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Congenital pulmonary airway malformation (CPAM) is classified into pathologically different types. These types are sometimes distinguishable by fetal lung MRI and are usually observed as higher-signal lesions on T2-weighted images than normal lung. We describe a case of unusual CPAM resembling neoplasms, with a lower signal than is found in normal lung. Histopathology showed a large number of mucogenic cells but found no evidence that could explain this feature on fetal MRI. An unusual low-signal mass associated with a pulmonary cyst in fetal lung on MRI may suggest an unusual type 1 CPAM.

In utero hematopoietic cell transplantation (IUHCT) has been performed in Mucopolysaccharidosis Type VII (MPSVII) mice, but a lifelong engraftment of allogeneic donor cells has not been achieved. In this study, we sought to confirm a lifelong engraftment of allogeneic donor cells immunologically matched to the mother and to achieve partial rescue of phenotypes in the original MPSVII strain through IUHCT by intravenous injection. We performed in vitro fertilization in a MPSVII murine model and transferred affected embryos to ICR/B6-GFP surrogate mothers in cases where fetuses receiving IUHCT were all homozygous. Lineage-depleted cells from ICR/B6-GFP mice were injected intravenously at E14.5. Chimerism was confirmed by flow cytometry at 4 weeks after birth, and β-glucuronidase activity in serum and several phenotypes were assessed at 8 weeks of age or later. Donor cells in chimeric mice from ICR/B6-GFP mothers were detected at death, and were confirmed in several tissues including the brains of sacrificed chimeric mice. Although the serum enzyme activity of chimeric mice was extremely low, the engraftment rate of donor cells correlated with enzyme activity. Furthermore, improvement of bone structure and rescue of reproductive ability were confirmed in our limited preclinical study. We confirmed the lifelong engraftment of donor cells in an original immunocompetent MPSVII murine model using intravenous IUHCT with cells immunologically matched to the mother without myeloablation, and the improvement of several phenotypes.

BACKGROUND Because there is limited information on fetal bradyarrhythmia associated with congenital heart defects (CHD), we investigated its prognosis and risk factors. METHODS AND RESULTS In our previous nationwide survey of fetal bradyarrhythmia from 2002 to 2008, 38 fetuses had associated CHD. Detailed clinical data were collected from secondary questionnaires on 29 fetuses from 18 institutions, and were analyzed. The 29 fetuses included 22 with isomerism, 4 with corrected transposition of the great arteries (TGA) and 3 with critical pulmonary stenosis; 14 had complete atrioventricular block (AVB), 8 had second-degree AVB, and 16 had sick sinus syndrome; 5 died before birth, and 10 died after birth (5 in the neonatal period). Neonatal and overall survival rates for fetal bradyarrhythmia with CHD were 66% and 48%, respectively. Pacemaker implantation was needed in 17 cases (89%). Beta-sympathomimetics were administered in utero in 13 cases and were effective in 6, but were not associated with prognosis. All cases of corrected TGA or ventricular rate ≥70 beats/min survived. A ventricular rate

Twin anemia-polycythemia sequence (TAPS) is characterized by large inter-twin hemoglobin value differences without inter-twin amniotic fluid discordance. The management of post-laser TAPS remains controversial. Hence, more studies on TAPS, together with the associated maternal complications and outcome of the fetuses and infants are needed. Between 2003 and 2012, we performed 287 cases of fetoscopic laser photocoagulation for twin-twin transfusion syndrome. Among the 114 who were placed under our care until delivery, three cases of TAPS occurred. In one case, we conducted intrauterine intravenous transfusion, while in the other two cases, we adopted expectant management. We performed an emergency caesarean section at 27-30 weeks of gestation in all cases due to a severe condition of anemia in the TAPS donor. Two cases with antenatal TAPS stage 4 had severe maternal complications; one had minute pulmonary embolism, while the other had Mirror syndrome. All three pairs of infants survived. One TAPS donor and one TAPS recipient had neurodevelopmental impairment; bilateral deafness at 9.5 years old and spastic paralysis at 2 years old, respectively. In conclusion, post-laser TAPS in a higher stage can cause severe maternal complications. Close observations for both fetuses and mothers are required for such cases.

Objective The aim of this study is to clarify the feasibility and efficacy of fetoscopic laser photocoagulation of placental vascular communicating vessels (FLP) on twin–twin transfusion syndrome (TTTS) after 26 weeks of gestation. Materials and Methods This is a prospective pilot study investigating all cases of TTTS between 26 weeks and 27 weeks during 2012 and 2013 in Japan. The primary endpoints in this study were the feasibility of FLP and rate of harmful complications for the mother's health. Also, perinatal prognosis was investigated. Results Six cases were enrolled and underwent FLP. Two of the six cases were classified preoperatively as Quintero Stage II and four cases were Stage III. FLP was completely achieved in all six cases. No severe maternal complications were noted during and immediately after the surgery. All but one case continued the pregnancies > 14 days after FLP. The median gestational age at delivery was 33.4 weeks (28.0–36.6 weeks). All 12 fetuses survived at the 28 th day in the neonatal period. No case was diagnosed with cerebral lesion at the neonatal period. Conclusion This prospective pilot study shows that FLP could be a therapeutic option for TTTS between 26 weeks and 27 weeks of gestation.

To elucidate clinical feature and anti-phospholipid antibody (aPL) profiles, including lupus anticoagulant (LA), anti-cardiolipin (CL) antibodies and anti-phosphatidylserine/prothrombin (PS/PT) antibodies, of pregnancy failure in patients with antiphospholipid antibody syndrome (APS) already treated with conventional therapy.Thirty-four women with a history of pregnancy who were diagnosed with APS between 2008 and 2016 were included in the study. We defined the successful pregnancy group as women who gave birth to a healthy baby over 1500 g after 34 weeks of pregnancy under conventional treatment (heparin and/or low-dose aspirin). The unsuccessful pregnancy group was defined as women whose pregnancy outcomes did not meet the aforementioned criteria despite the conventional therapy. The clinical features and aPL profiles were compared between the two groups.Fifteen women were classified into the unsuccessful pregnancy group; seven women were in the successful pregnancy group. Having history of both thrombosis and pregnancy morbidity and LA positivity were significantly more prevalent in the unsuccessful pregnancy group than in the successful pregnancy group (p .05, respectively). In contrast, single positivity of anti-CL antibody was negatively associated with APS-associated pregnancy morbidity under the conventional treatment (p .01). The proportion of anti-PS/PT IgG-positive patients was significantly higher in the unsuccessful pregnancy group (p = .02, OR 18.7, 95% CI 1.50, 232.29) with high concordance rate with LA (97% consistence).History of both thrombosis and pregnancy morbidity and the positivity of LA and/or anti-PS/PT-IgG, not but anti-CL-antibodies were correlated with APS-associated pregnancy morbidity refractory to conventional treatment. Clinical feature and aPL profiles might help us to make risk assessment for adverse pregnancy outcomes in patients with APS.

The objective of this study is to assess the outcomes and risk factors of fetal bradycardia after external cephalic version (ECV).We performed a retrospective study of women who underwent ECV after 35 weeks of gestation in 2010-2016. We assessed the birth outcomes, including umbilical cord artery pH, according to the duration of fetal bradycardia and the risk factors for bradycardia.Among 390 cases, 189 (48.5%) cases showed fetal bradycardia during or immediately after ECV. The duration of fetal bradycardia was1 min (n = 82, 43.4%),5 min (n = 168, 88.9%); and10 min (n = 186, 98.4%). All cases showed a good prognosis. Fetal bradycardia lasting10 min occurred in three cases; emergency cesarean section was performed in each case, with delivery after 12-4 min of bradycardia. Two of three cases showed low Apgar scores at 5 min, with an umbilical cord arterial pH of7.1. Lower maternal BMI and a prolonged ECV procedure were significantly associated with bradycardia (p for trend: .016 and .015, respectively).Fetal bradycardia lasting10 min after ECV was a risk factor for asphyxia. Thus, delivery should be completed within 10 min after bradycardia. A low maternal BMI and a prolonged ECV procedure were risk factors for bradycardia after ECV.

The aim of this study was to review fetoscopic laser photocoagulation (FLP), which ablates placental vascular anastomoses to treat twin–twin transfusion syndrome (TTTS). A review of studies reporting on the procedures, outcomes, complications and nonconventional applications of FLP for TTTS was conducted. FLP has been established as the primary treatment for monochorionic twin pregnancy associated with TTTS at 16–26 weeks. FLP is the only therapy that directly addresses the underlying pathophysiology. The recent technique modification of FLP, referred to as the ‘Solomon technique’, induces selective coagulation to connect the anastomoses ablation sites and has been introduced to reduce residual anastomoses. The perinatal survival following FLP improved significantly with advances in the technique after its introduction. The recent survival rates of both twins and at least one twin are 70% and more than 90%, respectively. However, there is still an 11–14% risk of long‐term neurodevelopment impairment. The premature rupture of membranes that leads to preterm labor is a common complication after FLP. FLP is a valuable treatment option for feto‐fetal transfusion syndrome in triplets and for TTTS after 26 weeks. FLP for selective intrauterine growth restriction may be potentially beneficial when accompanied by abnormal Doppler findings and oligohydramnios. FLP is the optimal treatment option for TTTS at 16–26 weeks of gestation. FLP appears to be applicable in triplets, TTTS after 26 weeks and cases of selective intrauterine growth restriction with abnormal Doppler findings and oligohydramnios. FLP is the most common and successful fetal intervention. Improvement in the neurodevelopmental outcomes after FLP is a future focus.

This study aimed to investigate developmental outcomes of Japanese babies born through Assisted Reproductive Technology (ART) at ages 2 and 3.The data were gathered from 1085 children in a hospital-based cohort study conducted in Japan. The children's level of development was assessed through a parent-rated questionnaire, the Kinder Infant Development Scale, which consists of nine developmental domains. We compared the development of children born through ART and those born naturally by conducting analyses of covariance. For the analyses, the effect of maternal age, family income, parental education and multiple birth were controlled for.At 24 months, no significant difference was found between children born through ART and those born naturally in development in any domain. At 36 months, a significant difference was found in development of Receptive language (F (1, 845) = 6.148, P = 0.013), Expressive language (F (1, 845) = 4.060, P = 0.044) and Language concept (F (1, 845) = 6.968, P = 0.008). For these domains, children born through ART had a significantly higher developmental age compared to children born naturally.At age 2, no significant difference was found between the children born through ART and those born naturally in nine developmental domains, although at age 3, the children born through ART showed significantly better language development than the children born naturally.

To assess the role of lung size and abnormal Doppler findings in the umbilical artery (UA) in determining the outcomes of fetuses with primary fetal hydrothorax (FHT) associated with hydrops who underwent thoracoamniotic shunting (TAS).This was a retrospective study at a single center. We included cases of primary FHT with hydrops who underwent TAS at our hospital between 2004 and 2016. We assessed the relationship between mortality until 28 days after birth and ultrasound findings, including absent or reversed end-diastolic velocity (AREDV) in the UA and the lung-to-thorax transverse area ratio (LTR), before and after TAS.Forty-one cases of primary FHT with hydrops underwent TAS. The median (range) gestational age at TAS was 28.5 (19.3-33.8) weeks. Bilateral pleural effusion was observed in 39 cases (95.1%). Among the 41 cases, 19 (46.4%) survived, 11 (26.8%) died in utero, and 11 (26.8%) died in the neonatal period. AREDV in the UA before and after TAS were not associated with mortality (P = 0.32 and 0.47, respectively). The odds ratio for mortality in LTR 0.2-0.3 before TAS was 0.62 (vs LTR0.2, P = 0.45) and that in LTR 0.2-0.3 and0.3 after TAS were 0.27 and 0.06, respectively (vs LTR0.2, P for trend0.01).A larger LTR after TAS was significantly associated with a better prognosis in hydropic primary FHT. The fetal lung size after the procedure may be a prognostic factor of primary FHT.

Background While several studies have demonstrated the increased risk of pregnancy complications for women of advanced age, few studies have focused on women with very advanced age (≥ 45), despite the increasing rate of pregnancy among such women. Furthermore, how such risks of increase in age differ by maternal characteristics are also poorly understood. Thus, we aimed to clarify pregnant outcomes among women with very advanced age and how the effect of age differs by method of conception and parity. Methods We used the national multicenter Japan Society of Obstetrics and Gynecology perinatal database, including 365,417 women aged 30 years or older who delivered a singleton between 2005 and 2011. We divided women into four groups based on age (years): 30–34, 35–39, 40–44, and ≥45, and compared risk of adverse birth outcomes between the groups using Poisson regression. Effect modification by parity and use of assisted reproductive technology (ART) was also evaluated. Results: Compared with women aged 30–34 years, women aged 45 or older had higher risk of emergency cesarean delivery [adjusted risk ratio (aRR): 1.77, 95% confidence interval (95% CI): 1.58–1.99], preeclampsia (aRR: 1.86, 95% CI: 1.43–2.42), severe preeclampsia (aRR: 2.03, 95% CI: 1.31–3.13), placenta previa (aRR: 2.17, 95% CI: 1.60–2.95), and preterm birth (aRR: 1.20, 95% CI: 1.04–1.39). The effect of older age on risk of emergency cesarean section, preeclampsia, and preterm birth were significantly greater among those who conceived naturally compared to those who conceived by ART. The effect on emergency cesarean section was stronger among primiparous women, whereas the risk of preeclampsia associated with older age was significantly greater among multiparous women. Conclusions Very advanced maternal age (≥ 45) was related to greater risk for adverse birth outcomes compared to younger women, especially for maternal complications including cesarean section, preeclampsia, severe preeclampsia, and placenta previa. The magnitude of the influence of age also differed by conception method and by parity.

Prenatal diagnosis of skeletal dysplasia by means of 3D skeletal CT examination is highly accurate. However, it carries a risk of fetal exposure to radiation. Model-based iterative reconstruction (MBIR) technology can reduce radiation exposure; however, to our knowledge, the lower limit of an optimal dose is currently unknown. The objectives of this study are to establish ultra-low-dose fetal CT as a method for prenatal diagnosis of skeletal dysplasia and to evaluate the appropriate radiation dose for ultra-low-dose fetal CT.Relationships between tube current and image noise in adaptive statistical iterative reconstruction and MBIR were examined using a 32-cm CT dose index (CTDI) phantom. On the basis of the results of this examination and the recommended methods for the MBIR option and the known relationship between noise and tube current for filtered back projection, as represented by the expression SD = (milliamperes)Noise increased in nearly inverse proportion to the square root of the dose in adaptive statistical iterative reconstruction and in inverse proportion to the fourth root of the dose in MBIR. Ultra-low-dose fetal CT was found to have a volume CTDI of 0.5 mGy. Prenatal diagnosis was accurately performed on the basis of ultra-low-dose fetal CT images that were obtained using this protocol. The level of fetal exposure to radiation was 0.7 mSv.The use of ultra-low-dose fetal CT with MBIR led to a substantial reduction in radiation exposure, compared with the CT imaging method currently used at our institution, but it still enabled diagnosis of skeletal dysplasia without reducing diagnostic power.

Although adult height is inversely related with the risk of chronic disease, the association between maternal height and ischaemic placental disease remains unclear.We used the national, multicentre Japan Society of Obstetrics and Gynecology perinatal database to assess the risk of preeclampsia, placental abruption, and small for gestational age (SGA) births (birthweight10th percentile), which together constitute the syndrome 'ischaemic placental disease', in relation to self-reported height in 218 412 women with no underlying diseases before pregnancy, who delivered singletons in 2005-11. Height was categorised into quartiles as well as considered in linear terms, and its effect on each outcome was estimated using multivariable log binomial regression adjusted for the maternal characteristics.The risk of preeclampsia, placental abruption, and SGA birth was inversely related to maternal height. In the adjusted model, mothers in the lowest quartile for height (155 cm) were at higher risk of preeclampsia (relative risk (RR) 1.35, 95% confidence interval (CI) 1.25, 1.45), placental abruption (RR 1.20, 95% CI 1.07, 1.34), and SGA (RR 1.96, 95% CI 1.90, 2.03) compared with mothers in the highest quartile (162 cm). When the association between height and outcomes was considered in linear terms, each 5 cm decrement in height was associated with an increased risk of preeclampsia (RR 1.11, 95% CI 1.09, 1.14), placental abruption (RR 1.04, 95% CI 1.01, 1.09), and SGA birth (RR 1.30, 95% CI 1.28, 1.31).Shorter height was associated with an increased risk of preeclampsia, placental abruption, and SGA birth.

Background. Caesarean scar pregnancy (CSP) is a rare ectopic pregnancy associated with life-threatening complications. To date, no therapeutic protocols have been established. Sono-guided local methotrexate (MTX) injection is a relatively easy and low-invasive treatment. Additional systemic MTX is sometimes needed for CSP cases, especially when β-subunit human chorionic gonadotropin (β-hCG) levels are >20,000 mIU/ml at diagnosis. We report on six cases of CSP treated with local MTX injection, five of which received combined local treatment. Methods. Under intravenous anesthesia, six CSPs including a case with β-hCG levels >20,000 mIU/ml received MTX injection to the gestational sac. Five cases received gestational sac aspiration. Three cases had additional local potassium chloride injection and one case had a saline injection aiming at the fetal heart beat concurrent with MTX injection. MTX was administered weekly if β-hCG levels stayed beyond the expected values. Outcomes. All cases achieved β-hCG normalization without additional systemic MTX, with one case having a successful pregnancy after treatment. Conclusion. Sono-guided local MTX injection with concurrent local treatment might be a potentially effective approach for CSP cases. The accumulation of further cases is necessary to confirm this.

Chronic histiocytic intervillositis (CHI) is an extremely rare pathological condition but is strongly associated with severe obstetric complications and has a high recurrence rate. The management of this condition has not yet been established. We describe herein the occurrence of CHI in the late second-third trimester in each of three consecutive pregnancies in a single patient with four previous consecutive early miscarriages. In this patient, each of the three complicated pregnancies was managed with one of the following, respectively: low-dose aspirin; heparin plus low-dose aspirin; and prednisolone plus low-dose aspirin. CHI was histologically confirmed in all three pregnancies, but the clinical results and pathology (e.g. extent of histiocytic infiltration) in each pregnancy clearly differed with treatment. Both combination treatments eventuated in a live birth. Immunosuppressive therapy seemed to produce better clinical results by restricting the extent of the affected areas. The elevated alkaline phosphatase associated with the CHI was assumed to have no clinical prognostic value.

BACKGROUND/OBJECTIVES Vegetable intake during childhood may reduce the risk of subsequent asthma. We verified the effect of maternal intake during pregnancy on asthma risk in offspring, which has rarely been studied. SUBJECTS/METHODS In a hospital-based birth cohort study conducted in Tokyo, we administered a food frequency questionnaire at two periods during the respondents' pregnancy: early and mid to late periods. In addition, a questionnaire including the International Study of Asthma and Allergies in Childhood questionnaire was conducted when the offspring were 2 years old. Multivariate Poisson regression adjusting for maternal baseline demographics was used to elucidate the association between maternal vegetable intake and the incidence of wheeze in the offspring. RESULTS Among 310 singletons, 82 (26.5%) experienced wheeze at 2 years of age. Women with the highest intake of cruciferous, and folate-rich vegetables during early pregnancy reported a significantly lower prevalence of wheeze in their child at 2 years of age in comparison with those who reported the lowest intake (adjusted risk ratio: 0.48 and 0.47, 95% confidence interval: 0.26-0.89, and 0.25-0.87, respectively). In trend analysis, a higher maternal intake of cruciferous, folate-rich vegetables, and total vegetables during early pregnancy was less likely to be associated with wheeze in the offspring at 2 years old (p for trend: 0.038

With increasing public concern about infertility and the frequent involvement of chromosomal anomalies in miscarriage, analyses of copy number variations (CNVs) have been used to identify the genomic regions responsible for each process of childbearing. Although associations between CNVs and diseases have been reported, many CNVs have also been identified in healthy individuals. Like other types of mutations, phenotypically indefinite CNVs may have been retained and accumulated during anthropogenesis. Therefore to distinguish causative variants from other variants is a formidable task. Furthermore, because previous studies have predominantly focused on European and African populations, comprehensive detection of common Asian CNVs is eagerly awaited. Here, using a high-resolution genotyping array and samples from 411 Japanese women with normal parity without significant complications, we have compiled 1043 copy number variable regions. In total, the collected regions cover 164 Mb, or up to 0.5% of the genome. The copy number differences in these regions may be irrelevant not only to infertility but also to a wide range of diseases. The utility of this resource in reducing the candidate pathogenetic variants, especially in Japanese subjects, is also demonstrated.

Objective The objective of this study is to evaluate the outcomes of fetoscopic laser photocoagulation (FLP) for a triplet gestation with feto-fetal transfusion syndrome (FFTS). Method On the basis of chorionicity, perinatal outcome at 28 days in triplets with FFTS after FLP were evaluated. Results Fetoscopic laser photocoagulation was completed for all 16 cases including nine dichorionic triamniotic (DT) cases and seven monochorionic triamniotic (MT) cases. The placenta was located anteriorly in six cases. The median gestational age at surgery was 21 (16–25) weeks, and the median operation time was 51 (25–125) minutes. Several technical maneuvers to complete the procedure in MT, such as trocar assistance in two cases, intentional septostomy of the dividing membrane in one, and double uterine entry in one, were used. The median gestational age at delivery was 31 (23–34) weeks. Overall perinatal survival in DT was 74% and that of MT was 95%. All 16 cases resulted in at least one survival, whereas three neonates survived in 44% of DT cases and in 86% of MT cases. Two MT neonates suffered severe intraventricular hemorrhages. Conclusions Fetoscopic laser photocoagulation for FFTS in MT as well as DT triplets seems a valuable treatment. © 2014 John Wiley & Sons, Ltd.

Although human term placenta-derived primary cytotrophoblasts (pCTBs) represent a good human syncytiotrophoblast (STB) model, in vitro culture of pCTBs is not always easily accomplished. Y-27632, a specific inhibitor of Rho-associated coiled-coil containing kinases (ROCK), reportedly prevented apoptosis and improved cell-to-substrate adhesion and culture stability of dissociated cultured human embryonic stem cells and human corneal endothelial cells. The Rho kinase pathway regulates various kinds of cell behavior, some of which are involved in pCTB adhesion and differentiation. In this study, we examined Y-27632's potential for enhancing pCTB adhesion, viability and differentiation. pCTBs were isolated from term, uncomplicated placentas by trypsin-DNase I-Dispase II treatment and purified by HLA class I-positive cell depletion. Purified pCTBs were cultured on uncoated plates in the presence of epidermal growth factor (10 ng/ml) and various concentrations of Y-27632. pCTB adhesion to the plates was evaluated by phase-contrast imaging, viability was measured by WST-8 assay, and differentiation was evaluated by immunofluorescence staining, expression of fusogenic genes and hCG-β production. Ras-related C3 botulinum toxin substrate 1 (Rac1; one of the effector proteins of the Rho family) and protein kinase A (PKA) involvement was evaluated by using their specific inhibitors, NSC-23766 and H-89. We found that Y-27632 treatment significantly enhanced pCTB adhesion to plates, viability, cell-to-cell fusion and hCG-β production, but showed no effects on pCTB proliferation or apoptosis. Furthermore, NSC-23766 and H-89 each blocked the effects of Y-27632, suggesting that Y-27632 significantly enhanced pCTB differentiation via Rac1 and PKA activation. Our findings suggest that Rac1 and PKA may be interactively involved in CTB differentiation, and addition of Y-27632 to cultures may be an effective method for creating a stable culture model for studying CTB and STB biology in vitro.

Ts1Cje mice have a segmental trisomy of chromosome 16 that is orthologous to human chromosome 21 and display Down syndrome-like cognitive impairments. Despite the occurrence of affective and emotional impairments in patients with Down syndrome, these parameters are poorly documented in Down syndrome mouse models, including Ts1Cje mice. Here, we conducted comprehensive behavioral analyses, including anxiety-, sociability-, and depression-related tasks, and biochemical analyses of monoamines and their metabolites in Ts1Cje mice. Ts1Cje mice showed enhanced locomotor activity in novel environments and increased social contact with unfamiliar partners when compared with wild-type littermates, but a significantly lower activity in familiar environments. Ts1Cje mice also exhibited some signs of decreased depression like-behavior. Furthermore, Ts1Cje mice showed monoamine abnormalities, including increased extracellular dopamine and serotonin, and enhanced catabolism in the striatum and ventral forebrain. This study constitutes the first report of deviated monoamine metabolism that may help explain the basis for abnormal behaviors, including the environmental stimuli-triggered hyperactivity, increased sociability and decreased depression-like behavior in Ts1Cje mice.

Since the advance online publication of this article, the authors of the above paper have noticed errors in the list of authors and affiliations. The article with correct author information now appears in this issue.

Objective: To find a risk factor for “uncomplicated” preeclampsia (PE) comparing blood biochemical parameters between women with uncomplicated PE and healthy pregnant women in each trimester of pregnancy. Methods: A retrospective study was performed on 83 cases of uncomplicated PE, selected from 434 patients with PE, disregarding subjects with other complications relevant to hypertension during pregnancy. The study was limited to women with PE occurring in the third trimester, and records of blood biochemical parameters were evaluated. Controls were recruited from 108 healthy volunteers with normal singleton pregnancies. Results: A significant decrease in total protein was observed in the uncomplicated PE group in the second trimester prior to the onset of clinical symptoms. Conclusion: Hypoproteinemia during pregnancy may be a risk factor for this pathophysiology, and the maintenance of sufficient protein in early pregnancy could contribute to prophylaxis for women with uncomplicated PE.

Coronary artery aneurysms (CAA) may occur in Kawasaki disease (KD). Patients with giant CAA (diameter >8 mm), in particular, have higher risk of myocardial infarction. Previous reports have demonstrated the necessity of anticoagulation therapy in such cases. The management of patients with KD complicated by giant CAA later in life, however, remains controversial. Here, we describe the strict management in the case of a 28-year-old pregnant Japanese woman with KD with giant CAA (diameter, 11 mm). Instead of warfarin, the patient was given low-dose aspirin and i.v. unfractionated heparin during pregnancy to prevent thrombosis in the giant CAA. At 38 weeks of gestation, she had spontaneous delivery of a healthy baby. No thrombotic or bleeding complications were observed. The strict anticoagulation therapy resulted in successful pregnancy and delivery without any adverse events.

Background: Fetal cardiac rupture is very rare and has been scarcely reported. Prenatal image diagnosis of fetal cardiac rupture is not well characterized. Case: An 18-week fetus with a pericardial mass and effusion revealed by ultrasound was suspected to have a pericardial tumor. Fetal demise occurred at 19 weeks’ gestation. Postmortem magnetic resonance image (MRI) found a pericardial mass diagnosed as a hematoma caused by cardiac rupture. Findings were confirmed by autopsy. Conclusion: MRI may be applicable for prenatal diagnosis of cardiac rupture.

Fetal anemia is caused by Rhesus (RhD) sensitization as a result of RhD incompatibility during pregnancy. The severe form of this disease can cause hydrops fetalis leading to intrauterine death. We experienced a highly sensitized 39-year-old woman with B Rh-negative blood. She had a history of three induced abortions and experienced perinatal death associated with hydrops fetalis. During the pregnancy prior to her most recent one, she was treated with double-filtration plasmapheresis (DFPP), high dose γ-globulin and intrauterine fetal blood transfusion (IUT). For her most recent pregnancy, we performed only weekly or fortnightly DFPP from 13 weeks until delivery. Anti-D antibody titer was maintained between 32 and 256 without any signs of fetal anemia. IUT was not required at any stage of the pregnancy. No adverse events were observed. She successfully delivered a healthy male infant weighing 2,289 g by Cesarean section at 35 weeks. Repeated DFPP may be an effective and safe strategy to reduce antibody titers in highly sensitized women with RhD-incompatible pregnancy, avoiding the need for IUT.

Purpose To identify the impact of the histological diagnosis on the prognosis of prenatally diagnosed sacrococcygeal teratoma (SCT), we analyzed the data obtained during prenatal surveillance and assessed the postnatal outcomes in a large cohort of fetuses with SCT in Japan. Methods A nationwide retrospective cohort study was conducted among 97 fetuses prenatally diagnosed with SCT between 2000 and 2009. Of these, 84 had a histological diagnosis. In addition, we conducted a second surveillance program of the prognosis of 72 patients who were reported to be alive at the initial surveillance conducted 2 years previously. Results The tumors comprised 51 (61 %) mature teratomas, 33 (39 %) immature teratomas and 0 (0 %) malignant teratomas. Immature teratomas were also associated with a significantly higher mortality rate (immature teratomas: 8/31, mature teratomas: 2/48). Late recurrence was observed in six of 72 cases (8.3 %). Among these six cases, recurrence with a malignant component was observed in four patients. All six patients were successfully treated. Conclusions Mature teratoma was the most common histological type observed in this study. The patients with immature teratomas exhibited an increased risk of mortality. Late recurrence was observed in 8.3 % of the cases.

Background Congenital diaphragmatic hernia is associated with cardiovascular malformation. Many prognostic factors have been identified for isolated congenital diaphragmatic hernia; however, reports of concurrent congenital diaphragmatic hernia and cardiovascular malformation in infants are limited. This study evaluated congenital diaphragmatic hernia associated with cardiovascular malformation in infants. Factors associated with prognosis for patients were also identified. Methods This retrospective cohort study was based on a Japanese survey of congenital diaphragmatic hernia patients between 2006 and 2010. Frequency and outcome of cardiovascular malformation among infants with congenital diaphragmatic hernia were examined. Severity of congenital diaphragmatic hernia and cardiovascular malformation were compared as predictors of mortality and morbidity. Results Cardiovascular malformation was identified in 76 (12.3%) of 614 infants with congenital diaphragmatic hernia. Mild cardiovascular malformation was detected in 19 (33.9%) and severe cardiovascular malformation in 37 (66.1%). Their overall survival rate at discharge was 46.4%, and the survival rate without morbidity was 23.2%. Mortality and morbidity at discharge were more strongly associated with severity of cardiovascular malformation (adjusted OR 7.69, 95%CI 1.96–30.27; adjusted OR 7.93, 95%CI 1.76−35.79, respectively) than with severity of congenital diaphragmatic hernia. Conclusions The prognosis for infants with both congenital diaphragmatic hernia and cardiovascular malformation remains poor. Severity of cardiovascular malformation is a more important predictive factor for mortality and morbidity than severity of congenital diaphragmatic hernia.

There are currently no factors that have been shown to predict gestational diabetes mellitus (GDM) during early pregnancy. The soluble (pro)renin receptor [s(P)RR] may contribute to the development of GDM.The objective of the study was to determine whether plasma s(P)RR concentrations during early pregnancy are associated with the development of GDM later in pregnancy.This prospective cohort study was conducted at a referral birth center. Pregnant women who first visited our hospital during the first trimester (14 weeks of gestation) between 2010 and 2011 were enrolled. Inclusion criteria included singleton pregnancy and the absence of preexisting diabetes mellitus. A total of 716 women participated in this study.The association of plasma s(P)RR concentrations with the onset of GDM later in pregnancy was measured.Among 716 participants, 44 (6.1%) had GDM and 672 (93.9%) did not. There were 176 participants in the first plasma s(P)RR concentration quartile (Q1:25.8 ng/mL), 179 in the second (Q2: 25.8-30.2 ng/mL), 181 in the third (Q3: 30.2-34.2 ng/mL), and 180 in the fourth (Q4:34.2 ng/mL). GDM distribution was 7 (4.0%) in Q1, 5 (2.8%) in Q2, 13 (7.2%) in Q3, and 19 (10.6%) in Q4. A multivariate model adjusted for baseline characteristics, medical complications, and gestational characteristics revealed that the risk of developing GDM among women in Q4 compared with Q1 was 2.90 (95% confidence interval 1.11-7.49).Increased s(P)RR concentrations during the first trimester may predict the development of GDM later in pregnancy.

In the present study, immunity against infectious diseases, which are capable of influencing both the mother and fetus during pregnancy and the infant in the postnatal period, were assessed in pregnant women to elucidate the necessity of vaccination during the childbearing age. It was determined that there was a trend of increases in the proportion of patients that had low antibody titers observed at a young age. Overall, after adjusting for age, low antibody titers of measles (≤ 4 via the neutralization test [NT]), rubella (≤ 16 via the hemagglutination inhibition [HI]), and varicella and mumps (plus minus or negative on the enzyme-linked immunosorbent assay [EIA]) indicated that the rates of necessity for vaccination against measles, rubella, varicella, and mumps were 27.6%, 16.1%, 3.9%, and 23.8%, respectively. In Japan, acquired immunity for measles, rubella, and mumps was dependent on vaccination, whereas acquired immunity for varicella was dependent on natural infection. We recommend that women be vaccinated after delivery, as these vaccines are live, and thereby, are contraindicated during pregnancy.

Aim To clarify perinatal outcomes of monoamniotic (MM) twin pregnancies. Material and Methods MM twins delivered in seven tertiary perinatal centers during the last decade were retrospectively evaluated. All pregnant women were scheduled to begin inpatient management at around 24 weeks of gestation and undergo a planned cesarean section beyond 32 weeks. Pregnancy outcomes, prevalence of fetal death and cord entanglement, perinatal mortality and neuromorbidity rate at discharge were examined. Results The study group comprised 38 MM twin pregnancies (76 fetuses). Cord entanglement was confirmed in 88% (30/34) of women, and fetal deaths occurred in nine women (eight were both fetal deaths, and one was single fetal death). The cord entanglement accounted for 65% (11/17) of the fetal deaths. The median gestational age at delivery was 31+3 weeks, but that for viable infants was 32+3 weeks; the median birth weight was 1642 g, the perinatal mortality rate was 2% (1/60), and the neuromorbidity rate was 8% (5/50). The overall survival rate was 75% (57/76). Conclusion Perinatal outcomes in our study were relatively good irrespective of high frequency of cord entanglement. Close fetal monitoring may allow MM twin pregnancies to extend gestational age, which may contribute to reduce both fetal death and neonatal morbidity by immaturity, although the best delivery weeks remained undetermined.

Objective The purpose of our study was to investigate the incidence of chorioamniotic membrane separation (CMS) after fetoscopic laser surgery and the association between CMS and preterm premature rupture of membranes (pPROM). We also analyzed the risk factors associated with the occurrence of CMS. Method Retrospective cohort study of 148 patients with twin–twin transfusion syndrome who underwent laser surgery at our institution from March 2003 to December 2009. Results Chorioamniotic membrane separation occurred in 29 of 148 (19.6%) patients. The presence of CMS strongly correlated with pPROM prior to 28weeks’ gestation. Multivariate analysis of the risk factors of pPROM

Objective To describe the safety and efficacy of thoracoamniotic shunting for fetal pleural effusion using a doublebasket catheter with a very small diameter (1.47mm). Method In this 2-year multicenter, prospective single-arm clinical studyregistered with the University hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN00001095); shunting was performed between 18w0d and 33w6d of gestation with this catheter in cases of fetal pleural effusions reaccumulating after thoracocentesis. The primary endpoint measures were maternal and fetal adverse effects and survival in the neonatal period. Results A total of 24 cases were included, of which 17 had hydrops (71%). The median gestational ages at shunting and delivery were 27.4 and 34.8weeks, respectively. There were no fetal deaths, lung injuries, or severe maternal complications. Preterm rupture of the membranes occurred in 7/24 (29%) cases at a median of 62days after the shunting. Preterm rupture of the membranes within 28days of the procedure occurred in 1/24 (4%) cases. Catheter displacement towards the fetal thoracic cavity occurred in 4/42 (10%) cases. The overall survival rate was 79% (19/24), whereas it was 71% (12/17) in the cases with hydrops. Conclusion Drainage of fetal pleural effusions with a double-basket shunt is safe and effective, and the shunt could be an alternative device. © 2012 John Wiley & Sons, Ltd.

The renin–angiotensin system is believed to influence blood pressure (BP) during pregnancy, but the associations between BP during pregnancy and the soluble form of the (pro)renin receptor (s[P]RR), a new component of the tissue renin–angiotensin system, remain undetermined. In this prospective cohort study of 437 pregnant women with normal BP (systolic 28 weeks) and at delivery averaged 29.7 ± 10.0, 31.3 ± 12.0, 39.2 ± 8.9, and 40.4 ± 10.2 ng/mL (mean±SD), respectively. A 1-ng/mL increase in plasma s(P)RR concentration in early pregnancy predicted systolic/diastolic BP elevation in the later 3 gestational stages: 0.11 (95% CI, 0.014–0.20)/0.093 (0.027–0.16) mm Hg for 20 to 24 weeks, 0.11 (0.029–0.19)/0.088 (0.027–0.15) mm Hg for 28 to 32 weeks, and 0.16 (0.058–0.26)/0.12 (0.043–0.19]) mm Hg for 36 to 40 weeks, respectively. Plasma s(P)RR concentrations in middle and late pregnancy were not associated with BP. Adjusted models revealed that women with plasma s(P)RR concentrations above the 75th percentile at delivery had a significantly increased risk of preeclampsia (odds ratio, 22.5 [95% CI, 1.8–279.9]). In conclusion, high circulating levels of s(P)RR at early pregnancy predicted a subsequent elevation in BP, and high concentrations at delivery were significantly associated with preeclampsia.

To investigate the rates of termination of pregnancy (TOP) for fetal chromosomal abnormalities and factors related to such parental decision in Japan.A multicenter retrospective cohort study of chromosomal abnormalities diagnosed before 22 weeks of gestation between April 2008 and March 2015. The pregnancy outcomes and parental decisions were investigated.Among 931 fetuses with chromosome abnormalities, the total TOP rate was 75.1% (699/931). TOP rates were 89.3% (585/655) in autosomal aneuploidies and 40.8% (51/125) in sex chromosome aneuploidies. Trisomy 21 showed the highest TOP rate (93.8% [390/416]) followed by trisomy 18 (84.5% [163/193]) and trisomy 13 (71.9% [23/32]). Indications for karyotyping were related to a parental decision for TOP (p 0.01): in cases of autosomal aneuploidy, with fetal abnormal ultrasound findings as the reference value, diagnoses made following positive results at non-invasive prenatal testing (adjusted odds ratio [OR]: 13.7, 95% confidence interval [CI] 4.07-45.9) and those because of advanced maternal age (adj. OR 2.91, 95% CI 1.15-7.35) were significantly more frequent.In Japan, pregnancies with fetal trisomy 21 are more likely to result in TOP when diagnosed in utero than any other chromosome anomaly. The indications for prenatal karyotyping strongly affect the decision to TOP. © 2016 John WileySons, Ltd.

To study the effects of gestational transient thyrotoxicosis (GTT) on pregnancy outcomes. This case–control study retrospectively analyzed 7976 women with singleton pregnancies whose thyroid function was measured before 16 weeks of gestation and who delivered at ≥22 weeks of pregnancy. GTT was defined as hyperthyroidism (free thyroxine [FT4] level: ≥95th percentile) in the early pregnancy, which normalized in mid-pregnancy without thyroid-stimulating hormone receptor antibodies. Using data extracted from electronic records, we examined the association between GTT and the pregnancy outcomes (preterm delivery, gestational age at delivery, pregnancy induced hypertension (PIH), preeclampsia, placental abruption, caesarian section, birth weight, low birth weight, Apgar score, cord pH, stillbirth at gestational week ≥22, and neonatal death). We classified the cases into quartiles according to their FT4 values during the early pregnancy and investigated the association with the gestational age at delivery. Two hundred and eight cases of GTT and 6317 cases with normal thyroid assessments were reviewed. GTT was associated with hyperemesis gravidarum, but not with stillbirth, preterm delivery, PIH, preeclampsia, placental abruption, or low birth weight. The gestation period was shorter in patients with GTT than in those with a normal thyroid function (38.69 ± 1.79 vs. 39.07 ± 1.64 weeks, p

This study aims to determine the prognostic factors and outcomes of primary fetal hydrothorax (FHT) and investigate the effects of fetal therapy.A nationwide survey was conducted on fetuses with primary FHT delivered after 22 weeks of gestation between January 2007 and December 2011 at perinatal centers.Among the 287 cases of primary FHT, the survival rates for those with and without hydrops were 58.0% (113/195) and 97.8% (90/92), respectively. The survival rates in the no-therapy, thoracocentesis, and thoracoamniotic shunting (TAS) groups in the hydropic cases and the non-hydropic cases were 59.7% (40/67), 51.5% (35/68), and 63.3% (38/60) and 98.1% (53/54), 96.3% (26/27), and 100% (11/11), respectively. The crude relative risk for death was 2.1 (p = 0.005) for fetuses diagnosed at 26 to 30 weeks of gestational age (vs ≥30 weeks), 2.3 (p = 0.001) for both skin edema and ascites, and 3.1 (p = 0.02) for bilateral pleural effusion. TAS was associated with a significant risk reduction for death in hydropic cases [adjusted relative risk 0.61, p = 0.01 (vs no fetal therapy)].Hydrops and an early gestational age at diagnosis (30 weeks of gestation), skin edema with ascites, and bilateral effusion predicted a poor prognosis in primary FHT cases. TAS was associated with a higher survival rate. © 2016 John WileySons, Ltd.

There are few reports on the prognosis of prenatally diagnosed trisomy 13 in relation to postnatal management. The aim of this study was to report on the prenatal and postnatal outcomes and postnatal management of trisomy 13 fetuses that were prenatally diagnosed at our center between 2003 and 2015. The data were retrospectively reviewed from medical records. Of the 31 cases of trisomy 13, 12 patients were diagnosed before 22 weeks of gestation, and 19 were diagnosed at or after 22 weeks of gestation. Nine families opted for termination of the pregnancy, 14 fetuses died, and 8 were born alive. Aggressive treatment was requested in two of the live births, with one patient achieving long-term survival (7 years). The other died during infancy (Day 61). One out of four who received palliative treatment is alive at two years of age with only nutrition supplementation. These three patients who achieved neonatal survival had few structural anomalies. Fetal death and early neonatal death are common in trisomy 13; however, fetuses that receive medical treatment for cases without major ultrasound abnormalities may achieve neonatal survival. Therefore, it is useful to provide comprehensive information, including precise ultrasound findings and treatment options, to parents with trisomy 13 fetuses during genetic counseling.

Maternal vitamin intake during pregnancy is crucial for pregnancy outcomes and the child's subsequent health. However, there are few valid instruments for assessing vitamin intake that address the effects of nausea and vomiting during pregnancy (NVP). This study aimed to investigate the validity of a FFQ concerning vitamin intake during early and late pregnancy with and without NVP. The participants comprised 200 Japanese pregnant women who completed the FFQ and from whom blood samples were taken in early and late pregnancy. Energy-adjusted dietary vitamin intakes (vitamin C, folate, vitamin B6, vitamin B12, vitamin A, vitamin E and vitamin D) from FFQ were compared with their blood concentrations. A subgroup of women with NVP was investigated. In early pregnancy, significant correlations between FFQ and biomarkers were observed for vitamin C (r0·27), folate (r0·18) and vitamin D (r0·26) in women with NVP and for vitamin A (r0·18), vitamin B12(r0·24) and vitamin D (r0·23) in women without NVP. No significant correlations were observed in either group for vitamins B6or E. In late pregnancy, similar significant associations were observed for vitamin C (r0·27), folate (r0·22), vitamin B6(r0·18), vitamin B12(r0·27) and vitamin A (r0·15); coefficients were higher among women without NVP. Our study demonstrates that the FFQ is a useful tool for assessing intake of several important vitamins in early and late pregnancy regardless of NVP status.

Thoracoamniotic shunting is the treatment of choice for management of the fetus with type 1 congenital pulmonary airway malformation. Thoracoamniotic shunting has been performed to reduce life-threatening risks such as fetal hydrops. However, caution is needed because of possible complications. Here, we report that thoracoamniotic shunting can cause histologic changes in the cyst epithelia. In 5 of 8 patients treated prenatally with thoracoamniotic shunting, squamous metaplasia in the cyst epithelia was seen; whereas squamous metaplasia was not found in 6 patients who were not treated with this procedure. Our results reveal that long-term exposure to the intrauterine environment could possibly lead to the change in the nature of cyst epithelium and consequent squamous metaplasia.

Aim: Measles during pregnancy has deleterious effects on both perinatal and maternal outcomes. In Japan, local epidemics of measles and cases of measles during pregnancy are still being reported; therefore, the seroprevalence of antibodies to measles is suspected to be still not sufficient. The aim of this study was to analyze the seroprevalence of antibodies to measles in Japanese pregnant women and estimate the percentage of these women who require vaccination or revaccination against measles. Material and Methods: We analyzed the seroprevalence of immunity to measles by the neutralization test in 10 349 pregnant women in the first trimester managed at the National Center for Child Health and Development between February 2004 and December 2010. The neutralization test titers were interpreted as follows: ≧1:8, seropositive; = 4, low-positive; ≦4, seronegative. Results: Of the total number of pregnant women tested, 7408 (71.6%) were seropositive, 1864 (18.0%) were low-positive, and 1079 (10.4%) were seronegative for measles antibodies, respectively. Conclusion: Our results revealed that 28% of our pregnant population was seronegative or low-positive for measles antibodies, and thought to require revaccination or vaccination. Screening for measles immunity might be advisable for women of childbearing age.

Aim: We investigated trends in early-onset group B streptococcal disease (EOD) after the introduction of culture-based screening in Japan. Material and Methods: A retrospective cohort study examined EOD trends in 9506 pregnancies and 10 715 neonates at our center from 2002 to 2009. Results: EOD occurred in four neonates (4/7332: 0.55/1000 live births). The EOD incidence among infants born to women positive for GBS by screening was 0.90 cases per 1000 live births (1/1107). In contrast, the EOD incidence among infants negative by GBS screening was 0.48 cases per 1000 live births (3/6225). Thus, of the four affected neonates, three had mothers who tested negative on antepartum GBS screening. Two neonates had symptoms of infection during labor and intrapartum antibiotic agents were administered. The other two neonates received no antibiotics because deliveries were uneventful and they were negative on GBS screening. Conclusion: The incidence of EOD is 0.90 cases per 1000 live births among GBS-positive women and 0.48 cases per 1000 live births among GBS-negative women. The results of our study implied that EOD can develop regardless of GBS screening and intrapartum clinical course, although the method of sample collection, indications for antibiotic prophylaxis, and the antibiotics regimen should be considered.

Complement component 9 (C9) deficiency is relatively common, especially in Japan. Here we present the case of a 27-year-old Japanese woman whose obstetric history involved three mid-trimester miscarriages (at 22 weeks', 18 weeks' and 21 weeks' gestation) and one early spontaneous miscarriage. Her fifth pregnancy was successfully managed by cervical cerclage at 13 weeks' gestation, followed by clindamycin administration (600 mg/day for 7 days) and progesterone injections (250 mg/week). She gave birth to a healthy 3326-g male infant at 40 weeks and 1 day gestation after natural onset of labor. After delivery, the serum complement components were analyzed. C9 protein and activity were undetectable in the patient's serum. We suggest that an immunologic disorder such as C9 deficiency should be considered as a potential complication of undiagnosed recurrent miscarriages.

Background: There are few large studies of fetal congenital bradyarrhythmia. The aim of the present study was to investigate the effects and risks of transplacental treatment for this condition. Methods and Results: Using questionnaires, 128 cases of fetal bradyarrhythmia were identified at 52 Japanese institutions from 2002 to 2008. Of the 128 fetuses, 90 had structurally normal hearts. Among these 90 fetuses, 61 had complete atrioventricular block (CAVB), 16 had second-degree AVB, 8 had sinus bradycardia, and 5 had other conditions. The 61 CAVB fetuses were divided into those who did (n=38) and those who did not (n=23) receive transplacental medication. Monotherapy with β-sympathomimetics, steroid monotherapy, and combination therapy with these agents was given in 11, 5 and 22 cases, respectively. Beta-sympathomimetics improved bradycardia (P 10 weeks on steroids (P=0.043). Conclusions: Treatment with β-sympathomimetics improved bradycardia, but survival rate did not differ significantly in fetuses with and without transplacental medication. It is recommended that steroid use should be limited to

The purpose of this study is to summarize the results from a survey on awareness of genetic counseling for pregnant women who wish to receive non-invasive prenatal testing (NIPT) in Japan. As a component of a clinical study by the Japan NIPT Consortium, genetic counseling was conducted for women who wished to receive NIPT, and a questionnaire concerning both NIPT and genetic counseling was given twice: once after pre-test counseling and again when test results were reported. The responses of 7292 women were analyzed. They expressed high satisfaction with the genetic counseling system of the NIPT Consortium (94%). The number of respondents who indicated that genetic counseling is necessary for NIPT increased over time. Furthermore, they highly valued genetic counseling provided by skilled clinicians, such as clinical geneticists or genetic counselors. The vast majority (90%) responded that there was sufficient opportunity to consider the test ahead of time. Meanwhile, women who received positive test results had a poor opinion and expressed a low-degree satisfaction. We confirmed that the pre-test genetic counseling that we conducted creates an opportunity for pregnant women to sufficiently consider prenatal testing, promotes its understanding and has possibilities to effectively facilitate informed decision making after adequate consideration. A more careful and thorough approach is considered to be necessary for women who received positive test results.