Objective Intra-amniotic inflammation (IAI) is a frequent complication occurring in preterm prelabour rupture of membrane (PPROM). We report a systematic review to assess the diagnostic potential of interleukin-6 (IL-6) as a marker of IAI.

Data sources For the purpose of this study, we followed a prospective protocol (International Prospective Register of Systematic Reviews, reg. CRD42024501132). We searched PubMed, Web of Science, Scopus, and ResearchRabbit from inception to March 2024.

Study eligibility criteria We included all eligible research articles reporting the concentration of IL-6 in association with IAI in PPROM. Along with amniotic fluid IL-6, prospective and retrospective cohort studies reporting neonatal morbidities, the correlation of IL-6 in amniotic fluid and IL-6 or other proteins in non-invasively collected samples (maternal blood, cervical fluid, and vaginal fluid) were included.

Methods The quality assessment of included studies was performed based on MINORS scoring for non-randomized comparative studies. The extracted data was analyzed using R programming language. Continuous outcomes were analyzed using the median difference and 95% confidence intervals under the inverse variance analysis method (random-effects model). Dichotomous outcomes were reported as risk ratios and 95% confidence intervals.

Results Of 1,133 records screened, we ultimately included 36 eligible studies. The vast majority of studies defined IAI with the threshold of amniotic fluid IL-6 at 2,600 pg/mL for ELISA, 3,000 pg/mL for ECLIA, and 745 pg/mL, if a lateral flow-based immunoassay point-of-care (POC) test was used. IAI was mostly defined according to IL-6 concentration in amniotic fluid, but there was a large-sized positive correlation with IL-6 concentration in cervical fluid and vaginal fluid. Also, IL-6 concentration positively reflected the response of reported proinflammatory proteins in amniotic fluid and cervical fluid (IL-8, MCP-1). Elevated concentration of IL-6 was associated with a higher proportion of bronchopulmonary dysplasia, respiratory distress syndrome, and early-onset neonatal sepsis. Finally, the occurrence of Ch. trachomatis, F. nucleatum, and S. anginosus was more frequent in microbial-associated IAI.

Conclusion Evaluating data from all included studies, we summarized that IL-6 is a versatile and worthwhile diagnostics marker for the diagnosis of microbial-associated and sterile IAI in PPROM with a potential to recognize IAI also in non-invasively collected samples.

Why was this study conducted?IAI in PPROM is a subclinical pathological state representing a risk of severe consequences for newborns. The question of the diagnostic potential of amniotic fluid IL-6 has been raised in the last two decades since there is a lack of reliable markers easily available in maternal blood. In this study, we therefore summarized the knowledge about IL-6 to assess its ability to uncover the ongoing but hidden inflammatory response associated with short-term neonatal outcome.

Key findings IL-6 is a valuable marker of microbial-associated and sterile IAI easily available in amniotic fluid as well as non-invasively collected cervical and vaginal fluids.

What does this add to what is known?This review demonstrates that IL-6 is a valuable marker of IAI associated with short-term neonatal morbidities in PPROM. Quantification of IL-6 enables the distinction of microbial-associated and sterile IAI and might also contribute to the diagnostics of IAI using non-invasively collected cervical or vaginal fluids.

The authors have declared no competing interest.

This study was funded by Ministry of Health of the Czech Republic, grant nr. NU21J-07-00058 and MH CZ-DRO (UHHK, 00179906).

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All data produced in the present study are available upon reasonable request to the authors