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Hypoxic-ischemic encephalopathy (HIE) is a major cause of neurological sequelae in (near-)term newborns. Despite the use of therapeutic hypothermia, a significant number of newborns still experience impaired neurodevelopment. Neuroimaging is the standard of care in infants with HIE to determine the timing and nature of the injury, guide further treatment decisions, and predict neurodevelopmental outcomes. Cranial ultrasonography is a helpful noninvasive tool to assess the brain before initiation of hypothermia to look for abnormalities suggestive of HIE mimics or antenatal onset of injury. Magnetic resonance imaging (MRI) which includes diffusion-weighted imaging has, however, become the gold standard to assess brain injury in infants with HIE, and has an excellent prognostic utility. Magnetic resonance spectroscopy provides complementary metabolic information and has also been shown to be a reliable prognostic biomarker. Advanced imaging modalities, including diffusion tensor imaging and arterial spin labeling, are increasingly being used to gain further information about the etiology and prognosis of brain injury. Over the past decades, tremendous progress has been made in the field of neonatal neuroimaging. In this review, the main brain injury patterns of infants with HIE, the application of conventional and advanced MRI techniques in these newborns, and HIE mimics, will be described.

Hypoxic-ischemic encephalopathy (HIE) is a major cause of neurological sequelae in (near-)term newborns. Despite the use of therapeutic hypothermia, a significant number of newborns still experience impaired neurodevelopment. Neuroimaging is the standard of care in infants with HIE to determine the timing and nature of the injury, guide further treatment decisions, and predict neurodevelopmental outcomes. Cranial ultrasonography is a helpful noninvasive tool to assess the brain before initiation of hypothermia to look for abnormalities suggestive of HIE mimics or antenatal onset of injury. Magnetic resonance imaging (MRI) which includes diffusion-weighted imaging has, however, become the gold standard to assess brain injury in infants with HIE, and has an excellent prognostic utility. Magnetic resonance spectroscopy provides complementary metabolic information and has also been shown to be a reliable prognostic biomarker. Advanced imaging modalities, including diffusion tensor imaging and arterial spin labeling, are increasingly being used to gain further information about the etiology and prognosis of brain injury. Over the past decades, tremendous progress has been made in the field of neonatal neuroimaging. In this review, the main brain injury patterns of infants with HIE, the application of conventional and advanced MRI techniques in these newborns, and HIE mimics, will be described.

Objective: To perform a temporal and geographical validation of a prognostic model, considered of highest methodological quality in a recently published systematic review, for predicting survival in very preterm infants admitted to the neonatal intensive care unit. The original model was developed in the UK and included gestational age, birthweight and gender. Design: External validation study in a population-based cohort. Setting: Dutch neonatal wards. Population or sample: All admitted white, singleton infants born between 23+0 and 32+6 weeks of gestation between 1 January 2015 and 31 December 2019. Additionally, the model’s performance was assessed in four populations of admitted infants born between 24+0 and 31+6 weeks of gestation: white singletons, non-white singletons, all singletons and all multiples. Methods: The original model was applied in all five validation sets. Model performance was assessed in terms of calibration and discrimination and, if indicated, it was updated. Main outcome measures: Calibration (calibration-in-the-large and calibration slope) and discrimination (c statistic). Results: Out of 6092 infants, 5659 (92.9%) survived. The model showed good external validity as indicated by good discrimination (c statistic 0.82, 95% CI 0.79–0.84) and calibration (calibration-in-the-large 0.003, calibration slope 0.92, 95% CI 0.84–1.00). The model also showed good external validity in the other singleton populations, but required a small intercept update in the multiples population. Conclusions: A high-quality prognostic model predicting survival in very preterm infants had good external validity in an independent, nationwide cohort. The accurate performance of the model indicates that after impact assessment, implementation of the model in clinical practice in the neonatal intensive care unit could be considered. Tweetable abstract: A high-quality model predicting survival in very preterm infants is externally valid in an independent cohort.

OBJECTIVE Direct injury to the corpus callosum (CC) due to neurosurgical interventions in infants with posthemorrhagic ventricular dilatation (PHVD) has not been reported in the literature. The authors observed a subset of infants who had suffered penetrating CC injury after neurosurgical interventions for PHVD and hypothesized that this pattern of injury may result in suboptimal CC maturation and neurodevelopmental impairment. METHODS In this multicenter, retrospective, observational study, 100 preterm and 17 full-term infants with PHVD were included and compared with 23 preterm controls. Both neonatal and postneonatal brain MRI scans were assessed for injury, and measurements were performed on postneonatal MRI scans at 2 years’ corrected age. Neurodevelopmental outcome was assessed at 2 years’ corrected age. RESULTS A total of 269 brain MRI scans of 140 infants were included. Of infants with PHVD, 48 (41%) had penetrating CC injury following neurosurgical interventions. The median (IQR) CC midsagittal surface area was smaller in infants with CC injury when compared with infants with PHVD who had intact CC and controls (190 mm2 [149–262 mm2] vs 268 mm2 [206–318 mm2] vs 289 mm2 [246–320 mm2], respectively; p < 0.001). In the univariate analysis, the area of the CC was associated with cognitive Z score (coefficient 0.009 [95% CI 0.005–0.012], p < 0.001) and motor Z score (coefficient 0.009 [95% CI 0.006–0.012], p < 0.001). In the multivariable model, CC injury was not independently associated with cognitive and motor Z score after adjusting for gestational age and presence of periventricular hemorrhagic infarction (coefficient 0.04 [95% CI −0.36 to 0.46] and −0.37 [95% CI −0.83 to 0.09], p = 0.7 and 0.1, respectively). CONCLUSIONS CC injury was not uncommon following neurosurgical interventions for PHVD in both preterm and full-term infants. At the age of 2 years, the CC midsagittal surface area was smaller in infants with injury, but CC injury was not independently associated with cognitive and motor outcomes at 2 years’ corrected age.

OBJECTIVE: Decompressing the ventricles with a temporary device is often the initial neurosurgical intervention for preterm infants with hydrocephalus. The authors observed a subgroup of infants who developed intraparenchymal hemorrhage (IPH) after serial ventricular reservoir taps and sought to describe the characteristics of IPH and its association with neurodevelopmental outcome. METHODS: In this multicenter, case-control study, for each neonate with periventricular and/or subcortical IPH, a gestational age-matched control with reservoir who did not develop IPH was selected. Digital cranial ultrasound (cUS) scans and term-equivalent age (TEA)-MRI (TEA-MRI) studies were assessed. Ventricular measurements were recorded prior to and 3 days and 7 days after reservoir insertion. Changes in ventricular volumes were calculated. Neurodevelopmental outcome was assessed at 2 years corrected age using standardized tests. RESULTS: Eighteen infants with IPH (mean gestational age 30.0 ± 4.3 weeks) and 18 matched controls were included. Reduction of the ventricular volumes relative to occipitofrontal head circumference after 7 days of reservoir taps was greater in infants with IPH (mean difference -0.19 [95% CI -0.37 to -0.004], p = 0.04). Cognitive and motor Z-scores were similar in infants with and those without IPH (mean difference 0.42 [95% CI -0.17 to 1.01] and 0.58 [95% CI -0.03 to 1.2]; p = 0.2 and 0.06, respectively). Multifocal IPH was negatively associated with cognitive score (coefficient -0.51 [95% CI -0.88 to -0.14], p = 0.009) and ventriculoperitoneal shunt with motor score (coefficient -0.50 [95% CI -1.6 to -0.14], p = 0.02) after adjusting for age at the time of assessment. CONCLUSIONS: This study reports for the first time that IPH can occur after a rapid reduction of the ventricular volume during the 1st week after the initiation of serial reservoir taps in neonates with hydrocephalus. Further studies on the use of cUS to guide the amount of cerebrospinal fluid removal are warranted.

Aims: Lidocaine is used to treat neonatal seizures refractory to other anticonvulsants. It is effective, but also associated with cardiac toxicity. Previous studies have reported on the pharmacokinetics of lidocaine in preterm and term neonates and proposed a dosing regimen for effective and safe lidocaine use. The objective of this study was to evaluate the previously developed pharmacokinetic models and dosing regimen. As a secondary objective, lidocaine effectiveness and safety were assessed. Methods: Data from preterm neonates and (near-)term neonates with and without therapeutic hypothermia receiving lidocaine were included. Pharmacokinetic analyses were performed using non-linear mixed effects modelling. Simulations were performed to evaluate the proposed dosing regimen. Lidocaine was considered effective if no additional anticonvulsant was required and safe if no cardiac adverse events occurred. Results: Data were available for 159 neonates; 50 (31.4%) preterm and 109 term neonates, of whom 49 (30.8%) were treated with therapeutic hypothermia. Lidocaine clearance increased with postmenstrual age by 0.69%/day (95% confidence interval 0.54–0.84%). During therapeutic hypothermia (33.5°C), lidocaine clearance was reduced by 21.8% (7.26%/°C, 95% confidence interval 1.63–11.2%) compared to normothermia (36.5°C). Simulations demonstrated that the proposed dosing regimen leads to adequate average lidocaine plasma concentrations. Effectiveness and safety were assessed in 92 neonates. Overall effectiveness was 53.3% (49/92) and 56.5% (13/23) for neonates receiving the proposed dosing regimen. No cardiac toxicity was observed. Conclusion: Lidocaine pharmacokinetics was adequately described across the entire neonatal age range. With the proposed dosing regimen, lidocaine can provide effective and safe treatment for neonatal seizures.

Objective. Neonates have a high risk of oxidative stress during anesthetic procedures. The predictive role of oxidative stress biomarkers on the occurrence of brain injury in the perioperative period has not been reported before. Methods. A prospective cohort study of patients requiring major surgery in the neonatal period was conducted. Biomarker levels of nonprotein-bound iron (NPBI) in plasma and F2-isoprostane in plasma and urine before and after surgical intervention were determined. Brain injury was assessed using postoperative MRI. Results. In total, 61 neonates were included, median gestational age at 39 weeks (range 31–42) and weight at 3000 grams (1400–4400). Mild to moderate brain lesions were found in 66%. Logistic regression analysis showed a significant difference between plasma NPBI in patients with nonparenchymal injury versus no brain injury: 1.34 umol/L was identified as correlation threshold for nonparenchymal injury (sensitivity 67%, specificity 91%). In the multivariable analysis, correcting for GA, no other significant relation was found with the oxidative stress biomarkers and risk factors. Conclusion. Oxidative stress seems to occur during anaesthesia in this cohort of neonates. Plasma nonprotein-bound iron showed to be associated with nonparenchymal injury after surgery, with values of 1.34 umol/L or higher. Risk factors should be elucidated in a more homogeneous patient group.

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.

ObjectiveTo compare a low versus a higher threshold for intervention in preterm infants with posthaemorrhagic ventricular dilatation.DesignMulticentre randomised controlled trial (ISRCTN43171322).Setting14 neonatal intensive care units in six countries.Patients126 preterm infants ≤34 weeks gestation with ventricular dilatation after grade III–IV haemorrhage were randomised to low threshold (LT) (ventricular index (VI) >p97 and anterior horn width (AHW) >6 mm) or higher threshold (HT) (VI>p97+4 mm and AHW >10 mm).InterventionCerebrospinal fluid tapping by lumbar punctures (LPs) (max 3), followed by taps from a ventricular reservoir, to reduce VI, and eventually a ventriculoperitoneal (VP) shunt if stabilisation of the VI below the p97+4 mm did not occur.Composite main outcome measureVP shunt or death.Results19 of 64 (30%) LT infants and 23 of 62 (37%) HT infants were shunted or died (P=0.45). A VP shunt was inserted in 12/64 (19%) in the LT and 14/62 (23%) infants in the HT group. 7/12 (58%) LT infants and 1/14 (7%) HT infants required shunt revision (PConclusionsThere was no significant difference in the primary composite outcome of VP shunt placement or death in infants with posthaemorrhagic ventricular dilatation who were treated at a lower versus a higher threshold for intervention. Infants treated at the lower threshold received more invasive procedures. Assessment of neurodevelopmental outcomes will provide further important information in assessing the risks and benefits of the two treatment approaches.

ObjectiveMorphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in this population are largely unknown. The objective of this study was to describe pharmacokinetics of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide in encephalopathic neonates treated with therapeutic hypothermia and to develop pharmacokinetics based dosing guidelines for this population.Study designTerm and near-term encephalopathic neonates treated with therapeutic hypothermia and receiving morphine were included in two multicenter cohort studies between 2008-2010 (SHIVER) and 2010-2014 (PharmaCool). Data were collected during hypothermia and rewarming, including blood samples for quantification of morphine and its metabolites. Parental informed consent was obtained for all participants.Results244 patients (GA mean (sd) 39.8 (1.6) weeks, BW mean (sd) 3,428 (613) g, male 61.5%) were included. Morphine clearance was reduced under hypothermia (33.5°C) by 6.89%/°C (95% CI 5.37%/°C- 8.41%/°C, pConclusionsClearance of morphine and its metabolites in neonates is affected by therapeutic hypothermia. The regimen suggested by the simulations will be sufficient in the majority of patients. However, due to the large interpatient variability a higher dose might be necessary in individual patients to achieve the desired effect.Trial registrationwww.trialregister.nl NTR2529.

Item does not contain fulltext OBJECTIVE: To compare changes in foetal, neonatal and perinatal mortality in the Netherlands in 2015, relative to 2004 and 2010, with changes in other European countries and regions. DESIGN: Descriptive population-wide study. METHOD: Data from 32 European countries and regions within the Euro-Peristat registration area were analysed. These countries and regions were grouped into: the Netherlands, Scandinavia, Western Europe and Eastern Europe. International differences in registration and policies were taken into account by using rates from 28 weeks gestation for foetal mortality and for 24 weeks gestation and beyond for neonatal mortality. Ranking was based on individual countries and regions. RESULTS: Foetal mortality decreased by 24% in the Netherlands, from 2.9 per 1,000 births in 2010 to 2.2 per 1,000 births in 2015; neonatal mortality decreased by 9%, from 2.2 to 2.0 per 1,000 live births. Perinatal mortality (the sum of foetal mortality and neonatal mortality) decreased by 18% from 5.1 to 4.2 per 1,000 births. The Netherlands moved from the 18th place in the European ranking in 2004 to the 10th place in 2015. CONCLUSION: Foetal, neonatal and perinatal mortality in the Netherlands decreased in 2015 when compared with 2004 and 2010. The country's position in the European ranking also improved. Explanations for this decrease are related to changes in the areas of organisation of care, population and risk factors. When mortality rates in other European countries and regions - particularly Scandinavia - are considered there is room for further improvement.

The pharmacokinetics (PK) of amoxicillin in asphyxiated newborns undergoing moderate hypothermia were quantified using prospective data (N = 125). The population PK was described by a 2-compartment model with a priori birthweight (BW) based allometric scaling. Significant correlations were observed between clearance (Cl) and postnatal age (PNA), gestational age (GA), body temperature (TEMP), and urine output (UO). For a typical patient with GA 40 weeks, BW3,000 g, 2 days PNA (i.e., TEMP 33.5 degrees C), and normal UO, Cl was 0.26 L/h (interindividual variability (IIV) 41.9%) and volume of distribution of the central compartment was 0.34 L/kg (IIV of 114.6%). For this patient, Cl increased to 0.41 L/h at PNA 5 days and TEMP 37.0 degrees C. The respective contributions of both covariates were 23% and 27%. Based onMonte Carlo simulations we recommend 50 and 75mg/kg/24h amoxicillin in three doses for patients with GA 36-37 and 38-42 weeks, respectively.

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. 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.

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.

Item does not contain fulltext AIM: Periventricular haemorrhagic infarction (PVHI) is a complication of preterm birth associated with cardiorespiratory instability. To date, the role of thrombophilia as a possible additional risk factor in infants with atypical timing and presentation of PVHI has not been investigated. METHOD: This was a retrospective cohort study of preterm infants who developed PVHI with an atypical timing and presentation either of antenatal onset or late in the postnatal course in the absence of a preceding sudden deterioration of their clinical condition. In infants with atypical PVHI mutation analysis of the factor V Leiden (G1691A), prothrombin (G20210A) gene, and C677T and A1298C polymorphisms in the MTHFR gene was performed, and plasma lipoprotein(a) and homocysteine levels were measured. RESULTS: Sixty-two preterm infants who presented with a PVHI were studied. Seventeen had an atypical presentation (seven males, 10 females; median birthweight 1170g [range 580-1990g]; median gestational age 30.6wks [range 28.7-33.7wks]). The typical PVHI group comprised 28 males and 17 females (median birthweight 1200g [range 670-2210g]; median gestational age 29.6wks [range 25.3-33.6wks]). Among the 17 infants with atypical presentation, the factor V Leiden mutation was found in seven infants (41%) as well as in the mothers of six of these seven infants; in one infant this was concomitant with a prothrombin gene mutation. A polymorphism in the MTHFR gene was also present in these infants. In two infants with an atypical presentation who were tested for this, a mutation in the COL4A1 gene was found (reported previously). All but two of the infants with an atypical presentation developed spastic unilateral cerebral palsy. INTERPRETATION: An atypical presentation of PVHI in preterm infants tends to occur more often in the presence of thrombophilia. Testing of thrombophilia, especially factor V Leiden and prothrombin gene mutation, is recommended in these infants. 01 februari 2012

During neonatal hypoxic-ischemic brain injury, activation of transcription of a series of genes is induced to stimulate erythropoiesis, anti-apoptosis, apoptosis, necrosis and angiogenesis. A key factor mediating these gene transcriptions is hypoxia-inducible factor-1alpha (HIF-1alpha). During hypoxia, HIF-1alpha protein is stabilized and heterodimerizes with HIF-1beta to form HIF-1, subsequently regulating the expression of target genes. HIF-1alpha participates in early brain development and proliferation of neuronal precursor cells. Under pathological conditions, HIF-1alpha is known to play an important role in neonatal hypoxic-ischemic brain injury: on the one hand, HIF-1alpha has neuroprotective effects whereas it can also have neurotoxic effects. HIF-1alpha regulates the transcription of erythropoietin (EPO), which induces several pathways associated with neuroprotection. HIF-1alpha also promotes the expression of vascular endothelial cell growth factor (VEGF), which is related to neovascularization in hypoxic-ischemic brain areas. In addition, HIF-1alpha has an anti-apoptotic effect by increasing the expression of anti-apoptotic factors such as EPO during mild hypoxia. The neurotoxic effects of HIF-1alpha are represented by its participation in the apoptotic process by increasing the stability of the tumor suppressor protein p53 during severe hypoxia. Moreover, HIF-1alpha plays a role in cell necrosis, by interacting with calcium and calpain. HIF-1alpha can also exacerbate brain edema via increasing the permeability of the blood-brain barrier (BBB). Given these properties, HIF-1alpha has both neuroprotective and neurotoxic effects after hypoxia-ischemia. These events are cell type specific and related to the severity of hypoxia. Unravelling of the complex functions of HIF-1alpha may be important when designing neuroprotective therapies for hypoxic-ischemic brain injury.

Randomised controlled trials have demonstrated that mild hypothermia reduces mortality and morbidity in full-term neonates who experience perinatal asphyxia. Hypothermia can be applied to the head or entire body, maintaining a temperature of 33-34°C for 72 hours. Treatment should be started within 6 hours after birth. An estimated 180-200 neonates may be eligible for this novel approach to neuroprotection each year in the Netherlands.

Two healthy breast-fed term infants were admitted to the neonatal unit with symptomatic hypoglycaemia and seizures. In both patients, risk factors (i.e. hypothermia) and symptoms ofhypoglycaemia went unrecognised until apnoea or seizures developed. Both patients required antiepileptic medication for neonatal seizures. One patient had isolated restricted growth in head circumference in the first year of life. Follow-up at II years showed cognitive impairment and epilepsy. The other patient had normal head circumference and mild global delay in neurological development at the age of 36 months. Severe symptomatic hypoglycaemia in healthy breast-fed term infants may cause severe brain damage. Early recognition of risk factors such as hypothermia lasting more than 3 hours is essential to preventing hypoglycaemia. The presence of risk factors warrants additional bottle-feeding to maintain sufficient intake until breastfeeding is adequately established. Any uncertainty regarding the symptoms of hypoglycaemia should be investigated promptly

Aim: In the present, prospective study, the relation between the levels of midazolam, its two active metabolites-1-hydroxy-midazolam (OH-midazolam) and 1-hydroxy-midazolam-glucuronide (glumidazolam)-and the aEEG were examined. Patients and methods: Fifteen full-term neonates with seizures due to hypoxic-ischaemic encephalopathy admitted to our NICU were included. Midazolam (loading dose 0.05 mg/kg in 10 min, maintenance dose 0.15 mg/kg/h) was used as an add-on anti-convulsant after phenobarbital and lidocaine because of continuing seizures. Amplitude-integrated EEG background pattern was scored at the start of midazolam and at the time of blood sampling as continuous normal voltage (CNV), discontinuous normal voltage (DNV), burst suppression (BS), continuous low voltage (CLV) or flat trace (FT). Serum levels of midazolam, OH-midazolam and glu-midazolam were measured at least 8 h after the start with HPLC. Results: In 11/15 patients, seizures were abolished with the addition of midazolam. In the remaining patients, seizure frequency was reduced in one and unchanged in three. Amplitude-integrated EEG background pattern at the start of midazolam was CNV in two, DNV in six, BS in five and CLV in two. Moderate, temporary suppression of the aEEG background pattern lasting less than 2 h was seen in four neonates. Amplitude-integrated EEG at midazolam sampling was CNV in two, DNV in seven, CLV in two and FT in four. Serum levels of midazolam ranged from 0.10 to 1.76 mg/l, OH-midazolam from 0.05 to 0.28 mg/l and glu-midazolam from 0.85 to 4.36 mg/l. Conclusions: A brief and moderate suppression of the aEEG background pattern immediately after midazolam was seen in four neonates for less than 2 h. Suppression at a later time point, i.e. after more than 8 h of midazolam infusion, was demonstrated almost exclusively in neonates with a poor background pattern, and therefore these patterns appear to be determined mainly by the severity of hypoxic-ischaemic encephalopathy.

The purpose of this study was to investigate whether combined inhibition of neuronal and inducible nitric oxide synthase (NOS) by 2-iminobiotin, free radical scavenging by allopurinol, and non-protein-bound iron chelation with deferoxamine improved cerebral oxygenation, electrocortical brain activity, and brain energy status during the first 24 h after hypoxia-ischemia (HI) in the newborn piglet. Forty-three newborn piglets were subjected to 1 h of severe HI by occluding both carotid arteries and phosphorous magnetic resonance spectroscopy (31P-MRS)-guided hypoxia, whereas five served as sham-operated controls. Upon reperfusion, piglets received vehicle (n=12), 2-iminobiotin (n=11), allopurinol (n=10), or deferoxamine (n=10). Cerebral oxygenation was recorded with near-infrared spectrophotometry (NIRS), electrocortical brain activity was assessed with amplitude-integrated EEG (aEEG), and cerebral energy status with 31P-MRS. The oxygenated hemoglobin (HbO2) and total hemoglobin (tHb) were significantly increased in vehicle-treated piglets compared with 2-iminobiotin-treated and deferoxamine-treated piglets. No change in deoxygenated Hb (HHb) was demonstrated over time. The aEEG was significantly preserved in 2-iminobiotin- and deferoxamine-treated piglets compared with vehicle-treated piglets. Allopurinol treatment was not as effective as 2-iminobiotin treatment after HI. Phosphocreatine/inorganic phosphate ratios (PCr/Pi) were significantly decreased for vehicle-treated piglets at 24 h post-HI, whereas 2-iminobiotin, allopurinol, and deferoxamine prevented the development of secondary energy failure. We speculate that the beneficial effects, especially of 2-iminobiotin, but also of deferoxamine, are due to reduced peroxynitrite-mediated oxidation.

Item does not contain fulltext OBJECTIVE: To determine to what extent the recommendations to actively treat preterm infants with a gestational age of 24 weeks upwards laid down in the guidelines 'Perinatal policy in cases of extreme prematurity' have influenced policy in Dutch perinatal centres in the first year after publication, and what the health outcomes were. DESIGN: Retrospective, descriptive study. METHOD: Our study population included all pregnant women who were admitted to a perinatal centre at 23 5/7 to 26 weeks gestation with a diagnosis of 'threatened preterm labour', and their preterm infants. We collected both obstetric data and data on survival and morbidity of the infants from the medical files. RESULTS: Of a total of 192 preterm infants 185 (96%) were born alive; 92% of these infants were admitted to the neonatal intensive care unit. Survival rates were 43% and 61% at 24 weeks and 25 weeks gestation, respectively. Short-term morbidity (bronchopulmonary dysplasia, retinopathy of the newborn, severe intraventricular haemorrhage, necrotising enterocolitis and persistant ductus arteriosus) occurred in 79% and 71% of the infants born at 24 weeks and 25 weeks gestation, respectively. CONCLUSIONS: The recommendations from these guidelines have been implemented swiftly in Dutch perinatal centres, and survival of extremely preterm infants has increased. This has imposed a considerable burden on the capacity of these centres. Little is yet known about the long-term (up to school-age) health and survival of these infants.

Perinatal brain injury at term is common and often manifests with neonatal encephalopathy including seizures. The most common aetiologies are hypoxic–ischaemic encephalopathy, intracranial haemorrhage and neonatal stroke. Besides clinical and biochemical assessment the diagnostic evaluation rely mostly on EEG and neuroimaging including cranial ultrasound and magnetic resonance imaging. The mechanisms underlying hypoxic–ischaemic brain injury are only partly understood but include excitotoxicity, mitochondrial perturbation, necrosis/apoptosis and inflammation. Neuroprotective treatment of newborns suffering from hypoxic–ischaemic encephalopathy with hypothermia has proven effective and has been introduced as a clinical routine. Ongoing studies are exploring various add-on therapies including erythropoietin, xenon, topiramate, melatonin and stem cells.

Developmental brain injury after extreme preterm birth, also known as ‘Encephalopathy of Prematurity (EoP)’, is commonly encountered in the neonatal intensive care unit and can lead to life-long neurodevelopmental impairments. At this time, treatment options to improve brain development after extreme preterm birth are still lacking. This thesis aimed to elucidate the cellular and molecular mechanisms underlying cerebral dysmaturation in EoP and to explore the potential of novel treatment options to improve brain development after extreme preterm birth. A double-hit mouse model of EoP was developed to investigate the underlying mechanisms of brain injury. In this model, the combination of postnatal hypoxia-ischemia and systemic inflammation caused transient global dysmaturation of the immature brain, closely mimicking the clinical situation. Experimental induction of EoP was associated with myelination deficits, impaired oligodendrocyte maturation, aberrant interneuron development, neuroinflammation, behavioral impairments and global volumetric deficits of white and gray matter structures. We used our validated mouse model to investigate whether intranasally administered mesenchymal stem cell (MSCs) can promote brain development after EoP. Early intranasal treatment with MSCs restored oligodendrocyte maturation and myelination, improved interneuron development and dampened astrocyte and microglia activation. Anatomical recovery was accompanied by improvement of functional outcome. MSCs were shown to exert their regenerative properties through adaptation of their secretome in situ, contributing to a cerebral environment permissive for endogenous repair through the release of trophic and anti-inflammatory factors. Delay of cell administration significantly reduced the therapeutic efficacy of MSCs. Modification of MSCs, with transient hypersecretion of selected growth factors, was shown to prolong the treatment window for effective MSC treatment after EoP. In a similar manner, the therapeutic potential of intranasal insulin-like growth factor 1 (IGF1) treatment was studied using our double-hit mouse model of EoP. Early intranasal administration of IGF1 was shown to boost oligodendrocyte maturation and restore interneuron abnormalities, thereby improving functional outcome. In contrast to MSC treatment, intranasal administration of IGF1 dampened astrocyte activation, but not microglia activity after EoP induction. We showed that this observation is likely the result of differential expression of the IGF1 receptor on cells of the brain. In our clinical study we explored the relationship between postnatal blood levels of IGF1 and its binding protein IGFBP3 and neurodevelopmental outcome after extreme preterm birth. In our cohort of extreme preterm infants, higher blood levels of IGFBP3, but not IGF1, were associated with a reduction in brain injury severity, increased regional brain volumes and improved white matter structural integrity at term. Future studies are needed to further investigate the potential role of IGFBP3 as an early biomarker for EoP. In conclusion, we propose that both early intranasal MSC and IGF1 treatment show great promise to support brain development after EoP. Additional studies, aimed at refining the optimal treatment protocol, are needed for future translation of these promising therapeutic strategies to clinical care.

In infants with post-hemorrhagic ventricular dilatation (PHVD), earlier interventions to bring the intraventricular pressure, therefore the ventricular size, down based on ultrasonographic assessments result in smaller ventricular volumes and less brain injury at term-equivalent age. PHVD also causes impaired microstructure of the critical brain structures in extremely preterm infants. Thus, earlier interventions for PHVD based on ultrasonographic assessments also result in reduced composite outcome of mortality and neurodevelopmental disability at 2 years corrected age. In infants with PHVD, rapid reduction of the ventricular pressure and volume during the first week after the commencement of serial reservoir taps may result in intraparenchymal hemorrhage (IPH) in the periventricular and/or subcortical white matter tissues, and these IPHs can affect cognitive outcomes when multifocal. Therefore, it is essential to perform serial cUS scans to guide the amount of cerebrospinal fluid removal via reservoir taps. Neurosurgical interventions, especially reservoir insertions, can cause injury to the CC and subsequent thinning of the CC. However, this phenomenon does not appear to be related to impaired neurodevelopmental outcomes at 2 years of age. Periventricular hemorrhagic infarction (PVHI), a severe form of germinal matrix and intraventricular hemorrhage continues to be a significant complication in very preterm infants and is an independent risk factor for both cognitive and motor impairment at 2 years corrected age and cognitive and motor outcomes are within the normal range in two-thirds, and cerebral palsy (CP) is seen in around 40% of PVHI survivors at 2 years corrected age. The majority (81%) of infants with CP can walk independently. These neurodevelopmental findings appear more favorable when compared to previous studies conducted more than a decade ago.

Enlargement of the cerebral ventricles is a relatively common phenomenon especially in extremely premature neonates, born below 28 weeks gestational age. In developed countries, the two main entities underlying neonatal ventricular enlargement – apart from congenital malformations – are, first, pressure driven post-haemorrhagic ventricular dilatation (PHVD) due to impaired cerebrospinal fluid dynamics following an intraventricular haemorrhage and, second, ex-vacuo ventriculomegaly due to diffuse white matter injury. Early recognition of neonatal ventriculomegaly and identification of the underlying condition is essential for clinicians to define the need for intervention and may, additionally, yield significant prognostic information. The main aims of this thesis were to optimize the early recognition of ventricular enlargement in neonates at risk and to explore the prognostic implications of cerebral ventriculomegaly among preterm infants. New reference values were established for several dimensions of the neonatal ventricles on cranial ultrasound, based on a cohort of 625 neonates born between 24-42 weeks gestational age. These reference values may further contribute to the timely diagnosis of neonatal ventriculomegaly and aid the clinician in evaluating the need for intervention for PHVD. At present, the optimal diagnostic and therapeutic approaches to neonates with PHVD are still a matter of debate. A survey among 32 European centres underlines the need to collaborate on an international consensus on the diagnosis and treatment of PHVD in order to achieve optimal care and long-term neurodevelopmental outcome for these infants. This thesis draws attention to specific effects of PHVD on the immature brain and elucidates potential mechanisms by which PHVD may affect neurodevelopmental outcome. PHVD was independently associated with altered brain volumes and white matter diffusion parameters in premature infants at term-equivalent age, in spite of early intervention in the majority of infants with PHVD. Reduced volumes were observed for deep grey matter, cerebellum, and extracerebral cerebrospinal volume on term MRI, whereas ventricular volumes were increased in association with PHVD. Ex-vacuo ventriculomegaly on cranial ultrasound or MRI at term-equivalent age was identified as an independent prognostic marker for adverse cognitive and motor outcome among preterm born infants.

To unravel the pathophysiology underlying the large percentage of preterm born infants that will demonstrate neurodevelopmental impairments during childhood, a better understanding of brain development during what would have been the third trimester of pregnancy is needed. The aim of this thesis was to study longitudinal brain development in extremely preterm infants. We did so by utilizing serial MRI scans of a cohort of preterm infants born before a gestation of 28 weeks, that were scanned around 30 weeks postmenstrual age and again around term-equivalent age. In this thesis, we show that volumetric measurements, the progression of cortical folding, microstructural development of the white matter and functional connectivity networks all confirm the central-peripheral and occipital-frontal gradient of brain development. Several clinical risk factors for deviations in brain development were studied and prolonged mechanical ventilation, whether as a representative of lung damage or of overall severity of illness, has the most severe negative influence on brain development throughout the different studies. By utilizing serial scans, we show that the remote effects of brain injury will become evident in the period between 30 and 40 weeks gestation, whereas the direct effects are already established by 30 weeks. Relating these findings to neurodevelopmental outcome around two years of age showed significant but modest effects, suggesting that outcome at a later age is needed to find deficits caused by mild brain injury. Punctate white matter lesions, nowadays the most common form of white matter injury in preterm infants, were seen in two distinctive patterns, suggestive of a difference in underlying pathology. Additional sequences (diffusion and susceptibility weighted imaging) are needed to reliably distinguish both. Volumetric growth showed regional differences with by far the largest growth in the cerebellum, which is also affected most by brain damage. The use of hydrocortisone for developing chronic lung disease, however, did not influence overall brain size or cerebellar volumes. While studying the progression of cortical folding, adult brain asymmetries were shown to develop already during the last ten weeks of gestation. In addition, cortical surface area and depth were correlated with neurodevelopmental outcomes at two years of age. Utilizing diffusion tensor imaging showed increases of fractional anisotropy in the white matter, but decreases in the cortex, fitting with the theory of cortical development. Damage to the corticospinal tracts in infants with cystic periventricular leukomalacia was seen within weeks after the insult, while the remote effects on thalamic volume develop over time and become clear at term-equivalent age. Finally, immature functional networks were already present at 30 weeks and were similar to adult networks. Both structural and functional connectivity networks develop between 30 weeks and term-equivalent age leading to an increase in integration capacity. Identifying these processes in brain development, taking place while preterm infants are cared for in a neonatal intensive care environment with all its stressors and complications, as well as the deviations caused by preterm birth, will help in finding better predictive strategies and protective therapies to improve cognitive and behavioural outcome for this vulnerable population.