Misao Kageyama

Neurodevelopment in full-term small for gestational age infants: A nationwide Japanese population-based study

OBJECTIVE To investigate neurological development in small for gestational age (SGA) infants, with a focus on full-term SGA infants. METHODS We analyzed data from a large, Japanese, nationwide, population-based longitudinal survey started in 2001. We restricted the study to participants born before 42weeks of gestation (n=46,563). Parents were asked questions about motor and language development when the children were 2.5years old, and about behavioral development at 5.5years. We analyzed the relationships between SGA status and development by logistic regression. Odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated for each outcome for full-term and preterm births, adjusting for potential infant- and parent-related confounding factors. We also calculated the population-attributable fractions to estimate the public impact of SGA births. RESULTS SGA full-term children were more likely to demonstrate developmental delays at 2.5years, e.g., being unable to walk alone (OR 3.0, 95% CI: 1.7, 5.3), compose a two-phrase sentence (OR 1.5, 95% CI: 1.2, 1.8), or use a spoon to eat (OR 1.5, 95% CI: 1.1, 1.9). SGA status also had some degree of negative impacts on behavioral problems at 5.5years among term children, e.g., being unable to listen without fidgeting (OR 1.2, 95% CI: 1.1, 1.3), or remain patient (OR 1.1, 95% CI: 1.0, 1.2). The public health impacts were comparable between full-term and preterm SGA children at 2.5years. CONCLUSION SGA is a risk factor for developmental delay, even in full-term infants, with non-negligible public health impacts.

Reading difficulty in school-aged very low birth weight infants in Japan

OBJECTIVE To investigate the prevalence of and the perinatal risk factors related to reading difficulty in school-aged very low birth weight infants (VLBWI) with normal intelligence. METHODS Subjects were 79 Japanese children in the second to fourth grade of elementary school who had been born at very low birth weight and who regularly visited a follow-up clinic at one of four hospitals. All members had a full-scale IQ score of 80 or higher. Perinatal information was obtained retrospectively from medical records. Each subject underwent four reading tasks, testing monomoratic syllable reading, word reading, non-word reading and short sentence reading. Subjects with an SD reading time score greater than 2.0 in two or more tasks were considered to have reading difficulty (RD). Furthermore we investigated the relations between RD and perinatal factors using logistic regression analysis adjusted for potential confounding factors. RESULTS Twenty-five (31.6%) out of 79 subjects had RD. We discovered that treated retinopathy of prematurity (tRoP) was a significant risk factor (adjusted OR=5.80, 95% confidence interval=1.51-22.33). CONCLUSION The rate of RD in school-aged VLBWI was higher than the estimated prevalence of dyslexia in Japan. Even in children with normal intelligence, long-term developmental follow-up including support for reading skills is necessary for VLBWI. Further investigation is desired to elucidate the relations between visual problems and RD in school-aged children.

Behavioral outcomes of school-aged full-term small-for-gestational-age infants: A nationwide Japanese population-based study

BACKGROUND Small for gestational age (SGA) birth is linked with neurological deficits among children at pre-school age, but the evidence is still limited on whether such deficits are still observable at school age. We investigated the association between SGA birth and behavioral development at school age among full-term infants. METHODS We analyzed data from a large, Japanese, nationwide, population-based longitudinal survey that started in 2001. We restricted the study participants to children born at 37-41weeks of gestation with information on birth weight and behavioral outcomes at 8years of age (n=33,795). Behavioral outcomes including three attentional problems and four aggressive behaviors queried at 8years of age by survey questions were used as outcome indicators. We then used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the associations between SGA birth and each outcome, adjusting for potential infant- and parent-related confounding factors. RESULTS Among full-term children, SGA children were more likely to interrupt people (OR 1.10, 95% CI 1.01, 1.20), unable to wait his/her turn (OR 1.17, 95% CI 1.00, 1.38), and destroy toys and/or books (OR 1.15, 95% CI 1.00, 1.31). CONCLUSIONS This is the largest study ever conducted on this issue. SGA birth is negatively associated with some attentional problems and aggressive behavior at school age among full-term children. Appropriate long-term developmental follow-up and support may be needed for full-term SGA infants.

Nephrocalcinosis and placental findings in neonatal bartter syndrome.

Neonatal Bartter syndrome (NBS) is an inherited renal tubular disorder associated with hypokalemic alkalosis. Here we report a case of genetically diagnosed NBS. Polyhydramnios was noted at 26 weeks. A boy was born at 31 weeks and 1 day, weighed 1344 g, and had an Apgar score of 8/8. We initiated indomethacin (IND) at a dose of 0.2 mg/kg/d on day 31, and increased it to approximately 3 mg/kg/d. However, his urinary calcium (Ca) levels remained unchanged. At 4 months of age, nephrocalcinosis was detected by ultrasound. The placenta weighed 700 g (+2.7 standard deviations). Although the proportion of terminal villi was consistent with the gestational age, many of them exhibited poorly dilated capillaries. Hemosiderin pigment was seen throughout the amniochorionic connective tissue and along about 50% of the trophoblast basement membrane (TBM). Von Kossa stain revealed the corresponding area of mineralization along the TBM. In our opinion, urinary Ca levels were high and did not change after IND initiation, indicating that nephrocalcinosis may be inevitable. Enhanced inflow of maternal plasma through the basement membrane would cause Ca deposition, given that the same finding was obtained in the case with polyhydramnios. The same mechanism would also explain the hemosiderin pigment distribution.

Utility of Maternal 6-Thioguanine Nucleotide Levels in Predicting Neonatal Pancytopenia

An infant with pancytopenia was born to a mother who used the common immunosuppressant azathioprine (AZA). Maternal and neonatal blood levels of 6-thioguanine nucleotides (6TGN; metabolite of AZA) were 1890 and 1480 pmol/8 × 108 red blood cells, respectively. Maternal 6TGN levels could be useful in predicting neonatal pancytopenia.

A Japanese case of β-ureidopropionase deficiency with dysmorphic features

β-Ureidopropionase deficiency is a rare autosomal recessive disease affecting the last step of pyrimidine degradation, and it is caused by a mutation in the UPB1 gene. Approximately 30 cases have been reported to date, with a phenotypical variability ranging from asymptomatic to severe neurological illness. Non-neurological symptoms have been rarely reported. We describe a case of this disease with developmental delay and dysmorphic features. Gas chromatography-mass spectrometry-based urine metabolomics demonstrated significant (⩾+4.5 standard deviation after logarithmic transformation) elevations of β-ureidopropionic acid and β-ureidoisobutyric acid, strongly suggesting a diagnosis of β-ureidopropionase deficiency. Subsequent quantitative analysis of pyrimidines by liquid chromatography-tandem mass spectrometry supported this finding. Genetic testing of the UPB1 gene confirmed compound heterozygosity of a novel mutation (c.976C>T) and a previously-reported mutation (c.977G>A) that is common in East Asians. β-Ureidopropionase deficiency is probably underdiagnosed, considering a wide phenotypical variability, non-specific neurological presentations, and an estimated prevalence of 1/5000-6000. Urine metabolomics should be considered for patients with unexplained neurological symptoms.

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.

Intelligence test at preschool-age predicts reading difficulty among school-aged very low birth weight infants in Japan

OBJECTIVE To elucidate whether the results of an intelligence test at preschool age are predictive of reading difficulty (RD) at school age among very low birth weight infants (VLBWI). METHODS Subjects were 48 Japanese children whose birth weight was <1500 g and who regularly visited a follow-up clinic. All subjects completed the Wechsler Intelligence Scale for Children-III (WISC-III) during the last grade of kindergarten, and four reading tasks during the second to fourth grade of elementary school. All participants had a full-scale intelligence quotient score of 85 or higher. Subjects with a standard deviation reading time score greater than 2.0 in two or more tasks were considered to have RD. We evaluated the associations between each WISC-III score and RD using logistic regression analyses. Furthermore, we performed receiver operating characteristic (ROC) analysis to determine a cutoff WISC-III score predictive of RD. RESULTS In the mutually-adjusted model, the adjusted odds ratio per 1 score increase of freedom from distractibility (FD) was 0.832 (95% confidence interval: 0.720-0.962). In the ROC analysis, an FD score of <95.5 was chosen as the cutoff value for predicting RD (sensitivity, 0.77; specificity, 0.74). CONCLUSION The present study indicated that a lower FD score at preschool age, which was associated with deficits in verbal working memory and attention, is a risk factor for RD at school age among Japanese VLBWI. Further investigation is desired to clarify the cognitive deficits underlying RD in Japanese-speaking preterm children, and to establish appropriate interventions for these children.

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.

Effects of the early administration of sivelestat sodium on bronchopulmonary dysplasia in infants: A retrospective cohort study

BACKGROUND Chorioamnionitis, or infiltration of the chorioamnion by neutrophils, is a risk factor associated with the development of bronchopulmonary dysplasia. Increased neutrophil elastase levels are observed in the tracheal aspirates of these patients. AIMS To examine the effects of early administration of the selective neutrophil elastase inhibitor sivelestat, which is used to treat acute lung injury in adults, on bronchopulmonary dysplasia in extremely premature infants. STUDY DESIGN Retrospective cohort study. SUBJECTS This study included extremely low-birth-weight infants born at a gestational age<28weeks. Patients were divided into groups based on the receipt of sivelestat. OUTCOME MEASURES The primary outcome was the rate of bronchopulmonary dysplasia-free survival at a postmenstrual age of 36weeks, and the secondary outcomes included various clinically significant factors of neonatal mortality and morbidity and adverse events. RESULTS Of the 1031 included neonates, 124 (12.0%) were treated with sivelestat. Significant differences between the groups were noted for gestational age, delivery method, fetal number, the frequency of chorioamnionitis, immunoglobulin M levels, and WBC counts. No differences were identified concerning the bronchopulmonary dysplasia-free survival rate at a postmenstrual age of 36weeks (adjusted odds ratio for sivelestat to control, 0.83; 95% confidence interval=0.53-1.30). Secondary outcomes did not significantly differ between the groups. CONCLUSIONS In extremely premature infants, early sivelestat use was not associated with an improved rate of survival without bronchopulmonary dysplasia at a postmenstrual age of 36weeks.