Ulipristal acetate versus gonadotropin-releasing hormone agonists prior to laparoscopic myomectomy (MYOMEX trial): Long term results of a double-blind randomized controlled trial.

OBJECTIVE: The aim of this study was to compare the effect of ulipristal acetate (UPA) and gonadotropin-releasing hormone agonists (GnRHa) before laparoscopic myomectomy on long term secondary outcomes of the MYOMEX-trial, regarding quality of life, ultrasound characteristics, hemoglobin levels 6 weeks post-operative, sexual function and menstrual bleeding control. A cost-analysis was also performed. Short-term primary and secondary outcomes are reported elsewhere. STUDY DESIGN: A double-blind, randomized, controlled, non-inferiority trial in nine hospitals in the Netherlands. Participants were randomized in a 1:1 ratio (block size of four, stratified per hospital) to either UPA or GnRHa pre-treatment. Additional placebo injections containing saline, respectively daily placebo tablets were given to both groups to ensure double-blinding. Surgery was performed within a month after the last tablet. Women were followed up until six months post-surgery. RESULTS: A total of 55 participants were randomized: 30 to the UPA- and 25 to the GnRHa-group between May 2015 and July 2017. Uterine volume at six weeks post-operative did not differ significantly between both pre-treatment groups with 170.1 cm3 (106.8-243.5; N = 29) vs. 152.8 cm3 (92.3-205.6; N = 23) for the UPA- and GnRHa-group respectively (p = 0.423). Hemoglobin levels six weeks post-operatively recovered back to baseline and were not significantly different between groups with 7.7 mmol/L for the UPA- vs. 8.1 mmol/L for the GnRHa-group (p = 0.157; mean difference -0.4 (CI -0.9, 0.2). Menstrual bleeding pattern, quality of life, effects on general and sexual health showed a significant improvement compared to baseline in both groups without any differences between the treatment groups. Symptom severity scores also decreased significantly at 6 week post-operatively compared to baseline, but did not differ between the treatment groups. Fibroid characteristics at baseline (e.g. mean diameter of largest fibroid) appeared not to be a confounding factor. An exploratory cost analysis showed no significant differences in absenteeism costs, total healthcare and societal costs, after adjustment for confounding factors. CONCLUSION: Pre-treatment prior to laparoscopic myomectomy with UPA compared to GnRHa has similar effects on bleeding pattern, menopausal symptoms, sexual functioning, symptom severity and quality of life from baseline up to six months post-operative. Due to the small sample size, these findings should be interpreted with caution. Also, no firm conclusions on costs could be made.

Ulipristal acetate vs gonadotropin-releasing hormone agonists prior to laparoscopic myomectomy (MYOMEX trial): Short-term results of a double-blind randomized controlled trial.

INTRODUCTION: Laparoscopic myomectomy can be difficult when fibroids are large and numerous. This may result in extensive intraoperative bleeding and the need for a conversion to a laparotomy. Medical pretreatment prior to surgery might reduce these risks by decreasing fibroid size and vascularization of the fibroid. We compared pretreatment with ulipristal acetate (UPA) vs gonadotropin-releasing hormone agonists (GnRHa) prior to laparoscopic myomectomy on several intra- and postoperative outcomes. MATERIAL AND METHODS: We performed a non-inferiority double-blind randomized controlled trial in nine hospitals in the Netherlands. Women were randomized between daily oral UPA for 12 weeks and single placebo injection or single intramuscular injection with leuprolide acetate and daily placebo tablets for 12 weeks. The primary outcome was intraoperative blood loss. Secondary outcomes were reduction of fibroid volume, suturing time, total surgery time and surgical ease. RESULTS: Thirty women received UPA and 25 women leuprolide acetate. Non-inferiority of UPA regarding intraoperative blood loss was not demonstrated. When pretreated with UPA, median intraoperative blood loss was statistically significantly higher (525 mL [348-1025] vs 280 mL[100-500]; P = 0.011) and suturing time of the first fibroid was statistically significantly longer (40 minutes [28-48] vs 22 minutes [14-33]; P = 0.003) compared with GnRHa. Pretreatment with UPA showed smaller reduction in fibroid volume preoperatively compared with GnRHa (-7.2% [-35.5 to 54.1] vs -38.4% [-71.5 to -19.3]; P = 0.001). Laparoscopic myomectomies in women pretreated with UPA were subjectively judged more difficult than in women pretreated with GnRHa. CONCLUSIONS: Non-inferiority of UPA in terms of intraoperative blood loss could not be established, possibly due to the preliminary termination of the study. Pretreatment with GnRHa was more favorable than UPA in terms of fibroid volume reduction, intraoperative blood loss, hemoglobin drop directly postoperatively, suturing time of the first fibroid and several subjective surgical ease parameters.

Differences in fibroid vascularity after three months of pre-treatment with leuprolide acetate or ulipristal acetate: A pilot study.

OBJECTIVES: To investigate differences in volume and fibroid vascularity expressed in vascular index after three months of (pre-)treatment with leuprolide acetate (LPA) or ulipristal acetate (UPA). STUDY DESIGN: Prospective pilot study of 23 premenopausal women with uterine fibroids. Patients who started with LPA or UPA and had at least one fibroid with a size between 3 and 12 cm, were included consecutively. Per patient one fibroid was evaluated. The ultrasound was performed at baseline and after three months using LPA or UPA using a standardized protocol. 3D scans were evaluated using VOCAL software to calculate outcomes of volume, vascular index (VI) without shell ("shell off") and of the inner shell. RESULTS: Four patients in the LPA group were additionally excluded from analyses due to insufficient quality of 3D scans. In the ten remaining patients (pre-)treated with LPA both volume and vascular indices of the fibroid reduced significantly after three months from a median of 224.3 cm3 (IQR 338.0) to 124.8 cm3 (IQR 186.1) (p = 0,05); median VI fibroid (shell off) reduced from 4.30 (IQR 4.72) to 0.93 (IQR 1.54) (p = 0,05); and VI inner capsule from 6.34 (IQR 7.51) to 1.28 (IQR 2.13) (p = 0,05). After UPA (n = 9) changes in fibroid volume and vascular indices did not reach statistical significance. Volume reduced from 248.5 cm3 (IQR 271.9) to 140.7 cm3 (IQR 209.4) (p > 0,05); median VI fibroid (shell off) from 2.97 (IQR 3.81) to 2.90 (IQR 4.82) (p > 0,05); and VI inner capsule from 2.56 (IQR 7.48) to 2.89 (IQR 4.83) (p > 0,05). A strong positive correlation was found between the VI of the fibroid (shell off) at baseline with the volume change after three months of LPA use (LPA r = 0.636, p = 0.048, 95% CI = -0.03 - 1.00). CONCLUSION: In this pilot study we observed a consistent and statistically significant decrease in VI and fibroid volume after three months of LPA treatment in patients with uterine fibroids. The decrease in fibroid volume and VI was less consistent after UPA use. The strong correlation between the VI at baseline and volume reduction, may in theory be used to predict the volume reduction after LPA.

The influence of the vaginal microbiota on preterm birth: A systematic review and recommendations for a minimum dataset for future research.

OBJECTIVE: This systematic review aims to identify, critically appraise and summarize the results of studies examining the relationship between the vaginal microbiota and preterm birth (PTB). METHODS: We searched the electronic databases Medline, EMBASE and the Cochrane Controlled Register of Trials for studies in any language reporting on vaginal microbiota and PTB published from 1990 to November 29th, 2017. We included any study that performed lower genital tract microbiota assessment in asymptomatic pregnant women and reported on spontaneous preterm birth, with either intact or ruptured membranes. RESULTS: The search strategy yielded 2171 unique citations, of which nine studies were eligible for inclusion in this review. In six studies an association was found between the composition of the vaginal microbiota and PTB, but findings differed between subgroups, ethnicities and degree of risk of PTB. In three studies no association was found. Two of these studies found a significant difference in richness and Shannon diversity between term and PTB. CONCLUSIONS: We have demonstrated that there is a paucity of molecular based, culture-independent studies that analyse the relationship between the vaginal microbiota and PTB as an outcome. The heterogeneity precluded a meta-analysis. Studies provide contradictory evidence and the quality of the clinical information in the studies is poor. To improve quality of future studies we have provided a database of essential and desirable items of quality that are method and topic specific.

Pre-treatment with GnRHa or ulipristal acetate prior to laparoscopic and laparotomic myomectomy: A systematic review and meta-analysis.

BACKGROUND: Myomectomy has potential risks of complications. To reduce these risks, medical pre-treatment can be applied to reduce fibroid size and thereby potentially decrease intra-operative blood loss, the need for blood transfusion and emergency hysterectomy. The aim of this systematic review and meta-analysis is to study the effectiveness of medical pre-treatment with Gonadotropin-releasing hormone agonists (GnRHa) or ulipristal acetate prior to laparoscopic or laparotomic myomectomy on intra-operative and post-operative outcomes. METHODS: We performed an extensive search in Embase.com, Wiley/Cochrane Library and PubMed in accordance with the Prisma guidelines. All studies published as full papers in peer reviewed journals using GnRHa or ulipristal acetate as medical pre-treatment independent of route of administration or dosage before laparotomic or laparoscopic myomectomy were included. The primary outcome was duration of surgery. Secondary outcomes were duration of enucleation, blood loss, degree of difficulty of surgery, identification of cleavage planes, proportion of vertical incisions, conversion rate, frequency of blood transfusions, post-operative complications, duration of hospital stay, frequency of recurrence of fibroids, frequency of uterine adhesions, recovery time and quality of life. No language restrictions were applied. Meta-analysis were performed where possible. FINDINGS: Twenty-three studies were included. In laparotomic myomectomy, pre-treatment with GnRHa decreases intra-operative blood loss with 97.39ml (95% CI -111.80 to -82.97) compared to no pre-treatment or placebo. Pre-treatment with GnRHa before laparoscopic myomectomies also shows a reduction in intra-operative blood loss by 23.03ml (95% CI -40.79 to -5.27) and in the frequency of blood transfusions (OR 0.17, 95% CI 0.05 to 0.55) compared to no pre-treatment. Only two retrospective cohort studies reported on pre-treatment with ulipristal acetate compared to no pre-treatment before laparoscopic myomectomy showing a statistically significant reduction in intra-operative blood loss, duration of surgery and frequency of blood transfusions after pre-treatment with ulipristal acetate. CONCLUSION: Administration of GnRHa prior to laparotomic myomectomy reduces blood loss and might decrease uterine adhesion formation. Pre-treatment with GnRHa before laparoscopic myomectomy reduces blood loss, the frequency of blood transfusions and might increase recurrence rate of fibroids, however it should be taken into account that some results are mainly based on cohort studies. Other pre-treatment agent ulipristal acetate has not been investigated sufficiently for relevant surgical outcomes.

Endometrial changes during ulipristal acetate use: A systematic review.

Ulipristal acetate is increasingly used for several clinical indications, like emergency contraception and pre-treatment of uterine fibroids. It has mixed progesterone agonist and antagonist effects in the myometrium and endometrium. Due to its progesterone antagonistic effect, an unopposed estrogen effect could occur which could cause (pre-)malignant lesions in the endometrium. Several studies have been performed to evaluate this possible increased risk for endometrial malignancies when using ulipristal acetate. The specific spectrum of morphological changes due to ulipristal acetate, named progesterone receptor modulator associated endometrial changes (PAEC), occurs to be reversible after discontinuing ulipristal acetate. In this systematic review we provide a detailed overview of the literature on histopathological endometrial changes and imaging characteristics of the endometrium in ulipristal acetate users. We performed an extensive search in Embase.com, Wiley/Cochrane Library and PubMed in accordance with the prisma guidelines. All studies published as full papers in peer reviewed journals using ulipristal acetate reporting on endometrial changes were included, independent of clinical indication, dosage taken and duration of therapy. No language restrictions were applied. Ten studies with a total of 1450 participants were included. Seven were randomized clinical trials and three prospective cohort studies. A quality assessment of all included studies was performed. In only five of ten studies an endometrial biopsy was performed during treatment. All of these studies described specific histological non-physiological endometrial changes (PAEC) due to ulipristal acetate, varying from 41 to 78.8% of all patients. Three of these studies also performed follow-up biopsies after discontinuing ulipristal acetate. The percentage of PAEC decreased from 62% to 0%, 78.8% to 0% and from 59% to 6-7% after the treatment period. In six of 1450 women (0.4%) endometrial hyperplasia was reported during or after ulipristal acetate use. Five were simple hyperplasia, one biopsy showed simple atypical endometrial hyperplasia that resolved into benign secretory endometrium by the end of the treatment. One case of endometrial adenocarcinoma was reported, however this does not seem to be related to ulipristal acetate use, since it was already present at the baseline biopsy. In eight of ten studies a transvaginal ultrasound or MRI was performed at any moment to assess the endometrial thickness before, during and after treatment. Most studies showed a transient increase of endometrial thickness during treatment, which returned to normal within a few weeks after discontinuing ulipristal acetate. Based on the literature found in this systematic review, follow-up after a maximum of four courses of ulipristal acetate did not report any non-reversible (pre-)malignant lesions of the endometrium. Most studies focused on short term use of ulipristal acetate and their follow-up period was limited. Therefore, we believe more information concerning long term (intermittent) use is needed before it can be concluded that its use is completely safe.

Is a multispecies probiotic mixture effective in constipation during pregnancy? 'A pilot study'.

BACKGROUND: Constipation during pregnancy is a common problem. Nowadays only few effective interventions are published preventing or treating constipation during pregnancy. However, their use is limited due to side-effects. This uncontrolled intervention study was performed to determine if a mixture of probiotics in the treatment of constipation during pregnancy is effective. METHODS: Women aged ≥ 18 years with functional constipation were included at the Obstetrical outpatient clinic and midwife practices. Patients received during four weeks a daily dose of Ecologic®Relief (Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Bifidobacterium longum W108, Lactobacillus casei W79, Lactobacillus plantarum W62 and Lactobacillus rhamnosus W71 (total 4*109 CFU)). For all analyses, the non-parametric paired Wilcoxon test was used. Primary outcome measure was change in defecation frequency. Secondary outcome measures were stool consistency, sensation of incomplete evacuation, sensation of anorectal obstruction, manual manoeuvres to facilitate defecation, abdominal pain, adverse effects, presence of reflux episodes and intake of Bisacodyl. RESULTS: 20 women were included. Defecation frequency significantly increased from 3.1 at baseline to 6.7 in week four (p < 0.01). Compared to baseline, a significant decrease in 1) sensation of anorectal obstruction from 90.0% to 45.0% (p < 0.01), 2) sensation of incomplete evacuation from 90.0% to 40.0% (p < 0.01), 3) straining during defecation from 100% to 65% (p = 0.01), 4) episodes of abdominal pain from 60% to 20% (p = 0.01) and 5) the presence of reflux episodes from 60% to 20% in week four (p = 0.01) was found. Other secondary outcomes did not decrease significantly. No side effects were reported. CONCLUSIONS: Ecologic®Relief is effective in the treatment of constipation during pregnancy. A randomised placebo controlled trial is required to confirm these data.