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Backgrounds: 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., Methods: 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., Results: 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., Conclusion: 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., Impact: 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., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

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.

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.

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 < 0.01) and the ratio of early diastolic transmitral to mitral annular velocity (E/e') (β = 0.41, p < 0.01). At 1 month after childbirth in women with singleton pregnancies, BNP and N-terminal precursor protein BNP (NT-proBNP) fragments immediately postpartum negatively correlated with the later E/e' (r = - 0.33, p = 0.02 and r = - 0.36, p < 0.01, respectively)., 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.

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.

Background: Prenatal 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., Methods: Using 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., Results: PA 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)., Conclusions: This study identified the possible effects of exposure to the death of a child on PA occurrence that adjusted for important confounding factors., Competing Interests: The authors have declared that no competing interests exist.

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) < 10.0 g/dL among infants born at gestational week (GW) ≥ 36 to unselected women., Materials and Methods: We reviewed the medical charts of 699 women giving birth to singleton infants at GW ≥ 36 with available data on MCA-PSV measured at GW ≥ 25 at the discretion of the attending physician. Multiple of the median (MoM) MCA-PSV (MCA-PSV MoM) > 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., (Copyright © 2019. Published by Elsevier B.V.)

Objective: Women with hypertensive disorders of pregnancy (HDP) show elevated risk of heart failure despite decreased circulating plasma volume compared with those with normotensive control pregnancies (NCP). This study was performed to better characterise the heart in women with HDP and determine whether high-sensitivity troponin I (hs-TnI) around childbirth predicts reduced left ventricular (LV) relaxation at 1 month postpartum., Methods: Echocardiography was performed longitudinally during the first, second and third trimesters and immediately postpartum within 1 week and 1 month postpartum in 24 women with HDP, with simultaneous determination of blood variables in comparison with 51 women with NCP., Results: Compared with NCP, HDP showed greater antepartum left atrial (LA) volume, LV mass and inferior vena cava (IVC) diameter, higher peripartum brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide and hs-TnI with the highest value immediately postpartum, and lower early diastolic mitral annular velocity (e') during pregnancy/postpartum. In analyses of data on HDP and NCP, hs-TnI at the third trimester as well as that immediately postpartum was negatively correlated with later e' at 1 month postpartum. The areas under the receiver operating characteristic curves were 0.82 and 0.81 for hs-TnI at the third trimester and immediately postpartum, respectively, in the prediction of reduced LV relaxation at 1 month postpartum., Conclusion: Reduced LV diastolic function and decreased splanchnic blood reservoir may contribute to the increased third trimester IVC diameter and LA volume in women with HDP. The rise in hs-TnI around childbirth was associated with poor LV relaxation ability at 1 month postpartum., Competing Interests: Competing interests: None declared.

Objective: This longitudinal study was performed to determine changes in echocardiography parameters in association with various biomarker levels in pregnancy/postpartum., Methods: Fifty-one healthy pregnant women underwent echocardiography with simultaneous determination of blood levels of five biomarkers at each of the first, second and third trimesters of pregnancy, immediately postpartum within 1 week after childbirth and approximately 1 month postpartum. Data on 255 echocardiography scans (five times per woman) and biomarkers were analysed., Results: Left ventricular end-diastolic dimension, left atrial (LA) volume index and left ventricular (LV) mass index increased with advancing gestation and reached the maximum immediately postpartum concomitant with the highest brain natriuretic peptide (BNP), N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hs-TnI) and creatine kinase MB levels. The inferior vena cava diameter was significantly reduced in the third trimester compared with that in the first trimester and the peak occurred immediately after childbirth. In 255 paired measurements, hs-TnI level was significantly positively correlated with LA volume index and LV mass index; BNP and NT-proBNP were significantly positively correlated with LA volume index and estimated glomerular filtration rate (eGFR) was significantly positively correlated with the average of early diastolic septal and lateral mitral annular velocity (e')., Conclusions: Maximal cardiac changes in morphology occurred postpartum within 1 week after childbirth, not during pregnancy. BNP/NT-proBNP, hs-TnI and eGFR reflected cardiac changes in pregnancy., Competing Interests: Competing interests: None declared.

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.

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., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

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; <1500g), term-small-for-gestational-age (term-SGA), and preterm-birth (PTB; <37 weeks) infants. We calculated relative risks (RRs) for PTB, VLBW, and term-SGA birth based on parental characteristics. The prevalence of PTB, VLBW, and term-SGA was 4.5%, 0.4%, and 6.5%, respectively. Aged parents and ART were risk factors for PTB and VLBW. Maternal alcohol drinking during pregnancy increased the risk; a parental educational level of ≥16 years reduced risk of term-SGA. Maternal pre-pregnancy BMI of <18.5 kg/m² increased the risk of PTB and term-SGA. The RR for low BMI was highest among mothers who have low educational level. Among various factors, appropriate nutritional education to maintain normal BMI is important to prevent PTB and term-SGA in Japan., Competing Interests: The authors declare they have no conflict of interest.

BackgroundGenetic variants responsible for childhood interstitial lung disease (chILD) have not been studied extensively in Japanese patients.MethodsThe 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.ResultsCausative 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.ConclusionMutations in SFTPC, NKX2.1, and FOXF1 were identified among Japanese infants and children with chILD, whereas ABCA3 mutations were rare.

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/m 2 ; 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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims: 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., Methods: 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., Results: 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 (P < 0.0001). 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)., Conclusions: 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., (© 2017 Japan Society of Obstetrics and Gynecology.)

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.

There have been no reports regarding imaging-documented bronchospasm in patients with amniotic fluid embolism (AFE). In a woman with scheduled cesarean section for placenta previa, transient bronchospasm and pulmonary hypertension were documented explaining a sudden drop in SpO 2 . Mild AFE was the most likely diagnosis in this patient.

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., (© 2017 Japan Society of Obstetrics and Gynecology.)

Background and Aim: 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., Methods: 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)., Results: 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) × 10 9 /L for PLC in the 541 women and was significantly lower in women with than without perinatal liver dysfunction; 75 (51-108) versus 86 (62-110)% and 179 (56-244) versus 203 (121-316) × 10 9 /L, respectively. Nineteen (86%) women with liver dysfunction showed AT ≤ 62% or thrombocytopenia (PLC ≤ 118 × 10 9 /L) perinatally, but five lacked thrombocytopenia throughout the perinatal period. The best cut-off (AT, 77%; PLC, 139 × 10 9 /L) suggested by receiver operating characteristic curve gave antenatal AT and PLC sensitivity of 59% and 41% with positive predictive value of 8.6% and 14%, respectively, and combined use of AT and PLC improved sensitivity to 73% (16/22) with positive predictive value of 9.2% for prediction of perinatal liver dysfunction., Conclusions: Reduced AT not accompanied by thrombocytopenia can precede liver dysfunction. Clinical introduction of AT may enhance the safety of pregnant women., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Aim: 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., Methods: 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., Results: 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., Conclusion: 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., (© 2017 Japan Society of Obstetrics and Gynecology.)

Aim: 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)., Methods: 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., Results: 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)., Conclusions: 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., (© 2017 Japan Society of Obstetrics and Gynecology.)

Aim: 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., Methods: 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., Results: 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)., Conclusions: 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., (© 2017 Japan Society of Obstetrics and Gynecology.)

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., (Copyright © 2017 the American Physiological Society.)

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., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Aim: This study was performed to determine risk factors for central serous chorioretinopathy (CSC) in pregnant women., Methods: 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., Results: 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., Conclusion: 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., (© 2017 Japan Society of Obstetrics and Gynecology.)

Aim: 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)., Methods: 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., Results: 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., Conclusion: 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., (© 2017 Japan Society of Obstetrics and Gynecology.)

Background: There have been few reports on the outcome of extracorporeal membrane oxygenation (ECMO) in newborn Japanese infants., Methods: A review was carried out of 61 neonates with ECMO between January 1995 and December 2015 at a single center. ECMO was used in neonates with oxygenation index >20 after conventional treatment. 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 h after birth), were analyzed in relation to outcome with respect to survival to hospital discharge (SHD)., Results: Survival to hospital discharge was achieved in 35 infants (57%), while the remaining 26 died during hospital stay. Gestational age at birth was significantly higher and number of days with ECMO was significantly lower in SHD infants compared with 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 vascular access mode (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 (86%, 12/14), persistent pulmonary hypertension associated with hypoxic ischemic encephalopathy (75%, 6/8), and emphysema (80%, 4/5). On stepwise logistic regression analysis two independent factors of SHD were identified: early ECMO (OR, 9.63; 95%CI: 2.47-37.6) and ECMO length <8 days (OR, 8.05; 95%CI: 1.94-33.5)., Conclusions: Neonates with early ECMO and those with ECMO duration <8 days may benefit from ECMO with respect to SHD., (© 2016 Japan Pediatric Society.)

Aim: 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., Methods: 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., Results: 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; P < 0.001), 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, P < 0.0001)., Conclusions: 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., (© 2016 Japan Society of Obstetrics and Gynecology.)

Marked fluid retention occurs in Ballantyne syndrome, but few reports are available on changes in cardiac morphology in this syndrome. A woman with generalized edema, dyspnea, fetal hydrops (skin edema and ascites), thickened placenta, and elevated plasma B-type natriuretic peptide level (344 pg/mL) was admitted to our hospital at gestational week (GW) 20 +3 . Blood pressure remained within the normal range. However, acute increases in left atrial volume index, pulmonary artery systolic pressure, and hyperdynamic left ventricular function (as evidenced by increased left ventricular ejection fraction to 74% with cardiac index of 5.1 L/min/m 2 ) occurred preceding fetal death at GW 21 +4 in the presence of increased inferior vena cava diameter (23 mm) and relatively low systemic vascular resistance of 752 dyn·s/cm 5 . These findings suggested life-threatening heart failure and required cesarean delivery at GW 21 +5 resulting in complete recovery. The placenta suggested cytomegalovirus infection., (© 2016 Japan Society of Obstetrics and Gynecology.)

Aim: 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., Methods: 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 count < 120 × 10 9 /L., Results: Thrombocytopenia (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 of <60%, compared to women with AT activity ≥66%., Conclusion: PIATD can occur in the absence of thrombocytopenia and PIATD women had higher risk of liver dysfunction even in the absence of thrombocytopenia., (© 2016 Japan Society of Obstetrics and Gynecology.)

Aim: 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., Methods: 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., Results: 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., Conclusion: 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., (© 2016 Japan Society of Obstetrics and Gynecology.)

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 2 nd 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 90 th 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, 2 nd trimester NCR was superior to FPR for PE prediction.

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/APO 2 ), and number of immature neutrophils between the two groups. Baseline a/APO 2 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/APO 2 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., (© 2016 Japan Pediatric Society.)

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., (© 2016 Nordic Federation of Societies of Obstetrics and Gynecology.)

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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Aim: This study was performed to determine the rate of pregnant occupants in motor vehicle accidents (MVA) and the frequency of seatbelt use in pregnancy in Japan., Methods: A questionnaire survey was conducted at seven centers located in Sapporo, targeting all 3952 women in gestational weeks 35-37 during the study period between June 2013 and January 2014. Information was collected on parity, driver's license, seatbelt use, seat preference, carrying Mother and Child Health Handbook when going out, and experience of occupant MVA during current pregnancy. Women who reported always using a seatbelt were classified as always seatbelt users (ASU)., Results: A total of 2420 women who were given questionnaires provided responses (response rate, 61%). Seventy women (2.9%) reported having experienced an occupant MVA during the current pregnancy. MVA rate was significantly lower for ASU than non-ASU (2.6% [55/2097] vs 4.6% [15/323], respectively, P < 0.0001), and for ASU women preferring the rear seat than for other women (1.3% [6/451] vs 3.3% [64/1969], respectively, P = 0.0282). MVA rate tended to be lower for women preferring the rear seat than the front seat (1.7% [10/575] vs 3.3% [60/1845], respectively, P = 0.0637). The number of ASU, 94% (2286/2420) before pregnancy, decreased significantly to 87% (2097/2420) after the current pregnancy (P < 0.0001)., Conclusion: The careful attitude of pregnant women toward driving safety may be associated with reduced risk of MVA in pregnancy. There is a need for an intensified campaign to promote seatbelt use among pregnant women., (© 2016 Japan Society of Obstetrics and Gynecology.)

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., (2016 BMJ Publishing Group Ltd.)

A woman with twin pregnancy had a gradual decline in anti-thrombin (AT) activity from 72% at gestational week (GW) 29 -3/7 , to 53% at GW31 -2/7 , and to 41% at GW32 -2/7 , at which time hypertension (148/90 mmHg) and proteinuria (protein-to-creatinine ratio [P/Cr], 0.79 mg/mg) developed in the presence of normal platelet count (159 × 10 9 /L) and serum aspartate aminotransferase/lactate dehydrogenase (22/164 IU/L). AT product was given three times to maintain AT activity >50% and blood pressure was maintained below 155/95 mmHg with no treatment, but generalized edema with a weekly weight gain of 4.9 kg and increased proteinuria (to P/Cr, 7.6 mg/mg) required cesarean section at GW33 -3/7 . This case highlights the occurrence of pregnancy-induced AT deficiency alone in the absence of any other abnormality, including hypertension, proteinuria, or thrombocytopenia. Measurement of AT activity was considered helpful for determination of the appropriate time for delivery in this patient., (© 2016 Japan Society of Obstetrics and Gynecology.)

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.

Background: Infant flow biphasic nasal continuous positive airway pressure (Bi-NCPAP) and regular NCPAP (Re-NCPAP) are equally useful with respect to the rate of successful weaning from mechanical ventilation. It remains unclear, however, whether Bi-NCPAP or Re-NCPAP is more effective for reducing apnea of prematurity (AOP)., Methods: A multicenter randomized controlled study was conducted of 66 infants assigned to receive Bi-NCPAP and 66 assigned to receive Re-NCPAP for respiratory support after extubation. Primary outcome was the number of AOP events during the 48 h observation period after successful extubation, defined as no reintubation and no adverse events associated with the use of NCPAP during the observation period. The secondary outcome was successful extubation. Reintubation was at the discretion of the attending physician., Results: Baseline characteristics were similar between the two groups. The number of AOP events during the 48 h observation period was significantly lower in infants with Bi-NCPAP than in those with Re-NCPAP (5.2 ± 6.5 vs 10.3 ± 10.9 per infant, respectively; P = 0.002). The rate of successful extubation tended to be greater in those with Bi-NCPAP than in those with Re-NCPAP (92.4%, 61/66 vs 80.3%, 53/66, respectively; P = 0.074). Adverse events occurred in only one of 132 infants: erosive dermatitis developed on the nose after application of Re-NCPAP. The risk of reintubation did not differ significantly between the two groups (7.6%, 5/66 for Bi-NCPAP vs 18.2%, 12/66 for Re-NCPAP; P = 0.117)., Conclusions: Bi-NCPAP was superior to Re-NCPAP for reduction of AOP following extubation., (© 2015 Japan Pediatric Society.)

Podocyte injury has been suggested to induce phenotypic alteration of glomerular podocytes and accelerate the detachment of podocytes from the glomeruli resulting in podocyturia. However, it is not clear whether podocyte phenotypic alteration occurs in the urine of women with preeclampsia (PE). Seventy-seven and 116 pelleted urine samples from 38 and 18 women at various stages of normal and PE pregnancies, respectively underwent quantitative analysis of podocyte-specific or associated protein mRNA expression, including podocin, nephrin, and synaptopodin using RT-PCR. Significant proteinuria in pregnancy (SPIP) is defined as protein:creatinine ratio (P/Cr, mg/mg) ≥ 0.27 in the urine supernatant. All three urine-pellet mRNAs expression levels were significantly positively correlated with P/Cr levels, suggesting that podocyturia increased with proteinuria. The podocin:nephrin mRNA ratio (PNR) and synaptopodin:nephrin mRNA ratio (SNR) increased significantly with increasing P/Cr, while the podocin:synaptopodin mRNA ratio (PSR) did not change significantly according to P/Cr, resulting in significantly higher PNR and SNR, but not PSR levels, in urine from PE women with than without SPIP. The PNR, SNR, and PSR in urine from PE women before onset of SPIP were comparable to those from controls. Thus, nephrin mRNA expression was reduced in the podocytes recovered from PE women.

Causes of intrauterine fetal death (IUFD) are uncertain in most placental mesenchymal dysplasia (PMD) cases. Our case showed high α-fetoprotein levels in the maternal circulation, markedly dilated subchorionic vessels, and neonatal hemoglobin concentration of 8.4 g/dL, suggesting that fetal anemia may explain some adverse outcomes in PMD pregnancies.

Previous studies have demonstrated that a light-dark cycle has promoted better sleep development and weight gain in preterm infants than constant light or constant darkness. However, it was unknown whether brief light exposure at night for medical treatment and nursing care would compromise the benefits brought about by such a light-dark cycle. To examine such possibility, we developed a special red LED light with a wavelength of >675 nm which preterm infants cannot perceive. Preterm infants born at <36 weeks' gestational age were randomly assigned for periodic exposure to either white or red LED light at night in a light-dark cycle after transfer from the Neonatal Intensive Care Unit to the Growing Care Unit, used for supporting infants as they mature. Activity, nighttime crying and body weight were continuously monitored from enrolment until discharge. No significant difference in rest-activity patterns, nighttime crying, or weight gain was observed between control and experimental groups. The data indicate that nursing care conducted at 3 to 4-hour intervals exposing infants to light for <15 minutes does not prevent the infants from developing circadian rest-activity patterns, or proper body growth as long as the infants are exposed to regular light-dark cycles.

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 90min 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 60min 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±45×10(9)/μl, P=0.036) in twin than singleton pregnancies, respectively. This was followed by significantly lower 3rd trimester platelet count (181±43 vs. 229±62×10(9)/l, P=0.009) with significantly greater mean platelet volume (8.0±1.2 vs. 7.1±1.1fl, 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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2016. Published by Elsevier B.V.)

Background: The dipstick test is widely used as a primary screening test for detection of significant proteinuria in pregnancy (SPIP). However, it often shows a false positive test result. This study was performed to determine which pregnant women should be recommended to undergo determination of urinary protein-to-creatinine ratio (mg/mg, P/Cr test) after dipstick test for confirmation of SPIP., Methods: This was a multicenter, prospective, and observational study of 2212 urine specimens from 1033 pregnant women who underwent simultaneous dipstick and P/Cr tests in the same spot urine samples at least once. SPIP was defined as P/Cr > 0.27. Preeclampsia was diagnosed in women with both hypertension and SPIP., Results: Preeclampsia, hypertension alone, and SPIP alone developed in 202 (20 %), 73 (7.1 %), and 120 (12 %) women, respectively. Creatinine concentration [Cr] varied greatly, ranging from 8.1 to 831 mg/dL in the 2212 urine samples. Rate of positive dipstick test results increased with increasing [Cr], while SPIP prevalence rate was lower in urine samples with higher [Cr], yielding higher false positive rates in samples with higher [Cr]. Postpartum urine samples had significantly lower [Cr] compared to those obtained antepartum (60 [8.7-297] vs. 100 [10-401] mg/dL, respectively). At the first P/Cr test among women with similar dipstick test results, the risk of having SPIP was consistently and significantly higher for hypertensive women than for normotensive women at any dipstick test result: 18 % (14/77) vs. 3.2 % (8/251), 47 % (26/55) vs. 8.7 % (37/425), 91 % (82/90) vs. 59 % (44/75) for negative/equivocal, 1+, and ≥ 2+ test results, respectively. The risk of SPIP was 16 % (9/55) for normotensive women when two successive antenatal urine samples showed a dipstick test result of 1 + ., Conclusions: For prediction of SPIP, the dipstick test was more likely to show a false positive result in concentrated urine samples with higher [Cr]. Hypertensive women with ≥ 1+ as well as normotensive women with ≥ 2+ on dipstick test should be advised to undergo the P/Cr test.

In a fetus with suspected heterotaxy syndrome, a decreased/absent baseline variability of fetal heart rate pattern developed at gestational week 36(+5) and continued for 5 days until birth at gestational week 37(+2), while repeat biophysical profile scorings with ultrasound were consistently unremarkable. This neonate weighing 2404 g with Apgar scores of 7 (1-min) and 8 (5-min) and umbilical arterial cord blood pH of 7.28 with base deficit of 3.9 mmol/L, showed a heart rate of 120 b.p.m. for 3 h after birth, but subsequently developed sinus bradycardia (84 b.p.m.) unresponsive to crying. Isoproterenol initiated 9 h after birth was effective in the increase of heart rate to 120 b.p.m. in this neonate. Brain magnetic resonance imaging at 16 days of age was unremarkable. The decreased/absent baseline variability of fetal heart rate pattern was speculated to have been caused by sinus node dysfunction, and not by reduced fetal oxygenation in this case., (© 2015 Japan Society of Obstetrics and Gynecology.)