Priya Bhide

BACKGROUND: Time‑lapse imaging (TLI) systems may improve the success of in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) by enabling undisturbed embryo culture and/or providing morphokinetic data to refine embryo selection. Despite several trials and aggregate meta-analyses showing uncertainty of benefit, there is little translation of evidence into guidelines. Heterogeneity in participant populations and algorithms used for TLI, although acknowledged in aggregate meta-analyses, remains unaddressed. OBJECTIVE AND RATIONALE: We conducted an individual participant data (IPD) meta-analysis to assess whether TLI improves reproductive outcomes and if effects vary by women or intervention characteristics. Our IPD meta-analysis enhances statistical power, allowing precise estimation of treatment effects and identification of subgroup differences. It overcomes the limitations of aggregate meta-analyses by enabling harmonised adjustment by participant-level baseline risk, testing treatment–covariate interactions and provides a comprehensive evaluation of TLI by leveraging diverse datasets from multiple studies that assess both undisturbed culture and morphokinetic-based embryo selection. The study implements rigorous data integrity and consistency checks to enhance the reliability and trustworthiness of its findings. SEARCH METHODS: We conducted an IPD meta-analysis of randomised controlled trials (RCTs) in women undergoing IVF/ICSI that used TLI systems. We evaluated overall TLI (undisturbed culture and morphokinetic-based embryo selection), undisturbed culture alone, and morphokinetic-based embryo selection alone. The primary outcome was live birth after a first fresh or frozen embryo transfer; other outcomes included clinical pregnancy, biochemical pregnancy loss, miscarriage, multiple pregnancy, minor and major congenital malformations, birth weight, and gestational age at birth. We included trials from the 2019 Cochrane review and updated searches of MEDLINE, EMBASE, CINAHL, and CENTRAL from 7 January 2019 to 9 May 2025 and repeated the search on 28 July 2026. We requested IPD from the authors of included trials. We assessed study-level risk of bias using the revised Cochrane risk-of-bias tool for RCTs (ROB2) and undertook integrity assessment of included studies. We performed a two-stage IPD meta-analysis. Results are presented as adjusted odds ratios (aOR) with 95% confidence intervals and adjusted absolute risk difference (aRD) estimates in a modified intention-to-treat population with pre-specified subgroup and sensitivity analyses. OUTCOMES: We included IPD from eight trials (n = 5642) for the primary analysis and added aggregate data from eight trials (n = 3452) for a sensitivity analysis. ROB2 assessment raised no concerns with the IPD-included trials. High-certainty evidence indicated no clinically important difference in live birth rates for overall TLI versus standard embryo incubation and selection (four trials, n = 2913, aOR 0.97, 95% CI 0.81–1.15, absolute risk difference(ARD) –0.7%, 95% CI –4.9% to 3.4%), undisturbed versus disturbed embryo culture (five trials, n = 2971, aOR 1.02, 95% CI 0.84–1.23, ARD 0.5%, 95% CI –4.1% to 5.0%), or morphokinetic-based versus standard embryo selection (three trials, n = 2937, aOR 0.92, 95% CI 0.78–1.07, ARD –2.0%, 95% CI –5.7% to 1.6%). No interaction was observed between the intervention effect and age, duration of undisturbed culture, day of embryo transfer, or type of embryo transfer (fresh or frozen) for live birth. Rates of clinical pregnancy, miscarriage, biochemical pregnancy loss, birthweight, and gestational age were similar between TLI systems and standard care across all comparisons. WIDER IMPLICATIONS: High-certainty evidence indicates that live birth rates with time-lapse imaging are comparable to those with standard embryo incubation and selection, providing a robust basis for clinical practice and guideline development. REGISTRATION NUMBER: PROSPERO CRD42024564332.

Introduction: Time-lapse imaging (TLI) systems for embryo incubation and assessment are hypothesised to improve the success rates of in vitro fertilisation (IVF) treatment by providing undisturbed culture conditions for embryos and/or providing more information on embryo development (morphokinetic parameters) to improve predictive accuracy for embryo selection. Despite numerous aggregate meta-analyses showing uncertainty of benefit, IVF clinics globally continue to invest significant resources into this technology with little translation of evidence into guidelines or policy frameworks. This may be attributed to heterogeneity in participant populations and/or variations in the use of TLI, as highlighted in the aggregate meta-analyses. Methods and analysis: Our research proposal for evidence synthesis using individual participant data meta-analysis will provide greater power than aggregate meta-analysis to detect differential treatment effects for effectiveness (live birth, clinical pregnancy) and safety (pregnancy loss, multiple births, congenital malformations) outcomes across three comparisons (overall effect, undisturbed culture and morphokinetic parameters). We will also analyse if there are specific subgroups of women who may benefit from the intervention and if variations in use of the intervention show any benefits. We have incorporated the results of the literature search used for the latest Cochrane review (7 January 2019) into this review and will include all the trials included therein. We will further update the literature search to include new evidence by searching the electronic databases MEDLINE, EMBASE, CINAHL and CENTRAL from 07/01/2019 to date, outcomes for all ongoing trials reported in the 2019 Cochrane review, trial registers for newer ongoing/completed trials and the citation lists of all the newly identified trials for any relevant references. The search strategy will include a combination of subject headings and text words relating to or describing the participants and the intervention, with no language restrictions. Two authors will independently screen the titles and abstracts, and full text of articles retrieved from the search, to finalise a list of trials suitable for inclusion in the review. We will include randomised controlled trials that assess TLI systems for either undisturbed culture and/or use of morphokinetic parameters for embryo selection in women having IVF/ICSI treatment using their own oocytes. Ethics and dissemination: Ethical approval is not required for this study. We plan to disseminate the findings of the research to all stakeholders, including the National Institute for Health and Care Excellence and other international guideline development groups, through publication in peer-reviewed journals, presentation at conferences, newsletters, meetings and websites of the funders, fertility charities and patient support groups. PROSPERO registration number: CRD42024564332.

Purpose of Review: Polycystic Ovary Syndrome (PCOS) affects 10–15% of women of reproductive age and is associated with a heightened risk of metabolic morbidity, exacerbated by insulin resistance and obesity. Current weight management strategies have limited effectiveness in reducing metabolic morbidity in this subgroup. This review examines the potential of Intensive Weight Management Programmes (IWMPs) and Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to reduce metabolic risks in women with PCOS, drawing from studies in both PCOS-specific and related populations. Recent Findings: IWMPs, including total diet replacement, achieve substantial and sustained weight loss (5–15% over 1–5 years) in individuals with obesity and type 2 diabetes, alongside improvements in metabolic markers like blood pressure and glycemic control. GLP-1 RAs, particularly semaglutide, similarly deliver significant weight loss (10–15% over 1–2 years) and metabolic benefits. While there is limited data specifically targeting PCOS, emerging studies suggest GLP-1 RAs can improve weight, insulin sensitivity, and menstrual regularity in this group. However, evidence for both interventions in PCOS remains insufficient. Summary: Women with PCOS face unique metabolic challenges, including heightened insulin resistance, compounded by obesity. While IWMPs and GLP-1 RAs are promising interventions, evidence for their effectiveness in PCOS-specific populations is insufficient. Addressing this research gap through targeted trials is essential to improve outcomes in individuals affected by PCOS and metabolic disorders.

Introduction: Intrauterine insemination (IUI) is one of the most widespread fertility treatments. However, IUI protocols vary significantly amongst fertility clinics. Various add‐on interventions have been proposed to boost success rates. These are mostly chosen arbitrarily or empirically. The aim of this systematic review and meta‐analysis is to assess the effectiveness and safety of add‐on interventions to the standard IUI protocol and to provide evidence‐based recommendations on techniques used to optimize the clinical outcomes of IUI treatment.Material and Methods: Systematic review and meta‐analyses were performed in accordance with PRISMA guidelines. A computerized literature search was performed from database inception to May 2023. Randomized controlled trials (RCTs) were included reporting on couples/single women undergoing IUI with any protocol for any indication using partner's or donor sperm. A meta‐analysis based on random effects was performed for each outcome and add‐on. Three authors independently assessed the trials for quality and risk of bias and overall certainty of evidence. Uncertainties were resolved through consensus. Primary outcomes were ongoing pregnancy rate (OPR) or live birth rate (LBR) per cycle/per woman randomized. Registration number PROSPERO: CRD42022300857.Results: Sixty‐six RCTs were included in the analysis (16 305 participants across 20 countries). Vaginal progesterone as luteal phase support in stimulated cycles was found to significantly increase LBR/OPR (RR 1.37, 95% CI 1.09–1.72, I² = 4.9%) (moderate/low certainty of the evidence). Endometrial scratch prior/during stimulated IUI cycles may increase LBR/OPR (RR 1.44, 95% CI 1.03–2.01, I² = 1.8%), but evidence is very uncertain. Results from two studies suggest that follicular phase ovarian stimulation increases LBR/OPR (RR 1.39, 95% CI 1.00–1.94, I² = 0%) (low certainty of evidence). No significant difference was seen for the primary outcome for the other studied interventions.Conclusions: The findings of this systematic review and meta‐analysis suggest that vaginal luteal phase progesterone support probably improves LBR/OPR in stimulated IUI treatments. In view of moderate/low certainty of the evidence more research is needed for solid conclusions. Further research is also recommended for the use of endometrial scratch and ovarian stimulation. Future studies should report on results according to subfertility background as it is possible that different add‐ons could benefit specific patient groups.

Background: There is no consensus on tests required to either diagnose unexplained infertility or use for research inclusion criteria. This leads to heterogeneity and bias affecting meta‐analysis and best practice advice.Objectives: This systematic review analyses the variability of inclusion criteria applied to couples with unexplained infertility. We propose standardised criteria for use both in future research studies and clinical diagnosis.Search strategy: CINAHL and MEDLINE online databases were searched up to November 2022 for all published studies recruiting couples with unexplained infertility, available in full text in the English language.Data collection and analysis: Data were collected in an Excel spreadsheet. Results were analysed per category and methodology or reference range.Main results: Of 375 relevant studies, only 258 defined their inclusion criteria. The most commonly applied inclusion criteria were semen analysis, tubal patency and assessment of ovulation in 220 (85%), 232 (90%), 205 (79.5%) respectively. Only 87/220 (39.5%) studies reporting semen analysis used the World Health Organization (WHO) limits. Tubal patency was accepted if bilateral in 145/232 (62.5%) and if unilateral in 24/232 (10.3%). Ovulation was assessed using mid‐luteal serum progesterone in 115/205 (56.1%) and by a history of regular cycles in 87/205 (42.4%). Other criteria, including uterine cavity assessment and hormone profile, were applied in less than 50% of included studies.Conclusions: This review highlights the heterogeneity among studied populations with unexplained infertility. Development and application of internationally accepted criteria will improve the quality of research and future clinical care.

Background: Freezing all embryos, followed by thawing and transferring them into the uterine cavity at a later stage (freeze-all), instead of fresh-embryo transfer may lead to improved pregnancy rates and fewer complications during in vitro fertilisation and pregnancies resulting from it. Objective: We aimed to evaluate if a policy of freeze-all results in a higher healthy baby rate than the current policy of transferring fresh embryos. Design: This was a pragmatic, multicentre, two-arm, parallel-group, non-blinded, randomised controlled trial. Setting: Eighteen in vitro fertilisation clinics across the UK participated from February 2016 to April 2019. Participants: Couples undergoing their first, second or third cycle of in vitro fertilisation treatment in which the female partner was aged < 42 years. Interventions: If at least three good-quality embryos were present on day 3 of embryo development, couples were randomly allocated to either freeze-all (intervention) or fresh-embryo transfer (control). Outcomes: The primary outcome was a healthy baby, defined as a live, singleton baby born at term, with an appropriate weight for their gestation. Secondary outcomes included ovarian hyperstimulation, live birth and clinical pregnancy rates, complications of pregnancy and childbirth, health economic outcome, and State–Trait Anxiety Inventory scores. Results: A total of 1578 couples were consented and 619 couples were randomised. Most non-randomisations were because of the non-availability of at least three good-quality embryos (n = 476). Of the couples randomised, 117 (19%) did not adhere to the allocated intervention. The rate of non-adherence was higher in the freeze-all arm, with the leading reason being patient choice. The intention-to-treat analysis showed a healthy baby rate of 20.3% in the freeze-all arm and 24.4% in the fresh-embryo transfer arm (risk ratio 0.84, 95% confidence interval 0.62 to 1.15). Similar results were obtained using complier-average causal effect analysis (risk ratio 0.77, 95% confidence interval 0.44 to 1.10), per-protocol analysis (risk ratio 0.87, 95% confidence interval 0.59 to 1.26) and as-treated analysis (risk ratio 0.91, 95% confidence interval 0.64 to 1.29). The risk of ovarian hyperstimulation was 3.6% in the freeze-all arm and 8.1% in the fresh-embryo transfer arm (risk ratio 0.44, 99% confidence interval 0.15 to 1.30). There were no statistically significant differences between the freeze-all and the fresh-embryo transfer arms in the live birth rates (28.3% vs. 34.3%; risk ratio 0.83, 99% confidence interval 0.65 to 1.06) and clinical pregnancy rates (33.9% vs. 40.1%; risk ratio 0.85, 99% confidence interval 0.65 to 1.11). There was no statistically significant difference in anxiety scores for male participants (mean difference 0.1, 99% confidence interval –2.4 to 2.6) and female participants (mean difference 0.0, 99% confidence interval –2.2 to 2.2) between the arms. The economic analysis showed that freeze-all had a low probability of being cost-effective in terms of the incremental cost per healthy baby and incremental cost per live birth. Limitations: We were unable to reach the original planned sample size of 1086 and the rate of non-adherence to the allocated intervention was much higher than expected. Conclusion: When efficacy, safety and costs are considered, freeze-all is not better than fresh-embryo transfer. Trial registration: This trial is registered as ISRCTN61225414. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 25. See the NIHR Journals Library website for further project information.

Objectives The relationship between smoking and ovarian reserve markers is inconclusive. The primary objective of our study was to assess the effect of cigarette smoking on the quantitative ovarian reserve parameters, serum anti-Mullerian hormone (AMH) and antral follicle count (AFC) as relevant to prediction of fertility outcomes in women seeking fertility treatment. Our secondary aims were to validate self-reported smoking behaviour using biomarkers and evaluate the association between biomarkers of ovarian reserve (serum AMH and AFC) with biomarkers of smoking exposure (breath carbon monoxide (CO) and urine cotinine levels). Design Prospective, cross-sectional study. Setting Single tertiary care fertility centre. Participants Women ≤35 years seeking fertility treatment. Primary outcome measures Serum AMH and AFC. Results Significant differences were found among current smokers, ex-smokers and never smokers for breath CO (F(2,97)=33.32, pConclusion We did not find a statistically significant difference in quantitative ovarian reserve markers between current smokers, ex-smokers and never smokers which would be clinically meaningful in our study population. We confirmed that self-reported smoking correlates well with quantitatively measured biomarkers of smoking. This validated the self-reported comparison groups to ensure a valid comparison of outcome measures. There was no significant association between biomarkers of smoking and biomarkers of ovarian reserve. We were also unable to demonstrate a correlation between the lifetime smoking exposure and ovarian reserve.

Background: Normal mature sperm have a considerably reduced number of mitochondria, which provide the energy required for progressive sperm motility. Literature suggests that disorders of sperm motility may be linked to abnormal sperm mitochondrial number and function.Objectives: To summarise the evidence from literature regarding the association of mitochondrial DNA copy numbers and semen quality with a particular emphasis on the sperm motility.Search strategy: Standard methodology recommended by Cochrane.Selection criteria: All published primary research reporting on the association between mitochondrial DNA copy numbers and semen quality.Data collection and analysis: Using standard methodology recommended by Cochrane we pooled results using a random effects model and the findings were reported as a standardised mean difference.Main results: We included ten studies. The primary outcome was sperm mitochondrial DNA copy numbers. A meta‐analysis including five studies showed significantly higher mitochondrial DNA copy numbers in abnormal semen analysis compared with normal semen analysis (standardised mean difference 1.08, 95% CI 0.74–1.43). Seven studies included in the meta‐analysis showed a significant negative correlation between mitochondrial DNA copy numbers and semen parameters. The quality of evidence was assessed as good to very good in 60% of studies.Conclusions: Our review demonstrates significantly higher mitochondrial DNA in human sperm cells of men with abnormal semen analysis in comparison to men with normal semen analysis.Tweetable There is significantly higher mitochondrial DNA in sperm cells of men with abnormal semen analysis in comparison to men with normal semen analysis.