Fetal Inflammatory Response Syndrome Research Articles

Fetal inflammatory response syndrome predicts early-onset sepsis and cystic periventricular leukomalacia in preterm neonates: A retrospective study.

Fetal inflammatory response syndrome (FIRS), the fetal equivalent of chorioamnionitis, is associated with poorer neonatal outcomes. FIRS is diagnosed through placental histology, namely by the identification of funisitis (inflammation of the umbilical cord) and chorionic vasculitis (inflammation of fetal vessels within the chorionic plate). The aim of this study was to identify and evaluate associations between FIRS and neonatal outcomes in preterm neonates. We performed a retrospective cohort study at a level III neonatal intensive care unit (NICU), from January 1st 2008 to December 31st 2022, involving all inborn neonates with a gestational age below 30 weeks. We compared preterm neonates based on whether their placental histology described funisitis with chorionic vasculitis (FCV) or not. The study included 113 preterms, 27 (23.9%) of those had FCV and 86 (76.1%) did not. After adjusting to gestational age, prolonged rupture of membranes and preeclampsia, FCV was independently associated with the development of early-onset sepsis (OR = 7.3, p = 0.021) and cystic periventricular leukomalacia (OR = 4.6, p = 0.004). The authors identified an association between FIRS and the development of early-onset sepsis and cystic periventricular leukomalacia, highlighting the importance of early detection and management of this condition in order to improve long-term neonatal outcomes.

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

BackgroundImproving 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.MethodsThis 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).ResultsSuPAR 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.ConclusionSoluble 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.

Recognition of Chorioamnionitis on the Cardiotocograph (CTG): The role of the “Chorio Duck Score”

Chorioamnionitis refers to the inflammation of the chorion and amnion by the bacteria and their toxins as well as by the inflammatory cytokines. Therefore, it is a fetal disease with the bacteria, their toxins as well as the fetal immunological responses involving inflammatory cytokines (interleukins, interferons, and tumour necrosis factor-alpha) exerting their detrimental effects within the fetal compartment (i.e., amniotic fluid, fetal membranes, the placenta, and fetal tissues and organs). The vast majority of fetal inflammation occurs as a result of an ascending infection (i.e., entry of the bacteria from the maternal genital tract through the cervix). Therefore, maternal signs (tachycardia and pyrexia) may not be observed until the late stages of the disease. Cardiotocograph (CTG) trace was introduced into clinical practice in the 1960s as a tool to timely recognise ongoing fetal hypoxic stress so that immediate action could be taken to avoid hypoxic ischaemic encephalopathy (HIE) and/ or intrapartum hypoxia-related perinatal deaths. Unfortunately, the CTG was introduced into clinical practice without any prior randomised controlled trials, which resulted in panicking and reacting to the observed morphology of fetal heart rate decelerations, which reflect an ongoing fetal compensatory response to reduce the myocardial workload. A sudden and reflex reduction of the heart rate in response to ongoing intermittent hypoxic stress (i.e., repetitive compression of the umbilical cord or interruptions in uteroplacental oxygenation due to uterine contractions) would ensure a reduction in myocardial oxygen demand and maintenance of aerobic metabolism to avoid the onset of anaerobic metabolism and production of lactic acid within the myocardium. Lack of understanding of fetal compensatory responses resulted in the illogical approach of grouping arbitrary features into different categories and then randomly combining them to classify the CTG traces into “Normal, Suspicious, and Pathological”. The same parameters were used in fetuses with chorioamnionitis with an alternative, inflammatory pathway of neurological injury. The international consensus guidelines of physiological interpretation of CTG produced by 44 CTG experts from 14 countries in 2018 ensured a paradigm shift and recommended classification of CTG traces based on the type of fetal hypoxia and fetal response to stress, by applying the knowledge of fetal physiology whilst interpreting CTG traces. During the last 5 years, research has highlighted CTG features in fetal neuro-inflammation, which include an absence of fetal heart rate cycling, the ZigZag Pattern, and sinusoidal patterns. The proposed “Chorio Duck Score” is a scoring system based on recently published scientific evidence on CTG features in subclinical and clinical chorioamnionitis to enable timely diagnosis of fetal systemic inflammatory response syndrome (FIRS). This will help avoid the continuation of super-imposed hypoxic stress (i.e., progressive increasing frequency, duration, and strength of uterine contractions) on the background fetal inflammation, to prevent fetal neurological injury.

Prenatal exposure to intra-amniotic infection with Ureaplasma species increases the prevalence of bronchopulmonary dysplasia

Objectives The present study investigated the relationship between bronchopulmonary dysplasia (BPD) and intra-amniotic infection with Ureaplasma species. Methods This was a single-center, retrospective cohort study. Patients with singleton pregnancies who underwent inpatient management at our department for preterm premature rupture of membranes (PPROM), preterm labor, cervical insufficiency, and asymptomatic cervical shortening at 22–33 gestational weeks were included. Amniocentesis was indicated for patients with PPROM or an elevated maternal C-reactive protein level (≥0.58 mg/dL). Patients with an amniotic fluid IL-6 concentration ≥3.0 ng/mL were diagnosed with intra-amniotic inflammation, while those with positive aerobic, anaerobic, M. hominis, and Ureaplasma spp. cultures were diagnosed with microbial invasion of the amniotic cavity (MIAC). Patients who tested positive for both intra-amniotic inflammation and MIAC were considered to have intra-amniotic infection. An umbilical vein blood IL-6 concentration >11.0 pg/mL indicated fetal inflammatory response syndrome (FIRS). The maternal inflammatory response (MIR) and fetal inflammatory response (FIR) were staged using the Amsterdam Placental Workshop Group Consensus Statement. Results Intra-amniotic infection with Ureaplasma spp. was diagnosed in 37 patients, intra-amniotic infection without Ureaplasma spp. in 28, intra-amniotic inflammation without MIAC in 58, and preterm birth without MIR/FIR and FIRS in 86 as controls. Following an adjustment for gestational age at birth, the risk of BPD was increased in patients with intra-amniotic infection with Ureaplasma spp. (adjusted odds ratio: 10.5; 95% confidence interval: 1.55–71.2), but not in those with intra-amniotic infection without Ureaplasma spp. or intra-amniotic inflammation without MIAC. Conclusion BPD was only associated with intra-amniotic infection with Ureaplasma species.

Prevalence of Fetal Inflammatory Response Syndrome and Villitis of Unknown Etiology in the Placenta of Saudi Women and Their Association with Baby Sex.

Long-term health consequences are influenced by circumstances that occur during pregnancy. The convergence of the maternal and fetal circulations occurs in the placenta, which is the first organ to develop. Placental pathology provides an accurate diagnosis of amniotic sac inflammation, and pathological alterations in preterm placentas provide evidence for the causes of numerous perinatal pathologies, including spontaneous preterm births. This retrospective study aimed to re-examine placentas regarded as normal by the Obstetrics and Gynecology Department at our institution. Thirty-seven male and forty-seven female placentas were collected following full-term delivery, and the grading and staging of any evident inflammatory responses were evaluated and correlated with the babies' sex. Full-thickness placental samples that were considered normal and not sent to the histopathology department were obtained from the central and marginal regions of placental discs. Morphological examination of the fresh placenta was conducted, and fetal and maternal inflammatory response syndromes were assessed. In addition, placental villitis of unknown etiology (VUE) and chronic deciduitis were evaluated. Immunohistochemistry was performed to evaluate the patterns of inflammation in the placenta using anti-CD8 and anti-CD68 antibodies. The correlation between silent pathologies and clinical complications or the development of fetal inflammatory response syndrome was measured. In this study, 17 (20%) maternal and 10 (12%) fetal samples showed inflammatory responses. The frequencies of chronic deciduitis and VUE were higher among pregnant Saudi women than previously reported, probably because fetal inflammatory response syndrome goes unnoticed in Saudi Arabia. In addition, the prevalence of fetal and maternal inflammatory responses was higher in the placentas of the mothers of males than in those of females, suggesting that differences occur in the inflammatory response in the placenta depending on the sex of the newborn. Grading placental inflammation (in cases of VUE) typically predicts the degree of maternal anti-fetal cellular rejection; therefore, increasing the number of placental samples sent for microscopic inspection may be preferable because of their significance in identifying the causes of chronic disorders.

Risk Factors and Mortality in Newborns with Persistent Pulmonary Hypertension: A Six-Year Single-Center Experience.

Persistent pulmonary hypertension (PPHT) of the newborn is a disorder of circulatory transition resulting in high pulmonary vascular resistance with extrapulmonary right-to-left shunts causing hypoxemia. In this study, our aim was to evaluate the risk factors, administered treatments, and mortality of patients followed in our neonatal intensive care unit (NICU) due to PPHT over the past six years. Patients diagnosed with PPHT and followed in the NICU between January 2017 and November 2022 were included in the study. The sociodemographic characteristics, diagnoses that could lead to pulmonary hypertension, the presence of congenital anomalies, the duration of respiratory support treatment and hospital follow-up, treatments administered for PPHT, and mortality rates were evaluated. Out of 21 patients diagnosed with persistent pulmonary hypertension, 9 of them (42.9%) were male. The mean gestational age of the patients was 37.6±3.7 weeks, and their birth weight was 3006±819grams. The APGAR scores at 1 and 5 minutes were 4(2-7) and 6(3-8), respectively. Risk factors during the antenatal period included fetal distress (38.1%), oligohydramnios (23.8%), intrauterine growth restriction (23.8%), gestational diabetes (14.3%), preeclampsia (4.8%), and chorioamnionitis (4.8%). The median duration of invasive mechanical ventilation for cases requiring respiratory support was 20.1 days, while the median duration of non-invasive ventilation was 3.7 days. Patients with a diagnosis of persistent pulmonary hypertension were treated with inhaled nitric oxide (iNO) in 76.2% of cases, milrinone in 66.7% of cases, sildenafil in 52.4% of cases, and iloprost in 14.3% of cases. The length of hospital stay for patients was 38.4 days, and 9 (42.9%) patients died. The patients who died had severe PPHT along with fetal inflammatory response syndrome (FIRS), congenital heart disease, pulmonary hypoplasia, pneumothorax, hypoxic-ischemic encephalopathy (HIE), and congenital anomalies. Persistent pulmonary hypertension, characterized by severe hypoxemia, is a neonatal emergency that necessitates early intervention, effective treatment of the underlying cause to prevent potential short-term and long-term morbidities and mortality. Effective treatment of the underlying cause in patients diagnosed with PPHT could reduce morbidity and mortality. It is inevitable to avoid the loss of patients with major abnormalities, severe comorbidities, and unpreventable organ dysfunctions.

Early heart rate variability changes during acute fetal inflammatory response syndrome: An experimental study in a fetal sheep model.

Fetal infection during labor with fetal inflammatory response syndrome (FIRS) is associated with neurodevelopmental disabilities, cerebral palsy, neonatal sepsis, and mortality. Current methods to diagnose FIRS are inadequate. Thus, the study aim was to explore whether fetal heart rate variability (HRV) analysis can be used to detect FIRS. In chronically instrumented near-term fetal sheep, lipopolysaccharide (LPS) was injected intravenously to model FIRS. A control group received saline solution injection. Hemodynamic, blood gas analysis, interleukin-6 (IL-6), and 14 HRV indices were recorded for 6 h. In both groups, comparisons were made between the stability phase and the 6 h following injection (H1-H6, respectively) and between LPS and control groups. Fifteen lambs were instrumented. In the LPS group (n = 8), IL-6 increased significantly after LPS injection (p < 0.001), confirming the FIRS model. Fetal heart rate increased significantly after H5 (p < 0.01). In our FIRS model without shock or cardiovascular decompensation, five HRV measures changed significantly after H2 until H4 in comparison to baseline. Moreover, significant differences between LPS and control groups were observed in HRV measures between H2 and H4. These changes appear to be mediated by an increase of global variability and a loss of signal complexity. As significant HRV changes were detected before FHR increase, these indices may be valuable for early detection of acute FIRS.

The role of neutrophils in chorioamnionitis.

Chorioamnionitis, commonly referred to as intrauterine infection or inflammation, is pathologically defined by neutrophil infiltration and inflammation at the maternal-fetal interface. Chorioamnionitis is the common complication during late pregnancy, which lead to a series of serious consequences, such as preterm labor, preterm premature rupture of the fetal membranes, and fetal inflammatory response syndrome. During infection, a large number of neutrophils migrate to the chorio-decidua in response to chemokines. Although neutrophils, a crucial part of innate immune cells, have strong anti-inflammatory properties, over-activating them can harm the body while also eliminating pathogens. This review concentrated on the latest studies on chorioamnionitis-related consequences as well as the function and malfunction of neutrophils. The release of neutrophil extracellular traps, production of reactive oxygen species, and degranulation from neutrophils during intrauterine infection, as well as their pathological roles in complications related to chorioamnionitis, were discussed in detail, offering fresh perspectives on the treatment of chorioamnionitis.

Amniotic fluid interleukin-6 and neutrophil gelatinase-associated lipocalin for predicting fetal inflammatory response syndrome based on histological chorioamnionitis and funisitis

ObjectiveWe aimed to analyze the predictive efficacy of amniotic fluid interleukin-6 (IL-6) and neutrophil gelatinase-associated lipocalin (NGAL) for fetal inflammatory response syndrome (FIRS)-related infection. Materials and methodsWe included singleton pregnancies classified into FIRS and non-FIRS groups. FIRS was defined as histologic chorioamnionitis and funisitis. Amniotic fluid samples were collected during vaginal delivery (VD) or cesarean section (CS). We compared amniotic fluid IL-6 and NGAL levels between the groups. ResultsForty-six pregnancies were analyzed and classified into 20 (43.5%) FIRS and 26 (56.5%) non-FIRS pregnancies. We observed significant differences in amniotic fluid IL-6 and NGAL. Amniotic fluid collection significantly influenced NGAL levels (p < 0.001). The area under the concentration–time curve (AUC), with optimal cutoff values, for amniotic fluid IL-6 and NGAL (VD and CS) levels was 0.948 (11,344 pg/mL), 0.800 (1180 ng/mL), and 0.946 (708 ng/mL), respectively. ConclusionAmniotic fluid IL-6 and NGAL levels showed equivalent predictive ability for FIRS-related infection.

Inflammation and Immune Reactions in the Fetus as a Response to COVID-19 in the Mother

Background: Contracting COVID-19 during pregnancy can harm both the mother and the unborn child. Pregnant women are highly likely to develop respiratory viral infection complications with critical conditions caused by physiological changes in the immune and cardiopulmonary systems. Asymptomatic COVID-19 in pregnant women may be accompanied by fetal inflammatory response syndrome, which has adverse consequences for the newborn’s life and health. Purpose: To conduct an inflammatory response assessment of the fetus due to the effects of COVID-19 on the mother during pregnancy by determining pro-inflammatory cytokines, cell markers, T regulatory cells, T cell response, evaluation of cardiac function, and thymus size. Materials and methods: A prospective study included pregnant women (n = 92). The main group consisted of 62 pregnant women with COVID-19 infection: subgroup 1—SARS-CoV-2 PCR-positive pregnant women 4–6 weeks before delivery (n = 30); subgroup 2—SARS-CoV-2 PCR-positive earlier during pregnancy (n = 32). The control group consisted of 30 healthy pregnant women. In all pregnant women, the levels of circulating cytokines and chemokines (IL-1α, IL-6, IL-8, IL-10, GM-CSF, TNF-α, IFN-γ, MIP-1β, and CXCL-10) were determined in the peripheral blood and after delivery in the umbilical cord blood, and an analysis was performed of the cell markers on dendritic cells, quantitative and functional characteristics of T regulatory cells, and specific T cell responses. The levels of thyroxine and thyroid-stimulating hormone were determined in the newborns of the studied groups, and ultrasound examinations of the thymus and echocardiography of the heart were also performed. Results: The cord blood dendritic cells of newborns born to mothers who suffered from COVID-19 4–6 weeks before delivery (subgroup 1) showed a significant increase in CD80 and CD86 expression compared to the control group (p = 0.023). In the umbilical cord blood samples of children whose mothers tested positive for COVID-19 4–6 weeks before delivery (subgroup 1), the CD4+CCR7+ T cells increased with a concomitant decrease in the proportion of naive CD4+ T cells compared with the control group (p = 0.016). Significantly higher levels of pro-inflammatory cytokines and chemokines were detected in the newborns of subgroup 1 compared to the control group. In the newborns of subgroup 1, the functional activity of T regulatory cells was suppressed, compared with the newborns of the control group (p &lt; 0.001). In all pregnant women with a severe coronavirus infection, a weak T cell response was detected in them as well as in their newborns. In newborns whose mothers suffered a coronavirus infection, a decrease in thymus size, transient hypothyroxinemia, and changes in functional parameters according to echocardiography were revealed compared with the newborns of the control group. Conclusions: Fetal inflammatory response syndrome can occur in infants whose mothers suffered from a COVID-19 infection during pregnancy and is characterized by the activation of the fetal immune system and increased production of pro-inflammatory cytokines. The disease severity in a pregnant woman does not correlate with SIRS severity in the neonatal period. It can vary from minimal laboratory parameter changes to the development of complications in the organs and systems of the fetus and newborn.

Retrospective analysis of leukemoid reactions in extremely preterm infants in a tertiary NICU from 2018–2021

Background Neonatal leukemoid reaction is associated with higher risk of mortality, chronic lung disease and has been associated with chorioamnionitis. Literature on extremely low birth weight infants with leukemoid reaction is limited. Objectives The aim of our study was to characterize the maternal and placental factors associated with neonatal leukemoid reaction and to describe outcomes of these ELBW infants. Our objective was to assess if there were maternal factors that would assist the decision-making process regarding the delivery of preterm infants at risk of chorioamnionitis and the sequelae of this inflammatory process. Methods This was a retrospective case-control study performed in a single, tertiary Maternity Hospital in Dublin. Two matched controls were identified for each case based on gestation and year of birth and data was collected on both the infants and their mothers. Results 7 extremely preterm neonates were identified as having a leukemoid reaction, defined as a total white cell count of >50,000 or in the first seven days of life. Baseline characteristics between the groups were similar. The median gestational age in the cases group was 24 + 4 weeks and in the control group was 24 + 1. The mean birthweight was 650 g in the cases group vs. 655 g in the control group. There was a higher percentage of males in the control group, 42.9% vs 28.6% in the cases. The preterm infants with leukemoid reaction had a longer duration of ventilation with a median of 18 days (7.5–23.5 days) compared to 6.5 days (2.8–24.5 days) in the control group. More infants in the leukemoid reaction group required inotropes for hypotension in the first 72 h after delivery (42.9% vs 7.1% in the controls, p value .169). Death or Bronchopulmonary dysplasia (BPD) occurred in 85.7% of the cases identified with a leukemoid reaction vs 71.4% of the controls matched. Median maternal CRP was higher in cases prior to delivery vs the controls (66 vs 18.1 mg/L, p-value = .2151). There was histological evidence of maternal inflammatory response in all cases with fetal inflammatory response in 71% of cases. Conclusions Leukemoid reaction in ELBW infants with evidence of maternal and fetal inflammatory response syndrome on placental histology is associated with a longer duration of initial ventilation, increased need for inotropes in the first 72 h after birth, higher rates of death, and BPD. Prospective studies are required to identify potential biomarkers such as proinflammatory cytokines, IL-6, which might aid the decision-making process in delivery.

Intrauterine activation of the fetal immune system in response to maternal COVID-19

Introduction. During pregnancy COVID-19 poses a serious threat to both maternal health and health of paired unborn child. Pregnant women have a high probability of complications due to respiratory viral infections followed by developing critical conditions caused by physiologically altered immune and cardiopulmonary systems. However, asymptomatic COVID-19 in pregnant women may be accompanied by fetal inflammatory response syndrome (FIRS) that results in unfavorable sequelae for neonatal life and health.Aim: to assess a fetal inflammatory response resulting from maternal COVID-19 in pregnancy.Materials and Мethods. A prospective randomized comparative study involving 92 pregnant women was carried out. The main group included 62 pregnant COVID-19 convalescent women: subgroup 1 consisted of 30 pregnant women found to be positive for SARS-CoV-2 by using polymerase chain reaction (PCR) 4–6 weeks before delivery; subgroup 2 – 32 pregnant women with SARS-CoV-2 detected by PCR earlier during pregnancy. The control group enrolled 30 healthy pregnant women. The level of circulating cytokines – interleukins (IL) IL-1α, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), macrophage inflammatory protein-1β (MIP-1β), C-X-C motif chemokine ligand 10 (CXCL-10) and cell markers (CD86, CD80, CD4, CD25, CD25, CCR7) were analyzed. In addition, all neonates underwent thymus gland ultrasound screening.Results. Cord blood dendritic cells from neonates born to mothers in subgroup 1 vs. control group showed a significantly upregulated expression of CD80 and CD86 (p = 0.023). Moreover, such cord blood samples in subgroup 1 were found to have increased percentage of CD4+, CCR7+ T cells paralleled with decreased proportion of naive CD4+ T cells as compared with control group (p = 0.016). It was found that count of maternal regulatory CD4+CD25+Foxp3+ T cells (Treg) did not differ significantly, whereas Treg cell functional activity in mothers with severe COVID-19 (subgroup 2) was significantly suppressed. Significantly higher level of neonatal proinflammatory cytokines and chemokines was detected in subgroup 1 vs. control group (p &lt; 0.05). However, the cytokines level in maternal peripheral blood samples in main and control groups upon delivery was changed insignificantly. SARS-CoV-2-positive pregnant women showed a strong antigen-specific T cell response. A reduced thymus size was found in neonates born to paired COVID-19 mothers.Conclusion. Fetal inflammatory response syndrome occurs upon COVID-19, which is characterized by activated fetal immune system and increased production of pro-inflammatory cytokines. The disease severity in pregnant women has no correlation with FIRS intensity during neonatal period and can vary from minimally altered laboratory parameters to developing sequelae at organ and body system levels.

Infection Induced Fetal Inflammatory Response Syndrome (FIRS): State-of- the-Art and Medico-Legal Implications-A Narrative Review.

Fetal inflammatory response syndrome (FIRS) represents the fetal inflammatory reaction to intrauterine infection or injury, potentially leading to multiorgan impairment, neonatal mortality, and morbidity. Infections induce FIRS after chorioamnionitis (CA), defined as acute maternal inflammatory response to amniotic fluid infection, acute funisitis and chorionic vasculitis. FIRS involves many molecules, i.e., cytokines and/or chemokines, able to directly or indirectly damage fetal organs. Therefore, due to FIRS being a condition with a complex etiopathogenesis and multiple organ dysfunction, especially brain injury, medical liability is frequently claimed. In medical malpractice, reconstruction of the pathological pathways is paramount. However, in cases of FIRS, ideal medical conduct is hard to delineate, due to uncertainty in diagnosis, treatment, and prognosis of this highly complex condition. This narrative review revises the current knowledge of FIRS caused by infections, maternal and neonatal diagnosis and treatments, the main consequences of the disease and their prognoses, and discusses the medico-legal implications.

Diagnostic accuracy of amniotic fluid interleukin‐6 for fetal inflammatory response syndrome

This study aimed to clarify the diagnostic accuracy of amniotic fluid interleukin-6 for fetal inflammatory response syndrome (FIRS). This retrospective cohort study was conducted in a single institution and targeted cases of preterm birth within 24 h after amniocentesis among singleton cases that underwent amniocentesis at our hospital for suspected intraamniotic inflammation (IAI) from gestational ages of 22-36 weeks between August 2014 and March 2020. FIRS was defined as >11.0pg/mL of umbilical cord blood interleukin-6. The analysis included 158 pregnant women. There was a strong correlation between amniotic fluid interleukin-6 and umbilical cord blood interleukin-6 (r=0.70, p < 0.001). The area under the receiver operating characteristic curve of amniotic fluid interleukin-6 for FIRS was 0.93, with a cutoff value of 15.5ng/mL, and showed high sensitivity and specificity (0.91 and 0.88, respectively). An amniotic fluid interleukin-6 cutoff value of ≥15.5ng/mL was associated with a significant risk of FIRS (adjusted odds ratio: 27.9; 95% confidence interval: 6.3-123.0; p < 0.001). The results of this study show that amniotic interleukin 6 alone can be used to diagnose FIRS prenatally. While there is a need for validation, it may be possible to treat IAI while preventing damage to the central nervous and respiratory systems in the uterus by keeping the amniotic fluid interleukin-6 below the cutoff value.

Fetal inflammatory response syndrome (FIRS): che cosa è, quando bisogna pensarci

The paper describes a case of severe hyperleukocytosis in a preterm with FIRS (Fetal Inflammatory Response Syndrome) associated with funisitis of umbilical cord and intrauterine inflammation. FIRS is a cause of leukocytosis in newborn, as well as leukemoid reaction in 21 trisomy, congenital leukemia, sepsis and steroid prophylaxis. Inflammatory response syndrome is associated with high mortality, neuroevolutive impairment and complication of prematurity like intraventricular haemorrhage, chronic lung disease, periventricular leukomalacia and sepsis.

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

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). 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). 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. 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.

Multi System Inflammatory Syndrome In Neonates (MIS-N): A Case Report

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy may increase the risk of stillbirth, neonatal death, preterm birth, low birth weight, fetal distress, and neonatal asphyxia (1). Vertical transmission of SARS-CoV-2 is under investigation. A few reports suggest the possibility of SARS-CoV-2 transmission from mothers to their neonates. The SARS-CoV-2 virus was reported as one of the rare causes of fetal inflammatory response syndrome (FIRS) (5) and is associated with multisystem inflammatory syndrome in children (MIS-C) (6).Most neonates have mild symptoms, but some develop multisystem involvement including respiratory distress, feeding intolerance, lethargy. Most of the infants have elevated biomarkers, positive septic screen, and elevated inflammatory markers. Infants diagnosed with MIS-N gradually improve after 2 doses of IVIG and IV Steroid ( Methylprednisolone).

POS-010 NEONATAL COVID-19 WITH ACUTE KIDNEY INJURY: EXPERIENCE WITH PERITONEAL DIALYSIS

Children are less severely affected by acute respiratory syndrome coronavirus 2 (SARS-CoV-2) than adults. The data available suggest that severe disease might be more common in infants and neonates than in older children. In a prospective UK population-based cohort study most babies were mildly affected, with cases of severe disease being very rare. The SARS-CoV-2 virus was reported as one of the rare causes of fetal inflammatory response syndrome (FIRS) and is associated with multisystem inflammatory syndrome in children (MIS-C).

Fetal inflammatory response syndrome and postnatal multi-system inflammatory syndrome in COVID-19-positive neonates

article: Fetal inflammatory response syndrome and postnatal multi-system inflammatory syndrome in COVID-19-positive neonates - Minerva Respiratory Medicine 2022 September;61(3):146-51 - Minerva Medica - Journals

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)-1β 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-1β titer in the maternal sera of GBS-infected dams. IL-1Ra decreased the levels of IL-1β, IL-6, chemokine (C-X-C motif) ligand 1 (CXCL1), and polymorphonuclear (PMN) infiltration in GBS-infected placenta. IL-1Ra treatment reduced the IL-1β 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.