Balloon catheters versus vaginal prostaglandins for labour induction (CPI Collaborative): an individual participant data meta-analysis of randomised controlled trials.

BACKGROUND: Induction of labour is one of the most common obstetric interventions globally. Balloon catheters and vaginal prostaglandins are widely used to ripen the cervix in labour induction. We aimed to compare the effectiveness and safety profiles of these two induction methods. METHODS: We did an individual participant data meta-analysis comparing balloon catheters and vaginal prostaglandins for cervical ripening before labour induction. We systematically identified published and unpublished randomised controlled trials that completed data collection between March 19, 2019, and May 1, 2021, by searching the Cochrane Library, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and PubMed. Further trials done before March 19, 2019, were identified through a recent Cochrane review. Data relating to the combined use of the two methods were not included, only data from women with a viable, singleton pregnancy were analysed, and no exclusion was made based on parity or membrane status. We contacted authors of individuals trials and participant-level data were harmonised and recoded according to predefined definitions of variables. Risk of bias was assessed with the ROB2 tool. The primary outcomes were caesarean delivery, indication for caesarean delivery, a composite adverse perinatal outcome, and a composite adverse maternal outcome. We followed the intention-to-treat principle for the main analysis. The primary meta-analysis used two-stage random-effects models and the sensitivity analysis used one-stage mixed models. All models were adjusted for maternal age and parity. This meta-analysis is registered with PROSPERO (CRD42020179924). FINDINGS: Individual participant data were available from 12 studies with a total of 5460 participants. Balloon catheters, compared with vaginal prostaglandins, did not lead to a significantly different rate of caesarean delivery (12 trials, 5414 women; crude incidence 27·0%; adjusted OR [aOR] 1·09, 95% CI 0·95-1·24; I2=0%), caesarean delivery for failure to progress (11 trials, 4601 women; aOR 1·20, 95% CI 0·91-1·58; I2=39%), or caesarean delivery for fetal distress (10 trials, 4441 women; aOR 0·86, 95% CI 0·71-1·04; I2=0%). The composite adverse perinatal outcome was lower in women who were allocated to balloon catheters than in those allocated to vaginal prostaglandins (ten trials, 4452 neonates, crude incidence 13·6%; aOR 0·80, 95% CI 0·70-0·92; I2=0%). There was no significant difference in the composite adverse maternal outcome (ten trials, 4326 women, crude incidence 22·7%; aOR 1·02, 95% CI 0·89-1·18; I2=0%). INTERPRETATION: In induction of labour, balloon catheters and vaginal prostaglandins have comparable caesarean delivery rates and maternal safety profiles, but balloon catheters lead to fewer adverse perinatal events. FUNDING: Australian National Health and Medical Research Council and Monash Health Emerging Researcher Fellowship.

Adjuvant use of melatonin for pain management in dysmenorrhea - a randomized double-blinded, placebo-controlled trial.

PURPOSE: Dysmenorrhea is a common, recurring, painful condition with a global prevalence of 71%. The treatment regime for dysmenorrhea includes hormonal therapies and NSAID, both of which are associated with side effects. A dose of 10 mg melatonin daily has previously been shown to reduce the level of pelvic pain in women with endometriosis. We chose to investigate how this regime, administered during the week of menstruation, would affect women with dysmenorrhea but without any signs of endometriosis, as adjuvant analgesic treatment. METHODS: Forty participants with severe dysmenorrhea were randomized to either melatonin or placebo, 20 in each group. Our primary outcome was pain measured with numeric rating scale (NRS); a difference of at least 1.3 units between the groups was considered clinically significant. Secondary outcomes were use of analgesics, as well as absenteeism and amount of bleeding. Mixed model was used for statistical analysis. RESULTS: Eighteen participants completed the study in the placebo group and 19 in the melatonin group. Mean NRS in the placebo group was 2.45 and 3.18 in the melatonin group, which proved to be statistically, although not clinically significant. CONCLUSION: This randomized, double-blinded, placebo-controlled trial could not show that 10 mg of melatonin given orally at bedtime during the menstrual week had better analgesic effect on dysmenorrhea as compared with placebo. However, no adverse effects were observed. CLINICAL TRIALS: NCT03782740 registered on 17 December 2018.

Prevalence and impact of dysmenorrhea in Swedish adolescents.

INTRODUCTION: The objective of this study was to estimate the prevalence of dysmenorrhea among adolescents and its effect on daily life. MATERIAL AND METHODS: A web-based questionnaire with questions regarding menstrual symptoms was distributed to all girls born in 2000 and residing in Stockholm City (n = 3998). Questions regarding pain severity, other menstrual-related symptoms, medical treatment, healthcare visits, and social and academic absenteeism were included in the questionnaire. RESULTS: A total of 1785 (45%) young women responded to the questionnaire. Of these, 1580 (89%, 95% CI 87-90) stated that they had dysmenorrhea. Severe dysmenorrhea, scores 8-10 on the numeric rating scale for pain, was reported by 574 of 1580 women (36%, 95% CI 34-39). Fatigue was reported by 1314 of 1580 women (83%, 95% CI 81-85), headache by 1296 (82%, 95% CI; 80-84), dyschezia by 578 (37%, 95% CI 34-39) and dysuria by 560 (35%, 95% CI 33-38). A suboptimal use of analgesics was reported. Hormonal therapy as pain treatment was used by 10% (157/1580, 95% CI 9-12). Healthcare facilities, including school nurses, had been visited by 525 of 1580 women (33%, 95% CI; 31-36). Doctors had been consulted by 7% (116/1580, 95% CI 6-9). Fifty-nine percent (930/1580, 95% CI 56-61) reported refraining from social activities due to dysmenorrhea. Absenteeism from school was reported to occur monthly by 228 of 1580 women (14%, 95% CI 13-16), and several times per year by 716 (45%, 95% CI 43-48). CONCLUSIONS: Our findings demonstrate that menstrual pain is prevalent among teenagers in Stockholm. The results indicate that many women are disabled in their daily life and that only a small number of women seek medical attention, although possible selection bias might have affected the results. Information and education are needed to optimize the use of existing treatment options and more awareness is needed to reduce normalization of disabling dysmenorrhea.

Heavy menstrual bleeding significantly affects quality of life.

OBJECTIVE: To investigate the prevalence of women subjectively experiencing heavy menstrual bleeding in the general population and their health-related quality of life (HRQoL) compared with women experiencing normal menstrual blood loss. DESIGN: Community-based cross-sectional descriptive survey on a randomized sample of the Swedish general population. SETTINGS: Invitation by e-mail to join an online questionnaire in Sweden, conducted in June 2012. POPULATION: 1547 women, aged 40-45 years old. METHODS: Web-based questionnaire consisting of disease-specific questions, concerning the perceptions of menstrual bleeding, in combination with the generic Short Form-36v2 (SF-36) Health Survey Questionnaire to evaluate HRQoL. RESULTS: We found that 32% of women experienced heavy menstrual bleeding, 39% normal menstrual blood loss, 15% light menstrual blood loss and 14% no menstruation. In general, menstrual bleeding was associated with negative perceptions and limited social and professional activities, although all areas were significantly more affected in women experiencing heavy menstrual bleeding than normal menstrual bleeding. The SF-36 showed that women experiencing heavy menstrual bleeding had significantly worse HRQoL compared with women with normal menstrual bleeding in all domains. CONCLUSION: Of women 40-45 years old, 32% experience heavy menstrual bleeding. These women have significantly worse HRQoL compared with women with normal menstruation patterns.

Adjuvant use of melatonin for pain management in endometriosis-associated pelvic pain-A randomized double-blinded, placebo-controlled trial.

Considering the pharmacological treatment options for endometriosis-associated pain are confined to hormonal therapy and analgesics, we studied the analgesic effect of 20 mg melatonin as an adjuvant therapy in women with endometriosis-associated pain. This randomized double-blinded, placebo-controlled trial was conducted at the Research Center for Womens' Health at Södersjukhuset, a university hospital in Stockholm, Sweden. Forty women from 18 to 50 years of age with endometriosis and severe dysmenorrhea with or without chronic pelvic pain were given 20 mg Melatonin or placebo orally daily for two consecutive menstrual cycles or months. The level of pain was recorded daily on the 11-point numeric rating scale, a difference of 1.3 units was considered clinically significant. Clincaltrials.gov nr NCT03782740. Sixteen participants completed the study in the placebo group and 18 in the melatonin group. The difference in endometriosis-associated pain between the groups showed to be non-significant statistically as well as clinically, 2.9 (SD 1.9) in the melatonin group and 3.3 (SD 2.0) in the placebo group, p = 0.45. This randomized, double-blinded, placebo-controlled trial could not show that 20 mg of melatonin given orally at bedtime had better analgesic effect on endometriosis-associated pain compared with placebo. No adverse effects were observed.

Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel.

Reproductive tract bleeding in women is a naturally occurring event during menstruation and childbirth. In women with menorrhagia, however, congenital bleeding disorders historically have been underdiagnosed. This consensus is intended to allow physicians to better recognize bleeding disorders as a cause of menorrhagia and consequently offer effective disease-specific therapies.

Low molecular weight heparin stimulates myometrial contractility and cervical remodeling in vitro.

OBJECTIVES: The low molecular weight heparin, Dalteparin, shortens human labor time. The aim of this study was to investigate if the mechanism behind this effect involves myometrial contractility and cervical ripening and if the anticoagulative activity is necessary for its effect. DESIGN: Experimental in vitro study. SETTING: Lund University and Karolinska Institute, Sweden. METHODS: The effect of low molecular weight heparins with or without anticoagulative properties on myometrial contractility was measured in vitro on smooth muscle strips from biopsies obtained at elective cesarean sections. The effects on cervical ripening were assessed in cervical fibroblasts cultured from explants of cervical biopsies obtained at delivery. MAIN OUTCOME MEASURES: Mean force and number of contractions in uterine smooth muscle strips and interleukin-8 (IL-8) secretion in cervical fibroblasts. RESULTS: Myometrial smooth muscle strips pretreated with low molecular weight heparins showed increased contractile activity compared to untreated smooth muscle strips. Secretion of IL-8 from cultured cervical fibroblasts was significantly increased after treatment with low molecular weight heparin. Both these effects were independent of anticoagulative activity of the low molecular weight heparin. CONCLUSIONS: A possible underlying mechanism for the shortened labor time after low molecular weight heparin treatment is enhanced myometrial contractility and an increased IL-8 secretion in cervical fibroblast, mimicking the final cervical ripening in vivo. Our data support the notion that anticoagulant activity is not required to promote labor.

An isopropanolic extract of black cohosh does not increase mammographic breast density or breast cell proliferation in postmenopausal women.

OBJECTIVE: The aim of this study was to determine the effects of the isopropanolic extract of black cohosh (Remifemin) on mammographic breast density and breast epithelial proliferation in healthy, naturally postmenopausal women with climacteric symptoms. DESIGN: This was a prospective, open, uncontrolled drug safety study in which baseline status was compared with status after 6 months of treatment by blinded observers. A total of 74 women were treated with 40 mg black cohosh daily, and 65 women completed the study. Mammograms were performed, and breast cells were collected by percutaneous fine needle aspiration biopsies at baseline and after 6 months. Mammographic density was quantified according to the Wolfe classification or a percentage scale. Breast cell proliferation was assessed using the Ki-67/MIB-1 monoclonal antibody. Safety was monitored by adverse event reporting, laboratory assessments, and measurement of the endometrium by vaginal ultrasound. RESULTS: None of the women showed any increase in mammographic breast density. Furthermore, there was no increase in breast cell proliferation. The mean change +/- SD in proportion of Ki-67-positive cells was -0.5% +/- 2.4% (median, 0.0; 95% CI = -1.32 to 0.34) for paired samples. The mean change in endometrial thickness +/- SD was 0.0 +/- 0.9 mm (median, 0.0). A modest number of adverse events were possibly related to treatment, but none of these were serious. Laboratory findings and vital signs were normal. CONCLUSIONS: The findings suggest that the isopropanolic extract of black cohosh does not cause adverse effects on breast tissue. Furthermore, our data do not indicate to any endometrial or general safety concerns during 6 months of treatment.

Age-Related Differences in Quality of Life in Swedish Women with Endometriosis.

OBJECTIVE: The purpose of this observational study was to evaluate the impact of endometriosis on quality of life (QoL) in different age groups of Swedish women with endometriosis. Recruitment occurred through the Endometriosis Association (Sweden) (n = 400) and five gynecology departments of five Swedish hospitals (n = 400). All voluntary female members of the patient organization and patients attending specialist clinics due to endometriosis (n = 800) were invited by sending them a questionnaire. An age- and gender-matched sample of the general Swedish population was used as a control group when analyzing SF-36 data. METHODS: A postal questionnaire (including SF-36) was distributed to 800 women. The questionnaire was evaluated by using descriptive statistics, and SF-36 was evaluated according to standard methods. RESULTS: Of the 449 (56%) self-administered questionnaires returned, 431 (96%) contained evaluable answers. Women with endometriosis have significantly lower SF-36 scores than the general female Swedish population, and the score depends on the women's age. Younger women experience more symptoms and have a lower QoL score compared with women in the older age group. CONCLUSION: Women with endometriosis have significantly lower QoL than the general female Swedish population and it depends on the women's age, where younger women express more symptoms and have a lower QoL compared with women in the older age group. Our results highlight that more healthcare resources should be focused on younger women with endometriosis.

On the correlation between local fibrinolytic activity in menstrual fluid and total blood loss during menstruation and effects of desmopressin.

The primary objective of this study was to investigate the correlation between fibrinolytic activity in menstrual fluid and total menstrual blood loss during menstruation. We also wanted to evaluate the influence of desmopressin nasal inhalation on the local fibrinolytic activity in menstrual fluid. Six women with objectively verified menorrhagia and six women with normal menstrual blood loss were examined. With a slender catheter introduced through the cervical canal, menstrual fluid was collected on the day in the cycle when the most intense bleeding occurred. The fibrinolytic activity in menstrual fluid was measured both as plasmin content using an amidolytic method with chromogenic substrate and with a fibrin plate method. A significant correlation between the amount of menstrual blood loss and fibrinolytic activity was found in menstrual fluid of both groups and with both methods. We could not find an increased fibrinolytic activity in menstrual fluid when the women with menorrhagia were treated with desmopressin nasal inhalation. Knowledge of the local factors influencing monthly blood loss can be valuable when searching for more effective medical treatment of menorrhagia. Apprehension that desmopressin should increase local fibrinolytic activity in menstrual fluid could not be confirmed.

Nonhormonal treatments for heavy menstrual bleeding.

BACKGROUND: The purpose of this review is to identify and compare nonhormonal medications for the treatment of idiopathic heavy menstrual bleeding (HMB) or menorrhagia. METHODS: Clinical trials were identified through a PubMed literature search. Titles and abstracts of identified studies were reviewed. Controlled clinical trials that evaluated nonhormonal medications in women with HMB in the absence of anatomic abnormalities other than small fibroids were selected for retrieval. Additional studies were identified from the reference lists of selected articles. Selected articles were comprehensively reviewed. RESULTS: All medications evaluated reduced menstrual blood loss (MBL); however, mean reductions in MBL were greatest with the hemostatic agents, tranexamic acid (TA) and ε-aminocaproic acid. Several TA studies also included evidence of improvement in health-related quality of life (HRQOL). Reductions in MBL were generally smaller and less consistent with nonsteroidal anti-inflammatory drug (NSAID) treatment. All medications reviewed were well tolerated. CONCLUSIONS: Nonhormonal medications used for HMB treatment differ in the extent of MBL reduction. TA was notable for consistent MBL reductions and improvement in HRQOL; other agents reviewed indicated less reduction in MBL or sufficient data were lacking for comparison.

Evaluation and management of acute menorrhagia in women with and without underlying bleeding disorders: consensus from an international expert panel.

Acute menorrhagia is a common gynecological disorder. Prevalence is high among women with inherited bleeding disorders and recent guidance for optimal management is lacking. Following a comprehensive review of the literature, an international expert panel in obstetrics, gynecology and hematology reached consensus on recommendations regarding the management of acute menorrhagia in women without a diagnosed bleeding disorder, as well as in patients with von Willebrand disease, platelet function disorders and other rare hemostatic disorders. The causes and predictors of acute menorrhagia are discussed and special consideration is given for the treatment of women on anticoagulation therapy. This review and accompanying recommendations will provide guidance for healthcare practitioners in the emergency management of acute menorrhagia.

Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial.

OBJECTIVE: To assess the efficacy and safety of an oral formulation of tranexamic acid for the treatment of heavy menstrual bleeding. METHODS: Adult women with heavy menstrual bleeding (mean menstrual blood loss 80 mL or more per cycle) were enrolled in a double-blind, placebo-controlled study. After two pretreatment menstrual cycles, women were randomized to receive tranexamic acid 3.9 g/d or placebo for up to 5 days per menstrual cycle through six cycles. To meet the prespecified three-component primary efficacy end point, mean reduction in menstrual blood loss from baseline with tranexamic acid treatment needed to be 1) significantly greater than placebo, 2) greater than 50 mL, and 3) greater than a predetermined meaningful threshold (36 mL or higher). Health-related quality of life was measured using a validated patient-reported outcome instrument. RESULTS: Women who received tranexamic acid (n=115) met all three primary efficacy end points: first, a significantly greater reduction in menstrual blood loss of -69.6 mL (40.4%) compared with -12.6 mL (8.2%) in the 72 women who received placebo (P<.001); reduction of menstrual blood loss exceeding a prespecified 50 mL; and last, reduction of menstrual blood loss considered meaningful to women. Compared with women receiving placebo, women treated with tranexamic acid experienced significant improvements in limitations in social or leisure and physical activities, work inside and outside the home, and self-perceived menstrual blood loss (P<.01). The majority of adverse events were mild to moderate in severity, and the incidence of gastrointestinal adverse events was comparable with placebo. CONCLUSION: In this study, a new oral tranexamic acid treatment was well tolerated and significantly improved both menstrual blood loss and health-related quality of life in women with heavy menstrual bleeding. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00386308. LEVEL OF EVIDENCE: I.

Progesterone withdrawal causes endothelin release from cultured human uterine microvascular endothelial cells.

BACKGROUND: Current theories on the physiology of menstrual bleeding in humans offers an explanation for the shedding of the endometrium as a result of a breakdown of the extracellular matrix due to an inflammatory reaction. The link between the fall in progesterone levels and these events is not clear. Neither has an explanation been presented for the vasoconstriction in the coiled arteries occurring during menses. We have hypothesized a chain of events where the fall in progesterone levels induces an upregulation of the thrombin receptor in the small uterine arteries leading to an increased thrombin response and subsequent endothelin release. METHODS: Endothelial cells from human umbilical cord (HUVECs) and from human small uterine arteries (UtMVECs) were cultured under conditions partly resembling the female hormonal cycle with progesterone withdrawal. RESULTS: Following progesterone increase and subsequent withdrawal, we found an increased production of thrombin receptor and an increased release of endothelin from UtMVECs compared with HUVECs. CONCLUSION: Endothelin release in response to progesterone withdrawal in UtMVECs can offer an explanation for the vasoconstriction seen in the coiled arteries during menses in humans.