Clinical significance of the presence of amniotic fluid 'sludge' in asymptomatic patients at high risk for spontaneous preterm delivery.

OBJECTIVES: To determine the clinical significance of the presence of amniotic fluid (AF) 'sludge' among asymptomatic patients at high risk for spontaneous preterm delivery. METHODS: This retrospective case-control study included 281 patients with (n = 66) or without (n = 215) AF 'sludge', who underwent transvaginal ultrasound examination between 13 and 29 completed weeks of gestation. Patients with threatened preterm labor, multiple gestation, fetal anomalies, placenta previa or uterine contractions were excluded. RESULTS: The prevalence of AF 'sludge' in the study population was 23.5% (66/281). The rates of spontaneous preterm delivery at < 28 weeks, < 32 weeks, < 35 weeks and < 37 weeks of gestation were 14.7% (29/197), 21.3% (46/216), 28.7% (62/216) and 42.1% (91/216), respectively. Patients with 'sludge' had: (1) a higher rate of spontaneous preterm delivery at < 28 weeks (46.5% (20/43) vs. 5.8% (9/154); P < 0.001), < 32 weeks (55.6% (25/45) vs. 12.3% (21/171); P < 0.001) and < 35 weeks (62.2% (28/45) vs. 19.9% (34/171); P < 0.001); (2) a higher frequency of clinical chorioamnionitis (15.2% (10/66) vs. 5.1% (11/215); P = 0.007), histologic chorioamnionitis (61.5% (40/65) vs. 28% (54/193); P < 0.001) and funisitis (32.3% (21/65) vs. 19.2% (37/193); P = 0.03); (3) a higher frequency of preterm prelabor rupture of membranes (PROM) (39.4% (26/66) vs. 13.5% (29/215); P < 0.001), lower gestational age at preterm PROM (median 24.7 (interquartile range (IQR), 22.3-28.1) weeks vs. 32.3 (IQR, 27.7-34.8) weeks; P < 0.001); and (4) shorter median ultrasound-to-delivery interval ('sludge' positive 127 days (95% CI, 120-134 days) vs. 'sludge' negative 161 days (95% CI, 153-169 days); P < 0.001) and ultrasound-to-preterm PROM interval ('sludge' positive 23 days (95% CI, 7-39 days) vs. 'sludge' negative 57 days (95% CI, 38-77 days); P = 0.003) than those without 'sludge'. AF 'sludge' was an independent explanatory variable for the occurrence of spontaneous preterm delivery at < 28 weeks, < 32 weeks and < 35 weeks, preterm PROM, microbial invasion of the amniotic cavity (MIAC) and histologic chorioamnionitis. Moreover, the combination of a cervical length < 25 mm and 'sludge' conferred an odds ratio of 14.8 and 9.9 for spontaneous preterm delivery at < 28 weeks and < 32 weeks, respectively. CONCLUSIONS: AF 'sludge' is an independent risk factor for spontaneous preterm delivery, preterm PROM, MIAC and histologic chorioamnionitis in asymptomatic patients at high risk for spontaneous preterm delivery. Furthermore, the combination of 'sludge' and a short cervix confers a higher risk for spontaneous preterm delivery at < 28 weeks and < 32 weeks than a short cervix alone.

Surfactant protein-A mRNA expression by human fetal membranes is increased in histological chorioamnionitis but not in spontaneous labour at term.

Surfactant protein-A (SP-A) is produced by the fetal lung, participates in innate immunity, and has been proposed to play a role in the initiation of parturition in mice. Amniotic fluid SP-A concentration increases as a function of gestational age, and SP-A protein has been demonstrated in human chorioamniotic membranes. This study was conducted to determine whether parturition at term, gestational age and chorioamnionitis in preterm delivery (PTD) are associated with changes in the expression of SP-A in the chorioamniotic membranes. Chorioamniotic membranes were obtained from women at term and women with PTD (n=58). SP-A mRNA and protein expression was detected in amniotic epithelial cells, chorionic trophoblasts and macrophages by in situ hybridization and immunohistochemistry. Quantitative real-time reverse transcription-PCR demonstrated predominant expression of SP-A1 mRNA, whose expression was 17.4-fold higher in patients with PTD with chorioamnionitis (n=15) than in those without (n=13) (p=0.018). While no difference was observed in SP-A1 mRNA expression in the chorioamniotic membranes of women at term not in labour (n=16) and those in labour (n=14) (p=0.87), the expression in term membranes was higher than that of membranes from women with PTD without chorioamnionitis (p=0.003). Analysis of JAR choriocarcinoma cells demonstrated SP-A1 mRNA expression that was up-regulated following lipopolysaccharide treatment. Furthermore, monocytic cell lines (THP-1 and U937) and peripheral blood monocytes (CD14+/CD115+) obtained from pregnant women also expressed SP-A1 mRNA and protein, suggesting the presence of autocrine/paracrine activation in vivo. Interestingly, a mid-trimester amniotic fluid sample obtained from a case of tracheal atresia contained SP-A (3.13 microg/ml), indicating the presence of SP-A of extrapulmonary origin. These findings suggest not only that SP-A expression is a part of the innate immune response deployed during chorioamniotic inflammation, but also that chorioamniotic membranes are a source of SP-A in the amniotic fluid with advancing gestation.

The use of high-dimensional biology (genomics, transcriptomics, proteomics, and metabolomics) to understand the preterm parturition syndrome.

High-dimensional biology (HDB) refers to the simultaneous study of the genetic variants (DNA variation), transcription (messenger RNA [mRNA]), peptides and proteins, and metabolites of an organ, tissue, or an organism in health and disease. The fundamental premise is that the evolutionary complexity of biological systems renders them difficult to comprehensively understand using only a reductionist approach. Such complexity can become tractable with the use of "omics" research. This term refers to the study of entities in aggregate. The current nomenclature of "omics" sciences includes genomics for DNA variants, transcriptomics for mRNA, proteomics for proteins, and metabolomics for intermediate products of metabolism. Another discipline relevant to medicine is pharmacogenomics. The two major advances that have made HDB possible are technological breakthroughs that allow simultaneous examination of thousands of genes, transcripts, and proteins, etc., with high-throughput techniques and analytical tools to extract information. What is conventionally considered hypothesis-driven research and discovery-driven research (through "omic" methodologies) are complementary and synergistic. Here we review data which have been derived from: 1) genomics to examine predisposing factors for preterm birth; 2) transcriptomics to determine changes in mRNA in reproductive tissues associated with preterm labour and preterm prelabour rupture of membranes; 3) proteomics to identify differentially expressed proteins in amniotic fluid of women with preterm labour; and 4) metabolomics to identify the metabolic footprints of women with preterm labour likely to deliver preterm and those who will deliver at term. The complementary nature of discovery science and HDB is emphasised.