A comprehensive review for defining cut-off values of oocyte, zygote, and embryo maturation arrest (OZEMA) due to maternal-effect genes: towards the establishment of clinical criteria.

study questionWhich clinical definition of oocyte, zygote, and embryo maturation arrest (OZEMA) merits genetic investigation? SUMMARY ANSWER: The diagnosis OZEMA is considered when: only two mature oocytes are obtained from six cumulus-oocyte complexes (COCs), only one zygote is obtained from six metaphase II oocytes (MIIs), or no blastocysts are obtained from six two-pronuclei zygotes (2PNs). WHAT IS KNOWN ALREADY: OZEMA is a cover term for various defects, including oocyte abnormalities, fertilization failure, cleavage arrest, and abnormal embryo development, often associated with specific genetic variants. While some variants in specific genes are associated with distinct phenotypes, others commonly display variable expressivity across cycles and patients. Currently, there are no standardized cut-off values defining the OZEMA disorder. STUDY DESIGN, SIZE, DURATION: This is a pooled secondary analysis of aggregated data extracted from published studies. A PubMed search was conducted to identify peer-reviewed original studies in the human reporting genetically confirmed cases of OZEMA. Studies were included if patients had displayed OZEMA in at least two medically assisted reproduction (MAR) cycles. In total, clinical and genetic data were extracted from 132 publications, including 521 patients and 39 genes. PARTICIPANTS/MATERIALS, SETTING,

methodsClinical phenotypes from 132 publications were classified into oocyte maturation arrest (OMA), zona pellucida abnormality (ZPA), fertilization failure (FF), zygote arrest (ZA), early embryo arrest (EEA), mixed phenotypes, and other abnormalities. Data at both cycle and patient levels were evaluated using ratios corresponding to key developmental milestones (ratio of MII/COC, 2PN/MII, cleaved embryos/2PN, blastocysts/2PN). These ratios were compared with the expected values Vienna Consensus binomial modeling to assess whether the observed proportions were significantly lower than the established competency thresholds (P < 0.05). MAIN RESULTS AND THE ROLE OF CHANCE: This review identified 39 OZEMA-associated genes. Analysis of 668 cycles from 253 patients carrying variants in 35 genes showed abnormal developmental outcomes in 93%, based on binomial modeling. Reliable diagnosis of OZEMA requires a sufficient number of COCs, MIIs, or 2PNs to distinguish true developmental impairment from normal biological variation. When these minimal thresholds are not reached, statistical power is insufficient to reliably confirm developmental arrest. Based on our findings, OZEMA is diagnosed when only two or fewer mature oocytes form from six COCs, one or no zygote forms from six MIIs, or no blastocysts form from six 2PNs. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective design and reliance exclusively on published data from women selected for poor IVF outcomes and the presence of variants in candidate OZEMA genes, which may introduce publication bias and reporting heterogeneity. Therefore, this study does not report on genetic yield from women with normal IVF outcomes. Variability in clinical protocols and genetic testing methods, limited ancestral diversity, and missing data across studies could contribute to confounding factors. WIDER IMPLICATIONS OF THE

findingsThis study is an important step toward understanding the clinical and genetic spectrum of OZEMA, highlighting the variability of and overlap between affected subphenotypes. Establishing cut-off values against consensus oocyte and embryo developmental competency levels provides a benchmark for more accurate classification. Importantly, this represents the most comprehensive analysis of published OZEMA cases with genetic variants to date, strengthening the reliability of the proposed clinical thresholds. These findings may guide personalized treatment strategies and genetic counseling, ultimately improving outcomes in MAR. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this study. The authors declare no competing interests. REGISTRATION NUMBER: Not applicable.