Mayumi Sugiura-Ogasawara

Problem: There is a paucity of studies on the incidence and predictors of thrombotic antiphospholipid syndrome (APS) after pregnancy in patients with recurrent pregnancy loss (RPL) and antiphospholipid antibodies (aPL). This prospective study aimed to assess the long‐term prognosis, including the occurrence of thrombosis and associated risk factors, in patients with aPL‐positive RPL and related obstetric APS manifestations. Method of Study: We examined patients with RPL and related obstetric APS manifestations who were positive for lupus anticoagulant (LA) based on APTT, Russell's viper venom time (RVVT), or β2glycoprotein I‐dependent anticardiolipin antibody (β2GPIaCL) IgG and visited Nagoya City University Hospital from 1994 to 2019. A survey was conducted in 2024 in which patients were asked to complete a questionnaire on the development of APS manifestations based on the American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria. Results: Data of 259 of 285 patients (90.5%) who responded to the questionnaire were analysed. The median follows‐up duration was 17 (4.6–31.1) years. Cumulatively, 9.6% (25/259) of patients with aPLs and 15.7% (18/114) of those with obstetric APS experienced thrombotic APS. LA‐APTT, LA‐RVVT, and β2GPIaCL IgG were independent predictors of thrombotic APS, with area under the curve values of 0.85 (0.73–0.97), 0.93 (0.87–0.99), and 0.80 (0.68–0.93), respectively. A history of intrauterine foetal death, early‐onset preeclampsia, no live birth, thrombosis and complications of systematic lupus erythematosus, and persistent aPL were predictive of thrombotic APS. Conclusion: Patients with RPL and aPL who exhibit the identified risk factors should undergo subsequent follow‐up after pregnancy. Further research is required to investigate the potential for thrombosis prevention.

Introduction Perinatal depression poses substantial risks to both mothers and their offspring. Given its chronic and recurrent nature, developing effective prevention strategies is crucial. Internet-based cognitive–behavioural therapy (iCBT) has shown promise. However, the efficacy of specific CBT skills and the influence of individual differences remain unclear. Methods and analysis This protocol describes two harmonised multicentre, open-label, six-arm randomised controlled trials. Across both trials, a total of 2400 pregnant women between 10 and 20 weeks of gestation will be enrolled. After completing psychoeducation (PE), participants will be randomised to either the control condition (PE only) or one of five CBT programmes: behavioural activation (BA), assertion training, BA+cognitive restructuring, BA + problem solving or BA + behaviour therapy for insomnia. The objectives of the study are: (1) to ascertain that the iCBT approach is effective in perinatal depression, (2) to identify active CBT skills for perinatal women and (3) to examine interactions between these CBT skills and individuals’ baseline characteristics to find personalised and optimised therapy for individual women. The primary outcome is the point prevalence of depression at 1 month postpartum, defined as scoring of 9 or higher on the Edinburgh Postnatal Depression Scale. Ethics and dissemination The study has been approved by the Kyoto University Graduate School of Medicine Ethics Committee (C1710) and Nagoya City University Certified Review Board (2024A007). Anonymised study results will be presented at conferences and published by the investigators in peer-reviewed journals. Trial registration number jRCTs042240162 (hospital-based, on-site trial) and jRCT1050250074 (nationwide online trial).

Purpose: No biomarkers specific to true unexplained recurrent pregnancy loss (RPL) have yet been identified. This study aimed to investigate the lipid profile of patients with unexplained RPL using metabolomic analyses. Methods: Comprehensive serum metabolomic profiling was performed using liquid chromatography–tandem mass spectrometry. Lipid metabolites were analyzed using orthogonal partial least squares discriminant analysis. Results: The final analysis included serum samples from 31 healthy non‐pregnant controls, 15 healthy pregnant controls, 32 non‐pregnant patients with RPL, 19 pregnant patients with RPL and euploid miscarriage, and 30 pregnant patients with RPL and aneuploid miscarriage. Compared with controls, the non‐pregnant RPL group exhibited higher levels of inflammation‐related metabolites, including 11‐dehydro‐thromboxane B2 (11‐dehydro‐TXB2), 12‐hydroxyeicosatetraenoic acid (HETE), and prostaglandin E2 (PGE2). Pregnant controls showed increased arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid metabolites. Comparisons between pregnant controls and patients with euploid or aneuploid miscarriages showed no clear separation. Enzyme‐linked immunosorbent assay confirmed elevated serum 11‐dehydro‐TXB2 in non‐pregnant patients with RPL. Conclusion: Patients with RPL display a distinct serum lipid signature in the non‐pregnant state, characterized by elevated levels of pro‐thrombotic and pro‐inflammatory eicosanoids, including 11‐dehydro‐TXB2, 12‐HETE, and PGE2. Further studies are warranted to clarify the potential utility of 11‐dehydro‐TXB2 as biomarkers for RPL.

Objective: International criteria for antiphospholipid syndrome (APS) include lupus anticoagulant (LA), anticardiolipin (aCL) IgG and IgM, and anti–β2‐glycoprotein I (β2GPI) IgG and IgM. However, evidence supporting their prognostic value or treatment efficacy in improving live birth rates is limited. The Lancet series on miscarriage recommends testing only for LA and aCL, excluding β2GPI. We aimed to examine whether commercially available antiphospholipid antibody (aPL)‐related tests have a prognostic value for obstetric APS. Methods: This prospective cohort study enrolled 1,237 pregnant women between July 2021 and March 2024. Women using heparin, including those with an obstetric APS diagnosis before pregnancy, were excluded. Pregnancy outcomes were followed until December 2024. The aPL‐related tests comprised LA (diluted activated partial prothrombin time and diluted Russell's viper venom time [LA‐RVVT]), aCL IgG, IgM, anti‐β2GPI IgG, IgM, anti β2GPI domain I IgG, phosphatidylserine‐dependent antiprothrombin IgG, IgM, protein S, and coagulation factor XII activity. Results: The prevalence rates of early‐onset preeclampsia, intrauterine fetal death (IUFD), and small for gestational age were 1.4% (17), 0.7% (9), and 0.9% (11), respectively. Logistic regression analysis revealed that LA‐RVVT and anti‐β2GPI IgG were each predictor of early‐onset preeclampsia and IUFD. The area under the curve for these conditions increased to about 0.8 when combined with a history of preeclampsia or IUFD, respectively. Conclusion: LA‐RVVT, anti‐β2GPI IgG, complications including hypertension, and a history of IUFD were valuable in identifying obstetric APS. The variation in test results across facilities limits the ability to establish consistent prognostic or treatment value for each aPL.

Aim: The aim was to explore the preventive effects of smartphone cognitive behavioral therapy (CBT) in addressing depression and anxiety in patients with recurrent pregnancy loss (RPL) due to lack of such previous studies. Methods: This was an exploratory decentralized, parallel‐group, multicenter, open, individually randomized, fully factorial trial. A total of 432 patients with RPL were randomized and patients who completed the psychoeducation component of the app within 2 weeks of consent were included. Five CBT components—namely, self‐monitoring, behavioral activation, cognitive restructuring, assertion training, and problem solving—were randomly assigned as present or absent, resulting in 2 ⁵ = 32 combinations. The primary outcomes were changes in Patient Health Questionnaire‐9 and Generalized Anxiety Disorder‐7 scores at weeks 8 and 12 from baseline. Results: A total of 419 patients were analyzed. The presence or absence of specific CBT components did not significantly affect patient outcomes. However, patients experienced a statistically significant overall reduction in depressive symptoms from baseline to weeks 8 and 12. Pre–post effect sizes for overall improvement ranged from −0.30 to −0.38 at week 8 and from −0.22 to −0.33 at week 12. No significant overall reduction in anxiety symptoms was observed. Conclusion: The CBT application significantly reduced depressive symptoms in patients with RPL; however, no specific CBT component showed superior effects. The findings did not indicate efficacy in comparison to the pure treatment‐as‐usual group. Further research is required to enhance its impact on anxiety and refine the selection and delivery of individual CBT components.

STUDY QUESTION: Can antinuclear antibodies (ANA) affect the subsequent live birth rate (LBR) in patients with unexplained recurrent pregnancy loss (RPL) in the absence of antiphospholipid antibodies (aPL)? SUMMARY ANSWER: Women with unexplained RPL have a high probability of live birth following a positive pregnancy test (>70%), being similar between those with positive and negative ANA testing, regardless of the cut-off value. WHAT IS KNOWN ALREADY: The RPL guidelines of the ESHRE state that ‘ANA testing can be considered for explanatory purposes’. However, there have been a limited number of studies on this issue and sample sizes have been small, and the impact of ANA on the pregnancy prognosis is unclear. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study was conducted at Nagoya City University Hospital between 2006 and 2019. The study included 1021 women with RPL without known cause. PARTICIPANTS/MATERIALS, SETTING, METHODS: Hysterosalpingography or 3D-ultrasound, chromosome analysis for both partners, blood tests for aPL, ANA, hypothyroidism, and diabetes mellitus were performed before a subsequent pregnancy. ANAs were measured by indirect immunofluorescence on Hep-2 cell slides. The cutoff dilution used was 1:40. In addition, patients were classified according to the ANA pattern on immunofluorescence staining: homogeneous, speckled, nucleolar, centromeric, peripheral, cytoplasmic, and others. LBRs were compared between ANA-positive and ANA-negative patients after excluding patients with antiphospholipid antibody syndrome, an abnormal chromosome in either partner and a uterine anomaly. MAIN RESULTS AND THE ROLE OF CHANCE: Considering the cut-off value = 1:40 dilution, the subsequent LBRs were 72.5% (256/353) for the ANA-positive group and 73.2% (489/668) for the ANA-negative group; odds ratio (OR) = 0.97, 95% CI = 0.72–1.29. After excluding the miscarriages occurring from embryonic aneuploidy, the biochemical pregnancy losses, and the ectopic pregnancies, LBRs were 92.8% (256/276) for the ANA-positive group and 93.0% (489/526) for the ANA-negative group: OR = 0.97 (95% CI = 0.55–1.70). Considering the cut-off value = 1:80 dilution, the subsequent LBRs were 75.0% (87/116) for the ANA-positive group and 72.7% (658/905) for the ANA-negative group; OR = 1.13 (95% CI = 0.72–1.76). After excluding the miscarriages occurring from embryonic aneuploidy, the biochemical pregnancy losses, and the ectopic pregnancies, LBRs were 89.7% (87/97) for the ANA-positive group and 93.3% (658/705) for the ANA-negative group: OR = 0.62 (95% CI = 0.30–1.27). Considering the cut-off value = 1:160 dilution, the subsequent LBRs were 82.4% (28/34) for the ANA-positive group and 72.6% (717/987) for the ANA-negative group; OR = 1.76 (95% CI = 0.72–4.29). After excluding the miscarriages occurring from embryonic aneuploidy, the biochemical pregnancy losses, and the ectopic pregnancies, LBR were 93.3% (28/30) for the ANA-positive group and 92.9% (717/772) for the ANA-negative group: OR = 1.07 (95% CI = 0.25–4.63). There was no difference in LBR between the 2 groups before or after adjustment for age and BMI, but ANA-positive patients were significantly older than ANA-negative patients when using the 1:40 dilution, and ANA-positive patients had significantly lower BMIs than ANA-negative patients when using the 1:80 dilution. LIMITATIONS, REASONS FOR CAUTION: A healthy control group was not established, making it impossible to compare ANA positivity rates between healthy controls and RPL patients. There were significant differences in age (1:40 dilution) and BMI (1:160 dilution) between the ANA-positive and ANA-negative groups. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that ANA testing is not useful to predict future pregnancy loss in women with RPL without known cause. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by MEXT Promotion of Distinctive Joint Research Center Program, Grant Number JPMXP0621467963 and used for English proofreading costs. There are no competing interests for all authors. TRIAL REGISTRATION NUMBER: N/A.