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PubMed2006

Anti-inflammatory therapy in the neonatal intensive care unit: present and future.

Inflammation has been linked to numerous adverse outcomes in newborns. This paper reviews several major sources of inflammation, methods to reduce exposure, current anti-inflammatory drug therapy and future research directions. The first major source of inflammation--chorioamnionitis--is often present long before delivery; postnatal interventions may not alter outcomes. Reducing the exposure of preterm infants to postnatal inflammatory stimuli such as mechanical ventilation and sepsis may be more effective than anti-inflammatory drug therapy in improving outcomes. If anti-inflammatory drug therapy is considered necessary, the only drug currently proven to decrease extubation failure and bronchopulmonary dsyplasia (BPD) is dexamethasone, which is associated with numerous side effects. Erythromycin treatment of Ureaplasma urealyticum has been ineffective in reducing BPD; are trials of azythromycin planned. Research may improve future outcomes by tailoring glucocorticoid dosage, duration and formulation in targeted populations and by developing agents to inhibit specific pro-inflammatory mechanisms.

Anti-Inflammatory Agents↗

PubMed2006

Inflammatory responses in the placenta and umbilical cord.

Histopathological examination of the placenta is the gold standard for evaluating antenatal inflammatory processes that might influence fetal development. Histological chorioamnionitis develops through a well-characterised stereotyped progression of maternal and fetal cellular stages that vary from patient to patient and are amenable to quantification. Increases in the intensity of these responses and their gradual transformation into a chronic phase are important variables that can adversely affect fetal physiology. Under recognised placental inflammatory lesions affecting the decidua, placental villi and fetal vessels are also potentially informative factors that should be taken into account in the studies of adverse pregnancy outcomes. This review summarises the relationships between aetiology, intensity, duration, characteristics and site of histological placental inflammation and suggests how these data may help to better understand the antenatal environment.

Chorioamnionitis↗

PubMed1992

Infection and labor. VIII. Microbial invasion of the amniotic cavity in patients with suspected cervical incompetence: prevalence and clinical significance.

OBJECTIVE: The purpose of this study was to determine the prevalence and clinical significance of microbial invasion of the amniotic cavity in patients presenting with cervical dilatation in the midtrimester of pregnancy. STUDY DESIGN: Amniocentesis for microbial studies was performed in women admitted with cervical dilatation > or = 2 cm, intact membranes, and without active labor between 14 and 24 weeks of gestation. Amniotic fluid was cultured for aerobic and anaerobic bacteria, as well as for mycoplasmas. Gram stain was performed on all samples. RESULTS: The prevalence of microbial invasion of the amniotic cavity was 51.5% (17/33). The most common microbial isolates were Ureaplasma urealyticum, Gardnerella vaginalis, Candida albicans, and Fusobacterium sp. All patients with microbial invasion of the amniotic cavity had complications. Patients who underwent cervical cerclage in the presence of a positive amniotic fluid culture had rupture of membranes, clinical chorioamnionitis, or pregnancy loss. On the other hand, the prognosis of patients with a negative amniotic fluid culture was better than that of patients with a positive culture. Of 16 patients with a negative amniotic culture, nine were delivered at > 34 weeks. CONCLUSIONS: (1) Microbial invasion of the amniotic cavity occurs frequently in women presenting with cervical dilatation in the midtrimester; (2) the microbiologic state of the amniotic cavity is an important prognostic factor for pregnancy outcome; (3) amniocentesis to determine the microbiologic characteristics of the amniotic cavity should be considered before a cerclage is placed in women presenting with cervical dilatation in the midtrimester.

Abortion, Spontaneous↗

PubMed1985

The association of subclinical infection with preterm labor: the role of C-reactive protein.

The role of subclinical intrauterine infection in preterm labor was evaluated prospectively in 40 patients and appropriate control subjects. The 24 preterm labor patients (60%) with a negative C-reactive protein value responded to tocolysis 95.8% of the time, with a mean delay of delivery of 35.5 days and a mean gestational age of 36.9 weeks. The 16 patients (40%) with a positive C-reactive protein value responded to tocolysis only 37.5% of the time, with a mean delay of delivery of 14.4 days and a mean gestational age of 33.2 weeks. Pathologic evidence of chorioamnionitis was present in 32.9% of 310 preterm deliveries as compared to only 22.3% of 1631 term deliveries. The presence of subclinical infection must be considered in cases of preterm labor, especially among patients for whom tocolytic therapy is unsuccessful.

Adult↗

PubMed1985

Capnocytophaga in the amniotic fluid of a woman in preterm labor with intact membranes.

Chorioamnionitis is thought to be uncommon with intact fetal membranes. A case is reported of a woman in preterm labor with intact membranes from whose amniotic fluid, placenta, and infant's gastric aspirate an unusual organism, Capnocytophaga, was identified. The findings are discussed.

Adult↗

PubMed1988

Ampicillin prophylaxis in preterm premature rupture of the membranes: a prospective randomized study.

It is hypothesized that ampicillin may treat subclinical deciduitis and prolong the "effective" latent period in patients with preterm premature rupture of the membranes. We studied 82 patients with preterm rupture of membranes who were managed expectantly and were randomly assigned either to receive ampicillin prophylaxis (n = 43) or not to receive ampicillin prophylaxis (n = 39). Patients were excluded from study entry on admission if they had suspected or frank chorioamnionitis, active preterm labor, a history of penicillin allergy, multiple gestation, or cervical cerclage. There were no significant differences between the groups in duration of membrane rupture prior to admission, gestational age at membrane rupture, use of steroids and tocolysis, and demographic factors. Life-table analysis showed that the risk of delivery was significantly lower for the group of patients receiving prophylactic ampicillin. The incidence of neonatal infection was significantly lower in the ampicillin group, 1 (2%) versus 6 (17%), p less than 0.04.

Ampicillin↗

PubMed1994

Low amniotic fluid glucose levels are a specific but not a sensitive marker for subclinical intrauterine infections in patients in preterm labor with intact membranes.

OBJECTIVE: The purpose of this study was to evaluate the ability of a low amniotic fluid glucose level, as defined by previously published thresholds, to identify a subclinical intrauterine infection in women in preterm labor with intact membranes. STUDY DESIGN: Amniotic fluid glucose levels, amniotic fluid cultures, and placental histologic characteristics were determined in women with preterm labor (n = 55) and in preterm controls (n = 58). These amniotic fluid glucose levels were compared between women with and without intrauterine infection using the Mann-Whitney U test. The sensitivity, specificity, and positive and negative predictive values for the identification of an intrauterine infection were determined with four different previously published amniotic fluid glucose threshold levels and the threshold from receiver-operator characteristic curve analysis of the study data. RESULTS: The median amniotic fluid glucose level was significantly lower in patients with positive amniotic fluid cultures (intraamniotic infection group) but was not lower in the group of patients with only histologic chorioamnionitis (extra-amniotic infection group), compared with noninfected controls. The sensitivity of a low amniotic fluid glucose level to detect both types of intrauterine infection ranged from 41% to 55%, depending on the threshold used. The specificity of a low amniotic fluid glucose level to detect an intrauterine infection ranged from 94% to 100%, the positive predictive value ranged from 86% to 100%, and the negative predictive value ranged from 70% to 80% with the same thresholds. CONCLUSION: Low amniotic fluid glucose levels are a specific but not a sensitive marker for either intraamniotic or extra-amniotic intrauterine infections in patients with preterm labor.

Amniotic Fluid↗

PubMed1994

Management of premature rupture of membranes at term: randomized trial.

OBJECTIVE: We hypothesize that expectant management in the presence of premature rupture of membranes at term would result in a lower cesarean birth rate with no increase in maternal, fetal, or neonatal infection. STUDY DESIGN: Term patients who consented to the study were randomly allocated either to expectant management for 48 hours or to induction of labor 8 hours after premature rupture of membranes. Premature rupture of membranes was confirmed by sterile speculum examination of the vagina. Patients randomized to expectant management were transferred to antenatal care and were not examined vaginally until they went into labor. Patients randomized to induction of labor had induction with oxytocin 8 hours after premature rupture of membranes. RESULTS: Two hundred sixty-two patients were randomized to the expectant management and induction of labor groups. The cesarean birth rate and the clinical diagnosis of postpartum endometritis was not significantly different in the two groups. Pathologic diagnosis of chorioamnionitis and funisitis, however, was significantly greater in the expectant management group (p < 0.05). Eight of the 15 babies with funisitis were admitted to the neonatal intensive care unit for therapy (two in the induction of labor group and six in the expectant management group, p < 0.05). CONCLUSION: Expectant management did not reduce the incidence of cesarean birth and increased the pathologic diagnosis of funisitis and newborn requirements for neonatal intensive care.

Cesarean Section↗

PubMed1994

Group B streptococci: results of a protocol of antepartum screening and intrapartum treatment.

OBJECTIVE: Our purpose was to evaluate and report the results of a protocol for the identification and treatment of all group B streptococcal carriers. STUDY DESIGN: In 1991 we instituted a protocol of antepartum cultures for group B streptococci on all pregnant women who attended clinics at the University of North Carolina Hospitals. Cultures were obtained from the lower third of the vagina and rectum at 24 to 28 weeks' gestation. Women with positive cultures were treated with intravenous antibiotics in labor. Women with signs of chorioamnionitis (through intrapartum assessment) were also treated in labor, regardless of carrier status. RESULTS: During the first 2 years of this protocol 1681 women were delivered. Forty percent of the women were from the private practice, 32% were black, and 62% were married. The group B streptococcal carriage rate was 14%. During the period of evaluation there were no infants infected with group B streptococci and no adverse reactions or complications among women who were treated with antibiotics. CONCLUSION: We found antepartum screening and intrapartum chemoprophylaxis of all group B streptococcal carriers to be an acceptable and effective protocol for reducing perinatal group B streptococcal infections.

Ampicillin↗

PubMed1997

Necrotizing funisitis: clinical significance and association with chronic lung disease in premature infants.

OBJECTIVES: Our purpose was to analyze the clinical significance of necrotizing funisitis, an unusual type of chronic inflammation of the umbilical cord, and to determine whether necrotizing funisitis is associated with chronic lung disease in premature infants. STUDY DESIGN: A total of 52 perinatal factors were prospectively assessed in 18 pregnant women and their fetuses in cases of chorioamnionitis at delivery occurring at 22 to 30 gestational weeks; a statistical comparison between the necrotizing funisitis group (n = 5) and the group without necrotizing funisitis (n = 18) was carried out. RESULTS: Significant correlations were found between necrotizing funisitis and the following factors: maternal serum C-reactive protein level on admission (p = 0.014), fetal distress (p = 0.044), umbilical artery blood pH value (p = 0.037) and polynuclear neutrophilic leukocyte count at birth (p = 0.014), chronic lung disease (p = 0.035), need for dexamethasone therapy for chronic lung disease (p = 0.029), duration of oxygen supplementation (p = 0.026), and length of hospital stay (p = 0.026). CONCLUSIONS: There was a significant association between necrotizing funisitis and development of chronic lung disease, suggesting that necrotizing funisitis is an important risk factor for the development of chronic lung disease.

Chorioamnionitis↗

PubMed1997

A randomized, prospective study comparing once-daily gentamicin versus thrice-daily gentamicin in the treatment of puerperal infection.

OBJECTIVE: The efficacy, safety, and antibiotic-related charges for once-daily gentamicin with twice-daily clindamycin were compared with those of thrice-daily dosing of these antibiotics. STUDY DESIGN: Patients with puerperal endometritis or with chorioamnionitis in labor assessed to be at risk for endometritis were randomized to receive gentamicin 4 mg/kg intravenously every 24 hours with clindamycin 1200 mg intravenously every 12 hours (experimental arm) or gentamicin 1.33 mg/kg intravenously and clindamycin 800 mg intravenously every 8 hours (conventional dosing interval arm). Primary outcomes included cure rates, mean length of treatment, antibiotic-related charges, and nephrotoxicity. Multiple logistic regression analysis was used to control for confounding variables. RESULTS: There were 135 and 137 patients randomized to the experimental and conventional interval arms, respectively. Cures were obtained in 94.1% and 87.6% of patients in the experimental and conventional arms, respectively (p = 0.06). The experimental arm had mean antibiotic charges of $250.79 versus $442.49 in the conventional arm (p < 0.0001). There was no permanent nephrotoxicity in either group. CONCLUSIONS: Once-daily gentamicin dosing with twice-daily clindamycin dosing is as efficacious and safe as the thrice-daily dosing of gentamicin and clindamycin for peripartum uterine infection. The experimental regimen results in substantial cost savings. The incidence of nephrotoxicity is low.

Adult↗

PubMed1998

Plasma ferritin, premature rupture of membranes, and pregnancy outcome.

OBJECTIVE: The objective of this study was to determine whether plasma ferritin levels predict maternal or neonatal outcomes in women with preterm rupture of membranes at <32 weeks' gestation. METHODS: Plasma from 223 women with premature rupture of membranes at <32 weeks' gestation who had participated in a randomized antibiotic trial were analyzed for ferritin at random assignment and at delivery, and the results were compared with the development of clinical chorioamnionitis, latency until delivery, neonatal sepsis, and a composite adverse neonatal outcome variable. RESULTS: The mean plasma ferritin level rose from 19.2 +/- 29.1 microgram/L on admission to 38.3 +/- 54.3 microgram/L at delivery, with a mean latency of 9.3 +/- 14.6 days. Plasma ferritin levels were significantly higher at both times in mothers whose infants acquired sepsis than in those whose infants did not, especially at delivery (68.5 +/- 96.3 microgram/L vs 32.5 +/- 40.5 microgram/L, P =.01), and neonatal sepsis was 2 to 3 times more common among women with plasma ferritin levels above the median than among those with levels below the median. CONCLUSIONS: Among women with premature rupture of membranes at <32 weeks' gestation, plasma ferritin levels were significantly associated with neonatal sepsis. These data suggest that higher plasma ferritin levels may serve as a marker of infection among women with premature rupture of membranes; however, the clinical utility of plasma ferritin levels in predicting neonatal outcome appears limited.

Adult↗

PubMed1998

A relaxin-mediated pathway to preterm premature rupture of the fetal membranes that is independent of infection.

OBJECTIVE: This study was designed to show whether the overexpression of relaxin in the decidua of patients with preterm premature rupture of the membranes is independent of or a consequence of chorioamnionitis. STUDY DESIGN: Two experiments were conducted. In the first experiment fetal membranes and decidua were collected from patients with preterm premature rupture of the membranes (n = 17) or preterm labor (n = 17) and were divided according to their degree of histologic infection. Messenger ribonucleic acid was isolated from the tissues and quantitative, sequential Northern analyses were carried out for the expression of human relaxin, interleukin-1beta, interleukin-6, and interleukin-8. The second experiment was aimed at increasing the numbers of messenger ribonucleic acid preparations in the two extreme categories, uninfected and severely infected tissues, with preterm premature rupture of the membranes and preterm labor. Some samples of messenger ribonucleic acid from the first experiment were rerun with the Northern analyses in the second experiment. These repeat samples showed no statistical differences in the results run at different times. Therefore the data from the respective groups of patients in both experiments were pooled for statistical analysis. RESULTS: In both the first experiment and in the pooled data of the two experiments the expression of the relaxin genes was significantly greater (P < .005) in the tissues from patients with preterm premature rupture of the membranes compared with those with preterm labor, in the absence of infection. No effect of the level of infection on the expression of relaxin was noted. In contrast, interleukin-6 gene expression was significantly increased (P < .05) in severely infected tissues, which was independent of whether the delivery was from preterm premature rupture of the membranes or preterm labor. The expression of the interleukin-1beta and interleukin-8 genes were only marginally increased even in severe infection. Marked patient variability in expression of the interleukin genes, especially in severe infection, was noted. CONCLUSION: A relaxin-mediated pathway that leads to preterm premature rupture of the membranes may exist independent of infection.

Adult↗

PubMed1998

The fetal inflammatory response syndrome.

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.

Acute-Phase Reaction↗

PubMed1998

Premature rupture of membranes at 34 to 37 weeks' gestation: aggressive versus conservative management.

OBJECTIVE: Our purpose was to compare induction of labor with preterm rupture of membranes between 34 and 37 weeks' gestation with expectant management. STUDY DESIGN: In this prospective investigation 120 gravid women at > or = 34 weeks 0 days and < 36 weeks 6 days of gestation were randomized to receive oxytocin induction (n = 57) or observation (n = 63). RESULTS: Estimated gestational age at rupture of membranes (34.3 +/- 1.4 weeks vs 34.5 +/- 1.4 weeks) and ultrasonographically estimated fetal weight (2230 +/- 321 gm vs 2297 +/- 365 gm) were equivalent between groups (not significant). Chorioamnionitis occurred more often (16% vs 2%, p = 0.007), and maternal hospital stay (5.2 +/- 6.8 days vs 2.6 +/- 1.6 days, p = 0.006) was significantly longer in the control group. Neonatal sepsis was also more common in the observation group (n = 3) than among induction patients (n = 0), but the difference was not statistically significant. CONCLUSION: Aggressive management of preterm premature rupture of the membranes at > or = 34 weeks 0 days of gestation by induction of labor is safe for the infant in our population and avoids maternal-neonatal infectious complications.

Adolescent↗

PubMed1999

Neonatal sepsis after betamethasone administration to patients with preterm premature rupture of membranes.

OBJECTIVE: We sought to determine the effect of antenatal betamethasone exposure on the incidence of early onset neonatal sepsis in patients with preterm premature rupture of membranes. STUDY DESIGN: We performed a nonconcurrent prospective analysis of infants delivered between 24 and 34 weeks' gestation after preterm premature rupture of membranes. Patients with preterm premature rupture of membranes were categorized into 3 groups on the basis of the following betamethasone exposures: (1) none (control subjects), (2) two 12-mg doses in a 24-hour interval on admission (single course), and (3) weekly administration after the initial single course (multiple courses). All included patients received prophylactic antibiotics for group B streptococci. Discrete data were tested for significance with the chi(2) test. Continuous data were tested for significance with an analysis of variance. Multiple logistic regression analysis was performed to determine the confounding effect of the multiple variables that were considered risk factors for early-onset neonatal sepsis. All P values of <.05 were considered significant. RESULTS: Three hundred seventy-four patients with preterm premature rupture of membranes were included, 203 of whom were evaluated in the control group, 99 in the single-course group, and 72 in the group receiving multiple courses of betamethasone. Early-onset neonatal sepsis was significantly associated with multiple courses of corticosteroids (P <.001) and gestational age (P =.002). Multiple courses of antenatal betamethasone were significantly associated with chorioamnionitis (P =.004) and endometritis (P =.004). Single-course corticosteroid administration was not significantly associated with any maternal or neonatal infectious complications. CONCLUSIONS: Multiple courses of antenatal betamethasone administered to patients with preterm premature rupture of membranes is associated with an increased risk of early-onset neonatal sepsis development.

Betamethasone↗

PubMed2002

Maternal serum and amniotic fluid cytokines in patients with preterm premature rupture of membranes with and without intrauterine infection.

OBJECTIVES: To evaluate the role of interleukins (IL-1, IL-6), tumor necrosis factor alpha (TNFalpha) and for the first time interferon gamma (IFNgamma) and epidermal growth factor (EGF) in the pathogenesis of premature rupture of membranes (PROM) with and without confirmed intrauterine infection. METHODS: Amniotic fluid was retrieved by transabdominal amniocentesis from 30 patients with PROM and 20 normal pregnant women with intact membranes of matched gestational age. Microbial state of amniotic cavity included culture for aerobic and anaerobic bacteria, mycoplasmas and ureaplasma whether or not clinical signs of chorioamnionitis were present. Maternal serum and amniotic fluid IL-1, IL-6, TNFalpha and IFNgamma concentrations were determined by the corresponding immunoradiometric assay, whereas EGF concentration was determined by a specific radioimmunoassay. RESULTS: Nearly all cases of PROM with infection revealed elevated amniotic fluid cytokines (IL-1beta, IL-6, TNFalpha, IFNgamma, EGF) whereas half of them revealed elevated serum cytokines. In cases of PROM without confirmed infection, there were no significant changes of maternal serum cytokines, whereas two-thirds of them revealed elevated amniotic fluid cytokines. CONCLUSIONS: The rise of cytokines in amniotic fluid of cases of PROM with infection may represent: (a) enhanced macrophage activity for immunosurveillance of the fetus; (b) a preparatory step for the initiation of labor; and (c) a valuable tests for diagnosing chorioamnioitis. The mechanism responsible for PROM in the presence or absence of infection is likely to be of different nature.

Adult↗

PubMed1986

Transplacental passage of intravenous immunoglobulin in the last trimester of pregnancy.

Immunoglobulin G was given intravenously (IVIgG) to pregnant women (27 to 36 weeks gestation) with signs of chorioamnionitis who were at risk for preterm delivery. Twenty-four patients received antibiotics alone (control group). Twenty-seven patients received the same antibiotics in combination with IVIgG, either 12 gm in 12 hours (low IVIgG dosage) or 24 gm on each of 5 consecutive days (high IVIgG dosage). Transplacental passage of IVIgG was shown to be a function of gestational age and of dose. Up to the thirty-second week of gestation, IgG infusions had no effect on IgG concentrations in cord sera. After that time, cord serum IgG levels were significantly higher in the high-dose group compared with the low-dose and control groups. All four subclasses of IgG, and two different antibodies present in the IVIgG preparation passed from the mother to the fetus. Thus the infused IgG mimicked the transplacental passage of endogenous IgG.

Chorioamnionitis↗