Predictability of the neurodevelopmental assessment based on the Kyoto Scale of Psychological Development 2001 at 18-24 months of corrected age and 3 years of age in identifying cognitive impairment at 6 years of age in very preterm infants: A retrospective study at a Japanese tertiary center.

BACKGROUND: It is unknown how accurately the current Japanese classification system for neurodevelopmental delay based on the assessment with the Kyoto Scale of Psychological Development (KSPD) at toddlerhood and pre-school periods predicts cognitive impairment at school age. METHODS: This single-center retrospective cohort study enrolled infants born at 22-29 weeks of gestational age. At 18-24 months of corrected age and 3 years of age, the patients were categorized according to the current Japanese criteria for neurodevelopmental delay based on their overall developmental quotient calculated using the KSPD-2001. Cognitive impairment at 6 years of age was classified according to the calculated or estimated full-scale intelligence quotient. The predictability of the current Japanese classification of neurodevelopmental delay for cognitive impairment at 6 years of age was investigated. RESULTS: Of 566 eligible patients, 364 (64 %) completed the protocol. The current classification for the neurodevelopmental delay showed significant agreement with the severity of cognitive impairment at 6 years of age. The sensitivity and specificity of the KSPD-2001-based assessment for any cognitive impairment at 6 years of age were 0.64 and 0.74 at 18-24 months of corrected age and 0.83 and 0.70 at 3 years of age. The corresponding sensitivity and specificity for moderate/severe cognitive impairment were 0.51 and 0.96 at 18-24 months of corrected age and 0.68 and 0.95 at 3 years of age. CONCLUSION: The KSPD-2001 is a useful tool to predict the severity of cognitive impairment at school age.

Changes in In-Hospital Survival and Long-Term Neurodevelopmental Outcomes of Extremely Preterm Infants: A Retrospective Study of a Japanese Tertiary Center.

OBJECTIVES: The objective of this study was to elucidate whether the survival and long-term neurodevelopmental outcomes of extremely preterm infants have improved in a Japanese tertiary center with an active treatment policy for infants born at 22-23 weeks of gestation. STUDY DESIGN: This single-centered retrospective cohort study enrolled extremely preterm infants treated at Saitama Medical Center, Saitama Medical University, from 2003 to 2014. Patients with major congenital abnormalities were excluded. Primary outcomes were in-hospital survival and severe neurodevelopmental impairment (NDI) at 6 years of age, which was defined as having severe cerebral palsy, severe cognitive impairment, severe visual impairment, or deafness. We assessed the changes in primary outcomes between the first (period 1; 2003-2008) and the second half (period 2; 2009-2014) of the study period and evaluated the association between birth-year and primary outcomes using multivariate logistic regression models. RESULTS: Of the 403 eligible patients, 340 (84%) survived to discharge. Among 248 patients available at 6 years of age, 43 (14%) were classified as having severe NDI. Between the 2 periods, in-hospital survival improved from 155 of 198 (78%) to 185 of 205 (90%), but severe NDI increased from 11 of 108 (10%) to 32 of 140 (23%). In multivariate logistic regression models adjusted for gestational age, birthweight, sex, singleton birth, and antenatal corticosteroids, the aOR (95% CI) of birth-year for in-hospital survival and severe NDI was 1.2 (1.1-1.3) and 1.1 (1.0-1.3), respectively. CONCLUSION: Mortality among extremely preterm infants has improved over the past 12 years; nevertheless, no significant improvement was observed in the long-term neurodevelopmental outcomes.

Oxidative and Inflammatory Markers Are Higher in Full-Term Newborns Suffering Funisitis, and Higher Oxidative Markers Are Associated with Admission.

The aim of this study was to assess whether oxidative and inflammatory mediators in the cord blood of newborns with funisitis and chorioamnionitis can serve as indicators of their inflammatory status, and whether there is a positive association between higher mediator levels and an increased risk of admission to the neonatal intensive care unit (NICU). This study was conducted prospectively in a neonatology department of a university hospital. In total, 52 full-term newborns were evaluated, including 17 funisitis cases, 13 chorioamnionitis cases, and 22 control newborns without funisitis or chorioamnionitis. Cord blood samples were measured for oxidative stress and inflammatory status markers. The oxidative stress markers included the total nitric oxide (NO), total hydroperoxide (TH), biological antioxidant potential (BAP), and TH/BAP ratio, comprising the oxidative stress index (OSI). Inflammatory markers included interleukin (IL)-1b, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNFα), interferon γ (IFNγ), and complement component C5a. TH, OSI, IL-1b, IL-6, and IL-8 concentrations were higher in the funisitis group than in the chorioamnionitis and control groups. C5a was higher in the funisitis and chorioamnionitis groups than in the control group. Among all enrolled newborns, 14 were admitted to the NICU. Multiple logistic regression analysis showed that elevated umbilical cord blood levels of OSI and TH were associated with a higher risk of admission to the NICU (OSI: R = 2.3, 95% CI 1.26-4.29, p = 0.007 and TH: R = 1.02, 95%CI = 1.004-1.040, p = 0.015). In conclusion, OSI and TH in cord blood from full-term newborns can provide an index of inflammatory status, and higher levels are associated with the risk of admission to the NICU and, therefore, could serve as an early indicator of inflammatory conditions in newborns.

Body temperature, heart rate and long-term outcome of cooled infants: an observational study.

BACKGROUND: Therapeutic hypothermia is a standard of care for neonatal encephalopathy; however, approximately one in two newborn infants fails to respond to this treatment. Recent studies have suggested potential relationships between body temperature, heart rate and the outcome of cooled infants. METHODS: The clinical data of 756 infants registered to the Baby Cooling Registry of Japan between January 2012 and December 2016 were analysed to assess the relationship between body temperature, heart rate and adverse outcomes (death or severe impairment at 18 months corrected age). RESULTS: A lower body temperature at admission was associated with adverse outcomes in the univariate analysis (P < 0.001), the significance of which was lost when adjusted for the severity of encephalopathy and other covariates. A higher body temperature during cooling and higher heart rate before and during cooling were associated with adverse outcomes in both univariate (all P < 0.001) and multivariate (P = 0.012, P < 0.001 and P < 0.001, respectively) analyses. CONCLUSIONS: Severe hypoxia-ischaemia might be a common causative of faster heart rates before and during cooling and low body temperature before cooling, whereas causal relationships between slightly higher temperatures during cooling and adverse outcomes need to be elucidated in future studies. IMPACT: In a large cohort of encephalopathic newborn infants, dual roles of body temperature to the outcome were shown; adverse outcomes were associated with a lower body temperature at admission and higher body temperature during cooling. A higher heart rate before and during cooling were associated with adverse outcomes. Severe hypoxia-ischaemia might be a common causative of faster heart rates before and during cooling and low body temperature before cooling. The exact mechanism underlying the relationship between slightly higher body temperature during cooling and adverse outcomes remains unknown, which needs to be elucidated in future studies.

Autologous cord blood cell therapy for neonatal hypoxic-ischaemic encephalopathy: a pilot study for feasibility and safety.

Neonatal hypoxic-ischaemic encephalopathy (HIE) is a serious condition; many survivors develop neurological impairments, including cerebral palsy and intellectual disability. Preclinical studies show that the systemic administration of umbilical cord blood cells (UCBCs) is beneficial for neonatal HIE. We conducted a single-arm clinical study to examine the feasibility and safety of intravenous infusion of autologous UCBCs for newborns with HIE. When a neonate was born with severe asphyxia, the UCB was collected, volume-reduced, and divided into three doses. The processed UCB was infused at 12-24, 36-48, and 60-72 hours after the birth. The designed enrolment was six newborns. All six newborns received UCBC therapy strictly adhering to the study protocol together with therapeutic hypothermia. The physiological parameters and peripheral blood parameters did not change much between pre- and postinfusion. There were no serious adverse events that might be related to cell therapy. At 30 days of age, the six infants survived without circulatory or respiratory support. At 18 months of age, neurofunctional development was normal without any impairment in four infants and delayed with cerebral palsy in two infants. This pilot study shows that autologous UCBC therapy is feasible and safe.

Nationwide epidemiological survey of holoprosencephaly in Japan.

BACKGROUND: Holoprosencephaly (HPE) is a congenital malformation with an estimated prevalence of 0.10-6.06 per 10 000 births but with no nationwide data specific to Japan. METHODS: This nationwide retrospective questionnaire survey was conducted from 2011 to 2013. All 467 training hospitals for perinatal and neonatal care certified by the Japan Society of Perinatal and Neonatal Medicine were contacted. The birth prevalence rate (BPR) was assessed from the primary survey and clinical characteristics from the secondary survey. RESULTS: We received valid responses from 253 hospitals in the primary survey (54.6%). Of 390 342 live births, 60 were diagnosed with HPE (23 males and 37 females), resulting in an actual BPR of 1.54 per 10 000 live births. The point estimate for HPE cases was 100 (95% confidence interval [CI]: 80.7-120), and the estimated BPR of HPE was calculated to be 0.32 per 10 000 live births (95% CI: 0.26-0.38) based on 3 117 853 live births according to Japanese national statistics during the study period. In the secondary survey, we obtained data for 49 cases (19 males and 30 females). Of these, 20 were alobar (40.8%), 20 were semilobar (40.8%), five were lobar (10.4%), and four were of unknown type. Genetic examination was performed in 37 of the 49 HPE patients and revealed that chromosomes 13, 18, and 7 were affected in eight, six, and four patients, respectively. CONCLUSIONS: This is the most extensive survey on holoprosencephaly to date in Japan. The estimated BPR was consistent with that reported in previous research.

Outcomes related to 10-min Apgar scores of zero in Japan.

OBJECTIVE: Apgar scores of zero at 10 min strongly predict mortality and morbidity in infants. However, recent data reported improved outcomes among infants with Apgar scores of zero at 10 min. We aimed to review the mortality rate and neurodevelopmental outcomes of infants with Apgar scores of zero at 10 min in Japan. DESIGN: Observational study. PATIENTS: Twenty-eight of 768 infants registered in the Baby Cooling Registry of Japan between 2012 and 2016, at >34 weeks' gestation, with Apgar scores of zero at 10 min who were treated with therapeutic hypothermia. INTERVENTIONS: We investigated the time of first heartbeat detection in infants with favourable outcomes and who had neurodevelopmental impairments or died. MAIN OUTCOME MEASURES: Clinical characteristics, mortality rate and neurodevelopmental outcomes at 18-22 months of age were evaluated. RESULTS: Nine (32%) of the 28 infants died before 18 months of age; 16 (57%) survived, but with severe disabilities and 3 (11%) survived without moderate-to-severe disabilities. At 20 min after birth, 14 of 27 infants (52%) did not have a first heartbeat, 13 of them died or had severe disabilities and one infant, who had the first heartbeat at 20 min, survived without disability. CONCLUSION: Our study adds to the recent evidence that neurodevelopmental outcomes among infants with Apgar scores of zero at 10 min may not be uniformly poor. However, in our study, all infants with their first heartbeat after 20 min of age died or had severe disabilities.

Body Temperature, Heart Rate, and Short-Term Outcome of Cooled Infants.

Therapeutic hypothermia following neonatal encephalopathy is neuroprotective. However, approximately one in two cooled infants still die or develop permanent neurological impairments. Further understanding of variables associated with the effectiveness of cooling is important to improve the therapeutic regimen. To identify clinical factors associated with short-term outcomes of cooled infants, clinical data of 509 cooled infants registered to the Baby Cooling Registry of Japan between 2012 and 2014 were evaluated. Independent variables of death during the initial hospitalization and survival discharge from the cooling hospital at ≤28 days of life were assessed. Death was associated with higher Thompson scores at admission (p < 0.001); higher heart rates after 3-72 hours of cooling (p < 0.001); and higher body temperature after 24 hours of cooling (p = 0.002). Survival discharge was associated with higher 10 minutes Apgar scores (p < 0.001); higher blood pH and base excess (both p < 0.001); lower Thompson scores (at admission and after 24 hours of cooling; both p < 0.001); lower heart rates at initiating cooling (p = 0.003) and after 24 hours of cooling (p < 0.001) and lower average values after 3-72 hours of cooling (p < 0.001); higher body temperature at admission (p < 0.001); and lower body temperature after 24 hours and lower mean values after 3-72 hours of cooling (both p < 0.001). Survival discharge was best explained by higher blood pH (p < 0.05), higher body temperature at admission (p < 0.01), and lower body temperature and heart rate after 24 hours of cooling (p < 0.01 and <0.001, respectively). Lower heart rate, higher body temperature at admission, and lower body temperature during cooling were associated with favorable short-term outcomes.

Therapeutic hypothermia for neonatal encephalopathy: a report from the first 3 years of the Baby Cooling Registry of Japan.

Therapeutic hypothermia is recommended for moderate and severe neonatal encephalopathy, but is being applied to a wider range of neonates than originally envisaged. To examine the clinical use of therapeutic hypothermia, data collected during the first 3 years (2012-2014) of the Baby Cooling Registry of Japan were analysed. Of 485 cooled neonates, 96.5% were ≥36 weeks gestation and 99.4% weighed ≥1,800 g. Severe acidosis (pH < 7 or base deficit ≥16 mmol/L) was present in 68.9%, and 96.7% required resuscitation for >10 min. Stage II/III encephalopathy was evident in 88.3%; hypotonia, seizures and abnormal amplitude-integrated electroencephalogram were observed in the majority of the remainder. In-hospital mortality was 2.7%; 90.7% were discharged home. Apgar scores and severity of acidosis/encephalopathy did not change over time. The time to reach the target temperature was shorter in 2014 than in 2012. The proportion undergoing whole-body cooling rose from 45.4% to 81.6%, while selective head cooling fell over time. Mortality, duration of mechanical ventilation and requirement for tube feeding at discharge remained unchanged. Adherence to standard cooling protocols was high throughout, with a consistent trend towards cooling being achieved more promptly. The mortality rate of cooled neonates was considerably lower than that reported in previous studies.

Coexistence of congenital diaphragmatic hernia and abdominal wall closure defect with chromosomal abnormality: two case reports.

BACKGROUND: We reported two rare cases of congenital diaphragmatic hernia with abdominal wall closure defect, which were not associated with septum transversum diaphragmatic defects or Fryns syndrome. CASE PRESENTATION: Case 1: a Japanese baby boy was delivered at 37 weeks' gestation by urgent cesarean section because of the diagnosis of severe fetal distress. Congenital diaphragmatic hernia with omphalocele was prenatally diagnosed with fetal ultrasound. A ruptured omphalocele was confirmed at delivery. A silo was established on the day of his birth; direct closure of his diaphragmatic defect and abdominal wall closure was performed on the fifth day after his birth. Trisomy 13 was confirmed by genetic examination. His postoperative course was uneventful and he was discharged 5 months postnatally with home oxygen therapy. He was readmitted because of heart failure and died at 6 months. Case 2: a Japanese baby boy, who was prenatally diagnosed with gastroschisis, was delivered at 35 weeks' gestation by urgent cesarean section because of the diagnosis of fetal distress. Silo construction using a wound retractor was performed on the day of his birth and direct abdominal closure was performed on the tenth day after his birth. Trisomy 21 was confirmed by genetic examination. Treatment for his respiratory distress was continued after surgery. A retrosternal hernia was revealed at 6 months and direct closure of retrosternal diaphragm with the resection of hernia sac was performed. His postoperative course was uneventful and he was discharged with home oxygen therapy. CONCLUSIONS: Attention should be paid to chromosomal abnormality in cases in which the coexistence of congenital diaphragmatic hernia and abdominal wall closure defect are observed.

Postnatal changes in skin water content in preterm infants.

BACKGROUND: Preterm infants have immature skin, which contributes to skin problems. Very little is known about postnatal changes in the skin, despite the clinical importance of this issue. AIM: To assess temporal changes in skin water content in preterm infants. STUDY DESIGN: A prospective observational study. SUBJECTS: Infants admitted to the neonatal intensive care unit were included in this study. OUTCOME MEASURES: Skin water content was measured at five different skin regions using dielectric methods at a depth of 1.5mm. Skin water content was measured on postnatal day 1 in 101 infants, and the correlation between skin water content and gestational week was analyzed. Measurements were also made on postnatal days 2, 3, and 7, and every 7days thereafter until the corrected age of 37weeks in 87 of the 101 infants. Temporal changes were statistically analyzed after dividing participants into seven groups by gestational age. RESULTS: On postnatal day 1, skin water content correlated inversely with gestational age at all skin regions. Skin water content decreased significantly over time, converging to the level of term infants by the corrected age of 32-35weeks. CONCLUSIONS: Skin water content at a depth of 1.5mm was related to corrected age and reached the level of term infants by the corrected age of approximately 32-35weeks.

Oxygen requirement and surfactant therapy in preterm infants after delivery.

BACKGROUND: Several reports have shown the beneficial effects of early or prophylactic surfactant therapy for preterm infants, who often develop respiratory distress syndrome. No report, however, has addressed which infants should receive surfactant therapy in the delivery room. Therefore, the aim of this study was to assess the validity of identifying infants who need surfactant therapy based on fraction of inspiratory oxygen (FiO2 ) requirement in the delivery room. METHODS: In this observational, retrospective study, FiO2 given in the delivery room, use of surfactant therapy, stable microbubble test (SMT) results, and changes in FiO2 both before and after surfactant therapy were reviewed in infants born at <33 weeks' gestation. RESULTS: Overall, 170 infants were included. Forty infants were given oxygen with FiO2 ≥0.6, and all received surfactant therapy. Of these 40 infants, FiO2 could be reduced in 36 (90%) by an average of 0.46 after surfactant therapy. SMT was done in 22 of 40 infants, and surfactant insufficiency was suspected in 20 (91%). In contrast, 81 of 102 infants (79%) with FiO2 <0.4 did not need surfactant therapy within 48 h after birth. CONCLUSIONS: Preterm infants who need FiO2 ≥0.6 in the delivery room appear to be at high risk of surfactant insufficiency and would benefit from surfactant. Surfactant therapy would provide a more effective resuscitation method for preterm infants, and thus a larger prospective study is needed to confirm these results.

Peripheral blood flow monitoring in an infant with septic shock.

Septic shock is associated with impaired vasoregulation, and treatment includes vasoactive drugs. Therefore, evaluation of vasoregulatory change is important. The present report describes the successful characterization of vasoregulatory change in response to a vasoactive drug during septic shock. A male infant born at 23 weeks' gestation developed septic shock. Severe hypotension developed, and treatment with colloid fluid and dopamine failed to increase blood pressure. With continuous measurement of skin blood flow using laser Doppler, noradrenaline was started. Based on changes in the blood flow, the dose was increased. At a dose of 1 µg/kg per min, skin blood flow in the foot decreased without any change in blood pressure. Subsequent blood transfusion succeeded in increasing both blood pressure and skin blood flow. It is concluded that decrease in foot blood flow reflects the vasoconstrictive effect of noradrenaline, although this finding must be validated in larger studies.

The baby cooling project of Japan to implement evidence-based neonatal cooling.

Therapeutic hypothermia was first recommended as a standard of care by international guidelines in 2010. However, at that time, the number of centers capable of providing standard cooling was limited even in Japan. The aim of this project was to implement a nationwide network of evidence-based cooling within 3 years. A taskforce was formed in June 2010 to undergo the primary nationwide practice survey, design of action plans, and the appraisal of interventions by involving all registered level-II/III neonatal intensive care units in Japan. Based on findings from the primary survey, aggressive action plans were introduced that focused on the formulation of clinical recommendations, facilitation of educational events, and opening of an online case registry. Findings from the follow-up survey (January 2013) were compared with the results from the primary survey (June 2010). Four workshops and three consensus meetings were held to formulate clinical recommendations, which were followed by the publication of practical textbooks, large-scale education seminars, and implementation of a case registry. A follow-up survey covering 253 units (response rate: 89.1%) showed that cooling centers increased from 89 to 135. Twelve prefectures had no cooling centers in 2010, whereas all 47 prefectures had at least one in 2013. In cooling centers, adherence to the standard cooling protocols and the use of servo-controlled cooling devices improved from 20.7% to 94.7% and from 79.8% to 98.5%, respectively. A rapid improvement in the national provision of evidence-based cooling was achieved. International consensus guidelines coupled with domestic interventions might be effective in changing empirical approaches to evidence-based practice.

Thoracoscopy-assisted removal of a thoracoamniotic shunt double-basket catheter dislodged into the fetal thoracic cavity: report of three cases.

The indications for and timing of surgical removal of a dislodged thoracoamniotic shunt double-basket catheter are not established, and the side effects of the dislodged into the thoracic cavity remain controversial. The double-basket catheter was designed to reduce the incidence of catheter dislodgement; however, we have encountered four cases of thoracoamniotic shunt double-basket catheter dislodgement into the fetal thorax. The dislodged shunt catheters were removed safely with thoracoscopic assistance within several days of birth, when additional treatments for pleural effusion were needed, such as thoracic drainage tube insertion and adhesion treatment of the thorax. We report the clinical courses of three of these cases of thoracoamniotic shunt tube dislocation. By waiting several days postnatally for stabilization of respiratory and circulatory status and the effective use of thoracoscopic assistance, the dislodged catheter was safely removed from the neonatal thorax. The accumulation of case reports will help establish suitable treatments, and their indication, for a dislodged thoracoamniotic shunt catheter within the fetal thoracic cavity.

Skin blood flow as a predictor of intraventricular hemorrhage in very-low-birth-weight infants.

BACKGROUND: Cardiovascular instability immediately after birth is associated with intraventricular hemorrhage (IVH) in very-low-birth-weight (VLBW) infants. For circulatory management, evaluation of organ blood flow is important. In this study, the relationship between peripheral perfusion within 48 h after birth and IVH was evaluated in VLBW infants. METHODS: In this prospective observational study involving 83 VLBW infants, forehead blood flow (FBF) and lower-limb blood flow (LBF) were measured for 48 h after birth using a laser Doppler flowmeter. Blood flow was compared between infants with and without IVH. Multivariate logistic regression analysis was performed to identify the risk factors for IVH. RESULTS: IVH developed in nine infants. In eight of these patients, IVH occurred after 24 h. LBF was lower in infants with IVH at 18 and 24 h and increased to the same level as that of infants without IVH at 48 h. Multivariate logistic regression analysis identified a correlation only between LBF and IVH at 18 h. CONCLUSION: These findings were consistent with the hypoperfusion-reperfusion theory, which states that IVH develops after reperfusion subsequent to hypoperfusion. We speculate that measurement of skin blood flow in addition to systemic and cerebral circulation may be helpful in predicting IVH.

Effect of dopamine on peripheral perfusion in very-low-birth-weight infants during the transitional period.

INTRODUCTION: Dopamine is one of the most frequently used inotropic drugs in neonatal intensive care units (NICUs); however, it does not seem to improve outcomes in premature infants. Given that the ultimate aim of cardiovascular management is to stabilize and maintain organ perfusion, an understanding of dopamine's effects on organ blood flow will help in judging when to use dopamine and how to titrate the dosage. Such an approach can lead to improved outcomes. This study aimed to evaluate the effects of dopamine on peripheral perfusion in very-low-birth-weight (VLBW) infants within 72 h of birth. METHODS: This prospective observational study identified and sampled 44 instances of initiation of dopamine treatment or increase in dopamine dose in 29 VLBW infants. Blood pressure, heart rate, and skin and subcutaneous blood flow were measured and compared before and after each instance. RESULTS: Blood pressure and skin and subcutaneous blood flow in the lower limbs increased after initiation of dopamine treatment or after dose increase. DISCUSSION: Dopamine increases blood pressure as well as skin and subcutaneous blood flow in VLBW infants despite its supposed vasoconstrictive action, indicating that it increases both perfusion pressure and blood flow and is devoid of overwhelming peripheral vasoconstrictive effects.