Comprehensive Analysis of the Expression and Functions of Pattern Recognition Receptors in Differentiated Cytotrophoblasts Derived from Term Human Placentas.

Pregnant women are exposed to various microbes, some of which can harm the mother and/or fetus and can lead to life-long morbidity and even death. The syncytiotrophoblast (STB) covers the placental villi and comes into direct contact with pathogens contained in the maternal blood and plays a key role in placental host defense. However, the precise mechanisms whereby the STB recognizes and responds to pathogenic microbes remain unclear. In this study, we comprehensively analyzed the expression of functional pattern recognition receptors, which are responsible for tissue defense against pathogens, in a primary STB model differentiated from highly purified human term cytotrophoblasts (CTBs). Screening for mRNA expression and multiplex cytokine/chemokine production demonstrated that differentiated CTBs (dCTBs) predominantly expressed dsRNA receptors, including TLR3, MDA5, and RIG-I. We confirmed that term human placentas also expressed TLR3. Transcriptome analysis revealed common and unique responses of dCTBs to a synthetic dsRNA (polyinosinic-polycytidylic acid) compared with human peripheral mononuclear cells. Moreover, polyinosinic-polycytidylic acid induced the release of type I and type III IFNs (IFN-ß, IFN-λ1, IFN-λ2, IFN-λ3), as well as mRNA expression of IFN-stimulated genes (IFIT1, MX1, and OAS1). dCTBs underwent apoptosis via the mitochondrial pathway in response to dsRNA stimulation. These results suggest that dsRNA receptors expressed on the STB are key players in antiviral defense in the placenta. Elucidation of the underpinnings of these defense processes can help us better understand the pathophysiology of viral infections during pregnancy.

Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia.

BACKGROUND: Observational studies have shown that fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data from randomized trials are lacking. METHODS: In this open-label trial conducted at centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with severe isolated congenital diaphragmatic hernia on the left side to FETO at 27 to 29 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcome was infant survival to discharge from the neonatal intensive care unit. We used a group-sequential design with five prespecified interim analyses for superiority, with a maximum sample size of 116 women. RESULTS: The trial was stopped early for efficacy after the third interim analysis. In an intention-to-treat analysis that included 80 women, 40% of infants (16 of 40) in the FETO group survived to discharge, as compared with 15% (6 of 40) in the expectant care group (relative risk, 2.67; 95% confidence interval [CI], 1.22 to 6.11; two-sided P = 0.009). Survival to 6 months of age was identical to the survival to discharge (relative risk, 2.67; 95% CI, 1.22 to 6.11). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (47% vs. 11%; relative risk, 4.51; 95% CI, 1.83 to 11.9), as was the incidence of preterm birth (75% vs. 29%; relative risk, 2.59; 95% CI, 1.59 to 4.52). One neonatal death occurred after emergency delivery for placental laceration from fetoscopic balloon removal, and one neonatal death occurred because of failed balloon removal. In an analysis that included 11 additional participants with data that were available after the trial was stopped, survival to discharge was 36% among infants in the FETO group and 14% among those in the expectant care group (relative risk, 2.65; 95% CI, 1.21 to 6.09). CONCLUSIONS: In fetuses with isolated severe congenital diaphragmatic hernia on the left side, FETO performed at 27 to 29 weeks of gestation resulted in a significant benefit over expectant care with respect to survival to discharge, and this benefit was sustained to 6 months of age. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT01240057.).

Establishment of a measurement system to evaluate breast milk transfer of biological agents using dry filter paper: A multi-institutional study.

AIMS: Information on breastfeeding and safety of biologics in infants is lacking due to difficulties in case collection. We evaluated methods for determining the concentration of biologics in breast milk using a dry filter method that can simplify the collection, storage and transport of breast milk. METHODS: To generate dried filter paper (DFP) samples, approximately 30 µL of breast milk was placed onto a Whatman 903 card and punched out. After extraction, the supernatant was measured using an enzyme-linked immunosorbent assay. Three concentrations of each drug were prepared in liquid breast milk (LBM) and DFP samples to determine their stability up to 28 days after storage at 2-8°C or -20°C for LBM and 25 ± 5°C for DFP. LBM and DFP samples were also provided by nursing mothers using biologics during lactation, and drug concentrations in both samples were compared. The agreement between the two measurement methods was confirmed by Bland-Altman analysis. RESULTS: Breast milk was provided by 12 mothers who used biologics (tocilizumab, abatacept, etanercept, golimumab, sarilumab and belimumab). The coefficients of variation for within-run and between-run precision for the six drugs were within 15% for both LBM and DFP, and accuracy was within 90%-110% of the quality controls. After 28 days, concentrations remained at more than 90%. The difference between the values obtained by each method was within the acceptable range of error (-12.1 to +16.6 ng/mL). CONCLUSIONS: A method for determining the concentration of biologics using DFP is expected to help improve pharmacotherapy for lactating women.

National registry of thoracoamniotic shunting using a double-basket catheter: A post-marketing surveillance registry of 295 patients with fetal hydrothorax.

OBJECTIVE: We report on the 1-year outcomes of fetuses who underwent thoracoamniotic shunting (TAS) with a double-basket catheter for fetal hydrothorax (FHT) using a national post-marketing surveillance registry. METHODS: This surveillance study was conducted for cases enrolled between 2011 and 2019. Preoperative, operative, and postoperative findings and outcomes had to be reported through the national surveillance website. RESULTS: Forty-three institutes enrolled 295 patients. In 60 patients, associated abnormalities were diagnosed after birth. Among the 235 patients with isolated hydrothorax, the survival rate at 1 year of age was 70.5%. Among these patients, 89% did not require oxygen or other respiratory support. The 1-year survival rate in complicated cases was 27%. Trisomy 21 was the most common associated problem (40%). Catheter associated problems, including dislocation (25%), obstruction (24%), and preterm rupture of the membranes (6%) were observed, but there were no severe maternal complications. TAS before 29.5 weeks of gestation (odds ratio [OR] 0.16) and skin edema and ascites (OR 0.06) were risk factors for death at one year, whereas appropriate shunt location for >28 days (OR 4.2) was a protective factor. CONCLUSION: We report a favorable survival rate in fetuses with isolated FHT treated with this double-basket catheter.

Assessment of mediastinal shift angles in congenital pulmonary airway malformation: a new fetal magnetic resonance imaging indicator of congenital lung disease.

BACKGROUND: The mediastinal shift angle is a new fetal magnetic resonance imaging (MRI) index that is reportedly correlated with postnatal survival in fetuses with congenital diaphragmatic hernia. However, its correlation in patients with congenital pulmonary airway malformation (CPAM) has not been assessed. OBJECTIVE: This study aimed to establish a normal range for the right/left mediastinal shift angles, to evaluate the mediastinal shift angle in fetuses with CPAM, to compare the mediastinal shift angle with the CPAM volume ratio, and to evaluate the predictive value of the mediastinal shift angle measurements. MATERIALS AND METHODS: To establish the normal range, we measured the mediastinal shift angle bilaterally in 124 fetuses without any lung abnormality (the control group). Subsequently, the mediastinal shift angle was measured in 32 fetuses pathologically diagnosed with CPAM. Moreover, the mediastinal shift angle and CPAM volume ratio were compared using fetal MRI. RESULTS: The mean values for the right/left mediastinal shift angles were 18.6°/26.3° and 39.2°/35.9° for control fetuses and fetuses with CPAM, respectively. The mediastinal shift angle and the CPAM volume ratio showed a positive statistical correlation. The area under the curve demonstrated high discriminatory accuracy for the mediastinal shift angle (0.76). CONCLUSION: The mediastinal shift angle has potential to replace the CPAM volume ratio for evaluating the severity of CPAM in fetal MRI.

Investigation of optimal weight gain during pregnancy: A retrospective analysis of the Japanese perinatal registry database.

AIM: This study aimed to determine the weight gain during pregnancy that minimizes the predicted probability of various perinatal adverse events according to the pre-pregnancy body mass index (BMI) and make recommendations for optimal weight gain in Japan. METHODS: The Japan Society of Obstetrics and Gynecology perinatal database for 2015-2017 was used. From the 719 723 deliveries included in this database, parturients with underlying diseases or missing data were excluded, and 419 114 deliveries were analyzed. A questionnaire survey was also conducted to weigh each perinatal adverse event. For each of the nine outcomes, a restricted cubic spline model was made to estimate the association between the "expected gestational weight gain at 40 weeks" and the outcome risk. RESULTS: Since the classes of medical facilities were generally the same, weights were assigned according to the mean of the questionnaires rather than by the class of the facility. For each pre-pregnancy BMI, the weight gains during pregnancy that minimized the predicted probability of various adverse perinatal events were 12-15, 10-13, 7-10, and upper limit of 5 kg for the underweight, normal-weight, obese 1, and obese ≥2 groups, respectively. CONCLUSIONS: The weight gain during pregnancy that minimizes the predicted probability of various perinatal adverse events according to the pre-pregnancy BMI was established.

Predictive factors for vaginal delivery by induction of labor in uncomplicated pregnancies at 40-41 gestational weeks: A Japanese prospective single-center cohort study.

AIM: We investigated cervical parameters predictive of vaginal delivery in elective labor induction among women at 40-41 gestational weeks. METHODS: This Japanese prospective single-center cohort study was conducted between July 2019 and June 2020. We enrolled women with an uncomplicated singleton pregnancy who underwent labor induction at 40-41 gestational weeks. We analyzed background characteristics and cervical parameters, including Bishop score, cervical length, posterior cervical angle, and changes in cervical parameters before and after cervical dilatation. The endpoint was the rate of vaginal delivery. RESULTS: Of 142 eligible participants, all 24 multiparous women underwent vaginal delivery. Among the nulliparous women (n = 118), the following categories showed significantly higher rates of vaginal delivery: Bishop scores of ≥6 before and after dilatation, compared with Bishop score <6 (adjusted prevalence ratio (aPR) [95% confidence interval (CI)]; 1.58 [1.17-2.13] and 1.56 [1.13-2.14], respectively) and cervical length of <10 and 10-20 mm before dilation, compared with cervical length of >30 mm (aPR [95% CI]; 1.47 [1.00-2.15] and 2.13 [1.42-3.18], respectively). The posterior cervical angle and other background characteristics showed no significant associations. Furthermore, women with cervical lengths of ≥20 mm before and <20 mm after dilatation showed a higher rate of vaginal delivery, compared to cervical length of ≥20 mm even after dilatation (aPR [95% CI]; 1.95 [1.19-3.20]). CONCLUSIONS: High Bishop score, short cervical length, and changes in cervical length with dilatation are potential independent predictors of vaginal delivery following elective labor induction in nulliparous women at 40-41 gestational weeks.

Predictive factors for successful external cephalic version with regional anesthesia.

AIM: We aimed to investigate predictive factors of successful external cephalic version (ECV) using regional anesthesia. METHODS: In this retrospective study, we included women who underwent ECV at our center from 2010 to 2022. The procedure had been conducted using regional anesthesia and the administration of intravenous ritodrine hydrochloride. The primary outcome was the success of ECV, which was defined as the rotation from a non-cephalic to a cephalic presentation. Primary exposures were maternal demographic factors and ultrasound findings at ECV. To determine predictive factors, we conducted a logistic regression analysis. RESULTS: Of 622 pregnant women who underwent ECV, missing data on any variables (n = 14) were excluded and the remaining 608 were analyzed. The success rate during the study period was 76.3%. Multiparous women had significantly higher success rates than primiparous women (adjusted odds ratio [OR]: 2.06 [95% confidence interval (CI): 1.31-3.25]). Women with a maximum vertical pocket (MVP) of <4 cm had significantly lower success rates than those with 4 cm < MVP ≤6 cm (OR: 0.56 [95% CI: 0.37-0.86]). The non-anterior placental location was associated with higher success rates than the anterior placental location (OR: 1.46 [95% CI: 1.00-2.17]). CONCLUSIONS: Multiparity, MVP >4 cm, and non-anterior placental locations were associated with successful ECV. These three factors could be useful for patient selection for successful ECV.

Gestational glycosuria, proteinuria, and borderline hypertension in pregnancy are predictors for the later onset of maternal chronic disease.

AIM: Although hypertensive disorders of pregnancy and gestational diabetes mellitus (DM) are risk factors for hypertension, DM, and kidney disease in later life, the association of gestational glycosuria, proteinuria, and borderline hypertension with these chronic diseases has been unclear. METHODS: This cross-sectional study was conducted between April 2017 and November 2020 at a Japanese tertiary hospital. Three variables listed in the Maternal and Child Health Handbook were analyzed: glycosuria, proteinuria, and systolic blood pressure (<130, 130-139, and ≥ 140 mmHg) during pregnancy. The incidences of DM, kidney disease, and hypertension self-reported by mothers of pregnant women on a questionnaire were assessed with logistic regression analysis. RESULTS: The 312 women completed the questionnaires an average of 35.8 ± 4.2 years after delivering their daughters. Risk for DM was significantly increased among women with glycosuria (adjusted odds ratio [aOR], 3.62; 95% confidence interval [CI], 1.21-10.9), and risk for kidney disease was significantly increased among women with proteinuria (aOR, 4.07; 95% CI, 1.29-12.9). Risk for hypertension was significant in women whose blood pressures were ≥ 140 mmHg (aOR, 4.26; 95% CI, 1.96-9.24), but the association between blood pressures of 130-139 mmHg and hypertension was not significant (aOR, 1.72; 95% CI, 0.95-3.11); however, a significant positive trend (p < 0.001) between increasing blood pressure and hypertension was observed. CONCLUSIONS: Gestational glycosuria, proteinuria, and increased blood pressure were associated with the development of maternal chronic diseases. These standard and inexpensive assessments may improve lifelong health management in women.

Randomized trial of advice from healthcare professionals to eliminate constriction by maternal clothing on the trunk to prevent preterm birth and improve health status.

AIM: Women's clothing during pregnancy may influence perinatal outcomes. A preliminary study suggested that midwives' advice to avoid wearing tight clothing during pregnancy may reduce the risk of preterm delivery. We examined the effects of such advice to pregnant women on the risk of preterm birth and health status during pregnancy. METHODS: An open-label evaluator-blinded randomized controlled trial was conducted at the National Centre for Child Health and Development in Tokyo, Japan. Normal pregnant women were randomly assigned to receive constrictive clothing elimination care or standard care at 20 weeks gestation. The control group was issued leaflets concerning anemia prevention at entry and skin care at 30 weeks' gestation, along with a brief explanation and answers to questions by midwives as standard care. The intervention group received advice from midwives concerning avoiding constrictive clothing in addition to standard care. The primary outcome was the incidence of preterm birth (<37 weeks). The secondary outcomes were 12 indicators related to preterm delivery or health status. RESULTS: Among 624 randomly assigned women, 599 (intervention group, n = 306; control group, n = 293) completed the study between February 2015 and August 2016. The incidence of preterm birth in the intervention and control groups was 4.2% (13/306) and 5.1% (15/293), respectively (p = 0.614). There were no significant differences regarding any secondary outcomes, including obstetric outcomes and physical/mental indicators, during pregnancy. CONCLUSIONS: Advice from midwives to avoid constrictive clothing during pregnancy did not influence the incidence of preterm birth or maternal health status. TRIAL REGISTRATION: UMIN000016853 (March 30, 2015).

Clinical features of fetal hydrothorax associated with mucopolysaccharidosis-VII.

Mucopolysaccharidosis (MPS)-VII, called Sly disease, is a lysosomal storage disorder that can cause fetal hydrops, including fetal hydrothorax (FHT). We describe two fetal cases that received thoracoamniotic shunting for FHT, which was later found to be associated with MPS-VII by exome sequencing. Bilateral FHT accompanied by skin edema and ascites was found before 20 weeks of gestation in both cases. One fetus died in utero at 35 weeks of gestation, and the other survived with preterm delivery at 30 weeks of gestation. Both cases inherited compound pathogenic variants of GUSB from parents. Comparison with previously reported primary FHT cases revealed distinct clinical features in MPS-VII-associated FHT: early gestational age at diagnosis (<26 weeks), bilateral effusion, skin edema with ascites, and poor survival. A genetic analysis would be considered for FHT cases, with consideration of shunting when they show early-onset bilateral effusions with skin edema and ascites.

Clinical features of women with thrombotic microangiopathy in pregnancy: A case series from a single Japanese tertiary perinatal care center.

AIM: Although perinatal thrombotic microangiopathy has become increasingly understood, the racial characteristics of patients with this condition remain unclear. Herein, we report the characteristics of patients with perinatal thrombotic microangiopathy at a single institution in Japan. METHODS: We conducted a retrospective study over a 5-year period from January 1, 2017, to December 31, 2021, using the electronic medical records of pregnant women who delivered at the perinatal center of our hospital. We extracted the data of those who developed perinatal thrombotic microangiopathy and evaluated their characteristics at the time of disease onset, final diagnosis, and maternal and fetal outcomes. RESULTS: Of the 10 224 deliveries that occurred during the 5-year period, only seven patients (0.06%) had perinatal thrombotic microangiopathy. The median pre-pregnant body mass index was 18.65 kg/m2 (minimum 17.3 kg/m2 , maximum 20.7 kg/m2 ). More than half of the patients were conceived by in-vitro fertilization, and 42% these had twin deliveries. Four patients had a history of rheumatic disease. The other three patients without underlying diseases developed thrombotic microangiopathy with HELLP syndrome, and one patient transitioned to atypical hemolytic uremic syndrome. CONCLUSIONS: Based on low body mass index and in-vitro fertilization, which are characteristic of Japanese women, medical complications and twin pregnancies may be a risk for thrombotic microangiopathy. Additionally, depending on the cause of thrombotic microangiopathy, its timing and onset differed.

Association between fetal sex and pregnancy outcomes among women with twin pregnancies: a multicenter cross-sectional study.

PURPOSE: To examine the frequency and to what extent fetal sex is associated with pregnancy outcomes among twin pregnancies, stratified by chorionicity. METHODS: This registry-based multicenter cross-sectional study was conducted using the Japan Society of Obstetrics and Gynecology perinatal database between 2007 and 2016. The sample population was restricted to women with twin pregnancies. The main pregnancy-related outcomes included preterm birth, very preterm birth, extremely preterm birth, preeclampsia, twin-to-twin transfusion syndrome (TTTS), and selective intrauterine growth restriction (s-IUGR). Birth weight, small for gestational age (SGA), and fetal death were also investigated. RESULTS: The primary analysis was performed based on 37,953 women, including 23,804 women with dichorionic diamniotic (DD) twins and 14,149 women with monochorionic diamniotic (MD) twins. Women with male/male DD twins had a significantly higher risk of preterm birth (adjusted risk ratio [aRR]: 1.07, 95% confidence interval [CI]: 1.03-1.10) and a lower risk of preeclampsia (aRR: 0.74, 95% CI: 0.62-0.88) than women with female/female DD twins. Women with male/male MD twins also had a significantly higher risk of preterm birth (aRR: 1.06, 95% CI: 1.04-1.09) than women with female/female MD twins. Risks of preeclampsia, TTTS, and s-IUGR did not differ by sex among MD pregnancies. Male SGA risk was significantly higher among male/male twins than among male/female DD twins. Among MD twins, risks of SGA and fetal death were significantly higher in male/male fetuses. CONCLUSIONS: This study demonstrated significant associations between fetal sex and several pregnancy outcomes in twin pregnancies, some of which differed by chorionicity.

[ANTIMICROBIAL ALLERGY ASSESSMENT DURING PREGNANCY FOR APPROPRIATE ANTIMICROBIAL USE AT DELIVERY].

BACKGROUND: Avoidance of suspect drugs based solely on a history of drug allergy is detrimental to disease outcomes. Many antimicrobial allergy labels are not usually true allergy. Some studies have demonstrated that antimicrobial allergy assessments can be safely performed on pregnant women. The purpose of this study was to examine the usefulness of antibiotic allergy assessment during pregnancy in Japan. METHODS: We reviewed pregnant women who reported antimicrobial allergies and were referred to the allergy center. Allergists conducted an interview and skin test and selected antibiotics that could be used at delivery. RESULTS: Twenty-four pregnant women were referred to as having antimicrobial allergies. Most of the suspected antimicrobials were cephalosporin (13 cases, 52%) and penicillin (9 cases, 36%). Five women were ruled out only by our interviews. Of the remaining 20 cases, 10 were immediate type, 6 were non-immediate type, and 4 were unknown. All 21 pregnant women who needed antimicrobials were able to use the first-line drugs (ß-lactam antimicrobials) at the time of delivery. No surgical site infections or allergic reactions were observed. CONCLUSION: Pregnant women with antimicrobial allergy labels could be evaluated by antimicrobial allergy assessment during pregnancy, and first-line antimicrobials were safely and properly used at delivery.

Public attitudes in the clinical application of genome editing on human embryos in Japan: a cross-sectional survey across multiple stakeholders.

Recent advances in genome editing technology are accompanied by increasing public expectations on its potential clinical application, but there are still scientific, ethical, and social considerations that require resolution. In Japan, discussions pertaining to the clinical use of genome editing in human embryos are underway. However, understanding of the public's sentiment and attitude towards this technology is limited which is important to help guide the debate for prioritizing policies and regulatory necessities. Thus, we conducted a cross-sectional study and administered an online questionnaire across three stakeholder groups: the general public, patients and their families, and health care providers. We received responses from a total of 3,511 individuals, and the attitudes were summarized and compared among the stakeholders. Based on the distribution of responses, health care providers tended to be cautious and reluctant about the clinical use of genome editing, while patients and families appeared supportive and positive. The majority of the participants were against the use of genome editing for enhancement purposes. Participants expressed the view that clinical use may be acceptable when genome editing is the fundamental treatment, the risks are negligible, and the safety of the technology is demonstrated in human embryos. Our findings suggest differences in attitudes toward the clinical use of genome editing across stakeholder groups. Taking into account the diversity of the public's awareness and incorporating the opinion of the population is important. Further information dissemination and educational efforts are needed to support the formation of the public's opinion.

The randomized Tracheal Occlusion To Accelerate Lung growth (TOTAL)-trials on fetal surgery for congenital diaphragmatic hernia: reanalysis using pooled data.

BACKGROUND: Two randomized controlled trials compared the neonatal and infant outcomes after fetoscopic endoluminal tracheal occlusion with expectant prenatal management in fetuses with severe and moderate isolated congenital diaphragmatic hernia, respectively. Fetoscopic endoluminal tracheal occlusion was carried out at 27+0 to 29+6 weeks' gestation (referred to as "early") for severe and at 30+0 to 31+6 weeks ("late") for moderate hypoplasia. The reported absolute increase in the survival to discharge was 13% (95% confidence interval, -1 to 28; P=.059) and 25% (95% confidence interval, 6-46; P=.0091) for moderate and severe hypoplasia. OBJECTIVE: Data from the 2 trials were pooled to study the heterogeneity of the treatment effect by observed over expected lung-to-head ratio and explore the effect of gestational age at balloon insertion. STUDY DESIGN: Individual participant data from the 2 trials were reanalyzed. Women were assessed between 2008 and 2020 at 14 experienced fetoscopic endoluminal tracheal occlusion centers and were randomized in a 1:1 ratio to either expectant management or fetoscopic endoluminal tracheal occlusion. All received standardized postnatal management. The combined data involved 287 patients (196 with moderate hypoplasia and 91 with severe hypoplasia). The primary endpoint was survival to discharge from the neonatal intensive care unit. The secondary endpoints were survival to 6 months of age, survival to 6 months without oxygen supplementation, and gestational age at live birth. Penalized regression was used with the following covariates: intervention (fetoscopic endoluminal tracheal occlusion vs expectant), early balloon insertion (yes vs no), observed over expected lung-to-head ratio, liver herniation (yes vs no), and trial (severe vs moderate). The interaction between intervention and the observed over expected lung-to-head ratio was evaluated to study treatment effect heterogeneity. RESULTS: For survival to discharge, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion was 1.78 (95% confidence interval, 1.05-3.01; P=.031). The additional effect of early balloon insertion was highly uncertain (adjusted odds ratio, 1.53; 95% confidence interval, 0.60-3.91; P=.370). When combining these 2 effects, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion with early balloon insertion was 2.73 (95% confidence interval, 1.15-6.49). The results for survival to 6 months and survival to 6 months without oxygen dependence were comparable. The gestational age at delivery was on average 1.7 weeks earlier (95% confidence interval, 1.1-2.3) following fetoscopic endoluminal tracheal occlusion with late insertion and 3.2 weeks earlier (95% confidence interval, 2.3-4.1) following fetoscopic endoluminal tracheal occlusion with early insertion compared with expectant management. There was no evidence that the effect of fetoscopic endoluminal tracheal occlusion depended on the observed over expected lung-to-head ratio for any of the endpoints. CONCLUSION: This analysis suggests that fetoscopic endoluminal tracheal occlusion increases survival for both moderate and severe lung hypoplasia. The difference between the results for the Tracheal Occlusion To Accelerate Lung growth trials, when considered apart, may be because of the difference in the time point of balloon insertion. However, the effect of the time point of balloon insertion could not be robustly assessed because of a small sample size and the confounding effect of disease severity. Fetoscopic endoluminal tracheal occlusion with early balloon insertion in particular strongly increases the risk for preterm delivery.

Association Between Birth Weight and Risk of Pregnancy-Induced Hypertension and Gestational Diabetes in Japanese Women: JPHC-NEXT Study.

BACKGROUND: Although prevalence of low birth weight has increased in the last 3 decades in Japan, no studies in Japanese women have investigated whether birth weight is associated with the risk of pregnancy complications, such as pregnancy-induced hypertension (PIH) and gestational diabetes mellitus (GDM). METHODS: We used data from the Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT), a population-based cohort study in Japan that launched in 2011. In the main analysis, we included 46,365 women who had been pregnant at least once, for whom information on birth weight and events during their pregnancy was obtained using a self-administered questionnaire. Women were divided into five categories according to their birth weight, and the relationship between birth weight and risk of PIH and GDM was examined using multilevel logistic regression analyses with place of residence as a random effect. RESULTS: Compared to women born with birth weight of 3,000-3,999 grams, the risk of PIH was significantly higher among women born <1,500 grams (adjusted odd ratio [aOR] 1.60; 95% confidence interval [CI], 1.17-2.21), 1,500-2,499 grams (aOR 1.16; 95% CI, 1.03-1.30), and 2,500-2,999 grams (aOR 1.13; 95% CI, 1.04-1.22). The risk of GDM was significantly higher among women born 1,500-2,499 grams (aOR 1.20; 95% CI, 1.02-1.42), albeit non-significant association among women in other birthweight categories. CONCLUSIONS: We observed an increased risk of PIH among women born with lower birth weight albeit non-significant increased risk of GDM among Japanese women.

A pregnant woman with thymoma-associated pure red cell aplasia.

BACKGROUND: Pure red cell aplasia (PRCA) is a hematological disorder characterized by anemia with severe reticulocytopenia caused by a marked reduction in erythroid precursors in the bone marrow. PRCA is known to be associated with pregnancy, but thymoma-associated PRCA during pregnancy is very rare, and its successful management has not been reported. CASE PRESENTATION: A 37-year-old primiparous woman with severe anemia was referred to our center at 27 weeks' gestation. She was diagnosed with PRCA based on bone aspiration findings at 33 weeks' gestation. Magnetic resonance imaging (MRI) revealed an anterior mediastinal mass 4 cm in size suspected of being thymoma. She was therefore diagnosed with thymoma-associated PRCA during pregnancy. Surgery for thymoma was planned after delivery, since the imaging findings were suggestive of early-stage thymoma (Masaoka stage I or II). With transfusion of a total 3,360 ml of red blood cells (RBCs) during pregnancy, the patient gave birth to a baby girl weighing 2,548 g at 40 weeks' gestation. The baby showed transient congenital cutaneous candidiasis. The placental pathology revealed subamniotic inflammation with a fungal structure. Treatment with topical anti-fungal cream immediately ameliorated the baby's skin lesion. Maternal anemia did not improve after delivery; however, the thymoma did not increase in size. At five months after delivery, the mother underwent thymectomy with oral cyclosporine A. A pathological examination revealed Masaoka stage II-a thymoma. She completely had recovered from anemia at six months after surgery. Cyclosporine A treatment was discontinued three years after surgery. Remission has been sustained for four years since surgery. CONCLUSIONS: A very rare case of thymoma-associated PRCA during pregnancy was diagnosed without any subjective symptoms and was expectantly managed, resulting in a good prognosis. Although bone marrow aspiration during pregnancy is an invasive test, it is important to confirm the diagnosis. Conservative management with blood transfusion was possible for early-stage thymoma-associated PRCA during pregnancy. Active surveys, including MRI, for PRCA during pregnancy led to the detection of thymoma at an early stage and the achievement of a preferable pregnancy outcome.

Diazoxide during pregnancy and lactation: drug levels in maternal serum, cord blood, breast milk, and infant serum: a case report.

Safety information on diazoxide for pregnant and lactating women with hypoglycemia is limited. In this case report, we assessed diazoxide concentrations in maternal and infant blood, cord blood, and breast milk. We described a 30-year-old pregnant woman diagnosed with hypoglycemia due to nesidioblastosis at 4 months of age. Before becoming pregnant, she was treated with oral diazoxide (75-375 mg). All medications were discontinued after she was discovered to be pregnant. During gestational week 25, diazoxide treatment was resumed at 150-175 mg daily for repeated hypoglycemic episodes. Diazoxide administration was continued in combination with diet treatment until delivery. Glucose levels were well controlled. During gestational week 40, a male infant weighing 3069 g was delivered via spontaneous vaginal delivery with no pregnancy or neonatal complications. Diazoxide concentrations detected in maternal serum at 2.5-11.6 h after oral treatment ranged from 12.4 to 32.7 µg/mL. In cord blood, the diazoxide concentration was 18.5 µg/mL at 7.2 h after the last dose. During lactation, no hypoglycemia or hyperglycemia was observed. The approximate calculated ratio of diazoxide in breast milk and maternal serum was 0.09. The calculated daily infant dose was 0.47 mg/kg/day. The relative infant dose via breast milk ranged from 3.1% to 5.9%. Diazoxide transferred from maternal blood to the fetus across the placenta. It also transferred into breast milk, but there were no harmful effects on the infant.

Pravastatin concentrations in maternal serum, umbilical cord serum, breast milk and neonatal serum during pregnancy and lactation: A case study.

WHAT IS KNOWN AND OBJECTIVE: Statins are associated with improved pregnancy outcomes in patients with preeclamptic antiphospholipid syndrome (APS) and intrauterine foetal death. Several studies showed that statins are not teratogenic. However, data characterizing placental transfer and excretion of pravastatin into breast milk are limited. CASE SUMMARY: We experienced two patients diagnosed with APS received 10 mg of pravastatin from the first trimester until delivery to prevent pre-eclampsia. Pravastatin concentrations in maternal serum, infant serum and cord blood were evaluated. The estimated maternal-foetal transfer ratios of pravastatin in the two patients were 25.5% and 23.8% respectively. Pravastatin was eliminated from neonatal serum within 2 days. Both infants developed normally with no drug-related adverse effects. Pravastatin was not detected in either patient's breast milk at 3 days after the last dose. WHAT IS NEW AND CONCLUSION: The infants delivered from the mothers who were treated with pravastatin during pregnancy had no apparent adverse effects.