Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT.

BACKGROUND: Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage. OBJECTIVES: (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding. DESIGN: A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding. SETTING: A total of 48 hospitals in the UK. PARTICIPANTS: Women aged 16-39 years with early pregnancy bleeding. INTERVENTIONS: Women aged 16-39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation. MAIN OUTCOME MEASURES: The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective. RESULTS: A total of 4153 women from 48 hospitals in the UK received either progesterone (n = 2079) or placebo (n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004). A significant post hoc subgroup effect (interaction test p = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval -£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation. CONCLUSIONS: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets. TRIAL REGISTRATION: Current Controlled Trials ISRCTN14163439, EudraCT 2014-002348-42 and Integrated Research Application System (IRAS) 158326. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 33. See the NIHR Journals Library website for further project information.

Miscarriage is a common complication of pregnancy that affects one in five pregnancies. Several small studies have suggested that progesterone, a hormone essential for maintaining a pregnancy, may reduce the risk of miscarriage in women presenting with early pregnancy bleeding. This research was undertaken to test whether or not progesterone given to pregnant women with early pregnancy bleeding would increase the number of live births when compared with placebo (dummy treatment). The women participating in the study had an equal chance of receiving progesterone or placebo, as determined by a computer; one group received progesterone (400 mg twice daily as vaginal pessaries) and the other group received placebo with an identical appearance. Treatment began when women presented with vaginal bleeding, were < 12 weeks of gestation and were found to have at least a pregnancy sac on an ultrasound scan. Treatment was stopped at 16 weeks of gestation, or earlier if the pregnancy ended before 16 weeks. Neither the participants nor their health-care professionals knew which treatment was being received. In total, 23,775 women were screened and 4153 women were randomised to receive either progesterone or placebo pessaries. Altogether, 2972 participants had a live birth after at least 34 weeks of gestation. Overall, the live birth rate in the progesterone group was 75% (1513 out of 2025 participants), compared with 72% (1459 out of 2013 participants) in the placebo group. Although the live birth rate was 3% higher in the progesterone group than in the placebo group, there was statistical uncertainty about this finding. However, it was observed that women with a history of one or more previous miscarriages and vaginal bleeding in their current pregnancy may benefit from progesterone. For women with no previous miscarriages, our analysis showed that the live birth rate was 74% (824 out of 1111 participants) in the progesterone group compared with 75% (840 out of 1127 participants) in the placebo group. For women with one or more previous miscarriages, the live birth rate was 75% (689 out of 914 participants) in the progesterone group compared with 70% (619 out of 886 participants) in the placebo group. The potential benefit appeared to be most strong for women with three or more previous miscarriages, who had a live birth rate of 72% (98 out of 137 participants) in the progesterone group compared with 57% (85 out of 148 participants) in the placebo group. Treatment with progesterone did not appear to have any negative effects.

The cost-effectiveness of progesterone in preventing miscarriages in women with early pregnancy bleeding: an economic evaluation based on the PRISM trial.

OBJECTIVES: To assess the cost-effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding. DESIGN: Economic evaluation alongside a large multi-centre randomised placebo-controlled trial. SETTING: Forty-eight UK NHS early pregnancy units. POPULATION: Four thousand one hundred and fifty-three women aged 16-39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac. METHODS: An incremental cost-effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages. MAIN OUTCOME MEASURES: Cost per additional live birth at ≥34 weeks of gestation. RESULTS: Progesterone intervention led to an effect difference of 0.022 (95% CI -0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI -£559 to £711) more than the mean cost in the placebo group. The incremental cost-effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014-0.096) and this was associated with a cost saving of £322 (95% CI -£1318 to £673). CONCLUSIONS: The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost-effective intervention, particularly for women with previous miscarriage(s). TWEETABLE ABSTRACT: Progesterone treatment is likely to be cost-effective in women with early pregnancy bleeding and a history of miscarriage.

A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy.

BACKGROUND: Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. RESULTS: A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups. CONCLUSIONS: Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.).

Nexplanon Subdermal Implant: Assessment of Sexual Profile, Metabolism, and Bleeding in a Cohort of Italian Women.

OBJECTIVES: To evaluate the impact on metabolism, bleeding, and sexual function of Nexplanon, a subdermal implant. STUDY DESIGN: We recruited women (n=101) receiving the Nexplanon implant at two university centers in Italy between 2011 and 2016 into this prospective, observational, multicenter research trial. Participants completed the Interview for Ratings of Sexual Function (IRSF) and the Female Sexual Function Index (FSFI) questionnaires before and 3 and 6 months after the implant was inserted. In addition, all blood parameters were assessed at these visits. All women were given a menstrual diary card and a pictorial blood assessment chart to record daily any vaginal bleeding. RESULTS: The studied metabolic parameters remained in the normal range, showing no alarming modifications: minimal statistical reductions (in aspartate aminotransferase, alanine aminotransferase, total cholesterol, triglycerides, and activated partial thromboplastin time) and increases (in glucose and prothrombin activity) were observed. Changes in IRSF score over 6 months showed a significant increase in pleasure, personal initiative, orgasm, intensity of orgasm, and satisfaction, and a significant decrease in anxiety and discomfort. Mean Body Mass Index decreased, and the weekly frequency of sexual intercourse increased. CONCLUSIONS: Nexplanon showed not only a lower metabolic and bleeding impact, but also important positive effects on sexual function. It expands the range of possibilities for women, 38 and couples, in the modern concepts of sexual and reproductive wellbeing.

Sangramento uterino anormal: proposta de abordagem do Grupo Heavy Menstrual Bleeding: Evidence-Based Learning for Best Practice (HELP) / Heavy menstrual bleeding: management proposal of the Heavy Menstrual Bleeding: Evidence-Based Learning for Best Practice Group (HELP)

O Sangramento Uterino Anormal (SUA) representa um problema de saúde pública complexo que pode acometer 1/3 das mulheres em todo o mundo. Apresenta um impacto negativo importante na qualidade de vida de mulheres e associa-se a elevados custos econômicos diretos e indiretos. Trata-se de uma condição desafiadora tanto para as mulheres afetadas quanto para os profissionais de saúde. A nomenclatura atribuída ao SUA é confusa e faltam ainda recomendações diagnósticas e terapêuticas padronizadas. Foi criado o grupo Heavy Menstrual Bleeding: Evidence-based Learning for Best Practice (HELP) com proposta abordar os aspectos inconclusivos do SUA. Foram avaliados 134 documentos, incluindo 121 artigos científicos e 14 revisões de medicamentos, para desenvolvimento dos protocolos HELP. Foram elaborados protocolos simplificados referentes ao diagnóstico e tratamento do SUA, visando contribuir de forma mais eficaz com os médicos em seus diferentes cenários de atuação. O roteiro diagnóstico sugerido, compreendendo perguntas chaves e ações específicas, sinaliza para indicação de métodos propedêuticos adicionais. O tratamento proposto visa reduzir a perda do sangue menstrual e melhorar de a qualidade de vida das pacientes.(AU)

Abnormal uterine bleeding (AUB) is a complex public health problem that can affect one third of women worldwide. It has a significant negative impact on quality of life of women and is associated with high direct and indirect economic costs. It is a challenging condition for both the women affected and for the health professionals. The nomenclature assigned to the AUB is confusing and still miss diagnostic and therapeutic recommendations standardized. The Heavy Menstrual Bleeding: Evidence-based Learning for Best Practice Group (HELP) was created with the proposal to address the inconclusive aspects of AUB. The group evaluated 134 documents, including 121 scientific articles and 14 reviews of drugs for the development of protocols HELP. Simplified protocols were drawn up relating to the diagnosis and treatment of AUB, to contribute more effectively with doctors at different scenarios of operation. The script diagnostic suggested, comprising keys questions and specific actions, can indicate additional diagnostic methods. The proposed treatment aims to reduce the loss of menstrual blood and improve the quality of life of patients.(AU)

Ultrasound assessment of endometrial cavity in perimenopausal women on oral progesterone for abnormal uterine bleeding: comparison of diagnostic accuracy of imaging with hysteroscopy-guided biopsy.

AIM: To investigate the effect of oral progesterone on the accuracy of imaging studies performed to detect endometrial pathology in comparison to hysteroscopy-guided biopsy in perimenopausal women on progesterone treatment for abnormal uterine bleeding. METHODS: The study population comprised of women aged 40-55 years with complaints of abnormal uterine bleeding who were also undergoing oral progesterone therapy. Women with a uterus ≥ 12 weeks' gestation size, previous abnormal endometrial biopsy, cervical lesion on speculum examination, abnormal Pap smear, active pelvic infection, adnexal mass on clinical examination or during ultrasound scan and a positive pregnancy test were excluded. A transvaginal ultrasound followed by saline infusion sonography were done. On the following day, a hysteroscopy followed by a guided biopsy of the endometrium or any endometrial lesion was performed. Comparison between the results of the imaging study with the hysteroscopy and guided biopsy was done. RESULTS: The final analysis included 83 patients. For detection of overall pathology, polyp and fibroid transvaginal ultrasound had a positive likelihood ratio of 1.65, 5.45 and 5.4, respectively, and a negative likelihood ratio of 0.47, 0.6 and 0.43, respectively. For detection of overall pathology, polyp and fibroid saline infusion sonography had a positive likelihood ratio of 4.4, 5.35 and 11.8, respectively, and a negative likelihood ratio of 0.3, 0.2 and 0.15, respectively. CONCLUSION: In perimenopausal women on oral progesterone therapy for abnormal uterine bleeding, imaging studies cannot be considered as an accurate method for diagnosing endometrial pathology when compared to hysteroscopy and guided biopsy.

Levonorgestrel-releasing intrauterine system vs. endometrial thermal ablation for menorrhagia.

OBJECTIVE: To evaluate the efficacy of a Levonorgestrel-releasing Intrauterine System (LNG-IUS) in controlling menorrhagia in comparison with endometrial thermal rollerball ablation. DESIGN: Seventy-nine consecutive patients with menorrhagia underwent either LNG-IUS insertion (n=42) or hysteroscopical endometrial thermal rollerball ablation (n=37) in a prospective, observational, comparative study. Women reported duration of uterine bleeding in days prior to, and six and 12 months after each intervention. Prior to each intervention, endometrial, cervical or other pathological conditions of the genital tract were excluded. GnRH analogues for endometrial suppression were given for ten weeks before endometrial ablation but not prior to LNG-IUS insertion. RESULTS: There were no differences in duration of uterine bleeding before each intervention in the two groups. The duration of uterine bleeding was lower in the LNG-IUS group as compared with endometrial ablation at six (p<0.001) and 12 months (p<0.001) after each intervention. Furthermore, the effect on reduction of bleeding was stronger in the LNG-IUS group as compared with the endometrial ablation group at six (p<0.001) and 12 months (p<0.001). CONCLUSIONS: The LNG-IUS was more efficacious than endometrial thermal ablation in reducing duration of uterine bleeding at six and 12 months post-intervention.

Cost-effectiveness of treatments for dysfunctional uterine bleeding in women who need contraception.

OBJECTIVE: This study aims to compare the cost-effectiveness of oral contraceptives (OCs), the levonorgestrel-releasing intrauterine system (LNG-IUS) and surgical management in treating dysfunctional uterine bleeding (DUB) in women not desiring additional children. METHOD: A Markov model was constructed from the perspective of the health services payers for a 5-year period. Treatment costs, DUB treatment success rates and contraception success rates were obtained through a literature review. RESULTS: In women not responding to an initial trial of OCs, surgical management was more effective than the LNG-IUS (95.5% vs. 92%) but at higher cost (US$4853 vs. US$2796 per woman). Among responders to OCs, continuing treatment with the LNG-IUS instead of OCs was more effective (92% vs. 90.4%) and less expensive (US$2796 vs. US$4711). For women naïve to medical therapy, the LNG-IUS and OCs had similar effectiveness, but cost for the LNG-IUS was lower (US$2796 vs. US$4895). In all scenarios, surgery followed if medical therapy failed; rates of primary method failure were 62.5% with OCs and 34% with the LNG-IUS at 12 months. CONCLUSIONS: Treatment strategies employing the LNG-IUS are the most cost-effective in managing DUB, regardless of whether a woman has previously tried OC therapy.

Climacteric symptoms and hormones.

Climacteric symptoms are so closely associated with the menopause to be practically considered its hallmark. However, symptoms can already appear before the onset of menopause. The frequency, extent and intensity of symptoms are dependent on social factors, body composition, race and geographical region. In about 20-25% of menopausal women they do not occur at all. These symptoms are most prominent in women who are suddenly deprived of their endogenous estrogen secretion, for instance by bilateral ovariectomy, particularly in younger women. Climacteric symptoms can to be subdivided into five categories: menstrual bleeding disorders; vegetative symptoms; psychosomatic symptoms; somatotrophic changes; and metabolic changes. For prevention and treatment of the various symptoms, estrogen/progestogen replacement therapy (HRT) or estrogen replacement therapy (ERT) in individualized dosages and various forms of applications are the most cost-effective modalities in order to control menopausal symptoms and restore organic function, or prevent all of this and improve women's quality of life. Recent publications indicate that gene polymorphisms may be associated with severe and persistent climacteric symptoms. This is also true for current and ever cigarette smokers.

[Hysteroscopic ablation of the endometrium in cases of dysfunctional uterine bleeding--advantage of preparations including zoladex]. / Khisteroskopska ablatsiia na endometriuma pri disfunktsionalni matochni kruvotechniia--predimstva na podgotovkata sus Zoladeks.

Hysteroscopic endometrial ablation (HEA) is a new alternative for patients with dysfunctional uterine bleeding (DUB), resistant to medical treatment. The relatively thin endometrium is a big advantage at the time of operation. In this article the results of an initial series of hysteroscopic operations (HEA) are given--as a whole and depending on preoperative treatment with GnRH-agonist. Seventeen patients with DUB underwent HEA. Six of them were pretreated with Goserelin acetate (Zoladex 3.6 mg, Astra Zeneca) two subcutaneous application at 28 days interval. The other 11 women were operated in the early postmenstrual period without medical pretreatment. Comparison was made between the two groups regarding preoperative endometrial thickness, operative time, operative complications, duration of hospital stay, change of the menstrual pattern after 6 and 12 months. Results showed 41.2% achievement of persistent amenorrhoea in patients as a whole (62.7% in the Zoladex group and 27.2% in the untreated group). Better results in the patients with Zoladex pretreatment (shorter operative time, higher incidence of amenorrhoea, patient's higher evaluation of the operation) can be explained with the reduced endometrial thickness at the time procedure. The authors consider the hysteroscopic roller-ball endometrial ablation as an upto-date cost-effective method for treatment of DUB. The method is quick, with very low incidence of complications, easy toleration, immediately recovery of the patient and the only possibility for women with high anaesthesiologic and operative risk. Two depot-doses of Zoladex before hysteroscopy lead to better intra- and postoperative results.

A cohort analysis of pre-menopausal women with dysfunctional uterine bleeding.

OBJECTIVE: To examine the clinical and cost outcomes of patients with dysfunctional uterine bleeding (DUB) who are treated with hysterectomy or not. DESIGN: A retrospective analysis of DUB patients over 30 months of treatment after initial diagnosis. SETTING: Patients with DUB from an HMO with over 200,000 enrollees. PARTICIPANTS: Study patients, all women with an initial diagnosis of DUB, were divided into two cohorts. Cohort 1 was women who had a hysterectomy (not for cancer); Cohort 2 was women who did not have a hysterectomy. MAIN OUTCOME MEASURES: Visit counts and costs, prescription counts and costs, hospital costs, and procedure counts. RESULTS: Hysterectomy patients in our dataset tend to have more prescriptions, higher prescription costs, more visits overall, higher visit costs, higher hospitalization costs, and higher total costs per member per month (PMPM) than non-hysterectomy patients. After surgery, the hysterectomy patients' costs and utilization PMPM are higher than those for the non-hysterectomy patients. CONCLUSIONS: There is wide variation in the treatment of patients with DUB. Clinical practice improvement studies are needed to determine the appropriate treatments based on patient characteristics to achieve better outcomes for lower costs.

Assessment of medical treatments for menorrhagia.

Although usually not life-threatening, dysfunctional uterine bleeding (DUB) can cause discomfort and disruption to life for many women. It has been poorly researched in the past, primarily because of difficulties in trying to accurately measure blood loss and response to treatment. There are several different therapies currently available but, for many, actual evidence of their efficacy is lacking from scientific data. Progestogens are the most frequently prescribed drugs for the treatment of DUB. Data support their use in anovulatory women but a number of comparative trials have shown that an overall reduction in blood loss of only 20% is achieved in ovulatory women. Their use, therefore, must be questioned as the first line of treatment. Combined oral contraceptives were at one time popular but whether the low-dose, current generation pills are equally effective awaits appropriate trials. Prostaglandin synthetase inhibitors can be useful, with up to a third of women with menorrhagia benefiting from a reduction of between 25% and 35% in blood loss. A proportionally greater reduction is seen in women with more excessive bleeding. Antifibrinolytic drugs have been shown to reduce menstrual blood loss in DUB by 50% and would be useful in women in whom oestrogens are contraindicated. Gonadotrophin-releasing hormone analogues are highly effective because of their ability to induce amenorrhoea, but long-term use is contraindicated because of their hypo-oestrogenic effects. One other effective therapy for menorrhagia has been danazol.(ABSTRACT TRUNCATED AT 250 WORDS)

Medication costs in different provider settings.

Comparison was made of the cost of medications between Shared Health Facilities (SHFs) or Medicaid Mills and a Neighborhood Health Center (NHC) for nine conditions in fields of adult medicine, pediatrics, and gynecology. A total of 10 cases from SHF reviews were matched by diagnosis, age, and length of time under care with those in the NHC. For otitis media and pharyngitis in children and questionable urinary tract infection and vaginitis in adult women, the average costs were significantly higher in the SHFs. Average costs for family planning services and vaginal bleeding were higher in the SHFs but not significantly so. Medication costs for children with asthma and adults with bronchitis and hypertension were approximately the same in both settings. The reasons for higher costs included greater use of more expensive antibiotics, concurrent use of decongestants and antihistamines for infectious conditions of childhood, and dispensing of medications on "shot-gun" basis without adequate diagnostic studies. The most striking difference was the additional average cost of $798 for hospitalization of the SHF patients with vaginal bleeding when D & C and surgery were performed. The NHC women had no hospitalizations as the recommended procedure of endocervical biopsy in the office was Center policy. Other quality inferences noted in the NHC, but not in SHFs, were routine performance of throat cultures for pharyngitis, wet smears for vaginitis, and deferral of treatment until cultures were received for urinary tract infection. The small number of cases for each condition and the large intersample variability were limiting factors in this study, but the findings do suggest that higher standards of care contribute to lower therapy costs.