Ureaplasma Species in Perinatal Disease: From the Age of Innocence to the Missing Villain.

Ureaplasma urealyticum and Ureaplasma parvum occupy an odd place in perinatal medicine: dismissed for decades as harmless residents of the female genital tract, they are now recognized as pathogens with real consequences for preterm newborns. This review traces that paradigm shift, from organisms once dismissed as harmless colonizers to pathogens now implicated in chorioamnionitis, preterm birth, and a range of serious neonatal morbidities, and describes the molecular mechanisms that underlie their pathogenicity: Toll-like receptor (TLR1/2/6/9)-mediated NF-κB and MyD88/IRAK4/TRAF6 signaling, NLRP3 inflammasome activation and pyroptosis, and blood-brain barrier disruption via claudin-5/occludin downregulation and MMP-mediated tight junction cleavage. We also review the evidence for biofilm-conferred antibiotic tolerance and the clinical associations between Ureaplasma colonization and intraventricular hemorrhage (pooled OR 1.62, 95% CI 1.23-2.13), bronchopulmonary dysplasia (pooled OR 2.30, 95% CI 1.65-3.20), late-onset sepsis, and neurodevelopmental impairment. Diagnosis remains a weak point: culture sensitivity is below 10% compared with polymerase chain reaction (PCR) testing, and no randomized trial has yet shown that microbiological eradication translates into better clinical outcomes-a gap we examine critically. Whether these organisms cause disease seems to depend on gestational age, bacterial load, serovar-specific virulence, and host immune competence. We argue that this conditionality calls for risk stratification rather than dismissal whenever Ureaplasma is identified in clinical specimens, and that the field needs a paradigm shift toward Ureaplasma screening in high-risk pregnancies and targeted neonatal PCR testing, backed by adequately powered interventional trials.