A Comparison of Obstetric Interventions and Outcomes Between Black and White Patients at an Urban Tertiary Medical Center.

The objective of the study is to evaluate whether rates of selected labor and delivery interventions and severe maternal morbidity (SMM) differ between Black and White pregnant patients. This retrospective observational cohort study included all Black or White pregnant patients who delivered at the University of Chicago Medical Center between January 2015 and December 2019. Data queried included demographic information, antepartum complications, preterm interventions, labor and delivery events, and neonatal outcomes. SMM was a composite outcome, including intensive care unit admission, blood transfusion, hysterectomy, eclampsia, cardiac arrest, or death. In total, 10,885 parturients (9001 Black and 1884 White) and 11,211 neonates (9254 born to Black and 1957 to White patients) were included in the study. Black patients were more likely to have preterm labor (3.51% vs. 1.86%, p = 0.0002) and no prenatal care (17.83% vs. 4.05%, p < 0.0001). There was no significant difference in the administration of magnesium sulfate for fetal neuroprotection (Black 44.78% vs. White 49.32%, p = 0.48) or antenatal corticosteroids (Black 67.83% vs. White 71.98%, p = 0.28) among those with preterm delivery. There was no significant difference in SMM (Black 2.24% vs. White 2.44%, p = 0.60), and SMM rates decreased over time (OR 0.79 per year, 95% CI: 0.72-0.87, p < 0.0001) for all patients. Black patients had more pregnancy complications, but their complications were addressed with similar rates of obstetrical interventions. In a high-resource setting, there was no difference in rates of SMM when compared to White patients.

Association of fetal sex with angiogenic factors in normotensive and hypertensive pregnancy states.

OBJECTIVES: With the incorporation of angiogenic biomarkers into clinical practice, identification of potential modifiers of the angiogenic profile, including fetal sex, is essential. STUDY DESIGN: In this retrospective cohort analysis, patients with hypertensive disorders of pregnancy (HDP) and normotensive pregnancies were enrolled upon admission to Labor and Delivery. Blood samples for angiogenic factors were assessed using an automated platform. Clinical and demographic information was abstracted from each patient's medical records. MAIN OUTCOME MEASURES: Soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF) levels and their ratio in relation to fetal sex in patients with normotensive pregnancies compared to those with HDP were evaluated. RESULTS: A total of 617 patients were analyzed (299 normotensive, 113 gestational hypertensive, 71 chronic hypertensive, and 134 preeclamptic patients). There was no difference between the number of patients who had a male fetus among preeclampsia and normotensive parturients (56.0 % vs 50.2 %, p = 0.26). Normotensive patients carrying a male fetus had significantly higher sFlt1 (pg/ml) (3168 [IQR: 2160-4945] vs 2678 [IQR: 1752-4271]; p = 0.01) and sFlt1/PlGF ratios (18 [IQR: 7-44] vs 12 [IQR: 5-30]; p = 0.01) in comparison to pregnant patients carrying a female fetus. This difference between fetal sexes was not observed in the angiogenic profile of patients with HDP. CONCLUSIONS: Our study of primarily Black, obese patients demonstrates that normotensive patients carrying a male fetus have a significantly higher sFlt1 and sFlt1/PlGF ratio as compared to those carrying a female fetus at term gestation. Fetal sex should be considered as a covariate when studying angiogenic factors in normotensive pregnant patients.

Angiogenic Biomarkers for Risk Stratification in Women with Preeclampsia.

BACKGROUND: Preeclampsia is a leading cause of maternal and neonatal mortality and morbidity worldwide. Diagnosis of the condition is currently limited to utilization of nonspecific signs and symptoms. However, identification of potential pathogenic biomarkers may support earlier diagnosis and ultimately improved prognosis. CONTENT: The current models of preeclampsia suggest that the disease has components of abnormal placentation, a degree of angiogenic imbalance and endothelial dysfunction. Angiogenic factors such as soluble fms-like tyrosine kinase-1 and soluble endoglin increase while placental growth factor concentrations decrease in the circulation weeks before the onset of the disease. Multiple studies have looked at the capacity of angiogenic factors for the prediction of preeclampsia and adverse pregnancy outcomes. SUMMARY: The goal of this review is to focus on the role of angiogenic factors in the pathogenesis of preeclampsia and use of angiogenic biomarkers for risk stratification, diagnosis, and prognosis of the disease.

Prevalence and management of severe intrapartum hypertension in patients with preeclampsia at an urban tertiary care medical center.

OBJECTIVES: Data on management of severe intrapartum hypertension is lacking. The aim of this study is to explore the proportion of timely interventions in severe, persistent intrapartum hypertension treatment by exploring the prevalence and management of intrapartum hypertension trends. STUDY DESIGN: This was a retrospective case-control study of pregnant women who delivered at the University of Chicago between January 2015 and March 2017. Patients with severe preeclampsia who underwent labor (either induced or spontaneous) were stratified into two groups: severe intrapartum hypertension and no severe intrapartum hypertension. MAIN OUTCOME MEASURES: Type of treatment and timing to treatment of severe hypertensive episodes were explored as well as prevalence of maternal adverse outcomes. RESULTS: A total of 95 patients with severe preeclampsia in labor were identified. In patients with persistent severe intrapartum hypertension (n = 52), 15 (28.9%) received treatment. Patients experiencing greater than three episodes of blood pressure elevation were more likely to receive treatment as compared to those with fewer episodes. There was no significant difference in severe maternal morbidity (SMM) between those treated within 60 min compared to those untreated or treated after 60 min (16.7% vs 27.5%; p = 0.71). CONCLUSIONS: Management protocols of intrapartum hypertensive episodes are variable or not universally implemented. Inadequately treated episodes of severe intrapartum hypertension trend towards higher rates of SMM.

Management of a Splenic Artery Aneurysm in the Third Trimester of Pregnancy.

BACKGROUND: Splenic artery aneurysm (SAA) is a rare but potentially fatal complication associated with high maternal and fetal mortality when occurring during pregnancy. CASE: A 29-year-old G4P3003 at 34 4/7 weeks of gestation was admitted with left upper quadrant pain and newly diagnosed SAA in the hilum. She was scheduled for embolization of the SAA but the night before went into labor. A multidisciplinary team discussion was held, and the patient underwent successful primary low transverse c-section via Pfannenstiel skin incision followed by laparoscopic splenectomy under general anesthesia. She delivered a male newborn with birth weight of 2855 and Apgar score of 8/5. Summary and Conclusion. Early diagnosis and management of SAA are key for improved maternal and fetal outcomes. Our case demonstrates that through a multidisciplinary approach and anticipation of the possible clinical scenarios, good outcomes can be achieved.

The profiles of soluble adhesion molecules in the "great obstetrical syndromes".

OBJECTIVE: The objective of this study was to determine the profiles of maternal plasma soluble adhesion molecules in patients with preeclampsia, small-for-gestational-age (SGA) fetuses, acute pyelonephritis, preterm labor with intact membranes (PTL), preterm prelabor rupture of the membranes (preterm PROM), and fetal death. MATERIALS AND METHODS: A cross-sectional study was conducted to determine maternal plasma concentrations of sE-selectin, sL-selectin, and sP-selectin as well as sICAM-1, sVCAM-1, and sPECAM-1 in patients with (1) an uncomplicated pregnancy (control, n = 100); (2) preeclampsia (n = 94); (3) SGA fetuses (in women without preeclampsia/hypertension, n = 45); (4) acute pyelonephritis (n = 25); (5) PTL (n = 53); (6) preterm PROM (n = 24); and (7) fetal death (n = 34). Concentrations of soluble adhesion molecules and inflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-8) were determined with sensitive and specific enzyme-linked immunoassays. RESULTS: In comparison to women with a normal pregnancy, (1) women with preeclampsia had higher median concentrations of sE-selectin, sP-selectin, and sVCAM-1, and a lower concentration of sL-selectin (all p values < .001); (2) patients with SGA fetuses had higher median concentrations of sE-selectin, sP-selectin, and sVCAM-1 (all p values < .05); (3) patients with a fetal death had higher median concentrations of sE-selectin and sP-selectin (all p values < .05); (4) patients with acute pyelonephritis had higher median plasma concentrations of sE-selectin, sICAM-1, and sVCAM-1 (all p values < .001); (5) patients with preeclampsia and acute pyelonephritis, plasma concentrations of sVCAM-1, sE-selectin, and sP-selectin correlated with those of the proinflammatory cytokines TNF-α and interleukin (IL)-8 (all p values < .05); (6) patients with PTL had a higher median concentration of sP-selectin and a lower median concentration of VCAM-1 (all p values < .05); and (7) women with preterm PROM had lower median concentrations of sL-selectin and sVCAM-1 (all p values < .05). CONCLUSIONS: The results of this study show that endothelial cell activation/dysfunction reflected by the plasma concentration of sE-selectin is not specific to preeclampsia but is present in pregnancies complicated by SGA fetuses, acute pyelonephritis, and fetal death. Collectively, we report that each obstetrical syndrome appears to have a stereotypical profile of soluble adhesion molecules in the peripheral circulation.

The Rising Triad of Cesarean Scar Pregnancy, Placenta Percreta, and Uterine Rupture: A Case Report and Comprehensive Review of the Literature.

As the rate of cesarean sections continues to rapidly rise, knowledge of diagnosis and management of cesarean scar pregnancies (CSPs) is becoming increasingly more relevant. CSPs rest on the continuum of placental abnormalities which include morbidly adherent placenta (accreta, increta, and percreta). A CSP poses a clinical challenge which may have significant fetal and maternal morbidity. At this point, no clear management guidelines and recommendations exist. Herein we describe the case of a second trimester CSP with rapid diagnosis and management in a tertiary care center. The case underscores the need for well-coordinated mobilization of resources and a multidisciplinary approach. A review of the literature is performed and deficits in universal management principles are underscored.

Atrial Fibrillation as a Rare Complication of the Use of Nifedipine as a Tocolytic Agent: A Case Report and Review of the Literature.

Calcium channel blockers are commonly used tocolytic agents on Labor and Delivery units worldwide as part of the management of preterm labor. Despite their overall reassuring safety profile, rare cardiovascular complications have been reported. In this report, we describe the case of threatened preterm labor managed with nifedipine with subsequent development of atrial fibrillation. This type of cardiac arrhythmia may have considerable consequences for both the mother and the fetus. The aim of this case report and comprehensive review of the literature is to raise awareness.

Comparison of rapid MMP-8 and interleukin-6 point-of-care tests to identify intra-amniotic inflammation/infection and impending preterm delivery in patients with preterm labor and intact membranes.

OBJECTIVE: Among patients presenting with preterm labor and intact membranes, those with intra-amniotic inflammation have adverse obstetrical and neonatal outcomes. The diagnosis of intra-amniotic inflammation can easily be made by detecting an elevated concentration of the cytokine interleukin (IL)-6 or the enzyme neutrophil collagenase, also known as matrix metalloproteinase (MMP)-8. The diagnostic performances of MMP-8 and IL-6 enzyme-linked immunosorbent assay tests are similar. Recently, a rapid test has become available for point-of-care determination of either MMP-8 or IL-6. The objectives of this study were to compare the diagnostic indices and predictive values between the rapid MMP-8 and IL-6 tests for the identification of intra-amniotic inflammation in patients with preterm labor and intact membranes. MATERIALS AND METHODS: We performed a retrospective cohort study including 124 women with singleton pregnancies who presented with symptoms of preterm labor and underwent transabdominal amniocentesis for the evaluation of microbial invasion of the amniotic cavity (MIAC). MIAC was defined according to amniotic fluid culture results (aerobic and anaerobic bacteria as well as genital Mycoplasmas). Amniotic fluid white blood cell (WBC) counts were determined using a hemocytometer chamber. An elevated amniotic fluid MMP-8 concentration was assessed using Yoon's MMP-8 Check® (cutoff: 10 ng/mL). An elevated amniotic fluid IL-6 concentration was scored when there was a positive result for the lateral flow-based immunoassay (cutoff: ≥745 pg/mL and ≥1000 pg/mL). In order to objectively compare rapid MMP-8 and rapid IL-6 tests to identify intra-amniotic inflammation, an amniotic fluid WBC count of ≥50 cells/mm3 was used to define intra-amniotic inflammation. RESULTS: (1) The rapid tests had the same sensitivity for the detection of intra-amniotic inflammation [85.7% (18/21) for all]; (2) the specificity of the rapid MMP-8 test was higher than that of the rapid IL-6 test (cutoff: 745 pg/mL) for the identification of intra-amniotic inflammation [72.8% (75/103) vs. 64.1% (66/103); p < 0.05]; and (3) there were no differences in the sensitivity and specificity between the rapid MMP-8 test and the rapid IL-6 test (cutoff:1000 pg/mL) in the identification of intra-amniotic inflammation. Of 13 patients with discrepant results between the rapid MMP-8 and rapid IL-6 tests, two had a positive MMP-8 but a negative rapid IL-6 test, and both delivered preterm - one within 24 h, and the other within 10 days - and both had acute histologic chorioamnionitis. On the other hand, there were 11 patients with a positive rapid IL-6 but a negative rapid MMP-8 result: 10 delivered preterm, 3 had acute histologic chorioamnionitis and 1 had subacute chorionitis. CONCLUSION: We conclude that the rapid MMP-8 test has a better specificity than the rapid IL-6 (cutoff: 745 pg/mL) assay for the detection of intra-amniotic infection. Moreover, we observed that among patients who were not identified as having intra-amniotic infection or inflammation by the standard cultivation technique and amniotic fluid WBC count, those who had a positive MMP-8 rapid test delivered preterm and had acute histologic chorioamnionitis.

Clinical chorioamnionitis at term VIII: a rapid MMP-8 test for the identification of intra-amniotic inflammation.

OBJECTIVE: Clinical chorioamnionitis is the most common infection/inflammatory process diagnosed in labor and delivery units worldwide. The condition is a syndrome that can be caused by (1) intra-amniotic infection, (2) intra-amniotic inflammation without demonstrable microorganisms (i.e. sterile intra-amniotic inflammation), and (3) maternal systemic inflammation that is not associated with intra-amniotic inflammation. The presence of intra-amniotic inflammation is a risk factor for adverse maternal and neonatal outcomes in a broad range of obstetrical syndromes that includes clinical chorioamnionitis at term. Although the diagnosis of intra-amniotic infection has relied on culture results, such information is not immediately available for patient management. Therefore, the diagnosis of intra-amniotic inflammation could be helpful as a proxy for intra-amniotic infection, while results of microbiologic studies are pending. A rapid test is now available for the diagnosis of intra-amniotic inflammation, based on the determination of neutrophil collagenase or matrix metalloproteinase-8 (MMP-8). The objectives of this study were (1) to evaluate the diagnostic indices of a rapid MMP-8 test for the identification of intra-amniotic inflammation/infection in patients with the diagnosis of clinical chorioamnionitis at term, and (2) to compare the diagnostic performance of a rapid MMP-8 test to that of a conventional enzyme-linked immunosorbent assay (ELISA) interleukin (IL)-6 test for patients with clinical chorioamnionitis at term. MATERIALS AND METHODS: A retrospective cohort study was conducted. A transabdominal amniocentesis was performed in patients with clinical chorioamnionitis at term (n=44). Amniotic fluid was analyzed using cultivation techniques (for aerobic and anaerobic bacteria as well as genital Mycoplasmas) and broad-range polymerase chain reaction (PCR) coupled with electrospray ionization mass spectrometry (PCR/ESI-MS). Amniotic fluid IL-6 concentrations were determined by ELISA, and rapid MMP-8 results were determined by Yoon's MMP-8 Check®. Intra-amniotic inflammation was defined as an elevated amniotic fluid IL-6 concentration ≥2.6 ng/mL, and intra-amniotic infection was diagnosed by the presence of microorganisms in the amniotic fluid accompanied by intra-amniotic inflammation. The diagnostic indices of Yoon's MMP-8 Check® for the identification of intra-amniotic inflammation were calculated. In order to objectively compare Yoon's MMP-8 Check® with the ELISA IL-6 test for the identification of intra-amniotic inflammation, we used an amniotic fluid white blood cell (WBC) count ≥50 cells/mm3 to define intra-amniotic inflammation. RESULTS: (1) A positive rapid MMP-8 test had a sensitivity of 82.4% (28/34), specificity of 90% (9/10), positive predictive value of 96.6% (28/29), negative predictive value of 60% (9/15), positive likelihood ratio 8.2 (95% CI 1.3-53.2), and negative likelihood ratio 0.2 (95% CI 0.1-0.4) for the identification of intra-amniotic inflammation (prevalence 77.3%); (2) a positive rapid MMP-8 test had a sensitivity of 91.7% (22/24), specificity of 65% (13/20), positive predictive value of 75.9% (22/29), negative predictive value of 86.7% (13/15), positive likelihood ratio of 2.6 (95% CI 1.4-4.8), and negative likelihood ratio of 0.1 (95% CI 0.03-0.5) for the identification of intra-amniotic infection; (3) the rapid MMP-8 test had a significantly higher specificity than the ELISA IL-6 test in the identification of intra-amniotic inflammation as determined by an amniotic fluid WBC count ≥50 cells/mm3. The sensitivity and accuracy of the rapid MMP-8 test were comparable to those of the ELISA IL-6 test; and (4) importantly, the rapid MMP-8 test had 100% sensitivity and 100% negative predictive value in the identification of neonates affected with fetal inflammatory response syndrome (FIRS). CONCLUSION: The rapid diagnosis of intra-amniotic inflammation is possible by analysis of amniotic fluid using a point-of-care test for MMP-8. Patients with a positive test are at risk of delivering a neonate affected with systemic inflammation, a risk factor for adverse neonatal outcome.

CXCL10 and IL-6: Markers of two different forms of intra-amniotic inflammation in preterm labor.

PROBLEM: To determine whether amniotic fluid (AF) CXCL10 concentration is associated with histologic chronic chorioamnionitis in patients with preterm labor (PTL) and preterm prelabor rupture of the membranes (PROM). METHOD OF STUDY: This study included 168 women who had an episode of PTL or preterm PROM. AF interleukin (IL)-6 and CXCL10 concentrations were determined by immunoassay. RESULTS: (i) Increased AF CXCL10 concentration was associated with chronic (OR: 4.8; 95% CI: 1.7-14), but not acute chorioamnionitis; (ii) increased AF IL-6 concentration was associated with acute (OR: 4.2; 95% CI: 1.3-13.7) but not chronic chorioamnionitis; and (iii) an increase in AF CXCL10 concentration was associated with placental lesions consistent with maternal anti-fetal rejection (OR: 3.7; 95% CI: 1.3-10.4). (iv) All patients with elevated AF CXCL10 and IL-6 delivered preterm. CONCLUSION: Increased AF CXCL10 concentration is associated with chronic chorioamnionitis or maternal anti-fetal rejection, whereas increased AF IL-6 concentration is associated with acute histologic chorioamnionitis.

Clinical chorioamnionitis at term: the amniotic fluid fatty acyl lipidome.

Clinical chorioamnionitis at term (TCC) is the most common obstetrical infliction diagnosed in labor and delivery units worldwide and is associated with a substantial increase in maternal and neonatal morbidity and mortality. This obstetrical complication is a heterogeneous condition, as only half of patients have detectable microorganisms in the amniotic cavity. Because bioactive lipids play a key role in the initiation and resolution of an inflammatory response, we aimed to characterize the amniotic fluid lipidome in patients with TCC. We studied the amniotic fluid of patients in the following groups: 1) spontaneous labor at term without clinical chorioamnionitis (TLB) and 2) spontaneous labor at term with clinical chorioamnionitis (TCC). The TCC group was subdivided into a) those with microbial invasion of the amniotic cavity (TCC-MIAC) and b) those without microbial invasion of the amniotic cavity (TCC-noMIAC). The amniotic fluid concentration of proinflammatory lipid mediators did not differ between patients in TLB with TCC. In contrast, concentration of lipids with anti-inflammatory/proresolution properties was significantly lower in all patients with TCC than in those with TLB. These results suggest that while proinflammatory lipid mediators are involved in infection-driven intra-amniotic inflammation, a relative deficiency of anti-inflammatory/proresolution lipid mediator biosynthesis is a characteristic of TCC.

Gastric fluid versus amniotic fluid analysis for the identification of intra-amniotic infection due to Ureaplasma species.

OBJECTIVE: Early neonatal sepsis is often due to intra-amniotic infection. The stomach of the neonate contains fluid swallowed before and during delivery. The presence of bacteria as well as neutrophils detected by culture or Gram stain of the gastric fluid during the first day of life is suggestive of exposure to bacteria or inflammation. We undertook this study to determine the relationship between gastric fluid analysis and amniotic fluid obtained by transabdominal amniocentesis in the detection of Ureaplasma species, the most frequent microorganisms responsible for intra-amniotic infection. MATERIALS AND METHODS: The study population consisted of 100 singleton pregnant women who delivered preterm neonates (<35 weeks) within 7 days of amniocentesis. Gastric fluid of newborns was obtained by nasogastric intubation on the day of birth. Amniotic fluid and gastric fluid were cultured for genital Mycoplasmas, and polymerase chain reaction (PCR) for Ureaplasma species was performed. Intra-amniotic inflammation was defined as an elevated amniotic fluid matrix metalloproteinase-8 concentration (>23 ng/mL). RESULTS: (1) Ureaplasma species were detected by culture or PCR in 18% (18/100) of amniotic fluid samples and in 5% (5/100) of gastric fluid samples; (2) among the amniotic fluid cases positive for Ureaplasma species, these microorganisms were identified in 27.8% (5/18) of gastric fluid samples; (3) none of the cases negative for Ureaplasma species in the amniotic fluid were found to be positive for these microorganisms in the gastric fluid; (4) patients with amniotic fluid positive for Ureaplasma species but with gastric fluid negative for these microorganisms had a significantly higher rate of intra-amniotic inflammation, acute histologic chorioamnionitis, and neonatal death than those with both amniotic fluid and gastric fluid negative for Ureaplasma species; and (5) no significant differences were observed in the rate of intra-amniotic inflammation, acute histologic chorioamnionitis, and neonatal death between patients with amniotic fluid positive for Ureaplasma species but with gastric fluid negative for these microorganisms and those with both amniotic fluid and gastric fluid positive for Ureaplasma species. CONCLUSIONS: Gastric fluid analysis has 100% specificity in the identification of intra-amniotic infection with Ureaplasma species. However, the detection of Ureaplasma species by culture or PCR in the gastric fluid of neonates at birth did not identify these microorganisms in two-thirds of cases with microbial invasion of the amniotic cavity. Thus, amniotic fluid analysis is superior to that of gastric fluid in the identification of intra-amniotic infection.

Clinical chorioamnionitis at term III: how well do clinical criteria perform in the identification of proven intra-amniotic infection?

OBJECTIVE: The diagnosis of clinical chorioamnionitis is based on a combination of signs [fever, maternal or fetal tachycardia, foul-smelling amniotic fluid (AF), uterine tenderness and maternal leukocytosis]. Bacterial infections within the amniotic cavity are considered the most frequent cause of clinical chorioamnionitis and an indication for antibiotic administration to reduce maternal and neonatal morbidity. Recent studies show that only 54% of patients with the diagnosis of clinical chorioamnionitis at term have bacteria in the AF and evidence of intra-amniotic inflammation. The objective of this study was to examine the performance of the clinical criteria for the diagnosis of chorioamnionitis to identify patients with microbial-associated intra-amniotic inflammation (also termed intra-amniotic infection). MATERIALS AND METHODS: This retrospective cross-sectional study included 45 patients with the diagnosis of clinical chorioamnionitis at term, whose AF underwent analysis for: 1) the presence of microorganisms using both cultivation and molecular biologic techniques [polymerase chain reaction (PCR) with broad primers], and 2) interleukin (IL)-6 concentrations by enzyme-linked immunosorbent assay. The diagnostic performance (sensitivity, specificity, accuracy, and likelihood ratios) of each clinical sign and their combination to identify clinical chorioamnionitis were determined using microbial-associated intra-amniotic inflammation [presence of microorganisms in the AF using cultivation or molecular techniques and elevated AF IL-6 concentrations (≥2.6 ng/mL)] as the gold standard. RESULTS: The accuracy of each clinical sign for the identification of microbial-associated intra-amniotic inflammation (intra-amniotic infection) ranged between 46.7% and 57.8%. The combination of fever with three or more clinical criteria did not substantially improve diagnostic accuracy. CONCLUSION: In the presence of a fever during labor at term, signs used to diagnose clinical chorioamnionitis do not accurately identify the patient with proven intra-amniotic infection (i.e., those with microorganisms detected by culture or molecular microbiologic techniques and an associated intra-amniotic inflammatory response).

Clinical chorioamnionitis at term IV: the maternal plasma cytokine profile.

INTRODUCTION: Fever is a major criterion for clinical chorioamnionitis; yet, many patients with intrapartum fever do not have demonstrable intra-amniotic infection. Some cytokines, such as interleukin (IL)-1, IL-6, interferon-gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α), can induce a fever. The objective of this study was to determine whether maternal plasma concentrations of cytokines could be of value in the identification of patients with the diagnosis of clinical chorioamnionitis at term who have microbial-associated intra-amniotic inflammation. METHODS: A retrospective cross-sectional study was conducted, including patients with clinical chorioamnionitis at term (n=41; cases) and women in spontaneous labor at term without clinical chorioamnionitis (n=77; controls). Women with clinical chorioamnionitis were classified into three groups according to the results of amniotic fluid culture, broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS), and amniotic fluid IL-6 concentration: 1) no intra-amniotic inflammation; 2) intra-amniotic inflammation without detectable microorganisms; or 3) microbial-associated intra-amniotic inflammation. The maternal plasma concentrations of 29 cytokines were determined with sensitive and specific V-PLEX immunoassays. Nonparametric statistical methods were used for analysis, adjusting for a false discovery rate of 5%. RESULTS: 1) The maternal plasma concentrations of pyrogenic cytokines (IL-1ß, IL-2, IL-6, IFN-γ, and TNF-α) were significantly higher in patients with clinical chorioamnionitis at term than in those with spontaneous term labor without clinical chorioamnionitis; 2) the maternal plasma concentrations of cytokines were not significantly different among the three subgroups of patients with clinical chorioamnionitis (intra-amniotic inflammation with and without detectable bacteria and those without intra-amniotic inflammation); and 3) among women with the diagnosis of clinical chorioamnionitis, but without evidence of intra-amniotic inflammation, the maternal plasma concentrations of pyrogenic cytokines were significantly higher than in patients with spontaneous labor at term. These observations suggest that a fever can be mediated by increased circulating concentrations of these cytokines, despite the absence of a local intra-amniotic inflammatory response. CONCLUSIONS: 1) The maternal plasma concentrations of pyrogenic cytokines (e.g. IL-1ß, IL-2, IL-6, IFN-γ, and TNF-α) are higher in patients with intra-partum fever and the diagnosis of clinical chorioamnionitis at term than in those in spontaneous labor at term without a fever; and 2) maternal plasma cytokine concentrations have limited value in the identification of patients with bacteria in the amniotic cavity. Accurate assessment of the presence of intra-amniotic infection requires amniotic fluid analysis.

Clinical chorioamnionitis at term VI: acute chorioamnionitis and funisitis according to the presence or absence of microorganisms and inflammation in the amniotic cavity.

OBJECTIVE: Neonates born to mothers with clinical chorioamnionitis at term are at an increased risk of infection. Acute subchorionitis, chorioamnionitis, and funisitis are considered placental histologic features consistent with acute inflammation according to the Society for Pediatric Pathology. The objectives of this study were to examine the performance of placental histologic features in the identification of: 1) microbial-associated intra-amniotic inflammation (intra-amniotic infection); and 2) fetal inflammatory response syndrome (FIRS). METHODS: This retrospective cohort study included women with the diagnosis of clinical chorioamnionitis at term (n=45), who underwent an amniocentesis to determine: 1) the presence of microorganisms using both cultivation and molecular biologic techniques [polymerase chain reaction (PCR) with broad range primers]; and 2) interleukin (IL)-6 concentrations by enzyme-linked immunosorbent assay (ELISA). The diagnostic performance (sensitivity, specificity, accuracy, and likelihood ratios) of placental histologic features consistent with acute inflammation was determined for the identification of microbial-associated intra-amniotic inflammation and FIRS. RESULTS: 1) The presence of acute histologic chorioamnionitis and funisitis was associated with the presence of proven intra-amniotic infection assessed by amniotic fluid analysis; 2) funisitis was also associated with the presence of FIRS; 3) the negative predictive value of acute funisitis ≥stage 2 for the identification of neonates born to mothers with intra-amniotic infection was <50%, and therefore, suboptimal to exclude fetal exposure to bacteria in the amniotic cavity; and 4) acute funisitis ≥stage 2 had a negative predictive value of 86.8% for the identification of FIRS in a population with a prevalence of 20%. CONCLUSION: Acute histologic chorioamnionitis and funisitis are associated with intra-amniotic infection and the presence of FIRS. However, current pathologic methods have limitations in the identification of the fetus exposed to microorganisms present in the amniotic cavity. Further studies are thus required to determine whether molecular markers can enhance the performance of placental pathology in the identification of neonates at risk for neonatal sepsis.

Clinical chorioamnionitis at term V: umbilical cord plasma cytokine profile in the context of a systemic maternal inflammatory response.

OBJECTIVE: Microbial invasion of the fetus due to intra-amniotic infection can lead to a systemic inflammatory response characterized by elevated concentrations of cytokines in the umbilical cord plasma/serum. Clinical chorioamnionitis represents the maternal syndrome often associated with intra-amniotic infection, although other causes of this syndrome have been recently described. The objective of this study was to characterize the umbilical cord plasma cytokine profile in neonates born to mothers with clinical chorioamnionitis at term, according to the presence or absence of bacteria and/or intra-amniotic inflammation. MATERIALS AND METHODS: A cross-sectional study was conducted, including patients with clinical chorioamnionitis at term (n=38; cases) and those with spontaneous term labor without clinical chorioamnionitis (n=77; controls). Women with clinical chorioamnionitis were classified according to the results of amniotic fluid culture, broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS) and amniotic fluid interleukin (IL)-6 concentration into three groups: 1) no intra-amniotic inflammation; 2) intra-amniotic inflammation without detectable microorganisms; or 3) microbial-associated intra-amniotic inflammation. A fetal inflammatory response syndrome (FIRS) was defined as an umbilical cord plasma IL-6 concentration >11 pg/mL. The umbilical cord plasma concentrations of 29 cytokines were determined with sensitive and specific V-PLEX immunoassays. Nonparametric statistical methods were used for analysis, adjusting for a false discovery rate of 5%. RESULTS: 1) Neonates born to mothers with clinical chorioamnionitis at term (considered in toto) had significantly higher median umbilical cord plasma concentrations of IL-6, IL-12p70, IL-16, IL-13, IL-4, IL-10 and IL-8, but significantly lower interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF)-α concentrations than neonates born to mothers with spontaneous term labor without clinical chorioamnionitis; 2) neonates born to mothers with clinical chorioamnionitis at term but without intra-amniotic inflammation had higher concentrations of IL-6, IL-12p70, IL-13, IL-4, IL-5, and IL-8, but lower IFN-γ, than neonates not exposed to clinical chorioamnionitis, suggesting that maternal fever in the absence of intra-amniotic inflammation leads to a change in the fetal cytokine network; 3) there were significant, positive correlations between maternal and umbilical cord plasma IL-6 and IL-8 concentrations (IL-6: Spearman correlation=0.53; P<0.001; IL-8: Spearman correlation=0.42; P<0.001), consistent with placental transfer of cytokines; 4) an elevated fetal plasma IL-6 (>11 pg/mL), the diagnostic criterion for FIRS, was present in 21% of cases (8/38), and all these neonates were born to mothers with proven intra-amniotic infection; and 5) FIRS was associated with a high concentration of umbilical cord plasma IL-8, IL-10 and monocyte chemoattractant protein (MCP)-1. CONCLUSIONS: Neonates born to mothers with clinical chorioamnionitis at term had higher concentrations of umbilical cord plasma cytokines than those born to mothers without clinical chorioamnionitis. Even neonates exposed to clinical chorioamnionitis but not to intra-amniotic inflammation had elevated concentrations of multiple cytokines, suggesting that intrapartum fever alters the fetal immune response.

Clinical chorioamnionitis at term II: the intra-amniotic inflammatory response.

OBJECTIVE: Recent studies indicate that clinical chorioamnionitis is a heterogeneous condition and only approximately one-half of the patients have bacteria in the amniotic cavity, which is often associated with intra-amniotic inflammation. The objective of this study is to characterize the nature of the inflammatory response within the amniotic cavity in patients with clinical chorioamnionitis at term according to the presence or absence of 1) bacteria in the amniotic cavity and 2) intra-amniotic inflammation. MATERIALS AND METHODS: A retrospective cross-sectional case-control study was conducted to examine cytokine and chemokine concentrations in the amniotic fluid (AF). Cases consisted of women with clinical chorioamnionitis at term (n=45). Controls were women with uncomplicated pregnancies at term who did not have intra-amniotic inflammation and were in labor (n=24). Women with clinical chorioamnionitis were classified according to the results of AF cultures, broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry, and AF concentration of interleukin-6 (IL-6) into those: 1) without intra-amniotic inflammation, 2) with microbial-associated intra-amniotic inflammation, and 3) with intra-amniotic inflammation without detectable bacteria. The AF concentrations of 29 cytokines/chemokines were determined using sensitive and specific V-PLEX immunoassays. RESULTS: 1) The AF concentrations of pro- and anti-inflammatory cytokines/chemokines such as interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin-4 (IL-4), macrophage inflammatory protein-1 beta (MIP-1ß), and interleukin-8 (IL-8) (except Eotaxin-3) were significantly higher in women with clinical chorioamnionitis at term than in controls (term labor without intra-amniotic inflammation); 2) patients with microbial-associated intra-amniotic inflammation, and those with intra-amniotic inflammation without detectable bacteria, had a dramatic differential expression of cytokines and chemokines in AF compared to patients with spontaneous labor without intra-amniotic inflammation. However, no difference could be detected in the pattern of the intra-amniotic inflammatory response between patients with intra-amniotic inflammation with and without detectable bacteria; and 3) in patients with clinical chorioamnionitis at term but without intra-amniotic inflammation, the behavior of cytokines and chemokines in the AF was similar to those in spontaneous labor at term. CONCLUSIONS: Patients with clinical chorioamnionitis who had microbial-associated intra-amniotic inflammation or intra-amniotic inflammation without detectable bacteria had a dramatic upregulation of the intra-amniotic inflammatory response assessed by amniotic fluid concentrations of cytokines. A subset of patients with term clinical chorioamnionitis does not have intra-amniotic infection/inflammation, as demonstrated by elevated AF concentrations of inflammation-related proteins, when compared to women in term labor with uncomplicated pregnancies, suggesting over-diagnosis. These observations constitute the first characterization of the cytokine/chemokine network in the amniotic cavity of patients with clinical chorioamnionitis at term.