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.

Antenatal Magnesium Sulfate Is Not Associated With Improved Long-Term Neurodevelopment and Growth in Very Low Birth Weight Infants.

BACKGROUND: Though antenatal magnesium sulfate (MgSO4) is widely used for fetal neuroprotection, suspicions about the long-term neuroprotection of antenatal MgSO4 have been raised. METHODS: We investigated short- and long-term outcomes of antenatal MgSO4 use for 468 infants weighing < 1,500 g with a gestational age of 24-31 weeks. RESULTS: Short-term morbidities and the risk of developmental delay, hearing loss, and cerebral palsy at a corrected age of 18-24 months and 3 years of age did not decrease in the MgSO4 group (infants who were exposed to MgSO4 for any purpose) or neuroprotection group (infants who were exposed to MgSO4 for fetal neuroprotection) compared with the control group (infants who were not exposed to MgSO4). The z-scores of weight, height, and head circumference did not increase in the MgSO4 group or neuroprotection group compared with the control group. CONCLUSION: Antenatal MgSO4 including MgSO4 for neuroprotection did not have beneficial effects on long-term neurodevelopmental and growth outcomes.

Mesenchymal Stromal Cells Primed by Toll-like Receptors 3 and 4 Enhanced Anti-Inflammatory Effects against LPS-Induced Macrophages via Extracellular Vesicles.

Although it has been suggested that toll-like receptor (TLR) 3 and TLR4 activation alters mesenchymal stromal cells (MSCs)' immunoregulatory function as anti- or pro-inflammatory phenotypes, we have previously confirmed that TLR4-primed hUCB-MSCs alleviate lung inflammation and tissue injury in an E. coli-induced acute lung injury (ALI) mouse model. Therefore, we hypothesized that strong stimulation of TLR3 or TLR4 prompts hUCB-MSCs to exhibit an anti-inflammatory phenotype mediated by extracellular vesicles (EVs). In this study, we compared the anti-inflammatory effect of TLR3-primed and TLR4-primed hUCB-MSCs against an LPS-induced ALI in vitro model by treating MSCs, MSC-derived conditioned medium (CM), and MSC-derived extracellular vesicles (EVs). LPS-induced rat primary alveolar macrophage and RAW 264.7 cells were treated with naïve, TLR3-, and TLR4-primed MSCs and their derived CM and EVs. Flow cytometry and ELISA were used to evaluate M1-M2 polarization of macrophages and pro-inflammatory cytokine levels, respectively. LPS-stimulated macrophages showed significantly increased pro-inflammatory cytokines compared to those of the normal control, and the percentage of M2 macrophage phenotype was predominantly low. In reducing the inflammatory cytokines and enhancing M2 polarization, TLR3- and TLR4-primed MSCs were significantly more effective than the naïve MSCs, and this finding was also observed with the treatment of MSC-derived CMs and EVs. No significant difference between the efficacy of TLR3- and TLR-primed MSCs was observed. Strong stimulation of TLR3- and TLR4-stimulated hUCB-MSCs significantly reduced pro-inflammatory cytokine secretion from LPS-induced macrophages and significantly enhanced the M2 polarization of macrophages. We further confirmed that TLR-primed MSC-derived EVs can exert anti-inflammatory and immunosuppressive effects alone comparable to MSC treatment. We hereby suggest that in the LPS-induced macrophage in vitro model, EVs derived from both TLR3 and TLR4-primed MSCs can be a therapeutic candidate by promoting the M2 phenotype.

SOCS3 Protein Mediates the Therapeutic Efficacy of Mesenchymal Stem Cells against Acute Lung Injury.

Mesenchymal stem cells (MSCs) have been studied as novel therapeutic agents because of their immunomodulatory properties in inflammatory diseases. The suppressor of cytokine signaling (SOCS) proteins are key regulators of the immune response and macrophage modulation. In the present study, we hypothesized that SOCS in MCSs might mediate macrophage modulation and tested this in a bacteria-induced acute lung injury (ALI) mouse model. The macrophage phenotype was observed in RAW264.7 alveolar macrophages exposed to lipopolysaccharide (LPS) in an in vitro model, and in the ALI mouse model induced by tracheal administration of Escherichia coli (1 × 107 CFU in 0.05mL PBS). In LPS-exposed RAW264.7 cells, the levels of markers of M1 macrophages, such as CD86 and pro-inflammatory cytokines (IL-1α, IL-1ß, IL-6 and TNF-α), significantly increased, but they significantly reduced after MSC treatment. Meanwhile, the levels of markers of M2 macrophages, such as CD204 and anti-inflammatory cytokines (IL-4 and IL-10), increased after LPS exposure, and further significantly increased after MSC treatment. This regulatory effect of MSCs on M1/M2 macrophage polarization was significantly abolished by SOCS3 inhibition. In the E. coli-induced ALI model, tissue injury and inflammation in the mouse lung were significantly attenuated by the transplantation of MSCs, but not by SOCS3-inhibited MSCs. The regulatory effect of MSCs on M1/M2 macrophage polarization was observed in the lung injury model but was significantly abolished by SOCS3 inhibition. Taken together, our findings suggest that SOCS3 is an important mediator for macrophage modulation in anti-inflammatory properties of MSCs.

Development of necrotizing enterocolitis in full-term infants with duct dependent congenital heart disease.

BACKGROUND: Although many studies have described an increased risk of necrotizing enterocolitis in duct dependent congenital heart diseases, very few have investigated its occurrence in full-term infants with duct dependent congenital heart diseases. METHODS: To evaluate the characteristics and risk factors of necrotizing enterocolitis, we performed a retrospective review of 355 full-term infants with duct dependent congenital heart diseases who received prostaglandin E1 therapy from April 2000 to May 2020. RESULTS: Necrotizing enterocolitis was observed in 10 patients (3.0%). Their average gestational age and birth weight were 38.2 weeks and 2783.5 g, respectively. The median age at diagnosis was 8.0 days (2-70 days). One patient was diagnosed with necrotizing enterocolitis stage IIA, five with stage IIB, two with stage IIIA, and two with stage IIIB; two (20%) received surgical treatment. The duct dependent pulmonary circulation group had higher frequencies of necrotizing enterocolitis (4.4%) than the duct dependent systemic circulation (2.0%) and parallel circulation (1.3%) groups. The necrotizing enterocolitis and the other groups had significantly different birth weight (2783.5 g vs 3170.9 g, respectively) and gestational age (38.2 weeks vs 39.1 weeks, respectively). Gestational age under 38 weeks (OR 8.87, p = 0.002), birth weight of < 2500 g (OR 5.1, p = 0.042), need for mechanical ventilation (OR 4.6, p = 0.021), parenteral nutrition (OR 107.7, p < 0.001), and functional single ventricle (OR 5.8, p = 0.009) were significant risk factors. The case-fatality rate was higher in the necrotizing enterocolitis (40.0%) than in the other group (8.3%, p = 0.009). CONCLUSIONS: Three percent of full-term infants with duct dependent congenital heart diseases developed necrotizing enterocolitis. Neonates with low birth weight, gestational age less than 38 weeks, functional single ventricle, or receiving assisted mechanical ventilation or parenteral nutrition are at increased risk.

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.

Mortality and Morbidities according to Time of Birth in Extremely Low Birth Weight Infants.

BACKGROUND: Although the overall quality of high-risk neonatal care has improved recently, there is still concern about a difference in the quality of care when comparing off-hour births and regular-hour births. Moreover, there are no data in Korea regarding the impact of time of birth on mortality and morbidities in preterm infants. METHODS: A total of 3,220 infants weighing < 1,000 g and born at 23-34 weeks in 2013-2017 were analyzed based on the Korean Neonatal Network data. Mortality and major morbidities were analyzed using logistic regression according to time of birth during off-hours (nighttime, weekend, and holiday) and regular hours. The institutes were sub-grouped into hospital group I and hospital group II based on the neonatal intensive care unit (NICU) care level defined by the mortality rates of < 50% and ≥ 50%, respectively, in infants born at 23-24 weeks' gestation. RESULTS: The number of births during regular hours and off-hours was similar. In the total population and hospital group I, off-hour births were not associated with increased neonatal mortality and morbidities. However, in hospital group II, increased early mortality was found in the off-hour births when compared to regular-hour births. CONCLUSION: Efforts to improve the overall quality of NICU are required to lower the early mortality rate in off-hour births. Also, other sensitive indexes for the evaluation of quality of NICU care should be further studied.

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.

The Impact of Surgical Intervention on Neurodevelopmental Outcomes in Very Low Birth Weight Infants: a Nationwide Cohort Study in Korea.

BACKGROUND: To investigate the incidence of surgical intervention in very low birth weight (VLBW) infants and the impact of surgery on neurodevelopmental outcomes at corrected ages (CAs) of 18-24 months, using data from the Korean Neonatal Network (KNN). METHODS: Data from 7,885 VLBW infants who were born and registered with the KNN between 2013 to 2016 were analyzed in this study. The incidences of various surgical interventions and related morbidities were analyzed. Long-term neurodevelopmental outcomes at CAs of 18-24 months were compared between infants (born during 2013 to 2015, n = 3,777) with and without surgery. RESULTS: A total of 1,509 out of 7,885 (19.1%) infants received surgical interventions during neonatal intensive care unit (NICU) hospitalization. Surgical ligation of patent ductus arteriosus (n = 840) was most frequently performed, followed by laser therapy for retinopathy of prematurity and laparotomy due to intestinal perforation. Infants who underwent surgery had higher mortality rates and greater neurodevelopmental impairment than infants who did not undergo surgery (P value < 0.01, both). On multivariate analysis, single or multiple surgeries increased the risk of neurodevelopmental impairment compared to no surgery with adjusted odds ratios (ORs) of 1.6 with 95% confidence interval (CI) of 1.1-2.6 and 2.3 with 95% CI of 1.1-4.9. CONCLUSION: Approximately one fifth of VLBW infants underwent one or more surgical interventions during NICU hospitalization. The impact of surgical intervention on long-term neurodevelopmental outcomes was sustained over a follow-up of CA 18-24 months. Infants with multiple surgeries had an increased risk of neurodevelopmental impairment compared to infants with single surgeries or no surgeries after adjustment for possible confounders.

Thrombin Preconditioning Boosts Biogenesis of Extracellular Vesicles from Mesenchymal Stem Cells and Enriches Their Cargo Contents via Protease-Activated Receptor-Mediated Signaling Pathways.

We investigated the role of protease-activated receptor (PAR)-mediated signaling pathways in the biogenesis of human umbilical cord blood-derived mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) and the enrichment of their cargo content after thrombin preconditioning. Immunoblot analyses showed that MSCs expressed two PAR subtypes: PAR-1 and PAR-3. Thrombin preconditioning significantly accelerated MSC-derived EV biogenesis more than five-fold and enriched their cargo contents by more than two-fold via activation of Rab5, early endosomal antigen (EEA)-1, and the extracellular signal regulated kinase (ERK)1/2 and AKT signaling pathways. Blockage of PAR-1 with the PAR-1-specific antagonist, SCH79797, significantly suppressed the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways and subsequently increased EV production and enriched EV cargo contents. Combined blockage of PAR-1 and PAR-3 further and significantly inhibited the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways, accelerated EV production, and enriched EV cargo contents. In summary, thrombin preconditioning boosted the biogenesis of MSC-derived EVs and enriched their cargo contents largely via PAR-1-mediated pathways and partly via PAR-1-independent, PAR-3-mediated activation of Rab5, EEA-1, and the ERK1/2 and AKT signaling pathways.

Thrombin Preconditioning Enhances Therapeutic Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells in Severe Neonatal Hypoxic Ischemic Encephalopathy.

We investigated whether thrombin preconditioning of human Wharton's jelly-derived mesenchymal stem cells (MSCs) improves paracrine potency and thus the therapeutic efficacy of naïve MSCs against severe hypoxic ischemic encephalopathy (HIE). Thrombin preconditioning significantly enhances the neuroprotective anti-oxidative, anti-apoptotic, and anti-cytotoxic effects of naïve MSCs against oxygen-glucose deprivation (OGD) of cortical neurons in vitro. Severe HIE was induced in vivo using unilateral carotid artery ligation and hypoxia for 2 h and confirmed using brain magnetic resonance imaging (MRI) involving >40% of ipsilateral hemisphere at postnatal day (P) 7 in newborn rats. Delayed intraventricular transplantation of 1 × 105 thrombin preconditioned but not naïve MSCs at 24 h after hypothermia significantly enhanced observed anti-inflammatory, anti-astroglial, and anti-apoptotic effects and the ensuing brain infarction; behavioral tests, such as cylinder rearing and negative geotaxis tests, were conducted at P42. In summary, thrombin preconditioning of human Wharton's jelly-derived MSCs significantly boosted the neuroprotective effects of naïve MSCs against OGD in vitro by enhancing their anti-oxidative, anti-apoptotic, and anti-cytotoxic effects, and significantly attenuated the severe HIE-induced brain infarction and improved behavioral function tests in vivo by maximizing their paracrine anti-inflammatory, anti-astroglial, and anti-apoptotic effects.

Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders.

Mesenchymal stem cell (MSC) transplantation represents the next breakthrough in the treatment of currently intractable and devastating neonatal disorders with complex multifactorial etiologies, including bronchopulmonary dysplasia, hypoxic ischemic encephalopathy, and intraventricular hemorrhage. Absent engraftment and direct differentiation of transplanted MSCs, and the "hit-and-run" therapeutic effects of these MSCs suggest that their pleiotropic protection might be attributable to paracrine activity via the secretion of various biologic factors rather than to regenerative activity. The transplanted MSCs, therefore, exert their therapeutic effects not by acting as "stem cells," but rather by acting as "paracrine factors factory." The MSCs sense the microenvironment of the injury site and secrete various paracrine factors that serve several reparative functions, including antiapoptotic, anti-inflammatory, antioxidative, antifibrotic, and/or antibacterial effects in response to environmental cues to enhance regeneration of the damaged tissue. Therefore, the therapeutic efficacy of MSCs might be dependent on their paracrine potency. In this review, we focus on recent investigations that elucidate the specifically regulated paracrine mechanisms of MSCs by injury type and discuss potential strategies to enhance paracrine potency, and thus therapeutic efficacy, of transplanted MSCs, including determining the appropriate source and preconditioning strategy for MSCs and the route and timing of their administration.

Mesenchymal stem cells transplantation attenuates brain injury and enhances bacterial clearance in Escherichia coli meningitis in newborn rats.

OBJECTIVE: Neonatal meningitis caused by Escherichia coli results in significant mortality and neurological disabilities, with few effective treatments. Recently, we demonstrated that human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) transplantation attenuated E. coli-induced severe pneumonia, primarily by reducing inflammation and enhancing bacterial clearance. This study aimed to determine whether intraventricular transplantation of hUCB-MSCs attenuated the brain injury in E. coli meningitis in newborn rats. METHODS: Meningitis without concomitant bacteremia was induced by intraventricular injection of 5 × 102 colony forming units of K1 (-) E. coli in rats at postnatal day (P)11, and hUCB-MSCs (1 × 105) were transplanted intraventricularly 6 h after induction of meningitis. Antibiotics was started 24 h after modeling. RESULT: Meningitis modeling induced robust proliferation of E. coli in the cerebrospinal fluid and increased mortality in rat pups, and MSC transplantation significantly reduced this bacterial growth and the mortality rate. Impaired sensorimotor function in the meningitis rats was ameliorated by MSCs injection. MSCs transplantation also attenuated meningitis caused brain injury including cerebral ventricular dilatation, brain cell death, reactive gliosis, and inflammatory response. CONCLUSION: Intraventricular transplantation of hUCB-MSCs significantly improved survival and attenuated the brain injury via anti-inflammatory and antibacterial effects in experimental neonatal E. coli meningitis.

The Youngest Survivor with Gestational Age of 215/7 Weeks.

The decision whether or not to resuscitate extremely low gestational age (GA) infants is recommended to be individualized according to antenatal counseling with parents, neonatologists, and obstetricians. A GA of 22°/7-236/7 weeks is generally considered as the lower end of the range where infants can be candidates for selective resuscitation. Below this lower end of periviable gestation, resuscitation is usually not considered and survivors are rarely reported. To date, the youngest survivor is an infant with a GA of 216/7 weeks reported in the English medical literature. Here, we report the case of a female infant, the first twin conceived through in vitro fertilization, with a GA of 215/7 weeks, who was resuscitated initially according to strong parental wishes after antenatal counseling and is still surviving at 43 months of age with fairly good neurodevelopmental outcome.

Two-Year Follow-Up Outcomes of Premature Infants Enrolled in the Phase I Trial of Mesenchymal Stem Cells Transplantation for Bronchopulmonary Dysplasia.

OBJECTIVE: To determine the long-term safety and outcomes of mesenchymal stem cells (MSCs) for bronchopulmonary dysplasia in premature infants enrolled in a previous phase I clinical trial up to 2 years of corrected age (CA). STUDY DESIGN: We assessed serious adverse events, somatic growth, and respiratory and neurodevelopmental outcomes at visit 1 (4-6 months of CA), visit 2 (8-12 months of CA), and visit 3 (18-24 months of CA) in a prospective longitudinal follow-up study up to 2 years' CA of infants who received MSCs (MSC group). We compared these data with those from a historical case-matched comparison group. RESULTS: One of 9 infants in the MSC group died of Enterobacter cloacae sepsis at 6 months of CA, the remaining 8 infants survived without any transplantation-related adverse outcomes, including tumorigenicity. No infant in the MSC group was discharged with home supplemental oxygen compared with 22% in the comparison group. The average rehospitalization rate in the MSC group was 1.4/patient because of respiratory infections during 2 years of follow-up. The mean body weight of the MSC group at visit 3 was significantly higher compared with that of the comparison group. No infant in the MSC group was diagnosed with cerebral palsy, blindness, or developmental delay; in the comparison group, 1 infant was diagnosed with cerebral palsy and 1 with developmental delay. CONCLUSIONS: Intratracheal transplantation of MSCs in preterm infants appears to be safe, with no adverse respiratory, growth, and neurodevelopmental effects at 2 years' CA. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01632475.

Antibacterial effect of mesenchymal stem cells against Escherichia coli is mediated by secretion of beta- defensin- 2 via toll- like receptor 4 signalling.

Recently, we demonstrated that intratracheal transplantation of human umbilical cord blood- derived mesenchymal stem cells (MSCs) attenuates Escherichia (E) coli- induced acute lung injury primarily by down- modulating inflammation and enhancing bacterial clearance iQn mice. This study was performed to elucidate the mechanism underlying the antibacterial effects of MSCs. The growth of E. coli in vitro was significantly inhibited only by MSCs or their conditioned medium with bacterial preconditioning, but not by fibroblasts or their conditioned medium. Microarray analysis identified significant up- regulation of toll- like receptors (TLR)- 2 and TLR- 4, and ß- defensin 2 (BD2) in MSCs compared with fibroblasts after E. coli exposure. The increased BD2 level and the in vitro antibacterial effects of MSCs were abolished by specific antagonist or by siRNA- mediated knockdown of TLR- 4, but not TLR- 2, and restored by BD2 supplementation. The in vivo down- modulation of the inflammatory response and enhanced bacterial clearance, increased BD2 secretion and the resultant protection against E. coli- induced pneumonia observed only with MSCs, but not fibroblasts, transplantation in mice, were abolished by knockdown of TLR- 4 with siRNA transfection. Our data indicate that BD2 secreted by the MSCs via the TLR- 4 signalling pathway is one of the critical paracrine factors mediating their microbicidal effects against E. coli, both in vitro and in vivo. Furthermore, TLR- 4 from the transplanted MSCs plays a seminal role in attenuating in vivo E. coli- induced pneumonia and the ensuing acute lung injury through both its anti- inflammatory and antibacterial effects.

Prophylactic versus Early Rescue Surfactant Treatment in Preterm Infants Born at Less than 30 Weeks Gestation or with Birth Weight Less than or Equal 1,250 Grams.

Prophylactic surfactant is known to be effective to reduce chronic lung disease in preterm infants compared with rescue surfactant treatment. In Korea, early prophylactic surfactant therapy was introduced in 2011. However, recently, the increased utilization of antenatal steroids and early stabilization through continuous positive airway pressure (CPAP) in the delivery room may have changed the risks and benefits of prophylactic surfactant therapy of infants at high risk of respiratory distress syndrome (RDS). We compared the effects and safety of prophylactic surfactant therapy (within 30 minutes after birth) and early selective surfactant therapy (within 3 hours after birth) in preterm infants born at < 30 weeks gestation or with birth weight ≤ 1,250 g. The clinical data of 193 infants in period 1 (from 2008 to 2010, early selective surfactant therapy group) were collected retrospectively; those of 191 infants in period 2 (from 2012 to 2014, prophylactic surfactant therapy group) were collected prospectively. Compared to period 1, the rate of intubation and surfactant use were significantly increased in period 2. The use of multiple doses of surfactant in period 2 was significantly increased compared with period 1. Despite more invasive and aggressive management in period 2, there was no difference in the duration of mechanical ventilation, the incidence of bronchopulmonary dysplasia (BPD) or death, and the risk of other adverse neonatal outcomes between the 2 groups. In conclusion, the benefit of prophylactic surfactant therapy in infants treated under current practices is no longer clear compared to early selective surfactant therapy.

MERS-CoV Infection in a Pregnant Woman in Korea.

Middle East respiratory syndrome (MERS) is a lethal respiratory disease - caused by MERS-coronavirus (MERS-CoV) which was first identified in 2012. Especially, pregnant women can be expected as highly vulnerable candidates for this viral infection. In May 2015, this virus was spread in Korea and a pregnant woman was confirmed with positive result of MERS-CoV polymerase chain reaction (PCR). Her condition was improved only with conservative treatment. After a full recovery of MERS, the patient manifested abrupt vaginal bleeding with rupture of membrane. Under an impression of placenta abruption, an emergent cesarean section was performed. Our team performed many laboratory tests related to MERS-CoV and all results were negative. We report the first case of MERS-CoV infection during pregnancy occurred outside of the Middle East. Also, this case showed relatively benign maternal course which resulted in full recovery with subsequent healthy full-term delivery without MERS-CoV transmission.

Mandatory Closure Versus Nonintervention for Patent Ductus Arteriosus in Very Preterm Infants.

OBJECTIVE: To determine whether a nonintervention approach for treating hemodynamically significant patent ductus arteriosus (PDA) is associated with decreased mortality and/or morbidity compared with a mandatory closure approach in extremely low birth weight infants. STUDY DESIGN: We reviewed the medical records of 178 infants of 23-26 weeks' gestational age with PDA, requiring ventilator treatment, and with hemodynamically significant PDA ≥2 mm in size. Mandatory closure was used during period I (July 2009 to December 2011, n = 81), and nonintervention was used during period II (January 2012 to June 2014, n = 97). RESULTS: During period I, 64% of infants were first treated with indomethacin, and 82% were ultimately ligated surgically. During period II, no infant was treated with indomethacin and/or ligation. The average postnatal day of PDA closure was day 13 and day 44 during periods I and II, respectively. There was significantly more use of diuretics and fluid restriction during period II compared with period I. There was no difference in mortality or morbidities such as necrotizing enterocolitis or intraventricular hemorrhage. The incidence of bronchopulmonary dysplasia (BPD) and the propensity score adjusted OR of BPD were significantly lower during period II compared with period I. CONCLUSIONS: Despite longer PDA exposure, nonintervention was associated with significantly less BPD compared with mandatory closure. Additional study is warranted to determine the benefits and risks of non-intervention for the hemodynamically significant PDA in extremely low birth weight infants.

Intratracheal transplantation of mesenchymal stem cells simultaneously attenuates both lung and brain injuries in hyperoxic newborn rats.

BACKGROUND: Bronchopulmonary dysplasia is an independent risk factor for adverse neurodevelopmental outcomes in premature infants. We investigated whether attenuation of hyperoxic lung injury with intratracheal transplantation of human umbilical cord blood-derived mesenchymal stem cells (MSCs) could simultaneously mitigate brain damage in neonatal rats. METHODS: Newborn Sprague-Dawley rats were exposed to hyperoxia or normoxia conditions for 14 d. MSCs (5 × 10(5) cells) were transplanted intratracheally at postnatal day (P) 5. At P14, lungs and brains were harvested for histological and biochemical analyses. RESULTS: Hyperoxic lung injuries, such as impaired alveolarization evident from increased mean linear intercept (MLI) and elevated inflammatory cytokine levels were significantly alleviated with MSC transplantation. Hyperoxia decreased brain weight, increased brain cell death, and induced hypomyelination. MSC transplantation significantly ameliorated hyperoxia-induced increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in the dentate gyrus and reduced myelin basic protein. In correlation analyses, brain weight and myelin basic protein (MBP) were significantly inversely correlated with lung MLI and inflammatory cytokines, while TUNEL-positive brain cell number showed a significant positive correlation with lung MLI. CONCLUSION: Despite no significant improvement in short-term neurofunctional outcome, intratracheal transplantation of MSCs simultaneously attenuated hyperoxic lung and brain injuries in neonatal rats, with the extent of such attenuation being closely linked in the two tissues.