Fetal membrane biomarker network diversity and disease functions induced by intra-amniotic pathogens.

PROBLEM: Intra-amniotic pathogens and by-products activate innate immune responses encompassing multitudes of signaling molecules and pathways that can result in spontaneous preterm birth (PTB). This study investigates fetal membrane response to bacterial stimulation using a bioinformatics approach. METHOD OF STUDY: Dysregulated biomarker (IL1-ß, IL-2, IL-8, IL-10, and TNF-α) data from fetal membranes at term stimulated with Ureaplasma urealyticum, Ureaplasma parvum, Mycoplasma hominis, E. coli, Group B Streptococci, Polyporhans gingivalis, or Gardnerella vaginalis with 50% (v/v) amniotic fluid (AF) were analyzed by Ingenuity Pathway Analysis. RESULTS: In racially stratified analysis, networks representing late-stage immune inflammation were seen in African-Americans in AF absence. Inflammation was dominant in AF presence as well. In Caucasians, late-stage immune response was dominant with AF, but not in its absence. CONCLUSIONS: Fetal membrane biofunctions in response to bacteria reflect early- and late-stage innate immune defenses that vary based on the presence of AF and subject race.

Group B Streptococcus colonization and higher maternal IL-1ß concentrations are associated with early term births.

Association between maternal Group B Streptococcus (GBS) colonization diagnosed between 35 and 37 weeks of gestation and early term birth (between 37 and 39 weeks) and maternal-fetal inflammatory response associated with this condition were tested. In this cohort study of women delivering at term at Centennial Women's Hospital in Nashville, TN, GBS status and other clinical and demographic data were obtained from medical records. Exposed women were those testing positive for GBS (GBS positive [n = 490]) and the unexposed tested negative for GBS (GBS negative [n = 1,127]). To determine the inflammatory response associated with GBS, a cross sectional study, maternal and fetal plasma biomarkers (IL-1ß, IL-2, IL-6, IL-8, and TNF-α) were measured in the same cohort. T-tests and logistic regression determined association between GBS status, biomarker concentrations and early term birth. Gestational age was reduced to 271.1 (95% CI 270.4, 271.1) for cases compared to 274.7 (95% CI 274.4, 275.1) days for controls (p < 0.0001). The odds of early term birth was increased by threefold in cases (OR 3.28; 95% CI 2.60-4.15; p < 0.0001). The mean birth weight in cases (3285.3 g) (95% CI 3242.6, 3327.9) was lower than the controls, 3373.8 g (95% CI 3348.9, 3398.7) (p = 0.0004). Maternal IL-1ß was greater in cases (22.8 ng/ml; range 5.2-157.7 ng/ml) compared to controls (5.7; range 2.4-69.5 ng/ml; p < 0.0001). IL-1ß was higher in fetal plasma in cases vs. controls (20.33 vs. 8.18 ng/ml; p = 0.01). A 10 ng/ml increase in maternal IL-1ß was associated with increased risk for GBS infection (OR: 1.628, CI: 1.163-2.278; p = 0.0045). GBS colonization shortened gestational age at term and IL-1ß concentration in maternal plasma is an indicator of GBS status.

Amniotic fluid and maternal race influence responsiveness of fetal membranes to bacteria.

Spontaneous preterm birth (PTB) and preterm prelabor rupture of membranes (pPROM) occur more frequently in African-American women than in other racial groups. This may be due to an enhanced inflammatory response to pathogens associated with the condition. It is also possible that amniotic fluid (AF) has different immunomodulatory properties in African-American women that increase their risk of PTB and pPROM. To test this, we cultured fetal membranes from European-American and African-American women with sterile medium (control), Escherichia coli, Gardnerella vaginalis, Group B streptococci (GBS), Polyporphorans gingivalis, Mycoplasma hominis, Ureaplasma urealyticum or Ureaplasma parvum in the presence and absence of 50% autologous AF. Cytokine concentrations were quantified in the conditioned medium. All bacterial species increased IL-8 production. IL-1ß and TNF-α production were stimulated by LPS, E. coli, and G. vaginalis compared with control, but responses to Group B streptococci and P. gingivalis were limited to IL-1ß and TNF-α respectively. Genital mycoplasmas stimulated TNF-α and IL-10 but had no effect on IL-1ß production. African-Americans had twice the IL-1ß response to E. coli as European-Americans (P=0.031). Conversely, European-Americans produced more IL-8 in response to LPS than African-Americans (P=0.026). AF had both pro- and anti-inflammatory properties that varied between races and pathogens. These results suggest that the host response to fetal membrane infections is complex and not generalizable. Interventions to prevent PTB and pPROM may need to be customized based on a patient's race, type of bacterial infection and factors in her AF.

A single-nucleotide polymorphism in the fetal catechol-O-methyltransferase gene is associated with spontaneous preterm birth in African Americans.

Catechol-O-methyltransferase (COMT) activity has been reported to be higher in African Americans (AA) than Caucasians (Cau). COMT converts 2- and 4-hydroxy (OH) estrogens to 2- and 4-methoxyestrogens, respectively, and can increase estrogenic milieu locally in tissues. To assess whether the increased incidence of preterm birth (PTB) among AA women is associated with single-nucleotide polymorphism (SNP) in the COMT gene, we examined variations in maternal and fetal COMT genes and their association with pregnancy outcomes (term vs preterm pregnancies) using 4 functional SNPs: rs4633, rs4680, rs4818, and rs6269 in both AA and Cau. We analyzed samples from 267 AA women (191 term and 76 preterm pregnancies) and 339 Cau (194 term and 145 preterm pregnancies) in this study. The results showed a significant difference (P < .05) in allele and genotype frequencies between term and preterm AA and Cau women in 3 SNPs in both maternal and fetal DNA. The analysis revealed that in AA fetal COMT genes, SNP rs4818 is associated with PTB at the allele (C; P < .001), genotype (C/C; P < .01), and 2- (P < .03) and 3 (P < .04)-window haplotype levels. Multidimensionality reduction analysis also showed a significant (P < .01) association between rs4818 and PTB. In conclusion, our study demonstrated that a synonymous polymorphism, rs4818 in the fetal COMT gene, is associated with PTB in AA.