Practice variations for fetal and neonatal congenital heart disease within the Children's Hospitals Neonatal Consortium.

BACKGROUND: Many aspects of care for fetuses and neonates with congenital heart disease (CHD) fall outside standard practice guidelines, leading to the potential for significant variation in clinical care for this vulnerable population. METHODS: We conducted a cross-sectional survey of site sponsors of the Children's Hospitals Neonatal Consortium, a multicenter collaborative of 41 Level IV neonatal intensive care units to assess key areas of clinical practice variability for patients with fetal and neonatal CHD. RESULTS: We received responses from 31 centers. Fetal consult services are shared by neonatology and pediatric cardiology at 70% of centers. Three centers (10%) routinely perform fetal magnetic resonance imaging (MRI) for women with pregnancies complicated by fetal CHD. Genetic testing for CHD patients is routine at 76% of centers. Preoperative brain MRI is standard practice at 5 centers (17%), while cerebral NIRS monitoring is regularly used at 14 centers (48%). Use of electroencephalogram (EEG) after major cardiac surgery is routine in 5 centers (17%). Neurodevelopmental follow-up programs are offered at 30 centers (97%). CONCLUSIONS: Many aspects of fetal and neonatal CHD care are highly variable with evolving shared multidisciplinary models. IMPACT: Many aspects of fetal and neonatal CHD care are highly variable. Genetic testing, placental examination, preoperative neuroimaging, and postoperative EEG monitoring carry a high yield of finding abnormalities in patients with CHD and these tests may contribute to more precise prognostication and improve care. Evidence-based standards for prenatal and postnatal CHD care may decrease inter-center variability.

Placental pathology associated with lenticulostriate vasculopathy (LSV) in preterm infants.

OBJECTIVE: Our aim was to examine the frequency and type of placental abnormalities in neonates with LSV. STUDY DESIGN: We prospectively reviewed cranial ultrasounds (cUS) from neonates born at ≤32 weeks of gestation at Parkland Hospital between 2012 and 2014. Our cohort included neonates with LSV and gestational age and sex matched controls with normal cUS. We retrieved placental pathology reports retrospectively and compared placental abnormalities in both groups. RESULTS: We reviewed 1351 cUS from a total of 407 neonates. Placental pathology evaluations were complete for 64/65 (98%) neonates with LSV and 68/70 (97%) matched controls. There were no significant differences for any type of placental abnormities between LSV and control groups. However, infants with highest stage LSV were more likely to have large for gestational age (LGA) placentas (p = 0.01). CONCLUSION: The association between LSV and LGA placenta may indicate a shared vascular response to an adverse prenatal environment.

Placental pathologic lesions associated with stroke in term neonates.

Objective: To determine the birth prevalence of perinatal stroke in term born infants at our high-volume delivery center and assess the frequency of both gross and histologic placental pathologies associated with perinatal stroke using the Amsterdam Placental Workshop Group Consensus Statement guidelines and definitions. Study Design: A single-center retrospective cohort study spanning 2010-2020. Results: There were 129,759 live births at Parkland Hospital during the study period and a total of 18 term born infants leading to a birth prevalence of 1 in 6,829 infants. Perinatal risk factors were found in all but one patient, and 74% presented with seizures. Pathologic placental examination was available in 56% of the cohort and only one patient had normal placental examination. Acute histologic chorioamnionitis was described in five placentas (50%) and an additional two had isolated umbilical and/or chorionic plate vasculitis with or without funisitis compared to a rate of 28% with acute inflammation in a Control group. Chronic inflammation in the form of villitis of unknown etiology was described in three of the acutely inflamed placentas and was high-grade in each of those while none of the placentas from our Control group showed evidence of any chronic lesion. Conclusion: Both acute and chronic placental inflammation are common in perinatal stroke; placental examination should be considered an essential component to the diagnostic workup.

Placental vascular malperfusion lesions in fetal congenital heart disease.

BACKGROUND: Fetuses with congenital heart disease are at increased risk of perinatal morbidity and mortality, which is highly influenced by their prenatal health. Placental function is vital for the health of the fetus, but increased rates of pathologic lesions of the placenta have been observed in pregnancies complicated by fetal congenital heart disease. OBJECTIVE: This study aimed to determine the prevalence of both gross and histologic placental pathologies in a cohort of pregnancies complicated by fetal congenital heart disease vs healthy controls using the Amsterdam Placental Workshop Group Consensus Statement sampling and definitions of placental lesions. STUDY DESIGN: This single-center retrospective cohort study included placental examinations from pregnancies diagnosed prenatally with fetal congenital heart disease between 2010 and 2019; moreover, control placentas were collected from pregnancies without maternal or fetal complications. Placentas were sampled and evaluated according to the Amsterdam Placental Workshop Group Consensus Statement and gross and histopathologic diagnoses determined. RESULTS: Approximately 80% of fetuses diagnosed with congenital heart disease (n=305) had a placental examination for comparison with controls (n=40). Of note, 239 placentas (78%) in the group with fetal congenital heart disease had at least 1 gross or histopathologic lesion compared with 11 placentas (28%) in the control group (P<.01). One-third of placentas complicated by fetal congenital heart disease met the criteria for small for gestational age, and 48% of placentas had one or more chronic lesions, including maternal vascular malperfusion (23% vs 0%; P<.01), villitis of unknown etiology (22% vs 0%; P<.01), fetal vascular malperfusion (20% vs 0%; P<.01), and other chronic lesions (16% vs 0%; P<.01). Acute inflammation was equally present in both the group with fetal congenital heart disease and the control group (28% vs 28%; P=1.00). Although gestational age and birthweight z score were similar between the 2 groups, birth head circumference was 1.5 cm less in pregnancies complicated by fetal congenital heart disease with a significantly lower z score compared with the control group (-0.52±1.22 vs 0.06±0.69; P<.01). CONCLUSION: Vascular malperfusion lesions and chronic forms of inflammation occur at markedly higher rates in placentas complicated by fetal congenital heart disease, which may contribute to the decreased head circumference at birth. Further work in neuroplacentology is needed to explore connections among cardiac defects, placental vascular malperfusion lesions, and fetal brain development.

Therapeutic Hypothermia in Transport Permits Earlier Treatment Regardless of Transfer Distance.

OBJECTIVE: Therapeutic hypothermia (TH) is currently the only effective therapy available to improve outcomes in neonates with hypoxic-ischemic encephalopathy (HIE) and has maximal effect when initiated within 6 hours of birth. Neonates affected by HIE are commonly born outside of cooling centers and transport is a barrier to timely initiation. In this study, we sought to determine if the initiation of servo-controlled TH in transport allowed neonates to reach target temperature earlier, without a significant delay in the transfer process, for both local and long-distance transport. STUDY DESIGN: In this single-center cohort study of neonates referred to a level IV neonatal intensive care unit for TH, we determined the chronologic age at which target temperature was reached for those cooled in transport. Short-term outcome measures were assessed, including survival, incidence of electrographic seizures, discharge feeding method, and length of hospitalization. RESULTS: In a study population of 85 neonates, those receiving TH during transport (n = 23), achieved target temperature (33-34°C) 77 minutes sooner (230 ± 71 vs. 307 ± 79 minutes of life (MOL); p < 0.001). Locally transported neonates (<15 miles) achieved target temperature 69 minutes earlier (215 ± 48 vs. 284 ± 74 MOL; p < 0.01). TH during long-distance transports allowed neonates to reach target temperature 81 minutes sooner (213 ± 85 vs. 294 ± 79 MOL; p < 0.01). Infants who were cooled in transport discharged 4 days earlier (13.7 ± 8 vs. 17.8 ± 13 days; p = 0.18) and showed a significantly higher rate of oral feeding at discharge (95 vs. 71%; p = 0.03). CONCLUSION: For those starting TH in transport, time to target temperature was decreased. In our cohort, cooling in transport was associated with improved short-term outcomes, although additional studies are needed to correlate these findings with long-term outcomes. KEY POINTS: · Therapeutic hypothermia started during transport allows shorter time to target temperature.. · Transfer was minimally delayed by starting cooling in transport.. · Cooling in transport was associated with increased rate of oral feeding at hospital discharge..

Neuroplacentology in congenital heart disease: placental connections to neurodevelopmental outcomes.

Children with congenital heart disease (CHD) are living longer due to effective medical and surgical management. However, the majority have neurodevelopmental delays or disorders. The role of the placenta in fetal brain development is unclear and is the focus of an emerging field known as neuroplacentology. In this review, we summarize neurodevelopmental outcomes in CHD and their brain imaging correlates both in utero and postnatally. We review differences in the structure and function of the placenta in pregnancies complicated by fetal CHD and introduce the concept of a placental inefficiency phenotype that occurs in severe forms of fetal CHD, characterized by a myriad of pathologies. We propose that in CHD placental dysfunction contributes to decreased fetal cerebral oxygen delivery resulting in poor brain growth, brain abnormalities, and impaired neurodevelopment. We conclude the review with key areas for future research in neuroplacentology in the fetal CHD population, including (1) differences in structure and function of the CHD placenta, (2) modifiable and nonmodifiable factors that impact the hemodynamic balance between placental and cerebral circulations, (3) interventions to improve placental function and protect brain development in utero, and (4) the role of genetic and epigenetic influences on the placenta-heart-brain connection. IMPACT: Neuroplacentology seeks to understand placental connections to fetal brain development. In fetuses with CHD, brain growth abnormalities begin in utero. Placental microstructure as well as perfusion and function are abnormal in fetal CHD.

Wavelet-based neurovascular coupling can predict brain abnormalities in neonatal encephalopathy.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is a leading cause of morbidity and mortality in neonates, but quantitative methods to predict outcomes early in their course of illness remain elusive. Real-time physiologic biomarkers of neurologic injury are needed in order to predict which neonates will benefit from therapies. Neurovascular coupling (NVC) describes the correlation of neural activity with cerebral blood flow, and the degree of impairment could predict those at risk for poor outcomes. OBJECTIVE: To determine if neurovascular coupling (NVC) calculated in the first 24-hours of life based on wavelet transform coherence analysis (WTC) of near-infrared spectroscopy (NIRS) and amplitude-integrated electroencephalography (aEEG) can predict abnormal brain MRI in neonatal HIE. METHODS: WTC analysis was performed between dynamic oscillations of simultaneously recorded aEEG and cerebral tissue oxygen saturation (SctO2) signals for the first 24 h after birth. The squared cross-wavelet coherence, R2, of the time-frequency domain described by the WTC, is a localized correlation coefficient (ranging between 0 and 1) between these two signals in the time-frequency domain. Statistical analysis was based on Monte Carlo simulation with a 95% confidence interval to identify the time-frequency areas from the WTC scalograms. Brain MRI was performed on all neonates and classified as normal or abnormal based on an accepted classification system for HIE. Wavelet metrics of % significant SctO2-aEEG coherence was compared between the normal and abnormal MRI groups. RESULT: This prospective study recruited a total of 36 neonates with HIE. A total of 10 had an abnormal brain MRI while 26 had normal MRI. The analysis showed that the SctO2-aEEG coherence between the group with normal and abnormal MRI were significantly different (p = 0.0007) in a very low-frequency (VLF) range of 0.06-0.2 mHz. Using receiver operating characteristic (ROC) curves, the use of WTC-analysis of NVC had an area under the curve (AUC) of 0.808, and with a cutoff of 10% NVC. Sensitivity was 69%, specificity was 90%, positive predictive value (PPV) was 94%, and negative predictive value (NPV) was 52% for predicting brain injury on MRI. This was superior to the clinical Total Sarnat score (TSS) where AUC was 0.442 with sensitivity 61.5%, specificity 30%, PPV 75%, and NPV 31%. CONCLUSION: NVC is a promising neurophysiological biomarker in neonates with HIE, and in our prospective cohort was superior to the clinical Total Sarnat score for prediction of abnormal brain MRI.

Intravoxel incoherent motion MR imaging analysis for diagnosis of placenta accrete spectrum disorders: A pilot feasibility study.

BACKGROUND: Placenta accreta spectrum (PAS) disorders occur when the placenta adheres abnormally to the uterine myometrium and can have devastating effects on maternal health due to risks of massive postpartum hemorrhage and possible need for emergency hysterectomy. PAS can be difficult to diagnose using routine clinical imaging with ultrasound and structural MRI. OBJECTIVE: To determine feasibility of using intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) analysis in the diagnosis of the placenta accreta spectrum disorders in pregnant women. METHODS: A total of 49 pregnant women were recruited including 14 with pathologically confirmed cases of PAS and 35 health controls without prior cesarean delivery and no suspected PAS by ultrasound. All women underwent diffusion-weighted imaging with an 8 b-value scanning sequence. A semi-automated method for image processing was used, creating a 3D object map, which was then fit to a biexponential signal decay curve for IVIM modeling to determine slow diffusion (Ds), fast diffusion (Df), and perfusion fraction (Pf). RESULTS: Our results demonstrated a high degree of model fitting (R2 ≥ 0.98), with Pf significantly higher in those with PAS compared to healthy controls (0.451 ± 0.019 versus 0.341 ± 0.022, p = 0.002). By contrast, no statistical difference in the Df (1.70 × 10-2 ± 0.38 × 10-2 versus 1.48 × 10-2 ± 0.08 × 10-2 mm2/s, p = 0.211) or Ds (1.34 × 10-3 ± 0.10 × 10-3 versus 1.45 × 10-3 ± 0.007 × 10-3 mm2/s, p = 0.215) was found between subjects with PAS and healthy controls. CONCLUSIONS: The use of MRI, and IVIM modeling in particular, may have potential in aiding in the diagnosis of PAS when other imaging modalities are equivocal. However, the widespread use of these techniques will require generation of large normative data sets, consistent sequencing protocols, and streamlined analysis techniques.

Cerebral Blood Flow Monitoring in High-Risk Fetal and Neonatal Populations.

Cerebrovascular pressure autoregulation promotes stable cerebral blood flow (CBF) across a range of arterial blood pressures. Cerebral autoregulation (CA) is a developmental process that reaches maturity around term gestation and can be monitored prenatally with both Doppler ultrasound and magnetic resonance imaging (MRI) techniques. Postnatally, there are key advantages and limitations to assessing CA with Doppler ultrasound, MRI, and near-infrared spectroscopy. Here we review these CBF monitoring techniques as well as their application to both fetal and neonatal populations at risk of perturbations in CBF. Specifically, we discuss CBF monitoring in fetuses with intrauterine growth restriction, anemia, congenital heart disease, neonates born preterm and those with hypoxic-ischemic encephalopathy. We conclude the review with insights into the future directions in this field with an emphasis on collaborative science and precision medicine approaches.

A retrospective segmentation analysis of placental volume by magnetic resonance imaging from first trimester to term gestation.

BACKGROUND: Abnormalities of the placenta affect 5-7% of pregnancies. Because disturbances in fetal growth are often preceded by dysfunction of the placenta or attenuation of its normal expansion, placental health warrants careful surveillance. There are limited normative data available for placental volume by MRI. OBJECTIVE: To determine normative ranges of placental volume by MRI throughout gestation. MATERIALS AND METHODS: In this cross-sectional retrospective analysis, we reviewed MRI examinations of pregnant females obtained between 2002 and 2017 at a single institution. We performed semi-automated segmentation of the placenta in images obtained in patients with no radiologic evidence of maternal or fetal pathology, using the Philips Intellispace Tumor Tracking Tool. RESULTS: Placental segmentation was performed in 112 women and had a high degree of interrater reliability (single-measure intraclass correlation coefficient =0.978 with 95% confidence interval [CI] 0.956, 0.989; P<0.001). Normative data on placental volume by MRI increased nonlinearly from 6 weeks to 39 weeks of gestation, with wider variability of placental volume at higher gestational age (GA). We fit placental volumetric data to a polynomial curve of third order described as placental volume = -0.02*GA3 + 1.6*GA2 - 13.3*GA + 8.3. Placental volume showed positive correlation with estimated fetal weight (P=0.03) and birth weight (P=0.05). CONCLUSION: This study provides normative placental volume by MRI from early first trimester to term gestation. Deviations in placental volume from normal might prove to be an imaging biomarker of adverse fetal health and neonatal outcome, and further studies are needed to more fully understand this metric. Assessment of placental volume should be considered in all routine fetal MRI examinations.

Cyanosis and Stroke due to Functional Cor Triatriatum Dexter in a Neonate.

Small remnants of the right valve of the sinus venosus are commonly found in adults, but the incidence and risk associated with these embryonic remnants in neonates are not well studied. The following report describes a cyanotic neonate with a large Eustachian valve remnant creating a functional cor triatriatum dexter who was initially diagnosed with persistent pulmonary hypertension of the newborn. The cyanosis in this infant improved over the first postnatal week with conservative management, but she suffered multifocal subcortical stroke, likely related to her intracardiac shunt. The clinical presentation and questions regarding long-term management of this rare diagnosis are explored.

Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke.

BACKGROUND AND PURPOSE: Bryostatin, a potent protein kinase C (PKC) activator, has demonstrated therapeutic efficacy in preclinical models of associative memory, Alzheimer disease, global ischemia, and traumatic brain injury. In this study, we tested the hypothesis that administration of bryostatin provides a therapeutic benefit in reducing brain injury and improving stroke outcome using a clinically relevant model of cerebral ischemia with tissue plasminogen activator reperfusion in aged rats. METHODS: Acute cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery (MCAO) in 18- to 20-month-old female Sprague-Dawley rats using an autologous blood clot with tissue plasminogen activator-mediated reperfusion. Bryostatin was administered at 6 hours post-MCAO, then at 3, 6, 9, 12, 15, and 18 days after MCAO. Functional assessment was conducted at 2, 7, 14, and 21 days after MCAO. Lesion volume and hemispheric swelling/atrophy were performed at 2, 7, and 21 days post-MCAO. Histological assessment of PKC isozymes was performed at 24 hours post-MCAO. RESULTS: Bryostatin-treated rats showed improved survival post-MCAO, especially during the first 4 days. Repeated administration of bryostatin post-MCAO resulted in reduced infarct volume, hemispheric swelling/atrophy, and improved neurological function at 21 days post-MCAO. Changes in αPKC expression and εPKC expression in neurons were noted in bryostatin-treated rats at 24 hours post-MCAO. CONCLUSIONS: Repeated bryostatin administration post-MCAO protected the brain from severe neurological injury post-MCAO. Bryostatin treatment improved survival rate, reduced lesion volume, salvaged tissue in infarcted hemisphere by reducing necrosis and peri-infarct astrogliosis, and improved functional outcome after MCAO.

Worsened outcome from middle cerebral artery occlusion in aged rats receiving 17ß-estradiol.

Although estrogens are neuroprotective in young adult animal models of stroke, clinical trials demonstrate that estrogens increase the incidence and severity of stroke in aged women. We have previously shown that experimental stroke pathophysiology differs between young adult and aged rats. The aim of this study was to determine the effects of 17ß-estradiol after middle cerebral artery occlusion and reperfusion in young adult and aged female rats. Focal embolic stroke was performed by middle cerebral artery occlusion with fibrin clot followed by reperfusion with i.v. human recombinant tissue plasminogen activator. Histological and functional outcomes were measured at 24 h after middle cerebral artery occlusion with fibrin clot. Aged rats treated with 17ß-estradiol had significantly increased infarct volumes compared with placebo-treated aged rats. Young adult rats treated with 17ß-estradiol had significantly decreased infarct volumes and improved functional outcome compared with ovariectomized young adult rats. Our results suggest that 17ß-estradiol may act in an age-dependent manner in the postischemic rat brain. In young adult rats, it is neuroprotective; chronic treatment with 17ß-estradiol during aging leads to worsened ischemic brain injury in aged female rats.

Potential age-dependent effects of estrogen on neural injury.

In 2000, approximately 10 million women were receiving hormone replacement therapy (HRT) for alleviation of menopausal symptoms. A number of prior animal studies suggested that HRT may be neuroprotective and cardioprotective. Then, in 2003, reports from the Women's Health Initiative (WHI) indicated that long-term estrogen/progestin supplementation led to increased incidence of stroke. A second branch of the WHI in women with prior hysterectomy found an even stronger correlation between estrogen supplementation alone and stroke incidence. Follow-up analyses of the data, as well as data from other smaller clinical trials, have also demonstrated increased stroke severity in women receiving HRT or estrogen alone. This review examines the studies indicating that estrogen is neuroprotectant in animal models and explores potential reasons why this may not be true in postmenopausal women. Specifically, age-related differences in estrogen receptors and estrogenic actions in the brain are discussed, with the conclusion that animal models of disease must closely mimic human disease to produce clinically relevant results.