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.

Clinical chorioamnionitis at term: definition, pathogenesis, microbiology, diagnosis, and treatment.

Clinical chorioamnionitis, the most common infection-related diagnosis in labor and delivery units, is an antecedent of puerperal infection and neonatal sepsis. The condition is suspected when intrapartum fever is associated with two other maternal and fetal signs of local or systemic inflammation (eg, maternal tachycardia, uterine tenderness, maternal leukocytosis, malodorous vaginal discharge or amniotic fluid, and fetal tachycardia). Clinical chorioamnionitis is a syndrome caused by intraamniotic infection, sterile intraamniotic inflammation (inflammation without bacteria), or systemic maternal inflammation induced by epidural analgesia. In cases of uncertainty, a definitive diagnosis can be made by analyzing amniotic fluid with methods to detect bacteria (Gram stain, culture, or microbial nucleic acid) and inflammation (white blood cell count, glucose concentration, interleukin-6, interleukin-8, matrix metalloproteinase-8). The most common microorganisms are Ureaplasma species, and polymicrobial infections occur in 70% of cases. The fetal attack rate is low, and the rate of positive neonatal blood cultures ranges between 0.2% and 4%. Intrapartum antibiotic administration is the standard treatment to reduce neonatal sepsis. Treatment with ampicillin and gentamicin have been recommended by professional societies, although other antibiotic regimens, eg, cephalosporins, have been used. Given the importance of Ureaplasma species as a cause of intraamniotic infection, consideration needs to be given to the administration of antimicrobial agents effective against these microorganisms such as azithromycin or clarithromycin. We have used the combination of ceftriaxone, clarithromycin, and metronidazole, which has been shown to eradicate intraamniotic infection with microbiologic studies. Routine testing of neonates born to affected mothers for genital mycoplasmas could improve the detection of neonatal sepsis. Clinical chorioamnionitis is associated with decreased uterine activity, failure to progress in labor, and postpartum hemorrhage; however, clinical chorioamnionitis by itself is not an indication for cesarean delivery. Oxytocin is often administered for labor augmentation, and it is prudent to have uterotonic agents at hand to manage postpartum hemorrhage. Infants born to mothers with clinical chorioamnionitis near term are at risk for early-onset neonatal sepsis and for long-term disability such as cerebral palsy. A frontier is the noninvasive assessment of amniotic fluid to diagnose intraamniotic inflammation with a transcervical amniotic fluid collector and a rapid bedside test for IL-8 for patients with ruptured membranes. This approach promises to improve diagnostic accuracy and to provide a basis for antimicrobial administration.

Syndecan-1 Level, a Marker of Endothelial Glycocalyx Degradation, Is Associated With Fetal Exposure to Chorioamnionitis and Is a Potential Biomarker for Early-Onset Neonatal Sepsis.

The goal of this investigation was to identify the association between Syndecan-1 (S1) serum levels in preterm newborns exposed to chorioamnionitis (CA) in utero and the potential of S1 as a biomarker of early-onset neonatal sepsis. A cohort of preterm newborns born <33 weeks gestational age was recruited. Within 48 hours of birth, 0.5 mL of blood was drawn to obtain S1 levels, measured via ELISA. Placentas were examined and classified as having (1) no CA, (2) CA without umbilical cord involvement, or (3) CA with inflammation of the umbilical cord (funisitis). S1 levels were compared between preterm newborns without exposure to CA verus newborns with exposure to CA (including with and without funisitis). Preterm newborns exposed to CA were found to have significantly elevated S1 levels compared to those unexposed. Although S1 levels could not differentiate fetal exposure to CA from exposure to CA with funisitis, the combined CA groups had significantly higher S1 levels compared to those not exposed to CA. S1 level has the potential to become a clinically useful biomarker that could assist in the management of mothers and preterm newborns with CA and funisitis. Furthermore, S1 level could aid in the diagnosis and treatment of early-onset neonatal sepsis.

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

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

Quantitative cervicovaginal fluid fetal fibronectin: A liquid biopsy for intra-amniotic inflammation.

INTRODUCTION: Intra-amniotic inflammation is causally linked to spontaneous preterm labor. The gold standard for the diagnosis of intra-amniotic inflammation is the determination of an amniotic fluid profile obtained from transabdominal amniocentesis, which is invasive. Cervicovaginal fluid fetal fibronectin (fFN) is a widely-used predictive biomarker for spontaneous preterm labor. The aims of this study are to determine (1) whether a quantitative cervicovaginal fluid fFN test can be used to identify the presence of intra-amniotic inflammation; and (2) an appropriate cut-off value of a cervicovaginal fluid fFN concentration for the identification of intra-amniotic inflammation. MATERIAL AND METHODS: This prospective cohort study included 78 patients with preterm labor and intact membranes who had a sample collected for quantitative cervicovaginal fluid fFN measurement and underwent transabdominal amniocentesis. Intra-amniotic inflammation was defined as an amniotic fluid interleukin-6 concentration ≥2.6 ng/mL. Clinicians were masked from the results of cervicovaginal fluid fFN and amniotic fluid interleukin-6 concentrations. Logistic regression analysis was used to determine which factors were significant predictors of intra-amniotic inflammation. The diagnostic indices of the cervicovaginal fluid fFN test for the identification of intra-amniotic inflammation were calculated. RESULTS: (1) Frequency of intra-amniotic inflammation was 26.9% (21/78); (2) the higher the cervicovaginal fluid fFN concentration, the greater the risk of intra-amniotic inflammation (p < 0.001); (3) cervicovaginal fluid fFN concentration ≥125 ng/mL had an area under the curve of 0.91 (95% confidence interval: 0.83-0.96) for the identification of intra-amniotic inflammation with 100% sensitivity, 100% negative predictive value, 82.46% specificity and a positive likelihood ratio of 5.7; and (4) cervicovaginal fluid fFN cut-off of 125 ng/mL had a significant higher predictive performance than the traditional cut-off (50 ng/mL) for the identification of intra-amniotic inflammation. CONCLUSIONS: Quantitative cervicovaginal fluid fFN with a cut-off of 125 ng/mL had a high sensitivity and a negative predictive value as well as a positive likelihood ratio for the identification of intra-amniotic inflammation. Its high sensitivity and negative predictive value can be used to decrease an index of suspicion of intra-amniotic inflammation. This test may be useful as an initial assessment test to select appropriate patients for amniocentesis to determine intra-amniotic inflammation.

Characteristics and Management of Chorioamnionitis at an Academic Centre in Ontario Before and After Implementation of an Order Set.

OBJECTIVES: Chorioamnionitis has implications for parturient and neonatal outcomes but is difficult to diagnose accurately. The particulars of management also differ between providers and between institutions. Clinical order sets have been shown to standardize and improve care. This study compares characteristics of chorioamnionitis and aspects of management before and after implementation of an order set. METHODS: Chart review facilitated comparison of 76 cases occurring prior to implementation of the order set and 66 cases occurring after. Characteristics of chorioamnionitis used for diagnosis and particulars of management were assessed. RESULTS: There was no significant difference in baseline characteristics between the groups. Parturient tachycardia was more prevalent in cases occurring after implementation of the order set but there was no difference in the percentage of cases meeting Gibb's criteria. Management of cases pre- and post-implementation of the order set differed only in antibiotic choice. Percentage of cases with blood cultures or placental examination performed did not differ. CONCLUSIONS: Overall, implementation of the order set did not significantly impact diagnosis of chorioamnionitis and altered management only with respect to antibiotic choice.

Intrapartum pyrexia, cardiotocography traces and histologic chorioamnionitis: a case-control study.

OBJECTIVES: To compare characteristics of labor, cardiotocography traces, and maternal and neonatal outcomes, in a cohort of pregnancies at term complicated by maternal intrapartum pyrexia, with or without a histologic diagnosis of chorioamnionitis. METHODS: This is a retrospective case-control study including pregnancies at term with detection of maternal intrapartum pyrexia, delivered between January 2020 and June 2021. Cardiotocography traces were entirely evaluated, since admission till delivery, and classified according to the International Federation of Obstetrics and Gynecology (FIGO) guideline. Maternal and neonatal outcomes were also recorded as secondary outcomes. Placentas have been studied according to the Amniotic Fluid Infection Nosology Committee. RESULTS: Forty four patients met the inclusion criteria and were included in the study cohort. There was a significant association between the use of oxytocin augmentation in labor and the histologic diagnosis of chorioamnionitis. A significative recurrence of loss and/or absence of accelerations at the point of pyrexia was also documented in women with histological chorioamnionitis compared to the others. CONCLUSIONS: Chorioamnionitis appears to be associated with myometrial disfunction, as suggested by the increased use of oxytocin augmentation during active labor of women at term with intrapartum pyrexia and histologic diagnosis of chorioamnionitis.

Chorioamnionitis and respiratory outcomes in prematurely born children: a systematic review and meta analysis.

INTRODUCTION: To conduct a systematic review and meta-analysis of the association between chorioamnionitis and respiratory outcomes of prematurely born children. CONTENT: Pubmed, Medline and Embase were searched for relevant studies. Studies were included if they assessed prematurely born children, who had been exposed to chorioamnionitis and had either lung function testing or assessment of wheeze or asthma following NICU discharge. Two reviewers independently screened the search results, applied inclusion criteria and assessed methodological quality. One reviewer extracted the data and these were checked by a second reviewer. SUMMARY: A total of 1,237 studies were identified, but only eight which included 35,000 infants, fulfilled the inclusion criteria. One study looked at both lung function results and wheeze or asthma in childhood. Four of five studies found an association between wheeze/asthma in childhood and exposure to chorioamnionitis: the overall Odds Ratio (OR) for developing wheeze/asthma in childhood was OR 1.71 (95 % CI: 1.55-1.89). Four studies looked at lung function in childhood, three of which showed no statistically significant association between chorioamnionitis exposure and altered lung function. One study found lower lung function in those exposed to chorioamnionitis and lower expiratory flows with increasing levels of chorioamnionitis (forced expiratory flow at 50 % of exhaled forced vital capacity (=FEF50) p=0.012, forced expiratory flow at 25-75 % of the forced vital capacity is exhaled (=FEF25-75) p=0.014). OUTLOOK: There was a significant association between chorioamnionitis and the development of wheeze or asthma in childhood, but overall not in impairment of lung function.

Distribution of cord inflammation in cases with clinical suspicion of chorioamnionitis.

INTRODUCTION: Identification of acute funisitis, a sign of foetal inflammatory response (FIR), is crucial as their presence is associated with ominous neonatal outcomes. Recommendation on which part of umbilical cord should be sampled to facilitate optimal identification of acute funisitis is limited. METHODS: This is a retrospective cross-sectional study over a seven-month duration recruiting all patients with clinical suspicion of chorioamnionitis and/or maternal intrapartum pyrexia. The distribution and the degree of cord inflammation were assessed. The cases were also evaluated for maternal inflammatory response (MIR) and chorionic vasculitis (CV). RESULTS: Of the 191 placentas, 88 (46.1%) had some degree of cord inflammation. Forty-nine (55.7%) had a differential in cord inflammation, with distal cord section (n = 38) demonstrating significant greater inflammation than that of proximal cord section (n = 11) (p<0.001). There were 20 cases with phlebitis only and 8 cases demonstrated arteritis only in either proximal or distal cord sections. Increasing magnitude of cord inflammation was significantly associated with increasing severity of MIR and the rate of CV (p<0.001). CV was observed in 25 (24.3%) cases showing absence of cord inflammation, while 12 (13.6%) cases with cord FIR demonstrated no CV. DISCUSSION: Inflammatory reaction can occur variably throughout the length of the umbilical cord and chorionic plate vessels, with greater inflammation seen in the distal cord section. We affirm the current Amsterdam recommendation of submitting at least two cross sections of the cord representing proximal and distal sites and two sections from placental parenchyma to facilitate the identification of FIR.

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).

Clinical characteristics and predictors of neonatal outcomes in chorioamnionitis at term gestation: A cohort study.

OBJECTIVE: To investigate the association between clinical and laboratory characteristics of chorioamnionitis in deliveries at term gestation with adverse neonatal outcomes. DESIGN: Retrospective cohort study. SETTING: The study is based on data from the Swedish Pregnancy Register, enriched with clinical data extracted from medical charts. SAMPLE: A cohort of 500 term singleton deliveries in Stockholm County with registered diagnosis of chorioamnionitis (based on the assessment of the responsible obstetrician) in the Swedish Pregnancy Register between 2014 and 2020. METHODS: Logistic regression was used to estimate odds ratios (ORs) as a measurement of the association between clinical and laboratory characteristics and neonatal complications. MAIN OUTCOME MEASURES: Neonatal infection and asphyxia-related complications. RESULTS: The prevalence of neonatal infection and asphyxia-related complications was 10% and 22%, respectively. First leukocyte count in the second tertile (OR 2.14, 95% CI 1.02-4.49), maximum C-reactive protein (CRP) level in the third tertile (OR 4.01, 95% Cl 1.66-9.68) and positive cervical culture (OR 2.22, 95% Cl 1.10-4.48) were associated with an increased risk of neonatal infection. Maximum level of CRP in the third tertile (OR 1.93, 95% Cl 1.09-3.41) and fetal tachycardia (OR 1.63, 95% Cl 1.01-2.65) were associated with an increased risk of asphyxia-related complications. CONCLUSIONS: Elevated inflammatory laboratory markers were associated with both neonatal infection and asphyxia-related complications, and fetal tachycardia was associated with asphyxia-related complications. Based on these findings, the incorporation of maternal CRP in the management of chorioamnionitis should be considered, and a continuous communication between obstetric and neonatal care extending past the delivery time point endorsed.

Predictors for histological chorioamnionitis among women with preterm prelabour rupture of membranes after dexamethasone treatment: a retrospective study.

OBJECTIVE: To investigate reliable biomarkers for predicting histological chorioamnionitis (HCA) in women with preterm prelabour rupture of membranes (PPROM). DESIGN: A retrospective study. SETTING: A maternity care hospital in Shanghai. POPULATION: Women with PPROM before 34+0/7  weeks of gestation. METHODS: Mean values of biomarkers were compared by two-way analysis of variance (ANOVA). Log-binomial regression models were used to assess the association between biomarkers and risk of HCA. A stepwise logistic regression model was used to develop a multi-biomarker prediction model and identify the independent predictors. The area under the receiver operating characteristic curve (AUC) was used to assess prediction performance. MAIN OUTCOME MEASURES: The ability of the individual biomarker and the combination of multiple biomarkers to predict HCA. RESULTS: In 157 mothers with PPROM, 98 (62.42%) women had HCA and 59 (37.58%) women did not have HCA. No significant differences were observed between the two groups in white blood cell, neutrophil or lymphocyte counts, whereas both high-sensitivity C-reactive protein (hsCRP) and procalcitonin (PCT) were significantly higher in the HCA group. HsCRP and PCT were found to be independently associated with the risk of HCA, and PCT had a larger AUC value than hsCRP (p < 0.05). The optimal multi-biomarker prediction model for HCA (AUC = 93.61%) included hsCRP at 72 hours and PCT at 48 and 72 hours, and PCT had a stronger prediction capacity than hsCRP. CONCLUSIONS: PCT could be a reliable biomarker for the early prediction of HCA in women with PPROM within 72 hours of dexamethasone treatment.

Validation of diagnosis codes for chorioamnionitis in medical encounter data, 2013-2018.

PURPOSE: Chorioamnionitis refers to intrauterine infection/inflammation that can be diagnosed clinically or from laboratory testing. This study aimed to validate chorioamnionitis International Classification of Diseases (ICD) codes using reference standards for clinical and histologic cases. METHODS: Department of Defense Birth and Infant Health Research program data identified a cohort of live deliveries at two United States military hospitals from 2013 to 2018. Deliveries were screened for chorioamnionitis using ICD codes from maternal delivery records; a sample of screen positive and negative deliveries was selected for chart review. Primary analyses validated deliveries using a reference standard for clinical chorioamnionitis; secondary analyses employed a reference standard that also included histologic cases, but were limited by temporal differences in availability of laboratory data. Sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values were calculated with 95% confidence intervals (CIs). RESULTS: Overall, 1857 deliveries (465 screen positive, 1392 screen negative) were eligible for analysis and 336 met the reference standard for clinical chorioamnionitis, yielding a PPV of 0.68 (95% CI 0.63, 0.72) and sensitivity of 0.76 (95% CI 0.72, 0.81). In secondary analyses, 390 deliveries met the reference standard for clinical or histologic chorioamnionitis, resulting in an overall PPV of 0.75 (95% CI 0.71, 0.79); in 2018, when more laboratory results were available, the PPV was 0.91 (95% CI 0.84, 0.97). NPV and specificity were ≥0.97 across reference standards. CONCLUSIONS: Chorioamnionitis ICD codes exhibited moderate correlation with clinical disease, suggesting challenges in using medical encounter data to isolate clinical cases from those only identified through laboratory testing.

Laboratory markers to identify acute histological chorioamnionitis in febrile parturients undergoing epidural analgesia: a retrospective study.

BACKGROUND: This study aimed to investigate the effect of the pathological staging of acute histological chorioamnionitis (HCA) on laboratory indicators and to conduct further studies to reassess the threshold values used by clinicians to identify acute HCA in febrile parturients undergoing epidural analgesia. METHODS: A retrospective study of febrile mothers receiving epidural analgesia at Nanjing Maternal and Child Health Care Hospital from January 1, 2018 to December 31, 2018. The participants were grouped by the progression of acute HCA, and the laboratory parameters were compared between groups. The ability of C-reactive protein (CRP), neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and monocyte-leukocyte ratio (M%), alone or in combination, to identify acute HCA in febrile parturients undergoing epidural analgesia was assessed using logistic regression and ROC curves. RESULTS: The area under the curve (AUC) of the best logistic regression model predicting HCA climbed to 0.706 (CRP + MLR). Maternal CRP, NLR, and MLR significantly and progressively increased with the progression of acute HCA (p < 0.0001). Based on the ROC curves, the following thresholds were selected to define increased laboratory indicators for identifying acute HCA: CRP ≥ 6.90 mg/L, NLR ≥ 11.93, and MLR ≥ 0.57. In addition, the AUC of the best logistic regression model predicting HCA ≥ stage 2 was 0.710, so these inflammatory markers were more precise in predicting HCA ≥ stage 2. CONCLUSION: Increased CRP (≥ 6.90 mg/L), NLR (≥ 11.93), and MLR (≥ 0.57) may help clinicians to identify early potential acute HCA in febrile parturients receiving epidural analgesia and to monitor progression to optimize clinical treatment options. TRIAL REGISTRATION: The study was registered in the Chinese Clinical Trial Registry on November 24, 2021 ( http://www.chictr.org.cn , ChiCTR2100053554).

Rapid diagnosis of intra-amniotic infection using nanopore-based sequencing.

OBJECTIVES: Early diagnosis and treatment of intra-amniotic infection is crucial. Rapid pathogen identification allows for a definite diagnosis and enables proper management. We determined whether the 16S amplicon sequencing performed by a nanopore sequencing technique make possible rapid bacterial identification at the species level in intra-amniotic infection. METHODS: Five cases of confirmed intra-amniotic infection, determined by either cultivation or 16S rDNA polymerase chain reaction (PCR) Sanger sequencing, and 10 cases of women who underwent mid-trimester genetic amniocentesis were included. DNA was extracted from amniotic fluid and PCR was performed on the full-length 16S rDNA. Nanopore sequencing was performed. The results derived from nanopore sequencing were compared with those derived from cultivation and Sanger sequencing methods. RESULTS: Bacteria were successfully detected from amniotic fluid using nanopore sequencing in all cases of intra-amniotic infection. Nanopore sequencing identified additional bacterial species and polymicrobial infections. All patients who underwent a mid-trimester amniocentesis had negative cultures, negative 16S PCR Sanger sequencing and nanopore sequencing. Identification of the microorganisms using nanopore sequencing technique at the bacterial species level was achieved within 5-9 h from DNA extraction. CONCLUSIONS: This is the first study demonstrating that the nanopore sequencing technique is capable of rapid diagnosis of intra-amniotic infection using fresh amniotic fluid samples.

Intra-amniotic inflammation in the mid-trimester of pregnancy is a risk factor for neuropsychological disorders in childhood.

OBJECTIVES: Intra-amniotic inflammation is a subclinical condition frequently caused by either microbial invasion of the amniotic cavity or sterile inflammatory stimuli, e.g., alarmins. An accumulating body of evidence supports a role for maternal immune activation in the genesis of fetal neuroinflammation and the occurrence of neurodevelopmental disorders such as cerebral palsy, schizophrenia, and autism. The objective of this study was to determine whether fetal exposure to mid-trimester intra-amniotic inflammation is associated with neurodevelopmental disorders in children eight to 12 years of age. METHODS: This is a retrospective case-control study comprising 20 children with evidence of prenatal exposure to intra-amniotic inflammation in the mid-trimester and 20 controls matched for gestational age at amniocentesis and at delivery. Amniotic fluid samples were tested for concentrations of interleukin-6 and C-X-C motif chemokine ligand 10, for bacteria by culture and molecular microbiologic methods as well as by polymerase chain reaction for eight viruses. Neuropsychological testing of children, performed by two experienced psychologists, assessed cognitive and behavioral domains. Neuropsychological dysfunction was defined as the presence of an abnormal score (<2 standard deviations) on at least two cognitive tasks. RESULTS: Neuropsychological dysfunction was present in 45% (9/20) of children exposed to intra-amniotic inflammation but in only 10% (2/20) of those in the control group (p=0.03). The relative risk (RR) of neuropsychological dysfunction conferred by amniotic fluid inflammation remained significant after adjusting for gestational age at delivery [aRR=4.5 (1.07-16.7)]. Of the 11 children diagnosed with neuropsychological dysfunction, nine were delivered at term and eight of them had mothers with intra-amniotic inflammation. Children exposed to intra-amniotic inflammation were found to have abnormalities in neuropsychological tasks evaluating complex skills, e.g., auditory attention, executive functions, and social skills, whereas the domains of reasoning, language, and memory were not affected in the cases and controls. CONCLUSIONS: Asymptomatic sterile intra-amniotic inflammation in the mid-trimester of pregnancy, followed by a term birth, can still confer to the offspring a substantial risk for neurodevelopmental disorders in childhood. Early recognition and treatment of maternal immune activation in pregnancy may be a strategy for the prevention of subsequent neurodevelopmental disorders in offspring.

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.

Wearable sensors for prediction of intraamniotic infection in women with preterm premature rupture of membranes: a prospective proof of principle study.

PURPOSE: To evaluate the use of wearable sensors for prediction of intraamniotic infection in pregnant women with PPROM. MATERIALS AND METHODS: In a prospective proof of principle study, we included 50 patients diagnosed with PPROM at the University Hospital Zurich between November 2017 and May 2020. Patients were instructed to wear a bracelet during the night, which measures physiological parameters including wrist skin temperature, heart rate, heart rate variability, and breathing rate. A two-way repeated measures ANOVA was performed to evaluate the difference over time of both the wearable device measured parameters and standard clinical monitoring values, such as body temperature, pulse, leucocytes, and C-reactive protein, between women with and without intraamniotic infection. RESULTS: Altogether, 23 patients (46%) were diagnosed with intraamniotic infection. Regarding the physiological parameters measured with the bracelet, we observed a significant difference in breathing rate (19 vs 16 per min, P < .01) and heart rate (72 vs 67 beats per min, P = .03) in women with intraamniotic infection compared to those without during the 3 days prior to birth. In parallel to these changes standard clinical monitoring values were significantly different in the intraamniotic infection group compared to women without infection in the 3 days preceding birth. CONCLUSION: Our results suggest that wearable sensors are a promising, noninvasive, patient friendly approach to support the early detection of intraamniotic infection in women with PPROM. However, confirmation of our findings in larger studies is required before implementing this technique in standard clinical management.

Placental Syphilis: A Comprehensive Review of Routine Histomorphology, HIV Co-infection, Penicillin Treatment, Immunohistochemistry, and Polymerase Chain Reaction.

Introduction: Placental examination is valuable for diagnosing congenital syphilis, but the classic histological triad is not always observed. This study aimed to identify additional morphological clues, evaluate the sensitivity of IHC and qPCR, and investigate the impact of HIV co-infection and penicillin treatment on placental morphology. Materials and methods: Two hundred and fifteen placental specimens with treponemal infection were reviewed. Morphological findings, IHC, and qPCR results were analyzed. Results: Chronic villitis (94%), acute chorioamnionitis (91.6%), and villous immaturity (65.6%) were the most common abnormalities. HIV co-infection and penicillin treatment were associated with reduced frequencies of inflammatory lesions. IHC and qPCR exhibited sensitivities of 74.4 and 25.8%, respectively, confirming the diagnosis in 42 cases with negative or unknown serology. Conclusion: Villitis, chorioamnionitis, and villous immaturity were identified as the predominant placental abnormalities. HIV co-infection and penicillin treatment can impact morphology and hamper the diagnosis. IHC and q-PCR are valuable adjuncts when serology is negative.

Association of clinical signs of chorioamnionitis with histological chorioamnionitis and neonatal outcomes in women with premature rupture of membranes.

Background: Premature rupture of membrane (PROM), especially when preterm or prolonged is associated with an increased risk of chorioamnionitis with its attendant feto-maternal complications. Aim: The study was aimed to determine the association of clinical signs of chorioamnionitis with histological chorioamnionitis and neonatal outcomes in women with PROM. Materials and Methods: Eligible participants with clinical diagnosis of PROM at gestational age of ≥28 weeks managed between December 2018 and June 2019 were consecutively recruited. Their sociodemographic characteristics, obstetrics history, and evidence of clinical chorioamnionitis using the Gibb's criteria were obtained. Following delivery, chorioamnionitis was histologically confirmed. Primary outcome measure was the proportion of women with PROM and histological chorioamnionitis that were detected clinically. Results: Of the 136 participants analyzed, 108 (79.4%) had term PROM, while 28 (20.6%) had preterm PROM (<37 weeks). The prevalence of histological chorioamnionitis was 50.0% compared to 16.2% using clinical indicators of infection. Histological chorioamnionitis was almost two times higher in preterm than term PROM (71.4% vs 38.9%). About two-third (67.6%) of the chorioamnionitis identified histologically were missed using clinical signs of chorioamnionitis. Clinical signs of chorioamnionitis had specificity of 100.0%, but low sensitivity (35.5%) and accuracy of 70.6%. A combination of three symptoms, maternal pyrexia and tachycardia, and fetal tachycardia appears to be the most reliable clinical indicator of chorioamnionitis in women with preterm PROM. There was a significant association between low birth weight, low Apgar score, NICU admission, and the presence of histological chorioamnionitis in women that had PROM. Conclusion: Clinical signs of chorioamnionitis have a low sensitivity and are not very accuracy in diagnosing chorioamnionitis in women with PROM.