Published papers

Background: Neonatal hypoglycaemia is one of the major metabolic disorders that causes irreversible brain injury. Assessing for maternal glucose metabolism disorders can predict and avoid this perinatal complication. Accordingly, diagnosing maternal gestational diabetes mellitus (GDM) is important in protecting neonatal neurological prognosis. However, there are various methods of screening for maternal GDM. The intervention for neonatal hypoglycaemia also varies within each guideline. Case presentation: A female infant was born at 37 weeks of gestation by vaginal delivery with no asphyxia. Her mother had no abnormal findings, including glucose metabolism disorders, upon periodic prenatal visits. Upon routine examination at the first hour of life, the baby was lethargic, pale, hypotonic, and rarely cried. An emergent systemic evaluation was performed, and she was diagnosed with severe hyperinsulinemic hypoglycaemia with blood glucose of 11 mg/dL and insulin of 2.7 µU/mL. She was soon fed with milk and her symptoms of hypoglycaemia was resolved before receiving intravenous glucose infusion. Her blood glucose level reached 78 mg/dL 3 h after delivery. She was discharged home with her mother on day 6 of age without relapse of hypoglycaemia. Upon review, we determined that the mother was diagnosed with GDM during her previous pregnancy but not during this current pregnancy. The infant had no developmental delay upon check-up at 6 months. Conclusions: The infant of this case was not a candidate for neonatal hypoglycaemia screening since her mother had no identifiable risk factors. This case suggests that previous maternal history of GDM might be the cause of neonatal hyperinsulinemic hypoglycaemia. Clinicians need to be aware of the possibility of hypoglycaemia among newborns with a maternal previous history of GDM, regardless of the mother’s current diagnosis. Immediate oral feeding can be one of the treatments, even for symptomatic neonatal severe hypoglycaemia, when rapid intravenous access is difficult. The present case also suggests the necessity of considering neonatal outcomes as well as maternal ones when screening for maternal disorders of glucose metabolism.

We report the case of a preterm small for gestational age male infant born at 24 weeks of gestation with a birth weight of 268 g who was discharged from our hospital without the requirement for home oxygen therapy or tube feeding. He did not experience severe intraventricular hemorrhage, periventricular leukomalacia, hearing disability, or any other serious complications. At that time (February 2019), according to the University of Iowa's Tiniest Babies Registry, he was the tiniest male infant in the world to survive without any serious complications other than severe retinopathy of prematurity that required laser therapy. Although the survival rate of infants with extremely low birth weight is improving worldwide, a high mortality rate and incidence of severe complications remain common for infants weighing <300 g at birth, particularly in male infants. In recent years, there have been frequent discussions regarding the ethical and social issues involved in treating extremely preterm infants weighing <400 g. Despite the challenges, reports of such infants surviving are increasing. Neonatal medicine has already achieved great success in treating infants weighing 400 g or more at birth. However, lack of evidence and experience may make physicians reluctant to treat infants weighing less than this. The present case demonstrates that intact survival of a marginally viable male infant with a birth weight of <300 g is possible with minimal handling and family involvement beginning shortly after birth. Our detailed description of the clinical course of this case should provide invaluable information to physicians around the world who treat such infants. This report will aid in the progress of neonatal medicine and help to address many of the social and ethical issues surrounding their care.

Introduction: The Japanese Neonatal Pain Guidelines Committee, led by the Japan Academy of Neonatal Nursing, uses the Grading of Recommendations, Assessment, Development, and Evaluation Working Group method to evaluate the quality of evidence and the strength of treatment recommendations. Ratings on the importance of outcomes related to neonatal pain have not been reported. This study aimed to reach a consensus on the importance of outcomes through a guideline panel composed of doctors, nurses, a nurse practitioner, a physical therapist, and families to ensure consistency in systematic reviews of neonatal pain and future revisions to the guidelines. Methods: A total of 26 professionals, including 21 medical personnel from clinical settings and academia and 5 parents from five family associations, participated in 3-stage eDelphi rounds. Results: The literature review and discussion identified 75 outcomes that were included in round one. The participants proposed three additional outcomes: 78 outcomes were scored in rounds two and three. Round three scores showed different stakeholder groups in terms of priority outcomes. Seventeen outcomes were included in the final core outcome and were considered critical for decision-making. Conclusion: Core outcomes of the development of neonatal pain guidelines in Japan were identified. The assessment process of importance from this study highlights the difference in the perspectives of medical providers and parents on neonatal pain, thus, involving parents in the assessment and as the spokesperson for the infant admitted to the neonatal intensive care unit is important for a more inclusive evaluation of pain prevention and management.

Previous studies suggest the importance of stable circadian environments for fetuses to achieve sound physiology and intrauterine development. This idea is also supported by epidemiological and animal studies, in which pregnant females exposed to repeated shifting of light–dark cycles had increased rates of reproductive abnormalities and adverse pregnancy outcomes. In response to such findings, artificial circadian environments with light–dark (LD) cycles have been introduced to NICUs to promote better physical development of preterm infants. Such LD cycles, however, may not be fully effective for preterm infants who are less than 30 weeks gestational age (WGA) since they are too premature to be adequately responsive to light. Instead, circadian rhythmicity of incubated preterm infants less than 30 WGA may be able to be developed through stimulation of the non-visual senses such as touch and sound.

Background: Among preterm infants, higher morbidities of neurological disturbances and developmental delays are critical issues. Resting-state networks (RSNs) in the brain are suitable measures for assessing higher-level neurocognition. Since investigating task-related brain activity is difficult in neonates, assessment of RSNs provides invaluable insight into their neurocognitive development. Methods: The participants, 32 term and 71 preterm neonates, were divided into three groups based on gestational age (GA) at birth. Cerebral hemodynamic activity of RSNs was measured using functional near-infrared spectroscopy in the temporal, frontal, and parietal regions. Results: High-GA preterm infants (GA ≥ 30 weeks) had a significantly stronger RSN than low-GA preterm infants and term infants. Regression analyses of RSNs as a function of postnatal age (PNA) revealed a steeper regression line in the high-GA preterm and term infants than in the low-GA infants, particularly for inter-area brain connectivity between the frontal and left temporal areas. Conclusions: Slower PNA-dependent development of the frontal–temporal network found only in the low-GA group suggests that significant brain growth optimal in the intrauterine environment takes place before 30 weeks of gestation. The present study suggests a likely reason for the high incidence of neurodevelopmental impairment in early preterm infants. Impact: Resting-state fNIRS measurements in three neonate groups differing in gestational age (GA) showed stronger networks in the high-GA preterm infants than in the term and low-GA infants, which was partly explained by postnatal age (PNA).Regression analyses revealed a similar PNA-dependence in the development of the inter-area networks in the frontal and temporal lobes in the high-GA and term infants, and significantly slower development in the low-GA infants.These results suggest that optimal intrauterine brain growth takes place before 30 weeks of gestation. This explains one of the reasons for the high incidence of neurodevelopmental impairment in early preterm infants.

Vitamin D deficiency during infancy has been associated with increased bone turnover rate and bone mineral loss. However, few studies have examined bone turnover markers (BTMs) for both bone formation and resorption in infants with vitamin D deficiency. Here, we analyzed serum concentrations of 25OHD, intact parathormone (iPTH), and BTMs including total alkaline phosphatase (ALP), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), and serum type I collagen N-telopeptide (NTx) as well as basic clinical characteristics of 456 infants (626 samples) aged less than 12 mo born at Saitama City Hospital, Japan (latitude 35.9? North) between January 2021 and December 2022. One hundred sixteen infants (147 samples) were classified as having vitamin D deficiency (25OHD < 12.0 ng/mL), and 340 infants (479 samples) had sufficient vitamin D levels (25OHD = 12.0 ng/mL). In addition to 25OHD and ALP, both TRACP-5b and sNTx were measured in 331 infants (418 samples), while 90 infants (105 samples) had only TRACP-5b measured and 101 infants (103 samples) had only sNTx measured. Statistical comparison of 104 subjects each in the vitamin D deficiency and sufficiency groups after matching for the background characteristics revealed that the vitamin D deficiency group had significantly higher levels of ALP and iPTH compared with the sufficiency group (P = <.0001, .0012, respectively). However, no significant differences were found in TRACP-5b and NTx levels between the 2 groups (P = .19, .08, respectively). Our findings suggest discordant responses between bone formation and resorption markers in subclinical vitamin D deficiency during infancy.

Lateral meningocele syndrome is characterized by multiple lateral meningoceles with a distinctive craniofacial appearance, hyperextensibility of the skin, and hypermobility of the joints. The syndrome is caused by heterozygous truncating variants in the last exon, exon 33, of the NOTCH3 gene. Here, we present a 2-year-old girl for whom an early genomic analysis allowed us to recognize the presence of lateral meningoceles and to begin early monitoring of her condition for possible neurological complications. She had a characteristic facial appearance, hyperextensibility of the skin and mobility of the joints, and developmental delays. Given that lateral meningocele syndrome is a rare syndrome, the existence of lateral meningoceles is suspected only when the causative gene is detected by genetic testing. MRI scans are unlikely to be performed in infancy in the absence of neurological symptoms suggestive of meningoceles. No formal guidelines have been established for the neurosurgical indications for lateral meningocele syndrome. Given the features of hyperextensibility of the skin and hypermobility of the joints, lateral meningocele syndrome can be categorized as a connective tissue disease and may be progressive, as with the dural ectasia in Marfan syndrome and Loeys-Dietz syndrome. Watchful monitoring of dural ectasia may be warranted in patients with lateral meningocele syndrome.

Background: Strict glycemic control is important to prevent perinatal complications in patients with gestational diabetes mellitus (GDM). Patients often require insulin injection, and frequent hospital visits are necessary to adjust the dose of insulin, which is considered burdensome for pregnant patients. Telemedicine may reduce the burden of hospital visits, and previous studies have reported its safety in GDM patients. This study aimed to evaluate the efficacy of telemedicine in GDM patients, focusing on patient satisfaction and health economic indicators. Methods: This is a single-center, two-arm, randomized, open-label parallel-group study. Subjects will be selected from the patient population attending the Department of Endocrinology, Metabolism, and Nephrology, Keio University School of Medicine, Japan. Patients diagnosed with GDM by an oral glucose tolerance test (OGTT) by 29 weeks and 6 days of gestation who have undergone self-monitoring of blood glucose (SMBG) and insulin injection are eligible for inclusion. In the intervention group, telemedicine will be administered using the MeDaCa telemedicine system developed by the Medical Data Card, Inc., Tokyo, Japan. Subjects in the control group will be examined face-to-face every 2–3 weeks, as usual. We set health economic indicators and patient satisfaction as the primary endpoints, and will perform a cost-consequence analysis. Glycemic control indicators and perinatal outcomes will be evaluated as secondary endpoints. Conclusions: Eligible patients are currently being recruited. Recruitment will be completed when the expected number of patients are enrolled.

Background: The etiology of Bednar's aphthae remains unclear. Our aim was to investigate the incidence of, and factors associated with, Bednar's aphthae in a Japanese newborn cohort. Methods: A retrospective cross-sectional study was conducted on neonates discharged from the well-baby nursery at Saitama City Hospital, Japan. The principal investigator carefully examined each neonate's oral cavity, up to and including the pharynx, with a light-emitting diode (LED) headlight to determine the presence of Bednar's aphthae. Maternal and neonatal clinical characteristics were first compared between neonates with and those without Bednar's aphthae by univariate analysis. Variables with significant inter-group differences upon univariate analysis were entered into a multivariable logistic-regression model. Results: This study enrolled 1996 infants. We observed Bednar's aphthae in 9.3% of the Japanese newborn infants who were included. When restricted to infants who were born via vaginal delivery, 13.2% of them had aphthae. Multivariable logistic regression analysis identified vaginal delivery (odds ratio = 6.19, p < 0.0001) in Model 1, and vaginal delivery (odds ratio = 6.73, p < 0.0001) and birth weight (odds ratio = 0.9995, p = 0.034) in Model 2 as independent risk factors for the disease. Conclusion: This is the first report of the prevalence of Bednar's aphthae among Japanese neonates. Vaginal delivery was identified as the strongest risk factor. Although confounding between mode of delivery and mechanical stimuli associated with sucking was not found in this study, the findings pave the way for a better understanding of the etiology of Bednar's aphthae.

A trisomy 21 neonate presented with congenital chylous pleural effusion and ascites that was refractory to conventional pharmacotherapy. Midodrine, an oral alpha-1-adrenoreceptor agonist, achieved remission of chylous effusion without any adverse effects. To the best of our knowledge, this is the first neonatal case of successful management of congenital chylous pleural effusion and ascites with midodrine.

Aim: The aim of this study was to determine clinician opinion regarding oxygen management in moderate-late preterm resuscitation. Methods: An anonymous online questionnaire was distributed through email/social messaging platforms to neonatologists in 21 countries (October 2020-March 2021) via REDCap. Results: Of the 695 respondents, 69% had access to oxygen blenders and 90% had pulse oximeters. Respondents from high-income countries were more likely to have oxygen blenders than those from middle-income countries (72% vs. 66%). Most initiated respiratory support with FiO2 0.21 (43%) or 0.3 (36%) but only 45% titrated FiO2 to target SpO2. Most (89%) considered heart rate as a more important indicator of response than SpO2. Almost all (96%) supported the need for well-designed trials to examine oxygenation in moderate-late preterm resuscitation. Conclusion: Most clinicians resuscitated moderate-late preterm infants with lower initial FiO2 but some cannot/will not target SpO2 or titrate FiO2. Most consider heart rate as a more important indicator of infant response than SpO2.Large and robust clinical trials examining oxygen use for moderate-late preterm resuscitation, including long-term neurodevelopmental outcomes, are supported amongst clinicians.

Hypoglycemia is one of the most significant problems in neonates born to mothers with gestational diabetes (GDM). This study aimed to identify novel predictors of hypoglycemia in neonates born to mothers with GDM. A total of 443 term singleton infants from mothers diagnosed with GDM and cared for at Keio University Hospital between January 2013 and December 2019 were included in this study. Neonatal hypoglycemia was defined as hypoglycemia of less than 47 mg/dL at 1 or 2 or 4 h after birth, according to previous studies. Among 443 full-term singleton neonates born to mothers with GDM, 200 developed hypoglycemia (45%). Gestational weight gain (GWG), HbA1c at 1st trimester, HbA1c at GDM diagnosis, and the incidence of insulin therapy in the neonatal hypoglycemia group were significantly higher than those in the non-neonatal hypoglycemia group (p = 0.016, p = 0.032, p = 0.011, and p = 0.017, respectively). Regarding the multiple regression analysis adjusted for nulliparity, GWG, and gestational weeks at delivery, the odds ratio for maternal HbA1c ≥5.2% at 1st trimester was 1.63 (p = 0.034), and maternal insulin therapy during pregnancy was 1.72 (p = 0.015). In conclusion, HbA1c in the 1st trimester and insulin therapy during pregnancy were good predictors of hypoglycemia in neonates born to GDM mothers, especially when their HbA1c was 5.2% or more. Further research will be necessary to improve the perinatal management of hypoglycemia.

Vitamin D seasonality has been reported in adults and children, suggesting that sunlight exposure has effects on 25(OH)D production. While vitamin D deficiency among infants has received significant attention, little is known about the extent to which vitamin D status during early infancy is affected by sunlight exposure. Here, we retrospectively analysed serum 25(OH)D levels of 692 samples obtained from healthy infants aged 1-2 months born at Saitama City Hospital, Japan (latitude 35·9° North) between August 2017 and September 2021. Data regarding the frequency of outdoor activities, formula intake and BMI were also collected and analysed. Month-to-month comparisons of vitamin D levels revealed significant variation in 25(OH)D levels in breastfed infants starting at 2 months, with maximal and minimal levels in September and January, respectively. An outdoor activity score of 0 was most common at 1 month (83·9 %) and a score of 3 was most common at 2 months (81·2 %), suggesting an increased amount of sunlight exposure at 2 months. Multiple linear regression analysis revealed the amount of formula intake to be significantly associated with vitamin D status at both 1 (t = 17·96) and 2 months (t = 16·30). Our results comprise the first evidence that seasonal variation of vitamin D begins at 2 months among breastfed infants from East Asia, though dietary intake appears to be the major determinant of vitamin D status. These findings provide new insights into the influence of dietary and non-dietary factors on vitamin D status during early infancy.

Brain complexity analysis using functional near-infrared spectroscopy (fNIRS) has attracted attention as a biomarker for evaluating brain development and degeneration processes. However, most methods have focused on the temporal scale without capturing the spatial complexity. In this study, we propose a spatial time-delay entropy (STDE) method as the spatial complexity measure based on the time-delay measure between two oxy-hemoglobin (∆[HbO]) or two deoxy-hemoglobin (∆[Hb]) oscillations within the 0.01-0.1 Hz frequency band. To do this, we analyze fNIRS signals recorded from infants in their sleeping state, children, adults, and healthy seniors in their resting states. We also evaluate the effects of various noise to STDE calculations and STDE’s performance in distinguishing various developmental age groups. Lastly, we compare the results with the normalized global spatial complexity (NGSC) and sample entropy (SampEn) measures. Among these measures, STDEHbO (STDE based on ∆[HbO] oscillations) performs best. The STDE value increases with age throughout childhood (p < 0.001), and then decreases in adults and healthy seniors in the 0.01-0.1 Hz frequency band. This trajectory correlates with cerebrovascular development and degeneration. These findings demonstrate that STDE can be used as a new tool for tracking cerebrovascular development and degeneration across a lifespan based on the fNIRS resting-state measurements.

Background: Several cut-off points for 25-hydroxyvitamin D (25(OH)D) levels have been proposed to determine vitamin D deficiency or insufficiency. However, the level for 25(OH)D deficiency in early infancy remains unclear. The serum 25(OH)D value at which parathyroid hormone level plateaus, called the “inflection point,” is considered the most appropriate criterion for defining an adequate vitamin D status. Methods: This was a single-center retrospective study involving 305 1-month-old and 252 2-month-old Japanese infants. Nonlinear segmented regression analysis was performed based on the correlation between 25(OH)D and parathyroid hormone levels to determine vitamin D deficiency cut-off points. Results: Inflection points were 7.90 ng/mL for 1-month-old (95% confidence interval, 6.31–9.49) and 6.74 ng/mL for 2-month-old (95% confidence interval, 5.80–7.68) Japanese infants, which were lower than previously reported. Cut-off values were also lower in the high-body mass index (BMI) group than in the low-BMI group for both 1-month and 2-month-old infants. Conclusion: These results imply the need for nutritional rickets prevention via policy recommendations in most full-term newborns in Japan. Although validation studies are required, these results can still be used to guide vitamin D insufficiency treatment options in early infancy.

The biological and neurological processes during the lifespan are dynamic with significant alterations associated with different stages of life. The phase and coupling of oxy-hemoglobin (Δ[HbO]) and deoxy-hemoglobin concentration changes (Δ[Hb]) measured by functional near-infrared spectroscopy (fNIRS) are shown to characterize the neurovascular and metabolic development of infants. However, the changes in phase and coupling across the human lifespan remain mostly unknown. Here, fNIRS measurements of Δ[HbO] and Δ[Hb] conducted at two sites on different age populations (from newborns to elderly) were combined. Firstly, we assessed the influence of random noise on the calculation of the phase difference and phase-locking index (PLI) in fNIRS measurement. The results showed that the phase difference is close to π as the noise intensity approaches -8 dB, and the coupling strength (i.e., PLI) presents a u-shape curve as the noise increase. Secondly, phase difference and PLI in the frequency range 0.01-0.10 Hz were calculated after denoising. It showed that the phase difference increases from newborns to 3-4-month-olds babies. This phase difference persists throughout adulthood until finally being disrupted in the old age. The children's PLI is the highest, followed by that of adults. These two groups' PLI are significantly higher than those of infants and the elderly (p < 0.001). Lastly, a hemodynamic model was used to explain the observations and found close associations with cerebral autoregulation and speed of blood flow. These results demonstrate that the phase-related parameters measured by fNIRS can be used to study the brain and assess brain health throughout the lifespan.

Hypothermia in newborns increases the risk of health complications and mortality. This study aimed to evaluate the effectiveness of using covers over snap-open access ports of a transport incubator to maintain the temperature within. The change in temperature inside the transport incubator was evaluated over a 15-min period at three ambient room temperatures (20 °C, 24 °C, and 28 °C), as well as for three snap-open access port conditions: closed, where ports are closed; open, where the two ports on one side are open; and covered, where the two ports on one side are open but a cover is used. The automatic temperature control of the incubator was set to 37 °C for all conditions. We repeated the same experiments three times. The temperature decrease inside the incubator was greater for the open than for the closed or covered access port conditions at all three 4 °C-increasing room temperatures (p < 0.05). The incubator temperature decreased as a function of decreasing room temperature only for the open condition, with no significant difference between the closed and covered conditions. Therefore, snap-open access port covers provide an option to maintain a constant temperature within the transport incubator, which may lower the risk of neonatal hypothermia.

Higher brain dysfunction, such as language delay, is a major concern among preterm infants. Cerebral substrates of cognitive development in preterm infants remain elusive, partly because of limited methods. The present study focuses on hemodynamic response patterns for brain function by using near-infrared spectroscopy. Specifically, the study investigates gestational differences in the hemodynamic response pattern evoked in response to phonetic changes of speech and cerebral hemispheric specialization of the auditory area in preterm infants (n = 60) and term infants (n = 20). Eighty neonates born between 26 and 41 weeks of gestational age (GA) were tested from 33 to 41 weeks of postmenstrual age (PMA). We analyzed the hemodynamic response pattern to phonemic and prosodic contrasts for multiple channels on temporal regions and the laterality index of the auditory area. Preterm infants younger than 39 weeks of PMA showed significantly atypical hemodynamic patterns, with an inverted response shape. Partial correlation analysis of the typicality score of hemodynamic response revealed a significant positive correlation with PMA. The laterality index of preterm infants from 39 weeks of PMA demonstrated a tendency rightward dominance for prosodic changes similar to term infants. We provide new evidence that alterations in hemodynamic regulation and the functional system for phonemic and prosodic processing in preterm infants catch up by their projected due dates.