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.

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.

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.

Brain-derived neurotrophic factor Val66Met variant on brain volumes in infants.

The brain-derived neurotrophic factor (BDNF) has many important roles in neurogenesis and neuronal health. BDNF is also involved in learning and memory. Individuals with BDNF-Val66Met variant (Met +) are at higher risk for neuropsychiatric disorders and have smaller hippocampi and amgydalae compared to those without this variant (Met -). Whether these smaller brain volumes are already present at birth is unknown and were evaluated. 66 newborn infants were genotyped for BDNF-rs6265 and had brain MRI scans. The T1-weighted images were automatically parcellated for hippocampus and amygdala, as well as the intracranial volume (ICV), total brain volume, total gray and white matter, using a multi-atlas label fusion method implemented in the MRICloud ( https://braingps.anatomyworks.org ). The segmented brain volumes were normalized to the ICV for group comparisons. The two infant groups were not different in their demographics and birth characteristics. However, compared to Met - infants, the Met + infants had smaller hippocampi (p = 0.013), smaller amygdalae (p = 0.041), and less steep age-related declines in total brain volume and % white matter volume. The smaller relative hippocampal and amygdala volumes in Met + infants suggest that the Met + genotype affected prenatal developmental processes. In addition, the slower age-dependent declines in the relative total brain and white matter volumes of the Met + group in this cross-sectional dataset suggest the BDNF-Val66Met variant might have an ongoing negative influence on the postnatal developmental processes.

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.

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.

Brain Development of Children With Single Ventricle Physiology or Transposition of the Great Arteries: A Longitudinal Observation Study.

To define the correlation between neuroanatomic and developmental outcomes of children with single ventricle (SV) or transposition of the great arteries (TGA), a prospective longitudinal study was performed in preschool and school-age children. Twenty-seven children with congenital heart disease (9, TGA; 18, SV) were included. Participants underwent 3-dimensional magnetic resonance imaging (MRI) and neurodevelopmental assessment at around 3 years (preschool age) and at 9 years (school age), and 48 healthy controls underwent MRI, and their data were used to derive best-fit models for normal brain volumes for comparisons with congenital heart disease patients. Total brain volume (TBV) and regional brain volumes remained significantly smaller in SV children than in TGA children at both time points, though the growth slope of TBV was not significantly different between the SV and TGA groups. Although the psychomotor developmental index at preschool was significantly lower in SV patients, the full-scale IQ at school age was not significantly lower in SV patients. There was a strong correlation between full-scale IQ and TBV (r = 0.49, P = 0.005). Despite the current best practices, persistently lower TBV was seen in SV patients until 9 years of age. For both the SV and TGA groups, TBV at 3 years was a strong predictor of TBV at 9 years. Since there was a correlation between TBV and IQ at 9 years, identification of factors that affect brain growth until 3 years will be imperative to improve patients' cognitive function at school age.

A Multi-Atlas Label Fusion Tool for Neonatal Brain MRI Parcellation and Quantification.

Structure-by-structure analysis, in which the brain magnetic resonance imaging (MRI) is parcellated based on its anatomical units, is widely used to investigate chronological changes in morphology or signal intensity during normal development, as well as to identify the alterations seen in various diseases or conditions. The multi-atlas label fusion (MALF) method is considered a highly accurate parcellation approach, and anticipated for clinical application to quantitatively evaluate early developmental processes. However, the current MALF methods, which are designed for neonatal brain segmentations, are not widely available. In this study, we developed a T1-weighted, neonatal, multi-atlas repository and integrated it into the MALF-based brain segmentation tools in the cloud-based platform, MRICloud. The cloud platform ensures users instant access to the advanced MALF tool for neonatal brains, with no software or installation requirements for the client. The Web platform by braingps.mricloud.org will eliminate the dependence on a particular operating system (eg, Windows, Macintosh, or Linux) and the requirement for high computational performance of the user's computers. The MALF-based, fully automated, image parcellation could achieve excellent agreement with manual parcellation, and the whole and regional brain volumes quantified through this method demonstrated developmental trajectories comparable to those from a previous publication. This solution will make the latest MALF tools readily available to users, with minimum barriers, and will expedite and accelerate advancements in developmental neuroscience research, neonatology, and pediatric neuroradiology.

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.

Clinical Factors That Affect the Relationship between Head Circumference and Brain Volume in Very-Low-Birth-Weight Infants.

BACKGROUND AND PURPOSE: Measuring head circumference (HC) in infants is an easy screening procedure with which to detect abnormalities in brain growth. It has been demonstrated that HC can predict total brain volume (TBV) in very-low-birth-weight (VLBW) infants. However, the correlation between HC and TBV was weaker than that observed in healthy term-born toddlers, suggesting that there are factors that influence the relationship between HC and TBV. The aim of this study was to identify the clinical risk factors that caused a deviation from the regression line obtained between HC and TBV. METHODS: The study population was based on 37 VLBW infants, who underwent a clinical magnetic resonance imaging (MRI) examination at a term-equivalent age, during 2013-2015, at Toyama University Hospital. The HC and the TBV were both adjusted for sex, multiple births, and postmenstrual age. The relationship between TBV/HC and clinical characteristics was evaluated. RESULTS: There was a positive correlation between HC and TBV (r = .58, P = .000168). Two clinical factors, the lower birth body weight (BBW) (r = .38, P = .02) and dolichocephaly (r = 0.46, P = .006), were identified as factors that negatively affected the TBV/HC ratio. After excluding infants with low BBW or with dolichocephaly, the correlation between HC and TBV was higher (r = .63). CONCLUSIONS: Although HC has predictive value for TBV in VLBW infants, care should be taken in infants with low BBW (BBW less than 600 g) or dolichocephaly (MRI-based cranial index less than .68), which were related to overestimation of TBV.

17OHP-C in patients with spontaneous preterm labor and intact membranes: is there an effect according to the presence of intra-amniotic inflammation?

PROBLEM: It is not known whether 17-alpha-hydroxyprogesterone caproate (17OHP-C) is effective for preventing preterm delivery with an episode of preterm labor (PTL) with or without intra-amniotic inflammation/infection. METHODS OF STUDY: This was a retrospective cohort study. One hundred and seven PTL patients were selected and divided into a 17OHP-C group (use of 17OHP-C: n = 53) and a no-treatment group (no use of 17OHP-C: n = 54). Moreover, the patients were divided into three subgroups (subgroup A: without intra-amniotic inflammation, B: with mild intra-amniotic inflammation, and C: with severe intra-amniotic inflammation) according to their level of amniotic interleukin (IL)-8, and perinatal prognosis was analyzed. RESULTS: Interval from admission to delivery (days) in the 17OHP-C group (76 [13-126], n = 34) was significantly longer than that in the no-treatment group (50 [8-104], n = 33; P = .012) in subgroup B. In cases without intra-amniotic microbes in subgroup B, a significant prolongation of gestational days was associated with the 17OHP-C group (79 [13-126], n = 25) compared with the no-treatment group (50 [8-104], n = 29; P = .029). However, there were no significant differences in subgroups A or C. CONCLUSION: 17OHP-C could prolong gestational period in limited PTL cases with sterile mild intra-amniotic inflammation.

Successful treatment of hemochromatosis with renal tubular dysgenesis in a preterm infant.

We report the first surviving case of neonatal hemochromatosis with renal tubular dysgenesis. Renal failure was treated with peritoneal dialysis. Although hepatic failure from neonatal hemochromatosis was progressive, repeated exchange transfusions improved jaundice and coagulopathy. The patient gained weight and received a liver transplantation from her father.

Neonatal acute megakaryoblastic leukemia mimicking congenital neuroblastoma.

We describe a neonate with abdominal distension, massive hepatomegaly, and high serum neuron-specific enolase level suggestive of congenital neuroblastoma. The patient died of pulmonary hemorrhage after therapy. Autopsy revealed that the tumor cells in the liver indicated acute megakaryocytic leukemia with the RBM15-MKL1 fusion gene.

A novel Wiskott-Aldrich syndrome protein mutation in an infant with thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) has not yet been reported to be associated with mutations in the Wiskott-Aldrich syndrome (WAS) gene. WAS is an X-linked recessive disorder characterized by thrombocytopenia, small platelet size, eczema, recurrent infections, and increased risk of autoimmune disorders and malignancies. A broad spectrum of mutations in the WAS protein (WASP) gene have been identified as causing the disease. In this study, we report on a 2-month-old Japanese boy who presented with cytomegalovirus (CMV) infection and TTP. The activity of von Willebrand factor cleaving metalloproteinase, ADAMTS13 was low and the antibody against ADAMTS13 was positive (3.6 Bethesda U/mL). Although TTP was improved by plasma exchange and steroid pulse therapy, thrombocytopenia persisted and regular transfusions of irradiated platelets were needed. Tiny platelets were found on a peripheral blood smear. CMV genome was positive in peripheral blood by polymerase chain reaction and the CMV viremia continued to persist despite intravenous gancyclovir therapy. Through direct sequencing of genomic DNA of the WASP gene in the patient, we identified a novel mutation of WASP gene: the seventh nucleotide in exon 11 (G) had been deleted (1345delG). This mutation causes a frameshift and a stop codon at amino acid 470. Western blotting demonstrated a truncated WAS protein. To our knowledge, this is the first report describing TTP in WAS patients with novel mutation in the WASP gene.