Delivery room intubation and neurodevelopment among extremely preterm infants.

BACKGROUND: The impact of delivery room intubation (DRI) on neurodevelopment in extremely preterm infants remains unclear. METHODS: We retrospectively analyzed data for infants born at 24-27 gestational weeks between 2003 and 2018. The primary outcome was neurodevelopmental impairment (NDI), defined as cerebral palsy or hearing, visual, or cognitive impairment at age 3 years. Secondary outcomes were NDI components and death before and after discharge from the neonatal intensive care unit. We conducted robust Poisson regression analyses, adjusting for perinatal confounders. RESULTS: The full cohort included 4397 infants with NDI data, of whom 3703 were intubated in the delivery room and 694 were not intubated in the delivery room. The mean gestational age and birth weight were 26.0 ± 1.1 weeks and 778 ± 184 g for infants with DRI and 26.6 ± 1.0 weeks and 873 ± 184 g for infants without DRI. Compared with infants without DRI, those with DRI had a higher risk for NDI (32.4% vs. 23.3%; adjusted risk ratio 1.18, 95% confidence interval: 1.01-1.37). There were no differences in secondary outcomes between infants with and without DRI. CONCLUSIONS: DRI was associated with an increased risk for NDI at age 3 years among extremely preterm infants. IMPACT: Few studies have examined the impact of delivery room intubation on neurodevelopment in infants born extremely preterm, and the results have been inconsistent. A total of 4397 infants born at 24-27 gestational weeks who had neurodevelopmental data at age 3 years were included in the present study. The present study found that delivery room intubation was associated with an increased risk for neurodevelopmental impairment at age 3 years among extremely preterm infants.

Respiratory Severity Score and Neurodevelopmental Outcomes at Age 3 Years in Extremely Preterm Infants.

OBJECTIVE: We aimed to examine the association between respiratory severity score (RSS; mean airway pressure × fraction of inspired oxygen) and neurodevelopmental outcomes in extremely preterm infants. STUDY DESIGN: This was a single-center, retrospective cohort study. We analyzed data from extremely preterm infants who were admitted to the neonatal intensive care unit at Okayama Medical Center between 2010 and 2019. Infants without invasive respiratory management during the first day of life were excluded. The exposure variable was the highest RSS during the first day of life. RSS was categorized into two groups: low (<3.5) and high (≥3.5) RSS. The primary outcome was death or neurodevelopmental impairment at age 3 years, defined as cognitive impairment (developmental quotient <70) or the presence of cerebral palsy. Secondary outcomes were the components of the primary outcome. We conducted robust Poisson regression analyses to investigate the association between RSS category and primary and secondary outcomes, adjusting for perinatal confounders. RESULTS: The cohort included 97 infants with neurodevelopmental data, of whom 34 and 63 infants were in the low- and high-RSS categories, respectively. The median (interquartile range) gestational age and birth weight were 26.0 (24.7-26.9) and 25.7 (24.6-26.7) weeks and 761 (584-866) and 806 (618-898) g for infants in the low- and high-RSS categories, respectively. Compared with infants in the low-RSS category, those in the high-RSS category had a greater risk of death or neurodevelopmental impairment at age 3 years (26.3 vs. 42.3%; adjusted risk ratio [RR], 2.0; 95% confidence interval [CI], 1.1-3.5) and neurodevelopmental impairment at age 3 years (17.6 vs. 28.6%; adjusted RR, 2.7; 95% CI, 1.3-5.9). CONCLUSION: High RSS (≥3.5) during the first day of life was associated with an increased risk of neurodevelopmental impairment at age 3 years in extremely preterm infants. KEY POINTS: · RSS is a valuable tool for assessing respiratory failure.. · RSS = Mean airway pressure × fraction of inspired oxygen.. · RSS at age 1 day was associated with neurodevelopment..

Predictive value of the Thompson score for short-term adverse outcomes in neonatal encephalopathy.

BACKGROUND: To explore the predictive value of the Thompson score during the first 4 days of life for estimating short-term adverse outcomes in neonatal encephalopathy. METHODS: This observational study evaluated infants with neonatal encephalopathy (≥36 weeks of gestation) registered in a multicenter cohort of cooled infants in Japan. The Thompson score was evaluated at 0-24, 24-48, 48-72, and 72-90 h of age. Adverse outcomes included death, survival with respiratory impairment (requiring tracheostomy), or survival with feeding impairment (requiring gavage feeding) at discharge. RESULTS: Of the 632 infants, 21 (3.3%) died, 59 (9.3%) survived with respiratory impairment, and 113 (17.9%) survived with feeding impairment. The Thompson score throughout the first 4 days accurately predicted death, respiratory impairment, or feeding impairment. The 72-90 h score showed the highest accuracy. A cutoff of ≥15 had a sensitivity of 0.85 and specificity of 0.92 for death or respiratory impairment, while a cutoff of ≥14 had a sensitivity of 0.71 and a specificity of 0.92 for death, respiratory or feeding impairment. CONCLUSION: A high Thompson score during the first 4 days of life, especially at 72-90 h could thus be useful for estimating the need for prolonged life support. IMPACT: The Thompson score on days 1-4 of age was useful in predicting death and respiratory or feeding impairments. The 72-90 h Thompson score showed the highest predictive capability. Owing to the rarity of withdrawal of life-sustaining treatment in Japan, 43% of infants with persistent severe encephalopathy with a Thompson score of ≥15 at 72-90 h of age could regain spontaneous breathing, be extubated, and survive without tracheostomy. Meanwhile, approximately 50% of infants who survived without tracheostomy required gavage feeding. Our results could provide useful information for clinical decision making regarding infants with persistent severe encephalopathy.

Long-Term Prognosis and Related Factors in Patients with Cirrhosis Treated with Balloon-Occluded Retrograde Transvenous Obliteration.

INTRODUCTION: Balloon-occluded retrograde transvenous obliteration (BRTO) was developed as an effective treatment for gastric varices in patients with cirrhosis. Because liver fibrosis in these patients is assumed to be advanced, their prognosis is expected to be poor. In this study, we investigated the prognosis and characteristics of the patients. METHODS: We enrolled 55 consecutive patients with liver cirrhosis treated with BRTO between 2009 and 2021 at our department. To evaluate factors related to variceal recurrence and long-term prognosis, survival analysis was performed on 45 patients, excluding those who died within 1 month, had an unknown prognosis, or whose treatments were converted to other treatments. RESULTS: During a mean follow-up period of 2.3 years, esophageal varices recurred in 10 patients and could be treated endoscopically. Non-alcoholic steatohepatitis (NASH) was related to the variceal recurrence (hazard ratio [HR] = 4.27, 95% CI: 1.17-15.5, p = 0.028). The survival rate after the procedure at 1, 3, and 5 years was 94.2%, 74.0%, and 63.5%, respectively, and 10 patients died of hepatocellular carcinoma (n = 6), liver failure (n = 1), sepsis (n = 1), and unknown reasons (n = 2). The estimated glomerular filtration rate (eGFR) level was proved to be a significant poor prognostic factor (HR = 0.96, 95% CI: 0.93-0.99, p = 0.023). The comorbid hypertension (HTN) was the main cause of low eGFR, and HTN was also significantly related to survival (HR = 6.18, 95% CI: 1.57-24.3, p = 0.009). Most of the patients with HTN were treated with calcium channel blocker and/or angiotensin receptor blocker. CONCLUSION: The clinical course of patients with cirrhosis treated with BRTO was dependent on the metabolic factors including renal function, comorbid HTN, and NASH.

Determinants of the effectiveness of bezafibrate combined with ursodeoxycholic acid in patients with primary biliary cholangitis.

BACKGROUND AND AIMS: For patients with primary biliary cholangitis (PBC) exhibiting suboptimal responses to ursodeoxycholic acid (UDCA), obeticholic acid (OCA), and bezafibrate (BZF) are currently used and shown to improve long-term outcomes. Nevertheless, we encounter patients who die or undergo liver transplantation (LT) even with combination treatment. In this study, we explored prognostic indicators in patients receiving combination treatment of UDCA and BZF. METHODS: We took advantage of the Japanese PBC registry and enrolled patients who received both UDCA and BZF therapy in 2000 or later. The covariates investigated included baseline covariates as well as treatment covariates. Two main outcomes (all-cause death or LT and liver-related death or LT) were assessed using multivariable-adjusted Cox proportional hazards models. RESULTS: In total, 772 patients were included. The median follow-up was 7.1 years. Using the Cox regression model, bilirubin (hazard ratio [HR] 6.85, 95% confidence interval [CI] 1.73-27.1, p = 0.006), alkaline phosphatase (HR 5.46, 95% CI 1.32-22.6, p = 0.019), and histological stage (HR 4.87, 95% CI 1.16-20.5, p = 0.031) were found associated with LT-free survival. For survival free from liver disease-related death or LT, albumin (HR 7.72, 95% CI 1.48-40.4, p = 0.016) and bilirubin (HR 14.5, 95% CI 2.37-88.5, p = 0.004) were found significantly associated. CONCLUSION: In patients with PBC receiving combination therapy, prognostic variables were similar to those in patients receiving UDCA monotherapy. These results indicate the importance of diagnosing patients with PBC at an earlier stage because of the reduced effectiveness of BZF at advanced stages.

Prolonged requirements for mechanical ventilation and tube feeding support predicted 18-month outcomes for neonatal encephalopathy.

AIM: We evaluated the predictive ability of prolonged requirements for mechanical ventilation or tube feeding support for 18-month composite outcomes in infants with hypoxic-ischaemic encephalopathy treated with hypothermia. METHODS: This retrospective, nationwide, observational study focused on newborn infants registered in Japan's Baby Cooling Registry between 1 January 2012 and 31 December 2016. The adverse outcomes were defined as death or survival with cerebral palsy, visual or auditory impairment or the requirement for mechanical ventilation or tube feeding at 18 months of age. RESULTS: Adverse outcomes occurred in 165 (28%) of the 591 children in the final cohort. These were predicted by prolonged dependence on mechanical ventilation or tube feeding for more than seven and more than 14 days. The respective values were positive predictive value 0.34 (95% CI 0.33-0.34) and 0.60 (95% CI 0.56-0.62), negative predictive value 0.97 (95% CI 0.91-0.99) and 0.93 (95% CI 0.90-0.95) and area under the curve 0.59 (95% CI 0.54-0.64) and 0.81 (95% CI 0.77-0.85). CONCLUSION: Prolonged dependence on mechanical ventilation or tube feeding for more than 14 days may be useful in predicting 18-month outcomes in newborn infants who have received therapeutic hypothermia.

Congenital intrahepatic portosystemic shunt with spontaneous resolution in a newborn with severe fetal growth restriction.

Owing to the advances in ultrasound, there are increasing reports of intrahepatic portosystemic shunt (IPSS) diagnosis in utero. However, few neonatal cases of IPSS diagnosed by abdominal ultrasonography screening at birth have been reported. This case demonstrated abdominal ultrasonography at birth was useful for the early detection of congenital IPSS.

Preterm birth and Kawasaki disease: a nationwide Japanese population-based study.

BACKGROUND: Previous studies showed that preterm birth increased the risk for hospital admissions in infancy and childhood due to some acute diseases. However, the risk of preterm children developing Kawasaki disease remains unknown. In the present study, we investigate whether preterm birth increased the morbidity of Kawasaki disease. METHODS: We included 36,885 (34,880 term and 2005 preterm) children born in 2010 in Japan. We examined the association between preterm birth and hospitalization due to Kawasaki disease using a large nationwide survey in Japan. RESULTS: In log-linear regression models that were adjusted for children's characteristics (sex, singleton birth, and parity), parental characteristics (maternal age, maternal smoking, paternal smoking, maternal education, and paternal income), and residential area, preterm infants were more likely to be hospitalized due to Kawasaki disease (adjusted risk ratio: 1·55, 95% confidence interval: 1.01-2.39). We then examined whether breastfeeding status modified the potential adverse effects of preterm birth on health outcome. Preterm infants with partial breastfeeding or formula feeding had a significantly higher risk of hospitalization due to Kawasaki disease compared with term infants with exclusive breastfeeding. CONCLUSIONS: Preterm infants were at a high risk for Kawasaki disease, and exclusive breastfeeding might prevent this disease among preterm infants. IMPACT: Previous studies showed that preterm birth increased the risk for hospital admissions in infancy and childhood due to some acute diseases, however, the risk of preterm children developing Kawasaki disease remains unknown. This Japanese large population-based study showed that preterm infants were at a high risk for Kawasaki disease for the first time. Furthermore, this study suggested that exclusively breastfeeding might prevent Kawasaki disease among preterm infants.

Sports participation and preterm birth: a nationwide birth cohort in Japan.

BACKGROUND: Children born preterm may be less physically active than children born term because of neurocognitive problems, reduced lung function, and poor physical fitness. We evaluated sports participation of children and adolescents who had been born preterm (<37 weeks) and early term (37-38 weeks) in 2001. METHODS: Data from a nationwide longitudinal survey (n = 47,015, including 2375 children born preterm) were analyzed. As indicators of sports participation, we used responses to questions about participation in sports clubs at 7 and 10 years old and in extracurricular school sports at 15 years old. RESULTS: Children born very preterm (25-31 weeks) and moderately to late preterm (32-36 weeks) were less likely to participate in sports clubs at 7, 10, and 15 years old than children born full term (39-41 weeks). Compared with children born full term, the adjusted risk ratios for participation in extracurricular school sports at 15 years old were 0.86 (95% confidence interval: 0.75-0.98) for children born very preterm, 0.92 (0.88-0.97) for children born moderately to late preterm, and 1.00 (0.98-1.02) for children born early term. CONCLUSIONS: Our findings suggest that preterm birth is associated with less participation in organized sports during childhood and adolescence than full-term birth. IMPACT: Research investigating associations between preterm birth and physical activity among children born in the 2000s is limited. This study shows that preterm birth was associated with less participation in organized sports during childhood and adolescence than full-term birth, especially in boys, and the participation in organized sports of children born preterm decreased as gestation shortened. During childhood, boys born early term were also less likely to participate in organized sports than boys born full term, suggesting a continuum with preterm births. These findings offer important additional insights into the limited evidence available for predicting future health outcomes for preterm infants.

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.

Neonatal sepsis and Kawasaki disease.

The purpose of this study is to clarify the relationship between neonatal sepsis and future development of Kawasaki disease (KD). We analyzed data from the National Hospital Organization Neonatal Intensive Care Unit (NHO-NICU) registry study in Japan. Participants in this study were children with a history of hospitalization in the NICU at the participating institutions from 2010 to 2014. A questionnaire was administered at age 3 years to obtain information about the patient's history of KD. There were 8275 infants who were eligible for this study. At 3 years of age, parents of 2161 children responded to the follow-up survey (follow-up rate, 26.1%). Multivariate logistic regression analysis adjusted for preterm birth, sex, use of antibiotics in the NICU, parity, and maternal smoking showed that children with neonatal sepsis were more likely to have a history of KD at 3 years of age (adjusted odds ratio [aOR]: 11.67, 95% confidence interval [CI]: 2.84-47.96). CONCLUSIONS: Among infants admitted to the NICU, neonatal sepsis might be associated with development of KD later in life. Further large studies are needed to elucidate the relationship between neonatal infections and KD development. WHAT IS KNOWN: • Preterm birth is known to be a risk factor for Kawasaki disease. •It is not yet known which factors related to preterm birth increase the risk of developing Kawasaki disease. WHAT IS NEW: •Neonatal sepsis is associated with an increased risk of subsequent development of Kawasaki disease. •Antibiotic use in the neonatal intensive care unit may also be an independent risk factor for subsequent development of Kawasaki disease.

Prenatal clinical manifestations in individuals with COL4A1/2 variants.

BACKGROUND: Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear. METHODS: We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail. RESULTS: Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly. CONCLUSIONS: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

Associations of Birth Weight for Gestational Age with Child Health and Neurodevelopment among Term Infants: A Nationwide Japanese Population-Based Study.

OBJECTIVE: To examine the association of specific Z-score categories of birth weight for gestational age with child health and neurodevelopment using a large nationwide survey in Japan, focusing on term infants. STUDY DESIGN: We included 36 321 children born in 2010. Hospitalization up to 66 months of age was used as an indicator of health status, and responses to questions about age-appropriate behaviors at 30 and 66 months of age were used to indicate neurobehavioral development. We conducted binomial log-linear regression analyses, controlling for child and parental variables. A restricted cubic spline function was used to model the relationship. RESULTS: Compared with children with birth weight appropriate for gestational age (-1.28 to 1.28 SDs of expected birthweight for gestational age), children who were small for gestational age (SGA) (<-1.28 SD) had higher risks of hospitalization and unfavorable neurobehavioral development, and the risks increased as SGA status became more severe. Compared with the appropriate for gestational age group, the adjusted risk ratios for hospitalization for all causes were 2.5 (95% CI, 1.7-3.6), 1.3 (95% CI, 1.1-1.6), and 1.1 (95% CI, 1.0-1.2) for children who were severely, moderately, and mildly SGA and 1.0 (95% CI, 0.9-1.1), 1.1 (95% CI, 0.9-1.2), and 1.4 (95% CI, 0.9-2.1) for children who were mildly, moderately, and severely large for gestational age, respectively. Severely large for gestational age children also had higher risks of unfavorable neurobehavioral development. These results were supported by spline analyses. CONCLUSIONS: Among term infants, the risks of unfavorable child health and neurodevelopment increased with the severity of SGA.

A pathogenic variant in the SETBP1 hotspot results in a forme-fruste Schinzel-Giedion syndrome.

Schinzel-Giedion syndrome (SGS; OMIM 269150) is an ultra-rare genetic disorder associated with a distinctive facial gestalt, congenital malformations, severe intellectual disability, and a progressive neurological course. The prognosis for SGS is poor, with survival beyond the first decade rare. Germline, de novo heterozygous variants in the SETBP1 gene cause SGS with the pathogenic variants associated with the SGS phenotype missense and confined to exon 4 of the gene, clustered in a four amino acid (12 bp) hotspot in the SKI homologous region of the SETBP1 protein. We report a patient with a de novo I871S variant within the SKI homologous region, which has been associated with the severe phenotype previously; but our patient has fewer features of SGS and a milder course. This is the first report of a forme-fruste phenotype in a patient with a pathogenic variant within the SGS hotspot on the SETBP1 gene and it highlights the importance of considering atypical clinical presentations in the context of severe ultra-rare genetic disorders.

Catch-Up Growth and Neurobehavioral Development among Full-Term, Small-for-Gestational-Age Children: A Nationwide Japanese Population-Based Study.

OBJECTIVE: To examine the relationship between catch-up growth of full-term, small for gestational age (SGA) children and their neurobehavioral development. STUDY DESIGN: Data were obtained from a population-based nationwide Japanese longitudinal survey that started in 2001. Study participants were full-term children with information on height at 2 years of age (n = 32 533). Catch-up growth for SGA infants was defined as achieving a height at 2 years of age of more than -2.0 standard deviations for chronological age. Logistic regression analyses were used to estimate ORs and 95% CIs for the associations of SGA and catch-up growth status with neurobehavioral development at 2.5 and 8 years of age, adjusting for potential infant- and parent-related confounding factors. RESULTS: Fifteen percent of term SGA infants failed to catch up in height. At 2.5 years of age, SGA children without catch-up growth were more likely to be unable to climb stairs (OR, 10.42; 95% CI, 5.55-19.56) and unable to compose a 2-word sentence (OR, 3.58; 95% CI, 1.81-7.08) compared with children with normal growth at birth. Furthermore, SGA children without catch-up growth were at increased risk for aggressive behaviors (OR, 3.85; 95% CI, 1.19-12.47) at 8 years of age. CONCLUSIONS: Continuous follow-up for full-term SGA infants with failure of catch-up growth or poor postnatal growth may be beneficial for early detection and intervention for behavioral problems.

Cover Image, Volume 176A, Number 3, March 2018.

The cover image, by Kei Tamai et al., is based on the Clinical Report Fetal ultrasonographic findings including cerebral hyperechogenicity in a patient with non-lethal form of Raine syndrome, DOI: 10.1002/ajmg.a.38598.

Fetal ultrasonographic findings including cerebral hyperechogenicity in a patient with non-lethal form of Raine syndrome.

Raine syndrome is a rare osteosclerotic bone dysplasia characterized by craniofacial anomalies and intracranial calcification. Most patients with Raine syndrome are of Arab ancestry and die during the neonatal period. We herein report a Japanese patient with non-lethal Raine syndrome who presented with characteristic cerebral hyperechogenicity and a hypoplastic nose by fetal ultrasonography. She was admitted to the NICU due to pyriform aperture stenosis. Craniofacial abnormalities, intracranial calcification, osteosclerosis, chondrodysplasia punctata, and a mutation of FAM20C was identified. She was subsequently discharged without surgical intervention and is now 2 years old with mild neurodevelopmental delays. Images of cerebral hyperechogenicity by fetal ultrasonography in a non-lethal case were described herein for the first time. This patient represents a rare occurrence of a child with Raine syndrome born to Japanese parents and confirms that this syndrome is not always lethal. Even if Raine syndrome is suspected in a fetus due to cerebral hyperechogenicity and a hypoplastic nose, cerebral hyperechogenicity without pulmonary hypoplasia does not always predict lethality or severe neurodevelopmental delays. The information provided herein will be useful for prenatal counseling.