A mixed-methods study to investigate feasibility and acceptability of an early warning score for preterm infants in neonatal units in Kenya: results of the NEWS-K study : Neonatal early warning scores in Kenya.

Preterm birth (< 37 weeks gestation) complications are the leading cause of neonatal mortality. Early-warning scores (EWS) are charts where vital signs (e.g., temperature, heart rate, respiratory rate) are recorded, triggering action. To evaluate whether a neonatal EWS improves clinical outcomes in low-middle income countries, a randomised trial is needed. Determining whether the use of a neonatal EWS is feasible and acceptable in newborn units, is a prerequisite to conducting a trial. We implemented a neonatal EWS in three newborn units in Kenya. Staff were asked to record infants' vital signs on the EWS during the study, triggering additional interventions as per existing local guidelines. No other aspects of care were altered. Feasibility criteria were pre-specified. We also interviewed health professionals (n = 28) and parents/family members (n = 42) to hear their opinions of the EWS. Data were collected on 465 preterm and/or low birthweight (< 2.5 kg) infants. In addition to qualitative study participants, 45 health professionals in participating hospitals also completed an online survey to share their views on the EWS. 94% of infants had the EWS completed at least once during their newborn unit admission. EWS completion was highest on the day of admission (93%). Completion rates were similar across shifts. 15% of vital signs triggered escalation to a more senior member of staff. Health professionals reported liking the EWS, though recognised the biggest barrier to implementation was poor staffing. Newborn unit infant to staff ratios varied between 10 and 53 staff per 1 infant, depending upon time of shift and staff type. A randomised trial of neonatal EWS in Kenya is possible and acceptable, though adaptations are required to the form before implementation.

Long acting progestogens versus combined oral contraceptive pill for preventing recurrence of endometriosis related pain: the PRE-EMPT pragmatic, parallel group, open label, randomised controlled trial.

OBJECTIVES: To evaluate the clinical effectiveness of long acting progestogens compared with the combined oral contraceptive pill in preventing recurrence of endometriosis related pain. DESIGN: The PRE-EMPT (preventing recurrence of endometriosis) pragmatic, parallel group, open label, randomised controlled trial. SETTING: 34 UK hospitals. PARTICIPANTS: 405 women of reproductive age undergoing conservative surgery for endometriosis. INTERVENTIONS: Participants were randomised in a 1:1 ratio using a secure internet facility to a long acting progestogen (depot medroxyprogesterone acetate or levonorgestrel releasing intrauterine system) or the combined oral contraceptive pill. MAIN OUTCOME MEASURES: The primary outcome was pain measured three years after randomisation using the pain domain of the Endometriosis Health Profile 30 (EHP-30) questionnaire. Secondary outcomes (evaluated at six months, one, two, and three years) included the four core and six modular domains of the EHP-30, and treatment failure (further therapeutic surgery or second line medical treatment). RESULTS: 405 women were randomised to receive a long acting progestogen (n=205) or combined oral contraceptive pill (n=200). At three years, there was no difference in pain scores between the groups (adjusted mean difference -0.8, 95% confidence interval -5.7 to 4.2, P=0.76), which had improved by around 40% in both groups compared with preoperative values (an average of 24 and 23 points for long acting progestogen and combined oral contraceptive pill groups, respectively). Most of the other domains of the EHP-30 also showed improvement at all time points compared with preoperative scores, without evidence of any differences between groups. Women randomised to a long acting progestogen underwent fewer surgical procedures or second line treatments compared with those randomised to the combined oral contraceptive pill group (73 v 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). CONCLUSIONS: Postoperative prescription of a long acting progestogen or the combined oral contraceptive pill results in similar levels of improvement in endometriosis related pain at three years, with both groups showing around a 40% improvement compared with preoperative levels. While women can be reassured that both options are effective, the reduced risk of repeat surgery for endometriosis and hysterectomy might make long acting reversible progestogens preferable for some. TRIAL REGISTRATION: ISRCTN registry ISRCTN97865475.

Metformin for endometrial hyperplasia.

BACKGROUND: Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates. Endometrial hyperplasia is a precancerous condition in women that can lead to endometrial cancer if left untreated. Endometrial hyperplasia occurs more commonly than endometrial cancer. Progesterone tablets that are currently used to treat women with endometrial hyperplasia are associated with adverse effects in up to 84% of women. A levonorgestrel intrauterine device may improve compliance, but it is invasive, is not acceptable to all women, and is associated with irregular vaginal bleeding in 82% of cases. Therefore, an alternative treatment for women with endometrial hyperplasia is needed. Metformin, a drug that is often used to treat people with diabetes, has been shown, in some human studies, to reverse endometrial hyperplasia. However, the effectiveness and safety of metformin for treatment of endometrial hyperplasia remain uncertain. This is an update of a review first published in 2017. OBJECTIVES: To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, PubMed, Embase, Google Scholar, OpenGrey, LILACS, and two trials registers from inception to 5 September 2022. We searched the bibliographies of all relevant studies, and contacted experts in the field for any additional trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cross-over trials comparing metformin (used alone or in combination with other medical therapies) versus placebo, no treatment, any conventional medical treatment, or any other active intervention for women with histologically confirmed endometrial hyperplasia of any type. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility, extracted data from included studies, assessed the risk of bias in the included studies, and assessed the certainty of the evidence for each outcome. We resolved disagreements by discussion or by deferring to a third review author. When study details were missing, review authors contacted the study authors. The primary outcome of this review was regression of endometrial hyperplasia histology (with or without atypia) towards normal histology. MAIN RESULTS: We included seven RCTs, in which a total of 387 women took part. In the comparison, Metformin plus megestrol versus megestrol alone, we rated the certainty of the evidence as low for the outcome, regression of endometrial hyperplasia. We rated the quality of the evidence as very low for the rest of the outcomes, in all three comparisons. Although there was a low risk of selection bias, there was a high risk of bias in the blinding of personnel and outcome assessment (performance bias and detection bias) in many studies. This update identified four new RCTs and six ongoing RCTs. Metformin versus megestrol We are uncertain whether metformin increases the regression of endometrial hyperplasia towards normal histology over megestrol (odds ratio (OR) 4.89, 95% confidence interval (CI) 1.56 to 15.32; P = 0.006; 2 RCTs, 83 participants; I² = 7%; very low-certainty evidence). This evidence suggests that if the rate of regression with megestrol is 61%, the rate of regression with metformin would be between 71% and 96%. It is unresolved whether metformin results in different rates of abnormal uterine bleeding or hysterectomy compared to megestrol. No study in this comparison reported progression of hyperplasia to endometrial cancer, recurrence of endometrial hyperplasia, health-related quality of life, or adverse effects during treatment. Metformin plus megestrol versus megestrol monotherapy The combination of metformin and megestrol may enhance the regression of endometrial hyperplasia towards normal histology more than megestrol alone (OR 3.27, 95% CI 1.65 to 6.51; P = 0.0007; 4 RCTs, 258 participants; I² = 0%, low-certainty evidence). This suggests that if the rate of regression with megestrol monotherapy is 54%, the rate of regression with the addition of metformin would be between 66% and 84%. In one study, 3/8 (37.5%) of participants who took metformin had nausea that settled without further treatment. It is unresolved whether the combination of metformin and megestrol results in different rates of recurrence of endometrial hyperplasia, progression of endometrial hyperplasia to endometrial cancer, or hysterectomy compared to megestrol monotherapy. No study in this comparison reported abnormal uterine bleeding, or health-related quality of life. Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system) monotherapy We are uncertain whether there is a difference between groups in the regression of endometrial hyperplasia towards normal histology (OR 0.29, 95% CI 0.01 to 7.56; 1 RCT, 46 participants; very low-certainty evidence). This evidence suggests that if the rate of regression with levonorgestrel monotherapy is 96%, the rate of regression with the addition of metformin would be between 73% and 100%. It is unresolved whether the combination of metformin and levonorgestrel results in different rates of abnormal uterine bleeding, hysterectomy, or the development of adverse effects during treatment compared to levonorgestrel monotherapy. No study in this comparison reported recurrence of endometrial hyperplasia, progression of hyperplasia to endometrial cancer, or health-related quality of life. AUTHORS' CONCLUSIONS: Review authors found insufficient evidence to either support or refute the use of metformin, specifically megestrol acetate, given alone or in combination with standard therapy, for the treatment of women with endometrial hyperplasia. Robustly designed and adequately powered randomised controlled trials, yielding long-term outcome data are still needed to address this clinical question.

Self-collected versus health-care professional taken swab for identification of vaginal-rectal colonisation with group B streptococcus in late pregnancy: a systematic review.

BACKGROUND: Testing for group B streptococcus (GBS) requires a vaginal-rectal swab in late pregnancy. OBJECTIVE: A systematic review of the test accuracy of a self-collected swab compared with a health-care professional collected swab in the diagnosis of GBS colonisation. SEARCH STRATEGY: The Cochrane Library (including the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects [DARE] and the Cochrane Central Register of Controlled Trials [CENTRAL]), EMBASE, MEDLINE and Trip were searched in May 2022. SELECTION CRITERIA: Randomised trials, test accuracy studies or diagnostic yield studies that compared the accuracy of a self-collected vaginal-rectal swab, compared to that taken by a health-care professional, for the detection of GBS colonisation in the third trimester. DATA COLLECTION AND ANALYSIS: Two researchers independently screened, selected studies, extracted data and assessed study quality. MAIN RESULTS: 10 studies, with 2578 women were included. Pooled sensitivity of self-collected swabs was 0.90 (95% confidence interval [CI] 0.81 to 0.95) and pooled specificity was 0.98 (95% CI 0.96 to 0.99). CONCLUSION: This study provides reassuring evidence that self-collected swabs for maternal GBS colonisation are highly accurate relative to swabs collected by health-care professionals. Women requiring a swab for GBS colonisation can self-swab with appropriate instructions if they choose. FUNDING: Personal fellowship from the University of Nottingham for KFW.

Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial.

Background: Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods: This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings: Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26-1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29-22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation: Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding: UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).

Combination of gefitinib and methotrexate to treat tubal ectopic pregnancy (GEM3): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy. METHODS: We performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m2) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930. FINDINGS: Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference -0·01, 95% CI -0·10 to 0·09; p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95% CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group. INTERPRETATION: In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions. FUNDING: National Institute of Health Research.

A randomized trial of synthetic osmotic cervical dilator for induction of labor vs dinoprostone vaginal insert.

BACKGROUND: Induction of labor is a commonly performed obstetrical intervention. Vaginal prostaglandin E2 (dinoprostone) is a first-choice agent. Mechanical methods of induction are slower in achieving cervical ripening but have a lower risk of adverse effects. OBJECTIVE: This study aimed to compare the efficacy, maternal and neonatal safety, and maternal satisfaction of a synthetic osmotic cervical dilator (Dilapan-S) with those of dinoprostone. STUDY DESIGN: This was an open-label superiority randomized controlled trial in 4 English hospitals. Eligible participants were women ≥16 years of age undergoing induction of labor for a singleton pregnancy at ≥37 weeks' gestation with vertex presentation and intact membranes. The women were randomly assigned to receive either Dilapan-S or dinoprostone using a telephone randomization system minimized by hospital, parity, body mass index, and maternal age. The induction agent was replaced as required until the cervix was assessed as favorable for labor by the Bishop score. The primary outcome was failure to achieve vaginal delivery (ieor a cesarean delivery being performed). The secondary outcome measures included maternal and neonatal adverse events. Analysis was by intention-to-treat, adjusting for design variables where possible. RESULTS: Between December 19, 2017 and January 26, 2021, 674 women were randomized (337 to Dilapan-S, and 337 to dinoprostone). The trial did not reach its planned sample size of 860 participants because of restrictions on research during the COVID-19 pandemic. The primary outcome was missing for 2 women in the dinoprostone group. Failure to achieve vaginal delivery (or a cesarean delivery being performed) occurred in 126 women (37.4%) allocated to Dilapan-S and in 115 (34.3%) women allocated to dinoprostone (adjusted risk difference, 0.02; 95% confidence interval, -0.05 to 0.10). There were similar maternal and neonatal adverse events between the groups. CONCLUSION: Women undergoing induction of labor with Dilapan-S have similar rates of cesarean delivery and maternal and neonatal adverse events compared with dinoprostone.

Rapid intrapartum test for maternal group B streptococcal colonisation and its effect on antibiotic use in labouring women with risk factors for early-onset neonatal infection (GBS2): cluster randomised trial with nested test accuracy study.

BACKGROUND: Mother-to-baby transmission of group B Streptococcus (GBS) is the main cause of early-onset infection. We evaluated whether, in women with clinical risk factors for early neonatal infection, the use of point-of-care rapid intrapartum test to detect maternal GBS colonisation reduces maternal antibiotic exposure compared with usual care, where antibiotics are administered due to those risk factors. We assessed the accuracy of the rapid test in diagnosing maternal GBS colonisation, against the reference standard of selective enrichment culture. METHODS: We undertook a parallel-group cluster randomised trial, with nested test accuracy study and microbiological sub-study. UK maternity units were randomised to a strategy of rapid test (GeneXpert GBS system, Cepheid) or usual care. Within units assigned to rapid testing, vaginal-rectal swabs were taken from women with risk factors for vertical GBS transmission in established term labour. The trial primary outcome was the proportion of women receiving intrapartum antibiotics to prevent neonatal early-onset GBS infection. The accuracy of the rapid test was compared against the standard of selective enrichment culture in diagnosing maternal GBS colonisation. Antibiotic resistance profiles were determined in paired maternal and infant samples. RESULTS: Twenty-two maternity units were randomised and 20 were recruited. A total of 722 mothers (749 babies) participated in rapid test units; 906 mothers (951 babies) were in usual care units. There was no evidence of a difference in the rates of intrapartum antibiotic prophylaxis (relative risk 1.16, 95% CI 0.83 to 1.64) between the rapid test (41%, 297/716) and usual care (36%, 328/906) units. No serious adverse events were reported. The sensitivity and specificity measures of the rapid test were 86% (95% CI 81 to 91%) and 89% (95% CI 85 to 92%), respectively. Babies born to mothers who carried antibiotic-resistant Escherichia coli were more likely to be colonised with antibiotic-resistant strains than those born to mothers with antibiotic-susceptible E. coli. CONCLUSION: The use of intrapartum rapid test to diagnose maternal GBS colonisation did not reduce the rates of antibiotics administered for preventing neonatal early-onset GBS infection than usual care, although with considerable uncertainty. The accuracy of the rapid test is within acceptable limits. TRIAL REGISTRATION: ISRCTN74746075 . Prospectively registered on 16 April 2015.

Parents, healthcare professionals and other stakeholders' experiences of caring for babies born too soon in a low-resource setting: a qualitative study of essential newborn care for preterm infants in Kenya.

OBJECTIVES: Prematurity is the leading cause of global neonatal and infant mortality. Many babies could survive by the provision of essential newborn care. This qualitative study was conducted in order to understand, from a family and professional perspective, the barriers and facilitators to essential newborn care. The study will inform the development of an early warning score for preterm and low birthweight infants in low and middle income countries (LMICs). SETTING: Single-centre, tertiary referral hospital in Nairobi, Kenya. PARTICIPANTS: Nineteen mothers and family members participated in focus group discussions and 20 key-informant interviews with professionals (healthcare professionals and policy-makers) were conducted. Focus group participants were identified via postnatal wards, the newborn unit and Kangaroo Mother Care (KMC) unit. Convenience and purposive sampling was used to identify professionals. OUTCOME MEASURES: Understanding facilitators and barriers to provision of essential newborn care in preterm infants. RESULTS: From 27 themes, three global themes emerged from the data: mothers' physical and psychological needs, system pillars and KMC. CONCLUSION: Meeting mothers' needs in the care of their babies is important to mothers, family members and professionals, and deserves greater attention. Functioning system pillars depended on a standardised approach to care and low cost, universally applicable interventions are needed to support the existing care structure. KMC was effective in both meeting mothers' needs, supporting existing care structures and also provided a space for the resolution of the dialectical relationship between families and hospital procedures. Lessons learnt from the implementation of KMC could be applied to the development of an early warning score in LMICs.

Gabapentin for chronic pelvic pain in women (GaPP2): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Chronic pelvic pain affects 2-24% of women worldwide and evidence for medical treatments is scarce. Gabapentin is effective in treating some chronic pain conditions. We aimed to measure the efficacy and safety of gabapentin in women with chronic pelvic pain and no obvious pelvic pathology. METHODS: We performed a multicentre, randomised, double-blind, placebo-controlled randomised trial in 39 UK hospital centres. Eligible participants were women with chronic pelvic pain (with or without dysmenorrhoea or dyspareunia) of at least 3 months duration. Inclusion criteria were 18-50 years of age, use or willingness to use contraception to avoid pregnancy, and no obvious pelvic pathology at laparoscopy, which must have taken place at least 2 weeks before consent but less than 36 months previously. Participants were randomly assigned in a 1:1 ratio to receive gabapentin (titrated to a maximum dose of 2700 mg daily) or matching placebo for 16 weeks. The online randomisation system minimised allocations by presence or absence of dysmenorrhoea, psychological distress, current use of hormonal contraceptives, and hospital centre. The appearance, route, and administration of the assigned intervention were identical in both groups. Patients, clinicians, and research staff were unaware of the trial group assignments throughout the trial. Participants were unmasked once they had provided all outcome data at week 16-17, or sooner if a serious adverse event requiring knowledge of the study drug occurred. The dual primary outcome measures were worst and average pain scores assessed separately on a numerical rating scale in weeks 13-16 after randomisation, in the intention-to-treat population. Self-reported adverse events were assessed according to intention-to-treat principles. This trial is registered with the ISRCTN registry, ISCRTN77451762. FINDINGS: Participants were screened between Nov 30, 2015, and March 6, 2019, and 306 were randomly assigned (153 to gabapentin and 153 to placebo). There were no significant between-group differences in both worst and average numerical rating scale (NRS) pain scores at 13-16 weeks after randomisation. The mean worst NRS pain score was 7·1 (standard deviation [SD] 2·6) in the gabapentin group and 7·4 (SD 2·2) in the placebo group. Mean change from baseline was -1·4 (SD 2·3) in the gabapentin group and -1·2 (SD 2·1) in the placebo group (adjusted mean difference -0·20 [97·5% CI -0·81 to 0·42]; p=0·47). The mean average NRS pain score was 4·3 (SD 2·3) in the gabapentin group and 4·5 (SD 2·2) in the placebo group. Mean change from baseline was -1·1 (SD 2·0) in the gabapentin group and -0·9 (SD 1·8) in the placebo group (adjusted mean difference -0·18 [97·5% CI -0·71 to 0·35]; p=0·45). More women had a serious adverse event in the gabapentin group than in the placebo group (10 [7%] of 153 in the gabapentin group compared with 3 [2%] of 153 in the placebo group; p=0·04). Dizziness, drowsiness, and visual disturbances were more common in the gabapentin group. INTERPRETATION: This study was adequately powered, but treatment with gabapentin did not result in significantly lower pain scores in women with chronic pelvic pain, and was associated with higher rates of side-effects than placebo. Given the increasing reports of abuse and evidence of potential harms associated with gabapentin use, it is important that clinicians consider alternative treatment options to off-label gabapentin for the management of chronic pelvic pain and no obvious pelvic pathology. FUNDING: National Institute for Health Research.

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.

Uterine-Artery Embolization or Myomectomy for Uterine Fibroids.

BACKGROUND: Uterine fibroids, the most common type of tumor among women of reproductive age, are associated with heavy menstrual bleeding, abdominal discomfort, subfertility, and a reduced quality of life. For women who wish to preserve their uterus and who have not had a response to medical treatment, myomectomy and uterine-artery embolization are therapeutic options. METHODS: We conducted a multicenter, randomized, open-label trial to evaluate myomectomy, as compared with uterine-artery embolization, in women who had symptomatic uterine fibroids and did not want to undergo hysterectomy. Procedural options included open abdominal, laparoscopic, or hysteroscopic myomectomy. The primary outcome was fibroid-related quality of life, as assessed by the score on the health-related quality-of-life domain of the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire (scores range from 0 to 100, with higher scores indicating a better quality of life) at 2 years; adjustment was made for the baseline score. RESULTS: A total of 254 women, recruited at 29 hospitals in the United Kingdom, were randomly assigned: 127 to the myomectomy group (of whom 105 underwent myomectomy) and 127 to the uterine-artery embolization group (of whom 98 underwent embolization). Data on the primary outcome were available for 206 women (81%). In the intention-to-treat analysis, the mean (±SD) score on the health-related quality-of-life domain of the UFS-QOL questionnaire at 2 years was 84.6±21.5 in the myomectomy group and 80.0±22.0 in the uterine-artery embolization group (mean adjusted difference with complete case analysis, 8.0 points; 95% confidence interval [CI], 1.8 to 14.1; P = 0.01; mean adjusted difference with missing responses imputed, 6.5 points; 95% CI, 1.1 to 11.9). Perioperative and postoperative complications from all initial procedures, irrespective of adherence to the assigned procedure, occurred in 29% of the women in the myomectomy group and in 24% of the women in the uterine-artery embolization group. CONCLUSIONS: Among women with symptomatic uterine fibroids, those who underwent myomectomy had a better fibroid-related quality of life at 2 years than those who underwent uterine-artery embolization. (Funded by the National Institute for Health Research Health Technology Assessment program; FEMME Current Controlled Trials number, ISRCTN70772394.).

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.).

Research Priorities in Pelvic Venous Disorders in Women: Recommendations from a Multidisciplinary Research Consensus Panel.

Pelvic venous disorders (PeVDs) in women can present with chronic pelvic pain, lower-extremity and vulvar varicosities, lower-extremity swelling and pain, and left-flank pain and hematuria. Multiple evidence gaps exist related to PeVDs with the consequence that nonvascular specialists rarely consider the diagnosis. Recognizing this, the Society of Interventional Radiology Foundation funded a Research Consensus Panel to prioritize a research agenda to address these gaps. This paper presents the proceedings and recommendations from that Panel.

MRI versus laparoscopy to diagnose the main causes of chronic pelvic pain in women: a test-accuracy study and economic evaluation.

BACKGROUND: Chronic pelvic pain (CPP) symptoms in women are variable and non-specific; establishing a differential diagnosis can be hard. A diagnostic laparoscopy is often performed, although a prior magnetic resonance imaging (MRI) scan may beneficial. OBJECTIVES: To estimate the accuracy and added value of MRI in making diagnoses of (1) idiopathic CPP and (2) the main gynaecological causes of CPP. To quantify the impact MRI can have on decision-making with respect to triaging for therapeutic laparoscopy and to conduct an economic evaluation. DESIGN: Comparative test-accuracy study with cost-effectiveness modelling. SETTING: Twenty-six UK-based hospitals. PARTICIPANTS: A total of 291 women with CPP. METHODS: Pre-index information concerning the patient's medical history, previous pelvic examinations and ultrasound scans was collected. Women reported symptoms and quality of life at baseline and 6 months. MRI scans and diagnostic laparoscopy (undertaken and interpreted blind to each other) were the index tests. For each potential cause of CPP, gynaecologists indicated their level of certainty that the condition was causing the pelvic pain. The analysis considered both diagnostic laparoscopy as a reference standard for observing structural gynaecological causes and consensus from a two-stage expert independent panel for ascertaining the cause of CPP. The stage 1 consensus was based on pre-index, laparoscopy and follow-up data; for stage 2, the MRI scan report was also provided. The primary analysis involved calculations of sensitivity and specificity for the presence or absence of each structural gynaecological cause of pain. A decision-analytic model was developed, with a 6-month time horizon. Two strategies, laparoscopy or MRI, were considered and populated with study data. RESULTS: Using reference standards of laparoscopic and expert panel diagnoses, MRI scans had high specificity but poor sensitivity for observing deep-infiltrating endometriosis, endometrioma, adhesions and ovarian cysts. MRI scans correctly identified 56% [95% confidence interval (CI) 48% to 64%] of women judged to have idiopathic CPP, but missed 46% (95% CI 37% to 55%) of those considered to have a gynaecological structural cause of CPP. MRI added significant value, over and above the pre-index information, in identifying deep-infiltrating endometriosis (p = 0.006) and endometrioma (p = 0.02) as the cause of pain, but not for other gynaecological structural causes or for identifying idiopathic CPP (p = 0.08). Laparoscopy was significantly more accurate than MRI in diagnosing idiopathic CPP (p < 0.0001), superficial peritoneal endometriosis (p < 0.0001), deep-infiltrating endometriosis (p < 0.0001) and endometrioma of the ovary (p = 0.02) as the cause of pelvic pain. The accuracy of laparoscopy appeared to be able to rule in these diagnoses. Using MRI to identify women who require therapeutic laparoscopy would lead to 369 women in a cohort of 1000 receiving laparoscopy unnecessarily, and 136 women who required laparoscopy not receiving it. The economic analysis highlighted the importance of the time horizon, the prevalence of CPP and the cut-off values to inform the sensitivity and specificity of MRI and laparoscopy on the model results. MRI was not found to be a cost-effective diagnostic approach in any scenario. CONCLUSIONS: MRI was dominated by laparoscopy in differential diagnosis of women presenting to gynaecology clinics with CPP. It did not add value to information already gained from history, examination and ultrasound about idiopathic CPP and various gynaecological conditions. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13028601. 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. 22, No. 40. See the NIHR Journals Library website for further project information.