BACKGROUND There is a wealth of information regarding interventions for treating subfertility. The majority of studies exploring interventions for improving conception rates also report on pregnancy outcomes. However, there is no efficient way for clinicians, researchers, funding organizations, decision-making bodies or women themselves to easily access and review the evidence for the effect of adjuvant therapies on key pregnancy outcomes in subfertile women. OBJECTIVE AND RATIONALE The aim was to summarize all published systematic reviews (SRs) of randomized controlled trials (RCTs) of interventions in the subfertile population, specifically reporting on the pregnancy outcomes of miscarriage and live birth. Furthermore, we aimed to highlight promising interventions and areas that need high-quality evidence. SEARCH METHODS We searched the Cochrane Database of Systematic Reviews and PubMed clinical queries SR filter (inception until July 2021) with a list of key words to capture all SRs specifying or reporting any miscarriage outcome. Studies were included if they were SRs of RCTs. The population was subfertile women (pregnant or trying to conceive) and any intervention (versus placebo or no treatment) was included. We adopted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) for determining the quality of the evidence. Exclusion criteria were overview reviews, reviews that exclusively reported on women conceiving via natural conception, reviews including non-randomized study designs or reviews where miscarriage or live birth outcomes were not specified or reported. OUTCOMES The primary outcome was miscarriage, defined as pregnancy loss <24 weeks of gestation. Data were also extracted for live birth where available. We included 75 published SRs containing 121 251 participants. There were 14 classes of intervention identified: luteal phase, immunotherapy, anticoagulants, hCG, micronutrients, lifestyle, endocrine, surgical, pre-implantation genetic testing for aneuploidies (PGT-As), laboratory techniques, endometrial injury, ART protocols, other adjuncts/techniques in the ART process and complementary interventions. The interventions with at least moderate-quality evidence of benefit in reducing risk of miscarriage or improving the chance of a live birth are: intrauterine hCG at time of cleavage stage embryo transfer, but not blastocyst transfer, antioxidant therapy in males, dehydroepiandrosterone in women and embryo medium containing high hyaluronic acid. Interventions showing potential increased risk of miscarriage or reduced live birth rate are: embryo culture supernatant injection before embryo transfer in frozen cycles and PGT-A with the use of fluorescence in situ hybridization. WIDER IMPLICATIONS This review provides an overview of key pregnancy outcomes from published SRs of RCTs in subfertile women. It provides access to concisely summarized information and will help clinicians and policy makers identify knowledge gaps in the field, whilst covering a broad range of topics, to help improve pregnancy outcomes for subfertile couples. Further research is required into the following promising interventions: the dose of progesterone for luteal phase support, peripheral blood mononuclear cells for women with recurrent implantation failure, glucocorticoids in women undergoing IVF, low-molecular-weight heparin for unexplained subfertility, intrauterine hCG at the time of cleavage stage embryo or blastocyst transfer and low oxygen concentrations in embryo culture. In addition, there is a need for high-quality, well-designed RCTs in the field of reproductive surgery. Finally, further research is needed to demonstrate the integrated effects of non-pharmacological lifestyle interventions.

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Study question Which semen parameters are predictive of treatment-dependent and treatment-independent reproductive outcomes? Summary answer Progressive motility predicted treatment-independent pregnancy, total motile sperm count (TMSC) predicted failed fertilisation with IVF and pregnancy following IUI, and morphology predicted pregnancy after IUI. What is known already Semen analysis, an essential component of any fertility work-up, is useful in identifying azoospermia and oligozoospermia, but its discriminatory capacity to identify fertile and infertile men has been questioned, including by the World Health Organisation (WHO). It has also been suggested that a combination of semen parameters has better predictive value than a single parameter. We conducted a systematic review of the literature to determine the association between different semen parameters and spontaneous (treatment-independent) pregnancy outcomes, as well as pregnancy outcomes following various fertility treatments (treatment-dependent outcomes). Study design, size, duration A protocol was registered prospectively with PROSPERO (CRD42021251988). A systematic search of MEDLINE, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials was undertaken to include papers published from 1st January 2000 to 25th May 2021. Studies were not limited by language. Two reviewers independently screened the search results and undertook data extraction. Risk of bias assessment was undertaken with the QUADAS-2 or QUIPS tool, depending on study design. Participants/materials, setting, methods Studies were eligible if they included men undergoing semen analysis for any indication and reported the accuracy of one or more semen analysis parameters in predicting treatment-dependent or treatment-independent reproductive outcomes – these included fertilisation rate, clinical pregnancy, live birth, and time to pregnancy. Studies were excluded if semen analysis was not the primary test being assessed or no reproductive outcomes were reported. Main results and the role of chance Of 5236 publications and 139 full-text articles, 62 studies were included. 52 studies reported treatment-dependent outcomes and 10 reported treatment-independent outcomes. Most treatment-dependent studies lacked key information and were rated as unclear risk of bias in at least one domain (79.3% overall). Half of the treatment-independent studies were high risk of bias in at least one domain. Of all semen parameters, progressive motility and sperm concentration predicted treatment-independent pregnancy outcomes. Three studies concluded progressive motility predicted pregnancy rates at a range of thresholds (threshold 24%: area under the curve (AUC) 0.909; <32% vs ≥ 32%: adjusted odds ratio (aOR) 4.2 (95% CI 1.1-15) and <50% vs ≥ 50%: aOR 2.8 (95% CI 1.3-6.1); per 10% reduction in progressive motility, pregnancy chances reduced by 11%: hazard ratio (HR) 0.89 (95% CI 0.85-0.93)). Sperm concentration predicted pregnancy within 6 months (≥20 vs < 20 million/ml, adjusted rate ratio 0.68 (95% CI 0.52-0.91)) and 12 months (adjusted HR 1.35 (95% CI 1.09-1.66)). In those undergoing IUI, pre-/post-wash TMSC and morphology predicted pregnancy, but with no clear threshold values. TMSC predicted “total fertilisation failure” in an IVF population (AUC 0.631-0.75). In an ICSI population, no semen parameter predicted fertilisation rate, pregnancy, or live birth rate. Limitations, reasons for caution Meta-analysis was not possible due to a wide range of cut-off values used for each semen parameter. Due to the low quality of the evidence included, poorly detailed female populations, and WHO manual methods often not being used for reporting, the findings of this review should be viewed with caution. Wider implications of the findings Whilst this review has identified certain semen parameters in isolation are predictive of pregnancy in treatment-dependent and treatment-independent scenarios, clear threshold values have not been identified. This questions the reporting of morphology as it is labour intensive to assess and is only predictive of pregnancy in a population having IUI. Trial registration number Not applicable