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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.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.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%).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.

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.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.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.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.

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.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.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.Children with in utero ZIKV exposure without CZS may demonstrate emerging differences in executive function, mood, and adaptive mobility that require continued evaluation.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.

The objective of the study was to describe the complexity of diagnosis and evaluation of Zika-exposed pregnant women/fetuses and infants in a U.S. Congenital Zika Program. Pregnant women/fetuses and/or infants referred for clinical evaluation to the Congenital Zika Program at Children’s National (Washington, DC) from January 2016 to June 2018 were included. We recorded the timing of maternal Zika-virus (ZIKV) exposure and ZIKV laboratory testing results. Based on laboratory testing, cases were either confirmed, possible, or unlikely ZIKV infection. Prenatal and postnatal imaging by ultrasound and/or magnetic resonance imaging (MRI) were categorized as normal, nonspecific, or as findings of congenital Zika syndrome (CZS). Of 81 women–fetus/infant pairs evaluated, 72 (89%) had confirmed ZIKV exposure; 18% of women were symptomatic; only a minority presented for evaluation within the time frame for laboratory detection. Zika virus could only be confirmed in 29 (40%) cases, was possible in 26 (36%) cases, and was excluded in 17 (24%) cases. Five cases (7%) had prenatal ultrasound and MRI findings of CZS, but in only three was ZIKV confirmed by laboratory testing. Because of timing of exposure to presentation, ZIKV infection could not be excluded in many cases. Neuroimaging found CZS in 7% of cases, and in many patients, there were nonspecific imaging findings that warrant long-term follow-up. Overall, adherence to postnatal recommended follow-up evaluations was modest, representing a barrier to care. These challenges may be instructive to future pediatric multidisciplinary clinics for congenital infectious/noninfectious threats to pregnant women and their infants.

BACKGROUND: The third trimester of gestation is a crucial phase of rapid brain development, but little has been reported on the trajectories of cerebral blood flow (CBF) in preterm infants in this period. PURPOSE: To quantify regional CBF in very preterm infants longitudinally across the ex utero third trimester and to determine its relationship with clinical factors associated with brain injury and premature birth. MATERIALS AND METHODS: In this prospective study, very preterm infants were enrolled for three longitudinal MRI scans, and 22 healthy full-term infants were enrolled for one term MRI scan between November 2016 and February 2019. Global and regional CBF in the cortical gray matter, white matter, deep gray matter, and cerebellum were measured using arterial spin labeling with postlabeling delay of 2025 msec at 1.5 T and 3.0 T. Brain injury and clinical risk factors in preterm infants were investigated to determine associations with CBF. Generalized estimating equations were used to account for correlations between repeated measures in the same individual. RESULTS: A total of 75 preterm infants (mean postmenstrual age [PMA]: 29.5 weeks ± 2.3 [standard deviation], 34.9 weeks ± 0.8, and 39.3 weeks ± 2.0 for each scan; 43 male infants) and 22 full-term infants (mean PMA, 42.1 weeks ± 2.0; 13 male infants) were evaluated. In preterm infants, global CBF was 11.9 mL/100 g/min ± 0.2 (standard error). All regional CBF increased significantly with advancing PMA (P ≤ .02); the cerebellum demonstrated the most rapid CBF increase and the highest mean CBF. Lower CBF was associated with intraventricular hemorrhage in all regions (P ≤ .05) and with medically managed patent ductus arteriosus in the white matter and deep gray matter (P = .03). Mean CBF of preterm infants at term-equivalent age was significantly higher compared with full-term infants (P ≤ .02). CONCLUSION: Regional cerebral blood flow increased significantly in preterm infants developing in an extrauterine environment across the third trimester and was associated with intraventricular hemorrhage and patent ductus arteriosus. © RSNA, 2021 Online supplemental material is available for this article.

Dandy-Walker malformation and Blake pouch cysts can have overlapping imaging features. The choroid plexus and associated taenia–tela choroidea complex are displaced inferolaterally in Dandy-Walker malformation and below the vermis in Blake pouch cysts. To determine the normal fetal and postnatal MR appearance of the choroid plexus and taenia–tela choroidea complex, and whether their location can help distinguish Dandy-Walker malformation from Blake pouch cysts. In this retrospective study, we evaluated brain MR exams from normal-appearing fetuses (gestational age 19–38 weeks) and infants, fetal and postnatal exams in Blake pouch cysts and Dandy-Walker malformation, and ambiguous cases equivocal for mild Dandy-Walker malformation and Blake pouch cysts. We documented choroid plexus and the taenia–tela choroidea complex location and axial and sagittal angles in each case. Then we contrasted and compared the original and updated fetal diagnoses based on taenia–tela choroidea complex and choroid plexus positions. The choroid plexus location and the taenia–tela choroidea complex location and angles varied significantly among normal exams, Blake pouch cyst exams and Dandy-Walker malformation exams (P

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.

Objective Report a single-center 12-year experience in the fetal diagnosis of diencephalic-mesencephalic junction dysplasia (DMJD) to expand the phenotype with Magnetic resonance imaging (MRI)-based classification, evaluate genetic etiologies, and ascertain outcomes. Methods Retrospective medical record and imaging review of all fetal MRI exams with DMJD were performed at our institution. Results Thirty-three pregnancies with fetal MRI findings of DMJD at 24 (18-37) weeks gestational age were studied; 70% were referred for fetal hydrocephalus. Three fetal MRI patterns were recognized. Type A (butterfly/hypothalamus-midbrain union) was seen in two cases (6%), Type B (partial thalamus-midbrain union) in 22 fetuses (70%), and Type C (complete/near complete midbrain-thalamic continuity) in nine fetuses (24%). L1CAM mutations were identified in four cases, and biallelic VRK1 variants in another. Among 14 live-born cases, 11 survived infancy, and 10 underwent postnatal brain MRI which confirmed the fetal MRI diagnosis in all but one case. Development was delayed in all surviving infants, most with additional neurological sequelae. Conclusions DMJD may be identified by prenatal MRI as early as 18 weeks gestation. We propose three distinct phenotypic forms of DMJD, Types A-C. Next-generation sequencing provides an underlying molecular diagnosis in some patients, but further studies on associated genetic diagnoses and clinical outcomes are indicated.

Autonomic nervous system function is critical for transition from in-utero to ex-utero life and is associated with neurodevelopmental and neuropsychiatric outcomes later in life. Adverse prenatal and neonatal conditions and exposures can impair or alter ANS development and, as a result, may also impact long-term neurodevelopmental outcomes. The objective of this article is to provide a broad overview of the impact of factors that are known to influence autonomic development during the fetal and early neonatal period, including maternal mood and stress during and after pregnancy, fetal growth restriction, congenital heart disease, toxic exposures, and preterm birth. We touch briefly on the typical development of the ANS, then delve into both in-utero and ex-utero maternal and fetal factors that may impact developmental trajectory of the ANS and, thus, have implications in transition and in long-term developmental outcomes. While many types of exposures and conditions have been shown to impact development of the autonomic nervous system, there is still much to be learned about the mechanisms underlying these influences. In the future, more advanced neuromonitoring tools will be required to better understand autonomic development and its influence on long-term neurodevelopmental and neuropsychological function, especially during the fetal period.

Gamma-aminobutyric acid (GABA) and glutamate are principal neurotransmitters essential for late gestational brain development and may play an important role in prematurity-related brain injury. In vivo investigation of GABA in the preterm infant with standard proton magnetic resonance spectroscopy (1H-MRS) has been limited due to its low concentrations in the developing brain, and overlap in the spectrum by other dominant metabolites. We describe early postnatal profiles of in vivo GABA and glutamate concentrations in the developing preterm brain measured by using the J-difference editing technique, Mescher-Garwood point resolved spectroscopy. We prospectively enrolled very preterm infants born ≤32 weeks gestational age and non-sedated 1H-MRS (echo time 68 ms, relaxation time 2000 ms, 256 signal averages) was acquired on a 3 Tesla magnetic resonance imaging scanner from a right frontal lobe voxel. Concentrations of GABA + (with macromolecules) was measured from the J-difference spectra; whereas glutamate and composite glutamate + glutamine (Glx) were measured from the unedited (OFF) spectra and reported in institutional units. We acquired 42 reliable spectra from 38 preterm infants without structural brain injury [median gestational age at birth of 28.0 (IQR 26.0, 28.9) weeks; 19 males (50%)] at a median postmenstrual age of 38.4 (range 33.4 to 46.4) weeks. With advancing post-menstrual age, the concentrations of glutamate OFF increased significantly, adjusted for co-variates (generalized estimating equation β = 0.22, p = 0.02). Advancing postnatal weeks of life at the time of imaging positively correlated with GABA + (β = 0.06, p = 0.02), glutamate OFF (β = 0.11, p = 0.02) and Glx OFF (β = 0.12, p = 0.04). Male infants had higher GABA + (1.66 ± 0.07 vs. 1.33 ± 0.11, p = 0.01) concentrations compared with female infants. For the first time, we report the early ex-utero developmental profile of in vivo GABA and glutamate stratified by age and sex in the developing brain of very preterm infants. This data may provide novel insights into the pathophysiology of neurodevelopmental disabilities reported in preterm infants even in the absence of structural brain injury.

The objective was to examine the discriminatory ability of electroencephalogram (EEG) delta power in neonates with hypoxic-ischemic encephalopathy (HIE) with well-defined outcomes. Prolonged continuous EEG recordings from term neonates with HIE during therapeutic hypothermia enrolled in a prospective observational study were examined. Adverse outcome was defined as death or severe brain injury by magnetic resonance imaging (MRI); favorable outcome was defined as normal or mild injury by MRI. Neonates were stratified by Sarnat grade of encephalopathy at admission. EEG was partitioned into 10-minute nonoverlapping artifact- and seizure-free epochs. Delta power was calculated and compared between the groups using receiver operating characteristic (ROC) analyses and Wilcoxon rank-sum tests. An area under the ROC curve >0.7 with P

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

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.

Different fetal ultrasound (US) nomograms of the head circumference (HC) have been established; however, comparisons between the detection rates of microcephaly among US nomograms are few and inconsistent. We aimed to compare the prenatal diagnostic rate of fetal microcephaly (FM) among four widely used US nomograms of the fetal HC, when applied to the same group of fetuses.We retrospectively identified singleton pregnancies complicated by fetal HC5th percentile for gestational age (GA) by US, without other risk factors for FM and with normal fetal brain MRI. Raw values of HC by US were converted to z-scores using four nomograms (Chervenak =Fifty one fetuses at a mean (±SD) GA of 28 (±4) weeks were included. The four nomograms resulted in different z-score values of the fetal HC for the same subject (Despite the use of similar prenatal cutoff z-score values of the fetal HC, the four nomograms led to different diagnostic rates of FM. More consistent diagnostic criteria are therefore needed to define FM, especially in the absence of other risk factors for FM and normal fetal brain MRI, since the prenatal diagnosis can affect pregnancy management.

Delivery of the newborn occurs either vaginally or via caesarean section. It is not known whether the mode of delivery and exposure to labor affects early autonomic nervous system (ANS) function, as measured by heart rate variability (HRV), or cortical electroencephalogram (EEG) activity. The objective of the study was to determine if autonomic function in newborns differs by mode of delivery. Simultaneous recording of EEG and electrocardiogram were collected in low-risk term newborns at

Purpose To compare early changes in autonomic nervous system (ANS) tone between newborns with complex congenital heart disease (CHD) and newborns without CHD. Methods We performed a case–control study of heart rate variability (HRV) in newborns with complex CHD [transposition of the great arteries (TGA) or hypoplastic left heart syndrome (HLHS)] and low-risk control newborns without CHD. Cases with CHD were admitted following birth to a pediatric cardiac intensive care unit and had archived continuous ECG data. Control infants were prospectively enrolled at birth. ECG data in cases and controls were analyzed for HRV in the time and frequency domains at 24 h of age. We analyzed the following HRV metrics: alpha short (αs), alpha long (αL), root mean square short and long (RMSs and RMSL), low-frequency (LF) power, normalized LF (nLF), high-frequency (HF) power, and normalized HF (nHF). We used ANOVA to compare HRV metrics between groups and to control for medication exposures. Results HRV data from 57 infants with CHD (TGA, n = 33 and HLHS, n = 24) and from 29 controls were analyzed. The HRV metrics αS, RMSL, LF, and nLF were significantly lower in infants with CHD than in the controls. Due to the effect of normalization, nHF was higher in CHD infants (P

The mature cerebral cortex has a topographically organized influence on reflex autonomic centers of the brainstem and diencephalon and sympathetic activation coming primarily from the right hemisphere and parasympathetic activation from the left. In the term newborn, the maturational status of this central autonomic system remains poorly understood. Sixteen term newborns admitted to Children’s National with unilateral middle cerebral artery (MCA) strokes (n = 8 left, n = 8 right) had archived continuous electrocardiograph (EKG) signals available. We compared stroke laterality and severity with indices of autonomic function, as measured by heart rate variability. We performed both time- and frequency-domain analyses on the R–R interval (RRi) over 24h of continuous EKG data at around 7 days of age. Right MCA stroke significantly increased sympathetic tone, while left MCA stroke increased parasympathetic tone. Regardless of laterality, stroke severity was associated inversely with sympathetic tone and positively with parasympathetic tone. Surprisingly, injury to either insular region had no significant autonomic effect. Phenobarbital blood levels were positively associated with sympathetic tone and inversely related to parasympathetic tone. Based on these findings, it is difficult to reconcile the functional topography of the central autonomic system in term newborns with that currently proposed for the normal mature brain. Further investigation is clearly needed.

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.To determine whether impaired early neonatal HRV is associated with pre-operative brain injury in CHD.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.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.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.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.

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

PURPOSE: The mature central autonomic network includes connectivity between autonomic nervous system brainstem centers and the cerebral cortex. The study objective was to evaluate the regional connectivity between the cerebral cortex and brainstem autonomic centers in term newborns by measuring coherence between high-density electroencephalography and heart rate variability as measured by electrocardiography. METHODS: Low-risk term newborns with birth gestational age 39–40 weeks were prospectively enrolled and studied using time-synced electroencephalography and electrocardiography for up to 60 minutes before discharge from the birth hospital. The cortico-autonomic nervous system association was analyzed using coherence between electroencephalography-delta power and heart rate variability. Heart rate variability measured parasympathetic tone (root mean square of successive differences of heart rate) and sympathetic tone (standard deviation of heart rate). RESULTS: One hundred and twenty-nine low-risk term infants were included. High coherence delta(-)root mean square of successive differences was found in central, bi-temporal, and occipital brain regions with less robust coherence delta-standard deviation in the central region and bi-temporal areas. CONCLUSIONS: Our findings describe a topography of cortico-autonomic connectivity present at term in low-risk newborns, which was more robust to parasympathetic than sympathetic brainstem centers and was independent of newborn state.

Background Posterior fossa anomalies can be diagnostic dilemmas during the fetal period. The prognosis for different diagnoses of the posterior fossa varies widely. We investigated whether fetal magnetic resonance imaging (MRI) and prenatal neurology consultation led to an alternate prognosis for fetuses referred due to concern for a fetal posterior fossa anomaly and concordance between pre- and postnatal diagnoses. Methods This is a retrospective study of cases referred to the Prenatal Pediatrics Institute at Children’s National Hospital from January 2012 to June 2018 due to concern for posterior fossa anomaly. Each encounter was scored for change in prognosis based upon clinical and fetal MRI report. Postnatal imaging was compared with prenatal imaging when available. Results In total, 180 cases were referred for fetal posterior fossa anomalies based on outside obstetric ultrasound and had both fetal MRI and a neurology consultation. Fetal MRI and neurology consultation resulted in a change in fetal prognosis in 70% of cases. The most common referral diagnosis in our cohort was Dandy-Walker continuum, but it was not often confirmed by fetal MRI. In complex cases, posterior fossa diagnosis and prognosis determined by fetal MRI impacted choices regarding pregnancy management. Postnatal imaging was obtained in 57 (47%) live-born infants. Fetal and postnatal prognoses were similar in 60%. Conclusions Fetal diagnosis affects pregnancy management decisions. The fetal-postnatal imaging agreement of 60% highlights the conundrum of balancing the timing of fetal MRI to provide the most accurate diagnosis of the posterior fossa abnormalities in time to make pregnancy management decisions.

Dandy-Walker malformation and Blake pouch cysts can have overlapping imaging features. The choroid plexus and associated taenia-tela choroidea complex are displaced inferolaterally in Dandy-Walker malformation and below the vermis in Blake pouch cysts.To determine the normal fetal and postnatal MR appearance of the choroid plexus and taenia-tela choroidea complex, and whether their location can help distinguish Dandy-Walker malformation from Blake pouch cysts.In this retrospective study, we evaluated brain MR exams from normal-appearing fetuses (gestational age 19-38 weeks) and infants, fetal and postnatal exams in Blake pouch cysts and Dandy-Walker malformation, and ambiguous cases equivocal for mild Dandy-Walker malformation and Blake pouch cysts. We documented choroid plexus and the taenia-tela choroidea complex location and axial and sagittal angles in each case. Then we contrasted and compared the original and updated fetal diagnoses based on taenia-tela choroidea complex and choroid plexus positions.The choroid plexus location and the taenia-tela choroidea complex location and angles varied significantly among normal exams, Blake pouch cyst exams and Dandy-Walker malformation exams (P0.01). Dandy-Walker malformation showed inferolateral displacement of the taenia-tela choroidea complex and choroid plexus distant from the vermis. Adding the taenia-tela choroidea complex and choroid plexus into the assessment improved diagnostic accuracy, especially in ambiguous cases.The location of the taenia-tela choroidea complex and choroid plexus provided additional diagnostic neuroimaging clues that could be used in conjunction with other conventional findings to distinguish Dandy-Walker malformation and Blake pouch cysts. Normal, Blake pouch cyst, and Dandy-Walker malformation cases differed with regard to taenia-tela choroidea complex and choroid plexus position. Inferolateral taenia-tela choroidea complex displacement distant from the vermian margin was characteristic of Dandy-Walker malformation.

In premature infants, we investigated whether the duration of extrauterine development influenced autonomic nervous system (ANS) maturation.We performed a longitudinal cohort study of ANS maturation in preterm infants. Eligibility included birth gestational age (GA) 37 weeks, NICU admission, and expected survival. The cohort was divided into three birth GA groups: Group 1 (≤29 weeks), Group 2 (30-33 weeks), and Group 3 (≥34 weeks). ECG data were recorded weekly and analyzed for sympathetic and parasympathetic tone using heart rate variability (HRV). Quantile regression modeled the slope of ANS maturation among the groups by postnatal age to term-equivalent age (TEA) (≥37 weeks).One hundred infants, median (Q1-Q3) birth GA of 31.9 (28.7-33.9) weeks, were enrolled: Group 1 (n = 35); Group 2 (n = 40); and Group 3 (n = 25). Earlier birth GA was associated with lower sympathetic and parasympathetic tone. However, the rate of autonomic maturation was similar, and at TEA there was no difference in HRV metrics across the three groups. The majority of infants (91%) did not experience significant neonatal morbidities.Premature infants with low prematurity-related systemic morbidity have maturational trajectories of ANS development that are comparable across a wide range of ex-utero durations regardless of birth GA.Heart rate variability can evaluate the maturation of the autonomic nervous system. Metrics of both the sympathetic and parasympathetic nervous system show maturation in the premature extrauterine milieu. The autonomic nervous system in preterm infants shows comparable maturation across a wide range of birth gestational ages. Preterm newborns with low medical morbidity have maturation of their autonomic nervous system while in the NICU. Modern NICU advances appear to support autonomic development in the preterm infant.

The objective of this article is to understand the complex role of the central autonomic nervous system in normal and complicated fetal-neonatal transition and how autonomic nervous system dysfunction can lead to brain injury. The central autonomic nervous system supports coordinated fetal transitional cardiovascular, respiratory, and endocrine responses to provide safe transition of the fetus at delivery. Fetal and maternal medical and environmental exposures can disrupt normal maturation of the autonomic nervous system in utero, cause dysfunction, and complicate fetal-neonatal transition. Brain injury may both be caused by autonomic nervous system failure and contribute directly to autonomic nervous system dysfunction in the fetus and newborn. The central autonomic nervous system has multiple roles in supporting transition of the fetus. Future studies should aim to improve real-time monitoring of fetal autonomic nervous system function and in supporting typical autonomic nervous system development even under complicated conditions.

The central autonomic nervous system (ANS) is essential for maintaining cardiovascular and respiratory homeostasis in the newborn and has a critical role in supporting higher cortical functions. At birth, the central ANS is maturing and is vulnerable to adverse environmental and physiologic influences. Critical connections are formed early in development between the ANS and limbic system to integrate psychological and body responses. The Polyvagal Theory, developed by Stephen Porges, describes how modulation of the autonomic vagal impulse controls social responses and that a broad range of neuropsychiatric disorders may be due to impaired vagal balance, with either deficient vagal tone or excessive vagal reactivity. Under additional circumstances of prematurity, growth restriction, and environmental stress in the fetus and newborn, the immature ANS may undergo "dysmaturation". Maternal stress and health as well as the intrauterine environment are also quite important and have been implicated in causing ANS changes in the infant and neuropsychiatric diseases in children. This review will cover the aspects of ANS development and maturation that have been associated with neuropsychiatric disorders in children.

Background Necrotizing enterocolitis (NEC) is a complication of prematurity with a high mortality rate. Currently, there are no reliable biomarkers capable of identifying infants at risk for developing NEC. We sought to determine the autonomic nervous system antecedents of NEC in premature infants, using heart rate variability (HRV). Materials and Methods HRV was quantified by retrieving archived electrocardiogram (EKG) data from 30 premature infants from 4 days prior, through 4 days after, the clinical NEC diagnosis. HRV metrics were compared with those on the diagnosis day using the receiver operating characteristic (ROC) analysis. Results HRV metrics showed a depression of autonomic tone that preceded the clinical NEC diagnosis by 2 days, and which recovered to baseline by 2 days after diagnosis (area under the curve [AUC] Conclusion Our studies suggest that readily accessible metrics of autonomic depression might expedite the diagnosis of NEC and its severity in a clinically meaningful manner. Clearly, these studies need to be extended prospectively to determine the diagnostic utility of this approach.

Background Congenital Zika infection can result in a spectrum of neurological abnormalities in the newborn. Newborns exposed to Zika virus in utero often have neuroimaging as part of their clinical evaluation. Methods Through the Congenital Zika Program at Children's National Health System in Washington DC, we performed fetal or neonatal neuroimaging, including magnetic resonance imaging and ultrasound, on over 70 fetuses or neonates with intrauterine Zika exposure. Novel findings on neonatal brain magnetic resonance imaging were observed in two instances. Results Gadolinium-contrast magnetic resonance imaging showed enhancement of multiple cranial nerves at three days of age on one infant. Another infant underwent magnetic resonance imaging at 16 days of age and was shown to have a chronic ischemic cerebral infarction. This infant had previously normal fetal magnetic resonance imaging. Conclusion Cranial nerve enhancement and cerebral infarction may be among the expanding list of neurological findings in congenital Zika infection. Postnatal brain magnetic resonance imaging should be considered for newborns exposed to Zika virus in utero .

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.

Objective To date, prenatal diagnosis of intracranial hemorrhage (ICH) is mainly based on ultrasound (US) findings rather than magnetic resonance imaging (MRI). We aimed to investigate the role of MRI in the diagnosis of fetal ICH among pregnancies referred to fetal MRI and to characterize the topography of fetal ICH using MRI. Methods We retrospectively identified fetal ICH cases diagnosed by MRI from 2008 to 2015 and reviewed their prenatal and postnatal medical records. Results Of the 2638 MRIs performed during the study period, 36 had ICH (median age 27 weeks). The most common US indication for MRI was a suspected cerebral anomaly (86%): 20 (55%) fetuses were referred for ventriculomegaly, 8 (22%) for ICH, and the other 8 had a variety of different indications. We distinguished two broad topographic patterns: (1) those related to hemorrhage of the periventricular germinal matrix (GMH, n = 24; 67%) and (2) those not related to GMH (non-GMH, n = 12; 33%). GMH fetuses were referred to MRI later (median 28 vs 22 weeks, p = 0.005). Intrauterine demise was more frequent in non-GMH (58% vs 4%, p

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.

OBJECTIVE To determine whether measures of heart rate variability are related to changes in temperature during rewarming after therapeutic hypothermia for hypoxic-ischemic encephalopathy. DESIGN Prospective observational study. SETTING Level 4 neonatal ICU in a free-standing academic children's hospital. PATIENTS Forty-four infants with moderate to severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia. INTERVENTIONS Continuous electrocardiogram data from 2 hours prior to rewarming through 2 hours after completion of rewarming (up to 10 hr) were analyzed. MEASUREMENTS AND MAIN RESULTS Median beat-to-beat interval and measures of heart rate variability were quantified including beat-to-beat interval SD, low and high frequency relative spectral power, detrended fluctuation analysis short and long α exponents (αS and αL), and root mean square short and long time scales. The relationships between heart rate variability measures and esophageal/axillary temperatures were evaluated. Heart rate variability measures low frequency, αS, and root mean square short and long time scales were negatively associated, whereas αL was positively associated, with temperature (p < 0.01). These findings signify an overall decrease in heart rate variability as temperature increased toward normothermia. CONCLUSIONS Measures of heart rate variability are temperature dependent in the range of therapeutic hypothermia to normothermia. Core body temperature needs to be considered when evaluating heart rate variability metrics as potential physiologic biomarkers of illness severity in hypoxic-ischemic encephalopathy infants undergoing therapeutic hypothermia.

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.

Objective To establish whether fetal cerebral vasoreactivity (CVRO2 ), following maternal hyperoxia, is predicted by fetal cerebral and uteroplacental Doppler pulsatility indices (PI) at baseline, fetal pulmonary vasoreactivity to oxygen (PVRO2 ), gestational age (GA), or sex. Methods Pulsatility index of middle (MCA), anterior (ACA), posterior cerebral (PCA), umbilical (UA), uterine (UtA), and branch of the pulmonary arteries (PA) were obtained, by ultrasound, before (baseline), during (hyperoxia) and after 15 minutes of maternal administration of 8 L/min of 100% oxygen, through a non-rebreathing face mask, in normal singleton pregnancies within 20 to 38 weeks' gestation. CVRO2 was defined as changes greater than zero in z score of PI of the cerebral arteries from baseline to hyperoxia. Logistic modeling was applied to identify CVRO2 predictors. Results A total of 97 pregnancies were eligible. In the overall population, median z scores of PI of MCA, ACA, and PCA did not differ between study phases. Based on the logistic model, baseline z scores for cerebral PI and GA were the best predictors of CVRO2 . Conclusions In low-risk pregnancies, fetal CVRO2 to hyperoxia does not occur uniformly but depends on cerebral PI and GA at baseline. These findings may provide useful reference points when oxygen is administered in high-risk pregnancies.

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.

We report a case of fetal cerebellar hemorrhage and hypoplasia, identified by fetal MRI after intrauterine blood transfusion at 21 weeks' gestation for treatment of severe anemia due to congenital Parvovirus infection. Postnatal MRI confirmed atrophy of bilateral cerebellar hemispheres and inferior vermis. Cerebellar capillaries may be extremely susceptible to hemodynamic changes in the setting of intrauterine blood transfusion due to severe anemia. Although the correlation between fetal intracranial anomalies and Parvovirus infection remains unclear, in this population, a detailed evaluation of the brain parenchyma should be considered prior to and after intrauterine blood transfusion.

Objectives The ability of the premature brain to extract and use oxygen has not been studied adequately. This study aimed to determine factors that influence fractional tissue oxygen extraction (FTOE) of the brain in premature infants using near-infrared spectroscopy (NIRS) and pulse oximetry. Study Design We prospectively studied FTOE in very low birth weight (BW) infants (< 1,500 g and ≤ 34 weeks' gestation). Factors affecting FTOE and its variability were examined using bivariate and linear regression models. FTOE variability was measured on two scales: short scales (3-20 seconds) and long scales (20-150 seconds). Results We examined 147 simultaneous NIRS and pulse oximetry recordings that were collected from 72 premature infants (gestational age [GA] = 28 weeks and BW = 1,036 g). In regression models, average FTOE correlated negatively with hemoglobin (Hb) and increased significantly in patients with severe intraventricular hemorrhage/periventricular leukomalacia. Both FTOE short- and long-scale variabilities correlated negatively with GA and positively with postnatal age (PNA). Moreover, FTOE long-scale variability was significantly reduced in infants supported with invasive ventilation. Conclusions In premature infants, cerebral oxygen extraction increased with reduced Hb and severe brain injury. Variability in oxygen extraction showed differential changes with GA and PNAs and was affected by invasive ventilation.