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Gravett MG, Novy MJ, Rosenfeld RG, et al. Diagnosis of Intra-amniotic Infection by Proteomic Profiling and Identification of Novel Biomarkers. JAMA. 2004;292(4):462–469. doi:10.1001/jama.292.4.462
Author Affiliations: Division of Reproductive Sciences, Oregon National Primate Research Center, Beaverton, Ore (Drs Gravett and Novy); Departments of Obstetrics and Gynecology (Dr Gravett) and Pediatrics (Drs Rosenfeld, Roberts, and Nagalla) and Division of Biostatistics, Public Health and Preventive Medicine (Dr Lapidus), Oregon Health and Science University, and ProteoGenix Inc (Drs Reddy, Jacob, and McCormack and Mr Turner), Portland, Ore; Lucile Packard Foundation for Children's Health, Palo Alto, Calif (Dr Rosenfeld); Department of Obstetrics and Gynecology, University of Washington (Drs Hitti and Eschenbach), Seattle.
Context Intra-amniotic infection (IAI) is commonly associated with preterm birth
and adverse neonatal sequelae. Early diagnosis of IAI, however, has been hindered
by insensitive or nonspecific tests.
Objective To identify unique protein signatures in rhesus monkeys with experimental
IAI, a proteomics-based analysis of amniotic fluid was used to develop diagnostic
biomarkers for subclinical IAI in amniotic fluid and blood of women with preterm
Design, Setting, and Participants Surface-enhanced laser desorption-ionization/time-of-flight mass spectrometry,
gel electrophoresis, and tandem mass spectrometry were used to characterize
amniotic fluid peptides in 19 chronically instrumented pregnant rhesus monkeys
before and after experimental IAI. Candidate biomarkers were determined by
liquid chromatography–tandem mass spectrometry. Polyclonal antibodies
were generated from synthetic peptides for validation of biomarkers of IAI.
Amniotic fluid peptide profiles identified in experimental IAI were subsequently
tested in a cohort of 33 women admitted to Seattle, Wash, hospitals between
June 25, 1991, and June 30, 1997, with preterm delivery at 35 weeks or earlier
associated with subclinical IAI (n = 11), preterm delivery at 35 weeks or
earlier without IAI (n = 11), and preterm contractions with subsequent term
delivery at later than 35 weeks (n = 11).
Main Outcome Measures Identification of peptide biomarkers for occult IAI.
Results Protein expression profiles in amniotic fluid showed unique signatures
of overexpression of polypeptides in the 3- to 5-kDa and 10- to 12-kDa molecular
weight ranges in all animals after infection and in no animal prior to infection.
In women, the 10- to 12-kDa signature was identified in all 11 patients with
subclinical IAI, in 2 of 11 with preterm delivery without IAI, and in 0 of
11 with preterm labor and term delivery without infection (P<.001). Peptide fragment analysis of the diagnostic peak in amniotic
fluid identified calgranulin B and a unique fragment of insulinlike growth
factor binding protein 1, which were also expressed in maternal serum. Mapping
of other amniotic fluid proteins differentially expressed in IAI identified
several immunoregulators not previously described in amniotic fluid.
Conclusions This proteomics-based characterization of the differential expression
of amniotic fluid proteins in IAI identified a distinct proteomic profile
in an experimental primate chorioamnionitis model that detected subclinical
IAI in a human cohort with preterm labor. These diagnostic protein expression
signatures, complemented by immunodetection of specific biomarkers in amniotic
fluid and in maternal serum, might have application in the early detection
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