Fetal inflammatory response in women with proteomic biomarkers characteristic of intra‐amniotic inflammation and preterm birth

Abstract

Objective To determine the relationship between presence of amniotic fluid (AF) biomarkers characteristic of inflammation (defensins 2 and 1, calgranulins C and A) and fetal inflammatory status at birth. Design Prospective observational cohort. Setting Tertiary referral University hospital Population 132 consecutive mothers (gestational age, median [interquartile range]: 29.6 [24.1-33.6] weeks), who had a clinically indicated amniocentesis to rule-out infection and their newborns. Methods Intra-amniotic inflammation was diagnosed by mass spectrometry SELDI-TOF. The AF proteomic fingerprint [Mass Restricted (MR) score] ranges from 0-4 (none to all biomarkers present). The intensity of intra-amniotic inflammation was graded based on the number of proteomic biomarkers: MR score 0: “no” inflammation; MR score 1-2: “minimal” inflammation; MR score 3-4: “severe” inflammation. At birth, cord blood was obtained for all cases. Severity of histological chorioamnionitis (HCA) and early onset neonatal sepsis (EONS) was based on established histological and hematological criteria. Interleukin-6 (IL-6) levels were measured by sensitive immunoassays. The cord blood-to-AF IL-6 ratio was used as an indicator of the differential inflammatory response in the fetal versus the AF compartment. Main Outcome Measures to relate proteomic biomarkers of intra-amniotic infection to cord blood IL-6 and to use the latter as the primary marker of fetal inflammatory response. Results Women with intra-amniotic inflammation delivered at an earlier gestational age (ANOVA, P<0.001) and had higher AF IL-6 levels (P<0.001). At birth, neonates of women with “severe” intra-amniotic inflammation had higher cord blood IL-6 levels (P=0.002) and a higher frequency of EONS (P=0.002). EONS was characterized by significantly elevated cord blood IL-6 levels (P<0.001). Out of the 39 neonates delivered by mothers with “minimal” intra-amniotic inflammation, 15 (39%) had umbilical cord blood IL-6 levels above the mean for the group, and 2 neonates had confirmed sepsis. The severity of the neutrophilic infiltrate in the chorionic plate (P<0.001), choriodecidua (P=0.002), umbilical cord (P<0.001), but not amnion (P>0.05) was an independent predictor of the cord blood-to-AF IL-6 ratio. Relationships were maintained following correction for gestational age, birthweight, amniocentesis-to delivery interval, cesarean delivery, status of the membranes, race, MR score, antibiotics and steroid exposure. Conclusion We provide evidence that presence in the AF of proteomic biomarkers characteristic of inflammation is associated with an increased inflammatory status of the fetus at birth. Neonates mount an increased inflammatory status and have positive blood cultures even in the context of “minimal” intra-amniotic inflammation.

Soluble TLR2 Is Present in Human Amniotic Fluid and Modulates the Intraamniotic Inflammatory Response to Infection

“…However, discrimination between self (host) and bacteria occurs primarily on the basis of specific chemical modifications and structural features that are unique to the bacterial wall (35). Unfortunately, in humans, the discriminatory ability of the innate immune system is not always optimal, and inappropriate control of the inflammatory course can lead to premature birth, tissue damage, or even maternal and fetal death (36,37,38). Various controlling mechanisms have been established to prevent and minimize excessive cytokine production and TLR activation.…”

“…A flowchart of the women enrolled in the study and subgroups of samples analyzed are presented in the supplemental Fig. 4 Amniotic fluid was retrieved from 109 women who had a clinically indicated amniocentesis in the following different populations: second trimester normal genetic karyotyping (GA median (range), 19 (15)(16)(17)(18)(19)(20)(21)(22)(23) wk, n ϭ 14), third trimester fetal lung maturity testing before cesarean delivery (GA, 37 (35)(36)(37)(38)(39) wk, n ϭ 14), and women admitted with symptoms of preterm labor who had an amniocentesis to rule out infection (GA, 28 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) wk, n ϭ 81). To avoid selection bias, women in this last group were selected from a prospective cohort of 463 consecutive patients enrolled at Yale New Haven Hospital from March 2004 to June 2008.…”

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

“…21 46e52, 71 Immediately evident was mislocalization of pp65, gB, and pp28, impaired transport of these proteins to MVBs, and failure to form a compact VAC that could reduce virus titers in infected AmEpCs. An innate immune response and prolonged IFN production that suppresses infection is usually transient because of expression of HCMV proteins that interfere with the response, which include pp65 delivery to the nucleus by incoming virions 72 and IE2 that functions as an IFN-b antagonist.…”

“…In conclusion, our studies of placentas from congenital infection and primary cells isolated from various donors and placentas from mid-gestation and late gestation suggest that persistent HCMV infection in fetal membranes could promote inflammation 20,21 and contribute to preterm labor and delivery. 27 Understanding the basis for persistent infection in AmEpCs could lead to therapeutic strategies to prevent congenital disease and pregnancy complications by targeting viral functions that promote persistence and enhancing host antiviral responses that suppress infection.…”

Oxidative Stress and Antioxidants: Preterm Birth and Preterm Infants

“…Treatment of maternal chorioamnionitis may minimize the ROS-induced fetal insult. (Buhimschi et al, 2009) Obviously, avoidance of neonatal conditions such as asphyxia, hyperoxia, and retinal phototherapy light exposure which can cause excessive release of free oxygen radicals are the best strategy in avoiding the oxidative stress in neonates. It is also important to consider the fact that infection, especially sepsis, is a significant source of oxidative stress.…”