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Proinflammatory cytokines: a link between chorioamnionitis and fetal brain injury.

OBJECTIVE: To review the etiology of impaired fetal neurodevelopment - in particular, the relationship between chorioamnionitis, cytokines, and cerebral palsy. DATA SOURCES: A MEDLINE search was performed for all clinical and basic science studies published in the English literature from 1966 to 2002. Key words or phrases used were chorioamnionitis, cerebral palsy, fetal brain damage, fetal CNS injury, infection in pregnancy, proinflammatory cytokines in pregnancy, proinflammatory cytokines in infection, and preterm labour or birth. All relevant human and animal studies were included. STUDY SELECTION: Fetal brain injury remains a major cause of lifelong morbidity, incurring significant societal and health care costs. It has been postulated that chorioamnionitis stimulates maternal/fetal proinflammatory cytokine release, which is damaging to the developing fetal nervous system. Elevated cytokine concentrations may interfere with glial cell development and proliferation in the late second trimester of pregnancy, when the central nervous system is most vulnerable. Increasing numbers of epidemiological and basic science studies found through MEDLINE searches support this hypothesis. Treatment options aimed at etiologic factors may lead to improved neurodevelopmental outcomes. CONCLUSIONS: Clearly, some relationship exists between chorioamnionitis, cytokines, and the development of cerebral palsy, but the severity and duration of exposure required to produce fetal damage remains unknown. Future research addressing these issues may aid in clinical decision-making. As well, the elucidation of mechanisms of cytokine action may aid in early treatment options to prevent or limit development of fetal brain injury.

Brain↗

Candida chorioamnionitis after serial therapeutic amniocenteses: a possible association.

BACKGROUND: Reduction amniocentesis is used in cases of severe polyhydramnios to decrease maternal discomfort and the risk of preterm labor. In a MEDLINE search (1966 to present, English language, keywords: amniocentesis, chorioamnionitis), no report of Candida chorioamnionitis after serial reduction amniocentesis exists. CASE: A 29-year-old primigravida with a history of four therapeutic amniocenteses for idiopathic polyhydramnios developed preterm labor at 30 and 5/7 weeks' gestation, rupture of membranes, and Candida albicans chorioamnionitis. Despite aggressive therapy with amphotericin B, the neonate succumbed to overwhelming systemic candidiasis. CONCLUSION: Serial amniocentesis may place patients at elevated risk for Candida chorioamnionitis and subsequent preterm delivery. Clinicians should consider early diagnostic amniocentesis in patients in preterm labor with a history of prior amniocentesis, and the routine Gram stain and culture of amniotic fluid.

Adult↗

Histologic chorioamnionitis: an occult marker of severe pulmonary hypertension in the term newborn.

OBJECTIVE: To determine whether the presence of histologic chorioamnionitis is associated with the severity of Persistent Pulmonary Hypertension of the Newborn (PPHN) as evidenced by the use of exogenous nitric oxide (iNO), high-frequency oscillatory ventilation (HFOV), extra-corporeal membrane oxygenation (ECMO) and/or death. METHODS: Retrospective chart review of term neonates > or =37 weeks gestation with PPHN. Placental pathology was reviewed. Primary outcome is the use of iNO. Secondary outcomes include the use of HFOV, ECMO and death. RESULTS: Over 2 years, 29 neonates fulfilled the entry criteria for the study. Interventions included iNO use n=14 (48%), HFOV n=7 (24%) and ECMO n=3 (10%); two neonates died. Histologic chorioamnionitis and/or funisitis was noted in 16 (55%) neonates. The presence of chorioamnionitis and/or funisitis (n=16) versus neither (n=13) was significantly associated with iNO use 11/16 (78%) versus 3/13 (22%) (p=0.02) and HFOV 7/16 (43%) versus 0/13 (0%) (p=0.008) but not to ECMO or death. CONCLUSION: The presence of histologic chorioamnionitis and/or funisitis is associated with more severe PPHN as indicated by the use of iNO as well as an increased requirement for more advanced respiratory support, that is, HFOV. The mechanism/s contributing to these findings are unclear.

Chorioamnionitis↗

Pre-term pre-labour rupture of membranes: effect of chorioamnionitis on overall neonatal outcome.

Our objective was to evaluate the association between clinical chorioamnionitis following preterm pre-labour rupture of membranes (PPROM) and adverse neonatal outcome. We compared retrospectively, adverse neonatal outcome of singleton pregnancies with documented PPROM who developed chorioamnionitis (cases) with those who did not (controls). Our result showed that poor neonatal outcome was significantly associated with chorioamnionitis (34% vs 13%; p = 0.008). This association was found on multiple logistic regression analysis to be independent (p < 0.05) of other risk factors for poor neonatal outcome, viz: latency period (p = 0.002) and gestational age at delivery (p < 0.001). We conclude that chorioamnionitis complicating PPROM worsen neonatal outcome. The implication of this on expectant management of PPROM is discussed.

Apgar Score↗

Maternal C-reactive protein for detection of chorioamnionitis: an appraisal.

Premature delivery is still a significant problem in obstetrics, and chorioamnionitis is an unwelcome complication. C-reactive protein (CRP) is a circulating marker of low-grade inflammation and the role of its measurement in clinical practice remains unclear for many conditions. It has been claimed that estimation of CRP is helpful in the diagnosis of chorioamnionitis, and this study aims to appraise such claims. Following review of the literature, six reports were recruited for further metanalysis, including 466 cases. The overall prevalence of chorioamnionitis was 41% (191/466). The overall diagnostic activity showed sensitivity, specificity, false-positives and false-negatives of 72.8%, 76.4%, 23.6% and 27.2%, respectively. Therefore, we can conclude that estimation of maternal CRP is not helpful in the detection of chorioamnionitis, compared with standard investigations.

C-Reactive Protein↗

Antibiotic administration in patients with preterm premature rupture of membranes reduces the rate of histological chorioamnionitis: a prospective, randomized, controlled study.

OBJECTIVE: To determine whether antibiotic administration in patients with preterm premature rupture of membranes is associated with a reduction in the rate of histological chorioamnionitis and funisitis. METHODS: One hundred consecutive patients with preterm premature rupture of membranes and no labor between 24 and 34 weeks were invited to participate in this study. Eligible patients randomly received either clindamycin-gentamicin for 7 days or placebo, and were managed expectantly until 35 weeks unless fetal or maternal indications developed. Microbial invasion of the amniotic cavity was defined as the presence of a positive amniotic fluid culture obtained by transabdominal amniocentesis. Cervicovaginal infection was diagnosed when bacterial vaginosis or a positive culture for cervicovaginal pathogens or facultative bacteria associated with a significant increase in the white blood cell count were found. Histological chorioamnionitis was based on the observation of polymorphonuclear leukocyte infiltration of the chorionic plate or the extraplacental fetal membranes. Funisitis was diagnosed in the presence of polymorphonuclear leukocyte infiltration into the umbilical vessel walls or Wharton jelly. Statistics were performed using contingency tables. RESULTS: Seventy-one patients with available histological study of the placenta were included. Thirty-five women received antibiotics and 36 were given placebo. Patients who received antibiotics had a significantly lower rate of histological chorioamnionitis than patients who received placebo (46% (16/35) vs. 69% (25/36), respectively; p < 0.05). This effect was more pronounced among women with microbial invasion of the amniotic cavity and/or cervicovaginal infection (58% vs. 89%, respectively; p < 0.01). Antibiotic therapy was associated with an increase in the frequency of placentas without histological abnormalities (29% vs. 6%; p < 0.01). The frequency of funisitis was not different between groups. CONCLUSION: Administration of antibiotics in patients with preterm premature rupture of membranes is associated with a significant reduction in the incidence of histological chorioamnionitis but it does not modify the frequency of funisitis.

Adolescent↗

Interleukin-8 in cord sera: a sensitive and specific marker for the detection of preterm chorioamnionitis.

Interleukin-8 (IL-8) exerts chemotactic activity on neutrophils at inflammatory sites to eliminate invading bacteria. To investigate whether the preterm fetus with chorioamnionitis produces IL-8, the titers of IL-8 were examined in sera of babies with (n = 38) and without chorioamnionitis (n = 34) using an EIA kit specific for IL-8. The infected babies had a significantly higher IL-8 titer than those not infected at 22-36 gestational weeks. The IL-8 titer was increased even in the mild histologic stage of chorioamnionitis and became much higher in the more severe stage. The IL-8 elevation, however, was remarkably suppressed by infusion of a steroid into the mother to promote fetal lung maturation. This retrospective study demonstrated that titration of IL-8 in cord serum is a more useful marker for the early detection of chorioamnionitis, because of its higher sensitivity and specificity, than conventional markers such as C-reactive protein.

Anti-Bacterial Agents↗

Regulation of placental monocyte chemotactic and activating factor during pregnancy and chorioamnionitis.

A number of placental cytokines participate in the feto-maternal defence mechanism. Monocyte chemotactic and activating factor (MCAF) is one of these chemokines. We investigated the pattern of placental MCAF production, the localization of MCAF-producing cells in the placenta, and alterations in its expression in chorioamnionitis. The amounts of MCAF protein produced by the placenta increased during pregnancy irrespective of the presence of uterine contraction. MCAF mRNA was expressed at equivalent levels in the first and second trimester placenta, but at higher levels in the third trimester placenta. Chorioamnionitis in the third trimester placenta induced a 10-fold increase in MCAF protein production and a 3-fold increase in MCAF mRNA level. Immunohistochemical analysis of the placenta revealed the MCAF-producing cells to be trophoblasts. Stimulation of placental cells with lipopolysaccharide augmented MCAF production. These results indicate unique transcriptional and developmental regulation of MCAF mRNA and protein production during pregnancy and chorioamnionitis. Placental MCAF may be involved in the feto-maternal defence mechanism by activating feto-placental and maternal monocytes in chorioamnionitis.

Blotting, Western↗

Oral clindamycin and histologic chorioamnionitis in women with abnormal vaginal flora.

OBJECTIVE: Oral clindamycin reduced late miscarriage and preterm birth in asymptomatic women with bacterial vaginosis or intermediate flora. We investigated whether clindamycin reduced the incidence of histologic chorioamnionitis as a mechanism for these beneficial effects. METHODS: This was a subanalysis of 126 participants from a larger randomized controlled trial. We compared the incidence of histologic chorioamnionitis between the clindamycin and placebo groups. Histologic chorioamnionitis was diagnosed by the presence of polymorphonuclear leukocytes, separately in the amnion and chorion, decidua, fetal surface of the placenta, the walls of fetal chorionic vessels, umbilical cord, or in the subchorionic fibrin layer. Microbiologic cultures were done on swabs from the space between the chorion and amnion layers. RESULTS: Histopathologic results were available for 122 placentas, 62 (51%) and 60 (49%) in the clindamycin and placebo groups, respectively. There were no significant differences in inflammation between the groups in the decidua (41% compared with 43%), membranes (25% compared with 41%), fetal vessels (16% compared with 14%), or subchorionic fibrin (32% compared with 34%). Adjusting for gestational age, ethnic origin, or history of miscarriage did not alter the results. There were no significant differences in the outcomes of pregnancy between women with and without inflammation, either before or after adjustment for treatment group. CONCLUSION: Although oral clindamycin reduced late miscarriage and preterm birth in women with abnormal vaginal flora, this effect is unlikely to be mediated through a reduction in the incidence of histologic chorioamnionitis. The relatively small size of the groups, however, does not allow us to rule out a real effect, especially given the lower rate of membrane inflammation observed in the clindamycin group. LEVEL OF EVIDENCE: I.

Abortion, Spontaneous↗

Chorioamnionitis associated with Crohn's disease and azathioprine treatment: a case report.

This paper reports a case of S. constellatus chorioamnionitis in a pregnant Crohn's disease patient who was taking azathioprine. Chorioamnionitis is a major cause of perinatal morbidity. Azathioprine, an immunosuppressive antimetabolite, is widely used to treat inflammatory bowel disease. Streptococcus constellatus is a Gram-positive bacterium that has not previously been associated with chorioamnionitis. A high index of suspicion for chorioamnionitis and unusual pathogens should be maintained in the management of obstetric patients on immunosuppressive agents.

Adult↗

Chorioamnionitis caused by Serratia marcescens in a non-immunocompromised host.

A 26 year old pregnant woman with antithrombin III deficiency developed recurrent septicaemia with Serratia marcescens. In spite of the administration of antibiotics, high grade fever persisted. She subsequently manifested lower abdominal pain, and spontaneous abortion occurred. After the abortion, she became completely afebrile. The amnion was turbid, and microscopic examination of the placenta showed haemorrhage and massive infiltration of neutrophils, suggestive of infectious chorioamnionitis. Pulsed field gel electrophoresis showed that isolates from the blood, urine, and vaginal discharge were genetically identical. Intravenous pyelography revealed that she had a bilateral completed double ureter. It was thought that a urinary tract anomaly caused infection with S marcescens, and the pathogen spread to the chorioamnion via the bloodstream. This is the first report of chorioamnionitis caused by S marcescens in a non-immunocompromised host. In addition, these findings indicate that the chorioamnion can serve as a site for persistent infection in normal pregnancies.

Abortion, Spontaneous↗

Placental lipid contents in preterm labor complicated by chorioamnionitis.

Fifteen decidua free placental samples from nine preterm deliveries without evidence of chorioamnionitis and six preterm deliveries with evidence of chorioamnionitis were analyzed for fatty acids contents. The percentage of arachidonic acid in phospholipids, in free fatty acids, in triglycerides and cholesterol esters were also measured in each sample. Arachidonic acid was found to be present in significantly increased amounts in the placentas of women with chorioamnionitis and preterm delivery, as compared to those of women with preterm delivery and the absence of chorioamnionitis.

Arachidonic Acids↗

Are complete blood cell counts useful in the evaluation of asymptomatic neonates exposed to suspected chorioamnionitis?

OBJECTIVE: Chorioamnionitis complicates 1% to 10% of pregnancies and increases the risk of neonatal infection. Women with chorioamnionitis receive intrapartum antibiotics, often resulting in inconclusive neonatal blood cultures. Peripheral neutrophil values are used frequently to assist in the diagnosis of neonatal infection and to determine duration of antibiotics; we sought to determine the utility of this approach. METHODS: A prospective observational study was performed in 856 near-term/term neonates who were exposed to suspected chorioamnionitis. Each received antibiotics for 48 hours unless clinical infection or positive blood cultures occurred. Peripheral neutrophils were measured serially and analyzed using the reference ranges of Manroe et al; an additional analysis of only the initial neutrophil values used the normal ranges of Schelonka et al. Results of neutrophil analyses were not used to determine duration of therapy. Fifty percent of asymptomatic neonates were seen postdischarge to ascertain recurrent infection. Local patient charges were examined. RESULTS: Ninety-six percent of neonates were asymptomatic and had negative cultures, and antibiotics were discontinued at 48 hours. A total of 2427 neutrophil counts were analyzed. Although abnormal neutrophil values were more frequent in infected or symptomatic neonates, 99% of asymptomatic neonates had > or = 1 abnormal value. The specificity and negative predictive values for abnormal neutrophil values ranged between 0.12 and 0.95 and 0.91 and 0.97, respectively; sensitivity was 0.27 to 0.76. Significant differences in interpretation of the initial neutrophil values were noted, depending on the normal values used. Follow-up was performed for 373 asymptomatic neonates until 3 weeks' postnatal age. Eight required rehospitalization; none had evidence of bacterial infection. If neutrophil values had been used to determine duration of antibiotics, then local costs would have increased by 76,000 dollars to 425,000 dollars per year. CONCLUSIONS: Single or serial neutrophil values do not assist in the diagnosis of early-onset infection or determination of duration of antibiotic therapy in asymptomatic, culture-negative neonates who are > or = 35 weeks' gestation and are delivered of women with suspected chorioamnionitis.

Adolescent↗

Abruptio placentae and chorioamnionitis-microbiological and histologic correlation.

BACKGROUND: To determine the association of chorioamnionitis with placental abruption. SUBJECT AND METHOD: Fifty pregnant women admitted with abruptio placentae were compared to an equally large control group in spontaneous labor with no history of antepartum hemorrhage. Swabs from the cervix and placental membranes were cultured for aerobic and anaerobic organisms. Placental membranes were studied histologically in 40 women of study group and 35 of control group for any evidence of chorioamnionitis. RESULTS: Specific organisms were isolated in 22 (44%) women in the study group and 19 (38%) women in the control group. The cervical swab microbiological flora was similar in both groups but isolation of specific organisms from placental membrane culture was higher in the study group (40%) compared to the controls (18% p<0.05). Evidence of histologic chorioamnionitis was higher in the study group 12/40 (30%), than in the control group 8/35 (22.85%), but the difference was not significant. CONCLUSION: The incidence of silent chorioamnionitis (placental membrane culture positivity) is higher in the abruptio placentae.

Abruptio Placentae↗

The role of maternal serum C-reactive protein and white blood cell count in the prediction of chorioamnionitis in women with premature rupture of membranes.

This study was performed to evaluate the diagnostic performance of maternal serum C-reactive protein, maternal white blood cell (WBC), and neutrophil counts in the detection of histologic chorioamnionitis. One hundred and twenty six pregnant women after at least 28 weeks of gestation with premature rupture of membranes (PROM) were studied. Blood samples for C-reactive protein, WBC and neutrophil counts were taken at delivery. Placental histology was evaluated for histologic chorioamnionitis. Maternal and neonatal complications were observed. Among women with and without histologic chorioamnionitis, the maternal WBC and neutrophil counts were different (P<0.05) but the maternal serum C-reactive protein was not. Cutoff values for C-reactive protein, WBC, and neutrophil counts were 0.5 mg/dL, 15,000 cell/mm3, and 80 per cent, respectively. Sensitivity and specificity were 56 per cent and 58 per cent for C-reactive protein, 60 per cent and 63 per cent for WBC count, and 62 per cent and 54 per cent for neutrophil count, respectively. In conclusion, the maternal serum C-reactive protein, WBC, and neutrophil counts have poor diagnostic performance for histologic chorioamnionitis.

Adolescent↗

[Maternal serum cytokines in labor, pregnancy and chorioamnionitis].

UNLABELLED: The purpose of our study was to compare maternal serum levels of interleukin-6, interleukin-8, tumor necrosis factor-alpha and interferon-gamma in gravidities, during spontaneous term and preterm labor and their relation to histologic chorioamnionitis. METHODS: We investigated 61 women: 10 in preterm labor, 36 in term labor and 15 healthy pregnant nonlabouring controls. Venous bloods for cytokines determinations were obtained during the first stage of labor and during routine screening tests. Titers of cytokines were measured by means of ELISA technique. All births after preterm deliveries were examined to establish histologic chorioamnionitis. RESULTS: Serum levels of IL-6 and IL-8 were significantly elevated both in term (mean: IL-6: 17.5 +/- 58 pg/ml; IL-8: 148 +/- 215 pg/ml) and preterm labor (IL-6: 23 +/- 44 pg/ml; IL-8: 332 +/- 389 pg/ml) when compared to nonlabouring gravidities (IL-6: 5 +/- 7 pg/ml; IL-8: 14 +/- 11 pg/ml). IL-6 and IL-8 titers were statistically similar in term and preterm labors and in patients with and without histologic chorioamnionitis. TNF-alpha and IFN-gamma were not statistically analyzed because only a few patients had detectable serum levels of these cytokines. CONCLUSION: Serum levels of IL-6 and IL-8 in both: term and preterm labor are elevated in comparison to nonlabouring gravidities. The elevated levels of these cytokines are not connected with coexisting chorioamnionitis.

Adult↗

[Histologic chorioamnionitis is associated with cerebral palsy].

OBJECTIVE: The objective of this study was to determine the interaction between histologic chorioamnionitis and unexplained neonatal cerebral palsy among low-birth-weight infants. METHODS: 105 preterm infants delivered under 1500 g between 2000-2004 were studied. The clinical data, the neonatal neuroimaging, the laboratory results finds and the histopathologic features of fetal parts (placenta, umbilical cord and membranes) were evaluated. RESULTS: During the study period cerebral palsy were detected in 7.6% (8/105) of the newborns. The frequency of silent histologic chorioamnionitis was 39.7% (31 cases). The rate of caesarean section was 80.9% (72/89 deliveries), and elective operation was made in 51 cases (70.1%). In a logistic regression analysis controlling for confounding factors, compared with data on uninfected infants, histologic chorioamnionitis was significantly associated with risk of unexplained cerebral palsy (p = 0.006). There was also significant interaction between the maternal genital infections and chorioamnionitis (p = 0.024), and the maternal infections and positive smear of neonatal gastric aspirates (p = 0.033). There was no significant association between of intrapartum distress, the maternal genital infections, the prematurity and the maternal complications (hypertension, preeclampsia, diabetes mellitus, IUGR). Neither mechanic nor hypoxic ischaemic encephalopathy were demonstrated. CONCLUSION: Intrauterine exposure to maternal infection was associated with a marked increase in risk for cerebral palsy in infants of birth weight less than 1500 g.

Adult↗

Intrauterine growth of infants with chorioamnionitis.

The relationship between chorioamnionitis and fetal growth was examined by analysing the data of 299 infants with chorioamnionitis and the data of 296 infants with normal placentas. Six parameters were used for estimation of fetal growth: birth weight, length, head circumference, ponderal index, the ratio of length to head circumference and gestational age. Chorioamnionitis was identified, when at least 10 neutrophils per microscopic high-power field were present in the plate of placenta. There was no significant difference between the two groups at full term infants. The comparison could not be made under 37 weeks of gestation. It was concluded that chorioamnionitis probably did not impair particularly the fetal growth.

Birth Weight↗