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.

Clinical factors associated with extended hospitalization in pediatric patients ≥3 years of age with respiratory syncytial virus or human metapneumovirus infection: A Japanese single-center, retrospective study.

Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) infections are common in children worldwide. However, the clinical factors related to extended hospitalization in Japanese patients aged ≥3 years remain elusive. We aimed to elucidate the clinical risk factors contributing to hospital stays ≥7 days in patients with RSV and hMPV infections. Patients ≥3 years of age who were hospitalized due to RSV or hMPV infection between 2014 to 2020 were included. Twenty-one RSV- and 27 hMPV-infected patients were enrolled. Patients were divided into 2 groups: hospitalization for ≥ and <7 days. Univariate and multivariate analyses determined the clinical risk factors contributing to hospital stay ≥7 days. The RSV- and hMPV-infected patients had similar clinical characteristics. The clinical risk factors contributing to extended hospitalization were analyzed in the 48 infected patients of the 2 groups. The presence of prophylactic antibiotics usage, co-bacterial colonization, and underlying diseases were extracted by univariate analysis (P < .05). In multivariate analysis, underlying diseases were determined as an independent clinical risk factor (odds ratio 8.09, P = .005). Underlying diseases contributed to extended hospitalization in RSV- or hMPV-infected patients ≥3 years of age.

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.

The gaze characteristics in preterm children: The appropriate timing for an eye-tracking tool.

BACKGROUND: An objective screening tool for autism spectrum disorder (ASD), also known as an eye-tracking tool, assesses the patient's abnormal gaze patterns and detects the risk of ASD. As this tool is generally used for children born at term, this study aimed to clarify the appropriate timing for using the tool for preterm children, factors that influence the timing, and evaluate their gaze characteristics using the Gazefinder®. METHOD: In 90 preterm children, a total of 125 eye-tracking tasks were completed and analyzed in 3-6, 7-9, 10-12, 13-18, and 19-32 months of corrected age (CA). The Gazefinder® was used to compare the mean fixation time percentage (MFP) in each CA and evaluate the gaze patterns. Perinatal factors associated with low MFP were also analyzed. RESULTS: Only 50% of the children scored ≥70% MFP at 3-6 months of CA. The MFP increased significantly after 7 months of CA (p = 0.0003), reached 90% at 13-18 months, and 100% at 19-32 months of CA. Chronic lung disease (CLD) was a clinical factor associated with low MFP (p = 0.036). Preterm children gazed more at eyes but gazed at mouths when the mouth moved. CONCLUSION: It is necessary for preterm children to begin using Gazefinder® atleast at ≥13 months of age, especially those complicated with CLD. Preterm children prefer gazing at social information just as typically developing children.

Changes in Cranial Shape and Developmental Quotient at 6 Months of Age in Preterm Infants.

The purpose of this study was to investigate changes in cranial shape among preterm neonates aged 1-6 months and the relationship between developmental quotient (DQ) and cranial shape at 6 months of age. Preterm infants who were hospitalized in our hospital were prospectively followed for 6 months. The cephalic index (CI) and cranial vault asymmetry index (CVAI) were evaluated at 1 (T1), 3 (T2), and 6 months (T3) of age and compared with those of the full-term infants. The relationship between CI or CVAI and DQ at T3 was analyzed using the Enjoji Scale of Infant Analytical Development. A total of 26 participants born at 34.7 ± 1.9 weeks of gestation were included. The CI increased with age (T1: 77.2%, T2: 82.9%, T3: 85.4%, p < 0.01). The prevalence of dolichocephaly at T3 did not significantly differ from that in full-term infants (15.4% vs. 4.5%, p = 0.08). CVAI did not significantly differ between preterm and full-term infants. The DQ showed no significant correlation with either the CI or CVAI (correlation coefficients: 0.23 for CI, -0.01; CVAI). Dolichocephaly improved over time in preterm infants and no relationship between cranial shape and development was observed in preterm infants at 6 months of age.

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 [...].

Restriction of SARS-CoV-2 replication in the human placenta.

Although SARS-CoV-2 can infect human placental tissue, vertical transmission is rare. Therefore, the placenta may function as a barrier to inhibit viral transmission to the foetus, though the mechanisms remain unclear. In this study, we confirmed the presence of the SARS-CoV-2 genome in human placental tissue by in situ hybridization with antisense probes targeting the spike protein; tissue staining was much lower when using sense probes for the spike protein. To the best of our knowledge, this is the first evidence directly indicating inefficient viral replication in the SARS-CoV-2-infected placenta. Additional studies are required to reveal the detailed mechanisms.

A prospective cohort study of newborns born to mothers with serum Toxoplasma gondii immunoglobulin M positivity during pregnancy.

INTRODUCTION: The aims were to investigate the clinical characteristics of Toxoplasma gondii (T. gondii) immunoglobulin (Ig) M-positive mothers and to clarify the incidences of serum T. gondii IgM or blood T. gondii DNA positivity in newborns born to the mothers and the actual congenital T. gondii infection. METHODS: Mothers with T. gondii IgM positivity and newborns born to the mothers from 2013 to 2020 were prospectively investigated. Serum T. gondii IgG and IgM were measured by enzyme-linked immunosorbent assay. Blood T. gondii DNA was detected by semi-nested polymerase chain reaction. Congenital T. gondii infection was diagnosed based on clinical characteristic manifestations with serum T. gondii IgG positivity at any age or T. gondii IgG positivity after 12 months of age. RESULTS: Among 71 T. gondii IgM-positive mothers, including one with triplets, 41% had low T. gondii IgG avidity index and 73% received maternal therapy. Among 73 newborns who were examined for serum T. gondii IgG and IgM at birth, none had clinical manifestations, and one (1.4%) had T. gondii IgM positivity. Among 32 newborns who were examined for blood T. gondii DNA at birth, two (6.3%) were positive. All patients with serum T. gondii IgM or blood T. gondii DNA positivity showed T. gondii IgG negativity within 12 months of age. CONCLUSIONS: A few newborns born to T. gondii IgM-positive mothers were suspected of having congenital T. gondii infection based on serum T. gondii IgM or blood T. gondii DNA testing at birth. However, none developed congenital T. gondii infection.

Awareness and knowledge of congenital cytomegalovirus infection among pregnant women and the general public: a web-based survey in Japan.

BACKGROUND: The best approach to reduce congenital cytomegalovirus infection (cCMVi) is to practice behaviors that reduce cytomegalovirus (CMV) transmission during pregnancy. Expanding awareness and knowledge of CMV is expected to result in increased practice of preventative behaviors. To this end, it is necessary to understand current awareness and knowledge of CMV. METHODS: This web-based cross-sectional survey assessed the awareness and knowledge of cCMVi among pregnant women and the general public in Japan. Participants aged 20-45 years (pregnant and non-pregnant women, and men) were identified from a consumer panel. Study outcomes (all participants) included awareness of cCMVi and other congenital conditions. Among those aware of cCMVi, outcomes included knowledge of CMV transmission routes, long-term outcomes of cCMVi, and behaviors to prevent CMV transmission during pregnancy. Outcomes limited to pregnant women included the practice of preventative behaviors and opinion on how easy it is to implement these behaviors. The data of the pregnant group (pregnant at the time of the survey) were compared with those of the general group (non-pregnant women and men). RESULTS: There were 535 participants in the pregnant group and 571 in the general group. Awareness of cCMVi was generally low (pregnant, 16.1%; general, 10.2%). Pregnant participants were significantly more aware of most congenital conditions than those in the general group, including cCMVi (P = 0.004). Knowledge about CMV/cCMVi was limited; there were no significant differences between the two groups for 24 of the 26 knowledge questions. A small proportion (one third or less) of pregnant women practiced behaviors to prevent the transmission of CMV, though most (73.3-95.3%) pregnant women who were aware of cCMVi considered such behaviors easy to implement. CONCLUSIONS: Awareness and knowledge of CMV/cCMVi is low among pregnant women in Japan; the level of knowledge is similar to that among the general public. This needs to be improved. Most pregnant women considered behaviors to prevent CMV transmission easy to perform, which indicates that effectively educating pregnant women regarding the long-term outcomes of cCMVi, CMV transmission routes, and preventative behaviors will contribute to a reduced incidence of cCMVi. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000041260 .

Survey of physician knowledge of congenital cytomegalovirus infection and clinical practices in Japan: A web-based survey.

ABSTRACT: Congenital cytomegalovirus infection (cCMVi) can cause serious and long-term effects in newborns. Without available vaccines or antiviral prophylaxis, prevention strategies for cCMVi and cytomegalovirus disease during pregnancy are limited to hygiene and behavioral interventions to prevent transmission. The objective of this study was to assess cCMVi-related awareness, knowledge, and physicians' actual and preferred clinical practices in Japan. This web-based cross-sectional survey was conducted using online panels. Survey invitations were sent by email to physicians (pediatricians, obstetricians, otolaryngologists, and internists). Participants were asked about their awareness of congenital conditions, including cCMVi. Participants who were aware of cCMVi were then asked additional questions related to the study objectives. Participants included 292 pediatricians, 245 obstetricians, 245 otolaryngologists, and 279 internists. Awareness of cCMVi was generally high (69.2%-97.6%). Pediatricians and obstetricians were most knowledgeable about cCMVi; however, responses to specific questions such as those pertaining to risk factors, patient counseling, and clinical management of cCMVi varied. For example, correct identification of potential cytomegalovirus transmission routes among pediatricians ranged from 36.8% to 65.6%. Survey results showed a discrepancy between responses when physicians were asked about their actual and preferred clinical practices to manage cCMVi. For example, although around 90% of obstetricians and pediatricians considered it preferred practice to educate pregnant women about cCMVi, only 60.1% of obstetricians reported being able to actually do so in current practice.This survey revealed that knowledge about cCMVi among Japanese physicians could be improved and identified variability in clinical practice.

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.

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.

Nutrient management in the intrapartum period in maternal maple syrup urine disease.

Women with congenital amino acid disorders, including maple syrup urine disease (MSUD), are at risk of metabolic crisis at delivery. There are still only a few case reports of maternal MSUD globally, and we are the first to report the successful perinatal management of a woman with classical MSUD in Japan. A healthy baby was delivered by scheduled cesarean section despite the presence of several uterine fibroids. With precise diet therapy and accurate preparation, she completed the postpartum period without metabolic decompensation. Although her clinical outcome was favorable, she experienced hypoproteinemia at delivery because the available branched-chain amino acid-free medical food did not contain sufficient protein to meet the recommended nutrient intake. Therefore, this case also indicates a potential issue regarding a shortage of variations in specific amino acid-free medical food in Japan, which should be addressed to achieve a better nutrient status of adults with MSUD and other amino acid disorders.

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.

Comparison of Two Hepatitis B Vaccination Strategies Targeting Vertical Transmission: A 10-Year Japanese Multicenter Prospective Cohort Study.

In 1985, a hepatitis B (HB) vaccination strategy against vertical HB virus transmission was introduced in Japan that recommended vaccination of infants at two, three, and five months of age (delayed strategy). This schedule was revised in 2013, recommending to vaccinate at birth and at 1 and 6 months of age (non-delayed strategy). We aimed to compare the vertical HB virus transmission rates and immunogenic responses between these two vaccination strategies. This Japanese multicenter prospective cohort study included 222 infants born between 2008 and 2017 to serum hepatitis B surface (HBs) antigen (HBsAg)-positive mothers. During the study period, 136 and 86 infants received delayed and non-delayed strategies, respectively. A positive vertical HB virus transmission was defined as a positive serum HBsAg status. Seropositive immunogenic response was defined as a serum anti-HBs titer of ≥10 mIU/mL. Post-vaccination serum HBsAg positivity rates did not differ significantly between the delayed (0/136 [0.0%, 95% confidence interval, 0.0-2.7%]) and non-delayed (2/86 [2.3%, 95% confidence interval, 0.3-8.1%]) strategy groups. Seropositive immunogenic response rates were 100.0% (136/136) and 97.7% (84/86), respectively. Although this study was under-powered to detect a statistically significant result, no vertical HB virus transmission was observed in the delayed strategy.