Modeling Developmental Changes in Caffeine Clearance Considering Differences between Pre- and Postnatal Period.

Taguchi et al. reported that postmenstrual age (PMA) is a promising factor in describing and understanding the developmental change of caffeine (CAF) clearance. The aim of the present study was to quantify how developmental changes occur and to determine the effect of the length of the gestational period on CAF clearance. We performed a nonlinear mixed effect model (NONMEM) analysis and evaluated the fit of six models. A total of 115 samples were obtained from 52 patients with a mean age of 34.3 ± 18.2 d. The median values of gestational age (GA) and postnatal age (PNA) were 196 and 31 d, respectively. Serum CAF levels corrected for dose per body surface area (BSA) (C/D ratioBSA) were dependent on PMA rather than PNA, which supports the findings of a previous study. NONMEM analysis provided the following final model of oral clearance: CL/F = 0.00603∙WT∙∙0.877GA ≤ 196 L/h. This model takes into account developmental changes during prenatal and postnatal periods separately. The model successfully described the variation in clearance of CAF. Our findings suggest that the dosage of CAF in preterm infants should be determined based not only on body weight (WT) but also on both PNA and GA.

Association between Cesarean section and neurodevelopmental disorders in a Japanese birth cohort: the Japan Environment and Children's Study.

BACKGROUND: The long-term effects of a Cesarean section (CS) birth on child neurodevelopment are of increasing interest. In this study, we examined the associations between mode of delivery and presence of neurodevelopmental disorders in toddlers. Moreover, given that the prevalence of several neurodevelopmental disorders such as autism spectrum disorder (ASD) is known to differ by sex, we also investigated these associations separately in male and female toddlers. METHODS: We investigated 65,701 mother-toddler pairs from the Japan Environment and Children's Study, a nationally representative children's cohort study. To investigate the associations between mode of delivery (CS or vaginal delivery) and neurodevelopmental disorders (motor delay, intellectual disability, and ASD) in 3-year-old toddlers as a whole and stratified by sex, we used logistic regression models to calculate adjusted odds ratios (aORs) with 95% confidence intervals (CIs). RESULTS: The morbidity of ASD at age 3 years was higher for children delivered by CS than those delivered vaginally (aOR 1.38, 95% CI 1.04-1.83). However, no such difference was evident in the case of motor delay or intellectual disability (aOR 1.33, 95% CI 0.94-1.89; aOR 1.18, 95% CI 0.94-1.49, respectively). In the analysis by sex, CS was not associated with increased risk of any of the neurodevelopmental disorders in males, but it was associated with increased risks of motor delay (aOR 1.88, 95% CI 1.02-3.47) and ASD (aOR 1.82, 95% CI 1.04-3.16) in females. CONCLUSIONS: This study provides evidence of significant associations between mode of delivery and neurodevelopmental disorders in early childhood. Females may be more sensitive to the effects of CS than males.

Effects of postnatal hydrocortisone on cytokine profile in extremely preterm infants.

BACKGROUND: Systemic hydrocortisone administration has been widely used in preterm infants who are at risk of bronchopulmonary dysplasia (BPD). However, the effects of hydrocortisone on cytokine profiles have not been examined. We aimed to investigate the effects of postnatal hydrocortisone treatment on serum cytokine levels in extremely preterm infants. METHODS: This is a retrospective study of 29 extremely preterm infants born at <28 weeks of gestational age. We obtained serum from blood samples collected during an early phase (5-20 days) and a late phase (28-60 days) after birth. We measured the levels of proinflammatory cytokines (tumor necrosis factors α and ß, interleukin (IL)-1ß, and IL-6), T-helper (Th) 1 cytokines (interferon-γ, IL-2, and IL-12p70), Th2 cytokines (IL-4, IL-5, and IL-10), Th17 cytokine IL-17A, and chemokine IL-8. The cytokine levels between the early and late phases were compared between infants who received postnatal hydrocortisone and those who did not. RESULTS: Thirteen infants (45%) received systemic hydrocortisone treatment at a median age of 15 days (IQR: 10.0-21.5) after birth due to respiratory deterioration. The percentage of BPD was higher in the steroid group than in the non-steroid group (P = 0.008). The ratio of IL-6 for the late-to-early phase was significantly lower in the steroid group than in the non-steroid group (P = 0.04). The concentration of the other cytokines remained unchanged between the phases. CONCLUSIONS: Although the postnatal hydrocortisone treatment provided for respiratory deterioration did not prevent the BPD development, hydrocortisone treatment might suppress IL-6 overproduction in extremely preterm infants.

Correlation between the Bayley-III at 3 years and the Wechsler Intelligence Scale for Children, Fourth Edition, at 6 years.

BACKGROUND: Although several studies have investigated the association between Bayley-III results in infancy and future intellectual development, conclusions remain unclear. We used the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 3 years of age and the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) at 6 years of age to assess the neurodevelopment of very low birthweight infants. METHODS: We investigated the correlation between Bayley-III's cognitive, language, and motor scores and the WISC-IV's Full-Scale Intelligence Quotient (FSIQ). We also determined the optimal cut-off value of Bayley-III to enter the normal development zone (FSIQ ≥ 85). RESULTS: We found a strong correlation between the Bayley-III and the FSIQ. Optimal cut-off scores of the Bayley-III to enter the normal range on the WISC-IV were 95 for the cognitive scale, 89 for the language scale, and 91 for the motor development scale. CONCLUSIONS: Although Bayley-III scores strongly correlated with the WISC-IV FSIQ, the lower normal limit of 85 on the Bayley-III suggests a potential overestimation of development in children who were VLBW infants.

Actual incidence of severe neonatal hypoglycemia in non-risk term neonates: A 10 year survey of all cases in Toyama Prefecture, Japan.

BACKGROUND: Severe neonatal hypoglycemia may cause irreversible neurological sequelae. Although blood glucose (BG) screening in term neonates without risk factors for hypoglycemia (non-risk neonates) is not recommended in the current guidelines, severe hypoglycemia can occur in such neonates. To evaluate the necessity of BG screening in non-risk neonates, it is important to determine the accurate incidence of severe hypoglycemia in those neonates. METHODS: We conducted a 10 year survey of all normal-weight term neonates diagnosed with severe neonatal hypoglycemia who were treated at secondary- and tertiary-level neonatal centers in Toyama Prefecture, Japan, between January 2011 and December 2020. RESULTS: During the study period, 11 cases of severe neonatal hypoglycemia (six of which occurred in non-risk neonates) were identified. The overall incidence of severe hypoglycemia was 1 in 5,827 normal-weight term births, and the incidence in non-risk neonates was 1 in 10 682 normal-weight term births. All of the cases in non-risk neonates were diagnosed as hyperinsulinemic hypoglycemia. CONCLUSIONS: This is the first population-based study to have identified the actual incidence of severe pathological neonatal hypoglycemia in non-risk neonates. The incidence was not low compared with those of the newborn screening disorders, justifying the necessity of BG screening even in non-risk neonates.

Effects of long-term antenatal magnesium sulfate administration on the bone mineralization of preterm infants.

AIM: To evaluate the relationship between long-term antenatal magnesium sulfate (MgSO4 ) administration and neonatal bone mineralization. METHODS: Infants born at 28-33 weeks of gestation (n = 163) were divided into three groups: long-term Mg administration group (infants received antenatal MgSO4 for ≥40 days), short-term Mg administration group (infants received antenatal MgSO4 for <40 days), and non-Mg group. Serum calcium, phosphorus, Mg, and alkaline phosphatase were measured weekly up to 1 month of age, and the bone speed of sound (SOS) values were measured using quantitative ultrasound (QUS) at 1 week and 1 month after birth. RESULTS: In the long-term Mg administration group, the serum calcium values were significantly lower, and the serum phosphorus, Mg, and alkaline phosphatase values were significantly higher than those in the non-Mg group at birth. Although these biochemical differences disappeared around the age of 2 weeks, the SOS values of the long-term Mg administration group were significantly lower than those of the non-Mg group both at 1 week and 1 month after birth (p = 0.02 and <0.001, respectively). When less than 10th percentile of SOS values at 1 month after birth in the non-Mg group was defined as poor bone mineralization, the cut-off value for the duration of antenatal MgSO4 administration was 67 days. CONCLUSIONS: Long-term antenatal MgSO4 administration affects bone mineralization during the early neonatal period, but the clinically acceptable duration of the administration based on its effects of bone mineralization assessed with QUS might be longer than a few weeks.

Pharmacokinetic Variability of Caffeine in Routinely Treated Preterm Infants: Preliminary Considerations on Developmental Changes of Systemic Clearance.

The purpose of this study was to clarify the variability of serum concentrations of caffeine (CAF) in preterm infants, and to deliberate on a better explanation for developmental changes of systemic clearance during the neonatal period. Forty-nine serum samples were obtained from 23 preterm neonates (age, 34.1 ± 18.8 d), and additive blood sampling was conducted periodically for 10 of the 23 patients after discontinuation of CAF treatment. The concentrations of CAF and its major metabolites were determined by liquid chromatography-tandem mass spectrometory. The serum concentrations of CAF were within therapeutic levels (5-25 µg/mL) in 37 samples and exceeded 25 µg/mL in the rest of the 12 samples, although no sample was in the toxic range (> 50 µg/mL). The inter- and intra-individual variability of the concentration to dose (C/D) ratio corrected for body surface area (BSA) was more negatively associated with postmenstrual age (PMA) rather than postnatal age (PNA). The serum concentrations of major metabolites were much smaller than those of CAF throughout the study, suggesting that the contribution of hepatic metabolism to drug elimination was small in the preterm infants under 241 d of PMA. The mean values for elimination half-life and oral clearance estimated in the 10 patients were 124.6 ± 44.6 h and 2.26 ± 0.73 mL/min/1.73 m2, respectively. Consequently, we confirmed that the exposure to CAF was considerably variable and provided additive insight that the C/D ratio corrected for patient's BSA and PMA are promising for describing and understanding the developmental change of clearance in preterm infants.

Association of cesarean birth with prevalence of functional constipation in toddlers at 3 years of age: results from the Japan Environment and Children's Study (JECS).

BACKGROUND: The association between delivery mode and subsequent development of diseases is a growing area of research. Cesarean delivery affects the diversity of the microbiota in the infant gut, which may be associated with gastrointestinal disorders, including functional constipation, in infants. In this study, we investigated the association between delivery mode and prevalence of functional constipation in 3-year-old Japanese toddlers. METHODS: This study used data from the Japan Environment and Children's Study, an ongoing nationwide birth cohort study. We analyzed 71,878 toddler-mother pairs. The presence of functional constipation was determined according to the Rome III diagnostic criteria. Odds ratios and 95% confidence intervals were calculated using logistic regression analysis. RESULTS: The prevalence of functional constipation in 3-year-old Japanese toddlers was estimated to be 12.3%. Logistic regression analysis revealed that the prevalence of functional constipation was higher in toddlers born by cesarean delivery (13.1%) compared with those born by vaginal delivery (12.1%), independent of 22 confounders (adjusted odds ratios = 1.064, 95% confidence interval = 1.004-1.128). CONCLUSIONS: We determined the prevalence of functional constipation in 3-year-old Japanese toddlers and found that delivery mode was associated with the prevalence of functional constipation in Japanese toddlers.

Neurodevelopmental outcomes at 3 years for infants with congenital heart disease and very-low birthweight.

BACKGROUND: Both congenital heart disease (CHD) and very-low birthweight (VLBW) infants are at a very high risk of neurodevelopmental delay. We investigated neurological development at 3 years in pediatric patients with CHD after surgical intervention, those of VLBW, and healthy controls. METHODS: We enrolled pediatric patients with CHD (n = 67), VLBW (n = 67), and healthy controls (n = 81). Infants with CHD were grouped into those with single ventricle and two ventricles, and infants with VLBW were grouped into those with birthweights of <1000 and 1000-1499 g. Neurodevelopmental outcomes at 3 years were evaluated using the Bayley Scales of Infant and Toddler Development, Third Edition. RESULTS: Compared with healthy controls, a significant deficit in the language, cognition, and motor skills scores were observed in infants with CHD and VLBW. Infants with a single ventricle exhibited significantly low scores in language and gross motor skills. No statistically significant difference was observed between the birthweight groups of <1000 and 1000-1499 g. CONCLUSION: Neurodevelopmental outcomes for infants with both CHD and VLBW showed impairment. Notably, neurodevelopmental delays in infants with a single ventricle were remarkable. Thus, because infants with both CHD and VLBW are at high risk of neurodevelopmental disorders, periodic developmental screenings and support are warranted for these children.

Congenital tuberculosis in an extremely preterm infant and prevention of nosocomial infection.

Congenital tuberculosis is a rare disease, especially in non-endemic countries. We present a preterm infant who developed congenital tuberculosis in a neonatal intensive care unit (NICU). The male patient, weighing 1140 g was born by cesarean section at 26 weeks gestation. The baby's respiratory condition suddenly deteriorated at 18 days old, and he was diagnosed with congenital tuberculosis after Gram stain revealed "ghost bacilli" in his tracheal aspirate. The mother, who was born in an endemic country, had fever with unknown cause during labor and was diagnosed with miliary tuberculosis after the infant was diagnosed. Both were successfully treated for tuberculosis with a four-drug regimen. The genotyping profiles of Mycobacterium tuberculosis were identical in both mother and baby based on variable number of tandem repeat (VNTR) analysis. The lineage was considered to be East-African Indian. To prevent nosocomial infection in the NICU, 23 potentially exposed infants received isoniazid for 2 months. Two infants showed a transient liver enzyme elevation that seemed to be due to isoniazid. For 10 months after the incident, there were no infants and medical staff who developed tuberculosis. Although the incidence of tuberculosis has steadily decreased in Japan, the percentage of foreign-born individuals has increased yearly, especially those of reproductive age. The evaluation of active tuberculosis should be considered in pregnant women with unexplained fever, history of tuberculosis, or emigration from high-burden areas.

In which preterm labor-patients is intravenous maintenance tocolysis effective?

AIM: We evaluated whether maintenance tocolysis (intravenous ritodrine hydrochloride and/or magnesium sulfate) was effective in cases of spontaneous preterm labor with intact membranes. METHODS: One hundred and thirty preterm labor patients who reached 36 weeks of gestation by maintenance tocolysis were selected. Immediate delivery (ID) after ceasing maintenance tocolysis was defined as an 'effective case'. The correlated factors between ID and no immediate delivery (NID) were statistically analyzed. RESULTS: Thirty-six patients delivered < two days after ceasing maintenance tocolysis (27.7%) and were defined as effective cases. Multiple logistic regression analysis revealed that amniotic fluid interleukin-8 at admission (≥ 2.3 ng/mL; odds ratio [OR] 5.6, 95% confidence interval [CI] 2.1-17.6; P < 0.001), pre-pregnancy body mass index (≤ 21.4; OR 5.3, 95% CI 2.0-16.2; P < 0.001) and cerclage (OR 3.6, 95% CI 1.1-11.8; P = 0.028) were independent factors correlated with ID (< 2 days). CONCLUSION: Maintenance tocolysis may be effective in limited cases with mild intra-amniotic inflammation, in lean women and in cerclage cases. Maintenance tocolysis should be ceased in cases without these clinical factors when clinical symptoms disappear.

Effect of preterm birth on growth and cardiovascular disease risk at school age.

BACKGROUND: Low birthweight is associated with increased risk for cardiovascular disease (CVD) in later life, but whether premature birth is also a risk factor for CVD has not been fully determined. The aim of this study was to investigate the relationship between gestational age and risk factors for CVD at school age. METHODS: Using medical check-up data of school children, the relationship between gestational age and height, weight, body mass index, blood pressure, and lipid profiles at ages 9 and 12 years were investigated in children born preterm and admitted to neonatal intensive care unit at birth (n = 182; 115 boys and 67 girls). These data were also compared between preterm small for gestational age (SGA) children and preterm appropriate for gestational age (AGA) children. RESULTS: Gestational age was positively associated with height, and inversely associated with systolic blood pressure at school age. Preterm SGA children were significantly shorter and lighter at 9 and 12 years of age compared with preterm AGA children, but there were no significant differences in any CVD risk factors between the groups. CONCLUSIONS: In preterm infants, a shorter duration of gestation is associated with higher systolic blood pressure at school age.

Intrauterine growth restriction modifies gene expression profiling in cord blood.

BACKGROUND: Small-for-gestational-age (SGA) newborns are at an increased risk for perinatal morbidity and mortality and development of metabolic syndromes such as cardiovascular disease and type 2 diabetes mellitus (T2DM) in adulthood. The mechanism underlying this increased risk remains unclear. In this study, genetic modifications of cord blood were investigated to characterize fetal change in SGA newborns. METHODS: Gene expression in cord blood cells was compared between 10 SGA newborns and 10 appropriate-for-gestational-age (AGA) newborns using microarray analysis. Pathway analysis was conducted using the Ingenuity Pathways Knowledge Base. To confirm the microarray analysis results, quantitative real-time polymerase chain reaction (RT-PCR) was performed for upregulated genes in SGA newborns. RESULTS: In total, 775 upregulated and 936 downregulated probes were identified in SGA newborns and compared with those in AGA newborns. Of these probes, 1149 were annotated. Most of these genes have been implicated in the development of cardiovascular disease and T2DM. There was good agreement between the RT-PCR and microarray analyses results. CONCLUSIONS: Expression of certain genes was modified in SGA newborns in the fetal period. These genes have been associated with metabolic syndrome. To clarify the association between modified gene expression in cord blood and individual vulnerability to metabolic syndrome in adulthood, these SGA newborns will be have long-term follow up for examination of genetic and postnatal environmental factors. Gene expression of cord blood can be a useful and non-invasive method of investigation of genetic alterations in the fetal period.

Memory B and memory plasma cells.

Vaccination provides a powerful means to control infections. It exploits and exemplifies the ability of the immune system to preserve the information that a specific pathogen has been encountered in the past. The cells and molecular mechanisms of immunological memory are still being discussed controversially. Here, we review the current concepts of memory B cells, the signals involved in their maintenance, and their role in enhanced secondary reactions. Memory plasma cells, secreting protective antibodies over lifetime, have been recognized only recently. Their characterization as cells resting in terms of proliferation and migration, and surviving in dedicated stromal niches, in the absence of antigen, has generated new concepts of how memory cells in general are organized by stroma cells, the 'resting memory'. In autoimmunity and chronic inflammation, memory B cells and memory plasma cells can be essential players, and they require special attention, as they do not respond to most conventional therapies. Their selective targeting will depend on a molecular understanding of their lifestyle.

A Neonatal Case of Lower Urinary Tract Obstruction and Imperforate Anus: Urethral Decompression Due to Rectourinary Fistula.

Lower urinary tract obstruction (LUTO) is a rare fetal condition associated with significant perinatal morbidity and mortality. Herein, we report a neonatal case of LUTO with anal atresia complicated by anhydramnios and pulmonary hypoplasia. After treatment for severe postnatal respiratory distress, the neonate underwent vesicostomy and colostomy. Postoperatively, respiratory status and renal function improved. This case highlights a unique feature where a large rectovesical fistula channeled fetal urine into the colon, which minimized obstructive damage to the urinary tract and preserved renal morphology. Fetal colonic dilatation and numerous enteroliths indicate urine influx into the intestinal tract. Our case suggests the importance of recognizing such exceptions in complete LUTO to predict postnatal outcomes diagnosed in utero.

Cesarean section and parenting stress: Results from the Japan Environment and Children's Study.

BACKGROUND: Accumulating evidence suggests a long-term health risk of cesarean section for the mother and child, but few studies have examined the link between cesarean section and parenting stress. Here, we examined this association by exploiting a large dataset. METHODS: Participants were 65,235 mothers participating in the Japan Environment and Children's Study, an ongoing nationwide birth cohort. Outcome variables were parenting stress assessed as total score and subscale scores (representing the difficult child, parental distress, and spouse factors) on the Japanese 19-item version of the Parenting Stress Index Short Form (J-PSI-SF). Exposures were the mode of delivery, the timing of the J-PSI-SF assessment (1.5, 2.5, and 3.5 years postpartum), and the interaction between them. Multivariate regression analysis was used to calculate adjusted ß coefficients and standard error of the means (SEMs). RESULTS: The J-PSI-SF total score was higher in the cesarean section group than in the vaginal delivery group (adjusted ß = 0.24, SEM = 0.09). This increase was primarily due to higher scores for the difficult child factor (adjusted ß = 0.18, SEM = 0.05) and not to higher scores for the parental distress or spouse factor. CONCLUSIONS: Cesarean section was associated with higher parenting stress, especially in relation to the difficult child factor. Our results highlight the importance of paying particular attention to the mental health of both mother and child in the case of cesarean section.

Caesarean section and childhood obesity at age 3 years derived from the Japan Environment and Children's Study.

Caesarean section (CS) birth is widely reported to be a risk factor for childhood obesity. Although susceptibility to childhood obesity is influenced by race and ethnicity, it is unclear whether this risk of childhood obesity with CS birth also applies in the Japanese population. We investigated the impact of CS birth on obesity at 3 years of age in Japanese children. We obtained data from 60,769 mother-toddler pairs in the Japan Environment and Children's Study, a large-scale birth cohort study. Obesity was determined by body mass index measured at 3 years of age. Analysis revealed that 11,241 toddlers (18.5%) had a CS birth and that 4912 toddlers (8.1%) were obese. The adjusted risk ratio for obesity at 3 years of age when born by CS compared with vaginal delivery, estimated using inverse probability of treatment weighting, was 1.16 (95% confidence interval 1.08-1.25). These results suggest that CS birth modestly increases the risk of obesity at 3 years of age in Japanese children.

Bone marrow of NZB/W mice is the major site for plasma cells resistant to dexamethasone and cyclophosphamide: implications for the treatment of autoimmunity.

Antibodies contribute to the pathogenesis of many chronic inflammatory diseases, including autoimmune disorders and allergies. They are secreted by proliferating plasmablasts, short-lived plasma cells and non-proliferating, long-lived memory plasma cells. Memory plasma cells refractory to immunosuppression are critical for the maintenance of both protective and pathogenic antibody titers. Here, we studied the response of plasma cells in spleen, bone marrow and inflamed kidneys of lupus-prone NZB/W mice to high-dose dexamethasone and/or cyclophosphamide. BrdU+, dividing plasmablasts and short-lived plasma cells in the spleen were depleted while BrdU- memory plasma cells survived. In contrast, all bone marrow plasma cells including anti-DNA secreting cells were refractory to both drugs. Unlike bone marrow and spleen, which showed a predominance of IgM-secreting plasma cells, inflamed kidneys mainly accommodated IgG-secreting plasma cells, including anti-DNA secreting cells, some of which survived the treatments. These results indicate that the bone marrow is the major site of memory plasma cells resistant to treatment with glucocorticoids and anti-proliferative drugs, and that inflamed tissues and secondary lymphoid organs can contribute to the autoreactive plasma cell memory. Therefore, new strategies targeting autoreactive plasma cell memory should be considered. This could be the key to finding a curative approach to the treatment of chronic inflammatory autoantibody-mediated diseases.