Improving survival in patients with trisomy 18.

The effects of medical and surgical interventions on the survival of patients with trisomy 18 have been reported, leading to changes in perinatal management and decision-making. However, few studies have fully reported the recent changes in survival and treatment of trisomy 18. We examined how treatment and survival of patients with trisomy 18 have changed over a decade in a Japanese pediatric tertiary referral center. This retrospective cohort study included patients with trisomy 18 who were admitted within the first 7 days of life at the Hyogo Prefectural Kobe Children's Hospital between 2008 and 2017. The patients were divided into early period (EP) and late period (LP) groups based on the birth year of 2008-2012 and 2013-2017, respectively. Changes in treatment and survival rates were compared between the two groups. A total of 56 patients were studied (29 in the EP group and 27 in the LP group). One-year survival rates were 34.5% and 59.3% in the EP and LP groups, respectively. The survival to discharge rate significantly increased from 27.6% in the EP group to 81.5% in the LP group (p < 0.001). The proportion of patients receiving surgery, especially for congenital heart defects, significantly increased from 59% in the EP group to 96% in the LP group (p = 0.001). In our single-center study, survival and survival to discharge were significantly improved in patients with trisomy 18, probably because of increased rate of surgical interventions. These findings may facilitate better decision-making by patients' families and healthcare providers.

A prospective cohort study of newborns born to mothers with serum Toxoplasma gondii immunoglobulin M positivity during pregnancy.

INTRODUCTION: The aims were to investigate the clinical characteristics of Toxoplasma gondii (T. gondii) immunoglobulin (Ig) M-positive mothers and to clarify the incidences of serum T. gondii IgM or blood T. gondii DNA positivity in newborns born to the mothers and the actual congenital T. gondii infection. METHODS: Mothers with T. gondii IgM positivity and newborns born to the mothers from 2013 to 2020 were prospectively investigated. Serum T. gondii IgG and IgM were measured by enzyme-linked immunosorbent assay. Blood T. gondii DNA was detected by semi-nested polymerase chain reaction. Congenital T. gondii infection was diagnosed based on clinical characteristic manifestations with serum T. gondii IgG positivity at any age or T. gondii IgG positivity after 12 months of age. RESULTS: Among 71 T. gondii IgM-positive mothers, including one with triplets, 41% had low T. gondii IgG avidity index and 73% received maternal therapy. Among 73 newborns who were examined for serum T. gondii IgG and IgM at birth, none had clinical manifestations, and one (1.4%) had T. gondii IgM positivity. Among 32 newborns who were examined for blood T. gondii DNA at birth, two (6.3%) were positive. All patients with serum T. gondii IgM or blood T. gondii DNA positivity showed T. gondii IgG negativity within 12 months of age. CONCLUSIONS: A few newborns born to T. gondii IgM-positive mothers were suspected of having congenital T. gondii infection based on serum T. gondii IgM or blood T. gondii DNA testing at birth. However, none developed congenital T. gondii infection.

Infiltrated regulatory T cells and Th2 cells in the brain contribute to attenuation of sepsis-associated encephalopathy and alleviation of mental impairments in mice with polymicrobial sepsis.

Sepsis-associated encephalopathy (SAE) increases not only morbidity and mortality but has been associated with long-lasting mental impairment after hospital discharge in septic patients. Recently, studies have shown that these mental impairments are caused by infection-induced neuroinflammation. However, the role of T cells in the pathogenesis of SAE and mental impairments remains unclear. Thus, in this study, we aimed to clarify how immune cells, especially T cells, influence the development and recovery of these disorders. In the cecal slurry (CS)-induced septic mouse model, we performed three different kinds of behavioral tests, open-field test, marble burying test, and forced swimming test, and observed anxiety-like behavior in septic mice. Additionally, increased interleukin (IL)-1ß and IL-6 expression levels, and infiltration of neutrophils and T cells were examined in the brain of septic mice, 10 days after sepsis onset. Twenty days after sepsis onset, the septic mice could recover the number of astrocytes. At day 30, expression levels of IL-1ß and tumor necrosis factor (TNF)-α returned to normal levels in the cerebral cortex of septic mice. Interestingly, resolution of neuroinflammation and alleviation of depression were delayed in septic mice treated with FTY720, which inhibits sphingosine-1-phosphate (S1P)-dependent lymphocyte egress from lymph nodes. On analyzing the brain T cells with or without FTY720 in septic mice, the FTY720 untreated mice presented increased regulatory T cells (Treg) and Th2 cells in the brain, whereas the FTY720 treated mice demonstrated increased Th17 in the brain at day 30. Furthermore, in FTY720 treated septic mice, the number of astrocytes in the cerebral cortex remained reduced at day 30. These results suggest that infiltrated Treg and Th2 cells contribute to the attenuation SAE and alleviate SAE-induce mental disorder by resolving neuroinflammation in the chronic phase of sepsis.

Efficacy of Valganciclovir Treatment Depends on the Severity of Hearing Dysfunction in Symptomatic Infants with Congenital Cytomegalovirus Infection.

Although earlier studies have shown that antiviral treatment regimens using valganciclovir (VGCV) improved hearing function in some infants with congenital cytomegalovirus (CMV) infection; its efficacy on the severity of hearing dysfunction is unclear. We conducted a prospective study among 26 infants with congenital CMV infections from 2009 to 2018. Oral VGCV (32 mg/kg/day) was administered for 6 weeks (November 2009 to June 2015; n = 20) or 6 months (July 2015 to March 2018, n = 6). Hearing function was evaluated by measuring the auditory brainstem response before VGCV treatment and at 6 months. Hearing dysfunction, defined as a V-wave threshold >40 dB, was categorized into: most severe, ≥91 dB; severe, 61⁻90 dB; and moderate, 41⁻60 dB. Hearing improvement was defined as a decrease of ≥20 dB from the pretreatment V-wave threshold. Of 52 ears in 26 infants with congenital CMV infection, 29 (56%) had hearing dysfunction, and of 29 ears, 16 (55%) improved after VGCV treatment. Although, 16 (84%) of 19 ears with moderate or severe hearing dysfunction improved after treatment (p < 0.001), 10 ears with the most severe form did not. In conclusion, VGCV treatment is effective in improving moderate and severe hearing dysfunction in infants with congenital CMV infection.

Diagnostic Value of Cytomegalovirus IgM Antibodies at Birth in PCR-Confirmed Congenital Cytomegalovirus Infection.

Although cytomegalovirus (CMV) DNA detection in urine is the standard method for diagnosing congenital cytomegalovirus infection (CCMVI), polymerase chain reaction (PCR) is not comprehensively available. Currently, the efficacy of CMV-specific IgM (CMV-IgM) and CMV-specific IgG (CMV-IgG) detection remains unclear. To determine the sensitivity and specificity of CMV-specific antibodies at birth, we investigated CMV-IgM and CMV-IgG titers in CCMVI cases and non-CCMVI controls, with confirmed diagnoses by urine quantitative real-time PCR within 3 weeks after birth. We included 174 infants with suspected CCMVI in whom serological testing was performed within the first 2 weeks after birth during 2012-2018. We classified the participants into a CCMVI group (n = 32) and non-CCMVI group (n = 142) based on their urine PCR results. The CMV-IgM-positive rate was 27/32 (84.4%) in the CCMVI group, compared with 1/142 (0.7%) in the non-CCMVI group (p < 0.0001). The positive CMV-IgG rates were 32/32 (100%) in the CCMVI group and 141/142 (99.3%) in the non-CCMVI group. The positive predictive value for CMV-IgM was high at 96.4% (27/28). This value may be sufficient for clinical use, especially in settings with limited resources where PCR is unavailable. However, CCMVI screening by CMV-IgM alone appears insufficient because of the considerable number of false-negative cases.

Sequence analyses of variable cytomegalovirus genes for distinction between breast milk- and transfusion-transmitted infections in very-low-birth-weight infants.

BACKGROUND: Cytomegalovirus (CMV) transmission to very-low-birth-weight infants (VLBWIs) sometimes induces serious clinical symptoms. Although breast milk is considered a major source of transmission, transfusion-transmitted CMV (TT-CMV) infection is often suspected when CMV disease develops after transfusion. Thus, it is clinically important to distinguish between transfusion-transmitted and breast milk-transmitted CMV infections. STUDY DESIGN AND METHODS: Study A: The incidence of acquired CMV transmission was prospectively investigated in 65 VLBWIs. Study B: To determine the transmission routes in 18 TT-CMV-suspected VLBWIs who had been reported in our hemovigilance system, we performed polymerase chain reaction for CMV DNA in fed breast milk and/or repository blood samples related to transfused leukoreduced blood products. Furthermore, we evaluated the identity of CMV strains in patients' urine/blood samples and fed breast milk by sequence analyses of variable CMV genes UL139 and UL146. RESULTS: Study A: Acquired CMV infection was found in 4 of 65 VLBWIs (6.2%). Study B: CMV DNA was detected in fed breast milk for 12 of 14 TT-CMV-suspected cases, for which breast milk was available. Furthermore, CMV DNA sequence-matching rates between fed breast milk and patients' urine/blood for both UL139 and UL146 genes were 100% or nearly 100% in 11 patients. In contrast, repository blood samples for 11 of 14 patients were CMV DNA negative. CONCLUSION: CMV is principally transmitted through breast milk in VLBWIs. The risk of TT-CMV seems to be extremely low when using leukoreduced blood products. Sequence analyses of the variable CMV genes are useful for evaluating CMV transmission routes.

Evaluation of BiliCare™ transcutaneous bilirubin device in Japanese newborns.

BACKGROUND: Non-invasive transcutaneous bilirubin (TcB) monitoring has been widely used to screen for hyperbilirubinemia. TcB measured using the recently developed BiliCare™ system, however, has not been fully evaluated. METHODS: One hundred and seven TcB measurements were obtained from 82 Japanese newborns ≥35 weeks' gestational age within 2 weeks after birth. Measurements were taken at the scaphoid fossa, conchal cavity, and lobe of the ear using BiliCare. BiliCare TcB were compared with total serum bilirubin (TB) and TcB obtained using another bilirubinometer (JM-105™). RESULTS: Transcutaneous bilirubin measured at all three sites significantly correlated with TB (r = 0.91, 0.93, and 0.93 at the scaphoid fossa, conchal cavity, and lobe, respectively). The mean differences were 0.1, -0.3, and 3.6 at the scaphoid fossa, conchal cavity, and lobe, respectively. BiliCare TcB at the scaphoid fossa significantly correlated with that using the JM-105 (r = 0.91). The mean difference was 0.0. BiliCare, however, produced a significantly higher and lower TcB than the JM-105 for TB <7 and ≥15 mg/dL, respectively. CONCLUSIONS: Transcutaneous bilirubin measurements taken at the scaphoid fossa or conchal cavity using BiliCare were more reliable than those at the earlobe. BiliCare TcB differed from those of the JM-105, for TB <7 or ≥15 mg/dL.

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

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

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

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

Incidence and Neonatal Risk factors of Short Stature and Growth Hormone treatment in Japanese Preterm Infants Born Small for Gestational Age.

Incidence and neonatal risk factors for short stature in preterm children born small for gestational age (SGA) have not been fully investigated in Japan. In this prospective study, infants born ≤32 weeks' gestational age (GA) from 2004-2015 were enrolled and followed for 3 years. Incidence of short children born SGA and short stature treated with growth hormone (GH) were investigated. Neonatal risk factors were analysed using univariate and multivariate analyses. GA cut-off value was determined using receiver operating characteristic (ROC) curve analyses. Of 604 infants born ≤32 weeks' GA, 76 (13%) were SGA at birth. Twenty-seven infants (36%) developed short stature at age 2 and 14 infants (19%) received GH treatment at age 3. GA, birthweight, birth length, birth head circumference, and chronic lung disease at 36 weeks' corrected GA were determined as risk factors by univariate analyses (p < 0.01). Multivariate analyses only revealed low GA as an independent risk factor. ROC curve analysis determined a cut-off value of 24 weeks' GA. Nineteen percent of preterm SGA infants ≤32 weeks' GA developed short stature treated with GH. A low GA at birth could be an early detection marker for short stature that requires GH treatment in preterm infants born SGA.

DNA methylation of the Rtl1 promoter in the placentas with fetal growth restriction.

BACKGROUND: Small for gestational age (SGA) babies experience fetal growth restriction because of placental insufficiency, and aberrant fetal growth has been linked to DNA methylation in the placenta. An imprinted gene encoding retrotransposon-like protein 1 (RTL1) is regulated by DNA methylation in the promoter region and plays a key role in placental development. We therefore investigated the DNA methylation status of RTL1 in the placenta of infants with severe SGA. METHODS: We extracted DNA from the placenta of appropriate for gestational age (AGA; gestational age 35 ± 6 weeks, birthweight 2292 ± 1006 g; n = 12), SGA (birthweight z-score ≤-2 SD, 33 ± 5 weeks, 1373 ± 580 g; n = 11), and severe SGA (birthweight z-score ≤-3 SD, 33 ± 4 weeks, 1145 g ± 423 g; n = 7) infants, and we determined the methylation rates of five CpG sites in the CG4 (82,275,427-82,275,737 in NT_026437 sequence, NCBI database) region of the RTL1 promoter by pyrosequencing. We defined hypermethylation (>75.5%) and hypomethylation (<45.6%) based on the average methylation rate exceeding ± two standard deviations (SD) in the AGA group, respectively, and compared these among groups. RESULTS: There was no significant difference in the average methylation of CpG1-5 (control 59%, SGA 60%, severe SGA 63%), but abnormal methylation (hyper-/hypo-methylation) in CpG1 differed significantly among the groups (control 0%, SGA 36%, severe SGA 71%). CONCLUSION: Infants with severe SGA have abnormal placental DNA methylation of CpG1 in the CG4 region of RTL1, suggesting the existence of disturbed epigenetic control in utero.

Prediction of poor neurological development in patients with symptomatic congenital cytomegalovirus diseases after oral valganciclovir treatment.

OBJECTIVE: This study aimed to evaluate the neurodevelopmental outcomes of infants with symptomatic congenital cytomegalovirus (SCCMV) disease after antiviral treatment and investigate the symptoms at birth associated with a developmental quotient (DQ) < 70. METHODS: In this prospective study conducted from 2009 to 2018, infants with SCCMV disease who received oral valganciclovir (VGCV; 32 mg/kg/day) for 6 weeks (November 2009 to June 2015) or 6 months (July 2015 to March 2018) were evaluated for their neurodevelopmental outcomes at around 18 months of corrected age. Sequelae were categorized as follows: no impairment with a DQ ≥ 80 and no hearing dysfunction; mild sequelae including unilateral hearing dysfunction or a DQ of 70-79; and severe sequelae with a DQ < 70, bilateral hearing dysfunction requiring hearing aids, blindness or epilepsy requiring anti-epileptic drugs. DQ was assessed using the Kyoto Scale of Psychological Development. Symptoms at birth associated with a DQ < 70 were determined using univariate and receiver operating characteristic curve analyses. RESULTS: Of the 24 treated infants, 21 reached > 18 months of corrected age. Six (29%) were no impairment, 4 (19%) had mild sequelae, and 11 (52%) developed severe sequelae. The symptoms at birth associated with a DQ < 70 were microcephaly and/or small for gestational age. CONCLUSION: In our cohort of infants with SCCMV disease after VGCV treatment, the incidence of severe sequelae at 18 months of corrected age was around 50%. When microcephaly and/or small for gestational age are seen at birth, a low DQ may appear even after oral VGCV treatment.

Fetal Primary Small Bowel Volvulus Associated with Acute Gastric Dilatation Detected by Ultrasonography.

Fetal intestinal volvulus is a rare condition, and fetal diagnosis of this disease is still challenging, especially in primary cases not accompanied by other comorbidities, such as intestinal malformations. Herein, we report a case of fetal primary small bowel volvulus associated with acute gastric dilatation detected by ultrasonography. We speculate that the mechanism of acute gastric dilatation in our case was peristatic malfunction of the whole intestine caused by a strangulated ileus resulting from fetal intestinal volvulus. In conclusion, acute gastric dilatation detected by fetal ultrasound can indicate the fetal intestinal volvulus.

Nontypeable Haemophilus Influenzae Sepsis in a Term Neonate.

We reported a term newborn case of early onset sepsis caused by nontypeable Haemophilus Influenzae (NTHi) with massive bacterial invasion in the placenta. Based on the consistent results of maternal placental pathology and neonatal bacterial culture, we diagnosed this as vertical transmission of NTHi via vaginal delivery. In general, NTHi infections occur in preterm infants, and our term infant case is very unusual. In conclusion, clinicians should consider NTHi as a cause of neonatal sepsis, even in term infants.

A Case of Congenital Complete Atrioventricular Block Treated with Transdermal Tulobuterol.

Congenital complete atrioventricular block (CCAVB) is a condition in which the atria and ventricles beat independently of each other. CCAVB cases require permanent pacemaker implantation until adulthood. Nevertheless, consensus regarding postnatal medical therapy for bradycardia has not been reached. Here we report the case of a newborn with CCAVB, whose intractable bradycardia was successfully treated with transdermal tulobuterol. Tulobuterol is a selective ß2-adrenoceptor agonist, widely used safely as bronchodilator in children. It also has positive inotropic and chronotropic effect via ß1-adrenoceptors. We believe the tulobuterol patch can be used as an optional therapy for CCAVB where pacemaker implantation is not available.

Gestational age-dependency of height and body mass index trajectories during the first 3 years in Japanese small-for-gestational age children.

Gestational age (GA) is thought to affect height growth in small-for-gestational age (SGA) children. However, the GA-specific trajectories in body mass index (BMI) and early appearances of adiposity rebound (AR) have not been fully investigated in a cohort of Japanese SGA children. A longitudinal cohort study was conducted with 1063 SGA children born in Kobe, Japan, with sufficient records from birth to 3 years of age. Subjects were divided into subgroups based on GA: 39-41 weeks GA (n = 723), 37-38 weeks GA (n = 256), 34-36 weeks GA (n = 62), and <34 weeks GA (n = 22). Height and BMI were assessed at 4 months, 9 months, 1.5 years, and 3 years of age. The catch-up rate for height was GA-dependent. Most children with 39-41 weeks GA (91%) caught up by 4 months of age; however, lower GA was associated with a slower elevation in the catch-up rate. The BMI trajectory during the first 3 years was also GA-dependent, with a change in GA dependency at a boundary of 37 weeks GA. Approximately 7% of SGA children had already developed AR before 3 years of age. In conclusion, growth patterns during infancy and early childhood in SGA children differ depending on GA.