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Purpose: Premature infants are prone to impaired neurodevelopmental outcomes due to brain injury or underdevelopment. However, these outcomes may be present without any brain lesions. The association between neonatal morbidities and the volume of segmentalbrain structures is not fully understood. Therefore, we analyzed the association between brain structure volumes, neonatal morbidities, and neurodevelopmental outcomesin extremepreterm infants. Methods: This retrospective cohort study included 158 extreme preterm infants, in whom brain magnetic resonance imaging at term equivalent age (TEA-MRI) and neurodevelopmental evaluation wereperformed at a corrected age of 18–24 months.Patients with congenital anomalies or significant brain lesions, such as high-grade intraventricular hemorrhage and periventricular leukomalacia were excluded. Medical records, including the Bayley Scales of Infant and Toddler Development 3rd Edition (BSID-III), of preterm infants were reviewed and analyzed. FreeSurfer infant software was used to evaluatebrain structures, while volumes of specific brain regions were adjusted for gestational age and postmenstrual age on MRI using multivariate regression analysis. Results: Preterm infants with neurodevelopmental impairment had smaller midbrain (aOR 0.804, 95% CI 0.647–0.998). Neonatal morbidities of preterm infants included respiratory distress syndrome (RDS), which was associated with a smaller volume of the medulla (aOR 0.593, 95% CI 0.387–0.908), ventral diencephalon (aOR 0.730, 95% CI 0.572–0.932), and putamen (aOR 0.874, 95% CI 0.788–0.969). Patent ductus arteriosus (PDA) requiring surgery was associated with a smaller volume of the pons (aOR 0.727, 95% CI 0.594–0.889) and vermis (aOR 0.766, 95% CI 0.646–0.907). Retinopathy of prematurity (ROP) requiring surgery was associated with a smaller pons volume (aOR 0.729, 95% CI 0.600–0.886). Necrotizing enterocolitis (NEC) requiring surgery was associated with a smaller volume of the pons (aOR 0.751, 95% CI 0.661–0.854), vermis (aOR 0.832, 95% CI 0.745–0.930), and cerebellum (aOR 0.974, 95% CI 0.960–0.989). Conclusions: Among preterm infants without significant brain injuries, smaller volume of midbrain was associated with impaired neurodevelopment. RDS and morbidities requiring surgery such as PDA, ROP, and NEC were associated with reduced segmental volumes of the brain in preterm infants.

Introduction: Surgical ligation for hemodynamically significant patent ductus arteriosus (PDA) is sometimes required in preterm infants; however, some patients experience worsened respiratory status after the surgery. This study aimed to evaluate the risk factors that could predict worsened respiratory outcomes after PDA ligation. Methods: A retrospective cohort study was performed on 57 preterm infants born at less than 32 weeks of gestational age and in whom the PDA was surgically ligated between January 2014 and December 2018 at Seoul National University Children’s Hospital. Participants were divided into two groups: infants with worsened respiratory outcomes 14 days after ligation and control. Worsened respiratory outcome was defined as increase in respiratory severity score (RSS) by 30% or more at 14 days after ligation compared to RSS before ligation, or death at 14 days after ligation. Results: Among the 57 PDA-ligated infants, 12 had worsened respiratory outcomes and 45 did not. The worsened respiratory outcomes were associated with oligohydramnios (adjusted OR 1.373, 95% CI 1.113-1.694.), histologic chorioamnionitis (adjusted OR 1.240, 95% CI 1.016-1.512), and decreased weight on the day of surgery (adjusted OR 0.999, 95% CI 0.999-0.999) compared to that in the control. Conclusion: Worsened respiratory outcomes after PDA ligation appeared to be associated with oligohydramnios, histologic chorioamnionitis, and weight on the day of surgery.

Purpose Febrile seizures (FS) are the most common seizures found in pediatric patients. Recently, microRNA (miRNA) have been used as a novel biomarker for the diagnosis of various diseases. This study aims to explore the exosomal miRNA expression profile of the cerebrospinal fluid (CSF) in atypical FS patients. Methods This is a case-control study including CSF specimens of 41 pediatric patients. The CSF specimens were categorized into FS and a control group. Microarray assays were performed to evaluate the CSF exosomal miRNA expression profile. Quantitative PCR (qPCR) assays were conducted to validate the microarray assay result. Bioinformatic analysis was performed to analyze the result. Results Thirteen (62%) patients in the FS group experienced complex FS. A total of 96 miRNAs were significantly expressed in the CSF study samples and 95 amongst them, exhibited higher expression in FS than in the control group. Further validation qPCR test indicated that the top 5 highly expressed miRNA (miR-4486, miR-6850-5p, miR-642b-3p, miR-7107-5p, miR-4281) showed same results as in the microarray assay. Bioinformatic analysis identified 455 target genes in the FS group. Conclusion FS patients displayed higher CSF exosomal miRNA profiles than the control. These altered miRNA profiles appeared to be related to complex FS.

Various perinatal morbidities may adversely affect postnatal nephrogenesis in preterm infants. Kidney ultrasonographic findings following acute kidney injury (AKI) have not been well described in preterm infants. Herein, we describe three cases of extremely preterm infants who showed abnormal kidney ultrasonographic findings resembling dysplasia of the kidneys following AKI. Their median gestational age and birth weight were 25+6 (range 23+3–26+6) weeks and 620 (480–840) g, respectively. All infants suffered severe AKI during their third to seventh week of life. Their kidney function recovered with conventional management. Kidney ultrasonographies performed after AKI revealed increased kidney echogenicity, loss of corticomedullary differentiation, and multiple cortical cysts, which were similar to cystic dysplasia of the kidneys and were absent in previous kidney imaging. Three infants eventually developed at least one of the long-term kidney sequelae following AKI, including proteinuria, hypertension, and elevated levels of serum creatinine or cystatin C as determined during the last follow-up at the corrected age of 9–18 months. Based on these cases, we can infer that AKI occurring during the early postnatal period may result in dysplasia of the kidneys with cortical cysts in extremely preterm infants, which may lead to chronic kidney disease in their later life. It is useful to follow up not only laboratory parameters but also kidney ultrasonographic findings in extremely preterm infants who suffered AKI during their early postnatal periods.

Growth charts are essential for monitoring the postnatal growth of preterm infants. The preterm postnatal follow-up study (PPFS) of the Intergrowth-21st Project provides new growth standards based on a longitudinal study. This study was conducted to investigate the prevalence of extrautrine growth restriction (EUGR) and the associated factors of EUGR in preterm infants, using the PPFS charts and the Fenton charts. Data of 1,356 infants with gestational age (GA) less than 28 weeks from the Korean Neonatal Network were analysed. The prevalence of small for gestational age (SGA) of weight and length was higher with the Intergrowth charts than with the Fenton charts. EUGR in weight and length was more prevalent when using the Fenton charts. Multivariate analysis showed that low GA, high birthweight z score, male, treated patent ductus arteriosus (PDA), necrotizing enterocolitis, intraventricular haemorrhage and duration of parenteral nutrition (PN) were associated with EUGR in weight by the Intergrowth charts. High birthweight z score, treated PDA and PN duration were associated with EUGR defined by the Fenton charts. Conclusion: Compared to the Fenton charts, SGA was more defined and EUGR was less prevalent in extremely low gestational infants, while EUGR defined by the Intergrowth charts categorized infants with adverse clinical courses more elaborately.What is Known:• Preterm infants are at risk of postnatal growth restriction (PGR), although optimal postnatal growth is important for the long-term outcomes.• Growth charts are essential tools to monitor the postnatal growth of preterm infants.What is New:• PGR of weight and length were less defined with the Intergrowth charts than the Fenton charts.• PGR defined by the Intergrowth preterm postnatal follow-up study (PPFS) chart categorized preterm infants with morbidities more elaborately than the Fenton charts. Electronic supplementary material The online version of this article (10.1007/s00431-020-03796-0) contains supplementary material, which is available to authorized users.

To compare the effects of noninvasive neurally adjusted ventilatory assist (NIV-NAVA) to nasal continuous positive airway pressure (NCPAP) in achieving successful extubation in preterm infants.This prospective, single-center, randomized controlled trial enrolled preterm infants born at30 weeks of gestation who received invasive ventilation. Participants were assigned at random to either NIV-NAVA or NCPAP after their first extubation from invasive ventilation. The primary outcome of the study was extubation failure within 72 hours of extubation. Electrical activity of the diaphragm (Edi) values were collected before extubation and at 1, 4, 12, and 24 hours after extubation.A total of 78 infants were enrolled, including 35 infants in the NIV-NAVA group and 35 infants in the NCPAP group. Extubation failure within 72 hours of extubation was higher in the NCPAP group than in the NIV-NAVA group (28.6% vs 8.6%; P = .031). The duration of respiratory support and incidence of severe bronchopulmonary dysplasia were similar in the 2 groups. Peak and swing Edi values were comparable before and at 1 hour after extubation, but values at 4, 12, and 24 hours after extubation were lower in the NIV-NAVA group compared with the NCPAP group.In the present trial, NIV-NAVA was more effective than NCPAP in preventing extubation failure in preterm infants.ClinicalTrials.gov: NCT02590757.

BackgroundThe definition of bronchopulmonary dysplasia (BPD) has been evolved recently from definition by the National Institute of Child Health and Human Development in 2001 (NICHD 2001) to the definition reported in 2018 (NICHD 2018) and that proposed by Jensen et al. in 2019 (NICHD 2019). The definition was developed based on the evolution of non-invasive respiratory support and to achieve better prediction of later outcomes. Our objective was to evaluate the association between different definitions of BPD and occurrence of pulmonary hypertension (PHN) and long term outcomes.MethodsThis retrospective study enrolled preterm infants born at ResultsAmong 354 infants, the gestational age and birth weight were the lowest in severe BPD based on the NICHD 2019 definition. In total, 14.1% of the study population experienced NDI and 19.0% were re-hospitalized owing to a respiratory illness. At a PMA of 36 weeks, PHN was identified in 9.2% of infants with any BPD. Multiple logistic regression analysis showed that the adjusted odds ratio (OR) for re-hospitalization was the highest for Grade 3 BPD of the NICHD 2019 criteria (5.72, 95% confidence interval [CI]: 1.37–23.92), while the adjusted OR of Grade 3 BPD was 4.96 (95% CI: 1.73–14.23) in the NICHD 2018 definition. Moreover, no association of the severity of BPD was found in the NICHD 2001 definition. The adjusted ORs for NDI (12.09, 95% CI: 2.52–58.05) and PHN (40.37, 95% CI: 5.15–316.34) were also the highest for Grade 3 of the NICHD 2019 criteria.ConclusionBased on recently suggested criteria by the NICHD in 2019, BPD severity is associated with long-term outcomes and PHN at a PMA of 36 weeks in preterm infants.

Cerebrospinal fluid (CSF) is a dynamic metabolically active body fluid that has many important roles and is commonly analyzed in pediatric patients, mainly to diagnose central nervous system infection and inflammation disorders. CSF components have been extensively evaluated as biomarkers of neurological disorders in adult patients. Circulating microRNAs in CSF are a promising class of biomarkers for various neurological diseases. Due to the complexity of pediatric neurological disorders and difficulty in acquiring CSF samples from pediatric patients, there are challenges in developing CSF biomarkers of pediatric neurological disorders. This review aimed to provide an overview of novel CSF biomarkers of seizure disorders, infection, inflammation, tumor, traumatic brain injuries, intraventricular hemorrhage, and congenital hydrocephalus exclusively observed in pediatric patients.

Background: Antenatal magnesium sulfate is widely used as a tocolytic, for maternal seizures, and for seizure prophylaxis in preeclampsia. Recent studies have suggested that antenatal magnesium sulfate use is associated with favorable neurodevelopmental outcomes in preterm infants. However, there are concerns regarding the effects of antenatal magnesium sulfate on neonates, especially regarding gastrointestinal morbidities. This study aims to explore the effects of antenatal magnesium sulfate on intestinal morbidities requiring surgery in preterm infants. Methods: This was a retrospective cohort study of 181 preterm infants who were born at less than 28 weeks of gestational age. Subjects were categorized as infants exposed to antenatal magnesium sulfate and those not exposed to antenatal magnesium sulfate. Results: Antenatal magnesium sulfate was associated with a decreased risk of surgical conditions of the intestine (OR 0.393, 95% CI 0.170–0.905). The multivariate analysis showed that the duration of antenatal magnesium sulfate use was associated with surgical conditions of the intestine (adjusted OR 0.766, 95% CI 0.589–0.997). In the

Background Antenatal magnesium sulfate is widely used as a tocolytic, for maternal seizures, and for seizure prophylaxis in preeclampsia. Recent studies have suggested that antenatal magnesium sulfate use is associated with favorable neurodevelopmental outcomes in preterm infants. However, there are concerns regarding the neonatal effects of antenatal magnesium sulfate, especially regarding gastrointestinal morbidities. This study aims to explore the effects of antenatal magnesium sulfate on intestinal morbidities requiring surgery in preterm infants.Methods This was a retrospective cohort study of 181 preterm infants who were born at less than 28 weeks of gestational age. Subjects were categorized as infants exposed to antenatal magnesium sulfate and those not exposed to antenatal magnesium sulfate.Results Antenatal magnesium sulfate was associated with a lower incidence of surgical conditions of the intestine (OR 0.393, 95% CI 0.170–0.905). Multivariate analysis showed that the duration of antenatal magnesium sulfate use was associated with surgical conditions of the intestine (adjusted OR 0.766, 95% CI 0.589–0.997). In the Conclusion Antenatal magnesium sulfate use appears to have a protective effect on intestinal morbidities requiring surgery in preterm infants in a duration-dependent manner. Association of antenatal magnesium sulfate use and decreased intestinal morbidities requiring surgery was more distinct in preterm infants

The prevalence of pregnancy-induced hypertension (PIH) and preeclampsia (PE) are 5–10% and 2–4%, respectively. PIH might affect angiogenesis in preterm neonates, but its association with bronchopulmonary dysplasia (BPD) remains controversial. This study evaluated the association between PIH and BPD in very low-birth weight infants. We retrospectively analysed the maternal, perinatal, and neonatal data of preterm infants born before 30 weeks of gestation, selected from the nationwide registry of very low-birth weight infants, between January 2013 and December 2014. As a result, 1,624 infants without maternal PIH (gestational age: 27.3 ± 1.8 weeks) and 203 infants with maternal PIH (28.0 ± 1.4 weeks, p

Altered hemodynamics associated with twin to twin transfusion syndrome (TTTS) can be manifested in the fetal and neonatal heart. This study evaluated the association between cardiac manifestations immediately after birth and brain injury in preterm infants with TTTS. Medical records of preterm infants who were born at

Spontaneous intestinal perforation (SIP) and surgical necrotizing enterocolitis (NEC) are intestinal conditions requiring surgical intervention in preterm infants. We aimed to compare the head growth and neurodevelopment of preterm infants with SIP and surgical NEC. A retrospective single-center study was performed in preterm infants born at less than 32 weeks of gestation and who had undergone surgery for NEC or SIP. Data from the Bayley Scales of Infant and Toddler Development 3rd Edition (Bayley-III) at 24 months of corrected age (CA) and the Korean Ages and Stages Questionnaire (K-ASQ) or Korean Developmental Screening Test (K-DST) at 36 months were collected. Among 82 eligible infants, 60 infants had surgical NEC, and 22 infants were diagnosed with SIP. Head growth was faster until CA 4 months in preterm infants with SIP than in those with surgical NEC. At 36 months, abnormal findings in the K-ASQ or K-DST were more prevalent in the NEC group than in the SIP group in the gross motor (48.2% vs. 0%, p = 0.015), fine motor (40.7% vs. 0%, p = 0.037), cognitive (55.6% vs. 12.5%, p = 0.047), and social domains (44.4% vs. 0%, p = 0.032). More studies evaluating the neurodevelopmental outcomes of preterm infants with surgical NEC and SIP are required.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease resulting in clinical and biochemical manifestations of extreme inflammation. Myelodysplastic syndrome (MDS) represents a heterogenous group of clonal hematopoietic disorders. The development of MDS is common in children with trisomy of chromosome 8. Here, we report a fatal case of 8-year-old girl who was admitted to the emergency department with status epilepticus, and later diagnosed with HLH associated with MDS and trisomy of chromosome 8. We believe this is the first reported case of HLH associated with MDS and trisomy 8 in a pediatric patient.

Purpose: The aim of this study was to investigate the potential effects of mild hypoxia in the mature and immature brain. Methods: We prepared organotypic slice cultures of the hippocampus and used hippocampal tissue cultures at 7 and 14 days in vitro (DIV) to represent the immature and mature brain, respectively. Tissue cultures were exposed to 10% oxygen for 60 minutes. Twenty-four hours after this hypoxic insult, propidium iodide fluorescence images were obtained, and the damaged areas in the cornu ammonis 1 (CA1), CA3, and dentate gyrus (DG) were measured using image analysis. Results: In the 7-DIV group compared to control tissue, hypoxia-exposed tissue showed decreased damage in two regions (CA1: 5.59%±2.99% vs. 4.80%±1.37%, P =0.900; DG: 33.88%±12.53% vs. 15.98%±2.37%, P =0.166), but this decrease was not statistically significant. In the 14-DIV group, hypoxia-exposed tissue showed decreased damage compared to control tissues; this decrease was not significant in the CA3 (24.51%±6.05% vs. 18.31%±3.28%, P =0.373) or DG (15.72%±3.47% vs. 9.91%±2.11%, P =0.134), but was significant in the CA1 (50.91%±5.90% vs. 32.30%±3.34%, P = 0.004). Conclusion: Although only CA1 tissues cultured for 14 DIV showed significantly less damage after exposure to hypoxia, the other tissues examined in this study showed a tendency towards less damage after hypoxic exposure. Therefore, mild hypoxia might play a protective role in the brain.

Neonatal cerebral sinovenous thrombosis (CSVT) is a rare disease with severe neu­ rological sequelae. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate cycle, and mutations in MTHFR are associated with vascular diseases. Here, we report the case of a newborn with MTHFR mutation­associated CSVT. Analysis of MTHFR in the patient detected heterozygous C677T (677CT) and A1298C (1298AC) mutations. Analysis of MTHFR in the patient's mother did not detect a C677T (677CC) mutation but detected a homozygous A1298C (1298CC) mutation. Our results suggest that the presence of heterozygous MTHFR C677T and A1298C mutations affect thrombophilic activity in the neonate, resulting in the development of refractory seizure and CSVT. Moreover, presence of the homozygous MTHFR A1298C mutation in the patient's mother, who did not show any symptoms associat­ ed with thrombophilic activity, and conditions during gestation may have affected the patient's condition.