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Objectives To investigate mechanisms of in utero death in normally formed fetuses by measuring amniotic fluid (AF) biomarkers for hypoxia (erythropoietin [EPO]), myocardial damage (cardiac troponin I [cTnI]) and brain injury (glial fibrillary acidic protein [GFAP]), correlated with risk factors for fetal death and placental histopathology. Methods This retrospective, observational cohort study included intrauterine deaths with transabdominal amniocentesis prior to induction of labor. Women with a normal pregnancy and an indicated amniocentesis at term were randomly selected as controls. AF was assayed for EPO, cTnI and GFAP using commercial immunoassays. Placental histopathology was reviewed, and CD15-immunohistochemistry was used. Analyte concentrations >90th centile for controls were considered "raised". Raised AF EPO, AF cTnI and AF GFAP concentrations were considered evidence of hypoxia, myocardial and brain injury, respectively. Results There were 60 cases and 60 controls. Hypoxia was present in 88% (53/60), myocardial damage in 70% (42/60) and brain injury in 45% (27/60) of fetal deaths. Hypoxic fetuses had evidence of myocardial injury, brain injury or both in 77% (41/53), 49% (26/53) and 13% (7/53) of cases, respectively. Histopathological evidence for placental dysfunction was found in 74% (43/58) of these cases. Conclusion Hypoxia, secondary to placental dysfunction, was found to be the mechanism of death in the majority of fetal deaths among structurally normal fetuses. Ninety-one percent of hypoxic fetal deaths sustained brain, myocardial or both brain and myocardial injuries in utero. Hypoxic myocardial injury was an attributable mechanism of death in 70% of the cases. Non-hypoxic cases may be caused by cardiac arrhythmia secondary to a cardiac conduction defect.

Objective: To describe a novel method (Fetal Intelligent Navigation Echocardiography (FINE)) for visualization of standard fetal echocardiography views from volume datasets obtained with spatiotemporal image correlation (STIC) and application of 'intelligent navigation' technology., Methods: We developed a method to: 1) demonstrate nine cardiac diagnostic planes; and 2) spontaneously navigate the anatomy surrounding each of the nine cardiac diagnostic planes (Virtual Intelligent Sonographer Assistance (VIS-Assistance®)). The method consists of marking seven anatomical structures of the fetal heart. The following echocardiography views are then automatically generated: 1) four chamber; 2) five chamber; 3) left ventricular outflow tract; 4) short-axis view of great vessels/right ventricular outflow tract; 5) three vessels and trachea; 6) abdomen/stomach; 7) ductal arch; 8) aortic arch; and 9) superior and inferior vena cava. The FINE method was tested in a separate set of 50 STIC volumes of normal hearts (18.6-37.2 weeks of gestation), and visualization rates for fetal echocardiography views using diagnostic planes and/or VIS-Assistance® were calculated. To examine the feasibility of identifying abnormal cardiac anatomy, we tested the method in four cases with proven congenital heart defects (coarctation of aorta, tetralogy of Fallot, transposition of great vessels and pulmonary atresia with intact ventricular septum)., Results: In normal cases, the FINE method was able to generate nine fetal echocardiography views using: 1) diagnostic planes in 78-100% of cases; 2) VIS-Assistance® in 98-100% of cases; and 3) a combination of diagnostic planes and/or VIS-Assistance® in 98-100% of cases. In all four abnormal cases, the FINE method demonstrated evidence of abnormal fetal cardiac anatomy., Conclusions: The FINE method can be used to visualize nine standard fetal echocardiography views in normal hearts by applying 'intelligent navigation' technology to STIC volume datasets. This method can simplify examination of the fetal heart and reduce operator dependency. The observation of abnormal echocardiography views in the diagnostic planes and/or VIS-Assistance® should raise the index of suspicion for congenital heart disease., (Published 2013. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: To determine the usefulness of a fetal ear length nomogram in the prenatal detection of fetal aneuploidy and to determine whether ear smallness in cases of aneuploidy is a primary or secondary event., Methods: Ear lengths of 447 singleton fetuses (October 1996 to October 1997)were prospectively evaluated between 14 and 41 weeks to establish a nomogram created by modeling the mean and SD separately. Records of aneuploid fetuses were retrospectively reviewed, and their ear lengths were plotted against the nomogram to determine detection rates, with ear length in or below the 10th and 50th percentiles for a given gestational age and biparietal diameter used as abnormal cutoffs., Results: The nomogram for fetal ear length measurements provided sufficient data to derive the 10th, 50th, and 90th percentiles on the basis of gestational age and biparietal diameter. The ear length of euploid fetuses was significantly correlated with gestational age (R2 = 0.96; P < .001) and biparietal diameter (R2 = 0.95; P < .001). From 96 aneuploid fetuses identified, 63 had ear lengths in or below the 10th percentile for gestational age (sensitivity, 66%). When using ear length against biparietal diameter, the sensitivities for all aneuploid fetuses for cutoffs at or below the 10th and 50th percentiles were 43% (40 of 93) and 83% (77 of 93), respectively., Conclusions: Most aneuploid fetuses have sonographically small ears (< or = 10th percentile for gestational age). This smallness is not entirely related to overall small fetal size, but in almost half the cases, the fetal ear length is disproportionately smaller than the biparietal diameter.

Objective: To describe the prenatal detection of fetal trisomy 18 through abnormal sonographic features and to determine the sensitivity of sonographically detecting fetuses with trisomy 18., Methods: All genetic and cytogenetic records of fetuses with trisomy 18 were reviewed retrospectively (1992-2002). From these, singleton fetuses who had prenatal sonography at our unit were identified. The maximal numbers of individual abnormalities from 1 sonographic examination (not limited to type of organ system) were recorded. Each abnormality was classified as major, minor, or "other," and each organ system was classified as abnormal only once, regardless of the number of individual abnormalities identified in that system. The sensitivity of sonography in detecting abnormalities of trisomy 18 was determined., Results: Of 38 fetuses identified with trisomy 18, all had 4 or more prenatally detected sonographic abnormalities (sensitivity of sonographic detection of fetuses with trisomy 18, 100%). The median number of abnormalities per examination was 8 (range, 4-19). Sonographically detected major abnormalities were cardiac (84%; n = 32), central nervous system (87%; n = 33), gastrointestinal (26%; n = 10), and genitourinary (16%; n = 6). Sonographically detected minor abnormalities were short ear length below the 10th percentile for gestational age (96%; n = 26/27), upper extremities and hands (95%; n = 36), lower extremities and feet (63%; n = 24), and face (53%; n = 20). Fifty percent (19 of 38) had choroid plexus cysts identified, but this was never an isolated finding., Conclusions: In experienced hands, the sensitivity of detecting fetal trisomy 18 on prenatal sonography is 100%, and all cases will have multiple anomalies visualized.

Preeclampsia is one of the "great obstetrical syndromes" in which multiple and sometimes overlapping pathologic processes activate a common pathway consisting of endothelial cell activation, intravascular inflammation, and syncytiotrophoblast stress. This article reviews the potential etiologies of preeclampsia. The role of uteroplacental ischemia is well-established on the basis of a solid body of clinical and experimental evidence. A causal role for microorganisms has gained recognition through the realization that periodontal disease and maternal gut dysbiosis are linked to atherosclerosis, thus possibly to a subset of patients with preeclampsia. The recent reports indicating that SARS-CoV-2 infection might be causally linked to preeclampsia are reviewed along with the potential mechanisms involved. Particular etiologic factors, such as the breakdown of maternal-fetal immune tolerance (thought to account for the excess of preeclampsia in primipaternity and egg donation), may operate, in part, through uteroplacental ischemia, whereas other factors such as placental aging may operate largely through syncytiotrophoblast stress. This article also examines the association between gestational diabetes mellitus and maternal obesity with preeclampsia. The role of autoimmunity, fetal diseases, and endocrine disorders is discussed. A greater understanding of the etiologic factors of preeclampsia is essential to improve treatment and prevention. [ABSTRACT FROM AUTHOR]

Intra-amniotic infection, defined by the presence of microorganisms in the amniotic cavity, is often accompanied by intra-amniotic inflammation. Occasionally, laboratories report the growth of bacteria or the presence of microbial nucleic acids in amniotic fluid in the absence of intra-amniotic inflammation. This study was conducted to determine the clinical significance of the presence of bacteria in amniotic fluid samples in the absence of intra-amniotic inflammation. A retrospective cross-sectional study included 360 patients with preterm labor and intact membranes who underwent transabdominal amniocentesis for evaluation of the microbial state of the amniotic cavity as well as intra-amniotic inflammation. Cultivation techniques were used to isolate microorganisms, and broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS) was utilized to detect the nucleic acids of bacteria, viruses, and fungi. Patients whose amniotic fluid samples evinced microorganisms but did not indicate inflammation had a similar perinatal outcome to those without microorganisms or inflammation [amniocentesis-to-delivery interval (p=0.31), spontaneous preterm birth before 34 weeks (p=0.83), acute placental inflammatory lesions (p=1), and composite neonatal morbidity (p=0.8)]. The isolation of microorganisms from a sample of amniotic fluid in the absence of intra-amniotic inflammation is indicative of a benign condition, which most likely represents contamination of the specimen during the collection procedure or laboratory processing rather than early colonization or infection. [ABSTRACT FROM AUTHOR]

Objective: Prostaglandins (PGs) are considered the universal mediators of parturition. Amniotic fluid PGE2and PGF2αconcentrations increase before the onset of spontaneous labor at term, as well as during labor. This study was conducted to determine if the concentrations of umbilical cord PGE2and PGF2α change with advancing gestational age, spontaneous labor at term, and preterm labor (with and without funisitis). Methods: Umbilical cord (UC) tissue samples were obtained from women (N = 158) with singleton pregnancies in the following groups: (1) term deliveries without labor (TNL;n = 20); (2) term deliveries with labor (TIL;n = 20); (3) spontaneous preterm deliveries (sPTD) with (n = 20) and without acute funisitis (n = 20); and (4) preeclampsia without labor (n = 78). The concentrations of PGs were determined in different locations of the UC. PGE2and PGF2αwere measured by specific immunoassays. Non-parametric statistics were used for analysis. Results: (1) In spontaneous preterm deliveries, the median UC PGE2concentration was higher in cases with funisitis than in those without funisitis (233.7 pg/µg versus 87.4 pg/µg of total protein,p = 0.001); (2) the median UC PGE2concentration in sPTD with funisitis was also higher than that obtained from samples who had undergone labor at term (233.7 pg/µg versus 116.1 pg/µg of total protein,p = 0.03); (3) the UC PGE2and PGF2αconcentration increased as a function of advancing gestational age before 36 weeks (PGE2: ρ = 0.59,p < 0.001; PGF2α: ρ = 0.39,p = 0.01), but not after 36 weeks (PGE2: ρ = −0.1,p = 0.5; PGF2α: ρ = −0.2,p = 0.2); (4) the median UC concentrations of PGE2and PGF2αat term was similar in samples obtained from women with and without labor (PGE2: TNL 133.7 pg/µg versus TIL 116.1 pg/µg of total protein,p = 0.9; PGF2α: TNL 8.4 pg/µg versus TIL 8.1 pg/µg of total protein,p = 0.7); and (5) there was no correlation between UC PG concentration and gestational age at term pregnancy (PGE2: ρ = 0.01,p = 0.9; PGF2α: ρ = 0.07,p = 0.7). Conclusions: (1) PGE2concentrations in the UC are higher in the presence of acute funisitis than in the absence of this lesion; (2) spontaneous labor at term was not associated with a change in the UC concentration of PGE2and PGF2α; and (3) the UC concentrations of PGE2and PGF2αincreased as a function of gestational age. We propose that UC PGs act as inflammatory mediators generated in the context of fetal systemic inflammation. [ABSTRACT FROM PUBLISHER]

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-1β), 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. [ABSTRACT FROM AUTHOR]

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-1β, 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-1β, 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: The objectives of this study were: 1) to determine the amniotic fluid (AF) microbiology of patients with the diagnosis of clinical chorioamnionitis at term using both cultivation and molecular techniques; and 2) to examine the relationship between intra-amniotic inflammation with and without microorganisms and placental lesions consistent with acute AF infection. Methods: The AF samples obtained by transabdominal amniocentesis from 46 women with clinical signs of chorioamnionitis at term were analyzed using cultivation techniques (for aerobic and anerobic bacteria as well as genital mycoplasmas) and broad-range polymerase chain reaction (PCR) coupled with electrospray ionization mass spectrometry (PCR/ESI-MS). The frequency of microbial invasion of the amniotic cavity (MIAC), intra-amniotic inflammation [defined as an AF interleukin 6 (IL-6) concentration ≥2.6 ng/mL], and placental lesions consistent with acute AF infection (acute histologic chorioamnionitis and/or acute funisitis) were examined according to the results of AF cultivation and PCR/ESI-MS as well as AF IL-6 concentrations. Results: 1) Culture identified bacteria in AF from 46% (21/46) of the participants, whereas PCR/ESI-MS was positive for microorganisms in 59% (27/46) - combining these two tests, microorganisms were detected in 61% (28/46) of patients with clinical chorioamnionitis at term. Eight patients had discordant test results; one had a positive culture and negative PCR/ESI-MS result, whereas seven patients had positive PCR/ESI-MS results and negative cultures. 2) Ureaplasma urealyticum (n=8) and Gardnerella vaginalis (n=10) were the microorganisms most frequently identified by cultivation and PCR/ESI-MS, respectively. 3) When combining the results of AF culture, PCR/ESI-MS and AF IL-6 concentrations, 15% (7/46) of patients did not have intra-amniotic inflammation or infection, 6.5% (3/46) had only MIAC, 54% (25/46) had microbial-associated intra-amniotic inflammation, and 24% (11/46) had intra-amniotic inflammation without detectable microorganisms. 4) Placental lesions consistent with acute AF infection were significantly more frequent in patients with microbial-associated intra-amniotic inflammation than in those without intra-amniotic inflammation [70.8% (17/24) vs. 28.6% (2/7); P=0.04]. Conclusion: Microorganisms in the AF were identified in 61% of patients with clinical chorioamnionitis at term; 54% had microbial-associated intra-amniotic inflammation, whereas 24% had intra-amniotic inflammation without detectable microorganisms. [ABSTRACT FROM AUTHOR]

Background The human fetus is able to mount a systemic inflammatory response when exposed to microorganisms. This stereotypic response has been termed the 'fetal inflammatory response syndrome' (FIRS), defined as an elevation of fetal plasma interleukin-6 (IL-6). FIRS is frequently observed in patients whose preterm deliveries are associated with intra-amniotic infection, acute inflammatory lesions of the placenta, and a high rate of neonatal morbidity. Recently, a novel form of fetal systemic inflammation, characterized by an elevation of fetal plasma CXCL10, has been identified in patients with placental lesions consistent with 'maternal anti-fetal rejection'. These lesions include chronic chorioamnionitis, plasma cell deciduitis, and villitis of unknown etiology. In addition, positivity for human leukocyte antigen (HLA) panel-reactive antibodies (PRA) in maternal sera can also be used to increase the index of suspicion for maternal anti-fetal rejection. The purpose of this study was to determine (i) the frequency of pathologic lesions consistent with maternal anti-fetal rejection in term and spontaneous preterm births; (ii) the fetal serum concentration of CXCL10 in patients with and without evidence of maternal anti-fetal rejection; and (iii) the fetal blood transcriptome and proteome in cases with a fetal inflammatory response associated with maternal anti-fetal rejection. Method of study Maternal and fetal sera were obtained from normal term ( n = 150) and spontaneous preterm births ( n = 150). A fetal inflammatory response associated with maternal anti-fetal rejection was diagnosed when the patients met two or more of the following criteria: (i) presence of chronic placental inflammation; (ii) ≥80% of maternal HLA class I PRA positivity; and (iii) fetal serum CXCL10 concentration >75th percentile. Maternal HLA PRA was analyzed by flow cytometry. The concentrations of fetal CXCL10 and IL-6 were determined by ELISA. Transcriptome analysis was undertaken after the extraction of total RNA from white blood cells with a whole-genome DASL assay. Proteomic analysis of fetal serum was conducted by two-dimensional difference gel electrophoresis. Differential gene expression was considered significant when there was a P < 0.01 and a fold-change >1.5. Results (i) The frequency of placental lesions consistent with maternal anti-fetal rejection was higher in patients with preterm deliveries than in those with term deliveries (56% versus 32%; P < 0.001); (ii) patients with spontaneous preterm births had a higher rate of maternal HLA PRA class I positivity than those who delivered at term (50% versus 32%; P = 0.002); (iii) fetuses born to mothers with positive maternal HLA PRA results had a higher median serum CXCL10 concentration than those with negative HLA PRA results ( P < 0.001); (iv) the median serum CXCL10 concentration (but not IL-6) was higher in fetuses with placental lesions associated with maternal anti-fetal rejection than those without such lesions ( P < 0.001); (v) a whole-genome DASL assay of fetal blood RNA demonstrated differential expression of 128 genes between fetuses with and without lesions associated with maternal anti-fetal rejection; and (vi) comparison of the fetal serum proteome demonstrated 20 proteins whose abundance differed between fetuses with and without lesions associated with maternal anti-fetal rejection. Conclusion We describe a systemic inflammatory response in human fetuses born to mothers with evidence of maternal anti-fetal rejection. The transcriptome and proteome of this novel type of fetal inflammatory response were different from that of FIRS type I (which is associated with acute infection/inflammation). [ABSTRACT FROM AUTHOR]

Objective: The fetal inflammatory response syndrome (FIRS) is present in a fraction of fetuses exposed to intraamniotic infection and is associated with the impending onset of labor and multisystem organ involvement. Neonates born with funisitis, the histologic counterpart of fetal systemic inflammation, are at increased risk for cerebral palsy and bronchopulmonary dysplasia. The aim of this study was to determine whether fetal and maternal granulocytes and monocytes have the phenotypic and metabolic characteristics of activation in cases with FIRS. Study design: A case-control study was conducted with umbilical cord and maternal blood samples obtained from patients who delivered preterm with (ns30) and without funisitis (ns15). The phenotypic characteristics of granulocytes and monocytes were examined using flow cytometry and monoclonal antibodies including CD11b, CD14, CD15, CD16, CD18, CD49d, CD62L, CD64, CD66b, and HLA-DR. Intracellular reactive oxygen species (iROS) were measured at the basal state and after stimulation (oxidative burst). A P-0.01 was considered statistically significant. Results: (1) Funisitis was associated with a significantincrease in the median mean channel brightness (MCB) of CD14, CD64, and CD66b on granulocytes and the MCB of CD64 on monocytes collected from umbilical cord blood. (2) The basal iROS production and oxidative burst were higher in the umbilical cord monocytes of neonates with funisitis than in those without funisitis. (3) There were no differences in the immunophenotype, basal iROS production, and oxidative burst in maternal granulocytes or monocytes between the study groups. Conclusion: Fetal systemic inflammation is associated with phenotypic and metabolic changes consistent with activation in fetal immune cells but not in maternal blood. [ABSTRACT FROM AUTHOR]

Background: Neutrophils are the most abundant white blood cells found in the amniotic cavity of women with intraamniotic infection and/or inflammation. The current belief is that these neutrophils are of fetal origin. However, abundant neutrophils have been found in the amniotic fluid of women with a severe acute maternal inflammatory response but without a severe fetal inflammatory response in the placenta, suggesting that these innate immune cells can also be of maternal origin or a mixture of both fetal and maternal neutrophils.Objective: We sought to investigate the origin of amniotic fluid neutrophils from women with intraamniotic infection and/or inflammation and to correlate these findings with acute histologic maternal and fetal inflammatory responses in the placenta.Study Design: Amniotic fluid was collected from 15 women with suspected intraamniotic infection and/or inflammation (positive microbiological cultures and/or interleukin-6 concentrations ≥2.6 ng/mL). Amniotic fluid neutrophils were purified by fluorescence-activated cell sorting, DNA was extracted, and DNA fingerprinting was performed. DNA fingerprinting was also performed in the umbilical cord and maternal blood DNA. Fluorescence in situ hybridization was assayed in women with male neonates. Blinded placental histopathological evaluations were conducted.Results: First, DNA fingerprinting revealed that 43% (6/14) of women who underwent a single amniocentesis had mostly fetal neutrophils in the amniotic fluid. Second, DNA fingerprinting showed that 36% (5/14) of the women who underwent a single amniocentesis had predominantly maternal neutrophils in the amniotic fluid. Third, DNA fingerprinting indicated that 21% (3/14) of the women who underwent a single amniocentesis had an evident mixture of fetal and maternal neutrophils in the amniotic fluid. Fourth, DNA fingerprinting revealed that a woman who underwent 2 amniocenteses (patient 15) had fetal neutrophils first, and as infection progressed, abundant maternal neutrophils invaded the amniotic cavity. Fifth, fluorescence in situ hybridization confirmed DNA fingerprinting results by showing that both fetal and maternal neutrophils were present in the amniotic fluid. Sixth, most of the women who had predominantly amniotic fluid neutrophils of fetal origin at the time of collection delivered extremely preterm neonates (71% [5/7]). Seventh, all of the women who had predominantly amniotic fluid neutrophils of maternal origin at the time of collection delivered term or late preterm neonates (100% [6/6]). Eighth, 2 of the women who had an evident mixture of fetal and maternal neutrophils in the amniotic fluid at the time of collection delivered extremely preterm neonates (67% [2/3]), and the third woman delivered a term neonate (33% [1/3]). Finally, most of the women included in this study presented acute maternal and fetal inflammatory responses in the placenta (87% [13/15]).Conclusion: Amniotic fluid neutrophils can be either predominantly of fetal or maternal origin, or a mixture of both fetal and maternal origin, in women with intraamniotic infection and/or inflammation. The findings herein provide evidence that both fetal and maternal neutrophils can invade the amniotic cavity, suggesting that both the fetus and the mother participate in the host defense mechanisms against intraamniotic infection. [ABSTRACT FROM AUTHOR]