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Abstract Background This study aimed to compare the echocardiographic changes and cardiac biomarkers between women with singleton and twin pregnancies. Methods From April 2014 to March 2016, this longitudinal cohort study invited pregnant women who were scheduled to give birth at Hokkaido University Hospital. We analyzed prospectively collected data on simultaneously determined echocardiographic parameters and blood cardiac markers of 44 women with singleton and 22 women with twin pregnancies. Furthermore, we tested the mixed-effect models for echocardiographic parameters and cardiac biomarkers. Results During the third trimester and immediately postpartum (within 1 week after childbirth), the mean left atrial volume index and brain natriuretic peptide (BNP) level were significantly higher in women with twin pregnancies than in those with singleton pregnancies. Women with twin pregnancies also had significantly smaller second-trimester inferior vena cava diameters and significantly higher third−trimester creatinine levels than those with singleton pregnancies. BNP positively correlated with the left atrial volume index (β = 0.49, p

Background: Low red blood cell folate concentrations during early pregnancy might cause neural tube defects. However, the association between folate concentrations and birth defects of other neural crest cell-derived organs remains unknown. We investigated the associations between birth defects and first-trimester serum folate concentrations in a birth-cohort study in Japan. Methods: In total, 14,896 women who were prior to 13 weeks of gestation were enrolled from 2003 through 2012. Birth defect information was obtained from medical records and questionnaires. The association between folate levels in the first trimester and birth defects categorized as ICD-10 cord defects and neural crest cell-derived organ defects was examined. The crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) per log-transformed folate concentration were calculated using logistic regression. Results: Blood samples were obtained at a mean of 10.8 weeks of gestation. Median serum folate level was 16.5 (interquartile range, 13.4–21.5) nmol/L, and the deficiency level (less than 6.8 nmol/L) was 0.7%. There were 358 infants with birth defects. The adjusted odds ratio for any birth defect, ventricular septal defects, and cleft lip was 0.99 (95% CI, 0.74–1.32), 0.63 (95% CI, 0.30–1.33), and 4.10 (95% CI, 0.96–17.58), respectively. There were no significant associations between first-trimester maternal serum folate and the risk of birth defects. Conclusions: We were unable to demonstrate a relationship between maternal serum folate in the first trimester and birth defects. Potential confounding factors may have influenced our results.

Objective: This study was performed to evaluate the application of fetal middle cerebral artery peak systolic velocity (MCA-PSV) for prediction of newborn anemia with umbilical cord blood hemoglobin concentration at birth (UCB-Hb) 1.5 was defined as a positive MCA-PSV test result. Results: The MCA-PSV test was applied 2309 times (313 and 1996 times during second and third trimesters, respectively) in 699 women. The results were positive in 4.4% (102/2309) of tests and at least once in 9.9% (69/699) of women. Anemic infants were born to one (1.4%) and six (1.0%) of 69 and 630 women with and without at least one positive test result, respectively. MoM determined 4, 3, and 2 weeks before birth showed significant weak negative correlations with UCB-Hb at birth (correlation coefficient: 0.298–0.325). Conclusions: Among unselected women giving birth at or near term, the MCA-PSV test was unsatisfactory for prediction of newborn anemia in this retrospective observational study. Keywords: Antenatal care, Fetal echocardiography, Middle cerebral artery peak systolic velocity, Newborn anemia, Prenatal diagnosis

Background: Prevalence rates of all anomalies classified as birth defects, including those identified before the 22nd gestational week, are limited in published reports, including those from the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). In our birth cohort study, we collected the data for all birth defects after 12 weeks of gestation. Methods: Subjects in this study comprised 19,244 pregnant women who visited one of 37 associated hospitals in the Hokkaido Prefecture from 2003 through 2012, and completed follow-up. All birth defects after 12 weeks of gestation, including 55 marker anomalies associated with environmental chemical exposures, were recorded. We examined parental risk factors for birth defects and the association between birth defects and risk of growth retardation. Results: Prevalence of all birth defects was 18.9/1,000 births. The proportion of patients with birth defects delivered between 12 and 21 weeks of gestation was approximately one-tenth of all patients with birth defects. Among those with congenital malformation of the nerve system, 39% were delivered before 22 weeks of gestation. All patients with anencephaly and encephalocele were delivered before 22 weeks of gestation. We observed different patterns of parental risk factors between birth defect cases included in ISBDSR and cases not included. Cases included in ISBDSR were associated with an increased risk of preterm birth. Cases not included in ISBDSR were associated with an increased risk of being small for gestational age at term. Conclusions: Data from our study complemented the data from ICBDSR. We recommend that birth defects not included in ICBDSR also be analyzed to elucidate the etiology of birth defects.

BackgroundPrenatal psychological stress may increase the risk of placental abruption (PA). This study aimed to clarify the effects of psychological distress during pregnancy and exposure to stressful life events in the year before or during pregnancy on the occurrence of PA in Japanese women.MethodsUsing a nationwide prospective birth cohort study, we obtained data from 103,099 women between January 2011 and March 2014. Information on exposure to 14 stressful life events and psychological distress (Kessler 6 scale) was collected using a self-administered questionnaire during pregnancy. Clinical diagnoses of PA were obtained from medical records. A total of 80,799 women with singleton births were analyzed using logistic regression models that adjusted for possible confounders.ResultsPA was diagnosed in 335 (0.4%) women. There was no significant difference in the Kessler 6 score during pregnancy between the PA group and non-PA group. Exposure to the death of a child in the year before or during pregnancy was significantly associated with PA in multigravid women (adjusted odds ratio [aOR] 3.57; 95% confidence interval [CI] 1.50-8.34). A spouse's loss of employment was significantly associated with PA in parous women (aOR 3.25; 95% CI 1.40-7.56).ConclusionsThis study identified the possible effects of exposure to the death of a child on PA occurrence that adjusted for important confounding factors.

Objective: This study was performed to determine how often Japanese women diagnosed as normoglycemic on first-trimester 75-g glucose tolerance test (75gGTT) later develop gestational diabetes mellitus (GDM). Material and methods: Sixty-two women with random plasma glucose (PG) level ≥ 105 mg/dL during the first trimester and subsequent first-trimester diagnosis of normoglycemia with 75gGTT underwent 50-g glucose challenge test (50gGCT) during the second trimester. Twenty-one with a positive 50gGCT result (60-m PG ≥ 140 mg/dL) underwent second-trimester 75gGTT. First-trimester random PG levels and 75gGTT results were compared between 21 and 41 women with positive and negative 50gGCT results, respectively. Changes in immunoreactive insulin (IRI) associated with 75gGTT were determined simultaneously. Results: All 21 women with a positive 50gGCT result showed normoglycemia on second-trimester 75gGTT. Thus, none of the 62 women developed GDM. Insulin resistance increased significantly in the 21 women with 75gGTT during the first and second trimesters, as indicated by increases in homeostasis model assessment for insulin resistance (HOMA-IR) and homeostasis model assessment for β-cell function (HOMA-β) with no significant changes in preload or afterload PG levels. Neither random PG levels (116 ± 12 vs. 116 ± 12 mg/dL, respectively) nor 75gGTT results (86 ± 6 vs. 84 ± 5 mg/dL for 0-minute [0-m] PG level, 130 ± 28 vs. 131 ± 25 mg/dL for 60-m PG, and 111 ± 19 vs. 118 ± 18 mg/dL for 120-m PG, respectively) during the first trimester differed significantly between the 41 and 21 women with negative and positive second-trimester 50gGCT results, respectively. Conclusion: Although insulin resistance increased in the second trimester, risk of developing GDM was < 1/62 among Japanese women in whom hyperglycemia was excluded with first-trimester GTT.

Preeclamptic twin pregnancy with larger gestational weight gain (GWG) is suggested to have a higher risk of peripartum cardiomyopathy (PPCM). This was true in a 5-year experience at a single center. A primiparous woman with twins and prepregnancy weight of 51.0 kg exhibited hypertension at gestational week (GW) 32−6/7 and GWG of 18.3 kg (6.0 kg and 2.9 kg during the last four weeks and one week of gestation, resp.) concomitant with generalized edema, gave birth at GW 34−4/7, developed proteinuria, cough, and dyspnea postpartum, and was diagnosed with preeclampsia and PPCM showing left ventricular ejection fraction of 34% and plasma BNP level of 1530 pg/mL. This was the only case of PPCM among 101 (12 with preeclampsia) and 3266 women with twin and singleton pregnancies, respectively. Thus, PPCM occurred significantly more often in women with preeclamptic twin pregnancies than in women with singleton pregnancies (8.3% [1/12] versus 0.0% [0/3266], P=0.0355). This patient showed the greatest weight gain of 6.0 kg during the last four weeks of gestation and the greatest weight loss of 19.2 kg during one month postpartum among 90 women with twin deliveries at GW ≥ 32.

Background: Bisphenol A (BPA) is widely used and BPA exposure is nearly ubiquitous in developed countries. While animal studies have indicated adverse health effects of prenatal BPA exposure including reproductive dysfunction and thyroid function disruption possibly in a sex-specific manner, findings from epidemiologic studies have not been enough to prove these adverse effects. Given very limited research on human, the aim of this study was to investigate associations between cord blood BPA levels and reproductive and thyroid hormone levels of neonates and whether associations differed by neonate sex.Methods: The study population included 514 participants of the Hokkaido study recruited from 2002 to 2005 at one hospital in Sapporo, Japan. The BPA level in cord blood was determined by ID-LC/MS/MS, and the limit of quantification was 0.040 ng/ml. We measured nine types of reproductive hormone levels in cord blood, and thyroid hormone levels were obtained from neonate mass screening test data. There were 283 subjects, who had both BPA and hormone levels measurements, included for the final analyses.Results: The geometric mean of cord blood BPA was 0.051 ng/ml. After adjustment, BPA level was negatively associated with prolactin (PRL) (β = -0.38). There was an interaction between infant sex and BPA levels on PRL; a weak negative association was found in boys (β = -0.12), whereas a weak positive association was found in girls (β = 0.14). BPA level showed weak positive association with testosterone, estradiol, and progesterone levels in boys. No association was found between BPA and thyroid hormone levels.Conclusions: Our findings suggested that fetal BPA levels might be associated with changes in certain reproductive hormone levels of neonates in a sex-specific manner, though further investigations are necessary. [ABSTRACT FROM AUTHOR]

Changes in hemodynamics and blood pressure occur shortly before and after childbirth regardless of the mode of delivery. This study aimed to test the hypothesis that parturition induces a temporal increase in podocyturia monitored by podocyte-specific protein podocin mRNA expression levels (Pod-mRNA). A total of 105 urine specimens, consisting of 43 and 62 from 18 and 20 otherwise healthy women with vaginal delivery (VD) and elective cesarean delivery (ECS), respectively, were studied. Determination of urine protein and creatinine (Cr) concentrations and quantitative analyses of Pod-mRNA, nephrin mRNA (Nep-mRNA), synaptopodin mRNA (SynmRNA), and aquaporin 2 mRNA expression were performed using RT-PCR in pelleted urine samples. Levels of mRNA expression were corrected by urine Cr concentration. Podocyturia increased significantly, concomitant with a significantly decreased Nep:Pod-mRNA ratio (NPR) in the urine, collected immediately before or after childbirth regardless of the delivery mode compared with urine collected before commencement of labor or on postpartum day 3 or later. Podocyturia was significantly negatively correlated with NPR [correlation coefficient (r) = -0.614/-0.750 for VD/ECS women, respectively], as well as the Syn:Pod-mRNA ratio. Systolic blood pressure exceeded 140 mmHg during labor in 50% of VD women, and mean arterial pressure was significantly positively correlated with podocyturia during labor in VD women (r = 0.733). Thus parturition induces a transient increase in urine podocytes with reduced Nep- and Syn-mRNA expressions. Glomerular podocytes with reduced Nep- and Syn-mRNA levels were suggested to be likely to detach from the glomerular basement membrane around childbirth. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the possibility of nephrinuria as a screening tool for the risk of pre-eclampsia (PE). Design: Prospective observational study. Setting: A single university hospital. Changes in urinary nephrin:creatinine ratio (NCR, ng/mg) and protein:creatinine ratio (PCR, mg/mg) in pregnancy were determined. Significant proteinuria in pregnancy (SPIP) was defined as PCR>0.27. PE was diagnosed in women with both SPIP and hypertension. Participants: 89 pregnant women in whom neither hypertension nor SPIP was present at enrolment, providing 31, 125 and 93 random urine samples during first, second and third trimesters, respectively. Results: PE developed in 14 of the 89 women. NCR increased with increasing PCR in 14 women with PE (correlation coefficient, 0.862; p<0.0001). In contrast, NCR did not change significantly despite significant increases in PCR in 75 women with normotensive pregnancies defined as neither SPIP nor hypertension, indicating that there was little increase in nephrinuria over the physiological range of proteinuria in pregnancy. Relative risk of later development of PE among asymptomatic second and third trimester women with NCR (ng/mg) >122 (95th centile value for 75 women with normotensive pregnancies) was 5.93 (95% CI 2.59 to 13.6; 60% (6/10) vs 10% (8/79)) and 13.5 (95% CI 3.31 to 55.0; 75% (6/8) vs 5.5% (2/36)), respectively, compared with women with NCR=122 at that time. Conclusions: Nephrinuria was unlikely to increase in normal pregnancy. A certain NCR cut-off may efficiently differentiate women at higher risk of PE. [ABSTRACT FROM AUTHOR]

The International Clearinghouse for Birth Defects, Surveillance and Research reports a rise in the prevalence rate of spina bifida in Japan. We determined first-trimester folate status of Hokkaido women and identified potential predictors. Participants were 15 266 pregnant women of the Hokkaido Study on Environment and Children's Health Cohort. Data were extracted from self-reported questionnaires and biochemical assay results. Demographic determinants of low folate status were younger maternal age (adjusted OR (AOR) 1.48; 95% CI 1.32, 1.66), lower educational level (AOR 1.27; 95% CI 1.17, 1.39) and lower annual income (AOR 1.11; 95% CI 1.01, 1.22). Plasma cotinine concentrations of 1.19-65.21 nmol/l increased the risk of low folate status (AOR 1.20; 95% CI 1.10, 1.31) and concentrations >65.21 nmol/l further increased the risk (AOR 1.91; 95% CI 1.70, 2.14). The most favourable predictor was use of folic acid (FA) supplements (AOR 0.19; 95% CI 0.17, 0.22). Certain socio-demographic factors influence folate status among pregnant Japanese women. Modifiable negative and positive predictors were active and passive tobacco smoking and use of FA supplements. Avoiding both active and passive tobacco smoking and using FA supplements could improve the folate status of Japanese women. [ABSTRACT FROM AUTHOR]

Objectives: Some women with isolated gestational proteinuria (IGP) later develop hypertension and are diagnosed with pre-eclampsia (PE). This study was performed to determine whether clinical features of such proteinuria preceding PE (P-PE) differ from those of other PE (O-PE). Design: Retrospective observational study after approval of the institutional review board of ethics. Setting: A single university hospital. Proteinuria was defined as a protein-to-creatinine ratio (mg/mg; P/Cr) of =0.27 in the spot urine specimen. IGP was defined as proteinuria in the absence of hypertension. P-PE was defined as PE in which proteinuria preceded hypertension by more than 2 days. Participants: All of 10 and 18 consecutive women with P-PE and O-PE, respectively, who gave birth between January 2008 and August 2013. Results: Proteinuria appeared earlier (at 30.2±3.0 vs 35.3±4.3 weeks, p=0.001), the P/Cr level was greater at birth (7.28±2.14 vs 3.19±2.49, p<0.001), net maternal weight gain during the last antenatal 1 week was greater (3.1±1.8 vs 1.3±1.7 kg, p=0.023) and length of pregnancy was shorter (32.5±1.9 vs 36.1±3.6 weeks, p=0.001) in women with P-PE than in O-PE. The duration of IGP was 10.0±5.9 days (range 3-20), and the time interval until delivery after diagnosis of PE was 6.1±8.2 days (range 0-23) in 10 women with P-PE. The P/Cr levels at birth were significantly inversely correlated with the antenatal lowest antithrombin activity and fibrinogen levels among the 28 women with PE. Conclusions: Women with P-PE were likely to exhibit greater proteinuria in the urine, greater water retention in the interstitial space and more enhanced coagulation--fibrinolysis, thus suggesting that they may constitute a more severe form of PE than women with O-PE do. [ABSTRACT FROM AUTHOR]

Background: Japan experienced two rubella outbreaks in the past decade (2004 and 2012 – 2013), resulting in 10 and 20 infants with congenital rubella syndrome (CRS), respectively. This study was performed to determine whether the seronegative rate was lower in multiparous women than in primiparous women in Japan. Methods: Hemagglutination inhibition (HI) test results during pregnancy were analyzed retrospectively in 11048 primiparous and 9315 multiparous women who gave birth at six hospitals in northern Japan in the 5-year study period (January 2008 through December 2012). Women with HI titer < 1:8 were defined as susceptible to rubella. Results: The seronegative rate was significantly lower in multiparous than primiparous women aged 30 – 31 years (2.3% [22/967] vs. 4.5% [66/1454], P = 0.0036), 36 – 37 years (3.4% [55/1601] vs. 5.7% [79/1389], P = 0.0030), and overall women (3.8% [350/9315] aged 34.7 ± 5.2 vs. 5.4% [597/11048] for 33.2 ± 5.9, P < 0.001). The susceptible fraction size did not differ largely according to hospital, ranging from 3.5% to 6.3%. Those for each year did not change markedly; 4.5% [150/3369], 5.2% [221/4268], 4.4% [195/4412], 4.6% [186/4056], and 4.6% [195/4258] for 2008, 2009, 2010, 2011, and 2012, respectively. Those for teenagers were consistently high: 22.7% [5/22], 20.7% [6/29], 20.6% [7/34], 13.0% [3/23], and 23.5% [4/17] for 2008, 2009, 2010, 2011, and 2012, respectively. Conclusions: The seronegative rate was significantly lower in multiparous than primiparous women. However, Japanese rubella vaccination programs were insufficient to eliminate CRS. [ABSTRACT FROM AUTHOR]

Objective: To determine how urine dipstick test, edema, and/or excessive weight gain (EWG, defined as 500g/week) at antenatal visits predict significant proteinuria (defined as a protein-to-creatinine ratio [P/Cr, mg/mg] 0.27) and preeclampsia. Methods: Data from 3279 antenatal visits between 30 and 36weeks of gestation were studied in 783 women with singleton pregnancies. In 24 preeclamptic pregnancies, data from 89 antenatal visits at and before diagnosis of preeclampsia were used. Spot P/Cr was determined in women with repeated positive dipstick test results in two successive antenatal visits or in those with a positive dipstick test result tested in the presence of hypertension. Results: Proteinuria on dipstick test, edema, and EWG appeared often in both women with and without preeclampsia; 66.7% vs. 27.7%, 83.3% vs. 44.1%, and 91.7% vs. 81.6%, respectively. However, repeated positive dipstick test results in two successive antenatal visits yielded sensitivity of 45.5%, specificity of 95.2%, and positive and negative predictive values of 30.0% and 97.4%, respectively, for detection of significant proteinuria and corresponding figures of 33.3%, 94.1%, 14.0%, and 98.0% for prediction of preeclampsia. Conclusion: Repeated positive dipstick test results in two successive antenatal visits warrant a need for a confirmation test of significant proteinuria. [ABSTRACT FROM AUTHOR]

We performed a retrospective review of medical charts regarding blood d-dimer levels determined cross-sectionally by the latex agglutination assay in 1952 samples from 1185 women to determine changes in d-dimer levels according to the stage of pregnancy. Three of 17 women in whom further investigations were performed were found to have clinical venous thromboembolism (VTE). The median and 95th percentile values of d-dimer (microgram/mL) in the 1182 women without clinical VTE, 0.54 and 2.41 at gestational week (GW) 4-13, increased gradually to 1.22 and 5.03 at GW 14-27, 1.81 and 6.18 at GW 28-35, and 2.13 and 5.85 at GW 36-42, respectively. A total of nine women (0.76%), including three women with clinical VTE, exhibited a d-dimer level >14.0 microgram/mL, which was well above the 99th percentile for any stage of pregnancy. Thus, 3 (33%) of the nine with a d-dimer level >14 microgram/mL developed clinical VTE, while none of the remaining 1176 women with a d-dimer level ?14 microgram/mL developed clinical VTE. Although further prospective studies are required, our results suggested that there is a certain cut-off d-dimer value that would allow us to differentiate between pregnant women with and without clinical VTE. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this study was to assess pregnancy loss patterns in women with repeated miscarriage (RM), according to fetal chromosome karyotypes and aetiologies of RM. METHODS: In this cohort study, 168 fetal chromosome karyotypes of miscarriages were investigated. The pregnancy loss patterns were compared between 75 miscarriages from RM women who had a history of two or more consecutive miscarriages and 93 miscarriages from control women whose previous pregnancies ended in live births without a history of RM. By serial ultrasonography, embryo loss (EL) was defined as miscarriage before fetal heat movement was identified and fetal loss (FL) as miscarriage after fetal heat movement was identified. The EL rate was calculated as EL/(EL+FL). RESULTS: The EL rate (66.7%) in miscarriages with normal karyotypes among RM women (n=42) was higher (P<0.05) than that (45.7%) in controls (n=46), while the EL rate (30.3%) in miscarriages with abnormal karyotypes among RM women (n=33) did not differ from that (25.5%) in the controls (n=47). The EL rate (71.4%) in miscarriages with normal karyotypes among unexplained RM women (n=21) was much higher (P<0.05) than that in the controls. CONCLUSIONS: By evaluating fetal karyotypes, we demonstrated for the first time that EL was predominant in miscarriages with normal karyotype among RM women. [ABSTRACT FROM AUTHOR]

Hypochondroplasia is an autosomal dominant skeletal dysplasia expressing postnatal onset of short stature with mild rhizomelic shortening of the limbs. This manifestation leads to restricted prenatal diagnosis of the disorder. We report here on a sporadic case of a hypochondroplastic baby, whose prenatal sonographic measurements were serially recorded from 19 weeks of gestation. Mild shortening of the limbs became manifest after 26 weeks of gestation. Biparietal diameter was within the normal range throughout gestation. Both parents were of average stature. A tentative diagnosis of a nonlethal short-limb skeletal dysplasia was made. At birth, the clinical manifestations of the neonate were not characteristic, but the radiographic features raised the possibility of hypochondroplasia. Molecular analyses revealed a C to G mutation at nucleotide 1659 of the fibroblast growth factor receptor 3 (FGFR3) gene, a common mutation in hypochondroplasia. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective The role of hyaluronic acid (HA)-binding proteins in cervical ripening has not been explored. We examined the ability of PGE2 to induce expression of the HA-binding protein, tumor necrosis factor-stimulated gene (TSG)6, in human cervical smooth muscle cells (hCSMC) and compared the PGE2 response to that of TNF-a. Methods hCSMC were stimulated with PGE2 or TNF-a to compare the expression of TSG-6. A 1.3-kb of the TSG-6 proximal promoter region was cloned and transfected into hCSMC. The cells were stimulated with PGE2 or TNF-a to determine the effect on TSG-6 promoter activity. Results TNF-a stimulated TSG-6 mRNA in a dose and time dependent manner (maximal response: 10 ng/ml after 6 hours). PGE2 stimulated TSG-6 mRNA, but the magnitude of response was less than that produced by TNF-a, and it was maximal after 24 hours. TNF-a and PGE2 stimulated secretion of TSG-6 as detected by Western blotting. The effects of PGE2 on secretion of TSG-6 were delayed compared to TNF-a. PGE2 increased TSG-6 promoter activity 1.75-fold. Paradoxically, TNF-a reduced TSG-6 promoter activity by 50%. Conclusion hCSMC express TSG-6; TSG-6 expression in hCSMC is regulated by PGE2 as well as TNF-a; responses of hCSMC to TNF-a and PGE2 are distinct in terms of magnitude and the time course; PGE2 and TNF-a exert different effects on the TSG-6 proximal promoter. [ABSTRACT FROM AUTHOR]

Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of a surfactant-like substance in alveolar spaces and hypoxemic respiratory failure. Genetic PAP (GPAP) is caused by mutations in genes encoding surfactant proteins or genes encoding a surfactant phospholipid transporter in alveolar type II epithelial cells. GPAP is also caused by mutations in genes whose products are implicated in surfactant catabolism in alveolar macrophages (AMs). We performed whole-exome sequence analysis in a family affected by infantile- onset PAP with hypogammaglobulinemia without causative mutations in genes associated with PAP: SFTPB, SFTPC, ABCA3, CSF2RA, CSF2RB, and GATA2. We identified a heterozygous missense variation in OAS1, encoding 2,'5'-oligoadenylate synthetase 1 (OAS1) in three affected siblings, but not in unaffected family members. Deep sequence analysis with next-generation sequencing indicated 3.81% mosaicism of this variant in DNA from their mother's peripheral blood leukocytes, suggesting that PAP observed in this family could be inherited as an autosomal-dominant trait from the mother. We identified two additional de novo heterozygous missense variations of OAS1 in two unrelated simplex individuals also manifesting infantile-onset PAP with hypogammaglobulinemia. PAP in the two simplex individuals resolved after hematopoietic stem cell transplantation, indicating that OAS1 dysfunction is associated with impaired surfactant catabolism due to the defects in AMs. [ABSTRACT FROM AUTHOR]

Background Fetomaternal hemorrhage (FMH) can cause severe morbidity. However, perinatal risk factors for long-term poor outcome due to FMH have not been extensively studied. Aims To determine which FMH infants are likely to have neurological sequelae. Study design A single-center retrospective observational study. Perinatal factors, including demographic characteristics, Kleihauer-Betke test, blood gas analysis, and neonatal blood hemoglobin concentration ([Hb]), were analyzed in association with long-term outcomes. Subjects All 18 neonates referred to a Neonatal Intensive Care Unit of Kagoshima City Hospital and diagnosed with FMH during a 15-year study period. All had a neonatal [Hb] < 7.5 g/dL and 15 of 17 neonates tested had Kleihauer-Betke test result > 4.0%. Outcome measures Poor long-term outcome was defined as any of the following determined at 12 month old or more: cerebral palsy, mental retardation, attention deficit/hyperactivity disorder, and epilepsy. Results Nine of the 18 neonates exhibited poor outcomes. Among demographic characteristics and blood variables compared between two groups with poor and favorable outcomes, significant differences were observed in [Hb] (3.6 ± 1.4 vs. 5.4 ± 1.1 g/dL, P = 0.01), pH (7.09 ± 0.11 vs. 7.25 ± 0.13, P = 0.02) and base deficits (17.5 ± 5.4 vs. 10.4 ± 6.0 mmol/L, P = 0.02) in neonatal blood, and a number of infants with [Hb] ≤ 4.5 g/dL (78%[7/9] vs. 22%[2/9], P = 0.03), respectively. The base deficit in neonatal arterial blood increased significantly with decreasing neonatal [Hb]. Conclusions Severe anemia causing severe base deficit is associated with neurological sequelae in FMH infants. [ABSTRACT FROM AUTHOR]