Temporal Relationship between Serum Levels of Interleukin-6 and C-Reactive Protein in Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy.

Objective C-reactive protein (CRP) is a useful marker of neonatal infection. Recent studies have shown that neonatal therapeutic hypothermia delays an elevation of CRP in infants with hypoxic-ischemic encephalopathy (HIE). This study investigated the time difference of peak levels of serum CRP and other inflammatory responses during therapeutic hypothermia. Study design We prospectively studied the serial serum data of CRP, interleukin-6 (IL-6), procalcitonin (PCT), and complete blood counts during the first week of life in HIE infants receiving therapeutic hypothermia. Results We identified 22 infants who received therapeutic hypothermia between August 2013 and July 2015. No infants developed clinically overt infections. The peak of serum levels of IL-6, PCT, and CRP were postnatal days 1, 2, and 4, respectively. White blood cells, neutrophils, and platelet counts gradually decreased from days 1 to 7. Early postnatal serum levels of IL-6 correlated with CRP on day 4 (IL-6 on day 2; r = 0.78, p < 0.001). Conclusion The peak value of CRP on day 4 might reflect the early production and secretion of IL-6 rather than an actual infection. Serial measurement of IL-6 might help avoid invasive sepsis workup and unnecessary change of antibiotics in infants.

Tailor-made circulatory management based on the stress-velocity relationship in preterm infants.

Preterm infants frequently experience pulmonary hemorrhage or cerebral intraventricular hemorrhage after birth. The immature myocardium of the left ventricle faces a high afterload after the baby is separated from the placenta. However, the preterm left ventricle has limited ability to respond to such an increase in afterload. This results in depressed cardiac function and a deterioration in hemodynamics. We speculated that the perinatal deterioration in cardiac performance would be closely related to serious hemorrhages. To prove our hypothesis, we studied the interrelationship between the perinatal changes in cardiac performance and the incidences of intraventricular and pulmonary hemorrhage. We obtained the stress-velocity relationship (rate-corrected mean fiber shortening velocity and end-systolic wall stress relationship) by M-mode echocardiography and arterial blood pressure measurement. We found that the incidences of intraventricular and/or pulmonary hemorrhages were higher in infants with an excessive afterload, which resulted in a decrease in the function of the left ventricle. We suggest that careful attention to keep the afterload at an acceptable level by vasodilator therapy and sedation may reduce or prevent these serious complications. In this review, we will discuss our data along with related literature.

Unilateral glomerulocystic kidney disease associated with tuberous sclerosis complex in a neonate.

We report a case of glomerular cystic kidney disease (GCKD) associated with tuberous sclerosis complex (TSC) in a neonate. The patient displayed progressive abdominal enlargement attributed to GCKD associated with TSC. After birth, the right kidney was resected because it compressed his liver and right lung, and possible malignancy could not be excluded. Macroscopically, the resected kidney was markedly enlarged, and histologically the kidney had numerous glomerular cysts accompanied by papillary epithelial growth. Notably, a small area of normal parenchyma was observed at the lower pole. The epithelial cells of the cysts displaying a papillary growth pattern were positive for mTOR, phosphorylated mTOR, and phosphorylated S6 ribosomal protein (p-S6). The morphologically noncystic, normal-looking tubular epithelium was also positive for p-S6. These results imply that one more molecular event might be necessary for cyst formation in GCKD associated with TSC, in addition to the activation of mTOR signaling.

TSH suppression after intravenous glucocorticosteroid administration in preterm infants.

BACKGROUND: Reports have described that, in adults, steroids suppress thyroid-stimulating hormone (TSH) and triiodothyronine (T3) and might suppress thyroxine (T4). No data have been reported for thyroid hormone changes before or after administration of glucocorticoid in preterm infants. AIMS: The aim of this study was to investigate short-term effects of thyroid hormones on preterm infants. INDEX CASES: We measured TSH, free T3 (FT3), and free T4 (FT4) before and after one or two doses of glucocorticoids administered to five infants at 29-37 weeks of corrected gestational age. RESULTS: Comparison of thyroid hormone levels before and 1 day after glucocorticoid administration showed that TSH significantly decreased by 76% (64%-87%), FT3 by 33% (10%-50%), and FT4 by 10% (3%-17%). The decline in TSH and FT3 was followed by an increase around the pretreatment level at 3-15 days after glucocorticoid administration. In two of the five infants, FT4 continued to decrease from 1 day after glucocorticoid administration. CONCLUSIONS: In preterm infants, assessing thyroid hormones after glucocorticoid therapy demands caution because very short-term administration causes marked changes.

Prenatal ultrasonographic findings and fetal/neonatal outcomes of body stalk anomaly.

We studied 27 cases that were post or prenatally diagnosed with body stalk anomaly (BSA) using medical records of prenatal ultrasound findings, pregnancy outcomes, and fetal/neonatal prognosis during 1992 to 2018. Termination of pregnancy was chosen in 15 cases. Of the remaining 12 cases, seven were stillbirths and five were live births. Of seven stillbirths, intrauterine fetal demise occurred before onset of labor in four cases at 17 to 20th weeks of pregnancy. Pregnancy was continued in eight cases. Median gestational age of delivery was 33rd weeks of pregnancy. Median birth weight was 1198 g (range:482-1914 g). Vaginal delivery was chosen in six and caesarean delivery in two cases. Among six vaginally delivered cases, three (50%) fetuses were stillborn. All five live born neonates died within a few hours (16-133 minutes). Eighteen cases were confirmed as BSA postnatally by placental examination or autopsy at our hospital. Main prenatal ultrasonographic findings of them were abdominal wall defect (100%), absence of the umbilical cord (72%), abnormal spine (61%), and abnormal legs (50%). The most characteristic prenatal ultrasonography findings of BSA were the absence of free umbilical cord in the amniotic cavity and the presence of abdominal organs into the extraembryonic celom through abdominal wall defects. The autopsy showed severe pulmonary hypoplasia with the median lung/body weight ratio of 0.61% (range:0.34-0.85%). There were no cases of maternal morbidities. Our study provides important information about the pregnancy outcome and the fetal/neonatal outcome of BSA cases for the parents whose fetuses are diagnosed with BSA prenatally.

Plectin deficiency leads to both muscular dystrophy and pyloric atresia in epidermolysis bullosa simplex.

Plectin is a cytoskeletal linker protein which has a long central rod and N- and C-terminal globular domains. Mutations in the gene encoding plectin (PLEC) cause two distinct autosomal recessive subtypes of epidermolysis bullosa: EB simplex (EBS) with muscular dystrophy (EBS-MD), and EBS with pyloric atresia (EBS-PA). Previous studies have demonstrated that loss of full-length plectin with residual expression of the rodless isoform leads to EBS-MD, whereas complete loss or marked attenuation of expression of full-length and rodless plectin underlies the more severe EBS-PA phenotype. However, muscular dystrophy has never been identified in EBS-PA, not even in the severe form of the disease. Here, we report the first case of EBS associated with both pyloric atresia and muscular dystrophy. Both of the premature termination codon-causing mutations of the proband are located within exon 32, the last exon of PLEC. Immunofluorescence and immunoblot analysis of skin samples and cultured fibroblasts from the proband revealed truncated plectin protein expression in low amounts. This study demonstrates that plectin deficiency can indeed lead to both muscular dystrophy and pyloric atresia in an individual EBS patient.

Manual expression and electric breast pumping in the first 48 h after delivery.

BACKGROUND: Early feeding for preterm infants via the mother's own milk is crucial for lowering morbidity and mortality. Obtaining the mother's milk in the first few days is sometimes difficult; an effective way of mediating this problem has not yet been established. The aim of the present study was therefore to investigate whether breast pumping using a hospital-grade electric pump was more effective in maximizing the available milk volume and more comfortable than manual expression in the first 48 h after birth. METHODS: A sequential cross-over study was performed in a maternity ward, in a tertiary perinatal center, Japan. Eleven women whose infants were admitted to the neonatal intensive care unit were sequentially allocated to either manual or electric breast expression (Symphony) for their first expression after 6 h following birth. The women then used the other method for the next expression, and continued to alternate between methods until seven sessions had been completed for each method. The time interval between expressions was 3 h. Main outcome measures were volume of milk expressed per session and pain assessment at each expression using the Wong and Baker face-scale. RESULTS: Net milk yield per woman was 2 mL manually (median; range: 0-12.6 mL) and 0.6 mL (0-7.2 mL) by electric expression (P < 0.05). The frequency of women stating no pain was higher for electric pumping than manual expression (90% vs 36%, respectively; P < 0.05). CONCLUSIONS: In the early postpartum period, the best way to obtain colostrum is by gentle manual expression. For mothers who feel pain during manual expression, use of the stimulation phase of the Symphony pump may be preferable.

A severe form of Ellis-van Creveld syndrome caused by novel mutations in EVC2.

Ellis-van Creveld syndrome (EvC MIM. #225500) is an autosomal recessive skeletal dysplasia characterised by thoracic hypoplasia, cardiac anomalies, acromesomelic limb shortening, and postaxial polydactyly. Affected individuals commonly manifest with cardiorespiratory failure as neonates but generally survive neonatal difficulties. We report here on affected Japanese sibs with a lethal phenotype of EvC caused by novel compound heterozygous mutations of EVC2, c.871-3 C > G and c.1991dupA.

Congenital Candida glabrata infection without specific nodules on the placenta and umbilical cord.

Two extremely premature infants died as a result of congenital Candida glabrata infection, and their placentas and umbilical cords were free of macroscopic Candida nodules. Because non-Candida albicans Candida infections are less likely to produce necrotic foci, we should not exclude Candida infections in the absence of macroscopic nodules on the placenta and umbilical cord.

Re-evaluation of chorioamnionitis and funisitis with a special reference to subacute chorioamnionitis.

Our purpose is to prove that prolonged inflammation of the chorionic plate, which we have termed subacute chorioamnionitis (SCAM), is a distinctive entity and should be differentiated from acute chorioamnionitis (ACAM) because it is an excellent prognostic indicator of chronic lung disease (CLD), including Wilson-Mikity syndrome (WMS). Ninety singleton placentas with stage-3 chorioamnionitis were delivered at 23 to 32 weeks of gestation during 1993 to 1996, and the infants survived more than 28 days. There were 49 placentas with stage 3 SCAM, 33 placentas with stage 3 ACAM, and 8 placentas with subacute necrotizing funisitis (SNF) and without inflammation of the chorionic plate. Fifty-three of gestation- and birthweight-matched placentas without chorioamnionitis were selected as control. To determine the risk factors for CLD, 27 clinical and 6 histological variables were analyzed. Logistic regression analysis showed that amniotic necrosis (AN) (P =.0168) and low birthweight (P =.0341) were the major contributing risk factors for CLD. SNF was not significantly related to CLD. Patients with SCAM (AN+, SNF-) were highly susceptible to CLD. In conclusion, SCAM, especially when associated with AN, seems to be a unique prognostic indicator of CLD.

Clinical characteristics and outcomes of Möbius syndrome in a children's hospital.

BACKGROUND: Möbius syndrome is a congenital disorder with facial and abducens palsy. Although a few case series studies have examined comorbid conditions in Möbius syndrome, follow-up and outcome data are sparse. OBJECTIVES: To examine the clinical characteristics and outcomes of Möbius syndrome. METHODS: Clinical data were reviewed for 10 patients. Neonatal history, neurological examination, comorbid anomalies, medical home care, outcomes, and neuroimaging were summarized. RESULTS: The patients' mean age was 7.3 ± 6.2 years. On neurological examination, absent blink reflex, jaw ankylosis, absent gag reflex, and tongue atrophy were frequently observed. Poland anomaly and clubfoot were present in three and six patients, respectively. Specific therapies required for patients included medical home care (six patients), suction apparatus (six), tube feeding (five), gastrostomy (two), tracheostomy (three), oxygen therapy (three), and home ventilator (two). Punctate calcification in the brainstem was observed in four patients. Pontine and medulla hypoplasia were detected on the basis of anteroposterior diameter in four and seven patients, respectively. Two patients had congenital hydrocephalus with aqueductal stenosis. Global developmental delay occurred in five patients. Three patients died. CONCLUSION: The rate of both the use of home medical devices and death was high in our patients. Möbius syndrome is extremely diverse, not only in clinical manifestation, but also outcome. Early multidisciplinary intervention is important to ensure an optimal outcome. Aqueductal stenosis is an occasional comorbid anomaly resulting from midbrain abnormality.

Magnetic resonance imaging regional T1 abnormalities at term accurately predict motor outcome in preterm infants.

OBJECTIVE: The aim of this study was to assess whether periventricular leukomalacia findings are sufficiently sensitive for predicting the severity of motor prognosis by conventional MRI in the near term. METHODS: Preterm infants with T1 hyperintensity or cysts in the periventricular regions on term MRI were selected, and their gross motor functions were evaluated at the age of 3 to 5 years. Sixty-two infants had findings of T1 hyperintensity or cysts, and except for infants with these findings, none were diagnosed later as periventricular leukomalacia. RESULTS: All 37 patients with cerebral palsy had periventricular lesions with T1 hyperintensity or cysts in the corona radiata above the posterior limb of the internal capsule on coronal sections. Small T1 hyperintensity lesions were seen on coronal slices and were often difficult to detect on axial slices. All of the 17 infants with T1 hyperintensity findings sparing the corona radiata above the posterior limb of the internal capsule showed normal motor development, irrespective of findings of ventriculomegaly. There was a tendency for the presence of widespread lesions in corona radiata above the posterior limb of the internal capsule to be correlated with the severity of motor handicap. CONCLUSIONS: Lesions in the corona radiata above the posterior limb of the internal capsule on a coronal view by term MRI were useful for predicting motor prognosis in preterm infants with periventricular leukomalacia.

Maternal, neonatal, and placental features associated with diffuse chorioamniotic hemosiderosis, with special reference to neonatal morbidity and mortality.

OBJECTIVE: Our purpose was to examine the significance of diffuse chorioamniotic hemosiderosis (DCH) on neonatal morbidity and mortality. METHODS: Using data from a retrospective case-control study, we analyzed 46 singleton placentas with DCH from infants who were delivered and/or admitted to the neonatal intensive care unit of Kanagawa Children's Medical Center during 1987-2001 and 92 control placentas without DCH from infants of comparable gestational age, birth weight, and duration. RESULTS: Mean and standard deviation of gestational age and infants' birth weight at delivery from the DCH group were 27 +/- 3 weeks and 939 +/- 342 g, respectively. Macroscopically, the placentas with DCH were more likely to show old peripheral blood clots (46% in the DCH group vs 8% in control group), subchorionic hematoma (20% vs 1%), and circumvallation (13% vs 1%). Histologically, amniotic necrosis was significantly more frequent in the DCH group (63% vs 24%). Of the obstetric factors, incidence of recurrent episodes of vaginal bleeding (70% vs 11%), oligohydramnios (59% vs 8%), and chronic abruption-oligohydramnios sequence (57% vs 5%) were significantly higher in the DCH group. Of the neonatal factors, persistent pulmonary hypertension of the newborn (29% vs 8%) and dry lung and/or pulmonary hypoplasia (20% vs 4%) were more common. However, respiratory distress syndrome was rare (15% vs 45%) in the DCH group. Neonatal death including stillbirth was increased in the DCH group but was not significant (24% vs 15%). Of infants who survived beyond day 28, chronic lung disease (CLD) was more frequent in the DCH group (51% vs 22%). The association of DCH, especially accompanied by amniotic necrosis, with CLD was still evident using likelihood ratio test. CONCLUSION: DCH is closely associated with preterm delivery, pulmonary hypertension of the newborn, and dry lung syndrome and is a significant risk factor for CLD.

Interleukin-6, interleukin-8, and soluble tumor necrosis factor receptor-I in the cord blood as predictors of chronic lung disease in premature infants.

OBJECTIVES: In order to predict the late-development of chronic lung disease of prematurity (CLD), cytokines in the cord blood were assessed in this study. STUDY DESIGN: Eighteen premature infants with CLD were enrolled. Cord blood plasma levels of cytokines of these infants and 12 control infants without CLD were measured including interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, soluble TNF receptor-I, and soluble IL-6 receptor using a cytometric bead array and an enzyme-linked immunosorbent assay. RESULTS: The cord blood IL-6, IL-8, and sTNFR-I levels were significantly elevated in CLD infants compared with those in control (P < .05). IL-1beta, IL-2, IL-4, IL-10, and IFN-gamma were undetectable in both groups. CLD infants with maternal chorioamnionitis had higher IL-6 than those without chorioamnionitis (P < .01). In CLD infants, IL-6 was higher in the infants who required prolonged oxygen therapy (P < .05). CONCLUSION: Elevated inflammatory cytokines in the cord blood are associated with the progression to CLD.