Maternal inflammatory response to microbial invasion of the amniotic cavity: analyses of multiple proteins in the maternal serum.

OBJECTIVE: To evaluate the maternal inflammatory response to microbial invasion of the amniotic cavity (MIAC) in women with preterm labor and preterm prelabor rupture of membranes using selected proteins in the maternal serum. DESIGN: A prospective cohort study. SETTING: Labor ward from Salgrenska University Hospital. The evaluation of the maternal inflammatory response in the presence of MIAC in preterm labor and preterm prelabor rupture of membranes. POPULATION: One hundred and sixteen women with preterm labor and 73 women with preterm prelabor rupture of membranes between the gestational ages of 22(+0) and 33(+6) weeks. METHODS: Twenty-seven maternal serum proteins were assayed by a multiple immunoassay. MAIN OUTCOME MEASURES: The maternal serum inflammatory response was evaluated according to the presence of MIAC. Data were stratified by gestational age. RESULTS: There were few differences in the maternal serum protein levels when MIAC was present in both preterm labor and preterm prelabor rupture of membranes. In preterm prelabor rupture of membranes, higher levels of interleukin-18 (median 654 vs. 361 pg/mL, p= 0.003) and lower levels of interleukin-1ß (9.5 vs. 19.9 pg/mL, p= 0.008) and monocyte chemotactic protein-1 (139.1 vs. 212.6 pg/mL, p= 0.039) were observed in women with MIAC. Interleukin-6 (20.8 vs. 13.9 pg/mL, p= 0.019) was the only biomarker that increased significantly in preterm labor complicated with MIAC. All of the differences between preterm labor and preterm prelabor rupture of membranes were observed at less than 32(+0) weeks of gestation. CONCLUSIONS: A weak maternal inflammatory response in the serum was observed in women with MIAC.

Intra-amniotic inflammation predicts microbial invasion of the amniotic cavity but not spontaneous preterm delivery in preterm prelabor membrane rupture.

OBJECTIVE: To predict microbial invasion of the amniotic cavity (MIAC) and spontaneous preterm delivery within seven days using a panel of selected proteins from amniotic fluid in a Swedish population of preterm prelabor membrane rupture (PPROM). DESIGN: Prospective cohort study. SETTING: Evaluation of intra-amniotic inflammation in preterm premature rupture of membranes. POPULATION: Sixty-six pregnant women with preterm prelabor membrane rupture at 22(+0) -33(+6) weeks' gestational age. Methods. Twenty-seven amniotic fluid proteins were assayed by a multiple immunoassay. MAIN OUTCOME MEASURES: The intra-amniotic inflammatory response was evaluated according to the presence of MIAC and the risk of spontaneous preterm delivery within seven days. A prediction model was constructed using logistic regression. RESULTS: The overall rates of MIAC and spontaneous preterm delivery within seven days were 20 and 50%, respectively. There was a higher inflammatory response in women with MIAC than in those without. Earlier gestational age at delivery and lower birthweight were observed in the presence of microbial invasion of the amniotic cavity. Amniotic fluid interleukin (IL)-6 and IL-10 were the best predictors of MIAC in terms of sensitivity (69%), specificity (81%), positive predictive value (47%), negative predictive value (91%) and a positive likelihood ratio of 3.6. There were no differences in intra-amniotic inflammatory response according to the risk of spontaneous preterm delivery within seven days. CONCLUSION: Amniotic fluid IL-6 and IL-10 are the best inflammatory biomarkers to predict MIAC in women with PPROM. Intra-amniotic inflammation does not predict the occurrence of spontaneous preterm delivery within seven days of PPROM.

The association between selected mid-trimester amniotic fluid candidate proteins and spontaneous preterm delivery.

Objective: The aim of this study was to explore inflammatory response and identify early potential biomarkers in mid-trimester amniotic fluid associated with subsequent spontaneous preterm delivery (PTD).Methods: A cohort study was performed at Sahlgrenska University Hospital/Östra, Gothenburg, Sweden, between 2008 and 2010. Amniotic fluid was collected from consecutive women undergoing mid-trimester transabdominal genetic amniocentesis at 14-19 gestational weeks. Clinical data and delivery outcome variables were obtained from medical records. The analysis included 19 women with spontaneous PTD and 118 women who delivered at term. A panel of 26 candidate proteins was analyzed using Luminex xMAP technology. Candidate protein concentrations were analyzed with ANCOVA and adjusted for plate effects.Results: The median gestational age at delivery was 35 + 3 weeks in women with spontaneous PTD and 40 + 0 weeks in women who delivered at term. Nominally significantly lower amniotic fluid levels of adiponectin (PTD: median 130,695 pg/mL (IQR 71,852-199,414) vs term: median 185,329 pg/mL (IQR (135,815-290,532)), granulocyte-macrophage colony stimulating factor (PTD: median 137 pg/mL (IQR 74-156) vs term: median 176 pg/mL (IQR 111-262)), and macrophage migration inhibitory factor (PTD: median 3025 pg/mL (IQR 1885-3891) vs term: median 3400 pg/mL (IQR 2181-5231)) were observed in the spontaneous PTD group, compared with the term delivery group, after adjusting for plate effects. No significant differences remained after Bonferroni correction for multiple comparisons.Conclusions: Our results are important in the process of determining the etiology behind spontaneous PTD but due to the non-significance after Bonferroni correction, the results should be interpreted with caution. Further analyses of larger sample size will be required to determine whether these results are cogent and to examine whether microbial invasion of the amniotic cavity or intra-amniotic inflammation occurs in asymptomatic women in the mid-trimester with subsequent spontaneous PTD.

Prediction of spontaneous preterm delivery in women with preterm labor: analysis of multiple proteins in amniotic and cervical fluids.

OBJECTIVE: To analyze whether specific proteins in amniotic and cervical fluids, alone or in combination with risk factors, can identify women in preterm labor with intact membranes who will deliver spontaneously within 7 days of sampling. METHODS: In a cohort of 89 women in preterm labor, amniotic and cervical fluids were collected between 22 and 33 weeks of gestation. Twenty-seven proteins were analyzed simultaneously using multiplex technology. Individual levels of each protein were compared and calculations performed to find associations among different proteins, background variables, and spontaneous preterm delivery within 7 days of sampling. The area under the curve (AUC) was calculated using receiver operating characteristic curve analysis, and prediction models were created based on stepwise logistic regression. RESULTS: We found two multivariable models that predicted spontaneous preterm delivery better than any single variable. One combined multivariable prediction model was based on amniotic macrophage inflammatory protein-1beta, cervical interferon-gamma, and monocyte chemotactic protein-1. This model predicted outcome with 91% sensitivity, 84% specificity, 78% positive predictive value, and 94% negative predictive value, with a likelihood ratio of 5.6 and AUC of 0.91. An alternative, noninvasive model based on cervical length, cervical interferon-gamma, interleukin-6, and monocyte chemotactic protein-1 predicted delivery within 7 days with 85% sensitivity, 82% specificity, 74% positive predictive value, and 90% negative predictive value, with a likelihood ratio of 4.7 and AUC of 0.91. CONCLUSION: A combination of proteins from amniotic fluid and cervical fluid or cervical length can help determine which women will deliver preterm. LEVEL OF EVIDENCE: II.

Expression of cytokines and chemokines in cervical and amniotic fluid: relationship to histological chorioamnionitis.

OBJECTIVE: To correlate cervical and amniotic fluid cytokines and macrophage-related chemokines to the development of histological chorioamnionitis (HCA) in patients with preterm labor (PTL) and preterm prelabor rupture of the membranes (PPROM). STUDY DESIGN: Cervical and amniotic fluid interleukin (IL)-6, IL-8, IL-18, monocyte chemotactic protein (MCP)-1, MCP-2, and MCP-3 from pregnant women (at

Monocyte chemotactic protein-2 and -3 in amniotic fluid: relationship to microbial invasion of the amniotic cavity, intra-amniotic inflammation and preterm delivery.

OBJECTIVE: To evaluate the presence of monocyte chemotactic protein (MCP)-2 and MCP-3 in cervical and amniotic fluid in women in preterm labor. STUDY DESIGN: Cervical and amniotic fluid was sampled from women with singleton pregnancies (< or =34 weeks) in preterm labor (n = 58). RESULTS: Monocyte chemotactic protein-2 (range: 80-583 pg/ml) and MCP-3 (range: 36-649 pg/ml) were detectable in 7/58 women in preterm labor. Monocyte chemotactic protein-3 was found significantly more often in amniotic fluid of women delivered within 7 days (P < 0.001), <34 weeks (P = 0.002), or with intra-amniotic inflammation (P < 0.001) and microbial invasion of the amniotic fluid (P = 0.003). Women in preterm labor had detectable levels of MCP-2 significantly more often if they gave birth before 34 weeks of gestation (P = 0.038) or had intra-amniotic inflammation (P = 0.042). CONCLUSIONS: The presence of MCPs in amniotic fluid of women in preterm labor was associated with preterm birth before 34 weeks of gestation (MCP-2 and MCP-3), microbial invasion (MCP-3), and inflammation (MCP-2 and MCP-3) of the amniotic cavity.

Interleukin-6 and interleukin-8 in cervical fluid in a population of Swedish women in preterm labor: relationship to microbial invasion of the amniotic fluid, intra-amniotic inflammation, and preterm delivery.

BACKGROUND: Intrauterine infection and inflammation in women with preterm labor are related to adverse perinatal outcome. Due to its subclinical nature, a correct diagnosis depends on retrieval of amniotic fluid. Amniocentesis is, however, not performed as a clinical routine because of its invasiveness. Hypothetically, cytokines in the cervical fluid may represent an alternative diagnostic approach. The aim was to examine cervical interleukin (IL)-6 and IL-8 in relation to microbial invasion of the amniotic fluid, intra-amniotic inflammation, and preterm birth in women in preterm labor. METHODS: Women with singleton pregnancies in preterm labor (<34 weeks of gestation) and intact membranes were included. Cervical (n = 91) and amniotic fluids (n = 56) were collected. Polymerase chain reaction for Ureaplasma urealyticum and Mycoplasma hominis and culture for aerobic and anaerobic bacteria were performed. IL-6 and IL-8 were analyzed with enzyme-linked immunosorbent assay. RESULTS: Non-lactobacillus-dominated biota was detected in cervical secretion in 25% (22/89) and the presence of micro-organisms in the amniotic fluid in 16% (9/56) of the patients. The presence of U. urealyticum in the cervical fluid (21/46) was associated with significantly higher levels of IL-6 in the secretion. IL-6 and IL-8 were significantly higher in cervical fluid of women with intra-amniotic infection and inflammation and in women who delivered < or =7 days and/or before 34 weeks of gestation. Cervical IL-6 > or = 1.7 ng/ml was related to intra-amniotic inflammation (relative risk: 2.67; range: 1.50-4.74) and had a sensitivity, specificity, positive predictive value, and negative predictive value of 58, 83, 75, and 69%, respectively, in the identification of intra-amniotic inflammation. Similar data were obtained for IL-8 > or = 6.7 ng/ml. CONCLUSIONS: High levels of cervical IL-6 and IL-8 are moderately predictive of intrauterine infection/inflammation and preterm delivery.

Monocyte chemotactic protein-1 in cervical and amniotic fluid: relationship to microbial invasion of the amniotic cavity, intra-amniotic inflammation, and preterm delivery.

OBJECTIVE: The purpose of this study was to evaluate the role of monocyte chemotactic protein-1 in cervical and amniotic fluid in women in preterm labor and with preterm premature rupture of membranes. STUDY DESIGN: Women with singleton pregnancies (

Microbial invasion and cytokine response in amniotic fluid in a Swedish population of women in preterm labor.

BACKGROUND: Previous studies indicate an association between intra-amniotic microbial invasion and/or inflammation and spontaneous preterm birth, but there is a limited amount of data available from Europe. The aim of this study was to investigate the occurrence of intra-amniotic microorganisms and cytokines (interleukin-6 and interleukin-8) in a Swedish population of women in preterm labor and their correlation with preterm birth. METHODS: Amniotic fluid was retrieved transabdominally from 61 patients in preterm labor before 34 weeks of gestation. Polymerase chain reaction analyses for Ureaplasma urealyticum and Mycoplasma hominis and culture for aerobic and anaerobic bacteria were performed. Interleukin-6 and interleukin-8 were analyzed with enzyme-linked immunosorbent assay. RESULTS: Microorganisms in amniotic fluid were detected in 10 patients (16%). Patients with detected bacteria in the amniotic fluid had significantly higher levels of interleukin-6 and interleukin-8. There was also an association between interleukin-6/-8, the amniocentesis-delivery interval (or= 1.5 ng/mL or interleukin-8 >or= 1.3 ng/mL was associated with an increased risk of delivery within 7 days (interleukin-6: relative risk 7.3; 95% confidence interval: 2.8-19; sensitivity 83%, specificity 87%; interleukin-8: relative risk 14, 95% confidence interval: 3.6-55, sensitivity 91%, specificity 87%). CONCLUSIONS: The occurrence of intra-amniotic microbial invasion and inflammation in this population of Swedish women in preterm labor was similar to data reported from populations with a higher incidence of preterm delivery. Amniotic interleukin-6 and interleukin-8 correlated with the presence of microorganisms and with preterm birth.

Interleukin-18 in cervical mucus and amniotic fluid: relationship to microbial invasion of the amniotic fluid, intra-amniotic inflammation and preterm delivery.

OBJECTIVE: To evaluate the relationship between interleukin (IL)-18 in cervical mucus and amniotic fluid and microbial invasion of amniotic fluid, preterm delivery and intra-amniotic inflammation in women in preterm labour, with preterm prelabour rupture of membranes and at term. DESIGN: A prospective follow up study. SETTING: Sahlgrenska University Hospital, Göteborg, Sweden. SAMPLE: Women with singleton pregnancies (<34 weeks) presenting with preterm labour (n = 87) or preterm prelabour rupture of membranes (n = 47) and women, not in labour, at term (n = 28). METHODS: Amniotic fluid was retrieved transabdominally. Cervical mucus was taken from the uterine cervix of women in preterm labour and at term. IL-18 was analysed with enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: IL-18 in relation to microbial invasion of the amniotic fluid, delivery within seven days or <34 weeks of gestation and intra-amniotic inflammation. RESULTS: The levels of IL-18 in cervical mucus and amniotic fluid were higher in women with preterm labour than in those not in labour at term. In the preterm labour group, significant associations were found between elevated IL-18 in amniotic fluid and microbial invasion of the amniotic fluid, as well as between delivery within seven days or <34 weeks of gestation and intra-amniotic inflammation. Delivery was delayed longer in the preterm prelabour rupture of membranes subgroup with IL-18 >or=1.0 ng/mL than in that with IL-18 <1.0 ng/mL. CONCLUSIONS: In the preterm labour group, high IL-18 in amniotic fluid (but not in the cervix) was associated with microbial invasion of the amniotic fluid, intra-amniotic inflammation and prompt delivery. On the other hand, elevated IL-18 in preterm prelabour rupture of the membranes group correlated with a longer interval to delivery.

Microbial invasion and cytokine response in amniotic fluid in a Swedish population of women with preterm prelabor rupture of membranes.

BACKGROUND: Previous studies have shown an association between intra-amniotic microbial invasion and/or inflammation and spontaneous preterm birth. The aim of this study was to investigate the occurrence of intra-amniotic microorganisms and cytokines [interleukin (IL)-6 and IL-8] in a Swedish population, with low incidence of preterm birth, of women with preterm prelabor rupture of membranes and their correlation to preterm birth. METHODS: Amniotic fluid was retrieved transabdominally from 58 patients with preterm prelabor rupture of membranes before 34 weeks of gestation. Polymerase chain reaction (PCR) analyses for Ureaplasma urealyticum and Mycoplasma hominis and culture for aerobic and anaerobic bacteria were performed. IL-6 and IL-8 were analyzed with enzyme-linked immunosorbent assay (ELISA). RESULTS: Microorganisms in amniotic fluid were detected in 13 patients (25%). Patients with bacteria detected in the amniotic fluid had significantly higher levels of IL-6 and IL-8. An amniotic fluid concentration of IL-6 >/= 0.80 ng/ml [relative risk 1.93, 95% confidence interval (CI) 1.13-3.29, sensitivity 63%, specificity 75%] was associated with an increased risk of delivery within 7 days. There was also an association between IL-8 and preterm birth (< 34 weeks). CONCLUSIONS: Intra-amniotic microbial invasion and inflammation in this population of Swedish women with preterm prelabor rupture of membranes were similar to data reported from populations with a higher incidence of preterm delivery. Amniotic IL-6 correlated to the presence of microorganisms and delivery within 7 days and IL-8 to delivery before 34 weeks.