Background <p>Preterm birth (PTB) remains a leading cause of neonatal morbidity and mortality worldwide. While conditions such as diabetes and hypertension have been linked to PTB, the contribution of multimorbidity, defined as the coexistence of two or more chronic conditions, has not been extensively quantified. This systematic review and meta-analysis evaluated the association between maternal multimorbidity and PTB risk.</p> Methods <p>This systematic review and meta-analysis followed PRISMA 2020 guidelines and was prospectively registered in PROSPERO (CRD420251086046). PubMed, Scopus, Web of Science, and EBSCOhost were searched from database inception to November 2025 for observational studies examining the association between multimorbidity and PTB. Eligible studies included pregnant women with two or more chronic conditions compared with those without any chronic conditions. Study quality was assessed using the Newcastle–Ottawa Scale (NOS). Adjusted risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random-effects models, using retrieved RRs or converted Odds Ratios (ORs) to RRs. Analysis was performed separately for different gestational age thresholds (&lt; 37 weeks and &lt; 28 weeks). Further subgroup analyses were also conducted based on the type of PTB, study design, sample size, geographical region, risk of bias, multimorbidity severity, timing of diagnosis and multimorbidity category. Heterogeneity was evaluated with the I² statistic, and publication bias with funnel plots and Egger’s test. Sensitivity analyses were performed for gestational age cut-offs and risk of bias using leave-one-out procedures and alternative estimators of between-study variance (REML, PM, and DL).</p> Results <p>Thirteen cohort studies including over 3&#xa0;million pregnancies met the inclusion criteria. Maternal multimorbidity was significantly associated with an increased risk of PTB (RR = 2.04, 95% CI 1.61–2.59; <i>p</i> &lt; 0.001). The association remained significant for births before 37 weeks (RR = 2.04, 95% CI 1.61–2.59). Significant associations were also observed for spontaneous PTB (RR = 1.46, 95% CI 1.13–1.89), in both prospective (RR = 1.70, 95% CI 1.29–2.24) and retrospective cohort studies (RR = 2.17, 95% CI 1.44–3.26), and across small (RR = 1.67, 95% CI 1.10–2.54), medium (RR = 1.56, 95% CI 1.29–1.90), and large (RR = 2.69, 95% CI 1.55–4.68) sample sizes. Likewise significant associations were identified in studies defining multimorbidity with higher clinical severity (RR = 2.44, 95% CI 1.33–4.47) and in those with moderate risk of bias (RR = 2.32, 95% CI 1.63–3.31). In addition, studies focusing on mental health-related multimorbidity showed a significant association with preterm birth (RR = 1.92, 95% CI 1.64–2.25), as did studies examining metabolic/cardiovascular multimorbidity (RR = 2.99, 95% CI 1.29–6.91) and those assessing mixed multimorbidity profiles (RR = 1.55, 95% CI 1.12–2.17). Sensitivity analyses, including leave-one-out procedures and alternative estimators (REML, PM, DL), confirmed the robustness of results. Although heterogeneity remained high in the analyses (I² &gt; 80%), there was no evidence of publication bias based on funnel plots or Egger’s test.</p> Conclusion <p>Maternal multimorbidity is associated with a significantly increased risk of PTB, highlighting the importance of comprehensive preconception and antenatal care for women with multiple chronic conditions. However, the findings should be interpreted with caution due to substantial heterogeneity, variation in multimorbidity definitions, and the observational design of the included studies. Further large-scale, high-quality prospective research using standardized definitions of multimorbidity and PTB is needed to strengthen the evidence base and clarify causal pathways.</p> Registration <p>PROSPERO: CRD420251086046.</p>