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To understand agreement between definitions of severe maternal morbidity (SMM), the reasons for disagreement and the impact the outcome definition may have on the measurement of ethnic and socioeconomic inequalities. A national cohort study using administrative data. The English National Health Service. Maternities leading to birth between 1st January 2013 and 31st March 2023 at a gestational age at birth of ≥ 20 weeks. The characteristics of maternities were described overall and according to SMM definition. Agreement and chance-adjusted agreement between definitions were calculated. Poisson regression was used to estimate relative risks (RRs) with 95% confidence intervals (95% CI) for SMM across ethnic and socioeconomic groups. SMM definitions were the USA's Centers for Disease Control and Prevention (CDC) without blood transfusion, the Canadian Perinatal Surveillance System (CPSS) definition, and the English Maternal Morbidity Outcome Indicator (EMMOI). There were 5 939 919 included maternities. Overall, SMM occurred in 1.4% (80 191/5 939 919), 2.7% (158 759/5 939 919) and 1.1% (67 745/5 939 919) of maternities according to the CDC, CPSS and EMMOI definitions, respectively. Chance-adjusted agreement was K = 0.67 for the CDC and EMMOI; 0.50 for the CPSS and EMMOI; and 0.52 for the CDC and CPSS, with 0.55 between all three definitions. Ethnic and socioeconomic inequalities varied by definition, with RR 1.96 (95% CI 1.90-2.01), 1.71 (1.67-1.74) and 1.98 (1.92-2.04) for the CDC, CPSS and EMMOI definitions, respectively, for Black women compared to White, and RR 1.37 (1.33-1.40), 1.18 (1.16-1.21) and 1.22 (1.19-1.26), respectively, for women living in most vs. least deprived areas. Among maternities with SMM, 55% (44 193/80 191), 41% (64 982/158 759) and 35% (23 905/67 745) had a diagnostic code for sepsis within the CDC, CPSS and EMMOI definitions, respectively. Sepsis was the only component of the SMM indicator for 51%, 44% and 33% of maternities within each of the definitions, respectively. Only 0.3%-0.6% of sepsis codes were associated with a code for shock. The same percentages for acute renal failure overall were 18% (14 159/80 191), 9% (14 842/158 759), and 22% (14 842/67 745), respectively, with acute renal failure representing the only component of the SMM indicator for 13%, 5% and 17%, respectively. Only 1.1%-1.2% of renal failure codes were associated with a procedural code for dialysis. The prevalence of SMM differed between national definitions and chance-adjusted agreement was only moderate. The majority of maternities defined as having SMM had only a single diagnostic code for either sepsis or acute renal failure. Only a small minority of maternities with a diagnosis of sepsis or acute renal failure had additional diagnoses or procedures indicative of life-threatening disease. Validation of the common diagnostic codes is needed to ensure that the measurement of SMM reliably captures and can inform the equitable prevention of severe complications.
To investigate and contrast the surgical effectiveness and oncological outcomes of total laparoscopic hysterectomy (TLH) versus total abdominal hysterectomy (TAH) in individuals diagnosed with endometrial cancer. Retrospective evaluation. Holy Cross Cancer Centre in Kielce, Poland. 1532 patients who underwent operative management over the period from 2002 to 2020. Survival outcomes were assessed using Kaplan-Meier analysis, and Cox proportional hazards models were applied to evaluate associations with recurrence-free survival (RFS) and overall survival (OS). Multivariable Cox models were adjusted for tumour stage, grade, histological subtype, lymphovascular space invasion, and lymphadenectomy-related variables. No adjustment for key confounders, including body mass index (BMI), comorbidity burden, adjuvant therapy, and year of surgery, was possible, which may introduce residual confounding and confounding by indication. Given the retrospective single-centre design and the extended study period, findings should be interpreted as associations rather than causal effects, as causal inference is inherently limited in this context. Comparative efficacy of TLH versus TAH in terms of surgical outcomes (operative time, blood loss, transfusion requirements, lymph node yield, hospital stay) and oncological outcomes (recurrence-free survival (RFS) and overall survival (OS)). TLH was associated with a significantly shorter mean operative time (121.16 ± 48.79 min vs. 159.26 ± 48.46 min; p < 0.001), lower intraoperative blood loss (median 200 mL in both groups, p = 0.016 indicating differences in distribution), reduced need for blood transfusion (0.6% vs. 5.5%; p = 0.003), more extensive lymphadenectomy (median 10 nodes vs. 6 nodes; p < 0.001) and shorter hospital stay (median 4 days vs. 7 days; p < 0.001). However, five-year overall survival (OS) and recurrence-free survival (RFS) were superior in the TAH group (p = 0.001 and p = 0.010, respectively). No statistically significant survival differences were observed between the two approaches in stage I disease (p > 0.05). These findings may be influenced by unmeasured confounding, selection bias, and temporal changes in clinical practice over the study period. TLH is associated with reduced surgical trauma and faster postoperative recovery, whereas differences in oncological outcomes between TLH and TAH should be interpreted with caution. No causal inference can be drawn due to the retrospective design, single-centre setting, and limited covariate adjustment, as residual confounding cannot be excluded. Surgical approach should be individualised based on patient risk profile, tumour characteristics and comorbidities.
Women with polycystic ovary syndrome (PCOS) exhibit a substantially increased risk of miscarriage, yet the underlying mechanisms remain inadequately understood. This study aimed to investigate whether specific gut microbial dysbiosis and metabolic disturbance are associated with and may potentially contribute to endometrial dysfunction and adverse pregnancy outcomes in women with PCOS. Prospective cohort study integrated with mechanistic experiments. Women's Hospital, School of Medicine, Zhejiang University, China (2022-2024). A total of 110 women with PCOS and 110 age- and body mass index-matched controls were enrolled. We performed 16S rRNA and metagenomic sequencing of gut microbiota, with untargeted and targeted serum metabolomics. Functional validation was conducted using primary human endometrial stromal cells and a PCOS rat model intervened with Parabacteroides merdae (P. merdae) supplementation or faecal microbiota transplantation. Gut microbiota composition, serum metabolites, endometrial senescence markers, and pregnancy outcomes. Women with PCOS exhibited significantly higher miscarriage rates than controls, accompanied by a marked depletion of P. merdae abundance and elevated serum levels of branched-chain amino acids, particularly isoleucine. Exogenous isoleucine induced cellular senescence in human endometrial stromal cells in a dose-dependent manner. Restoration of P. merdae levels in the PCOS rat model resulted in decreased serum isoleucine levels, amelioration of the senescent endometrial phenotype, and reduction in the fetal resorption rate. These findings suggest that P. merdae depletion and the concurrent accumulation of isoleucine may be associated with endometrial senescence and elevated risk of miscarriage, suggesting the possible involvement of a gut microbiota-metabolite pathway in PCOS-related reproductive dysfunction. These results also provide a mechanistic basis for future translational investigations.
Adverse maternal and perinatal outcomes such as preeclampsia, small-for-gestational age (SGA) and preterm birth remain major global health concerns. Beyond known high-risk placental features, emerging evidence suggests lateral placenta to be associated with impaired uteroplacental blood flow resulting in placenta dysfunction and adverse outcomes. A better understanding of these associations requires synthesizing both crude and adjusted effect estimates from available evidence. To comprehensively review and synthesize available evidence on the association between lateral placenta and adverse maternal and perinatal outcomes. MEDLINE (PubMed), EMBASE, Scopus and Cochrane CENTRAL were searched on 25th August, 2025. Studies that assessed the association between lateral placentation and adverse maternal and perinatal outcomes in singleton pregnancies. Data were independently extracted by two reviewers. The random-effects model was used to pool estimates of both crude and adjusted odds ratios (ORs) with corresponding 95% confidence interval (CI). Statistical heterogeneity was assessed by the I2 statistic and Cochran's Q test. Twenty one eligible studies with a total of 162 727 singleton pregnancies were included in the meta-analyses. Lateral placenta was associated with preeclampsia (OR = 1.65, 95% CI: 1.25, 2.19, I2 = 41.0%), SGA (OR = 1.40, 95% CI: 1.17, 1.68, I2 = 69.0%), preterm birth < 34 weeks (OR = 2.10, 95% CI: 1.62, 2.72, I2 = 0.0%), preterm birth < 37 weeks (OR = 1.50, 95% CI: 1.26, 1.80, I2 = 60.5%), retained placenta (OR = 2.52, 95% CI: 1.60, 3.95, I2 = 87.7%), and non-vertex foetal presentation at birth (OR = 1.50, 95% CI: 1.19, 1.89, I2 = 28.6%). Two individual studies reported independent association between lateral placenta and preeclampsia; with adjusted odds ratio (aOR) of 2.04 (95% CI: 1.28, 3.25) and 1.32 (95% CI: 1.04, 1.67). Pooled adjusted OR (95% CI) demonstrated increased odds of SGA (aOR = 1.84, 95% CI: 1.33, 2.53, I2 = 0.0%), and retained placenta (aOR = 4.43, 95% CI: 1.70, 11.53, I2 = 76.1%). Marginal increase in odds was noted for preterm birth < 34 weeks (aOR = 2.14, 95% CI: 1.34, 3.41, I2 = 0.00%) and preterm birth < 37 weeks (aOR = 1.54, 95% CI: 1.11, 2.13, I2 = 38.8%). Lateral placenta is associated with increased odds of preeclampsia, SGA, preterm birth, non-vertex foetal presentation, and retained placenta. After controlling for confounders, lateral placenta remained independently associated with increased odds of SGA, preterm birth, and retained placenta. More studies that adjust for confounders are, however, needed to further clarify and strengthen the evidence base of this independent association.
To compare Vaginal Hysterectomy (VH) with Vaginal Assisted Natural Orifice Transluminal Endoscopic Surgery (NOTES) hysterectomy (VANH) as a day-care procedure. Single-blind, multicentre randomised controlled trial. Two Dutch non-academic teaching hospitals. Women aged ≥ 18 years undergoing hysterectomy for benign indications. Women were randomised 1:2 (VH or VANH). Primary outcome was SDD. Secondary outcomes included operative time, rate of elective salpingectomies, intraoperative blood loss, complications (Clavien-Dindo), pain scores (NRS) and analgesic use, post-operative recovery (RI-10), and quality of life (EQ-5D-5L). Analyses were performed on an intention-to-treat basis. A total of 113 patients were included in the analyses (n = 42 VH, and n = 71 VANH). SDD occurred significantly more frequently in the VANH group (87.3%) than VH group (71.4%; OR 2.76, 95% CI 1.04-7.25; p = 0.04). VANH was associated with a significantly shorter operative time (median 55 min versus 65 min; p = 0.005), less blood loss (median 50 mL vs. 150 mL; p < 0.001) and more often elective opportunistic salpingectomy compared to VH (100% vs. 77.4%; p = 0.008). NRS were significantly lower in the VANH group the first hour post-operative (3 vs. 1, p < 0.001). Post-operative complications (VH 9.5% vs. VANH 15.5%; p = 0.34), readmission (VH 4.8% vs. VANH 8.5%; p = 0.47), analgesic use, recovery, and quality of life were not statistically significant. VANH is a safe and effective alternative to VH, offering a higher likelihood of SDD, shorter operative time, reduced blood loss, and more often an elective salpingectomy, without increased complications or differences in pain, recovery, or quality of life.
Pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality, with risk factors reported across a vast literature base fragmented between social and clinical factors. To develop a comprehensive conceptual framework of the strongest risk factors and their relationships contributing to pre-eclampsia incidence. Medline, Embase, Health Technology Assessments and Database of Abstracts of Reviews of Effects, Cochrane Library were searched. Reviews, randomized controlled trials and cohort studies (> 1000 participants), reporting social and clinical factors associated with pre-eclampsia were included. The strongest factors, defined as those with at least moderate strength of association and quality of evidence using GRADE, were compiled from our previously published individual frameworks to create a combined conceptual framework. Indirect associations were searched and the strongest indirect factors were added. The conceptual framework integrated 35 social and clinical determinants of pre-eclampsia. Key modifiable factors included BMI, interlinked with chronic hypertension/elevated blood pressure in early pregnancy, type 2 diabetes mellitus, and obstructive sleep apnoea, as well as antenatal care attendance, interconnected with maternal/work stress and prenatal micronutrient supplementation. Other modifiable factors included smoking, antiphospholipid syndrome, infection, exposure to occupational hazards, distance to health facility, maternal heat exposure in early gestation, and UV-B exposure. There are strong social factors alongside clinical factors associated with pre-eclampsia incidence. Interwoven relationships between factors highlight the multifactorial aetiology of pre-eclampsia. Many determinants were potentially modifiable, which provides actionable intervention points for clinical care and public health strategies.
To quantify the discrepancy between anatomical and motor levels in foetuses with open spinal dysraphism and identify prenatal factors associated with this difference. We also examined associations between anatomical level and ultrasound findings. Retrospective observational study. Single tertiary referral centre. A total of 187 foetuses diagnosed with open spinal dysraphism between 2011 and 2022. Anatomical level was defined as the highest non-closed vertebra on ultrasound. Motor level was determined through dynamic assessment of the most caudal active muscle group. The anatomical-motor level difference was calculated, and linear regression analyses were used to evaluate associated clinical and ultrasound variables, adjusting for anatomical level. Difference between anatomical and motor levels; association of ultrasound features with anatomical level. In 85.0% of foetuses, the motor level was more caudal than the anatomical level, with a median difference of two vertebral segments (range -3 to +15). Greater discrepancies were associated with myeloschisis compared to myelomeningocele (adjusted coefficient: 0.78, p < 0.001). Bilateral talipes and kyphosis were linked to smaller discrepancies. Higher anatomical levels were significantly associated with ventriculomegaly and vertebral anomalies. In foetuses with open spinal dysraphism, the motor level assessed by prenatal ultrasound is frequently more caudal than the anatomical level, with a discrepancy in over 80% of cases. The magnitude is influenced by lesion type and anatomical height, with myeloschisis and higher lesions showing greater differences. Additionally, anatomical level correlates with several ultrasound findings, including ventriculomegaly and vertebral anomalies.
To assess the internal consistency of the Hadlock normal range for estimated fetal weight (EFW) and its clinical implications. Methodological analysis and retrospective observational audit. Tertiary maternity hospital in Oxford, UK. Women with a non-anomalous singleton pregnancy. Reanalysis of the original Hadlock reference EFW chart using functional data analysis (FDA) and penalised functional regression (PFFR-GAM), and systematic bias assessment across gestation. Retrospective EFW centile analysis in a population of pregnancies undergoing a growth scan between 35 + 0 and 36 + 6 weeks, calculating the EFW centile using both the published reference chart (chart-derived centile) and the reported regression equation (equation-derived centile). Agreement between chart-derived and equation-derived centiles and the corresponding differences in classification of fetuses below the 3rd and 10th centiles. There is a statistically significant disparity between the chart-derived and equation-derived centiles, most pronounced in the 3rd and 10th centiles where clinical implications are critical. The 3rd and 10th chart-derived centiles approximately correspond to the 1st and 6th equation-derived centiles. Conversely, the equation-derived 10th centile corresponds to the chart-derived 17th centile. In a population of 21 874 pregnancies undergoing a growth scan between 35 + 0 and 36 + 6 weeks, the chart classified 4.2% as below the 10th centile, compared with 7.2% using the equation, with an absolute difference of 3.0% (95% CI 2.8%-3.3%; McNemar's test; p < 0.001). Also, the chart classified 0.8% under the 3rd centile, compared with 2.3% using the equation, with an absolute difference of 1.5% (95% CI 1.3%-1.7%; McNemar's test; p < 0.001). Systematic disparity exists between the published chart- and equation-derived centiles in the original Hadlock growth reference. The equation-derived centiles are closer to the expected nominal proportions of our population, whereas the chart-derived centiles significantly underestimate the incidence of small for gestational age.
To compare labour dynamics between nulliparous women with IVF/ICSI and spontaneous conception, and to assess the effect of epidural analgesia on the timing and incidence of vaginal birth using time-to-event methods. Matched retrospective cohort study. Tertiary referral centre, Bologna, Italy. A total of 124 IVF/ICSI and 248 maternal age-matched spontaneous conceptions undergoing induction of labour at ≥ 37 weeks between January 2019 and December 2023. Time-to-vaginal-delivery patterns were evaluated using smoothed instantaneous hazard (SIH) functions. Caesarean delivery was treated as a competing event, and subhazard ratios (sHR) were estimated using Fine-Grey regression. Analyses were stratified by epidural analgesia and adjusted for cervical dilation at induction, body mass index at term, and induction-related variables. Labour dynamics and cumulative incidence of vaginal delivery over time. Among 372 inductions, spontaneous conceptions had higher vaginal delivery rates than IVF/ICSI pregnancies (85.1% vs. 72.6%, p = 0.005) and shorter active labour (167 vs. 272 min, p < 0.001). SIH curves showed earlier and more sustained peaks with late-labour rebound in spontaneous conceptions, whereas IVF/ICSI pregnancies exhibited flatter, persistently lower hazards. IVF/ICSI conception was associated with a significantly lower cumulative incidence of vaginal birth (sHR 0.67, p < 0.001). Epidural analgesia delayed the timing but did not reduce the overall likelihood of vaginal delivery in spontaneous conceptions, while no significant effect was observed in IVF/ICSI pregnancies. Labour dynamics differ by mode of conception. IVF/ICSI pregnancies show reduced labour progression and earlier transition to caesarean delivery.
To investigate the association between postpartum haemorrhage (PPH) severity and the subsequent risk of premature ovarian failure (POF), with blood transfusion used as a marker of severe PPH: DESIGN: Nationwide population-based retrospective cohort study. Korean National Health Insurance Service (KNHIS) database. Women who delivered in Korea between 2015 and 2016. Women were followed from delivery until diagnosis of POF, attainment of 40 years of age, or 31 December 2021. PPH was identified using International Classification of Diseases, 10th Revision (ICD-10) codes. Red blood cell (RBC) transfusion during the delivery hospitalization was used as the primary indicator of PPH severity. POF was defined as ovarian failure before 40 years of age. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Incident premature ovarian failure. Among 745 125 women, 78 225 (10.5%) experienced PPH and 3552 (0.48%) developed POF during follow-up. When stratified by transfusion status, women with PPH requiring RBC transfusion had a markedly higher risk of POF (adjusted HR 2.058, 95% CI 1.668-2.539, p < 0.0001), whereas PPH without transfusion was associated with only a borderline association (adjusted HR 1.108, 95% CI 0.993-1.237, p = 0.066). A significant dose-response relationship was observed between RBC transfusion volume and POF risk, with adjusted HRs increasing progressively from 1.749 (95% CI 1.314-2.329) for 1 unit to 2.507 (95% CI 1.792-3.507) for 2-3 units and 2.894 (95% CI 1.439-5.820) for ≥ 4 units (p < 0.0001). Severe PPH requiring blood transfusion is associated with a substantially increased risk of premature ovarian failure in this nationwide population-based cohort. These findings support the importance of long-term endocrine surveillance and reproductive counselling for women who experience transfusion-requiring PPH.
To examine the physical, psychological, social, and functional impact of heavy menstrual bleeding (HMB) using a mixed-methods approach. Mixed-methods online survey. A UK-wide sample of adults assigned female at birth with lived experience of HMB. Participants were recruited between June and July 2024 via social media, menstrual-health charities and the Katie's Team and Co-Production Collective networks. Participants completed an online questionnaire comprising multiple-choice and open-ended items. Qualitative data were analysed inductively using thematic analysis and quantitative data were summarised descriptively. Findings were integrated to understand the multi-dimensional impact of HMB. Patient and public involvement informed survey development. Menstrual cycle characteristics; self-reported physical, psychological, social, and functional impacts of HMB. 105 participants were included. Most reported bleeding lasting ≥ 6 days and long-standing HMB beginning early in their reproductive lives. Severe or very severe impact was reported across physical health (83%), mental health (73%), social participation (83%), and sexual relationships (59%). Qualitative findings highlighted profound fatigue, symptoms consistent with anaemia, pain, cognitive difficulties, and night-time disruption. Participants described pervasive anxiety regarding leakage, altered career or study trajectories, and adverse effects on intimacy and relationships. Many structured daily routines around access to toilets and sanitary protection. Experiences of stigma and unmet healthcare needs were common. Among participants, HMB was associated with quality of life impairment across multiple domains, extending far beyond bleeding volume. These findings underscore the importance of holistic, patient-centred management, including timely investigation, appropriate medical therapy, and psychosocial support.
Menopause, marked by hormonal decline and menstrual cessation, is associated with various symptoms. Socio-demographic and behavioural factors may influence symptom type and severity. Understanding these associations can inform better symptom management. To identify factors associated with the presence and severity of menopausal symptoms through systematic review and meta-analysis. We searched Medline, Embase, CINAHL and Cochrane for studies on demographic, behavioural, or health factors linked to vasomotor, vaginal dryness and joint symptoms in women aged 40-60. Studies reporting odds ratios or raw numbers for symptom presence or severity were included. Studies were combined for meta-analysis, reporting odds ratios and 95% confidence intervals. Quality assessment was performed to quantify the risk of bias. Of 9228 screened articles, 61 were meta-analysed. Compared with White women, Black women had higher odds of vasomotor symptom presence (OR 1.65, 1.41-1.94) and severity (OR 1.91, 1.10-3.29), and vaginal dryness presence (OR 1.27, 1.10-1.47), while Asian had lower vasomotor symptom presence and severity (OR 0.40, 0.22-0.72; OR 0.55, 0.53-0.56). Higher education (OR 1.31, 1.09-1.56), high income (OR 1.41, 1.01-1.97) and depression (OR 2.36, 1.51-3.70) were associated with increased presence of vasomotor symptoms. Smoking and obesity were associated with both presence (OR 1.63, 1.30-2.04 and 1.35, 1.02-1.78) and severity (OR 1.56, 1.07-2.27 and 1.42, 1.11-1.83) of vasomotor symptoms. Socio-demographic and behavioural factors, including ethnicity, education, income, smoking, obesity and depression, influence menopausal symptoms, highlighting the need for personalised care. PROSPERO number: CRD42023459154.
To develop antenatal prediction models for shoulder dystocia and birth trauma using routinely collected maternal and sonographic variables. Retrospective cohort study. Single tertiary referral centre in the UK. All singleton term liveborn pregnancies delivered between January 2016 and November 2024 with a third-trimester ultrasound performed at or beyond 36 weeks' gestation. Multivariable logistic regression was used to develop antenatal prediction models for shoulder dystocia and birth trauma, incorporating maternal characteristics and fetal biometry including abdominal circumference (AC; centile or mm) and estimated fetal weight (EFW; grams or centile). Model performance was assessed using tests for multicollinearity, discrimination (area under the ROC curve, AUC) and calibration. Shoulder dystocia and birth trauma, the latter defined as a composite of shoulder dystocia, postpartum haemorrhage requiring blood transfusion, caesarean delivery at full dilatation, or hypoxic-ischaemic encephalopathy (HIE ≥ 1). A total of 24 334 singleton term pregnancies were included; 432 (1.8%) were complicated by shoulder dystocia and 1210 (5.0%) by birth trauma. The model including maternal characteristics and AC centile demonstrated the best discrimination. For shoulder dystocia, the apparent AUC was 0.706 (95% CI 0.682-0.730); the optimism-corrected AUC after bootstrap validation was 0.699. For birth trauma, the apparent AUC was 0.669 (95% CI 0.654-0.685); the optimism-corrected AUC was 0.665. At a 10% false-positive rate, sensitivity was 31.5% for shoulder dystocia and 22.8% for birth trauma, compared with 20.4% and 14.0%, respectively, using EFW ≥ 90th centile. Antenatal models combining fetal AC centile with maternal risk factors outperform EFW-based thresholds currently used in clinical practice. Although discrimination was modest, the model may be useful for antenatal risk stratification and counselling, rather than as a stand-alone clinical test. Such models may help identify pregnancies at increased risk of delivery-related complications associated with fetal overgrowth and inform future studies evaluating targeted interventions.
Menopausal hormone therapy (MHT) remains the most effective treatment for vasomotor symptoms (VMS) and other manifestations of menopause; however, its use is limited in women with contraindications to oestrogen. Progestogen monotherapy, though historically underutilized, represents a viable alternative in this population. This narrative review summarizes the indications, efficacy, and limitations of progestogen monotherapy as MHT. A structured literature search identified systematic reviews, guidelines, randomized controlled trials, and cohort studies evaluating progestogen monotherapy for menopausal symptom management, bone health, and oncologic safety. Evidence supports its use in patients with contraindications specific to oestrogen, including those with certain gynecologic malignancies (e.g., low-grade endometrial stromal sarcoma, select ovarian cancers), prior venous thromboembolism, coronary artery disease, compensated liver disease, and endometriosis. Contraindications to progestogen monotherapy are limited to unexplained abnormal vaginal bleeding and personal history of breast cancer, with caution utilised in patients with meningioma. Clinical data demonstrate that progestogens provide significant VMS relief, with efficacy observed across oral, intramuscular, and transdermal preparations. Micronized progesterone shows additional benefits for sleep quality, while synthetic progestins such as medroxyprogesterone acetate, megestrol acetate, and norethindrone acetate variably confer bone protection. Effects on mood appear neutral overall. Breast cancer risk associated with progestogen monotherapy remains uncertain due to limited and underpowered studies. Despite promising evidence, research is constrained by heterogeneous methodologies, small sample sizes, and lack of contemporary trials directly comparing progestogen monotherapy with standard MHT or nonhormonal alternatives. In conclusion, progestogen monotherapy is an effective, well-tolerated, and under-recognized therapeutic option for women with contraindications to oestrogen-containing MHT. Its optimal use may be tailored to clinical context: micronized progesterone for sleep disturbance, norethindrone acetate for bone health, or progestins with known antineoplastic properties in hormone-sensitive tumours. Larger, high-quality studies are needed to better define long-term safety and efficacy.
To evaluate whether the IOTA ADNEX model and the Two-Step Strategy improve triage and referral of adnexal masses in routine gynaecologic care compared with the RMI and to identify an appropriate malignancy-risk threshold. Prospective multicenter cohort study. Thirteen non-tertiary hospitals and clinics and one tertiary referral hospital in Denmark. A complete-case cohort of 966 patients with adnexal masses. Malignancy risk was estimated using prospectively collected clinical data, ultrasound findings, and CA125 levels. Reference standard was histopathology or ≥ 12 months of clinical follow-up. Performance was evaluated across predefined thresholds (1%-30% for ADNEX/Two-Step Strategy (modified benign descriptors + ADNEX); ≥ 200 for RMI), stratified by centre type. Negative and positive predictive values (NPV, PPV), sensitivity, referral rates to assess correct and incorrect referrals. In non-tertiary centres, NPVs were ≥ 96% for IOTA models versus 95% for RMI; corresponding values in the tertiary centre were 82%-100% versus 78%. PPVs increased with higher thresholds and approached RMI at 20% threshold. In non-tertiary centres, where referral decisions are made, a 15% threshold provided the most favourable balance between sensitivity (~63%) and referral rate (~14%). At thresholds ≥ 25%, referral rates were similar to RMI (~8%), with only marginal gains in sensitivity (~50% vs. 39%). Most additionally detected tumours were stage I ovarian cancers or borderline tumours. For masses classified as benign by modified benign descriptors, ADNEX showed high NPVs but low PPVs and negligible net benefit, providing limited additional diagnostic value over the Two-Step Strategy. IOTA-based models improve early detection but increase referral rates. A 15% risk threshold appears to offer a clinically reasonable balance between early detection of malignancy and referral burden, based on observed trade-offs between detection and referral rates. ClinicalTrials.gov identifier: NCT04188652.
Development and validation of two prediction models for obstetric anal sphincter injury (OASI). Population-based cohort study. Nationwide (the Netherlands). Data from the Netherlands Perinatal Registry, describing nulliparous women who delivered a singleton live born infant in cephalic presentation at term from 2016 to 2020, with spontaneous (SVD) or operative vaginal delivery (OVD). Based on literature and clinical expertise, a set of potential predictors was defined and derived from the national perinatal registry. A predictive model was constructed, and accessible nomograms provided. Internal and temporal external validation was performed. OASI rate. The risk of OASI in 171 046 women with SVD was 4.1%. After logistic regression with step-wise backward selection using Akaike Information Criterion (AIC), ten predictors were retained. These were: mediolateral episiotomy (MLE), expected fetal birth weight, duration of the 2nd stage, occipitoposterior presentation, induction of labour, epidural analgesia, Asian ethnicity, maternal age, gestational age and fetal sex. The final model had a moderate discriminative ability (AUC 0.67, 95% CI 0.67-0.68) and excellent calibration (Brier score 0.039). The average risk of OASI in 37 547 women with OVD was 3.5%. Seven predictors were retained in the model: MLE, expected fetal birth weight, duration 2nd stage of labour, occipitoposterior fetal presentation, epidural analgesia, Asian ethnicity and gestational age. The final model had moderate discrimination (AUC 0.68, 95% CI 0.67-0.70) and excellent calibration (Brier score 0.032). A prediction model for OASI was developed and validated for both nulliparous women with spontaneous vaginal delivery and with operative vaginal delivery. These models can form a basis to identify women with a high risk of OASI.
To investigate whether lithium exposure in pregnancy is associated with spontaneous preterm birth, congenital malformations and abnormal fetal growth. Statewide retrospective cohort study. Victoria, Australia. 867 454 births (2009-2020), including 234 (0.03%) exposed to lithium during pregnancy. Inverse probability weighted regression adjustment to investigate the association between maternal lithium use and perinatal outcomes. Spontaneous preterm birth (< 37 weeks' gestation), large for gestational age (LGA) (birthweight > 90th percentile), macrosomia (birthweight > 4000 g), major congenital malformations, congenital cardiac malformations. Lithium use was associated a two-fold increased risk of spontaneous preterm birth compared with unexposed pregnancies (8.1% vs. 2.4%; adjusted relative risk [aRR] 2.18, 95% CI 1.45-3.30). Lithium was associated with an increased risk of an LGA infant (13.7% vs. 6.4%; aRR 1.94, 95% CI 1.36-2.76), and congenital cardiac malformations (3.0% vs. 0.8%; aRR 2.64, 95% CI 1.26-5.53). Lithium was not associated with an altered risk of major congenital malformations overall (aRR 1.51, 95% CI 0.92-2.50). Restricting the cohort to women with bipolar disorder or schizophrenia diagnoses, associations remained between lithium exposure and spontaneous preterm birth (aRR 1.88, 95% CI 1.06-3.32) and birth of an LGA infant (aRR 1.68, 95% CI 1.07-2.65). In our study, lithium exposure during pregnancy was associated with a two-fold increased risk of spontaneous preterm birth. Lithium use was also associated with an increased risk of cardiac malformations and having an LGA infant. These findings may be useful for shared decision-making around lithium use during pregnancy.
To examine the association between urinary protein excretion (UPE) level in preeclampsia and long-term risk of maternal hypertension, chronic kidney disease (CKD), and cardiovascular disease (CVD). Nationwide, population-based cohort study utilising routinely collected individual-level data from medical databases. Denmark, 1998-2018, with follow-up through 2021. All pregnancies ≥ 20 weeks among women aged ≥ 15 years. We calculated cumulative incidences (risks) of hypertension, CKD, and CVD by preeclampsia status, including UPE level (no/mild versus moderate/severe, based on established urine protein/albumin cutoffs). Adjusted risk differences and risk ratios were computed for women with preeclampsia compared with those without, adjusting for age, smoking, obesity, residential region, and year. 10-year risk, adjusted risk difference, and risk ratio of hypertension, CKD and CVD by preeclampsia status and UPE level. Among 286 078 pregnant women, 9538 (3.3%) developed preeclampsia, which was associated with higher risks of later hypertension, CKD or CVD. Among women with preeclampsia with no/mild UPE, 10-year risks were 11.9% (95% CI: 10.9-13.0) for hypertension, 1.2% (95% CI: 0.9-1.6) for CKD and 1.1% (95% CI: 0.8-1.5) for CVD. With moderate/severe UPE, 10-year risks were 16.0% (95% CI: 14.6-17.5) for hypertension, 5.1% (95% CI: 4.3-5.9) for CKD and 1.2% (95% CI: 0.8-1.7) for CVD. For hypertension and CVD, adjusted risk differences and risk ratios were similar across UPE levels, whereas CKD risk increased with higher UPE. Preeclampsia is associated with increased long-term maternal risk of hypertension, CKD, and CVD. Higher UPE levels correlate with higher risk of later hypertension and CKD.
To quantify and compare the gestational age (GA)-specific risks of stillbirth across pre-pregnancy body mass index (BMI) categories, stratified by pre-pregnancy diabetes status: DESIGN: Retrospective population-based cohort study. United States from 2022 to 2023. Singleton live and stillbirths between 20 and 43 weeks' gestation. Data were obtained from the live birth and fetal death certificates available from the National Center for Health Statistics. We used Piecewise Additive Mixed Models to assess the GA-specific relationship between pre-pregnancy BMI and stillbirth in women with and without pre-pregnancy diabetes mellitus adjusted for confounders. Results were expressed as gestational age-specific adjusted hazard ratios (aHR), and weekly risk estimates from 37 to 40 weeks' gestation. Stillbirth. A total of 6 923 146 women were included of which 187 734 (2.7%) were underweight, 2 631 390 (38.0%) had normal BMI, 1 915 636 (27.7%) were overweight, and 1 169 109 (16.9%), 591 078 (8.5%), and 428 199 (6.1%) had obesity class I, II and III, respectively. Overall, stillbirth rates increased with increasing BMI and were higher in women with pre-pregnancy diabetes (16.6 per 1 000 total births) than those without these conditions (4.4 per 1 000 total births). The gestational age-specific associations between elevated BMI and stillbirth differed depending on the presence of pre-pregnancy diabetes across all gestational weeks. For example, at 31 weeks' gestation, the aHR for women with a BMI of 40 kg/m2 vs. 20 kg/m2 and diabetes was 0.68 (95% CI = 0.54 to 0.85), while the same aHR for a non-diabetic pregnancy was 1.22 (95% CI = 1.13, 1.33). Absolute risks were highest in diabetic women with class III obesity. Among obese women, the optimal gestational age for delivery depends on the presence of other risk factors such as pre-pregnancy diabetes.
To compare the efficacy, safety and tolerability of elagolix with dienogest in women with moderate-to-severe endometriosis-associated pain. A multicentre, double-blind, double-dummy, randomised, parallel-group, active-controlled, non-inferiority phase III study. Nineteen clinical centres across India. Women (18-49 years) diagnosed with endometriosis and experiencing moderate-to-severe pain. Participants were randomised (1:1) to receive oral elagolix (150 mg once daily) or dienogest (2 mg once daily) for 24 weeks. The primary outcome was change in endometriosis-related pain (Numeric Rating Scale [NRS]) from baseline to Day 85. Secondary outcomes included changes in NRS (Day 169), dysmenorrhoea, non-menstrual pelvic pain (NMPP) scores (Days 85 and 169), rescue medication use, patient global impression of change (PGIC), adverse events and bone mineral density. Of 340 patients screened, 230 were randomised (115 per group). At Day 85, both arms showed similar reductions in NRS pain scores with a treatment difference of 0.04 (95% CI: -0.3, 0.37) [p = 0.9747] demonstrating non-inferiority as upper 95% CI was below pre-specified margin of 1.5. At Day 169, both arms showed comparable improvements in overall pain, dysmenorrhoea and NMPP from baseline (p = 0.9372, p = 0.8884, and p = 0.9616, respectively). Rescue medication use and PGIC were comparable between treatment arms. Adverse event incidence was similar (elagolix: 14.8%; dienogest: 19.1%), with no serious TEAEs or discontinuations. No significant bone mineral density changes were observed. Elagolix demonstrated non-inferiority to dienogest with an acceptable safety and tolerability profile, supporting its use in managing endometriosis-associated pain. ClinicalTrials.gov identifier: CTRI/2023/01/049292.