The influence of chorioamnionitis on respiratory drive and spontaneous breathing of premature infants at birth: a narrative review.

Most very premature infants breathe at birth but require respiratory support in order to stimulate and support their breathing. A significant proportion of premature infants are affected by chorioamnionitis, defined as an umbrella term for antenatal inflammation of the foetal membranes and umbilical vessels. Chorioamnionitis produces inflammatory mediators that potentially depress the respiratory drive generated in the brainstem. Such respiratory depression could maintain itself by delaying lung aeration, hampering respiratory support at birth and putting infants at risk of hypoxic injury. This inflammatory-mediated respiratory depression may contribute to an association between chorioamnionitis and increased requirement of neonatal resuscitation in premature infants at birth. This narrative review summarises mechanisms on how respiratory drive and spontaneous breathing could be influenced by chorioamnionitis and provides possible interventions to stimulate spontaneous breathing.  Conclusion: Chorioamnionitis could possibly depress respiratory drive and spontaneous breathing in premature infants at birth. Interventions to stimulate spontaneous breathing could therefore be valuable. What is Known: • A large proportion of premature infants are affected by chorioamnionitis, antenatal inflammation of the foetal membranes and umbilical vessels. What is New: • Premature infants affected by chorioamnionitis might be exposed to higher concentrations of respiratory drive inhibitors which could depress breathing at birth. • Premature infants affected by chorioamnionitis seem to be associated with a higher and more extensive requirement of resuscitation at birth.

Chorioamnionitis and neonatal outcomes.

Chorioamnionitis or intrauterine inflammation is a frequent cause of preterm birth. Chorioamnionitis can affect almost every organ of the developing fetus. Multiple microbes have been implicated to cause chorioamnionitis, but "sterile" inflammation appears to be more common. Eradication of microorganisms has not been shown to prevent the morbidity and mortality associated with chorioamnionitis as inflammatory mediators account for continued fetal and maternal injury. Mounting evidence now supports the concept that the ensuing neonatal immune dysfunction reflects the effects of inflammation on immune programming during critical developmental windows, leading to chronic inflammatory disorders as well as vulnerability to infection after birth. A better understanding of microbiome alterations and inflammatory dysregulation may help develop better treatment strategies for infants born to mothers with chorioamnionitis.

Protective placental inflammatory and oxidative stress responses are attenuated in the context of twin pregnancy and chorioamnionitis in assisted reproduction.

PURPOSE: Assisted reproduction technologies (ART) are associated with increased risks of pregnancy complications and obstetric interventions. Here, we aimed to determine if ART affects placental inflammation and oxidative stress as a mechanism for unfavorable pregnancy outcomes. METHODS: The levels of six cytokines (IFN-γ, IL-1ß, IL-6, IL-8, IL-10, TNFα) were measured using multiplex ELISA. The activity of four antioxidant enzymes (glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase, superoxide dismutase) and levels of two antioxidants (GSH, vitamin E) were measured using commercial/in-house assays. Markers were compared between ART and unassisted pregnancies, and then groups were stratified using ICD9/10 codes to determine differences in specific clinical contexts. RESULTS: In unassisted twin pregnancies, there was a trend of decreased cytokine levels (IL-1ß, IL-6, IL-8, TNFα, p < 0.05), but cytokines in ART twins were the same or higher. Additionally, GST and GPx activities were lower in unassisted twins, and vitamin E levels were higher in ART twins (p < 0.05). In pregnancies complicated by chorioamnionitis, there was a trend of increased cytokine levels in unassisted pregnancies (IL-1ß, IL-6, and IL-8, p < 0.05). No increase was observed in ART, and IFN-γ and TNFα were decreased (p < 0.05). Placental GST and GPx activities were higher in unassisted pregnancies with chorioamnionitis compared to ART (p < 0.05). CONCLUSION: Attenuation of protective placental inflammatory and oxidative stress responses may play a role in the underlying pathogenesis of negative birth outcomes in ART, expanding our understanding of adverse pregnancy outcomes when ART is used to conceive.

Budesonide with surfactant decreases systemic responses in mechanically ventilated preterm lambs exposed to fetal intra-amniotic lipopolysaccharide.

BACKGROUND: Chorioamnionitis is associated with increased rates of bronchopulmonary dysplasia (BPD) in ventilated preterm infants. Budesonide when added to surfactant decreased lung and systemic inflammation from mechanical ventilation in preterm lambs and decreased the rates and severity of BPD in preterm infants. We hypothesized that the addition of budesonide to surfactant will decrease the injury from mechanical ventilation in preterm lambs exposed to intra-amniotic (IA) lipopolysaccharide (LPS). METHODS: Lambs at 126 ± 1 day GA received LPS 10 mg IA 48 h prior to injurious mechanical ventilation. After 15 min, lambs received either surfactant mixed with: (1) saline or (2) Budesonide 0.25 mg/kg, then ventilated with normal tidal volumes for 4 h. Injury markers in the lung, liver, and brain were compared. RESULTS: Compared with surfactant alone, the addition of budesonide improved blood pressures, dynamic compliance, and ventilation, while decreasing mRNA for pro-inflammatory cytokines in the lung, liver, and multiple areas of the brain. LPS caused neuronal activation and structural changes in the brain that were not altered by budesonide. Budesonide was not retained within the lung beyond 4 h. CONCLUSIONS: In preterm lambs exposed to IA LPS, the addition of budesonide to surfactant improved physiology and markers of lung and systemic inflammation. IMPACT: The addition of budesonide to surfactant decreases the lung and systemic responses to injurious mechanical ventilation preterm lambs exposed to fetal LPS. Budesonide was present in the plasma by 15 min and the majority of the budesonide is no longer in the lung at 4 h of ventilation. IA LPS and mechanical ventilation caused structural changes in the brain that were not altered by short-term exposure to budesonide. The budesonide dose of 0.25 mg/kg being used clinically seems likely to decrease lung inflammation in preterm infants with chorioamnionitis.

Betamethasone as a potential treatment for preterm birth associated with sterile intra-amniotic inflammation: a murine study.

OBJECTIVES: Preterm birth remains the leading cause of perinatal morbidity and mortality worldwide. Preterm birth is preceded by spontaneous preterm labor, which is commonly associated with sterile intra-amniotic inflammation; yet, no approved treatment exists for this clinical condition. Corticosteroids are the standard of care to improve neonatal outcomes in women at risk of preterm birth. Herein, we first validated our model of alarmin-induced preterm birth. Next, we investigated whether treatment with betamethasone could prevent preterm birth resulting from sterile intra-amniotic inflammation in mice. METHODS: Under ultrasound guidance, the first cohort of dams received an intra-amniotic injection of the alarmin high-mobility group box-1 (HMGB1, n=10) or phosphate-buffered saline (PBS, n=9) as controls. A second cohort of dams received HMGB1 intra-amniotically and were subcutaneously treated with betamethasone (n=15) or vehicle (n=15). Dams were observed until delivery, and perinatal outcomes were observed. RESULTS: Intra-amniotic HMGB1 reduced gestational length (p=0.04), inducing preterm birth in 40% (4/10) of cases, of which 100% (4/4) were categorized as late preterm births. Importantly, treatment with betamethasone extended the gestational length (p=0.02), thereby reducing the rate of preterm birth by 26.6% (from 33.3% [5/15] to 6.7% [1/15]). Treatment with betamethasone did not worsen the rate of neonatal mortality induced by HMGB1 or alter weight gain in the first three weeks of life. CONCLUSIONS: Treatment with betamethasone prevents preterm birth induced by the alarmin HMGB1. This study supports the potential utility of betamethasone for treating women with sterile intra-amniotic inflammation.

Maternal azithromycin therapy for Ureaplasma parvum intraamniotic infection improves fetal hemodynamics in a nonhuman primate model.

BACKGROUND: Ureaplasma parvum infection is a prevalent cause of intrauterine infection associated with preterm birth, preterm premature rupture of membranes, fetal inflammatory response syndrome, and adverse postnatal sequelae. Elucidation of diagnostic and treatment strategies for infection-associated preterm labor may improve perinatal and long-term outcomes for these cases. OBJECTIVE: This study assessed the effect of intraamniotic Ureaplasma infection on fetal hemodynamic and cardiac function and the effect of maternal antibiotic treatment on these outcomes. STUDY DESIGN: Chronically catheterized pregnant rhesus monkeys were assigned to control (n=6), intraamniotic inoculation with Ureaplasma parvum (107 colony-forming units/mL, n=15), and intraamniotic infection plus azithromycin treatment (12.5 mg/kg twice a day intravenously, n=8) groups. At approximately 135 days' gestation (term=165 days), pulsed and color Doppler ultrasonography was used to obtain measurements of fetal hemodynamics (pulsatility index of umbilical artery, ductus venosus, descending aorta, ductus arteriosus, aortic isthmus, right pulmonary artery, middle cerebral artery and cerebroplacental ratio, and left and right ventricular cardiac outputs) and cardiac function (ratio of peak early vs late transmitral flow velocity [marker of ventricular function], Tei index [myocardial performance index]). These indices were stratified by amniotic fluid proinflammatory mediator levels and cardiac histology. RESULTS: Umbilical and fetal pulmonary artery vascular impedances were significantly increased in animals from the intraamniotic inoculation with Ureaplasma parvum group (P<.05). Azithromycin treatment restored values to control levels. Amniotic fluid prostaglandin F2 alpha levels were significantly higher in animals with abnormal umbilical artery pulsatility index (>1.1) than in those with normal blood flow (P<.05; Spearman ρ=0.6, P<.05). In the intraamniotic inoculation with Ureaplasma parvum group, left ventricular cardiac output was significantly decreased (P<.001), and more animals had abnormal right-to-left ventricular cardiac output ratios (defined as >1.6, P<.05). Amniotic fluid interleukin-6 concentrations were elevated in cases of abnormal right-to-left ventricular cardiac output ratios compared with those in normal cases (P<.05). CONCLUSION: Fetal hemodynamic alterations were associated with intraamniotic Ureaplasma infection and ameliorated after maternal antibiotic treatment. Doppler ultrasonographic measurements merit continuing investigation as a diagnostic method to identify fetal cardiovascular and hemodynamic compromise associated with intrauterine infection or inflammation and in the evaluation of therapeutic interventions or clinical management of preterm labor.

A perfect storm: fetal inflammation and the developing immune system.

Histologic chorioamnionitis is an inflammatory disorder of the placenta that commonly precedes preterm delivery. Preterm birth related to chorioamnionitis and fetal inflammation has been associated with a risk for serious inflammatory complications in infancy. In addition, preterm infants exposed to chorioamnionitis may be more susceptible to infection in the neonatal intensive care unit and possibly later in life. A significant body of work has established an association between chorioamnionitis and inflammatory processes. However, the potential consequences of this inflammation on postnatal immunity are less understood. In this review, we will discuss current knowledge regarding the effects of fetal exposure to inflammation on postnatal immune responses.

Implementation of the Neonatal Sepsis Calculator in Early-Onset Sepsis and Maternal Chorioamnionitis.

BACKGROUND: Utilization of the neonatal sepsis calculator published by Kaiser Permanente is rapidly increasing. This freely available online tool can be used in assessment of early-onset sepsis (EOS) in newborns 34 weeks' gestation or more based on maternal risk factors and neonatal examination. However, many hospitals lack standard guidelines for its use, leading to provider discomfort with practice change. PURPOSE: The goal of this project was to study the antibiotic use rate for EOS at a level III neonatal intensive care unit and create standardized guidelines and staff education for using the sepsis calculator. Our ultimate goal was to decrease antibiotic use for EOS in newborns 34 weeks' gestation or more. METHODS: A standard quality improvement Plan-Do-Study-Act (PDSA) model was utilized with a plan to study the problem, implement the intervention, and test again for improvement. The primary outcome of interest was a decrease in the use of antibiotics for EOS in neonates 34 weeks' gestation or more. RESULTS: Over a 4-month period, prior to sepsis calculator implementation, antibiotic use for suspected EOS was 11% and blood culture was done on 14.8% of live births. After implementation of the sepsis calculator and completion of the PDSA cycle, sepsis calculator use was greater than 95%, antibiotic use dropped significantly to 5% (P = .00069), and blood culture use dropped to 7.6% (P = .00046). IMPLICATIONS FOR PRACTICE: Staff education and systematic intervention using a PDSA model can significantly impact patient care, decreasing the administration of antibiotics to infants at risk for sepsis. IMPLICATIONS FOR RESEARCH: Future research is needed to decrease antibiotic use in premature infants less than 34 weeks' gestation with similar risk factors and clinical features.Video Abstract available at https://journals.na.lww.com/advancesinneonatalcare/Pages/videogallery.aspx?videoId=34&autoPlay=true.

Decreased expression of progesterone receptor membrane component 1 in fetal membranes with chorioamnionitis among women with preterm birth.

PURPOSE: Progesterone receptor membrane component 1 (PGRMC1) have anti-inflammatory and anti-apoptotic properties. This study aimed to determine the expression of PGRMC1 in fetal membranes among women with preterm labor (PTL), preterm premature rupture of membranes (PPROM), and acute histologic chorioamnionitis (HCA) during preterm birth. METHODS: Full thickness fetal membranes were obtained from women with gestational age-matched (32-34 weeks of gestational age), and categorized as PTL without HCA (PTL, n = 10), PPROM without HCA (PPROM, n = 10), PPROM with HCA (HCA, n = 10), and term without labor and HCA (term birth (TB), n = 9). The expression of PGRMC1 was assessed using western blot and Immunohistochemistry (IHC). As CD14 is a component of the innate immune system during inflammation, CD14 was used as inflammatory indicator. Nonparametric statistics were used for analysis. RESULTS: PGRMC1 expression for all of preterm birth was lower than in TB (P = 0.01). In HCA, PGRMC1 expression was significantly decreased compared to that in PTL and PPROM (P = 0.006. P = 0.001, respectively). PGRMC1 expression in PPROM was higher than that in PTL (P = 0.002). There was a negative correlation between PGRMC1 and CD 14/ß-actin ratio (r = - 0.518; P = 0.002). IHC showed that PGRMC1 was predominant in the cytoplasm of cells, these results were consistent with those of the western blot analysis. CONCLUSION: Preterm birth with PTL, PPROM, and especially HCA is associated with a decreased PGRMC1 in fetal membranes and inversely associated with increased CD 14.

Fetal Portal System Flowmetry and Intra-Amniotic Inflammation in Preterm Prelabor Rupture of Membranes.

OBJECTIVES: To determine the pulsatility index (PI) in the fetal splenic vein, the main portal vein, the left portal vein, and the ductus venosus with respect to the presence or absence of intra-amniotic inflammation (IAI) in preterm prelabor rupture of membranes (PPROM). METHOD: Women with singleton pregnancies and PPROM, ranging in gestational age from 22+0 to 36+6 weeks, were included. Amniotic fluid samples were obtained by transabdominal amniocentesis and the amniotic fluid level of interleukin-6 (IL-6) was assessed by a point-of-care test. Doppler examination of the selected veins was performed, and the PI was assessed. IAI was defined as amniotic fluid levels of IL-6 ≥745 pg/mL. RESULTS: In total, 42 women were included. Fetuses with IAI compared with those without IAI exhibited a higher PI in the splenic vein (p = 0.005) and the main portal vein (p = 0.05). No differences were observed in the left portal vein PI (p = 0.36) and the ductus venosus PI (p = 0.98). CONCLUSION: IAI was associated with increased fetal splenic vein PI and main portal vein PI in PPROM. The absence of changes in the left portal vein PI and ductus venosus PI supports the local cause of the finding.

Spatiotemporal distribution of small ubiquitin-like modifiers during human placental development and in response to oxidative and inflammatory stress.

KEY POINTS: The post-translational modification of target proteins by SUMOylation occurs in response to stressful stimuli in a variety of organ systems. Small ubiquitin-like modifier (SUMO) isoforms 1-4 have recently been identified in the human placenta, and are upregulated in the major obstetrical complication of pre-eclampsia. This is the first study to characterize the spatiotemporal distribution of SUMO isoforms and their targets during placental development across gestation and in response to stress induced by pre-eclampsia and chorioamnionitis. Keratins were identified as major targets of placental SUMOylation. The interaction with SUMOs and cytoskeletal filaments provides evidence for SUMOylation possibly contributing to underlying dysfunctional trophoblast turnover, which is a hallmark feature of pre-eclampsia. Further understanding the role of individual SUMO isoforms and SUMOylation underlying placental dysfunction may provide a target for a novel therapeutic candidate as an approach for treating pre-eclampsia complicated with placental pathology. ABSTRACT: SUMOylation is a dynamic, reversible post-translational modification that regulates cellular protein stability and localization. SUMOylation occurs in response to various stressors, including hypoxia and inflammation, features common in the obstetrical condition of pre-eclampsia. SUMO isoforms 1-4 have recently been identified in the human placenta, but less is known about their role in response to pre-eclamptic stress. We hypothesized that SUMOylation components have a unique spatiotemporal distribution during placental development and that their subcellular localization can be further modulated by extra-cellular stressors. Placental SUMO expression was examined across gestation. First-trimester human placental explants and JAR cells were subjected to hypoxia or TNF-α cytokine, and subcellular translocation of SUMOs was monitored. SUMOylation target proteins were elucidated using mass spectrometry and proximity ligation assay. Placental SUMO-1 and SUMO-4 were restricted to villous cytotrophoblast cells in first trimester and syncytium by term, while SUMO-2/3 staining was evenly distributed throughout the trophoblast across gestation. In placental villous explants, oxidative stress induced hyperSUMOylation of SUMO-1 and SUMO-4 in the syncytial cytoplasm, whereas SUMO-2/3 nuclear expression increased. Oxidative stress also upregulated cytoplasmic SUMO-1 and SUMO-4 protein expression (P < 0.05), similar to pre-eclamptic placentas. Keratins were identified as major targets of placental SUMOylation. Oxidative stress increased the cytokeratin-7 to SUMO-1 and SUMO-4 interactions, while inflammatory stress increased its interaction with SUMO-2/3. Overall, SUMOs display a unique spatiotemporal distribution in normal human placental development. Our data indicate SUMOylation in pre-eclampsia, which may impair the stability of cytoskeleton filaments and thus promote trophoblast shedding into the maternal circulation in this condition.

Gestational age at time of in utero lipopolysaccharide exposure influences the severity of inflammation-induced diaphragm weakness in lambs.

The preterm diaphragm is functionally immature compared with its term counterpart. In utero inflammation further exacerbates preterm diaphragm dysfunction. We hypothesized that preterm lambs are more vulnerable to in utero inflammation-induced diaphragm dysfunction compared with term lambs. Pregnant ewes received intra-amniotic (IA) injections of saline or 10 mg lipopolysaccharide (LPS) 2 or 7 days before delivery at 121 days (preterm) or ∼145 days (term) of gestation. Diaphragm contractile function was assessed in vitro. Plasma cytokines, diaphragm myosin heavy chain (MHC) isoforms, and oxidative stress were evaluated. Maximum diaphragm force in preterm control lambs was significantly lower (22%) than in term control lambs ( P < 0.001). Despite similar inflammatory cytokine responses to in utero LPS exposure, diaphragm function in preterm and term lambs was affected differentially. In term lambs, maximum force after a 2-day LPS exposure was significantly lower than in controls (by ~20%, P < 0.05). In preterm lambs, maximum forces after 2-day and 7-day LPS exposures were significantly lower than in controls (by ~30%, P < 0.05). Peak twitch force after LPS exposure was significantly lower in preterm than in controls, but not in term lambs. In term lambs, LPS exposure increased the proportion of MHC-I fibers, increased twitch contraction times, and increased fatigue resistance relative to controls. In preterm diaphragm, the cross-sectional area of embryonic MHC fibers was significantly lower after 7-day versus 2-day LPS exposures. We conclude that preterm lambs are more vulnerable to IA LPS-induced diaphragm dysfunction than term lambs. In utero inflammation exacerbates diaphragm dysfunction and may increase susceptibility to postnatal respiratory failure.

Is there a relationship between fetal sex and placental pathological characteristics in twin gestations?

BACKGROUND: Placenta plays a central role in mediating growth and development of fetuses. Sex-specific placentas may complicate this role. METHODS: The study aimed at investigating the association between fetal sex and placental pathological findings in twin gestations using generalized estimating equation modeling. We used a large population-based clinical data born in British Columbia (BC) and linked the fetal-maternal data to hand-searched pathology reports of 1493 twin placentas from twins born in BC Women hospital. We analyzed the data using generalized estimating equations taking the cluster nature of twins into consideration. RESULTS: About 26.5% of twins were monochorionic and 73.5% were dizygotic. Most twins were male (51.3%). About 2/3 of twins were sex concordant (66.6%). Of the sex concordant twins, similar percentages were male-male (34.7%) and female-female (31.2%). Of the sex discordant twins, the male-female (33.3%) group constituted about 1/3 of the whole population. Adjusted for chorionicity, birth weight discordance ≥30% and gestational age, the odds of chorionitis (1.38, 95% CI = 1.04-1.84), anastomosis (1.63, 95% CI = 1.22-2.19), unequal sharing of placenta (1.72, 95% CI = 1.11-2.64), placental inflammation (1.30, 95% CI = 1.05-1.62) and lesions (1.83, 95% CI = 1.02-3.31) were higher in male twins compared with females. Twins of either sex from sex-discordant pairs were less likely to have placental anastomosis compared to the reference category. Males from male-male pairs had higher odds of unequal placental sharing (74% higher) and composite inflammation (52% higher) compared with the reference twins. CONCLUSION: Our findings suggest a relationship between sex and placental pathological results.

Histologic Funisitis and Likelihood of Intrauterine Inflammation or Infection: A Case-Control Study.

OBJECTIVE: The objective of this study was to ascertain the likelihood of isolated maternal fever and suspected intrauterine inflammation or infection or both (Triple I) among cases of histologic chorioamnionitis with funisitis (HCF) at term. STUDY DESIGN: In this case-control study, placental pathology records were reviewed to identify term singleton laboring patients with HCF. Controls (1:1) were matched for gestational age. RESULTS: During the 6-month period, there were 2,399 term deliveries of laboring women. Of 1,552 (65%) term placentas examined, 4% (n = 60) had HCF.Features of Triple I were significantly more common among cases than controls: (1) isolated maternal fever of ≥100.4°F, twice, at least 30 minutes apart (p = 0.014); (2) fever with fetal tachycardia (p = 0.029); 3) fever with either fetal tachycardia or white blood cell count greater than 15,000 per mm3 (p = 0.034). The feature of Triple I with the highest sensitivity at 10% (95% confidence intervals [CI] 4-21%) was isolated maternal fever using ≥100.4°F on two occasions. The specificity for all features was consistently 100% (95% CI 91-100%). CONCLUSION: To our knowledge, this is the first report on HCF and Triple I features. Though the sensitivity of Triple I to identify HCF is low, specificity is excellent.

High Mobility Group-Box 1 (HMGB1) levels are increased in amniotic fluid of women with intra-amniotic inflammation-determined preterm birth, and the source may be the damaged fetal membranes.

BACKGROUND: High Mobility Group Box-1 (HMGB1) is considered a prototype alarmin molecule. Upon its extracellular release, HMGB1 engages pattern recognition receptors and the Receptor for Advanced Glycation End-products (RAGE) followed by an outpouring of inflammatory cytokines, including interleukin (IL)-6. METHODS: We assayed the amniotic fluid (AF) levels of HMGB1 and IL-6 in 255 women that either had a normal pregnancy outcome or delivered preterm. Immunohistochemistry on fetal membranes was used for cellular localization and validation of immunoassay findings. HMGB1 also was analyzed in amniochorion tissue explants subjected to endotoxin. RESULTS: AF HMGB1 levels are not gestational age regulated but are increased in women with intra-amniotic inflammation and preterm birth. The likely source is the damaged amniochorion, as demonstrated by immunohistochemistry and explant experiments. CONCLUSIONS: Our research supports a role for HMGB1 in the inflammatory response leading to preterm birth. As a delayed phase cytokine, in utero exposure to elevated AF HMGB1 levels may have an impact on the newborn beyond the time of birth.

Meconium aspiration syndrome: a role for fetal systemic inflammation.

BACKGROUND: Meconium aspiration syndrome (MAS) is a leading cause of morbidity and mortality in term infants. Meconium-stained amniotic fluid (MSAF) occurs in approximately 1 of every 7 pregnancies, but only 5% of neonates exposed to MSAF develop MAS. Why some infants exposed to meconium develop MAS while others do not is a fundamental question. Patients with MSAF have a higher frequency of intraamniotic inflammation/infection than those with clear fluid. We propose that fetal systemic inflammation is a risk factor for the development of MAS in patients with MSAF. OBJECTIVE: We sought to investigate whether intraamniotic inflammation and funisitis, the histopathologic landmark of a fetal inflammatory response, predispose to MAS. STUDY DESIGN: A prospective cohort study was conducted from 1995 through 2009. Amniotic fluid (AF) samples (n = 1281) were collected at the time of cesarean delivery from women who delivered singleton newborns at term (gestational age ≥38 weeks). Intraamniotic inflammation was diagnosed if the AF concentration of matrix metalloproteinase-8 was >23 ng/mL. Funisitis was diagnosed by histologic examination if inflammation was present in the umbilical cord. RESULTS: The prevalence of MSAF was 9.2% (118/1281), and 10.2% (12/118) of neonates exposed to MSAF developed MAS. There were no significant differences in the median gestational age or umbilical cord arterial pH at birth between neonates who developed MAS and those who did not (each P > .1). Mothers whose newborns developed MAS had a higher median of AF matrix metalloproteinase-8 (456.8 vs 157.2 ng/mL, P < .05). Newborns exposed to intraamniotic inflammation had a higher rate of MAS than those who were not exposed to intraamniotic inflammation [13.0% (10/77) vs 0% (0/32), P = .03], as did those exposed to funisitis [31.3% (5/16) vs 7.3% (6/82); relative risk, 4.3; 95% confidence interval, 1.5-12.3]. Among the 89 newborns for whom both AF and placental histology were available, MAS was more common in patients with both intraamniotic inflammation and funisitis than in those without intraamniotic inflammation and funisitis [28.6% (4/14) vs 0% (0/28), P = .009], while the rate of MAS did not show a significant difference between patients with intraamniotic inflammation alone (without funisitis) and those without intraamniotic inflammation and funisitis [10.9% (5/46) vs 0% (0/28)]. CONCLUSION: The combination of intraamniotic inflammation with fetal systemic inflammation is an important antecedent of MAS. This concept has implications for the understanding of the mechanisms of disease responsible for MAS and for the development of prognostic models and therapeutic interventions for this disorder.

Intra-amniotic pharmacological blockade of inflammatory signalling pathways in an ovine chorioamnionitis model.

Intrauterine inflammation (IUI) associated with infection is the major cause of preterm birth (PTB) at <32 weeks' gestation and accounts for ∼40% of all spontaneous PTBs. Pharmacological strategies to prevent PTB and improve fetal outcomes will likely require both antimicrobial and anti-inflammatory therapies. Here we investigated the effects of two cytokine-suppressive anti-inflammatory drugs (CSAIDs), compounds that specifically target inflammatory signalling pathways, in an ovine model of lipopolysaccharide (LPS)-induced chorioamnionitis. Chronically catheterized ewes at 116 days gestation (n = 7/group) received an intra-amniotic (IA) bolus of LPS (10 mg) plus vehicle or CSAIDS: TPCA-1 (1.2 mg/kg fetal weight) or 5z-7-oxozeaenol (OxZnl; 0.4 mg/kg fetal weight); controls received vehicle (dimethylsulphoxide). Amniotic fluid (AF), fetal and maternal blood samples were taken 0, 2, 6, 12, 24 and 48 h later; tissues were taken at autopsy (48 h). Administration of TPCA-1 or OxZnl abrogated the stimulatory effects of LPS (P < 0.01 versus vehicle control) on production of PGE2 in AF, with lesser (non-significant) effects on IL-6 production. Fetal membrane polymorphonuclear cell infiltration score was significantly higher in LPS versus vehicle control animals (P < 0.01), and this difference was absent with TPCA-1 and OxZnl treatment. LPS-induced systemic fetal inflammation was highly variable, with no significant effects of CSAIDs observed. Lung inflammation was evident with LPS exposure, but unaffected by CSAID treatment. We have shown in a large animal model that IA administration of a single dose of CSAIDs can suppress LPS-induced IA inflammatory responses, while fetal effects were minimal. Further development and investigation of these compounds in infectious models is warranted.

Modified obstetric early warning scoring systems (MOEWS): validating the diagnostic performance for severe sepsis in women with chorioamnionitis.

OBJECTIVE: We sought to compare the predictive power of published modified obstetric early warning scoring systems (MOEWS) for the development of severe sepsis in women with chorioamnionitis. STUDY DESIGN: This was a retrospective cohort study using prospectively collected clinical observations at a single tertiary unit (Chicago, IL). Hospital databases and patient records were searched to identify and verify cases with clinically diagnosed chorioamnionitis during the study period (June 2006 through November 2007). Vital sign data (heart rate, respiratory rate, blood pressure, temperature, mental state) for these cases were extracted from an electronic database and the single worst composite recording was identified for analysis. Global literature databases were searched (2014) to identify examples of MOEWS. Scores for each identified MOEWS were derived from each set of vital sign recordings during the presentation with chorioamnionitis. The performance of these MOEWS (the primary outcome) was then analyzed and compared using their sensitivity, specificity, positive and negative predictive values, and receiver-operating characteristic curve for severe sepsis. RESULTS: Six MOEWS were identified. There was wide variation in design and pathophysiological thresholds used for clinical alerts. In all, 913 women with chorioamnionitis were identified from the clinical database. In all, 364 cases with complete data for all physiological indicators were included in analysis. Five women developed severe sepsis, including 1 woman who died. The sensitivities of the MOEWS in predicting the severe deterioration ranged from 40-100% and the specificities varied even more ranging from 4-97%. The positive predictive values were low for all MOEWS ranging from <2-15%. The MOEWS with simpler designs tended to be more sensitive, whereas the more complex MOEWS were more specific, but failed to identify some of the women who developed severe sepsis. CONCLUSION: Currently used MOEWS vary widely in terms of alert thresholds, format, and accuracy. Most MOEWS have not been validated. The MOEWS generally performed poorly in predicting severe sepsis in obstetric patients; in general severe sepsis was overdetected. Simple MOEWS with high sensitivity followed with more specific secondary testing is likely to be the best way forward. Further research is required to develop early warning systems for use in this setting.

Responses of the spleen to intraamniotic lipopolysaccharide exposure in fetal sheep.

BACKGROUND: Intrauterine inflammation activates the fetal immune system and can result in organ injury and postnatal complications in preterm infants. As the spleen is an important site for peripheral immune activation, we asked how the fetal spleen would respond to intrauterine inflammation over time. We hypothesized that intraamniotic lipopolysaccharide (IA LPS) exposure induces acute and persistent changes in the splenic cytokine profile and T-cell composition that may contribute to the sustained fetal inflammatory response after chorioamnionitis. METHODS: Fetal sheep were exposed to IA LPS 5, 12, and 24 h and 2, 4, 8, or 15 d before delivery at 125 d of gestational age (term = 150 d). Splenic cytokine mRNA levels and cleaved caspase-3, CD3, and Foxp3 expression were evaluated. RESULTS: IA LPS increased interleukin (IL)1, IL4, IL5, and IL10 mRNA by twofold 24 h after injection. Interferon gamma increased by fivefold, whereas IL23 decreased 15 d post-LPS exposure. Cleaved caspase-3-positive cells increased 2 and 8 d after LPS exposure. CD3 immunoreactivity increased within 5 h with increased Foxp3-positive cells at 12 h. CONCLUSION: Intrauterine inflammation induced a rapid and sustained splenic immune response with persistent changes in the cytokine profile. This altered immune status may drive sustained inflammation and injury in other fetal organs.

Severe fetal acidemia in cases of clinical chorioamnionitis in which the infant later developed cerebral palsy.

BACKGROUND: The umbilical arterial pH (UApH) in cases of clinically apparent chorioamnionitis (CAM) in which the infant later develop severe cerebral palsy (CP) has not yet been fully investigated. The objective of this study was to determine the UApH in CAM cases in which the infant later develop severe CP. METHODS: A review was conducted unti1 April 2014 among 324 infants with CP diagnosed to be caused by antenatal and/or intrapartum conditions, as determined by the Japan Council for Quality Health Care. Eighty-six infants born at over 34 weeks of gestation with an abnormal FHR pattern during labor were selected. The subjects were divided into the following two groups: cases with (Group I, n = 19) and those without (Group II, n = 67) clinical CAM. Severe fetal acidemia was defined as a pH of less than 7.0. RESULTS: The frequency of severe acidemia in Groups 1 and II was 26.3 and 74.6 %, respectively. In addition, the frequency of severe acidemia was significantly less in Group I (odds ratio (OR) 0.12, 95 % confidence interval (CI) 0.03-0.53) than in Group II, while the frequency of fetal tachycardia was greater in Group I (OR 7.61, 95 % CI 1.82-31.7) than in Group II, after adjusting for confounding effects. CONCLUSIONS: The frequency of severe acidemia was lower in the cases of clinical CAM in which the infant later developed severe cerebral palsy than in the cases without clinical CAM. The relation of fetal tachycardia to CP with clinical CAM, but not to acidemia, should be reevaluated in such cases.