Kyo Hoon Park

Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1β, and tumor necrosis factor-α), neonatal brain white matter lesions, and cerebral palsy

Abstract 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-α, interleukin-1β, 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-α, interleukin-1β, 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 p p CONCLUSIONS: Infants at risk for development of brain white matter lesions can be identified by the concentrations of interleukin-6 and interleukin-1β 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.(Am J Obstet Gynecol 1997;177:19-26.)

Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-α, interleukin-1β, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia

Abstract 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-α, interleukin-1β, and interleukin-8 and the occurrence of bronchopulmonary dysplasia in the neonate was examined in 69 patients who were delivered of preterm neonates (≤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-α, interleukin-1β, 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 p 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. (Am J Obstet Gynecol 1997;177:825-30.)

Experimentally-induced intrauterine infection causes fetal brain white matter lesions in rabbits

OBJECTIVEnPeriventricular 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.nnnSTUDY DESIGNnRabbits 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.nnnRESULTSnForty-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.nnnCONCLUSIONnExperimental ascending intrauterine infection can cause fetal brain white matter lesions.

Maternal blood C-reactive protein, white blood cell count, and temperature in preterm labor: A comparison with amniotic fluid white blood cell count**

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.

Association of oligohydramnios in women with preterm premature rupture of membranes with an inflammatory response in fetal, amniotic, and maternal compartments

OBJECTIVEnThis 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.nnnSTUDY DESIGNnAmniotic 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 </=35 weeks) within 3 days of amniocentesis were included in this study. Amniotic fluid was cultured for aerobic and anaerobic bacteria and for genital mycoplasmas. The intensity of the inflammatory response was evaluated by the following: presence of clinical and histologic chorioamnionitis; amniotic fluid concentrations of interleukin 6, interleukin 1beta, and tumor necrosis factor alpha; amniotic fluid white blood cell count; and interleukin 6 concentrations in umbilical cord plasma at birth. Proinflammatory cytokines were measured with specific and sensitive immunoassays.nnnRESULTSnThirty-two percent (19/59) of patients had an amniotic fluid index </=5 cm. Patients with an amniotic fluid index </=5 cm had significantly higher rates of positive amniotic fluid culture results and clinical and histologic chorioamnionitis; higher median amniotic fluid concentrations of interleukin 6, interleukin 1beta, and tumor necrosis factor alpha; and higher median cord plasma concentrations of interleukin 6 than did those with an amniotic fluid index >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.nnnCONCLUSIONnOligohydramnios in women with preterm premature rupture of membranes is associated with an inflammatory response in the fetal, amniotic, and maternal compartments.

Matrix metalloproteinase 3 in parturition, premature rupture of the membranes, and microbial invasion of the amniotic cavity.

Abstract Objective. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are expressed in many inflammatory conditions and contribute to connective tissue breakdown. Stromelysin 1 [matrix metalloproteinase 3 (MMP-3)], a novel member of this family, is produced in the context of infection and is able to activate the latent forms of other MMPs. The purpose of this study was to determine if parturition (either term or preterm), premature rupture of the membranes (PROM), and microbial invasion of the amniotic cavity are associated with changes in amniotic fluid concentrations of MMP-3. Study design. A cross-sectional study was conducted, which included women who underwent transabdominal amniocentesis (n = 365) in the following categories: (1) mid-trimester with a subsequent normal pregnancy outcome (n = 84) and a subsequent fetal loss (n = 10); (2) preterm labor with intact membranes without microbial invasion of the amniotic cavity who delivered at term (n = 36), or prematurely (n = 50), and preterm labor with microbial invasion of the amniotic cavity (n = 25); (3) preterm PROM with (n = 25) and without (n = 26) microbial invasion of the amniotic cavity; (4) term with intact membranes in the absence of microbial invasion of the amniotic cavity, in labor (n = 52) and not in labor (n = 31); and (5) term with PROM in the absence of microbial invasion of the amniotic cavity and not in labor (n = 26). MMP-3 concentrations in amniotic fluid were measured by a sensitive and specific immunoassay that was validated for amniotic fluid. MMP-3 concentrations were normalized using logarithmic transformation for statistical analysis. Parametric statistics were used and a p value <0.05 was considered statistically significant. Results. (1) MMP-3 was detected in 99.5% (363/365) of amniotic fluid samples, and its concentration did not change with advancing gestational age. (2) Spontaneous parturition at term and preterm was associated with a significant increase in amniotic fluid MMP-3 concentrations (p = 0.04 and p = 0.002, respectively). (3) Spontaneous rupture of membranes in term and preterm gestations was not associated with significant changes in amniotic fluid MMP-3 concentrations. (4) Intra-amniotic infection was associated with a significant increase in amniotic fluid MMP-3 concentrations in both women with preterm labor and intact membranes (p = 0.03), and women with preterm PROM (p = 0.02). (5) Subsequent fetal loss after genetic amniocentesis was not associated with significant changes in mid-trimester concentrations of amniotic fluid MMP-3. Conclusions. (1) MMP-3 is a physiologic constituent of amniotic fluid. (2) MMP-3 may play a role in the mechanisms of human parturition and in the regulation of the host response to intrauterine infection.

Noninvasive prediction of intra-amniotic infection and/or inflammation in preterm premature rupture of membranes.

Objective: To develop a model based on noninvasive parameters to predict the probability of intra-amniotic infection and/or inflammation (IAI) in women with preterm premature rupture of membranes (PPROMs). Methods: Maternal blood was collected for determination of the C-reactive protein (CRP) level and white blood cell (WBC) count immediately after amniocentesis in 171 consecutive women with PPROMs. Intra-amniotic infection and/or inflammation was defined as a positive amniotic fluid (AF) culture and/or an elevated AF interleukin 6 level (≥2.6 ng/mL). Results: A risk score based on a model including maternal blood CRP, WBC, parity, and gestational age was calculated for each patient. The model was shown to have an adequate goodness of fit (P = .516), and the area under the receiver–operating characteristic curve was 0.848, indicating very good discrimination. Conclusion: The noninvasive model based on maternal blood CRP, WBC, parity, and gestational age is highly predictive of IAI in women with PPROMs.

Amniotic Fluid Tumor Necrosis Factor-Alpha Is a Marker for the Prediction of Early-Onset Neonatal Sepsis in Preterm Labor

Background: Our purpose was to determine whether amniotic fluid concentrations of tumor necrosis factor-α are of value in the prediction of early-onset neonatal sepsis (proven or suspected) in patients with preterm labor and intact membranes. Methods: The relationship between amniotic fluid tumor necrosis factor-α concentrations and early-onset neonatal sepsis was examined in 59 consecutive patients with preterm labor and intact membranes who delivered preterm neonates within 72 h after transabdominal amniocentesis. Early-onset neonatal sepsis was defined either as the presence of a positive blood culture or as suspected sepsis within 72 h of delivery. Tumor necrosis factor-α was determined by enzyme-linked immunosorbent assays. Results: Patients delivering neonates with early-onset neonatal sepsis had significantly higher median amniotic fluid TNF-α concentrations than patients delivering neonates without early-onset neonatal sepsis (p < 0.0005). An amniotic fluid tumor necrosis factor-α concentration ≧41 pg/ml had a sensitivity of 82% (23/29) and specificity of 79% (38/48) in the prediction of early-onset neonatal sepsis. Multiple logistic regression indicated that elevated amniotic fluid tumor necrosis factor-α (≧41 pg/ml) was the only independent predictor of early-onset neonatal sepsis (odds ratio 12.9, 95% confidence interval 1.3–125.3, p = 0.01) after correction for known confounding variables. Conclusions: (1) Amniotic fluid tumor necrosis factor-α is a marker for the prediction of early-onset neonatal sepsis in patients with preterm labor and intact membranes. (2) Amniotic fluid tumor necrosis factor-α is a better independent predictor of early-onset neonatal sepsis than placental histologic finding or amniotic fluid culture.

Comparative study of induction of labor in nulliparous women with premature rupture of membranes at term compared to those with intact membranes: Duration of labor and mode of delivery

Aim:u2002 To evaluate the effect of premature rupture of membranes (PROM) at term on the duration of labor and mode of delivery in comparison with intact membranes in nulliparous women with an unfavorable cervix whose labor was induced.

Relationship between Twin-to-twin Delivery Interval and Umbilical Artery Acid-base Status in the Second Twin

The purpose of this study was to determine the effect of twin-to-twin delivery interval on umbilical artery acid-base status of the second twin at birth. This was a retrospective cohort study of all live-born twins with measured acid-base status in umbilical arterial blood who were delivered after 34 weeks gestation from June 2003 to February 2006. Twins with any maternal or fetal complications were excluded. Subjects were divided into two groups based on the mode of delivery of the first twin: normal cephalic vaginal deliveries (n=40) or cesarean deliveries (n=67). The inter-twin differences in umbilical arterial blood pH, PCO2, PO2, and base excess in twin newborns born vaginally were significantly greater than the corresponding differences in those born by cesarean section. A significant positive correlation was found between twin-to-twin delivery interval and inter-twin difference in umbilical arterial blood pH in twin newborns born vaginally. The umbilical arterial blood pH of the second twin was less than 7.0 in 14% (2/14) in cases delivered more than 20 min after the first twin. The umbilical arterial blood gas status of the second twin worsened with increasing twin-to-twin delivery interval, and pathologic fetal acidemia (pH < 7.0) might develop in the second twin when the twin-to-twin delivery interval was greater than 20 min.