Metabolomic profiles of preterm small-for-gestational age infants.

We aimed to characterize the metabolomic profiles in preterm small-for-gestational age (SGA) infants using cord blood. We conducted a gestational age (GA)-matched case-control study that included 30 preterm infants who were categorized into two groups: SGA infants, with a birth weight (BW) < 10th percentile for GA (n = 15) and non-SGA infants, with BW ≥ 10th percentile for GA (n = 15). SGA infants with chromosomal or genetic abnormalities were excluded. At birth, the umbilicus was double-clamped, and the cord blood was sampled from the umbilical vein. Metabolomic analyses were performed using capillary electrophoresis time-of-flight mass spectrometry. The median GA at birth was not significantly different between the two groups [SGA, 32 (26-36) weeks; non-SGA, 32 (25-35) weeks; p = 0.661)]. Of the 255 metabolites analyzed, 19 (7.5%) showed significant differences between SGA and non-SGA infants. There were significant reductions in the carnosine, hypotaurine, and S-methylcysteine levels in SGA infants as compared to non-SGA infants (p < 0.05). Carnosine was correlated with gestational age, BMI before pregnancy, body weight gain during pregnancy (p = 0.002, p = 0.023, and p = 0.020, respectively). In conclusion, preterm SGA infants have low levels of cord blood antioxidative- and antiglycation-related metabolites, making them vulnerable to oxidative stress.

Procalcitonin-Based Antibiotic Use for Neonatal Early-Onset Bacterial Infections: Pre- and Post-Intervention Clinical Study.

We previously reported the 95th percentile cutoff value of the serum procalcitonin (PCT) reference curve for diagnosing early-onset bacterial infection. We aimed to verify the effectivity of these novel diagnostic criteria by comparing antibiotic use and incidence of early-onset bacterial infection between pre- and post-introduction periods. We included newborns admitted to our neonatal intensive care unit who underwent blood tests within 72 h after birth between 2018 and 2022. The neonates were divided into the pre-intervention (admitted before the introduction, n = 737) or post-intervention (admitted after the introduction, n = 686) group. The days of antibiotics therapy (DOT) per 1000 patient days up to 6 days after birth, percentage of antibiotic use, and incidence of early-onset bacterial infection were compared between the groups. The post-intervention group had significantly lower DOT per 1000 patient days (82.0 days vs. 211.3 days, p < 0.01) and percentage of newborns receiving antibiotics compared with the pre-intervention group (79 (12%) vs. 280 (38%), respectively, p < 0.01). The incidence of early-onset bacterial infections did not differ between the groups (2% each, p = 0.99). In conclusion, our diagnostic criteria using the 95th percentile cutoff value of the serum PCT reference curve for early-onset bacterial infection were proven safe and effective, promoting appropriate use of antibiotics.

Body Fat-Reducing Effects of Whey Protein Diet in Male Mice.

This study investigated the mechanism of reducing body fat via whey protein diet. Pregnant mice were fed whey or casein, and their offspring were fed by birth mothers. After weaning at 4 weeks, male pups received the diets administered to their birth mothers (n = 6 per group). At 12 weeks of age, body weight, fat mass, fasting blood glucose (FBG), insulin (IRI), homeostatic model assessment of insulin resistance (HOMA-IR), cholesterol (Cho), triglyceride (TG), the expression levels of lipid metabolism-related genes in liver tissues and metabolomic data of fat tissues were measured and compared between the groups. The birth weights of pups born were similar in the two groups. Compared to the pups in the casein group, at 12 weeks of age, pups in the whey group weighed less, had significantly lower fat mass, HOMA-IR and TG levels (p < 0.01, p = 0.02, p = 0.01, respectively), and significantly higher levels of the antioxidant glutathione and the anti-inflammatory 1-methylnicotinamide in fat tissues (p < 0.01, p = 0.04, respectively). No differences were observed in FBG, IRI, Cho levels (p = 0.75, p = 0.07, p = 0.63, respectively) and expression levels of lipid metabolism-related genes. Whey protein has more antioxidant and anti-inflammatory properties than casein protein, which may be its mechanism for reducing body fat.

Usefulness of Thin-Slice Contrast-Enhanced Computed Tomography in Detecting Perforation Site in Congenital Biliary Dilatation: A Case Report.

The site of perforation is difficult to identify preoperatively in many cases with spontaneous perforation of congenital biliary dilatation (CBD). We report a case of spontaneous perforation of CBD in which the perforation site was identified preoperatively using thin-slice contrast-enhanced computed tomography (CT). The patient was a girl aged 1 year and 4 months. She was admitted to our hospital because of vomiting and diarrhea that had continued for 3 days prior to admission. Abdominal contrast CT on admission showed dilated common bile duct, thickening of the gall bladder wall, and marked ascites. In addition, an area of low density with a diameter of 1 cm was detected near the neck of the gallbladder. We evaluated the area via thin-slice contrast-enhanced CT and detected a defect in the wall of the bile duct. Cholangiography revealed abnormal confluence of the pancreaticobiliary duct and a protein plug in the common duct. A diagnosis of CBD with perforation of the bile duct was made, and surgery was performed. The intraoperative findings matched that seen on the enhanced CT. There are some reports of pseudocysts and fluid retention around the perforation site; however, no reports are found in which the perforation site was confirmed by preoperative CT. If localized fluid retention is observed in cases with biliary perforation, confirmation with thin-slice contrast-enhanced CT might be useful for identifying the perforation site.

Association of umbilical cord insulin-like growth factor 1 levels with severe retinopathy in extremely preterm infants.

BACKGROUND: The association between umbilical cord blood insulin-like growth factor 1 (IGF-1) levels and retinopathy of prematurity (ROP) remains unclear. This study aimed to investigate whether umbilical cord blood IGF-1 levels can predict the development of severe ROP in extremely preterm infants. METHODS: This hospital-based retrospective cohort study included infants born at <37 weeks gestational age (GA) between 2019 and 2021 and then classified them into the two GA groups: extremely preterm, <28 weeks and preterm infants, 28-36 weeks. Extremely preterm infants were further subclassified into two groups according to the laser treatment as follows: the severe ROP (ROP-Tx) and ROP (No ROP-Tx) groups. Median umbilical cord blood IGF-1 values were compared between the groups. Perinatal risk factors were identified by univariate and multivariate analyses. Finally, umbilical cord IGF-1 cut-off values requiring ROP treatment with laser were determined by receiver operating characteristic (ROC) curve analyses. RESULTS: A total of 205 infants were enrolled, with 32 being extremely preterm (ROP-Tx: n = 11; No ROP-Tx: n = 21) and 173 being preterm. IGF-1 levels were significantly lower in extremely preterm (13.5 ng/mL) than preterm infants (36 ng/mL, p < 0.001). In extremely preterm infants, IGF-1 levels were significantly lower in the ROP-Tx group than the No ROP-Tx group (10 vs. 19 ng/mL, respectively, p = 0.024). Only GA, umbilical cord blood IGF-1 levels, birth head circumference, and birth chest circumference were identified as risk factors by univariate analysis (p < 0.05). Multivariate analysis showed that only umbilical cord blood IGF-1 was an independent risk factor (odds ratio: 1.26, p = 0.021). ROC curves revealed an IGF-1 cut-off value of 14 ng/mL. CONCLUSION: The need of laser treatment for ROP was found to be associated with low umbilical cord blood IGF-1 levels in extremely preterm infants. Umbilical cord blood IGF-1 can be used as a biomarker for the risk of developing severe ROP.

Correction: Go et al. Diagnostic Accuracy of Biomarkers for Early-Onset Neonatal Bacterial Infections: Evaluation of Serum Procalcitonin Reference Curves. Diagnostics 2020, 10, 839.

In the original publication [...].

Association of Plasma Cortisol Levels with Gestational Age and Anthropometric Values at Birth in Preterm Infants.

There are no study reports to clarify the association between gestational age (GA) or anthropometric values at birth, and plasma cortisol levels in the blood of preterm infants at birth and at one month of age. This hospital-based retrospective cohort study included infants born at <37 weeks' gestation between 2019 and 2021. First, the association between plasma cortisol level and GA or anthropometric values at birth (birth weight standard deviation score [SDS], birth length SDS, and birth head circumference SDS) was identified by regression and multiple regression analyses. Second, plasma cortisol levels in the umbilical cord at birth and at one month of age were compared between small-for-gestational age (SGA) and non-SGA infants. Sixty-one preterm infants were enrolled (SGA: 24 and non-SGA: 37). Plasma cortisol levels at birth were significantly associated with GA. Plasma cortisol levels at one month of age were associated with GA and birth head circumference SDS. Plasma cortisol levels at birth were significantly higher in SGA than non-SGA (p = 0.010). GA was an independent determinant of plasma cortisol levels at birth. SGA infants had a high plasma cortisol level at birth; resulting in speculation that a high plasma cortisol level at birth may predict abnormal neurological outcomes.

A Non-Obese Hyperglycemic Mouse Model that Develops after Birth with Low Birthweight.

The number of low birthweight (LBW) infants weighing below 2500 g has not decreased in Japan. This study aimed to develop an adult non-obese hyperglycemic mouse model born with LBW to study the pathogenesis. At 16.5 days of gestation, transient intrauterine ischemia (blocked blood flow in both uterine arteries for 15 min) was performed in a subgroup of pregnant mice (group I). Non-occluded dams were used as sham controls (group C). After birth, female pups in each group were weaned at 4 weeks of age and reared on the normal diet until 8 weeks of age (n = 7). Fasting blood glucose levels, serum immunoreactive insulin (IRI), and body composition were then measured. Metabolite analyses was performed on the liver tissues. Birthweight was significantly lower in group I compared with group C. Pups from group I remained underweight with low fat-free mass and showed hyperglycemia with high serum IRI and homeostasis model assessment of insulin resistance levels, indicating insulin resistance. Metabolite analyses showed significantly reduced adenosine triphosphate and nicotinamide adenine dinucleotide production and increased lactic acid in group I. The pathogenesis of our non-obese hyperglycemic mouse model may be due to increased myogenic insulin resistance based on mitochondrial dysfunction and reduced lean body mass.

Percentile-Based Reference Values of Umbilical Cord Blood Insulin-like Growth Factor 1 in Japanese Newborns.

We aimed to create percentile-based reference values of the umbilical cord blood insulin-like growth factor-1 (IGF-1) levels in Japanese newborns, as these values have not yet been established. A total of 259 newborns were classified into four gestational-age-at-birth (GA) groups: extremely preterm (<28 weeks); early preterm (28−33 weeks); late preterm (34−36 weeks); and term (≥37 weeks). They were further subclassified as small-for-gestational-age (SGA) or non-SGA. The 10th, 25th, 50th, 75th, and 90th percentiles of the umbilical cord blood IGF-1 levels were calculated and compared between the groups by using reference values of 9, 18, 33, 52, and 71 ng/mL, respectively. In the extremely preterm group, the IGF-1 levels were significantly lower than those in the early preterm, late preterm, and term groups (13.5, 24.0, 44.5, and 47.5 ng/mL, respectively; p < 0.001). The umbilical cord blood IGF-1 levels in the SGA newborns were significantly lower than those in the non-SGA newborns in all subgroups. In multivariate analyses, the GA and birth weight standard deviation scores were independent determinant factors for the umbilical cord blood IGF-1 levels. Thus, we established percentile-based reference values of umbilical cord blood IGF-1 in Japanese newborns; these reference values can be applied on the basis of the extent of prematurity and the SGA status.

Adrenal cytomegaly with elevated serum androgen levels in a patient with Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is infrequently associated with adrenocortical carcinoma (ACC) or non-hormone-producing adrenal cytomegaly, but we recently, encountered a single case of adrenal cytomegaly in a patient with BWS, which was difficult to distinguish from androgen-producing adrenocortical carcinoma (ACC). Here, we describe the case of a 4-month-old female who presented with clitoromegaly, hemihypertrophy, and an adrenal mass identified during the prenatal period. The mass was located in detected at the left suprarenal region and detected at 20 weeks of gestational age. At birth, she also presented with clitoromegaly and elevated serum levels of 17α-hydroxyprogesterone, dehydroepiandrosterone, and testosterone at birth and experienced hyper-insulinemic hypoglycemia, which improved following diazoxide therapy. We initially suspected androgen-producing ACC with metastasis and the left adrenal mass was resected accordingly when the patient reached 4 months of age. However, histological examination revealed adrenal cytomegaly. Genetic analysis revealed paternal uniparental disomy, and the patient was finally diagnosed as having BWS. Resection of the left adrenal gland restored the serum androgen levels to normal physiological levels without any recurrence. While it is reasonably well known that BWS is sometimes accompanied by virilization due to androgen-producing ACC, our findings are among the first to suggest that adrenal cytomegaly can also increase androgen hormone production. Thus, we propose that adrenal cytomegaly should be considered one of the differential diagnoses when accompanied with hyperandrogenism in BWS patients.

Parenchymal calcification is associated with the neurological prognosis in patients with congenital rubella syndrome.

Congenital rubella syndrome (CRS) results from maternal rubella virus infection in early pregnancy. Abnormal neuroimaging findings have been analyzed in a small number of CRS patients in the past; however, their clinical significance has been poorly addressed. Therefore, we have investigated the neuroimaging findings of 31 patients with CRS from previous studies. The most common finding was parenchymal calcification, which was observed in 18 of 31 patients (58.1%). A multivariable logistic regression model showed that it was associated with psychomotor or mental retardation (p = 0.018), suggesting that parenchymal calcification in CRS could be a prognostic factor.

Clinical Evaluation of a Novel Urine Collection Kit Using Filter Paper in Neonates: An Observational Study.

Urine bags are commonly used to collect urine samples from neonates. However, the sample can be contaminated by stool, or detachment of the bag due to body movement can lead to failure of the collection. A qualitative urine collection kit containing ten filter papers of 3.2 mm diameter was developed and clinically verified among 138 neonates. During a single diaper change (approximately 3 h), the rate of urine collection was calculated. Urine collection was considered to be successful if any filter paper in the urine collection sheet turned from blue to white. Of the 127 neonates who passed urine, 122 had a change in the filter paper. The urine collection rate was 96%, with changes in all 10 filter papers observed in 98 neonates (80%). Urine collection rate was not influenced by sex (p = 1.00), age at collection (p = 0.72), preterm birth (p = 1.00), low birth weight (p = 0.92), or fecal contamination (p = 1.00). The incidence of dermatitis was not higher than in the group in which urine bags were used (urine collection kit: 2/68 [3%]; urine bag: 5/68 [7%]; p = 0.44). Novel urine collection kits using filter paper can collect samples from neonates safely and with a high probability of success.

Unique and abnormal subependymal pseudocysts in a newborn with mitochondrial disease.

Neonatal mitochondrial disease is occasionally observed in patients with intraventricular cysts in the brain. Atypical morphology is rarely seen in these cysts. Here, we report a case of neonatal lethal mitochondrial disease with IBA57 gene mutation. We have, for the first time, described a subependymal pseudocyst (SEPC) with a fluctuating membrane. Our findings suggest that SEPCs with fluctuating membranes can be a potential diagnostic indicator of neonatal mitochondrial disease.

Novel Physique Index for the Screening of Skeletal Dysplasia at Birth.

This study aimed to devise a novel physique index and investigate its accuracy in identifying newborns with skeletal dysplasia in comparison with head circumference (HC)/height (HT) ratio. The birth weight (W), HT, and HC at birth of 1500 newborns were retrospectively collected. The linear regression equations and coefficients of determination (R2) were determined. The formulated equation was corrected by the mean weight for gestational age at birth (Wcorr) as a novel physique index for screening skeletal dysplasia. The index accuracy was assessed using receiver operating characteristic (ROC) curves in 11 newborns by fetal ultrasound and compared with that of the HC/HT ratio. The R2 values between W and HT, (HT)2, and (HT) 3 were 0.978, 0.990, and 0.993, respectively. Those between W and HC, (HC)2, and (HC)3 were 0.974, 0.984, and 0.988, respectively. W/Wcorr × (HC/HT)3 was used as a novel physique index. Seven newborns had skeletal dysplasia. Our novel physique index had a higher area under the curve (AUC), sensitivity, and specificity than the HC/HT ratio (AUC: 1.00 vs. 0.86, sensitivity: 1.00 vs. 0.86, and specificity: 1.00 vs. 0.75, respectively). Our novel physique index was more accurate than HC/HT ratio and has the potential to accurately identify newborns with skeletal dysplasia.

Successful Treatment of Hyperbilirubinemia by Monitoring Serum Unbound Bilirubin in an Extremely Preterm Infant with Bacterial Infection.

BACKGROUND: Bacterial infections and some antibiotics show displacer effects on bilirubin-albumin binding and increase unbound bilirubin (UB) but not total bilirubin (TB) in serum. METHODS: A case study was conducted to show a successful treatment of hyperbilirubinemia by monitoring UB. RESULTS: In an extremely preterm infant with bloodstream bacterial infection caused by methicillin-resistant coagulase-negative staphylococci, 2 days after high-dose ampicillin and regular-dose amikacin were initiated, UB markedly increased, but TB did not. After vancomycin was substituted, UB decreased immediately with phototherapy and intravenous albumin infusion. CONCLUSIONS: When using antibiotics, the clinicians should be mindful regarding the displacer effect on bilirubin-albumin binding.

Diagnostic Accuracy of Biomarkers for Early-Onset Neonatal Bacterial Infections: Evaluation of Serum Procalcitonin Reference Curves.

To date, no clinical studies have compared the accuracy of serum procalcitonin (PCT) reference curves. We aimed to validate the diagnostic accuracy of previously reported serum PCT reference curves and to determine which biomarkers among a cut-off value over the 95th percentile in the serum PCT reference curve, white blood cell (WBC) count, and C-reactive protein (CRP) and immunoglobulin M (IgM) levels, have the highest diagnostic accuracy for early-onset neonatal bacterial infections. This retrospective cohort study assessed 16 preterm and 23 term infants with suspected bacterial infections within 72 h after birth. Each infant group was divided into two subgroups: confirmed- and non-infection. The diagnostic accuracy was determined using the Youden index. The reference curves by Fukuzumi et al. in preterm and term infants had the highest Youden indexes: 1.000 and 0.324, respectively. Among preterm infants, the Youden index for PCT was 1.000. Among term infants, the Youden index for a combination of PCT, CRP, and WBC and/or IgM was 1.000. In conclusion, a serum PCT level over the 95th percentile on the reference curve for preterm infants and a combination of PCT and CRP levels with WBC count and/or IgM levels for term infants provided sufficient diagnostic accuracy.

Heart-rate evaluation using fetal ultrasonic Doppler during neonatal resuscitation.

BACKGROUND: The objective of the present study was to verify the speed and accuracy of fetal ultrasonic Doppler (fetal Doppler) in measuring heart rate of newborns at rest, including preterm, low-birthweight infants, and its efficacy during neonatal resuscitation, including cases of neonatal asphyxia. METHODS: A three-lead electrocardiogram and fetal Doppler were used to measure resting heart rates in 100 newborns, including 48 preterm, low-birthweight infants, at 0 to 72 h after birth. Times to display heart rate were compared between electrocardiogram and fetal Doppler by the Bland-Altman analysis and Wilcoxon signed-rank test. The time required for the fetal Doppler to measure heart rate during neonatal resuscitation was also assessed. RESULTS: In 100 newborns, the mean error of the resting heart rate in 1,293 measurement points was 0.07 beats/min. To display the heart rate, the fetal Doppler required a median time of 5 s, and electrocardiogram required a median time of 10 s (P < 0.001). During neonatal resuscitation, the heart rate was measured within 10 s in 18 of 21 cases (86%) and displayed with a median time of 5 s; this was measured in all neonatal asphyxia cases (9/9, 100%). CONCLUSIONS: Fetal Doppler can measure heart rate in newborns accurately and rapidly and is useful for evaluating heart rate not only at rest but also during neonatal resuscitation, especially in asphyxia.