Background: Despite various genomic approaches used in prior studies investigating association of maternal genetic variability with spontaneous preterm birth (sPTB), results show inconsistency and contradictions. Objectives: To: conduct a systematic review of studies analysing the association between maternal genetic variants and sPTB; evaluate retrieved studies based on selection criteria; classify studies into hypothesis-based and hypothesis-free; perform a meta-analysis to identify the strongest associations. Search Strategy: PubMed, Scopus and reference lists were searched until October 2023. 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. Main Results: 81 studies met eligibility criteria: 72 utilized a hypothesis-based and 9 a hypothesis-free approach. 34 studies qualified for a meta-analysis revealing a significant association in TNF-α (rs1800629) gene for alleles, additive and recessive genetic models (P<0.05). From the hypothesis-free approach, 7 variants in 5 genes (EBF1, EESEC, HSPA1L, ASTN1, MAST1) reached global significance (P < 5 x10 ^-8). Conclusions: No specific genes or variants were clearly associated with the risk of sPTB. Among hypothesis-based studies, limited gene overlap indicates inconsistent SNP associations. TNF-α (rs1800629) emerges as the only with a modest signal for future analyses. Additional 5 genes from the hypothesis-free approach showed a globally significant association. Funding: / Keywords: Preterm Birth, Genetic Association Study, Genome-Wide Association Study, Exome Sequencing