Background: Preterm prelabor rupture of the fetal membranes (PPROM) increases the risk of neonatal mortality and morbidity. The etiology behind the condition is multifactorial but believed to result from an overactivation of inflammatory pathways. This systematic review aimed to synthesize the literature behind first-trimester biomarkers associated with PPROM and compare it to literature within the same area for preterm birth. Methods: A search strategy was performed in PubMed, Embase, and CINAHL from 1993 to 2024 resulting in 14,889 articles screened by two independent authors and presented according to PRISMA guidelines. The biomarkers from the included articles were categorized into four medical headings: The immune system, metabolism and endocrinology, hematology, and reproduction. Results: Biomarkers associated with PPROM were primarily related to the immune system. C-reactive protein (CRP) and white blood cells (WBC) were often investigated for an association with PPROM but displayed divergent results of varying quality. Decreased concentrations of placental growth factor (PlGF) were associated with PPROM and spontaneous preterm birth, potentially highlighting a shared etiology, making soluble fms-like tyrosine kinase-1 (sFlt-1) interesting to investigate as well. Conclusion: Most biomarkers were examined in single studies, providing limited data to make significant conclusions about each biomarker. This review encourages further investigation of CRP, WBC, PlGF, and sFlt-1.