Breast-feeding rate comparison by parity and delivery age in Japan.

BACKGROUND: To examine the effects of maternal age on breast-feeding, we classified mothers who delivered vaginally aged 20-42 into 1-year age groups and investigated breast-feeding states. We also studied differences between primiparas and multiparas in breast-feeding. METHODS: The subjects were 2,605 primipara mothers (age at delivery ranged from 16to 45 years; the gestational age of their infants ranged from 37 to 42 weeks, birthweight ranged from 2,501 to 4,300 g) and 3,261 multipara mothers (age 18-45 years; the gestational age of their infants ranged from 37-42 weeks, and their birthweight ranged from 2,502-4,726 g) at 12 baby-friendly hospitals in Japan. RESULTS: The percentage of infants exclusively breast-fed at 1 week and 1 month after birth in the primipara mothers was 80% among mothers in their 20s but lower than 60% among mothers aged above 35. On the other hand, the percentage of infants exclusively breast-fed in the multipara mothers was almost 90% among mothers in their 20s and remained at 70% or over among mothers in their 40s. The percentage of infants exclusively breast-fed was significantly higher in the multipara mothers than in the primipara mothers in many age groups at both 1 week and 1 month of age. CONCLUSIONS: The percentage of infants exclusively breast-fed rate decreased as the maternal age increased. We found that multipara mothers can breast-feed even in their 40s, but primipara mothers may encounter difficulty breast-feeding at ages above 35. Our results suggest a need to consider not only their age but number of children, i.e., breast-feeding experience, to provide effective support to breast-feeding mothers.

Risk factors for cefazolin-resistant febrile urinary tract infection in children.

BACKGROUND: Febrile urinary tract infection (fUTI) is a common bacterial infection among children. This study investigated the risk factors for fUTI caused by cefazolin-resistant bacteria in children. METHODS: The medical records of patients with fUTI hospitalized between April 2014 and March 2020 were retrospectively analyzed. The patients were divided into two groups based on the cefazolin susceptibility of the infection-causing bacteria: cefazolin-resistant and cefazolin-susceptible groups. RESULTS: The records of 80 patients were evaluated. The median age was 5.0 months (range 0.5-119.4 months). Cefazolin-susceptible bacteria were detected in 60 patients (75.0%). Significant differences were noted between the cefazolin-resistant and cefazolin-susceptible groups regarding UTI-related antimicrobial prophylaxis and recurrence of UTI within 3 months (P = 0.0318 and P = 0.00876, respectively). However, no significant differences were observed between these two groups regarding renal anomalies, or UTI history. Logistic regression analysis revealed that the recurrence of UTI within 3 months was an independent, significant risk factor for cefazolin-resistant fUTI (odds ratio 3.81, 95% confidence interval: 1.07-13.5, P = 0.0388). Six patients who were empirically treated with antibiotics ineffective against the infection-causing bacteria recovered from fever before these antibiotics were switched to those effective against the infection-causing bacteria. CONCLUSIONS: In children, a recurrence of UTI within 3 months is a risk factor for fUTI caused by cefazolin-resistant bacteria. Recognizing these risk factors before initiating fUTI treatment in children may support treatment with narrower-spectrum antibiotics, such as first-generation cephalosporins (e.g., cefazolin).

Wakayama Medical University Hospital perinatal helicopter ambulance service: 14 year review.

BACKGROUND: In 2003, a perinatal helicopter air ambulance service was introduced for remote areas of Wakayama and Mie prefectures, Japan, but its long-term impact on perinatal medicine has not yet been analyzed. METHODS: A retrospective observational study was conducted on helicopter air ambulance cases recorded between January 2003 and December 2016 at Wakayama Medical University Hospital (WMUH). RESULTS: During that period, 61 pregnant mothers were transferred by helicopter air ambulance to WMUH. Between 2003 and 2009, the mean period from transfer to birth was 0.6 weeks, whereas between 2008 and 2016, this increased to 1.6 weeks, and the survival rate of infants born after transfer did not differ significantly (84.2%, 32/38 versus 82.1%, 23/28). Seventy-three neonates were transferred. The number transferred between 2003 and 2009 was 46, whereas this decreased to 27 between 2010 and 2016. The neonatal mortality rate in south Wakayama plus south Mie gradually decreased. The reasons for the longer period from transfer to birth, and the decrease in the rate of very low-birthweight infants after transfer may be due to development in the management of threatened premature labor, and the earlier transfer of such cases by regional obstetricians. The reasons for the decline in neonatal transfer may have included the development of fetal diagnostic techniques and improved efficiency of neonatal ground-transport in the South Wakayama region. CONCLUSION: The helicopter air ambulance is an important form of medical transportation in the south Kii peninsula.

Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome.

RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes.

Acute fatty liver of pregnancy associated with fetal mitochondrial trifunctional protein deficiency.

Acute fatty liver of pregnancy (AFLP) is a devastating disorder of the maternal liver in the third trimester. Recent studies have demonstrated an association between AFLP and fetal fatty acid oxidation disorders. Here, we report a case of AFLP caused by fetal mitochondrial trifunctional protein (TFP) deficiency. A 21-year-old parous woman presented with nausea, genital bleeding and abdominal pain at 33 weeks of gestation. Laboratory data revealed hepatic failure and disseminated intravascular coagulopathy. The patient underwent emergency cesarean section and was diagnosed with AFLP from the clinical characteristics. She was successfully treated with frequent plasma exchange. The newborn presented severe heart failure and died on the 39th day after birth. Tandem mass spectrometry indicated long-chain fatty acid oxidation disorder. Gene analysis demonstrated homozygous mutation in exon 13 of HADHB, the gene responsible for mitochondrial TFP deficiency. The parents carried a heterozygous mutation at the same location in HADHB.

Adverse perinatal and neonatal outcomes in patients with chronic abruption-oligohydramnios sequence.

AIM: Chronic abruption-oligohydramnios sequence (CAOS) is a clinical condition with lasting vaginal bleeding and oligohydramnios because of chronic placental abruption, which seems to cause preterm labor and neonatal chronic lung disease (CLD). This prompted us to explore the correlation between perinatal/neonatal outcomes and CAOS. METHODS: Patients with suspected risk of abortion with recurrent vaginal bleeding were divided into CAOS and non-CAOS groups, and we compared the perinatal/neonatal outcomes between these two groups. To examine the impact of chorioamnionitis (CAM) on the prognosis of CAOS, we also compared outcomes between the CAOS group and gestational-age-matched preterm labor due to CAM (CAM group). RESULTS: In the CAOS and non-CAOS groups, initial vaginal bleeding was seen at the first trimester. However, its duration was significantly longer in the CAOS group. Additionally, neonatal birthweight was lower, and small-for-gestational-age (SGA) incidence was higher in the CAOS group. CLD was observed in most infants from CAOS patients. In the comparison between CAOS and CAM groups, birthweight was lower and SGA incidence was higher in the CAOS group. Moreover, CLD incidence and neonatal mortality were significantly higher, despite the lower incidence of severe CAM in the CAOS group. Finally, multivariate analysis demonstrated that duration of bleeding was a significant predictive factor for CAOS. CONCLUSIONS: Our observations demonstrated that patients with CAOS were a high-risk group for poor perinatal/neonatal outcomes. Moreover, episodes of recurrent and prolonged uterine bleeding were predictive factors for CAOS. During the first trimester, prolonged bleeding is an important sign as one symptom of CAOS.

Safety of Low-Dose Oral Food Challenges for Hen's Eggs, Cow's Milk, and Wheat: Report from a General Hospital without Allergy Specialists in Japan.

An oral food challenge (OFC) is useful for managing food allergies. However, because OFCs have the risk of severe allergic reactions, including anaphylaxis, conducting OFCs under this situation without allergy specialists is difficult. To investigate the safety of a low-dose OFC for eggs, milk, and wheat in a general hospital without allergy specialists. We retrospectively analyzed the medical records of children who were hospitalized in a general hospital without allergy specialists for a low-dose OFC of egg, milk, or wheat between April 2018 and March 2021. The records of 108 patients were evaluated. The median age was 15.8 months (range: 7.5-69.3 months). Challenged foods were eggs (n = 81), milk (n = 23), and wheat (n = 4). Fifty-three (49.0%) patients showed positive allergic reactions. Thirty-five (66.0%) patients showed grade 1 (mild), 18 (34.0%) showed grade 2 (moderate), and none showed grade 3 (severe) reactions. The interventions comprised antihistamines (n = 18), prednisolone (n = 3), inhaled Β2-agonist (n = 2). No patients required adrenaline and no deaths occurred. Low-dose OFCs may be safe in a general hospital without allergy specialists. Conducting a low-dose OFC may be essential in food allergy practice.

Gestational Age-Dependent Reference Ranges for Albumin Levels in Cord Serum.

BACKGROUND: To diagnose hypoalbuminemia in newborns, it is essential to establish a definition applicable to those with a different gestational age (GA) and clinical conditions. A positive correlation between serum albumin levels and GA has been reported, but the study was limited to small numbers of newborns. We therefore investigated the GA-dependent reference ranges for serum albumin levels using cord venous blood (UC-Alb levels) from a large number of newborns delivered at a tertiary perinatal center. METHODS: Albumin levels were assessed in 2,917 newborns at 22-41 weeks of GA after exclusion of those with congenital disorders. Linear regression analysis was used to correlate GA and UC-Alb levels. After calculation of the percentile values of UC-Alb levels for each week of GA, the distributions were approximated by the least-squares method. To validate the determined linear approximation of the 5%ile value, the UC-Alb levels in newborns with hydrops fetalis and gastroschisis were used. RESULTS: A significant positive correlation between GA and UC-Alb levels was found (rs = 0.701, p < 0.001, respectively). The distribution of the 5%ile of UC-Alb levels (Y) by GA (X) was approximated as a straight line (Y = 0.062 × X + 0.326, R2 = 0.951). Among the 59 and 18 newborns with hydrops fetalis and gastroschisis, 51 (86.4%) and 15 (83.3%), respectively, were below the line. CONCLUSIONS: We established GA-dependent reference ranges for serum albumin levels, which may be useful to accurately diagnose hypoalbuminemia in newborns.

Changes in maternal and child health outcomes after introduction of a helicopter into perinatal transportation in Japan.

To examine the effect of perinatal helicopter transportation on maternal and child health. Helicopter transportation for the sparsely populated southern areas of Wakayama and Mie prefectures was introduced in June 2003. Maternal and child health statistics for 2000-2002 and 2004-2006 were compared between the south and north regions of the prefectures. There were 9 maternal transports from south Wakayama, 2 from north Wakayama, and 5 from south Mie in 2004-2006; and 13 neonatal transports from south Wakayama and 7 from north Wakayama during the same period. Decreases in neonatal and perinatal mortalities in 2004-2006 compared to 2000-2002 were greater in south Wakayama than in north Wakayama (-0.31 vs. -0.28, and -0.57 vs. -0.18, respectively); and greater in south Mie than in north Mie (-0.90 vs. -0.49, and -2.49 vs. -1.48, respectively). The changes in the number of maternal deaths between 2000-2002 and 2004-2006 were 0 in south Wakayama, 1 in north Wakayama, -2 in south Mie, and -1 in north Mie, with the greatest change occurring in south Mie. Use of a helicopter for perinatal transportation can possibly improve maternal and child health in sparsely populated areas far away from urban areas.

Incidence of Kawasaki disease before and during the COVID-19 pandemic: a retrospective cohort study in Japan.

Background: Epidemiological studies in Kawasaki disease (KD) have suggested infectious aetiology. During the COVID-19 pandemic, measures for mitigating SARS-CoV-2 transmission also suppress the circulation of other contagious microorganisms. The primary objective is to compare the number and incidence of KD before and during the COVID-19 pandemic in Japan, and the secondary objective is to investigate temporal association between the KD epidemiology and activities of SARS-CoV-2 and other viral and bacterial infections. Methods: A retrospective cohort study was conducted between 2016 and 2020 in Kobe, Japan. We collected information of hospitalised KD children in Kobe. Child population was identified through the resident registry system. Activity of COVID-19 and 11 other infectious diseases was derived from a public health monitoring system. Monthly change of KD incidence was analysed using a difference-in-difference regression model. Results: Throughout the study period, 1027 KD children were identified. KD had begun to decline in April 2020, coinciding with the beginning of the COVID-19 pandemic. The number of KD cases (n=66) between April and December 2020 was 40% of the average in the same period in 2016-2019 (165/year). Annual KD incidence was 315, 300, 353, 347 and 188/100 000 children aged 0-4 years in 2016-2020, respectively. The difference-in-difference value of KD incidence was significantly reduced in the fourth quarter in 2020 (-15.8, 95% CI -28.0 to -3.5), compared with that in 2016-2019. Sentinel surveillance showed a marked decrease of all infectious diseases except exanthema subitum after the beginning of the COVID-19 pandemic. There were 86 COVID-19 cases aged <10 years and no KD children associated with COVID-19. Conclusion: This study showed that the number and incidence of KD was dramatically reduced during the COVID-19 pandemic in Japan. This change was temporally associated with decreased activities of various infectious diseases other than COVID-19, supporting the hypothesis of infection-triggered pathogenesis in KD.

Cytotoxic T-lymphocyte-associated antigen 4 gene polymorphisms in Japanese children with infection-associated hemophagocytic lymphohistiocytosis.

OBJECTIVE: This study examined whether genetic polymorphisms in cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a negative regulator of T cells, are associated with infection-associated hemophagocytic lymphohistiocytosis (IHLH) in Japanese children. METHODS: We investigated the alleles of four polymorphisms in the CTLA-4 gene [-318CT, +49AG, CT60 and a dinucleotide repeat length polymorphism (AT)n] in 43 Japanese children with IHLH and 100 healthy Japanese controls. The hyper-polymorphic (AT)n alleles were divided into two types; the shortest allele (designated as AT(7)) and the longer alleles (designated as AT(>)(7)). RESULTS: A significant difference in the distribution of the (AT)n genotype was found between patients and controls (p = 0.028). Also, the frequency of the AT(>)(7) allele was significantly higher in the patients with IHLH than in the controls (p = 0.007). No significant linkage disequilibrium was found between each polymorphism. With regard to laboratory data, patients homozygous for the CTLA-4 AT(>)(7) allele showed significantly higher serum levels of lactate dehydrogenase and soluble interleukin-2 receptor than patients with the other alleles. CONCLUSION: These results suggest that CTLA-4 polymorphisms might play a role in the development of IHLH in Japanese children.

The plasma angiotensin II level increases in very low-birth weight infants with neonatal chronic lung disease.

BACKGROUND: Angiotensin II (AII) has been reported to play an important role in organ fibrosis, and a local renin-angiotensin-system (RAS) has been demonstrated in the lungs. However, the relationship of the RAS to chronic lung disease of the newborn (CLD) remains obscure. OBJECTIVE: To investigate the plasma AII levels throughout the neonatal period in very low-birth weight (VLBW) infants and examine the possible factors that might affect the AII levels. STUDY DESIGN: The study includes 20 VLBW infants. Blood samples were collected on days 0, 7, 21 and 35 and plasma AII levels were assayed using an enzyme immunoassay. The data were analyzed by a multiple linear regression analysis with the plasma AII level as the dependent variable and significant factors determined based on a univariate analysis as independent variables. RESULTS: The geometric mean of the plasma AII concentrations on days 0, 7, 21 and 35 was 51 pg/mL, 86 pg/mL, 132 pg/mL, and 50 pg/mL, respectively. On day 21, only CLD (p<0.01) had a highly significant association with the plasma AII level. On day 35, birth weight (p<0.05) and CLD (p<0.01) had a highly significant association with the plasma AII level. This analysis confirmed CLD to be the most significant factor associated with plasma AII level on days 21 and 35. CONCLUSION: These findings suggest that higher levels of plasma AII in VLBW infants appear to be related to the development of CLD.

SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.

Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.

Correlation between echocardiographic superior vena cava flow and short-term outcome in infants with asphyxia.

OBJECTIVES: To assess the relationship between superior vena cava (SVC) flow and short-term outcome in infants with perinatal asphyxia. METHODS: Infants in sequence born after more than 35 weeks of gestation who had been hospitalized at the NICU and normal neonatal wards of Wakayama Medical University between May 2005 and September 2010 were recruited for this observational cohort study. The study eligibility criterion was the presence of perinatal asphyxia, as evidenced by abnormal fetal heart rate monitoring and an Apgar score of 7 or less at 1 min or need for resuscitation using positive pressure ventilation. SVC flow was measured in the first three days of life by Doppler echocardiography as described by Kluckow and Evans. Short-term outcome was defined as poor if MRI demonstrated bilateral lesions of the basal ganglia and thalamus and/or multicystic encephalomalacia due to hypoxic ischemia. RESULTS: In the head cooling group, SVC flow in infants with a good outcome was lower than that in infants with a poor outcome at 12h (36.9±7.7 vs. 113.4±42.4 ml/kg/min (p=0.01)), 24h (75.2±25.3 vs. 155.6±45.7 ml/kg/min (p=0.03)), and 48 h (92.5±34.2 vs. 161.1±46.7 ml/kg/min (p=0.04)) after birth. SVC flow decreased promptly after introduction of head cooling in infants who had a good outcome, whereas it increased gradually after head cooling in those who had a poor outcome. CONCLUSION: We speculate that regulation of brain circulation is disrupted in infants with asphyxia who show a poor outcome.

Central hypothyroidism in infants who were born to mothers with thyrotoxicosis before 32 weeks' gestation: 3 cases.

We describe 3 infants who were born to mothers with Graves' disease and developed central hypothyroidism that persisted for >6 months after birth. Two were preterm infants, and the other was a term infant who was born to a euthyroid mother who had been treated with an antithyroid drug since week 31 of gestation. These cases suggest that passage of thyroid hormones can occur from a thyrotoxic mother to the fetus and that the gestational period earlier than 32 weeks may be the critical time for development of central hypothyroidism.