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Background: Despite various genomic approaches used in prior studies investigating the association of maternal genetic variability with spontaneous preterm birth (sPTB), results show inconsistency and contradictions., Objectives: To conduct a systematic review of studies analyzing the association between maternal genetic variants and sPTB, evaluate retrieved studies based on selection criteria, classify studies into hypothesis-based and hypothesis-free, and perform a meta-analysis to identify the strongest associations., Search Strategy: PubMed, Scopus, and reference lists were searched until October 2024., Selection Criteria: English-language, case-control, cross-sectional, and prospective cohort studies examining the association between maternal genetic variations and sPTB were included., Data Collection and Analysis: Data on authors, publication year, ethnicity, genes/variants, P values, study type, sample size, inclusion criteria, and methods were collected. The association strength was estimated using odds ratios with 95% confidence intervals., Results: Eighty-one studies met eligibility criteria: 73 utilized a hypothesis-based and 14 a hypothesis-free approach. Thirty-five studies qualified for a meta-analysis, revealing a significant association in tumor necrosis factor α (rs1800629) gene for alleles and additive and recessive genetic models (P ≤ 0.05). From the hypothesis-free approach, 13 genes reached global significance in association with sPTB (P < 5 × 10 -8 )., Conclusions: No single gene or variant was consistently associated with sPTB risk among studies. Hypothesis-based analyses highlighted tumor necrosis factor α (rs1800629) as a modest signal, while hypothesis-free approaches identified 13 genes with genome-wide significance, pointing to new research directions in understanding sPTB genetics., (© 2024 International Federation of Gynecology and Obstetrics.)