. Current management of many high-risk pregnancies cannot address placental maldevelopment or injury, given the standard tools available to clinicians. Once accurate biomarkers of placental development and function are constructed, the subsequent steps will be to introduce maternal and fetal therapeutics targeting at optimizing placental function. Applying these biomarkers in future studies will allow for real-time assessments of safety and efficacy of novel interventions aimed at improving maternal-fetal well-being.

Predicting neurodevelopmental outcomes in high-risk neonates remains challenging despite advances in neonatal care. Early and accurate characterization of infants at risk for neurodevelopmental delays is necessary to best identify those who may benefit from existing early interventions and novel therapies that become available. Although neuroimaging is a promising biomarker in the prediction of neurodevelopmental outcomes in high-risk infants, it requires additional resources and expertise. Despite many advances in neonatal neuroimaging, there remain limitations in relating early neuroimaging findings with long-term outcomes; further studies are necessary to determine the optimal protocols to best identify high-risk patients and improve neurodevelopmental outcome prediction.

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.

Sengers syndrome is a rare autosomal recessive mitochondrial disease characterized by lactic acidosis, hypertrophic cardiomyopathy and bilateral cataracts. We present here a case of neonatal demise, within the first day of life, who initially presented with severe lactic acidosis, with evidence of both chorioamnionitis and cardiogenic shock. Initial metabolic labs demonstrated a severe lactic acidosis prompting genetic testing which revealed a homozygous pathogenic variant for Sengers syndrome in AGK, c.979A > T; p.K327*. In addition to the canonical features of Sengers syndrome, our patient is the first reported case with liver dysfunction extending the phenotypic spectrum both in terms of severity and complications. This case also highlights the importance of maintaining a broad differential for congenital lactic acidosis.

Premature infants are born prior to a critical window of rapid placental nutrient transfer and fetal growth—particularly brain development—that occurs during the third trimester of pregnancy. Subsequently, a large proportion of preterm neonates experience extrauterine growth failure and associated neurodevelopmental impairments. Human milk (maternal or donor breast milk) is the recommended source of enteral nutrition for preterm infants, but requires additional fortification of macronutrient, micronutrient, and energy content to meet the nutritional demands of the preterm infant in attempts at replicating in utero nutrient accretion and growth rates. Traditional standardized fortification practices that add a fixed amount of multicomponent fortifier based on assumed breast milk composition do not take into account the considerable variations in breast milk content or individual neonatal metabolism. Emerging methods of individualized fortification—including targeted and adjusted fortification—show promise in improving postnatal growth and neurodevelopmental outcomes in preterm infants.

Objective The relationship between placental and fetal brain growth is poorly understood, and difficult to assess. The objective of this study was to interrogate placental and fetal brain growth in healthy pregnancies and those complicated by fetal growth restriction (FGR). Study Design In a prospective, observational study, pregnant women with normal pregnancies or pregnancies complicated by FGR underwent fetal MR imaging. Placental, global and regional brain volumes were calculated. Results 114 women (79 controls and 35 FGR) underwent MR imaging (median GA 30 weeks, range 18 –39). All measured volumes increased exponentially with advancing GA. Placental, total brain, cerebral and cerebellar volumes were smaller in FGR compared to controls (p

Background Due to the high-frequency of routine interventions in an intensive care setting, electrocardiogram (ECG) recordings from sick infants are highly non-stationary, with recurrent changes in the baseline, alterations in the morphology of the waveform, and attenuations of the signal strength. Current methods lack reliability in identifying QRS complexes (a marker of individual cardiac cycles) in the non-stationary ECG. In the current study we address this problem by proposing a novel approach to QRS complex identification. Method Our approach employs lowpass filtering, half-wave rectification, and the use of instantaneous Hilbert phase to identify QRS complexes in the ECG. We demonstrate the application of this method using ECG recordings from eight preterm infants undergoing intensive care, as well as from 18 normal adult volunteers available via a public database. We compared our approach to the commonly used approaches including Pan and Tompkins (PT), gqrs , wavedet , and wqrs for identifying QRS complexes and then compared each with manually identified QRS complexes. Results For preterm infants, a comparison between the QRS complexes identified by our approach and those identified through manual annotations yielded sensitivity and positive predictive values of 99% and 99.91%, respectively. The comparison metrics for each method are as follows: PT (sensitivity: 84.49%, positive predictive value: 99.88%), gqrs (85.25%, 99.49%), wavedet (95.24%, 99.86%), and wqrs (96.99%, 96.55%). Thus, the sensitivity values of the four methods previously described, are lower than the sensitivity of the method we propose; however, the positive predictive values of these other approaches is comparable to those of our method, with the exception of the wqrs approach, which yielded a slightly lower value. For adult ECG, our approach yielded a sensitivity of 99.78%, whereas PT yielded 99.79%. The positive predictive value was 99.42% for both our approach as well as for PT. Conclusions We propose a novel method for identifying QRS complexes that outperforms common currently available tools for non-stationary ECG data in infants. For stationary ECG our proposed approach and the PT approach perform equally well. The ECG acquired in a clinical environment may be prone to issues related to non-stationarity, especially in critically ill patients. The approach proposed in this report offers superior reliability in these scenarios.

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.

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.

Phase differences of two signals in perfect synchrony exhibit a narrow band distribution, whereas the phase differences of two asynchronous signals exhibit uniform distribution. We assess the statistical significance of the phase synchronization between two signals by using a signed rank test to compare the distribution of their phase differences to the theoretically expected uniform distribution for two asynchronous signals. Using numerical simulation of a second order autoregressive (AR2) process, we show that the proposed approach correctly identifies the coupling between the AR2 process and the driving white noise. We also identify the optimal p-value that distinguishes coupled scenarios from uncoupled ones. To identify the limiting cases, we study the phase synchronization between two independent white noises as a function of bandwidth of the filter in a different second simulation. We identify the frequency bandwidth below which the proposed approach fails and suggest using a data-driven approach for those scenarios. Finally, we demonstrate the application of this approach to study the coupling between beat-to-beat cardiac intervals and continuous blood pressure obtained from critically-ill infants to characterize the baroreflex function.

Fetal lung interstitial tumor (FLIT) is a rare fetal malignancy that is typically diagnosed in the postnatal period, or, if recognized prenatally can mimic a benign lesion such as congenital pulmonary airway malformation. We present the earliest case of a FLIT tumor described by ultrasound and MRI at 26 weeks of gestation. Our case highlights features suggestive of FLIT including presentation later in gestation in combination with findings on fetal MRI such as a solid appearance with radiating curved bands of high signal within and along the periphery of the lesion (not as intensely high signal as the typical CPAM), possibly detailing a radiographic signature for these tumors. The role of betamethasone for these tumors is not known.

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. 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. 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. 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.

This cohort study examines the association between parental socioeconomic status measures and brain volume and cortical features among fetuses., Key Points Question Is parental socioeconomic status associated with fetal brain development? Findings In this cohort study of 144 healthy pregnant women and their fetuses, low parental socioeconomic status was associated with decreased regional fetal brain tissue volume and increased brain gyrification. Meaning This cohort study found that parental socioeconomic status was associated with altered fetal brain morphology as measured by quantitative magnetic resonance imaging techniques, which may serve as an early biomarker associated with childhood neurodevelopmental disorders., Importance Children raised in settings with lower parental socioeconomic status are at increased risk for neuropsychological disorders. However, to date, the association between socioeconomic status and fetal brain development remains poorly understood. Objective To determine the association between parental socioeconomic status and in vivo fetal brain growth and cerebral cortical development using advanced, 3-dimensional fetal magnetic resonance imaging. Design, Setting, and Participants This cohort study of fetal brain development enrolled 144 healthy pregnant women from 2 low-risk community obstetrical hospitals from 2012 through 2019 in the District of Columbia. Included women had a prenatal history without complications that included recommended screening laboratory and ultrasound studies. Exclusion criteria were multiple gestation pregnancy, known or suspected congenital infection, dysmorphic features of the fetus, and documented chromosomal abnormalities. T2-weighted fetal brain magnetic resonance images were acquired. Each pregnant woman was scanned at up to 2 points in the fetal period. Data were analyzed from June through November 2020. Exposures Parental education level and occupation status were documented. Main Outcomes and Measures Regional fetal brain tissue volume (for cortical gray matter, white matter, cerebellum, deep gray matter, and brainstem) and cerebral cortical features (ie, lobe volume, local gyrification index, and sulcal depth) in the frontal, parietal, temporal, and occipital lobes were calculated. Results Fetal brain magnetic resonance imaging studies were performed among 144 pregnant women (median [interquartile range] age, 32.5 [27.0-36.1] years) with gestational age from 24.0 to 39.4 weeks; 75 fetuses (52.1%) were male, and 69 fetuses (47.9%) were female. Higher parental education level was associated with significantly increased volume in the fetal white matter (mothers: β, 2.86; 95% CI, 1.26 to 4.45; P = .001; fathers: β, 2.39; 95% CI, 0.97 to 3.81; P = .001), deep gray matter (mothers: β, 0.16; 95% CI, 0.002 to 0.32; P = .048; fathers: β, 0.16; 95% CI, 0.02 to 0.31; P = .02), and brainstem (mothers: β, 0.06; 95% CI, 0.02 to 0.10; P = .01; fathers: β, 0.04; 95% CI, 0.004 to 0.08; P = .03). Higher maternal occupation status was associated with significantly increased volume in the fetal white matter (β, 2.07; 95% CI, 0.88 to 3.26; P = .001), cerebellum (β, 0.17; 95% CI, 0.04 to 0.29; P = .01), and brainstem (β, 0.03; 95% CI, 0.001 to 0.07; P = .04), and higher paternal occupation status was associated with significantly increased white matter volume (β, 1.98; 95% CI, 0.71 to 3.25; P

Importance Maternal psychological distress during pregnancy is associated with adverse obstetric outcomes and neuropsychiatric deficits in children. Currently unavailable in vivo interrogation of fetal brain function could provide critical insights into the onset and timing of altered neurodevelopmental trajectories. Objective To investigate the association between prenatal maternal stress, anxiety, and depression and in vivo fetal brain resting state functional connectivity. Design, Setting, and Participants This cohort study included pregnant women scanned between January 2016 and April 2019. A total of 50 pregnant women with healthy pregnancies were prospectively recruited from low-risk obstetric clinics in the Washington DC area and were scanned at Children’s National in Washington DC. Exposures Maternal stress, anxiety, and depression. Main Outcomes and Measures The association of prenatal maternal stress, anxiety, and depression with whole-brain connectivity was analyzed using multivariate distance matrix regression. Prenatal maternal stress, anxiety, and depression were assessed using the Perceived Stress Scale, Spielberger State Anxiety Inventory and Spielberger Trait Anxiety Inventory, and the Edinburgh Postnatal Depression Scale, respectively. Whole-brain connectivity was measured from 100 functionally defined regions of interest. Results This study analyzed 59 resting-state functional connectivity magnetic resonance image data sets from the fetuses (mean [SD] gestational age, 33.52 [4 weeks]) of 50 healthy pregnant women (mean [SD] age, 33.77 [5.51]). Mean (SD) scores for the questionnaires were as follows: Spielberger State Anxiety Inventory, 26.66 (6.72) (range, 20-48); Spielberger Trait Anxiety Inventory, 28.09 (6.62) (range, 20-50); Perceived Stress Scale, 9.27 (5.13) (range, 1-25); and Edinburgh Postnatal Depression Scale 3.24 (2.84) (range, 0-14). Prenatal maternal anxiety scores measured using the Spielberger Trait and State Anxiety Inventories were associated with differences in fetal connectivity (Spielberger State Anxiety Inventory: pseudo-R2 = 0.019,P = .04; Spielberger Trait Anxiety Inventory: pseudo-R2 = 0.021,P = .007). Interhemispheric connections, such as those involving the parietofrontal and occipital association cortices, were associated with reduced maternal prenatal anxiety, and those between the brainstem and sensorimotor areas were associated with higher anxiety scores. Conclusions and Relevance In this cohort study, an association was found between prenatal maternal anxiety and disturbances in fetal brain functional connectivity, suggesting altered fetal programming. Early onset of functional deviations suggests the need for more widespread screening of pregnant women for symptoms of anxiety.