Urine Desmosine as a Novel Biomarker for Bronchopulmonary Dysplasia and Postprematurity Respiratory Disease in Extremely Preterm or Low Birth Weight Infants.

OBJECTIVE: This study aimed to evaluate whether elevated urine desmosine levels at 3 weeks of age were associated with severe radiological findings, bronchopulmonary dysplasia (BPD), and post-prematurity respiratory disease (PRD) in extremely preterm (EP) or extremely low birth weight (ELBW) infants. STUDY DESIGN: This study recruited 37 EP (22-27 completed weeks) or ELBW (<1,000 g) infants. Urine was collected between 21 and 28 postnatal days, and desmosine was measured using an enzyme-linked immunosorbent assay kit; the urine creatinine level was also measured. Bubbly/cystic lungs were characterized by emphysematous chest X-rays on postnatal day 28. Furthermore, provision of supplemental oxygen or positive-pressure respiratory support at 40 weeks' postmenstrual age defined BPD, and increased medical utilization at 18 months of corrected age defined PRD. The desmosine/creatinine threshold was determined by receiver operating characteristic analysis. The adjusted risk and 95% confidence interval (CI) for elevated urine desmosine/creatinine levels were estimated by logistic regression analysis. RESULTS: Elevated urine desmosine/creatinine levels higher than the threshold were significantly associated with bubbly/cystic lungs (8/13 [61.5%] vs. 2/24 [8.3%], p = 0.001), BPD (10/13 [76.9%] vs. 8/24 [33.3%], p = 0.02), and PRD (6/13 [46.2%] vs. 2/24 [8.3%], p = 0.01). After adjusting for gestational age, birth weight, and sex, the urine desmosine/creatinine levels were significantly higher in those who were highly at risk of bubbly/cystic lungs (odds ratio [OR], 13.2; 95% CI, 1.67-105) and PRD (OR, 13.8; 95% CI, 1.31-144). CONCLUSION: Elevated urine desmosine/creatinine levels on the third postnatal week were associated with bubbly/cystic lungs on day 28 and PRD at 18 months of corrected age in EP or ELBW infants. KEY POINTS: · Urine desmosine was prospectively measured in 3-week-old EP/ELBW infants.. · Elevated urine desmosine levels were associated with emphysematous radiological findings on day 28, PRD at 18 months of corrected age.. · Urine desmosine may be a promising biomarker indicating lung damage in EP/ELBW infants..

Japanese original delayed hepatitis B vaccination provides adequate immunogenicity against mother-to-child hepatitis B virus infection in preterm infants: A nationwide survey in Japan.

OBJECTIVE: We aimed to evaluate immunogenicity following Japanese original delayed hepatitis B (HB) vaccinations for prevention of mother-to-child HB infection in preterm infants. METHODS: A nationwide survey in Japan was conducted at certified neonatology facilities in 2014. Eighty-four preterm infants born from a serum hepatitis B surface (HBs) antigen-positive mother were included. We collected data on the following parameters: gestational age, birth weight (BW), age at HB vaccination, age at examination of serum anti-HBs titer, and serum anti-HBs titer. The delayed HB vaccination schedule was 3 doses of HB vaccines at 2, 3 and 5 months of age. A seropositive immunogenic response to HB vaccination was defined as an anti-HBs titer ≥10 mIU/mL. Seropositive rates were calculated in all participants. Four subgroups based on BW were as follows: <1000 g (n = 13), 1000-1499 g (n = 16), 1500-1999 g (n = 26), and ≥2000 g (n = 29). RESULTS: Among 84 preterm infants who completed the delayed vaccination schedule, 82 (98%) achieved seropositive anti-HBs titer at a median age of 6 months. Seropositive rates of infants <1000 g, 1000-1499 g, 1500-1999 g, and ≥2000 g were 92%, 94%, 100%, and 100%, respectively. CONCLUSION: The Japanese original delayed HB vaccinations achieved sufficient seropositive rates in preterm infants and provide immunogenicity against mother-to-child HB infection.

Development of a Novel Algorithm to Detect Atrial Fibrillation Using an Automated Blood Pressure Monitor With an Irregular Heartbeat Detector.

BACKGROUND: Atrial fibrillation (AF), which contributes to an increased risk of stroke, frequently remains undetected, suggesting an unmet need for easier and more reliable AF screening. The reports on screening AF using an Omron blood pressure (BP) monitor with an irregular heartbeat (IHB) detector show inconsistent results, so the aim of this study was to develop a novel algorithm to accurately diagnose AF with 3 BP measurements using an Omron automated BP monitor with IHB detector.Methods and Results:In total, 303 general cardiac patients were included. Real-time single-lead ECG revealed AF in 44 patients. BP measurement was performed 3 times per patient using the Omron BP monitor HEM-907, and the number of IHBs detected was recorded. Based on these data, we developed the following algorithm: ≥1 IHB is detected during at least 2 of 3 BP measurements and the maximum number of IHBs detected is ≥2. Using this algorithm, we achieved a sensitivity of 95.5% and specificity of 96.5%, for diagnosing AF. CONCLUSIONS: The novel algorithm with 3 BP measurements using the Omron automated BP monitor with IHB detector showed high sensitivity and specificity for diagnosing AF in general cardiac patients.

Nationwide survey of neonatal invasive fungal infection in Japan.

Invasive fungal infection (IFI) is a life-threating infectious disease in high-risk neonates. Strategies for the treatment and prevention of IFI in neonates in Japan remain unclear. We conducted a nationwide retrospective survey to determine IFI incidence between January 2014 and October 2015. Primary survey questionnaires were submitted to 309 medical facilities that regularly treat high-risk neonates. The questionnaire assessed IFI incidence during the study period, methods for preventing fungal infection in early delivery neonates, and methods for preventing mother-to-child fungal transmission. The secondary questionnaire was for facilities that had IFI cases and replied to the primary questionnaire. In total, 128 medical facilities (41.4%) completed the primary questionnaire, 17/128 facilities recorded 23 proven or probable IFI cases. Estimated annual IFI incidence was 0.33/1000 live births of hospitalized neonates. Patient data at IFI onset were available for all 23 patients. Birth weight was < 1000 g in 18 patients. Causative microorganisms were identified in 22 patients. Candida species (n = 21) were the most common pathogens, and one patient had mucormycosis. The mortality rate was 17.4%. Regarding neonatal fungal prophylaxis, 55/128 facilities (43.0%) reported administering therapy. The most frequently used prophylactic drugs were fluconazole, then micafungin. Fungal prophylaxis for mothers who showed fungal colonization was performed in 30/128 facilities (23.4%). Oxiconazole vaginal tablets were most commonly used as prophylaxis for high-risk mothers. In Japan, the diagnosis, treatment, and prevention of neonatal IFI varied. Continuous surveillance and treatment regimen for neonatal IFI are required to improve outcomes in high-risk neonates.

Risk factors associated with a decreased estimated glomerular filtration rate based on cystatin C levels in school-age children with extremely low birthweight.

AIM: A single centre retrospective cohort study was designed to investigate the estimated glomerular filtration rate (eGFR) in school-age children born with extremely low birthweight (ELBW) and to determine risk factors predictive of decreased eGFR. METHODS: We compared eGFR based on cystatin C (CysC-eGFR) between school-age children born with ELBW (ELBW group, n = 48; median gestational age: 26.9 weeks; median birthweight: 792 g) and children born at term (control group, n = 48). The ELBW group was then further divided into a decreased CysC-eGFR subgroup (eGFR <90 mL/min per 1.73 m2 , n = 20) and a normal CysC-eGFR subgroup (n = 28), and perinatal background factors were compared. RESULTS: The ELBW group showed a significantly lower CysC-eGFR compared with the control group (P < 0.001). Comparison between the decreased and normal CysC-eGFR subgroups in the ELBW group showed that children with lower birthweight, shorter gestational age, lower 5-min Apgar score, longer length of mechanical ventilation, lower weight gain in the first 11 weeks, chronic lung disease, and postnatal corticosteroid administration had significantly decreased CysC-eGFR. Multivariate logistic regression showed that a lower 5-min Apgar score was the only independent risk factor for decreased CysC-eGFR. CONCLUSIONS: CysC-eGFR might already be decreased at school age in children born with ELBW. Renal assessment in regular follow-up examinations is recommended.

Safety of Bifidobacterium breve (BBG-01) in preterm infants.

BACKGROUND: Since 1982, viable cells of Bifidobacterium breve (BBG-01) have been used in pediatric patients for clinical conditions such as intractable infantile diarrhea, preterm status, and pediatric surgery. Although the efficacy of BBG-01 has been widely reported, adverse events related to the use of BBG-01 have been reported in very few cases. METHODS: In order to trace adverse events seen by 109 doctors in 88 medical institutions where BBG-01 was used, a questionnaire survey of the number of occurrences and details of each case was conducted. RESULTS: Eighty-six clinicians (70 institutions) responded to the questionnaire (response rate, 78.9%). Number of respondents according to department of diagnosis (no. BBG-01-treated infants) was as follows: pediatrics, 29 respondents (10 938 patients); premature and newborn medicine, 26 (10 677 patients); obstetrics and gynecology, 1 (1212 patients) and pediatric surgery, 22 (169 patients). More than 90% of the total BBG-01-treated patients (23 092 patients) were in the departments of premature and newborn medicine and pediatrics, and BBG-01 had been used mainly in preterm infants and children with intractable diarrhea. Adverse events occurred in two extremely premature infants with functional ileus due to starch aggregates as vehicle, and in two surgical neonates with bacteremia caused by B. breve genetically identical to BBG-01, and no serious adverse events with poor outcome were reported. CONCLUSION: Adverse events related to the use of BBG-01 have an extremely low incidence and are mild in severity, thus ensuring the superior safety of this preparation.

Lethal hypophosphatasia successfully treated with enzyme replacement from day 1 after birth.

UNLABELLED: Hypophosphatasia (HPP) is a rare metabolic bone disease caused by loss-of-function mutations in the gene ALPL encoding the tissue nonspecific alkaline phosphatase (TNSALP). There is a broad range of severity in the phenotype of HPP, and the most severe form exhibits perinatal lethality without mineralization of the skeleton. Here, we describe a female infant with perinatal lethal HPP diagnosed in utero. She was treated with a recombinant ALP (asfotase alfa) as an enzyme replacement therapy (ERT), which started from 1 day after birth. She required invasive ventilation immediately upon birth and demonstrated severe hypomineralization of whole body bone. Severe respiratory insufficiency was controlled by intensive respiratory care with high-frequency oscillation ventilation and nitric oxide inhalation and deep sedation just after birth. Bone mineralization improved with treatment; improvements were visible by 3 weeks of age and continued with treatment. Serum calcium levels decreased following treatment, resulting in hypocalcemia and convulsion, and calcium supplementation was required until 3 months of treatment. She was weaned from mechanical ventilation and has now survived more than 1 year. CONCLUSION: This case demonstrates the success of ERT in treating the severest HPP and highlights the importance of early diagnosis and intervention for these patients.

In vitro activity of five quinolones and analysis of the quinolone resistance-determining regions of gyrA, gyrB, parC, and parE in Ureaplasma parvum and Ureaplasma urealyticum clinical isolates from perinatal patients in Japan.

Ureaplasma spp. cause several disorders, such as nongonococcal urethritis, miscarriage, and preterm delivery with lung infections in neonates, characterized by pathological chorioamnionitis in the placenta. Although reports on antibiotic resistance in Ureaplasma are on the rise, reports on quinolone-resistant Ureaplasma infections in Japan are limited. The purpose of this study was to determine susceptibilities to five quinolones of Ureaplasma urealyticum and Ureaplasma parvum isolated from perinatal samples in Japan and to characterize the quinolone resistance-determining regions in the gyrA, gyrB, parC, and parE genes. Out of 28 clinical Ureaplasma strains, we isolated 9 with high MICs of quinolones and found a single parC gene mutation, resulting in the change S83L. Among 158 samples, the ParC S83L mutation was found in 37 samples (23.4%), including 1 sample harboring a ParC S83L-GyrB P462S double mutant. Novel mutations of ureaplasmal ParC (S83W and S84P) were independently found in one of the samples. Homology modeling of the ParC S83W mutant suggested steric hindrance of the quinolone-binding pocket (QBP), and de novo prediction of peptide structures revealed that the ParC S84P may break/kink the formation of the α4 helix in the QBP. Further investigations are required to unravel the extent and mechanism of antibiotic resistance of Ureaplasma spp. in Japan.

Long-term alpha-tocopherol supplements may improve mental development in extremely low birthweight infants.

AIM: Methods to improve the mental development of extremely low birthweight (ELBW) children are currently lacking. We assessed the effects of long-term supplementation of alpha-tocopherol on the neurological development of 259 school-aged ELBW children. METHODS: Extremely low birthweight participants were divided into three groups: group A with no alpha-tocopherol supplementation (n = 121); group B with the supplementation for <6 months (n = 104) and group C with the supplementation for more than 6 months (n = 34). We analysed the participants' data at birth and between the ages of one-and-a-half to 8 years and evaluated potential factors associated with intellectual disabilities. RESULTS: Children from group C had the best outcome. The groups' mean gestational weeks and mean ventilator days were as follows: 27.5 weeks, 16.1 days (group A); 25.7 weeks, 41.7 days (group B); and 25.1 weeks, 75.5 days (group C). Multivariate regression analysis revealed that the odds ratios for impaired mental development at 8 years were 1.5 in group B and 0.19 (p = 0.017) in group C, compared with 1.0 in group A. The association between the duration of alpha-tocopherol administration and performance intelligence quotient (IQ) was dose dependent (p = 0.03). CONCLUSION: Long-term supplementation of alpha-tocopherol appeared to improve mental development, in particular, performance IQ, in school-aged ELBW children.

Mesenteric hernia causing bowel obstruction in very low-birthweight infants.

Internal hernia through a mesenteric defect, called mesenteric hernia, is an uncommon cause of acute intestinal obstruction in newborns. Strangulated mesenteric hernia results in intestinal necrosis or perforation and progressive deterioration with fatal outcome, especially when it occurs in low-birthweight infants. We report two very low-birthweight (VLBW) infants, who presented with acute intestinal obstruction related to mesenteric defect. The initial diagnosis was meconium obstruction in those cases, which is a common cause of bowel obstruction occurring in VLBW infants. Correct diagnosis of mesenteric hernia was difficult in these cases because of rapid deterioration and non-specific radiological findings. Awareness of the possibility of rare mesenteric hernia causing acute intestinal obstruction and surgical intervention in an appropriate timeframe are important for rescuing VLBW infants with such organic abnormalities.

Prevalence of MRSA colonization in Japanese neonatal care unit patients in 2011.

BACKGROUND: The neonatal intensive care unit (NICU) is a high-risk setting for transmission of methicillin-resistant Staphylococcus aureus (MRSA). The recent prevalence of colonization with MRSA in patients and its control measures are unknown in Japanese NICU. We investigated the prevalence of MRSA colonization in patients and measures to control and prevent health-care-associated transmission in Japanese NICU in 2011. METHODS: A nationwide survey was performed in facilities certified as training hospitals for neonatologists. Data in NICU and growing care units (GCU) were collected and analyzed regarding surveillance cultures for MRSA and the proportion of MRSA-colonized patients in September 2011. Trends in the proportion of MRSA-colonized patients and the measures to control and prevent health-care-associated MRSA transmission were investigated in the surveyed NICU in 2000, 2003, and 2011. RESULTS: A total of 168 NICU and 158 GCU were analyzed. The proportions of NICU and GCU that conducted regular surveillance cultures for MRSA were 81% and 66%, respectively. MRSA colonization was not found in 53% of NICU and in 45% of GCU. The percentage of NICU reported to be free of MRSA colonization increased over time. Use of alcohol-based hand rub and gloves by clinical staff and cohorting for identified MRSA-positive patients became more common in 2011 than in 2000 or 2003. CONCLUSIONS: Approximately half of Japanese NICU did not observe any patients with MRSA colonization in September 2011. Control and prevention measures have changed to use of alcohol-based hand rub and gloves in the last decade.

Application of transcutaneous carbon dioxide tension monitoring with low electrode temperatures in premature infants in the early postnatal period.

OBJECTIVE: The aim of this article is to evaluate the accuracy, precision, and safety of transcutaneous carbon dioxide tension (TcPCO2) monitoring at different electrode temperatures in preterm infants in the early postnatal period. STUDY DESIGN: A total of 26 neonates with a median birth weight of 974 g (432-1,694 g) and gestational age of 28.0 weeks (26.1-31.3 weeks) were studied in the first 5 days of life. A total of 252 simultaneous pairs (TcPCO2 and arterial carbon dioxide tension [PaCO2]) were analyzed at 38, 39, and 40°C at 26 and 27 weeks, and at 38, 39, 40, and 42°C at 28 to 31 weeks. RESULTS: The mean difference of TcPCO2 and PaCO2 (bias) increased from 3.93 mm Hg at 42°C to 5.64 mm Hg at 40°C, 6.58 mm Hg at 39°C, and 6.07 mm Hg at 38°C. Standard deviation (SD) of the bias increased from 4.17 mm Hg at 42°C to 4.76 mm Hg at 40°C, 5.29 mm Hg at 39°C, and 5.07 mm Hg at 38°C. Adverse skin lesions were not observed. CONCLUSION: TcPCO2 measurements are the most accurate and precise at an electrode temperature of 42°C. However, in premature babies, monitoring at 38, 39, and 40°C is possible provided a bias correction of 6 mm Hg and SD of 5 mm Hg are applied.

Triple A syndrome in Japan.

INTRODUCTION: Triple A syndrome is an autosomal recessive disease, characterized by esophageal achalasia, alacrima, and adrenal insufficiency, as well as involvement of the central, peripheral, and autonomic nervous systems. This disease mimics amyotrophic lateral sclerosis in some patients. The causative gene encodes ALADIN, a nuclear pore complex (NPC) component. Only 5 patients have been reported in Japan. METHODS: We conducted the first nationwide survey of triple A syndrome. Identified mutants were expressed as GFP-fusion proteins in cultured cells. RESULTS: Two new patients were identified, and 1 had a novel mutation (p.Ser182fsX19). All mutant proteins tested were mislocalized from NPC to cytoplasm. CONCLUSIONS: The most consistent neurological manifestation of triple A syndrome in Japanese patients was progressive bulbospinal muscular atrophy with both upper and lower motor neuron involvement, which mimicked motor neuron disease, similar to that seen in patients in Western countries. The identification of the new patients suggests that more cases are undiagnosed in Japan.

Neonatal lupus erythematosus complicated by improved congenital complete heart block.

Complete congenital heart block (CCHB) accompanied with neonatal lupus erythematosus is caused by an immune reaction between maternal anti-Ro/SSA antibodies and the fetal heart and is generally considered an irreversible process. This reaction mostly occurs before 30 weeks' gestation, especially between the 20th and 24th week. Reported here is an atypical case of neonatal lupus erythematosus with CCHB detected after 32 weeks' gestation that showed postnatal improvement in the degree of heart block after preterm delivery and immunoglobulin use. The clinical condition of the infant worsened with an increase in heart rate due to possible cardiomyopathy induced by the immune reaction.

Parenteral-nutrition-associated liver disease after intestinal perforation in extremely low-birthweight infants: consequent lethal portal hypertension.

BACKGROUND: Parenteral nutrition (PN)-associated liver dysfunction (PNALD) in term infants usually manifests as intrahepatic cholestasis, which recovers with enteral nutrition (EN) in most cases; however, as the number of extremely low-birthweight infants (ELBWI) has been increasing, and consequently intestinal diseases associated with ELBWI have been increasing, more intractable PNALD has been encountered after surgical treatment in ELBWI, which does not resolve or rather worsens with EN. METHODS: Three cases of ELBWI with intestinal perforation, which developed PNALD and eventually died of hepatic failure with intractable portal hypertension, were reviewed. Their gestational age and birthweight ranged from 23 to 26 weeks, and from 434 to 968 g, respectively. The intestinal diseases included necrotizing enteritis in two and meconium-related ileus with focal intestinal perforation in one. RESULTS: The duration of total PN without EN in the three cases was 17, 24 and 24 days, respectively. The interval between the introduction of PN and the onset of PNALD was 14, 4 and 18 days, respectively. A marked elevation of serum endotoxin level was detected in both cases of necrotizing enteritis. Histopathological study of the liver revealed marked cholestasis, significant hepatic necrosis with fibrosis, and proliferation of ductules in all these cases, which was responsible for portal hypertension. CONCLUSIONS: PN after gastrointestinal disorders in ELBWI may cause refractory PNALD, which does not resolve, or rather worsens with the resumption of EN. Portal hypertension secondary to hepatic necrosis may be responsible for the exacerbation with the resumption of EN.

Annexin A2 in amniotic fluid: correlation with histological chorioamnionitis, preterm premature rupture of membranes, and subsequent preterm delivery.

AIM: The aim of this study was to determine whether amniotic fluid levels of annexin A2, a phospholipid-binding protein that is abundant in amnion and regulates fibrin homeostasis, are associated with histological chorioamnionitis, preterm premature rupture of the membranes, and subsequent preterm delivery. MATERIALS AND METHODS: Amniotic fluid was obtained from 55 pregnant women with preterm labor and/or preterm premature rupture of the membranes before 32weeks of gestation, and amniotic fluid levels of annexin A2 were measured with a sandwich enzyme-linked immunosorbent assay. RESULTS: Amniotic fluid levels of annexin A2 in patients with histological chorioamnionitis was higher than that in the remainder (P=0.053), whereas amniotic fluid levels of annexin A2 in patients with preterm premature rupture of the membranes was significantly higher than that in the remainder (P=0.002). Amniotic levels of annexin A2 was a fair test (area under receiver-operator characteristic curve=0.679), and amniotic fluid levels of annexin A2>878.2ng/mL had a sensitivity of 68.8%, a specificity of 65.2%, a positive predictive value of 73.3%, and a negative predictive value of 60.0% for predicting delivery within 2weeks after amniotic fluid sampling. Furthermore, the combined use of amniotic fluid cut-off levels of 878.2ng/mL for annexin A2 and 13.3ng/mL for interleukin-8 improved the specificity (91.3%) and the positive predictive value (89.5%). CONCLUSIONS: We identified amniotic fluid levels of annexin A2, especially in combination with amniotic fluid levels of interleukin-8, as a novel predictive marker for preterm delivery.

Frequent use of fresh frozen plasma is a risk factor for venous thrombosis in extremely low birth weight infants: a matched case-control study.

Percutaneously inserted central catheters (PICCs) are often used in neonatal medicine. Venous thrombosis (VT) is one of the complications associated with PICC use. According to some reports, fresh frozen plasma (FFP) may be a risk factor for VT. The purpose of this study was to determine whether FFP use is associated with VT in extremely low birth weight infants (ELBWIs). We performed a matched case-control study on risk factors for VT in ELBWIs born over a period of 5 years in the neonatal intensive care unit of a tertiary hospital. Controls were infants from the unit matched for gestational age and birth weight. We performed univariate analyses and created receiver operating characteristic (ROC) curves for the cut-off values of continuous parameters such as FFP. We also conducted multivariate conditional logistic regression analysis and calculated adjusted odds ratios and their 95% confidence intervals. Thirteen VT cases and 34 matched controls were examined. Using an ROC curve, FFP by day 5 > 50 mL/kg was selected as the cut-off value. In multivariate conditional logistic regression analysis, FFP by day 5 > 50 mL/kg exhibited an adjusted odds ratio of 5.88 (95% confidence interval: 1.12-41.81, p = 0.036). FFP by day 5 > 50 mL/kg may be a risk factor for VT in ELBWIs.

Transient chaotic rotating waves in a ring of unidirectionally coupled symmetric Bonhoeffer-van der Pol oscillators near a codimension-two bifurcation point.

Propagating waves in a ring of unidirectionally coupled symmetric Bonhoeffer-van der Pol (BVP) oscillators were studied. The parameter values of the BVP oscillators were near a codimension-two bifurcation point around which oscillatory, monostable, and bistable states coexist. Bifurcations of periodic, quasiperiodic, and chaotic rotating waves were found in a ring of three oscillators. In rings of large numbers of oscillators with small coupling strength, transient chaotic waves were found and their duration increased exponentially with the number of oscillators. These exponential chaotic transients could be described by a coupled map model derived from the Poincaré map of a ring of three oscillators. The quasiperiodic rotating waves due to the mode interaction near the codimension-two bifurcation point were evidently responsible for the emergence of the transient chaotic rotating waves.

Epidemiology of Congenital Rubella Syndrome Related to the 2012-2013 Rubella Epidemic in Japan.

This study assessed the epidemiological characteristics of 45 congenital rubella syndrome cases in Japan following the 2012-2013 rubella epidemic. Rubella still poses significant health burdens and the uptake of rubella-containing vaccines among women of childbearing age should be improved.