Continued versus discontinued oxytocin stimulation in the active phase of labour (CONDISOX): individual management based on artificial intelligence - a secondary analysis.

BACKGROUND: Current guidelines regarding oxytocin stimulation are not tailored to individuals as they are based on randomised controlled trials. The objective of the study was to develop an artificial intelligence (AI) model for individual prediction of the risk of caesarean delivery (CD) in women with a cervical dilatation of 6 cm after oxytocin stimulation for induced labour. The model included not only variables known when labour induction was initiated but also variables describing the course of the labour induction. METHODS: Secondary analysis of data from the CONDISOX randomised controlled trial of discontinued vs. continued oxytocin infusion in the active phase of induced labour. Extreme gradient boosting (XGBoost) software was used to build the prediction model. To explain the impact of the predictors, we calculated Shapley additive explanation (SHAP) values and present a summary SHAP plot. A force plot was used to explain specifics about an individual's predictors that result in a change of the individual's risk output value from the population-based risk. RESULTS: Among 1060 included women, 160 (15.1%) were delivered by CD. The XGBoost model found women who delivered vaginally were more likely to be parous, taller, to have a lower estimated birth weight, and to be stimulated with a lower amount of oxytocin. In 108 women (10% of 1060) the model favoured either continuation or discontinuation of oxytocin. For the remaining 90% of the women, the model found that continuation or discontinuation of oxytocin stimulation affected the risk difference of CD by less than 5% points. CONCLUSION: In women undergoing labour induction, this AI model based on a secondary analysis of data from the CONDISOX trial may help predict the risk of CD and assist the mother and clinician in individual tailored management of oxytocin stimulation after reaching 6 cm of cervical dilation.

High-Dose Vitamin D Supplementation Significantly Affects the Placental Transcriptome.

Vitamin D deficiency is a highly prevalent obstetrical concern associated with an increased risk of complications like pre-eclampsia, gestational diabetes, and growth retardation. Vitamin D status in pregnancy is also linked to long-term offspring health, e.g., the risk of obesity, metabolic disease, and neurodevelopmental problems. Despite the suspected role of vitamin D in placental diseases and fetal development, there is limited knowledge on the effect of vitamin D on placental function. Thus, we performed next-generation RNA sequencing, comparing the placental transcriptome from uncomplicated term pregnancies receiving the often-recommended dose of 10 µg vitamin D/day (n = 36) with pregnancies receiving 90 µg/day (n = 34) from late first trimester to delivery. Maternal vitamin D status in the first trimester was also considered. We found that signaling pathways related to cell adhesion, immune function, and neurodevelopment were affected, supporting that increased vitamin D supplementation benefits placental function in established pregnancies without severe vitamin D deficiency, also underlining the importance of vitamin D in brain development. Specific effects of the first trimester vitamin D status and offspring sex were also identified. Further studies are warranted, addressing the optimal vitamin status during pregnancy with a focus on organ-specific vitamin D needs in individual pregnancies.

Vaginal CO2 laser therapy for genitourinary syndrome in breast cancer survivors-VagLaser study protocol: a randomized blinded, placebo-controlled trial.

BACKGROUND: Vaginal CO2 laser therapy is a new treatment option for genitourinary syndrome of menopause. Its potential is particularly interesting in breast cancer survivors, where existing treatment options often are insufficient as hormonal treatment is problematic in these women. The objective of this study is to investigate the effectiveness of vaginal laser treatment for alleviation of genitourinary syndrome of menopause in breast cancer survivors treated with adjuvant endocrine therapy. The secondary objective is to explore the importance of repeated vaginal laser treatment and the long-term effects in this patient population. METHODS: VagLaser consist of three sub-studies; a dose response study, a randomized, participant blinded, placebo-controlled study and a follow-up study. All studies include breast cancer survivors in adjuvant endocrine therapy, and are conducted at the Department of Obstetrics and Gynecology, Randers Regional Hospital, Denmark. The first participant was recruited on 16th of February 2023. Primary outcome is vaginal dryness. Secondary subjective outcomes are vaginal pain, itching, soreness, urinary symptoms and sexual function. Secondary objective outcomes are change in vaginal histology (punch biopsy), change in vaginal and urine microbiota, and change in vaginal pH. DISCUSSION: More randomized controlled trials, with longer follow-up to explore the optimal treatment regimen and the number of repeat vaginal laser treatments for alleviation the symptoms of genitourinary syndrome of menopause in breast cancer survivors treated with endocrine adjuvant therapy, are needed. This study will be the first to investigate change in vaginal and urine microbiota during vaginal laser therapy in breast cancer survivors. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06007027 (registered 22 August, 2023). PROTOCOL VERSION: Version 1, Date 13.11.2023.

Vitamin D Deficiency is Associated With Increased Plasminogen Activator Inhibitor 1/Plasminogen Activator Inhibitor 2 Ratio in Pregnancy.

BACKGROUND: Vitamin D deficiency has recently been suggested as an independent risk factor for thrombosis. Notably, vitamin D deficiency is common in pregnant populations, whom already have an increased thrombotic risk. However, pregnant women are commonly excluded from studies investigating the hemostatic system, and knowledge on the impact of vitamin D on hemostasis in pregnancy is therefore limited. METHODS: A cross-sectional study comparing the hemostatic profile of pregnant women (gestational week 12.9 ± 0.7) with vitamin D deficiency (≤50 nmol/L) (n = 70) and high adequate vitamin D status (≥100 nmol/L) (n = 59). RESULTS: Vitamin D deficient women displayed increased plasminogen activator inhibitor 1 levels and an increased plasminogen activator inhibitor 1/plasminogen activator inhibitor 2 ratio, even after adjusting for factors with potential influence on hemostasis (body mass index, smoking and use of fish oil supplements). CONCLUSIONS: Vitamin D deficiency is associated with increased plasminogen activator inhibitor 1/plasminogen activator inhibitor 2 ratio in pregnant women. As an increased plasminogen activator inhibitor 1/plasminogen activator inhibitor 2 ratio with high plasminogen activator inhibitor 1 levels may increase thrombotic risk and is associated with the development of pregnancy complications, further research is needed to determine the optimal vitamin D supplementation in pregnancy.

Quantitative strain elastography of the uterine cervix assessed by the GE Voluson E10 system in combination with a force-measuring device.

OBJECTIVE: During pregnancy, the stiffness of the cervical tissue decreases long before the cervical length decreases. Therefore, several approaches have been proposed in order to ensure a more objective assessment of cervical stiffness than that achieved by digital evaluation. Strain elastography has shown promising results. This technique is based on an ultrasound assessment of the tissue deformation that occurs when the examiner applies pressure on the tissue with the ultrasound probe. However, the results are only semi-quantitative as they depend on the unmeasured force used by the examiner. We, therefore, hypothesized that a force-measuring device applied to the handle of the ultrasound probe may render the technique quantitative. With this approach, the stiffness is the force (measured by the device) divided by the compression (measured by the elastography platform). One perspective is the early identification of women at risk of preterm birth in whom cervical stiffness may decrease long before cervical shortening. Another perspective is cervical evaluation when planning labor induction. In this feasibility study, we aimed to evaluate how quantitative strain elastography performs when a commercially available strain elastography platform (by which the algorithm is unavailable) is combined with a custom-made, force-measuring device. We studied how the assessments were associated with the gestational age in women with uncomplicated pregnancies and how they were associated with cervical dilatation time from 4 to 10 cm in women undergoing labor induction. METHODS: In the analysis, we included quantitative strain elastography assessments from 47 women with uncomplicated singleton pregnancies, with gestational age between 12+0 and 40+0, and from 27 singleton term-pregnant women undergoing labor induction. The force-measuring device was mounted on the handle of a transvaginal probe. The strain values (i.e. the compression of the cervical tissue) were obtained by the elastography software of the ultrasound scanner (GE Voluson E10). The region of interest was placed within the central part of the anterior cervical lip. Based on the force data and strain values, we calculated the outcomes cervical elastography indexGE (CEIGE) and the cervical strength indexGE (CEIGE x cervical length: CSIGE). RESULTS: The average CEIGE was 0.24 N at week 12 and 0.15 N at week 30-34. For CSIGE these figures were 8.2 and 4.7 N mm, respectively (p = 0.002). Among women undergoing labor induction, the CEIGE was associated with a cervical dilatation time (4-10 cm) beyond 7 h. For nulliparous women, this area under the ROC curve was 0.94. CONCLUSION: Quantitative strain elastography may constitute a tool for the evaluation of a uterine cervix with normal length in women at risk of preterm birth and in women undergoing labor induction. The performance of this tool deserves evaluation in larger clinical trials.

Vitamin D in pregnancy (GRAVITD) - a randomised controlled trial identifying associations and mechanisms linking maternal Vitamin D deficiency to placental dysfunction and adverse pregnancy outcomes - study protocol.

BACKGROUND: The prevalence of vitamin D deficiency is high among pregnant women. Vitamin D deficiency in pregnancy is associated with increased risk of adverse pregnancy outcomes especially complications related to placental dysfunction and insulin resistance. The objective of this study is to investigate if a higher dose of vitamin D supplementation in pregnancy reduces the prevalence of vitamin D deficiency and prevents adverse pregnancy outcome with special emphasize on preeclampsia, foetal growth restriction and gestational diabetes. METHODS: GRAVITD is a double-blinded randomised trial with parallel groups where all pregnant women attending the free of charge national nuchal translucency scan programme in gestational week 10-14 at Randers Regional Hospital are invited to participate. Enrolment started in June 2020. Participants are randomised in a two armed randomization with a 1:1 allocation ratio into 1) control group - receives 10 µg of vitamin D or 2) intervention group - receives 90 µg of vitamin D. A total of 2000 pregnant women will be included. Maternal blood samples and questionnaires describing life-style habits are collected upon enrolment. For half of the participants blood samples and questionnaires will be repeated again in 3rd trimester. Blood samples will be analysed for 25-hydroxy-vitamin D using high-performance liquid chromatography coupled with tandem mass spectrometry. Upon delivery, placental tissue and umbilicalcord blood will be collected and information on maternal and fetal outcomes will be exstracted from medical records. The primary outcomes are serum levels of 25-hydroxy-vitamin D ≥ 75 nmol/L and the rate of preeclampsia, foetal growth restriction and gestational diabetes. Secondary outcome includes identification and impact on placental functions related to vitamin D. A tertiary outcome is to initiate a cohort of children born from mothers in the trial for future follow-up of the effects of vitamin D on childhood health. DISCUSSION: Provided that this trial finds beneficial effects of a higher dose of vitamin D supplementation in pregnancies, official recommendations can be adjusted accordingly. This will provide a low-cost and easily implementable adjustment of prenatal care which can improve health for both mother and child during pregnancy and beyond. TRIAL REGISTRATION: ClinicalTrial.gov: NCT04291313 . Registered February 17, 2020.

Continued versus discontinued oxytocin stimulation in the active phase of induced labour: Factors associated with unexpectedly high rates of conversion to open label oxytocin in the CONDISOX trial.

OBJECTIVE: To examine the factors associated with unexpectedly high rates of conversion to open label oxytocin in the CONDISOX trial of continuation versus discontinuation of oxytocin infusion during induced labour. DESIGN: Secondary retrospective analysis of data from a prospective randomised controlled trial. SETTING: Nine hospitals in Denmark and one in the Netherlands between 8 April 2016 and 30 June 2020. POPULATION OR SAMPLE: 1200 women having labour induced. METHODS: Analysis of outcomes by actual management. MAIN OUTCOME MEASURES: Mode of delivery and associated variables. RESULTS: Switching to open label oxytocin (42.4% overall) was associated with nulliparity, an unripe cervix, larger babies and higher rates of delivery by caesarean section. CONCLUSIONS: In the CONDISOX trial, slow labour was associated with features suggesting a higher 'resistance to progress', often prompting the use of open-label oxytocin infusion rather than study medication.

Clinical utility of p16/Ki67 dual-stain cytology for detection of cervical intraepithelial neoplasia grade two or worse in women with a transformation zone type 3: A cross-sectional study.

OBJECTIVE: To evaluate the clinical utility of p16/Ki67 dual-stain (DS) compared with cytology for detecting cervical intraepithelial lesion grade two or worse (CIN2+) in women with a transformation zone type 3 (TZ3). DESIGN: Cross-sectional study. SETTING: Colposcopy clinics in Central Denmark Region. POPULATION: Women aged 45 years or older referred for colposcopy because of an abnormal screening test. METHODS: All women had a cervical sample collected for cytology and DS testing and underwent large-loop excision of the transformation zone (LLETZ). MAIN OUTCOME MEASURE: Sensitivity, specificity and negative (NPV) and positive (PPV) predictive values of DS for CIN2+ detection were compared to those of cytology. RESULTS: Of 166 women eligible, 93 (56.0%) were included in the final analysis. Median age was 68 years (interquartile range [IQR] 63.4-70.5 years). Most women were postmenopausal (95.7%) and referred based on a positive human papillomavirus screening test (86.0%). Fifty-two women (55.9%) were DS-positive, 29 (55.8%) of whom had CIN2+ detected. Twenty-seven (29.0%) women had atypical squamous cells of undetermined significance or worse (ASC-US+), and CIN2+ was detected in 21 women (77.8%). DS had a higher sensitivity (96.7% versus 70.0% p = 0.021) and NPV (97.6% versus 86.4%, p = 0.018) compared with cytology for CIN2+ detection. In contrast, the specificity (63.5% versus 90.5% p < 0.001) and PPV (55.8% versus 77.8%, p = 0.001) were lower for DS compared with cytology. CONCLUSIONS: Dual stain may be a valuable risk marker to guide clinical management of women with a TZ3. The superior NPV of DS suggests that a diagnostic excision may safely be avoided in DS-negative women.

Levels of anxiety in women aged ≥45 years undergoing diagnostic large loop excision of the transformation zone: A longitudinal study.

OBJECTIVE: To measure anxiety levels in women aged ≥45 years undergoing diagnostic large loop excision of the transformation zone (LLETZ) at the first colposcopy visit. DESIGN: Longitudinal study. SETTING: Three colposcopy clinics in the Central Denmark Region. POPULATION: Women aged ≥45 years undergoing diagnostic LLETZ. METHODS: Women completed the State-Trait Anxiety Inventory (STAI) and Short Form 12 (mental and physical health) questionnaires before, immediately after, and at 1 and 6 months after LLETZ. MAIN OUTCOME MEASURES: STAI state anxiety median scores were calculated and stratified by health status, by letter with information about screening result and by LLETZ results. RESULTS: Of 109 eligible women, 11 were excluded, leaving 98 women for the final analyses. Response rates ranged from 84.7% to 100%. Overall, state anxiety levels were low; however, a decrease was observed from before to immediately after the LLETZ (33.4 vs 29.3, p < 0.001). The anxiety levels remained stable up to 6 months after LLETZ. Women with poor mental health were more likely to have higher anxiety levels compared with women with good mental health (before LLETZ, RR 3.77, 95% CI 2.12-6.70; 1 month after LLETZ, RR 3.37, 95% CI 1.59-7.15; 6 months after LLETZ, RR 1.93, 95%CI 1.06-3.51). CONCLUSIONS: Overall, colposcopy and diagnostic LLETZ in women aged ≥45 years were not associated with high levels of anxiety. Anxiety levels were highest before colposcopy, and the women seemed to experience immediate relief afterwards. Women with poor mental health had the highest anxiety levels throughout the study, which might call for special attention.

Is Vitamin D Deficiency Prothrombotic? A Systematic Review.

Observational studies indicate a relationship between vitamin D deficiency and an increased risk of venous and arterial thrombotic events, but the underlying mechanisms behind this association are uncertain. This systematic review explores if there is an association between decreased vitamin D levels and a prothrombotic profile. The systematic literature search initially identified 3,214 studies (published until December 21, 2021) investigating the relationship between vitamin D and numerous hemostatic parameters. After the screening process, 18 observational and intervention studies fulfilled the inclusion criteria and were included in this systematic review. Parameters of primary hemostasis, secondary hemostasis, and fibrinolysis were investigated in six, thirteen, and fifteen of these studies, respectively. Most of the eligible studies did not identify significant associations between decreased vitamin D levels and hemostatic parameters. Some conflicting results were found between decreased vitamin D levels and thrombin generation parameters and the tissue factor pathway inhibitor. Conflicting results were also found between decreased vitamin D levels and fibrinolytic parameters, although the evidence may point toward weak associations with some regulators of fibrinolysis, mostly decreased tissue type plasminogen activator. Overall, our systematic review did not identify any definitive link between vitamin D deficiency and a prothrombotic profile, which might otherwise help explain the observed association between vitamin D deficiency and increased risk of thrombotic events. Moreover, there is no clinical evidence to confirm or refute a possible antithrombotic effect of vitamin D. Larger high-quality randomized controlled trials are needed to better elucidate the link between vitamin D deficiency and a prothrombotic risk profile.

Risk of atypical hyperplasia and endometrial carcinoma after initial diagnosis of non-atypical endometrial hyperplasia: A long-term follow-up study.

OBJECTIVES: The strong association between atypical endometrial hyperplasia and endometrial carcinoma is well established, but data on the risk of atypical hyperplasia and carcinoma in Danish women with non-atypical endometrial hyperplasia are almost non-existent. This study aimed to investigate the prevalence of atypical hyperplasia and endometrial carcinoma diagnosed within 3 months of initial diagnosis (defined as concurrent disease) and the risk of atypical hyperplasia and carcinoma more than 3 months after initial diagnosis (classified as progressive disease) in Danish women initially diagnosed with non-atypical endometrial hyperplasia. DESIGN: This cohort study recruited 102 women diagnosed with non-atypical endometrial hyperplasia at Randers Regional Hospital in Randers, Denmark, between 2000 and 2015. METHODS: The endometrium was evaluated by transvaginal ultrasound examination and office mini-hysteroscopy with biopsies in all non-hysterectomized women. Data regarding subsequent hysterectomy or endometrial sampling were obtained from medical records and the Danish Pathology Registry (Patobank). RESULTS: A total of 15 women were diagnosed with atypical hyperplasia or carcinoma during follow-up. Concurrent atypical hyperplasia or carcinoma was seen in 2.9% (3/102), and among women who remained at risk for more than 3 months after initial diagnosis of non-atypical endometrial hyperplasia (n = 94), progression to atypical hyperplasia or carcinoma was seen in 13% (median follow-up 5.2 years, range 3.6 months to 15.1 years). Sixty-six percent of the women with progressive disease were diagnosed with atypical hyperplasia or carcinoma more than 1 year after initial diagnosis, but only two were diagnosed later than 5 years (5.2 and 9 years). CONCLUSIONS: The risk of being diagnosed with atypical endometrial hyperplasia or endometrial carcinoma more than 5 years after an initial diagnosis of non-atypical endometrial hyperplasia seems to be low in Danish women. Specialized follow-up more than 5 years after diagnosis of non-atypical endometrial hyperplasia may not be warranted.

Cervical intraepithelial neoplasia in women with transformation zone type 3: cervical biopsy versus large loop excision.

OBJECTIVE: To compare the proportion of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) in cervical biopsies with that in large loop excision of the transformation zone (LLETZ) specimens in women aged ≥45 years with transformation zone type 3 (TZ3). DESIGN: Multicentre cross-sectional study. SETTING: Three colposcopy clinics in the Central Denmark Region. POPULATION: Women aged ≥45 years referred to colposcopy as a result of a positive human papillomavirus (HPV) test and/or abnormal cytology and with TZ3 at colposcopy. METHODS: Women had multiple biopsies taken and an LLETZ was performed. MAIN OUTCOME MEASURES: Histologically confirmed CIN2+ in biopsies compared with that in LLETZ specimens. RESULTS: Of 166 eligible women at colposcopy, 102 women with paired data from biopsies and LLETZ specimens were included for final analysis. The median age was 67.7 years (IQR 62.6-70.4 years), and most were postmenopausal (94.1%) and had undergone HPV-based screening (81.3%). The CIN2+ detection rate was significantly higher in LLETZ specimens than in biopsies (32.4% vs 14.7%, difference 17.7%, 95% CI 6.3-29.0%), resulting in more than half of CIN2+ cases being missed in biopsies (54.5%, 95% CI 36.4-71.9%). The overall agreement between biopsies and LLETZ was 82.4% (95% CI 73.6-89.2%). CONCLUSIONS: CIN2+ detection is underestimated in women aged ≥45 years with TZ3 if detection relies on the results of biopsies alone. To reduce the risk of underdiagnosis and overtreatment, future studies should explore the use of new biomarkers for risk stratification to improve discrimination between women at increased risk of CIN2+ who need to undergo LLETZ and women who may undergo follow-up.

Risk of deep vein thrombosis and pulmonary embolism after gynecological day surgery.

OBJECTIVE: To investigate the risk of venous thromboembolism (VTE) in Danish women operated within a day surgery setting and to evaluate whether the current use of thromboprophylaxis without using graduated elastic compression stockings (GCS) is an appropriate treatment to prevent VTE. STUDY DESIGN: A retrospective cohort study including women who underwent laparoscopic hysterectomy or vaginal prolapse operation for benign disease from January 2014 to December 2017 at the Gynecology Day Surgery Unit, Regional Hospital of Randers, Denmark. The primary outcome was VTE diagnosed within three months postoperatively. Only one dose of pharmacological thromboprophylaxis (PTP) was given to women stratified at high risk of VTE. None of the women used GCS. RESULTS: A total of 671 women were included. Vaginal prolapse operations were performed on 626 women, and laparoscopic hysterectomy on 45 women. PTP was used for only 220 (32.8%) of these women. A total of 346 (51.5%) women were stratified as at high risk of VTE according to the national recommendations. Only 218 (63%) of these women received PTP, while 128 women (37%) did not receive PTP. The incidence of VTE within three months postoperatively was 0%. Only 13 (1.9%) of the women were readmitted within 14 days postoperatively due to hemorrhaging or hematoma; six out of these 13 women (46%) received PTP postoperatively. Re-operation was performed in seven (1%) women due to hemorrhaging, and three out of the seven (42.9%) had PTP postoperatively. CONCLUSION: The risk of VTE in Danish women operated within a day surgery setting is probably very low since we found no cases of VTE in our setup. The beneficial effect of routine use of GCS and one dose of PTP postoperatively given to all women who had undergone MIS in a day surgery setting are questioned. One dose of PTP postoperatively without GCS can be considered to only women stratified as high-risk of VTE until there is more evidence whether these women actually need thromboprophylaxis postoperatively at all. PRECIS: The incidence of VTE in women undergoing laparoscopic hysterectomy or vaginal prolapse operation in a day surgery setting without using graduated elastic compression stockings is very low.

A force-measuring device combined with ultrasound-based elastography for assessment of the uterine cervix.

INTRODUCTION: In this feasibility study, we hypothesize that the evaluation of cervical biomechanical strength can be improved if cervical length measurement is supplemented with quantitative elastography, which is a technique based on conventional ultrasound elastography combined with a force-measuring device. Our aims were to: (a) develop a force-measuring device; (b) introduce a cervical elastography index (CEI) and a cervical strength index (CSI; defined as cervical length × CEI); (c) evaluate how these indexes assess the cervical softening that takes place during normal pregnancy; and (d) how these indexes predict the cervical dilatation time from 4 to 10 cm. MATERIAL AND METHODS: An electronic force-measuring device was mounted on the handle of the transvaginal probe, allowing for force measurement when conducting elastography. The study group concerned with normal cervical softening included 44 unselected pregnant women. Outcomes were CEI and CSI at different gestational ages. The study group for labor induction included 26 singleton term pregnant women admitted for labor induction. Outcome was defined as cervical dilatation time from 4 to 10 cm. Elastography measured the changes in mean gray value (intensity) during manual compressions. Region of interest was set within the anterior cervical lip. RESULTS: We found that the mean of all variables regarding cervical softening decreased from early to late pregnancy: ie cervical length from 34 to 29 mm, CEI from 0.17 to 0.11 N, and CSI from 5.9 to 3.1 N mm. Moreover, the cervical dilatation time during labor induction was associated with CEI, although not statistically significantly (area under the ROC curve of 0.67), but not with the Bishop score, the cervical length, or the CSI. CONCLUSIONS: We propose that quantitative elastography based on changes in the intensity of the B-mode ultrasound recording, in combination with a force-measuring device on the handle of the vaginal probe, deserves further investigation as an approach for evaluation of cervical biomechanical strength.

Risk of precancerous cervical lesions in women using a hormone-containing intrauterine device and other contraceptives: a register-based cohort study from Denmark.

STUDY QUESTION: Is the risk of high-grade precancerous cervical lesions and/or is the risk of lesion progression increased in users of a hormone-containing intrauterine device (HIUD) compared with users of other contraceptive methods. SUMMARY ANSWER: Women starting use of HIUD had the same subsequent risk of cervical intraepithelial neoplasia 3+ (CIN3+) as copper IUD (CIUD) users, and both groups tended to have lower risks than oral contraceptives (OC) users. WHAT IS KNOWN ALREADY: HIUDs may cause inflammatory and immunosuppressive changes that may potentially affect the risk of persistent human papillomavirus infection and precancerous cervical lesions. STUDY DESIGN, SIZE, DURATION: A Danish population-based cohort study was conducted using register data from 2008 to 2011 on 26-50-year-old users of HIUD (n = 60 551), CIUD (n = 30 303), or OC (n = 165 627). PARTICIPANTS/MATERIALS, SETTING, METHODS: Within each user group, women were divided into two groups; normal cytology or abnormal diagnosis before start of contraceptive use (baseline). Follow-up histology and cytology diagnoses were registered during the 5 years after baseline. Adjusted relative risks (aRR) and 95% CI were calculated for precancerous cervical lesions in HIUD users compared with CIUD and OC users. MAIN RESULTS AND THE ROLE OF CHANCE: Women with normal cytology at baseline: at follow-up HIUD users had the same risk of CIN3 or higher (3+) as CIUD users; aRR 1.08 (95% CI 0.94-1.22). For the HIUD and CIUD groups compared with OCs, the risks of CIN3+ were lower: aRR 0.63 (95% CI 0.57-0.69) and aRR 0.58 (95% CI 0.52-0.65), respectively. The same was observed for CIN2 risks: aRR 0.86 (95% CI 0.76-0.96) and aRR 0.68 (95% CI 0.58-0.79) for HIUD and CIUD groups, respectively. Women with abnormal diagnosis at baseline: a lower progression risk, except for CIN2+ at baseline, was observed in HIUD users compared with OC users. Similar progression risks were found in HIUD and CIUD users. There were no differences between the three contraceptive groups in persistence or regression of present lesions. LIMITATIONS, REASONS FOR CAUTION: We adjusted for age, education, and region of residence as a proxy for socio-economic factors. Data on smoking and sexual behavior were not available thus we cannot exclude some differences between the three user groups. WIDER IMPLICATIONS OF THE FINDINGS: These findings suggest that women may safely use HIUDs. STUDY FUNDING/COMPETING INTEREST(S): A.P. Møller Foundation for the Advancement of Medical Science, Else and Mogens Wedell-Wedellborgs Fund, Direktør Emil C. Hertz og Hustru Inger Hertz Fund, and the Fund for Development of Evidence Based Medicine in Private Specialized Practices. EL is principle investigator for a study with HPV-test-kits provided by Roche. The other authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

Continued versus discontinued oxytocin stimulation in the active phase of labour (CONDISOX): double blind randomised controlled trial.

OBJECTIVE: To determine whether discontinuing oxytocin stimulation in the active phase of induced labour is associated with lower caesarean section rates. DESIGN: International multicentre, double blind, randomised controlled trial. SETTING: Nine hospitals in Denmark and one in the Netherlands between 8 April 2016 and 30 June 2020. PARTICIPANTS: 1200 women stimulated with intravenous oxytocin infusion during the latent phase of induced labour. INTERVENTION: Women were randomly assigned to have their oxytocin stimulation discontinued or continued in the active phase of labour. MAIN OUTCOME MEASURE: Delivery by caesarean section. RESULTS: A total of 607 women were assigned to discontinuation and 593 to continuation of the oxytocin infusion. The rates of caesarean section were 16.6% (n=101) in the discontinued group and 14.2% (n=84) in the continued group (relative risk 1.17, 95% confidence interval 0.90 to 1.53). In 94 parous women with no previous caesarean section, the caesarean section rate was 7.5% (11/147) in the discontinued group and 0.6% (1/155)in the continued group (relative risk 11.6, 1.15 to 88.7). Discontinuation was associated with longer duration of labour (median from randomisation to delivery 282 v 201 min; P<0.001), a reduced risk of hyperstimulation (20/546 (3.7%) v 70/541 (12.9%); P<0.001), and a reduced risk of fetal heart rate abnormalities (153/548 (27.9%) v 219/537 (40.8%); P<0.001) but rates of other adverse maternal and neonatal outcomes were similar between groups. CONCLUSIONS: In a setting where monitoring of the fetal condition and the uterine contractions can be guaranteed, routine discontinuation of oxytocin stimulation may lead to a small increase in caesarean section rate but a significantly reduced risk of uterine hyperstimulation and abnormal fetal heart rate patterns. TRIAL REGISTRATION: ClinicalTrials.gov NCT02553226.

Cervical cancer prevention among older women - challenges in screening, diagnostic workup and treatment.

Cervical cancer incidence and mortality have declined dramatically after screening for cervical cancer was implemented. Yet, studies have reported high cervical cancer incidence and mortality rates at older age despite low HPV prevalence and incidence of precursor lesions. The underlying reason for these findings remains unclear. However, it is well known that the impact of screening depends not only on the uptake and effectiveness of screening but also on the uptake and effectiveness of diagnostic workup (ie colposcopy), treatment and follow-up. In older women, sensitivity of screening and performance of colposcopy are impaired due to age-dependent changes to the cervix. In this commentary, we aimed to discuss challenges in screening and clinical management of older women, and to identify crucial areas of particular interest for future research.

Clinical relevance of routine transvaginal ultrasound in women referred with pelvic organ prolapse.

BACKGROUND: The aim of this study was to investigate the prevalence of incidental findings on transvaginal ultrasound scan in women referred with pelvic organ prolapse by a general practitioner and to investigate which further examinations and treatments were performed as a result of these findings. METHODS: This was a retrospective cohort study that investigated women with pelvic organ prolapse referred to the outpatient urogynaecological clinics at Randers Regional Hospital and Aarhus University Hospital, Denmark. RESULTS: A total of 521 women were included and all of them were examined with a routine transvaginal ultrasound scan and a gynaecological examination. Prolapse symptoms only and no specific indication for transvaginal ultrasound scan were seen in 507 women (97.3%), while 14 women (2.7%) received scans on indication. Among the latter women, five (35.7%) had cancer. In the women with solely prolapse symptoms, 59 (11.6%) had incidental findings on transvaginal ultrasound scan, but all were benign. However, two patients were later diagnosed with cancer unrelated to the initial ultrasound findings. The treatment was extended with further examinations not related to POP in 19 of the women (32.2%) with incidental ultrasound findings. CONCLUSION: The prevalence of incidental ultrasound findings was not high in the women referred with pelvic organ prolapse and no additional symptoms, and all these findings were benign. However, it should be considered that these findings resulted in further investigations and changes to the patients' initial treatment plans. A meticulous anamnesis and digital vaginal examination are crucial to rule out the need for vaginal ultrasound.

Dynamic Spectral Imaging Colposcopy Versus Regular Colposcopy in Women Referred With High-Grade Cytology: A Nonrandomized Prospective Study.

OBJECTIVE: The aim of the study was to evaluate the sensitivity of dynamic spectral imaging (DSI) colposcopy compared with regular colposcopy for women referred with high-grade cervical cytology. METHODS: In a prospective, nonrandomized, multicenter study, we included women referred for colposcopy at hospital gynecology clinics with high-grade cytology. Women were examined using either a regular or DSI colposcope. In both groups, colposcopists located 1 area viewed as most suspicious. In the DSI group, this was done before viewing the DSI map. Subsequently, an area was chosen based on the worst color of the DSI map, and further additional biopsies were taken. All women had 4 cervical biopsies taken, all analyzed separately. The main outcome was sensitivity to find cervical intraepithelial neoplasia grade 2 or worse (CIN2+). RESULTS: A total of 261 women were examined using DSI colposcopy, and 156 women were examined using regular colposcopy. The sensitivity for finding CIN2+ when using the DSI technology as an adjunctive technology was found to be 82.2% (95% CI = 75.9-87.4), based on an average of 1.4 biopsies. This was corresponding in sensitivity to 2 biopsies taken using regular colposcopy (80.3%; 95% CI = 72.3-86.8). There was no difference in sensitivity for CIN+ between the groups when 3 or more biopsies were taken. CONCLUSIONS: We found that the DSI colposcope may help direct biopsy placement; however, the improvement is based on small differences in needed biopsies and the clinical significance of this may be small. Multiple biopsies were still superior.

Can the dynamic spectral imaging (DSI) color map improve colposcopy examination for precancerous cervical lesions? A prospective evaluation of the DSI color map in a multi-biopsy clinical setting.

BACKGROUND: Colposcopy serves as a subjective examination of the cervix with low sensitivity to detect cervical intraepithelial dysplasia (CIN) grade 2 or worse (CIN2 +). Dynamic spectral imaging (DSI) colposcopy has been developed to provide an objective element to cervix examinations and has been proven to increase sensitivity of detecting CIN2 + . We aimed to assess the performance of the DSI color map and compared it to histological diagnoses of cervical biopsies in determining the CIN grade present. METHODS: Women were included in a consecutive, prospective manner at Randers Regional Hospital, Denmark. Women were eligible to participate if they were referred for colposcopy due to abnormal cervical smear (threshold: ≥ ASCUS) or follow-up after previously diagnosed CIN. All women had four biopsies taken, one directed by colposcopists alone prior to viewing the DSI color map, one directed by the worst color on the respective DSI color map, and two additional biopsies. All biopsies were analyzed separately. We calculated sensitivity, specificity, positive predictive values, and negative predictive values (NPVs) with 95% confidence intervals (CIs). RESULTS: A total of 800 women were recruited. Of these, 529 (66.1%) were eligible for inclusion. The sensitivity of the DSI color map was found to be 48.1% (95% CI 41.1-55.1) in finding CIN grade 2 or worse (CIN2 +) when compared to the histological diagnosis of the DSI directed biopsy. This was 42.5% (95% CI 36.7-48.5) when compared to the final histological diagnosis of all four cervical biopsies and with an NPV of 53.5% (95% CI 50.5-56.5). CONCLUSION: The worst color indicated by the DSI map might not consistently reflect the true grade of cervical dysplasia present. Thus, even though the DSI color map indicates low-grade changes, colposcopists should still consider taking biopsies from the area as high-grade changes might be present. TRIAL REGISTRATION: NCT04249856, January 31 2020 (retrospectively registered).