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PubMed2006

Contribution of inflammation to lung injury and development.

Inflammation interferes with lung development in model systems and is present chronically in the lungs of preterm infants who develop bronchopulmonary dysplasia (BPD). Antenatal inflammation is very commonly associated with preterm deliveries, but there is generally minimal information about the duration, intensity, or organisms associated with chorioamnionitis. In preterm lamb models, chorioamnionitis causes a lung injury similar to BPD and also causes clinical lung maturation. Continuous exposure of the developing lung before and after delivery to inflammation may be central to the development of BPD.

Animals↗

PubMed2006

Antenatal inflammation induced TGF-beta1 but suppressed CTGF in preterm lungs.

Chorioamnionitis is frequently associated with preterm birth and increases the risk of adverse outcomes such as bronchopulmonary dysplasia (BPD). Transforming growth factor (TGF)-beta1 is a key regulator of lung development, airway remodeling, lung fibrosis, and regulation of inflammation, and all these processes contribute to the development of BPD. Connective tissue growth factor (CTGF) is a downstream mediator of some of the profibrotic effects of TGF-beta1, vascular remodeling, and angiogenesis. TGF-beta1-induced CTGF expression can be blocked by TNF-alpha. We asked whether chorioamnionitis-associated antenatal inflammation would regulate TGF-beta1, the TGF-beta1 signaling pathway, and CTGF in preterm lamb lungs. Fetal sheep were exposed to 4 mg of intra-amniotic endotoxin or saline for 5 h, 24 h, 72 h, or 7 days before preterm delivery at 125 days gestation (full term = 150 days). Intra-amniotic endotoxin increased lung TGF-beta1 mRNA and protein expression. Elevated TGF-beta1 levels were associated with TGF-beta1-induced phosphorylation of Smad2. CTGF was selectively expressed in lung endothelial cells in control lungs, and intra-amniotic endotoxin caused CTGF expression to decrease to 30% of control values and TNF-alpha protein to increase. The antenatal inflammation-induced TGF-beta1 expression and Smad signaling in the fetal lamb lung may contribute to impaired lung alveolarization and reduced lung inflammation. Decreased CTGF expression may inhibit vascular development or remodeling and limit lung fibrosis during remodeling. These effects may contribute to the impaired alveolar and pulmonary vascular development that is the hallmark of the new form of BPD.

Animals↗

PubMed2002

Maternal glucocorticoids increase endotoxin-induced lung inflammation in preterm lambs.

Antenatal betamethasone (Beta) is widely used in women with asymptomatic chorioamnionitis at risk for preterm delivery, but its effects on fetal inflammation are unstudied. Groups of ewes at 109 +/- 1 days of gestation received the following treatments: intra-amniotic (IA) saline (control), 0.5 mg/kg intramuscular Beta, 10 mg IA endotoxin (Endo), and Beta + 2 h later Endo (Beta + Endo). Beta suppressed Endo-induced lung inflammation at 1 day. However, compared with Endo 5 days after treatment, Beta + Endo lambs had increased alveolar neutrophils, proinflammatory cytokine mRNA expression, and serum amyloid A3 (SAA3) mRNA expression. IL-1beta mRNA expression was localized to the inflammatory cells, whereas SAA3 mRNA expression was induced in the bronchial epithelium and the inflammatory cells. Compared with Endo, Beta + Endo lambs had increased lung inflammation but equivalent lung volumes 15 days after treatment. The late increase in inflammation in the Beta + Endo animals suggests that glucocorticoids impair the ability of the preterm lung to downregulate Endo-induced inflammation after fetal clearance of the glucocorticoids. These results have implications for lung inflammation and bronchopulmonary dysplasia in preterm infants exposed to chorioamnionitis and maternal glucocorticoids.

Acute-Phase Reaction↗

PubMedDate not supplied

Effects of antibiotic treatment on the concentrations of interleukin-6 and interleukin-8 in cervicovaginal fluid.

OBJECTIVE: We investigated to see the effect of antibiotics on interleukin (IL)-6 and IL-8 in cervicovaginal fluid in patients with premature rupture of the membranes. STUDY DESIGN: Cervicovaginal fluid was sampled on admission and before delivery for measurement of IL-6 and IL-8 from 31 patients with less than 35 weeks of gestation. Concentrations of IL-6 and IL-8 were measured by ELISA. RESULTS: The concentrations of IL-6 in cervicovaginal fluid in patients who were delivered because of clinical chorioamnionitis with antibiotics (n = 6) were significantly higher than in patients who were delivered because of active labor with (n = 14, p = 0.0133) and without antibiotics (n = 11, p = 0.0067). A significant change in the concentrations of IL-6 and IL-8 in cervicovaginal fluid was not observed in patients with and without antibiotics who were delivered because of active labor. CONCLUSIONS: The concentrations of IL-6 and IL-8 in cervicovaginal fluid might be influenced by the presence of clinical chorioamnionitis, but not by antibiotic administration.

Anti-Bacterial Agents↗

PubMed2005

The clever fetus: responding to inflammation to minimize lung injury.

Clinical and experimental information indicate that fetal exposure to inflammation can induce lung maturation. This inflammation may be chronic and indolent. We present clinical and experimental information that challenge assumptions about chorioamnionitis associated infection/inflammatory exposures to the fetus. We question the assumption that the fetal compartment is sterile, and that delivery is inevitable if chronic infection/inflammation is present. We demonstrate that the preterm fetus can develop a brisk and adequate inflammatory response, and the fetus also can quickly modulate and downregulate inflammation to prevent injury. The fetus at risk of early preterm delivery may be exposed to both chorioamnionitis and glucocorticoids. Both exposures can either increase or decrease fetal inflammatory responses depending on the timing of the exposures. The immunomodulatory ability of the fetus to fetal exposures remains an unexplored research field.

Animals↗

PubMed1997

Interleukin-4, interleukin-10, and soluble tumor necrosis factor receptors in cord blood.

OBJECTIVE: We assessed cord blood for levels of interleukin-4 (IL-4), interleukin-10 (IL-10), and p55 (sTNFR-I) and p75 (sTNFR-II) soluble tumor necrosis factor receptors. STUDY DESIGN: Umbilical cord IL-4, IL-10, tumor necrosis factor alpha (TNF alpha), sTNFR-I, and sTNFR-II were measured in 21 normal appropriately grown newborns delivered vaginally (normal pregnancy), and 3 abnormal pregnancies (1 preterm delivery, 1 premature rupture of membranes with chorioamnionitis, and 1 abruptio placentae with fetal and neonatal distress). Umbilical cord arterial blood pH and PO2 were also measured. RESULTS: The TNF alpha, sTNFR-I, and sTNFR-II were detectable in all cord blood samples in normal pregnancies. IL-4 was detected in 10 of 21 samples (47.6%), and IL-10 was undetectable in normal pregnancies. IL-10 could be detected in the cases with chorioamnionitis and abruptio placentae. Soluble tumor necrosis factor receptors in the case with preterm delivery and the case with abruptio placentae were elevated compared with the levels in control samples. CONCLUSION: Both the p55 and p75 soluble tumor necrosis factor receptors are physiologic constituents of term cord blood. An immunosuppressive role of IL-10 and a protective role of soluble tumor necrosis factor receptors are suggested in abnormal pregnancies. However, in view of the small number of abnormal pregnancies, these observations must be considered preliminary.

Abruptio Placentae↗

PubMed1993

Intrauterine infections and their association with stillbirth and preterm birth in Maputo, Mozambique.

Subclinical intrauterine infections during pregnancy in Mozambican women were studied in an attempt to elucidate their potential association with adverse pregnancy outcome, particularly stillbirth and preterm birth. A total of 39 stillbirths and 21 preterm live births were compared with 121 term live births. Extraplacental membranes and amniotic fluid were studied to ascertain the presence or absence of chorioamnionitis and of antibacterial activity in amniotic fluid. It was found that signs of maternal subclinical disease in extraplacental membranes in combination with an absence of antibacterial activity in amniotic fluid was overrepresented in stillbirths and preterm births in relation to term live births. A tentative conclusion is that a lack of antibacterial activity in amniotic fluid and established chorioamnionitis represent a vicious combination with strongly negative significance for the fetal outcome.

Amniotic Fluid↗

PubMed2001

Antenatal infection/inflammation and postnatal lung maturation and injury.

Chorioamnionitis is frequently associated with preterm deliveries before 30 weeks gestation. Chorioamnionitis correlates both with an increased risk of bronchopulmonary dysplasia and with a decreased risk of respiratory distress syndrome. Both interleukin-1alpha and endotoxin can induce inflammation in the fetal lungs and lung maturation after preterm birth when given by intra-amniotic injection. Inflammation can also result in an arrest of alveolarization, and this lung developmental abnormality is prominent in the lungs of preterm infants that die of bronchopulmonary dysplasia. The mechanisms by which infection/inflammation can have both beneficial and injurious effects on the preterm lung remain to be characterized.

Chorioamnionitis↗

PubMed2004

Inflammatory markers in intrauterine and fetal blood and cerebrospinal fluid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants.

Recent evidence strongly implicates the inflammatory response to intrauterine infection in the pathogenesis of neonatal brain and lung injury. We hypothesized that lung and brain injury in preterm infants occurs during a common developmental window of vulnerability as the result of an inflammatory response in different compartments. To determine whether inflammatory markers in these compartments are associated with bronchopulmonary dysplasia (BPD) or cranial ultrasound (CUS) abnormalities in infants <33 wk gestation age (GA) and <1501 g birth weight, we analyzed placental pathology and serum and cerebrospinal fluid (CSF) IL-6, IL-1beta, and tumor necrosis factor-alpha (TNF-alpha) concentrations in 276 infants. Logistic regressions were performed stratified by GA. Histologic chorioamnionitis was significantly associated with BPD in infants </=28 wk GA (OR 3.6, p = 0.027). Maternal stage of chorioamnionitis significantly correlated with severity of BPD. Presence of a fetal inflammatory response indicated by fetal vasculitis or elevated cytokines was not associated with the development of BPD. Serum IL-6 >/=17 pg/mL was associated with an abnormal CUS in infants >28 wk GA (OR 3.36, p = 0.023) but not </=28 wk GA. CSF concentrations of IL-6 >/=6.5 pg/mL and TNF-alpha >/=3 pg/mL were associated with abnormal CUS in infants </=28 wk GA (IL-6 OR 3.0; TNF-alpha OR 3.5; p < 0.05 each case) but not >/=28 wk GA. These data suggest that in infants </=28 wks GA, BPD may be initiated by inflammatory mediators in amniotic fluid, but brain injury may involve variations in the systemic inflammatory response.

Brain Injuries↗

PubMed2003

Biovar diversity of Ureaplasma urealyticum in amniotic fluid: distribution, intrauterine inflammatory response and pregnancy outcomes.

OBJECTIVE: The objective of this study was to determine the distribution of two biovars of Ureaplasma urealyticum (parvo and T960) in human amniotic fluid and to examine whether the magnitude of the intrauterine inflammatory response and pregnancy outcomes are different between patients with microbial invasion of the amniotic cavity with "parvo biovar" and those with "T960 biovar". STUDY DESIGN: This cohort included 77 preterm singleton pregnancies (gestational age < 37 weeks) in whom U. urealyticum was detected from amniotic fluid using the polymerase chain reaction (PCR). Amniotic fluid was obtained by transabdominal amniocentesis. Amniotic fluid was cultured for aerobic and anaerobic bacteria as well as mycoplasmas. U. urealyticum was biotyped by PCR methods. Amniotic fluid inflammatory response was determined by amniotic fluid white blood cell count and interleukin-6 concentration. RESULTS: 1) The "parvo biovar" was detected in 82% (63/77) and "T960 biovar" was in 18% (14/77) of cases; 2) U. urealyticum was isolated by conventional culture method from amniotic fluid in 56% (35/63) of cases with positive for "parvo biovar" and in 50% (7/14) of cases with positive for "T960 biovar"; 3) There were no significant differences in the median gestational age at amniocentesis, gestational age at delivery, birth weight, amniotic fluid white blood cell count, amniotic fluid interleukin-6 concentration and the rates of clinical chorioamnionitis, histologic chorioamnionitis, funisitis and neonatal morbidity between patients in the two biovar groups. CONCLUSIONS: 1) The "parvo biovar" is more frequently isolated from amniotic fluid of preterm gestations than the "T960 biovar"; 2) Biovar diversity of U. urealyticum in amniotic fluid was not associated with different pregnancy outcome and magnitude of the intraamniotic inflammatory response.

Amniocentesis↗

PubMed1987

A dipstick test for infection in preterm premature rupture of the membranes.

Microbiological analysis of amniotic fluid obtained by amniocentesis is increasingly employed in preterm premature rupture of the membranes (PPROM) to predict those patients at increased risk of chorioamnionitis. Although liquor culture appears the most accurate predictor, a role exists for rapid but slightly less accurate testing. In this study, a dipstick (Cytur-test) which predicts the presence of leukocytes was evaluated in amniotic fluid. Twenty-one samples were obtained by amniocentesis from 25 women with PPROM at gestation 26-34 weeks. The dipstick predicted 5 out of 6 specimens with a positive culture and 12 of 14 with a negative culture (figure 1). Its accuracy as a predictor of a positive culture was similar to microscopy for polymorphs, with sensitivities of 83.3% and 80% respectively and specificities of 85.7% and 92.3%. Neither test proved as predictive of histological chorioamnionitis due to 6 patients delivering greater than 48 hours after amniocentesis who may have developed infection subsequent to the demonstration of sterile liquor.

Amniocentesis↗

PubMed1999

Antimicrobial prevention of early-onset group B streptococcal sepsis: estimates of risk reduction based on a critical literature review.

OBJECTIVE: To identify interventions that reduce the attack rate for early-onset group B streptococcal (GBS) sepsis in neonates. STUDY DESIGN: Literature review and reanalysis of published data. RESULTS: The rate of early-onset GBS sepsis in high-risk neonates can be reduced by administration of antibiotics. Treatment during pregnancy (antepartum prophylaxis) fails to reduce maternal GBS colonization at delivery. With the administration of intravenous ampicillin, the risk of early-onset infection in infants born to women with preterm premature rupture of membranes is reduced by 56% and the risk of GBS infection is reduced by 36%; addition of gentamicin may increase the efficacy of ampicillin. Treatment of women with chorioamnionitis with ampicillin and gentamicin during labor reduces the likelihood of neonatal sepsis by 82% and reduces the likelihood of GBS infection by 86%. Universal administration of penicillin to neonates shortly after birth (postpartum prophylaxis) reduces the early-onset GBS attack rate by 68% but is associated with a 40% increase in overall mortality and therefore is contraindicated. Intrapartum prophylaxis, alone or combined with postnatal prophylaxis for the infants, reduces the early-onset GBS attack rate by 80% or 95%, respectively. CONCLUSIONS: Women with chorioamnionitis or premature rupture of membranes and their infants should be treated with intravenous ampicillin and gentamicin. Intrapartum antimicrobial prophylaxis may be appropriate for other women whose infants are at increased but less extreme risk, and supplemental postpartum prophylaxis may be indicated for some of their infants. Selection of appropriate candidates and prophylaxis strategies requires careful consideration of costs and benefits for each patient. group B streptococcus, neonatal sepsis, early-onset sepsis, prevention, prophylaxis.

Age of Onset↗

PubMed2002

Placental features in preterm infants with periventricular leukomalacia.

OBJECTIVE: Evaluation of the placenta provides some important insights into pathophysiologic changes that take place during the prenatal and intrapartum process. We investigated the relationship between placental findings and periventricular leukomalacia (PVL) to obtain a better understanding of its cause. METHODS: Thirty-two preterm infants with PVL delivered before 34 weeks' gestation, between 1990 and 1999, were classified into 4 groups according to the onset of brain injury assumed from ultrasonographic presentation and clinical course: 2 Antenatal, 22 Peripartum, 5 Postnatal, and 3 in an unknown time of onset group. We evaluated the gross and histopathologic features of the placentas of each group and compared them with those of a control group matched by birth weight and gestational age in terms of the frequency of major placental findings. Potential confounding factors were controlled in logistic regression analyses. RESULTS: Gross lesions with disturbance of uteroplacental circulation, including massive retroplacental hematoma, extensive infarction or thrombosis, and marked basal or perivillous fibrin deposition, were observed more frequently in the Antenatal + Peripartum combined subgroup than in the controls (41.7% vs 13.7%). Placentas from the Antenatal + Peripartum subgroup also demonstrated a significantly higher frequency of ischemic changes in villi, based on histopathologic examination, as compared with the control group (54.2% vs 13.7%). These associations remained after adjustment for confounding factors in logistic regression analyses (odds ratio: 4.04, 95% confidence interval: 1.40-11.67; and odds ratio: 7.28, 95% confidence interval: 2.50-21.20; respectively). Frequencies of chorioamnionitis and twin placentation tended to be higher in PVL cases than in the controls, although the differences were not statistically significant (46.9% vs 37.9%, 37.5% vs 20.0%, respectively). CONCLUSIONS: These results suggest that disturbed placental circulation underlies the development of PVL in the majority of cases with prenatal and peripartum brain injury. In chorioamnionitis cases, certain additional factors were suggested in the genesis of PVL. Thus, placental examination is essential for elucidating the pathophysiologic changes leading to PVL in the perinatal process.

Chorioamnionitis↗

PubMed2006

Myelopoiesis in the liver of stillborns with evidence of intrauterine infection.

CONTEXT: Chorioamnionitis is the maternal and fetal response to an ascending intrauterine infection. The fetal response is manifested by funisitis and chorionic vasculitis, or as neutrophils within pulmonary spaces. Human hematopoiesis occurs in the liver primarily during the 6th to 22nd weeks of gestation. OBJECTIVE: To establish the relationship between the presence of an intrauterine infection and the degree of fetal hepatic myelopoiesis in second- and third-trimester fetuses. DESIGN: Liver and lungs from 49 fetal autopsies, 20 to 41 weeks of gestational age, and their associated placentas and membranes were analyzed for evidence of intrauterine infection and hepatic myelopoiesis. Hematoxylin-eosin-stained sections from fixed tissues were evaluated for the presence of amnionic fluid infection, defined by the presence of acute chorioamnionitis or funisitis. The degree of portal hematopoiesis, myelopoiesis and intra-alveolar neutrophils was assessed semiquantitatively with hematoxylin-eosin-stained sections and immunohistochemically with antimyeloperoxidase. The Kruskal-Wallis 1-way analysis of variance and the Wilcoxon-Mann-Whitney test were used to determine the significance of any observed difference. RESULTS: The degree of portal and lobular myelopoiesis was significantly greater with the presence of inflammation in both the membranes and umbilical cord, and correlated with the presence of intra-alveolar neutrophils (P < .001). A high correlation between the hematoxylin-eosin and immunohistochemistry assessment of myeloid cells was noted. CONCLUSIONS: There is increased portal and lobular myelopoiesis in 20-week to 41-week gestational age fetal livers that is associated with intrauterine ascending infection. The presence of increased portal or lobular myelopoiesis suggests the presence of an active fetal response to an intrauterine ascending infection.

Adult↗

PubMed1999

[Symptomless amniotic infection related to pregnancy outcome].

Placental histology in 984 pregnancies (758 term and 226 preterm) occurring during the years 1995 to 1998 was investigated and amniotic cavity cultures were taken during 918 cesarean sections. Histology revealed placental infection in 20.3% of placentas. Chorioamnionitis was confirmed in 119 out of 758 term pregnancies (15.7%) while in 81 out of 226 preterm pregnancies (35.8%); the difference is highly significant (chi 2 = 26.6, p < 0.01). Bacteriological culture resulted in bacterial growth in 19.7% of all cases (181/918), its frequency was significant higher in premature births (54/133, 40.3% chi 2 = 25.2, p < 0.01) as compared with pregnancies carried to term. Recovery of any organism from the amniotic cavity was strongly associated with chorioamnionitis confirmed by histology. Comparison of the rates of indicating placental infection found in this study and a study performed between 1981 and 1983, showed that the program aiming at detection and treatment of silent intrauterine infection has only partially been successful.

Adult↗

PubMed2001

Intrauterine infection may be a major cause of stillbirth in Sweden.

AIM OF THE STUDY: To investigate intrauterine infection as a cause for unexplained stillbirth. METHODS: Chorioamnionitis was studied in a material of stillbirths (117 subjects from the years 1985-1994) from a region in the south Sweden. Control material (126 alive and healthy newborns and with healthy mothers) was gathered from the same region. RESULTS: Chorioamnionitis was a common diagnosis both with stillbirths and 'healthy' deliveries (82 and 68%, respectively). Extension of the inflammation to decidua basalis was seven times more common among stillbirths than among controls (odds ratio 7.2, confidence interval 2.8-21.9). The most common bacteria found at cultures were Escherichia coli, Coagulase negative staphylococcus, Enterococcus faecalis and group B Streptococcus. The risk for stillbirth was doubled if both inflammation and bacteria were present (odds ratio 2.3, confidence interval 0.92-5.8). Meconium discharge was more common among stillbirths than controls (odds ratio=4.7, confidence interval 1.7-14). There were no differences in any respect regarding macerated and non-macerated stillbirths. Our findings are similar to the results from studies in developing countries except for the higher incidence of stillbirths in such countries. CONCLUSIONS: Thus, a large part of otherwise unexplained stillbirths might be due to ascending infections.

Adult↗

PubMed2002

Listeria infection during pregnancy: a 10 year experience.

BACKGROUND: Although Listeria monocytogenes is widely distributed in nature, it rarely causes clinical infection in previously healthy people. This microorganism, however, may cause severe invasive disease in pregnant women and newborns. OBJECTIVES: To investigate--in our pregnant population--the impact, severity and outcome of listeriosis on both mother and fetus. METHOD: The study was carried out at a level III, university two-hospital complex. In a retrospective chart review of 65,022 parturients during a 10 year period (1990-1999), we identified and evaluated 11 pregnant patients and their offspring with Listeria infection. RESULTS: Chorioamnionitis with multiple placental abscesses were observed in all five placentae examined. Clinically, 4 of 11 parturients had a cesarean section for fetal distress (36.3%), as compared to the 14% mean CS rate in our general population. Two of 11 had a late abortion (18.1%), as compared with the 4% rate in our hospital. Four of 11 had premature labor (36%), which was about four times the rate in our population. Finally, although no intrauterine fetal death was recorded in our series, there was one neonatal death of a term infant (1/11, 9%), which is about 10 times higher than our corrected perinatal mortality rate. CONCLUSIONS: If not promptly and adequately treated, listeriosis in pregnancy may present serious hazards to the fetus and newborn through direct infection of the placenta and chorioamnionitis.

Adult↗

PubMed2002

[Prognostic and therapeutic value of biologic signs of infection in the management of preterm labor (amniocentesis excepted)].

During threatened preterm delivery, both general and local signs of infection increase the risks of amniotic infection, premature rupture of membranes, preterm delivery, and neonatal and/or maternal morbidity of infectious origin. Nonetheless, as antibiotics have not been sufficiently studied to be proved of benefit in chorioamnionitis with intact membranes, search for these general (C Reactive Protein, hyperleucocytosis) or cervical/vaginal (Group B Streptococcus, Escherichia Coli, bacterial vaginosis) signs of infection have not been proved to be really necessary. We have to except Group B Streptococcus, which have to be searched during weeks that precede delivery: in those cases where it is shown to be present in the cervix or the vagina, antibiotics must be prescribed during delivery (ANAES recommendation). Finally, it must be emphasized that these recommendations are mainly based on the absence of studies specifically done to prove the benefits or risks of antenatal antibiotics - or fetal extraction - in case of chorioamnionitis with intact membranes. Systematic vaginal and blood samples (CRP, leukocytes, vaginal micro-organisms) would be helpful in determining the appropriate option in those situations.

Amniocentesis↗