Abstract
Abstract
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.
Keywords: Meta-Analysis, Reproductive medicine, Subfertility
STRENGTHS AND LIMITATIONS OF THIS STUDY.
An individual participant data (IPD) meta-analysis enhances statistical power, allowing precise estimation of treatment effects and identification of subgroup differences.
This IPD meta-analysis provides a comprehensive evaluation of time-lapse imaging for in vitro fertilisation as it leverages diverse datasets from multiple studies that evaluate both undisturbed culture and morphokinetic parameters.
The study implements rigorous data integrity and consistency checks to enhance the reliability and trustworthiness of its findings.
Limited availability of participant-level data may exclude some trials, reducing statistical power and generalisability and introducing potential bias.
Despite increased power, the study may still be underpowered to detect rare adverse events like congenital malformations.
Introduction
Rationale
In vitro fertilisation (IVF) is an expensive treatment with limited success rates, with UK, European and global live birth rates ranging from 14% to 24%.1,3 Embryo selection remains a major challenge, and the National Institute for Health and Care Excellence (NICE) has highlighted the need for research to improve it.4
Time-lapse imaging (TLI) is an increasingly used ‘add-on’ in IVF labs, hypothesised to improve outcomes by providing undisturbed culture conditions and additional embryo development data for selection.5 Randomised controlled trials (RCTs) and aggregate meta-analyses have not shown clear advantages for live birth rates, yet IVF centres continue to invest in TLI.6,10 Despite widespread adoption, evidence of benefit remains uncertain.
This may be due to beliefs that benefits exist for specific patient subgroups or with particular usage protocols. However, key gaps prevent translation into clinical guidance. These include: (1) limited definitive evidence for effects in subgroups such as older women, those with prior IVF failure, or by ethnicity;1 11 (2) lack of detail on technical variations and IVF protocols and (3) underpowered studies for safety outcomes like pregnancy loss and multiple births. No health economic analyses are currently available.
Individual participant data (IPD) meta-analysis can address these gaps by analysing raw data across trials, enabling evaluation of treatment-covariate interactions, differential effects by usage protocols and better detection of rare outcomes.12 Unlike aggregate data, IPD can model individual risk factors and avoid biases from selective reporting. It can also increase the number of participants and events included, using anonymised existing data and reducing research waste. Our proposed IPD meta-analysis will include data from the latest trials not captured in the most recent Cochrane review.6 11 13 14 It aims to provide robust evidence to inform clinical and funding guidelines for TLI use in IVF. This is essential for supporting patients, clinics, funders and policymakers.
If TLI is beneficial—generally or in targeted groups—it may improve success rates, shorten time to pregnancy, reduce complications and lower costs. If ineffective, its use can be reconsidered, preventing unnecessary expense and resource allocation. Either outcome offers meaningful benefits for health systems and patients.
Objectives
To determine, using IPD meta-analysis, whether TLI improves reproductive outcomes of IVF/ICSI treatment and if the benefits vary according to the participant characteristics and/or the type of intervention.
To evaluate the effects of TLI (overall as a single system) in women undergoing IVF/ICSI, and for each type of intervention (undisturbed culture, morphokinetic parameters) on reproductive outcomes for effectiveness (live birth rate, clinical pregnancy rate) and safety (pregnancy loss, multiple birth rate, minor and major congenital malformations).
To assess the differential effects of the interventions according to the participant characteristics (age, ethnicity, previous unfavourable reproductive outcomes) and intervention characteristics (duration of undisturbed culture, day of embryo transfer) on reproductive outcomes.
Methods and analysis
This systematic review and IPD meta-analysis will be conducted according to the Cochrane Handbook for Systematic Reviews of Intervention12 and its results will be reported following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses of IPD statement.15 The present protocol is written in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol 2015.16 The detailed statistical analysis plan is available as online supplemental Appendix 1. The work for this project commenced on 01/10/2023 and is ongoing.
Eligibility criteria
Inclusion criteria
We will include trials meeting the criteria below.
Study design
RCTs using one or more of the comparisons detailed below.
Population
Women having IVF/ICSI (Intracytoplasmic sperm injection) treatment using their own oocytes.
Intervention
The use of TLI systems for either undisturbed culture and/or use of morphokinetic parameters for embryo selection.
As the benefit of the TLI intervention may be either due to undisturbed embryo culture or the use of morphokinetic parameters for embryo selection, three intervention groups will be considered.
TLI systems using both undisturbed embryo culture and morphokinetic parameters for embryo selection.
TLI systems using only undisturbed embryo culture and standard morphology for embryo selection.
Incubators using standard/disturbed embryo incubation and standard morphology for embryo selection.
Comparisons
Based on the three intervention groups, three hypotheses will be tested:
Testing undisturbed culture: TLI using undisturbed embryo culture compared with standard/disturbed embryo incubation and standard morphology for embryo selection in both groups—B versus C.
Testing morphokinetic parameters for embryo selection: using morphokinetic parameters for embryo selection compared with standard morphology for embryo selection with similar embryo culture conditions in both groups (either disturbed or undisturbed)—A versus B.
Testing the overall system: TLI using both undisturbed embryo culture and morphokinetic parameters for embryo selection compared with standard/disturbed embryo incubation and standard morphology for embryo selection—A versus C.
Control
This group will vary with the different comparisons as discussed above.
Outcomes
All outcomes will be assessed for the first embryo transfer after egg collection—either fresh or frozen embryo transfer (as in elective freeze all cycles)
Primary outcome: live birth rate (when live birth is missing it will be imputed by ongoing pregnancy, defined as a pregnancy that has a gestational sac with fetal heart activity at 12 weeks or later, as confirmed by ultrasound).
Secondary outcomes for effectiveness: clinical pregnancy rate.
Safety outcomes: pregnancy loss, multiple pregnancy rate, incidence of minor and major congenital malformations, birth weight, gestational age at birth.
Exclusion criteria
Quasi‐randomised and other controlled trials, trials that randomised oocytes or embryos rather than women and cross‐over trials.
Information sources
We have incorporated the results of the literature search used for the latest Cochrane review (2019) into this review and will include all the trials included therein. We will further update the literature search to include new evidence (published and unpublished, with no language restrictions) that has appeared since the literature search for the 2019 Cochrane review (7 January 2019). We will search the electronic databases MEDLINE, EMBASE, CINAHL and CENTRAL from 7 January 2019 2019 to date. We will search for the outcomes for all ongoing trials reported in the 2019 Cochrane review and further search the trial registers, International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for newer ongoing/completed trials. We will also search the citation lists of all the newly identified trials for any relevant references.
Search strategy
The search strategy will include a combination of subject headings and text words relating to or describing the participants and the intervention. The draft search strategy for EMBASE can be seen in online supplemental Appendix 2. A similar strategy will be used for the other databases searched.
Selection process
Two authors will independently screen the titles and abstracts of articles retrieved from the search. The full texts of potentially suitable articles will be assessed for suitability for the review. In the case of disagreement, a third author will be consulted and a consensus reached for inclusion/exclusion of the trial in question. A list of trials suitable for inclusion in the review will be finalised. We will contact the authors of all the trials finalised for inclusion in the review to request study level and anonymised individual patient level data, incorporating individual data sharing agreements.
Data management
Data collection process
Individual data sharing agreements will be made between trial authors and the study sponsor (Queen Mary University of London). Data will be stored on a secure server with restricted access to the study team. Each of the sites will be required to adhere to all the information governance and ISO 27001 security standards. Operating procedures will be followed for the secure transfer, storage, handling, backup and restore of data to comply with organisational policies in relation to Information Governance, including Data Protection, Confidentiality, Caldicott Principles, Information Security and Records Management. Following the acquisition of data, we will use peer-reviewed robust methods to assess the quality of the data, resolve queries and extract, clean, format and harmonise the relevant data. For studies with unavailable IPD, we will extract appropriate aggregate study-level data for inclusion in the review.
Data items
We will collect relevant study level and participant level data related to study design and methodology, participants, intervention and outcomes. Where applicable, we will standardise or translate variables within the IPD datasets to ensure common scales or measurements across studies. The complete list of data items is detailed in online supplemental Appendix 3.
IPD integrity
For each eligible RCT, data will be deidentified before transfer to a secure server. We will assess integrity using the principles of IPD integrity tools for RCTs to investigate the trustworthiness of the trials.17,22 A prespecified investigator will assess the data integrity by performing internal consistency checks and by attempting to replicate the results of the analysis as published in the RCT report. These data integrity tests will include the analysis of baseline data distribution as well as the analysis of outliers or abnormal patterns within the data. Study authors will be contacted to provide missing data and to resolve queries arising from these integrity checks. Once queries have been resolved, clean data will be uploaded to the main study database.
Outcomes and prioritisation
We will report on clinically relevant outcomes related to efficacy and safety of the intervention.23
Primary outcome
Live birth rate after the first fresh/frozen (in elective freeze all cycles) embryo transfer (live birth rate event—multiple births count as a single live birth event). When live birth is missing, it will be imputed by ongoing pregnancy, defined as a pregnancy that has a gestational sac with fetal heart activity at 12 weeks or later, as confirmed by ultrasound.
Secondary outcome for effectiveness
Clinical pregnancy rate (gestational sac±fetal heart confirmed by ultrasound).
Safety outcomes
Pregnancy loss (biochemical pregnancy (loss between positive pregnancy test and clinical pregnancy), miscarriage (loss between clinical pregnancy and 24 weeks of gestation), stillbirth (loss between 24 weeks of gestation to birth)), multiple pregnancy rate (more than one gestational sac±fetal heart confirmed by ultrasound), minor and major congenital malformations, birth weight and gestational age at birth.
Risk of bias in individual studies
Two authors will independently assess the risk of bias at study level in included studies using the Risk of Bias version 2 (RoB 2): A revised Cochrane risk-of-bias tool for randomised trials.24 We will evaluate included studies for the adequacy of sequence generation and allocation concealment, adequacy of blinding of couples, providers and outcome assessors, completeness of outcome data, risk of selective outcome reporting and risk of other potential sources of bias. In addition, this assessment tool distinguishes between the scenarios of intention to treat (ITT) and per protocol. Any disagreements between authors will be resolved by consulting a third author to achieve consensus.
Specification of outcomes and effect measures
For all outcomes in this review (dichotomous data), we will present the pooled intervention effect as an OR with 95% CIs.
Data synthesis
Synthesis methods
Overall effect and subtypes of intervention
We will evaluate the effect of interventions through a one-step meta-analysis based on a multilevel mixed effects logistic regression model with study included as random effect. The model will assess the impact of the two components of the intervention, namely undisturbed culture and embryo selection based on morphokinetics, as well as the interaction between them to determine any synergistic effects. While it is improbable that confounding effects will be present since the data are derived from RCTs, there may be between-study heterogeneity due to differences in participants and/or technical procedures. To account for this heterogeneity, the analysis will be adjusted for any baseline imbalance in the primary covariates, such as age, ethnicity, body mass index, attempt, type, category and duration of infertility, type of embryo transfer (fresh/frozen), day of transfer, number of embryos transferred and the type of time lapse system used. Between-study heterogeneity will be estimated using the between-study variance (‘tau-squared’). If convergence issues arise with the one-step models, a two-step meta-analysis will be conducted as an alternative. In the two-step approach, intervention effect estimates will first be calculated separately for each trial using logistic regression, and then pooled across studies using a random-effects meta-analysis framework. These analyses will be conducted for all primary and secondary outcomes. These analyses will be applied to all primary and secondary outcomes.
For the three coprimary contrasts, we will control the family-wise type I error rate at two-sided α=0.05 using the Holm-Bonferroni stepdown procedure. All three p values will be calculated and ranked from smallest to largest; the smallest p value will be tested against α/3=0.0167, the second smallest (if the first is significant) against α/2=0.025, and the largest (if the first two are significant) against α=0.05. A contrast is declared statistically significant only if it meets its respective Holm threshold, thereby preserving strong control of the overall 5 % false positive rate while treating all primary hypotheses on an equal hierarchical level.
Exploration of variation in effects: differential effect by subgroups (treatment-covariate interactions)
We will investigate if the impact of the intervention varies based on participant characteristics (age, ethnicity, previous unfavourable reproductive outcomes (no fertilisation, failure of embryo development, poor embryo quality, multiple unsuccessful treatments/miscarriages)) across all comparisons. We will also assess the impact of variations in the intervention. For the comparison between disturbed and undisturbed culture, we will consider the impact of the duration of undisturbed culture in the intervention arm and number of disturbances during standard incubation for the same duration of the culture. For the comparison between the use of morphokinetic parameters and standard morphological assessment, we will consider the impact of embryo selection protocols and duration of incubation when morphokinetic parameters are assessed (the day of embryo transfer). This will be by extending the one-stage meta-analysis framework to include treatment-covariate interactions, with continuous variables kept continuous to avoid arbitrary dichotomisation, and potential non-linear relationships and interactions modelled appropriately. Our IPD meta-analysis will improve the power to identify genuine subgroup effects and allow us to assess the consistency of the subgroup effect across studies rather than being a chance finding in a single study. Any subgroup analyses will be considered as exploratory, non-confirmatory analyses.
Additional analyses
Sensitivity analysis
We will conduct several sensitivity analyses to ensure the robustness of our findings. First, we will investigate the impact of studies with unavailable IPD by extracting appropriate aggregate study-level data and combining them with the available IPD using a two-stage random-effects IPD meta-analysis. The primary analysis will use an ITT approach, including all participants as originally allocated, regardless of adherence to the assigned intervention. An ‘as-treated’ analysis will then be performed, categorising participants based on the intervention actually received to account for any deviations from the initial allocation. Additionally, a per-protocol analysis will be conducted, excluding participants who did not adhere to the protocol (protocol violators). Finally, when possible, we will compare the results of the one-step IPD meta-analysis approach with those of a two-step approach, where individual study estimates are first derived and then combined. These analyses aim to evaluate the impact of different methodological choices and data availability on the results.
Dealing with missing data
We will deal with missing data using a multiple imputation strategy based on chained equations. Outcome variables will be used for the imputation strategy, but cases with imputed outcomes will not be used in the final analysis.
Meta biases
Publication bias is a concern in all types of meta-analyses, including IPD meta-analyses. We will address this issue by generating funnel plots that plot the effect sizes against the sample size (or its SE) of each study. We will examine the symmetry of the plot using Egger’s tests to identify any potential publication bias.
Confidence in cumulative evidence
The Grading of Recommendations Assessment, Development and Evaluation criteria will be used to assess the overall quality of evidence incorporating risk of bias from the studies, indirectness, inconsistency, imprecision and publication bias.25
Monitoring and auditing
The sponsor or delegate retains the right to audit any study, study site or central facility. In addition, any part of the study may be audited by the funders where applicable. On-site monitoring will be performed for the co-ordinating site but will be minimal as this is an observational study with a statistical methodology. Monitoring will focus on data integrity and compliance of all local data information governance processes.
Insurance and indemnity
The insurance that Queen Mary has in place provides cover for the design and management of the study as well as ‘no fault compensation’ for participants, which provides an indemnity to participants for negligent and non-negligent harm.
Patient and public involvement
We plan to involve patients and the public in the dissemination plans of our research.
Ethics and dissemination
No ethical approval was needed for this study. The review is registered on PROSPERO: CRD42024564332.
The outputs of this IPD meta-analysis will provide high quality evidence to inform the formulation of guidelines for the use and funding of this intervention. We plan to disseminate the findings of the research to all stakeholders such as international societies for reproductive medicine, representatives from European Society for Human Reproduction and Embryology, Fertility Society of Australia and American Society for Reproductive Medicine, clinical community, user groups, funding bodies and the general public. The dissemination to clinicians and clinical professional bodies will be through publications in high impact peer reviewed journals and presentations at major national and international conferences. We plan to publish the study protocol in an open access journal. Dissemination to the participants and the general public will be done through newsletters, websites of international societies for obstetrics, gynaecology and reproductive medicine, and meetings and websites of the funders, fertility charities and patient support groups. We plan to disseminate the findings to funding stakeholders with a view to incorporating the findings of the study into public funding for IVF/ICSI, practice and policy. There is currently no international guidance on the use of TLI in IVF/ICSI. NICE and other international guideline development groups will be informed of the results of the study, which will be important for their guideline updates.
Supplementary material
The funders have no role in the design and development of the study protocol.
Footnotes
Funding: This work is supported by Barts Charity G-002682 and Department of Obstetrics and Gynaecology, Chinese University of Hong Kong.
Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2025-101761).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Patient and public involvement: Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
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