Novel Biomarkers: Soluble Urokinase-Type Plasminogen Activator Receptor and Procalcitonin- and Histological Chorioamnionitis after Preterm Premature Rupture of Membranes.

Fetal inflammatory response syndrome or infection after preterm premature rupture of membranes (PPROM) increases neonatal morbidity in preterm deliveries. Biochemical markers from the amniotic fluid (AF) have been used to evaluate possible intra-amniotic infection during the asymptomatic phase after PPROM. This study aimed to describe whether soluble urokinase-type plasminogen activator receptor (suPAR) or procalcitonin (PCT) from AF or maternal sera could reveal fetal inflammatory response or infection after PPROM. AF and maternal serum samples were collected weekly after PPROM (23+ 0 - 34+ 6 gestational weeks) until delivery from twenty women and two women with possible chorioamnionitis with intact membranes. Levels of suPAR, PCT, interleukin-6 (IL-6), glucose, lactate dehydrogenase (LDH), and bacterial PCR were determined from AF and suPAR and PCT and IL-6 from maternal sera. Fetal infection or inflammation response were determined by the histology of the placenta after delivery. AF glucose was significantly lower and AF LDH higher in the fetal site histologic chorioamnionitis (HCA) group, while AF suPAR concentrations tended to be higher in this group. AF suPAR correlated significantly with AF glucose and LDH. Based on receiver operating characteristic (ROC) analysis, AF glucose had the best predictability for fetal site histological chorioamnionitis. The findings of AF PCT were insignificant considering HCA. AF glucose had the highest accuracy in predicting fetal site histologic chorioamnionitis. AF suPAR may be a promising marker; however, our findings were limited by a small study population.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

The adenosine deaminase family acting on RNA 1 can be a useful diagnostic biomarker in chorioamnionitis.

INTRODUCTION: Chorioamnionitis (CAM) involves infection and inflammation of the chorion and amniotic membrane, but there are still no effective diagnostic biomarkers for CAM. METHODS: We investigated the correlation between RNA editing enzyme Adenosine deaminase family acting on RNA 1 (ADAR1) and CAM in chorion and amniotic membrane specimens derived from premature rupture of the membrane (PROM), CAM (pathologically diagnosed), and clinical CAM (clinically diagnosed) patients using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: ADAR1 was upregulated in the chorion and amniotic membrane specimens of CAM and clinical CAM patients (p < 0.001 and p = 0.005). ADAR1 had a significantly higher area under the curve (AUC) (0.735 and 0.828) than markers of inflammation characteristics in diagnosing CAM and clinical CAM patients. ADAR1 also had significantly higher AUC (0.701 and 0.837) than clinical characteristics for CAM and clinical CAM patients. DISCUSSION: ADAR1 can be a useful diagnostic biomarker in CAM patients.

Clinical utility of gastric fluid cytokine levels in preterm infants for predicting histological chorioamnionitis.

BACKGROUND: The risk of various complications, such as neonatal death, early onset sepsis, and chronic lung disease, is increased in infants born to mothers with chorioamnionitis (CAM). However, predicting the diagnosis of histological CAM (hCAM) in the early postnatal period is challenging for clinicians due to pathological considerations. Therefore, an early diagnostic tool for hCAM is needed. Gastric fluid at birth is considered a suitable biomarker for predicting the intrauterine environment because most of its components are from amniotic fluid, and the sampling technique is less invasive. This study aimed to evaluate the clinical utility of cytokines in the gastric fluid of preterm infants at birth as predictors of hCAM. METHODS: We retrieved gastric fluid and serum from 21 preterm infants with a gestational age of ≤ 32 weeks within 1 h after birth and used cytometric bead array to measure the concentrations of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-alpha, and interferon-gamma. We compared the cytokine concentrations in the gastric fluid and serum of the preterm infants born to mothers with or without hCAM. RESULTS: The gastric fluid, serum IL-6, and serum IL-10 concentrations were significantly higher in the hCAM group than that in the non-hCAM group. The best cutoff values for predicting hCAM was > 2,855 pg/mL and > 315 pg/mL for IL-6 in the gastric fluid and serum, respectively. Receiver operating characteristic curves showed that gastric fluid IL-6 concentrations correlated more strongly with the presence of hCAM than serum IL-6 concentrations. CONCLUSION: IL-6 in the gastric fluid at birth may be a more promising biomarker for predicting the presence of hCAM than that in serum. IL-6 concentration analysis in the gastric fluid at birth might help to diagnose hCAM immediately after birth and improve the prognosis of preterm infants.

Changes in serum inflammatory factors in group B streptococcal infection and their predictive value for premature rupture of membranes complicated by chorioamnionitis.

Objective: The aim of this study as to unveil changes in serum inflammatory factors in pregnant women with genital tract group B Streptococcus (GBS) infection and their predictive value for premature rupture of membranes (PROM) complicated by chorioamnionitis (CS) and adverse pregnancy outcomes. Methods: The value of serum inflammatory factor levels in predicting PROM complicating CS and adverse pregnancy outcomes in GBS-infected pregnant women was evaluated by ELISA. Results: Serum IL-6, TNF-α, PCT and hs-CRP levels were higher in pregnant women with GBS infection. The combined diagnosis of these factors had excellent diagnostic value in PROM complicating CS and adverse pregnancy outcomes. Conclusion: Joint prediction of IL-6, TNF-α, PCT and hs-CRP has the best predictive value for PROM complicating CS and adverse pregnancy outcomes.

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Short-term variation of the fetal heart rate as a marker of intraamniotic infection in pregnancies with preterm prelabor rupture of membranes: a historical cohort study.

INTRODUCTION: Intraamniotic infection (IAI) and subsequent early-onset neonatal sepsis (EONS) are among the main complications associated with preterm prelabor rupture of membranes (PPROM). Currently used diagnostic tools have been shown to have poor diagnostic performance for IAI. This study aimed to investigate whether the exposure to IAI before delivery is associated with short-term variation of the fetal heart rate in pregnancies with PPROM. METHODS: Observational cohort study of 678 pregnancies with PPROM, delivering between 24 + 0 and 33 + 6 gestational weeks from 2012 to 2019 in five labor units in Stockholm County, Sweden. Electronic medical records were examined to obtain background and exposure data. For the exposure IAI, we used the later diagnosis of EONS in the offspring as a proxy. EONS is strongly associated to IAI and was considered a better proxy for IAI than the histological diagnosis of acute chorioamnionitis, since acute chorioamnionitis can be observed in the absence of both positive microbiology and biochemical markers for inflammation. Cardiotocography traces were analyzed by a computerized algorithm for short-term variation of the fetal heart rate, which was the main outcome measure. RESULTS: Twenty-seven pregnancies were categorized as having an IAI, based on the proxy diagnosis of EONS after birth. Fetuses exposed to IAI had significantly lower short-term variation values in the last cardiotocography trace before birth than fetuses who were not exposed (5.25 vs 6.62 ms; unadjusted difference: -1.37, p = 0.009). After adjustment for smoking and diabetes, this difference remained significant. IAI with a later positive blood culture in the neonate (n = 12) showed an even larger absolute difference in STV (-1.65; p = 0.034), with a relative decrease of 23.5%. CONCLUSION: In pregnancies with PPROM, fetuses exposed to IAI with EONS as a proxy have lower short-term variation of the fetal heart rate than fetuses who are not exposed. Short-term variation might be useful as adjunct surveillance in pregnancies with PPROM.

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.

Antibiotic administration reduced intra-amniotic inflammation 7 days after preterm premature rupture of the membranes with intra-amniotic infection.

OBJECTIVE: Intra-amniotic infections increase the risk of preterm delivery and short- and long-term fetal morbidity; however, no consensus exists on the choice of antimicrobial agents as treatment for these infections. We aimed to examine the efficacy of intravenous administration of sulbactam/ampicillin (SBT/ABPC) and azithromycin (AZM) for intra-amniotic infection in patients with preterm premature rupture of membranes (PPROM). METHODS: This study followed a single-centered retrospective cohort design. We compared changes in interleukin 6 (IL-6) levels and the load of Ureaplasma species DNA in the amniotic fluid between singleton pregnancy patients with intra-amniotic infection (Group A) and without either intra-amniotic inflammation (IAI) or microbial invasion of the amniotic cavity (MIAC) (Group B) who developed PPROM between week 22, day 0 and week 33, day 6 of gestation and maintained pregnancy for ≥7 d after diagnosis (August 2014 to April 2020). Patients in Group A were treated with SBT/ABPC and AZM, whereas those in Group B were treated with ABPC and AZM or clarithromycin. RESULTS: Thirty-one patients with IAI and 48 patients without either IAI or MIAC at diagnosis of PPROM underwent pregnancy/delivery management at our hospital. Following the study population selection, we evaluated six patients in Group A and 13 patients in Group B. Amniotic fluid IL-6 concentrations at the initial amniocentesis were high, ranging from 11.7 ng/mL to 139.2 ng/mL, indicating a state of severe IAI in all six patients in Group A. In five of the six patients in Group A, the amniotic fluid cultures during the first amniocentesis included Ureaplasma species only. In both groups, the amniotic fluid IL-6 concentration at the follow-up amniocentesis was lower than that at the initial amniocentesis (Group A: follow-up median 3.06 ng/mL [quartiles, 1.75-6.74], initial median 30.53 ng/mL [quartiles, 15.60-67.07], p＝.03; Group B: follow-up median 0.40 ng/mL [quartiles, 0.18-0.69], initial median 0.96 ng/mL [quartiles, 0.65-1.42], p＝.005); Group A showed a greater decrease than Group B (p < .001). No difference was found between the microbial loads of Ureaplasma species DNA in the initial and follow-up amniocentesis (p = .13). CONCLUSIONS: In patients with PPROM and intra-amniotic infection, IL-6 levels in the amniotic fluid decreased significantly from before antimicrobial administration to day 7. This decrease is thought to be mainly due to the effects of intravenous AZM. The efficacy of AZM in patients with PPROM needs to be further confirmed via randomized controlled studies in the future.

Predictive value of serum inflammatory markers for histological chorioamnionitis among women with preterm premature rupture of membranes after undergoing cervical cerclage.

PURPOSE: To determine the predictive value of maternal White Blood Cells (WBC), neutrophils, and C-Reactive Protein (CRP) for diagnosing Histological Chorioamnionitis (HCA) among women with Preterm Premature Rupture of Membranes (PPROM) who underwent cervical cerclage. METHODS: A retrospective cross-sectional study was conducted among women with singleton pregnancy and PPROM, who underwent cervical cerclage during 2018-2020. RESULTS: A total of 55 eligible women were included in the final analysis, including 36 (61.02%) cases with HCA and 19 (38.98%) without HCA. Women with HCA had higher WBC count (12.31 ± 2.80) × 109/L and neutrophil count (9.67 ± 2.90)×109/L than those without HCA (10.35 ± 2.53) × 109/L and 7.82 ± 2.82 × 109/L, respectively) (both p < 0.05). The cut-off value of WBC count at 10.15×109/L was found to be the most effective in identifying HCA, with an Area Under Curve (AUC) of 0.707 (95% CI: 0.56-0.86; p = 0.012), sensitivity of 86.11%, specificity of 57.90%, Positive Predictive Value (PPV) of 79.49%, Negative Predictive Value (NPV) of 68.75%, and Youden index of 0.44. The combination of WBC + neutrophil had a slightly higher (AUC = 0.711, 95% CI: 0.57-0.86; p = 0.011), specificity (68.42%), and PPV (81.25%), but lower sensitivity (72.22%), than the WBC count alone. A cut-off value of neutrophil at 7.46 × 109/L was effective in identifying HCA, with an AUC of 0.689 (95% CI: 0.53-0.84; p = 0.022). DISCUSSION: Combination use of WBC+neutrophil was found to be the most accurate predictor of HCA among women with PPROM after surgery of cervical cerclage.

Inflammatory biomarkers in the cervicovaginal fluid to identify histologic chorioamnionitis and funisitis in women with preterm labor.

OBJECTIVE: We investigated the association between altered levels of inflammatory proteins in the cervicovaginal fluid (CVF) and acute histologic chorioamnionitis (HCA) and funisitis in women with preterm labor (PTL). METHODS: In this study, a total of 134 consecutive singleton pregnant women with PTL (at 23+0-34+0 weeks) who delivered preterm (at  < 37 weeks) and from whom CVF samples were collected at admission were retrospectively enrolled. The CVF levels of haptoglobin, interleukin-6/8, kallistatin, lipocalin-2, matrix metalloproteinase (MMP)-8, resistin, S100 calcium-binding protein A8, and serpin A1 were determined using enzyme-linked immunosorbent assay. The placentas were histologically analyzed after delivery. RESULTS: Multiple logistic regression analyses showed significant associations between elevated CVF interleukin-8 and resistin levels and acute HCA after adjusting for baseline covariates (e.g., gestational age at sampling). CVF haptoglobin, interleukin-6/8, kallistatin, MMP-8, and resistin levels were significantly higher in women with funisitis than in those without, whereas the baseline covariates were similar between the two groups (P > 0.1). The area under the receiver operating characteristic curves of the aforementioned biomarkers ranged from 0.61 to 0.77 regarding each outcome. Notably, HCA risk significantly increased with increasing CVF levels of interleukin-8 and resistin (P for trend  < 0.05). CONCLUSIONS: Haptoglobin, interleukin-6/8, kallistatin, MMP-8, and resistin were identified as potential inflammatory CVF biomarkers predictive of acute HCA and funisitis in women with PTL. Moreover, the risk severity of acute HCA may be associated with the degree of the inflammatory response in the CVF (particularly based on interleukin-8 levels).

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

OBJECTIVE: We 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 METHODS: We 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. RESULTS: Forty-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. CONCLUSION: Amniotic fluid IL-6 and NGAL levels showed equivalent predictive ability for FIRS-related infection.

Relationship of maternal inflammatory response and fetal inflammatory response to duration and intensity of intra-amniotic infection and inflammation.

INTRODUCTION: We aimed to use two indices, amniotic fluid interleukin-6 (IL-6) concentration at diagnosis and diagnosis-to-delivery interval, to clarify the frequencies of maternal inflammatory response (MIR) and fetal inflammatory response (FIR) in the placenta of patients with intra-amniotic infection and intra-amniotic inflammation (IAI). METHODS: This is a single-center retrospective cohort study. From August 2014 to April 2020, participants were diagnosed with IAI with or without microbial invasion of the amniotic cavity (MIAC) using amniocentesis. IAI was defined as concentrations of amniotic IL-6 ≥ 2.6 ng/mL. MIAC was defined as a positive amniotic fluid culture. IAI with MIAC was defined as an intra-amniotic infection. We calculated the cut-off values for IL-6 concentration in the amniotic fluid at diagnosis and the diagnosis-to-delivery interval for MIR-positive cases among those with intra-amniotic infection. RESULTS: The amniotic fluid IL-6 concentration at diagnosis and diagnosis-to-delivery interval were 15.8 ng/mL and 12 h, respectively. Among cases with intra-amniotic infection, MIR was 98% (52/53) positive, i.e., when either of the two cut-off values was exceeded. There were no significant differences between the frequencies of MIR and FIR. In cases with IAI but no MIAC, the frequencies of MIR and FIR were significantly lower than those with intra-amniotic infection, except when neither of the two cut-off values was exceeded. DISCUSSION: We clarified the MIR- and FIR-positive cases in intra-amniotic infection and cases with IAI but no MIAC according to condition, including the diagnosis-to-delivery interval.

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

AIM: This study aimed to clarify the diagnostic accuracy of amniotic fluid interleukin-6 for fetal inflammatory response syndrome (FIRS). METHODS: 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 >11.0 pg/mL of umbilical cord blood interleukin-6. RESULTS: 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 15.5 ng/mL, and showed high sensitivity and specificity (0.91 and 0.88, respectively). An amniotic fluid interleukin-6 cutoff value of ≥15.5 ng/mL was associated with a significant risk of FIRS (adjusted odds ratio: 27.9; 95% confidence interval: 6.3-123.0; p < 0.001). CONCLUSIONS: 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.

Association of clinical signs of chorioamnionitis with histological chorioamnionitis and neonatal outcomes.

BACKGROUND: Chorioamnionitis is a risk factor for fetal and neonatal outcomes. Therefore, predicting histological chorioamnionitis (HCA) and neonatal outcomes using clinical parameters could be helpful in management and preventing morbidities. OBJECTIVE: To determine if parameters of clinical chorioamnionitis (CCA) would be associated with HCA and neonatal outcomes. STUDY DESIGN: In this cohort study using a retrospective design, we analyzed the performance of signs of CCA in predicting HCA, and neonatal outcomes. Data were extracted from the electronic health record for all neonates with documented CCA delivered at our institution from 2011 to 2016. We compared our findings based on the old ACOG definition of CCA and the new definition released in 2017 - maternal fever plus any of fetal tachycardia, maternal leukocytosis, and purulent vaginal discharge. Maternal tachycardia and uterine tenderness were removed from the new criteria. Neonatal laboratory samples on admission, 12 h and 24 h were used to define the three time points of neonatal suspected sepsis. RESULTS: There were 530 mothers-infant dyads with chorioamnionitis. Seventy-three were preterm, and 457 were term. Eighty-eight percent of the preterm mothers had CCA, and HCA was present in 62.5% of 72 preterm placentas. Preterm infants with placental HCA significantly had lower birth weight, gestational age, placental weight, and more infants with lower 5-minute Apgar scores, compared to those with no HCA. In preterm infants, maternal urinary tract infection was significantly associated with decreased odds for HCA (OR 0.22, CI 0.10 - 0.71). More preterm babies with suspected sepsis criteria at the 3 time points had HCA (all p ≤ .01). In the term cohort, 95.4% and 65.6% had CCA and HCA, respectively. In term infants (n = 457), maternal leukocytosis (p = .002) and prolonged rupture of membranes (PROM; p = 002) were associated with HCA. Suspected sepsis was associated with PROM (p = .04), HCA (p = .0001), and maternal leukocytosis (p ≤ .05) in at least 1 of the 3 time points. CONCLUSION: Though maternal leukocytosis was significantly associated with the presence of HCA in the term cohort, there were no CCA criteria that accurately predicted presence of HCA in either the preterm or the term infants.

Estimated time to emergence of secondary intra-amniotic infection or inflammation since the onset of the preterm premature rupture of membranes.

OBJECTIVE: Prematurity is the most important prognostic factor for infants born following preterm premature rupture of membranes (PPROM). Therefore, when PPROM occurs between 22 and 33 weeks of gestation, prolonging pregnancy is recommended. Determination of management strategies requires screening for the presence of intra-amniotic infection or inflammation at the time of PPROM diagnosis. If intra-amniotic infection/inflammation is not detected, it is important to monitor the patient to diagnose any new infection/inflammation. We examined the period from PPROM to secondary intra-amniotic infection/inflammation and associated factors. MATERIALS AND METHODS: This retrospective study was conducted at a single facility. We examined 26 patients who experienced PPROM between 26 and 33 weeks of gestation and were negative for intra-amniotic infection/inflammation at the time of diagnosis and underwent serial amniocentesis. Antibiotic therapy comprising ampicillin, amoxicillin, and clarithromycin for 7 days was started after the first amniocentesis. The period from PPROM to secondary intra-amniotic infection/inflammation was analyzed using a Kaplan-Meier survival curve. The onset of intra-amniotic infection/inflammation was considered as the time at which amniotic fluid bacterial culture results became positive, the time when amniotic fluid Interleukin (IL)-6 increased beyond 2.6 ng/mL, or the day of delivery if histological chorioamnionitis was observed in the delivered placenta. Patients were treated as censored if no intra-amniotic infection/inflammation could be confirmed in the amniotic fluid and delivered placenta. RESULTS: The median time from PPROM to secondary intra-amniotic infection/inflammation was 18 days. Six patients developed intra-amniotic infection/inflammation, while 13 patients without intra-amniotic infections/inflammation delivered fewer than 7 days after PPROM. No confounding factors at the time of PPROM diagnosis were associated with the time from PPROM until secondary intra-amniotic infection/inflammation. CONCLUSIONS: The time between PPROM and onset of secondary intra-amniotic infection/inflammation appears prolonged. Treatments other than antimicrobial agents may need to be added to prolong pregnancy.

Parámetros del líquido amniótico para diagnóstico de respuesta inflamatoria en parto pretérmino / Amniotic fluid parameters for the diagnosis of inflammatory response in preterm delivery

OBJETIVO: Evaluar el rendimiento del Gram, la glucosa y los leucocitos en líquido amniótico para el diagnóstico de respuesta inflamatoria fetal y materna en pacientes con parto pretérmino. MÉTODO: Estudio de rendimiento de pruebas diagnósticas. Se incluyeron 63 pacientes a quienes se les realizó amniocentesis por sospecha de infección intraamniótica. Se estudió la placenta y se comparó con el Gram, la glucosa y el recuento de leucocitos en líquido amniótico para ver su relación con la respuesta inflamatoria. Se evaluaron la sensibilidad, la especificidad, las razones de verosimilitud (LR, likelihood ratio), los valores predictivos y el valor de kappa. RESULTADOS: Las pruebas con mejor rendimiento fueron en conjunto la glucosa 50/mm3 en líquido amniótico, con una especificidad del 94,3% (intervalo de confianza del 95% [IC95%]: 84,6-98,1), LR + 8,83 (IC95%: 2,5-31,2) y kappa de 0,48 (IC95%: 0,15-0,82). También se consideró la propuesta de un nuevo punto de corte para el recuento de leucocitos en líquido amniótico en la respuesta inflamatoria fetal. CONCLUSIONES: La combinación del recuento de leucocitos en líquido amniótico y los valores de glucosa mejora el rendimiento para el diagnóstico de respuesta inflamatoria fetal en comparación con la histopatología de la placenta, lo que proporciona información útil para el enfoque de los recién nacidos.

OBJECTIVE: To evaluate the performance of Gram, glucose and leukocytes in amniotic fluid for the diagnosis of fetal and maternal inflammatory response in patients with preterm delivery. METHOD: A diagnostic performance test study was carried out. Sixty-three patients with preterm labor were included who underwent amniocentesis due to suspected intra-amniotic infection. Histopathology of the placenta was studied and compared with the Gram result, glucose and leukocyte count in amniotic fluid, and their relationship with the maternal and fetal inflammatory response. Sensitivity, specificity, likelihood ratios, predictive values, and kappa were evaluated. RESULTS: The tests with the best performance were overall glucose 50/mm3 in amniotic fluid for the diagnosis of the fetal inflammatory response, with a specificity of 94.3% (95% confidence interval [95% CI]: 84.6-98.1%), likelihood positive ratio 8.83 (95% CI: 2.5-31.2) and kappa of 0.48 (95% CI: 0.15-0.82). A new cut-off point for leukocyte count in amniotic fluid to diagnose fetal inflammatory response was proposed. CONCLUSIONS: The combination of amniotic fluid leukocyte count and amniotic fluid glucose values improves performance for the diagnosis of inflammatory response compared with placental histopathology, providing useful information for newborns approach.

Calprotectin levels in amniotic fluid in relation to intra-amniotic inflammation and infection in women with preterm labor with intact membranes: A retrospective cohort study.

OBJECTIVE: To evaluate the concentrations of calprotectin in amniotic fluid with respect to intra-amniotic inflammation and infection and to assess the presence or absence of bacteria in the amnio-chorionic niche with respect to presence or absence of intra-amniotic inflammation. STUDY DESIGN: Seventy-nine women with singleton pregnancies and preterm labor with intact membranes (PTL) were included in the study. Amniotic fluid was collected at the time of admission by amniocentesis and calprotectin levels were analyzed from frozen/thawed samples using ELISA. Interleukin (IL)-6 concentration was measured by point-of-care test. Samples from amniotic fluid and the amnio-chorionic niche (space between amniotic and chorionic membranes) were microbiologically analyzed. Microbial invasion of the amniotic cavity (MIAC) was diagnosed based on a positive PCR result for Ureaplasma species, Mycoplasma hominis, 16S rRNA or positive culture. Intra-amniotic inflammation (IAI) was defined as amniotic fluid point-of-care IL-6 concentration ≥ 745 pg/mL. The cohort of included women was divided into 4 subgroups based on the presence or absence of IAI/MIAC; i) intra-amniotic infection, ii) sterile IAI, iii) intra-amniotic colonization and iv) neither MIAC nor IAI. RESULTS: Women with intra-amniotic infection had a significantly higher intra-amniotic calprotectin concentration (median; 101.6 µg/mL) compared with women with sterile IAI (median; 9.2 µg/mL), women with intra-amniotic colonization (median; 2.6 µg/mL) and women with neither MIAC nor IAI (median 4.6 µg/mL) (p = 0.001). Moreover, significantly higher amniotic fluid calprotectin concentration was seen in women who delivered within 7 days (p = 0.003). A significant negative correlation was found between amniotic fluid calprotectin and gestational age at delivery (rho = 0.32, p = 0.003). Relatively more bacteria in the amnio-chorionic niche were found in the sterile IAI group compared with the other groups. CONCLUSIONS: Calprotectin concentrations in amniotic fluid were significantly higher in the intra-amniotic infection group compared with the other groups. Moreover, the bacterial presence in the amnio-chorionic niche was higher in IAI group.

Fetal and maternal inflammatory response in the setting of maternal intrapartum fever with and without clinical and histologic chorioamnionitis.

BACKGROUND: Both infectious and noninfectious causes of maternal fever have been linked to adverse neonatal outcomes including low Apg0ar scores, respiratory distress, hypotonia, and neonatal seizures. Even in the absence of infection, the occurrence of intrapartum fever is a strong risk factor for poor long-term neonatal developmental outcomes, including encephalopathy, cerebral palsy, and neonatal death. OBJECTIVE: The primary objective of this study was to compare intrapartum and postpartum maternal and fetal umbilical cord serum levels of cytokines RANTES, interferon-É£, interleukin-1ß, interleukin-2, interleukin-4, interleukin-6, interleukin-8, interleukin-10, interleukin-13, and tumor necrosis factor-α among nonfebrile patients, febrile patients without clinical chorioamnionitis, and febrile patient with clinical chorioamnionitis. STUDY DESIGN: This study was conducted at the Richmond University Medical Center from May 15, 2020 to July 16, 2019. During this time, we recruited 30 nonfebrile patients at >36 gestational weeks who were in labor and collected umbilical cord and pre- and postdelivery maternal serum samples to evaluate the cytokine levels. Placentas were collected for pathologic review and to evaluate the histopathologic findings. These results were compared with 121 patients who developed a fever of >38°C during labor. The febrile patients were further divided based on the presence or absence of clinical chorioamnionitis. A secondary analysis was performed based on the presence of absence of histologic chorioamnionitis. Statistical analysis was performed using IBM Statistical Package for the Social Sciences version 25.0. For the 3 group comparisons, a P value of <.017 was considered statistically significant after application of a Bonferroni correction. RESULTS: A total of 151 patients were included in the study; 30 were nonfebrile patients, 46 were febrile patients with a diagnosis of clinical chorioamnionitis, and 75 were febrile patients without clinical chorioamnionitis. Compared with nonfebrile patients, umbilical cord serum interferon-É£, interleukin-1ß, interleukin-6, interleukin-8, RANTES, and tumor necrosis factor-α levels were elevated in the presence of maternal hyperthermia irrespective of the diagnosis of clinical chorioamnionitis. Interleukin-6 umbilical cord levels were more than doubled from 63.60 pg/mL (6.09-1769.03 pg/mL) in febrile patients with no clinical chorioamnionitis to 135.77 pg/mL (1.86-6004.78 pg/mL) in febrile patients with clinical chorioamnionitis, making it the only cytokine that was significantly different between these 2 groups. When comparing the intrapartum maternal serum, we found a significant elevation in the interleukin-10, RANTES, and tumor necrosis factor-α levels in the febrile group irrespective of the presence of clinical chorioamnionitis when compared with the nonfebrile group. In the postpartum maternal blood evaluations, tumor necrosis factor-α was the only cytokine that was significantly higher in febrile patients than in nonfebrile controls. CONCLUSION: In the setting of intrapartum fever, maternal cytokine profiles were similar irrespective of the diagnosis of clinical chorioamnionitis. Even in the absence of clinical or histologic chorioamnionitis, maternal hyperthermia induced elevations in fetal cytokines.

Preterm prelabor rupture of membranes without microbial invasion of the amniotic cavity and intra-amniotic inflammation: a heterogeneous group with differences in adverse outcomes.

OBJECTIVE: The absence of microbial invasion of the amniotic cavity and intra-amniotic inflammation at the time of hospital admission is the most common condition associated with preterm prelabor rupture of membranes (PPROM). Although the intensity of intra-amniotic inflammatory response does not exceed the threshold for the diagnosis of intra-amniotic inflammation in this subgroup of PPROM, whether there could be differences in outcomes concerning the intensity of intra-amniotic inflammatory response remains unclear. Therefore, the main aims of this study on PPROM without microbial invasion of the amniotic cavity and intra-amniotic inflammation were (i) to characterize the association between the intensity of intra-amniotic inflammatory response, measured according to amniotic fluid interleukin (IL)-6 concentrations, and the presence of acute histological chorioamnionitis and acute inflammation in the amnion; (ii) to characterize the association between the intensity of intra-amniotic inflammatory response and fetal inflammatory response, and (iii) to describe the short-term morbidity of infants based on the intensity of intra-amniotic inflammatory response. METHODS: This retrospective study included 131 women with singleton pregnancies with PPROM without microbial invasion of the amniotic cavity and intra-amniotic inflammation between gestational ages of 24 + 0 and 36 + 6 weeks and who had delivered within 72 h of membrane rupture. Microbial invasion of the amniotic cavity was assessed based on a combination of cultivation and non-cultivation methods. Intra-amniotic inflammation was characterized based on the amniotic fluid IL-6 concentration. In addition, a histopathological assessment of the placenta was performed. Fetal inflammatory response syndrome was characterized according to IL-6 concentration in the umbilical cord blood of >11 pg/mL. Based on the quartiles of IL-6 concentrations in the amniotic fluid, these women were divided into four subgroups (from the lowest to the highest IL-6 concentrations). RESULTS: IL-6 concentrations in amniotic fluid were higher in women with acute histological chorioamnionitis (median: 819 pg/mL vs. 520 pg/mL; p = .003) and with acute inflammation of the amnion (median: 1116 pg/mL vs. 533 pg/mL; p = .0002) than in women without these complications. The rates of acute histological chorioamnionitis and acute inflammation of the amnion were the highest in the subgroup with IL-6 concentrations above the 75th percentile in amniotic fluid (chorioamnionitis, p = .02; amnion, p = .0002). No differences in IL-6 concentrations in amniotic fluid were identified between women with and without a fetal inflammatory response syndrome (p = .40). The rate of fetal inflammatory response syndrome did not vary among the amniotic fluid IL-6 quartile subgroups of women. Moreover, no differences were noted in short-term neonatal outcomes among the amniotic fluid IL-6 quartile subgroups. CONCLUSION: A higher intensity of the intra-amniotic inflammatory response, measured by amniotic fluid IL-6 concentrations, is associated with a higher rate of acute inflammatory lesions in the placenta in the subset of PPROM pregnancies without microbial invasion of the amniotic cavity and intra-amniotic inflammation.