Detailed statistical analysis plan for ALBINO: effect of Allopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome - a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III).

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.

Distinctive Amplitude-Integrated EEG Ictal Pattern and Targeted Therapy with Carbamazepine in KCNQ2 and KCNQ3 Neonatal Epilepsy: A Case Series.

BACKGROUND: Carbamazepine (CBZ) is effective in treating KCNQ2/3-related seizures, which may present with a distinctive amplitude-integrated electroencephalography (aEEG) pattern. OBJECTIVE: To assess how improved recognition of the distinctive aEEG ictal pattern associated with KCNQ2/3 variants has enabled early and effective targeted therapy with CBZ. METHODS: Retrospective descriptive study of five neonates with KCNQ2/3 pathogenic gene variants admitted at a level 3 neonatal intensive care unit (NICU) over an 8-year period. RESULTS: The distinctive ictal aEEG pattern was recognized in four neonates after an average of 61.5 hours (minimum 12 hours, maximum 120 hours) from the first electroclinical seizure and prompted the use of CBZ that was effective in all. The two most recently diagnosed patients could avoid polytherapy as they received CBZ as the first and second antiseizure medication, respectively. Three out of five patients with continuous normal voltage (CNV), sleep-wake cycling (SWC), and shorter postictal suppression had normal neurodevelopmental outcome. Regarding the remaining two infants, one was not trialed with CBZ and had a high seizure burden, both presented with a prolonged postictal suppression, no SWC, and had moderate-to-severe developmental delay. Genetic results became available after the neonatal period in all but one of the infants, who had a prenatal diagnosis. CONCLUSION: Recognition of the distinctive ictal aEEG pattern in the NICU allowed early and effective targeted therapy with CBZ in four neonates, well before genetic results became available. Furthermore, a CNV background pattern with SWC and short postictal suppression were associated with normal developmental outcomes.

Symptomatic Subdural Hygroma Following Acinetobacter Meningitis in an Infant.

We present a case of a full-term newborn with prenatal congenital heart disease, admitted to a level III neonatal intensive care unit. After undergoing a surgical palliation procedure, he experienced a complicated recovery, including nosocomial sepsis with isolation of Acinetobacter nosocomialis in both blood and cerebrospinal fluid. Subsequently, he developed focal clonic seizures that were refractory to antiepileptic drugs, and imaging studies revealed the presence of a subdural hygroma. Surgical drainage was performed, resulting in the resolution of the seizures. This report highlights the rare occurrence of Acinetobacter meningitis unrelated to neurosurgery and its progression to subdural hygroma in an infant, emphasizing the importance of recognizing such complications as potential causes of refractory seizures following infectious processes.

Early recognition of characteristic conventional and amplitude-integrated EEG patterns of seizures in SCN2A and KCNQ3-related epilepsy in neonates.

PURPOSE: Early recognition of seizures in neonates secondary to pathogenic variants in potassium or sodium channel coding genes is crucial, as these seizures are often resistant to commonly used anti-seizure medications but respond well to sodium channel blockers. Recently, a characteristic ictal amplitude-integrated electroencephalogram (aEEG) pattern was described in neonates with KCNQ2-related epilepsy. We report a similar aEEG pattern in seizures caused by SCN2A- and KCNQ3-pathogenic variants, as well as conventional EEG (cEEG) descriptions. METHODS: International multicentre descriptive study, reporting clinical characteristics, aEEG and cEEG findings of 13 neonates with seizures due to pathogenic SCN2A- and KCNQ3-variants. As a comparison group, aEEGs and cEEGs of neonates with seizures due to hypoxic-ischemic encephalopathy (n = 117) and other confirmed genetic causes affecting channel function (n = 55) were reviewed. RESULTS: In 12 out of 13 patients, the aEEG showed a characteristic sequence of brief onset with a decrease, followed by a quick rise, and then postictal amplitude attenuation. This pattern correlated with bilateral EEG onset attenuation, followed by rhythmic discharges ending in several seconds of post-ictal amplitude suppression. Apart from patients with KCNQ2-related epilepsy, none of the patients in the comparison groups had a similar aEEG or cEEG pattern. DISCUSSION: Seizures in SCN2A- and KCNQ3-related epilepsy in neonates can usually be recognized by a characteristic ictal aEEG pattern, previously reported only in KCNQ2-related epilepsy, extending this unique feature to other channelopathies. Awareness of this pattern facilitates the prompt initiation of precision treatment with sodium channel blockers even before genetic results are available.

Novel Arthrogryposis Multiplex Congenita Presentation in a Newborn With Pierpont Syndrome.

Pierpont syndrome is a rare and recently described multiple congenital anomaly syndrome, classically characterized by global developmental delay, distinctive facial dysmorphic features, and abnormal fat distribution in distal limbs. Only few cases were previously documented. We report a case of a term male neonate admitted to the neonatal intensive care unit because of feeding difficulties. Intrauterine growth restriction, microcephaly, and bilateral equinovarus foot were diagnosed in the second trimester, and prenatal array comparative genomic hybridization showed no abnormality. Physical examination revealed bilateral flexion deformities of wrists, elbows, knees and clubfoot, large hands and feet, deep palmar and plantar grooves, and calcaneo-plantar fat pads. Craniofacial dysmorphism, axial hypotonia, and hypoactivity were also observed. Due to the presence of congenital and non-progressive joint contractures, arthrogryposis multiplex congenita (AMC) was considered. A comprehensive diagnostic workup, including a Next Generation Sequencing target panel, was performed but did not establish a diagnosis. The clinical exome identified an heterozygous pathogenic variant in the TBL1XR1 gene (NM_001321194.1: c.1337A>G, p.[Tyr446Cys]), allowing Pierpont syndrome diagnosis. Our case stands out for reporting the novel AMC presentation in a Pierpont syndrome newborn. The broader and precocious genetic testing proved to be an essential clarifying diagnostic tool. Our patient supports the relation between the p.Tyr446Cys sequence variant in TBL1XR1 gene with this rare syndrome, reinforcing its association with a distinctive and recognizable phenotype, as well as expanding its clinical features to include AMC.

Use of Therapeutic Hypothermia in Sudden Unexpected Postnatal Collapse: A Retrospective Study.

INTRODUCTION: Sudden and unexpected postnatal collapse is a rare event with potentially dramatic consequences. Intervention approaches are limited, but hypothermia has been considered after postnatal collapse. The aim of this study was to analyse sudden and unexpected postnatal collapse cases that underwent therapeutic hypothermia in the five Portuguese hypothermia centres. MATERIAL AND METHODS: In this multicentre, retrospective and descriptive study, clinical, ultrasonography, amplitude-integrated electroencephalography and brain magnetic resonance findings of newborns with postnatal collapse that underwent therapeutic hypothermia are reported (2010 - 2018). Statistical analysis was performed by using IBM SPSS Statistics version 21. RESULTS: Twenty-two cases of sudden and unexpected postnatal collapse were referred for therapeutic hypothermia (82% outborn), all ≥ 36 weeks, with Apgar 5´ ≥ 8. Collapse occurred during the first two hours in 73% (all < 24 hours), 50% during skin-to-skin care, 55% related to feeding and 23% during co-bedding. Moderate-severe encephalopathy and severe acidosis were observed (median: Thompson score 16, pH 6.90, base deficit 22 mmol/L). Amplitude-integrated electroencephalogram was abnormal in 95% and magnetic resonance imaging showed severe brain injury in 46%. The mortality rate was 50%. A possible cause was identified in 27%. DISCUSSION: The incidence rate of 2.7 sudden cases of postnatal collapse per 100 000 births, is possibly under-estimated. All infants suffered the collapse in the first day, mostly within the first two hours, as reported before. Possible causes were identified in less than a third of cases, but multiple predisposing conditions were identified, suggesting that prevention may be possible. Newborn positioning and skin-to-skin care have been the most discussed practices. A significant proportion of infants had poor outcomes. Lower Thompson score, electroencephalogram amplitude normalization and normal magnetic resonance imaging seemed to indicate better outcomes. Although conclusive trials on therapeutic hypothermia after postnatal collapse are not available, its use has been considered individually. No severe adverse effects directly related to hypothermia were registered in this study, but the results do not allow drawing meaningful conclusions. CONCLUSION: In our national sample of 22 infants who suffered sudden and unexpected postnatal collapse and underwent therapeutic hypothermia, a significant proportion had poor outcomes. Absolute conclusions from our experience with hypothermia in postnatal collapse cannot be drawn, but systematic reporting of cases and long-term clinical evaluation would facilitate understanding of the real benefits of hypothermia. As this procedure has not been validated with clinical trials for this indication, its use should be considered on a case-by-case approach. The potentially avoidable nature of unexpected postnatal collapse is evident from its association with certain behaviours and risk factors. Surveillance practices during the first hours should be implemented, whilst the benefits of breastfeeding and skin-to-skin care should continue to be widely promoted.

Introdução: O colapso pós-natal súbito inesperado, apesar de raro, condiciona potenciais consequências dramáticas. As intervenções terapêuticas são limitadas, mas a hipotermia induzida tem sido considerada após estes eventos. O objetivo deste estudo foi analisar os casos de colapso pós-natal súbito inesperado submetidos a hipotermia induzida nos cinco centros portugueses que a realizam. Material e Métodos: Estudo descritivo retrospetivo multicêntrico dos recém-nascidos submetidos a hipotermia induzida após colapso pós-natal entre 2010 e 2018. Foram analisadas as variáveis clínicas, a monitorização por eletroencefalograma de amplitude integrada e imagem por ultrassonografia e a ressonância magnética cerebral. A análise estatística foi efetuada com apoio do IBM SPSS Statistics version 21. Resultados: Foram submetidos a hipotermia terapêutica por colapso súbito 22 recém-nascidos, 82% outborn, todos com 36 ou mais semanas de gestação e Apgar 5´ ≥ 8. A situação ocorreu nas primeiras duas horas de vida em 73% (todos com menos de 24 horas de vida), 50% no contacto pele-a-pele, 55% associados à amamentação e 23% durante partilha de cama. Os recém-nascidos observados apresentaram encefalopatia moderada a grave e acidose grave (mediana: Thompson 16, pH 6,90, défice bases 22 mmol/L). Entre os recém-nascidos, 95% registaram alteração no eletroencefalograma e 46% padrões graves de ressonância cerebral. A taxa de mortalidade foi de 50%. Identificaram-se possíveis causas em 27%. Discussão: Estimou-se uma incidência de 2,7 casos de colapso pós-natal súbito inesperado por cada 100 000 nascimentos, um valor possivelmente subestimado. O colapso ocorreu no primeiro dia em todas as crianças, a maioria nas primeiras duas horas, tal como descrito em publicações anteriores. Identificaram-se possíveis causas em menos de um terço dos casos, mas múltiplas condições predisponentes foram referidas, o que sugere a possibilidade de adoção de medidas preventivas. O posicionamento do recém-nascido e o contacto pele-a-pele têm sido as práticas mais discutidas. Uma proporção significativa das crianças teve uma evolução desfavorável. Um desfecho mais positivo parece ter ocorrido nos casos em que se verificaram valores inferiores na escala de Thompson, normalização do eletroencefalograma de amplitude integrada e ressonância magnética normal. Embora não estejam disponíveis ensaios conclusivos sobre a utilização da hipotermia terapêutica após o colapso pós-natal, o seu uso tem sido considerado individualmente. Nesta revisão não foram observados efeitos adversos diretamente relacionados com o procedimento, mas os resultados não permitem obter conclusões significativas. Conclusão: Na nossa amostra nacional de 22 crianças que sofreram colapso súbito pós-natal e submetidas a hipotermia terapêutica, uma proporção significativa teve uma evolução desfavorável. A nossa experiência e a raridade da entidade clínica não permitem delinear conclusões precisas sobre a aplicação da hipotermia induzida no colapso pós-natal súbito inesperado, pelo que se considera essencial a prevenção. O benefício desta terapêutica poderá ser clarificado através do registo sistemático dos casos e do seguimento a longo prazo das crianças. Embora não existam ensaios clínicos que permitam a sua validação após estes eventos, a hipotermia induzida deve ser uma opção a considerar individualmente. A associação do colapso pós-natal com determinados comportamentos e fatores de risco evidenciam a sua potencial prevenção. Devem ser implementadas estratégias de monitorização nas primeiras horas de vida que permitam simultaneamente a contínua promoção da amamentação e do contacto pele-a-pele.

Clinicopathological features of neonatal subcutaneous fat necrosis and its implications.

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Detailed statistical analysis plan for the SafeBoosC III trial: a multinational randomised clinical trial assessing treatment guided by cerebral oxygenation monitoring versus treatment as usual in extremely preterm infants.

BACKGROUND: Infants born extremely preterm are at high risk of dying or suffering from severe brain injuries. Treatment guided by monitoring of cerebral oxygenation may reduce the risk of death and neurologic complications. The SafeBoosC III trial evaluates the effects of treatment guided by cerebral oxygenation monitoring versus treatment as usual. This article describes the detailed statistical analysis plan for the main publication, with the aim to prevent outcome reporting bias and data-driven analyses. METHODS/DESIGN: The SafeBoosC III trial is an investigator-initiated, randomised, multinational, pragmatic phase III trial with a parallel group structure, designed to investigate the benefits and harms of treatment based on cerebral near-infrared spectroscopy monitoring compared with treatment as usual. Randomisation will be 1:1 stratified for neonatal intensive care unit and gestational age (lower gestational age (< 26 weeks) compared to higher gestational age (≥ 26 weeks)). The primary outcome is a composite of death or severe brain injury at 36 weeks postmenstrual age. Primary analysis will be made on the intention-to-treat population for all outcomes, using mixed-model logistic regression adjusting for stratification variables. In the primary analysis, the twin intra-class correlation coefficient will not be considered. However, we will perform sensitivity analyses to address this. Our simulation study suggests that the inclusion of multiple births is unlikely to significantly affect our assessment of intervention effects, and therefore we have chosen the analysis where the twin intra-class correlation coefficient will not be considered as the primary analysis. DISCUSSION: In line with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines, we have developed and published this statistical analysis plan for the SafeBoosC III trial, prior to any data analysis. TRIAL REGISTRATION: ClinicalTrials.org, NCT03770741. Registered on 10 December 2018.

Pulmonary involvement in neonatal lupus: a challenging diagnosis - case report and literature review.

INTRODUCTION: Pulmonary involvement is relatively frequent in adult and juvenile patients with Systemic Lupus Erythematosus (SLE), but its occurrence in newborns with Neonatal Lupus Erythematosus (NLE) is exceedingly rare. CASE REPORT: A mother with SLE and positive anti-SSA/Ro and anti-SSB/La delivered a preterm newborn with third-degree heart block and positive anti-SSA/Ro confirmed postnatally. A temporary pacemaker was placed at D3 and a definitive pacemaker only at D15 due to sepsis with concurrent mild respiratory failure. Despite adequate antibiotic therapy, negative cultures and decreasing inflammatory parameters, at D17 severe respiratory failure ensued, requiring mechanical ventilation. Chest x-ray showed symmetrical interstitial infiltrates. Acute Lupus Pneumonitis (ALP) and Pulmonary Embolism were suspected and the chest angio-CT revealed diffuse ground glass opacities. After 3 methylprednisolone pulses he improved rapidly. DISCUSSION: The diagnosis of ALP in NLE, mostly one of exclusion, is a challenge. A high degree of suspicion and a multidisciplinary approach to these patients are fundamental in order not to delay establishing a diagnosis. Although few reports in the literature, early aggressive treatments are probably crucial for a favorable outcome without long-term sequelae.

A Distinctive Ictal Amplitude-Integrated Electroencephalography Pattern in Newborns with Neonatal Epilepsy Associated with KCNQ2 Mutations.

BACKGROUND: Recurrent and prolonged seizures are harmful for the developing brain, emphasizing the importance of early seizure recognition and effective therapy. Amplitude-integrated electroencephalography (aEEG) has become a valuable tool to diagnose epileptic seizures, and, in parallel, genetic etiologies are increasingly being recognized, changing the paradigm of the workup and management of neonatal seizures. OBJECTIVE: To report the ictal aEEG pattern in neonates with KCNQ2-related epilepsy. SUBJECTS AND METHODS: In this multicenter descriptive study, clinical data and aEEG findings of 9 newborns with KCNQ2 mutations are reported. RESULTS: Refractory seizures occurred in the early neonatal period with similar seizure type, including tonic features, apnea, and desaturation. A distinct aEEG seizure pattern, consisting of a sudden rise of the lower and upper margin of the aEEG, followed by a marked depression of the aEEG amplitude, was found in 8 of the 9 patients. Prompt recognition of this pattern led to early treatment with carbamazepine in the 2 most recent cases. CONCLUSION: Early recognition of the electroclinical phenotype by using aEEG may direct genetic testing and a precision medicine approach with sodium channel blockers in neonates with KCNQ2 mutations.

A Comparison of the Thompson Encephalopathy Score and Amplitude-Integrated Electroencephalography in Infants with Perinatal Asphyxia and Therapeutic Hypothermia.

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.

Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACD/MPV): A Case Series.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, fatal, developmental lung disorder, which usually presents as persistent pulmonary hypertension of the newborn (PPHN) unresponsive to treatment. The authors present their own experience with three cases admitted during the last 15 years.

[Neonatal seizures in a tertiary neonatal intensive care unit]. / Convulsões neonatais numa unidade de cuidados intensivos neonatais terciária.

INTRODUCTION: Seizures are frequent in the neonatal period. They can be idiopathic, be caused by organic brain anomalies or by metabolic disturbances. OBJECTIVE: Evaluation of the etiologic diagnosis and clinical evolution of the newborns with neonatal seizures admitted at one tertiary neonatal intensive care unit. MATERIAL AND METHODS: Retrospective review of the clinical files of the newborns with neonatal seizures, during a period of eight years. RESULTS: Neonatal seizures occurred in 91 cases. Seventy nine (86.8%) received anticonvulsant therapy during clinical seizure. Image and/or electrophysiological studies were performed in the majority of newborns (86.8%). Etiology was identified in 51.6% of the 91 cases studied, being the more frequent situations: central nervous system bleeding (11 cases), hypoxic-ischemic encephalopathy (10 cases) and electrolytes disturbances (7 cases). Mortality rate was 16.5%. The newborns followed in our hospital had good neurodevelopment, in 70.2% of cases but in 10.6% was detected important neurodevelopment impairment, including cerebral palsy. CONCLUSIONS: Anomalies in the cranial ultrasound and in the electroencephalography were correlated with clinical evolution. They still are first line exams in the initial approach to this pathology.

Diagnosis and cause of death in a neonatal intensive care unit--how important is autopsy?

OBJECTIVES: To characterize mortality in a tertiary referral Neonatal Intensive Care Unit (NICU) in Portugal and evaluate the concordance between ante-mortem and post-mortem diagnoses. METHODS: Retrospective review of the clinical and pathological records of infants who died in five consecutive years was done. Pathological findings and clinical diagnoses were compared and classified according to general concordance and to modified Goldman classification. RESULTS: During the referred period, 1938 patients were admitted to the NICU, with a mortality rate of 5.7% (110 patients). The median of age at death was 10.5 days and the most frequent causes of death were congenital malformations and prematurity with its complications. Autopsy was performed in 53 patients resulting in a 48.2% overall autopsy rate. There was complete agreement between pathological and clinical diagnoses in 18 cases (34%) and additional findings were identified in 22 cases; in 13 cases (24.5%), the diagnosis was revised or established by pathology. Five autopsies revealed information relevant for genetic counseling. CONCLUSION: Despite the high agreement rate between clinical and pathological diagnoses, autopsy frequently added important data, including several cases in which it established the diagnosis or provided information relevant for parental counseling regarding future pregnancies.