O-213 Cytoplasmic strings in human in-vitro embryos: a promising indicator for enhanced live-birth outcomes – a systematic review and meta-analysis

Abstract Study question Does the presence and characteristics of cytoplasmic strings (CS) in human in-vitro blastocysts influence pregnancy and in-vitro fertilisation (IVF) outcomes? Summary answer The presence of cytoplasmic strings in human in-vitro blastocysts is associated with higher livebirth rates (LBR), clinical pregnancy rates (CPR) and morphological quality. What is known already CS are transient structures consisting of thin filamentous connections (filopodia) that traverse the blastocoel, connecting the inner cell mass to the mural trophectoderm in blastocysts. While animal studies have observed CS for years, their role in embryogenesis remains unclear. Initially considered abnormal in expanded blastocysts, recent time-lapse studies on human in-vitro embryos suggest CS may indicate a higher developmental potential. Although morphological and morphokinetic assessment guidelines now include CS, their impact on embryo viability remains inconclusive due to limited evidence on clinical outcomes. Study design, size, duration This systematic review and meta-analysis followed PRISMA guidelines. PubMed, Embase, Medline, Cochrane Library, and Web of Science were searched using predefined MeSH terms from 1946 till 12/2024. Studies were selected per PICO framework, screened independently and back-reference searched. Inclusion criteria were population; pre-implantation embryo, intervention; ‘CS and related terms’. Meta-analysis required a control of blastocysts without CS and reporting primary outcome; LBR or secondary outcomes; CPR, embryo quality. Exclusion criteria were ‘non-human’ and ‘non-English language’. Participants/materials, setting, methods The systematic review comprised 23 publications (7 reviews and 15 studies) assessed for bias using Newcastle-Ottawa Scale. Data were extracted from 11 studies for meta-analysis following standardised methods. RevMan, Stata, or R were used for analysis and employed fixed- or random-effects models based on heterogeneity (Cochran’s Q, I²). Effect sizes were reported as odds ratios (OR), or mean differences. Publication bias was assessed via funnel plots and Egger’s test, with sensitivity and subgroup analyses performed. Main results and the role of chance Meta-analysis of 11 studies (1 case-control and 10 cohort) included 6,952 blastocysts analysed for CS presence; 4,064 exhibited CS (CS+), while 2,888 did not (CS−). Across the 11 studies CS+ prevalence ranged from 25.05% to 93.00%. Pooled analysis from six studies reporting LBR demonstrated higher LBR associated with CS+ blastocysts (OR = 1.76, 95% CI: 1.02–3.06, I² = 33%, n = 2,527 transferred blastocysts). Similarly, increased CPR in CS+ blastocysts was observed across five studies (OR = 2.26, 95% CI: 1.03–4.97, I² = 66%, n = 1,963). However, when studies at risk of bias were excluded, this was no longer significant (OR = 1.60, 95% CI: 0.97–2.64, I² = 0%, n = 1,787). CS+ blastocysts also demonstrated higher odds of being classified as good-quality, and maintained this after accounting for potential biases (OR = 4.56, 95% CI: 3.57–5.83, I² = 0%, n = 1,826). Additionally, morphokinetic differences between CS+ and CS− blastocysts will be presented. The literature review revealed limited data on filopodia in human pre-implantation embryos. Some studies included in the systematic review, but not the meta-analysis, reported CS composition (F-actin), slight-to-moderate inter-/intra-observer agreement in CS assessment, and CS presence in human in-vivo blastocysts. One study was excluded due to incomplete data. Limitations, reasons for caution For some outcomes, data could not be included in meta-analyses due to incompatible or incomplete data in the publications. High level of heterogeneity is present throughout studies, likely secondary to IVF methodological differences and inter- and intra-observer variability on reporting on CS. Wider implications of the findings Our meta-analysis demonstrated a positive correlation between CS and improved IVF outcomes. Further research is necessary into the biological role of CS in embryogenesis and their potential influence on embryo viability. Integrating CS assessment into blastocyst evaluation protocols could refine embryo selection strategies, ultimately improving pregnancy success rates in IVF. Trial registration number No

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