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Results from pragmatic trials should reflect the comparative treatment effects encountered in patients in real-life clinical practice to guide treatment decisions. Therefore pragmatic trials should focus on outcomes that are relevant to patients, clinical practice, and treatment choices. This 6(th) paper in the series (see box) discusses different types of outcomes and their suitability for pragmatic trials, design choices for measuring these outcomes and their implications and challenges. Measuring outcomes in pragmatic trials should not interfere with real-world clinical practice to ensure generalizability of trial results and routinely collected outcomes should be prioritized. Typical outcomes include mortality, morbidity, functional status, wellbeing and resource use. Surrogate endpoints are typically avoided as primary outcome. It is important to measure outcomes over a relevant time horizon and to obtain valid and precise results. As pragmatic trials are often open-label a less subjective outcome can reduce bias. Methods that decrease bias or enhance precision of the results, such as standardization and blinding of outcome assessment, should be considered when a high risk of bias or high variability is expected. The selection of outcomes in pragmatic trials should be relevant for decision making as well as feasible in terms of executing the trial in the context of interest. Therefore this should be discussed with all stakeholders as early as feasible to ensure the relevance of study results for decision making in clinical practice and the ability to perform the study.

This paper addresses challenges of identifying, enrolling and retaining participants in a in a trial conducted within a routine care setting. All patients that are potential candidates for the treatments in routine clinical practice should be considered eligible for a pragmatic trial. To ensure generalizability, the recruited sample should have a similar distribution of the treatment effect modifiers as the target population. In practice this can be best achieved by including - within the selected sites - all patients without further selection. If relevant heterogeneity between subgroups is expected, increasing the relative proportion of the subgroup of patients in the heterogeneous trial could be considered (oversampling), or a separate trial in this subgroup can be planned. Selection will nevertheless occur. Low enrolment and loss to follow-up can introduce selection and can jeopardize validity as well as generalizability. Pragmatic trials are conducted in clinical practice rather than in a dedicated research setting, which could reduce recruitment rates. However, if a trial poses a minimal burden to the physician and the patient, and routine clinical practice is maximally adhered to, the participation rate may be high and loss to follow-up will not be a specific problem for pragmatic trials.

OBJECTIVE: To assess the effectiveness of curettage versus expectant management in women with an incomplete evacuation of the uterus after misoprostol treatment for first trimester miscarriage. STUDY DESIGN: We conducted a multicenter cohort study alongside a randomized clinical trial (RCT) between June 2012 until July 2014. 27 Dutch hospitals participated. Women with an incomplete evacuation after misoprostol treatment for first trimester miscarriage who declined to participate in the RCT, received treatment of their preference; curettage (n=65) or expectant management (n=132). A successful outcome was defined as an empty uterus on sonography at six weeks or uneventful clinical follow-up. We furthermore assessed complication rate and (re)intervention rate RESULTS: Of the 197 women who declined to participate in the RCT, 65 preferred curettage and 132 expectant management. A successful outcome was observed in 62/65 women (95%) in the surgical group versus 112/132 women (85%) in the expectant group (RR 1.1, 95% CI 1.03-1.2), with complication rates of 6.2% versus 2.3%, respectively (RR 2.7, 95% CI 0.6-12). CONCLUSION: In women with an incomplete evacuation of the uterus after misoprostol treatment, expectant management is an effective and safe option. This finding could restrain the use of curettage in women that have used misoprostol in the treatment of first trimester miscarriage.

Objective: Preterm birth is the most common cause of neonatal morbidity and mortality. Around one third of preterm deliveries starts with preterm prelabor rupture of membranes (PPROM). The aim of this trial was to study the effect of prolonged tocolysis with nifedipine versus placebo in women with PPROM on perinatal outcome and prolongation of pregnancy. Study design: The Apostel IV was a nationwide multicenter randomized placebo controlled trial. We included women with PPROM without contractions between 24(+0) and 33(+6) weeks of gestation. Participants were randomly allocated to daily 80 mg nifedipine or placebo, until the start of labor, with a maximum of 18 days. The primary outcome measure was a composite of poor neonatal outcome, including perinatal death, bronchopulmonary dysplasia, periventricular leukomalacia >grade 1, intraventricular hemorrhage >grade 2, necrotizing enterocolitis > stage 1 and culture proven sepsis. Secondary outcomes were gestational age at delivery and prolongation of pregnancy. Analysis was by intention to treat. To detect a reduction of poor neonatal outcome from 30% to 10%,120 women needed to be randomized. Trial registry: NTR 3363. Results: Between October 2012 and December 2014 we randomized 25 women to nifedipine and 25 women to placebo. Due to slow recruitment the study was stopped prematurely. The median gestational age at randomization was 29.9 weeks (IQR 27.7-31.3) in the nifedipine group and 27.0 weeks (IQR 24.7-29.9) in the placebo group. Other baseline characteristics were comparable. The adverse perinatal outcome occurred in 9 neonates (33.3%) in the nifedipine group and 9 neonates (32.1%) in the placebo group (RR 1.04, 95% CI 0.49-2.2). Two perinatal deaths occurred, both in the nifedipine group. Bronchopulmonary dysplasia was seen less frequently in the nifedipine group (0% versus 17.9%; p= 0.03). Prolongation of pregnancy did not differ between the nifedipine and placebo group (median 11 versus 8 days, HR 1.02; 95% CI 0.58-1.79). Conclusion: This randomized trial did not show a beneficial effect of prolonged tocolysis on neonatal outcomes or prolongation of pregnancy in women with PPROM without contractions. However, since results are based on a small sample size, a difference in effectiveness cannot be excluded. Crown Published by

AIM: To describe the vaginal microcirculatory architecture and capillary density parameters using sidestream dark-field imaging (SDFI), and determine feasibility and reliability of this method. METHODS: In nine healthy female volunteers SDFI measurements were performed at two different time points in the luteal phase of the menstrual cycle. Non-invasive tissue micro-angioarchitecture and vaginal capillary density measurements were assessed independently by two observers. Agreement was expressed with mean differences between the measurements of both observers and the limits of agreement. Inter- and intra-observer agreement was quantified with the intra-class correlation coefficient (ICC). RESULTS: Vaginal microcirculatory assessment with the SDFI device was easy in use, painless and well accepted by the participants. Morphologically, the vaginal microcirculation revealed an array of single hairpin-shaped capillary loops distributed homogeneously across an imaged tissue segment. The intra-observer assessment of the capillary density measurements (comparing two measurement time points of one observer) showed good agreement with an ICC ranging from 0.62 to 0.85. The inter-observer assessments of the capillary density measurements (comparing assessments of two observers at one time point) revealed very good agreement, with small differences between observers and an ICC of more than 0.9. CONCLUSIONS: This is the first report on both microcirculatory architecture and quantitative microcirculatory parameters of the vagina with the use of SDFI. Micro-vessels of the vagina show a recognizable pattern in our study population of young, healthy women. SDFI gives a reproducible assessment of the vaginal microcirculation offering the researcher a wide field of applications. Neurourol. Urodynam. 34:723-729, 2015. © 2014 Wiley Periodicals, Inc.

Background Pregnant women were excluded from clinical trials until the 1990s, but the Food and Drug Administration nowadays allows - and even encourages - responsible inclusion of pregnant women in trials with adequate safety monitoring. Still, randomized trials in pregnant women face specific enrolment challenges. Previous studies have focused on barriers to trial participation in studies that had failed to recruit sufficient participants. Our aim was to identify barriers and motivators for participation in a range of clinical trials being conducted in the Netherlands, regardless of recruitment performance. Methods We performed a qualitative case control study in women who had been asked in 2010 to participate in one of eight clinical trials during pregnancy or shortly after giving birth. Both participants and non-participants of these clinical trials were invited for a face-to-face interview that addressed motives for participation and non-participation. We started the interview in an open fashion, asking the women for their main motive for participation or non-participation. When no new information emerged in this open part, we continued with a semi-structured interview, guided by a topic list. Transcripts of the interviews were analysed using a constant-comparative approach. Two researchers identified barriers and facilitators for participation, conjoined into main themes. Results Of 28 women invited for the interview, 21 agreed to be interviewed (12 participants and 9 non-participants). For 5 of the 12 participants, contribution to scientific research was their main motive, while 5 had participated because the intervention seemed favorable and was not available outside the trial. Key motives for non-participation (n = 9) were a negative association or a dislike of the intervention, either because it might do harm (n = 6) or for practical reasons (n = 3). Combining the open and topic list guided interviews we constructed seven main themes that influence the pregnant women’s decision to participate: external influence, research and healthcare, perception own situation, study design, intervention, information and counselling, and uncertainty. Conclusions Among seven main themes that influence pregnant women’s decision to participate, uncertainty about scientific research or the intervention was reported to be of considerable importance. Measures should be taken to habituate pregnant women more to scientific research, and further evaluation of opt-out consent deserves attention. Electronic supplementary material The online version of this article (doi:10.1186/s12884-015-0641-x) contains supplementary material, which is available to authorized users.