How does fetal inflammatory response syndrome change fetal response to hypoxia? An experimental study in a fetal sheep model.

INTRODUCTION: Fetal inflammatory response syndrome associated with acidosis during labor is a high-risk situation for the fetus. This study evaluated hemodynamic, gasometric, and heart rate variability changes during acute fetal inflammatory response syndrome associated with hypoxia, compared with isolated hypoxia. MATERIAL AND METHODS: Acute fetal inflammatory response syndrome was obtained via an intravenously injection of lipopolysaccharide derived from Escherichia coli. Hypoxia was induced by repeated umbilical cord occlusions during three phases: mild, moderate, and severe umbilical cord occlusions. Two groups were created with chronically instrumented near-term fetal sheep: one group with isolated hypoxia, the other with hypoxia and fetal inflammatory response syndrome. Hemodynamic, gas parameters, and fetal heart rate variability were compared between the groups. RESULTS: The hypoxia and fetal inflammatory response syndrome group had a higher mortality rate (n = 4/9) compared with the hypoxia group (n = 0/9). Gasometric state was altered earlier in case of lipopolysaccharide injection (pH = 7.22 (7.12-7.24) vs 7.28 (7.23-7.34) p = 0.01; lactate = 10.3 mmol/L (9.4-11.0) vs 6.0 mmol/L (4.1-8.2) p < 0.001 after mild occlusions). After mild occlusions, the hypoxia and fetal inflammatory response syndrome group had higher values on seven heart rate variability parameters compared with the hypoxia group. After moderate occlusions, two parameters remained significantly higher. CONCLUSIONS: During fetal inflammatory response syndrome, fetal adaptation to hypoxia is impaired. In case of fetal infection, acidosis during labor is likely to become severe more rapidly, requiring closer fetal monitoring during labor.

Soluble urokinase plasminogen activator receptor in vaginally collected amniotic fluid predicting fetal inflammatory response syndrome: a prospective cohort study.

BACKGROUND: Improving noninvasive antenatal diagnosis of fetal inflammatory response syndrome (FIRS) can assist in the evaluation of prenatal risk and reduce perinatal outcomes. This study aimed to determine whether soluble urokinase-type plasminogen activator receptor (suPAR) in vaginally collected amniotic fluid is significant in identifying FIRS after preterm premature rupture of membranes before 34 weeks of gestation. METHODS: This was a prospective cohort study of 114 pregnant women and their newborns after preterm premature rupture of membranes at 22-34+6 weeks of gestation. SuPAR was evaluated using an enzyme-linked immunosorbent assay in vaginally collected amniotic fluid. Patients were classified according to the presence or absence of FIRS. FIRS was defined by umbilical cord blood interleukin-6 level > 11 pg/mL or histological funisitis. The data were analyzed using the R package (R-4.0.5). RESULTS: SuPAR was detected in all amniotic fluid samples with a median of 26.23 ng/mL (interquartile range (IQR), 15.19-51.14). The median level of suPAR was higher in the FIRS group than in the non-FIRS group, 32.36 ng/mL (IQR, 17.27-84.16) vs. 20.46 ng/mL (IQR, 11.49-36.63) (P = 0.01), respectively. The presence of histological chorioamnionitis significantly increased the suPAR concentration in the FIRS group (P < 0.001). The areas under the curve for FIRS and FIRS with histological chorioamnionitis were 0.65 and 0.74, respectively, with an optimum cutoff value of 27.60 ng/mL. Controlling for gestational age, the cutoff of suPAR more than 27.60 ng/mL predicted threefold higher odds for FIRS and sixfold higher odds for FIRS with histologic chorioamnionitis. CONCLUSION: Soluble urokinase-type plasminogen activator receptor in vaginally obtained amniotic fluid may assist in evaluating prenatal risk of FIRS in patients after preterm premature rupture of membranes before 34 weeks of gestation.

Daily monitoring of vaginal interleukin 6 as a predictor of intraamniotic inflammation after preterm premature rupture of membranes - a new method of sampling studied in a prospective multicenter trial.

OBJECTIVES: (A) To introduce a new technique for vaginal fluid sampling (biocompatible synthetic fiber sponge) and (B) evaluate the collected vaginal fluid interleukine-6 (IL-6vag)-concentration as a new diagnostic tool for daily monitoring of intrauterine inflammation after preterm premature rupture of membranes (PPROM). Secondary objectives were to compare the potential to predict an intrauterine inflammation with established inflammation parameters (e.g., maternal white blood cell count). METHODS: This prospective clinical case-control diagnostic accuracy multicenter study was performed with women after PPROM (gestational age 24.0/7 - 34.0/7 weeks). Sampling of vaginal fluid was performed once daily. IL-6vag was determined by electrochemiluminescence-immunoassay-kit. Neonatal outcome and placental histology results were used to retrospectively allocate the cohort into two subgroups: 1) inflammation and 2) no inflammation (controls). RESULTS: A total of 37 cases were included in the final analysis. (A): Measurement of IL-6 was successful in 86% of 172 vaginal fluid samples. (B): Median concentration of IL-6vag in the last vaginal fluid sample before delivery was significantly higher within the inflammation group (17,085 pg/mL) compared to the controls (1,888 pg/mL; p=0.01). By Youden's index an optimal cut-off for prediction an intrauterine inflammation was: 6,417 pg/mL. Two days before delivery, in contrast to all other parameters IL-6vag remained the only parameter with a sufficient AUC of 0.877, p<0.001, 95%CI [0.670-1.000]. CONCLUSIONS: This study established a new technique for vaginal fluid sampling, which permits assessment of IL-6vag concentration noninvasively in clinical daily routine monitoring.

Significance of pathological examination of the placenta, with a focus on intrauterine infection and fetal growth restriction.

Chorioamnionitis (CAM) is associated with abortion, premature labor and neonatal disorders. In this condition, precise pathological diagnosis of the placenta is very important. Besides histological examination, macroscopic examination of the placenta is indispensable. Diagnostic points and complications of CAM are emphasized in this paper. Blanc's classification (revised by Nakayama) is introduced for the accurate determination of CAM stage. Principles of classification based on the causes of fetal growth restriction (FGR) (mainly resulting from placental pathology) are also described. Children born with FGR have high disease-related morbidity. In these cases, placental examination can be a useful prognostic tool. Placental pathology is associated not only with the underlying cause of FGR, but also with infant prognosis.

One-step radiosynthesis of 18F-IRS: A novel radiotracer targeting mutant EGFR in NSCLC for PET/CT imaging.

EGFR (epidermal growth factor receptor) targeted therapy has shown great success in clinical comparing with chemotherapy in EGFR mutation NSCLCs. Such as, gefitinib, first generation EGFR TKI, has obviously prolonged the FPS (progression free survival) of the subgroup of patients, but to those who did not get a certain mutation in EGFR kinase domain, the outcome is poor. In view of this situation, scientists have synthesized many radiotracers for selecting the right people by PET/CT imaging to NSCLC TKI therapy. In this study, we developed a novel PET radiotracer 18F-IRS in one-step with a radio yield 20% (non-corrected), radiochemistry>98.5%, specific activity>105GBq/µmol, the pharmacokinetics and capacity of the tracer binding to mutant EGFR were evaluated both in vitro and in vivo.

Correlation between intrapartum CTG findings and interleukin-6 levels in the umbilical cord arterial blood: A prospective cohort study.

OBJECTIVE: to investigate the correlation between the intrapartum CardioTocoGraphic (CTG) findings "suggestive of fetal inflammation" ("SOFI") and the interleukin (IL)-6 level in the umbilical arterial blood. STUDY DESIGN: prospective cohort study conducted at a tertiary maternity unit and including 447 neonates born at term. METHODS: IL-6 levels were systematically measured at birth from a sample of blood taken from the umbilical artery. The intrapartum CTG traces were retrospectively reviewed by two experts who were blinded to the postnatal umbilical arterial IL-6 values as well as to the neonatal outcomes. The CTG traces were classified into "suggestive of fetal inflammation (SOFI)" and "no evidence of fetal inflammation (NEFI) according to the principles of physiologic interpretation the CTG traces. The CTG was classified as "SOFI" if there was a persistent fetal heart rate (FHR) increase > 10 % compared with the observed baseline FHR observed at the admission or at the onset of labor without any preceding repetitive decelerations. The occurrence of Composite Adverse Outcome (CAO) was defined as Neonatal Intensive Care Unit (NICU) or Special Care Baby Unit (SCBU) admission due to one or more of the following: metabolic acidaemia, Apgar score at 5 min ≤ 7, need of neonatal resuscitation, respiratory distress, tachypnoea/polypnea, jaundice requiring phototherapy, hypotension, body temperature instability, poor perinatal adaptation, suspected or confirmed early neonatal sepsis. MAIN OUTCOME MEASURES: To compare the umbilical IL-6 values between the cases with intrapartum CTG traces classified as "SOFI" and those classified as "NEFI"; to assess the correlation of umbilical IL-6 values with the neonatal outcome. RESULTS: 43 (9.6 %) CTG traces were categorized as "SOFI"; IL-6 levels were significantly higher in this group compared with the "NEFI" group (82.0[43.4-325.0] pg/ml vs. 14.5[6.8-32.6] pg/mL; p <.001). The mean FHR baseline assessed 1 h before delivery and the total labor length showed an independent and direct association with the IL-6 levels in the umbilical arterial blood (p <.001 and p = 0.005, respectively). CAO occurred in 33(7.4 %) cases; IL-6 yielded a good prediction of the occurrence of the CAO with an AUC of 0.72 (95 % CI 0.61-0.81). CONCLUSION: Intrapartum CTG findings classified as "SOFI" are associated with higher levels of IL-6 in the umbilical arterial blood.

Changes in Relative Counts of Different Leukocyte Subpopulations in Peripheral and Umbilical Cord Blood of Women With Preterm Prelabor Rupture of Membranes With Respect to Intraamniotic Inflammation and Fetal Inflammatory Response Syndrome.

OBJECTIVE: The aim of this study was to evaluate changes in the relative counts of different leukocyte subsets in peripheral and umbilical cord blood in pregnancies complicated by preterm prelabor rupture of membranes (PPROM) with respect to the presence of intraamniotic inflammation (IAI) and fetal inflammatory response syndrome (FIRS). METHODS: Fifty-two women with singleton pregnancies complicated by PPROM were included in this study. From samples of peripheral and umbilical cord blood, relative counts of these leukocyte subpopulations were determined using multicolor flow cytometry: granulocytes, monocytes, lymphocytes, T cells and their subpopulations, B cells and their subpopulations, and NK cells and their subpopulations. IAI was defined as increased concentrations of interleukin 6 in the amniotic fluid. Amniotic fluid samples were obtained by transabdominal amniocentesis. RESULTS: Women with IAI had higher relative counts of monocytes (p = 0.04) in peripheral blood. There was an increased relative number of granulocytes (p = 0.003) and a decreased number of lymphocytes (p = 0.0048), helper CD4+ T cells (p = 0.019), NK cells (p = 0.0001) within leukocytes, NK cells within lymphocytes (p = 0.003) and CD16+ NK cells within NK cells (p = 0.005) in umbilical cord blood samples of women with FIRS. However, after adjusting the results for gestational age at sampling, all differences disappeared. CONCLUSIONS: The presence of IAI or FIRS is not accompanied by significant changes in the relative counts of immune cells in peripheral blood or umbilical cord blood in pregnancies complicated by PPROM.

Warming appears as the main risk of non-adaptedness for western Mediterranean relict fir forests under expected climate change scenarios.

Circum-Mediterranean firs are considered among the most drought-sensitive species to climate change. Understanding the genetic basis of trees' adaptive capacity and intra-specific variability to drought avoidance is mandatory to define conservation measures, thus potentially preventing their extinction. We focus here on Abies pinsapo and Abies marocana, both relict tree species, endemic from south Spain and north Morocco, respectively. A total of 607 samples were collected from eight nuclei: six from Spanish fir and two from Moroccan fir. A genotyping by sequencing technique called double digestion restriction site-associated DNA sequencing (ddRAD-seq) was performed to obtain a genetic matrix based on single-nucleotide polymorphisms (SNPs). This matrix was utilized to study the genetic structure of A. pinsapo populations and to carry out selection signature studies. In order to understand how Spanish fir and Moroccan fir cope with climate change, genotype-environment associations (GEAs) were identified. Further, the vulnerability of these species to climate variations was estimated by the risk of non-adaptedness (RONA). The filtering of the de novo assembly of A. pinsapo provided 3,982 SNPs from 504 out of 509 trees sequenced. Principal component analysis (PCA) genetically separated Grazalema from the rest of the Spanish populations. However, FST values showed significant differences among the sampling points. We found 51 loci potentially under selection. Homolog sequences were found for some proteins related to abiotic stress response, such as dehydration-responsive element binding transcription factor, regulation of abscisic acid signaling, and methylation pathway. A total of 15 associations with 11 different loci were observed in the GEA studies, with the maximum temperature of the warmest month being the variable with the highest number of associated loci. This temperature sensitivity was also supported by the risk of non-adaptedness, which yielded a higher risk for both A. pinsapo and A. marocana under the high emission scenario (Representative Concentration Pathway (RCP) 8.5). This study sheds light on the response to climate change of these two endemic species.

The significance of TNF-α and MMP-8 concentrations in non-invasively obtained amniotic fluid predicting fetal inflammatory response syndrome.

OBJECTIVE: To determine the significance of tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-8 (MMP-8) in vaginally obtained amniotic fluid predicting fetal inflammatory response syndrome (FIRS) after preterm premature rupture of membranes (PPROM). METHODS: In this prospective case-control study, TNF-α and MMP-8 concentrations were evaluated in vaginally obtained amniotic fluid from women with PPROM at 22-34 weeks of pregnancy. Biomarkers' concentrations were determined using an enzyme-linked immunosorbent assay. Patients were divided into two groups: the FIRS group (cord blood interleukin-6 > 11 pg/ml or histological funisitis) and the non-FIRS group (without these findings). The data were analyzed using R package (R-4.0.5). RESULTS: The median TNF-α and MMP-8 concentrations in amniotic fluid from the 145 women included in the study were higher in the FIRS group than in the non-FIRS group. The area under the curve of TNF-α and MMP-8 was 0.77 and 0.75, respectively. The TNF-α concentration cut-off predicting FIRS was 89.20 pg/ml and was 170.76 pg/ml for MMP-8. In regression analysis, MMP-8 concentration was an independent predictor for FIRS. An MMP-8 concentration greater than 170 ng/ml and a TNF-α concentration greater than 89 pg/ml increased the odds of FIRS 7.62 and 14.92 times, respectively. CONCLUSIONS: MMP-8 and TNF-α concentrations in vaginally obtained amniotic fluid may be good predictors for FIRS after PPROM before 34 weeks of pregnancy. The non-invasive amniotic fluid analysis could be an alternative method to invasive amniocentesis.

The Inflammatory Cytokine Imbalance for Miscarriage, Pregnancy Loss and COVID-19 Pneumonia.

Pregnancy can be defined a vascular event upon endocrine control. In the human hemo-chorial placentation the chorionic villi penetrate the wall of the uterine spiral arteries, to provide increasing amounts of nutrients and oxygen for optimal fetal growth. In any physiological pregnancy the natural maternal response is of a Th1 inflammatory type, aimed at avoiding blood loss through the arteriolar wall openings. The control of the vascular function, during gestation as in any other condition, is achieved through the action of two main types of prostanoids: prostaglandin E2 and thromboxane on the one hand (for vasoconstriction and coagulation), prostacyclin on the other (for vasodilation and blood fluidification). The control of the maternal immune response is upon the responsibility of the fetus itself. Indeed, the chorionic villi are able to counteract the natural maternal response, thus changing the inflammatory Th1 type into the anti-inflammatory Th2. Clinical and experimental research in the past half century address to inflammation as the leading cause of abortion, pregnancy loss, premature delivery and related pulmonary, cerebral, intestinal fetal syndromes. Increased level of Interleukin 6, Interleukin 1-beta, Tumor Necrosis Factor-alfa, Interferon-gamma, are some among the well-known markers of gestational inflammation. On the other side, COVID-19 pneumonia is a result of extensive inflammation induced by viral replication within the cells of the respiratory tract. As it may happen in the uterine arteries in the absence of an effective fetal control, viral pneumonia triggers pulmonary vascular coagulation. The cytokines involved in the process are the same as those in gestational inflammation. As the fetus breathes throughout the placenta, fetal death from placental thrombosis is similar to adult death from pulmonary thrombosis. Preventing and counteracting inflammation is mandatory in both conditions. The most relevant literature dealing with the above-mentioned concepts is reviewed in the present article.

Temperature and precipitation gradients determine biomass in Birch (Betula spp.) and Fir (Abies spp.) in Eurasia.

Forest ecosystems are sinks of atmospheric carbon and maintain annual temperature. On the other hand, climate change entails changes in all the biota structures and functions, including forest cover and biomass. Temperature and precipitation are the main deterministic factors in species biomass change. Therefore, we compared the biomass of Betula spp. and Abies spp. at the stand level along trans-Eurasian hydrothermal gradients. We analyzed the biomass database of Betula and Abies forest stands in Eurasia. Climate variables explained about 14 and 16% of the total biomass variability in Betula and Abies, respectively. Our results showed that increasing temperature and precipitation positively impacted fir biomass. However, a negative impact was reported on needles and branches due to insufficient humidity. In birch forests, positive trends occur from cold to warm climate zones, but only when there is inadequate water supply. A negative correlation was reported in the moist areas. Most of the birch biomass components only increased in the precipitation gradient in cold climate zones. This positive trend transformed to negative in warm zones (except for branches). We modeled the possible temporal biomass change of tree species based on its territorial pattern in Eurasia using the principle of space-for-time substitution. The developments of models for the main forest-forming species of Eurasia allow us to predict changes in the productivity of the forest cover of Eurasia.

Protective Effects of Interleukin-1 Blockade on Group B Streptococcus-Induced Chorioamnionitis and Subsequent Neurobehavioral Impairments of the Offspring.

Group B Streptococcus (GBS) is one of the most common bacteria isolated in human chorioamnionitis. Placental infection due to GBS is a major risk factor for fetal organ injuries, preterm birth, perinatal morbidity and mortality, and life-long multiorgan morbidities. Preclinical and clinical studies have shown that GBS-induced infection drives polymorphonuclear (PMN) cell infiltration within the placenta, the hallmark of human chorioamnionitis. In preclinical and clinical studies, the upregulation of interleukin(IL)-1ß in the placenta and maternal/fetal blood was associated with a high risk of neurodevelopmental impairments in the progeny. We hypothesized that targeted IL-1 blockade administered to the dam alleviates GBS-induced chorioamnionitis and the downstream fetal inflammatory response syndrome (FIRS). IL-1 receptor antagonist (IL-1Ra) improved the gestational weight gain of GBS-infected dams and did not worsen the infectious manifestations. IL-1Ra reduced the IL-1ß titer in the maternal sera of GBS-infected dams. IL-1Ra decreased the levels of IL-1ß, IL-6, chemokine (C-X-C motif) ligand 1 (CXCL1), and polymorphonuclear (PMN) infiltration in GBS-infected placenta. IL-1Ra treatment reduced the IL-1ß titer in the fetal sera of GBS-exposed fetuses. IL-1 blockade also alleviated GBS-induced FIRS and subsequent neurobehavioral impairments of the offspring without worsening the outcome of GBS infection. Altogether, these results showed that IL-1 plays a key role in the physiopathology of live GBS-induced chorioamnionitis and consequent neurobehavioral impairments.

Herpesvirus-infected Hofbauer cells activate endothelial cells through an IL-1ß-dependent mechanism.

INTRODUCTION: Placental viral infections are associated with fetal inflammation and adverse pregnancy outcomes. However, there have been limited studies on how placental macrophages in the villous and adjacent fetal umbilical endothelial cells respond to a viral insult. This study aimed to evaluate the communication between Hofbauer cells (HBCs) and human umbilical vein endothelial cells (HUVECs) during a viral infection. METHODS: HBCs were either uninfected or infected with the γ-herpesvirus, MHV-68, and the conditioned medium (CM) collected. HUVECs were exposed to HBC CM and the levels of the pro-neutrophilic response markers: IL-8; E-selectin; intercellular adhesion molecule 1 (ICAM-1); and vascular adhesion molecule 1 (VCAM-1) measured by ELISA and qPCR. The role of HBC-derived IL-1ß was investigated using an IL-1ß blocking antibody (Ab) or IL-1 receptor antagonist (IL-1Ra). RESULTS: MHV-68 infection of HBCs induced a significant increase in IL-1ß secretion. CM from infected HBCs induced HUVEC expression of IL-8, E-selectin, VCAM-1, ICAM-1 mRNA, and secretion of IL-8. The HUVEC response to the CM of MHV-infected HBCs was inhibited by a neutralizing IL-1ß Ab and by IL-1Ra. DISCUSSION: Virally-induced HBC IL-1ß activates HUVECs to generate a pro-neutrophilic response. This novel cell-cell communication pathway may play an important role in the genesis of fetal inflammation associated with placental viral infection.

Fetal inflammatory response is positively correlated with the progress of inflammation in chorionic plate.

INTRODUCTION: No information exists about the relationship among the progress of inflammation in chorionic-plate, fetal inflammatory response (FIR), funisitis, amnionitis and early-onset neonatal sepsis (EONS) in patients with either preterm labor or preterm premature rupture of membranes (preterm-PROM). The objective of current study is to examine this issue. METHODS: Study population included 247 singleton preterm gestations (21.6 weeks ≤ gestational age at delivery≤36 weeks) who had either preterm-labor or preterm-PROM with acute placental inflammation. We examined the intensity of FIR, and the frequency of fetal inflammatory response syndrome (FIRS), funisitis, amnionitis and proven or suspected EONS according to the progress of inflammation in chorionic-plate. The intensity of FIR was measured with umbilical cord plasma (UCP)-CRP concentration (ng/ml) at birth, and FIRS was defined as an elevated UCP-CRP concentration (≥200 ng/ml). The progress of inflammation in chorionic-plate was divided with a slight modification from previously reported-criteria as follows: stage-0, inflammation-free chorionic-plate; stage-1, inflammation restricted to subchorionic fibrin (SCF); stage-2, inflammation in the connective tissue (CT) of chorionic-plate without chorionic vasculitis; stage-3, chorionic vasculitis. RESULTS: 1) Stage-0, stage-1, stage-2 and stage-3 of inflammation in chorionic-plate were present in 36.8% (91/247), 29.6% (73/247), 25.5% (63/247), and 8.1% (20/247) of cases; 2) UCP-CRP concentration at birth was significantly and positively correlated with the progress of inflammation in chorionic-plate (Spearman's rank correlation test, P < .000001, γ = 0.391 and Kruskal-Wallis test, P < .001); 3) Moreover, FIRS, funisitis, amnionitis, and EONS were significantly more frequent as a function of the progress of inflammation in chorionic-plate. DISCUSSION: The intensity of FIR and the frequency of FIRS were positively correlated with the progress of inflammation in chorionic-plate in patients with either PTL or preterm-PROM. This suggests chorionic-plate may be an independent compartment for the analysis of inflammation.

Neuroimaging findings associated with the fetal inflammatory response syndrome.

The fetal inflammatory response syndrome (FIRS) is a condition whereby the fetus mounts an inflammatory response to intrauterine infection/inflammation. Clinical consequences include preterm premature rupture of membranes (PPROM), spontaneous preterm delivery, neonatal sepsis, bronchopulmonary dysplasia, and brain and other organ injury. Mechanisms leading to brain injury in FIRS have been investigated in animal and human studies. We review the neuroimaging findings of brain injury in FIRS, which overlap those of hypoxic-ischemic injury, and clinical correlation is necessary for a correct diagnosis. FIRS should be considered the primary diagnosis when neuroimaging findings such as periventricular leukomalacia are identified in preterm children born as a consequence of PPROM and spontaneous preterm labor. Additionally, FIRS should be considered in term infants who do not have the most common features of HIE (e.g. a sentinel event). Systematic histopathologic examination of the placenta and umbilical cord and/or detection of characteristic inflammatory markers in such cases are needed to establish the correct diagnosis.

Fetal Inflammatory Response Syndrome and Cerebral Oxygenation During Immediate Postnatal Transition in Preterm Neonates.

Introduction: Fetal inflammatory response syndrome (FIRS), defined as elevated umbilical cord blood interleukin-6 (IL-6) values > 11 pg/ml, is associated with an increased risk of neonatal morbidity and mortality. The primary aim of the present study was to evaluate a potential influence of FIRS on cerebral oxygen saturation (crSO2) and fractional tissue oxygen extraction (cFTOE) during immediate postnatal transition in preterm neonates. The secondary aim was to analyze the potential influence of FIRS on cerebral injury and mortality. Methods: Secondary outcome parameters of prospective observational studies were analyzed. Preterm neonates with measured IL-6 values from umbilical cord blood and cerebral near-infrared spectroscopy (NIRS) measurements during immediate transition after birth were included. Preterm neonates with FIRS (FIRS group) were matched 1:1 for gestational age (± 1 week) to preterm neonates without FIRS (non-FIRS group). crSO2, cFTOE, arterial oxygen saturation (SpO2), heart rate (HR), and fraction of inspired oxygen (FiO2) were compared between both groups. In addition, cerebral injury and mortality were compared between both groups. Results: A total of 46 preterm neonates were included. Twenty-three neonates in the FIRS group [median gestational age 32.1 (IQR 30.3-33.0) weeks; median IL-6 19.7 (IQR 12.2-37.0) pg/ml] were compared to 23 neonates in the non-FIRS group [gestational age: 32.0 (30.4-33.1) weeks; IL-6: 5.4 (3.0-6.7) pg/ml]. cFTOE showed significantly lower values within the first 4 min and a trend toward lower values in minute 5 after birth in the FIRS group. There were no significant differences in crSO2 within the first 15 min after birth between the two groups. SpO2 was significantly lower in minutes 5 and 6 and HR was significantly lower in minutes 2 and 4 after birth in the FIRS group compared to the non-FIRS group. Survival without cerebral injury was similar in both groups. Conclusion: In preterm neonates with FIRS the crSO2 was similar despite significantly lower cFTOE values during the first minutes after birth. This observation may be a result of compromised oxygen consumption and delivery in the first minutes after birth in neonates with FIRS.

Neonatal and Childhood Outcomes Following Preterm Premature Rupture of Membranes.

Preterm premature rupture of membranes (PPROM) is almost uniformly associated with preterm birth and thus sequelae of prematurity explain many of the complications associated with this condition. However, the unique inflammatory environment and oligohydramnios associated with PPROM may impart unique neonatal and childhood morbidity compared with other preterm birth pathways.

The fetal inflammatory response syndrome: the origins of a concept, pathophysiology, diagnosis, and obstetrical implications.

The fetus can deploy a local or systemic inflammatory response when exposed to microorganisms or, alternatively, to non-infection-related stimuli (e.g., danger signals or alarmins). The term "Fetal Inflammatory Response Syndrome" (FIRS) was coined to describe a condition characterized by evidence of a systemic inflammatory response, frequently a result of the activation of the innate limb of the immune response. FIRS can be diagnosed by an increased concentration of umbilical cord plasma or serum acute phase reactants such as C-reactive protein or cytokines (e.g., interleukin-6). Pathologic evidence of a systemic fetal inflammatory response indicates the presence of funisitis or chorionic vasculitis. FIRS was first described in patients at risk for intraamniotic infection who presented preterm labor with intact membranes or preterm prelabor rupture of the membranes. However, FIRS can also be observed in patients with sterile intra-amniotic inflammation, alloimmunization (e.g., Rh disease), and active autoimmune disorders. Neonates born with FIRS have a higher rate of complications, such as early-onset neonatal sepsis, intraventricular hemorrhage, periventricular leukomalacia, and death, than those born without FIRS. Survivors are at risk for long-term sequelae that may include bronchopulmonary dysplasia, neurodevelopmental disorders, such as cerebral palsy, retinopathy of prematurity, and sensorineuronal hearing loss. Experimental FIRS can be induced by intra-amniotic administration of bacteria, microbial products (such as endotoxin), or inflammatory cytokines (such as interleukin-1), and animal models have provided important insights about the mechanisms responsible for multiple organ involvement and dysfunction. A systemic fetal inflammatory response is thought to be adaptive, but, on occasion, may become dysregulated whereby a fetal cytokine storm ensues and can lead to multiple organ dysfunction and even fetal death if delivery does not occur ("rescued by birth"). Thus, the onset of preterm labor in this context can be considered to have survival value. The evidence so far suggests that FIRS may compound the effects of immaturity and neonatal inflammation, thus increasing the risk of neonatal complications and long-term morbidity. Modulation of a dysregulated fetal inflammatory response by the administration of antimicrobial agents, anti-inflammatory agents, or cell-based therapy holds promise to reduce infant morbidity and mortality.

Fetal inflammatory response syndrome (FIRS) and outcome of preterm neonates - a prospective analytical study.

OBJECTIVES: To estimate the incidence of fetal inflammatory response syndrome (FIRS) in preterm neonates and correlate it with immediate and one-year neurodevelopmental outcome. MATERIALS AND METHODS: This prospective observational analytical study, in preterm neonates with gestational age between 26 and 34 weeks was conducted from May 2014 to December 2015 in a tertiary care hospital in South India. FIRS was defined as the presence of either elevated levels of interleukin-6 (IL-6) in cord blood ≥11 pg/ml and/or the placental histopathology showing evidence of fetal inflammatory response. One hundred and twenty neonates were recruited. During delivery 2 ml cord blood for interleukin-6 and placenta were collected and stored appropriately. Based on presence/absence of FIRS (IL-6 in cord blood ≥11 pg/ml and or features of placental fetal inflammation), neonates were grouped into two groups. The neonatal and maternal characteristics between two groups were compared. The short-term outcome parameters during NICU stay and neurodevelopmental outcome at one year of corrected age was compared between groups. RESULTS: Among the 120 infants studied, 19 expired. Out of 101 babies discharged, 87 were followed up till corrected 1 year of age. On examination of placenta and cord blood, 50 neonates had evidence of FIRS (41.6%). So there were 50 neonates in FIRS and 70 in NO-FIRS group. The mean gestational age, birth weight, and gender distribution were comparable between the two groups. Mortality [OR: 2.44 (CI: 1.14-5.26)] and early hypotension [OR: 2.13 (CI: 1.1-4.2)] were significantly higher in the FIRS group. The neurodevelopmental assessment at corrected age of 1 year showed that infants with FIRS had lower mean motor developmental quotient by developmental assessment scale for Indian infants (DASII) [87.6 ± 9.15 versus 93.07 ± 9.3, p < .04]. CONCLUSIONS: FIRS has a significant role on survival and neurodevelopmental outcome of preterm infants.