Current Status and Associated Factors of Post-Hemorrhagic Hydrocephalus in Infants of 22 to 28 Weeks Gestation With Severe Intraventricular Hemorrhage in Korea: A Nationwide Cohort Study.

BACKGROUND: Post-hemorrhagic hydrocephalus (PHH), a common complication of severe intraventricular hemorrhage (IVH) in very low birth weight (BW) infants, is associated with significant morbidity and poor neurological outcomes. The objective of this study was to assess the current status of PHH and analyze the risk factors associated with the necessity of treatment for PHH in infants born between 22 and 28 weeks of gestation, specifically those with severe IVH (grade 3 or 4). METHODS: The analysis was conducted on 1,097 infants who were born between 22-28 gestational weeks and diagnosed with severe IVH, using data from the Korean Neonatal Network. We observed that the prevalence of PHH requiring treatment was 46.3% in infants with severe IVH. RESULTS: Higher rates of mortality, transfer during admission, cerebral palsy, and ventriculoperitoneal shunt after discharge were higher in infants with PHH than in those without PHH. PHH in severe IVH was associated with a higher rate of pulmonary hemorrhage, seizures, and IVH grade 4 in the entire cohort. In addition, it was associated with a lower rate of small for gestational age and chorioamnionitis. In the subgroup analysis, high BW, outborn status, pulmonary hemorrhage, seizure, sepsis, and IVH grade 4 were associated with a higher incidence of PHH between 22 and 25 gestational weeks (GW). In infants born between 26 and 28 GW, a higher incidence of PHH was associated with seizures and IVH grade 4. CONCLUSION: It is necessary to maintain meticulous monitoring and neurological intervention for infants with PHH not only during admission but also after discharge. In addition, identifying the clinical factors that increase the likelihood of developing PHH from severe IVH is crucial.

Mesenchymal Stem Cells Reduce the Extracellular Mitochondrial DNA-Mediated TLR9 Activation in Neonatal Hyperoxia-Induced Lung Injury.

Mitochondrial DNA (mtDNA) released from dead or injured cells can activate inflammation, and mesenchymal stem cell (MSC) transplantation can reduce inflammation and injury. However, it has not been tested whether the release of mtDNA can be reduced by MSC transplantation. We hypothesized that the level of extracellular mtDNA would be increased after hyperoxia-induced lung injury but reduced after lung injury attenuation by MSC therapy in our newborn rat model. In an in vitro study using a rat lung epithelial L2 cell line, we found that the level of extracellular mtDNA was significantly increased with H2O2-induced cell death but reduced after MSC co-incubation. In an in vivo study, we confirmed that the levels of cell death, extracellular mtDNA, and inflammatory cytokines were significantly increased in hyperoxic newborn rat lungs but reduced after MSC transplantation. The levels of extracellular mtDNA were significantly and positively correlated with the levels of the inflammatory cytokines. The TLR9/MyD88/NF-κB pathway, which is activated by binding to mtDNA, was also significantly upregulated but downregulated after MSC transplantation. We found a significant positive correlation between inflammatory cytokines and extracellular mtDNA in intubated neonates. The levels of inflammatory cytokines and extracellular mtDNA changed over time in a similar pattern in transtracheal aspirate samples from intubated neonates. In conclusion, increased levels of extracellular mtDNA are associated with increased inflammation in hyperoxia-induced lung injury, and attenuation of lung inflammation by MSC therapy is associated with reduced levels of extracellular mtDNA.

Optimal Protocols and Management of Clinical and Genomic Data Collection to Assist in the Early Diagnosis and Treatment of Multiple Congenital Anomalies.

Standardized protocols have been designed and developed specifically for clinical information collection and obtaining trio genomic information from infants affected with congenital anomalies (CA) and their parents, as well as securing human biological resources. The protocols include clinical and genomic information collection on multiple CA that were difficult to diagnose using pre-existing screening methods. We obtained human-derived resources and genomic information from 138 cases, including 45 families of infants with CA and their parent trios. For the clinical information collection protocol, criteria for target patient selection and a consent system for collecting and utilizing research resources are crucial. Whole genome sequencing data were generated for all participants, and standardized protocols were developed for resource collection and manufacturing. We recorded the phenotype information according to the Human Phenotype Ontology term, and epidemiological information was collected through an environmental factor questionnaire. Updating and recording of clinical symptoms and genetic information that have been newly added or changed over time are significant. The protocols enabled long-term tracking by including the growth and development status that reflect the important characteristics of newborns. Using these clinical and genetic information collection protocols for CA, an essential platform for early genetic diagnosis and diagnostic research can be established, and new genetic diagnostic guidelines can be presented in the near future.

Five-year follow-up of phase II trial of stromal cells for bronchopulmonary dysplasia.

BACKGROUND: We previously performed a phase II randomised double-blind clinical trial of mesenchymal stromal cell (MSCs) transplantation to prevent bronchopulmonary dysplasia in extremely premature infants. Subsequently, we followed the infants enrolled in this clinical trial to determine the safety and effectiveness of MSCs against bronchopulmonary dysplasia at 5-year follow-up. METHODS: We evaluated infants at 5 years of age receiving placebo or MSCs in a prospective follow-up study. RESULTS: In terms of the primary end point of composite respiratory morbidities, including respiratory problem-related readmission, emergency department visits or oxygen therapy, the MSC group had a rate of 60.7% for composite morbidities, while the control group showed a tendency of higher rate of 83.9% for the same outcomes without statistical significance. In terms of the secondary outcomes, the MSC group infants showed a tendency of being less likely to visit emergency department (control 67.7% vs MSC 35.7%) and to receive oxygen therapy (control 29.0% vs MSC 3.6%). No difference was observed in the incidence of respiratory problem-related hospital readmission or wheezing episodes between the groups. CONCLUSION: Intratracheally instilled MSCs showed the possibility of potential to decrease respiratory symptom-related emergency department visits and oxygen therapy episodes in infants born extremely preterm during the 5 years after a phase II randomised controlled, double-blind trial of MSCs transplantation for bronchopulmonary dysplasia. This small size study suggests preliminary insights that can be further tested using larger sample sizes. TRIAL REGISTRATION NUMBER: NCT01897987.

Stem cells for neonatal brain injury - Lessons from the bench.

Neonatal brain injury resulting from various intractable disorders including intraventricular hemorrhage and hypoxic ischemic encephalopathy still remains a major cause of mortality and morbidities with few effective treatments. Recent preclinical research results showing the pleiotropic neuroprotective effects of stem cell therapy, specifically mesenchymal stem cells (MSCs), suggest that MSCs transplantation might be a promising new therapeutic modality for neuroprotection against the currently intractable and devastating neonatal brain injury with complex multifactorial etiology. This review summarizes recent advances in preclinical stem cell research for treating neonatal brain injury with a focus on the important issues including the mechanism of neuroprotection, and determining the ideal cell source, route, timing and dose of MSCs transplantation.

Neonatal Intensive Care Quality Level-Dependent Variations in the Survival Rate of Infants with a Birth Weight of 500 g or Less in Korea: A Nationwide Cohort Study.

OBJECTIVE: Recent evidence suggests that the survival of peri-viable infants with birth weight (BW) ≤500 g could be improved with better care practices in the neonatal intensive care unit (NICU). This study aimed to investigate the care quality level of NICU-dependent variations in the survival rate of infants with BW ≤500 g. METHODS: To determine the quality of NICU care-dependent variations in the survival rate, 226 eligible infants of BW ≤500 g and ≥22 weeks gestation registered in the Korean Neonatal Network between 2013 and 2017 were grouped according to the survival rates of infants at 23-24 weeks gestation, reflecting the care quality level of each NICU as group I (≥50%, n = 107) and group II (<50%, n = 119). RESULTS: The survival rate of group I infants (40.2%, 43/107) was significantly higher than that of group II infants (14.3%, 17/119). Significantly reduced deaths from birth to the age of 7 days due to cardiorespiratory causes were the primary contributors to improved survival. In multivariable Cox hazard model analyses, besides the gestational age and BW, antenatal steroid use, cesarean section, pH, and base excess at admission were associated with improved infant survival. CONCLUSIONS: The survival rate of pre-viable infants with BW ≤500 g could be improved by providing better NICU quality care practices, including better cardiorespiratory management starting from delivery room resuscitation.

Comprehensive Evaluation of the NeoBase 2 Non-derivatized MSMS Assay and Exploration of Analytes With Significantly Different Concentrations Between Term and Preterm Neonates.

Background: Despite the popularity of the NeoBase 2 Non-derivatized MSMS assay (PerkinElmer, Turku, Finland), there are no reports of its comprehensive evaluation, including the ability to distinguish transient tyrosinemia of the newborn (TTN) from tyrosinemia type 1 (TYR 1) using succinylacetone (SUAC). No newborn screening (NBS) cutoffs for preterm neonates in the Korean population have been suggested. We evaluated the NeoBase 2 assay and identified analytes requiring different cutoffs in preterm neonates. Methods: Residual NBS dried blood spot samples and proficiency testing (PT) materials of the Newborn Screening Quality Assurance Program and the Korean Association of External Quality Assessment Service were used. Precision, accuracy, limit of detection (LOD), lower limit of quantification (LLOQ), linearity, recovery, carryover, and performance of SUAC were evaluated. Cutoffs were determined, and analytes requiring different cutoffs in preterm neonates were investigated. Results: Mean CVs for within-run and between-day precision were within 15%. Accuracy analysis indicated high agreement with in-house derivatized assay results and results of other PT participants. All analytes demonstrated acceptable LOD, LLOQ, and linearity. Recoveries were acceptable, except for SUAC. Carryover was negligible. Cutoffs were established for all analytes; Tyr, adenosine, and C20:0-lysophosphatidylcholine required different cutoffs in preterm neonates. Differential diagnosis of TYR 1 and TTN was successful with simultaneous Tyr and SUAC measurement. Conclusions: The NeoBase 2 assay demonstrated satisfactory performance. The additional analytes provide a wider diagnostic coverage, and the simultaneous measurement of Tyr and SUAC is efficient in excluding TYR 1. The new cutoffs for preterm neonates may decrease false-positive rates, without compromising diagnostic sensitivity.

Early Discontinuation of Levothyroxine Treatment Is Safe and Feasible in Extremely Low Birth Weight Infants with Delayed Hyperthyrotropinemia.

BACKGROUND: While recent pieces of evidence suggest that discontinuation of levothyroxine replacement therapy (LRT) earlier than the current guidelines of 3 years is possible, the optimal duration of LRT for delayed hyperthyrotropinemia in extremely low birth weight infants (ELBWIs) remains unknown. OBJECTIVE: This study aimed to investigate the feasibility of early discontinuation of LRT for delayed hyperthyrotropinemia in ELBWIs. METHODS: The medical records of 92 ELBWIs who had shown delayed hyperthyrotropinemia, defined as a delayed rise in thyroid-stimulating hormone (TSH) levels to >20 µIU/mL after initial normal TSH level, were retrospectively reviewed to determine whether the duration of LRT affects the short-term outcomes at discharge from neonatal intensive care unit (NICU) and the long-term outcomes at the corrected age (CA) of 2 years. The infants were grouped into: no LRT required group (n = 21), short-term LRT given until the time of NICU discharge - 90 ± 64 (13-211) days group (n = 36), and long-term LRT given - 749 ± 333 (339-1,967) days group (n = 35). RESULTS: While mortality in the no LRT required group was significantly higher than that in the long-term LRT group, no significant differences were observed in short-term outcomes at discharge from NICU and long-term growth and neurodevelopmental outcomes at CA of 2 years between the short- and long-term LRT groups. CONCLUSIONS: Termination of LRT at around the time of discharge from NICU in well, clinically stable ELBWIs who have delayed hyperthyrotropinemia appears to be safe and feasible and avoids the risk of overtreatment.

Mesenchymal Stem Cells and Formyl Peptide Receptor 2 Activity in Hyperoxia-Induced Lung Injury in Newborn Mice.

Formyl peptide receptor (FPR) 2 is known to play a critical role in regulating inflammation, including either the pro-inflammatory or pro-resolving effects. However, its role in neonatal hyperoxia-induced lung injury has not been delineated. In this study, we investigate whether mesenchymal stem cells (MSCs) attenuate hyperoxia-induced neonatal lung injury by regulating FPR2 activity. We observed a significant increase in FPR2 levels in alveolar macrophages (RAW264.7 cells) after H2O2-induced stress, which decreased after MSC treatment. In the H2O2-induction model, increased levels of inflammatory cytokines (IL-1α and TNF-α) were significantly reduced in RAW264.7 cells after treatment with WRW4, an inhibitor of FPR2, or MSCs. Viability of lung epithelial cells and endothelial cells was significantly improved when cultured in the conditioned media of RAW264.7 cells treated with WRW4 or MSCs, compared to when cultured in the conditioned media of control RAW265.7 cells exposed to H2O2. For the in vivo study, wild-type and FPR2 knockout (FPR2-/-) C57/BL6 mouse pups were randomly exposed to 80% oxygen or room air from postnatal day (P) 1 to P14. At P5, 2 × 105 MSCs were transplanted intratracheally. MSCs reduced the elevated FPR2 activity at P7 and improved the decreased FPR2 activity as well as the increased immuno-stained FPR2 activity in alveolar macrophages in hyperoxic lungs at P14. Both FPR2-/- and MSCs similarly attenuated impaired alveolarization and angiogenesis, and increased apoptosis and inflammation of hyperoxic lungs without synergistic effects. Our findings suggest that the protective effects of MSCs in hyperoxic lung injury might be related to indirect modulation of FPR2 activity, at least of alveolar macrophages in neonatal mice.

Association Between Retinopathy of Prematurity in Very-Low-Birth-Weight Infants and Neurodevelopmental Impairment.

PURPOSE: To evaluate the impact of retinopathy of prematurity (ROP) severity and the treatment of very-low-birth-weight infants (VLBWIs) on neurodevelopmental impairment in early childhood. DESIGN: Prospective cohort study. METHOD: This was a prospective cohort study. The data were obtained from the Korean Neonatal Network (KNN), a nationwide registry for VLBWIs. Infants who were born from 2013 to 2015 and underwent ROP evaluation at birth and neurodevelopmental examinations at corrected ages of 18 to 24 months were included in the study. Infants with a history of meningitis or severe congenital anomalies were excluded. The VLBWI patients were grouped into no ROP, no treatment-requiring ROP (non-TR-ROP), and treatment-requiring ROP (TR-ROP) groups. Neurodevelopmental impairment was defined as participants who had at least 1 developmental problem according to the Bayley Scales of Infant and Toddler Development-2nd Edition (Bayley-II; <70), Bayley Scales of Infant and Toddler Development-3rd Edition (Bayley-III; <70), and Korean Developmental Screening Test (K-DST) tests (below -1 SD), and the Korean Ages and Stages Questionnaire (K-ASQ) (below the threshold) and Gross Motor Function Classification System (GMFCS; at level 2 or above). Multivariable logistic regression analysis was performed to evaluate the association between ROP and neurodevelopmental impairment. RESULT: Among 3132 infants, 1093 (34.9%) had ROP. Among the ROP infants, 644 were not treated for ROP (non-TR-ROP group) and 449 received ROP treatments (TR-ROP group). The patients in the TR-ROP group had an increased risk of developing neurodevelopmental problems compared to those in the no ROP group (odds ratio [OR] = 1.72, 95% CI = 1.33-2.21). The TR-ROP group had a higher risk of all 3 types of neurodevelopmental problems: mental (OR = 1.62, 95% CI = 1.25-2.09), social (OR = 1.62, 95% CI = 1.12-2.09), and motor (OR = 1.69, 95% CI = 1.31-2.18). The risk of neurodevelopmental problems in patients treated with laser therapy did not differ from that in patients treated with anti-vascular endothelial growth factor (anti-VEGF) therapy (OR = 1.17, 95% CI = 0.73-1.88). CONCLUSION: ROP was independently associated with neurodevelopmental impairment in early childhood. The type of ROP treatment (anti-VEGF or laser treatment) did not affect neurodevelopmental impairment in patients in the TR-ROP group.

Mesenchymal-Stem-Cell-Derived Extracellular Vesicles Attenuate Brain Injury in Escherichia coli Meningitis in Newborn Rats.

We recently reported that transplantation of mesenchymal stem cells (MSCs) significantly reduced bacterial growth and brain injury in neonatal meningitis induced by Escherichia coli (E. coli) infection in newborn rats. As a next step, to verify whether the MSCs protect against brain injury in a paracrine manner, this study was designed to estimate the efficacy of MSC-derived extracellular vesicles (MSC-EVs) in E. coli meningitis in newborn rats. E. coli meningitis was induced without concomitant bacteremia by the intra-cerebroventricular injection of 5 × 102 colony-forming units of K1 (-) E. coli in rats, at postnatal day 11. MSC-EVs were intra-cerebroventricularly transplanted 6 h after the induction of meningitis, and antibiotics were administered for three consecutive days starting at 24 h after the induction of meningitis. The increase in bacterial growth in the cerebrospinal fluid measured at 24 h after the meningitis induction was not significantly reduced following MSC-EV transplantation. However, an increase in brain cell death, reactive gliosis, and inflammation following meningitis were significantly attenuated after MSC-EV transplantation. Taken together, our results indicate that MSCs show anti-apoptotic, anti-gliosis, and anti-inflammatory, but not antibacterial effects, in an EV-mediated paracrine manner in E. coli-induced neonatal meningitis.

Effect of levothyroxine supplementation in extremely low birth weight infants with transient hypothyroxinemia of prematurity.

This study aimed to determine the short- and/or long-term outcomes of levothyroxine replacement therapy in extremely low birth weight (ELBW) infants with transient hypothyroxinemia of prematurity (THOP). The medical records of 335 ELBW infants with THOP were reviewed retrospectively to identify whether levothyroxine treatment affects short- and/or long-term outcomes at a corrected age of 2 years. The infants were arbitrarily grouped based on thyroxine (T4) (free T4 [fT4]) levels into group 1 (n = 142), which included infants with T4 (fT4) levels < 2.5 (0.5) ng/dl, and group 2 (n = 193), which included those with T4 (fT4) levels ranging from ≥ 2.5 (0.5) ng/dl to < 4.5 (0.9) ng/dl. Levothyroxine replacement therapy was not associated with beneficial short- or long-term outcomes in ELBW infants with THOP. Short-term outcomes, such as mortality and composite morbidities, and long-term outcomes, such as failure to achieve catch-up height at a corrected age of 2 years, were significantly higher in group 1 than in group 2, regardless of levothyroxine treatment status. Levothyroxine replacement therapy is not associated with short-or long-term advantages in ELBW infants with THOP. This study suggests that the severity of THOP may be the major determinant of adverse outcomes in ELBW infants with THOP, rather than levothyroxine treatment.

Intratracheal Transplantation of Mesenchymal Stem Cells Attenuates Hyperoxia-Induced Microbial Dysbiosis in the Lungs, Brain, and Gut in Newborn Rats.

We attempted to determine whether intratracheal (IT) transplantation of mesenchymal stem cells (MSCs) could simultaneously attenuate hyperoxia-induced lung injuries and microbial dysbiosis of the lungs, brain, and gut in newborn rats. Newborn rats were exposed to hyperoxia (90% oxygen) for 14 days. Human umbilical cord blood-derived MSCs (5 × 105) were transplanted via the IT route on postnatal day (P) five. At P14, the lungs were harvested for histological, biochemical, and microbiome analyses. Bacterial 16S ribosomal RNA genes from the lungs, brain, and large intestine were amplified, pyrosequenced, and analyzed. IT transplantation of MSCs simultaneously attenuated hyperoxia-induced lung inflammation and the ensuing injuries, as well as the dysbiosis of the lungs, brain, and gut. In correlation analyses, lung interleukin-6 (IL-6) levels were significantly positively correlated with the abundance of Proteobacteria in the lungs, brain, and gut, and it was significantly inversely correlated with the abundance of Firmicutes in the gut and lungs and that of Bacteroidetes in the lungs. In conclusion, microbial dysbiosis in the lungs, brain, and gut does not cause but is caused by hyperoxic lung inflammation and ensuing injuries, and IT transplantation of MSCs attenuates dysbiosis in the lungs, brain, and gut, primarily by their anti-oxidative and anti-inflammatory effects.

Thrombin Preconditioning Improves the Therapeutic Efficacy of Mesenchymal Stem Cells in Severe Intraventricular Hemorrhage Induced Neonatal Rats.

Severe intraventricular hemorrhage (IVH) remains a major cause of high mortality and morbidity in extremely preterm infants. Mesenchymal stem cell (MSC) transplantation is a possible therapeutic option, and development of therapeutics with enhanced efficacy is necessary. This study investigated whether thrombin preconditioning improves the therapeutic efficacy of human Wharton's jelly-derived MSC transplantation for severe neonatal IVH, using a rat model. Severe neonatal IVH was induced by injecting 150 µL blood into each lateral ventricle on postnatal day (P) 4 in Sprague-Dawley rats. After 2 days (P6), naïve MSCs or thrombin-preconditioned MSCs (1 × 105/10 µL) were transplanted intraventricularly. After behavioral tests, brain tissues and cerebrospinal fluid of P35 rats were obtained for histological and biochemical analyses, respectively. Thrombin-preconditioned MSC transplantation significantly reduced IVH-induced ventricular dilatation on in vivo magnetic resonance imaging, which was coincident with attenuations of reactive gliosis, cell death, and the number of activated microglia and levels of inflammatory cytokines after IVH induction, compared to naïve MSC transplantation. In the behavioral tests, the sensorimotor and memory functions significantly improved after transplantation of thrombin-preconditioned MSCs, compared to naïve MSCs. Overall, thrombin preconditioning significantly improves the therapeutic potential and more effectively attenuates brain injury, including progressive ventricular dilatation, gliosis, cell death, inflammation, and neurobehavioral functional impairment, in newborn rats with induced severe IVH than does naïve MSC transplantation.

Increased Risk of Meconium-Related Ileus in Extremely Premature Infants Exposed to Antenatal Magnesium Sulfate.

INTRODUCTION: We experienced an increased incidence of meconium-related ileus (MRI) in extremely premature infants (EPIs) while adopting the antenatal magnesium sulfate (MgSO4) protocol for fetal neuroprotection in our neonatal intensive care unit. This study aimed to test whether antenatal MgSO4 use was associated with increased risk of MRI in EPIs. METHODS: The incidences of complicated MRI requiring aggressive enema or surgical intervention and other intestinal complications were compared among period 1 (January 2012-December 2013, n = 79), before adoption of the antenatal MgSO4 protocol for fetal neuroprotection; period 2 (January 2014-March 2016, n = 72), when the protocol was adopted; and period 3 (April 2016-September 2018, n = 75), when the protocol was temporarily withdrawn due to concern regarding intestinal complications in EPIs. RESULTS: Despite similar baseline clinical characteristics among infants across the study periods, the MRI and MRI with surgical treatment incidences were higher in period 2 than those in periods 1 and 3 (13% vs. 8% and 6%, p = 0.391, and 11% vs. 0% and 1%, p = 0.001, respectively). In multivariable analysis, exposure to antenatal MgSO4 independently increased the risk of MRI (adjusted odds ratio, 3.8; 95% confidence interval, 1.4, 10.6). CONCLUSION: Antenatal MgSO4 may increase the risk of MRI, frequently requiring surgical intervention, in EPIs with a gestational age of 25 weeks or less.

Neonatal outcome comparisons between preterm infants with or without early pulmonary hypertension following prolonged preterm premature rupture of membranes before 25 gestational weeks in Korean Neonatal Network.

OBJECTIVE: To determine the outcomes of very low birth weight infants (VLBWIs) following maternal mid-trimester prolonged preterm premature rupture of membranes (PPROM) and subsequent early pulmonary hypertension (PH). DESIGN: Prospective cohort study. SETTING: A nationwide web-based registry of VLBWIs from 67 neonatal intensive care units. PATIENTS: VLBWIs registered on the Korean Neonatal Network and born between 23 and 34 gestational weeks. METHODS: VLBWIs exposed to maternal PPROM prior to 25 gestational weeks and lasting ≥7 days (PPROM25, n = 402) were matched 1:1 with infants not exposed or exposed within 24 h to PPROM (CON, n = 402), using propensity score matching. The PPROM25 group was subdivided into PPROM25 groups with or without early PH, defined as exposure to inhaled nitric oxide or other pulmonary vasodilators to treat PH within 3 days of life. Clinical variables and major outcomes were compared, and risk factors for mortality and morbidities were analyzed. RESULTS: Of 1790 infants with maternal PPROM, the PPROM25 group comprised 402 (22.5%) infants. Survival rates were similar between the CON and PPROM25 groups (71.6% vs 74.4%); however, the incidence of bronchopulmonary dysplasia (BPD) differed (47.8% and 60.2%, p < .05). Infants in the PPROM25 group with early PH had higher mortality (55.6%) and more severe intraventricular hemorrhage (IVH) (31.7%) than infants in the PPROM25 group without early PH (21.9% and 14.3%, respectively; p < .05). In multivariate analysis, lower 5 min Apgar score and the presence of oligohydramnios increased the risk of development of early PH. The presence of PPROM25 was founded to be a significant risk factor for BPD and early PH in relation to mortality and severe IVH, respectively. CONCLUSIONS: In VLBWIs, prolonged exposure to maternal mid-trimester PPROM increased the risk of BPD. Subsequent early PH immediately after birth increased mortality and severe IVH, thus, requires special attention.

Conservative Management of Patent Ductus Arteriosus Is Feasible in the Peri-Viable Infants at 22-25 Gestational Weeks.

The purpose of this study was to determine the natural course of hemodynamically significant (HS) patent ductus arteriosus (PDA) with conservative management and whether the presence or prolonged duration of HS PDA affected mortality/morbidities in infants at 22-25 weeks estimated gestational age (EGA). We retrospectively reviewed the medical records of 77 infants born at 22-25 weeks EGA, stratified into 22-23 weeks (n = 21) and 24-25 weeks EGA (n = 56). HS PDA was present in 77%, 76%, and 77%, and open ductus at discharge was 12%, 13%, and 12% in the total and at 22-23 and 24-25 weeks EGA infants, respectively. For backup rescue treatment, 7% and 5% of the infants received oral ibuprofen and device closure, respectively. A mortality rate of 9% was found in the HS PDA (+) infants, significantly lower than the 28% in HS PDA (-) infants. There are no significant differences in morbidities. In multivariate analyses, the presence and/or prolonged duration of HS PDA was not associated with increased mortality or morbidity. Spontaneous closure of HS PDA was achieved through conservative management in the peri-viable infants at 22-25 weeks EGA.

BDNF-Overexpressing Engineered Mesenchymal Stem Cells Enhances Their Therapeutic Efficacy against Severe Neonatal Hypoxic Ischemic Brain Injury.

We investigated whether irradiated brain-derived neurotropic factor (BDNF)-overexpressing engineered human mesenchymal stem cells (BDNF-eMSCs) improve paracrine efficiency and, thus, the beneficial potency of naïve MSCs against severe hypoxic ischemic (HI) brain injury in newborn rats. Irradiated BDNF-eMSCs hyper-secreted BDNF > 10 fold and were >5 fold more effective than naïve MSCs in attenuating the oxygen-glucose deprivation-induced increase in cytotoxicity, oxidative stress, and cell death in vitro. Only the irradiated BDNF-eMSCs, but not naïve MSCs, showed significant attenuating effects on severe neonatal HI-induced short-term brain injury scores, long-term progress of brain infarct, increased apoptotic cell death, astrogliosis and inflammatory responses, and impaired negative geotaxis and rotarod tests in vivo. Our data, showing better paracrine potency and the resultant better therapeutic efficacy of the irradiated BDNF-eMSCs, compared to naïve MSCs, suggest that MSCs transfected with the BDNF gene might represent a better, new therapeutic strategy against severe neonatal HI brain injury.

Cesarean section was not associated with mortality or morbidities advantage in very low birth weight infants: a nationwide cohort study.

This study investigated the role of cesarean section (CS) in mortality and morbidity of very-low-birth-weight infants (VLBWIs) weighing less than 1500 g. This nationwide prospective cohort study of the Korean Neonatal Network consisted of 9,286 VLBWIs at 23-34 gestational weeks (GW) of age between 2013 and 2017. The VLBWIs were stratified into 23-24, 25-26, 27-28 and 29-34 GW, and the mortality and morbidity were compared according to the mode of delivery. The total CS rate was 78%, and was directly proportional to gestational age. The CS rate was the lowest at 61% in case of infants born at 23-24 GW and the highest at 84% in VLBWIs delivered at 29-34 GW. Contrary to the significantly lower total mortality (12%) and morbidities including sepsis (21%) associated with CS than vaginal delivery (VD) (16% and 24%, respectively), the mortality in the 25-26 GW (26%) and sepsis in the 27-28 GW (25%) and 29-34 GW (12%) groups were significantly higher in CS than in VD (21%, 20% and 8%, respectively). In multivariate analyses, the adjusted odds ratios (ORs) for mortality (OR 1.06, 95% CI 0.89-1.25) and morbidity including sepsis (OR 1.12, 95% CI 0.98-1.27) were not significantly reduced with CS compared with VD. The adjusted ORs for respiratory distress syndrome (1.89, 95% CI 1.59-2.23) and symptomatic patent ductus arteriosus (1.21, 95% CI 1.08-1.37) were significantly increased with CS than VD. In summary, CS was not associated with any survival or morbidity advantage in VLBWIs. These findings indicate that routine CS in VLBWIs without obstetric indications is contraindicated.