Using heart rate variability to predict neurological outcomes in preterm infants: a scoping review.

Infants born preterm are at higher risk of neurological complications, including intraventricular haemorrhage and white matter injury. After discharge, these infants may experience adverse neurodevelopmental outcomes and exhibit lower educational attainment. Early detection of brain injury and accurate prediction of neurodevelopmental impairment would allow early intervention and support. Heart rate variability (HRV) describes the variation of time intervals between each subsequent heartbeat. HRV is controlled by the autonomic nervous system, which may be affected by hypoxia and compromised blood flow. While HRV has primarily been investigated in neonatal sepsis, the association between HRV, brain injury and neurodevelopmental outcomes in preterm infants is less established. The present scoping review examines the utility of HRV monitoring for predicting short-term and long-term neurological outcomes in preterm infants. Following systematic search of Medline, Embase, Web of Science and the Cochrane Library, 15 studies were included. Nine studies examined the relationship between HRV and brain injury, with all but two showed an association. Eight studies examined the relationship between HRV and long-term outcomes and all eight found an association. This scoping review suggests that decreased HRV in the neonatal period is associated with short- and long-term neurodevelopmental outcomes in preterm infants. IMPACT: Changes in heart rate variability correlate with the occurrence of intraventricular haemorrhage in preterm infants. A decrease in heart rate variability may precede the development of intraventricular haemorrhage. Alterations in heart rate variability correlate with long-term neurodevelopmental outcomes. Significant variability exists in metrics used in assessing heart rate variability.

Noninvasive Neurally Adjusted Ventilation in Postextubation Stabilization of Preterm Infants: A Randomized Controlled Study.

OBJECTIVE: 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. STUDY DESIGN: This prospective, single-center, randomized controlled trial enrolled preterm infants born at <30 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. RESULTS: 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. CONCLUSIONS: In the present trial, NIV-NAVA was more effective than NCPAP in preventing extubation failure in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02590757.

Extrauterine growth restriction in extremely preterm infants based on the Intergrowth-21st Project Preterm Postnatal Follow-up Study growth charts and the Fenton growth charts.

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.

Cystic dysplasia of the kidneys in extremely preterm infants following acute kidney injury.

BACKGROUND: 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. CASE-DIAGNOSIS/TREATMENT: 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. CONCLUSIONS: 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.

A Rare Case of Hemophagocytic Lymphohistiocytosis Associated With Myelodysplastic Syndrome and Trisomy 8 in a Pediatric Patient.

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.

Therapeutic hypothermia for preterm infants 34-35 weeks gestational age with neonatal encephalopathy.

OBJECTIVE: To evaluate the short-term outcomes and safety of therapeutic hypothermia (TH) for neonatal encephalopathy in preterm infants at 34-35 weeks of gestation. STUDY DESIGN: A matched retrospective cohort study of 20 preterm infants at 34-35 weeks of gestation and 40 infants at 36 weeks of gestation or more who received TH between the years 2015-2021. RESULT: Short-term outcomes of preterm infants at 34-35 weeks of gestation who received TH were comparable with infants at 36 weeks or more of gestation who received TH regarding seizures, intraventricular hemorrhage, blood transfusions, subcutaneous fat necrosis, brain injury on magnetic resonance imaging, and mortality. These findings were consistent when short-term outcomes were adjusted for birthweight. CONCLUSION: TH in preterm infants at 34-35 weeks of gestation is feasible and safe in our study population.

Association of newer definitions of bronchopulmonary dysplasia with pulmonary hypertension and long-term outcomes.

Background: The 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. Methods: This retrospective study enrolled preterm infants born at < 32 weeks of gestation between 2014 and 2018. The association between re-hospitalization owing to a respiratory illness until a corrected age (CA) of 24 months, neurodevelopmental impairment (NDI) at a CA of 18-24 months, and PHN at a postmenstrual age (PMA) of 36 weeks was evaluated, with the severity of BPD defined based on these three definitions. Results: Among 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. Conclusion: Based 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.

Promising candidate cerebrospinal fluid biomarkers of seizure disorder, infection, inflammation, tumor, and traumatic brain injury in pediatric patients.

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.

Neurodevelopmental outcomes and volumetric analysis of brain in preterm infants with isolated cerebellar hemorrhage.

Background: Cerebellar hemorrhage (CBH) is a major form of cerebellar injury in preterm infants. We aimed to investigate the risk factors and neurodevelopmental outcomes of isolated CBH and performed volumetric analysis at term-equivalent age. Methods: This single-centered nested case-control study included 26 preterm infants with isolated CBH and 52 infants without isolated CBH and any significant supratentorial injury. Results: Isolated CBH was associated with PCO2 fluctuation within 72 h after birth (adjusted odds ratio 1.007, 95% confidence interval 1.000-1.014). The composite score in the motor domain of the Bayley Scales of Infant and Toddler Development at 24 month of corrected age was lower in the punctate isolated CBH group than that in the control group (85.3 vs. 94.5, P = 0.023). Preterm infants with isolated CBH had smaller cerebellum and pons at term-equivalent age compared to the control group. Isolated CBH with adverse neurodevelopment had a smaller ventral diencephalon and midbrain compared to isolated CBH without adverse neurodevelopmental outcomes. Conclusions: In preterm infants, isolated CBH with punctate lesions were associated with abnormal motor development at 24 months of corrected age. Isolated CBH accompanied by a smaller ventral diencephalon and midbrain at term equivalent had adverse neurodevelopmental outcomes.

Head Growth and Neurodevelopment of Preterm Infants with Surgical Necrotizing Enterocolitis and Spontaneous Intestinal Perforation.

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.

Antenatal magnesium sulfate and intestinal morbidities in preterm infants with extremely low gestational age.

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 <26 weeks of gestational age subgroup, the use of antenatal magnesium sulfate was significantly associated with decreased intestinal morbidities requiring surgery (adjusted OR 0.234, 95% CI 0.060-0.922). 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 <26 weeks of gestational age.

Exosomal microRNA expression profiles of cerebrospinal fluid in febrile seizure patients.

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.

The Association of Pregnancy-induced Hypertension with Bronchopulmonary Dysplasia - A Retrospective Study Based on the Korean Neonatal Network database.

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 < 0.001) were included. Birth weight was higher in the non-PIH group, compared with the PIH group (1027.4 ± 250.2 vs. 876.4 ± 261.5 g, p < 0.001). Multivariate logistic regression showed that PIH was associated with BPD (adjusted OR 1.474, 95% confidence interval 1.025-2.121), after adjusting for confounders, including small-for-gestation age (SGA). The result of present study is consistent with the current concept of BPD as an early form of pulmonary vascular disease, for both PIH and BPD are attributed by abnormal vascular formation.

Early postnatal cardiac manifestations are associated with perinatal brain injury in preterm infants with twin to twin transfusion syndrome.

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 <35 weeks of gestation with TTTS and admitted to the neonatal intensive care unit at Seoul National University Children's Hospital between January 2011 and January 2018 were reviewed. TTTS was prenatally diagnosed and staged according to the Quintero criteria. Echocardiographic findings, brain ultrasound and MRI imaging findings were analyzed. Fifty-three infants were enrolled in this study. Thirty-two infants (60.3%) were treated by fetoscopic laser coagulation. Brain injury developed in 15 infants (28.3%). Hypotension within the first week and immediate postnatal cardiac manifestations were more prevalent in the brain injury group. In the multivariate analysis, acute kidney injury and cardiac manifestations, such as ventricular dysfunction and tricuspid regurgitation, were statistically associated with brain injury in the study population. Immediate postnatal cardiac manifestations, such as ventricular dysfunction and tricuspid regurgitation, can serve as surrogate markers for perinatal hemodynamic disturbance, which are associated with early neonatal brain injury in preterm infants with TTTS.

Neuroprotective effects of mild hypoxia in organotypic hippocampal slice cultures.

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.