Safety and accuracy of neonatal continuous glucose monitoring.

BACKGROUND: Hypoglycemia is a significant problem for all neonates and requires minimally invasive and reliable monitoring. The primary objective of this study was to verify the safety and accuracy of the continuous glucose monitoring (CGM) of full-term neonates using Freestyle Libre, a flash glucose monitoring (FGM) device. METHODS: The study was conducted on 20 neonates. Shortly after birth, we placed the FGM sensor on the outside of the neonates' thighs. We scanned the CGM values at 60, 120, 180, and 360 min after birth and simultaneously obtained blood glucose values with plantar capillaries by heel puncture. The neonates wore the sensors for up to 6 h and then they were removed. RESULTS: Of the 75 data points to be measured, 65 points (86.7%) were obtained by scan. There was no change in the sensor attachment site in 12 of 18 completed cases in this study but we observed slight induration in four cases (22.2%) and slight redness in one case (5.5%) at the sensor puncture site. A moderate correlation was observed between the CGM and blood glucose values. The CGM values tended to be low at 120, 180, and 360 min after birth, and tended to be high only at 60 min after birth. CONCLUSIONS: The CGM device was safe to wear on the neonate and the CGM data correlated well with blood glucose levels. There was dissociation between CGM data and blood glucose levels in the acute period soon after birth when the blood glucose levels changed rapidly.

Accuracy of transcutaneous bilirubin level measured by a JM-105 bilirubinometer.

BACKGROUND: Transcutaneous bilirubin (TcB) measurement is useful, but dissociation with total serum bilirubin (TSB) is a clinical problem in measurement. We verified the accuracy of the latest version of the JM-105 jaundice meter. METHODS: The TcB, TSB, and hematocrit (Hct) measurements obtained in the first 4 days of life in 2788 term neonates were analyzed. RESULTS: When divided into 2-mg/dL classes, the difference between the TcB and TSB measurements did not change as TcB increased, but both overestimation and underestimation of TcB increased as TcB increased. At TcB greater than 11 mg/dL, inaccurate measurements with dissociation greater than 2 mg/dL exceeded 10% of the TcB measurements. The Hct value was associated with overestimation and underestimation. CONCLUSION: To evaluate neonatal jaundice accurately, it is desirable to measure TSB by blood sampling before discharge from obstetrics or in the case of worsening jaundice on day 4 or 5 of life.

Transmission of extended-spectrum cephalosporin-resistant Salmonella harboring a blaCMY-2-carrying IncA/C2 plasmid chromosomally integrated by ISEcp1 or IS26 in layer breeding chains in Japan.

Dissemination of extended-spectrum cephalosporin (ESC)-resistant Salmonella is a public health concern in the egg production industry. ESC-resistant Salmonella often acquires the bla gene via insertion sequences (ISs). Therefore, this study aimed to assess antimicrobial resistance in Salmonella from Japanese layer breeding chains and egg processing chains, and determine the genetic profiles of IS-like elements in ESC-resistant Salmonella. Antimicrobial susceptibility testing was performed on 224 isolates from 49 facilities involving layer breeder farms, hatcheries, pullet-rearing farms, and layer farms in breeding chains along with egg processing chains. ESC-resistant Salmonella strains were whole-genome sequenced. Among them, 40 (17.9%) were resistant to at least streptomycin, tetracycline, ampicillin, chloramphenicol, cefpodoxime, nalidixic acid, ciprofloxacin, and/or kanamycin despite lacking resistance to azithromycin and meropenem. Moreover, 15 were ESC-resistant Salmonella harboring blaCMY-2 (Salmonella enterica serovar Ohio, n=12; S. Braenderup, n=1; untypeable with O7:b:-, n=1) and blaCTX-M-14 (S. Cerro, n=1). IncA/C2 plasmids containing ISEcp1, IS26, and multiple antimicrobial resistance genes (including blaCMY-2) were identified in S. Ohio isolates from pullet-rearing and layer farms belonging to the same company. Chromosomal integration of partial or whole IncA/C2 plasmids was seen with two S. Ohio isolates via ISEcp1 or IS26, respectively. Antimicrobial resistance genes such as blaCMY-2 might be transmitted among the upper and the lower levels of layer breeding chains via the replicon type IncA/C2 plasmids containing ISEcp1 and IS26.

Effects of Season of Birth and Meteorological Parameters on Serum Bilirubin Levels during the Early Neonatal Period: A Retrospective Chart Review.

To establish whether serum bilirubin levels vary in healthy term neonates according to seasonal variations and meteorological factors, we retrospectively studied 3344 healthy term neonates born between 2013 and 2018. Total serum bilirubin (TSB) levels were measured on the fourth day after birth. The monthly and seasonal variations in TSB levels and clinical and meteorological effects on TSB levels were assessed. In the enrolled neonates, the median TSB level was 195 µmol/L. The TSB level peaked in December and was the lowest in July, but the variation was not statistically significant. The TSB level was significantly higher in the cold (October to March) than in the warm season (April to September; p = 0.01). The comparison between seasonal differences according to sex showed TSB levels were significantly higher in the cold than in the warm season in male infants (p = 0.001), whereas no significant difference was observed in female infants. A weakly negative but significant association existed between TSB levels and the mean daily air temperature (r = -0.07, p = 0.007) in only the male population; the female population showed no significant correlation between TSB levels and meteorological parameters. The season of birth is an etiological factor in neonatal jaundice, with an additional influence from sex.

Hemodynamic changes in neonates born to mothers with Graves' disease.

PURPOSE: Cardiac insufficiency is a major morbidity in neonatal hyperthyroidism. It is important to assess the hemodynamics in neonates born to mothers with Graves' disease (GD). This study prospectively evaluated the hemodynamic changes in neonates born to mothers with GD. METHODS: Overall, 80 newborns were enrolled. Thirty-six neonates were born to mothers with GD who were positive for thyroid-stimulating hormone (TSH) receptor antibody (TRAb), and 44 were born to mother negative for TRAb. The serum levels of TSH, free triiodothyronine (FT3), free thyroxine (FT4), and N-terminal-pro-B-type natriuretic peptide (NT-proBNP), the cardiac output, and cardiac index (CI) evaluated by echocardiography were compared between the two groups at several postnatal points (day of delivery and 5, 10, and 30 days of life). RESULTS: The TRAb-positive newborns had higher FT4 levels and CI on Day 5 (both p < 0.05) and higher FT3 (p < 0.05) and FT4 levels (p < 0.01) and CI (p < 0.01) but lower TSH levels (p < 0.05) on Day 10 than the TRAb-negative newborns. The TRAb-positive newborns had significantly higher NT-proBNP levels on Days 5 (median 752 vs. 563 pg/mL, p = 0.034) and 10 (median 789 vs. 552 pg/mL, p = 0.002) than the TRAb-negative newborns. CONCLUSIONS: Hemodynamic changes in neonates born to TRAb-positive mothers with GD resulted in a higher CI and NT-proBNP levels than in those with TRAb-negative mothers from postnatal days 5 to 10.

The association between congenital heart disease and small for gestational age with regard to the prevalence and outcomes.

AIM: To evaluate the association between small for gestational age (SGA) and the prevalence of congenital heart disease (CHD) and the association of the SGA status with the outcomes among infants with CHD. METHODS: Echocardiography was performed within the first 5 days of life in 5664 consecutive infants. Infants were classified into four groups according to the presence or absence of SGA and CHD. All CHD infants were followed up until either spontaneous resolution of all cardiac lesions, invasive intervention or death. All newborns without CHD were followed for mortality until the final follow-up date. RESULTS: A total of 303 infants were diagnosed with CHD, while 610 were diagnosed with SGA. Among the CHD infants, 56 were SGA, and 247 were not. A multivariable logistic regression analysis showed that the adjusted odds ratio of SGA (9.71, P < .001) was significantly higher than that of other parameters concerning predictors of invasive intervention or death. The mortality rate in the presence of both SGA and CHD (hazard ratio: 33.6, P < .001) was markedly higher than in the absence of both. CONCLUSION: SGA was a significant predictor of invasive intervention for CHD. The combination of CHD and SGA carried a high risk of death beyond that of either alone.

De novo ZBTB7A variant in a patient with macrocephaly, intellectual disability, and sleep apnea: implications for the phenotypic development in 19p13.3 microdeletions.

Interstitial microdeletions at chromosome 19p13.3 are frequently associated with a constellation of clinical features including macrocephaly, characteristic face, intellectual disability, and sleep apnea. Previous studies in 25 patients with 19p13.3 microdeletions have revealed loss of MAP2K2 in 24 patients and that of PIAS4 and ZBTB7A in 23 patients, suggesting that these three adjacent genes are candidate genes for the phenotypic development in 19p13.3 microdeletions. We identified a de novo likely pathogenic heterozygous missense variant of ZBTB7A (NM_015898.3:c.1152C>G, p.(Cys384Trp)) in a Japanese boy with macrocephaly, intellectual disability, and sleep apnea. This variant affects the conserved cysteine residue forming the coordinate bond with Zn2+ ion at the first zinc finger domain, and is predicted to exert a dominant-negative effect because of the generation of homo- and hetero-dimers with the wild-type and variant ZBTB7A proteins. The results argue for a critical relevance of ZBTB7A to the development of most, but probably not all, of the 19p13.3 microdeletion phenotype.

Successful Management of Pulmonary Arterial Hypertension by Monitoring N-Terminal Pro-B-Type Natriuretic Peptide Serum Levels in a Preterm Infant with Chronic Lung Disease: A Case Report.

We measured the serial changes in N-terminal probrain natriuretic peptide (NT-proBNP) levels in a 6-month-old male infant with chronic lung disease (CLD) complicated by pulmonary arterial hypertension (PAH). The patient was born at the 24th week of gestation weighing 695 g. At 1 month after birth, an echocardiogram confirmed the diagnosis of CLD with PAH. He was treated with inhaled nitric oxide (iNO) and oral sildenafil and discharged from the hospital. At 190 days of age, the patient was readmitted to our department because of a viral upper respiratory infection. At 195 days of age, his respiratory condition worsened with pulmonary edema and his NT-proBNP level was determined to be 10,117 pg/mL. The patient was immediately administered iNO, and his respiratory condition improved, and NT-proBNP levels decreased. However, he experienced repeated severe cyanosis attacks. Before the attacks, his NT-proBNP level was > 1,000 pg/mL. Therefore, we continuously administered iNO until his NT-proBNP level decreased to < 1,000 pg/mL. We safely discontinued iNO administration at 473 days of age. In conclusion, serial change in NT-proBNP is a surrogate marker with prognostic value in patients with PAH associated with CLD.

Can echocardiographic screening in the early days of life detect critical congenital heart disease among apparently healthy newborns?

BACKGROUND: Delayed diagnosis of critical congenital heart disease (CCHD) carries a serious risk of mortality, morbidity, and handicap. As echocardiography is commonly used to diagnose congenital heart disease (CHD), echocardiographic investigations in newborns may be helpful in detecting CCHD earlier and with higher sensitivity than when using other screening methods. The present study aimed to evaluate the effectiveness of echocardiographic screening for CCHD in a tertiary care center. METHODS: A retrospective chart review was conducted among newborns delivered at Hamamatsu University Hospital between June 2009 and May 2016. The study included consecutive newborns who underwent early echocardiographic screening (within the first 5 days of life) performed by pediatric cardiologists, were born at ≥36 weeks of gestation, had a birthweight ≥2300 g, and were cared for in the well-baby nursery. Newborns admitted to the neonatal intensive care unit, as well as those with prenatal diagnosis of CHD and/or clinical symptoms or signs of CHD were excluded. Four CHD outcome categories were defined: critical, serious, clinically significant, and clinically non-significant. RESULTS: A total of 4082 live newborns were delivered during the study period. Of 3434 newborns who met the inclusion criteria and had complete echocardiography data, 104 (3.0%) were diagnosed as having CHD. Among these, none was initially diagnosed as having critical or serious CHD. Of the 95 newborns who continued follow-up with a cardiologist, 61 (64%) were determined to have non-significant CHDs that resolved within 6 months of life. Review of excluded newborns revealed nine cases of critical or serious CHD; among these newborns, six were diagnosed prenatally and three had some clinical signs of CHD prior to hospital discharge. CONCLUSIONS: In our tertiary care center, echocardiography screening within the first 5 days of life did not help improve CCHD detection rate in newborns without prenatal diagnosis or clinical signs of CHD. Echocardiographic screening may be associated with increased rate of false-positives (defects resulting in clinically non-significant CHDs) in newborns without prenatal diagnosis or suspicion of CHD.

Hypertrophic pyloric stenosis following persistent pulmonary hypertension of the newborn: a case report and literature review.

BACKGROUND: Although persistent pulmonary hypertension of the newborn (PPHN) and infantile hypertrophic pyloric stenosis (HPS) are both well-known diseases that occur in early infancy, PPHN complicated by HPS is rare. As nitric oxide (NO) is an important mediator of biological functions, on both the vascular endothelium and smooth muscle cells, the decreased production of NO might play a role in the pathogenesis of both PPHN and HPS. We present the case of a neonate who developed HPS following PPHN, including a detailed review on research published to date, and we discuss the pathogenesis of PPHN and HPS. CASE PRESENTATION: A female neonate born at 38 weeks of gestation, weighing 3140 g, developed PPHN due to meconium aspiration syndrome. Intensive treatment with high frequency oscillations and inhaled NO were initiated, and sildenafil and bosentan were added. She gradually recovered. At 15 days of age, the patient developed recurrent vomiting after feeding and the diagnosis of HPS was made. Intravenous atropine therapy was started at 20 days of age, but the efficacy was clinically unsatisfactory. The coadministration with transdermal nitroglycerin improved the symptoms, and oral feeding was successfully re-introduced. CONCLUSIONS: Our patient recovered from both PPHN and HPS using NO-related medications. A decrease in NO synthesis is likely to be a common pathway for PPHN and HPS.

Mutation analysis of FGFR1-3 in 11 Japanese patients with syndromic craniosynostoses.

Syndromic craniosynostoses usually occur as single gene disorders. In this study, we analyzed FGFR1-3 genes in four patients with Crouzon syndrome (CS), four patients with Pfeiffer syndrome type 2 (PS-2), one patient with Jackson-Weiss syndrome (JWS), and two patients (sisters) with Muenke syndrome (MS). FGFR2 and FGFR3 mutations were identified in 10 of the 11 patients. Notably, we found a novel FGFR2 p.Asn549Thr mutation in a patient with CS, and a novel FGFR2 p.Ser347Cys mutation in a patient with JWS (thus, this patient was turned out to have an FGFR2-related PS-variant). We also identified an FGFR2 p.Ser252Leu mutation in a phenotypically normal father of a daughter with CS, and an FGFR3 p.Pro250Arg mutation in a mildly macrocephalic father of sisters with MS. These findings, together with previous data, imply that the same FGFR2 mutations can be associated with a wide range of phenotypes including clinically different forms of syndromic craniosynostosis and apparently normal phenotype, depending on other (epi)genetic and environmental factors. Thus, genetic studies are recommended not only for obviously affected individuals but also for family members with apparently normal phenotype or non-specific subtle abnormal phenotype, to allow for pertinent genetic counseling. © 2016 Wiley Periodicals, Inc.

International normalized ratio testing with a point-of-care coagulometer in 1-month-old infants: A comparison with Normotest.

INTRODUCTION: Early infants are at risk of vitamin K (VK) deficiency-associated bleeding unless they receive VK prophylaxis. A coagulation screening test might be necessary to detect prophylactic failure, but it is rarely conducted owing to the difficulty of blood sampling. CoaguChek XS is a portable, point-of-care (POC) coagulation analyzer that determines international normalized ratios (INRs) using only small volumes of blood. Although POC tests assessing INR have become widespread for adults, studies have not been performed in early infancy. This study aimed to determine the reference interval (RI) for INR for 1-month-old infants using the CoaguChek XS and to compare INRs with Normotest (NT) values to evaluate its efficacy as a VK deficiency screening test. MATERIALS AND METHODS: This study included 578 consecutive 1-month-old, healthy, term infants who underwent a 1-month health checkup. CoaguChek XS INRs and NT values were analyzed for each subject. RESULTS: The enrolled neonates were orally administered VK 6-12h and 4days after birth. An INR RI for 1-month-old infants was established using the CoaguChek XS (range of 0.9-1.1). On the other hand, the NT RI was 69%-130%. We observed a significant inverse correlation between INRs and NT values. CONCLUSIONS: Our study is the first to establish an INR RI using the CoaguChek XS for 1-month-old, healthy, term infants. CoaguChek XS INR was more convenient to test than NT. However, we could not demonstrate its efficacy as a VK deficiency screening test because no infant had an aberrant NT value or a bleeding disorder.

Seasonal variation in the international normalized ratio of neonates and its relationship with ambient temperature.

BACKGROUND: The morbidity and mortality rates due to cardiovascular events such as myocardial infarction are known to exhibit seasonal variations. Moreover, changes in the ambient temperature are reportedly associated with an increase in these events, which may potentially involve blood coagulation markers. Bleeding due to vitamin K deficiency in neonates, which is associated with high mortality and a high frequency of neurological sequelae, is more commonly observed during the summer season and in warm regions in Japan. To determine the presence of seasonal variation and the influence of ambient temperature on blood coagulation markers in healthy term neonates, we assessed the international normalized ratio (INR) values measured using CoaguChek XS. METHODS: We studied 488 consecutive healthy term neonates who were born at a perinatal center between July 2012 and June 2013. The INR values were measured using CoaguChek XS in 4-day-old neonates who received nursing care in the newborn nursery throughout the duration of hospitalization. The seasonal variations in the INR values and environmental effects on the INR were assessed. RESULTS: The mean monthly INR values peaked in July (1.13 ± 0.08), whereas the lowest values were observed in January (1.05 ± 0.08). Higher levels of INR were observed during the summer season (June to August) than during the winter season (December to February). Simple linear regression analysis indicated the presence of weakly positive but significant correlations between INR and outdoor temperature (r = 0.25, p < 0.001), outdoor relative humidity (r = 0.19, p < 0.001), and room relative humidity (r = 0.24, p < 0.001), and the presence of a significant negative correlation between INR and room temperature (r = -0.13, p = 0.02). Furthermore, multiple linear regression analysis showed that only outdoor temperature significantly influenced the INR. CONCLUSIONS: A seasonal variation in the INR values was observed among neonates, possibly due to the variation in ambient temperature. Even though the neonates received nursing care in the newborn nursery that was constantly air-conditioned, the outdoor temperature was the most influential factor on INR.

Clinical and molecular studies in four patients with SRY-positive 46,XX testicular disorders of sex development: implications for variable sex development and genomic rearrangements.

We report four patients with SRY-positive 46,XX testicular disorders of sex development (46,XX-TDSD) (cases 1-4). Case 1 exhibited underdeveloped external genitalia with hypospadias, case 2 manifested micropenis and cases 3 and 4 showed normal external genitalia. The Xp;Yp translocations occurred between the X- and the Y-differential regions in case 1, between PRKX and inverted PRKY in case 2 and between the X-chromosomal short arm pseudoautosomal region and the Y-differential regions in cases 3 and 4. The distance of the Yp breakpoint from SRY was ~0.75 Mb in case 1, ~6.5 Mb in case 2, ~2.3 Mb in case 3 and ~72 kb in case 4. The Xp;Yp translocation occurred within an 87-bp homologous segment of PRKX and PRKY in case 2, and between non-homologous regions with addition of an 18-bp sequence of unknown origin in case 4. X-inactivation analysis revealed random inactivation in cases 1-4. The results argue against the notion that undermasculinization in 46,XX-TDSD is prone to occur when translocated Yp materials are small (<100 kb of the Y-differential region), and imply that the Xp;Yp translocations result from several mechanisms including non-allelic homologous recombination and non-homologous end joining.

International normalized ratio testing with point-of-care coagulometer in healthy term neonates.

BACKGROUND: Neonates routinely receive vitamin K to prevent vitamin K deficiency bleeding, which is associated with a high mortality rate and a high frequency of neurological sequelae. A coagulation screening test might be necessary to detect prophylactic failure or incomplete prophylaxis. However, venous access and the volume of blood required for such testing can be problematic. CoaguChek XS is a portable device designed to monitor prothrombin time while only drawing a small volume of blood. Although the device is used in adults and children, studies have not been performed to evaluate its clinical utility in neonates, and the reference value is unknown in this population. The objectives of the present study were to determine the reference intervals (RIs) for international normalized ratio (INR) using the CoaguChek XS by capillary puncture in healthy term neonates, to evaluate factors that correlate with INR, and to evaluate the device by assessing its ease of use in clinical practice. METHODS: This study included 488 healthy term neonates born at a perinatal center between July 2012 and June 2013. The INRs determined by CoaguChek XS were measured in 4-day-old neonates. RESULTS: The enrolled neonates were orally administered vitamin K 6-12 h after birth. A RI for INRs in 4-day-old neonates was established using the CoaguChek XS with a median value of 1.10 and a range of 0.90-1.30. A significant difference in the INR was noted between male (median value, 1.10; RI, 0.90-1.30) and female (median value, 1.10; RI, 0.90-1.24) neonates (p = 0.049). The INR was found to correlate with gestational age, birth weight, and hematocrit value. CONCLUSIONS: The CoaguChek XS device is safe, fast, and convenient for performing INR assays in neonates. Our study is the first to establish a RI for INRs that were measured using the CoaguChek XS in healthy term neonates.

Glucose-6-phosphate dehydrogenase deficiency and adrenal hemorrhage in a filipino neonate with hyperbilirubinemia.

We report on a Filipino neonate with early onset and prolonged hyperbilirubinemia who was delivered by a vacuum extraction due to a prolonged labor. Subsequent studies revealed adrenal hemorrhage and glucose-6-phosphate dehydrogenase (G6PD) deficiency. It is likely that asphyxia and resultant hypoxia underlie the occurrence of adrenal hemorrhage and the clinical manifestation of G6PD deficiency and that the presence of the two events explains the early onset and prolonged hyperbilirubinemia of this neonate. Our results represent the importance of examining possible underlying factors for the development of severe, early onset, or prolonged hyperbilirubinemia.

Prevalence of congenital heart disease assessed by echocardiography in 2067 consecutive newborns.

AIM: There are discrepancies in the reported prevalence of congenital heart disease (CHD). This study prospectively evaluated the prevalence of CHD in consecutive newborns using echocardiographic screening. METHODS: A cohort screening study was conducted in an unselected series of all live-birth newborns. Two-dimensional and colour Doppler echocardiography was performed at 0-4 days of life in 2067 consecutive neonates who were born at the Hamamatsu University Hospital, Japan, between May 2005 and April 2010. RESULTS: There were 104 cases of CHD in the 2067 live births. Ventricular septal defect and patent ductus arteriosus were the most frequent cardiac abnormalities. The prevalence of newborns with CHD who had signs or symptoms of CHD and/or required invasive intervention was 21.3 per 1000 live births. However, 60 patients (29.0 per 1000 live births) with CHD were asymptomatic and did not need invasive intervention. The overall prevalence of CHD in this series was 50.3 per 1000 live births. CONCLUSION: This prospective study using echocardiography for all newborns shows a higher prevalence of CHD than almost all of the previous studies.

Case of polyhydramnios complicated by Opitz G/BBB syndrome.

Opitz G/BBB syndrome is a congenital disorder characterized by midline defects, such as hypertelorism, cleft lip and/or palate, hypospadias, and by dysphagia often caused by laryngo-tracheo-esophageal abnormalities. We experienced a case of polyhydramnios in a male dichorionic diamniotic (DD) twin, who was diagnosed with Opitz G/BBB syndrome after birth. It is suggested that severe dysphagia was causatively associated with the development of polyhydramnios. In cases of Opitz G/BBB syndrome, boys are usually more heavily affected than girls, who generally manifest only hypertelorism. In the differential diagnosis of polyhydramnios of unidentified cause in male fetuses, it may be helpful to consider maternal facial characteristics, especially hypertelorism.

Bifidobacterium septicemia associated with postoperative probiotic therapy in a neonate with omphalocele.

We report the one case of sepsis caused by Bifidobacterium breve administered as probiotic therapy. Probiotics can be a potential cause of an invasive disease and should be used with care in vulnerable patients.