Amniotic Fluid Interleukin-6 Levels Research Articles

Association between interleukin-6 levels in amniotic fluid after rupture of membranes during labour at term pregnancy and successful vaginal delivery: a prospective cohort study

We compared the mean interleukin-6 (IL-6) level in the amniotic fluid after rupture of membranes during labour at term pregnancy according to the delivery methods through prospective cohort study. Cases with premature rupture of membranes, multifetal pregnancy, and major congenital anomalies were excluded. Amniotic fluid was obtained from vaginal canal immediately after spontaneous rupture of membranes. A total of 47 cases were analysed, and 72.3% (34/47) had successful vaginal delivery. The mean concentration of IL-6 in the amniotic fluid was significantly higher in the vaginal delivery group than in the caesarean section group (5,229 pg/mL vs. 1,702 pg/mL, p = .022). The concentration of IL-6 from the amniotic fluid tended to increase as the cervical dilatation increased. The association between high IL-6 level (>2,500 pg/mL) and successful vaginal delivery was not significant after adjusting the degree of cervical dilatation in multivariate logistic regression analysis. IMPACT STATEMENT What is already known on this subject ? Multiparity, active and strong uterine contractions, dilated cervical os, and the position of foetal head are known clinical factors affecting the successful vaginal delivery. There are few studies on markers for successful vaginal delivery in patients with labour. What do the results of this study add ? The mean value of IL-6 concentration from the amniotic fluid collected from vagina immediately after rupture of membranes was significantly higher in the patients who had resulted in successful vaginal delivery than those who had failed. What are the implications are of these findings for clinical practice and/or further research ? Measurement of IL-6 concentration in the amniotic fluid from vaginal canal in patients with labour might help to predict the successful vaginal delivery and shorten the time before decision of caesarean section.

Amniotic fluid neutrophil gelatinase-associated lipocalin and L-type fatty acid-binding protein in predicting fetal inflammatory response syndrome.

To analyze the effectiveness of amniotic fluid neutrophil gelatinase-associated lipocalin and L-type fatty acid-binding protein as predictive factors for fetal inflammatory response syndrome. We classified single pregnancy cases into the fetal inflammatory response syndrome and nonfetal inflammatory response syndrome groups. We collected amniotic fluid at vaginal delivery and cesarean section and compared the patient characteristics, maternal white blood cell count, C-reactive protein level, and amniotic fluid interleukin-6; neutrophil gelatinase-associated lipocalin; and L-type fatty acid-binding protein levels between the groups. We further analyzed the relationship between L-type fatty acid-binding protein levels and neonatal clinical outcomes. We analyzed 129 pregnancies, of which 36 and 93 (27.9% and 72.1%, respectively) were classified into the fetal inflammatory response syndrome and nonfetal inflammatory response syndrome groups, respectively. We observed significant differences in the maternal white blood cell counts and amniotic fluid interleukin-6 and neutrophil gelatinase-associated lipocalin levels. On the multivariate analysis, the useful predictive factors were maternal white blood cell count and amniotic fluid interleukin-6 and neutrophil gelatinase-associated lipocalin levels. Furthermore, the level of L-type fatty acid-binding protein was significantly higher in the transient tachypnea of the newborn and postnatal respiratory support group than in the control group. The maternal white blood cell count and amniotic interleukin-6 and neutrophil gelatinase-associated lipocalin levels were effective predictors of fetal inflammatory response syndrome. Amniotic fluid L-type fatty acid-binding protein level was an effective predictor of neonatal respiratory support.

Amniotic fluid glucose level in PPROM pregnancies: a glance at the old friend

Introduction To determine the amniotic fluid glucose levels in pregnancies complicated by preterm prelabor rupture of membranes (PPROM) based on the presence of microbial invasion of the amniotic cavity and/or intra-amniotic inflammation. Methods of Study A total of 142 women with singleton pregnancies complicated by PPROM between gestational ages 24 + 0 and 36 + 6 weeks were included. Amniocentesis was performed at the time of admission. The assessments of microbial invasion of the amniotic cavity (using both cultivation and non-cultivation techniques) and intra-amniotic inflammation (amniotic fluid interleukin-6 levels ≥ 3000 pg/mL) were performed on all the women. Based on the presence of microbial invasion of the amniotic cavity and/or intra-amniotic inflammation, the women were further categorized into the subgroups: (i) intra-amniotic infection (the presence of both microbial invasion of the amniotic cavity and intra-amniotic inflammation); (ii) sterile intra-amniotic inflammation (the presence of intra-amniotic inflammation without microbial invasion of the amniotic cavity); (iii) colonization (the presence of microbial invasion of the amniotic cavity without intra-amniotic inflammation); and (iv) negative amniotic fluid (the absence of either microbial invasion of the amniotic cavity or intra-amniotic inflammation). Amniotic fluid glucose levels were assessed using enzymatic reference method with hexokinase. Results There was a difference in the amniotic fluid glucose levels among the women with intra-amniotic infection, sterile intra-amniotic inflammation, colonization, and those with negative amniotic fluid (p < .0001). No difference was found in the amniotic fluid glucose levels between women with intra-amniotic infection and those with sterile intra-amniotic inflammation [infection: median 11.6 mg/dL (0.7 mmol/L) vs. sterile: median 6.3 mg/dL (0.4 mmol/L); p = .41] and between women with colonization and negative amniotic fluid [colonization: median 21.6 mg/dL (1.2 mmol/L) vs. negative: median 23.4 mg/dL (1.3 mmol/L; p = .67]. Women with intra-amniotic infection and sterile intra-amniotic inflammation had lower amniotic fluid glucose levels than women with colonization and with negative amniotic fluid in crude analysis as well as after adjustment for gestational age at sampling. Amniotic fluid glucose level of 10 mg/dL (0.56 mmol/L) was the optimal concentration for the identification of intra-amniotic inflammation in women with PPROM. Conclusions The presence of intra-amniotic inflammation was associated with lower amniotic fluid glucose levels in singleton pregnancies complicated with PPROM. An amniotic fluid glucose level of 10 mg/dL (0.56 mmol/L) was the optimal concentration for the identification of intra-amniotic inflammation in PPROM pregnancies. In the absence of better amniotic fluid markers, amniotic glucose could be used as a marker of intra-amniotic inflammation, with very good specificity in PPROM pregnancies.

Evaluation of second trimester amniotic fluid ADAMTS4, ADAMTS5, interleukin-6 and tumor necrosis factor-α levels in patients with gestational diabetes mellitus.

To test the hypothesis that altered A Disintegrin and Metalloproteinase Domains with Thrombospondins motifs (ADAMTS) is implicated in the etiopathogenesis of gestational diabetes mellitus (GDM). All pregnant women who underwent elective amniocentesis for karyotype analysis between January 1, 2016, and January 1, 2018, were included in this study. From this cohort, the study group consisting of 20 patients diagnosed with GDM was selected and compared against a control group consisting of 20 age- and body mass index (BMI)-matched patients without GDM. ADAMTS4, ADAMTS5, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels were compared in the second trimester amniotic fluid of patients with GDM and normoglycemic pregnant women. No significant differences were observed between GDM and control groups regarding age, BMI, gestational age at amniocentesis and indication for amniocentesis. Mean amniotic fluid ADAMTS4 and ADAMTS5 levels were significantly increased in the GDM group compared with the control group (253.5 ± 18.7 pg/mL and 188.5 ± 21.3 pg/mL, P < 0.001; 192.9 ± 16.4 pg/mL and 154.8 ± 19.9 pg/mL, P = 0.021, respectively). Significant increases in IL-6 and TNF-α levels were also detected in the amniotic fluid of GDM patients relative to controls (136.2 ± 17.3 pg/mL and 98.3 ± 11.5 pg/mL, P < 0.001; 154.2 ± 12.5 pg/mL and 86.2 ± 10.8 pg/mL, P < 0.001, respectively). The data presented here suggest that increased levels of ADAMTS4, ADAMTS5, IL-6 and TNF-α may play an important role in the progression of GDM.

Influence of perinatal inflammation on the neurodevelopmental outcome of premature infants

Objective To evaluate the influence of perinatal inflammation on neurodevelopmental outcome of premature infants. Study design From a retrospective cohort study of women with preterm labor with intact membranes or preterm prelabor rupture of membranes (PPROM) with an amniocentesis to rule out intra-amniotic inflammation (IAI) and microbial invasion of the amniotic cavity (MIAC), we evaluated neurodevelopmental outcome of their infants born between 24.0 and 34.0 weeks gestation. Women with clinical chorioamnionitis at admission were excluded. Neurodevelopmental outcome was screened with the Ages & Stages Questionnaire (ASQ)-3. We analyzed the relationship between an altered ASQ-3 and antenatal, intra-partum and post-partum factors related to perinatal inflammation. Result Among 98 infants evaluated, 22% had an abnormal score. Amniotic fluid interleukin-6 levels and early-onset sepsis (EOS) were independent factors of an altered ASQ-3 with delivery <26.0 weeks being the strongest predictor. Conclusions In premature infants, the presence of IAI, delivery <26.0 weeks and EOS were found to be independent factors of an altered ASQ-3.

Impact of microbial invasion of amniotic cavity and the type of microorganisms on short-term neonatal outcome in women with preterm labor and intact membranes.

The objective of this study was to evaluate the impact of microbial invasion of the amniotic cavity and the type of microorganisms on pregnancy and short-term neonatal outcomes in women with preterm labor. Prospective observational cohort study including women with preterm labor from 22.0 to 36.0 weeks. Microbial invasion of the amniotic cavity was defined based on amniotic fluid aerobic/anaerobic/mycoplasma cultures, and intra-amniotic inflammation on amniotic fluid interleukin-6 levels. Demographic data and pregnancy outcomes were compared among women exposed to microbial invasion of the amniotic cavity by Ureaplasma spp., women with microbial invasion of the amniotic cavity by other microorganisms, and a No-microbial invasion of the amniotic cavity/No-intra-amniotic inflammation group. The short-term neonatal outcome was evaluated in women delivering after 24.0 weeks. We included 228 women with preterm labor. Microbial invasion of the amniotic cavity occurred in 35% (80/228), 28% (22/80) being caused by Ureaplasma spp. Gestational age at admission and at delivery were significantly earlier and the rate of delivery at <24.0 weeks' gestation and of women who further developed clinical chorioamnionitis were significantly higher in women with microbial invasion of the amniotic cavity by microorganisms other than Ureaplasma spp. However, after 24 weeks, regardless of the microorganisms isolated, the short-term neonatal outcome was similar between women exposed to microbial invasion of the amniotic cavity and the No-microbial invasion of the amniotic cavity/No-intra-amniotic inflammation group when gestational age was considered. Microbial invasion of the amniotic cavity by microorganisms other than Ureaplasma spp. was associated with earlier gestational age at admission and at delivery, and a higher rate of preterm delivery <24.0 weeks and of women who developed clinical chorioamnionitis. However, we did not find differences in the short-term neonatal outcome between women exposed to microbial invasion of the amniotic cavity and the no-microbial invasion of the amniotic cavity/no-intra-amniotic inflammation group delivering after 24.0 weeks' gestation when adjusted by gestational age at delivery.

Gestational age is more important for short-term neonatal outcome than microbial invasion of the amniotic cavity or intra-amniotic inflammation in preterm prelabor rupture of membranes.

The aim of this study was to evaluate, in women with preterm prelabor rupture of membranes (PPROM), the impact on short-term neonatal outcome of microbial invasion of the amniotic cavity (MIAC), intra-amniotic inflammation (IAI), and the microorganisms isolated in women with MIAC, when gestational age is taken into account. Prospective cohort study. We included women with PPROM (22.0-34.0 weeks of gestation) with available information about MIAC, IAI and short-term neonatal outcome. MIAC was defined as positive aerobic/anaerobic/genital Mycoplasma culture in amniotic fluid. Definition of IAI was based on interleukin-6 levels in amniotic fluid. Main outcome measures were Apgar score <7 at 5 min, umbilical artery pH ≤7.0, days in the neonatal intensive care unit, and composite neonatal morbidity, including any of the following: intraventricular hemorrhage grade III-IV, respiratory distress syndrome, early-onset neonatal sepsis, periventricular leukomalacia, necrotizing enterocolitis, and fetal or neonatal death. Labor was induced after 32.0 weeks if lung maturity was confirmed; and otherwise after 34.0 weeks. MIAC and IAI were found in 38% (72/190) and 67% (111/165), respectively. After adjustment for gestational age at delivery, no differences in short-term neonatal outcome were found between women with either MIAC or IAI, compared with the non-infection/non-inflammation ("No-MIAC/No-IAI") group. Furthermore, short-term neonatal outcome did not differ between the MIAC caused by Ureaplasma spp. group, the MIAC caused by other microorganisms group and the "No-MIAC/No-IAI" group. Gestational age at delivery seems to be more important for short-term neonatal outcome than MIAC or IAI in PPROM.

Non-Invasive Prediction of Histologic Chorioamnionitis in Women with Preterm Premature Rupture of Membranes.

PurposeTo develop a model based on non-invasive clinical and ultrasonographic parameters for predicting the likelihood of subsequent histologic chorioamnionitis in women with preterm premature rupture of membranes (PPROM) and to determine whether the inclusion of invasive test results improves the predictive value of the model.Materials and MethodsThis retrospective cohort study included 146 consecutive women presenting with PPROM (20–33 weeks). Transvaginal ultrasonographic assessment of cervical length was performed. Maternal serum C-reactive protein (CRP) levels and white blood cell (WBC) counts were measured after amniocentesis. Amniotic fluid (AF) obtained by amniocentesis was cultured, and interleukin-6 (IL-6) levels and WBC counts were determined. The primary outcome measure was histologic chorioamnionitis.ResultsRisk scores based on serum CRP concentrations and gestational age (model 1) were calculated for each patient. The model was shown to have adequate goodness of fit and an area under the receiver operating characteristic curve (AUC) of 0.742. When including AF test results (e.g., AF IL-6 levels) in model 1, serum CRP concentrations were found to be insignificant, and thus, were excluded from model 2, comprising AF IL-6 levels and gestational age. No significant difference in AUC was found between models 1 and 2.ConclusionFor women with PPROM, the newly developed model incorporating non-invasive parameters (serum CRP and gestational age) was moderately predictive of histologic chorioamnionitis. The inclusion of invasive test results added no predictive information to the model in this setting.

Interleukin-6 and C-reactive protein levels in the amniotic fluid as indicators of preterm delivery in Turkish women

Objective: The aim of this study was to determine the value of amniotic fluid interleukin-6 (IL-6) and C-reactive protein (CRP) levels in the prediction of preterm delivery in singleton pregnancies without any known risk factors for preterm delivery in Turkish women. Materials and Methods: Patients in the present perinatology department who underwent mid-trimester genetic amniocentesis due to evidence of increased risk of aneuploidy in their prenatal serum screening tests were included in the study. A sample of amniotic fluid from each patient was assessed for IL-6 and CRP. Concentrations of IL-6 and CRP in the amniotic fluid of preterm delivery and term delivery groups were compared. Results: Of 151 singleton pregnancies, 142 participants were included in the study. The participants were assigned to either the preterm or term delivery group based on pregnancy outcome. IL-6 levels in the amniotic fluid were significantly higher in the preterm delivery group, and there was a statistically significant negative correlation between IL-6 concentrations in the amniotic fluid and gestational age at delivery (correlation coefficient (CC): -18.5%, p p = 0.068). Conclusion: Measuring IL-6 in the amniotic fluid can identify women at risk of preterm delivery. Because it is not acceptable to perform amniocentesis for this screening, it is more convenient for patients in whom genetic amniocentesis is performed.

N-acetyl-cysteine (NAC) attenuates LPS-induced maternal and amniotic fluid oxidative stress and inflammatory responses in the preterm gestation

Maternal infection is associated with oxidative stress and inflammation. We sought to determine whether N-acetyl-cysteine can decrease maternal oxidative stress and the inflammatory response in preterm gestation. Pregnant rats 16 days, were treated with (1) lipopolysaccharide, (2) N-acetyl-cysteine 120 minutes after lipopolysaccharide, or (3) saline solution (intraperitoneal). Six hours after lipopolysaccharide administration, serum lipid peroxide formation (LPO), tumor necrosis factor-α, interleukin-6, and interleukin-1β levels in maternal serum and amniotic fluid were determined. Lipopolysaccharide significantly increased maternal serum lipid peroxide formation (24-118.5 nmol/mL; P < .05), and maternal serum and amniotic fluid tumor necrosis factor-α, interleukin-6, and interleukin-1β. N-acetyl-cysteine treatment after lipopolysaccharide significantly attenuated lipid peroxide formation (47.5 nmol/mL) and proinflammatory cytokines response in maternal serum and amniotic fluid. Maternal and amniotic fluid oxidative stress and inflammatory stimulation are attenuated by N-acetyl-cysteine even when administered after lipopolysaccharide. These results suggest that N-acetyl-cysteine may protect the fetus from adverse sequelae associated with inflammatory stimulation.

Fetal inflammatory response in women with proteomic biomarkers characteristic of intra-amniotic inflammation and preterm birth.

To determine the relationship between presence of amniotic fluid (AF) biomarkers characteristic of inflammation (defensins 2 and 1 and calgranulins C and A) and fetal inflammatory status at birth. Prospective observational cohort. Tertiary referral University hospital. One hundred and thirty-two consecutive mothers (gestational age, median [interquartile range]: 29.6 [24.1-33.1] weeks) who had a clinically indicated amniocentesis to rule out infection and their newborns. Intra-amniotic inflammation was diagnosed by mass spectrometry surface-enhanced-laser-desorption-ionization time of flight (SELDI-TOF). The AF proteomic fingerprint (mass-restricted [MR] score) ranges from 0-4 (none to all biomarkers present). The intensity of intra-amniotic inflammation was graded based on the number of proteomic biomarkers: MR score 0: 'no' inflammation, MR score 1-2: 'minimal' inflammation and MR score 3-4: 'severe' inflammation. At birth, cord blood was obtained for all women. Severity of histological chorioamnionitis and early-onset neonatal sepsis (EONS) was based on established histological and haematological criteria. Interleukin-6 (IL-6) levels were measured by sensitive immunoassays. The cord blood-to-AF IL-6 ratio was used as an indicator of the differential inflammatory response in the fetal versus the AF compartment. To relate proteomic biomarkers of intra-amniotic infection to cord blood IL-6 and to use the latter as the primary marker of fetal inflammatory response. Women with intra-amniotic inflammation delivered at an earlier gestational age (analysis of variance, P<0.001) and had higher AF IL-6 levels (P<0.001). At birth, neonates of women with severe intra-amniotic inflammation had higher cord blood IL-6 levels (P=0.002) and a higher frequency of EONS (P=0.002). EONS was characterised by significantly elevated cord blood IL-6 levels (P<0.001). Of the 39 neonates delivered by mothers with minimal intra-amniotic inflammation, 15 (39%) neonates had umbilical cord blood IL-6 levels above the mean for the group and 2 neonates had confirmed sepsis. The severity of the neutrophilic infiltrate in the chorionic plate (P<0.001), choriodecidua (P=0.002), umbilical cord (P<0.001) but not in the amnion (P>0.05) was an independent predictor of the cord blood-to-AF IL-6 ratio. Relationships were maintained following correction for gestational age, birthweight, amniocentesis-to-delivery interval, caesarean delivery, status of the membranes, race, MR score and antibiotics and steroid exposure. We provide evidence that presence of proteomic biomarkers characteristic of inflammation in the AF is associated with an increased inflammatory status of the fetus at birth. Neonates mount an increased inflammatory status and have positive blood cultures even in the context of minimal intra-amniotic inflammation.

N-acetyl-cysteine suppresses amniotic fluid and placenta inflammatory cytokine responses to lipopolysaccharide in rats

Maternal infections may induce placental, amniotic and, potentially, fetal inflammatory responses. As cytokine responses may be mediated by oxidative stress, we determined whether the antioxidant N-acetyl-cysteine (NAC), can attenuate maternally induced amniotic and placental cytokine responses to maternal infection (modeled by lipopolysaccharide [LPS]). Gestation day 18 pregnant rats were (1) treated with LPS (100 microg/kg, body weight; intraperitoneally) alone; (2) pretreated with NAC (300 mg/kg body weight; intraperitoneally) 30 minutes before LPS; (3) posttreated with NAC 120 minutes after LPS; or (4) treated with NAC 30 minutes before and 120 minutes after LPS. Six hours after LPS administration, maternal serum and amniotic fluid interleukin-6 (IL-6) and IL-10 levels, and placental IL-6 messenger RNA levels were determined. LPS increased maternal serum IL-6 (50 +/- 25 to 3444 +/- 584 pg/mL) and IL-10 (40 +/- 20 to 958 +/- 339 pg/mL) and amniotic fluid IL-6 (59 +/- 25 to 891 +/- 128 pg/mL). Pretreatment and/or posttreatment with NAC attenuated IL-6 in the maternal serum and amniotic fluid and IL-10 in the amniotic fluid. LPS also induced placental IL-6 messenger RNA that was inhibited by treatment with NAC before and after LPS. NAC inhibition of inflammatory responses may protect the fetus from potential long-term sequelae.

Interleukin-6, but not relaxin, predicts outcome of rescue cerclage in women with cervical incompetence

Objective We investigated the potential roles of relaxin and subclinical intra-amniotic inflammation by quantitating amniotic fluid relaxin and interleukin-6 concentrations for the prediction of outcome of rescue cerclage in women with cervical incompetence. Study design Cervical incompetence was diagnosed when cervical dilatation exceeded 2 cm with intact but bulging membranes and no detectable uterine activity. Each woman underwent amniocentesis to facilitate the performance of a rescue cerclage between 15 and 27 weeks of gestation (n = 40 women). Forty-five additional women who underwent amniocentesis for chromosomal testing between 16 and 27 weeks of gestation served as a control group. All control patients were delivered of chromosomally normal infants at>37 weeks of gestation. All cases and control patients were singleton gestations. Interleukin-6 and relaxin were determined in all amniotic fluid samples by enzyme-linked immunosorbent assay. Results Amniotic fluid interleukin-6 levels were significantly higher in women with cervical incompetence than in control patients (control patients, 50.4 pg/mL [range, 19.4-97.4 pg/mL] vs cervical incompetence patients, 5459.1 pg/mL [range, 1131.4-14425.7 pg/mL] ; P < .001). In contrast to interleukin-6, relaxin levels did not differ between the 2 groups (control patients, 67.5 pg/mL [range, 35.1-153.5 pg/mL] vs cervical incompetence patients, 45.6 pg/mL [range, 30.1-75.5 pg/mL]; P = .061). There was a significant difference in interleukin-6 levels in women with shorter latencies ( P < .01 for all latency intervals that were examined: delivery within 24 hours, 3 days, 7 days, before 33 and 37 completed weeks of gestation). Linear regression analysis with the use of the latency interval from cerclage to delivery as the dependent and with interleukin-6 as the independent variable revealed a significant inverse relationship ( r = −0.62; P < .001 after log transformation of interleukin-6). There was no relationship on regression analysis between relaxin and the latency interval. Conclusion Amniotic fluid interleukin-6 is increased in patients with cervical incompetence, which suggests that subclinical inflammation may contribute to cervical incompetence. Further, an elevated interleukin-6 level predicts a cerclage short-latency interval between cerclage and delivery. In contrast with interleukin-6, amniotic fluid relaxin does not appear to contribute to cervical incompetence–induced cervical dilation.

Systemic administration of betamethasone delays endotoxin-induced preterm labor in the murine model

Objective: The purpose of this study was to determine whether the administration of betamethasone decreases the endotoxin-induced preterm parturition rate and inhibits the risk of cytokines in the murine model. Study design: Endotoxin was administered intraperitoneally at gestational day 15 (75% of gestation). In phase I, the duration of gestation was measured in 36 gravid C3H/HeOu mice that were equally divided into four treatment groups: control, endotoxin only, and two different dose regimens of betamethasone followed by endotoxin. In phase II, maternal serum and amniotic fluid concentrations of cytokines (interleukin-1α, tumor necrosis factor-α, and interleukin-6) were measured at 4 hours after endotoxin injection in 44 gravid mice divided equally in the four treatment groups. Results: The group that was exposed only to endotoxin was delivered at a significantly earlier gestational age compared with the control group (16.2 ± 0.4 days vs 19.6 ± 0.2 days; P < .01). The two groups that were pretreated with betamethasone before the endotoxin were delivered at gestational ages similar to the control group. There was a marked increase of tumor necrosis factor-α and interleukin-6 levels in amniotic fluid of mice that were treated with endotoxin only compared with the control group (P < .001). No difference in cytokine levels was found in those mice that were premedicated with betamethasone compared with the control group. Conclusion: Antenatal administration of betamethasone to mice delayed preterm parturition that was induced by endotoxin. Elevations of amniotic fluid cytokine concentrations that were observed with endotoxin were not observed with pretreatment with betamethasone. (Am J Obstet Gynecol 2003;188:439-43.)

Elevated amniotic fluid ferritin levels are associated with inflammation-related pregnancy loss following mid-trimester amniocentesis

Objective: Occult infection accounts for up to 12% of pregnancy losses following genetic amniocentesis. Elevated serum and cervical fluid levels of ferritin, an acute-phase reactant, have been associatedwith spontaneous preterm delivery. We determined the association between amniotic fluid (AF) ferritin levels and post-amniocentesis pregnancy loss.Methods: We performed a case-control studyinvolving 66 women with a non-anomalous fetus who had a spontaneous pregnancy loss within 30 days following genetic amniocentesis and 66 term controls matched for maternal age, gestational age, time oftest and indication for amniocentesis. Amniotic fluid ferritin and interleukin-6 (IL-6) levels were measured using commercially available kits.Results: Mean (± SD) AF ferritin levelswere similar between the cases (19.3 ± 21.4 ng/ml) and the controls (19.8 ± 22.7 ng/ml) (p = 0.9). Mean (± SD) AF IL-6 levels were significantly higher in the women with post-amniocentesispregnancy loss (4.0 ± 13.1 ng/ml) than in controls (0.5 ± 0.7 ng/ml) (p = 0.04). A significant proportion (12.1%, 8/66) of the women with postamniocentesis pregnancy loss had elevatedamniotic fluid IL-6 levels (> 3 SD, 2.5 ng/ml) indicating inflammation, as compared to none in the control group (p = 0.01). In this subgroup of women with pregnancy loss and elevated IL-6 levels,AF ferritin levels were significantly elevated (52.0 ± 45.5 ng/ml) compared to the level in women who had a term delivery (19.8 ± 22.7 ng/ml) (p = 0.002), and were strongly correlatedwith IL-6 levels among the cases (r = 0.67, p < 0.001).Conclusion: The strong correlation of AF ferritin with IL-6 levels, along with the high ferritin values in cases withhigh AF IL-6, indicates that ferritin is a marker of inflammation in asymptomatic women destined to have an early pregnancy loss.

Amniotic fluid matrix metalloproteinase-9 and interleukin-6 in predicting intra-amniotic infection

OBJECTIVE: To assess the potential role of amniotic fluid (AF) matrix metalloproteinase-9 and interleukin-6 in predicting intra-amniotic infection. METHODS: Eighty-four women with singleton gestations with preterm contraction, preterm labor, preterm premature rupture of membranes, or clinical suspicion of intra-amniotic infection were studied. Amniotic fluid was obtained by transabdominal amniocentesis before starting any treatment. Intra-amniotic infection was defined as the presence of a positive AF culture. Amniotic fluid glucose concentration, leukocytes, matrix metalloproteinase-9, and interleukin-6 were determined. RESULTS: Amniotic fluid matrix metalloproteinase-9 and interleukin-6 levels were significantly higher in women with intra-amniotic infection than in those without. With intra-amniotic infection, levels of matrix metalloproteinase-9 significantly correlated with interleukin-6 ( r = 0.813, P < .001). Each of matrix metalloproteinase-9 and interleukin-6 significantly correlated with AF leukocytes and inversely correlated with AF glucose. Using AF cutoff levels of 13.6 ng/mL for matrix metalloproteinase-9 and 11.4 ng/mL for interleukin-6, the sensitivity, specificity, and positive and negative predictive values for diagnosing intra-amniotic infection were 77% versus 73%, 100% versus 79%, 100% versus 61%, and 90% versus 86%, respectively. Combining AF matrix metalloproteinase-9 with interleukin-6 slightly improved the sensitivity and the negative predictive values in diagnosing intra-amniotic infection. CONCLUSIONS: Amniotic fluid matrix metalloproteinase-9 and interleukin-6 are significantly elevated in women with intra-amniotic infection. Amniotic fluid matrix metalloproteinase-9 is an accurate biochemical marker in predicting intra-amniotic infection with better sensitivity, specificity, and positive and negative predictive values than interleukin-6.

The relationship between cervical dilatation, interleukin-6 and interleukin-8 during term labor.

To determine interleukin-6 and interleukin-8 levels in amniotic fluid, retroplacental blood and maternal serum and relate these values with cervical dilatation in term labor. Prospective study. n=78 healthy women undergoing term cesarean section, divided into four groups: controls, n=42, (elective cesarean section; no contractions, membrane rupture or cervical dilatation); latent labor, n=12, (latent phase labor; cervix <2 cm dilated); established labor, n=12, (active labor, cervix 2-5 cm); advanced labor, n=12, (active labor, cervix >5 cm). Interleukin-6 and interleukin-8 were determined by ELISA (pg/ml), placenta and placental bed biopsy examined histopathologically, and amniotic fluid also microbiologically. Results were expressed as median and ranges or mean and standard deviations, as appropriate. For statistical analysis, Mann-Whitney U-tests or Kruskal-Wallis tests were used as applicable (Statview 4.5). Power and linear regression analyses were performed. p<0.05 was considered significant, p<0.001 highly significant. Compared with controls, IL-6 and IL-8 increased significantly with cervical dilatation in all compartments tested for almost all labor groups (p<0.05 to p<0.0001). Significant changes were also seen between latent and advanced labor groups in some compartments (p<0.05), but not between established and advanced labor groups. Intrauterine infection was excluded in any of the patients clinically and on histopathological or microbiological analysis of placentae and amniotic fluid. In term labor without intraamniotic infection, interleukin-6 and interleukin-8 at the fetomaternal interface and in maternal serum rise significantly with cervical dilatation. These cytokines could be used as markers of active labor if vaginal examination is not applicable.

Amniotic Fluid Interleukin-6 and the Risk of Early-Onset Sepsis Among Preterm Infants

Background High concentrations of interleukin-6 (IL-6) have been demonstrated in amniotic fluid (AF) from women with intra-amniotic infection. Recent studies have reported that IL-6 levels in AF were related to an increase in neonatal morbidity; moreover, higher IL-6 plasma levels have been observed in neonates with sepsis. Methods A cohort study was carried out at the National Institute of Perinatology in Mexico City. Inclusion criteria were the following: 1) preterm singleton pregnancy; 2) intact membranes at time of enrollment, and 3) written informed consent. Women with other complications of pregnancy were excluded. Newborn sepsis during the first 72 h was defined as early-onset sepsis. Amniotic fluid was obtained at the moment of delivery. Amniotic fluid IL-6 (AF IL-6) was determined by enzyme-linked immunoassays. Results Ninety-three women met the criteria for enrollment in the study and 31 (33%) of their newborns had early-onset neonatal sepsis. The mean AF IL-6 in mothers of septic newborns was 5779 ± 2804 pg/ml compared to 729 ± 382 pg/ml in mothers with non-infected neonates ( p <0.001). AF IL-6 concentrations higher than 1250 pg/ml were significantly associated with early-onset sepsis (OR 33.3; 95% CI 9.4–117.3) ( p < 0.001). Gestational age under 32 weeks was also associated with neonatal sepsis (OR 2.56; 95% CI 1.2–9) ( p = 0.002). Women whose infants developed neonatal sepsis had a higher frequency of clinical chorioamnionitis ( p = 0.02). Conclusions IL-6 determination in AF may be a useful indicator to identify neonates with higher risk of in utero bacterial infection.

The significance of amniotic fluid interleukin-6 levels in preterm labour.

This study was performed to determine the prevalence of subclinical intraamniotic infection in patients with preterm labour and intact membranes, and to evaluate the significance of interleukin-6 levels for diagnosis and prognosis of tocolysis failure, amniocentesis-delivery interval and neonatal mortality and morbidity. Transabdominal amniocentesis was performed on 74 randomly-selected patients with preterm labour and intact membranes. The prevalence of amniotic fluid infection in this group was found to be 33.7% (25 of 74). The most sensitive test to identify the intraamniotic infection was found to be the measurement of interleukin-6 level. However the most specific test was confirmed to be Gram staining. Interleukin-6 level measurement was the best test to correlate with positive amniotic fluid culture and histological chorioamnionitis. Also, interleukin-6 level measurement had the advantage of predicting preterm delivery risk and neonatal complications compared to the other tests.

Interleukin-6 Concentrations in Cervical Secretions in the Prediction of Intrauterine Infection in Preterm Premature Rupture of the Membranes

The objective of this study was to determine the value of interleukin-6 (IL-6) in cervical secretion to diagnose microbial invasion of the amniotic cavity in patients with premature rupture of the membranes. Cervical secretions were sampled immediately before amniocentesis in 124 patients with singleton pregnancies and preterm premature rupture of the membranes. Gestational age ranged between 24 and 32 weeks. Amniotic fluid was cultured and IL-6 measured in amniotic fluid and cervical secretions. A total of 33.8% (21/124) of the amniotic fluid cultures had positive results. In cervical secretions the median concentration of IL-6 was 672 pg/ml (range 5–1,250) in the presence of intra-amniotic infection in contrast to 95.5 pg/ml (range 12–640) in women with negative amniotic fluid culture (p ≤0.001). There were no differences between IL-6 concentrations in the cervical secretions of patients with or without obvious leakage of amniotic fluid. A significant relationship was found between IL-6 levels in amniotic fluid and in cervical secretions (ρ = 0.74, p ≤0.001). An IL-6 level in cervical secretions >200 pg/ml had a sensitivity of 78.5%, a specificity of 73.1% and a relative risk of 4.6 for intra-amniotic infection. Receiver-operator characteristics curve analysis showed that IL-6 assay in cervical secretions is comparable to IL-6 assay in amniotic fluid in predicting intra-amniotic infection (p = 0.468).In conclusion, intra-amniotic infection is associated with increased levels of IL-6 and concentrations in cervical secretions are related to amniotic levels. The measurement of IL-6 in cervical secretions may help to noninvasively identify intra-amniotic infection among pregnancies with preterm premature rupture of membranes.