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Objective: To analyze the effect of a type II collagen mutation on craniofacial development in transgenic Del1 mice.Design: Samples from homozygous (+/+) and heterozygous (+/-) transgenic Del1 mice harboring mutations in the type II collagen gene as well as non-transgenic (-/-) littermates were collected at days 12.5, 14.5, 16.5 and 18.5 of gestation. The cartilaginous and bony elements of the craniofacial skeleton were analyzed after staining with alcian blue, alizarin red S and von Kossa. The expression patterns of type II, IX and X collagens and aggrecan were analyzed by immunohistochemistry and in situ hybridization.Results: Several abnormalities were observed in the craniofacial skeleton of transgenic Del1 mice. These include an overall retardation of chondrogenesis and osteogenesis in Del1 +/+ mice, and to a lesser extent also in Del1+/- mice. Characteristic findings in Del1 +/+ mice included a reduced anterioposterior length, a smaller size of the mandible, a palatal cleft and a downward bending snout. We also detected retarded ossification of calvarial bones in Del1 +/+ and +/- mice when compared with Del1 -/- mice. A surprising finding was the presence of both type II and X collagens and their mRNAs in the periosteum of the cranial base.Conclusion: The present study confirms the important role of type II collagen mutation in craniofacial development and growth. In addition to affecting endochondral ossification, the type II collagen mutation also disturbs intramembranous ossification in the developing craniofacial skeleton. [ABSTRACT FROM AUTHOR]

The expression of osteonectin gene was studied in developing human fetuses by Northern analysis and in situ hybridization. The highest levels of osteonectin mRNA were detected in RNA extracted from calvarial bones, growth plates, and skin. Low mRNA levels were present in several parenchymal tissues. In situ hybridization of developing long bones revealed three cell types with high osteonectin mRNA levels: osteoblasts, cells of the periosteum, and hypertrophic chondrocytes. Weaker signals were detected in osteocytes, fibroblasts of tendons, ligaments and skin, and in cells of the epidermis. Apart from the hypertrophic chondrocytes, only low osteonectin mRNA levels were seen in cartilage. The localization of osteonectin mRNA in fetal growth plates is consistent with the hypothesis that the protein plays a role in the mineralization of bone and cartilage matrices. [ABSTRACT FROM AUTHOR]

Background: Perinatal asphyxia often leads to hypoxic-ischemic encephalopathy (HIE) with a high risk of neurodevelopmental consequences. While moderate and severe HIE link to high morbidity, less is known about brain effects of perinatal asphyxia with no or only mild HIE. Here, we test the hypothesis that cortical activity networks in the newborn infants show a dose-response to asphyxia., Methods: We performed EEG recordings for infants with perinatal asphyxia/HIE of varying severity (n = 52) and controls (n = 53) and examined well-established computational metrics of cortical network activity., Results: We found graded alterations in cortical activity networks according to severity of asphyxia/HIE. Furthermore, our findings correlated with early clinical recovery measured by the time to attain full oral feeding., Conclusion: We show that both local and large-scale correlated cortical activity are affected by increasing severity of HIE after perinatal asphyxia, suggesting that HIE and perinatal asphyxia are better represented as a continuum rather than the currently used discreet categories. These findings imply that automated computational measures of cortical function may be useful in characterizing the dose effects of adversity in the neonatal brain; such metrics hold promise for benchmarking clinical trials via patient stratification or as early outcome measures., Impact: Perinatal asphyxia causes every fourth neonatal death worldwide and provides a diagnostic and prognostic challenge for the clinician. We report that infants with perinatal asphyxia show specific graded responses in cortical networks according to severity of asphyxia and ensuing hypoxic-ischaemic encephalopathy. Early EEG recording and automated computational measures of brain function have potential to help in clinical evaluation of infants with perinatal asphyxia., (© 2023. The Author(s).)

Objective: To evaluate the utility of a fully automated deep learning -based quantitative measure of EEG background, Brain State of the Newborn (BSN), for early prediction of clinical outcome at four years of age., Methods: The EEG monitoring data from eighty consecutive newborns was analyzed using the automatically computed BSN trend. BSN levels during the first days of life (a of total 5427 hours) were compared to four clinical outcome categories: favorable, cerebral palsy (CP), CP with epilepsy, and death. The time dependent changes in BSN-based prediction for different outcomes were assessed by positive/negative predictive value (PPV/NPV) and by estimating the area under the receiver operating characteristic curve (AUC)., Results: The BSN values were closely aligned with four visually determined EEG categories (p < 0·001), as well as with respect to clinical milestones of EEG recovery in perinatal Hypoxic Ischemic Encephalopathy (HIE; p < 0·003). Favorable outcome was related to a rapid recovery of the BSN trend, while worse outcomes related to a slow BSN recovery. Outcome predictions with BSN were accurate from 6 to 48 hours of age: For the favorable outcome, the AUC ranged from 95 to 99% (peak at 12 hours), and for the poor outcome the AUC ranged from 96 to 99% (peak at 12 hours). The optimal BSN levels for each PPV/NPV estimate changed substantially during the first 48 hours, ranging from 20 to 80., Conclusions: We show that the BSN provides an automated, objective, and continuous measure of brain activity in newborns., Significance: The BSN trend discloses the dynamic nature that exists in both cerebral recovery and outcome prediction, supports individualized patient care, rapid stratification and early prognosis., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To assess whether computational electroencephalogram (EEG) measures during the first day of life correlate to clinical outcomes in infants with perinatal asphyxia with or without hypoxic-ischemic encephalopathy (HIE)., Methods: We analyzed four-channel EEG monitoring data from 91 newborn infants after perinatal asphyxia. Altogether 42 automatically computed amplitude- and synchrony-related EEG features were extracted as 2-hourly average at very early (6 h) and early (24 h) postnatal age; they were correlated to the severity of HIE in all infants, and to four clinical outcomes available in a subcohort of 40 newborns: time to full oral feeding (nasogastric tube NGT), neonatal brain MRI, Hammersmith Infant Neurological Examination (HINE) at three months, and Griffiths Scales at two years., Results: At 6 h, altogether 14 (33%) EEG features correlated significantly to the HIE grade ([r]= 0.39-0.61, p < 0.05), and one feature correlated to NGT ([r]= 0.50). At 24 h, altogether 13 (31%) EEG features correlated significantly to the HIE grade ([r]= 0.39-0.56), six features correlated to NGT ([r]= 0.36-0.49) and HINE ([r]= 0.39-0.61), while no features correlated to MRI or Griffiths Scales., Conclusions: Our results show that the automatically computed measures of early cortical activity may provide outcome biomarkers for clinical and research purposes., Impact: The early EEG background and its recovery after perinatal asphyxia reflect initial severity of encephalopathy and its clinical recovery, respectively. Computational EEG features from the early hours of life show robust correlations to HIE grades and to early clinical outcomes. Computational EEG features may have potential to be used as cortical activity biomarkers in early hours after perinatal asphyxia., (© 2024. The Author(s).)

Background: Despite therapeutic hypothermia (TH) and neonatal intensive care, 45-50% of children affected by moderate-to-severe neonatal hypoxic-ischemic encephalopathy (HIE) die or suffer from long-term neurodevelopmental impairment. Additional neuroprotective therapies are sought, besides TH, to further improve the outcome of affected infants. Allopurinol - a xanthine oxidase inhibitor - reduced the production of oxygen radicals and subsequent brain damage in pre-clinical and preliminary human studies of cerebral ischemia and reperfusion, if administered before or early after the insult. This ALBINO trial aims to evaluate the efficacy and safety of allopurinol administered immediately after birth to (near-)term infants with early signs of HIE., Methods/design: The ALBINO trial is an investigator-initiated, randomized, placebo-controlled, double-blinded, multi-national parallel group comparison for superiority investigating the effect of allopurinol in (near-)term infants with neonatal HIE. Primary endpoint is long-term outcome determined as survival with neurodevelopmental impairment versus death versus non-impaired survival at 2 years., Results: The primary analysis with three mutually exclusive responses (healthy, death, composite outcome for impairment) will be on the intention-to-treat (ITT) population by a generalized logits model according to Bishop, Fienberg, Holland (Bishop YF, Discrete Multivariate Analysis: Therory and Practice, 1975) and ."will be stratified for the two treatment groups., Discussion: The statistical analysis for the ALBINO study was defined in detail in the study protocol and implemented in this statistical analysis plan published prior to any data analysis. This is in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines., Trial Registration: ClinicalTrials.gov NCT03162653. Registered on 22 May 2017., (© 2024. The Author(s).)

Aim: We aimed to describe clinical practices and criteria for discharge of very preterm infants in Nordic neonatal units., Methods: Medical directors of all 89 level-2 and level-3 units in Denmark, Finland, Iceland, Norway and Sweden were invited by e-mail to complete a web-based multiple-choice survey with the option to make additional free-text comments., Results: We received responses from 83/89 units (93%). In all responding units, discharge readiness was based mainly on clinical assessment with varying criteria. In addition, 36% used formal tests of cardiorespiratory stability and 59% used criteria related to infant weight or growth. For discharge with feeding tube, parental ability to speak the national language or English was mandatory in 45% of units, with large variation among countries. Post-discharge home visits and video-consultations were provided by 59% and 51%, respectively. In 54% of units, parental preparation for discharge were not initiated until the last two weeks of hospital stay., Conclusion: Discharge readiness was based mainly on clinical assessment, with criteria varying among units despite similar population characteristics and care structures. This variation indicates a lack of evidence base and may unnecessarily delay discharge; further studies of this matter are needed. Earlier parental preparation and use of interpreters might facilitate earlier discharge., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Aim: Organisation of care, perinatal and neonatal management of very preterm infants in the Nordic regions were hypothesised to vary significantly. The aim of this observational study was to test this hypothesis., Methods: Information on preterm infants in the 21 greater healthcare regions of Denmark, Finland, Iceland, Norway and Sweden was gathered from national registers in 2021. Preterm birth rates, case-mix, perinatal interventions, neonatal morbidity and survival to hospital discharge in very (<32 weeks) and extremely preterm infants (<28 weeks of gestational age) were compared., Results: Out of 287 642 infants born alive, 16 567 (5.8%) were preterm, 2389 (0.83%) very preterm and 800 (0.28%) were extremely preterm. In very preterm infants, exposure to antenatal corticosteroids varied from 85% to 98%, live births occurring at regional centres from 48% to 100%, surfactant treatment from 28% to 69% and use of mechanical ventilation varied from 13% to 77% (p < 0.05 for all comparisons). Significant regional variations within and between countries were also seen in capacity in neonatal care, case-mix and number of admissions, whereas there were no statistically significant differences in survival or major neonatal morbidities., Conclusion: Management of very preterm infants exhibited significant regional variations in the Nordic countries., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Introduction: Cognitive development is characterized by the structural and functional maturation of the brain. Diffusion-weighted magnetic resonance imaging (dMRI) provides methods of investigating the brain structure and connectivity and their correlations with the neurocognitive outcome. Our aim was to examine the relationship between early visual abilities, brain white matter structures, and the later neurocognitive outcome., Methods: This study included 20 infants who were born before 28 gestational weeks and followed until the age of 6.5 years. At term age, visual alertness was evaluated and dMRI was used to investigate the brain white matter structure using fractional anisotropy (FA) in tract-based spatial statistics analysis. The JHU DTI white matter atlas was used to locate the findings. The neuropsychological assessment was used to assess neurocognitive performance at 6.5 years., Results: Optimal visual alertness at term age was significantly associated with better visuospatial processing (p < .05), sensorimotor functioning (p < .05), and social perception (p < .05) at 6.5 years of age. Optimal visual alertness related to higher FA values, and further, the FA values positively correlated with the neurocognitive outcome. The tract-based spatial differences in FA values were detected between children with optimal and nonoptimal visual alertness according to performance at 6.5 years., Conclusion: We provide neurobiological evidence for the global and tract-based spatial differences in the white matter maturation between extremely preterm children with optimal and nonoptimal visual alertness at term age and a link between white matter maturation, visual alertness and the neurocognitive outcome at 6.5 years proposing that early visual function is a building block for the later neurocognitive development., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Data on the cerebral effects of analgesic and sedative drugs are needed for the development of safe and effective treatments during neonatal intensive care. Electroencephalography (EEG) is an objective, but interpreter-dependent method for monitoring cortical activity. Quantitative computerized analyses might reveal EEG changes otherwise not detectable., Methods: EEG registrations were retrospectively collected from 21 infants (mean 38.7 gestational weeks; range 27-42) who received dexmedetomidine during neonatal care. The registrations were transformed into computational features and analyzed visually, and with two computational measures quantifying relative and absolute changes in power (range EEG; rEEG) and cortico-cortical synchrony (activation synchrony index; ASI), respectively., Results: The visual assessment did not reveal any drug effects. In rEEG analyses, a negative correlation was found between the baseline and the referential frontal (rho = 0.612, p = 0.006) and parietal (rho = -0.489, p = 0.035) derivations. The change in ASI was negatively correlated to baseline values in the interhemispheric (rho = -0.753; p = 0.001) and frontal comparisons (rho = -0.496; p = 0.038)., Conclusion: Cerebral effects of dexmedetomidine as determined by EEG in newborn infants are related to cortical activity prior to DEX administration, indicating that higher brain activity levels (higher rEEG) during baseline links to a more pronounced reduction by DEX. The computational measurements indicate drug effects on both overall cortical activity and cortico-cortical communication. These effects were not evident in visual analysis.

Aim: This study investigated minor impairments in neurological, sensorimotor, and neuropsychological functioning in extremely preterm-born (EPT) children compared to term-born children. The aim was to explore the most affected domains and to visualize their co-occurrences in relationship maps., Methods: A prospective cohort of 56 EPT children (35 boys) and 37 term-born controls (19 boys) were assessed at a median age of 6 years 7 months with Touwen Neurological Examination, Movement Assessment Battery for Children, 2nd edition (MABC-2), Sensory Integration and Praxis Test (SIPT), and a Developmental Neuropsychological Assessment, 2nd edition (NEPSY-II). Altogether 20 test domains were used to illustrate the frequency of impaired test performances with a bar chart profile and to construct relationship maps of co-occurring impairments., Results: The EPT children were more likely to perform inferiorly compared to the term-born controls across all assessments, with a wider variance and more co-occurring impairments. When aggregating all impaired test domains, 45% of the EPT children had more impaired domains than any term-born child (more than five domains, p  < 0.001). Relationship maps showed that minor neurological dysfunction (MND), NEPSY-II design copying, and SIPT finger identification constituted the most prominent relationship of co-occurring impairments in both groups. However, it was ten times more likely in the EPT group. Another relationship of co-occurring MND, impairment in NEPSY-II design copying, and NEPSY-II imitation of hand positions was present in the EPT group only., Interpretation: Multiple minor impairments accumulate among EPT children at six years, suggesting that EPT children and their families may need support and timely multi-professional interventions throughout infancy and childhood., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Niutanen, Lönnberg, Wolford, Metsäranta and Lano.)

Objective: This study evaluated the accuracy of neonatal amplitude-integrated electroencephalography (aEEG) brain monitoring for predicting development of postneonatal epilepsy after perinatal hypoxic ischemic encephalopathy (HIE)., Methods: We studied a population-based cohort of 85 consecutive neonates with moderate-to-severe HIE that had aEEG started <12 hours postnatally. We marked electrographic seizures and graded each hour of the aEEG background as inactive, burst-suppression, or continuous without or with sleep cycling. These aEEG parameters were compared to outcome at 4-years age (deceased, epilepsy, cerebral palsy without epilepsy, favorable), which was available for 80 children., Results: At group level, total seizure burden (p = 0.003), maximum hourly seizure burden (p = 0.007), and aEEG background recovery (p < 0.001) were all significantly associated with outcome. At individual level six children developed epilepsy, and the most accurate predictors for later epilepsy were inactive aEEG at 24 hours (accuracy 97%, positive predictive value 100%, two false negatives) and inactive aEEG at the onset of seizures (accuracy 97%, sensitivity of 100%, one false positive)., Conclusions: At individual level aEEG background recovery was a better predictor for later epilepsy than neonatal seizures, although both were associated with epilepsy at group level., Significance: Poor aEEG background recovery predicts development of epilepsy after perinatal HIE at individual level., Competing Interests: Conflict of interest statement None of the authors has any conflict of interest to disclose., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Long-term EEG monitoring in neonatal intensive care units (NICU) is challenged with finding solutions for setting up and maintaining a sufficient recording quality with limited technical experience. The current study evaluates different solutions for the skin-electrode interface and develops a disposable EEG cap for newborn infants. Several alternative materials for the skin-electrode interface were compared to the conventional gel and paste: conductive textiles (textured and woven), conductive Velcro, sponge, super absorbent hydrogel (SAH), and hydro fiber sheets (HF). The comparisons included the assessment of dehydration and recordings of signal quality (skin interphase impedance and powerline (50 Hz) noise) for selected materials. The test recordings were performed using snap electrodes integrated into a forearm sleeve or a forehead band along with skin-electrode interfaces to mimic an EEG cap with the aim of long-term biosignal recording on unprepared skin. In the hydration test, conductive textiles and Velcro performed poorly. While the SAH and HF remained sufficiently hydrated for over 24 h in an incubator-mimicking environment, the sponge material was dehydrated during the first 12 h. Additionally, the SAH was found to have a fragile structure and was electrically prone to artifacts after 12 h. In the electrical impedance and recording comparisons of muscle activity, the results for thick-layer HF were comparable to the conventional gel on unprepared skin. Moreover, the mechanical instability measured by 1-2 Hz and 1-20 Hz normalized relative power spectrum density was comparable with clinical EEG recordings using subdermal electrodes. The results together suggest that thick-layer HF at the skin-electrode interface is an effective candidate for a preparation-free, long-term recording, with many advantages, such as long-lasting recording quality, easy use, and compatibility with sensitive infant skin contact.

Aim: To characterise the spectrum of findings in sequential neurological examinations, general movements (GM) assessment and magnetic resonance imaging (MRI) of infants with perinatal asphyxia., Methods: The prospective cohort study of term infants with perinatal asphyxia treated at Helsinki University Hospital's neonatal units in 2016-2020 used Hammersmith Neonatal Neurological Examination (HNNE) and brain MRI at 2 weeks and Hammersmith Infant Neurological Examination (HINE) and GM assessment at 3 months of age., Results: Analysis included 50 infants: 33 displaying perinatal asphyxia without hypoxic-ischaemic encephalopathy (HIE), seven with HIE1 and 10 with HIE2. Of the infants with atypical HNNE findings, 24/25 perinatal asphyxia without HIE cases, 5/6 HIE1 cases and all 10 HIE2 cases showed atypical findings in the HINE. The HINE identified atypical spontaneous movements significantly more often in infants with white matter T2 hyperintensity., Conclusion: In this cohort, most infants with perinatal asphyxia, with or without HIE, presented atypical neurological findings in sequential examinations. The profile of neurological findings for children with perinatal asphyxia without HIE resembled that of children with HIE. White matter T2 hyperintensity was associated with atypical spontaneous movements in the HINE and was a frequent MRI finding also in perinatal asphyxia without HIE., (© 2021 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Objective: The aim of this study was to evaluate the ability of the neonatal neurobehavioral characteristics to act as an indicator for later neurodevelopment and neurocognitive performance. Methods: Sixty-six infants born extremely preterm (<28 gestational weeks) were followed until 6.5 years. Neurobehavior at term age was assessed by the behavior subscale of the Hammersmith Neonatal Neurological Examination (HNNE) using dichotomic rating, optimal, and non-optimal. The Griffiths Mental Developmental Scales (GMDS) at 2 years, and the Wechsler Intelligence Scales at 6.5 years, and a Neuropsychological Assessment at 6.5 years were used to assess neurodevelopment and neurocognitive performance including social cognition skills. Results: An optimal auditory orientation at term age was associated with better developmental quotients (DQ) in Personal-Social, and Hearing-Language GMDS subscale at 2 years ( p < 0.05). An optimal visual alertness was associated with better Total ( p < 0.01), Locomotor ( p < 0.001), and Eye-Hand Coordination ( p < 0.01) DQs at 2 years, and with sensorimotor function ( p < 0.001) and social perception ( p < 0.01) tests at 6.5 years. Conclusion: The neurobehavioral characteristics of newborns might serve as a precursor of social cognition skills and the HNNE behavior subscale offers a tool to identify infants at risk for later deficits in neurodevelopment and social cognition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Aho, Metsäranta, Lönnberg, Wolford and Lano.)

Objective: We assessed in extremely preterm born (EPB) children whether secondary somatosensory cortex (SII) responses recorded with magnetoencephalography (MEG) at term-equivalent age (TEA) correlate with neurodevelopmental outcome at age 6 years. Secondly, we assessed whether SII responses differ between 6-year-old EPB and term-born (TB) children., Methods: 39 EPB children underwent MEG with tactile stimulation at TEA. At age 6 years, 32 EPB and 26 TB children underwent MEG including a sensorimotor task requiring attention and motor inhibition. SII responses to tactile stimulation were modeled with equivalent current dipoles. Neurological outcome, motor competence, and general cognitive ability were prospectively evaluated at age 6 years., Results: Unilaterally absent SII response at TEA was associated with abnormal motor competence in 6-year-old EPB children (p = 0.03). At age 6 years, SII responses were bilaterally detectable in most EPB (88%) and TB (92%) children (group comparison, p = 0.69). Motor inhibition was associated with decreased SII peak latencies in TB children, but EPB children lacked this effect (p = 0.02)., Conclusions: Unilateral absence of an SII response at TEA predicted poorer motor outcome in EPB children., Significance: Neurophysiological methods may provide new means for outcome prognostication in EPB children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Extremely low gestational age newborns (ELGANs) are at risk of neurodevelopmental impairments that may originate in early NICU care. We hypothesized that early oxygen saturations (SpO 2 ), arterial pO 2 levels, and supplemental oxygen (FiO 2 ) would associate with later neuroanatomic changes., Methods: SpO 2 , arterial blood gases, and FiO 2 from 73 ELGANs (GA 26.4 ± 1.2; BW 867 ± 179 g) during the first 3 postnatal days were correlated with later white matter injury (WM, MRI, n = 69), secondary cortical somatosensory processing in magnetoencephalography (MEG-SII, n = 39), Hempel neurological examination (n = 66), and developmental quotients of Griffiths Mental Developmental Scales (GMDS, n = 58)., Results: The ELGANs with later WM abnormalities exhibited lower SpO 2 and pO 2 levels, and higher FiO 2 need during the first 3 days than those with normal WM. They also had higher pCO 2 values. The infants with abnormal MEG-SII showed opposite findings, i.e., displayed higher SpO 2 and pO 2 levels and lower FiO 2 need, than those with better outcomes. Severe WM changes and abnormal MEG-SII were correlated with adverse neurodevelopment., Conclusions: Low oxygen levels and high FiO 2 need during the NICU care associate with WM abnormalities, whereas higher oxygen levels correlate with abnormal MEG-SII. The results may indicate certain brain structures being more vulnerable to hypoxia and others to hyperoxia, thus emphasizing the role of strict saturation targets., Impact: This study indicates that both abnormally low and high oxygen levels during early NICU care are harmful for later neurodevelopmental outcomes in preterm neonates. Specific brain structures seem to be vulnerable to low and others to high oxygen levels. The findings may have clinical implications as oxygen is one of the most common therapies given in NICUs. The results emphasize the role of strict saturation targets during the early postnatal period in preterm infants., (© 2021. The Author(s).)

Background: Somatosensory evoked potentials (SEPs) offer an additional bedside tool for outcome prediction after perinatal asphyxia., Aims: To assess the reliability of SEPs recorded with bifrontoparietal amplitude-integrated electroencephalography (aEEG) brain monitoring setup for outcome prediction in asphyxiated newborns undergoing therapeutic hypothermia., Study Design: Retrospective observational single-center study., Subjects: 27 consecutive asphyxiated full- or near-term newborns (25 under hypothermia) that underwent median nerve aEEG-SEPs as part of their clinical evaluation at the neonatal intensive care unit of Helsinki University Hospital., Outcome Measures: aEEG-SEP classification (present, absent or unreliable) was compared to classification of SEPs recorded with a full EEG montage (EEG-SEP), and outcome determined from medical records at approximately 12-months-age. Unfavorable outcome included death, cerebral palsy, or severe epilepsy., Results: The aEEG-SEP and EEG-SEP classifications were concordant in 21 of the 22 newborns with both recordings available. All five newborns with bilaterally absent aEEG-SEPs had absent EEG-SEPs and the four with outcome information available had an unfavorable outcome (one was lost to follow-up). Of the newborns with aEEG-SEPs present, all with follow-up exams available had bilaterally present EEG-SEPs and a favorable outcome (one was lost to follow-up). One newborn with unilaterally absent aEEG-SEP at 25 h of age had bilaterally present EEG-SEPs on the next day, and a favorable outcome., Conclusions: aEEG-SEPs recorded during therapeutic hypothermia on the first postnatal days are reliable for assessing brain injury severity. Adding SEP into routine aEEG brain monitoring offers an additional tool for very early outcome prediction after birth asphyxia., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the accuracy of hypoxic ischemic encephalopathy (HIE) grade, and neonatal neurophysiological and neuroimaging measures for predicting development of infantile spasms syndrome (IS) or other postneonatal, infantile onset epilepsy after perinatal HIE., Methods: We examined a population-based cohort of 92 consequent infants with moderate-to-severe HIE. The HIE grade and neonatal neuroimaging (MRI) and neurophysiology (EEG and somatosensory evoked potentials, SEPs) findings were compared to the development of IS or other epilepsy within the first year of life., Results: Out of 74 surviving infants with follow-up information, five developed IS and one developed a focal onset epilepsy. They all had recovered from severe HIE. All survivors with inactive neonatal EEG (recorded within the first few postnatal days, n = 4) or the most severe type of brain injury in MRI (n = 3) developed epilepsy (positive predictive value, PPV 100 %). Bilaterally absent SEPs had 100 % sensitivity and 75 % PPV for epilepsy. A combination of absent SEPs and a poor MRI finding (combined deep and cortical gray matter injury) resulted in higher PPV (86 %) without lowering sensitivity (100 %). Follow-up EEGs showed recurrent epileptiform activity already between 1- and 2-months age in those that developed epilepsy, distinguishing them from those surviving without epilepsy., Conclusions: Poor neonatal neuroimaging and neurophysiological findings provide accurate prediction for development of infantile onset epilepsy after HIE. Of the neonates with severe HIE, the ones with severe neonatal MRI and neurophysiological abnormalities need frequent follow-up, including repeated EEGs, for early detection of IS., Competing Interests: Declaration of Competing Interest None of the authors has any conflict of interest to disclose., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Analysis of scalar maps obtained by diffusion tensor imaging (DTI) produce valuable information about the microstructure of the brain white matter. The DTI scanning of child populations, compared with adult groups, requires specifically designed data acquisition protocols that take into consideration the trade-off between the scanning time, diffusion strength, number of diffusion directions, and the applied analysis techniques. Furthermore, inadequate normalization of DTI images and non-robust tensor reconstruction have profound effects on data analyses and may produce biased statistical results. Here, we present an acquisition sequence that was specifically designed for pediatric populations, and describe the analysis steps of the DTI data collected from extremely preterm-born young school-aged children and their age- and gender-matched controls. The protocol utilizes multiple software packages to address the effects of artifacts and to produce robust tensor estimation. The computation of a population-specific template and the nonlinear registration of tensorial images with this template were implemented to improve alignment of brain images from the children., Competing Interests: The authors declare no conflict of interest., (© 2020 The Author(s). Published by Elsevier B.V.)

Aim: Preterm birth poses concerns in daily functioning and behaviour in childhood, possibly connected to sensory processing disorder. This review aimed to systematically identify assessments, incidence and nature of sensory processing disorder in preterm-born infants and children., Methods: We searched literature through CINAHL-EBSCOhost, Cochrane, Ovid/PsychINFO, PubMed/Medline, Scopus and Google Scholar, published until November 2018. We included electronically available, peer-reviewed studies of preterm-born children that applied standardised sensory processing assessments. We excluded studies of preterm-born children with major neurodevelopmental impairments., Results: We identified 27 studies of premature children, aged from birth to 9 years 7 months. The assessments represented three versions of Sensory Profile questionnaires and three clinical tests, Test of Sensory Functions in Infants, the Miller Assessment for Preschoolers, and the Sensory Integration and Praxis Test. The studies revealed wide variation of atypical sensory processing: 28%-87% in sensory modulation, 9%-70% in somatosensory processing and 20%-70% in sensory-based motor processing., Conclusion: Preterm-born children exhibited elevated risk for sensory processing disorder from infancy into school age. Routine screening of sensory processing, intervention intervals and parental consultations should be considered in ameliorating sensory processing and neurocognitive development. Moreover, a larger body of intervention studies is needed., (© 2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Preterm birth poses a risk for neurocognitive and behavioral development. Preterm children, who have not been diagnosed with neurological or cognitive deficits, enter normal schools and are expected to succeed as their term-born peers. Here we tested the hypotheses that despite an uneventful development after preterm birth, these children might exhibit subtle abnormalities in brain function and white-matter microstructure at school-age. We recruited 7.5-year-old children born extremely prematurely (<28 weeks' gestation), and age- and gender-matched term-born controls (≥37 weeks' gestation). We applied fMRI during working-memory (WM) tasks, and investigated white-matter microstructure with diffusion tensor imaging. Compared with controls, preterm-born children performed WM tasks less accurately, had reduced activation in several right prefrontal areas, and weaker deactivation of right temporal lobe areas. The weaker prefrontal activation correlated with poorer WM performance. Preterm-born children had higher fractional anisotropy (FA) and lower diffusivity than controls in several white-matter areas, and in the posterior cerebellum, the higher FA associated with poorer visuospatial test scores. In controls, higher FA and lower diffusivity correlated with faster WM performance. Together these findings demonstrate weaker WM-related brain activations and altered white matter microstructure in children born extremely preterm, who had normal global cognitive ability., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: We sought to evaluate the associations between umbilical artery pH and base excess and neurodevelopmental outcome at four years of age., Methods: This study comprised 84 588 singleton children born alive at term in 2005-2011 in the hospital district of Helsinki and Uusimaa in Finland. Data from the maternity hospital information system were linked to the data from the Medical Birth Register and the Hospital Discharge Register. Neurodevelopmental morbidity included cerebral palsy, epilepsy, intellectual or sensorineural impairment., Results: After adjustment for maternal and perinatal factors, a combination of pH <7.00 and base excess <-16.00 was associated with infant death (adjusted odds ratio 19.97; 95% confidence interval 5.38-74.17). Values of pH 7.00-7.10 were associated with cerebral palsy (adjusted odds ratio 2.40; 95% confidence interval 1.05-5.47). A combination of low five-minute Apgar score and umbilical artery base excess <-16.00 showed the highest positive predictive value (9.1%) for neurodevelopmental impairments. When umbilical artery pH <7.00 was included, a positive predictive value of 25.0% was observed for infant mortality., Conclusion: Low umbilical artery pH and base excess at birth were the poor predictors of long-term neurodevelopmental morbidity in an unselected population. However, these parameters might be useful in assessing the risk of infant mortality., (©2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia., Methods: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion., Discussion: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia., Trial Registration: NCT03162653, www.ClinicalTrials.gov , May 22, 2017.

Objective: The unspecific symptoms of neonatal stroke still challenge its bedside diagnosis. We studied the accuracy of routine electroencephalography (EEG) and simultaneously recorded somatosensory evoked potentials (EEG-SEP) for diagnosis and outcome prediction of neonatal stroke., Methods: We evaluated EEG and EEG-SEPs from a hospital cohort of 174 near-term neonates with suspected seizures or encephalopathy, 32 of whom were diagnosed with acute ischemic or hemorrhagic stroke in MRI. EEG was scored for background activity and seizures. SEPs were classified as present or absent. Developmental outcome of stroke survivors was evaluated from medical records at 8- to 18-months age., Results: The combination of continuous EEG and uni- or bilaterally absent SEP (n = 10) was exclusively seen in neonates with a middle cerebral artery (MCA) stroke (specificity 100%). Moreover, 80% of the neonates with this finding developed with cerebral palsy. Bilaterally present SEPs did not exclude stroke, but predicted favorable neuromotor outcome in stroke survivors (positive predictive value 95%)., Conclusions: Absent SEP combined with continuous EEG background in near-term neonates indicates an MCA stroke and a high risk for cerebral palsy., Significance: EEG-SEP offers a bedside method for diagnostic screening and a reliable prediction of neuromotor outcome in neonates suspected of having a stroke., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Placentation is characterized by extensive cell proliferation and neovascularization, which is similar to the processes observed in the development of cancer. Nonetheless, little is known about the relation between abnormal placentation, such as placental abruption, and cancer., Material and Methods: Data on women with placental abruption in a singleton pregnancy between 1971 and 2005 (n = 7804) were collected from the Finnish Hospital Discharge Registry and the Finnish Medical Birth Registry. The cohort was then linked with the Finnish Cancer Registry records until the end of 2013. Standardized incidence ratios (SIRs) were calculated for different cancers by dividing the observed numbers of cancers by those expected. The expected numbers were based on national cancer incidence rates., Results: During follow-up, 597 cancers were found among women with a history of placental abruption. The overall risk of cancer was not increased (SIR 0.95, 95% CI 0.88-1.02). However, the history of placental abruption was associated with an increased risk of lung cancer (SIR 1.51, 95% CI 1.05-2.10) and thyroid cancer (SIR 1.47, 95% CI 1.04-2.02). A decreased risk was found for breast cancer (SIR 0.85, 95% CI 0.75-0.96). The risk of rectal cancer was also decreased, although these numbers were small (SIR 0.49, 95% CI 0.20-1.01)., Conclusions: Overall, the risk of lung cancer was increased, and the risk of breast cancer decreased, in women with a history of placental abruption. These observations can be explained to some extent by risk factors or risk markers for placental abruption. The increased risk of thyroid cancer may be explained by surveillance bias.

Background and Objectives: Placental abruption causes asphyxia and leads to high perinatal mortality. Our objective was to study the overall mortality and causes of death among children born after placental abruption., Methods: Data on children born from singleton pregnancies complicated by placental abruption between 1987 and 2005 were collected from the Finnish Medical Birth Register, the Hospital Discharge Register, and the Cause-of-Death Register. A reference group consisted of children born from pregnancies without placental abruption. After excluding stillbirths, the final study sample comprised 3888 children born after placental abruption (index children) and 12 530 referent children. The main outcome measure was overall mortality., Results: By the end of 2013, there were 280 deaths among the index children and 107 deaths among the referent children. Compared with the referent children, the overall mortality among the index children was significantly increased (hazard ratio: 8.70; 95% confidence interval 6.96-10.90). During the neonatal period (0-27 days) the mortality was nearly 15-fold (14.8; 10.9-20.0), birth-related asphyxia being the leading cause of death (108; 34-341). The mortality remained high during days 28 to 365 (10.3; 4.83-21.8) and beyond 365 days (1.70; 1.03-2.79). Furthermore, the overall mortality was increased among the index children born at 32 to 36 + 6 gestational weeks (2.77; 1.54-4.98) and at ≥37 weeks (4.98; 3.54-6.99) and among children with a birth weight of 2500 g or more (5.94; 4.33-8.14)., Conclusions: The impact of abruption on offspring mortality extends far beyond the perinatal period. This is mainly due to birth-related asphyxia and prematurity-related consequences., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)