IVF versus IUI with ovarian stimulation for unexplained infertility: a collaborative individual participant data meta-analysis.

BACKGROUND: IVF and IUI with ovarian stimulation (IUI-OS) are widely used in managing unexplained infertility. IUI-OS is generally considered first-line therapy, followed by IVF only if IUI-OS is unsuccessful after several attempts. However, there is a growing interest in using IVF for immediate treatment because it is believed to lead to higher live birth rates and shorter time to pregnancy. OBJECTIVE AND RATIONALE: Randomized controlled trials (RCTs) comparing IVF versus IUI-OS had varied study designs and findings. Some RCTs used complex algorithms to combine IVF and IUI-OS, while others had unequal follow-up time between arms or compared treatments on a per-cycle basis, which introduced biases. Comparing cumulative live birth rates of IVF and IUI-OS within a consistent time frame is necessary for a fair head-to-head comparison. Previous meta-analyses of RCTs did not consider the time it takes to achieve pregnancy, which is not possible using aggregate data. Individual participant data meta-analysis (IPD-MA) allows standardization of follow-up time in different trials and time-to-event analysis methods. We performed this IPD-MA to investigate if IVF increases cumulative live birth rate considering the time leading to pregnancy and reduces multiple pregnancy rate compared to IUI-OS in couples with unexplained infertility. SEARCH METHODS: We searched MEDLINE, EMBASE, CENTRAL, PsycINFO, CINAHL, and the Cochrane Gynaecology and Fertility Group Specialised Register to identify RCTs that completed data collection before June 2021. A search update was carried out in January 2023. RCTs that compared IVF/ICSI to IUI-OS in couples with unexplained infertility were eligible. We invited author groups of eligible studies to join the IPD-MA and share the deidentified IPD of their RCTs. IPD were checked and standardized before synthesis. The quality of evidence was assessed using the Risk of Bias 2 tool. OUTCOMES: Of eight potentially eligible RCTs, two were considered awaiting classification. In the other six trials, four shared IPD of 934 women, of which 550 were allocated to IVF and 383 to IUI-OS. Because the interventions were unable to blind, two RCTs had a high risk of bias, one had some concerns, and one had a low risk of bias. Considering the time to pregnancy leading to live birth, the cumulative live birth rate was not significantly higher in IVF compared to that in IUI-OS (4 RCTs, 908 women, 50.3% versus 43.2%, hazard ratio 1.19, 95% CI 0.81-1.74, I2 = 42.4%). For the safety primary outcome, the rate of multiple pregnancy was not significantly lower in IVF than IUI-OS (3 RCTs, 890 women, 3.8% versus 5.2% of all couples randomized, odds ratio 0.78, 95% CI 0.41-1.50, I2 = 0.0%). WIDER IMPLICATIONS: There is no robust evidence that in couples with unexplained infertility IVF achieves pregnancy leading to live birth faster than IUI-OS. IVF and IUI-OS are both viable options in terms of effectiveness and safety for managing unexplained infertility. The associated costs of interventions and the preference of couples need to be weighed in clinical decision-making.

Checklist to assess Trustworthiness in RAndomised Controlled Trials (TRACT checklist): concept proposal and pilot.

OBJECTIVES: To propose a checklist that can be used to assess trustworthiness of randomized controlled trials (RCTs). DESIGN: A screening tool was developed using the four-stage approach proposed by Moher et al. This included defining the scope, reviewing the evidence base, suggesting a list of items from piloting, and holding a consensus meeting. The initial checklist was set-up by a core group who had been involved in the assessment of problematic RCTs for several years. We piloted this in a consensus panel of several stakeholders, including health professionals, reviewers, journal editors, policymakers, researchers, and evidence-synthesis specialists. Each member was asked to score three articles with the checklist and the results were then discussed in consensus meetings. OUTCOME: The Trustworthiness in RAndomised Clinical Trials (TRACT) checklist includes 19 items organised into seven domains that are applicable to every RCT: 1) Governance, 2) Author Group, 3) Plausibility of Intervention Usage, 4) Timeframe, 5) Drop-out Rates, 6) Baseline Characteristics, and 7) Outcomes. Each item can be answered as either no concerns, some concerns/no information, or major concerns. If a study is assessed and found to have a majority of items rated at a major concern level, then editors, reviewers or evidence synthesizers should consider a more thorough investigation, including assessment of original individual participant data. CONCLUSIONS: The TRACT checklist is the first checklist developed specifically to detect trustworthiness issues in RCTs. It might help editors, publishers and researchers to screen for such issues in submitted or published RCTs in a transparent and replicable manner.

Individual participant data meta-analysis of trials comparing frozen versus fresh embryo transfer strategy (INFORM): a protocol.

INTRODUCTION: Existing randomised controlled trials (RCTs) comparing a freeze-all embryo transfer strategy and a fresh embryo transfer strategy have shown conflicting results. A freeze-all or a fresh transfer policy may be preferable for some couples undergoing in-vitro fertilisation (IVF), but it is unclear which couples would benefit most from each policy, how and under which protocols. Therefore, we plan a systematic review and individual participant data meta-analysis of RCTs comparing a freeze-all and a fresh transfer policy. METHODS AND ANALYSIS: We will search electronic databases (Medline, Embase, PsycINFO and CENTRAL) and trial registries (ClinicalTrials.gov and the International Clinical Trials Registry Platform) from their inception to present to identify eligible RCTs. We will also check reference lists of relevant papers. The search was performed on 23 September 2020 and will be updated. We will include RCTs comparing a freeze-all embryo transfer strategy and a fresh embryo transfer strategy in couples undergoing IVF. The primary outcome will be live birth resulting from the first embryo transfer. All outcomes listed in the core outcome set for infertility research will be reported. We will invite the lead investigators of eligible trials to join the Individual participant data meta-analysis of trials comparing frozen versus fresh embryo transfer strategy (INFORM) collaboration and share the deidentified individual participant data (IPD) of their trials. We will harmonise the IPD and perform a two-stage meta-analysis and examine treatment-covariate interactions for important baseline characteristics. ETHICS AND DISSEMINATION: The study ethics have been granted by the Monash University Human Research Ethics Committee (Project ID: 30391). The findings will be disseminated via presentations at international conferences and publication in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42021296566.

Sexual function in reproductive-aged women following radiotherapy: a cross sectional study.

Background While female sexual dysfunction post-radiation therapy has been previously described, much of the literature is focused on older, often postmenopausal, women; and neglects the experiences of younger populations. Our study aims to describe the changes in sexual functioning following radiotherapy among women of a reproductive age. Methods A cross-sectional survey was conducted on reproductive-aged women post-radiation therapy. Information on sexual frequency, pleasure, discomfort and habit was collected and compared to responses from healthy women of comparable ages. Results Reproductive-aged women post-radiotherapy experienced decreased pleasure, more discomfort and had less sexual activity than healthy controls. However, sexual habit was comparable. Conclusions Our findings illustrated that most domains of sexual function are negatively affected in our study population. Understanding the sexual sequelae of radiation therapy may help guide clinicians in counselling their patients and planning their future needs.

Effectiveness of antenatal corticosteroids at term: Can we trust the data that 'inform' us?

Randomized controlled trials (RCTs) are a cornerstone for the assessment of the effectiveness of interventions. Appropriate randomization, design, sample size, statistical analyses, and conduct that reduces the risk of bias, enhance the chance they will deliver true research findings. The credibility of RCTs is difficult to assess without objective evidence of compliance with Good Clinical Practice standards. Remarkably, no mechanisms are in place both in the initial peer review process and during meta-analysis to assess these, and little guidance on how to assess data where research integrity cannot be confirmed (e.g. where data originated from a setting without established infrastructure or an era preceding current standards). We describe the case of the use of antenatal steroids. When these drugs are used in early preterm birth, their benefits outweigh the harms. However, later in pregnancy, and specifically at term, this balance is less clear. We describe that the four randomised clinical trials that inform clinical practice through the Cochrane meta-analysis, for various reasons, lack clear governance which makes it difficult to verify provenance and reliability of the data. We conclude that transparency and assessment of data credibility need to be inbuilt both at the time of publication and at the time of meta-analysis. This will drive up standards and encourage appropriate interpretation of results and the context from which they were derived.

Perinatal risk factors for low and moderate five-minute Apgar scores at term.

OBJECTIVE: To evaluate the specific maternal and perinatal variables associated with a low (≤3) or moderate (4-6) Apgar score, compared to a high (≥7) score. STUDY DESIGN: This was a retrospective, cohort study of 58429 term singleton babies born at the Mater Mother's Hospital in Brisbane, Australia in 2007-2013. Maternal demographics, socio-economic status using the Australian Socioeconomic Index for Areas (SEIFA) score, obstetric factors, and birth outcomes were compared for neonates grouped into three categories based on their five-minute Apgar: low (≤3), moderate (4-6) and high (≥7). The low- and moderate-score cohorts were individually compared to the high-score cohort using both univariate and multivariate analysis. RESULTS: Logistic regression analysis confirmed that of the variables analysed, only maternal public insurance status (OR 2.1, 95% CI 1.5-3.1), breech presentation (OR 2.4, 95% CI 1.1-4.6), other non-cephalic presentation (OR 9.5, 95% CI 2.2-25.4), intramuscular narcotic use (OR 2.3, 95% CI 1.5-3.5), and presence of meconium (OR 3.7, 95% CI 2.5-5.4) were significantly associated with low Apgar scores. Variables significantly associated with a moderate score were: SEIFA ≤50th centile (OR 1.6, 95% CI 1.2-2.0) and 61st to 70th centile (OR 1.31, 95% CI 0.9-1.8) categories, maternal public insurance status (OR 2.7, 95% CI 2.2-3.3), nulliparity (OR 2.0, 95% CI 1.7-2.5), emergency caesarean birth (OR 2.6, 95% CI 2.1-3.2), instrumental birth (OR 2.3, 95% CI 1.9-2.9), and presence of meconium (OR 2.6, 95% CI 2.1-3.2). CONCLUSIONS: Factors associated with low and moderate Apgar scores vary in type and degree of influence. Distinctions in the perinatal background can help predict newborn compromise and accelerate delivery of care.