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. 2020 Aug;25(4):101146.
doi: 10.1016/j.siny.2020.101146. Epub 2020 Oct 23.

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

Eunjung Jung  1 , Roberto Romero  2 , Lami Yeo  1 , Ramiro Diaz-Primera  1 , Julio Marin-Concha  1 , Robert Para  1 , Ashley M Lopez  1 , Percy Pacora  1 , Nardhy Gomez-Lopez  3 , Bo Hyun Yoon  4 , Chong Jai Kim  5 , Stanley M Berry  1 , Chaur-Dong Hsu  6
Affiliations

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

Eunjung Jung et al. Semin Fetal Neonatal Med. 2020 Aug.

Abstract

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.

Keywords: Cerebral palsy; Chorioamnionitis; Congenital dermatitis; Cytokines; FIRS; Fetal cytokine release syndrome; Fetal cytokine storm; Fetal hematophagocytic syndrome; Fetal macrophage activation-like syndrome; Funisitis; Interleukin-6; Intra-amniotic infection; Intra-amniotic inflammation; Neonatal encephalopathy; Neonatal morbidity; Neonatal sepsis; Neuroinflammation perinatal morbidity; Premature birth; Prematurity; Preterm labor; Preterm prelabor rupture of the membranes (preterm PROM); Retinopathy of prematurity; Sensorineuronal hearing loss.

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Conflict of interest statement

Declaration of competing interest

The authors report no conflicts of interest.

Figures

Fig. 1.
Fig. 1.
Fetuses with fetal inflammatory response syndrome (FIRS) have a shorter intrauterine stay than those without FIRS. Mothers were admitted with preterm premature rupture of membranes and patients were not in labor at admission. The interval between the procedure and delivery reflects duration of pregnancy and spontaneous onset of labor. Fetuses with fetal plasma IL-6 concentrations greater than 11 pg/mL have a shorter procedure-to-delivery interval than those with plasma IL-6 concentrations of 11 pg/mL or less (median 0.8 days [range 0.1–5 days] vs. median 6 days [range 0.2–33.6 days]; respectively; P < 0.05). (Modified with permission from Romero R, Gomez R, Ghezzi F et al.: A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol 1998; 179:186–193.).
Fig. 2.
Fig. 2.
Duration of pregnancy according to whether or not there is intraamniotic inflammation and fetal systemic inflammation (FIRS). The key determinant of pregnancy duration is fetal systemic inflammation regardless of the inflammatory status of the amniotic cavity, as reflected by the procedure-to-delivery interval. The inflammatory status of the amniotic cavity and the fetus was assessed with interleukin-6 (IL-6) concentrations. A white color fetus represents no inflammation [defined as fetal plasma (FP) IL-6 less than 11 pg/mL]. A red color fetus represents fetal systemic inflammation (FP IL-6 greater than 11 pg/mL). The amniotic fluid compartment is either white (no intraamniotic inflammation) or yellow in color (intraamniotic inflammation present). The cut-off value of 7.9 ng/ml was used to define intra-amniotic inflammation. The number of patients in each group is depicted (n). (Reproduced with permission from Romero R, Gomez R, Ghezzi F et al: A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol 179:186–193, 1998.).
Fig. 3.
Fig. 3.
Fetal inflammatory response syndrome (FIRS) was associated with a higher severe neonatal morbidity than the absence of FIRS. FIRS was defined as a fetal plasma IL-6 >11 pg/mL. This was calculated using logistic regression to adjust for gestational age and other covariates. (Reproduced and modified with permission from Gomez R, Romero R, Ghezzi F et al.: The fetal inflammatory response syndrome. Am J Obstet Gynecol 179:194–202, 1998.).
Fig. 4.
Fig. 4.
The fetal inflammatory response syndrome (FIRS) is associated with multi-systemic involvement. Clinical and/or experimental evidence suggests that there is involvement of the organs displayed in the figure. The data to support this conclusion is reviewed in the article. (Modified with permission from Gotsch F, Romero R, Kusanovic JP, Mazaki-Tovi S, Pineles B, Erez O, Espinoza J, Hassan SS. Fetal Inflammatory Response Syndrome. Clinical Obstetrics and Gynecology 50:652–683; 2007).
Fig. 5.
Fig. 5.
Meconium aspiration syndrome (MAS) is more likely to occur in patients with meconium-stained amniotic fluid if intraamniotic inflammation and fetal inflammatory response syndrome ascertained by funisitis are present. Frequency of MAS in the context of intraamniotic inflammation and funisitis. Neonates exposed to both intraamniotic inflammation and funisitis were at significantly greater risk of MAS than newborns exposed to neither of these 2 conditions [28.6% (4/14) vs 0% (0/28), P = 0.009]. In contrast, newborns exposed to only intraamniotic inflammation without funisitis were not at greater risk of MAS than newborns exposed to neither of these 2 conditions [10.9% (5/46) vs 0% (0/28); P = 0.15]. MAS did not occur in the absence of intraamniotic inflammation. (Reproduced with permission from Lee J, Romero R, Lee KA et al. Meconium aspiration syndrome: a role for fetal systemic inflammation. Am J Obstet Gynecol 214:366.e1–9, 2016.).
Fig. 6.
Fig. 6.
The higher the umbilical cord plasma concentration of C-reactive protein (CRP), the more severe the inflammatory process in the umbilical cord, assessed by the severity of funisitis by stage. (Reproduced with permission from Oh JW, Park CW, Moon KC et al. The relationship among the progression of inflammation in umbilical cord, fetal inflammatory response, early-onset neonatal sepsis, and chorioamnionitis. PLoS One 14:e0225328, 2019.).
Fig. 7.
Fig. 7.
Funisitis is inflammation of the umbilical vein, either or both umbilical arteries, and the Wharton’s jelly. Serial sections of the umbilical cord were taken at 1 mm intervals and showed neutrophil infiltration of the umbilical vein (dashed line). (Reproduced with permission from Kim CJ, Yoon BH, Kim M et al. Histo-topographic distribution of acute inflammation of the human umbilical cord. Pathol Int 51:861–5, 2001.).
Fig. 8.
Fig. 8.
The peripheral blood transcriptome of fetuses with fetal inflammatory response syndrome (FIRS) is dramatically different from that of fetuses with-outlammatory response syndrome (FIRS). Similar results have been reported in patients with pediatric sepsis and after volunteers have been given bacterial endotoxin. Transcriptome analysis of white blood cells collected from the umbilical cord in patients with preterm labor and preterm prelabor rupture of membranes was performed. Red color depicts upregulation, while green color depicts downregulation. Displayed are the 296 genes that were differentially upregulated in leukocytes from neonates with FIRS and the 252 that were decreased (False discovery rate <0.05). (Reproduced with permission from Madsen-Bouterse SA, Romero R, Tarca AL et al. The transcriptome of the fetal inflammatory response syndrome. Am J Reprod Immunol 63:73–92, 2010.).
Fig. 9.
Fig. 9.
Differentially expressed genes in umbilical cord blood according to the presence or absence of fetal inflammatory response syndrome (FIRS). The data were generated by qRT-PCR. Genes were selected after the results of microarray analysis. Altered abundance of genes within ontological categories of immune response and inflammation (a), MHC II receptor activity (b), carbohydrate metabolism (c) and signal transduction (d) was confirmed using qRT-PCR. Box-plots include 50% of the data with the middle line showing the median value; P < 0.05 for all genes is shown when modeled using GEE. Depending on the statistical method used, 93–95% of the genes tested confirmed the change observed by microarray analysis. (Reproduced with permission from Madsen-Bouterse SA, Romero R, Tarca AL et al. The transcriptome of the fetal inflammatory response syndrome. Am J Reprod Immunol 63:73–92, 2010.).
Fig. 10.
Fig. 10.
Transcriptome analysis of fetal blood using whole genome DASL® assay according to the presence or absence of fetal inflammatory response syndrome (FIRS) type II that is associated with maternal anti-fetal rejection. A clustered heat map based on the top 200 differentially expressed genes displays two main clusters: one dominated by samples of the fetal inflammatory response associated with maternal anti-fetal rejection group (FIRS II) (left) and one dominated by samples in the control group (right). (Reproduced with permission from Lee J, Romero R, Chaiworapongsa T et al. Characterization of the fetal blood transcriptome and proteome in maternal anti-fetal rejection: evidence of a distinct and novel type of human fetal systemic inflammatory response. Am J Reprod Immunol 70:265–84, 2013.).
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