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OBJECTIVES To characterize, using magnetic resonance imaging (MRI), the distribution of blood flow and oxygen transport in human fetuses with subtypes of congenital heart disease (CHD) that present with neonatal cyanosis. METHODS Blood flow was measured in the major vessels of 152 late-gestation human fetuses with CHD and 40 gestational-age-matched normal fetuses, using cine phase-contrast MRI. Oxygen saturation (SaO2 ) was measured in the major vessels of 57 fetuses with CHD and 40 controls. RESULTS Compared with controls, we found lower combined ventricular output in fetuses with single-ventricle physiology, with the lowest being observed in fetuses with severe forms of Ebstein's anomaly. Obstructive lesions of the left or right heart were associated with increased flow across the contralateral side. Pulmonary blood flow was reduced in fetuses with Ebstein's anomaly, while those with Ebstein's anomaly and tricuspid atresia had reduced umbilical flow. Flow in the superior vena cava was elevated in fetuses with transposition of the great arteries, normal in fetuses with hypoplastic left heart, tetralogy of Fallot or tricuspid atresia and reduced in fetuses with Ebstein's anomaly. Umbilical vein SaO2 was reduced in fetuses with hypoplastic left heart or tetralogy of Fallot. Ascending aorta and superior vena cava SaO2 were reduced in nearly all CHD subtypes. CONCLUSIONS Fetuses with cyanotic CHD exhibit profound changes in the distribution of blood flow and oxygen transport, which result in changes in cerebral, pulmonary and placental blood flow and oxygenation. These alterations of fetal circulatory physiology may influence the neonatal course and help account for abnormalities of prenatal growth and development that have been described in newborns with cyanotic CHD. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Continuous data capture technology is becoming more common. Establishing analytic approaches for continuous data could aid in understanding the relationship between physiology and clinical outcomes.Our objective was to design a retrospective analysis for continuous physiologic measurements and their relationship with new brain injury over time after cardiac surgery.Retrospective cohort study in the Cardiac Critical Care Unit at the Hospital for Sick Children in patients after repair of transposition of the great arteries (TGA) or single ventricle (SV) lesions.Continuously acquired physiologic measurements for up to 72 hours after cardiac surgery were analyzed for association with new brain injury by MRI. Distributions of heart rate (HR), systolic blood pressure (BP), and oxygen saturation (SpoSeventy-seven patients (60 TGA; 17 SV) were included. New brain injury was seen in 26 (34%). In SV patients, with and without new brain injury, respectively, in the first 24 hours after cardiac surgery, the median (interquartile range) HR was 172.0 beats/min (bpm) (169.7-176.0 bpm) versus 159.6 bpm (145.0-167.0 bpm); systolic BP 74.8 (67.9-78.5 mm Hg) versus 68.9 mm Hg (61.6-70.9 mm Hg). Higher postoperative HR (parameter estimate, 19.4; 95% CI, 7.8-31;Retrospective analysis of continuous physiologic measurements can provide insight into changes in postoperative physiology over time and their relationship with new brain injury. This technique could be applied to assess relationships between physiologic data and many patient interventions or outcomes.

KEY POINTS The application of fetal cardiovascular magnetic resonance imaging (CMR) to assess fetal cardiovascular physiology and cardiac function through the quantification of ventricular volumes has previously been investigated, but the approach has not yet been fully validated. Ventricular output measurements calculated from heart rate and stroke volumes (SV) of the right and left ventricles measured by ventricular volumetry (VV) exhibited a high level of agreement with phase-contrast (PC) blood flow measurements in the main pulmonary artery and ascending aorta, respectively. Ejection fraction of the right ventricle, which is lower than that of the left ventricle in postnatal subjects, was similar to the left ventricular ejection fraction in the fetus; probably due to the different loading conditions present in the fetal circulation. This study provides evidence to support the reliability of VV in the sheep fetus, providing evidence for its use in animal models of human diseases affecting the fetal circulation. ABSTRACT The application of ventricular volumetry (VV) by cardiovascular magnetic resonance imaging (CMR) in the fetus remains challenging due to the small size of the fetal heart and high heart rate. The reliability of this technique in utero has not yet been established. The aim of this study was to assess the feasibility and reliability of VV in a fetal sheep model of human pregnancy. Right and left ventricular outputs by stroke volume (SV) measured using VV were compared with 2D phase-contrast (PC) CMR measurements of blood flow in the main pulmonary artery (MPA) and ascending aorta (AAo). At 124-140 days (d) gestation, singleton bearing Merino ewes underwent CMR under general anaesthesia using fetal femoral artery catheters, implanted at 109-117d, to trigger cine steady state free precession acquisitions of ventricular short-axis stacks. The short-axis cine stacks were segmented at end-systole and end-diastole, yielding right and left ventricular SV, ejection fraction, and cardiac outputs (SV × heart rate). PC cine acquisitions of MPA and AAo were analysed to measure blood flow, which served as comparators for the right and left cardiac outputs by VV. There was good correlation and agreement between VV and PC measures of ventricular outputs with no significant bias (r2 = 0.926; P

The recent demonstration of normal development of preterm sheep in an artificial extrauterine environment has renewed interest in artificial placenta (AP) systems as a potential treatment strategy for extremely preterm human infants. However, the feasibility of translating this technology to the human preterm infant remains unknown. Here we report the support of 13 preterm fetal pigs delivered at 102 ± 4 days (d) gestation, weighing 616 ± 139 g with a circuit consisting of an oxygenator and a centrifugal pump, comparing these results with our previously reported pumpless circuit (n = 12; 98 ± 4 days; 743 ± 350 g). The umbilical vessels were cannulated, and fetuses were supported for 46.4 ± 46.8 h using the pumped AP versus 11 ± 13 h on the pumpless AP circuit. Upon initiation of AP support on the pumped system, we observed supraphysiologic circuit flows, tachycardia, and hypertension, while animals maintained on a pumpless AP circuit exhibited subphysiologic flows. On the pumped AP circuit, there was a progressive decline in umbilical vein (UV) flow and oxygen delivery. We conclude that the addition of a centrifugal pump to the AP circuit improves survival of preterm pigs by augmenting UV flow through the reduction of right ventricular afterload. However, we continued to observe the development of heart failure within a matter of days.

The recent demonstration of normal development of preterm sheep in an artificial extrauterine environment has renewed interest in artificial placenta (AP) systems as a potential treatment strategy for extremely preterm human infants. However, the feasibility of translating this technology to the human preterm infant remains unknown. Here we report the support of 13 preterm fetal pigs delivered at 102±4 days (d) gestation, weighing 616±139g with a circuit consisting of an oxygenator and a centrifugal pump, comparing these results with our previously reported pumpless circuit (n=12; 98±4d; 743±350g). The umbilical vessels were cannulated, and fetuses were supported for 46.4±46.8 hours using the pumped AP versus 11±13 hours on the pumpless AP circuit. Upon initiation of AP support on the pumped system, we observed supraphysiologic circuit flows, tachycardia, and hypertension, while animals maintained on a pumpless AP circuit exhibited subphysiologic flows. On the pumped AP circuit, there was a progressive decline in UV flow and oxygen delivery. We conclude that the addition of a centrifugal pump to the AP circuit improves survival of preterm pigs by augmenting UV flow through the reduction of right ventricular afterload. However, we continued to observe the development of heart failure within a matter of days.

ObjectiveTo test the hypothesis that delayed brain development in fetuses with d-transposition of the great arteries or hypoplastic left heart syndrome heightens their postnatal susceptibility to acquired white matter injury.MethodsThis is a cohort study across 3 sites. Subjects underwent fetal (third trimester) and neonatal preoperative magnetic resonance imaging of the brain to measure total brain volume as a measure of brain maturity and the presence of acquired white matter injury after birth. White matter injury was categorized as no-mild or moderate-severe based on validated grading criteria. Comparisons were made between the injury groups.ResultsA total of 63 subjects were enrolled (d-transposition of the great arteries: 37; hypoplastic left heart syndrome: 26). White matter injury was present in 32.4% (n=12) of d-transposition of the great arteries and 34.6% (n=8) of those with hypoplastic left heart syndrome. Overall total brain volume (taking into account fetal and neonatal scan) was significantly lower in those with postnatal moderate-severe white matter injury compared with no-mild white matter injury after adjusting for age at scan and site in d-transposition of the great arteries (coefficient: 14.8mL, 95% confidence interval, -28.8 to -0.73, P=.04). The rate of change in total brain volume from fetal to postnatal life did not differ by injury group. In hypoplastic left heart syndrome, no association was noted between overall total brain volume and change in total brain volume with postnatal white matter injury.ConclusionsLower total brain volume beginning in late gestation is associated with increased risk of postnatal moderate-severe white matter injury in d-transposition of the great arteries but not hypoplastic left heart syndrome. Rate of brain growth was not a risk factor for white matter injury. The underlying fetal and perinatal physiology has different implications for postnatal risk of white matter injury.

Purpose To test and implement a motion-robust and respiratory-resolved 3D Radial Flow framework that addresses the need for rapid, high resolution imaging in neonatal patients with congenital heart disease. Methods A 4-point velocity encoding and 3D radial trajectory with double-golden angle ordering was combined with bulk motion correction (from projection center of mass) and respiration phase detection (from principal component analysis of heartbeat-averaged data) to create motion-robust 3D velocity cardiac time-averaged data. This framework was tested in a whole-chest digital phantom with simulated bulk and realistic physiological motion. In vivo imaging was performed in 20 congenital heart disease infants under feed-and-sleep with submillimeter isotropic resolution in ~3 min. Flows were validated against clinical 2D PCMRI and whole-heart visualizations of blood flow were performed. Results The proposed framework resolved all simulated digital phantom motion states (mean ± standard error: rotation - azimuthal = 0.29 ± 0.02°; translation - Ty = 1.29 ± 0.12 mm, Tz = -0.27 ± 0.13 mm; rotation+translation - polar = 0.49 ± 0.16°, Tx = -2.47 ± 0.51 mm, Tz = 5.78 ± 1.33 mm). Measured timing errors of peak expiration across all signal-to-noise ratio values were 22% of the true respiratory period (range = [404-489 ± 298-334] ms). For in vivo imaging, motion correction improved 3D Radial Flow measurements (no correction: R2 = 0.62, root mean square error = 0.80 L/min/m2 , Bland-Altman bias [limits of agreement] = -0.21 [-1.40, 0.94] L/min/m2 ; motion corrected, expiration: R2 = 0.90, root mean square error = 0.46 L/min/m2 , bias [limits of agreement] = 0.06 [-0.49, 0.62] L/min/m2 ). Respiratory-resolved 3D velocity visualizations were achieved in various neonatal pathologies pre- and postsurgical correction. Conclusion 3D cardiac flow may be visualized and accurately quantified in neonatal subjects using the proposed framework. This technique may enable more comprehensive hemodynamic studies in small infants.

Background: Brain growth differences are apparent between different types of cyanotic congenital heart disease, but the underlying mechanism remains unclear. Here, we explored and characterized longitudinal cerebral hemodynamic and oxygen metabolism profiles and their relationships to brain growth patterns in infants with single ventricle physiologies (SV) and transposition of the great arteries (TGA). We hypothesized that there are marked differences in cerebral oxygen metabolism in those with SV compared with TGA. Methods: Cerebral blood flow (CBF), oxygen delivery (CDO2) and consumption (CVO2) and brain growth were measured in 103 term newborns with SV and TGA using MRI at pre- and post-surgery and at follow-up. We measured whole brain size by segmenting a 3D steady state free precession acquisition. Cerebral blood flow was measured using phase contrast imaging of the neck vessels and cerebral venous blood oxygen saturation was derived from T2 oximetry of the superior sagittal sinus. TGAs were divided into those with and without ventricular septums. Results: CBF profiles were similar between the 3 lesion groups. Cerebral oxygen delivery trends increased but were not significantly different between cardiac groups. We observed that this may be mediated by different mechanisms: an increase in arterial saturation in TGAs, and an increase in hemoglobin concentration in SVs. Cerebral oxygen consumption in SV infants remained low (p = 0.54) while that of TGA increased over time (TGA IVS p < 0.001; TGA VSD p Conclusions: In conclusion, there are characteristic differences in hemodynamic adaptations between SVs and TGAs. Changes in oxygen metabolism may be facilitating brain growth trajectories. This informs us of possible mechanisms involved during a time of critical brain development.

Objectives The aims of this study were to: i) determine the spectrum of brain injury and ii) compare brain volumes between pre- and postoperative brain MRI in the infants receiving extracorporeal membrane oxygenation compared with those who did not require extracorporeal membrane oxygenation. Design Cohort study of infants with D-transposition of the great arteries or single ventricle physiology. Brain volume (cm) was measured using a segmentation of a volumetric T1-weighted gradient echo sequence. Brain imaging findings (intraventricular hemorrhage, white matter injuries, and stroke) were analyzed with respect to known clinical risk factors for brain injury and adverse neurodevelopmental outcomes. Clinical factors were collected by retrospective chart review. The association between brain volume and extracorporeal membrane oxygenation was evaluated using generalized estimating equations to account for repeated measures. Setting Prospective and single-centered study. Patients One hundred nine infants (median gestational age, 39.1 wk) with D-transposition of the great arteries (n = 77) or single ventricle physiology (n = 32) were studied pre- and postoperatively with MRI as per clinical protocol. Interventions None. Measurements and main results Of the 28 infants (26%) receiving extracorporeal membrane oxygenation, 19 (68%) were supported with extracorporeal membrane oxygenation once, and nine (32%) were supported 2-4 times. On postoperative MRI, new white matter injury was found in only five (17%) of the extracorporeal membrane oxygenation infants versus 40 (49%) in the non-extracorporeal membrane oxygenation group (p = 0.073). The rate of stroke (9% vs 10%), intraventricular hemorrhage (24% vs 29%), and hypoxic ischemia (3% vs 14%) did not differ between the non-extracorporeal membrane oxygenation and extracorporeal membrane oxygenation groups (all p > 0.5). Accounting for D-transposition of the great arteries or single ventricle physiology diagnosis, infants requiring extracorporeal membrane oxygenation had slower brain volume with single (β = -1.67) or multiple extracorporeal membrane oxygenation runs ([β = -6.54]; overall interaction p = 0.012). Conclusions Patients with d-transposition of the great arteries or single ventricle physiology undergoing extracorporeal membrane oxygenation at our center have a similar incidence of brain injury but more significant impairment of perioperative brain volumes than those not requiring extracorporeal membrane oxygenation.

Background: Brain injury, impaired brain growth, and long-term neurodevelopmental problems are common in children with transposition of the great arteries. We sought to identify clinical risk factors for brain injury and poor brain growth in infants with transposition of the great arteries undergoing the arterial switch operation, and to examine their relationship with neurodevelopmental outcome. Methods: The brains of 45 infants with transposition of the great arteries undergoing surgical repair were imaged pre- and postoperatively using magnetic resonance imaging. Brain weight z scores were calculated based on brain volume and autopsy reference data. Brain injury scores were determined as previously described. Neurodevelopment was assessed at 18 months using the Bayley-III scores of infant development. The relationships between clinical variables, brain injury, perioperative brain growth, and 18-month Bayley-III scores were analyzed. Results: On preoperative imaging, moderate or severe white matter injury was present in 10 of 45 patients, whereas stroke was seen in 4 of 45. A similar prevalence of injury was seen on postoperative imaging, and we were unable to identify any clinical risk factors for brain injury. Brain weight z scores decreased perioperatively in 35 of 45 patients. The presence of a ventricular septal defect ( P =0.009) and older age at surgery ( P =0.007) were associated with impaired perioperative brain growth. When patients were divided into those undergoing surgery during the first 2 weeks of life (32/45) versus those being repaired later (13/45), infants repaired later had significantly worse perioperative brain growth (late repair postoperative brain weight z = –1.0±0.90 versus early repair z = –0.33±0.64; P =0.008). Bayley-III testing scores fell within the normal range for all patients, although age at repair ( P =0.03) and days of open chest ( P =0.03) were associated with a lower composite language score, and length of stay was associated with a lower composite cognitive score ( P =0.02). Conclusions: Surgery beyond 2 weeks of age is associated with impaired brain growth and slower language development in infants with transposition of the great arteries cared for at our center. Although the mechanisms underlying this association are still unclear, extended periods of cyanosis and pulmonary overcirculation may adversely impact brain growth and subsequent neurodevelopment.

Objective To investigate preoperative cerebral hemodynamics in newborns with congenital heart disease. We hypothesized that cerebral blood flow and oxygen delivery would be decreased in newborns with congenital heart disease compared with controls. Methods Using a "feed-and-sleep" approach to performing neonatal magnetic resonance imaging, we measured cerebral blood flow by using a slice prescription perpendicular to the right and left internal carotid arteries and basilar artery at the level of the clivus. We calculated brain volume by segmenting a 3-dimensional steady-state free procession acquisition of the whole brain, allowing quantification of cerebral blood flow indexed to brain volume. Cerebral oxygen delivery was calculated as the product of cerebral blood flow and preductal systemic arterial oxygen content obtained via a combination of conventional pulse oximetry and laboratory analysis of venous blood samples for hemoglobin concentration. Results A complete set of measurements were obtained in 32 newborns with heart disease and 31 controls. There was no difference in gestational age between the heart disease and control groups. There was no difference in cerebral blood flow compared with controls (103.5 ± 34.0 vs 119.7 ± 40.4 mL/min), whereas cerebral oxygen delivery was significantly lower in the congenital heart disease subjects (1881 ± 625.7 vs 2712 ± 915.7 mL O2 /min). Ten newborns with congenital heart disease had diffuse excessive high signal intensity in their white matter and 2 had white matter injury whereas another 5 had both. Conclusions Newborns with unrepaired cyanotic congenital heart disease have decreased cerebral oxygen delivery due to arterial desaturation. If brain growth and development are adversely affected through oxygen conformance, our findings could have clinical implications in terms of timing of surgical repair.

Doppler ultrasound measurements of the peak systolic velocity of the middle cerebral artery can be used to noninvasively diagnose fetal anemia but are less precise following fetal blood transfusion and in late gestation. We have previously demonstrated the feasibility of estimating fetal hematocrit in vitro using magnetic resonance imaging relaxation times. Here we report the use of magnetic resonance imaging as a noninvasive tool to accurately detect fetal anemia in vivo.This study has 2 objectives: (1) to determine the feasibility and accuracy of magnetic resonance imaging in estimating hematocrit in anemic fetuses and (2) to compare magnetic resonance imaging and middle cerebral artery Doppler in detecting moderate to severe fetal anemia.Fetuses undergoing fetal blood sampling or transfusion underwent magnetic resonance imaging examinations prior to and following their procedures at 1.5 Tesla (Siemens Avanto). A modified Look-Locker inversion pulse sequence and TTwenty-three fetuses were assessed during 33 magnetic resonance imaging scans. The mean absolute difference between the laboratory and magnetic resonance imaging-estimated hematocrit was 0.06 ± 0.05 with a correlation of 0.77 (P.001) determined by a multilevel, mixed-effects model adjusting for the repeated measurements from the same participants, multiple gestation pregnancies, and the scan type (ie, before or after transfusion scan). Bland-Altman analysis revealed a systematic bias of -0.03 between the magnetic resonance imaging and fetal blood sampling measurements. Magnetic resonance imaging and middle cerebral artery Doppler had similar sensitivities of approximately 90% to detect moderate to severe anemia. However, magnetic resonance imaging had a higher specificity (93% [13/14], 95% confidence interval, 66-100%) than Doppler (71% [10/14], 95% confidence interval, 42-92%).Moderate to severe fetal anemia can be detected noninvasively by magnetic resonance imaging with high sensitivity and specificity. Our results suggest an adjunct role for magnetic resonance imaging in fetuses with suspected anemia, particularly following previous transfusion and in late gestation.

Background Microstructural evidence of white matter (WM) dysmaturation in the brains of newborns with congenital heart disease (CHD) using MRI has been previously shown [1]. Further, delayed WM development confers an increased risk of WM injury before and after neonatal cardiac surgery [2]. WM injury is associated with a high incidence of subsequent neurodevelopmental deficits and fetal interventions to improve brain development in the setting of CHD are currently being investigated. We wished to compare the utility of our previously described parameters in another cohort of CHD newborns, and assess the performance of a new parameter (WM T2 relaxation) for discerning differences in WM maturation.

Background Congenital heart disease (CHD) is associated with in utero brain dysmaturation and abnormal cerebral vasculature [1,2]. Phase contrast (PC) MRI allows non-invasive quantification of cerebral blood flow (CBF) and, combined with arterial oxygen saturation (SaO2) and haemoglobin (Hgb) concentration, can measure cerebral oxygen delivery (CDO2). We hypothesized that CDO2 would be lower in newborns with CHD than normals.