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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 p p = 0.02 and r = − 0.36, p Conclusions The intravascular cardiac load reached maximum within 1 week after childbirth and was greater in women with twin pregnancies than in those with singleton pregnancies. BNP/NT-proBNP significantly positively correlated with LA volume index and E/e’. In women with singleton pregnancies, BNP secreted immediately after childbirth might improve the diastolic functions 1 month after childbirth.

Japanese studies on the association between maternal alcohol consumption and fetal growth are few. This study assessed the effect of maternal alcohol consumption on fetal growth.This prospective birth cohort included 95,761 participants enrolled between January 2011 and March 2014 in the Japan Environment and Children's Study. Adjusted multiple linear and logistic regression models were used to assess the association between prenatal alcohol consumption and infant birth size.Consumption of a weekly dose of alcohol in the second/third trimester showed a significant negative correlation with standard deviation (SD; Z) scores for body weight, body length, and head circumference at birth, respectively. Consumption of a weekly dose of alcohol during the second/third trimester had a significant positive correlation with incidences of Z-score ≤ -1.5 for birth head circumference. Associations between alcohol consumption in the second/third trimester and Z-score ≤ -1.5 for birth weight or birth length were not significant. Maternal alcohol consumption in the second/third trimester above 5, 20, and 100 g/week affected body weight, body length, and head circumference at birth, respectively.Low-to-moderate alcohol consumption during pregnancy might affect fetal growth. Public health policies for pregnant women are needed to stop alcohol consumption during pregnancy.This study examined the association between maternal alcohol consumption and fetal growth restriction in 95,761 pregnant Japanese women using the prospective birth cohort. Maternal alcohol consumption in the second/third trimester more than 5, 20, and 100 g/week might affect fetal growth in body weight, body length, and head circumference, respectively. The findings are relevant and important for educating pregnant women on the adverse health effects that prenatal alcohol consumptions have on infants.

Objectives Previous studies indicated a significant association between small for gestational age (SGA) in infants and their parents’ socioeconomic status (SES). Thus, this study aimed to examine if parental factors, such as maternal smoking, and the pre-pregnancy body mass index (BMI) could mediate the associations between parental SES and SGA. Methods The participants of this study were pregnant women who enrolled in an ongoing birth cohort study, the Hokkaido study, during the first trimester of their pregnancies. A total of 14,593 live singleton births were included in the statistical analysis, of which 1011 (6.9%) were SGA. Two structural equation models were employed to evaluate the associations between parental SES, parental characteristics, and SGA. Results The effect of low SES on SGA was directly mediated by maternal pre-pregnancy BMI, smoking during the third trimester, and alcohol consumption during the first trimester in the first model, which was based the assumption of independent associations between mediating factors. In the second model, which additionally considered the mediating factors from the first model, smoking during pregnancy mediated decline in parental SES, consequently increased SGA. Moreover, an increase in pregnancy smoking status increased the prevalence of lower maternal pre-pregnancy BMI and its effect on SGA. Conclusions for Practice In this study, we observed the independent mediating effect of maternal pre-pregnancy BMI, smoking, and alcohol consumption during pregnancy on low SES and, consequently, SGA, with the additional mediating pathway of SES to smoking to low BMI on SGA.

Two prospective multicenter studies demonstrated that a soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio cutoff of ≤38 can rule out preeclampsia within 1 week with a negative predictive value (NPV) of 99.3% (PROGNOSIS) and 98.6% (PROGNOSIS Asia). We report a subanalysis of the Japanese cohort from the PROGNOSIS Asia study. Pregnant women with suspected preeclampsia between gestational weeks 18 + 0 days and 36 + 6 days were enrolled at eight Japanese sites. Primary objectives: Assess the performance of the Elecsys® sFlt-1/PlGF ratio cutoff ≤38 to rule out preeclampsia within 1 week and of the cutoff >38 to rule in preeclampsia within 4 weeks. Key secondary objectives: Prediction of maternal and fetal adverse outcomes (MAOs/FAOs) and their relationship with duration of pregnancy. Of 192 women enrolled, 180 (93.8%)/175 (91.1%) were evaluable for primary/combined endpoint analyses. Overall preeclampsia prevalence was 13.3%. A sFlt-1/PlGF ratio of ≤38 provided an NPV of 100% (95% confidence interval [CI], 97.5–100) for ruling out preeclampsia within 1 week, and a ratio of >38 provided a positive predictive value of 32.4% (95% CI, 18.0–49.8) for ruling in preeclampsia within 4 weeks. The area under the curve for the prediction of preeclampsia/maternal/fetal adverse outcomes within 1 week was 94.2% (95% CI, 89.3–97.8). After adjusting for gestational age and final preeclampsia status, Cox regression indicated a 2.8-fold greater risk of imminent delivery for women with a sFlt-1/PlGF ratio >38 versus ≤38. This subanalysis of Japanese women with suspicion of preeclampsia showed high predictive value for a Elecsys sFlt-1/PlGF ratio cutoff of 38 for short-term prediction of preeclampsia.

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.

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.

Although the effects of prenatal passive smoking on birth weight have been reported, the effects of metabolic gene polymorphisms on passive smoking have not been studied. Therefore, we investigated the effects of maternal passive smoking and metabolic gene polymorphisms on child growth up to 3years of age using cotinine as a biomarker. We included 1356 Japanese participants in a prospective cohort between 2003 and 2007 (cotinine levels at the third trimester≤0.21ng/mL and 0.22 to 11.48ng/mL for non-passive and passive smokers, respectively), and measured child outcomes such as weight, length, head circumference, and Kaup index. Additionally, we analyzed cytochrome P450 1A1 (CYP1A1), epoxide hydrolase 1 (EPHX1), and two N-acetyltransferase 2 (NAT2) genotypes using real-time polymerase chain reaction methods. Associations were investigated using multiple regression models. Kaup index gain from birth up to 3years of age was significantly smaller in children born to passive smokers than in those born to non-passive smokers (-0.34kg/m2; 95% confidence interval: -0.67, -0.01). Maternal CYP1A1 genotype was not associated with prenatal passive smoking and Kaup index gain, but was significantly associated with prenatal passive smoking and head circumference gain from birth up to 3years of age (-0.75cm; 95% confidence interval: -1.39, -0.12). Thus, this study suggests that prenatal passive smoking may have potent effects on postnatal growth from birth up to 3years of age. Moreover, children with maternal CYP1A1 genotype may be more susceptible to the effects of prenatal passive smoking.

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 (Syn-mRNA), 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.

Background H19 and IGF2 genes are imprinted and involved in regulating fetal and placental growth. The H19 differentially methylated region (DMR) is paternally methylated and maternally unmethylated and regulates the imprinted expression of H19 and IGF2. Epimutation at the H19-DMR in humans results in congenital growth disorders, Beckwith-Wiedemann and Silver-Russell syndromes, when erroneously its maternal allele becomes methylated and its paternal allele becomes unmethylated, respectively. Although H19 and IGF2 have been assessed for their involvement in pregnancy complications including fetal growth restriction (FGR) and pregnancy-induced hypertension (PIH)/hypertensive disorder of pregnancy (HDP) intensively in the last decade, it is still not established whether epimutation at the H19-DMR in the placenta results in pathogenic conditions in pregnancy. We aimed to assess the frequency of H19-DMR epimutation and its effects on the allelic expression patterns of H19 and IGF2 genes among normal and abnormal pregnancy cases. Results We enrolled two independently collected sets of placenta samples from normal pregnancies as controls and common pregnancy complications, FGR and PIH (HDP). The first set consisted of 39 controls and 140 FGR and/or PIH cases, and the second set consisted of 29 controls and 62 cases. For these samples, we initially screened for DNA methylation changes at H19-DMR and IGF2-DMRs by combined bisulfite restriction analysis, and further analyzed cases with methylation changes for their allelic methylation and expression patterns. We identified one case each of FGR and PIH showing hypomethylation of H19-DMR and IGF2-DMRs only in the placenta, but not in cord blood, from the first case/control set. For the PIH case, we were able to determine the allelic expression pattern of H19 to be biallelically expressed and the H19/IGF2 expression ratio to be highly elevated compared to controls. We also identified a PIH case with hypomethylation at H19-DMR and IGF2-DMRs in the placenta from the second case/control set. Conclusions Placental epimutation at H19-DMR was observed among common pregnancy complication cases at the frequency of 1.5% (3 out of 202 cases examined), but not in 68 normal pregnancy cases examined. Alteration of H19/IGF2 expression patterns due to hypomethylation of H19-DMR may have been involved in the pathogenesis of pregnancy complications in these cases. Electronic supplementary material The online version of this article (10.1186/s13148-019-0712-3) contains supplementary material, which is available to authorized users.

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

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.

Background There have been few reports regarding outcomes after extracorporeal membrane oxygenation (ECMO) in newborn Japanese infants. Methods A review of 61 neonates with ECMO through January 1995 at a single center was performed. ECMO was used in neonates with oxygenation index > 20 after conventional treatments. Background factors, such as etiology, vascular access mode (veno–venous [VV] or veno–arterial [VA]), number of days with ECMO, and early ECMO (within 24 hours after birth), were analyzed in relation to outcome with respect to survival to hospital discharge (SHD). Results SHD was achieved in 35 (57%) infants, while the remaining 26 died during the hospital stay. Gestational age at birth was significantly higher and number of days with ECMO was significantly lower in SHD infants compared to those with adverse outcome (median, 4.0 vs. 5.5 days, respectively, P = 0.008). The SHD rate was significantly higher for those with VV than VA (78% [18/23] vs. 45% [17/38], respectively, P = 0.016), and for those with than without early ECMO (72% [28/39] vs. 32% [7/22], respectively, P = 0.003). The SHD rate was relatively high in neonates with meconium aspiration syndrome (MAS) (86% [12/14]), persistent pulmonary hypertension (PPHN) associated with hypoxic ischemic encephalopathy (HIE) (75% [6/8]), and emphysema (80% [4/5]). Stepwise logistic regression analysis identified two independent risk factors for SHD including early ECMO (OR [95%CI], 9.63 [2.47 – 37.6]) and ECMO length < 8 days (8.05 [1.94 – 33.5]). Conclusions Neonates having early ECMO and those with ECMO duration less than 8 days may have benefited from ECMO with respect to SHD. This article is protected by copyright. All rights reserved.

Background There have been no previous studies regarding whether combined use of Polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) and continuous hemodiafiltration (CHDF) is helpful in the treatment of preterm infants with systemic inflammatory response syndrome (SIRS) and hypercytokinemia. Methods A retrospective review was carried out of 18 SIRS infants born at gestational week 24–28. Eight with blood interleukin (IL)-6 ≥ 1000 pg/mL were treated actively with 2 h PMX-DHP followed by 2 h PMX-DHP and CHDF. Ten with IL-6 < 500 pg/mL were treated conventionally (with neither PMX-DHP nor CHDF) and served as controls. Results Demographic characteristics were similar except for IL-6, arterial-to-alveolar oxygen tension ratio (a/APO2), and number of immature neutrophils between the two groups. Baseline a/APO2 was significantly lower in infants with than without active treatment (0.44 vs 0.67, respectively, P = 0.002). After 4 h treatment, the IL-6 decreased to < 500 pg/mL in all eight infants, and a/APO2 improved significantly to 0.62 (P = 0.006). Bronchopulmonary dysplasia occurred in a similar proportion (63%, 5/8 vs 80%, 8/10, respectively), but the number of days on inhaled oxygen (30 vs 47 days, respectively, P = 0.033) and tracheal intubation (36 vs 51 days, respectively, P = 0.040) was significantly lower in infants with than without active treatment. Prevalence of adverse events was similar (13%, 1/8 vs 50%, 5/10 for active vs conventional treatment, respectively). Conclusion Active treatment with PMX-DHP and CHDF was helpful in the reduction of days on inhaled oxygen and tracheal intubation in preterm SIRS infants with hypercytokinemia. Further prospective randomized studies are warranted.

Introduction Some pregnant women develop significant proteinuria in the absence of hypertension. However, clinical significance of isolated gestational proteinuria (IGP) is not well understood. This study aimed to determine the prevalence of IGP in singleton pregnancies and the proportion of women with IGP who subsequently developed preeclampsia (IGP-PE) among all PE cases. Material and methods This was an observational study of 6819 women with singleton pregnancies at 12 centers, including 938 women with at least once determination of protein-to-creatinine ratio (P/Cr). Significant proteinuria in pregnancy (SPIP) was defined as P/Cr (mg/mg) level >0.27. IGP was defined as SPIP in the absence of hypertension. Gestational hypertension (GH) preceding preeclampsia (GH-PE) was defined as preeclampsia (PE) in which GH preceded SPIP. Simultaneous PE (S-PE) was defined as PE in which both SPIP and hypertension occurred simultaneously. Results IGP and PE were diagnosed in 130 (1.9%) and 158 (2.3%) of 6819 women, respectively. Of 130 women with IGP, 32 (25%) progressed to PE and accounted for 20% of all women with PE. Hence, women with IGP had a relative risk of 13.1 (95% CI; 9.2–18.5) for developing PE compared with those without IGP [25% (32/130) vs. 1.9% (126/6689)]. At diagnosis of SPIP, P/Cr levels already exceeded 1.0 more often in women with S-PE than in those with IGP-PE [67% (33/49) vs. 44% (14/32), respectively, p = 0.031]. Conclusions IGP is a risk factor for PE, and IGP-PE accounts for a considerable proportion (20%) of all PE.

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.

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.

Background Gestational thrombocytopenia is more likely to occur in twin than singleton pregnancies. However, it is unclear whether platelets are more reactive in twin than singleton pregnancies. Methods Changes in spontaneous platelet aggregation and concomitant fall in platelet count were examined over 90 min after blood sampling in 171 and 52 citrated whole blood (CWB) samples from 59 and 17 women with singleton and twin pregnancies, respectively. Soluble P-selectin (sP-selectin) levels in the plasma were also determined. Results CWB 60 min after blood sampling during 2nd trimester exhibited significantly larger numbers of platelet aggregates (1297 ± 1600 vs. 497 ± 432/μl, P = 0.040) concomitant with significantly greater net decrease in platelet count (152 ± 55 vs. 115 ± 45 × 109/μl, P = 0.036) in twin than singleton pregnancies, respectively. This was followed by significantly lower 3rd trimester platelet count (181 ± 43 vs. 229 ± 62 × 109/l, P = 0.009) with significantly greater mean platelet volume (8.0 ± 1.2 vs. 7.1 ± 1.1 fl, P = 0.021) in twin than singleton pregnancies, respectively. The 3rd trimester sP-selectin per platelet was significantly higher in twin than singleton pregnancies. Conclusions Platelets were more reactive in the 2nd trimester of twin than singleton pregnancies. This enhanced platelet reactivity may explain the decreased platelet count in the 3rd trimester of twin pregnancy.

There have been few reports on the effects of everolimus on the fetus, but none of six infants with documented everolimus exposure in utero had congenital malformations. A 32-year-old nulliparous woman on everolimus (5.0 mg/day) for renal angiomyolipoma (AML) due to tuberous sclerosis complex (TSC) was found to be pregnant at gestational week (GW) 7-5/7, at which time everolimus was withheld. To control AML in this patient, transarterial embolization was performed in the right and left kidneys at GW 21 and 24, respectively, and everolimus was reinitiated at GW 25. The patient gave birth at GW 37 to a normally formed infant weighing 3057 g, but who had cardiac tumors thought to be rhabdomyomas due to inherited TSC. Thus, although data are still limited, everolimus may be promising with respect to teratogenicity. Everolimus concentration in the maternal and umbilical cord blood at birth was 1.1 ng/mL and 1.0 ng/mL, respectively.

From 1985 to 2013, the mean birth weight of infants in Japan decreased from 3120 g to 3000 g, and the low-birth-weight rate among live births increased from 6.3% to 9.6%. No prospective study has elucidated the risk factors for poor fetal growth and preterm birth in recent Japanese parents, such as increased parental age, maternal body figure, assisted reproductive technology (ART), and socioeconomic status. Participants were mother-infant pairs (n = 18,059) enrolled in a prospective birth cohort in Hokkaido, Japan from 2002 to 2013. Parental characteristics were obtained via self-reported questionnaires during pregnancy. Medical records helped identify very-low-birth-weight (VLBW

Autophagy is activated by environment unfavorable for survival and requires Atg9a protein. Mice heterozygous for p57(Kip2), devoid of the imprinted paternal allele (p57(Kip2+/-)), are known to develop hypertension during pregnancy. To determine whether fetal Atg9a is involved in the intrauterine survival and growth of fetal mice, this study was performed on Atg9a heterozygous (Atg9a(+/-)) pregnant mice with and without p57(Kip2+/-). The pregnant mice heterozygous for both knockout alleles of Atg9a and p57(Kip2) (Atg9a(+/-)/p57(Kip2+/-)), but not those heterozygous for Atg9a alone, developed hypertension during pregnancy. Placental expression of Atg9a mRNA was significantly decreased in the Atg9a(-/-) mice compared to Atg9a(+/-) or Atg9a(+/+) mice. The Atg9a(-/-) fetal mice exhibited significantly retarded growth and were more likely to die in utero compared to Atg9a(+/+) and Atg9a(+/-) fetal mice. Growth retardation was observed in the presence of maternal hypertension in Atg9a(-/-) fetal mice. These results suggest that Atg9a(-/-) fetal mice from pregnant dams heterozygous for both knockout alleles of Atg9a and p57(Kip2) are more susceptible to hypertensive stress than fetuses with intact autophagic machinery.

Background It was recently suggested that platelet reactivity is reduced in early pregnancy. This study was performed to determine whether the citrated whole blood from 33 pregnant women in their first trimester showed spontaneous platelet aggregation and whether it differed in extent from that of 11 non-pregnant women. Methods The platelet count and number of platelet aggregates (PA) were serially determined in the same citrated whole blood specimens at 15, 30, 45, 60, 75, and 90 min after blood sampling using a hematology analyzer. Results The number of PA increased significantly at 30 min and thereafter in both groups, but was consistently lower for pregnant than non-pregnant women over the 90-min observation period. The platelet count decreased significantly in a time-dependent manner in both groups, but was significantly lower at 30 and 90 min for non-pregnant than pregnant women. The number of PA showed a significant positive correlation with net decrease in platelet count for both pregnant and non-pregnant women. PA counts were also significantly positively correlated with the mean platelet volume. Conclusion Platelet reactivity monitored by the increase in number of PA and the fall in platelet count was reduced in early pregnancy compared with non-pregnant healthy controls.

There has been an increasing demand for interventional radiology (IR) procedures for the treatment of severe postpartum hemorrhage (PPH) (also called critical hemorrhage in obstetrics). The Japanese Society of Interventional Radiology Guideline Committee developed the practical guidelines for IR procedures for severe PPH using evidence-based methodology. This article aimed to describe the rationale for developing these guidelines and to provide the answers for clinical questions about IR procedures consisting of current available evidence and the consensus among experts.

This literature review was conducted to provide better counsel to pregnant women who erroneously took angiotensin receptor blockers (ARBs) during the second and/or third trimesters regarding infant outcomes. Information was available on 83 fetuses in 34 literature reports, including one that we encountered recently. Fourteen pregnancies were terminated, and six were unknown regarding status of amniotic fluid volume (AFV). Fifty-eight and five fetuses did and did not show oligohydramnios, respectively, after being exposed to ARBs. Of the 58 fetuses that presented with oligohydramnios, 57 were exposed to ARBs at gestational week (GW) ⩾ 20, and 19 exhibited resolution of oligohydramnios 1-6 weeks after cessation of ARBs. The 24 mothers without oligohydramnios at delivery ceased taking ARBs earlier (GW of 26.8 ± 5.1 vs. 31.8 ± 4.0, respectively, P = 0.000) and had longer duration of gestation after cessation of ARBs (8.4 ± 5.2 vs. 0.7 ± 2.3 weeks, respectively, P = 0.000). The mothers without oligohydramnios also had better outcomes in terms of favorable infant outcomes (63% (15/24) vs. 15% (6/39), respectively, P = 0.000) and infant mortality rates (13% (3/24) vs. 56% (22/39), respectively, P = 0.001) than the 39 with oligohydramnios. Thus, a favorable outcome may be feasible if the fetuses are not indicated for prompt delivery at presentation and exhibit normal AFV or resolution of oligohydramnios after cessation of ARBs. Although the prevalence rate of oligohydramnios was high in this study, it may have been due to publication bias. A prospective study suggested a lower prevalence rate than that reported in the present study.

SummaryIt was the study objective to evaluate whether low levels of plasma protein S (PS) activity, free PS, protein C (PC) activity and coagulation factor XII (FXII) during early pregnancy are related to adverse pregnancy outcomes. Peripheral blood samples were obtained at 8–14 gestational weeks (GW) from a consecutive series of 1,220 women. The levels of plasma PS activity, free PS, PC activity, and FXII were measured. Cut-off values were defined as < 1st, < 5th, and < 10th percentiles of values obtained from 933 women whose pregnancies ended in normal deliveries without complications. PS activity of < 10th percentile yielded risks of pregnancy-induced hypertension (PIH) and severe PIH, while free PS level of < 5th percentile yielded a risk of preeclampsia. FXII level of < 1st percentile yielded a risk of premature delivery (PD) at < 34 GW. None was associated with PD at < 37 GW, fetal growth restriction or fetal loss. A multivariate analysis demonstrated that PS activity of < 10th percentile (odds ratio 5.9, 95 % confidence interval 1.7–18.1) and body mass index (BMI) ≥ 25 kg/m2 (4.3, 1.1–13.3) were independent risk factors for severe PIH. Similarly, free PS level of < 5th percentile (4.4, 1.0–14.3) and BMI ≥ 25 kg/m2 (4.0, 1.3–10.9) were independent risk factors for pre-eclampsia. In conclusion, women with low levels of plasma PS activity and free PS during early pregnancy might have increased risks of PIH, severe PIH or pre-eclampsia. Women with low FXII level might have an increased risk of PD at < 34 GW.

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.

A 36-year-old nulliparous woman developed pre-eclampsia at gestational week (GW) 28(–6/7). Cardiac status was checked regularly. Heart rate of 93 beats per minute (bpm) with left atrial diameter (LAD) of 35 mm, left ventricular hypertrophy and inferior vena cava diameter (IVCD) of 8 mm at GW 32(–0/7) decreased to 48 bpm with an expanded IVCD to 25 mm, dilated left atrium (LAD to 39 mm), increased pulmonary arterial pressure, increased systemic vascular resistance (approximate 3000 dyn s/cm(5)) and biphasic intrarenal venous flow pattern 3.5 hours prior to childbirth at GW 32(–3/7). Epigastralgia, tachycardia (160 bpm) and marked hypertension (201/111 mm Hg) occurring 2 hours after echocardiography necessitated caesarean section, with subsequent development of HELLP syndrome. Acute fluid shift from the splanchnic vasculature to central vasculature may have occurred causing HELLP syndrome as a result from vasospasm associated with sympathetic hyperactivity. The cause of bradycardia prior to tachycardia remains unclear.

The objective of this study was to determine how many pregnant Japanese women with diabetes mellitus (DM)/gestational diabetes mellitus (GDM) experience perinatal mortality in the presence of fetal anomalies.Our investigation included data from 205 secondary/tertiary obstetric facilities located widely in Japan. The Japan Ministry of Health, Labour and Welfare Vital Statistics of Japan was used for comparison.Of 237 941 women giving birth at 205 hospitals, 1796 (0.8%) and 13 037 (5.5%) had DM and GDM, respectively. The perinatal mortality rates (per 1000 births) were 10.6 (19/1796) for women with DM, 5.2 (68/13037) for women with GDM, and 3.7 (7612/2039504) for the general Japanese population. Detailed information was available for 63 (72%) of the 87 perinatal deaths occurring in women with diabetes including DM and GDM; fetal anomalies were associated with 40% (25/63) of perinatal deaths, exceeding 16% (1211/7612) in the general Japanese population (P0.0001). The leading four fetal anomalies associated with perinatal mortality in women with diabetes were fetal trisomy (6 cases: 1 of trisomy-13 and 5 of trisomy-18), non-immune hydrops fetalis (5 cases), cardiac deformities (3 cases) and holoprosencephaly (2 cases).Perinatal mortality was more likely to occur in women with glucose intolerance. In the Japanese infants that succumbed to perinatal mortality, fetal anomaly was more prevalent in those born to women with a glucose intolerance than in those born to the general population.

The original publication is available at www.springerlink.com, This questionnaire survey was conducted at 11 hospitals in Japan to determine vaccination coverage against seasonal influenza and the prevalence rate of influenza among pregnant Japanese women. Of 2,808 postpartum women who gave birth at the 11 hospitals during the study period from March 1, 2014, to July 31, 2014, 1,713 (61 %) participated in this study and 876 (51 %) reported having received vaccination against influenza in or after October 2013. Women aged < 25 years had a significantly lower vaccination rate than those aged a parts per thousand yen25 years (31 % vs. 53 %, respectively; p = 0.0000). Eighty-seven (5.1 %) and 1,626 (94.9 %) women did and did not contract influenza, respectively. Although prior birth did not affect overall vaccination coverage (50 % for primiparous vs. 53 % for multiparous), multiparous women had a significantly higher rate of contracting influenza than primiparous women, irrespective of vaccination status (5.6 % vs. 2.2 % [p = 0.0216] and 9.7 % vs. 3.5 % [p = 0.0003] for women with and without vaccination, respectively). The 2013-2014 vaccination program significantly reduced the influenza infection rate by 35 % (3.9 % vs. 6.3 % for women with and without vaccination, respectively; p = 0.0272). Seventy-two (83 %) of the 87 women took antiviral agents for the treatment of influenza and two (2.3 %) required hospitalization. These results suggested that pregnant Japanese women had a high level of concern regarding seasonal influenza. However, campaigns targeting young pregnant Japanese women, as well as multiparous women, for vaccination are needed in order to further reduce the incidence of influenza among pregnant Japanese women.

BACKGROUND: Genetic variations associated with interstitial lung diseases (ILD) have not been extensively studied in Japanese infants. METHODS: Forty-three infants with unexplained lung dysfunction were studied. All 43, 22, and 17 infants underwent analyses of surfactant protein (SP)-C gene (SFTPC) and ATP-binding cassette A3 gene (ABCA3), SP-B gene (SFTPB), and SP-B western blotting, respectively. Two and four underwent assessment of granulocyte macrophage colony-stimulating factor-stimulating phosphorylation of signal transducer and activator of transcription-5 (pSTAT-5) and analyses of FOXF1 gene (FOXF1), respectively. RESULTS: ILD were diagnosed clinically in nine infants: four, three, and two had interstitial pneumonitis, hereditary pulmonary alveolar proteinosis (hPAP), and alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), respectively. Genetic variations considered responsible were detected in six (67%) of the nine infants with ILD: three with hPAP (SFTPC p.Leu45Arg and p.Gln145fs, and ABCA3 p.Arg1583Trp/p.Val1495CysfsX21), two with interstitial pneumonitis (SFTPC p.Lys63Glu and p.Ser72Asn/p.Gly100Ala), and one with ACD/MPV (FOXF1 p.Leu300ArgfsX79). None showed SFTPB mutations or defects in pSTAT-5. The 17 bron-choalveolar lavage or tracheal aspirates contained enough SP-B protein. CONCLUSION: The SP-C abnormality was most prevalent, and SP-B deficiency was rare in Japanese infants with hereditary-ILD.

Purpose The purpose of this study is to assess pregnancy outcomes of women treated with a novel neuraminidase inhibitor, laninamivir, during pregnancy. Methods A retrospective review of pregnancy outcomes of 112 pregnant women who were given laninamivir for treatment of influenza was performed. Possible adverse events, including miscarriages, preterm birth, foetal malformation and any neonatal morbidity requiring treatment, were assessed. Results Seventeen, 39, 46 and 10 women were administered a single inhaled dose of 20 or 40mg of laninamivir at gestational week (GW) 3–11, 12–21, 22–36 and 37 or more, respectively. One (1.8%) of 56 women with laninamivir at GW

Purpose To investigate whether planning of pregnancy in women with epilepsy affects seizure control during pregnancy and to compare the maternal and neonatal outcomes in planned and unplanned pregnancies. Methods This was a retrospective cohort study of 153 pregnant women with epilepsy who were treated at the University of Tsukuba Hospital and Hokkaido University Hospital between 2003 and 2011. Twenty-one pregnancies were excluded due to insufficient data. Data of patients followed by neurologists during their planned pregnancies (planned-pregnancy group, n =51) were compared to those of patients referred to neurologists after conception for managing epilepsy during pregnancy (unplanned-pregnancy group, n =81). The treatment profile for epilepsy, seizure control, and maternal and neonatal outcomes in both groups were compared using Chi-square test or Fisher's exact test and Mann–Whitney U test. Results Compared to the unplanned-pregnancy group, the planned-pregnancy group showed a significantly greater proportion of patients receiving monotherapy with antiepileptic drugs (80% vs. 61%: planned vs. unplanned, P =0.049) and those not requiring valproic acid (77% vs. 56%, P =0.031). Furthermore, the frequency of epileptic seizures (16% vs. 35%, P =0.018) and changes in antiepileptic drugs (24% vs. 41%, P =0.042) were significantly lower in the planned-pregnancy group than in the unplanned-pregnancy group. No significant intergroup differences were noted in the obstetric complications and neonatal outcomes, including congenital malformations. Conclusion For women with epilepsy, planning of pregnancy is associated with good seizure control during pregnancy and less fetal exposure to antiepileptic drugs.

To determine whether the use of uterotonics, including oxytocin and prostaglandins, increases the risk of abruptio placentae and eclampsia. A retrospective analysis was conducted among 260,174 Japanese women at term. Demographic characteristics were studied as possible candidates for risk factors of abruptio placentae and eclampsia using multivariate logistic regression analyses. A total of 1,058 (0.41 %) and 147 (0.06 %) women developed abruptio placentae and eclampsia, respectively. Abruptio placentae and eclampsia occurred in 177 (0.29 %) and 42 (0.07 %) of the 61,857 women treated with uterotonics, respectively. Multivariate regression analyses indicated that uterotonics did not increase risk of developing either abruptio placentae or eclampsia. Primiparity [odds ratio (95 % confidence interval) 1.41 (1.24–1.60)], age ≥35 years [1.17 (1.03–1.33)], and presence of hypertension [2.42 (1.93–3.03)] were significant independent risk factors for abruptio placentae, while advancing gestation [0.67 (0.63–0.71)] decreased risk of abruptio placentae. Primiparity [odds ratio (95 % confidence interval) 4.06 (2.49–6.63)], age

To examine the pathophysiology of reductions in antithrombin (AT) activity during pregnancy and to better characterize the laboratory features of pregnant women with severely depressed AT activity.Laboratory variables for blood samples obtained within 5 d prior to delivery were compared among three women groups with severely depressed (45%, n = 6), modestly depressed (45-69%, n = 10), and normal AT activity levels (70%, n = 134).Pregnancy-induced hypertension was present in 16.7% (1/6), 30.0% (3/10), and 9.0% (12/134) of the women with the above-mentioned AT activities, respectively. The AT activities were significantly and negatively correlated with the D-dimer, urate, and creatinine levels. The D-dimer level was significantly and negatively correlated with the fibrinogen level. Women with AT activity45% exhibited markedly elevated levels of hemoglobin and liver enzymes and a significantly lower level of fibrinogen than the other women groups, while the platelet count did not differ among the three groups.Enhanced thrombin generation was involved in the decrease in AT activity. AT activity can decrease in the absence of thrombocytopenia. The liver dysfunction that was seen in cases with severely depressed AT activity may have resulted from impairments in liver perfusion caused by microthromboses generated as a result of the relative lack of AT and/or the shortage of circulating plasma in women with reduced AT activities.

Introduction: The differences in the D-dimer rise between women with singleton and multifetal pregnancies have not been studied extensively. Materials and Methods: D-Dimer levels were determined in 1089 blood specimens from 1089 women in various stages of pregnancy, including 977 and 112 women with singleton and multifetal pregnancies, respectively. None of the 1089 women developed hypertension or clinical venous thromboembolism during pregnancy or in the postpartum period. Results: The D-dimer levels were significantly and positively correlated with gestational week at examination in women with singleton or multifetal pregnancies. The D-dimer levels (mu g/ml, mean +/- SD [number of specimens]) determined at the 1st trimester did not differ significantly (0.81 +/- 0.82 [102] for singleton vs. 1.20 +/- 0.77 [7] for multifetal), but those at the 2nd (1.61 +/- 1.45 [216] vs. 2.62 +/- 2.26 [59]) and 3rd (2.37 +/- 2.22 [659] vs. 4.02 +/- 2.14 [46]) trimesters were significantly higher in women with multifetal than singleton pregnancies. The 90th percentile value was 4.31 mu g/ml for 1089 specimens. A significantly greater number of women exceeded 4.31 mu g/ml during the 2nd (16.9% vs. 5.6%, P = 0.0043) and 3rd (34.8% vs. 10.6%, P < 0.0001) trimesters among those with multifetal than with singleton pregnancies. Conclusions: The degree of D-dimer rise in pregnancy was greater in women with multifetal than with singleton pregnancies. (C) 2013 Elsevier Ltd. All rights reserved.

SummaryMucosal-associated invariant T (MAIT) cells play an important physiological role in host pathogen defense and may also be involved in inflammatory disorders and multiple sclerosis. The rarity and inefficient expansion of these cells have hampered detailed analysis and application. Here, we report an induced pluripotent stem cell (iPSC)-based reprogramming approach for the expansion of functional MAIT cells. We found that human MAIT cells can be reprogrammed into iPSCs using a Sendai virus harboring standard reprogramming factors. Under T cell-permissive conditions, these iPSCs efficiently redifferentiate into MAIT-like lymphocytes expressing the T cell receptor Vα7.2, CD161, and interleukin-18 receptor chain α. Upon incubation with bacteria-fed monocytes, the derived MAIT cells show enhanced production of a broad range of cytokines. Following adoptive transfer into immunocompromised mice, these cells migrate to the bone marrow, liver, spleen, and intestine and protect against Mycobacterium abscessus. Our findings pave the way for further functional analysis of MAIT cells and determination of their therapeutic potential.

Objective. To test the hypothesis that the blood antithrombin (AT) activity is correlated with the plasma aldosterone concentration (PAC), the plasma renin activity (PRA), and/or the PAC-to-PRA ratio during the late stage of pregnancy. Methods. The AT activity, PAC, and PRA were determined within 7 days prior to delivery in 47 women, consisting of 30 normotensive and 6 hypertensive women with singleton pregnancies and 11 normotensive women with twin pregnancies. Results. The median values of the 47 women were 86% of the normal activity level for the AT activity, 442 pg/mL for the PAC, 3.7 ng/mL/h for the PRA, and 108 pg/mL per ng/mL/h for the PAC-to-PRA ratio. Women with an AT activity ≤86% had a significantly lower PRA and a higher PAC-to-PRA ratio than women with an AT activity >86% (3.5 ± 3.0 vs. 6.6 ± 4.7 ng/mL/h for PRA, p = 0.008; 156 ± 109 vs. 97 ± 46 pg/mL per ng/h for PAC-to-PRA ratio, p = 0.021). The AT activity was significantly correlated positively with the PRA and negatively with the PAC-to-PRA ratio. Conclusions. The existence of a common pathophysiological background between a reduced AT activity and a reduced PRA during the late stage of pregnancy was suggested.

Objective To review clinical features and short-term outcomes of triplet pregnancies among Japanese women. Methods A retrospective analysis was carried out among 320 Japanese women with triplet pregnancies (8 monochorionic, 75 dichorionic, and 150 trichorionic triplets; 87 with unknown placental chorionicity) who delivered at 22 gestational weeks or more between January 2005 and December 2008. Results Delivery was by cesarean for 315 (98%) women. Gestational age at delivery was 32.3 ± 2.8 weeks (mean ± SD) and 33.2 weeks (median), and 97%, 61%, and 14% of women delivered at less than 37, less than 34, and less than 30 gestational weeks, respectively. For live-born infants, mean birth weight was 1762 ± 437 g, 1608 ± 396 g, and 1406 ± 380 g for the heaviest, middle, and lightest triplet, respectively. Eighteen (5.6%) women experienced perinatal mortality (3 triplets for 1 woman, 2 triplets for 4 women, and 1 triplet for 13 women). Perinatal mortality was 25 deaths per 1000 deliveries, and decreased with increasing number of chorionic membranes (125, 44, and 20 per 1000 mono-, di-, and trichorionic triplet deliveries, respectively). Conclusion Short-term outcomes were good among triplet pregnancies in Japan. The data may be useful for counseling Japanese women with triplet pregnancies.

Objectives: To determine whether a low serum folate level during the first trimester predicts subsequent late abortion, preterm birth, or fetal growth restriction (FGR). Study design: A prospective cohort study involving 5,075 women whose serum folate levels were measured during the first trimester. The participants were informed of their serum folate levels. Results: The pregnancy duration, birthweight, rate of late abortion/preterm birth, and the rate of FGR did not differ significantly among four groups classified according to folate status. The mean serum folate levels did not differ among quartiles classified according to the gestational week at the time of delivery. Nineteen of the 20 women with folate deficiency gave birth at term to infants with a birthweight of 3,132 ± A 321 g; only one infant had FGR. Conclusion: Low serum folate levels during the first trimester were not associated with the risk of late abortion, preterm birth, or FGR.

Urine podocin mRNA expression and urine podocin : nephrin mRNA expression ratio (PNR) increase with increasing proteinuria during pregnancy complicated with pre-eclampsia (PE). This suggests that urine podocytes with reduced nephrin mRNA expression are abundant in pathological podocyturia. The aim of this study was therefore to determine post-partum changes in podocyturia and PNR in relation to proteinuria after pre-eclampsia (PE).A total of 137 peripartum urine specimens, consisting of 72 and 65 from 24 and 30 women with PE and normotensive control pregnancies (NCP), respectively, were studied. Determination of urine protein and creatinine concentration and quantitative analysis of podocyte-specific podocin and nephrin mRNA expression were carried out using reverse transcription-polymerase chain reaction in pelleted urine samples. Podocyturia was monitored via urine podocin mRNA expression. Podocyturia and proteinuria were normalized by urine creatinine concentration.Podocyturia and urine PNR decreased with decreasing proteinuria as well as with increasing time after delivery in the urine from PE women. In physiological proteinuria (i.e. protein : creatinine ratio [P/Cr] 0.005-0.1 mg/mg), however, both podocyturia and PNR were significantly greater in the urine from PE women compared with NPC women, although P/Cr was similar between the groups (median, 0.037 mg/mg for PE vs 0.029 mg/mg for NCP).Podocyturia decreases with decreasing proteinuria in PE women after childbirth. In PE women, however, pathological podocyturia consisting of podocytes with decreased nephrin mRNA expression persisted even after proteinuria decreased to a level similar to that in NCP women.

This study was performed to determine the associations between serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) levels at mid-gestation with the risk of small-for-gestational-age (SGA) neonates born at gestational week (GW) ≥ 36 in healthy women.PlGF and sFlt-1 concentrations were determined at GW 24-27 in 183 women with births at GW ≥ 36, but without gestational diabetes mellitus and hypertension.Thirteen (7.1%) SGA neonates were born. Median (range) GW at blood sampling was similar between women with and without SGA (25 [24-25] and 24 [24-27], respectively, P = 0.671). Pre-pregnancy body mass index (BMI) and PlGF levels were significantly lower in women with than without SGA, while sFlt-1 levels and sFlt-1 : PlGF ratio (sFlt-1/PlGF) did not differ significantly between the two groups. PlGF and sFlt-1/PlGF, but not BMI or sFlt-1, showed significant correlations with birthweight z-score; the correlation was positive for PlGF and negative for sFlt-1/PlGF. Women with PlGF level 10th percentile and those with sFlt-1/PlGF level 90th percentile showed significantly increased risk of SGA compared to those with respective counterpart characteristics; relative risk was 3.8 (95% confidence interval, 1.3-11.3; 21% [4/19] vs 5.5% [9/164]) for PlGF and 7.9 (95% confidence interval, 3.0-20.8, 33.3% [6/18] vs 4.2% [7/165]) for sFlt-1/PlGF.Maternal PlGF and sFlt-1/PlGF determined during GW 24-27 were associated with the risk of SGA neonates born at GW ≥ 36, even in women with uncomplicated pregnancies.

This prospective observational study compare urine nephrin:creatinine ratio (NCR, ng/mg) with serum soluble fms-like tyrosine kinase-1:placental growth factor ratio (FPR, pg/pg) for preeclampsia (PE) prediction among unselected asymptomatic pregnant women in 2nd trimester. NCR and FPR were determined in 254 paired urine/blood samples collected simultaneously from 254 women at median gestational week (GW) 24 (range, 22–27) without hypertension or significant proteinuria in pregnancy (SPIP). Fifteen (5.9%) developed SPIP and hypertension at GW 34.0 (26.0–38.6) and 35.3 (27.6–38.6), respectively, and were diagnosed with PE at GW 35.7 (27.6–38.6). The 90th percentile level determined in 239 women normotensive throughout pregnancy gave NCR (139) sensitivity and positive predictive values (PPV) of 60% (9/15) and 27% (9/33), while those for serum FPR (4.85) were 40% (6/15) and 20% (6/30), respectively. Relative risks (95%CI) of later PE were 10.0 (3.82–26.4; 27% [9/33] vs. 2.7% [6/221]) and 4.98 (1.91–13.0; 20% [6/30] vs. 4.0% [9/224]) for NCR-positive and FPR-positive women, respectively. Cut-offs suggested by ROC gave NCR (86.6) sensitivity and PPV of 87% (13/15) and 17% (13/79), and FPR (8.8) values of 40% (6/15) and 40% (6/15), respectively. Thus, 2nd trimester NCR was superior to FPR for PE prediction.

Liver dysfunction with decreased antithrombin (AT) activity and/or thrombocytopenia is life threatening in pregnant women. Whether AT is clinically useful for prediction of liver dysfunction remains unclear.A total of 541 women were registered prospectively at gestational week 34.7 (20.0-41.4) with available data on antenatal AT and platelet count (PLC).Liver dysfunction defined as serum aspartate aminotransferase 45 IU/L concomitant with lactate dehydrogenase 400 IU/L occurred in five women antenatally (≤ 2 weeks before delivery) and in 17 women post-partum (within 1 week post-partum). Median (5th-95th) antenatal value was 85 (62-110)% for AT and 202 (118-315) × 10Reduced AT not accompanied by thrombocytopenia can precede liver dysfunction. Clinical introduction of AT may enhance the safety of pregnant women.

Background: Genetic variants responsible for childhood interstitial lung disease (chILD) have not been studied extensively in Japanese patients. Methods: The study population consisted of 62 Japanese chILD patients. Twenty-one and four patients had pulmonary hypertension resistant to treatment (PH) and hypothyroidism, respectively. Analyses of genetic variants were performed in all 62 patients for SFTPC and ABCA3, in all 21 PH patients for FOXF1, and in a limited number of patients for NKX2.1. Results: Causative genetic variants for chILD were identified in 11 (18%) patients: SFTPC variants in six, NKX2.1 variants in three, and FOXF1 variants in two patients. No patients had ABCA3 variants. All three and two patients with NKX2.1 variants had hypothyroidism and developmental delay, respectively. We found six novel variants in this study. Conclusion: Mutations in SFTPC, NKX2.1, and FOXF1 were identified among Japanese infants and children with chILD, whereas ABCA3 mutations were rare.

Dipstick results for proteinuria are affected by urine concentration, and thus urine creatinine concentration ([Cr]). This study was performed to determine whether spot urine [Cr] changes significantly during pregnancy, leading to a significantly different false-negative rate (FNR) on dipstick test between trimester.The [Cr] and protein concentrations ([P]) were analyzed in 631 spot urine samples with negative/equivocal dipstick from 425 pregnant women. False-negative dipstick was defined as [P] : [Cr] ratio (P/Cr)0.27 mg/mg.Median [Cr] was 117 mg/dL (range, 6.5-326 mg/dL), 72 mg/dL (range, 4.3-477 mg/dL), and 73 mg/dL (range, 8.4-396 mg/dL) in the first (n = 96), second (n = 344), and third (n = 191) trimester urine samples, respectively (P = 0.000, Kruskal-Wallis). Both [P] and P/Cr increased significantly with advancing gestation. FNR 9.4% (18/191) in the third trimester was significantly higher than that of 0.0% (0/96) in the second trimester and that of 0.5% (2/344) in the third trimester. In the 20 urine samples with false-negative dipstick, median [Cr] was 47.0 mg/dL (range, 11.0-358 mg/dL) and the proportion of samples with dilute urine, that is, [Cr]47 mg/dL, was significantly higher than in the remaining 611 urine samples (50%, 10/20 vs 28%, 174/611, respectively, P = 0.046).Urine samples in the second and third trimesters were more likely to be diluted compared with the first trimester. This was associated with high FNR in third trimester urine samples.

This study was performed to determine risk factors for central serous chorioretinopathy (CSC) in pregnant women.This retrospective observational study was performed in a cohort of all 1881 women giving birth at a single center. The hospital database was searched to abstract all women diagnosed with pre-eclampsia (PE) as well as those visiting the eye clinic during the current pregnancy. Medical chart review was performed in all women diagnosed with CSC and PE.PE developed in 73 (3.9%) women, six (8.2%) of whom visited the eye clinic for problems occurring in the current pregnancy; 47 of 1808 (2.6%) women without PE visited the eye clinic (P = 0.015). Four women were identified as having developed CSC after onset of PE, and none of those without PE developed CSC (5.5% [4/73] vs 0.0% [0/1808], respectively, P 0.0001). Stepwise regression analysis selected four risk factors for CSC: hematocrit value 38.0% (odds ratio [OR], 22.9; 95% confidence interval [CI], 2.12-247), serum creatinine 0.7 mg/dL (OR, 21.7; 95%CI, 1.12-422), time interval from diagnosis of PE until delivery 14 days (OR, 20.0; 95%CI, 1.87-214), and urine protein : creatinine ratio (mg/mg) 4.5 (OR, 15.7; 95%CI, 0.81-304). Hematocrit value 38.0% was finally identified as the only independent risk factor (OR, 22.9; 95%CI, 2.12-1716) for CSC in PE women.CSC was likely to occur in PE women, especially in those with hemoconcentration as a result of plasma leakage from the circulating blood due to increased vascular permeability.

Hyperfiltration is a cause of podocyturia and occurs physiologically in the kidney of pregnant women. Podocyturia is increased in preeclamptic pregnancies, but it is unclear whether there is also any increase in uncomplicated pregnancies. This study was performed to examine whether podocyturia and urine aquaporin 2 mRNA expression are increased in healthy pregnant women (PW) compared to healthy non-pregnant women (NPW).Eleven urines obtained from 11 NPW and longitudinal 76 urines from 40 PW with uncomplicated pregnancies (median number [range] of urine samples/person, 2 [1 - 3]) were studied. Determination of protein and creatinine concentrations and number of cells in urine other than blood cells, and quantitative analyses of the mRNA expression of aquaporin 2 (AQP2-mRNA), podocin (Pod-mRNA), and nephrin (Nep-mRNA) were performed using RT-PCR in pelleted urine samples. Podocyturia was monitored with urine Pod- and Nep-mRNA expression levels normalized relative to creatinine.Urine cell density and urine AQP2-, Pod-, and Nep-mRNA expression normalized relative to creatinine were significantly higher in PW than NPW. The number of cells per milligram of creatinine was significantly positively correlated with expression of all three mRNAs with correlation coefficients (R-value) of 0.442, 0.481, and 0.561 for Pod-, Nep-, and AQP2-mRNA, respectively. AQP2-mRNA expression was strongly (R 0.8) positively correlated with both Pod- and Nep-mRNA expression.Podocyturia monitored by Pod- and Nep-mRNA expression and urine cells expressing AQP2-mRNA were increased in uncomplicated pregnancies compared to healthy non-pregnant women. Urine cells expressing AQP2-mRNA increased with increasing podocyturia in healthy women.

The aim of this study was to determine whether women with pregnancy-induced antithrombin deficiency (PIATD) had higher risk of liver dysfunction in the absence of thrombocytopenia.We carried out a retrospective observational study at five centers in all 129 women with incidentally found PIATD among 5249 maternities and 129 control women without PIATD matched for number of fetuses and gestational week at delivery. PIATD was diagnosed in women with antenatal antithrombin (AT) activities of ≤75% followed by a further decrease to ≤65% peripartum. Liver dysfunction was defined as serum aspartate aminotransferase 45 IU/L concomitant with lactate dehydrogenase 400 IU/L. Thrombocytopenia was defined as platelet count120 × 10Thrombocytopenia (22% [28/129] vs 5.4% [7/129], P = 0.0001) and liver dysfunction (16% [20/129] vs 0.0% [0/129], P = 0.0000) occurred significantly more often in PIATD than in control women. Of the 20 women with liver dysfunction, 15 (75%) had PIATD, but not thrombocytopenia. Thus, even in the absence of thrombocytopenia, liver dysfunction occurred significantly more often in PIATD than in control women (15% [15/101] vs 0.0% [0/122], respectively, P = 0.0000). The relative risk (95% confidence interval) of liver dysfunction was 28.6 (1.64-500) for women with AT activity of 60-65% and 52.4 (3.17-865) for women with AT activity of60%, compared to women with AT activity ≥66%.PIATD can occur in the absence of thrombocytopenia and PIATD women had higher risk of liver dysfunction even in the absence of thrombocytopenia.

We report a pregnant woman who was monitored by echocardiography and determination of blood variables, including components of the renin–angiotensin–aldosterone system (RAAS), cardiac biomarkers and soluble fms-like tyrosine kinase-1 (sFlt-1), during and after the development of Ballantyne syndrome. Generalised maternal oedema with dyspnoea following fetal and placental hydrops necessitated a caesarean section at 33 weeks of gestation. Changes in blood variables and simultaneous echocardiography changes indicated acutely enhanced RAAS and hyperdynamic left ventricular function in response to excessive volume overload (as evidenced by brain-type natriuretic peptide level of 523 pg/mL) in the absence of increased systemic vascular resistance. Elevated sFlt-1 (15 600 pg/mL) and human chorionic gonadotrophin (404 000 IU/L) levels were also noted. The increased plasma aldosterone concentration (2070 pg/mL) may have been responsible for the increase in circulating plasma volume, and the increased sFlt-1 level was responsible for generalised maternal oedema. It remains unclear which factor(s) triggered RAAS activation.

This retrospective study was performed to determine the frequency of malformed infants born at a tertiary center in Hokkaido, Japan. The accuracy of prenatal diagnosis rates was also investigated.An observational study was performed using data of 1509 and 1743 newborn infants at a single center during two study periods, 2005-2009 (first) and 2010-2014 (second), respectively. Cases including minor anomalies (accessory auricle, nevus and fistula auris congenita) were not included.In total, 274 and 569 malformations were identified in 191 and 337 newborn infants in the first and second study periods, respectively. The number of malformed infants increased significantly over time (13% [191/1509] vs 19% [337/1743], respectively; P0.001), mainly as a result of an increase in cases of congenital heart disease (CHD), from 59 to 141 (31% [59/191] vs 42% [141/337] of all malformed infants in the first and second periods, respectively). The overall accurate prenatal diagnosis rate improved over time from 47% (128/274) to 58% (329/569) because of significant improvements in accurate prenatal diagnosis of CHD subtypes (23% [16/70] vs 65% [151/232] in the first and second periods, respectively, P0.0001).The frequency of malformed newborns was higher in the tertiary center than in the general population. The increased number of cases with prenatal suspicion and diagnosis of CHD contributed to the increased frequency of malformed infants during the study period.

Podocyte depletion in the kidney is associated with end-stage kidney disease (ESKD). Pre-eclampsia (PE) increases the risk of ESKD in later life. This study was performed to determine whether nephrinuria (soluble nephrin in the urine) is correlated with proteinuria and/or podocyturia (podocytes in the urine) in PE women.Eighty-three urine samples, consisting of 45 and 38 samples from 27 normotensive and nine PE women, respectively, underwent simultaneous determination of nephrin, protein, and creatinine concentrations in the urine supernatant and quantitative analysis of podocyte-specific protein mRNA expression. This included podocin (Pod-mRNA) and nephrin (Nep-mRNA), using real-time polymerase chain reaction in the pelleted urine. Nephrinuria and proteinuria were corrected by creatinine concentration. Pod- and Nep-mRNA expression levels were corrected by GAPDH.Nephrinuria, proteinuria, Pod-mRNA expression, and Nep-mRNA expression all increased with advancing gestation in PE women, while not in normotensive women. The nephrinuria was strongly correlated with proteinuria (R = 0.901, P 0.001), Pod-mRNA expression level (R = 0.824, P 0.001), and Nep-mRNA expression level (R = 0.724, P 0.001) in urine samples from PE women, while the nephrinuria was significantly correlated with proteinuria alone (R = 0.419, P 0.005) in urine samples from normotensive women.Nephrinuria reflected well the degrees of proteinuria and podocyturia in PE women. This suggested that increased nephrinuria/proteinuria was associated with podocyte loss in the kidneys of PE women.