Association between pregnant women fasting duration and neonatal hypoglycemia: A prospective cohort study.

OBJECTIVE: To evaluate the association between maternal fasting time before delivery and the occurrence of hypoglycemia in neonates immediately after birth. METHODS: This prospective single-center cohort study included pregnant women who delivered at the study institution between October 2021 and January 2023 and their neonates. The primary outcome was the incidence of neonatal hypoglycemia after birth, defined as a blood glucose level less than 47 mg/dL. Fasting time was categorized into quartiles, and the association between maternal fasting time and neonatal hypoglycemia was investigated. The crude or adjusted odds ratios of maternal fasting time for neonatal hypoglycemia were calculated using logistic regression analysis. RESULTS: The study included 663 pregnant women and 696 neonates. Compared with the reference group with a short fasting time of 4.3 h or less, the adjusted odds ratios for neonatal hypoglycemia were 1.47 (95% confidence interval [CI] 0.70-3.20) for middle fasting time (4.3-9.8 h), 4.05 (95% CI 2.02-8.56) for long fasting time (9.8-14.6 h), and 4.99 (95% CI 2.59-10.25) for very long fasting time (>14.6 h). In the subgroup analysis, the association between maternal fasting time and neonatal hypoglycemia showed different trends according to the mode of delivery. CONCLUSION: Maternal fasting time over 9-10 h before delivery was associated with the occurrence of neonatal hypoglycemia. Obstetrical management, considering not only maternal safety but also neonatal hypoglycemia prevention, is required.

Pulmonary hypertension with bronchopulmonary dysplasia: Aichi cohort study.

BACKGROUND: The incidence of pulmonary hypertension (PH) associated with bronchopulmonary dysplasia (BPD) has not been investigated in regional cohorts. The aim of this study was to clarify the incidence of PH associated with BPD in all very low birthweight infants (VLBWIs) born during the study period in Aichi Prefecture, Japan. METHODS: We conducted a retrospective observational cohort study of all VLBWIs born in Aichi Prefecture. The inclusion criteria were VLB, birth between 1 January 2015 and 31 December 2015, and admission to any neonatal intensive care unit in Aichi Prefecture. BPD28d and BPD36w were defined as the need for supplemental oxygen or any respiratory support at 28 days of age or 36 weeks of postmenstrual age (PMA). The primary outcome was the incidence of PH after 36 weeks' PMA (PH36w) in VLBWIs with BPD28d and BPD36w. The secondary outcomes were the clinical factors related to PH36w in BPD36w patients. Mann-Whitney U-test and Fisher's exact test were used for univariate analysis. Differences were considered statistically significant at P < 0.05. Risk ratio (RR) and 95% confidence interval (CI) were also evaluated. RESULTS: A total of 441 patients were analyzed. A total of 217 and 131 patients met the definition of BPD28d and BPD36w, respectively. Nine patients were diagnosed with PH36w (4.2% and 6.9% of the BPD28d and BPD36w patients, respectively). The presence of oligohydramnios (RR, 2.71; 95% CI: 1.55-4.73, P = 0.014) and sepsis (RR, 3.62; 95% CI: 1.51-8.63, P = 0.025) was significant in the PH36w patients. CONCLUSIONS: The incidence of PH36w was 4.2% and 6.9% in the BPD28d and BPD36w patients, respectively. Oligohydramnios and sepsis were significantly associated with PH36w in VLBWIs.

TREC/KREC Newborn Screening followed by Next-Generation Sequencing for Severe Combined Immunodeficiency in Japan.

PURPOSE: The aim of this study is to evaluate the usefulness of T cell receptor excision circle (TREC) and/or kappa-deleting recombination excision circle (KREC) measurements integrated with diagnostic next-generation sequencing (NGS) analysis using a severe combined immunodeficiency (SCID) newborn screening (NBS) program. METHODS: TREC and/or KREC values were measured in 137,484 newborns between April 2017 and December 2021 using EnLite TREC (n = 80,791) or TREC/KREC kits (n = 56,693). For newborns with positive screening results, diagnostic NGS analysis was performed with a 349-gene panel to detect genetic mutations associated with primary immunodeficiencies (PIDs). RESULTS: A total of 145 newborns (0.11%) had abnormal TREC and/or KREC values, and a genetic diagnosis was established in 2 patients with SCID (1 in 68,742 newborns) (IL2RG-SCID and reticular dysgenesis) and 10 with non-SCID PIDs with T and/or B cell deficiencies (1 in 13,748 newborns) using NGS analysis. Furthermore, TREC values of 2849 newborns were measured and confirmed the significant correlation between the results of both TREC and TREC/KREC kits (P < 0.001) and naïve T cell counts. CONCLUSIONS: We performed the first large-scale TREC and TREC/KREC NBS programs in Japan. Our NBS programs followed by the diagnostic NGS analysis for newborns with abnormal TREC and/or KREC values are useful for the early identification and rapid molecular evaluation of not only SCID but also different non-SCID PIDs.

Admission temperature of very low birth weight infants and outcomes at three years old.

The lower body temperature of preterm newborns at admission to neonatal intensive care units (NICUs) is inversely associated with their morbidities and mortalities before discharge. This retrospective cohort study aimed to determine whether admission rectal temperature in very low birth weight infants (VLBWIs) is independently associated with a composite outcome of death or moderate-to-severe neurodevelopmental impairments as defined by a performance developmental quotient of < 70 at three years of age. VLBWIs admitted to the NICU between April 2010 and March 2016 were assesed. Developmental assessment was completed in 216 newborns. Nine and two infants died before and after discharge, respectively. A higher admission temperature was associated with a lower incidence of death or moderate-to-severe neurodevelopmental impairments with adjustment for gestational age, sex, antenatal steroid use, Apgar score, severe intraventricular hemorrhage, and severe bronchopulmonary dysplasia (odds ratio [OR] 0.424; 95% confidence interval [CI] 0.250-0.717; p = 0.001). The admission temperature remained as an independent variable of adverse outcome at three years of age even when the study cohort was limited to surviving infants (OR 0.448; 95% CI 0.259-0.774; p = 0.004). Further studies are needed to assess whether avoiding low body temperature at admission results in better long-term neurodevelopmental outcomes in VLBWIs.

Two Japanese patients with Noonan syndrome-like disorder with loose anagen hair 2.

Noonan syndrome-like disorder with loose anagen hair (NSLH) is a rare disease characterized by typical features of Noonan syndrome with additional findings of relative or absolute macrocephaly, loose anagen hair, and a higher incidence of intellectual disability. NSLH1 is caused by a heterozygous mutation in the SHOC2 gene on chromosome 10q25, and NLSH2 is caused by a heterozygous mutation in the Protein phosphatase one catalytic subunit beta (PPP1CB) gene on chromosome 2p23. Protein phosphatase1 (PP1), encoded by PPP1CB, forms a complex with SHOC2 and dephosphorylates RAFs, which results in activation of the signaling cascade and contribution to Noonan syndrome pathogenesis. Here, we report two genetically confirmed Japanese patients with NSLH2 having the same de novo mutation in PPP1CB presenting prominent-hyperteloric-appearing eyes and a tall forehead similar to individuals carrying a mutation in PPP1CB, c.146C > G; p.Pro49Arg, which is different from typical facial features of Noonan syndrome. They also showed short stature, absolute macrocephaly, and loose anagen hair like NSLH1: however, growth hormone deficiency often seen in NSLH1 caused by SHOC2 mutation was absent. Although a number of Noonan syndrome and NSLH1 patients have shown blunted or no response to GH therapy, linear growth was promoted by recombinant human growth hormone (rhGH) in one of our patients. Since another NSLH2 patient with good response to rhGH treatment was reported, rhGH therapy may be effective in patients with NSLH2.

Global developmental delay, systemic dysmorphism and epilepsy in a patient with a de novo U2AF2 variant.

U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an essential pre-mRNA splicing factor in an early step of splicing. Alternative splicing plays an important role in neuronal development, and disorders of RNA processing steps are implicated in neurological disorders. Recently, the large trio whole-exome sequencing study reported U2AF2 as a novel gene significantly associated with developmental disorders: however, the clinical details of patients with U2AF2 variants were not available. Here, we report an individual with a de novo U2AF2 variant (c.445C>T, p.(Arg149Trp)) using trio-based whole-exome sequencing. This residue was positioned in the RNA recognition motif 1 which recognizes a polypyrimidine-tract splice site signal. The patient showed global developmental delay, intellectual disability, epilepsy, short stature, microcephaly, facial dysmorphism, intermittent exotropia, bilateral ptosis, muscle hypotonia and thin corpus callosum, indicating that U2AF2-related disorder could include systemic dysmorphisms, epilepsy and brain malformation along with global developmental delay.

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.

Prognostic factors of hydrops fetalis with pleural effusion.

BACKGROUND: Hydrops fetalis (HF) has a low survival rate, particularly in the case of preterm birth. In addition, the severity index of HF has not been fully investigated yet. The aim of this study was to clarify the prognostic factors of HF with pleural effusion. METHODS: All live-born HF patients with pleural effusion, except for chromosomal abnormality or complex congenital heart disease, born from 2009 to 2013 in Aichi Prefecture in Japan were included. Prenatal, perinatal, and postnatal information was obtained from the medical records and was retrospectively analyzed. RESULTS: Forty-one HF patients with pleural effusion were included, and 28 patients (68%) survived. On multivariate logistic stepwise analysis, gestational birth week (OR, 0.71; 95% CI: 0.52-0.96, P = 0.027) and standard deviation (SD) score of the birthweight (OR, 1.74; 95% CI: 1.01-2.99, P = 0.045) were significant factors for postnatal death. All patients with both ≥32 gestational weeks and <3.0 birthweight SD score survived. CONCLUSIONS: Combined with the gestational weeks data, birthweight SD score may be useful to estimate the prognosis of HF with pleural effusion.

Introducing Internet Retailing of OTC Drugs in Japan: Revision of the Pharmaceutical Affairs Law.

Only the low-risk category of over-the-counter (OTC) drugs was permitted to be sold via the Internet, which was stipulated by the ordinance of the Minister of Health, Labour and Welfare under the Pharmaceutical Affairs Law in Japan. Two Japanese retailers of OTC drugs, who want to retail OTC drugs via the Internet, launched proceedings against the rule, and the Supreme Court gave a decision that the ministerial ordinance is illegal and invalid. The Ministry of Health, Labour and Welfare immediately started discussion to make rules for Internet retailing of OTC drugs. Finally, a bill designed to enable Internet retailing of OTC drugs was passed by the Diet on December 5, 2013, and the act was promulgated on December 13. The act was enforced on June 12, 2014. This article briefly touches on the decision process and also illustrates the key points of the new rules for Internet retailing.

Down-regulation of CD5 expression on activated CD8+ T cells in familial hemophagocytic lymphohistiocytosis with perforin gene mutations.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled activation of T cells and macrophages with overproduction of cytokines. Familial HLH type 2 (FHL2) is the most common form of primary HLH and is caused by mutations in PRF1. We have recently described a significant increase in the subpopulation of CD8(+) T cells with clonal expansion and CD5 down-regulation in Epstein-Barr virus associated-HLH, which represented a valuable tool for its diagnosis. However, this unusual phenotype of CD8(+) T cells has not been investigated fully in patients with FHL2. We performed immunophenotypic analysis of peripheral blood and measured serum pro-inflammatory cytokines in five patients with FHL2. All patients showed significantly increased subpopulations of activated CD8(+) T cells with down-regulation of CD5, which were negligible among normal controls. Analysis of T-cell receptor Vß repertoire suggested the reactive and oligoclonal expansion of these cells. The proportion of the subset declined after successful treatment concomitant with reduction in the serum levels of cytokines in all patients except one who continued to have a high proportion of the subset and died. These findings suggest that down-regulation of CD5 on activated CD8(+) T cells may serve as a useful marker of dysregulated T cell activation and proliferation in FHL2.

Late-onset circulatory dysfunction of premature infants and late-onset periventricular leukomalacia.

BACKGROUND: The sudden appearance of hypotension and oliguria without obvious cause following stable circulation and respiration in preterm infants is frequent in Japan. Such episodes are referred to as late-onset circulatory dysfunction of premature infants (LCD). Volume expanders and inotropic agents are often ineffective against this condition, whereas i.v. steroids are significantly effective. A major problem is that cystic periventricular leukomalacia (PVL) often develops a few weeks after an episode. The aim of the present study was to clarify the risk factors, including LCD, related to cystic PVL. METHODS: A case-control study was performed for preterm infants who were delivered at <33 weeks of gestation and admitted to seven neonatal intensive care units in Japan. Cystic PVL infants were stratified into early-onset PVL diagnosed within 28 days of age and late-onset PVL diagnosed after more than 28 days of age. The reported and new risk factors for PVL, for each group of PVL infants, and for all PVL infants, were compared with controls. RESULTS: Thirty-two infants were diagnosed with cystic PVL (17 early-onset and 15 late-onset). All PVL infants significantly differed from controls on Apgar score, number of abortions and pregnancies, intraventricular hemorrhage, and LCD. LCD was diagnosed in 28.1% of both PVL groups compared with 6.3% of controls (P = 0.02). Multivariate analysis demonstrated significant association between late-onset PVL and LCD. CONCLUSION: LCD was significantly associated with cystic PVL, especially late-onset PVL. Elucidating the cause of LCD might reduce the incidence of PVL and improve the neurological prognosis of preterm infants.

The sex differences of cerebrospinal fluid levels of interleukin 8 and antioxidants in asphyxiated newborns.

Newborn males are more sensitive to brain injury than newborn females are. The aim of the present study was to find an explanation for this. We used the neuron-specific enolase (NSE) levels in the cerebrospinal fluid (CSF) for the classification of 32 newborns (19 males and 13 females) on their fifth postnatal day. The NSE levels were higher than normal (8.4 +/- 1.6 ng/mL) in 10 newborn males and 6 females and were, respectively, considered asphyxiated male and female groups. The remaining newborns, 9 males and 7 females, had normal CSF levels of NSE and were considered normal newborn male and female groups. The CSF samples were measured for 12 cytokines, using a cytokine array kit, and for total hydroperoxide and biological antioxidant potentials (BAPs), using the free radical analytic system. Among the 12 cytokines measured, only interleukin 8 (IL-8) was properly detected. The CSF levels of IL-8 were higher in the asphyxiated newborn females than in the other three groups. The mean CSF levels of BAPs in the asphyxiated newborn females were higher compared with the other three groups, but significance was detected only in comparison with the BAP levels in the CSF samples of the normal newborn males. There were no differences in total hydroperoxide levels among the groups. There are sex-related differences in the CSF levels of IL-8 and antioxidants in asphyxiated newborns, with higher levels in newborn females; this might contribute in the sexual dimorphism regarding the fact that females have better protection from brain injury than the males.

Periventricular leukomalacia with late-onset circulatory dysfunction of premature infants: correlation with severity of magnetic resonance imaging findings and neurological outcomes.

The incidence of late-onset circulatory dysfunction (LCD) of premature infants, which is characterized by sudden hypotension and oliguria, has recently increased in Japan. This condition suddenly occurs after several days of age without obvious causes in preterm infants with stable respiration and circulation. Intravenous steroids frequently improve the hypotension. The main problem with LCD is the subsequent and frequent onset of periventricular leukomalacia (PVL), and neurological development appears to be worse in PVL patients with LCD than those without LCD. The aim of this study was to determine whether the severity of magnetic resonance imaging (MRI) findings and neurological outcomes differ between infants who developed PVL after LCD and those who developed PVL without LCD. We retrospectively studied preterm infants who were delivered at less than 33 weeks of gestation between the years 2000 and 2003. During the study period, 10 and 26 infants developed PVL with and without LCD, respectively. The incidence of severe or moderate MRI findings was significantly higher in PVL patients with LCD (100%) than those without LCD (50%; p < 0.05). The incidence of severe cerebral palsy was 88% in PVL infants with LCD and 43% in PVL infants without LCD (p < 0.05). Moreover, the incidence of visual disorders was significantly higher in PVL infants with LCD (63%) than those without LCD (9%; p < 0.01). In conclusion, neurological outcomes are worse in preterm infants who develop PVL with LCD than those without LCD, which is well correlated to the severity judged by MRI findings.

Development and characterization of a novel porcine model of neonatal sepsis.

Sepsis and its sequela remain a major source of morbidity and mortality in neonates despite advances in antimicrobials and aggressive supportive care. Many models of neonatal sepsis have been developed for investigating the pathophysiology of this disease and application of therapy, and a model with an infectious focus is closer to clinical reality. To establish an animal model that mimics the clinical characteristics of neonatal sepsis, the cecal devascularization and perforation procedure was implemented on 15 mixed-strain newborn piglets, which produced an infectious focus that acted as a continuous source of microorganisms to the peritoneal cavity. The mean survival time in animals with sepsis was 10.4 h (range 5.5-17.9 h), whereas all of the sham-operated control animals survived more than 24 h. Animals with sepsis showed a gradual significant decrease in the mean systemic blood pressure (mSBP; 71 +/- 3 mmHg in sepsis vs. 64 +/- 3 mmHg in control at 3 h, 38 +/- 7 mmHg in sepsis vs. 59 +/- 4 mmHg in control at 6 h, mean +/- SEM). They also showed an increase of serum levels of endotoxin (5.6 x 10 +/- 4.5 x 10 pg/mL in sepsis vs. 6.0 x 10 +/- 3.8 x 10 pg/mL in control at 6 h). Serum levels of TNF-alpha in the animals with sepsis became significantly higher than the control animals at 0 h (96 +/- 31 pg/mL in sepsis vs. 12 +/- 1 pg/mL in control) and remained significantly higher than all through the experiment. Serum levels of IL-6 in animals with sepsis showed a gradual increase (484 +/- 231 pg/mL in sepsis in its peak at 6 h vs. 24 +/- 5 pg/mL in control), however, there were no significant differences in serum IL-10 levels between the groups. Microorganisms detected in the blood of animals with sepsis were gram-negative enteric and anaerobic organisms. These results suggested that this model mimics the clinical state of neonatal sepsis and hence may have significant implications for the treatment of sepsis, including its use as a model in further investigations.

Reduction of pleural effusion by OK-432 in a fetus complicated with congenital hydrothorax.

A 29-year-old, primiparous woman was referred to our hospital at 21 weeks of gestation because of right pleural effusion in the fetus shown by routine ultrasonographic examination. Cytology revealed abundant lymphocytes, suggesting chylothorax. We removed the pleural effusion and injected OK-432 into the chest cavity at 24 and 25 weeks of gestation. Pleural effusion declined and an adhesion between the lung surface and the pleural membrane seemed to form. At 33 weeks of gestation, a female infant was born by cesarean section (1,090 g and Apgar score 6/8). Although she demonstrated slight retraction and tachypnea, management could be achieved by administration of oxygen alone without mechanical ventilation. Later, the baby was diagnosed as suffering from the Cornelia de Lange syndrome with characteristic features. OK-432 injections could thus prevent complications of chylothorax and hypoplastic lungs, without injury to either the baby or the mother.

Nitric oxide further attenuates pulmonary hypertension in magnesium-treated piglets.

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) commonly appears as a complication of several pulmonary and non-pulmonary diseases. The hypoxia possibly inhibits Ca2+ +/- dependent K+ channels, thus resulting in membrane depolarization of pulmonary smooth muscle cells, which leads to the opening of Ca2+ channels and Ca2+ entry, resulting in contraction of the vascular smooth muscle. However, magnesium (Mg2+) is an antagonist of Ca2+. We studied the effect of magnesium sulfate on the treatment of hypoxia-induced pulmonary hypertension and compared to the site of action of nitric oxide (NO). METHODS: Zero-day-old piglets were used in each experiment. The effects of Mg2+ were tested in each hypoxic, normoxic and hyperoxic states. Once the desired physical state was achieved, Mg2+ was administered at a dose of 100 mg/kg approximately every 10 min. In order to determine the exact mechanism of the Mg2+, Nw-nitro-l-arginine (LNNA), a NO synthase-inhibitor, was administered simultaneously with Mg2+ in some of the experiments. RESULTS: There was a significant correlation between the percent reduction of the pulmonary arterial pressure (PAP) caused by magnesium and the level of oxygen (O2) present in the pulmonary artery. The greatest amount of reduction was seen in the hypoxic condition where the least amount of O2 is found. A further reduction in the PAP was seen when NO was given at the end of the Mg2+ trials. There was no significant reduction seen in the systemic arterial pressure. CONCLUSIONS: Inhaled NO further reduced the PAP in piglets already treated with Mg2+.

Prenatal diagnosis of lissencephaly (type II) by ultrasound and fast magnetic resonance imaging.

We report a case of lissencephaly which could be diagnosed by detailed examination during pregnancy. We first found bilateral enlarged ventricles in the fetus by routine abdominal ultrasonography at mid-pregnancy. Fast scanning MRI subsequently allowed confirmation of a diagnosis of lissencephaly during pregnancy.