AbstractBackgroundDespite various genomic approaches used in prior studies investigating the association of maternal genetic variability with spontaneous preterm birth (sPTB), results show inconsistency and contradictions.ObjectivesTo 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 strategyPubMed, Scopus, and reference lists were searched until October 2024.Selection criteriaEnglish‐language, case–control, cross‐sectional, and prospective cohort studies examining the association between maternal genetic variations and sPTB were included.Data collection and analysisData 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.ResultsEighty‐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).ConclusionsNo 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.