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Objective: Interleukin 18 is a proinflammatory pleiotropic cytokine that has been implicated in the host defense against infection. This study was undertaken to determine whether interleukin 18 concentrations change in the maternal, fetal, and amniotic fluid compartments with labor (term and preterm) and microbial invasion of the amniotic cavity., Study Design: Amniotic fluid was assayed for interleukin 18 in samples obtained from 285 patients in the following groups: (1) term not in labor (n = 22), in labor (n = 19), and with microbial invasion of the amniotic cavity (n = 16); (2) preterm labor who delivered at term (n = 38), who delivered preterm but without microbial invasion of the amniotic cavity (n = 41), and preterm labor with microbial invasion of the amniotic cavity (n = 24); (3) preterm premature rupture of membranes without microbial invasion of the amniotic cavity (n = 30) and with microbial invasion of the amniotic cavity (n = 34); (4) term premature rupture of membranes not in labor (n = 20) and term premature rupture of membranes in labor (n = 19); and (5) midtrimester (n = 22). In addition, cord and maternal plasma samples from women at term not in labor (n = 20) and in labor (n = 20) were assayed for interleukin 18., Results: (1) Interleukin 18 was detectable in all amniotic fluid samples and maternal and umbilical cord blood samples. (2) Interleukin 18 concentrations increased with advancing gestational age (r = 0.47; P <.0001). (3) Microbial invasion of the amniotic cavity in either preterm or term parturition was associated with a significant increase in the amniotic fluid concentration of interleukin 18 (preterm labor without microbial invasion of the amniotic cavity: median, 14.95 pg/mL; range, 3.9-277.0 pg/mL; vs preterm labor with microbial invasion of the amniotic cavity: median, 20.75 pg/mL; range, 5.53-160.21 pg/mL; P <.02; term labor without microbial invasion of the amniotic cavity: median, 18.73 pg/mL; range, 5.09-95.44 pg/mL; vs term labor with microbial invasion of the amniotic cavity: median, 24.35 pg/mL; range, 10.07-144.42 pg/mL; P<.004). (4) Both term and preterm parturition were associated with a modest increase in amniotic fluid interleukin 18 concentrations, although this trend did not reach statistical significance. (5) Rupture of membranes at term was associated with a significant decrease in amniotic fluid interleukin 18 concentrations (intact membranes: median, 14.96 pg/mL; range, <3.89-26.07 pg/mL; vs rupture of membranes: median, 10.1 pg/mL; range, 4.29-21.44 pg/mL; P <.001)., Conclusion: (1) Interleukin 18 is increased in cases of microbial invasion of the amniotic cavity. (2) Interleukin 18 is detectable in the amniotic, maternal, and fetal compartments. (3) We propose that this novel cytokine plays a role in the host defense against infection.

Objective: The fetal inflammatory response syndrome is a subclinical condition frequently present in preterm labor and preterm premature rupture of the membranes and is associated with increased perinatal morbidity and mortality. Tumor necrosis factor alpha is a mediator of septic shock and death, and it exerts its biologic effects by interacting with 2 receptors, TNF-R1 and TNF-R2. Soluble tumor necrosis factor receptors can buffer the biologic activity and protect against the deleterious effects of tumor necrosis factor alpha. The purpose of this study was to determine the behavior of soluble tumor necrosis factor receptors in fetuses with and without fetal inflammatory response syndrome., Study Design: Fetal blood sampling was performed in patients with preterm labor (n = 95) and preterm premature rupture of the membranes (n = 39). Control samples were obtained from fetuses who were undergoing blood sampling for clinical indications and had normal outcomes (n = 21). Fetal inflammatory response syndrome was defined as a fetal plasma interleukin 6 concentration >11 pg/mL. Concentrations of interleukin 6 and TNF-R1 and TNF-R2 were determined by use of sensitive and specific immunoassays. Analysis of covariance was used for statistical analysis., Results: (1) TNF-R1 and TNF-R2 were detectable in all samples, and their concentrations decreased with advancing gestational age (r = -0.8 and r = -0.7; P<.0001 and P<.001, respectively). (2) The mean fetal plasma concentrations of TNF-R1 and TNF-R2 were significantly higher in fetuses with fetal inflammatory response syndrome than in those without the syndrome after adjustment for gestational age and fetal membrane status (TNF-R1: no fetal inflammatory response syndrome, mean +/- SE, 3473.7+/-128.8 pg/mL; vs fetal inflammatory response syndrome, mean +/- SE, 4079.9+/-190.7 pg/mL; P<.005; TNF-R2: no fetal inflammatory response syndrome, mean +/- SE, 6033.2+/-235.4 pg/mL; vs. fetal inflammatory response syndrome, mean +/- SE, 7783.1+/-342.8 pg/mL; P<.0001). (3) Fetuses of patients who delivered within 72 hours of cordocentesis had significantly higher concentrations of TNF-R1 and TNF-R2 receptors than those with longer latency periods (P<.05 for each)., Conclusion: The fetal inflammatory response syndrome is associated with increased availability of the soluble receptors of tumor necrosis factor alpha in fetal plasma. These factors may attenuate the deleterious effects of tumor necrosis factor alpha.

Objective: Our aim was to determine whether interleukin-6 concentrations in cervical fluid samples are of value in the identification of microbial invasion of the amniotic cavity, prediction of the duration of the latency period, and assessment of the risk of neonatal complications in preterm premature rupture of membranes., Study Design: A cohort study was performed in 86 patients with preterm premature rupture of membranes. Amniotic fluid and cervical fluid were collected. Amniotic fluid was cultured for aerobic and anaerobic bacteria, as well as mycoplasmas. Interleukin 6 was measured by a sensitive and specific immunoassay. The receiver operating characteristic curve, logistic regression, and survival techniques were used for analysis., Results: (1) Patients with a positive amniotic fluid culture had a significantly higher median cervical fluid interleukin 6 concentration than those with negative results (median, 528 pg/mL; range, 174-825 pg/mL; vs median, 169 pg/mL; range, 8-986 pg/mL; P <.0001). (2) A cervical fluid interleukin 6 concentration of >350 pg/mL had a sensitivity of 92% and a specificity of 78% in the identification of a positive amniotic fluid culture. (3) Patients with a cervical fluid interleukin 6 concentration of >350 pg/mL had a significantly shorter median interval to delivery and higher rate of funisitis, preterm delivery within 2 days and 7 days, and the occurrence of significant neonatal morbidity than did those with a cervical fluid interleukin 6 concentration of <350 pg/mL (P <.05 for each). (4) The increased perinatal morbidity remained significant after adjustment for gestational age (P <.05). (5) There was a strong correlation between cervical fluid concentrations and amniotic fluid concentrations of interleukin 6 (P <.001)., Conclusion: Cervical fluid interleukin 6 determinations are of value in the assessment of the likelihood of microbial invasion of the amniotic cavity, impending preterm delivery, and the occurrence of significant neonatal complications in the setting of preterm premature rupture of membranes.

Objective: Matrix metalloproteinases (MMP-9 and MMP-2) have been implicated in the digestion of fetal membranes. The purpose of this study was to determine the amniotic fluid concentrations of active forms of MMP-2 and MMP-9 and to explore the participation of these enzymes in labor (term and preterm), rupture of membranes (term and preterm), and microbial invasion of the amniotic cavity., Study Design: A cross-sectional study was conducted with 291 women in the following categories: (1) term not in labor, (2) term in labor, (3) preterm labor and intact membranes who delivered at term, (4) preterm labor who delivered preterm, (5) preterm labor with microbial invasion of the amniotic cavity, (6) preterm premature rupture of membranes without microbial invasion of the amniotic cavity, (7) preterm premature rupture of membranes with microbial invasion of the amniotic cavity, (8) term premature rupture of membranes not in labor, and (9) mid trimester. Active forms of MMP-2 and MMP-9 were measured by a novel assay that uses a substrate developed by protein engineering., Results: (1) MMP-2 and MMP-9 were detected in 88% and 96% of amniotic fluid samples, respectively (255/291 and 279/291). (2) The concentrations of active forms of MMP-2 and MMP-9 changed with advancing gestational age. (3) Spontaneous term parturition was associated with a significant increase in the median concentration of the active forms of MMP-9 (P <.005) and a significant decrease in the median concentration of the active forms of MMP-2 (P <.003). (4) Preterm labor with intact membranes leading to preterm delivery in the absence of infection was associated with a significant increase in the median concentration of the active forms of MMP-9 (P <.005) but not of the active forms of MMP-2 (P =.2). (5) Rupture of membranes (either term or preterm) was associated with a significant increase in the concentration of the active forms of MMP-9 and with a significant decrease in the concentration of the active forms of MMP-2 (P <.005 for term and P <.03 and P <.003 for preterm, respectively). (6) Microbial invasion of the amniotic cavity in women with preterm premature rupture of membranes was also associated with a significant increase in the concentration of the active forms of MMP-9 (P <.03) and a decrease in the concentration of the active forms of MMP-2 (P <.05). (7) Microbial invasion of the amniotic cavity in patients with preterm labor was associated with a significant increase in the median concentration of the active forms of MMP-9 (P <.005) but not of the active forms of MMP-2 (P =.6)., Conclusion: Spontaneous rupture of membranes (either term or preterm), parturition (either term or preterm), and microbial invasion of the amniotic cavity were associated with significant increases in the amniotic fluid concentration of the active forms of MMP-9. In contrast, the concentration of the active forms of MMP-2 either decreased or remained the same in these conditions. Our observations provide evidence for a novel regulation of gelatinolytic activity in vivo.

Objective: Rupture of membranes is thought to result from the effects of physical forces in localized areas of the membranes weakened by the degradation of structural collagens. Matrix metalloproteinases are enzymes that degrade extracellular matrix components and have been implicated in membrane rupture. The objective of this study was to determine whether spontaneous rupture of membranes is associated with a change in the amniotic fluid concentration of interstitial collagenase (matrix metalloproteinase 1 [MMP-1]), a major collagenase., Study Design: A cross-sectional study was conducted to determine MMP-1 concentrations in amniotic fluid from 353 women in the following categories: (1) term with intact membranes not in labor and in labor, (2) preterm labor who delivered at term, (3) preterm labor who delivered preterm without microbial invasion of the amniotic cavity, (4) preterm labor who delivered preterm with microbial invasion of the amniotic cavity, (5) preterm premature rupture of membranes with and without microbial invasion of the amniotic cavity, (6) term premature rupture of membranes not in labor and in labor, and (7) mid trimester of pregnancy. Microbial invasion of the amniotic cavity was determined by an amniotic fluid culture positive for microorganisms. MMP-1 concentrations in amniotic fluid were determined by means of sensitive and specific immunoassays., Results: (1) MMP-1 was detectable in 81.3% of amniotic fluid samples (287/353), and its concentrations increased with advancing gestational age (r = 0.4; P <.001). (2) Preterm premature rupture of membranes was associated with a significant increase in the median amniotic fluid concentration of MMP-1 (P =.02). (3) Women with term premature rupture of membranes had a significantly lower amniotic fluid MMP-1 concentration than those with intact membranes at term not in labor (P <.001). (4) Microbial invasion of the amniotic cavity in patients in preterm labor with intact membranes and in patients with preterm premature rupture of membranes was also associated with significant increases in the median amniotic fluid MMP-1 concentrations (P <.05 and P <.01, respectively). (5) Patients with preterm premature rupture of membranes and microbial invasion of the amniotic cavity had a significantly higher median amniotic fluid MMP-1 concentration than those with intact membranes and microbial invasion of the amniotic cavity (P =.01). (6) Neither term nor preterm parturition was associated with changes in amniotic fluid MMP-1 concentrations (P =.6 and P =.3, respectively)., Conclusion: (1) Collagenase 1 (MMP-1) is a physiologic constituent of amniotic fluid. (2) Preterm premature rupture of membranes (in both the presence and absence of infection) was associated with an increase in the amniotic fluid MMP-1 concentrations. (3) Neither term nor preterm parturition was associated with a significant increase in the amniotic fluid concentration of MMP-1.

Objective: Lactoferrin is an iron-binding protein with antimicrobial properties. This study was undertaken to determine whether amniotic fluid concentrations of this protein change with gestational age, infection, labor, and rupture of membranes., Study Design: This cross-sectional study included women who underwent transabdominal amniocentesis (n = 268) in the following groups: (1) mid trimester of pregnancy; (2) preterm labor who delivered at term, preterm labor who delivered preterm with intra-amniotic infection, and preterm labor who delivered preterm without intra-amniotic infection; (3) preterm premature rupture of membranes in the presence or absence of intra-amniotic infection; (4) term with intact membranes not in labor, in labor, and in labor with intra-amniotic infection; and (5) premature rupture of membranes at term not in labor. In addition, lactoferrin concentrations were determined in maternal plasma and cord blood of patients at term not in labor. Lactoferrin concentration was measured with an immunoassay., Results: (1) Lactoferrin was detectable in 85.4% (229/268) of amniotic fluid samples, not detectable in all fluid obtained in the mid trimester, and detectable in all maternal and cord plasma samples. (2) The concentration of lactoferrin increased with advancing gestational age (r = 0.68; P <.0001). (3) Intra-amniotic infection was associated with significant increases in amniotic fluid lactoferrin concentrations in patients with preterm labor (no intra-amniotic infection median, 1641.2 ng/mL; range, <1.24-35,090.0 ng/mL; vs intra-amniotic infection median, 3833.6 ng/mL; range, 746.0-47,020.0 ng/mL; P <.001), term labor (no intra-amniotic infection median, 2085.8 ng/mL; range, 425.0-23,230.0 ng/mL; vs intra-amniotic infection median, 5627.0 ng/mL; range, <1.24-19,220.0 ng/mL; P <. 001), and preterm premature rupture of membranes (no intra-amniotic infection median, 2190 ng/mL; range, <1.24-7456.1 ng/mL; vs intra-amniotic infection median, 3449.3 ng/mL; range, <1.24-83,600. 0; P <.01). (4) Spontaneous labor at term but not preterm was associated with a significant decrease in amniotic fluid lactoferrin concentration (P <.05). (5) Spontaneous term parturition was associated with a significant increase in umbilical cord plasma lactoferrin concentration (P <.005)., Conclusion: (1) Intra-amniotic infection was consistently associated with dramatically increased concentrations of lactoferrin in amniotic fluid. (2) Term parturition was associated with a significant increase in lactoferrin concentration in the fetal compartment (umbilical cord blood) and a decrease in the amniotic compartment. We propose that lactoferrin is part of the repertoire of host defense mechanisms against intra-amniotic infection.

Objectives: The mechanisms by which microbial invasion of the amniotic cavity leads to membrane weakening and rupture are poorly understood. Recently, endogenous host enzymes have been implicated in this process. Matrix metalloproteinases are a family of potent enzymes that degrade components of the extracellular matrix. Collagen type I provides the main tensile strength of the fetal membranes. Matrix metalloproteinase 8 (MMP-8), or neutrophil collagenase, degrades interstitial collagens, acting preferentially on collagen type I. This study was undertaken (1) to determine whether MMP-8 is present in amniotic fluid and whether its concentrations are changed in preterm and term labor and membrane rupture with and without intra-amniotic infection and (2) to determine whether the amniotic fluid concentrations of MMP-8 in labor at term are different in the lower and upper uterine compartments., Study Design: A cross-sectional study was conducted and transabdominal amniocentesis was performed in women in the following categories: (1) midtrimester (n = 25), (2) preterm labor in the presence and absence of microbial invasion of the amniotic cavity (n = 86), (3) preterm premature rupture of the membranes in the presence and absence of microbial invasion of the amniotic cavity (n = 51), (4) term patients in labor and not in labor (n = 51), and (5) term premature rupture of membranes (n = 20). Additional paired samples of amniotic fluid were retrieved by transabdominal amniocentesis (upper compartment) and transvaginal amniocentesis (lower or forebag compartment) from 14 term patients (28 samples) in spontaneous labor with intact membranes. Amniotic fluid MMP-8 concentrations were determined with a sensitive and specific immunoassay., Results: MMP-8 was detected in 95.4% (249/261) of all samples. (1) Spontaneous human parturition was associated with a significant increase in amniotic fluid concentrations of MMP-8 in both term and preterm gestation. Term (no labor median, 3.3 ng/mL; range, <0.06-38.6 ng/mL; vs labor median, 16.6 ng/mL; range, 0. 33-1650 ng/mL; P <.05). Patients with preterm labor who delivered preterm (in the absence of microbial invasion of the amniotic cavity) had a significantly higher median amniotic fluid MMP-8 concentration than those with preterm labor who delivered at term (preterm labor, term delivery median, 3.1 ng/mL; range, <0.06-415.1 ng/mL; vs preterm labor, preterm delivery median, 32.5 ng/mL; range, <0.06-6006.6 ng/mL;P <.003). (2) Spontaneous rupture of membranes in preterm gestation but not in term gestation was associated with elevated amniotic fluid concentrations of MMP-8. Preterm gestation (preterm labor, intact membranes median, 3.1 ng/mL; range, <0.06-415. 1 ng/mL; vs preterm premature rupture of membranes median, 35.1 ng/mL; range, 0.71-1184.1 ng/mL; P <.05). Term gestation (intact membranes median, 3.3 ng/mL; range, 0.24-38.6 ng/mL; vs rupture of membranes median, 5.6 ng/mL; range, 0.22-19.8 ng/mL; P =.9). (3) Microbial invasion of the amniotic cavity was associated with a significant increase in amniotic fluid MMP-8 concentration in patients with preterm labor and intact membranes, as well as in patients with preterm premature rupture of membranes. Preterm labor (no microbial invasion of the amniotic cavity, preterm delivery median, 32.5 ng/mL; range, <0.06-6006.6 ng/mL; vs microbial invasion of the amniotic cavity median, 208.1 ng/mL; range, 4.2-14,600 ng/mL; P <.001). Preterm premature rupture of membranes (no microbial invasion of the amniotic cavity median, 35.1 ng/mL; range, 0.71-1184. 1 ng/mL; vs microbial invasion of the amniotic cavity median, 317.9 ng/mL; range, 2.16-14,500 ng/mL; P <.01). (4) The median amniotic fluid MMP-8 concentrations were significantly higher in fluid obtained from the forebag compartment than in that obtained from the upper compartment (median, 66.2 ng/mL; range, 7.4-170 ng/mL; vs median, 13.3 ng/mL; range, 2-170 ng/mL; respectively; P <.01). (ABSTRACT TRUNCATED)

Objective: The aim of this study was to determine whether fetal exposure to intra-amniotic inflammation and a systemic fetal inflammatory response (funisitis) are associated with the development of cerebral palsy at the age of 3 years., Study Design: This cohort study included 123 preterm singleton newborns (gestational age at birth, /=3 years. The presence of intra-amniotic inflammation was determined by elevated amniotic fluid concentrations of proinflammatory cytokines such as interleukins 6 and 8 and by amniotic fluid white blood cell count. Cytokine concentrations were measured with sensitive and specific immunoassays. Funisitis was diagnosed in the presence of neutrophil infiltration into the umbilical vessel walls or Wharton jelly. Cerebral palsy was diagnosed by neurologic examination at the age of 3 years., Results: Newborns with subsequent development of cerebral palsy had a higher rate of funisitis and were born to mothers with higher median concentrations of interleukins 6 and 8 and higher white blood cell counts in the amniotic fluid compared with newborns without subsequent development of cerebral palsy (funisitis: 75% [9/12] vs 23% [24/105]; interleukin 6: median, 18.9 ng/mL; range, 0. 02-92.5 ng/mL; vs median, 1.0 ng/mL; range, 0.01-115.2 ng/mL; interleukin 8: median, 13.0 ng/mL; range, 0.1-294.5 ng/mL; vs median, 1.2 ng/mL; range, 0.05-285.0 ng/mL; white blood cell count: median, 198 cells/mm(3); range, 0->1000 cells/mm(3); vs median, 3 cells/mm(3); range, 0-19,764 cells/mm(3); P <.01 for each). After adjustment for the gestational age at birth, the presence of funisitis and elevated concentrations of interleukins 6 and 8 in amniotic fluid significantly increased the odds of development of cerebral palsy (funisitis: odds ratio, 5.5; 95% confidence interval, 1.2-24.5; interleukin 6: odds ratio, 6.4; 95% confidence interval, 1. 3-33.0; interleukin 8: odds ratio, 5.9; 95% confidence interval, 1. 1-30.7; P <.05 for each)., Conclusion: Antenatal exposure to intra-amniotic inflammation and evidence of a systemic fetal inflammatory response (funisitis) are strong and independent risk factors for the subsequent development of cerebral palsy at the age of 3 years.

Objective: Interleukin 16 is a proinflammatory cytokine that promotes the recruitment of nonclonotypic T cells and eosinophils to sites of inflammation and induces resistance to activation-induced apoptosis. This peptide has no homology with members of the chemokine family and is produced by epithelial cells. No information is available about the expression of this cytokine during human pregnancy. This study was conducted to determine whether interleukin 16 is present in amniotic fluid and to examine the effects of labor and intrauterine infection on the concentrations of this cytokine., Study Design: A cross-sectional study was constructed with 230 women in the following groups: (1) mid- trimester (n = 25); (2) term not in labor (n = 25), term in labor (n = 25), and term premature rupture of membranes not in labor (n = 40); (3) preterm labor and intact membranes with (n = 21) and without (n = 42) intra-ammiotic infection; and (4) preterm premature rupture of membranes in the presence (n = 29) and absence (n = 23) of microbial invasion of the amniotic cavity. Interleukin 16 concentration was measured with sensitive and specific immunoassays validated for amniotic fluid. Data were analyzed with nonparametric statistics., Results: (1) Interleukin 16 was detected in 87.8% (202/230) of amniotic fluid samples. (2) Amniotic fluid interleukin 16 concentrations were significantly higher in women in the midtrimester than in those at term not in labor (median, 321.5 pg/mL; range, 146.9-1185.8 pg/mL; vs median, 85.9 pg/mL; range, <25-409.8 pg/mL; P <.001). (3) Labor at term was not associated with a significant increase in the median amniotic fluid interleukin 16 concentration. (4) Patients with preterm labor who delivered preterm had a significantly higher median amniotic fluid interleukin 16 concentration than those with preterm labor who delivered at term (median, 328.1 pg/mL; range, 38. 9-4660 pg/mL; vs median, 119.8 pg/mL; range, <25-558.5 pg/mL;P <.05). (5) Microbial invasion of the amniotic cavity was associated with a significant increase in median amniotic fluid interleukin 16 concentration in patients with preterm labor and intact membranes (microbial invasion of the amniotic cavity: median, 839 pg/mL; range, <25-8620 pg/mL; vs no microbial invasion of the amniotic cavity: median, 119.8 pg/mL; range, <25-558.5 pg/mL; P <.001) and in patients with preterm premature rupture of the membranes (microbial invasion of the amniotic cavity: median, 1005.8 pg/mL; range, <25-4590 pg/mL; vs no microbial invasion of the amniotic cavity: median, 204.9 pg/mL; range, 42.6-2347 pg/mL; P <.05). (6) Spontaneous rupture of the membranes at term but not preterm was associated with a significant decrease in amniotic fluid concentrations of interleukin 16 (term premature rupture of the membranes: median, <25 pg/mL; range, <25-231.2 pg/mL; vs term intact membranes: median, 85.9 pg/mL; range, <25-409.8 pg/mL; P <.05)., Conclusions: Amniotic fluid interleukin-16 concentrations decreased with advancing gestational age. Women with preterm labor that led to preterm delivery and women with microbial invasion of the amniotic cavity had higher interleukin 16 amniotic fluid concentrations than those with preterm labor who delivered at term or those with sterile amniotic fluid. Microbial invasion of the amniotic cavity but not spontaneous labor at term or rupture of membranes was associated with increased concentrations of interleukin 16 in amniotic fluid.

Objective: The common terminal pathway of parturition describes the anatomic, biochemical, endocrine, and clinical events present in the fetus and mother in both term and preterm labor. Labor at term is thought to result from physiologic activation of this pathway, whereas preterm labor is the result of pathologic activating events. The purpose of this study was to determine whether physiologic and pathologic activation could be discerned by the analysis of a cytokine-receptor signaling system. Tumor necrosis factor alpha and its soluble receptors were used as probes because of their pivotal role in the regulation of several processes activated during parturition. Soluble receptors are thought to buffer the biologic and potentially deleterious effects of tumor necrosis factor alpha in pathologic conditions., Study Design: The in vivo concentrations of tumor necrosis factor alpha and its soluble receptors were studied in patients in term labor and preterm labor. Amniotic fluid was retrieved from 175 women and tumor necrosis factor alpha, tumor necrosis factor receptor 1, and tumor necrosis factor receptor 2 concentrations were measured by highly sensitive immunoassays. Patients were classified in the following groups: (1) term labor (n = 29), (2) term not in labor (n = 29), (3) preterm labor leading to term delivery (n = 34), (4) preterm labor without infection resulting in preterm delivery (n = 34), (5) preterm labor with intra-amniotic infection (n = 23), and (6) second trimester (n = 26)., Results: Tumor necrosis factor alpha and tumor necrosis factor receptor 1 concentrations decreased with advanced gestational age (r = -0.51 and r = -0.7; P <.01 for each). (1) Patients in spontaneous term labor had a higher median concentration of tumor necrosis factor alpha than those at term not in labor (median, 6.4 pg/mL; range, 2.4->500 pg/mL vs median, 4.1 pg/mL; range, 1.1-22.7 pg/mL; P <.01) but had lower concentrations of tumor necrosis factor receptor 1 (median, 3.2 ng/mL; range, 1.3-9.1 ng/mL vs median, 4.2 ng/mL; range, 1.6-8.3; P <.001) and tumor necrosis factor receptor 2 (median, 5.5 ng/mL; range, 0.73-12.8 ng/mL vs median, 6.8 ng/mL; range, 2.9-12.9 ng/mL; P <.01). (2) In contrast, patients with preterm labor leading to preterm delivery had higher concentrations of tumor necrosis factor alpha (median, 12.3 pg /mL; range, 1.5->500 pg/mL vs median, 4.8 pg/mL; range, 1-60.9 pg/mL; P <.01), tumor necrosis factor receptor 1 (median, 8.8 ng/mL; range, 2.5-38 ng/mL vs median, 6.2 ng/mL; range, 1.4-28 ng/mL; P <.05), and tumor necrosis factor receptor 2 (median, 8.5 ng/mL; range, 3.5-45.4 ng/mL vs median, 6.1 ng/mL; range, 1.99-14.1 ng/mL; P <.01) than patients with preterm labor who delivered at term. (3) Microbial invasion of the amniotic cavity was associated with dramatic increases in the concentrations of tumor necrosis factor alpha (median, 93.5 pg/mL; range, 1.2->500 pg/mL) and its soluble receptors tumor necrosis factor receptor 1 (median, 8.8 ng/mL; range, 2.1-36.7 ng/mL) and tumor necrosis factor receptor 2 (median, 11.8 ng/mL; range, 3.4-46. 3 ng/mL), concentrations that were significantly higher than in those with preterm labor who delivered at term and those who delivered preterm but were not infected., Conclusion: The tumor necrosis factor alpha and tumor necrosis factor alpha soluble receptor profiles are different in term and preterm parturition. Our observations provide support for the thesis that preterm parturition is a pathologic condition. Increased tumor necrosis factor alpha soluble receptor concentrations may attenuate the deleterious effects of the excess of tumor necrosis factor alpha found in pathologic labor.

Objective: The purpose of this study was to test the hypothesis that a systemic fetal inflammatory response is a risk factor for the subsequent development of bronchopulmonary dysplasia in preterm neonates., Study Design: The relationship between interleukin 6 concentrations in umbilical cord plasma at birth and the occurrence of bronchopulmonary dysplasia was examined in 203 preterm births (25-34 weeks). Ninety-six patients underwent transabdominal amniocentesis within 5 days of birth. The relationship between umbilical cord plasma interleukin 6 concentration and bronchopulmonary dysplasia was compared with the relationship between amniotic fluid interleukin 6 concentration and bronchopulmonary dysplasia. Interleukin 6 was measured by specific immunoassay. Logistic regression was used for statistical analysis., Results: Bronchopulmonary dysplasia was diagnosed in 17% (34/203) of the infants. Neonates in whom bronchopulmonary dysplasia developed had a significantly higher median interleukin 6 concentration in umbilical cord plasma at birth than did those in whom bronchopulmonary dysplasia did not develop (median, 68.3 pg/mL and range, 0.3-6150.0 pg/mL vs median, 6.9 pg/mL and range 0-19,230.0 pg/mL; P <.001). This difference remained significant after adjustment for gestational age at birth (odds ratio, 4.2; 95% confidence interval, 1.6-11.2). Logistic regression analysis indicated that an elevated umbilical cord plasma interleukin 6 concentration was a better predictor of the development of bronchopulmonary dysplasia than was an elevated amniotic fluid interleukin 6 concentration (P <.005)., Conclusion: An elevated interleukin 6 concentration in umbilical cord plasma at birth is an independent risk factor for the development of bronchopulmonary dysplasia. These data support the concept that the injury responsible for bronchopulmonary dysplasia in a subset of neonates may begin before birth and is associated with the development of a fetal systemic inflammatory response, as determined by plasma concentrations of interleukin 6.

Objective: RANTES (regulated on activation, normal T cell expressed and secreted), a potent and versatile chemokine, is capable of attracting monocytes, lymphocytes, basophils, and eosinophils. This cytokine has been implicated in the regulation of the inflammatory response and in the recruitment of macrophages to the implantation site in early pregnancy. RANTES messenger ribonucleic acid and protein have been detected in fetal tissue and first-trimester trophoblast in response to bacterial endotoxin. The purpose of this study was to determine whether intrauterine infection, parturition (preterm and term), and gestational age affect the amniotic fluid concentrations of RANTES in human pregnancy., Study Design: A cross-sectional study was designed to examine the relationship between labor, microbial invasion of the amniotic cavity, gestational age, and RANTES expression in amniotic fluid. Amniotic fluid was obtained from 214 women in the following groups: (1) midtrimester (n = 22), (2) preterm labor with intact membranes in the presence (n = 20) or absence (n = 74) of microbial invasion of the amniotic cavity, (3) term, not in labor (n = 44) and term, in labor in the presence (n = 27) and absence (n = 27) of microbial invasion of the amniotic cavity. Microbial invasion of the amniotic cavity was defined as a positive amniotic fluid culture for microorganisms. RANTES concentrations were determined by use of a sensitive and specific immunoassay., Results: (1) Amniotic fluid RANTES concentrations decrease with advancing gestational age (r = 0. 43; P <.01). (2) Labor at term was associated with an increase in median concentrations of RANTES (labor-median, 8.4 pg/mL; range, <1.3-94.4 vs no labor-median, <1.3 pg/mL; range, <1.3-230.3; P <.01). (3) Women with preterm labor who delivered preterm (no microbial invasion of the amniotic cavity) had a higher median concentration of amniotic fluid RANTES than those who delivered at term (median, 12.7 pg/mL; range, <1.3-928 vs median, <1.3 pg/mL; range, <1.3-127. 5; P <.001). (4) Microbial invasion of the amniotic cavity was associated with a significant increase in median amniotic fluid RANTES in both preterm and term labor (preterm labor with microbial invasion of the amniotic cavity-median, 51.6 pg/mL; range, <1.3-2290 vs preterm labor without microbial invasion of the amniotic cavity-median, 12.7 pg/mL; range, <1.3-928 and vs preterm labor with delivery at term-median, <1.3 pg/mL; range, <1.3-127.5; P <.001 for each; term labor with microbial invasion of the amniotic cavity-median, 16.8 pg/mL; range, <1.3-171.4 vs term labor without microbial invasion of the amniotic cavity-median, 8.4 pg/mL; range, <1.3-94.4; P <.05 and vs no labor and no microbial invasion of the amniotic cavity-median, 1.4 pg/mL; range, <1.3-230.3; P <.001 and P <.05, respectively)., Conclusion: These results support a role for RANTES in the mechanisms of human parturition and in the regulation of the host response to intrauterine infection.

Objective: This study was undertaken to examine whether oligohydramnios in women with preterm premature rupture of membranes is associated with evidence of fetal, amniotic, and maternal inflammatory responses., Study Design: Amniotic fluid index was measured before the performance of amniocentesis in patients with preterm premature rupture of membranes. Fifty-nine patients who were delivered of preterm neonates (gestational age 5 cm (positive amniotic fluid culture result, 79% [15/19] vs 30% [12/40]; clinical chorioamnionitis, 37% [7/19] vs 5% [2/40]; histologic chorioamnionitis, 100% [17/17] vs 69% [24/35]; median amniotic fluid interleukin 6 concentration, 13.5 ng/mL; range, 0.2-142.2 ng/mL vs 3.0 ng/mL and 0.001-115.2 ng/mL; median amniotic fluid interleukin 1beta concentration, 348.0 pg/mL; range, 0.7->80, 000 pg/mL vs 36.6 pg/mL and 0-2075 pg/mL; median amniotic fluid tumor necrosis factor alpha concentration, 132.0 pg/mL; range, 0-1600 pg/mL vs 11.2 pg/mL and 0-1305 pg/mL; median cord plasma interleukin 6 concentration, 49.7 pg/mL; range, 4.4-7400 pg/mL vs 9. 1 pg/mL and 0-5211 pg/mL; P <.05 for each). There was no significant difference between the 2 groups of patients in the mean umbilical artery pH at birth., Conclusion: Oligohydramnios in women with preterm premature rupture of membranes is associated with an inflammatory response in the fetal, amniotic, and maternal compartments.

Objective: Spontaneous rupture of the fetal membranes occurs after the commencement of labor in 90% of cases. Recent evidence indicates that the process of parturition requires not only an increase in myometrial contractility and cervical ripening, but also degradation of extracellular matrix in fetal membranes (i.e., leakage of fibronectin into cervico-vaginal secretions). This study was undertaken to determine if parturition is associated with in vivo evidence of increased bioavailability of matrix metalloproteinases-9 (MMP-9) and its inhibitor, tissue inhibitor of metalloproteinases-1(TIMP-1)., Methods: A cross-sectional study was conducted with women in the following categories: 1) midtrimester (n = 25); 2) preterm labor and intact membranes in the absence of intraamniotic infection (n = 78); 3) term not in labor (n = 25); and 4) term with intact membranes in labor (n = 25). MMP-9, and TIMP-1 were measured using sensitive and specific immunoassays., Results: 1) Spontaneous labor at term was associated with a significant increase in MMP-9 but not in TIMP-1.2) Women with preterm labor who delivered prematurely had significantly higher concentrations of MMP-9 but not TIMP-1 in amniotic fluid than those with preterm labor who delivered at term. 3) The concentrations of TIMP-1 decreased with advancing gestational age. In contrast, MMP-9 concentrations did not change with advancing gestational age., Conclusions: Spontaneous human parturition is associated with specific changes in the enzymatic machinery responsible for extracellular matrix degradation.

Six monoclonal antibodies that recognize porcine brain pyridoxal kinase have been selected and designated as PK67, PK86, PK91, PK144, PK252 and PK275. A total of six monoclonal antibodies recognizing different epitopes of the enzyme were obtained, of which four inhibited the enzyme activity. When total proteins of porcine brain homogenate separated by SDS-PAGE were subjected to monoclonal antibodies, a single reactive protein band of molecular weight 39 kDa which comigrated with purified porcine pyridoxal kinase was detected. Using the anti-pyridoxal kinase antibodies as probes, the cross reactivities of brain pyridoxal kinase from human and other mammalian tissues and from avian sources were also investigated. Among human and all animal tissues tested, immunoreactive bands on Western blots appeared to have the same molecular mass of 39 kDa. These results indicate that mammalian brains contain only one major type of immunologically similar pyridoxal kinase, although some properties of the enzymes reported previously differed from one another.

Objective: Ureaplasma urealyticum is the microorganism most frequently isolated from the amniotic fluid of women with preterm labor and preterm premature rupture of the membranes, yet the significance of amniotic fluid infection exclusively caused by this microorganism is unclear. This study was conducted to examine the presence and intensity of the inflammatory response in the fetal, amniotic, and maternal compartments in patients with preterm premature rupture of membranes and amniotic fluid infection with U urealyticum., Study Design: One hundred twenty patients with preterm premature rupture of the membranes who delivered preterm neonates (gestational age 80,000] pg/mL vs 3.4 [0-1449] pg/mL; median and range of amniotic fluid white blood cell count, 306 [0-19,764] cells/mm3 vs 3 [0-7956] cells/mm3; median and range of cord interleukin-6, 20.0 [2. 3-1199.6] pg/mL vs 6.7 [0-5550] pg/mL; histologic chorioamnionitis, 100% [22/22] vs 42% [30/72]; P <.01 for each) but was similar to values of patients with a positive amniotic fluid culture for other bacteria or mixed microorganisms., Conclusion: Patients with preterm premature rupture of membranes and microbial invasion of the amniotic cavity with U urealyticum are associated with a robust host inflammatory response in the fetal, amniotic, and maternal compartments.

Objective: The role of steroid hormones in the control of human parturition has been a subject of debate. Activation of the fetal hypothalamic-pituitary-adrenal axis leading to an increase in plasma cortisol is followed by the onset of parturition in sheep. In contrast, androgens, specifically, dehydroepiandrosterone sulfate, have been implicated in the control of parturition in nonhuman primates. The purpose of this study was to determine the relationship between human fetal plasma cortisol and dehydroepiandrosterone sulfate and the onset of preterm labor in patients with preterm premature rupture of the membranes., Study Design: Fetal blood sampling was performed in 51 patients with preterm premature rupture of membranes who were not in labor on admission. Amniotic fluid was cultured for aerobic and anaerobic bacteria and mycoplasmas. Corticosteroids had not been administered before fetal blood sampling. Cortisol and dehydroepiandrosterone sulfate were measured with sensitive and specific immunoassays. Analysis was conducted with nonparametric statistics and survival analysis., Results: (1) Patients who went into spontaneous labor and delivered within 7 days of cordocentesis had a significantly higher median level of fetal plasma cortisol but not of dehydroepiandrosterone sulfate than those delivered after 7 days (for fetal plasma cortisol: median 8.35 [4.7 to 12.4] micrograms/dL vs median 4.75 [3.0 to 10.4] micrograms/dL, P <.0001; for fetal plasma dehydroepiandrosterone sulfate: median 154.4 [8.6 to 333.8] micrograms/dL vs median 194.6 [96.7 to 402.5] micrograms/dL, P =.09). (2) The cordocentesis-to-delivery interval was significantly shorter in patients with a fetal plasma cortisol value of >/=7 micrograms/dL (derived by receiver-operating characteristic curve analysis) than in those with fetal cortisol <7 micrograms/dL (median 49 [4 to 1849] hours vs median 325 [11 to 2590] hours, P <.001). (3) Fetal plasma cortisol, but not maternal cortisol, was an independent predictor of the duration of pregnancy after we adjusted for gestational age and the results of amniotic fluid culture (hazards ratio 2.9, P <.05). (4) There was a significant correlation between fetal plasma cortisol and fetal plasma interleukin-6 (r = 0.3, P <.05). (5) A strong relationship was found between the fetal plasma cortisol/dehydroepiandrosterone sulfate ratio and the interval to delivery (P <.005)., Conclusion: An elevation in fetal plasma cortisol but not dehydroepiandrosterone sulfate was followed by the onset of spontaneous preterm labor in patients with preterm premature rupture of the membranes.

Twenty-two placentas were investigated for the presence and patterns of inflammation by extensive examination, and divided into four groups: 1) term vaginal delivery [group I; n=6]; 2) term cesarean section delivery [group II; n=5]; 3) preterm vaginal delivery [group III; n=4], and 4) preterm cesarean section delivery [group IV; n=7]. In group I, all had deciduitis, and choriodeciduitis/ chorionitis was present in two cases (33.3%). In group II, four cases (80%) showed deciduitis and/or choriodeciduitis/chorionitis; three of these had intact membranes. In group III, three cases (75%) showed deciduitis, and two had chorionitis. In group IV, three cases (42.9%) showed no evidence of inflammation, three had deciduitis and one had deciduitis/chorioamnionitis. In all groups, membranitis was more severe, confined to the inner and mid segments in general, and deciduitis, choriodeciduitis/chorionitis and chorioamnionitis tended to overlap. The study newly demonstrates major characteristics of placental inflammation: higher prevalence and severity of inflammation in the inner segments of membrane and at the periphery of the placenta. Taking this histotopography into account, it is desirable to take sections from the placental margin, and the current concept of placental inflammation as a surrogate marker of intrauterine infection should be reevaluated.

Objective: The objective of this study was to determine the frequency and clinical significance of a systemic inflammatory response as defined by an elevated plasma interleukin-6 concentration in fetuses with preterm labor or preterm premature rupture of membranes., Study Design: Amniocenteses and cordocenteses were performed in 157 patients with preterm labor and preterm premature rupture of membranes. Written informed consent and multi-institutional review board approvals were obtained. Amniotic fluid was cultured for aerobic and anaerobic bacteria, as well as mycoplasmas. Amniotic fluid and fetal plasma interleukin-6 concentrations were measured with a sensitive and specific immunoassay. Statistical analyses included contingency tables, receiver operating characteristic curve analysis, and multiple logistic regression., Results: One hundred five patients with preterm labor and 52 patients with preterm premature rupture of membranes were included in this study. The overall prevalence of severe neonatal morbidity (defined as the presence of respiratory distress syndrome, suspected or proved neonatal sepsis, pneumonia, bronchopulmonary dysplasia. intraventricular hemorrhage, periventricular leukomalacia, or necrotizing enterocolitis) among survivors was 34.8% (54/155). Neonates in whom severe neonatal morbidity developed had higher concentrations of fetal plasma interleukin-6 than fetuses without development of severe neonatal morbidity (median 14.0 pg/mL, range 0.5 to 900 vs median 5.2 pg/mL, range 0.3 to 900, respectively; P < .005). Multivariate analysis was performed to explore the relationship between the presence of a systemic fetal inflammatory response and subsequent neonatal outcome. To preserve a meaningful temporal relationship between the results of fetal plasma interleukin-6 concentrations and the occurrence of severe neonatal morbidity, the analysis was restricted to 73 fetuses delivered within 7 days of cordocentesis who survived. The prevalence of severe neonatal morbidity in this subset of patients was 53.4% (39/73). A fetal plasma interleukin-6 cutoff value of 11 pg/mL was used to define the presence of a systemic inflammatory response. The prevalence of a fetal plasma interleukin-6 level > 11 pg/mL was 49.3% (36/73). Fetuses with fetal plasma interleukin-6 concentrations > 11 pg/mL had a higher rate of severe neonatal morbidity than did those with fetal plasma interleukin-6 levels < or = 11 pg/mL (77.8% [28/36] vs 29.7% [11/37], respectively; P < .001). Stepwise logistic regression analysis demonstrated that the fetal plasma interleukin-6 concentration was an independent predictor of the occurrence of severe neonatal morbidity (odds ratio 4.3, 95% confidence interval 1 to 18.5) when adjusted for gestational age at delivery, the cause of preterm delivery (preterm labor or preterm premature rupture of membranes), clinical chorioamnionitis, the cordocentesis-to-delivery interval, amniotic fluid culture, and amniotic fluid interleukin-6 results., Conclusion: A systemic fetal inflammatory response, as determined by an elevated fetal plasma interleukin-6 value, is an independent risk factor for the occurrence of severe neonatal morbidity.

Objective: To determine the relationship between the presence of Ureaplasma urealyticum in the amniotic cavity and adverse maternal and perinatal outcome in women with preterm labor., Methods: Amniocentesis was performed in 181 patients with preterm labor and intact membranes. Amniotic fluid (AF) was cultured for aerobic and anaerobic bacteria and mycoplasmas. Patients were divided into three groups according to the results of AF culture: those with negative AF cultures (n=160), those with positive AF cultures and in whom the only microbial isolate was U urealyticum (n=11), and those with positive cultures for non-ureaplasmas or mixed microorganisms (n=10). Survival techniques were used for analysis., Results: The prevalence of positive AF cultures in which the only microbial isolate was Uurealyticum was 6.1% (11 of 181), and of positive cultures with non-ureaplasmas or mixed microorganisms was 5.5% (10 of 181). The amniocentesis-to-delivery interval was significantly shorter in patients with positive cultures limited to U urealyticum than in those with negative cultures (median 7 [range 0.1-149] hours versus median 264 [0.1-2659] hours, P < .001). Preterm delivery within 48 hours, 72 hours, and 7 days was more frequent in patients with U urealyticum in the AF than in those with sterile AF (48 hour: 91% versus 33%; 72 hour: 91% versus 36%; 7 days: 100% versus 45%, P < .001 for each). Patients with positive AF cultures limited to U urealyticum had a significantly higher rate of adverse perinatal outcome than those with negative culture. Adverse outcomes included low gestational age at birth, low birth weight, histologic chorioamnionitis, significant neonatal morbidity, and perinatal death., Conclusion: Microbial invasion of the amniotic cavity with U urealyticum is a risk factor for impending preterm delivery and adverse perinatal outcome.

Objective: There is no evidence for the participation of the human fetus in the mechanisms responsible for the onset of preterm labor. We propose that preterm labor in the setting of infection results from the actions of proinflammatory cytokines secreted as part of the fetal and/or maternal host response to microbial invasion. The objective of this study was to determine whether a systemic fetal inflammatory response, defined as an elevation of fetal plasma interleukin-6 concentrations, has a temporal relationship with the commencement of labor., Study Design: After informed consent was obtained, amniocentesis and cordocentesis were performed in 41 patients with preterm premature rupture of membranes who were not in labor on admission. Amniotic fluid was cultured for both aerobic and anaerobic bacteria, as well as for mycoplasmas. Fetal plasma interleukin-6 was assayed by a sensitive and specific immunoassay. Statistical analyses included contingency tables and survival analysis with time-dependent Cox regression hazard modeling., Results: Microbial invasion of the amniotic cavity was present in 58.5% (24/41) of patients. Fetuses with fetal plasma interleukin-6 concentrations > 11 pg/mL had a higher rate of spontaneous preterm delivery within 48 and 72 hours of the procedure than those with fetal plasma interleukin-6 levels < or = 11 pg/mL (88% vs 29% and 88% vs 35%, respectively; P < .05 for all comparisons). Moreover, patients with initiation of labor and delivery within 48 hours of the procedure had a higher proportion of fetuses with plasma interleukin-6 values > 11 pg/mL than patients delivered > 48 hours (58% [7/12] vs 8% [1/13], respectively; P < .05). Survival analysis indicated that fetuses with elevated fetal plasma interleukin-6 levels had a shorter cordocentesis-to-delivery interval than those without elevated fetal plasma interleukin-6 concentrations (median 0.8 days [range 0.1 to 5] vs median 6 days [range 0.2 to 33.6], respectively; P < .05). Time-dependent Cox regression hazard modeling indicated that fetal plasma interleukin-6 level was the only covariate significantly associated with the duration of pregnancy after we adjusted for gestational age, amniotic fluid interleukin-6 level, and the microbiologic state of the amniotic cavity (P < .01)., Conclusion: A systemic fetal proinflammatory cytokine response is followed by the onset of spontaneous preterm parturition in patients with preterm premature rupture of membranes.

Objective: To determine if an intrauterine sub-clinical inflammatory process is a risk factor for the development of bronchopulmonary dysplasia., Methods: A cohort study was conducted in patients who met the following criteria: (1) Singleton gestation; (2) preterm labor or preterm premature rupture of the membranes; (3) amniocentesis for microbiologic studies of the amniotic fluid and (4) delivery between 24 and 28 weeks of gestation. Bronchopulmonary dysplasia was defined as the need for supplemental oxygen for 28 days or longer after birth, associated with compatible chest radiographic findings. Amniotic fluid interleukin-8, was measured using a specific immunoassay. Logistic regression analysis and bootstrap procedure were used for statistical purposes., Results: Forty-seven patients met the inclusion criteria for this study. Among these patients, the prevalence of bronchopulmonary dysplasia was 23.4% (11/47). Amniotic fluid culture was positive in 21 out of 47 (44.7%) patients. Median (range) amniotic fluid interleukin-8 concentration was higher in patients whose neonates subsequently developed bronchopulmonary dysplasia than in those who did not (17 [9.8-583.7] ng ml(-1) versus 9.6 [0.91-744] ng ml(-1), P=0.057). An amniotic fluid IL-8 level greater than 11.5 ng ml(-1) was far more common in mothers whose fetuses went on to develop bronchopulmonary dysplasia than in those who did not (10/11 [90.9%] versus 17/36 [47%]; P=0.01). This relationship remained significant even after correcting for the effect of gestational age and birthweight (Odds ratio: 11.9; P<0.05)., Conclusion: Sub-clinical intrauterine inflammation is a risk factor for the subsequent development of bronchopulmonary dysplasia. We propose that in utero aspiration of fluid with high concentration of pro-inflammatory mediators may contribute to the lung injury responsible for the development of bronchopulmonary dysplasia.

Objective: Periventricular leukomalacia, a common brain white matter lesion in preterm neonates, is a major risk factor for cerebral palsy. Epidemiologic studies have demonstrated an association between infection and periventricular leukomalacia. The purpose of this study was to determine whether ascending intrauterine infection could cause brain white matter lesions in the fetal rabbit., Study Design: Rabbits with timed pregnancies underwent hysteroscopy at 20 to 21 days of gestation (70%). Animals were allocated in a ratio of 2:1 for inoculation with either Escherichia coli (0.2 ml containing 10(3) to 10(4) colony-forming units) or sterile saline solution. Both groups were treated with ampicillin-sulbactam (Unasyn, 100 mg/kg per day; Pfizer, Seoul) every 8 hours until they were killed 5 to 6 days after hysteroscopy. Histologic examination of the placentas and fetal brains was conducted., Results: Forty-five animals underwent hysteroscopy; 31 were inoculated with E. coli and 14 with sterile saline solution. At the time the animals were killed, the rate of intrauterine infection was higher and there were fewer live fetuses in the E. coli-inoculated animals than in the saline solution group. Histologic evidence of brain white matter damage was identified in 12 fetuses born to 10 E. coli-inoculated rabbits but none in the saline solution group (p < 0.05). All rabbits with brain white matter lesions had evidence of intrauterine infection. Evidence of white matter damage included increased karyorrhexis, rarefaction, and disorganization of white matter. Apoptosis was demonstrated in areas of white matter damage by immunohistochemical studies., Conclusion: Experimental ascending intrauterine infection can cause fetal brain white matter lesions.

Objective: Our purpose was to test the hypothesis that neonates who develop bronchopulmonary dysplasia have higher amniotic fluid concentrations of proinflammatory cytokines than those who do not develop bronchopulmonary dysplasia., Study Design: The relationship between amniotic fluid concentrations of interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 and the occurrence of bronchopulmonary dysplasia in the neonate was examined in 69 patients who were delivered of preterm neonates (< or = 33 weeks) within 5 days of amniocentesis. Cytokines were measured by specific immunoassays., Results: Bronchopulmonary dysplasia was diagnosed in 19% (13/69) of newborns. Median amniotic fluid concentrations of interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 concentrations were significantly higher in mothers whose infants had bronchopulmonary dysplasia than in mothers whose infants did not have bronchopulmonary dysplasia (p < 0.05 for each). Neonates who had bronchopulmonary dysplasia were delivered at earlier gestational ages and had lower birth weights than those without bronchopulmonary dysplasia. The differences in median amniotic fluid interleukin-6, interleukin-1 beta, and interleukin-8 between these two groups remained significant after we adjusted for the effect of gestational age at birth (p < 0.05 for each)., Conclusions: (1) Antenatal exposure to proinflammatory cytokines is a risk factor for the development of bronchopulmonary dysplasia; (2) the injury responsible for bronchopulmonary dysplasia in a subset of neonates may begin before birth.

Objective: Periventricular leukomalacia, a common neonatal brain white matter lesion, is a major risk factor for cerebral palsy. Subclinical chorioamnionitis is a risk factor for the development of periventricular leukomalacia, and inflammatory cytokines have been implicated as central mediators of brain injury in this disorder. To elucidate the relationship between the local expression of cytokines and periventricular leukomalacia, we studied neonatal brains to determine whether high expression of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 was observed in these lesions., Study Design: Immunohistochemical staining for cytokines (tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6) was performed in 10% formalin-fixed, paraffin-embedded brain sections of 17 cases with periventricular leukomalacia. Specimens were obtained from autopsies performed between 1987 and 1994. Brain sections from 17 cases of neonatal deaths without periventricular leukomalacia lesions matched for gestational age at birth, duration of postnatal survival, and presence or absence of infection-related morbidity were used as controls., Results: The expression of tumor necrosis factor-alpha, interleukin-1 beta, or interleukin-6 was demonstrated in 88% (15/17) of cases with and in 18% (3/17) of cases without periventricular leukomalacia (p < 0.001). Cytokines were expressed mainly in hypertrophic astrocytes and microglial cells. The expression of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 was identified in 82% (14/17), 29% (5/17), and 71% (12/17) of cases of periventricular leukomalacia, respectively. However, a significantly lower proportion of cases without periventricular leukomalacia expressed tumor necrosis factor-alpha (18%, 3/17) and interleukin-6 (6%, 1/17) than those with the disorder (p < 0.005 for each)., Conclusions: Expression of tumor necrosis factor-alpha and interleukin-6 was observed more frequently in brain lesions with periventricular leukomalacia than in those without periventricular leukomalacia. These findings provide strong support for the hypothesis that proinflammatory cytokines play a role in the genesis of periventricular leukomalacia.

Objective: Ultrasonographically detectable neonatal brain white matter lesions are the most important identifiable risk factor for cerebral palsy. Inflammatory cytokines released during the course of intrauterine infections have been implicated in the genesis of brain white matter lesions and subsequent cerebral palsy. This study was undertaken to determine whether fetuses who subsequently were diagnosed to have periventricular brain white matter lesions could be identified by determining the concentrations of inflammatory cytokines in the amniotic fluid., Study Design: Women with complicated preterm gestations underwent amniocentesis for clinical indications. Amniotic fluid concentrations of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and the natural interleukin-1 receptor antagonist were determined by immunoassay. Periventricular white matter lesions of the neonate were diagnosed by neurosonography. Univariate and multivariate analyses were conducted., Results: Ninety-four women and their neonates were included in the study; white matter lesions were diagnosed in 24% (23/94) of the newborns. The mothers of newborns with brain white matter lesions had higher median concentrations of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 (but not interleukin-1 receptor antagonist) in amniotic fluid than did those who were delivered of newborns without white matter lesions (p < 0.01 for each). Acute histologic chorioaminionitis was more common in the placentas of neonate with white matter lesions than in those without these lesions (82% [18/22] vs 42% [30/71], p < 0.005). Neonates with white matter lesions were delivered at a lower mean gestational age and birth weight and had a higher rate of significant complications (including respiratory distress syndrome, intraventricular hemorrhage, and infection-related complications) than did those without white matter lesions. The differences in median interleukin-1beta and interleukin-6 levels between these two groups remained significant after adjustment for gestational age and birth weight (interleukin-6: odds ratio 5.7, 95% confidence interval 1.3 to 24.4; interleukin-1beta: odds ratio 4.4, 95% confidence interval 1.1 to 17.0). Of the 94 newborns included in this study, 11 died before age 6 months and eight had cerebral palsy; all eight had white matter lesions and elevated cytokine levels in amniotic fluid. Histologic chorioamnionitis was more common in the placentas of neonates with cerebral palsy than in those without cerebral palsy (86% [6/7] vs 44% [33/75], p < 0.05)., Conclusions: Infants at risk for development of brain white matter lesions can be identified by the concentrations of interleukin-6 and interleukin-1beta in amniotic fluid. Our findings support the hypothesis that inflammatory cytokines released during the course of intrauterine infection play a role in the genesis of brain white matter lesions.

Objective: To determine whether the administration of anticytokine agents, the interleukin-1 receptor antagonist (IL-1ra) and a soluble tumor necrosis factor receptor Fc fusion protein (sTNFR-Fc), prevents endotoxin-induced preterm delivery in mice., Methods: C3H/HeN pregnant mice at 15 days of gestation (70% gestation) were randomized to receive phosphate-buffered saline (PBS) or lipopolysaccharide (LPS) (50 micrograms/mouse) intraperitoneally (i.p.). Randomly selected PBS- or LPS-treated mice were additionally treated intravenously (i.v.), i.p., or subcutaneously (s.c.) every 3 hours with IL-1ra (1-50 mg) or every 12 hours with sTNFR-Fc (200-400 micrograms) beginning 1 hour before LPS injection. Animals were observed for vaginal bleeding and preterm delivery., Results: Mice treated i.p. with 50 micrograms LPS (n = 13) had a shorter injection-to-delivery interval than mice treated similarly with PBS (n = 19) (median 13.5 hours, range 10-105 versus median 86.8 hours, range 53-120, respectively; P < .001). Saline-treated mice given 10 mg IL-1ra every 3 hours i.p. (n = 3) or 200 micrograms sTNFR-Fc every 12 hours i.v. (n = 4) had similar injection-to-delivery intervals as PBS-treated control mice (median 70 hours, range 70-76 versus median 58 hours, range 50-120, respectively). Similarly, LPS-treated mice given PBS every 3 hours (n = 20) had injection-to-delivery intervals comparable to LPS-treated mice (n = 13) (median 15.5 hours, range 9.8-92 versus median 13.5 hours, range 10-105, respectively). Lipopolysaccharide-treated mice given i.p. injections of 1 (n = 4), 10 (n = 31), or 50 (n = 15) mg of IL-1ra every 3 hours did not have longer injection-to-delivery intervals compared with LPS-treated mice (n = 13) (medians 11.6, 15, 14.5 and 13.5 hours; ranges 10.8-12, 8-95, 11-92, and 10-105, respectively). Lipopolysaccharide-treated mice given i.v. injections of 200 (n = 4) or 400 (n = 9) micrograms sTNFR-Fc every 12 hours did not have longer injection-to-delivery intervals compared with LPS-treated mice (n = 8) (medians 23.3, 22.5, and 21.9 hours; ranges 14.8-33, 15-95.5, and 15.5-44, respectively). The median injection-to-delivery interval of LPS-treated mice given both IL-1ra (10 mg) every 3 hours i.p. and sTNFR-Fc (200 micrograms) every 12 hours i.v. (n = 5) was not different from that of LPS-treated mice (median 26 hours, range 24.5-72 versus median 13.5 hours, range 10-105, respectively; P > .05)., Conclusion: The anticytokine agents IL-1ra and sTNFR-Fc did not prevent preterm delivery or prolong pregnancy in endotoxin-induced preterm labor in mice.

Objective: To compare the diagnostic performance of maternal blood C-reactive protein, white blood cell count (WBC), and amniotic fluid (AF) WBC in the identification of positive AF culture, histologic and clinical chorioamnionitis, and neonatal morbidity in women with preterm premature rupture of membranes (PROM)., Methods: Maternal blood was collected for the determination of C-reactive protein and WBC at the time of amniocentesis from 90 women with preterm PROM. Amniotic fluid was cultured for aerobic and anaerobic bacteria as well as mycoplasmas. Amniotic fluid WBC was determined for research purposes. Receiver operating characteristic curve and logistic regression were used for statistical analysis., Results: The prevalence of positive AF culture was 28% (25 of 90). Women with positive AF culture and clinical chorioamnionitis had significantly higher median C-reactive protein, WBC, and AF WBC than did women without these conditions (P < .05), whereas women with histologic chorioamnionitis and significant neonatal morbidity had higher median C-reactive protein and AF WBC, but not WBC, than those without the conditions (P < .05). An AF WBC of at least 20 cells per mm3 had a greater sensitivity than C-reactive protein (cutoff, 0.7 mg/dL) and WBC (cutoff, 13,000 cells per mm3) in the detection of positive AF culture and histologic chorioamnionitis. Logistic regression analysis indicated that among AF WBC, C-reactive protein, and WBC, AF WBC was the best predictor of positive AF culture (odds ratio [OR] 24.2, 95% confidence interval [CI] 6.0, 97.5, P < .001), histologic (OR 74.0, 95% CI 7.4, 736.3, P < .001) and clinical chorioamnionitis (OR 8.9, 95% CI 0.9, 85.6, P = .057), and neonatal morbidity (OR 4.3, 95% CI 1.1, 16.6, P < .05)., Conclusion: Amniotic fluid WBC performs better than C-reactive protein and maternal blood WBC in the diagnosis of positive AF culture, histologic and clinical chorioamnionitis, and neonatal morbidity in women with preterm PROM.

Objective: Periventricular leukomalacia, a common brain white matter lesion in preterm neonates, is a major risk factor for cerebral palsy. Recently, cytokines (i.e., tumor necrosis factor and interleukin-1(beta)) have been implicated as mediators for the development of periventricular leukomalacia. The purpose of this study was to examine the relationship between umbilical cord plasma levels of tumor necrosis factor-alpha, interleukin-1(beta), interleukin-6, and interleukin-1 receptor antagonist and the occurrence of periventricular leukomalacia in preterm neonates., Study Design: Umbilical cord blood was collected from 172 consecutive preterm births (25 to 36 weeks). Periventricular leukomalacia-associated lesions were diagnosed by brain ultrasonography within the first 3 days of life. Tumor necrosis factor-alpha, interleukin-1(beta) interleukin-6, and interleukin-1 receptor antagonist were measured by sensitive and specific enzyme-linked immunoassay methods. Umbilical cord arterial pH was measured at birth. Statistical analysis was performed with multiple logistic regression and receiver operating characteristic curve analysis., Results: Periventricular leukomalacia-associated lesions were present in 14.5% (25/172) of infants. Plasma concentrations of interleukin-6 but not of tumor necrosis factor-alpha, interleukin-1(beta), and interleukin-1 receptor antagonist were significantly higher in neonates with periventricular leukomalacia-associated lesions than in those without these lesions (median 718, range < 226 to 32,000 pg/ml vs median < 226, range < 226 to 43,670 pg/ml; p < 0.0001). An interleukin-6 value > or = 400 pg/ml had a sensitivity of 72% (18/25) and a specificity of 74% (108/147) in the identification of periventricular leukomalacia-associated lesions. Multivariate analysis showed that umbilical cord interleukin-6 was an independent risk factor for periventricular leukomalacia (odds ratio 6.2, p < 0.002) after correction for known confounding variables (i.e., gestational age at birth, umbilical artery pH, chorioamnionitis)., Conclusions: Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with periventricular leukomalacia-associated lesions. Our data support the hypothesis that periventricular leukomalacia may be the result of cytokine-mediated brain injury.

Objective: To compare the diagnostic and prognostic performance of maternal blood C-reactive protein, white blood cell count (WBC), and temperature with that of amniotic fluid (AF) WBC in preterm labor., Methods: One hundred two women with preterm labor and intact membranes were studied. Maternal blood was collected to measure C-reactive protein concentration and WBC, and maternal temperature was also measured. Amniotic fluid obtained by amniocentesis was cultured and WBC determined. Receiver operating characteristic curve, logistic regression, and survival techniques were used for analysis., Results: Patients with acute histologic chorioamnionitis had significantly higher median C-reactive protein concentration, WBC, temperature, and AF WBC than patients without this lesion (P < .05). Receiver operating characteristic curve and survival analysis demonstrated that an elevated C-reactive protein, WBC, or AF WBC was strongly associated with the likelihood of histologic chorioamnionitis, shorter interval to delivery, clinical chorioamnionitis, and neonatal morbidity (P < .05 for each). Of all the tests, AF WBC was the best independent predictor of a positive AF culture (odds ratio [OR] 16.8), interval to delivery (hazard ratio 5.7), clinical chorioamnionitis (OR 15.2), neonatal sepsis (OR 16.8), and significant neonatal complications (OR 7.4), after other confounding variables were adjusted (P < .05 for each)., Conclusion: An elevated C-reactive protein, WBC, or AF WBC identified patients with intrauterine infection and adverse perinatal outcomes. Amniotic fluid WBC was a better independent predictor of these outcomes than C-reactive protein, WBC, or temperature.

A total of 39 placentas, whose gestational ages ranged from 8 to 41 weeks, were analyzed for bcl-2 expression using immunohistochemistry and immunoblotting. Immunohistochemically, both intracytoplasmic and nuclear expression of bcl-2 was observed in villous and extravillous trophoblasts, villous mesenchymal cells and capillary endothelial cells, villous macrophages, intermediate trophoblasts, amnionic epithelium, and even in decidua and endometrial glandular epithelium in early gestational periods. The degree of expression significantly decreased in the placentas after the gestational period of 32 weeks which coincides with the declining phase of placental increase. On immunoblotting lysates of 10(4) cells from single cell suspensions of fresh placentas, bcl-2 was detected in the placentas of 22 and 33 gestational weeks, but it was negligible or absent in three term placentas. The results of the present study suggest two possible implications on the role of bcl-2 in placenta: 1) it may be a type of proliferation or maturation-related marker, especially of trophoblasts, which show decreased expression along with terminal differentiation and maturation, and 2) because the primary role of bcl-2 is the inhibition of programmed cell death (PCD), the decrease in placental bcl-2 around term may be a parturition-associated biological change.

Objective: Our purpose was to determine whether amniotic fluid concentrations of interleukin-6 are of value in the antenatal diagnosis of acute inflammatory lesions (histologic chorioamnionitis) of preterm placenta and in the prediction of perinatal morbidity and mortality., Study Design: The relation among placental histologic findings, perinatal outcome, and amniotic fluid interleukin-6 concentrations was examined in 50 consecutive patients who delivered preterm neonates within 72 hours after amniocentesis. Interleukin-6 was determined by enzyme-linked immunosorbent assays. Receiver-operator characteristic curve was used for analysis., Results: Patients with acute histologic chorioamnionitis had significantly higher median amniotic fluid interleukin-6 concentrations than patients without histologic chorioamnionitis (median 70.8 ng/ml, range 0.7 to 499.2 ng/ml vs median 2.9 ng/ml, range 0.8 to 16.0 ng/ml, respectively; p < 0.00001). An amniotic fluid interleukin-6 concentration > 17 ng/ml had a sensitivity of 79% (23/29) and a specificity of 100% (21/21) in the diagnosis of acute histologic chorioamnionitis and a sensitivity of 69% (18/26) and a specificity of 79% (19/24) in the prediction of significant neonatal morbidity (defined as neonatal sepsis, respiratory distress syndrome, pneumonia, intraventricular hemorrhage, bronchopulmonary dysplasia, or necrotizing enterocolitis) and mortality. These sensitivities were significantly higher than those of amniotic fluid culture (79% vs 38%, p < 0.005; 69% vs 27%, p < 0.01, respectively)., Conclusions: Amniotic fluid interleukin-6 is a sensitive test for the prospective diagnosis of acute histologic chorioamnionitis and the identification of neonates at risk for significant morbidity and mortality.

Objective: An abnormal umbilical artery Doppler waveform is a risk factor for adverse perinatal outcome. However, it has not been established whether this is related to the earlier gestational age at delivery of fetuses with abnormal Doppler findings or whether Doppler findings are an independent predictor of perinatal outcome. Our purpose was to determine whether an abnormal Doppler umbilical artery waveform is associated with adverse perinatal outcome even after the gestational age at delivery is controlled for as a confounding variable in patients with preeclampsia., Study Design: Umbilical artery velocimetry studies were performed within 7 days of delivery in 72 consecutive patients admitted to our unit with preeclampsia. Adverse perinatal outcome was defined as fetal distress requiring cesarean delivery. Apgar score < 7 at 5 minutes, significant neonatal morbidity, or perinatal death. Significant neonatal morbidity was defined as neonatal sepsis, intraventricular hemorrhage (grade > or = 2), respiratory distress syndrome, pneumonia, bronchopulmonary dysplasia, acute renal failure, or necrotizing enterocolitis. Stepwise multiple logistic regression and receiver-operator characteristic curve analysis were used., Results: Patients with abnormal umbilical artery velocimetry had a significantly higher rate of complications, including cesarean section for fetal distress, preterm delivery, low Apgar scores, significant neonatal morbidity, and perinatal death, than did patients with a normal waveform. Receiver-operator characteristic curve and stepwise logistic regression analysis indicated that an abnormal umbilical artery waveform was a significant independent predictor for the development of adverse perinatal outcome (odds ratio 14.2, p < 0.005) after other confounding variables were adjusted., Conclusion: An abnormal Doppler umbilical artery waveform is a strong and independent predictor of adverse perinatal outcome in patients with preeclampsia.

Problem: This study was conducted to determine whether: (1) gestational age, parturition, and microbial invasion of the amniotic cavity (MIAC) are associated with changes in amniotic fluid concentrations of immunoreactive macrophage inflammatory protein-1 alpha; (2) amniotic fluid concentrations of macrophage inflammatory protein-1 alpha are correlated with the white blood cell count and the concentrations of interleukin-8 in amniotic fluid., Method: Amniotic fluid was retrieved by amniocentesis from 126 patients; 54 women with preterm labor and intact membranes (no MIAC-delivery at term, N = 21; no MIAC-preterm delivery, N = 16; MIAC-preterm delivery, N = 17); 62 patients at term (no labor, N = 19; labor-no MIAC, N = 20; labor-MIAC, N = 23); and 10 patients in the midtrimester of pregnancy. Amniotic fluid was cultured for aerobic, anaerobic and Mycoplasma species. Determinations of amniotic fluid macrophage inflammatory protein-1 alpha and interleukin-8 were performed with immunoassays validated for amniotic fluid (sensitivity: 14.2 pg/ml and 0.3 ng/ml, respectively). Kruskal-Wallis analysis of variance (ANOVA) for censored data, Mann-Whitney U test and Spearman's rank correlation were performed for analysis., Results: 1) Amniotic fluid macrophage inflammatory protein-1 alpha was present in only 31.0% (9/29) of patients not in labor (midtrimester and term). 2) Patients with preterm labor and MIAC had higher amniotic fluid concentrations of macrophage inflammatory protein-1 alpha than those without MIAC (no MIAC-delivery at term: median 0.0 pg/ml, range 0.0-221.2; no MIAC-preterm delivery: median 37.4 pg/ml, range 0.0-494.6; MIAC-preterm delivery: median 7171.0 pg/ml, range 402.5-37994.0; P < 0.00001). 3) Among patients at term, MIAC was associated with higher concentrations of amniotic fluid macrophage inflammatory protein-1 alpha than patients without MIAC (no labor: median 0.0 pg/ml, range 0.0-25.6; labor-no MIAC: median 16.7 pg/ml, range 0.0-161.6; labor-MIAC: median 103.8 pg/ml, range 0.0-4349.0, P < 0.001). 4) Among patients in preterm labor, a strong correlation was found between amniotic fluid concentrations of macrophage inflammatory protein-1 alpha and interleukin-8 (r = 0.9, P < 0.00001) and between amniotic fluid macrophage inflammatory protein-1 alpha concentrations and amniotic fluid white blood cell count (r = 0.6, P < 0.0001)., Conclusions: (1) Macrophage inflammatory protein-1 alpha is undetectable in most amniotic fluid samples from patients in the midtrimester of pregnancy and at term not in labor. (2) Microbial invasion of the amniotic cavity is associated with increased concentrations of immunoreactive amniotic fluid macrophage inflammatory protein-1 alpha in both term and preterm gestations. (3) Amniotic fluid macrophage inflammatory protein-1 alpha concentrations significantly correlate with interleukin-8 levels and white blood cell count in amniotic fluid. Our data strongly suggest a role for macrophage inflammatory protein-1 alpha in the mechanisms responsible for the recruitment of leukocytes into the amniotic cavity during the course of intrauterine infection.

Background: Although several investigators have attempted to define the normal values of umbilical cord blood pH and gases, there is considerable controversy about the optimal cutoff values to diagnosis intrauterine asphyxia. A possible reason for this might be that several studies have included data from fetuses born after different duration of labor., Objective: To determine the effect of labor and the duration of second stage on labor on umbilical arterial acid-base status at birth in healthy term infants., Methods: Umbilical artery acid-base status was determined in patients (n = 356) who met the following criteria: 1) singleton term pregnancy with no significant medical, obstetric, or neonatal complications; 2) vertex presentation if delivered vaginally; 3) neither regional nor general anesthesia applied if delivered vaginally; 4) no use of oxytocin; 5) normal fetal heart rate patterns; 6) clear amniotic fluid; 7) Apgar scores at 1 and 5 min > or = 7; 8) appropriate fetal weight for gestational age. Patients were divided into three groups. A-patients delivered by cesarean section (CS) in the absence of labor (n = 135); B-patients delivered by CS during first stage of labor (n = 62); C-patients with vaginal birth (n = 159). A Kruskal-Wallis ANOVA with post-hoc procedures and stepwise multiple regression analysis were performed., Results: 1) There were significant differences in cord arterial acid-base values between study groups (pH: no labor CS, 7.27 +/- 0.05 vs labor CS, 7.26 +/- 0.05 vs vaginal birth, 7.24 +/- 0.07, p < 0.00001). 2) There was a significant fall in cord arterial pH and bicarbonate concentrations with increased duration of second stage of labor in newborns born vaginally (pH: duration of second stage, 1-30 min, 7.25 +/- 0.07 vs 31-60 min, 7.22 +/- 0.06 vs > 61 min, 7.21 +/- 0.07, p < 0.05). 3) Analysis of confounding variables which could influence the cord pH such as parity, use of vacuum, gestational age, maternal age, and birth weight by stepwise multiple regression analysis indicated that only the duration of second stage of labor pain had a significant relationship with cord blood pH., Conclusion: There is a significant fall in umbilical artery pH and bicarbonate with the presence of labor and increased duration of second stage of labor in healthy term neonates. This should be taken into consideration in evaluating neonatal well-being by cord blood pH and acid-base measurements.

Our objective was to determine if a reduced volume of amniotic fluid is a risk factor for microbial invasion of the amniotic cavity in women with rupture of membranes at term. Transabdominal amniocentesis under ultrasound guidance was used to evaluate the microbiological state of the amniotic cavity in 53 patients with term premature rupture of membranes before vaginal examination. Amniotic fluid index was measured prior to the procedure in all cases. The prevalence of microbial invasion of the amniotic cavity was 32.1% (17/53). Women with microbial invasion of the amniotic cavity had a significantly lower median amniotic fluid index than did women without evidence of infection (median 4.4 cm, range 1.0-8.1 vs. median 7.8 cm, range 1.3-14.4, respectively; p < 0.001). An amniotic fluid index of < 5 cm had a sensitivity of 71% (12/17) a specificity of 89% (32/36), a positive predictive value of 75% (12/16) and a negative predictive value of 87% (32/37) in the prediction of microbial invasion of the amniotic cavity. Among women who delivered vaginally, those with an amniotic fluid index of < 5 cm had a higher rate of endometritis than those with an amniotic fluid index of >or= 5 cm (19% (3/16) vs. 0% (0/26), respectively; p < 0.05). We conclude that women with term premature rupture of membranes and an amniotic fluid index of < 5 cm are at an increased risk for microbial invasion of the amniotic cavity and puerperal infection after a vaginal delivery., (Copyright 1994 International Society of Ultrasound in Obstetrics and Gynecology)

Objective: Fetal hypoxia-acidosis is part of the terminal pathway leading to intrauterine fetal death. A central premise of antepartum surveillance is that identification and timely delivery of the hypoxic or acidotic fetus will prevent intrauterine death and decrease long-term neurologic damage. The optimal method to identify fetal hypoxia-acidosis has not been determined. We attempted to compare the performance of the biophysical profile score and umbilical artery Doppler velocimetry in the identification of fetal acidemia, hypoxemia, and hypercarbia as determined by pH and gas analysis of fetal blood obtained by cordocentesis., Study Design: Fetal biophysical profile and umbilical artery Doppler velocimetry studies were performed before cordocentesis in 24 patients (26 to 40 weeks). Umbilical vein pH and blood gas values were determined in all cases. The pulsatility index of the umbilical artery was obtained with pulsed Doppler equipment. Receiver-operator characteristic curve analysis and stepwise multiple logistic regression were performed to examine the relationship between biophysical profile score, umbilical artery Doppler velocimetry, and acid-base status., Results: The prevalence of fetal acidemia (pH 2 SD below the mean for gestational age) was 41.7% (10/24). There was a significant relationship between the change in umbilical artery pulsatility index and fetal acidemia (chi 2 = 26.6, p < 0.001) and hypercarbia (chi 2 = 22.9, p < 0.001), but not hypoxemia (chi 2 = 1.0, p > 0.1), and between the biophysical profile score and fetal acidemia (chi 2 = 11.1, p < 0.001) and hypercarbia (chi 2 = 9.0, p < 0.005), but not hypoxemia (chi 2 = 2.3, p > 0.1). Stepwise multiple logistic regression demonstrated that umbilical artery Doppler velocimetry was a better explanatory variable for acidemia and hypercarbia than the biophysical profile score., Conclusion: A strong relationship between the degree of fetal acidemia and hypercarbia and the results of umbilical artery Doppler velocimetry and biophysical profile was found. However, umbilical artery Doppler velocimetry was a better explanatory variable for these outcome than the biophysical profile score.

Objective: Our goal was to compare the value of amniotic fluid tests in the detection of microbial invasion of the amniotic cavity and in the relationship with the amniocentesis-to-delivery interval and neonatal complications in patients with preterm labor and intact membranes., Study Design: Amniotic fluid was retrieved by transabdominal amniocentesis from 120 patients with preterm labor and intact membranes. Fluid was cultured for aerobic and anaerobic bacteria and for mycoplasmas. Amniotic fluid analysis included a Gram stain, white blood cell count, glucose and interleukin-6 determinations. Logistic regression and Cox's proportional hazards model were used for analysis., Results: (1) The prevalence of positive amniotic fluid cultures was 9.2% (11/120); (2) patients with microbial invasion had a shorter amniocentesis-to-delivery interval and a higher neonatal complications rate than patients with a negative culture; (3) the most sensitive test for the detection of microbial invasion of the amniotic cavity was amniotic fluid interleukin-6 determinations (cutoff 11.3 ng/ml) (sensitivity; for interleukin-6 100%, for glucose 81.8%, for white blood cell count 63.6%, and for Gram stain 63.6%; p < 0.05 for all comparisons); (4) the most specific test was the Gram stain of amniotic fluid (specificity: for Gram stain 99.1%, for white blood cell count 94.5%, for interleukin-6 82.6%, and for glucose 81.6%; p < 0.01 for all); (5) of all amniotic fluid tests, interleukin-6 determinations were the only ones that had significant relationship with the amniocentesis-to-delivery interval and neonatal complications., Conclusion: Interleukin-6 concentrations in amniotic fluid are better indicators of microbial invasion of the amniotic cavity, amniocentesis-to-delivery interval, and neonatal complications than the amniotic fluid Gram stain, glucose concentration, or white blood cell count.

Objective: Our aim was to compare the value of amniotic fluid tests for the detection of microbial invasion of the amniotic cavity and in the prediction of the amniocentesis-to-delivery interval and neonatal complications in patients with preterm premature rupture of membranes., Study Design: Amniotic fluid was obtained by transabdominal amniocentesis from 110 consecutive patients with preterm premature rupture of membranes. Fluid was cultured for aerobic and anaerobic bacteria, as well as mycoplasmas. Amniotic fluid analysis included a Gram stain examination, white blood cell count, and glucose and interleukin-6 determinations. Logistic regression and survival techniques (proportional hazards model) were used for statistical analysis., Results: (1) The prevalence of positive amniotic fluid cultures in patients with preterm premature rupture of membranes was 38% (42/110); (2) patients with microbial invasion had a shorter amniocentesis-to-delivery interval and a higher neonatal complication rate than patients with negative cultures; (3) the most sensitive test for the detection of microbial invasion of the amniotic cavity was amniotic fluid interleukin-6 determinations (cutoff 7.9 ng/ml) (sensitivity: for IL-6 80.9%; for white blood cell count 57.1%; for glucose 57.1%; for Gram stain 23.8%; p < 0.05 for all comparisons); (4) the most specific test for the detection of microbial invasion was the Gram stain of amniotic fluid (specificity: for Gram stain 98.5%; for white blood cell count 77.9%; for interleukin-6 75%; for glucose 73.5%; p < 0.01 for all); (5) of all amniotic fluid tests, interleukin-6 determination was the only test that had significant clinical value in the prediction of the amniocentesis-to-delivery interval and neonatal complications., Conclusion: Interleukin-6 concentrations in amniotic fluid are a better predictor of microbial invasion of the amniotic cavity, amniocentesis-to-delivery interval and neonatal complications than the amniotic fluid Gram stain, glucose, or white blood cell count in patients with preterm premature rupture of membranes.

Problem: The purpose of this study was to determine if amniotic fluid concentrations of the interleukin-6 (IL-6) are of value in diagnosis of microbial invasion of the amniotic cavity and in the prediction of failure of tocolysis, preterm delivery and perinatal morbidity and mortality., Method: Amniotic fluid was obtained by transabdominal amniocentesis from 146 consecutive patients admitted with the diagnosis of preterm labor and intact membranes. Fluid was cultured for aerobic and anaerobic bacteria as well as for mycoplasmas. Amniotic fluid IL-6 levels were measured using a monoclonal antibody-based enzyme-linked immunosorbent assay with a sensitivity of 0.03 ng/ml. Logistic regression and Cox's proportional hazards model were used to examine the effect of several variables on dichotomous outcomes or interval to delivery., Results: Patients with a positive amniotic fluid culture had a significantly higher amniotic fluid IL-6 concentrations than patients with a negative culture (median 91.2 ng/ml, range 0.9 to 437 ng/ml versus median 0.4 ng/ml, range < 0.3 to 195 ng/ml, respectively; P < .0001). An amniotic fluid IL-6 concentration of greater than or equal to 11.3 ng/ml had a sensitivity of 93.3% (14 of 15) and a specificity of 91.6% (120 of 131). All patients with an amniotic fluid IL-6 concentration above 11.3 ng/ml and a negative amniotic fluid culture (N = 11) delivered preterm and all placenta available for examination (N = 7) had histologic evidence of chorioamnionitis. Amniotic fluid concentrations of IL-6 were an independent predictor of preterm delivery, amniocentesis-to-delivery interval and neonatal morbidity and mortality. Moreover, IL-6 concentrations added significant information to the prediction of these outcomes to that provided only by clinical information such as cervical dilatation, gestational age at admission or at delivery., Conclusion: IL-6 is a sensitive and rapid test for the detection of microbial invasion of the amniotic cavity and for identifying women at risk for spontaneous preterm delivery and neonates at risk for morbidity and mortality.

To determine if abnormal umbilical artery velocimetry is associated with a higher rate of perinatal morbidity in pregnancies in which the outcome is not manifested by a small for gestational age (SGA) fetus, perinatal outcome was compared according to the results of Doppler umbilical artery velocimetry. Doppler study was performed in 328 singleton pregnancies with non-SGA fetuses within 7 days of delivery. The prevalence of abnormal Doppler studies was 10%. Patients with abnormal umbilical artery velocimetry had a significantly higher rate of complications, including cesarean section for fetal distress, preterm delivery, low Apgar scores, congenital anomalies, admission to the neonatal intensive care unit, and perinatal death, than patients with a normal umbilical artery velocimetry. Ten perinatal deaths were associated with major congenital anomalies. Moreover, in the absence of congenital anomalies patients with abnormal Doppler results also had a significantly higher incidence of adverse perinatal outcome compared with patients with normal umbilical artery velocimetry. Our data suggest that even the non-SGA fetus with an abnormal Doppler umbilical artery waveform ratio is at increased risk for poor perinatal outcome.

Persistent fetal bradycardia necessiating emergency cesarean section is uncommon but a serious complication of ultrasound-guided cordocentesis. The cause of this complication, however, is not completely known. Reported here is a case of tetanic uterine contraction after fetal blood sampling via cordocentesis.

In 105 singleton pregnancies in which cesarean section was performed before the onset of labor, the efficacy of Doppler umbilical velocimetry in identifying fetal acidosis was determined and compared with fetal biophysical profile. Doppler velocimetry showed a significant correlation with the umbilical artery pH and was also a sensitive indicator of fetal acidosis, comparable to the biophysical profile score. Patients were classified into four groups. Groups with abnormal Doppler results showed a significantly higher prevalence of fetal acidosis, and all the fetuses with abnormal Doppler results were either in acidosis or in a growth-retarded state. Our data lend further support to the clinical validity of Doppler umbilical velocimetry in identifying fetal acidosis or compromise.

Back pain and paraplegia are uncommon presenting symptoms/signs of aortic aneurysms. Extensive destructive changes were noted in the lower lumbar vertebrae in a 79-year-old man with an aneurysm that had eroded into the spine. The association of back pain with vertebral body erosion requires evaluation for vertebral or paravertebral abscess, neoplasia, and aortic aneurysm. Arteriography is usually required to demonstrate continuity with the vertebral body and to exclude the coincidental association of an aortic aneurysm with another pathology, i.e., neoplasm. Aggressive surgical treatment is recommended for any rapidly expanding aneurysm. The natural history of the untreated lesion is one of rapid demise.

A case of hemobilia from a pancreatic pseudocyst which developed after cholecystostomy and aspiration of the pseudocyst, intended to relieve biliary obstruction, is discussed. These previously reported cases are briefly reviewed.

To delineate differences between scar and non-scar pulmonary carcinoma, the charts, autopsy protocols and chest roentgenograms of 80 male patients (autopsied) between 1975 and 1980, were reviewed. Nineteen patients (24%) had documented scar carcinomas. The comparison revealed scar carcinomas to possess certain distinctive features: A higher histologic distribution of adenocarcinoma (58% versus 15% in non-scars) and the frequent presentation (53%) with only nonpulmonary symptoms and signs related to metastasis. In scar carcinomas both bronchoscopy and sputum cytology were ineffective as initial diagnostic tools since chest findings were absent or minimal. Chest x-ray was negative in 9 of the 19 patients with scar cancer and remained negative until death in seven. In 10 of 19 instances, pulmonary scar carcinomas presented with only nonpulmonary symptoms and showed a tendency to metastasize while clinically undetectable. The differences noted between scar and non-scar carcinomas of the lung appear to depend on the peripheral location of these tumors and not on the adenocarcinoma histology.