Akihide Ohkuchi

Objectives: To identify potential risk factors – among maternal factors, pre‐eclampsia (PE)‐specific biomarkers and estimated risks derived from the first‐trimester Fetal Medicine Foundation (FMF) triple test – that are associated with the subsequent development of preterm PE, and to evaluate predictors of any‐onset PE using time‐to‐event analysis, in high‐risk women receiving low‐dose aspirin prophylaxis. Methods: This was a secondary analysis of a multicenter stepped‐wedge cluster randomized trial, including 18 maternity/diagnostic units from 10 regions in Asia between August 2019 and February 2022. The study population comprised women with a singleton pregnancy identified as being at high risk for preterm PE (estimated risk ≥ 1:100) according to the first‐trimester FMF triple test, who subsequently received low‐dose aspirin prophylaxis. A locally estimated scatterplot smoothing (LOESS) curve was applied initially to explore the relationship between the incidence of preterm PE and the estimated risk. Based on the trend observed in the LOESS curve, participants were categorized into five estimated risk groups: 1:2 to 1:5, 1:6 to 1:10, 1:11 to 1:20, 1:21 to 1:50 and 1:51 to 1:100. Logistic and Cox regression analyses were performed to identify independent predictors of preterm PE and to evaluate the risk of delivery with PE, respectively. Results: Among 2919 high‐risk pregnant women receiving aspirin prophylaxis, 280 (9.6%) developed PE, including 107 (3.7%) who developed preterm PE. Chronic hypertension (adjusted odds ratio (aOR), 1.835 (95% CI, 1.070–3.146)), mean arterial pressure (MAP) multiples of the median (MoM) > 1.149 (aOR, 2.162 (95% CI, 1.434–3.261)) and higher estimated risk were associated with higher odds of preterm PE. Compared to women with an estimated risk of 1:51 to 1:100, those with estimated risks of 1:2 to 1:5, 1:6 to 1:10 and 1:11 to 1:20 had a 16‐fold (aOR, 15.845 (95% CI, 8.166–30.746)), eight‐fold (aOR, 7.674 (95% CI, 3.925–15.004)) and three‐fold (aOR, 3.454 (95% CI, 1.802–6.622)) higher odds of developing preterm PE, respectively, whereas no significant difference was observed in those with an estimated risk of 1:21 to 1:50 (aOR, 1.343 (95% CI, 0.722–2.499)). On Cox regression analysis, chronic hypertension was associated with a three‐fold higher risk of delivering with PE (adjusted hazard ratio (aHR), 2.979 (95% CI, 2.154–4.120)), while MAP MoM > 1.149 increased the risk by 66% (aHR, 1.659 (95% CI, 1.304–2.111)). Compared with the reference group (estimated risk of 1:51 to 1:100), the risk of delivering with PE increased progressively across estimated risk groups, with aHRs of 1.435 (95% CI, 1.051–1.959), 2.408 (95% CI, 1.653–3.508), 4.058 (95% CI, 2.658–6.197) and 7.053 (95% CI, 4.588–10.841) for the 1:21 to 1:50, 1:11 to 1:20, 1:6 to 1:10, and 1:2 to 1:5 estimated risk groups, respectively. Conclusions: Chronic hypertension, elevated MAP and higher estimated risk are associated with the earlier development of PE in women identified as high risk by the first‐trimester FMF triple test, despite low‐dose aspirin prophylaxis. Incorporating these factors into the risk stratification framework may improve the detection of residual risk in first‐trimester screening and prevention strategies, thereby supporting the development of more effective preventive measures. © 2026 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Aim: To clarify the clinical characteristics, diagnostic course, and presumed etiologies of severe cerebral palsy associated with perinatal cerebral infarction, and to compare cases in which cerebral infarction was diagnosed during and after the neonatal period. Methods: This retrospective registry‐based study used data from the Japan Obstetric Compensation System for Cerebral Palsy between 2009 and 2022. Severe cerebral palsy cases associated with cerebral infarction were identified. The clinical characteristics and diagnostic courses of cerebral infarction were evaluated and compared between neonatally diagnosed cases and post‐neonatally diagnosed cases. Results: Of the 85 cases of cerebral infarction analyzed, neonatally diagnosed cases accounted for 40 (47.1%) and post‐neonatally diagnosed cases for 44 (51.8%); 1 case was diagnosed prenatally. Neonatal diagnosis was more frequently triggered by seizures, apnea, respiratory distress, or neuroimaging during NICU hospitalization, whereas most post‐neonatal diagnoses followed recognition of motor impairment. Neonatally diagnosed cases more frequently exhibited a non‐reassuring fetal status, lower umbilical artery pH, lower Apgar scores, and neonatal asphyxia. However, no significant differences were observed in median age at the recognition of motor impairment (7 months in both groups) or severe brain injury findings between neonatally and post‐neonatally diagnosed cases. Potential contributing conditions were identified in 15.3% of cases. Conclusions: Similar timing of motor impairment recognition and frequency of severe brain injury findings between the two groups may suggest that differences in cerebral infarction diagnostic timing may primarily reflect different clinical triggers for neuroimaging. The etiology and timing of infarction onset remained unclear in many cases.

Atypical superimposed preeclampsia (sPE) developing before 20 weeks of gestation is extremely rare, and its pathophysiology remains unclear. We herein report three women with underlying chronic hypertension or IgA nephropathy who developed severe hypertension, worsening proteinuria, and fetal growth restriction or fetal death before 20 weeks of gestation. All cases showed markedly elevated soluble fms‐like tyrosine kinase‐1/placental growth factor (sFlt‐1/PlGF) ratios (617–1357), and placental pathology demonstrated maternal vascular malperfusion. Maternal clinical manifestations promptly improved after the termination of pregnancy. All three women subsequently achieved successful pregnancies with appropriate management. These results suggest that atypical sPE shares the angiogenic imbalance and placental pathology characteristic of conventional preeclampsia. Although limited by the small number of cases, these results provide additional insights into the pathophysiology of atypical sPE and suggest a role for angiogenic biomarkers in evaluating placental dysfunction.

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.

Small extracellular vesicles (small EVs) play pivotal roles in intercellular communication and pregnancy maintenance, but their clinical significance in preeclampsia (PE) remains unclear. We obtained plasma samples from non-pregnant women, healthy pregnant women, and patients with early-onset (EoPE) and late-onset PE (LoPE). Small EVs were isolated using ultracentrifugation and validated using transmission electron microscopy and nanoparticle tracking analysis; in addition, Western blotting was performed to identify suitable surface markers for plasma-derived small EVs. In our analysis, we consistently detected cluster of differentiation 9 (CD9), whereas classical markers such as cluster of differentiation 63 (CD63) and tumor susceptibility gene 101 (TSG101) were absent. In a prospective, nested case–control study, we analyzed first-trimester samples by using a CD9-based ELISA for small-EV quantification. The number of small EVs did not significantly differ between non-pregnant and healthy pregnant women regardless of the gestational age. However, EVs were significantly elevated in both EoPE (3.5-fold) and LoPE (1.5-fold) compared with matched controls. First-trimester EV levels did not show differences between women who later developed PE and normal controls. These findings indicate that CD9 is a promising marker for plasma-derived small EVs and that an elevated number of small EVs is associated with established PE but has limited predictive value in early pregnancy. Further studies are required to elucidate the cellular origin and clinical implications of small EVs in PE.

We aimed to investigate the effects of serum sFlt-1/PlGF ratio levels in women with suspected or confirmed early-onset preeclampsia and super-imposed preeclampsia (PE/SPE) on composite and individual adverse maternal and fetal outcomes, stratified by gestational age at blood sampling (<34, 34–36, and ≥37 weeks). We also evaluated whether serum sFlt-1/PlGF ratio levels influenced the time interval from blood sampling to delivery. This prospective cohort study assessed serum levels of sFlt-1, PlGF, and the sFlt-1/PlGF ratio in women with suspected or confirmed PE/SPE admitted to a tertiary maternal-fetal-neonatal center between 2012 and 2023. Finally, 241 women were analyzed. An elevated sFlt-1/PlGF ratio at <34 weeks of gestation, but not at 34–36 or ≥37 weeks, was significantly associated with composite adverse maternal and fetal outcomes in women with suspected or confirmed PE/SPE. An sFlt-1/PlGF ratio of 400 was identified as the optimal cut-off level for predicting composite adverse maternal and fetal outcomes at <34 weeks. Among women with suspected or confirmed early-onset PE/SPE, HELLP syndrome alone was significantly associated with an sFlt-1/PlGF ratio ≥400. Additionally, the sFlt-1/PlGF ratio was significantly higher in women with HELLP syndrome, abnormal umbilical artery Doppler findings, or non-reassuring fetal status (NRFS) requiring immediate delivery, compared with those without these conditions. Furthermore, the interval from blood sampling to delivery significantly shortened with increasing sFlt-1/PlGF ratio. In conclusion, elevated sFlt-1/PlGF ratios were significantly associated with HELLP syndrome, abnormal umbilical artery Doppler findings, and NRFS requiring immediate delivery in women with suspected or confirmed early-onset PE/SPE. The sFlt-1/PlGF ratio at <34 weeks of gestation, but not at 34–36 or ≥37 weeks, was associated with composite adverse maternal and fetal outcomes in women with suspected or confirmed preeclampsia and super-imposed preeclampsia (PE/SPE). In women with suspected or confirmed early-onset PE/SPE, the sFlt-1/PlGF ratio was significantly higher not only in those with HELLP syndrome, but also in those with abnormal umbilical artery Doppler findings and non-reassuring fetal status (NRFS) requiring immediate delivery. Among women with suspected or confirmed early-onset PE/SPE, time to delivery from blood sampling decreased with increasing sFlt-1/PlGF ratio

Aim: To describe how decreased fetal movement (DFM) was managed in patients with fetomaternal hemorrhage (FMH) and to evaluate the diagnostic limitations of this condition in real‐world settings. Methods: This retrospective cohort study included individuals who developed FMH with cerebral palsy from the Japanese nationwide cerebral palsy registry between 2009 and 2022. We investigated whether patients experienced DFM or were prenatally diagnosed with FMH. Furthermore, we assessed how DFM was managed. Results: This study included 57 patients who developed FMH with cerebral palsy, and none were prenatally diagnosed with FMH. DFM was present in 43/57 (75.4%) patients. A sinusoidal pattern was observed in 29/57 (50.9%) patients, and elevated middle cerebral artery peak systolic velocity (MCA‐PSV) was detected in 6/10 (60.0%) patients who underwent this test. Of the 43 patients with DFM, 42 (97.7%) sought medical care for this symptom; however, only 12 (27.9%) underwent examinations on the same day as the onset of DFM, and 9 (20.9%) were admitted on that same day. Furthermore, 6/43 (14.0%) were instructed to stay home after telephone consultation or medical examination for this symptom. In five of the 43 patients (11.6%) who experienced DFM, the initial non‐stress test was reactive. However, all these patients eventually developed either a non‐reactive or non‐reassuring fetal status. Conclusions: DFM was prevalent among pregnancies complicated by FMH; however, it was often inadequately managed, resulting in diagnostic delays. Furthermore, fetal heart rate monitoring and MCA‐PSV evaluations had diagnostic limitations. To facilitate early treatment, clinicians need to promptly assess preceding DFM while recognizing the limitations of existing tests.

Background: Small extracellular vesicles (small EVs) play pivotal roles in intercellular communication and pregnancy maintenance. Their clinical significance in preeclampsia (PE) remains unclear. Methods: Plasma samples were obtained from non-pregnant women, healthy pregnant women, and patients with early-onset (EoPE) and late-onset PE (LoPE). Small EVs were isolated by ultracentrifugation and validated using transmission electron microscopy and nanoparticle tracking analysis. Western blotting was performed to identify suitable surface markers for plasma-derived small EVs. The quantification was conducted using a cluster of differentiation 9 (CD9)-based ELISA. A prospective nested case-control study analyzed >1,400 first-trimester samples. Results: CD9 was consistently detected in plasma-derived small EVs, whereas classical markers such as cluster of differentiation 63 (CD63) and tumor susceptibility gene 101 (TSG101) were absent. the number of small EVs did not significantly differ between non-pregnant and healthy pregnant women regardless of the gestational age. However, EVs were significantly elevated in both EoPE (3.5-fold) and LoPE (1.5-fold) compared with matched controls. First-trimester EV levels did not show the difference between women who later developed PE and normal controls. Conclusions: CD9 is a promising marker for plasma-derived small EVs. Elevated numbers of small EVs are associated with established PE but show limited predictive value in early pregnancy. Further studies are required to elucidate the cellular origin and clinical implications of small EVs in PE.

Aim: Currently, the medical term "preterm preeclampsia (PE)" is not included in the Japan Society of the Study of Hypertension in Pregnancy (JSSHP) classification of hypertensive disorders of pregnancy.Methods: We searched PubMed for studies using the term "preterm PE" on October 1, 2024, with the following combination of keywords: "preterm preeclampsia" OR "preterm pre-eclampsia."Results: A total of 479 articles were identified. The term "preterm PE" first appeared in 1994. From 2011 to 2023, the number of studies using the term "preterm PE" gradually increased, reaching 62 in 2023. The studies using the term "preterm PE" involved prediction of preterm PE (i.e., preterm-delivery PE). Current studies predicting preterm PE focus on competing risks models using maternal factors, biophysical markers, and biomarkers in the first trimester, and an established competing risks model for predicting preterm PE is available on the website of the Fetal Medicine Foundation (FMF). However, the term "preterm PE" has been used with different meanings (preterm-onset vs. preterm-delivery PE).Conclusions: Both definitions of preterm PE have merits and demerits. Therefore, not only preterm-delivery PE but also preterm-onset PE should be evaluated simultaneously as primary outcomes when predicting preterm PE.

Aim: We reviewed case reports of acute fatty liver of pregnancy (AFLP) in Japan and summarized its characteristics, including coagulation factors, fibrinolytic factors, and platelet counts.Methods: PubMed/Medline and Ichushi databases from 2000 to 2022 were used to survey articles related to AFLP, and 93 articles (102 patients) were ultimately identified.Results: The characteristics of the coagulation and fibrinolysis systems in AFLP were as follows: the prothrombin time‐international normalized ratio and activated partial prothrombin time were prolonged (median value [quartiles]: 1.59 [1.31, 2.02] and 47.5 s [28.2, 97.5], respectively), and antithrombin and alpha 2‐antiplasmin levels were low (23.0% [17.0, 33.0] and 44.6%, respectively), indicating non‐productive coagulopathy due to severe liver damage. The concentrations of the thrombin‐antithrombin complex and fibrinogen/fibrin degradation products were high (60.0 ng/mL [49.1, 82.8] and 49.2 μg/mL [20.8, 143.7], respectively), while the level of fibrinogen was low (82.0 mg/dL [52.5, 153.5]), suggesting disseminated intravascular coagulation with increased coagulation activity. A platelet count ≥12 × 10⁴/μL was detected in approximately 70% of AFLP cases, and the median was within the normal range (16.1 × 10⁴/μL [11.1, 19.2]).Conclusions: Coagulopathy changes in AFLP may be based on non‐productive coagulopathy of coagulation and fibrinolytic factors as well as disseminated intravascular coagulation with mild or no thrombocytopenia.