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Introduction: Hypoxic-ischemic encephalopathy (HIE) affects 1-2 per 1,000 births and is associated with mortality and long-term neurodevelopmental challenges. At present, therapeutic hypothermia (TH) is the only neuroprotective intervention for these infants. This study examines whether HIE severity, clinical management during TH, and post-rewarming outcomes have changed since its introduction 15 years ago., Methods: Neonatal characteristics, HIE severity, management during TH, and post-rewarming MRI of all infants with HIE undergoing TH between 2008 and 2023 were compared across three five-year epochs. Linear regression was used to estimate annual changes over time., Results: In total, 252 infants underwent TH. Median gestational age (39.5 weeks), birth weight (3,376 g), and time to start TH (4.25 h) remained stable over time. Apgar score at 5 min (p = 0.031) and lowest pH <1 h postpartum (p = 0.020) increased over time. Thompson score at 1-3 h decreased across epochs (p = 0.046). There was an increase in percentage with normal-mild aEEG background patterns on admission (p = 0.041) and a decrease in aEEG-confirmed seizures (p < 0.001) and antiseizure medication (p < 0.001). Inotropic support decreased (p = 0.007), and use of invasive mechanical ventilation decreased over the last 5 years. Mortality (28.6%) and post-rewarming composite adverse outcome (i.e., neonatal mortality and/or adverse MRI score) (37.9%) remained unchanged. Number of infants seen at 2-year follow-up increased (p < 0.001)., Conclusion: Over the last 15 years, we treated more infants with milder HIE, as indicated by lower Thompson and milder aEEG scores, and the need for invasive cardiorespiratory support declined. However, there were no improvements in composite adverse outcome (mortality and/or adverse MRI score)., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Brain injury patterns of preterm infants with perinatal asphyxia (PA) are underreported. We aimed to explore brain magnetic resonance imaging (MRI) findings and associated neurodevelopmental outcomes in these newborns., Methods: Retrospective multicenter study included infants with gestational age (GA) 24.0-36.0 weeks and PA, defined as ≥2 of the following: (1) umbilical cord pH ≤7.0, (2) 5-min Apgar score ≤5, and (3) fetal distress or systemic effects of PA. Findings were compared between GA <28.0 (group 1), 28.0-31.9 (group 2), and 32.0-36.0 weeks (group 3). Early MRI (<36 weeks postmenstrual age or <10 postnatal days) was categorized according to predominant injury pattern, and MRI around term-equivalent age (TEA, 36.0-44.0 weeks and ≥10 postnatal days) using the Kidokoro score. Adverse outcomes included death, cerebral palsy, epilepsy, severe hearing/visual impairment, or neurodevelopment <-1 SD at 18-24 months corrected age., Results: One hundred nineteen infants with early MRI (n = 94) and/or MRI around TEA (n = 66) were included. Early MRI showed predominantly hemorrhagic injury in groups 1 (56%) and 2 (45%), and white matter (WM)/watershed injury in group 3 (43%). Around TEA, WM scores were highest in groups 2 and 3. Deep gray matter (DGM) (aOR 15.0, 95% CI: 3.8-58.9) and hemorrhagic injury on early MRI (aOR 2.5, 95% CI: 1.3-4.6) and Kidokoro WM (aOR 1.3, 95% CI: 1.0-1.6) and DGM sub-scores (aOR 4.8, 95% CI: 1.1-21.7) around TEA were associated with adverse neurodevelopmental outcomes., Conclusion: The brain injury patterns following PA in preterm infants differ across GA. Particularly DGM abnormalities are associated with adverse neurodevelopmental outcomes., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objectives: Corticosteroids are used to prevent or treat lung disease of prematurity. While neurological side effects have been reported, detailed effects on cerebellar growth are unknown. This study aimed to compare cerebellar growth in premature infants who received dexamethasone or hydrocortisone to premature infants who did not receive postnatal corticosteroids., Study Design: Retrospective case-control study in infants born at a gestational age of <29 weeks and admitted to two level 3 neonatal intensive care units. Exclusion criteria were severe congenital anomalies and cerebellar or severe supratentorial lesions. Infants were treated with dexamethasone (unit 1) or hydrocortisone (unit 2) for chronic lung disease. Controls (unit 1) did not receive postnatal corticosteroids. Sequential head circumference (HC) and ultrasound measurements of transcerebellar diameter (TCD), biparietal diameter (BPD), and corpus callosum-fastigium length (CCFL) were performed until 40 weeks' postmenstrual age (PMA). Growth was assessed using linear mixed models correcting for PMA at measurement, sex, HC z-score at birth, and a propensity score indicating illness severity. Group differences before treatment were assessed using linear regression., Results: 346 infants were included (68 dexamethasone, 37 hydrocortisone, 241 controls). Before starting corticosteroids, TCD, BPD, and HC measurements did not differ between patients and controls at a comparable PMA. After starting treatment, both types of corticosteroid had a negative association with TCD growth. BPD, CCFL, and HC growth were not negatively affected., Conclusion: Administration of dexamethasone and hydrocortisone are both associated with impaired cerebellar growth in premature infants without evident negative associations with cerebral growth., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: The brain magnetic resonance imaging (MRI) result is a major predictor for the outcome of term infants with perinatal asphyxia who underwent therapeutic hypothermia. In daily practice, no uniform method is used to assess these images., Purpose: The aim of this study was to determine which MRI-score best predicts adverse outcome at 24 months of age and has the highest inter-rater reliability., Methods: Four MRI scoring systems for term infants with perinatal asphyxia were selected: Rutherford score, Trivedi score, Weeke score, and NICHD NRN score. Experienced blinded raters retrospectively evaluated the brain MR Images of 161 infants using all four scoring systems. Long-term outcome (the composite outcome death or adverse outcome, and its separate components) were routinely assessed by standardized testing at the age of 24 months. The predictive accuracy was assessed by logistic regression analyses and expressed as area under the ROC curve (AUC). The inter-rater reliability of the scores was calculated by the weighted Kappa or intraclass correlation. A sensitivity analysis using only high-quality MRI scans was performed., Results: All four MRI scoring systems demonstrated an AUC of >0.66 for the prediction of adverse outcome and ≥0.80 for the prediction of death. The inter-rater reliability analyses demonstrated the highest reliability for the Weeke and Trivedi scores. When only assessing the high-quality scans, the AUC increased further., Conclusion: All four MRI brain scores proved reliable predictors for an adverse outcome at 24 months of age. The Weeke and Trivedi score demonstrated the highest inter-rater reliability. The use of high-quality MRI further improved prediction., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Introduction: There is large variability in kidney function and injury in neonates with neonatal encephalopathy (NE) treated with therapeutic hypothermia (TH). Acute kidney injury (AKI) definitions that apply categorical approaches may lose valuable information about kidney function in individual patients. Centile serum creatinine (SCr) over postnatal age (PNA) may provide more valuable information in TH neonates., Methods: Data from seven TH neonates and one non-TH-treated, non-NE control cohorts were pooled in a retrospective study. SCr centiles over PNA, and AKI incidence (definition: SCr ↑≥0.3 mg/dL within 48 h, or ↑ ≥1.5 fold vs. the lowest prior SCr within 7 days) and mortality were calculated. Repeated measurement linear models were applied to SCr trends, modeling SCr on PNA, birth weight or gestational age (GA), using heterogeneous autoregressive residual covariance structure and maximum likelihood methods. Findings were compared to patterns in the control cohort., Results: Among 1,136 TH neonates, representing 4,724 SCr observations, SCr (10th-25th-50th-75th-90th-95th) PNA centiles (day 1-10) were generated. In TH neonates, the AKI incidence was 132/1,136 (11.6%), mortality 193/1,136 (17%). AKI neonates had a higher mortality (37.2-14.3%, p < 0.001). Median SCr patterns over PNA were significantly higher in nonsurvivors (p < 0.01) or AKI neonates (p < 0.001). In TH-treated neonates, PNA and GA or birth weight explained SCr variability. Patterns over PNA were significantly higher in TH neonates to controls (801 neonates, 2,779 SCr)., Conclusions: SCr patterns in TH-treated NE neonates are specific. Knowing PNA-related patterns enable clinicians to better assess kidney function and tailor pharmacotherapy, fluids, or kidney supportive therapies., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Retinopathy of prematurity (ROP) remains an important cause for preventable blindness. Aside from gestational age (GA) and birth weight, risk factor assessment can be important for determination of infants at risk of (severe) ROP., Methods: Prospective, multivariable risk-analysis study (NEDROP-2) was conducted, including all infants born in 2017 in the Netherlands considered eligible for ROP screening by pediatricians. Ophthalmologists provided data of screened infants, which were combined with risk factors from the national perinatal database (Perined). Clinical data and potential risk factors were compared to the first national ROP inventory (NEDROP-1, 2009). During the second period, more strict risk factor-based screening inclusion criteria were applied., Results: Of 1,287 eligible infants, 933 (72.5%) were screened for ROP and matched with the Perined data. Any ROP was found in 264 infants (28.3% of screened population, 2009: 21.9%) and severe ROP (sROP) (stage ≥3) in 41 infants (4.4%, 2009: 2.1%). The risk for any ROP is decreased with a higher GA (odds ratio [OR] 0.59 and 95% confidence interval [CI] 0.54-0.66) and increased for small for GA (SGA) (1.73, 1.11-2.62), mechanical ventilation >7 days (2.13, 1.35-3.37) and postnatal corticosteroids (2.57, 1.44-4.66). For sROP, significant factors were GA (OR 0.37 and CI 0.27-0.50), SGA (OR 5.65 and CI 2.17-14.92), postnatal corticosteroids (OR 3.81 and CI 1.72-8.40), and perforated necrotizing enterocolitis (OR 7.55 and CI 2.29-24.48)., Conclusion: In the Netherlands, sROP was diagnosed more frequently since 2009. No new risk factors for ROP were determined in the present study, apart from those already included in the current screening guideline., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Background: Critically ill neonates are at high risk of kidney injury, mainly in the first days of life. Acute kidney injury (AKI) may be underdiagnosed due to lack of a uniform definition. In addition, long-term renal follow-up is limited., Objective: To describe incidence, etiology, and outcome of neonates developing AKI within the first week after birth in a cohort of NICU-admitted neonates between 2008 and 2018. Renal function at discharge in infants with early AKI was assessed., Methods and Subjects: AKI was defined as an absolute serum Cr (sCr) value above 1.5 mg/dL (132 μmol/L) after the first 24 h or as stage 2-3 of the NIDDK neonatal definition. Clinical data and outcomes were collected from medical records and retrospectively analyzed., Results: From January 2008 to December 2018, a total of 9,376 infants were admitted to the NICU of Wilhelmina Children's Hospital/UMC Utrecht, of whom 139 were diagnosed with AKI during the first week after birth. In 72 term infants, the most common etiology was perinatal asphyxia (72.2%), followed by congenital kidney and urinary tract malformations (CAKUT) (8.3%), congenital heart disease (6.9%), and sepsis (2.8%). Associated conditions in 67 preterm infants were medical treatment of a hemodynamic significant PDA (27.2%), -CAKUT (21%), and birth asphyxia (19.4%). Among preterm neonates and neonates with perinatal asphyxia, AKI was mainly diagnosed by the sCr >1.5 mg/dL criterion. Renal function at discharge improved in 76 neonates with AKI associated with acquired conditions. Neonates with stage 3 AKI showed increased sCr values at discharge. Half of these were caused by congenital kidney malformations and evolved into chronic kidney disease (CKD) later in life. Neurodevelopmental outcome (NDO) at 2 years was favorable in 93% of surviving neonates with detailed follow-up., Conclusion: During the first week after birth, AKI was seen in 1.5% of infants admitted to a level III NICU. Renal function at discharge had improved in most neonates with acquired AKI but not in infants diagnosed with stage 3 AKI. Long-term renal function needs further exploration, whereas NDO appears to be good., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Introduction: Prediction of neurodevelopmental outcome in infants with hypoxic-ischemic encephalopathy remains an important challenge. Various studies have shown that the predictive ability of different modalities changed after the introduction of therapeutic hypothermia. This paper reviews the diagnostic test accuracy of the different modalities that are being used to predict neurodevelopmental outcomes following therapeutic hypothermia., Methods: A systematic literature search was performed using Embase and PubMed. Two reviewers independently included eligible studies and extracted data. The quality of the studies was assessed using the Quality in Prognosis Studies Tool. Meta-analyses were performed where possible., Results: Forty-seven articles and 3 conference abstracts were included, reporting on 3,072infants of whom 39% died or had an adverse neurodevelopmental outcome. A meta-analysis could be performed using 37 articles on (amplitude-integrated) electroencephalography (EEG), conventional magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and proton magnetic resonance spectroscopy (1H-MRS). Amplitude-integrated EEG (aEEG) at 24 and 72 h showed similar high diagnostic OR, while aEEG at 6 h and EEG performed less, both due to a low specificity. For MRI, most studies reported scoring systems in which early (<8 days) MRI performed better than late (≥8 days) MRI. Injury to the posterior limb of the internal capsule on MRI or to the thalami on DWI were strong individual predictors, as was an increased lactate/N-acetylaspartate peak on 1H-MRS., Conclusions: In the era of therapeutic hypothermia, the different modalities remain good predictors of neurodevelopmental outcome. However, timing should be taken into account. aEEG may initially be false positive and gets more reliable after 24 h. In contrast, MRI should be used during the first week, as its predictive value decreases afterwards., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Introduction: Neonatal seizures are common and caused by a variety of underlying disorders. There is increasing evidence that neonatal seizures result in further brain damage., Objective: To describe the time interval between diagnosis of amplitude-integrated electroencephalography (aEEG)-confirmed seizures and administration of anti-epileptic drugs (AEDs)., Methods: Single-centre retrospective cohort study, with full-term infants (n = 106) admitted to a level III neonatal intensive care unit between 2012 and 2017 with seizures confirmed on 2-channel aEEG and corresponding raw electroencephalography traces, treated with AEDs. The time interval between the first seizure on the aEEG registration and AED administration was calculated. Factors associated with early treatment were analysed., Results: The median time interval of initiating treatment of aEEG-confirmed seizures was 01:50 h (interquartile range 00:43-4:30 h). Treatment of aEEG-confirmed seizures was initiated <1 h in 34/106 infants (32.1%), between 1 and 2 h in 21/106 infants (19.8%), 2-4 h in 23/106 infants (21.7%), 4-8 h in 14/106 infants (13.2%), and ≥8 h in 14/106 infants (13.2%). Seizures treated <1 h were significantly more often recognized by the seizure detection algorithm (SDA) compared to seizures treated >1 h (67 vs. 42%, p = 0.02) and showed more clinical signs (79.4 vs. 37.5%, p < 0.01). There was no difference for out-of-office hours (23.5 vs. 22.2%, p = 0.88)., Conclusion: With only 32.1% of the seizures being treated <1 h, there is room for improvement. Timely treatment occurred more often when seizures were clinical or recognised by the SDA. aEEG is a helpful tool for diagnosing seizures 24/7., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Introduction: Adverse outcomes have been reported in infants with mild neonatal encephalopathy (NE). Increasing clinical experience with the application of therapeutic hypothermia (TH) may have resulted in the treatment of newborns with milder NE during recent years., Objective: To determine whether infants treated with TH in the initial years following implementation had a higher degree of NE than infants treated during subsequent years., Methods: Infants with NE treated with TH from February 2008 until July 2017 were included. Thompson and Sarnat scores, amplitude-integrated electroencephalography (aEEG) background patterns before the start of TH, and neurodevelopmental outcome at 2 years were compared between infants treated from February 2008 until October 2012 (period 1) and infants treated from November 2012 until July 2017 (period 2)., Results: 211 newborns with NE were treated with TH (period 1: n = 109, period 2: n = 102). Sarnat scores in period 1 and 2 were mild in 7.3 vs. 28.4%, moderate in 66.1 vs. 44.1%, and severe in 26.6 vs. 22.5%, respectively (p = 0.008). Thompson scores were lower in period 2 (median = 9, IQR 7-12) than in period 1 (median = 10, IQR 8.5-13.5, p = 0.018). The aEEGs and neurodevelopmental outcomes were comparable between the periods., Conclusions: Based on Thompson and Sarnat scores, but not aEEG background patterns, infants treated during the second period had milder NE than infants treated during the first years following implementation of TH. There was no difference in 2 years neurodevelopmental outcome. Further research is necessary to evaluate the value of TH for infants with clinically mild NE., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Background: Autopsy rates in neonatal intensive care unit (NICU) patients who died are declining worldwide. Postmortem magnetic resonance imaging (MRI) is suggested as adjunct to or substitute for autopsy., Objective: The aim of this paper was to determine the additional diagnostic value of autopsy in NICU patients and whether autopsy findings were potentially detectable using postmortem MRI., Methods: From 2008 to 2015, 298 infants died during admission to our NICU. Permission for unrestricted, nonforensic autopsy was obtained in 100 (33.6%) of these 298 infants. Retrospectively, autopsy reports and medical records of NICU patients were compared. Additional autopsy findings were graded according to the Goldman system, grading the clinical relevance of additional findings. In addition, the potential detectability of these additional findings on postmortem MRI was assessed., Results: Additional findings obtained by autopsy were found in 48% of the cases, divided into major (Goldman I/II, 24%) and minor (Goldman III/IV, 24%) additional findings. Major additional findings were significantly more often found in patients with a lower gestational age, and minor additional findings in patients with a higher postnatal age at death. Of all patients with additional findings determined by autopsy, 56.3% would most likely not have been detected using postmortem MRI., Conclusions: Our results emphasize the still very important role of autopsy in the NICU setting and show that conventional autopsy could probably not be completely substituted by postmortem MRI., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Background: Preterm infants show a decreased tortuosity in all proximal segments of the cerebral vasculature at term-equivalent age (TEA). Recently MRI techniques were developed to measure cerebral blood flow (CBF) based on phase-contrast images., Objectives: We hypothesized that arterial CBF corrected for brain size differs between full-term and preterm infants at TEA., Methods: 344 infants without major brain abnormalities had a cranial MRI for clinical reasons including phase-contrast magnetic resonance angiography (PC-MRA) around TEA (mean 41.1 ± SD 1.2 weeks). This cohort consisted of 172 preterm infants (gestational age at birth 24.1-31.9 weeks) and 172 term-born infants (gestational age at birth 37.0-42.6 weeks). The total CBF in milliliters/minute was calculated by adding the blood flow of the carotid and basilar arteries, and compared to age at scan, body weight, and several parameters of estimated brain size., Results: After logarithmic transformation, total CBF was associated with body weight, estimated brain weight, head circumference, and 2D brain surface measurements at TEA. Total CBF was significantly (9-12%) higher in term compared to preterm infants after correction for 2D brain surface measurements, head circumference or postmenstrual age at MRI (p < 0.05)., Conclusions: Total CBF as measured by PC-MRA was associated with body and (estimated) brain weight and 2D brain surface measurements and was higher in term compared to preterm born infants., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Background: Animal models suggest that neuroprotective effects of therapeutic hypothermia (TH) after perinatal asphyxia are reduced in infants with early-onset sepsis., Objectives: To assess the outcome of infants with perinatal asphyxia, neonatal encephalopathy, and TH in the presence of early-onset sepsis., Methods: In a retrospective cohort of 1,084 infants with perinatal asphyxia and TH, the outcome of 42 infants (gestational age 36.1-42.6 weeks and birth weight 2,280-5,240 g) with proven sepsis (n = 14) and probable sepsis (n = 28) was analyzed. Death, cerebral palsy, or a delayed development at 2 years was considered an adverse outcome., Results: Sepsis was caused mostly by group B streptococci (n = 17), other Gram-positive bacteria (n = 5), and Candida albicans (n = 1). Of the 42 infants, 9 (21.4%) died, and 5 (11.9%) showed impairments on follow-up. The outcome is comparable to the previously reported outcome of infants with TH without early-onset sepsis., Conclusion: A good outcome was reported in the majority of infants with perinatal asphyxia, TH, and early-onset sepsis. Cooling should not be withheld from these infants., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Background: Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance., Objectives: To assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines., Methods: Data were collected in the prospective multicentre PharmaCool study. In the present study, neonates treated with therapeutic hypothermia and receiving midazolam and/or phenobarbital were included. Plasma concentrations of phenobarbital and midazolam including its metabolites were determined in blood samples drawn on days 2-5 after birth. Pharmacokinetic analyses were performed using non-linear mixed effects modelling; clinical effectiveness was defined as no use of additional anti-epileptic drugs., Results: Data were available from 113 (phenobarbital) and 118 (midazolam) neonates; 68 were treated with both medications. Only clearance of 1-hydroxy midazolam was influenced by hypothermia. Phenobarbital co-administration increased midazolam clearance by a factor 2.3 (95% CI 1.9-2.9, p < 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam., Conclusions: Therapeutic hypothermia does not influence clearance of phenobarbital or midazolam in (near-)term neonates with hypoxic-ischaemic encephalopathy. A phenobarbital dose of 30 mg/kg is advised to reach therapeutic concentrations. Phenobarbital co-administration significantly increased midazolam clearance. Should phenobarbital be substituted by non-CYP3A inducers as first-line anticonvulsant, a 50% lower midazolam maintenance dose might be appropriate to avoid excessive exposure during the first days after birth., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Objective: The aim of this study was to evaluate whether a new MRI scoring system for preterm non-haemorrhagic white matter injury (WMI), derived from the analysis of the natural evolution of WMI throughout the neonatal period until term-equivalent age, can be used for outcome prediction., Methods: Eighty-two infants <36 weeks gestation with WMI diagnosed from sequential cranial ultrasound and confirmed on neonatal MRI were retrospectively included. WMI was classified in four grades of severity. Neurodevelopmental data at a median age of 24 months were analysed., Results: In 74 surviving children WMI severity was strongly associated with the presence and severity of cerebral palsy (CP) and other neurodevelopmental impairments (Spearman's rank correlation 0.88, p < 0.001). Only 3 children with grade I WMI (9%) developed CP (all ambulant) and their developmental scores were not different to those from the controls, although they started walking significantly later (p = 0.036). Of the 6 children with grade II, 83% developed CP (mild in most), whereas 91% of the 34 children with grade III had CP (moderate-severe in 76%) and all had some degree of neurodevelopmental impairment. Three children with grade III WMI did not develop CP; their imaging showed, in contrast to children who developed CP, that the cysts did not affect the corticospinal tracts; also, myelin in the posterior limb of the internal capsule appeared normal in 2 children and suboptimal in 1., Conclusions: This MRI scoring system for preterm WMI can be used to predict neurodevelopmental outcomes. Individualized assessment of the site of lesions and the progression of myelination improves prognostic accuracy., (© 2019 S. Karger AG, Basel.)

Background: Magnetic resonance imaging (MRI) is the standard neuroimaging technique to assess perinatal asphyxia-associated brain injury in full-term infants. Diffusion-weighted imaging (DWI) is most informative when assessed during the first week after the insult., Objectives: To study the DWI abnormalities of the thalamus and basal ganglia in full-term infants with perinatal asphyxia., Methods: Fifty-five (near) term infants (normothermia n = 23; hypothermia n = 32) with thalamus and/or basal ganglia injury were included. MRI findings were assessed visually and quantitatively calculating apparent diffusion coefficient (ADC) values. Thalamus/basal ganglia ADC ratios were calculated to analyze the differences between these areas. Infants with an early MRI (days 1-3) or later MRI (days 4-7) were compared., Results: Isolated extensive thalamic injury was seen early, and focal thalamic and basal ganglia injury was seen later. On the early MRI, visual assessment underestimated abnormalities in the basal ganglia (59% abnormal vs. 90% abnormal on quantitative assessment; p = 0.015), suggesting the need for quantitative assessment. In infants treated with hypothermia, the thalamus/basal ganglia ADC ratio was lower., Conclusions: Both visual analysis and quantitative evaluation of cerebral MRI after perinatal asphyxia are needed, especially during the first few days after birth. Timing of ADC changes is influenced by therapeutic hypothermia., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Background: In previous studies clinical signs or amplitude-integrated electroencephalography (aEEG)-based signs of encephalopathy were used to select infants with perinatal asphyxia for treatment with hypothermia., Aim: The objective of this study was to compare Thompson encephalopathy scores and aEEG, and relate both to outcome., Subjects and Methods: Thompson scores, aEEG, and outcome were compared in 122 infants with perinatal asphyxia and therapeutic hypothermia. Of these 122 infants, 41 died and 7 had an adverse neurodevelopmental outcome. A receiver operating characteristics (ROC) analysis was also performed., Results: Thompson scores were higher in infants with more abnormal aEEG background patterns (ANOVA, p < 0.001). The ROC analysis demonstrated that a Thompson score of 11 or higher or an aEEG background pattern of continuous low voltage or worse was associated with an adverse outcome (AUC 0.84 for both)., Conclusions: High Thompson scores and a suppressed aEEG background pattern are associated with an adverse outcome after perinatal asphyxia and therapeutic hypothermia. Further studies are needed to identify the best technique with which to select patients for therapeutic hypothermia., (© 2017 The Author(s) Published by S. Karger AG, Basel.)

Background: Very preterm infants often show germinal matrix-intraventricular hemorrhage (GMH-IVH) on cranial ultrasound (cUS)., Aim: To determine the impact of low-grade GMH-IVH on early neurodevelopmental outcome in very preterm infants., Methods: A retrospective case-control study in very preterm infants with and without low-grade GMH-IVH on cUS. Additional magnetic resonance imaging (MRI) was available in all infants with a gestational age (GA) <28 weeks and high-risk infants >28 weeks. Infants were seen at 2 years' corrected age to assess neurodevelopment., Results: In total, 136 infants (GA 24-32 weeks) with low-grade GMH-IVH on cUS were matched with 255 controls. Outcome data was available for 342 (87%) infants. Adverse outcome (i.e., cerebral palsy [CP], neurodevelopmental delay) was present in 11 (9%) cases and 20 (9%) controls. No statistically significant differences in outcome were found between cases and controls. Additional MRI was performed in 165/391 infants (42%) and showed additional lesions in 73 (44%) infants that could explain subsequent development of CP in 2 out of 5 infants and epilepsy in 1 of 2 infants., Conclusion: Very preterm infants with low-grade GMH-IVH on cUS have a similar early neurodevelopmental outcome compared with controls. Additional MRI showed mostly subtle abnormalities that were missed with cUS, but these could not explain subsequent development of CP and developmental delay in all infants., (© 2017 S. Karger AG, Basel.)

Objective: Cranial magnetic resonance imaging (MRI) is associated with neurodevelopmental outcome in full-term infants with neonatal encephalopathy (NE) following presumed perinatal asphyxia. The aim of this study is to relate 2-dimensional measurements of the basal ganglia and thalami (BGT) and cerebellum in the first week after birth and after 3 months with neurodevelopmental outcome at 18 months., Methods: Retrospectively, 29 full-term infants with NE following presumed perinatal asphyxia who had a cranial MRI in the first week after birth were studied serially. One- and 2-dimensional measurements were obtained and related to different patterns of brain injury, and neurodevelopmental outcome at 18 months. A Griffiths developmental quotient <85 or cerebral palsy was considered adverse., Results: On the first MRI, the adverse outcome group showed increased basal ganglia width (42.1 ± 0.1 vs. 40.3 ± 0.3 mm, p < 0.001), thalamic width (40.3 ± 0.1 vs. 39.3 ± 1.0 mm, p < 0.001), and basal ganglia surface (1,230 ± 21 vs. 1,199 ± 36 mm2, p = 0.007) compared to the favorable outcome group. In the BGT lesions group, basal ganglia width and thalamic width were increased compared to the watershed infarction group (42.1 ± 0.1 vs. 40.9 ± 0.8 mm, p < 0.001, and 40.3 ± 0.1 vs. 39.9 ± 0.5 mm, p = 0.01, respectively). On the second MRI, cerebellar width was larger in the favorable outcome group (p = 0.025). There was a greater increase in dimensions between both MRI time points for basal ganglia width (p = 0.014), basal ganglia surface (p = 0.028) and thalamic width (p = 0.012) in the favorable outcome group., Conclusions: One- and 2-dimensional measurements for basal ganglia surface, BGT width and cerebellar width are associated with neurodevelopmental outcome at 18 months., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

Background and Objective: Severe neonatal anaemia can impair cerebral oxygen supply. Data on long-term outcomes following severe neonatal anaemia are scarce., Methods: Clinical data and neurodevelopmental outcome of 49 (near) term infants with haemoglobin concentration after birth <6.0 mmol/l were retrospectively collected and analysed. In a subgroup of 28 patients, amplitude-integrated EEG was available and in 25 infants cerebral MRI was obtained. Infants were followed up at 14-35 months of age and assessed with the Griffiths Scale of Mental Development or Bayley Scale of Infant Development., Results: Eighteen patients (37%) died during the neonatal period. In 25 patients MRI was performed. A predominant pattern of injury on MRI was seen in the basal ganglia and thalami in 7 patients (28%), whereas some form of white matter injury was present in 16 (64%) and a combination in 3 (12%). Follow-up data were available for 26 patients (84% of survivors). Formal assessment of neurodevelopmental outcome was performed in 20 of 31 (65%) infants who survived (median age: 19 months, range: 14-35). Sixteen infants (80%) had a developmental quotient appropriate for age in the first 2 years after birth. On motor outcome, 1 patient (5%) scored below average (Z-score -1.10). One patient developed cerebral palsy., Conclusion: Early neurodevelopmental outcome in surviving patients with severe neonatal anaemia was within the normal range in the majority of the survivors. MRI showed mild-to-moderate white matter injury in two thirds of the infants. Prospectively collected data with a longer follow-up period are needed., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

Background: Midazolam is used as an anticonvulsant in neonatology, including newborns with perinatal asphyxia treated with hypothermia. Hypothermia may affect the safety and effectiveness of midazolam in these patients., Objectives: The objective was to evaluate the anticonvulsant effectiveness and hemodynamic safety of midazolam in hypothermic newborns and to provide dosing guidance., Methods: Hypothermic newborns with perinatal asphyxia and treated with midazolam were included. Effectiveness was studied using continuous amplitude-integrated electroencephalography. Hemodynamic safety was assessed using pharmacokinetic-pharmacodynamic modeling with plasma samples and blood pressure recordings (mean arterial blood pressure) under hypothermia., Results: No effect of therapeutic hypothermia on pharmacokinetics could be identified. Add-on seizure control with midazolam was limited (23% seizure control). An inverse relationship between the midazolam plasma concentration and mean arterial blood pressure could be identified. At least one hypotensive episode was experienced in 64%. The concomitant use of inotropes decreased midazolam clearance by 33%., Conclusions: Under therapeutic hypothermia, midazolam has limited add-on clinical anticonvulsant effectiveness after phenobarbital administration. Due to occurrence of hypotension requiring inotropic support, midazolam is less suitable as a second-line anticonvulsant drug under hypothermia., (© 2015 S. Karger AG, Basel.)

Background: The perfusion index (PI) derived from pulse oximetry readings represents the ratio of pulsatile (arterial blood) and nonpulsatile contributors to infrared light absorption. PI has been shown to correlate with cardiac performance. In theory, PI is readily available on every pulse oximeter; therefore, no additional sensors or infant handling are required. Currently, reference values are lacking in (preterm) neonates and the association with common clinical conditions is unclear., Objectives: To establish reference values for the PI in premature infants and at the same time determine the influence of common clinical conditions., Methods: PI was prospectively monitored on the lower limb for 72 h in 311 neonates born with a gestational age <32 weeks between January 2011 and December 2013. Longitudinal mixed-effects modeling was used. Linear, quadratic, and cubic models were explored. Main effects and interactions were investigated., Results: A squared model (0-24 h) followed by a linear model (24-72 h) provided the best fit of the data. PI was lowest around 12-18 h after birth and showed a steady increase thereafter. PI was positively related with female gender, gestational age, and pulse pressure. Negative associations were found with SIMV/HFOV ventilation, dopamine administration, mean arterial blood pressure, and arterial oxygen saturation. Although more complex, the general association with a patent ductus arteriosus was positive., Conclusion: PI varied according to several clinical conditions. The association with common clinical factors suggests that PI might be used for monitoring neonatal hemodynamics and possibly as an additional guidance for interventions., (© 2015 S. Karger AG, Basel.)

Background: Congenital cytomegalovirus (cCMV) infection early in pregnancy may result in major disabilities. Cerebral abnormalities detected using cranial ultrasound (cUS) and magnetic resonance imaging (MRI) have been related to neurological sequelae., Objective: To evaluate the additional value of MRI and assess the relationship between time of infection during pregnancy and outcome in infants with cCMV infection., Methods and Study Design: Demographic and clinical data were collected in infants with cCMV infection (1992-2013). Trimester of infection, neuro-imaging results and outcome were reviewed. Cerebral abnormalities were categorized into none, mild (lenticulostriate vasculopathy, germinolytic cysts, high signal intensity on T2-weighted images) and severe (migrational disorder, ventriculomegaly, cerebellar hypoplasia). Results were statistically analysed., Results: Thirty-six infants were eligible for analysis. cUS was performed in all and cranial MRI in 20 infants. Migrational disorders were only diagnosed using MRI (p < 0.01). In 17 infants trimester of infection was ascertained. Seven out of 10 infants infected during the first trimester had severe abnormalities on cUS (5 confirmed on MRI) and adverse sequelae; 3 had no/mild abnormalities on cUS/MRI and normal outcome. Two out of 3 infants infected during the second trimester with no/mild abnormalities on cUS/MRI had normal outcome; 1 with mild cUS and MRI abnormalities developed sensorineural hearing loss. Four infants infected during the third trimester with no/mild abnormalities on cUS/MRI had normal outcome., Conclusion: Infants with a first trimester cCMV infection are most at risk of severe cerebral abnormalities and neurological sequelae. MRI, and not cUS, enables an early diagnosis of migrational disorders, which can improve prediction of outcome., (© 2015 S. Karger AG, Basel.)

Germinal matrix-intraventricular haemorrhage (GMH-IVH) remains a serious problem in the very and extremely preterm infant. This article reviews current methods of diagnosis, treatment and neurodevelopmental outcome in preterm infants with low-grade and severe GMH-IVH. We conclude that there is still no consensus on timing of intervention and treatment of infants with GMH-IVH, whether or not complicated by post-haemorrhagic ventricular dilatation. The discrepancies between the studies underline the need for international collaboration to define the optimal strategy for these infants.

Background: Therapeutic hypothermia was introduced in the Netherlands and Flanders, Belgium, in 2008. Since then, an increasing number of patients has been treated - up to 166 in 2010. Complications and outcome were registered in an online database., Objectives: The aim of this study was to analyse complications and outcome after implementation., Methods: Data were retrieved from an online database to which all centres had contributed., Results: In 3 years, 332 patients were treated. Excluding 24 patients with congenital abnormalities or metabolic disorders, mortality was 31.8%. Of the 210 survivors without congenital malformations, 21 had cerebral palsy, another 19 a developmental delay of more than 3 months at the age of at least 24 months, and 2 had severe hearing loss. The total adverse outcome, combining death and adverse neurodevelopment, in 308 patients without congenital malformations is 45.5%, which is similar to that of the large trials., Conclusions: The introduction of therapeutic hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders has been rapid and successful, with results similar to findings in the randomised controlled trials., (Copyright © 2013 S. Karger AG, Basel.)

Background: Detection of white matter (WM) abnormalities on MRI is important regarding the neurodevelopmental outcome in preterm infants. The long-term neurodevelopmental outcome of preterm infants with postnatal cytomegalovirus (CMV) infection has not been studied extensively., Objectives: We aimed to assess WM microstructure in preterm infants with postnatal CMV infection using diffusion tensor imaging., Methods: Infants <32 weeks' gestational age (GA) admitted to our hospital between 2007 and 2010, who had cerebral diffusion tensor imaging at term-equivalent age (40 weeks' GA) were included. CMV PCR in urine collected at term-equivalent age was performed to diagnose postnatal CMV infection. Congenital infection was excluded. In the frontal, parietal and occipital WM mean diffusivity, fractional anisotropy (FA), radial and axial diffusivity were calculated. Neurodevelopmental outcome was assessed at 16 months' corrected age using Griffiths' Mental Developmental Scales., Results: Twenty-one postnatally infected and 61 noninfected infants were eligible. Both groups were comparable regarding GA, birth weight and age at MRI. There was a significant difference in median FA of the occipital WM between infected and noninfected infants (0.13 [IQR 0.11-0.16] versus 0.16 [IQR 0.14-0.18], p = 0.002). There were no differences in short-term neurodevelopmental outcome between infected and noninfected infants., Conclusions: A significantly reduced FA suggests microstructural changes in the occipital WM of postnatally infected infants. These microstructural changes do not appear to result in impaired neurodevelopmental outcome at 16 months' corrected age., (Copyright © 2013 S. Karger AG, Basel.)

Background: We hypothesized that color Doppler-measured cerebral blood flow velocity (CD-CBFV) as measured in the three feeding arteries of the brain can be used as an estimator of global cerebral blood flow., Patients and Methods: CD-CBFV was determined as soon as possible after determination of phase-contrast magnetic resonance angiography-measured blood volume flow (PC-MRA BVF) by adding up angle-corrected time-averaged mean flow velocities of both internal carotid arteries and basilar artery. 30 newborns (gestational age ranging from 25 to 42 weeks; actual weight ranging from 1,050 to 5,858 g; postconceptional age ranging from 225 to 369 days) were investigated., Results: Doppler-determined CBFV ranged from 37 to 131 cm/s with a median of 69 cm/s. CD-CBFV showed a positive correlation with actual weight (r = 0.56, p < 0.01) and postconceptional age (r = 0.53, p < 0.01). CD-CBFV correlated positively with PC-MRA-measured BVF (r = 0.51, p < 0.01). Gestational age at birth, mechanical ventilation or gender did not influence this relationship. The limits of agreement, however, are wide, especially at higher CD-CBFV- and PC-MRA-measured BVF., Conclusion: CD-CBFV may be used as a non-invasive trend-monitoring tool to detect gross changes in global cerebral blood flow in the unstable and sick neonate., (Copyright © 2012 S. Karger AG, Basel.)

Background: Preterm infants with progressive post-hemorrhagic ventricular dilatation (PHVD) in the absence of associated parenchymal lesions may have a normal neurodevelopmental outcome., Objectives: To evaluate neurodevelopmental and cognitive outcomes among preterm infants with severe intraventricular hemorrhage (IVH) and PHVD requiring neurosurgical intervention., Methods: 32 preterm infants were admitted to a neonatal intensive care unit with PHVD requiring neurosurgical intervention, and were seen in the follow-up clinic for standardized cognitive, behavioral and neurological assessments between 5 and 8 years of age. Only preterm infants with a gestational age (GA) of <30 weeks, as well as preterm and full-term infants with PHVD and full-term infants with perinatal asphyxia are seen in our follow-up clinic at this age. There were 23 infants with a GA of <30 weeks in this study population. For these 23, matched controls were available and compared with the IVH group., Results: The majority (59.4%) had no impairments. None of the children with grade III and 8 of the 15 children (53%) with grade IV hemorrhage developed cerebral palsy. More subtle motor problems assessed with the Movement-ABC score were seen in 39% (n = 9); the mean IQ of all children was 93.4, and 29% of the children had an IQ of <85 (-1 SD). Timing of intervention did not have a beneficial effect on outcome. With respect to cognition, no significant differences were found between the IVH and the control group., Conclusion: The majority of the children in our population had no impairments. Cerebral palsy was not seen in any of the infants with a grade III hemorrhage., (Copyright © 2011 S. Karger AG, Basel.)

Perinatal hypoxia-ischemia or birth asphyxia is a serious complication with a high mortality and morbidity. For decades, neuroprotective options have been explored to reduce reperfusion and reoxygenation injury to the brain, which accounts for a substantial part of birth asphyxia-related brain damage. In this review, we focus on neuroprotective strategies with a long-term follow-up, reported in both experimental and clinical studies. Strategies related to modification of excitatory neurotransmitter production and action, reduction in free radical production and inflammation and neoneurogenesis will be briefly summarized. Since hypothermia has been proven to be beneficial for a selected group of asphyxiated neonates, we assume that a combination of this treatment option with a pharmacological means of neuroprotection will be the appropriate approach in the future. Finally, it is important to consider possible gender effects in view of the discussed pharmacological strategies., ((c) 2008 S. Karger AG, Basel.)

Background: Spinal cord injury has been reported after perinatal asphyxia in full-term neonates., Objectives: To examine the role of excessive nitric oxide production in perinatal spinal cord injury., Subjects and Methods: Tissue samples of 18 full-term neonates who died of hypoxic-ischemic encephalopathy were analyzed for the presence of nitrotyrosine (NT)., Results: NT was demonstrated in 5 of these 18 neonates. In addition, activated caspase 3, a marker of apoptosis, and CD68, as a marker of inflammation, could be demonstrated in some infants., Conclusions: excessive nitric oxide production and subsequent NT formation is seen in spinal cord tissue after severe perinatal asphyxia. This finding may be relevant for the development of neuroprotective strategies., (Copyright (c) 2007 S. Karger AG, Basel.)