Satoru Takeda

BACKGROUND: In preeclampsia, prolonging pregnancy decreases the risks of fetal morbidity and death. This study aimed to evaluate the efficacy and safety of antithrombin in prolonging pregnancy early-onset severe preeclampsia. METHODS: This was a randomized, double-blind, placebo-controlled study involving women with early-onset preeclampsia from 61 institutions. Participants developed early-onset severe preeclampsia from 24+0 to 31+6 weeks’ gestation and had ≤100% antithrombin activity. Two groups were created, with random and blinded assignment of the participants 1:1 to a placebo (saline) group (n=92) or a recombinant human antithrombin-gamma (rhAT-gamma) group (n=90). The number of days from treatment initiation to delivery was recorded in each group, as the primary end point. RESULTS: Pregnancy was prolonged by 13 days (95% CI, 10.4–15.6) in the placebo group and 16.9 days (95% CI, 13.8–20.0) in the rhAT-gamma group ( P =0.07). Compared with the placebo group, hemorrhage-related adverse events occurred at a 19.0% higher rate in the rhAT-gamma group (mean difference [95% CI, 4.3%–32.7%]), and anemia occurred at a 16.8% higher rate (mean difference [95% CI, 2.0%–30.6%]). CONCLUSIONS: No significant difference in pregnancy prolongation was found between the placebo and rhAT-gamma participants with early-onset severe preeclampsia. However, compared with the placebo group, the rhAT-gamma group appeared to have higher rates of hemorrhage-related adverse events and anemia. REGISTRATION: URL: https://jrct.niph.go.jp/en-top ; Unique identifier: jRCT2080224912. URL: https://clinicaltrials.gov/ ; Unique identifier: NCT04182373.

Background: Both depression and emesis (nausea and vomiting) are commonly seen during pregnancy. The two often coexist but their symptomatic structure and causal relationships remain unclear. Aim: To identify a clinical cluster with depression and emesis together among pregnant women. Methods: Using two independent follow-up data (Study 1 with women of 10 to 13 weeks of gestation [N = initially 382 and follow-up 129] and Study 2 with women of 12 to 15 weeks of gestation [N = initially 696 and follow-up 245]) sets of pregnant women, we measured depressed mood, loss of interest and three emesis symptoms (nausea, vomiting, and retching). The samples were re-examined with an interval. Results: The 5 symptoms were substantially correlated with each other at each time point and factor analyses identified two factors reflecting depression and emesis. However, depression and emesis were associated with clinical correlates in a very similar manner. Two-step cluster analysis yielded only two clusters: one with and another without depression and emesis simultaneously. Taxometrics indicated dimensionality rather than taxonicity. Conclusion: Findings suggest that emesis and depression during pregnancy are two discrete aspects of a single clinical phenomenon that we propose to name emesis-depression complex.

Background: Fetal growth restriction is associated with perinatal morbidity and mortality. Early identification of women having at-risk fetuses can reduce perinatal adverse outcomes. Objectives: To assess the predictive performance of existing models predicting fetal growth restriction and birthweight, and if needed, to develop and validate new multivariable models using individual participant data. Design: Individual participant data meta-analyses of cohorts in International Prediction of Pregnancy Complications network, decision curve analysis and health economics analysis. Participants: Pregnant women at booking. External validation of existing models (9 cohorts, 441,415 pregnancies); International Prediction of Pregnancy Complications model development and validation (4 cohorts, 237,228 pregnancies). Predictors: Maternal clinical characteristics, biochemical and ultrasound markers. Primary outcomes: fetal growth restriction defined as birthweight c-statistic, calibration slope, calibration-in-the-large) for each model and pooled using random-effects meta-analysis. Heterogeneity was quantified using τ² and 95% prediction intervals. We assessed the clinical utility of the fetal growth restriction model using decision curve analysis, and health economics analysis based on National Institute for Health and Care Excellence 2008 model. Results: Of the 119 published models, one birthweight model (Poon) could be validated. None reported fetal growth restriction using our definition. Across all cohorts, the Poon model had good summary calibration slope of 0.93 (95% confidence interval 0.90 to 0.96) with slight overfitting, and underpredicted birthweight by 90.4 g on average (95% confidence interval 37.9 g to 142.9 g). The newly developed International Prediction of Pregnancy Complications-fetal growth restriction model included maternal age, height, parity, smoking status, ethnicity, and any history of hypertension, pre-eclampsia, previous stillbirth or small for gestational age baby and gestational age at delivery. This allowed predictions conditional on a range of assumed gestational ages at delivery. The pooled apparent c-statistic and calibration were 0.96 (95% confidence interval 0.51 to 1.0), and 0.95 (95% confidence interval 0.67 to 1.23), respectively. The model showed positive net benefit for predicted probability thresholds between 1% and 90%. In addition to the predictors in the International Prediction of Pregnancy Complications-fetal growth restriction model, the International Prediction of Pregnancy Complications-birthweight model included maternal weight, history of diabetes and mode of conception. Average calibration slope across cohorts in the internal-external cross-validation was 1.00 (95% confidence interval 0.78 to 1.23) with no evidence of overfitting. Birthweight was underestimated by 9.7 g on average (95% confidence interval −154.3 g to 173.8 g). Limitations: We could not externally validate most of the published models due to variations in the definitions of outcomes. Internal-external cross-validation of our International Prediction of Pregnancy Complications-fetal growth restriction model was limited by the paucity of events in the included cohorts. The economic evaluation using the published National Institute for Health and Care Excellence 2008 model may not reflect current practice, and full economic evaluation was not possible due to paucity of data. Future work: International Prediction of Pregnancy Complications models’ performance needs to be assessed in routine practice, and their impact on decision-making and clinical outcomes needs evaluation. Conclusion: The International Prediction of Pregnancy Complications-fetal growth restriction and International Prediction of Pregnancy Complications-birthweight models accurately predict fetal growth restriction and birthweight for various assumed gestational ages at delivery. These can be used to stratify the risk status at booking, plan monitoring and management. Study registration: This study is registered as PROSPERO CRD42019135045. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/148/07) and is published in full in Health Technology Assessment; Vol. 28, No. 14. See the NIHR Funding and Awards website for further award information.

Nuclear factor of activated T cells 5 (NFAT5) and cyclooxygenase 2 (COX2; PTGS2) both participate in diverse pathologies including cancer progression. However, the biological role of the NFAT5-COX2 signaling pathway in human endometrial cancer has remained elusive. The present study explored whether NFAT5 is expressed in endometrial tumors and if NFAT5 participates in cancer progression. To gain insights into the underlying mechanisms, NFAT5 protein abundance in endometrial cancer tissue was visualized by immunohistochemistry and endometrial cancer cells (Ishikawa and HEC1a) were transfected with NFAT5 or with an empty plasmid. As a result, NFAT5 expression is more abundant in high-grade than in low-grade endometrial cancer tissue. RNA sequencing analysis of NFAT5 overexpression in Ishikawa cells upregulated 37 genes and downregulated 20 genes. Genes affected included cyclooxygenase 2 and hypoxia inducible factor 1α (HIF1A). NFAT5 transfection and/or treatment with HIF-1α stabilizer exerted a strong stimulating effect on HIF-1α promoter activity as well as COX2 expression level and prostaglandin E2 receptor (PGE2) levels. Our findings suggest that activation of NFAT5—HIF-1α—COX2 axis could promote endometrial cancer progression.

Tokophobia is regarded as the intensive fear of childbirth that some pregnant women have. However, little is known about the psychopathological details of tokophobia (fear of childbirth). Between 2020 and 2021, a total of 10 pregnant women (nine nulliparae and one multipara) with a strong fear of childbirth were referred by obstetricians. Semi-structured psychopathological interviews were conducted, and two cases were judged to have obsession, three an overvalued idea, and one secondary delusion. Three were characterised by both obsession and overvalued idea and one by both obsession and secondary delusion. In total, six cases had features of an overvalued idea. All of the participants except one had a lifetime history of a specific phobia. In addition, their history included social phobia in two cases, panic disorder in one case, obsessive–compulsive disorder (other than tokophobia) in two cases, depressive disorder in two cases, bipolar disorder in two cases, and PTSD in six cases. To conclude, this study showed that tokophobia was not a phobic disorder but a kind of overvalued idea that requires specific assessment and treatment.

Aims: To determine the association between drinking habits and social factors among women undergoing assisted reproductive technology (ART) treatment in Japan. Methods: The study participants who provided answers for the questionnaire concerning alcohol consumption were 1017 female patients undergoing ART treatment were enrolled in the Japan-Female Employment and Mental Health in assisted reproductive technology (J-FEMA) study between August and December 2018. Patient characteristics, including demographic, clinical, and socioeconomic status, were assessed using a self-administered questionnaire which was distributed only once during the period, regardless of their first or follow-up examination. We defined current drinkers who drank ≥46 g of ethanol per week as the habitual drinking group. The risk factors for habitual drinking were analyzed using multivariable-adjusted logistic regression. Results: The proportion of habitual drinkers was 15.5% in this study population. The multivariable-adjusted odds ratios (95% confidence interval) for habitual drinking were 2.27 (0.99–5.21) for women aged ≥35 years versus those <35 years, 4.26 (1.98–9.16) for women having partners who currently drink compared to those with partners without current drinking, 1.84 (1.08–3.12) for women without a history of childbirth versus those with, and 1.77 (1.00–3.14) for working women compared with those not working. Conclusions: In our study, habitual drinking among women undergoing ART treatment was significantly associated with older age, no history of childbirth, partner’s current drinking status, and working.

The shoulder width (width of the parascapular cross-section) is the greatest among various body widths and thus, it may complicate the passage of the fetus through the pelvis. The shoulder width is at its greatest when the arms are elevated in the breech presentation. It is important to understand three principles to deform or reduce the shoulder width, deliver a trapped shoulder, or align the shoulder axis with the wider diameter of the pelvis.: (1) elevation or descent of the unilateral shoulder joint (avoiding simultaneous entry of both shoulders into the pelvis); (2) internal rotation of the shoulder joint (reduction of the shoulder width and contact of the forearm with the chest wall); and (3) matching the shoulder axis to the pelvic oblique diameter or transverse diameter. In cases of shoulder dystocia, (1) the anterior shoulder is first guided into the pelvis to prevent the simultaneous entry of both shoulders (suprapubic pressure), however, advancement of the posterior (opposite) shoulder, is also possible (Schwartz method). (2) Pushing the shoulder forward (internal rotation of the shoulder joint: [Rubin method, Woods corkscrew method]) reduces the shoulder width. Internal rotation of the shoulder is induced by a forward-pushing maneuver from the fetal back. (3) As the oblique and transverse diameters are greater than the anteroposterior diameter in the plane of the pelvic inlet, the fetus should be guided for the shoulder axis to match the oblique or transverse diameter, rather than the anteroposterior diameter (Woods corkscrew method, reverse corkscrew method). The classical method of freeing the shoulders and arms in the breech presentation is performed as follows: (2) the posterior shoulder is first pushed forward and downward from the fetal back (internal rotation of the shoulder joint), with the fetal forearm closely contacting the chest wall. Then, (1) the shoulder is extracted downward by pulling the elbow joint of the posterior shoulder to deliver the arm. (3) The shoulder axis should match the oblique diameter. Freeing the arm leads to the advancement of the posterior shoulder, because this maneuver is performed while the fetal trunk is pulled upward. Freeing the shoulder and arm should always be performed from the fetal back with the same-side hand. In cases of arm elevation or a nuchal arm, internal rotation of the shoulder joint is particularly important. The upper arm and forearm should be made to descend in such a manner that they contact the face and head.

Background: A negative response towards a current pregnancy consists of two elements: unwantedness of and unhappiness about the current pregnancy. Little is clear about whether pregnant women can be categorized in terms of unwantedness and unhappiness as well as what the correlates are of these categories. Methods: An internet survey of 696 women in their first trimester of pregnancy examined the participants’ intention of and emotional reaction towards pregnancy, borderline personality traits, adult attachment style, depression, fear of childbirth, obsessive-compulsive symptoms, fetal bonding disorder, avoidance of taking part in child care, and consideration about termination of pregnancy (TOP). About one third of the participants were followed up with in their second trimester. Results: Two-step cluster analysis using the participants’ intention of and emotional reaction towards pregnancy revealed three groups of pregnant women: those who wanted and were happy about the pregnancy (Cluster 1), those who were unhappy about the pregnancy (Cluster 2), and those who did not intend to be pregnant but were happy about pregnancy (Cluster 3). Cluster 2 women, but not Cluster 3 women, were likely to be single, with borderline personality traits as well as unstable adult attachment styles, accompanied by depression, fear of childbirth, obsessive-compulsive symptoms, and fetal bonding disorder. They were more likely to avoid caring for the baby after childbirth and consider TOP. Conclusion: Expectant women who were unhappy about their pregnancy were at risk of psychological adjustment and need specific perinatal mental health assessment and care.

Intense fear of childbirth by expectant women is called tokophobia. Because there are no qualitative studies targeting women with an intense fear of childbirth in Japan, it is unknown whether there is any link between the type of fear of objects/situations among tokophobic women and their psychological/demographic background. Furthermore, there is no available summary of the lived experience of Japanese women with tokophobia. This study aims to identify the intensity patterns of various types of fear among the participants and summarize the lived experience of having intense fear of childbirth. A qualitative descriptive study was conducted using a semi-structured interview. Pregnant women with an intense fear of childbirth participated in individual interviews facilitated by a psychiatrist and a midwife. Audio recordings of the interviews were transcribed and analyzed using a content analysis approach. The number of participants was ten. The types of feared objects varied individually and these were categorized as being related to either prospective or retrospective fear. The participants’ experiences were grouped into three categories: difficulty in daily life, preoccupied negative expectation towards childbirth, and psychological adaptation to the upcoming childbirth. The results imply that women with tokophobia continuously suffer from fear in their daily life; hence, a special approach is needed to detect and reduce their fear.

Little is known about the causality of antenatal depression (AND). We focused on the causal relationships between AND, fear of childbirth (FOC), and obsessive-compulsive symptoms (OCS) during the COVID-19 pandemic in Japan. We also examined whether the perceived threat of COVID-19 is associated with AND. Participants were recruited for an Internet survey conducted in December 2020. A total of 245 pregnant women completed the online survey at 12 to 15 weeks’ gestational age (Time 1) and approximately 10 weeks later (Time 2). AND was estimated using the first two diagnostic items of Major Depressive Episode. The estimated prevalence of AND was 4.5% and 2.9% at Time 1 and Time 2, respectively. At both time points, no association was found between AND and the perception of COVID-19 threat. Structural equation modeling showed that AND predicted OCS (β = 0.16, p < 0.001), which, in turn, predicted FOC (β = 0.09, p = 0.042); FOC, in turn, predicted AND (β = 0.23, p < 0.001). AND, OCS, and FOC were predicted by borderline personality traits. Insecure adult attachment influenced AND and FOC via the perceived negative impact of the current pregnancy. Perinatal care providers should assess the personality and perception of pregnancy to prevent depression and pay attention to symptoms such as FOC and OCS in addition to those of depression.