Sterile intra-amniotic inflammation in asymptomatic patients with a sonographic short cervix: prevalence and clinical significance

Objective: To determine the frequency and clinical significance of sterile and microbial-associated intra-amniotic inflammation in asymptomatic patients with a sonographic short cervix.

Methods: Amniotic fluid (AF) samples obtained by transabdominal amniocentesis from 231 asymptomatic women with a sonographic short cervix [cervical length (CL) ≤25?mm] were analyzed using cultivation techniques (for aerobic and anaerobic as well as genital mycoplasmas) and broad-range polymerase chain reaction (PCR) coupled with electrospray ionization mass spectrometry (PCR/ESI-MS). The frequency and magnitude of intra-amniotic inflammation [defined as an AF interleukin (IL)-6 concentration ≥2.6?ng/mL], acute histologic placental inflammation, spontaneous preterm delivery (sPTD), and the amniocentesis-to-delivery interval were examined according to the results of AF cultures, PCR/ESI-MS and AF IL-6 concentrations.

Results: Ten percent (24/231) of patients with a sonographic short cervix had sterile intra-amniotic inflammation (an elevated AF IL-6 concentration without evidence of microorganisms using cultivation and molecular methods). Sterile intra-amniotic inflammation was significantly more frequent than microbial-associated intra-amniotic inflammation [10.4% (24/231) versus 2.2% (5/231); p?p?p?Conclusion: Sterile intra-amniotic inflammation is more common than microbial-associated intra-amniotic inflammation in asymptomatic women with a sonographic short cervix, and is associated with increased risk of sPTD (<34 weeks). Further investigation is required to determine the causes of sterile intra-amniotic inflammation and the mechanisms whereby this condition is associated with a short cervix and sPTD.     

Four-dimensional fetal echocardiography with spatiotemporal image correlation (STIC): a systematic study of standard cardiac views assessed by different observers.

OBJECTIVE: To test the agreement between observers and reproducibility of a technique to display standard cardiac views of the left and right ventricular outflow tracts from four-dimensional volume datasets acquired with Spatiotemporal Image Correlation (STIC). METHODS: A technique was developed to obtain dynamic multiplanar images of the left ventricular outflow tract (LVOT) and right ventricular outflow tract (RVOT) from volume datasets acquired with STIC. Volume datasets were acquired from fetuses with normal cardiac anatomy. Twenty volume datasets of satisfactory quality were pre-selected by one investigator. The data was randomly assigned for a blinded review by two independent observers with previous experience in fetal echocardiography. Only one volume dataset was used for each fetus. After a training session, the observers obtained standardized cardiac views of the LVOT and RVOT, which were scored on a scale of 1 to 5, based on diagnostic value and image quality (1=unacceptable, 2=marginal, 3=acceptable, 4=good, and 5=excellent). Median scores and interquartile range, as well as inter- and intraobserver agreement were calculated for each view. RESULTS: The mean menstrual age at the time of volume acquisition was 25.5+/-4.5 weeks. Median scores (interquartile range) for LVOT images, obtained by the first and second observers, were 3.5 (2.25-5.00) and 4 (3.00-5.00), respectively. The median scores (interquartile range) for RVOT images obtained by the first and second observers were 3 (3.00-5.00) and 3 (2.00-4.00), respectively. The interobserver intraclass correlation coefficient for the LVOT was 0.693 (95% CI 0.380-0.822), and 0.696 (95% CI 0.382-0.866) for the RVOT. For the intraobserver agreement analysis, observer 1 gave higher scores to the LVOT the second time the volumes were analyzed [LVOT: 3.50 (2.25-5.00) vs. 5.00 (4.00-5.00, p=0.008)]. CONCLUSION: STIC can be reproducibly used to evaluate fetal cardiac outflow tracts by independent examiners. Slightly better image quality rating scores during the intraobserver variability trial suggests the presence of a learning curve for the manipulation and analysis of volume data obtained by STIC.     

A short cervix in women with preterm labor and intact membranes: a risk factor for microbial invasion of the amniotic cavity

OBJECTIVE: The purpose of this study was to determine whether there was a relationship between sonographic cervical length and the presence of culture-proven microbial invasion of the amniotic cavity in women with preterm labor and intact membranes. STUDY DESIGN: Ultrasonography and amniocentesis were performed in 401 patients admitted with preterm labor (22-35 weeks) and cervical dilatation of < or = 3 cm, as assessed by digital examination. Cervical length was determined by transvaginal ultrasound at admission. Outcome variables were the presence of microbial invasion of the amniotic cavity (defined as a positive amniotic fluid culture) and the occurrence of preterm delivery before 35 weeks. Contingency tables, chi2 test, receiver-operator characteristic (ROC) curves, and logistic regression were used for statistical analysis. RESULTS: The prevalence of microbial invasion of the amniotic cavity was 7% (28/401). Spontaneous preterm delivery (< or = 35 weeks) occurred in 21.4% (82/384) of patients. ROC curve analysis showed a significant relationship between the frequency of microbial invasion of the amniotic cavity and the length of the uterine cervix (area under the curve: 0.77; P < .005). Patients with a cervical length < 15 mm had a higher rate of a positive amniotic fluid culture than patients with a cervical length > or = 15 mm (26.3% [15/57] vs. 3.8% [13/344], respectively; P < .05). Moreover, patients with a short cervix (defined as < 15 mm) were more likely to deliver spontaneously before 35 weeks, 32 weeks, within 7 days, and within 48 hours of admission ( P < .05 for all comparisons). Forty percent of patients (161/401) had a cervical length > or = 30 mm. These patients had a very low risk of microbial invasion of the amniotic cavity (1.9% [3/161]), spontaneous delivery < or = 35 weeks (4.5% [7/154]), < or = 32 weeks (2.6% [2/76]), within 7 days (1.9% [3/154]), and within 48 hours (0% [0/154]) of admission. CONCLUSION: Endovaginal ultrasonographic examination of the uterine cervix in women with preterm labor identifies patients at increased risk for intrauterine infection.     

Evidence for fetal involvement in the pathologic process of clinical chorioamnionitis

OBJECTIVE: Clinical and histologic chorioamnionitis have recently been identified as risk factors for cerebral palsy. Proinflammatory cytokines have been implicated in the mechanisms that are responsible for brain injury in cases of intrauterine infection. The purpose of this study was to determine whether clinical chorioamnionitis, which is a maternal syndrome, is associated with an elevation in the fetal plasma interleukin-6 (IL-6) that is indicative of fetal inflammation. STUDY DESIGN: A cross-sectional study was designed to determine plasma concentrations of IL-6 in umbilical venous blood from patients with clinical chorioamnionitis (n = 26) and a control group (n = 111). Umbilical cord blood was obtained at the time of delivery. Plasma concentrations of IL-6 were measured with a sensitive and specific immunoassay. Nonparametric statistics were used for analysis. RESULTS: Plasma concentrations of IL-6 were detectable in all samples of umbilical venous plasma. The median concentration of plasma IL-6 was higher in neonates born to mothers with clinical chorioamnionitis than in neonates born to mothers in the control group (clinical chorioamnionitis: median, 27.46 pg/mL; range, 1.3-5550.0 pg/mL; vs control: median, 2.13 pg/mL; range, 0.6-812.3 pg/mL; P <.001). Sixty-two percent of neonates (16/26) who were born to women with clinical chorioamnionitis had fetal plasma concentrations of IL-6 >11 pg/mL and 54% (14/26) had fetal plasma concentrations of IL-6 >18 pg/mL (these cutoff points have been used previously to define the fetal inflammatory response syndrome). CONCLUSION: Umbilical vein plasma concentrations of interleukin-6 are elevated in the neonates who were born to mothers with clinical chorioamnionitis, which suggests that the inflammatory process that is responsible for the maternal syndrome of clinical chorioamnionitis frequently involves the human fetus.     

CXCL10/IP-10: a missing link between inflammation and anti-angiogenesis in preeclampsia?

OBJECTIVE: Interferon (IFN)-gamma inducible protein, CXCL10/IP-10, is a member of the CXC chemokine family with pro-inflammatory and anti-angiogenic properties. This chemokine has been proposed to be a key link between inflammation and angiogenesis. The aim of this study was to determine whether preeclampsia and delivery of a small for gestational age (SGA) neonate are associated with changes in maternal serum concentration of CXCL10/IP-10. STUDY DESIGN: This cross-sectional study included patients in the following groups: (1) non-pregnant women (N = 49); (2) women with normal pregnancies (N = 89); (3) patients with preeclampsia (N = 100); and (4) patients who delivered an SGA neonate (N = 78). SGA was defined as birth weight below the 10th percentile. Maternal serum concentrations of CXCL10/IP-10 were measured by sensitive immunoassay. Non-parametric statistics were used for analysis. RESULTS: (1) Patients with normal pregnancies had a significantly higher median serum concentration of CXCL10/IP-10 than non-pregnant women (median 116.1 pg/mL, range 40.7-1314.3 vs. median 90.3 pg/mL, range 49.2-214.7, respectively; p = 0.002); (2) no significant correlation was found between maternal serum concentration of CXCL10/IP-10 and gestational age (between 19 and 38 weeks); (3) there were no differences in median serum CXCL10/IP-10 concentrations between patients who delivered an SGA neonate and those with normal pregnancies (median 122.4 pg/mL, range 37.3-693.5 vs. median 116.1 pg/mL, range 40.7-1314.3, respectively; p > 0.05); (4) patients with preeclampsia had a higher median serum concentration of CXCL10/IP-10 than normal pregnant women (median 156.4 pg/mL, range 47.4-645.9 vs. median 116.1 pg/mL, range 40.7-1314.3, respectively; p < 0.05); (5) patients with preeclampsia had a higher median concentration of CXCL10/IP-10 than those who delivered an SGA neonate (median 156.4 pg/mL, range 47.4-645.9 vs. median 122.4 pg/mL, range 37.3-693.5, respectively; p < 0.05). CONCLUSIONS: Patients with preeclampsia have significantly higher serum concentrations of CXCL10/IP-10 than both normal pregnant women and mothers who have SGA neonates. These results are likely to reflect an anti-angiogenic state as well as an enhanced systemic inflammatory response in patients with preeclampsia. Alternatively, since preeclampsia and SGA share several mechanisms of disease, it is possible that a higher concentration of this chemokine may contribute to the clinical presentation of preeclampsia in patients with a similar intrauterine insult.     

Phenotypic and metabolic characteristics of maternal monocytes and granulocytes in preterm labor with intact membranes.

OBJECTIVE: Experimental and clinical studies support a role for the fetus in the control of the onset of labor. Fetal systemic inflammation, but not a maternal inflammatory response, has been linked to the onset of preterm labor and delivery on the basis of the determination of inflammatory cytokines in fetal and maternal blood. We propose that parturition requires fetomaternal cooperation and that inflammation is an integral part of the parturitional process. This study used flow cytometry, a sensitive technique for the detection of intravascular inflammation, to assess whether maternal inflammation is present in preterm labor. STUDY DESIGN: A prospective cross-sectional study was performed including patients with preterm labor (n = 55) and women with normal pregnancy (n = 50). Intravascular inflammation was studied by using flow cytometry. Maternal blood was assayed to determine granulocyte and monocyte phenotype by using monoclonal antibodies, which included the following cluster of differentiation (CD) markers: CD11b, CD14, CD15, CD16, CD18, CD49d, CD62L, CD64, CD66b, and HLA-DR. Oxidative burst and generation of basal intracellular oxygen radical species were assessed. Statistical analysis was conducted with the use of nonparametric methods. A P value of <.01 was considered statistically significant. RESULTS: Preterm labor was associated with a significant increase in the median mean channel brightness of CD11b, CD15, and CD66b on granulocytes and median mean channel brightness of CD11b and CD15 on monocytes. The ratio of oxidative burst over basal intracellular oxygen radical species in both granulocytes and monocytes was increased in preterm labor (P <. 01). CONCLUSION: Preterm labor with intact membranes is associated with phenotypic and metabolic changes of maternal granulocytes and monocytes.     

Evaluation of Utero-placental and Fetal Hemodynamic Parameters Throughout Gestation in Pregnant Mice Using High-Frequency Ultrasound

Throughout gestation, changes in maternal and fetal Doppler parameters in pregnant mice, similar to those obtained in human fetuses, were detected using high-frequency ultrasound with a 55-MHz linear probe. In the uterine arteries (UtA), fetal umbilical artery (UA) and fetal ductus venosus (DV) peak systolic velocity increased (UtA, p = 0.04; UA, p = 0.0004; DV, p = 0.02), end-diastolic velocity increased (UtA, p < 0.001; UA, p < 0.0001; DV, p = 0.01) and resistance index decreased (UtA, p = 0.0004; UA, p = 0.0001; DV, p = 0.04) toward the end of pregnancy. In the middle cerebral and carotid arteries, end diastolic velocity increased (p = 0.02 and p < 0.0001) and resistance index decreased (both vessels, p < 0.0001). There was a reduction in the pulsatile pattern in the umbilical vein (p < 0.05). The increased velocities and reduced resistance index suggest a progressive increment in blood flow to the fetal mouse toward the end of pregnancy. Fetal and utero-placental vascular parameters in CD-1 mice can be reliably evaluated using high-frequency ultrasound.