Tsubasa Koda

Neurological outcomes in symptomatic congenital cytomegalovirus-infected infants after introduction of newborn urine screening and antiviral treatment

BACKGROUND Newborn screening for urinary cytomegalovirus (CMV) and early introduction of antiviral treatment are expected to improve neurological outcomes in symptomatic congenital CMV-infected infants. This cohort study prospectively evaluated neurological outcomes in symptomatic congenital CMV-infected infants following the introduction of hospital-based newborn urinary CMV screening and antiviral treatment. SUBJECTS/METHODS Following institutional review board approval and written informed consent from their parents, newborns were prospectively screened from 2009 to 2014 for urinary CMV-DNA by PCR within 1 week after birth at Kobe University Hospital and affiliated hospitals. CMV-positive newborns were further examined at Kobe University Hospital, and those diagnosed as symptomatic were treated with valganciclovir for 6 weeks plus immunoglobulin. Clinical neurological outcomes were evaluated at age ⩾12 months and categorized by the presence and severity of neurologic sequelae. RESULTS Urine samples of 6348 newborns were screened, with 32 (0.50%) positive for CMV. Of these, 16 were diagnosed with symptomatic infection and 12 received antiviral treatment. Four infants developed severe impairment (33%), three developed mild impairment (25%), and five developed normally (42%). CONCLUSIONS This is the first Japanese report of neurological assessments in infants with symptomatic congenital CMV infection who received early diagnosis and antiviral treatment. Urinary screening, resulting in early diagnosis and treatment, may yield better neurological outcomes in symptomatic congenital CMV-infected infants.

Serum unbound bilirubin as a predictor for clinical kernicterus in extremely low birth weight infants at a late age in the neonatal intensive care unit

BACKGROUND This study aimed to evaluate peak serum total bilirubin (TB) and unbound bilirubin (UB) levels in preterm infants with clinical kernicterus (KI) who were diagnosed by clinical findings during infancy. DESIGN/SUBJECTS For this multicenter retrospective study, 18 Japanese extremely low birth weight (ELBW) infants with clinical KI were included. Clinical KI was diagnosed based on the presence of motor developmental impairment with/without athetosis, and abnormal magnetic resonance imaging or brainstem auditory evoked potential findings during infancy. High and low TB or UB levels were defined as serum TB levels ⩾ and <15 mg/dL or serum UB levels ⩾ and <0.8 μg/dL, respectively. The clinical characteristics of KI preterm infants were analyzed. The proportion of infants with high or low serum TB levels and with high or low serum UB levels was then investigated. Sensitivity and specificity were calculated. RESULTS In 18 KI infants, the median age when serum TB levels peaked was 28 days after birth. In eight KI infants with low serum TB levels, 88% of them had high serum UB levels. For comparison of the number of infants who had high or low serum TB and UB levels, the sensitivity was 90% and specificity was 13%. CONCLUSIONS Serum TB and UB levels peak at a later age than expected. Chronic serum UB monitoring may be helpful for identifying ELBW infants at risk for developing KI, even when they do not have high serum TB levels.

Association of a vascular endothelial growth factor polymorphism with the development of bronchopulmonary dysplasia in Japanese premature newborns

Our objective was to correlate vascular endothelial growth factor (VEGF) genetic polymorphisms with the risk of bronchopulmonary dysplasia (BPD) development in premature newborns. Fifty-five newborns with BPD (BPD: median gestational age [GA]: 27 weeks, birthweight [BW]: 786 g) and 42 newborns without BPD (non-BPD: median GA: 29 weeks, BW: 1,165 g), who were born at <32 weeks gestational age and were admitted to Kobe University Hospital, were included. BPD was defined as oxygen dependency at 36 weeks postmenstrual age. Genomic DNA was extracted from the umbilical cord, cord blood, or buccal mucosa. Six VEGF genotypes (-1498T > C, -1154G > A, -634C > G, -7C > T, 936C > T, and 1612G > A) were determined by DNA sequencing. Clinical characteristics, and allele and genotype frequencies of VEGF in the BPD and non-BPD groups were analyzed. G allele frequencies in -634C > G of the BPD group were significantly higher than in the non-BPD group (66.4% vs. 50%, P = 0.02). -634C > G genotype distributions differed significantly between the BPD and non-BPD groups (BPD: CC 7%/CG 53%/GG 40%; non-BPD: CC 24%/CG 52%/GG 24%; P = 0.04). Multivariate logistic regression showed that duration of ventilation, VEGF-634G > C G alleles, and male gender were independent risk factors for BPD. In conclusion, polymorphism VEGF -634C > G may influence the risk of BPD.

Current incidence of clinical kernicterus in preterm infants in Japan.

Clinical kernicterus in preterm infants has recently been reported in Japan, diagnosed on the basis of clinical findings during the neonatal and infancy periods. We investigated the incidence of clinical kernicterus in preterm infants <30 weeks gestational age (GA) based on a nationwide survey conducted in 233 certified educational facilities for neonatologists. The numbers of infants admitted and infants who died within 14 days after birth during 2011, and the number of infants who subsequently developed clinical kernicterus, were recorded. A total of 2720 infants were analyzed, representing 59% (2720/4623) of all preterm live births <30 weeks GA in Japan in 2011. Of these, 159 (5.8%) died within 14 days after birth, similar to the national rate. Five infants developed clinical kernicterus in infancy (5/2720, 0.18%). The current incidence of clinical kernicterus in Japan is therefore estimated at 1.8 per 1000 live births <30 weeks GA.

Is bilirubin/albumin ratio correlated with unbound bilirubin concentration?

Background:  The American Academy of Pediatrics guidelines recommend that the total bilirubin (TB)/albumin (Alb) ratio (B/A ratio), instead of serum concentration of unbound bilirubin (UB), can be used with TB for determining treatment modality for jaundiced newborns ≥35 weeks of gestation. It is unknown, however, whether the B/A ratio is actually correlated with serum UB.

Incidence of short stature at 3 years of age in late preterm infants: a population-based study

Objectives This study aimed to investigate the incidence of short stature at 3 years of age in a Japanese cohort of late preterm infants who were born at 34–36 weeks’ gestational age (GA). We compared these late preterm infants with term infants (37–41 weeks’ GA), and evaluated the effect of birth weight on the incidence of short stature. Methods A longitudinal population-based study of 26 970 neonates who were born between 34 weeks’ and 41 weeks’ GA in 2006–2008 was conducted in Kobe, Japan. Of these neonates, 1414 were late preterm and 25 556 were term infants. The late preterm infants were then divided into three subgroups based on birth weight as determined by Japanese neonatal anthropometric charts for GA at birth: large-for-GA (n=140), appropriate-for-GA (AGA, n=1083), and small-for-GA (SGA, n=191). The incidence of short stature at 3 years of age was calculated in the late preterm group and compared with that in the term group, and between the AGA and SGA groups with late preterm birth. Results The incidence of short stature in the late preterm group was 2.9%, which was significantly higher than that in the term group (1.4%). Late preterm SGA infants developed short stature with a significantly higher (9.4%) incidence than that of late preterm AGA infants (2.1%). Conclusions The incidence of short stature in 3-year-old children who were late preterm infants has a 2-fold higher risk than that in term infants. The risk of developing short stature is increased 4.5-fold if they are SGA.

Disorders of bilirubin binding to albumin and bilirubin-induced neurologic dysfunction.

Bilirubin-induced neurologic dysfunction (BIND) is a syndrome of subtle bilirubin neurotoxic disorders. The risk for developing BIND in newborns usually increases with elevated serum/plasma concentrations of unconjugated bilirubin. This risk is further increased by disorders of bilirubin binding to albumin, which includes a reduction in serum albumin concentrations or in the bilirubin-binding capacity and affinity of albumin, and the presence of displacing substances or infection. Serum unbound bilirubin (UB) concentration may be an ideal marker that reflects changes in bilirubin binding to albumin. Kernicterus, the chronic and with the most severe manifestations beyond BIND, is diagnosed by the presence of motor impairments with athetosis, abnormal magnetic resonance imaging, and/or brainstem auditory-evoked potential findings during infancy and childhood. Preterm infants sometimes have acute bilirubin encephalopathy without marked hyperbilirubinemia, such that bilirubin neurotoxicity occurs at bilirubin thresholds lower than usually associated with kernicterus. Disorders of bilirubin binding to albumin may be associated with the clinical signs of neurological injury associated with the lower bilirubin levels observed in preterm infants.

Low total IgM values and high cytomegalovirus loads in the blood of newborns with symptomatic congenital cytomegalovirus infection

Abstract Aims: Neurological outcomes differ considerably between symptomatic and asymptomatic infants with congenital cytomegalovirus (CMV) infection. Our objective was to characterize laboratory markers in symptomatic newborns in comparison with asymptomatic newborns with congenital CMV infection. Methods: Ten newborns with symptomatic and 13 newborns with asymptomatic congenital CMV infection were included in this 3-year prospective cohort study. Total immunoglobulin M (IgM), CMV-IgM, CMV antigenemia, and CMV-DNA in blood and urine were measured and their positive rates and quantitative values compared between the symptomatic and asymptomatic groups. Results: Fifty percent of newborns in the symptomatic group were positive based on total IgM; this was significantly lower than in the asymptomatic group (100%). Quantitative total IgM values were significantly lower, and there were significantly more copies of CMV-DNA in the blood of symptomatic newborns than in asymptomatic newborns (median values for total IgM: 14 vs. 43 mg/dL and blood CMV-DNA: 3.2×102 vs. 3.5×101 copies/106 white blood cells). CMV-IgM, CMV antigenemia, and urine CMV-DNA did not differ significantly between groups. Conclusion: Low total IgM values and high blood CMV loads were associated with the presence of symptoms in newborns with congenital CMV infection.

Novel treatment strategy for Japanese newborns with high serum unbound bilirubin

Serum unbound bilirubin (UB) is a measure of bilirubin not bound to albumin, and has been reported to be better than total bilirubin level at identifying infants at risk of developing bilirubin‐induced neurotoxicity, including auditory abnormalities. A detailed treatment strategy for newborns with high serum UB has not been established. The aim of this study was to assess auditory outcomes in newborns with serum UB ≥1.00 μg/dL who were treated according to a novel treatment protocol.

Prevalence of small for gestational age (SGA) and short stature in children born SGA who qualify for growth hormone treatment at 3 years of age: Population-based study

To treat children born small for gestational age (SGA) with severe short stature, treatment with growth hormone (GH) has been approved in the USA, Europe, and Japan, but no population‐based studies have reported their prevalence. The aims of this study were to investigate the prevalence of SGA and short stature in children born SGA who qualify for GH treatment at 3 years of age in a Japanese population.