Neonatal persistent pulmonary hypertension related to a novel TBX4 mutation: case report and review of the literature.

TBX4 gene, located on human chromosome 17q23.2, encodes for T-Box Transcription Factor 4, a transcription factor that belongs to the T-box gene family and it is involved in the regulation of some embryonic developmental processes, with a significant impact on respiratory and skeletal illnesses. Herein, we present the case of a female neonate with persistent pulmonary hypertension (PH) who underwent extracorporeal membrane oxygenation (ECMO) on the first day of life and then resulted to have a novel variant of the TBX4 gene identified by Next-Generation Sequencing. We review the available literature about the association between PH with neonatal onset or emerging during the first months of life and mutations of the TBX4 gene, and compare our case to previously reported cases. Of 24 cases described from 2010 to 2023 sixteen (66.7%) presented with PH soon after birth. Skeletal abnormalities have been described in 5 cases (20%). Eleven cases (46%) were due to de novo mutations. Three patients (12%) required ECMO. Identification of this variant in affected individuals has implications for perinatal and postnatal management and genetic counselling. We suggest including TBX4 in genetic studies of neonates with pulmonary hypertension, even in the absence of skeletal abnormalities.

Elevated S100B urine levels predict seizures in infants complicated by perinatal asphyxia and undergoing therapeutic hypothermia.

OBJECTIVES: Seizures (SZ) are one of the main complications occurring in infants undergoing therapeutic hypothermia (TH) due to perinatal asphyxia (PA) and hypoxic ischemic encephalopathy (HIE). Phenobarbital (PB) is the first-line therapeutic strategy, although data on its potential side-effects need elucidation. We investigated whether: i) PB administration in PA-HIE TH-treated infants affects S100B urine levels, and ii) S100B could be a reliable early predictor of SZ. METHODS: We performed a prospective case-control study in 88 PA-HIE TH infants, complicated (n=44) or not (n=44) by SZ requiring PB treatment. S100B urine levels were measured at 11 predetermined monitoring time-points from first void up to 96-h from birth. Standard-of-care monitoring parameters were also recorded. RESULTS: S100B significantly increased in the first 24-h independently from HIE severity in the cases who later developed SZ and requested PB treatment. ROC curve analysis showed that S100B, as SZ predictor, at a cut-off of 2.78 µg/L achieved a sensitivity/specificity of 63 and 84 %, positive/negative predictive values of 83 and 64 %. CONCLUSIONS: The present results offer additional support to the usefulness of S100B as a trustable diagnostic tool in the clinical daily monitoring of therapeutic and pharmacological procedures in infants complicated by PA-HIE.

Perinatal asphyxia does not influence presepsin levels in neonates: A prospective study.

AIM: To compare Presepsin (presepsin) levels in plasma and urine of uninfected newborn infants with perinatal asphyxia with those of controls. METHODS: In this prospective study, we enrolled 25 uninfected full-term infants with perinatal asphyxia and 19 controls. We measured presepsin levels in whole blood or urine. In neonates with perinatal asphyxia, we compared presepsin levels in blood and urine at four time points. RESULTS: In neonates with perinatal asphyxia, blood and urinary presepsin levels matched each other at any time point. At admission, the median presepsin value in blood was similar in both groups (p = 0.74), while urinary levels were higher in hypoxic neonates (p = 0.05). Perinatal asphyxia seemed to increase serum CRP and procalcitonin levels beyond normal cut-off but not those of presepsin. CONCLUSION: In uninfected neonates with perinatal asphyxia, median blood and urinary presepsin levels matched each other at any point in the first 72 h of life and seemed to be slightly affected by the transient renal impairment associated with perinatal hypoxia in the first 12 h of life. Perinatal asphyxia did not influence presepsin levels within the first 72 h of life, while those of CRP and procalcitonin increased.

The role of point-of-care ultrasound in the management of neonates with congenital diaphragmatic hernia.

In the last few years, current evidence has supported the use of point-of-care ultrasound (POCUS) for a number of diagnostic and procedural applications. Considering the valuable information that POCUS can give, we propose a standardized protocol for the management of neonates with a congenital diaphragmatic hernia (CDH-POCUS protocol) in the neonatal intensive care unit. Indeed, POCUS could be a valid tool for the neonatologist through the evaluation of 1) cardiac function and pulmonary hypertension; 2) lung volumes, postoperative pleural effusion or pneumothorax; 3) splanchnic and renal perfusion, malrotations, and/or signs of necrotizing enterocolitis; 4) cerebral perfusion and eventual brain lesions that could contribute to neurodevelopmental impairment. In this article, we discuss the state-of-the-art in neonatal POCUS for which concerns congenital diaphragmatic hernia (CDH), and we provide suggestions to improve its use. IMPACT: This review shows how point-of-care ultrasound (POCUS) could be a valid tool for managing neonates with congenital diaphragmatic hernia (CDH) after birth. Our manuscript underscores the importance of standardized protocols in neonates with CDH. Beyond the well-known role of echocardiography, ultrasound of lungs, splanchnic organs, and brain can be useful. The use of POCUS should be encouraged to improve ventilation strategies, systemic perfusion, and enteral feeding, and to intercept any early signs related to future neurodevelopmental impairment.

A New Pattern of Brain and Cord Gadolinium Enhancement in Molybdenum Cofactor Deficiency: A Case Report.

Molybdenum cofactor deficiency (MoCD) is a rare and severe autosomal recessive in-born error of metabolism caused by the mutation in MOCS1, MOCS2, MOCS3 or GEPH genes, with an incidence ranging between 1 in 100,000 and 200,000 live births. The clinical presentation with seizures, lethargy and neurologic deficits reflects the neurotoxicity mediated via sulphite accumulation, and it occurs within the first hours or days after birth, often leading to severe neurodegeneration and the patient's death within days or months. The Imaging of Choice is a brain-specific MRI technique, which is usually performed without contrast and shows typical radiological findings in the early phase, such as diffuse cerebral oedema and infarction affecting the cortex and the basal ganglia and the white matter, as well as in the late phase, such as multicystic encephalomalacia. Our case report represents a novelty in the field, since the patient underwent a contrast-enhanced MRI to exclude a concomitant infectious disease. In the frame of the clinical presentation and laboratory data, we describe the MoCD Imaging findings for MRI morphological and advanced sequences, presenting a new contrast-enhanced MRI pattern characterized by the diffuse and linear leptomeningeal enhancement of brain, cord and spinal roots. The early identification of molybdenum cofactor deficiency is crucial because it may lead to the best multidisciplinary therapy for the patient, which is focused on the prompt and optimal management of the complications.

Vocal Cord Paralysis and Feeding Difficulties as Early Diagnostic Clues of Congenital Myasthenic Syndrome with Neonatal Onset: A Case Report and Review of Literature.

Herein, we present a newborn female with congenital vocal cord paralysis who required a tracheostomy in the neonatal period. She also presented with feeding difficulties. She was later diagnosed with a clinical picture of congenital myasthenia, associated with three variants of the MUSK gene: the 27-month follow-up was described. In particular, the c.565C>T variant is novel and has never been described in the literature; it causes the insertion of a premature stop codon (p.Arg189Ter) likely leading to a consequent formation of a truncated nonfunctioning protein. We also systematically collected and summarized information on patients' characteristics of previous cases of congenital myasthenia with neonatal onset reported in the literature to date, and we compared them to our case. The literature reported 155 neonatal cases before our case, from 1980 to March 2022. Of 156 neonates with CMS, nine (5.8%) had vocal cord paralysis, whereas 111 (71.2%) had feeding difficulties. Ocular features were evident in 99 infants (63.5%), whereas facial-bulbar symptoms were found in 115 infants (73.7%). In one hundred sixteen infants (74.4%), limbs were involved. Respiratory problems were displayed by 97 infants (62.2%). The combination of congenital stridor, particularly in the presence of an apparently idiopathic bilateral vocal cord paralysis, and poor coordination between sucking and swallowing may indicate an underlying congenital myasthenic syndrome (CMS). Therefore, we suggest testing infants with vocal cord paralysis and feeding difficulties for MUSK and related genes to avoid a late diagnosis of CMS and improve outcomes.

Neurodevelopmental and genetic findings in neonates with intracranial arteriovenous shunts: A case series.

Background: Despite the latest advances in prenatal diagnosis and postnatal embolization procedures, intracranial arteriovenous shunts (AVSs) are still associated with high mortality and morbidity rates. Our aim was to evaluate the presentation and clinical course, the neurodevelopmental outcome, and the genetic findings of neonates with AVSs. Methods: In this retrospective observational study, medical records of neonates with cerebral AVSs admitted to our hospital from January 2020 to July 2022 were revised. In particular, we evaluated neuroimaging characteristics, endovascular treatment, neurophysiological features, neurodevelopmental outcomes, and genetic findings. Results: We described the characteristics of 11 patients with AVSs. Ten infants (90.9%) required embolization during the first three months of life. In 5/9 infants, pathological electroencephalography findings were observed; of them, two patients presented seizures. Eight patients performed Median Nerve Somatosensory Evoked Potentials (MN-SEPs): of them, six had an impaired response. We found normal responses at Visual Evoked Potentials and Brainstem Auditory Evoked Potentials. Eight patients survived (72.7%) and were enrolled in our multidisciplinary follow-up program. Of them, 7/8 completed the Bayley-III Scales at 6 months of corrected age: none of them had cognitive and language delays; conversely, a patient had a moderate delay on the Motor scale. The remaining survivor patient developed cerebral palsy and could not undergo Bayley-III evaluation because of the severe psychomotor delay. From the genetic point of view, we found a novel pathogenic variant in the NOTCH3 gene and three additional genomic defects of uncertain pathogenicity. Conclusion: We propose SEPs as an ancillary test to discern the most vulnerable infants at the bedside, particularly to identify possible future motor impairment in follow-up. The early identification of a cognitive or motor delay is critical to intervene with personalized rehabilitation treatment and minimize future impairment promptly. Furthermore, the correct interpretation of identified genetic variants could provide useful information, but further studies are needed to investigate the role of these variants in the pathogenesis of AVSs.

Predictive Value of MRI in Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is a severe pathology, and no unique predictive biomarker has been identified. Our aims are to identify associations of perinatal and outcome parameters with morphological anomalies and ADC values from MRI. The secondary aims are to define a predictive ADC threshold value and detect ADC value fluctuations between MRIs acquired within 7 days (MR0) and at 1 year (MR1) of birth in relation to perinatal and outcome parameters. METHODS: Fifty-one term children affected by moderate HIE treated with hypothermia and undergoing MRI0 and MRI1 were recruited. Brain MRIs were evaluated through the van Rooij score, while ADC maps were co-registered on a standardized cerebral surface, on which 29 ROIs were drawn. Statistical analysis was performed in Matlab, with the statistical significance value at 0.05. RESULTS: ADC0 < ADC1 in the left and right thalami, left and right frontal white matter, right visual cortex, and the left dentate nucleus of children showing abnormal perinatal and neurodevelopmental parameters. At ROC analysis, the best prognostic ADC cut-off value was 1.535 mm2/s × 10-6 (sensitivity 80%, specificity 86%) in the right frontal white matter. ADC1 > ADC0 in the right visual cortex and left dentate nucleus, positively correlated with multiple abnormal perinatal and neurodevelopmental parameters. The van Rooij score was significantly higher in children presenting with sleep disorders. CONCLUSIONS: ADC values could be used as prognostic biomarkers to predict children's neurodevelopmental outcomes. Further studies are needed to address these crucial topics and validate our results. Early and multidisciplinary perinatal evaluation and the subsequent re-assessment of children are pivotal to identify physical and neuropsychological disorders to guarantee early and tailored therapy.

Maternal-Fetal Infections (Cytomegalovirus, Toxoplasma, Syphilis): Short-Term and Long-Term Neurodevelopmental Outcomes in Children Infected and Uninfected at Birth.

(1) Background: Infections in pregnancy can lead to miscarriage, premature birth, infections in newborns, and developmental disabilities in babies. Infected infants, symptomatic at birth, can have long-term sequelae, and asymptomatic babies are also at increased risk of developing long-term sensorineural outcomes. Targeted therapy of the pregnant mother can reduce fetal and neonatal harm. (2) Aim of the study: To explore the association between symptoms and time of onset of long-term sequelae in infected children born from mothers who contracted an infection during pregnancy, by a long-term multidisciplinary follow-up. (3) Methods: For up to 2−4 years, we evaluated cognitive, motor, audiological, visual, and language outcomes in infants with symptomatic and asymptomatic congenital infections and in uninfected infants. (4) Results: 186 infants born from women who acquired Cytomegalovirus infection (n = 103), Toxoplasma infection (n = 50), and Syphilis (n = 33) during pregnancy were observed. Among them, 119 infants acquired the infection in utero. Infected infants, symptomatic at birth, obtained lower scores on the Cognitive and Motor Scale on Bayley-III compared to asymptomatic and uninfected infants (p = 0.026; p = 0.049). Many severe or moderate sequelae rose up within the first year of life. At 24 months, we observed sequelae in 24.6% (14/57) of infected children classified as asymptomatic at birth, compared to 68.6% (24/35) of symptomatic ones (χ2 = 15.56; p < 0.001); (5) Conclusions: Infected babies symptomatic at birth have a worse prognosis than asymptomatic ones. Long-term sequelae may occur in infected children asymptomatic at birth after the first year of life. Multidisciplinary follow-up until 4−6 years of age should be performed in all infected children, regardless of the presence of symptoms at birth.

Use of Antibiotics in Preterm Newborns.

Due to complex maturational and physiological changes that characterize neonates and affect their response to pharmacological treatments, neonatal pharmacology is different from children and adults and deserves particular attention. Although preterms are usually considered part of the neonatal population, they have physiological and pharmacological hallmarks different from full-terms and, therefore, need specific considerations. Antibiotics are widely used among preterms. In fact, during their stay in neonatal intensive care units (NICUs), invasive procedures, including central catheters for parental nutrition and ventilators for respiratory support, are often sources of microbes and require antimicrobial treatments. Unfortunately, the majority of drugs administered to neonates are off-label due to the lack of clinical studies conducted on this special population. In fact, physiological and ethical concerns represent a huge limit in performing pharmacokinetic (PK) studies on these subjects, since they limit the number and volume of blood sampling. Therapeutic drug monitoring (TDM) is a useful tool that allows dose adjustments aiming to fit plasma concentrations within the therapeutic range and to reach specific drug target attainment. In this review of the last ten years' literature, we performed Pubmed research aiming to summarize the PK aspects for the most used antibiotics in preterms.

Early predictors of abnormal MRI patterns in asphyxiated infants: S100B protein urine levels.

OBJECTIVES: The early detection and stratification of asphyxiated infants at higher risk for impaired neurodevelopment is challenging. S100B protein is a well-established biomarker of brain damage, but lacks conclusive validation according to the "gold standard" methodology for hypoxic-ischemic encephalopathy (HIE) prognostication, i.e. brain MRI. The aim of the present study was to investigate the predictive role of urinary S100B concentrations, assessed in a cohort of HIE infants receiving therapeutic hypothermia (TH), compared to brain MRI. METHODS: Assessment of urine S100B concentrations was performed by immunoluminometric assay at first void and at 4, 8, 12, 16, 20, 24, 48, 72, 96, 108 and 120-h after birth. Neurologic evaluation, routine laboratory parameters, amplitude-integrated electroencephalography, and cerebral ultrasound were performed according to standard protocols. Brain MRI was performed at 7-10 days of life. RESULTS: Overall, 74 HIE neonates receiving TH were included in the study. S100B correlated, already at first void, with the MRI patterns with higher concentrations in infants with the most severe MRI lesions. CONCLUSIONS: High S100B urine levels soon after birth constitute trustable predictors of brain injury as confirmed by MRI. Results support the reliability of S100B in clinical daily practice and open the way to its inclusion in the panel of parameters used for the selection of cases suitable for TH treatment.

From Fetal to Neonatal Neuroimaging in TORCH Infections: A Pictorial Review.

Congenital infections represent a challenging and varied clinical scenario in which the brain is frequently involved. Therefore, fetal and neonatal neuro-imaging plays a pivotal role in reaching an accurate diagnosis and in predicting the clinical outcome. Congenital brain infections are characterized by various clinical manifestations, ranging from nearly asymptomatic diseases to syndromic disorders, often associated with severe neurological symptoms. Brain damage results from the complex interaction among the infectious agent, its specific cellular tropism, and the stage of development of the central nervous system at the time of the maternal infection. Therefore, neuroradiological findings vary widely and are the result of complex events. An early detection is essential to establishing a proper diagnosis and prognosis, and to guarantee an optimal and prompt therapeutic perinatal management. Recently, emerging infective agents (i.e., Zika virus and SARS-CoV2) have been related to possible pre- and perinatal brain damage, thus expanding the spectrum of congenital brain infections. The purpose of this pictorial review is to provide an overview of the current knowledge on fetal and neonatal brain neuroimaging patterns in congenital brain infections used in clinical practice.

Clinical and Neurodevelopmental Characteristics of Enterovirus and Parechovirus Meningitis in Neonates.

Background: Non-polio-enteroviruses (EV) and human parechoviruses (HPeV) are small RNA viruses, which in newborns cause infections with a wide range of severity. Today molecular biology tools allow us to diagnose viral meningitis in neonates, sparing patients from useless antibiotics. Data on neurodevelopmental outcome of children who contract enterovirus meningitis in early childhood are still limited in the literature. Aims: To evaluate the neurodevelopmental outcome of newborns with documented enterovirus and parechovirus meningitis contracted within the first months of life. Methods: Enterovirus and parechovirus were detected on cerebrospinal fluid (CSF) and plasma by RT-PCR. The virological typing was done according to WHO recommendations. During the hospitalization each neonate underwent many diagnostic and instrumental examinations, to evaluate any neurological lesions attributable to the infection. After the discharge children entered in an outpatient interdisciplinary assessment process, comprehensive of the administration of Bayley III scales up to 12 months old. Results: We observed longitudinally 30 children, born at term (mean GA 39.7 ± 0.8 weeks, mean birthweight was 3,457 ± 405 grams), who contracted enterovirus and parechovirus meningitis within the first month of life (mean age at diagnosis was 15.8 ± 7.33 days). We were able to perform the genetic typing only on 15/30 (50.0%) cerebrospinal fluid (CSF) samples from 15 neonates. We found MRI anomalies in 9/26 observed neonates (34.6%): one of them presented brainstem abnormality that are specific of enteroviral central nervous system (CNS) involvement. During the follow up children displayed an overall normal neurodevelopment and no deficit in visual and hearing areas. The mean cognitive (105.19 ± 8.71), speech (100.23 ± 8.22) and motor (97.00 ± 8.98) composite scores, assessed by Bayley III, were normal in 29/30 (96.7%). Despite this, children with pathological brain magnetic resonance imaging (MRI) scored significantly lower (p = 0.01) than children with normal brain MRI on cognitive subscale at 12 months of life. Conclusions: Early enterovirus infections can be associated to brain MRI abnormalities, more frequently the earlier the infection. Although within a normal range, our children with pathological brain MRI scored significantly lower than those with normal brain MRI on cognitive subscale at 12 months of life.

Use of Meropenem and Other Antimicrobial Lock Therapy in the Treatment of Catheter-Related Blood Stream Infections in Neonates: A Retrospective Study.

(1) Background: Newborns admitted to Neonatal Intensive Care Units (NICUs) often require the placement of central vascular catheters (CVC), which are a major risk factor for hospital infection. Numerous strategies exist to prevent central line-associated blood stream infections (CLABSIs) and catheter-related bloodstream infections (CRBSIs), with only a few offering options to save the catheter when it is impossible to replace. CRBSIs continue to be a major problem for neonates in NICUs. Most CRBSIs are resistant to systemic antibiotics due to the presence of intraluminal bacterial biofilm. Therefore, catheter removal is frequently necessary when a CRBSI occurs. The so-called Antibiotic Lock Therapy (ALT) is an antimicrobial therapeutic strategy which seems to be promising in neonates when catheter removal is difficult due to critical conditions. To date, evidence about the use of ALT in the neonatal period is still fragmentary, since only poor and heterogeneous data exist. (2) Methods: We report our successful experience with ALT in seriously ill neonates with CRBSI for whom the replacement of the catheter could have been life threatening. (3) Results: ALT repetitively performed for at least 12 h was effective in 11 out of 13 infants (84.6%). It was not effective in two infants in whom ALT was performed for only 6 h. Moreover, we present new data about the stability testing of meropenem for its use during ALT in neonates. (4) Conclusions: When CRBSI occurs-bearing in mind that the optimal management is catheter removal if antibiotic therapy is not effective within 48 h-ALT seems to be a valid alternative therapy when removal is impractical due to critical conditions.

Increase of Parkin and ATG5 plasmatic levels following perinatal hypoxic-ischemic encephalopathy.

Brain injury at birth is an important cause of neurological and behavioral disorders. Hypoxic-ischemic encephalopathy (HIE) is a critical cerebral event occurring acutely or chronically at birth with high mortality and morbidity in newborns. Therapeutic strategies for the prevention of brain damage are still unknown, and the only medical intervention for newborns with moderate-to-severe HIE is therapeutic hypothermia (TH). Although the neurological outcome depends on the severity of the initial insult, emerging evidence suggests that infants with mild HIE who are not treated with TH have an increased risk for neurodevelopmental impairment; in the current clinical setting, there are no specific or validated biomarkers that can be used to both correlate the severity of the hypoxic insult at birth and monitor the trend in the insult over time. The aim of this work was to examine the presence of autophagic and mitophagic proteins in bodily fluids, to increase knowledge of what, early at birth, can inform therapeutic strategies in the first hours of life. This is a prospective multicentric study carried out from April 2019 to April 2020 in eight third-level neonatal intensive care units. All participants have been subjected to the plasma levels quantification of both Parkin (a protein involved in mitophagy) and ATG5 (involved in autophagy). These findings show that Parkin and ATG5 levels are related to hypoxic-ischemic insult and are reliable also at birth. These observations suggest a great potential diagnostic value for Parkin evaluation in the first 6 h of life.

Neonatal Cerebral Venous Thrombosis following Maternal SARS-CoV-2 Infection in Pregnancy.

A possible consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the development of an exacerbated thrombophilic status, and cerebral venous thrombosis (CVT) is a rare but possible complication of SARS-CoV-2 infection reported both in adults and in children. The present case report describes the clinical course of a term neonate showing extended CVT of unclear origin, whose mother had developed SARS-CoV-2 infection during the third trimester of pregnancy. We speculate that the prothrombotic status induced by maternal SARS-CoV-2 infection may have played a pathophysiological role in the development of such severe neonatal complication. Further investigations are required to confirm such hypothesis.

Incidence of umbilical vein catheter-associated thrombosis of the portal system: A systematic review and meta-analysis.

BACKGROUND: The use of umbilical venous catheters (UVCs) in the perinatal period may be associated with severe complications, including the occurrence of portal vein thrombosis (PVT). AIM: To assess the incidence of UVC-related PVT in infants with postnatal age up to three months. METHODS: A systematic and comprehensive database searching (PubMed, Cochrane Library, Scopus, Web of Science) was performed for studies from 1980 to 2020 (the search was last updated on November 28, 2020). We included in the final analyses all peer-reviewed prospective cohort studies, retrospective cohort studies and case-control studies. The reference lists of included articles were hand-searched to identify additional studies of interest. Studies were considered eligible when they included infants with postnatal age up to three months with UVC-associated PVT. Incidence estimates were pooled by using random effects meta-analyses. The quality of included studies was assessed using the Newcastle-Ottawa scale. The systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. RESULTS: Overall, 16 studies were considered eligible and included in the final analyses. The data confirmed the relevant risk of UVC-related thrombosis. The mean pooled incidence of such condition was 12%, although it varied across studies (0%-49%). In 15/16 studies (94%), diagnosis of thrombosis was made accidentally during routine screening controls, whilst in 1/16 study (6%) targeted imaging assessments were carried out in neonates with clinical concerns for a thrombus. Tip position was investigated by abdominal ultrasound (US) alone in 1/16 (6%) studies, by a combination of radiography and abdominal US in 14/16 (88%) studies and by a combination of radiography, abdominal US and echocardiography in 1/16 (6%) studies. CONCLUSION: To the best of our knowledge, this is the first systematic review specifically investigating the incidence of UVC-related PVT. The use of UVCs requires a high index of suspicion, because its use is significantly associated with PVT. Well-designed prospective studies are required to assess the optimal approach to prevent UVC-related thrombosis of the portal system.

Heart rate variability as possible marker of brain damage in neonates with hypoxic ischemic encephalopathy: a systematic review.

Heart rate variability (HRV) is currently considered the most valuable non-invasive test to investigate the autonomic nervous system function, based on the fact that fast fluctuations might specifically reflect changes of sympathetic and vagal activity. An association between abnormal values of HRV and brain impairment has been reported in the perinatal period, although data are still fragmentary. Considering such association, HRV has been suggested as a possible marker of brain damage also in case of hypoxic-ischemic encephalopathy following perinatal asphyxia. The aim of the present manuscript was to review systematically the current knowledge about the use of HRV as marker of cerebral injury in neonates suffering from hypoxic-ischemic encephalopathy. Findings reported in this paper were based on qualitative analysis of the reviewed data. Conclusion: A growing body of research supports the use of HRV as non-invasive, bedside tool for the monitoring of hypoxic-ischemic encephalopathy. The currently available data about the role of HRV as prognostic tool in case of hypoxic ischemic encephalopathy are promising but require further validation by future studies. What is Known: • Heart rate variability (HRV) is a non-invasive monitoring technique to assess the autonomic nervous system activity. • A correlation between abnormal HRV and cerebral injury has been reported in the perinatal period, and HRV has been suggested as possible marker of brain damage in case of hypoxic-ischemic encephalopathy. What is New: • HRV might provide precocious information about the entity of brain injury in asphyxiated neonates and be of help to design early, specific, and personalized treatments according to severity. • Further investigations are required to confirm these preliminary data.

Early predictors of perinatal brain damage: the role of neurobiomarkers.

The early detection of perinatal brain damage in preterm and term newborns (i.e. intraventricular hemorrhage, periventricular leukomalacia and perinatal asphyxia) still constitute an unsolved issue. To date, despite technological improvement in standard perinatal monitoring procedures, decreasing the incidence of perinatal mortality, the perinatal morbidity pattern has a flat trend. Against this background, the measurement of brain constituents could be particularly useful in the early detection of cases at risk for short-/long-term brain injury. On this scenario, the main European and US international health-care institutions promoted perinatal clinical and experimental neuroprotection research projects aimed at validating and including a panel of biomarkers in the clinical guidelines. Although this is a promising attempt, there are several limitations that do not allow biomarkers to be included in standard monitoring procedures. The main limitations are: (i) the heterogeneity of neurological complications in the perinatal period, (ii) the small cohort sizes, (iii) the lack of multicenter investigations, (iv) the different techniques for neurobiomarkers assessment, (iv) the lack of consensus for the validation of assays in biological fluids such as urine and saliva, and (v), the lack of reference curves according to measurement technique and biological fluid. In the present review we offer an up-to-date overview of the most promising developments in the use of biomarkers in the perinatal period such as calcium binding proteins (S100B protein), vasoactive agents (adrenomedullin), brain biomarkers (activin A, neuron specific enolase, glial fibrillary acidic protein, ubiquitin carboxyl-terminal hydrolase-L1) and oxidative stress markers.