The impact of cyclooxygenase inhibitor use on urinary prostaglandin metabolites in preterm infants.

BACKGROUND: There is limited evidence on the association between the clinical course of patent ductus arteriosus (PDA) and prostaglandin (PG) metabolites. This study aimed to determine the influence of PDA treatment on urinary PG metabolite excretion in very-low-birth-weight (VLBW) infants. METHODS: Urine samples were collected from 25 VLBW infants at 1, 3, and 7 days of age. Infants were separated into two groups: a PDA-treated group that received a cyclooxygenase-2 (COX) inhibitor (n = 12) and a control group that did not receive a COX inhibitor during the first 7 days after birth (n = 13). Urinary PG metabolite tetranor prostaglandin E2 metabolite (t-PGEM) and tetranor prostaglandin D2 metabolite (t-PGDM) levels were analyzed using liquid chromatography-tandem mass spectrometry. RESULTS: Urinary t-PGEM excretion levels were not significantly different between the groups at 1, 3, and 7 days of age. Urinary t-PGDM excretion levels at 1 day of age were higher in PDA-treated infants than in control infants (median [interquartile range]: 5.5 [2.6, 12.2] versus 2.1 [1.0, 3.9] ng/mg creatinine; p = 0.017); however, among PDA-treated infants, the levels were significantly lower at 3 and 7 days than at 1 day of age (5.5 [2.6, 12.2] versus 3.4 [1.7, 4.5] and 4.0 [1.7, 5.3] ng/mg creatinine, respectively; p < 0.05). The urinary t-PGDM excretion level in the control group did not significantly differ among the time points. CONCLUSION: PDA and COX inhibitor administration affected PG metabolism in VLBW infants. Our results indicated that urinary t-PGDM excretion was significantly associated with PDA-treatment in preterm infants.

Use of Head and Chest Circumference Ratio as an Index of Fetal Growth Retardation in Preterm Infants.

We evaluated the relationship between fetal growth in preterm babies using the head circumference (HC)/chest circumference (CC) ratio and other anthropometric parameters at birth and at school age. Data were collected from 187 very low birth weight (VLBW) children born at less than 30 weeks of gestational age (GA) at birth and at 6 years. We assessed the correlation between the HC/CC ratio and body weight (BW), body length (BL), and HC z-scores at birth, and BW, body height (BH), and body mass index (BMI) z-scores at 6 years. Multiple regression analysis showed that BW z-score, BL z-score, and HC z-score at birth were significantly associated with HC/CC at birth. The BMI z-score at 6 years was also significantly associated with HC/CC at birth. The HC/CC ratio at birth is a reliable parameter for evaluating fetal growth restriction and a possible predictor of physical growth in VLBW children.

Growth Trajectories during the First 6 Years in Survivors Born at Less Than 25 Weeks of Gestation Compared with Those between 25 and 29 Weeks.

We aimed to determine the differences in the growth trajectories of the youngest gestational survivors (<25 weeks' gestation) up to 6 years of age compared to those of older gestational ages. Preterm infants were divided into two groups: 22−24 weeks' gestation (male (M) 16, female (F) 28) and 25−29 weeks' gestation (M 84, F 59). Z-scores of body weight (BW), body length (BL), and body mass index (BMI) were derived from Japanese standards at 1, 1.5, 3, and 6 years of corrected age. Comparisons between the two groups by sex were made using the Wilcoxon test and linear regression analysis to examine the longitudinal and time-point associations of anthropometric z-scores, the presence of small for gestational age (SGA), and the two gestational groups. BW, BL, BMI, and z-scores were significantly lower in the 22−24 weeks group at almost all assessment points. However, there were no significant differences in BW, BL, BMI, and z-scores between the two female groups after 3 years. BMI z-scores were significantly associated with the youngest gestational age and the presence of SGA at all ages in males, but not in females. The youngest gestational age had a greater influence in males on the z-score of anthropometric parameters up to 6 years of age.

Associations between size at birth and size at 6 years among preterm infants: a retrospective cohort study.

BACKGROUND: Little is known about the relationship between fetal growth and size at school age in children born prematurely. We evaluated the relationships between gestational age and anthropometric z-scores at birth and size at 6 years of age in very-low-birthweight infants born at <30 weeks' gestation. METHODS: We collected data from the medical records of 187 preterm children at birth and 6 years of age. We evaluated correlations between gestational age and z-scores for weight, body length, and head circumference at birth and z-scores for weight, height, and body mass index at 6 years of age. RESULTS: Simple regression analysis showed that, in boys and the overall group, gestational age and z-scores for weight, body length, and head circumference at birth had significant association with z-scores for weight, height, and body mass index at 6 years of age. No significant associations were found in girls, except for weight z-scores at 6 years with gestational age and head circumference z-scores at birth. Multiple regression analysis showed that gestational age and length z-score at birth were significantly and independently associated with weight and height z-score at 6 years. Gestational age was also significantly and independently associated with body mass index z-score at 6 years. CONCLUSION: Gestational age and fetal growth in length (assessed with the birth-length z-score) were associated with anthropometric z-scores at 6 years in very-low-birthweight children born at <30 weeks of gestation, especially in boys.

Analysis of Factors Associated With Body Mass Index at Ages 18 and 36 Months Among Infants Born Extremely Preterm.

Importance: The development of neonatology has been associated with improved survival among infants born extremely preterm, and understanding their long-term outcomes is becoming increasingly important. However, there is little information on body mass index (BMI) among these children. Objective: To determine factors associated with BMI at ages 18 months and 36 months among infants born extremely preterm. Design, Setting, and Participants: This retrospective, multicenter cohort study was conducted using data from the Neonatal Research Network Japan database for 8838 infants born at gestational ages 23 to 28 weeks with data on BMI at 18 months and 36 months. Data were analyzed from April 2018 through June 2021. Exposures: BMI and BMI z score at ages 18 months and 36 months were regressed with gestational age, intrauterine growth restriction (IUGR) status, and complications during pregnancy and the neonatal period separately by presence of multiple pregnancy and sex. Main Outcomes and Measures: BMI and BMI z score at ages 18 months and 36 months. Results: Among 16 791 eligible infants born extremely preterm, 8838 infants were included in the analysis. There were 7089 infants born from single pregnancies (mean [SD] gestational age, 26.0 [1.6] weeks; 3769 [53.2%] boys; mean [SD] birth weight, 847 [228] g) and 1749 infants born from multiple pregnancies (mean [SD] gestational age, 26.3 [1.5] weeks; 903 [51.6%] boys; mean [SD] birth weight, 860 [217] g). In single pregnancies, every week of increased gestational age was associated with an increase in BMI of 0.21 (95% CI, 0.17-0.25) among boys and 0.20 (95% CI, 0.15-0.25) among girls at age 18 months and 0.21 (95% CI, 0.18-0.24) among boys and 0.21 (95% CI, 0.18-0.24) among girls at age 36 months. There was an interaction association between gestational age and IUGR among boys at age 36 months, with a decrease in the change associated with gestational age of 0.12 (95% CI, 0.05-0.19). Every week of increased gestational age in single pregnancies was associated with an increase in BMI z score of 0.14 (95% CI, 0.17-0.21) among boys and 0.17 (95% CI, 0.13-0.21) among girls at age 18 months and 0.19 (95% CI, 0.16-0.22) among boys and 0.17 (95% CI, 0.15-0.20) among girls at age 36 months. Among single pregnancies, IUGR was associated with a decrease in BMI among boys (0.59 [95% CI, 0.23-0.95]) and girls (0.75 [95% CI, 0.39-1.11]) and BMI z score among boys 0.85 [95% CI, 0.25-0.95)] and girls (0.67 [95% CI, 0.36-0.97] at age 18 months and BMI among boys (0.44 [95% CI, 0.17-0.18]) and girls (0.84 [95% CI, 0.55-1.12]) and BMI z score among boys (0.46 [95% CI, 0.21-0.71]) and girls (0.77 [95% CI, 0.53-1.01]) at age 36 months. In multiple pregnancies, IUGR was associated with a decrease in BMI z score at age 36 months among boys (0.26 [95% CI, 0.42-0.89]) and girls (0.29 [95% CI, 0.22-0.79]). In single pregnancies intraventricular hemorrhage (IVH) was associated with a decrease in BMI of 0.47 (95% CI, 0.21-0.73) among boys and 0.42 (95% CI, 0.13-0.71) among girls at age 18 months and 0.53 (95% CI, 0.32-0.74) among boys and 0.31 (95% CI, 0.07-0.54) among girls at age 36 months. IVH was associated with a decrease in BMI z score in single pregnancies of 0.63 (95% CI, 0.20-0.41) among boys and 0.35 (95% CI, 0.12-0.60) among girls at age 18 months and 0.53 (95% CI, 0.34-0.71) among boys and 0.30 (95% CI, 0.11-0.50) among girls at age 36 months. Similar associations were seen in multiple pregnancies. Conclusions and Relevance: This study found that gestational age, the presence of IUGR and multiple pregnancy, and IVH complications were associated with infant BMI at ages 18 months and 36 months. These findings suggest that these complicating factors should be considered when setting growth targets and nutrition strategies for infants born extremely preterm.

IGF1 gene is epigenetically activated in preterm infants with intrauterine growth restriction.

BACKGROUND: IGF1 is a key molecule in the regulation of growth and metabolism. Low IGF1 secretion is known to cause growth restriction in childhood, as well as deregulated lipid metabolism, cardiovascular disease, and diabetes in adulthood. The IGF1 gene P2 promoter is highly methylated, resulting in low secretion of IGF1 in small infants and children. However, it is unknown when this methylation occurs. The aim of study was to clarify the point when this epigenetic program occurs during intrauterine development. We analyzed 56 preterm infants born before 32 weeks of gestation, including 19 intrauterine growth restriction (IUGR) infants whose birth weights were lower than - 2SD calculated by the Japanese datasets. We extracted genomic DNA from whole blood at birth; methylation of the six CpG sites in the IGF1 P2 promoter was analyzed by the bisulfite amplicon method using the MiSeq platform. RESULTS: In contrast to term infants and children, the methylation of all six CpG sites positively correlated with body weight and body length at birth. IGF1 P2 promoter methylation levels were significantly reduced in all six CpG sites in infants with IUGR. CONCLUSIONS: These findings indicated that the IGF1 gene is epigenetically activated before 32 weeks of gestation in infants with IUGR and that the activated gene may become suppressed after this time point. This study may provide new insights to prevent the onset of adult diseases and to aid in nutritional management for preterm birth infants in neonatal intensive care units.

Intrauterine growth restriction affects z-scores of anthropometric parameters during the first 6 years in very low-birth-weight-children born at less than 30 weeks of gestation.

OBJECTIVE: Little is known about physical constitution outcomes for very preterm infants. Here, we compare z-scores of anthropometric parameters up to 6 years of age in children born with very low birth weight (VLBW) at less than 30 weeks of gestation, with or without intrauterine growth restriction (IUGR). DESIGN: Participants were divided into four subgroups: male (M), small for gestational age (SGA) (n = 30); M, appropriate for gestational age (AGA) (n = 59); female (F), SGA (n = 24); and F, AGA (n = 61). z-Scores of body weight (BW), body length (BL), and body mass index (BMI) were assessed at birth, 1 year corrected age, 3 years of age, and 6 years of age. RESULTS: For boys, BW and BMI were significantly lower among SGA children than among AGA children at all assessments, but there was no difference in BL at 3 or 6 years. For girls, BW and BL were significantly lower among SGA children than among AGA children at all assessments, but no difference was detected in BMI after 1.5 years. No significant variation in the z-score of BW or BMI in either SGA group was observed after 1 year. BL z-score in all groups gradually increased until 6 years of age. CONCLUSION: IUGR affects BW and BMI in boys and BW and BL in girls during the first 6 years in VLBW children born at less than 30 weeks of gestation. SGA children did not catch up in BW or BMI from 1 to 6 years of age.

Association between the frequency of bedwetting and late preterm birth in children aged ≥5 years.

AIM: We examined the associations between late preterm (LPT) birth children aged ≥5 years and the frequency of bedwetting. Moreover, those who were born full-term/low birthweight (BW), LPT/low BW, LPT/normal BW and LPT/low BW were compared. METHODS: In total, we evaluated 614 patients who underwent assessments for frequent bedwetting at the three hospitals from January 2014 to December 2016. Data at the initial visit were collected from the electronic medical records. We assessed the patients' bladder diaries and questionnaires containing detailed information on demographics and frequency of bedwetting per month. Neonatal data were collected from the Maternal and Child Health Handbook. RESULTS: Frequency of bedwetting in the LPT/low BW group was higher than in the term/low BW group (28 vs. 22.5, p < 0.05). However, the frequency between the LPT/normal BW group and the LPT/low BW group was not significantly different (28 vs. 28, p = 1.00). Multiple regression analyses were conducted to eliminate potential confounding factors, attention-deficit/hyperactivity disorder and intellectual disability, but results were not changed. CONCLUSION: This study revealed that LPT/low BW was associated with increased frequency of bedwetting in children. The results suggest that gestational age should be considered when examining patients with severe bedwetting.

Postnatal relative adrenal insufficiency results in methylation of the glucocorticoid receptor gene in preterm infants: a retrospective cohort study.

Background: To investigate the relationship between early-life stress and glucocorticoid receptor (GR) gene methylation, which may result in long-lasting neurodevelopmental impairment, we performed a longitudinal analysis of the methylation ratio within the GR gene promoter 1F region using next-generation sequencing in preterm infants.Cell-free DNA was extracted from the frozen serum of 19 preterm birth infants at birth and at 1 and 2 months after birth. All were admitted to the neonatal intensive care unit of Juntendo University Shizuoka Hospital between August 2014 and May 2016 and suffered from chronic lung disease (CLD).Through bisulfite amplicon sequencing using an Illumina Miseq system and Bismark-0.15.0 software, we identified the rate of cytosine methylation. Results: Patients' sex and body weight standard deviation were extracted as the associated independent variables at birth. Sex, glucocorticoid administration for treating CLD, and postnatal invasive procedures (surgical operation and blood sampling) were extracted as the associated independent variables at 1 month. Methylation rates increased significantly between postnatal 1 and 2 months at 9 of the 39 CpG sites. Postnatal glucocorticoid administration to treat circulatory collapse was the most-associated independent variable with a positive regression coefficient for a change in methylation rate at these nine CpG sites. It also influenced the methylation ratio at 22 of the 39 CpG sites at 2 months of age. The standard deviation (SD) score at birth was extracted as an independent variable, with a negative regression coefficient at 9 of the 22 CpG sites together with glucocorticoid administration. Conclusions: The results of this study indicate that a prenatal environment that results in intrauterine growth restriction and postnatal relative adrenal insufficiency requiring glucocorticoid administration leads to GR gene methylation. That, in turn, may result in neurodevelopmental disabilities.

Correlations between feeding type and blood ionized magnesium levels in Japanese preterm infants.

Although magnesium (Mg) contents are different between breast milk and formula, few studies have investigated the blood Mg level in breast fed or formula fed preterm infants. We examined the influence of feeding type on serum Mg and whole blood ionized Mg (iMg) levels in preterm infants soon after birth. We included 115 preterm infants born between gestational weeks 32 and 35. Infants were separated into two groups: breast milk (BM) dominant group (n = 30) receiving ≥70% of Mg intake from BM and mixed-fed (MF) group (n = 85) receiving ≥30% of Mg intake from formula. Blood levels of Mg, iMg, Ca, and iCa at day 1 of age and at discharge from the hospital were compared between the groups. No differences in the Mg and iMg levels at day 1 of age were observed between the two groups. The Mg and iMg levels at discharge were significantly lower (P < 0.05) in the BM group than in the MF group; 0.86 (interquartile range 0.81-0.91) versus 0.91 (0.86-0.99) mmol/L and 0.46 (0.41-0.51) versus 0.52 (0.47-0.57) mmol/L, respectively. There were no differences in the Ca and iCa levels between the two groups. By stepwise multiple regression analysis, the percentage of BM intake was a significant independent predictor of the Mg and iMg levels. The feeding type influenced serum Mg and blood iMg levels in preterm infants soon after birth. Further studies are needed to investigate the influence of Mg on growth and the optimal range of blood Mg levels.

Transplantation of allogeneic adipose-derived mesenchymal stem cells in a cerebral palsy patient (Retracted).

This article was retracted on 25/08/2017.

Effect of PMX-DHP for sepsis due to ESBL-producing E. coli in an extremely low-birthweight infant.

We report a case of early onset sepsis caused by (CTX for cefotaximase and M for Munich)-type extended-spectrum ß-lactamase-producing Escherichia coli (ESBL E. coli) in a preterm infant weighing 601 g. He was given meropenem and treated for endotoxin absorption with polymyxin B-immobilized fibers with only 8 mL of priming volume. The patient survived without any short-term neurological or respiratory sequelae. The choice of antibiotics is particularly important in seriously ill neonates with sepsis due to ESBL-producing organisms. Polymyxin B hemoperfusion might be an innovative therapy for severe neonatal sepsis and could improve outcome even in an extremely low-birthweight infant.

Effect of insulin-like growth factor-I during the early postnatal period in intrauterine growth-restricted rats.

BACKGROUND: Insulin-like growth factor-I (IGF-I) is essential for perinatal growth and development; low serum IGF-I has been observed during intrauterine growth restriction (IUGR). We investigated the effects of recombinant human (rh) IGF-I in IUGR rats during the early postnatal period. METHODS: Intrauterine growth restriction was induced by bilateral uterine artery ligation in pregnant rats. IUGR pups were divided into two groups injected daily with rhIGF-I (2 mg/kg; IUGR/IGF-I, n = 16) or saline (IUGR/physiologic saline solution (PSS), n = 16) from postnatal day (PND) 7 to 13. Maternal sham-operated pups injected with saline were used as controls (control, n = 16). Serum IGF-I and IGF binding proteins (IGFBP) 3 and 5 were measured on PND25. The expression of Igf-i, IGF-I receptor (Igf-ir), Igfbp3, and 5 mRNA in the liver and brain was measured using real-time polymerase chain reaction on PND25. Immunohistochemical staining of the liver for IGF expression was performed. RESULTS: Mean bodyweight on PND3 and PND25 in the IUGR pups (IUGR/IGF-I and IUGR/PSS) was significantly lower than that of the control pups. Serum IGF-I and hepatic Igf-ir mRNA in the IUGR pups were significantly lower than those in the control pups. In the IUGR/IGF-I group, hepatic Igfbp3 mRNA and liver immunohistochemical staining were increased. In the IUGR/PSS and control pups, there were no significant differences between these two groups in serum IGFBP3 and IGFBP5, hepatic Igf-i and Igfbp-5 mRNA, or brain Igf mRNA. CONCLUSIONS: No benefits on body and brain weight gain but an effective increase in hepatic IGFBP-3 was observed after treatment with 2 mg/kg rhIGF-I during the early postnatal period.

A case of congenital diaphragmatic hernia with intradiaphragmatic pulmonary sequestration: case report and literature review.

Extralobar pulmonary sequestration (EPS) can occasionally be found incidentally in congenital diaphragmatic hernia (CDH). Extralobar pulmonary sequestration usually arises in the chest or the abdomen; rarely in the diaphragm. We report a neonatal case of antenatally diagnosed CDH associated with intradiaphragmatic EPS.

Postnatal epigenetic modification of glucocorticoid receptor gene in preterm infants: a prospective cohort study.

OBJECTIVE: To examine the environmental effects on cytosine methylation of preterm infant's DNA, because early life experiences are considered to influence the physiological and mental health of an individual through epigenetic modification of DNA. DESIGN: A prospective cohort study, comparison of epigenetic differences in the glucocorticoid receptor (GR) gene between healthy term and preterm infants. SETTING: Neonatal Intensive Care Unit in a Japanese University Hospital. PARTICIPANTS: A cohort of 40 (20 term and 20 preterm) infants was recruited on the day of birth, and peripheral blood was obtained from each infant at birth and on postnatal day 4. MAIN OUTCOME MEASURES: The methylation rates in the 1-F promoter region of the GR gene using the Mquant method. RESULTS: The methylation rate increased significantly between postnatal days 0 and 4 in preterm infants but remained stable in term infants. Thus, the methylation rate was significantly higher in preterm than in term infants at postnatal day 4. Several perinatal parameters were significantly correlated with this change in the methylation rate. Logistic regression analysis revealed that methylation rates at postnatal day 4 predicted the occurrence of later complications that required glucocorticoid administration during the neonatal period. No gene polymorphism was detected within the GR promoter region analysed. CONCLUSIONS: Although further large-scale studies are needed to detect the environmental factors that explain the difference in epigenetic modification among infants after birth, our data show that the postnatal environment influences epigenetic programming of GR expression through methylation of the GR gene promoter in premature infants, which may result in relative glucocorticoid insufficiency during the postnatal period.

[Blood, urine and CSF analysis].

This is an interpretative article concerning about the biomarkers of patients with acute encephalitis and acute encephalopathy. Firstly, examinations from blood and/or CSF specimens for the diagnosis of patients with encephalitis are considered using two guidelines. One is the guidelines for the management of encephalitis prepared by an Expert Panel of the Infectious Disease Society of America (IDSA). The other is those prepared by the European Federation of Neurological Societies (EFNS). CSF PCR is most useful to detect the pathogen (usually virus) of acute encephalitis. Secondly, a brief outline of acute encephalopathy associated with viral infections from the standpoint of examination is given. Finally, biomarkers of brain injury are considered through a systematic review in term neonatal encephalopathy.