Range of protein induced by vitamin K absence or antagonist-II levels in neonates at birth.

Protein induced by vitamin K absence or antagonist-II (PIVKA-II) is avitamin K (VK) deficiency indicator in neonates. However, PIVKA-II detection frequency in neonatal blood at birth and the correlation between PIVKA-II and gestational age are unclear. We retrospectively analyzed infants admitted to our institution between June 1, 2018, and March 31, 2022, whose clinical and PIVKA-II data were available, and classified them into preterm and term infant groups. Overall incidence of PIVKA-II-positive cases (≥ 50 mAU/mL) was 42.8%, including 0.6% apparent VK deficiency (≥ 5000 mAU/mL), 3.1% experimental VK deficiency (1000-4999 mAU/mL), and 10.7% latent VK deficiency (200-999 mAU/mL) cases. Incidence of PIVKA-II-positive cases was significantly higher in the term group than in the preterm group (49.4% vs. 29.7%, p < 0.001). Gestational age correlated with PIVKA-II levels (r2 = 0.117, p < 0.0001). Median serum PIVKA-II levels and incidence of PIVKA-II-positive cases (≥ 50 mAU/mL, 16.4%) were lower at 5 days after birth than at birth, possibly reflecting the postnatal VK prophylaxis impact. Only one infant was diagnosed with VK deficiency bleeding (PIVKA-II levels, at birth: 10,567 mAU/mL; at day 5: 2418 mAU/mL). Thus, serum PIVKA-II levels after birth weakly correlated with gestational age. VK deficiency was more common in term infants than in preterm infants.

Association of Neonatal Serum Creatinine Concentration with Maternal Serum Creatinine Concentration and Birth Weight.

BACKGROUND: The serum creatinine (SCr) concentration in neonates is generally high for its body size, compared to those of infants. The aim of the present study was to investigate the effect of maternal SCr on neonatal SCr through measurements of prenatal maternal SCr and neonatal SCr from birth to postnatal Day 5. In addition, postnatal changes in SCr were compared between term and preterm infants, given that few studies have addressed this topic. METHODS: The retrospective study subjects were 151 neonates whose Scr was measured consecutively from birth to postnatal Day 5 and 124 mothers whose SCr was measured prenatally. RESULTS: There were significant correlations between maternal SCr and neonatal SCr at birth (r = 0.858, p < 0.001) and on postnatal Day 1 (r = 0.235, p < 0. 001). The SCr of term infants (median 0.69 mg/dL, range 0.54 - 0.96 mg/ dL) were higher than those of preterm infants (median 0.63 mg/dL, range 0.43 - 1.23 mg/dL, p < 0.001) at birth; however, these values were reversed on postnatal Day 1 (Term: median 0.75 mg/dL, range 0.51 - 1.13 mg/dL, Pre-term: median 0.88 mg/dL, range 0.56 - 1.25 mg/dL, p < 0.001). There were differences in the timing of reaching to peak SCr between preterm and term neonates. In addition, birth weight might affect SCr concentrations after birth. CONCLUSIONS: The results of this study suggest that neonatal SCr is influenced by maternal SCr, although the effect disappears by postnatal Day 2. Moreover, glomerular filtration rate differs between term and preterm infants.

Influence of UGT1A1 Genetic Variants on Free Bilirubin Levels in Japanese Newborns: A Preliminary Study.

BACKGROUND: Free bilirubin (Bf) is a better marker than total serum bilirubin (TSB) for predicting bilirubin encephalopathy (BE). To date, two UGT1A1 genetic variants (rs4148323 and rs3064744) have been associated with neonatal hyperbilirubinemia; however, the direct association between UGT1A1 variants and Bf levels in newborns has not been elucidated. METHODS: We retrospectively analyzed the clinical data of 484 infants, including the genotype data of two UGT1A1 genetic variants. We divided the infants into a high Bf group (Bf ≥ 1.0 µg/dL, n = 77) and a non-high Bf group (Bf < 1.0 µg/dL, n = 407), based on the peak Bf values. Logistic regression analysis was performed to calculate the odds ratios (ORs) for each variant allele compared to wild-type alleles. RESULTS: The frequencies of the A allele in rs4148323 and (TA)7 allele in rs3064744 in the high Bf group (29% and 4%, respectively) were significantly different from those in the non-high Bf group (16% and 12%, respectively). In logistic regression analysis, for rs4148323, the A allele was significantly associated with an increased risk of hyper-free bilirubinemia over the G allele (adjusted OR: 1.80, 95% confidence interval [CI]: 1.19-2.72, p < 0.01). However, for rs3064744, the (TA)7 allele was significantly associated with a decreased risk of hyper-free bilirubinemia over the (TA)6 allele (adjusted OR: 0.42, 95% CI: 0.18-0.95, p = 0.04). CONCLUSIONS: This study is the first to show that the A allele in rs4148323 is a risk factor and that the (TA)7 allele in rs3064744 is a protective factor for developing hyper-free bilirubinemia in Japanese newborns.

Neonatal Pseudohypoaldosteronism Type-1 in Japan.

(1) Background: Pseudohypoaldosteronism type 1 (PHA-1) is a disorder caused by renal tubular resistance to aldosterone and is characterized by problems with sodium regulation. PHA-1 is typically divided into primary PHA-1, which is caused by genetic mutation, and secondary PHA-1, which is associated with urinary tract abnormality. However, data on the clinical features of PHA-1 among newborn infants are limited. (2) Methods: We conducted a nationwide prospective surveillance study of neonatal PHA in Japan from 1 April 2019 to 31 March 2022 as part of a rare disease surveillance project of the Japan Society for Neonatal Health and Development. (3) Results: Fifteen cases (male:female = 7:8), including four primary, four secondary, and seven non-classified cases, were reported during the study period. The median gestational age and birthweight were 34 weeks (28-41) and 1852 g (516-4610), respectively. At the onset, the median serum Na and K levels were 132 mEq/L (117-137) and 6.3 mEq/L (4.7-8.3), respectively. The median plasma renin activity was 45 ng/mL/h (3.1-310, n = 9), active renin concentration was 1017 pg/mL (123-2909, n = 6), and serum aldosterone concentration was 5310 pg/mL (3250-43,700). (4) Conclusions: Neonatal PHA-1 was more common among preterm infants with no male predominance. It developed immediately after birth in cases without genetic or renal complications.

Long use of continuous positive airway pressure protects against the development of treatment-requiring retinopathy of prematurity.

Although preterm infant mortality is low, the proportion of patients with treatment-requiring retinopathy of prematurity (TR-ROP) is high in Japan. Various multicenter studies have reported the risk factors for TR-ROP; however, no large-scale studies have been conducted in Japan. We retrospectively analyzed 13,645 infants born at < 28 weeks' gestation (January 1, 2009-December 31, 2018), and registered in the Neonatal Research Network of Japan database. TR-ROP was defined as ROP requiring retinal laser photocoagulation and/or intravitreal anti-vasoendothelial growth factor drugs. Multivariable logistic regression analysis was performed to identify factors associated with TR-ROP development. The median gestational age of enrolled infants was 26 weeks (interquartile range [IQR], 24-27 weeks), median birth weight was 760 g (IQR, 620-918 g). Proportion of patients with TR-ROP was 30.3%. TR-ROP was significantly associated with birth at < 26 weeks' gestational age (adjusted odds ratio [aOR] 1.54), blood transfusion (aOR 1.49), invasive ventilation ≥ 28 days (aOR 1.41), sepsis (aOR 1.29), birth weight < 750 g (aOR 1.28), intraventricular hemorrhage (aOR 1.33), delayed achievement of full enteral feeding > 14 days (aOR 1.28), and continuous positive airway pressure (CPAP) therapy ≥ 28 days (aOR 0.79). Supplemental oxygen ≥ 28 days was not associated with TR-ROP development. Lower gestational age at birth and birth weight, blood transfusion, prolonged invasive ventilation, sepsis, intraventricular hemorrhage, and delayed achievement of full enteral feeding were risk factors for TR-ROP, whereas CPAP use was protective against TR-ROP.

Protective Role of an Initial Low-Dose Septic Challenge against Lethal Sepsis in Neonatal Mice: A Pilot Study.

Neonatal sepsis is characterized by systemic bacterial invasion followed by a massive inflammatory response. At present, no therapeutic strategy has been found that significantly reduces the mortality of neonatal sepsis. We aimed to investigate the protective role of an initial low-dose septic challenge for the prevention of subsequent lethal sepsis in a mouse model. A stock cecal slurry (CS) solution was prepared from adult ceca. The LD83 (1.5 mg CS/g) was used for all animals. An initial challenge of normal saline (NS) or 0.5 mg CS/g (non-lethal dose) was administered at four days of age, then 1.5 mg CS/g was administered intraperitoneally at seven days of age (72 h post-initial challenge), and survival was monitored. Initial exposure to NS (n = 10) resulted in 90% mortality following exposure to the LD83 CS dose in contrast to an initial exposure to CS (n = 16), which significantly decreased mortality to 6% (p < 0.0001), reduced blood bacterial counts, attenuated inflammatory responses, and suppressed lipid mediators. Initial exposure to a non-lethal CS dose prior to exposure to a lethal CS dose significantly reduces sepsis mortality, a protective effect that might be mediated by modulating abnormal systemic inflammatory responses.

Change in Viral Load during Antiviral Therapy Is Not Useful for the Prediction of Hearing Dysfunction in Symptomatic Congenital Cytomegalovirus Infection.

For symptomatic congenital cytomegalovirus infections (CCMVI), the usefulness of changes in viral load during valganciclovir (VGCV) treatment for the prediction of hearing dysfunction (HD) is unclear. To determine the utility of viral load change in the whole blood or urine for the prediction of HD, we performed a retrospective study to compare viral load changes during VGCV treatment between CCMVI infants with (n = 12) or without (n = 8) HD at six months of corrected age, whose blood and urine viral loads were measured continuously for eight weeks from April 2009 to December 2019. There was no significant difference in the changes in both the blood and urine viral loads after the initiation of VGCV treatment between CCMVI infants between the groups. Moreover, this negative result was maintained in the analysis for each six weeks or six months treatment period. In conclusion, the change in viral load during antiviral therapy is not useful for the prediction of HD at six months of corrected age in symptomatic CCMVI.

Correlation between Severity of Fetal Growth Restriction and Oxidative Stress in Severe Small-for-Gestational-Age Infants.

Severe small-for-gestational-age (sSGA) infants exhibit increased mortality and morbidity. Oxidative stress is suggested to be involved in intrauterine growth restriction. This retrospective study aimed to evaluate the oxidative stress level at birth in an sSGA population. Sera of 28 sSGA (sSGA group) and 31 non-sSGA (control group) infants, born at our hospital between March 2017 and March 2020, were evaluated. Oxidative stress (derivative of reactive oxidative metabolites: d-ROM level), biological antioxidant potential (BAP) level, and the ratio of d-ROM/BAP level (oxidative stress index: OSI) were measured. The sSGA group had a significantly lower birth weight (BW), BW z-score, head circumference, and height than the control group (all p < 0.05). No significant difference was noted in the BAP level; sSGA infants exhibited a significantly higher d-ROM level than control infants. sSGA infants showed a significantly increased OSI compared with control infants, and the BW z-score was inversely correlated with d-ROM levels and OSI in sSGA infants (R2 = 0.300; p < 0.01 and R2 = 0.319; p = 0.02, respectively) but not in controls. In conclusion, sSGA infants, including preterm infants, exhibited higher oxidative stress at birth. The severity of fetal growth restriction was significantly correlated with oxidative stress levels at birth in sSGA infants.

Administration of intravenous benzylpenicillin in 13 infants born to mothers with syphilis infection: A case series.

The incidence of syphilis infection among pregnant women is persistently high in Japan and in several developed countries. Here, we report the utility of intravenous benzylpenicillin in 13 infants born to mothers with syphilis infection. Because the recommended treatment (intramuscular benzathine benzylpenicillin) is not available in Japan, we intravenously administered benzylpenicillin for 10 days, which is used for treatment in high-risk cases. The administration of benzylpenicillin in low-risk infants resulted in an extended duration of parent-to-infant separation and increased the infants' exposure to invasive procedures. Thus, establishing evidence of the adequacy of no-treatment follow-up in low-risk groups and introducing intramuscular injections of benzathine benzylpenicillin may improve the management of infants suspected with congenital syphilis in Japan.

The Role of Heme Oxygenase-1 Promoter Polymorphisms in Perinatal Disease.

Heme oxygenase (HO) is the rate-limiting enzyme in the heme catabolic pathway, which degrades heme into equimolar amounts of carbon monoxide, free iron, and biliverdin. Its inducible isoform, HO-1, has multiple protective functions, including immune modulation and pregnancy maintenance, showing dynamic alteration during perinatal periods. As its contribution to the development of perinatal complications is speculated, two functional polymorphisms of the HMOX1 gene, (GT)n repeat polymorphism (rs3074372) and A(-413)T single nucleotide polymorphism (SNP) (rs2071746), were studied for their association with perinatal diseases. We systematically reviewed published evidence on HMOX1 polymorphisms in perinatal diseases and clarified their possible significant contribution to neonatal jaundice development, presumably due to their direct effect of inducing HO enzymatic activity in the bilirubin-producing pathway. However, the role of these polymorphisms seems limited for other perinatal complications such as bronchopulmonary dysplasia. We speculate that this is because the antioxidant or anti-inflammatory effect is not directly mediated by HO but by its byproducts, resulting in a milder effect. For better understanding, subtyping each morbidity by the level of exposure to causative environmental factors, simultaneous analysis of both polymorphisms, and the unified definition of short and long alleles in (GT)n repeats based on transcriptional capacity should be further investigated.

A Preterm Case of Cow's Milk Allergy Presenting with Recurrent Ascites Treated with Donor Breast Milk.

We report a case of a preterm infant who developed cow's milk allergy. This male infant presented with recurrent ascites and was successfully treated with donated breast milk. He was born at 24 weeks' gestation with a birthweight of 506 g. From day 20, infant formula, soy protein-based formula, and casein-hydrolyzed formula were used due to insufficient maternal lactation. This resulted in abdominal distention, generalized edema, and recurrent ascites. We diagnosed him with cow's milk allergy since these symptoms improved on exclusive breast milk feeding. No recurrence of symptoms occurred when donated breast milk was used in combination with the mother's own milk. Ascites should be regarded as a clinical symptom of neonatal cow's milk allergy. Donated breast milk may be effective in the treatment of the allergy if breastfeeding is not available.

Bilirubin/albumin (B/A) ratios correlate with unbound bilirubin levels in preterm infants.

BACKGROUND: A strong correlation between the bilirubin/albumin (B/A) ratio and unbound bilirubin (UB) levels in newborns ≥35 weeks of gestation has been reported. However, in preterm infants, the usefulness of B/A ratios remains unclear. METHODS: We obtained serum from 381 newborns <35 weeks of gestation. UB levels were measured using the glucose oxidase-peroxidase method. Total serum bilirubin (TB) and albumin (Alb) concentrations were measured spectrophotometrically. Samples were then stratified into two groups based on the infant's phototherapy use. B/A ratios were calculated and correlated with UB levels. Samples taken from infants prior to or never receiving phototherapy (No PTx) were then stratified by gestational age (GA) epochs: 22-27, 28-29, 30-31, and 32-34 weeks and B/A ratios correlated with UB levels. RESULTS: B/A ratios significantly correlated with UB levels in samples from the No PTx cohort (n = 1250; y = 1.83x - 0.15, r2 = 0.93) when compared with samples from infants post-phototherapy (Post-PTx, n = 2039; y = 1.05x + 0.09, r2 = 0.69). Even when stratified by GA, the correlation remained. CONCLUSIONS: In preterm infants <35 weeks of gestation, B/A ratios correlated with UB levels better in infants prior to or never receiving phototherapy than in those infants receiving phototherapy. IMPACT: The bilirubin/albumin (B/A) ratio significantly correlates with unbound bilirubin (UB) levels in preterm infants <35 weeks of gestation. The B/A ratio can be used as an index of UB levels in preterm infants <35 weeks of gestation. The B/A ratio is useful, especially when UB measurements are not available, for managing hyperbilirubinemia in preterm infants.

Neurodevelopmental Outcomes at 18 Months of Corrected Age for Late Preterm Infants Born at 34 and 35 Gestational Weeks.

To date, the difference in neurodevelopmental outcomes between late preterm infants (LPI) born at 34 and 35 gestational weeks (LPI-34 and LPI-35, respectively) has not been elucidated. This retrospective study aimed to evaluate neurodevelopmental outcomes at 18 months of corrected age for LPI-34 and LPI-35, and to elucidate factors predicting neurodevelopmental impairment (NDI). Records of all LPI-34 (n = 93) and LPI-35 (n = 121) admitted to our facility from 2013 to 2017 were reviewed. Patients with congenital or chromosomal anomalies, severe neonatal asphyxia, and without developmental quotient (DQ) data were excluded. Psychomotor development was assessed as a DQ using the Kyoto Scale of Psychological Development at 18 months of corrected age. NDI was defined as DQ <80 or when severe neurodevelopmental problems made neurodevelopmental assessment impossible. We compared the clinical characteristics and DQ values between LPI-34 (n = 62) and LPI-35 (n = 73). To elucidate the factors predicting NDI at 18 months of corrected age, we compared clinical factors between the NDI (n = 17) and non-NDI (n = 118) groups. No significant difference was observed in DQ values at 18 months of corrected age between the groups in each area and overall. Among clinical factors, male sex, intraventricular hemorrhage (IVH), hyperbilirubinemia, and severe hyperbilirubinemia had a higher prevalence in the NDI group than in the non-NDI group, and IVH and/or severe hyperbilirubinemia showed the highest Youden Index values for predicting NDI. Based on the results of this study, we can conclude that no significant difference in neurodevelopmental outcomes at 18 months of corrected age was observed between LPI-34 and LPI-35. Patients with severe hyperbilirubinemia and/or IVH should be considered to be at high risk for developing NDI.

Changes in awareness and knowledge concerning mother-to-child infections among Japanese pregnant women between 2012 and 2018.

This study aimed to investigate the long-term changes in awareness of and knowledge about mother-to-child infections across 6 years in Japan. A questionnaire survey was conducted at our facility from October 2012 to January 2018, and the study periods were divided into 4 phases comprising 16 months each. A multiple-choice questionnaire assessed participants' awareness of the following 13 pathogens of mother-to-child infections: cytomegalovirus (CMV), Toxoplasma gondii (T. gondii), hepatitis B virus, rubella virus, herpes simplex virus, parvovirus B19, hepatitis C virus, human immunodeficiency virus, human T cell leukemia virus type-1, measles virus, varicella-zoster virus, Chlamydia trachomatis, and Treponema pallidum. For the selected four pathogens (i.e., CMV, rubella virus, T. gondii, and parvovirus B19), the questionnaire also evaluated participants' knowledge of transmission routes, the most susceptible time of infection that could yield severe fetal disease during pregnancy, the maximum frequency of fetal infection in cases of maternal infection, and methods to prevent maternal infection. In total, 1433 pregnant Japanese women were included in this study. There was no secular change in awareness of the pathogens concerning mother-to-child infections over time, and we also clarified that the detailed knowledge of the four pathogens of typical mother-to-child infections did not improve. Since knowledge about methods to prevent maternal infection is still insufficient for all pathogens, further advocacy is required to prevent mother-to-child infections.

Prediction of Neurodevelopmental Impairment in Congenital Cytomegalovirus Infection by Early Postnatal Magnetic Resonance Imaging.

INTRODUCTION: Congenital cytomegalovirus infection (CCMVI) may result in neurodevelopmental impairments (NDIs) such as hearing loss, developmental delay, epilepsy, and cerebral palsy. We aimed to investigate the potential for brain magnetic resonance imaging (MRI) to predict NDI in patients with CCMVI. METHODS: We studied infants with CCMVI who were referred to our hospital from April 2010 to October 2018 and underwent a brain MRI within 3 months since birth. We screened for 6 classic presentations of CCMVI including ventriculomegaly, periventricular cysts, hippocampal dysplasia, cerebellar hypoplasia, migration disorders, and white matter abnormalities. Images were interpreted by a blinded pediatric radiologist. NDI was defined as having a developmental quotient <80, hearing dysfunction, blindness, or epilepsy requiring anti-epileptic drugs at approximately 18 months of corrected age. RESULTS: The study involved 42 infants with CCMVI (median gestational age 38 weeks, birthweight 2,516 g). At least one abnormal finding was detected in 28 (67%) infants. Abnormal findings consisted of 3 cerebellar hypoplasia (7%), 7 migration disorders (17%), 26 white matter abnormalities (62%), 12 periventricular cysts (28%), 1 hippocampal dysplasia (2%), and 20 ventriculomegaly (48%). Abnormal findings were significantly more prevalent in infants with clinical symptoms (21/24, 91%) than in those without (7/19, 37%, p < 0.01). For NDI prediction, having ≥2 of ventriculomegaly, periventricular cysts, and white matter abnormality produced the highest Youden index values (0.78). CONCLUSION: Infants with CCMVI with at least 2 of the abovementioned specific brain image abnormalities may be at high risk of developing NDI.

Recombinant human thrombomodulin attenuated sepsis severity in a non-surgical preterm mouse model.

Neonatal sepsis is characterised by dysregulated immune responses. Lipid mediators (LMs) are involved in the regulation of inflammation. Human recombinant thrombomodulin (rhTM), an anticoagulant, has anti-inflammatory effects and might be useful for sepsis treatment. A stock caecal slurry (CS) solution was prepared from adult caeca. To induce sepsis, 1.5 mg/g of CS was administered intraperitoneally to 4 d-old wild-type FVB mouse pups. Saline (Veh-CS) or rhTM (3 or 10 mg/kg; rhTM3-CS or rhTM10-CS) was administered subcutaneously 6 h prior to sepsis induction, and liver LM profiles at 3 and 6 h post-sepsis induction and survival up to 7 days were examined. Mortality was significantly lower (47%) in the rhTM3-CS group and significantly higher (100%) in the rhTM10-CS group, compared with the Veh-CS group (79%, p < 0.05). Eleven LMs (12-HEPE, EPA, 14-HDHA, DHA, PD1, PGD2, 15d-PGJ2, 12S-HHT, lipoxin B4, 12-HETE, AA) were significantly increased at 3 h, and five LMs (5-HEPE, 15-HEPE, 18-HEPE, 17-HDHA, PD1) were significantly increased at 6 h post-sepsis induction. Increased EPA, DHA, 12S-HHT, lipoxin B4, and AA were significantly suppressed by rhTM pre-treatment. rhTM was protective against neonatal sepsis. This protective effect might be mediated via LM modulation. Further post-sepsis studies are needed to determine clinical plausibility.

Insulin therapy for hyperglycemia in neonatal sepsis using a preterm mouse model.

BACKGROUND: Stress-induced hyperglycemia is a frequent complication of neonatal sepsis. Hyperglycemia induces oxidative stress and immunosuppression. We investigated the glucose kinetics and effect of insulin administration during stress-induced hyperglycemia in a neonatal sepsis mouse model. METHODS: A stock cecal slurry (CS) solution was prepared from adult cecums and 3.0 mg of CS/g (LD40 ) was administered intraperitoneally to 4-day-old FVB mouse pups. Blood glucose levels were measured at 1.5, 3, 6, and 9 h post-sepsis induction and compared with basal levels. Two different doses of ultrafast-acting insulin were administered subcutaneously, and blood glucose levels and survival rates were monitored. RESULTS: Blood glucose levels were significantly higher than those of baseline levels with a peak at 3 h, which progressively decreased from 6 to 9 h post-sepsis induction. Insulin treatment reduced post-sepsis-induced hyperglycemia at 1.5 and 3 h. The mortality rate of CS-only pups (39%) was similar to that of CS + 1 U/kg insulin pups (60%). However, the mortality rate of CS + 5 U/kg insulin pups (82%) was significantly higher than that of CS-only pups. CONCLUSIONS: Marked hyperglycemia was induced immediately after post-sepsis induction, and the high-dose insulin treatment increased mortality post-induction. Stress-induced hyperglycemia could therefore be a physiological and protective response for preterm sepsis, and aggressive treatment of this hyperglycemia might be contraindicated.