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

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

Complex Trajectories of Brain Development in the Healthy Human Fetus.

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

The Impact of Surgical Patent Ductus Arteriosus Closure on Autonomic Function in Premature Infants.

Background Patent ductus arteriosus (PDA) is a common complication of prematurity and a risk factor for poor outcome. Infants undergoing surgical PDA ligation are at highest risk for neurodevelopmental injury. Autonomic dysfunction has been described in premature infants with PDA. Aim To interrogate the autonomic nervous system by analysis of advanced heart rate variability (HRV) metrics before and after surgical closure of the PDA. Study Design Prospective, observational study. Subjects Twenty-seven infants born before 28 weeks' gestation were included in this study. Methods Continuous electrocardiogram data were sampled at a rate of 125 Hz for a total of 6 hours before and 6 hours after 30 hours of surgical closure. HRV was determined by detrended fluctuation analysis to calculate the short and long root mean square (RMSL and RMSS) and α components at two time scales (long and short). Results Gestational age (GA) was positively associated with RMSL, RMSS, and αS and was negatively associated with αL. There was no difference between RMSs, RMSL, αS, or αL before and after surgery; however, median heart rate was lower after surgery (p < 0.01). Conclusion Advancing GA is highly associated with increasing HRV; however, surgical ligation does not affect HRV in the postoperative period.

Cerebrospinal Fluid and Parenchymal Brain Development and Growth in the Healthy Fetus.

OBJECTIVE: The objective of this study was to apply quantitative magnetic resonance imaging to characterize absolute cerebrospinal fluid (CSF) development, as well as its relative development to fetal brain parenchyma in the healthy human fetus. DESIGN: We created three-dimensional high-resolution reconstructions of the developing brain for healthy fetuses between 18 and 40 weeks' gestation, segmented the parenchymal and CSF spaces, and calculated the volumes for the lateral, third, and fourth ventricles; extra-axial CSF space; and the cerebrum, cerebellum, and brainstem. From these data, we constructed normograms of the resulting volumes according to gestational age and described the relative development of CSF to fetal brain parenchyma. RESULTS: Each CSF space demonstrated major increases in volumetric growth during the second half of gestation: third ventricle (23-fold), extra-axial CSF (11-fold), fourth ventricle (8-fold), and lateral ventricle (2-fold). Total CSF volume was related to total brain volume (p < 0.01), as was lateral ventricle to cerebral volume (p < 0.01); however, the fourth ventricle was not related to cerebellar or brainstem volume (p = 0.18-0.19). RELEVANCE: Abnormalities of the CSF spaces are the most common anomalies of neurologic development detected on fetal screening using neurosonography. Normative values of absolute CSF volume, as well as relative growth in comparison to intracranial parenchyma, provide valuable insight into normal fetal neurodevelopment. These data may provide important biomarkers of early deviations from normal growth, better distinguish between benign variants and early disease, and serve as reference standards for postnatal growth and development in the premature infant.

Baroreflex dysfunction in sick newborns makes heart rate an unreliable surrogate for blood pressure changes.

BACKGROUND: Cerebral pressure passivity (CPP) in sick newborns can be detected by evaluating coupling between mean arterial pressure (MAP) and cerebral blood flow measured by near infra-red spectroscopy hemoglobin difference (HbD). However, continuous MAP monitoring requires invasive catheterization with its inherent risks. We tested whether heart rate (HR) could serve as a reliable surrogate for MAP in the detection of CPP in sick newborns. METHODS: Continuous measurements of MAP, HR, and HbD were made and partitioned into 10-min epochs. Spectral coherence (COH) was computed between MAP and HbD (COHMAP-HbD) to detect CPP, between HR and HbD (COHHR-HbD) for comparison, and between MAP and HR (COHMAP-HR) to quantify baroreflex function (BRF). The agreement between COHMAP-HbD and COHHR-HbD was assessed using ROC analysis. RESULTS: We found poor agreement between COHMAP-HbD and COHHR-HbD in left hemisphere (area under the ROC curve (AUC) 0.68) and right hemisphere (AUC 0.71). Baroreflex failure (COHMAP-HR not significant) was present in 79% of epochs. Confining comparison to epochs with intact BRF showed an AUC of 0.85 for both hemispheres. CONCLUSIONS: In these sick newborns, HR was an unreliable surrogate for MAP required for the detection of CPP. This is likely due to the prevalence of BRF failure in these infants.

Impaired cerebral autoregulation and brain injury in newborns with hypoxic-ischemic encephalopathy treated with hypothermia.

Impaired cerebral autoregulation may contribute to secondary injury in newborns with hypoxic-ischemic encephalopathy (HIE). Continuous, noninvasive assessment of cerebral pressure autoregulation can be achieved with bedside near-infrared spectroscopy (NIRS) and systemic mean arterial blood pressure (MAP) monitoring. This study aimed to evaluate whether impaired cerebral autoregulation measured by NIRS-MAP monitoring during therapeutic hypothermia and rewarming relates to outcome in 36 newborns with HIE. Spectral coherence analysis between NIRS and MAP was used to quantify changes in the duration [pressure passivity index (PPI)] and magnitude (gain) of cerebral autoregulatory impairment. Higher PPI in both cerebral hemispheres and gain in the right hemisphere were associated with neonatal adverse outcomes [death or detectable brain injury by magnetic resonance imaging (MRI), P < 0.001]. NIRS-MAP monitoring of cerebral autoregulation can provide an ongoing physiological biomarker that may help direct care in perinatal brain injury.

Circadian rhythm development in preterm infants. The role of postnatal versus postmenstrual age.

BACKGROUND, AIMS: Circadian rhythm maturation may be disturbed in premature infants undergoing neonatal intensive care. We used continuous heart rate recordings across the entire neonatal intensive care period to study circadian rhythm development in preterm infants and to evaluate the roles of postmenstrual (PMA) versus postnatal age (PNA). MATERIALS AND METHODS: The circadian rhythm was calculated using a cosine fit of heart rate. The circadian rhythm amplitudes were averaged weekly and studied relative to PMA and PNA using the linear mixed effects models, adjusting for clinical variables that could affect the heart rate. The daily circadian rhythms were used to create grand averages for PMA groups: ≤31, 32-35, and > 35 weeks, and for PNA groups: ≤30, 31-60, and > 60 days. RESULTS: Sixty-six infants were evaluated as part of an ongoing prospective study with gestational ages between 23 and 36 weeks. The PMA (1.47 × 10-2 beats per minute (bpm)/week, P = 2.07 × 10-8) and PNA (1.87 × 10-2 bpm/day; P = 1.86 × 10-6) were significantly associated with the circadian rhythm amplitude independent of covariates. Infants ≤31 weeks' PMA and ≤30 days PNA, the phase of circadian rhythm amplitude grand averages showed a peak at night and a nadir during the day. Hereafter the circadian rhythm phase reversed to that established for mature individuals. The highest circadian rhythm amplitudes present >35 weeks' PMA and > 60 days PNA. CONCLUSIONS: Our results indicate circadian rhythm matures with advancing gestation. The reversed circadian rhythm phase during the early postnatal period could be due to premature exposure to the ex-utero environment and warrant further study.

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

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

Measuring intrauterine growth in healthy pregnancies using quantitative magnetic resonance imaging.

OBJECTIVE: The aim of this study was to determine in utero fetal-placental growth patterns using in vivo three-dimensional (3D) quantitative magnetic resonance imaging (qMRI). STUDY DESIGN: Healthy women with singleton pregnancies underwent fetal MRI to measure fetal body, placenta, and amniotic space volumes. The fetal-placental ratio (FPR) was derived using 3D fetal body and placental volumes (PV). Descriptive statistics were used to describe the association of each measurement with increasing gestational age (GA) at MRI. RESULTS: Fifty-eight (58) women underwent fetal MRI between 16 and 38 completed weeks gestation (mean = 28.12 ± 6.33). PV and FPR varied linearly with GA at MRI (rPV,GA = 0.83, rFPR,GA = 0.89, p value < 0.001). Fetal volume varied non-linearly with GA (p value < 0.01). CONCLUSIONS: We describe in-utero growth trajectories of fetal-placental volumes in healthy pregnancies using qMRI. Understanding healthy in utero development can establish normative benchmarks where departures from normal may identify early in utero placental failure prior to the onset of fetal harm.

Placental abnormalities in congenital heart disease.

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.

Cerebral venous volume changes and pressure autoregulation in critically ill infants.

OBJECTIVE: To determine whether ventilator-related fluctuations in cerebral blood volume (CBV) are associated with cerebral pressure passivity. STUDY DESIGN: 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. RESULTS: 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 < 0.001), which was positively associated with brain injury (p < 0.001). CONCLUSION: In sick newborns, ventilator-related CBV fluctuations may predispose to cerebral pressure passivity, which may predispose to an adverse neonatal outcome.

Neuroimaging for Neurodevelopmental Prognostication in High-Risk Neonates.

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.

Non-Invasive Placental Perfusion Imaging in Pregnancies Complicated by Fetal Heart Disease Using Velocity-Selective Arterial Spin Labeled MRI.

The placenta is a vital organ for fetal growth and development during pregnancy. Congenital heart disease (CHD) is a leading cause of morbidity and mortality in newborns. Despite the parallel development of the placenta and fetal heart early in pregnancy, very few studies suggested an association between placental dysfunction and fetal CHD. In this study, we report placental perfusion of healthy pregnancies and pregnancies complicated by fetal CHD measured using advanced fetal MRI techniques. We studied forty-eight pregnant women (31 healthy volunteers and 17 with fetal CHD) that underwent fetal MRI during their second or third trimester of pregnancy. Placental perfusion imaging was performed using velocity-selective arterial spin labeling (VSASL) and 3D image acquisition with whole-placenta coverage. In pregnancies with fetal CHD, global placental perfusion significantly decreased and regional variation of placental perfusion significantly increased with advancing gestational age; however, no such correlation was found in healthy pregnancies. Also, global placental perfusion was significantly higher in fetal CHD versus controls, in the lateral side-lying patient position versus supine, and in the posterior placental position versus anterior placental position. This study reports for the first time non-invasive whole-placenta perfusion imaging in utero. These data suggest that placental VSASL may serve as a potential biomarker of placental dysfunction in fetuses diagnosed with CHD.

Cerebral pressure passivity in newborns with encephalopathy undergoing therapeutic hypothermia.

We extended our recent modification of the power spectral estimation approach to quantify spectral coherence. We tested both the standard and the modified approaches on simulated data, which showed that the modified approach was highly specific and sensitive to the coupling introduced in the simulation while the standard approach lacked these features. We also applied the modified and standard approaches to quantify the pressure passivity in 4 infants receiving therapeutic hypothermia. This was done by measuring the coupling between continuous cerebral hemoglobin differences and mean arterial blood pressure. Our results showed that the modified approach identified a lower pressure passivity index (PPI, percent time the coherence was above a predefined threshold) than the standard approach (P = 0.0027).