Challenging management of a baby with congenital multiple intestinal atresia, trisomy 18 and extremely low birth weight: a case report.

BACKGROUND: Extremely low birth weight (< 1000 g) still influences postsurgical prognosis in the neonatal and infantile periods. Additionally, the life expectancy of neonates with trisomy 18 is extremely poor owing to various comorbidities. Therefore, it takes courage to perform laparotomy for the purpose of treatment of congenital multiple intestinal atresia in a baby with an unpredictable life prognosis. CASE PRESENTATION: Fetal ultrasonography revealed cardiac malformation, intestinal dilation, and physical characteristics suggestive of a chromosomal abnormality in this case. The patient was diagnosed with trisomy 18 after birth, with an extremely low birth weight. An atrial septal defect, ventricular septal defect, dilated jejunum, and a very thin collapsed small intestine were found on ultrasonography. With a diagnosis of congenital small intestinal atresia, a challenging laparotomy was done at 3 days of age, with jejunal atresia and multiple distal small intestinal atresia were observed. The jejunal end and distal small intestinal stump were separated into stomas at the wound edge. Hypertrophic pyloric stenosis developed at the age of 3 months and resolved with medication. The patient gained weight (2 kg) by daily stool injection into anal side of the intestine and decompression against poor peritonitis of dilated jejunum using enteral feeding tube for the long period. Finally, we could perform intestinal reconstruction safely and successfully at the age of 9 months. Tracheotomy was performed due to difficulty in extubation associated with chronic lung disease. The patient was discharged at the age of 1 year and 3 months, and no major problems were noted at the age of 2 years. CONCLUSIONS: We treat congenital intestinal atresia in extremely low birth weight infants with severe chromosomal abnormalities and severe cardiac malformations as follows: Stoma creation is performed quickly to avoid deterioration of the patient's hemodynamics. After that, while continuing enteric management, palliative cardiovascular surgery is performed as necessary, and the patient's body weight and intestinal tract status are determined to allow safe intestinal reconstruction.

Prolonged requirements for mechanical ventilation and tube feeding support predicted 18-month outcomes for neonatal encephalopathy.

AIM: We evaluated the predictive ability of prolonged requirements for mechanical ventilation or tube feeding support for 18-month composite outcomes in infants with hypoxic-ischaemic encephalopathy treated with hypothermia. METHODS: This retrospective, nationwide, observational study focused on newborn infants registered in Japan's Baby Cooling Registry between 1 January 2012 and 31 December 2016. The adverse outcomes were defined as death or survival with cerebral palsy, visual or auditory impairment or the requirement for mechanical ventilation or tube feeding at 18 months of age. RESULTS: Adverse outcomes occurred in 165 (28%) of the 591 children in the final cohort. These were predicted by prolonged dependence on mechanical ventilation or tube feeding for more than seven and more than 14 days. The respective values were positive predictive value 0.34 (95% CI 0.33-0.34) and 0.60 (95% CI 0.56-0.62), negative predictive value 0.97 (95% CI 0.91-0.99) and 0.93 (95% CI 0.90-0.95) and area under the curve 0.59 (95% CI 0.54-0.64) and 0.81 (95% CI 0.77-0.85). CONCLUSION: Prolonged dependence on mechanical ventilation or tube feeding for more than 14 days may be useful in predicting 18-month outcomes in newborn infants who have received therapeutic hypothermia.

Predictive value of the Thompson score for short-term adverse outcomes in neonatal encephalopathy.

BACKGROUND: To explore the predictive value of the Thompson score during the first 4 days of life for estimating short-term adverse outcomes in neonatal encephalopathy. METHODS: This observational study evaluated infants with neonatal encephalopathy (≥36 weeks of gestation) registered in a multicenter cohort of cooled infants in Japan. The Thompson score was evaluated at 0-24, 24-48, 48-72, and 72-90 h of age. Adverse outcomes included death, survival with respiratory impairment (requiring tracheostomy), or survival with feeding impairment (requiring gavage feeding) at discharge. RESULTS: Of the 632 infants, 21 (3.3%) died, 59 (9.3%) survived with respiratory impairment, and 113 (17.9%) survived with feeding impairment. The Thompson score throughout the first 4 days accurately predicted death, respiratory impairment, or feeding impairment. The 72-90 h score showed the highest accuracy. A cutoff of ≥15 had a sensitivity of 0.85 and specificity of 0.92 for death or respiratory impairment, while a cutoff of ≥14 had a sensitivity of 0.71 and a specificity of 0.92 for death, respiratory or feeding impairment. CONCLUSION: A high Thompson score during the first 4 days of life, especially at 72-90 h could thus be useful for estimating the need for prolonged life support. IMPACT: The Thompson score on days 1-4 of age was useful in predicting death and respiratory or feeding impairments. The 72-90 h Thompson score showed the highest predictive capability. Owing to the rarity of withdrawal of life-sustaining treatment in Japan, 43% of infants with persistent severe encephalopathy with a Thompson score of ≥15 at 72-90 h of age could regain spontaneous breathing, be extubated, and survive without tracheostomy. Meanwhile, approximately 50% of infants who survived without tracheostomy required gavage feeding. Our results could provide useful information for clinical decision making regarding infants with persistent severe encephalopathy.

Three-year outcome following neonatal encephalopathy in a high-survival cohort.

This study investigated the 3-year clinical outcomes in relation to the severity of encephalopathy in high-survival infants who underwent therapeutic hypothermia. This retrospective observational study was conducted in level II/III neonatal intensive care units in Japan. The nationwide cohort included 474 infants registered in the Baby Cooling Registry of Japan between January 2012 and December 2016. Clinical characteristics, mortality rate and severe neurological impairment at age 3 years were evaluated. Of the infants, 48 (10.4%), 291 (63.1%) and 122 (26.5%) had mild, moderate and severe encephalopathy, respectively, upon admission. By age 3, 53 (11.2%) infants died, whereas 110 (26.1%) developed major disabilities. The mild group survived up to age 3. In the moderate group, 13 (4.5%) died and 44 (15.8%) developed major disabilities. In the severe group, 39 (32.0%) died by age 3. Adverse outcomes were observed in 100 (82.0%) infants. Mortality was relatively low in all subgroups, but the incidence of major disabilities was relatively high in the severe group. The relatively low mortality and high morbidity may be due to Japanese social and ethical norms, which rarely encourage the withdrawal of intensive life support. Cultural and ethical backgrounds may need to be considered when assessing the effect of therapeutic interventions.

Body temperature, heart rate and long-term outcome of cooled infants: an observational study.

BACKGROUND: Therapeutic hypothermia is a standard of care for neonatal encephalopathy; however, approximately one in two newborn infants fails to respond to this treatment. Recent studies have suggested potential relationships between body temperature, heart rate and the outcome of cooled infants. METHODS: The clinical data of 756 infants registered to the Baby Cooling Registry of Japan between January 2012 and December 2016 were analysed to assess the relationship between body temperature, heart rate and adverse outcomes (death or severe impairment at 18 months corrected age). RESULTS: A lower body temperature at admission was associated with adverse outcomes in the univariate analysis (P < 0.001), the significance of which was lost when adjusted for the severity of encephalopathy and other covariates. A higher body temperature during cooling and higher heart rate before and during cooling were associated with adverse outcomes in both univariate (all P < 0.001) and multivariate (P = 0.012, P < 0.001 and P < 0.001, respectively) analyses. CONCLUSIONS: Severe hypoxia-ischaemia might be a common causative of faster heart rates before and during cooling and low body temperature before cooling, whereas causal relationships between slightly higher temperatures during cooling and adverse outcomes need to be elucidated in future studies. IMPACT: In a large cohort of encephalopathic newborn infants, dual roles of body temperature to the outcome were shown; adverse outcomes were associated with a lower body temperature at admission and higher body temperature during cooling. A higher heart rate before and during cooling were associated with adverse outcomes. Severe hypoxia-ischaemia might be a common causative of faster heart rates before and during cooling and low body temperature before cooling. The exact mechanism underlying the relationship between slightly higher body temperature during cooling and adverse outcomes remains unknown, which needs to be elucidated in future studies.

A case of a parthenogenetic 46,XX/46,XY chimera presenting ambiguous genitalia.

Sex-chromosome discordant chimerism (XX/XY chimerism) is a rare chromosomal disorder in humans. We report a boy with ambiguous genitalia and hypospadias, showing 46,XY[26]/46,XX[4] in peripheral blood cells. To clarify the mechanism of how this chimerism took place, we carried out whole-genome genotyping using a SNP array and microsatellite analysis. The B-allele frequency of the SNP array showed a mixture of three and five allele combinations, which excluded mosaicism but not chimerism, and suggested the fusion of two embryos or a shared parental haplotype between the two parental cells. All microsatellite markers showed a single maternal allele. From these results, we concluded that this XX/XY chimera is composed of two different paternal alleles and a single duplicated maternal genome. This XX/XY chimera likely arose from a diploid maternal cell that was formed via endoduplication of the maternal genome just before fertilization, being fertilized with both X and Y sperm.

Outcomes related to 10-min Apgar scores of zero in Japan.

OBJECTIVE: Apgar scores of zero at 10 min strongly predict mortality and morbidity in infants. However, recent data reported improved outcomes among infants with Apgar scores of zero at 10 min. We aimed to review the mortality rate and neurodevelopmental outcomes of infants with Apgar scores of zero at 10 min in Japan. DESIGN: Observational study. PATIENTS: Twenty-eight of 768 infants registered in the Baby Cooling Registry of Japan between 2012 and 2016, at >34 weeks' gestation, with Apgar scores of zero at 10 min who were treated with therapeutic hypothermia. INTERVENTIONS: We investigated the time of first heartbeat detection in infants with favourable outcomes and who had neurodevelopmental impairments or died. MAIN OUTCOME MEASURES: Clinical characteristics, mortality rate and neurodevelopmental outcomes at 18-22 months of age were evaluated. RESULTS: Nine (32%) of the 28 infants died before 18 months of age; 16 (57%) survived, but with severe disabilities and 3 (11%) survived without moderate-to-severe disabilities. At 20 min after birth, 14 of 27 infants (52%) did not have a first heartbeat, 13 of them died or had severe disabilities and one infant, who had the first heartbeat at 20 min, survived without disability. CONCLUSION: Our study adds to the recent evidence that neurodevelopmental outcomes among infants with Apgar scores of zero at 10 min may not be uniformly poor. However, in our study, all infants with their first heartbeat after 20 min of age died or had severe disabilities.

Combination of furosemide and fludrocortisone as a loading test for diagnosis of distal renal tubular acidosis in a pediatric case.

Renal tubular acidosis (RTA) is a rare disease caused by a defect of urinary acidification. The ammonium chloride loading test is the gold standard method for determining the type of RTA. However, because this test has some side effects (e.g., nausea, vomiting, and stomach discomfort), applying this test for pediatric cases is difficult. Recently, a loading test with the combination of furosemide and fludrocortisone was reported to be an alternative to the ammonium chloride loading test, with 100% sensitivity and specificity in adult's cases. We report the first pediatric case of distal RTA in a patient who was successfully diagnosed by a drug loading test with the combination of furosemide and fludrocortisone without any side effects. We also performed genetic analysis and detected a known pathogenic variant in the SLC4A1 gene. The combination loading test of furosemide and fludrocortisone is a useful and safe diagnostic tool for pediatric cases of RTA.

Body Temperature, Heart Rate, and Short-Term Outcome of Cooled Infants.

Therapeutic hypothermia following neonatal encephalopathy is neuroprotective. However, approximately one in two cooled infants still die or develop permanent neurological impairments. Further understanding of variables associated with the effectiveness of cooling is important to improve the therapeutic regimen. To identify clinical factors associated with short-term outcomes of cooled infants, clinical data of 509 cooled infants registered to the Baby Cooling Registry of Japan between 2012 and 2014 were evaluated. Independent variables of death during the initial hospitalization and survival discharge from the cooling hospital at ≤28 days of life were assessed. Death was associated with higher Thompson scores at admission (p < 0.001); higher heart rates after 3-72 hours of cooling (p < 0.001); and higher body temperature after 24 hours of cooling (p = 0.002). Survival discharge was associated with higher 10 minutes Apgar scores (p < 0.001); higher blood pH and base excess (both p < 0.001); lower Thompson scores (at admission and after 24 hours of cooling; both p < 0.001); lower heart rates at initiating cooling (p = 0.003) and after 24 hours of cooling (p < 0.001) and lower average values after 3-72 hours of cooling (p < 0.001); higher body temperature at admission (p < 0.001); and lower body temperature after 24 hours and lower mean values after 3-72 hours of cooling (both p < 0.001). Survival discharge was best explained by higher blood pH (p < 0.05), higher body temperature at admission (p < 0.01), and lower body temperature and heart rate after 24 hours of cooling (p < 0.01 and <0.001, respectively). Lower heart rate, higher body temperature at admission, and lower body temperature during cooling were associated with favorable short-term outcomes.

Evaluation index for asymmetric ventricular size on brain magnetic resonance images in very low birth weight infants.

OBJECTIVE: Asymmetric ventriculomegaly is often evident on brain magnetic resonance imaging (MRI) in very low birth weight infants (VLBWI) and is interpreted as white matter injury. However, no evaluation index for asymmetric left-right and anterior-posterior ventricular sizes has been established. METHODS: In this retrospective multicenter cohort study, brain T2-weighted MRI was performed at term-equivalent ages in 294 VLBWI born between 2009 and 2011. The value of a lateral ventricular index (LVI) to evaluate asymmetric ventricular size, as well as the relationship between the LVI value and walking at a corrected age of 18 months was investigated. At the level of the foramen of Monro in a horizontal slice, asymmetry between the left and right sides and between the anterior and posterior horns was identified by the corrected width and was detected by a low concordance rate and κ statistic value. An LVI representing the sum of the widths of the four horns of the lateral ventricle corrected for cerebral diameter was devised. RESULTS: Asymmetric left-right and anterior-posterior ventricular sizes were confirmed. The LVI value was significantly higher in the non-walking VLBWI group (n = 39) than in the walking VLBWI group (n = 255; 18.2 vs. 15.8, p = 0.02). An LVI cut-off value of 21.5 was associated with non-walking. Multivariate analysis revealed that an LVI value >21.5 was an independent predictor of walking disability at the corrected age of 18 months (odds ratio 2.56, p = 0.008). CONCLUSIONS: The LVI value calculated via MRI may predict walking disability at a corrected age of 18 months in VLBWI.

Therapeutic hypothermia for neonatal encephalopathy: a report from the first 3 years of the Baby Cooling Registry of Japan.

Therapeutic hypothermia is recommended for moderate and severe neonatal encephalopathy, but is being applied to a wider range of neonates than originally envisaged. To examine the clinical use of therapeutic hypothermia, data collected during the first 3 years (2012-2014) of the Baby Cooling Registry of Japan were analysed. Of 485 cooled neonates, 96.5% were ≥36 weeks gestation and 99.4% weighed ≥1,800 g. Severe acidosis (pH < 7 or base deficit ≥16 mmol/L) was present in 68.9%, and 96.7% required resuscitation for >10 min. Stage II/III encephalopathy was evident in 88.3%; hypotonia, seizures and abnormal amplitude-integrated electroencephalogram were observed in the majority of the remainder. In-hospital mortality was 2.7%; 90.7% were discharged home. Apgar scores and severity of acidosis/encephalopathy did not change over time. The time to reach the target temperature was shorter in 2014 than in 2012. The proportion undergoing whole-body cooling rose from 45.4% to 81.6%, while selective head cooling fell over time. Mortality, duration of mechanical ventilation and requirement for tube feeding at discharge remained unchanged. Adherence to standard cooling protocols was high throughout, with a consistent trend towards cooling being achieved more promptly. The mortality rate of cooled neonates was considerably lower than that reported in previous studies.

A Fatal Case of Congenital Langerhans Cell Histiocytosis with Disseminated Cutaneous Lesions in a Premature Neonate.

Background. The outcome of neonates with congenital cutaneous Langerhans cell histiocytosis (LCH) is variable. Observations. We report a case of LCH in a female premature neonate born at 33-week gestation. She had disseminated cutaneous lesions, which consisted of hemorrhagic papules and vesicles, with sparse healthy skin areas, and the hands and feet were contracted with scarring and blackened. She was in respiratory failure although no apparent pulmonary or bone lesions on X-rays were noted. Skin biopsy confirmed a diagnosis of LCH due to observation of CD1a+ Langerhans cells, which lacked expression of E-cadherin and CD56. The patient died 57 hours after birth. Conclusions. Based on this case and the literature survey, the outcome of premature babies with congenital cutaneous LCH lesions is noted to be unfavorable, with the majority of such cases suffering from multisystem disease.

A 12p13 GRIN2B deletion is associated with developmental delay and macrocephaly.

N-methyl D-aspartate receptor subtype 2B (GluN2B), encoded by GRIN2B, is one of the components of the N-methyl D-aspartate receptor protein. Aberrations in GRIN2B have been reported to be responsible for various types of neurodevelopmental disorders. We report a Japanese boy with an ~2 Mb interstitial deletion in 12p13 involving the entire GRIN2B gene, who presented with intellectual disability, motor developmental delay and marked macrocephaly.

Screening for Hyperbilirubinemia in Japanese Very Low Birthweight Infants Using Transcutaneous Bilirubinometry.

OBJECTIVES: To assess the accuracy of transcutaneous bilirubin (TcB) measurements at 5 different body sites in Japanese very low birthweight (VLBW) infants and to determine a cut-off value of TcB to detect total serum/plasma bilirubin (TB) levels ≥10 mg/dL (171 µM). STUDY DESIGN: In a prospective multicenter study, 85 Japanese VLBW infants were enrolled from 5 neonatal intensive care units during the study period. A total of 383 blood samples from infants not receiving phototherapy or ≥24 hours postphototherapy were analyzed. TcB was measured at the forehead, sternum, upper back, lower abdomen, and waist within 1 hour of blood collection. Linear regression analysis and Bland-Altman plots were used to compare TcB values at each site with TB levels. The TcB cut-off value for detecting TB ≥10 mg/dL was determined by receiver operating characteristics curve analysis. RESULTS: TcB significantly correlated with TB, but the coefficient of determination varied among the sites (forehead: 0.5294, sternum: 0.6488, upper back: 0.6321, lower abdomen: 0.5430, waist: 0.7396). At a TcB value ≥8, the sensitivity was 100% at the sternum and upper back, 85% at the waist, 84% at the forehead, and 64% at the lower abdomen to detect TB ≥10 mg/dL. CONCLUSIONS: In Japanese VLBW infants, the accuracy of TcB measurements varies according to body site. TcB ≥8 on the sternum or upper back is more reliable than that on the forehead, lower abdomen, or waist to detect TB levels ≥10 mg/dL.

Pharmacological interventions in the newborn piglet in the first 24 h after hypoxia-ischemia. A hemodynamic and electrophysiological perspective.

The purpose of this study was to investigate whether combined inhibition of neuronal and inducible nitric oxide synthase (NOS) by 2-iminobiotin, free radical scavenging by allopurinol, and non-protein-bound iron chelation with deferoxamine improved cerebral oxygenation, electrocortical brain activity, and brain energy status during the first 24 h after hypoxia-ischemia (HI) in the newborn piglet. Forty-three newborn piglets were subjected to 1 h of severe HI by occluding both carotid arteries and phosphorous magnetic resonance spectroscopy ((31)P-MRS)-guided hypoxia, whereas five served as sham-operated controls. Upon reperfusion, piglets received vehicle (n=12), 2-iminobiotin (n=11), allopurinol (n=10), or deferoxamine (n=10). Cerebral oxygenation was recorded with near-infrared spectrophotometry (NIRS), electrocortical brain activity was assessed with amplitude-integrated EEG (aEEG), and cerebral energy status with (31)P-MRS. The oxygenated hemoglobin (HbO(2)) and total hemoglobin (tHb) were significantly increased in vehicle-treated piglets compared with 2-iminobiotin-treated and deferoxamine-treated piglets. No change in deoxygenated Hb (HHb) was demonstrated over time. The aEEG was significantly preserved in 2-iminobiotin- and deferoxamine-treated piglets compared with vehicle-treated piglets. Allopurinol treatment was not as effective as 2-iminobiotin treatment after HI. Phosphocreatine/inorganic phosphate ratios (PCr/P(i)) were significantly decreased for vehicle-treated piglets at 24 h post-HI, whereas 2-iminobiotin, allopurinol, and deferoxamine prevented the development of secondary energy failure. We speculate that the beneficial effects, especially of 2-iminobiotin, but also of deferoxamine, are due to reduced peroxynitrite-mediated oxidation.

Changes in cerebral haemodynamics, regional oxygen saturation and amplitude-integrated continuous EEG during hypoxia-ischaemia and reperfusion in newborn piglets.

Perinatal asphyxia models are necessary to obtain knowledge of the pathophysiology of hypoxia-ischaemia (HI) and to test potential neuroprotective strategies. The present study was performed in newborn piglets to obtain information about simultaneous changes in cerebral oxygenation and haemodynamics and electrocortical brain activity during a 60-min period of HI and up to 2 h of reperfusion using near infrared spectrophotometry (NIRS) and the amplitude-integrated EEG (aEEG). HI was induced by occluding both carotid arteries and decreasing the fraction of inspired oxygen (FiO(2)) to 0.08-0.12 for 60 min. The mean arterial blood pressure (MABP) and heart rate increased, the oxygenated haemoglobin (O(2)Hb) decreased, and the deoxygenated haemoglobin (HHb) increased, but total haemoglobin (tHb) remained stable during the 60-min HI period. The regional oxygen saturation (rSO(2)) was significantly decreased during the whole HI period, as was the electrocortical brain activity. Upon reperfusion and reoxygenation, the MABP normalised to baseline values but the heart rate remained increased. O(2)Hb and HHb recovered to baseline values and tHb remained unchanged. As indicated by the unchanged tHb values during the HI period, it was suggested that compensatory cerebral perfusion occurred during this period, probably via the vertebrobasilar arterial system. Furthermore, in this model a clear hyperperfusion period directly upon reperfusion and reoxygenation is not present. rSO(2) showed a quick recovery to baseline values, but the aEEG-measured electrocortical brain activity remained reduced following HI. In conclusion, the rSO(2) and aEEG showed a different time profile following perinatal asphyxia. The stable tHb during HI and reperfusion in this model differs from observations in human neonates.