Composite adverse outcomes in obstetric studies: a systematic review.

BACKGROUND: Composite outcomes are increasingly being used in obstetric trials. The aim of this systematic review is to critically appraise the use of composite outcomes in obstetric RCTs with an intention of identifying limitations and providing potential solutions for future research. METHODS: The study protocol was prospectively registered. Medline, Embase, Cochrane Databases and www.clinicaltrials.gov were searched for randomized controlled trials (RCTs) published in English between 1999 and 2019, using search terms related to pregnancy and composite outcomes. STUDY ELIGIBILITY CRITERIA: RCTs involving an obstetric condition that reported on a composite outcome. STUDY APPRAISAL AND SYNTHESIS METHODS: Screening and data extraction were performed in duplicate, and a descriptive synthesis and critical appraisal of composite obstetric outcomes, is presented. RESULTS: Of the 4170 results screened, we identified 156 RCTs, reporting on 181 composite outcomes. Of these, 158 composite outcomes related to general morbidity and mortality, either exclusively maternal (n=20), fetal-neonatal [perinatal] (n=116) or maternal and perinatal (n=22) were included in the final analysis. Obstetric composite outcomes included between two and 16 components. Components that comprised these composite outcomes were often dissimilar in terms of severity and frequency of occurrence, unlikely to have similar relative risk reductions and sometimes unrelated to the study's primary objective - important pre-requisites to consider while constructing composite outcomes. In addition, composite adverse obstetric outcomes often do not incorporate the perspectives of pregnant persons, embrace a holistic view of health or consider outcomes related to both members of the mother-fetus dyad. CONCLUSIONS: Composite outcomes are being increasingly used as primary outcomes in obstetric RCTs, based on which study conclusions are drawn and clinical recommendations made. However, there is a lack of consistency with regard to what components should be included within a composite adverse obstetric outcome and how these components should be measured. The use of novel research methods such as concept mapping may be able to address some of the limitations with the development of composite adverse obstetric outcomes, to inform future research.

Does pre-operative urodynamics lead to better outcomes in management of urinary incontinence in women? A linked systematic review and meta-analysis.

The use of preoperative urodynamics as a standard investigation for urinary incontinence (UI) has long been a subject of debate, with a lack of robust evidence to demonstrate improved patients' outcomes. We aim to compare the clinical and cost effectiveness of urodynamics versus office clinical evaluation only, prior to the treatment of UI. We conducted three linked systematic reviews and meta-analyses of randomised controlled trials (RCTs) comparing urodynamics assessment versus clinical evaluation only in women prior to 1) non-surgical treatment of UI, 2a) surgical treatment of stress urinary incontinence (SUI) and 2b) invasive treatment for overactive bladder (OAB). Women with severe pelvic organ prolapse, previous continence surgery and neuropathic bladder were excluded. Primary outcomes were patient-reported and objective success post-treatment. Secondary outcomes were adverse events, quality of life, sexual function and health economic measures. We searched MEDLINE, Embase and Cochrane Central Register of Controlled Trials databases for each category, which was last updated on January 2019. Study selection, risk of bias assessment and data extraction were performed independently by two reviewers. The random effects model was used to assess risk ratio and mean difference with 95% confidence interval. Statistical heterogeneity was assessed by I2 statistics and the quality of evidence by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Four RCTs compared urodynamics versus clinical evaluation only prior to non-surgical management of UI. Treatment consisted of pelvic floor muscle training, with or without pharmacological therapy. Meta-analysis of 150 women showed no evidence of significant difference in the patient-reported and objective success rates between groups (P = 0.520, RR: 0.91, 95% Cl 0.69-1.21, I2 = 0% and P = 0.470, RR:0.87, 95% Cl 0.59-1.28, I2 = n/a, respectively). Seven RCTs were identified for surgical management of SUI. The majority of women underwent mid-urethral tape procedures (retropubic or transobturator approach). Meta-analysis of 1149 women showed no evidence of significant difference in patient-reported (P = 0.850, RR:1.01, 95% CI 0.88-1.16, I2 = 53%) and objective success between groups (P = 0.630, RR:1.02, 95% CI 0.95-1.08, I2 = 28%). There was no significant difference in incidence of voiding dysfunction, de novo urgency, and urinary tract infection between groups. No RCTs were identified for invasive management of OAB. In conclusion, limited evidence shows that routine urodynamics prior to non-surgical management of UI or surgical management of SUI is not associated with improved treatment outcomes, when compared to clinical evaluation only. Well-designed clinical trials are needed to evaluate the clinical and cost-effectiveness of routine urodynamics prior to surgical management of SUI and OAB.

Oral medications including clomiphene citrate or aromatase inhibitors with gonadotropins for controlled ovarian stimulation in women undergoing in vitro fertilisation.

BACKGROUND: Gonadotropins are the most commonly used medications for controlled ovarian stimulation in in vitro fertilisation (IVF). However, they are expensive and invasive, and are associated with the risk of ovarian hyperstimulation syndrome (OHSS). Recent calls for more patient-friendly regimens have led to growing interest in the use of clomiphene citrate (CC) and aromatase inhibitors with or without gonadotropins to reduce the burden of hormonal injections. It is currently unknown whether regimens using CC or aromatase inhibitors such as letrozole (Ltz) are as effective as gonadotropins alone. OBJECTIVES: To determine the effectiveness and safety of regimens including oral induction medication (such as clomiphene citrate or letrozole) versus gonadotropin-only regimens for controlled ovarian stimulation in IVF or intracytoplasmic sperm injection (ICSI) treatment. SEARCH METHODS: We searched the following databases: Cochrane Gynaecology and Fertility Group Specialised Register (searched January 2017), the Cochrane Central Register of Controlled Trials (CENTRAL CRSO), MEDLINE (1946 to January 2017), Embase (1980 to January 2017), and reference lists of relevant articles. We also searched trials registries ClinicalTrials.gov (clinicaltrials.gov/) and the World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch/Default.aspx). We handsearched relevant conference proceedings. SELECTION CRITERIA: We included randomized controlled trials (RCTs). The primary outcomes were live-birth rate (LBR) and OHSS. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial eligibility and risk of bias. We calculated risk ratios (RR) and Peto odds ratio (OR) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences (MD) for continuous outcomes. We analyzed the general population of women undergoing IVF treatment and (as a separate analysis) women identified as poor responders. We assessed the overall quality of the evidence using the GRADE approach. MAIN RESULTS: We included 27 studies in the updated review. Most of the new trials in the updated review included poor responders and evaluated Ltz protocols. We could perform meta-analysis with data from 22 studies including a total of 3599 participants. The quality of the evidence for different comparisons ranged from low to moderate. The main limitations in the quality of the evidence were risk of bias associated with poor reporting of study methods, and imprecision.In the general population of women undergoing IVF, it is unclear whether CC or Ltz used with or without gonadotropins compared to use of gonadotropins along with gonadotropin-releasing hormone (GnRH) agonists or antagonists resulted in a difference in live birth (RR 0.92, 95% CI 0.66 to 1.27, 4 RCTs, n = 493, I2 = 0%, low-quality evidence) or clinical pregnancy rate (RR 1.00, 95% CI 0.86 to 1.16, 12 RCTs, n = 1998, I2 = 3%, moderate-quality evidence). This means that for a typical clinic with 23% LBR using a GnRH agonist regimen, switching to CC or Ltz protocols would be expected to result in LBRs between 15% and 30%. Clomiphene citrate or Ltz protocols were associated with a reduction in the incidence of OHSS (Peto OR 0.21, 95% CI 0.11 to 0.41, 5 RCTs, n = 1067, I2 = 0%, low-quality evidence). This means that for a typical clinic with 6% prevalence of OHSS associated with a GnRH regimen, switching to CC or Ltz protocols would be expected to reduce the incidence to between 0.5% and 2.5%. We found evidence of an increase in cycle cancellation rate with the CC protocol compared to gonadotropins in GnRH protocols (RR 1.87, 95% CI 1.43 to 2.45, 9 RCTs, n = 1784, I2 = 61%, low-quality evidence). There was moderate quality evidence of a decrease in the mean number of ampoules used,) and mean number of oocytes collected with CC with or without gonadotropins compared to the gonadotropins in GnRH agonist protocols, though data were too heterogeneous to pool.Similarly, in the poor-responder population, it is unclear whether there was any difference in rates of live birth (RR 1.16, 95% CI 0.49 to 2.79, 2 RCTs, n = 357, I2 = 38%, low-quality evidence) or clinical pregnancy (RR 0.85, 95% CI 0.64 to 1.12, 8 RCTs, n = 1462, I2 = 0%, low-quality evidence) following CC or Ltz with or without gonadotropin versus gonadotropin and GnRH protocol. This means that for a typical clinic with a 5% LBR in the poor responders using a GnRH protocol, switching to CC or Ltz protocols would be expected to yield LBRs between 2% to 14%. There was low quality evidence that the CC or Ltz protocols were associated with an increase in the cycle cancellation rate (RR 1.46, 95% CI 1.18 to 1.81, 10 RCTs, n = 1601, I2 = 64%) and moderate quality evidence of a decrease in the mean number of gonadotropin ampoules used and the mean number of oocytes collected, though data were too heterogeneous to pool. The adverse effects of these protocols were poorly reported. In addition, data on foetal abnormalities following use of CC or Ltz protocols are lacking. AUTHORS' CONCLUSIONS: We found no conclusive evidence indicating that clomiphene citrate or letrozole with or without gonadotropins differed from gonadotropins in GnRH agonist or antagonist protocols with respect to their effects on live-birth or pregnancy rates, either in the general population of women undergoing IVF treatment or in women who were poor responders. Use of clomiphene or letrozole led to a reduction in the amount of gonadotropins required and the incidence of OHSS. However, use of clomiphene citrate or letrozole may be associated with a significant increase in the incidence of cycle cancellations, as well as reductions in the mean number of oocytes retrieved in both the general IVF population and the poor responders. Larger, high-quality randomized trials are needed to reach a firm conclusion before they are adopted into routine clinical practice.