Morbidity and Mortality Trends in Preterm Infants of <32 Weeks Gestational Age with Severe Intraventricular Hemorrhage : A 14-Year Single-Center Retrospective Study.

OBJECTIVE: Owing to advances in critical care treatment, the overall survival rate of preterm infants born at a gestational age (GA) <32 weeks has consistently improved. However, the incidence of severe intraventricular hemorrhage (IVH) has persisted, and there are few reports on in-hospital morbidity and mortality. Therefore, the aim of the present study was to investigate trends surrounding in-hospital morbidity and mortality of preterm infants with severe IVH over a 14-year period. METHODS: This single-center retrospective study included 620 infants born at a GA <32 weeks, admitted between January 2007 and December 2020. After applying exclusion criteria, 596 patients were included in this study. Infants were grouped based on the most severe IVH grade documented on brain ultrasonography during their admission, with grades 3 and 4 defined as severe. We compared in-hospital mortality and clinical outcomes of preterm infants with severe IVH for two time periods : 2007-2013 (phase I) and 2014-2020 (phase II). Baseline characteristics of infants who died and survived during hospitalization were analyzed. RESULTS: A total of 54 infants (9.0%) were diagnosed with severe IVH over a 14-year period; overall in-hospital mortality rate was 29.6%. Late in-hospital mortality rate (>7 days after birth) for infants with severe IVH significantly improved over time, decreasing from 39.1% in phase I to 14.3% in phase II (p=0.043). A history of hypotension treated with vasoactive medication within 1 week after birth (adjusted odds ratio, 7.39; p=0.025) was found to be an independent risk factor for mortality. When comparing major morbidities of surviving infants, those in phase II were significantly more likely to have undergone surgery for necrotizing enterocolitis (NEC) (29.2% vs. 0.0%; p=0.027). Additionally, rates of late-onset sepsis (45.8% vs. 14.3%; p=0.049) and central nervous system infection (25.0% vs. 0.0%; p=0.049) were significantly higher in phase II survivors than in phase I survivors. CONCLUSION: In-hospital mortality in preterm infants with severe IVH decreased over the last decade, whereas major neonatal morbidities increased, particularly surgical NEC and sepsis. This study suggests the importance of multidisciplinary specialized medical and surgical neonatal intensive care in preterm infants with severe IVH.

Myelin toxicity of chlorhexidine in zebrafish larvae.

BACKGROUND: Chlorhexidine gluconate (CHG) is a topical antiseptic solution recommended for skin preparation before central venous catheter placement and maintenance in adults and children. Although CHG is not recommended for use in children aged <2 months owing to limited safety data, it is commonly used in neonatal intensive care units worldwide. We used zebrafish model to verify the effects of early-life exposure to CHG on the developing nervous system, highlighting its impact on oligodendrocyte development and myelination. METHODS: Zebrafish embryos were exposed to different concentrations of CHG from 4 h post fertilization to examine developmental toxicity. The hatching rate, mortality, and malformation of the embryos/larvae were monitored. Oligodendrocyte lineage in transgenic zebrafish embryos was used to investigate defects in oligodendrocytes and myelin. Myelin structure, locomotor behavior, and expression levels of genes involved in myelination were investigated. RESULTS: Exposure to CHG significantly induced oligodendrocyte defects in the central nervous system, delayed myelination, and locomotor alterations. Ultra-microstructural changes with splitting and fluid-accumulated vacuoles between the myelin sheaths were found. Embryonic exposure to CHG decreased myelination, in association with downregulated mbpa, plp1b, and scrt2 gene expression. CONCLUSION: Our results suggest that CHG has a potential for myelin toxicity in the developing brain. IMPACT: To date, the neurodevelopmental toxicity of chlorhexidine gluconate (CHG) exposure on the developing brains of infants remains unknown. We demonstrated that CHG exposure to zebrafish larvae resulted in significant defects in oligodendrocytes and myelin sheaths. These CHG-exposed zebrafish larvae exhibited structural changes and locomotor alterations. Given the increased CHG use in neonates, this study is the first to identify the risk of early-life CHG exposure on the developing nervous system.

Survey of Korean pediatrician's perceptions of barriers to and improvements in breastfeeding.

BACKGROUND: Although the benefits of breastfeeding are broadly acknowledged with the efforts of the government and several medical societies, the rate of exclusive breastfeeding through 6 months is lower in Korea than in developed countries. PURPOSE: This study aimed to investigate pediatricians' perceptions of breastfeeding barriers and the current breastfeeding counseling environment and propose government policies to encourage breastfeeding in Korea. METHODS: Fourteen survey questions were developed during meetings of Korean Society of Breastfeeding Medicine experts. The Korean Pediatric Society emailed a structured questionnaire to domestic pediatricians registered as official members of the Korean Pediatric Society on May 4, 2021, and June 3, 2021. This study examined the survey responses received from 168 pediatricians. RESULTS: The 168 respondents included 62 professors, 53 paid doctors, and 53 private physicians. Breastfeeding was recommended by 146 Korean pediatricians (86.9%). However, only 99 responders (59%) currently provide breastfeeding counseling in hospitals. Most respondents stated providing less than 15 minutes of breastfeeding counseling time in the clinic. Moreover, 89.88% of the respondents responded that they would participate in breastfeeding counseling education if an appropriate breastfeeding counseling program was newly established. CONCLUSION: This study showed that, although Korean pediatricians had a positive attitude toward breastfeeding, limited counseling was provided for parents. Along with policy support to improve the medical environment through the establishment of an appropriate breastfeeding counseling program, high-quality counseling and an increased breastfeeding rate are expected.

Survey on the Status of Breastfeeding in Korean Medical Institution Workers.

BACKGROUND: Human breast milk is essential and provides irreplaceable nutrients for early humans. However, breastfeeding is not easy for various reasons in medical institution environments. Therefore, in order to improve the breastfeeding environment, we investigated the difficult reality of breastfeeding through questionnaire responses from medical institution workers. METHODS: A survey was conducted among 179 medical institution workers with experience in childbirth within the last five years. The survey results of 175 people were analyzed, with incoherent answers excluded. RESULTS: Of the 175 people surveyed, a total of 108 people (61.7%) worked during the day, and 33 people (18.9%) worked in three shifts. Among 133 mothers who stayed with their babies in the same nursing room, 111 (93.3%) kept breastfeeding for more than a month, but among those who stayed apart, only 10 (71.4%) continued breastfeeding for more than a month (P = 0.024). Ninety-five (88.0%) of daytime workers, 32 (94.1%) two-shift workers, and 33 (100%) three-shift workers continued breastfeeding for more than a month (P = 0.026). Workers in general hospitals tended to breastfeed for significantly longer than those that worked in tertiary hospitals (P = 0.003). A difference was also noted between occupation categories (P = 0.019), but a more significant difference was found in the comparison between nurses and doctors (P = 0.012). Longer breastfeeding periods were noted when mothers worked three shifts (P = 0.037). Depending on the period planned for breastfeeding prior to childbirth, the actual breastfeeding maintenance period after birth showed a significant difference (P = 0.002). Of 112 mothers who responded to the question regarding difficulties in breastfeeding after returning to work, 87 (77.7%) mentioned a lack of time caused by being busy at work, 82 (73.2%) mentioned the need for places and appropriate circumstances. CONCLUSION: In medical institutions, it is recommended that environmental improvements in medical institutions, the implementation of supporting policies, and the provision of specialized education on breastfeeding are necessary to promote breastfeeding.

Association of delayed initiation of non-invasive respiratory support with pulmonary air leakage in outborn late-preterm and term neonates.

The frequency of non-invasive respiratory support use has increased in neonates of all gestational ages with respiratory distress (RD). However, the impact of delayed initiation of non-invasive respiratory support in outborn neonates remains poorly understood. This study aimed to identify the impact of the delayed initiation of non-invasive respiratory support in outborn, late-preterm, and term neonates. Medical records of 277 infants (gestational age of ≥ 35 weeks) who received non-invasive respiratory support as primary respiratory therapy < 24 h of age between 2016 and 2020 were retrospectively reviewed. Factors associated with respiratory adverse outcomes were investigated in 190 outborn neonates. Infants with RD were divided into two groups: mild (fraction of inspired oxygen [FiO2] ≤ 0.3) and moderate-to-severe RD (FiO2 > 0.3), depending on their initial oxygen requirements from non-invasive respiratory support. The median time for the initiation of non-invasive respiratory support at a tertiary center was 3.5 (2.2-5.0) h. Male sex, a high oxygen requirement (FiO2 > 0.3), high CO2 level, and respiratory distress syndrome were significant factors associated with adverse outcomes. Subgroup analysis revealed that in the moderate-to-severe RD group, delayed commencement of non-invasive respiratory support (≥ 3 h) was significantly associated with pulmonary air leakage (p = 0.033). CONCLUSION: Our study shows that outborn neonates with moderate-to-severe RD, who were treated with delayed non-invasive respiratory support, were associated with an increased likelihood of pulmonary air leakage. Additional prospective studies are required to establish the optimal timing and methods of non-invasive respiratory support for outborn, late-preterm, and term infants. WHAT IS KNOWN: • Non-invasive respiratory support is widely used in neonates of all gestational ages. • Little is known on the impact of delayed initiation of non-invasive respiratory support in outborn, late preterm, and term neonates. WHAT IS NEW: • Male sex, high oxygen requirement (FiO2 >0.3), high initial CO2 level, and respiratory distress syndrome significantly correlated with adverse outcomes. • Outborn late-preterm and term neonates with high oxygen requirement who were treated with delayed non-invasive respiratory support indicated an increased likelihood of pulmonary air leakage.

Size of Patent Ductus Arteriosus and Echocardiographic Markers of Shunt Volume in Preterm Infants Based on Postnatal Age.

Objective: This study was conducted in order to compare the strength of correlation between echocardiographic markers of shunt volume and patent ductus arteriosus (PDA) diameter based on postnatal age. Methods: This retrospective study focused on preterm infants (aged <32 weeks of gestation) admitted to the Neonatal Intensive Care Unit of Korea University Ansan Hospital, between April 2014 and December 2017, who studied serial targeted neonatal echocardiography (TNE) for PDA during hospitalization. The association between echocardiographic characteristics and duct size was divided into the following days: within 3 days (very early, VE), 4-7 days after birth (early, E), and after 8 days of birth (late, L). Results: We found 113 assessments conducted on 57 infants in the VE period, 92 assessments on 40 infants in the E period, and 342 assessments on 37 infants in the L period. Median gestational age and birth weight were 28+2 weeks of gestation and 1,115 g, respectively. In the univariate regression analysis, we found a statistically significant correlation between PDA diameter and all TNE markers in the E and L days, but not in the VE period. Only ductal velocity [coefficient of determination (R 2) = 0.224], antegrade left pulmonary artery diastolic flow velocity (R 2 = 0.165), left ventricular output (LVO)/superior vena cava (SVC) flow ratio (R 2 = 0.048), and E/A wave ratio (R 2 = 0.092) showed weak correlations with PDA diameter in the VE period. The slopes of the regressions showed significant changes based on postnatal age in the maximum ductal velocity, left atrium/aorta ratio, LVO/SVC flow ratio, and LVO. Conclusions: It is difficult to predict the echocardiographic markers of shunt volume based on the PDA diameter in preterm infants younger than 4 days. A better understanding of the changes in the hemodynamic consequences of PDA based on postnatal age is needed when considering treatment.

Factors associated with neurodevelopment in preterm infants with systematic inflammation.

BACKGROUND: Several studies have suggested that adverse neurodevelopment could be induced by systemic inflammation in preterm infants. We aimed to investigate whether preterm infants with systemic inflammation would have impaired neurodevelopment and which biomarkers and neurophysiologic studies during inflammation are associated with poor neurodevelopment. METHODS: This prospective cohort study enrolled infants born before 30 weeks of gestation or with birth weight < 1250 g. Infants were grouped according to the presence of systemic inflammation: Control (no inflammation, n = 49), I (systemic inflammation, n = 45). Blood and cerebrospinal fluid samples for markers of brain injury and inflammation were collected and amplitude-integrated electroencephalography (aEEG) was performed within 4 h of septic workup. We evaluated aEEG at 35 weeks postmenstrual age (PMA), head circumference at 36 weeks PMA, and brain MRI at discharge. The Bayley Scales of Infant and Toddler Development III (Bayley-III) was performed at a corrected age (CA) of 18 months. RESULTS: The I group had more white matter injuries (2 vs. 26.7%, Control vs. I, respectively) at the time of discharge, lower brain functional maturation (9.5 vs. 8), and smaller head size (z-score - 1.45 vs. -2.12) at near-term age and poorer neurodevelopment at a CA of 18 months than the control (p < 0.05). Among the I group, the proportion of immature neutrophils (I/T ratios) and IL-1 beta levels in the CSF were associated with aEEG measures at the day of symptom onset (D0). Seizure spike on aEEG at D0 was significantly correlated with motor and social-emotional domains of Bayley-III (p < 0.05). The I/T ratio and CRP and TNF-α levels of blood at D0, white matter injury on MRI at discharge, head circumference and seizure spikes on aEEG at near-term age were associated with Bayley-III scores at a CA of 18 months. CONCLUSIONS: Systemic inflammation induced by clinical infection and NEC are associated with neurodevelopmental impairment in preterm infants. The seizure spike on aEEG, elevated I/T ratio, CRP, and plasma TNF-alpha during inflammatory episodes are associated with poor neurodevelopment.

Perinatal Outcomes Associated with Latency in Late Preterm Premature Rupture of Membranes.

This study aims to evaluate the perinatal outcomes of preterm premature rupture of membrane (PPROM) with latency periods at 33 + 0-36 + 6 weeks of gestation. This retrospective case-control study included women with singleton pregnancies who delivered at 33 + 0-36 + 6 weeks at Korea University Ansan Hospital in South Korea between 2006-2019. The maternal and neonatal characteristics were compared between different latency periods (expectant delivery ≥72 h vs. immediate delivery <72 h). Data were compared among 345 women (expectant, n = 39; immediate delivery, n = 306). There was no significant difference in maternal and neonatal morbidities between the groups, despite the younger gestational age in the expectant delivery group. Stratified by gestational weeks, the 34-week infants showed a statistically significant lower exposure to antenatal steroids (73.4% vs. 20.0%, p < 0.001), while the incidence of respiratory distress syndrome (12.8%) and the use of any respiratory support (36.8%) was higher than those in the 33-week infants, without significance. Our study shows that a prolonged latency period (≥72 h) did not increase maternal and neonatal morbidities, and a considerable number of preterm infants immediately delivered at 34 weeks experienced respiratory complications. Expectant management and antenatal corticosteroids should be considered in late preterm infants with PPROM.

Hemodynamics of different volumes of red blood cell transfusion in preterm infants.

BACKGROUND: Although many controversies exist regarding the risk of red blood cell (RBC) transfusions, half of preterm infants born at <32 weeks of gestational age receive such transfusions because of anemia of prematurity. Because of the costs and risks associated with multiple transfusions, it has been suggested that a large transfusion volume reduces the number of transfusions. However, there have been persistent concerns that RBC transfusion might lead to volume overload. METHODS: We examined the impacts of large (20 mL/kg) compared to standard volume (15 mL/kg) transfusions on the hemodynamic variables of stable, electively transfused, preterm infants, by serially measuring echocardiographic parameters and plasma B-type natriuretic peptide levels. RESULTS: A total of 39 infants born at <34 weeks of gestation and aged >2 weeks at the time of enrollment were randomly allocated to either a standard volume (15 mL/kg) or a large volume (20 mL/kg) group. Significant reductions in cardiac output and transient increases in plasma B-type natriuretic peptide levels were found after RBC transfusion in both the standard and large volume (20 mL/kg) groups. However, these changes were not significantly different between the two groups. CONCLUSIONS: Large-volume transfusions could be tolerable in stable preterm infants with anemia.

Effectiveness of nCPAP for moderate preterm infants compared to BiPAP: A Randomized, Controlled Non-Inferiority Trial.

BACKGROUND: Bilevel positive airway pressure (BiPAP) has recently been used in preterm infants with respiratory distress as an alternative to nasal continuous positive airway pressure (nCPAP) because, theoretically, BiPAP is thought to be more effective than nCPAP. However, the results of some studies comparing nCPAP with BiPAP as the initial respiratory support were controversial. The aim of this study is to compare the clinical effectiveness and safety of nCPAP with BiPAP at gestational ages of 30+0 to 34+6  weeks. METHODS: A total of 93 infants with gestational ages of 30+0 to 34+6  weeks, who presented with respiratory distress within 24 h after birth, were randomized to the nCPAP group or the BiPAP group. The primary outcome was the incidence of treatment failure with these two non-invasive respiratory support devices. Criteria for treatment failure included any of the following: respiratory acidosis (PaCO2 >65 mmHg with pH <7.2), hypoxia (FiO2 >0.4), or apnea (>2-3 episodes of apnea/h). RESULTS: There was no statistically significant difference in treatment failure between the two groups (P = 0.576). The risk difference comparing treatment failure rate between nCPAP and BiPAP groups was -4.7% (95% CI: -21.5-11.9). CONCLUSIONS: Nasal continuous positive airway pressure is not inferior to BiPAP as an initial management of respiratory distress in these premature infants. We therefore conclude that nCPAP can be used as an initial management for preterm infants at gestational age of between 30 and 35 weeks as a substitute for BiPAP.

Risk factors for treatment failure of heated humidified high-flow nasal cannula as an initial respiratory support in newborn infants with respiratory distress.

BACKGROUND: Humidified high-flow nasal cannula (HHFNC) has gained popularity because it is easier to use, more comfortable for babies, and advantageous for mother-infant bonding. HHFNC is not inferior to other non-invasive ventilators for preventing adverse outcomes, but more studies are needed to ensure the safe use of HHFNC as an initial respiratory support for newborns. The aim of this study was to investigate risk factors for treatment failure of HHFNC as an initial respiratory support in newborns with respiratory distress after birth. METHODS: We included 97 newborns who required non-invasive respiratory support within 24 h after birth. The success group included 68 infants who were successfully managed only on HHFNC, and 29 infants were the failure group who required other respiratory support because of respiratory acidosis, hypoxia, or apnea. RESULTS: Compared with the success group, the failure group had lower GA, a higher rate of antenatal steroid use, prolonged rupture of membrane, lower pH, higher pCO2 on blood-gas analysis after HHFNC application and higher incidence of respiratory distress syndrome of newborn (RDS). After adjusting for GA, higher FiO2 settings during acidosis, hypercarbia after the application of HHFNC shown on blood-gas analysis and the presence of RDS remained significant. The rate of treatment failure was 16.2% for ≥36 weeks, 19.3% for ≥34 weeks, and 22.1% for ≥33 weeks. CONCLUSION: Treatment failure of HHFNC should be considered a risk for newborns of less than 34 weeks and infants with respiratory distress from RDS. Higher FiO2 settings during HHFNC, and acidosis and hypercarbia after the application of HHFNC shown on blood-gas analysis may help identify high-risk newborns for other non-invasive ventilators or intubation.

Developmental outcomes of preterm infants with bronchopulmonary dysplasia-associated pulmonary hypertension at 18-24 months of corrected age.

BACKGROUND: Owing to advances in the critical care of premature infants with bronchopulmonary dysplasia (BPD), BPD-associated pulmonary hypertension (PH) is becoming a growing concern. However, only few investigations were available on neurodevelopmental outcomes in preterm infants with PH. Therefore, this study aimed to identify the impact of PH on growth and neurodevelopment at 18-24 months of corrected age (CA). METHODS: We retrospectively analyzed the medical records of 394 infants (aged < 28 weeks of gestation) admitted to the neonatal intensive care unit between 2005 and 2014. Among the surviving infants, 123 returned for follow-up evaluations including the Bayley Scales of Infant and Toddler Development, third Edition (Bayley-III) screening tests and growth assessment at 18-24 months of CA. Among the 81 infants with moderate or severe BPD, 20 met the criteria for PH. Baseline characteristics and outcomes were compared in infants who developed BPD-associated PH (PH group, n = 20) and moderate or severe BPD infants who did not develop PH (non-PH group, n = 61). RESULTS: Compared to the non-PH group, the PH group showed significantly lower cognitive (85 vs. 95, p = 0.004), language (81 vs. 89, p = 0.040), and motor (88 vs. 94, p = 0.010) scores of the Bayley-III at 18-24 months of CA. Cognitive delay was found in 45.0% (9/20) of PH infants. In addition, z-scores of weight (- 1.4 ± 1.3 vs. -0.6 ± 1.1%, p = 0.011) and HC (- 1.2 ± 1.8 vs. 0.53 ± 1.0%, p = 0.035) were significantly lower in the BPD with PH group. With the subgroup analysis in infants with severe BPD only, the cognitive score was consistently lower and poorer and weight gain after discharge was identified in infants with PH and severe BPD. CONCLUSION: PH was a worsening factor of non-optimal growth and poor neurodevelopmental outcome in preterm infants with BPD at 18-24 months of CA. Our findings suggest the importance of close developmental follow-up and recognition of that risk to help optimize the outcome of preterm infants with PH.

The Impact of Atrial Left-to-Right Shunt on Pulmonary Hypertension in Preterm Infants with Moderate or Severe Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is a well-known complication of prematurity; however, the additional impact of a left-to-right interatrial shunt on this condition remains poorly understood. The aim of the present study was to identify the significance of atrial left-to-right shunt lesions in PH infants with moderate or severe BPD. METHODS: The medical records of 383 preterm infants (gestational age of < 32 weeks) who were diagnosed with BPD between 2005 and 2013 were retrospectively reviewed. Baseline characteristics such as interatrial shunts and outcomes were compared between the infants who developed PH (n = 50) and infants who did not (n = 144). Infants with hemodynamically significant residual patent ductus arteriosus were excluded. Among the infants diagnosed with PH (n = 50), the outcomes were compared between the patients with (n = 21) and without atrial shunts (n = 29) at 36 weeks corrected postmenstrual age. RESULTS: Fifty (15%) preterm infants with BPD were diagnosed with PH. The number of infants with a history of atrial shunt lesions was significantly higher in the PH group than in the non-PH group (42% vs. 15.3%, respectively). The adjusted odds ratio for PH in the atrial shunt group was 3.8 (95% confidence interval, 1.8-8.0), compared to PH-BPD infants without an atrial shunt. CONCLUSION: The presence of an atrial left-to-right shunt was associated with PH in preterm infants with moderate or severe BPD. Close follow up is needed for infants with interatrial shunts, and a more tailored prognostic evaluation and treatment are recommended.