Diagnostic tests for the prediction of histological chorioamnionitis and funisitis in pregnant women with preterm premature rupture of membranes: A systematic review.

BACKGROUND: Infection of the amniotic cavity is an important driver and/or consequence of preterm prelabour rupture of membranes (PPROM). Prediction of infection is challenging, limiting guidance for interventions during the antenatal period. Infection typically triggers a host inflammatory response, and non-invasive indirect markers of the maternal or fetal inflammatory response have been reported in the context of PPROM and intra-amniotic infection. Some of these markers have also been tested in amniotic fluid (AF) samples. AIMS: This study compared markers of the inflammatory response in women with PPROM against the outcome standard of histological chorioamnionitis (HCA) or funisitis (FUS). METHODS: Searches were conducted for studies reporting diagnostic test sensitivity and specificity for proven HCA or FUS in pregnant women with PPROM after 20 weeks' gestation. Weighted mean pooled sensitivity (Se), specificity (Sp), positive predictive value, negative predictive value, diagnostic odds ratio and 95% confidence intervals were calculated for each of the selected diagnostic tests. RESULTS: Except ultrasonographic detection of fetal thymic involution, almost all index tests analysed showed relatively low sensitivity. Maternal white cell count, interleukin-6 (IL-6) and AF IL-6 had credible specificity. Testing of AF markers, while more consistent than serum markers, showed no clear diagnostic accuracy improvement. CONCLUSIONS: There is a clear lack of evidence for the reliability of any individual diagnostic test to assist in the detection of HCA or FUS in women with PPROM. Combining several markers into a predictive model for improved diagnosis may be worth investigating.

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.

Frozen Section of Placental Membranes and Umbilical Cord: A Valid Diagnostic Tool for Early-Onset Neonatal Sepsis Management.

Early-onset neonatal sepsis (EONS), a serious infection in newborns within 3 days, is challenging to diagnose. The current methods often lack accuracy, leading to unnecessary antibiotics or delayed treatment. This study investigates the role of the frozen section examination of placental membranes and umbilical cord (FSMU) to improve EONS diagnosis in the daily lab practice. This retrospective study reviewed data from 59 neonates with EONS risk factors who underwent FSMU according to our institutional protocol. Concordance between the FSMU and the Final Pathological Report (FPR) was assessed. The FSMU demonstrated a high concordance (Kappa = 0.88) for funisitis diagnosis, with excellent accuracy (98.3%). A moderate concordance was observed for chorioamnionitis stage and grade. The FSMU shows promise as a rapid and accurate tool for diagnosing EONS, particularly for funisitis. This study suggests that the FSMU could be a valuable tool for EONS diagnosis, enabling a more judicious antibiotic use and potentially improving outcomes for newborns.

Stage III Chorioamnionitis is Associated with Reduced Risk of Severe Retinopathy of Prematurity.

OBJECTIVE: To identify whether histologically confirmed chorioamnionitis (hCAM) is associated with development of retinopathy of prematurity (ROP). STUDY DESIGN: We retrospectively analyzed 2 different cohorts. Cohort 1 was the national database of newborns in Japan born at ≤1500g or <32 weeks' gestation (January 2003 through April 2021, n = 38 013). Cohort 2 was babies born at <1500g from a single institution in Tsuchiura, Japan, (April 2015 through March 2018, n = 118). RESULTS: For Cohort1, after adjusting for potential confounders, stage III CAM (n = 5554) was associated with lower odds of severe ROP (stage ≥3 or required peripheral retinal ablation) by 14% (OR: 0.86; 95% CI: 0.78-0.94]. CAM of stage I (n = 3277) and II (n = 4319) was not associated with the risk of ROP. For Cohort 2, the odds of severe ROP were significantly reduced in moderate to severe hCAM groups (stage II, OR: 0.06, 95% CI: 0.05-0.82; stage III, OR: 0.10, 95% CI: 0.01-0.84). Neonates with funisitis, comorbidity of hCAM, and a finding of fetal inflammatory response had lower odds of severe ROP (OR: 0.11; 95% CI: 0.01-0.93). CONCLUSIONS: After adjusting for confounders, severe hCAM with fetal inflammatory response was associated with reduced risk of ROP.

Case Report: A neonatal case of cryopyrin-associated periodic syndrome with severe funisitis and neonatal asphyxia.

Cryopyrin-associated periodic syndrome (CAPS) is a genetic disorder and autoinflammatory disease characterized by chronic inflammation throughout the body. The most severe form of CAPS, Chronic Infantile Neurologic Cutaneous, and Articular (CINCA) syndrome, also known as Neonatal Onset Multisystem Inflammatory Disease (NOMID), has three main features: skin rash, CNS involvement, and joint symptoms. Although these symptoms are typically reported shortly after birth, there have been a few reports of prenatal inflammation. Here, we report our experience managing a case of a CAPS infant born in severe neonatal asphyxia due to a ruptured cord associated with severe funisitis. The baby was born at 38 weeks and 6 days of gestation, weighing 2,898 g, through an ultra-emergency Caesarian section prompted by variable deceleration. The Apgar score was 1 point at 1 min and 4 points at 5 min, necessitating intensive care due to hypoxic-ischemic encephalopathy. Upon delivery, it was observed that the umbilical cord had partially ruptured at the site of attachment to the baby, accompanied by arterial hemorrhage. Umbilical cord rupture was considered to be the cause of the sudden decrease in fetal heart rate. Pathological examination also showed that the inflammation of the cord was more severe on the side attached to the fetus and on the arterial side, suggesting that the inflammation had extended from the fetus. The father carried a genetic mutation associated with CINCA syndrome/NOMID (NLRP3 c.2068G>A p.Glu690Lys Hetero), which was also found in the child. Histopathologic examination of the placenta and umbilical cord can provide crucial insights into the intrauterine onset of inflammation, which is the first manifestation of CINCA syndrome/NOMID in newborns. It should be noted that births with a genetic predisposition to CAPS may have complications related to the placenta and umbilical cord.

Relationship between chorioamnionitis or funisitis and lung injury among preterm infants: meta-analysis involved 16 observational studies with 68,397 participants.

BACKGROUND: Chorioamnionitis (CA) can cause multiple organ injuries in premature neonates, particularly to the lungs. Different opinions exist regarding the impact of intrauterine inflammation on neonatal respiratory distress syndrome (NRDS) and bronchopulmonary dysplasia (BPD). We aim to systematically review the relationship between CA or Funisitis (FV) and lung injury among preterm infants. METHODS: We electronically searched PubMed, EMbase, the Cochrane library, CNKI, and CMB for cohort studies from their inception to March 15, 2023. Two reviewers independently screened literature, gathered data, and did NOS scale of included studies. The meta-analysis was performed using RevMan 5.3. RESULTS: Sixteen observational studies including 68,397 patients were collected. Meta-analysis showed CA or FV increased the lung injury risk (OR = 1.43, 95%CI: 1.06-1.92). Except for histological chorioamnionitis (HCA) (OR = 0.72, 95%CI: 0.57-0.90), neither clinical chorioamnionitis (CCA) (OR = 1.86, 95%CI: 0.93-3.72) nor FV (OR = 1.23, 95%CI: 0.48-3.15) nor HCA with FV (OR = 1.85, 95%CI: 0.15-22.63) had statistical significance in NRDS incidence. As a result of stratification by grade of HCA, HCA (II) has a significant association with decreased incidence of NRDS (OR = 0.48, 95%CI: 0.35-0.65). In terms of BPD, there is a positive correlation between BPD and CA/FV (CA: OR = 3.18, 95%CI: 1.68-6.03; FV: OR = 6.36, 95%CI: 2.45-16.52). Among CA, HCA was positively associated with BPD (OR = 2.70, 95%CI: 2.38-3.07), whereas CCA was not associated with BPD (OR = 2.77, 95%CI: 0.68-11.21). HCA and moderate to severe BPD (OR = 25.38, 95%CI: 7.13-90.32) showed a positive correlation, while mild BPD (OR = 2.29, 95%CI: 0.99-5.31) did not. CONCLUSION: Currently, evidence suggests that CA or FV increases the lung injury incidence in premature infants. For different types of CA and FV, HCA can increase the incidence of BPD while decreasing the incidence of NRDS. And this "protective effect" only applies to infants under 32 weeks of age. Regarding lung injury severity, only moderate to severe cases of BPD were positively correlated with CA.

Early changes in serum interleukin-6 levels in extremely premature newborns for detecting fetal inflammation.

BACKGROUND: Fetal inflammatory response syndrome (FIRS) is defined by elevated levels of inflammatory cytokines circulating in fetal blood, which may result in preterm morbidities. Serum interleukin-6 (IL-6) level has been reported to be a good indicator of FIRS; however, changes in IL-6 levels after birth remain to be elucidated. Herein, we characterized early changes in serum IL-6 levels in extremely premature newborns (EPNs, < 28 wks gestation), and then determined the cut-off values for detecting fetal inflammation at each postnatal epoch. METHODS: In this single-center study, 49 EPNs were retrospectively studied. Serum IL-6 measurements are routinely performed at delivery, 1-3, 6-12, and 24-36 h of life. Receiver operating characteristic (ROC) curve analyses were performed for detecting the presence of funisitis, the histologic counterpart of FIRS. RESULTS: Overall, serum IL-6 levels were significantly elevated at 1-3 (298 [31-4719] pg/mL) and 6-12 (29 [2-12,635] pg/mL) hours of life, then returned to at-delivery levels at 24-36 h of life. When comparing serum IL-6 levels at each postnatal epoch, the levels at delivery, 1-3, and 6-12 h of life were significantly higher in the EPNs with funisitis. Serum IL-6 cut-off values at delivery, 1-3, 6-12, and 24-36 h of life for the presence of funisitis were 20, 572, 290, and 13 pg/mL with area under ROCs of 0.75, 0.71, 0.68, and 0.53, respectively. CONCLUSIONS: Serum IL-6 levels in EPNs significantly increase early after birth, then decrease to at-delivery levels by 24-36 h of life. Therefore, postnatal age-dependent cut-off values of serum IL-6 might be considered for detecting fetal inflammation with confirmed funisitis.

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.

Antibiotic treatment reduces the intensity of intraamniotic inflammation in pregnancies with idiopathic vaginal bleeding in the second trimester of pregnancy.

BACKGROUND: Idiopathic bleeding in the second trimester of pregnancy complicates <1% of all pregnancies. This pregnancy complication can be caused by alterations in local hemostasis in the decidua due to infection/inflammation in the choriodecidual niche. This condition is associated with intraamniotic inflammatory complications. Antibiotic therapy effectively reduces the intensity of intraamniotic inflammation in certain pregnancy pathologies. However, whether antibiotic administration can reduce the intensity of the intraamniotic inflammatory response or eradicate microorganisms in patients with idiopathic bleeding during the second trimester of pregnancy remains unclear. OBJECTIVE: This study primarily aimed to determine whether antimicrobial agents can reduce the magnitude of intraamniotic inflammation in patients with idiopathic bleeding in the second trimester of pregnancy by assessing the concentration of interleukin-6 in the amniotic fluid before and after 7 days of antibiotic treatment. The secondary aim was to determine whether treatment with a combination of antibiotics altered the microbial load of Ureaplasma species DNA in amniotic fluid. STUDY DESIGN: This retrospective cohort study included singleton-gestation patients with idiopathic bleeding between 15+0 and 27+6 weeks who underwent transabdominal amniocentesis at the time of admission. Follow-up amniocentesis was performed in a subset of patients unless abortion or delivery occurred earlier. Concentrations of interleukin-6 were measured in the amniotic fluid samples, and the presence of microbial invasion of the amniotic cavity was assessed using culture and molecular microbiological methods. Intraamniotic inflammation was defined as an interleukin-6 concentration ≥3000 pg/mL in the amniotic fluid samples. RESULTS: A total of 36 patients with idiopathic bleeding in the second trimester of pregnancy were included. All the patients underwent initial amniocentesis. Patients with intraamniotic inflammation (n=25) were treated using a combination of antibiotics consisting of intravenous ceftriaxone, intravenous metronidazole, and peroral clarithromycin. The patients without intraamniotic inflammation (n=11) were treated expectantly. In total, 25 patients delivered 7 days after admission. All patients with intraamniotic inflammation at the initial amniocentesis who delivered after 7 days underwent follow-up amniocentesis. Treatment with antibiotics decreased the interleukin-6 concentration in the amniotic fluid at follow-up amniocentesis compared with that at the initial amniocentesis in patients with intraamniotic inflammation (median [interquartile range]: 3457 pg/mL [2493-13,203] vs 19,812 pg/mL [11,973-34,518]; P=.0001). Amniotic fluid samples with Ureaplasma species DNA had a lower microbial load at the time of follow-up amniocentesis compared with the initial amniocentesis (median [interquartile range]: 1.5×105 copies DNA/mL [1.3×105-1.7×105] vs 8.0×107 copies DNA/mL [6.7×106-1.6×108]; P=.02). CONCLUSION: Antibiotic therapy was associated with reduced intraamniotic inflammation in patients with idiopathic bleeding in the second trimester complicated by intraamniotic inflammation. Moreover, antibiotic treatment has been associated with a reduction in the microbial load of Ureaplasma species DNA in the amniotic fluid.

The histologic fetal inflammatory response and neonatal outcomes: systematic review and meta-analysis.

OBJECTIVE: This study aimed to investigate the prognostic role of concomitant histological fetal inflammatory response with chorioamnionitis on neonatal outcomes through a systematic review and meta-analysis of existing literature. DATA SOURCES: The primary search was conducted on October 17, 2021, and it was updated on May 26, 2023, across 4 separate databases (MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, and Scopus) without using any filters. STUDY ELIGIBILITY CRITERIA: Observational studies reporting obstetrical and neonatal outcomes of infant-mother dyads with histological chorioamnionitis and histological fetal inflammatory response vs infant-mother dyads with histological chorioamnionitis alone were eligible. Studies that enrolled only preterm neonates, studies on neonates born before 37 weeks of gestation, or studies on neonates with very low birthweight (birthweight <1500 g) were included. The protocol was registered with the International Prospective Register of Systematic Reviews (registration number: CRD42021283448). METHODS: The records were selected by title, abstract, and full text, and disagreements were resolved by consensus. Random-effect model-based pooled odds ratios with corresponding 95% confidence intervals were calculated for dichotomous outcomes. RESULTS: Overall, 50 studies were identified. A quantitative analysis of 14 outcomes was performed. Subgroup analysis using the mean gestational age of the studies was performed, and a cutoff of 28 weeks of gestation was implemented. Among neonates with lower gestational ages, early-onset sepsis (pooled odds ratio, 2.23; 95% confidence interval, 1.76-2.84) and bronchopulmonary dysplasia (pooled odds ratio, 1.30; 95% confidence interval, 1.02-1.66) were associated with histological fetal inflammatory response. Our analysis showed that preterm neonates with a concomitant histological fetal inflammatory response are more likely to develop intraventricular hemorrhage (pooled odds ratio, 1.54; 95% confidence interval, 1.18-2.02) and retinopathy of prematurity (pooled odds ratio, 1.37; 95% confidence interval, 1.03-1.82). The odds of clinical chorioamnionitis were almost 3-fold higher among infant-mother dyads with histological fetal inflammatory response than among infant-mother dyads with histological chorioamnionitis alone (pooled odds ratio, 2.99; 95% confidence interval, 1.96-4.55). CONCLUSION: This study investigated multiple neonatal outcomes and found association in the case of 4 major morbidities: early-onset sepsis, bronchopulmonary dysplasia, intraventricular hemorrhage, and retinopathy of prematurity.

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).

Maternal and peripartum risk factors for acute funisitis among term deliveries complicated by intraamniotic infection.

BACKGROUND: Acute funisitis-the histologic diagnosis of inflammation within the umbilical cord-represents a fetal inflammatory response and has been associated with adverse neonatal outcomes. Little is known regarding the maternal and intrapartum risk factors associated with the development of acute funisitis among term deliveries complicated by intraamniotic infection. OBJECTIVE: This study aimed to identify the maternal and intrapartum risk factors associated with developing acute funisitis among term deliveries complicated by intraamniotic infection. STUDY DESIGN: After institutional review board approval, we conducted a retrospective cohort study of term deliveries affected by clinical intraamniotic infection at a single tertiary center between 2013 and 2017, with placental pathology consistent with histologic chorioamnionitis. The exclusion criteria included intrauterine fetal demise, missing delivery information or placental pathology, and documented congenital fetal abnormalities. Maternal sociodemographic, antepartum, and intrapartum factors were compared among patients with acute funisitis on pathology to those without acute funisitis using bivariate statistics. Regression models were developed to estimate the adjusted odds ratios. RESULTS: Of 123 patients meeting the inclusion criteria, 75 (61%) had acute funisitis on placental pathology. Compared with placental specimens without acute funisitis, acute funisitis was observed more frequently among patients with maternal BMI ≥30 kg/m2 (58.7% vs 39.6%, P=.04) and labor courses with increased rupture of membrane duration (17.3 vs 9.6 hours, P=.001). Use of fetal scalp electrode was observed less frequently in acute funisitis (5.3% vs 16.7%, P=.04) than cases without acute funisitis. In regression models, maternal BMI ≥30 kg/m2 (adjusted odds ratio, 2.67; 95% confidence interval, 1.21-5.90) and rupture of membrane >18 hours (adjusted odds ratio, 2.48; 95% confidence interval, 1.07-5.75) were significantly associated with acute funisitis. Fetal scalp electrode use (adjusted odds ratio, 0.18; 95% confidence interval, 0.04-0.71) was negatively associated with acute funisitis. CONCLUSION: In term deliveries with intraamniotic infection and histologic chorioamnionitis, maternal BMI ≥30 kg/m2, and rupture of membrane>18 hours were associated with acute funisitis on placental pathology. As insight into the clinical impact of acute funisitis grows, the ability to predict which pregnancies are at the greatest risk for its development may allow for a tailored approach to predicting neonatal risk for sepsis and related comorbidity.

Retinopathy of prematurity and placental histopathology findings: A retrospective cohort study.

Aim: Retinopathy of prematurity (ROP) is a biphasic vaso-proliferative disease that has the potential to cause blindness. In addition to prematurity and hyperoxia, perinatal infection and inflammation have been reported to play a critical role in the pathogenesis of ROP. The aim of this study was to assess the association between placental inflammation and the severity of ROP. Methods: A retrospective study of infants (<30 weeks of gestational age) born at the King Edward Memorial Hospital, a tertiary perinatal center in Western Australia. Results: A total of 878 infants were included in this study (ROP stage 0-2 = 829; 3 or more = 49). The presence of maternal chorioamnionitis appeared to show signs of an association with reduced odds of severe ROP: mild chorioamnionitis OR=0.43 (95% CI: 0.17, 1.05) and severe chorioamnionitis OR=0.68 (95% CI: 0.29, 1.60). A strong association was observed for oxygen supplementation at 36 weeks (OR: 5.16; p < 0.001), exposure to postnatal steroids (OR: 6.65; p < 0.001), and receipt of platelet transfusion (OR: 8.21; p < 0.001). Conclusion: Maternal chorioamnionitis or fetal chorioamnionitis was associated with reduced odds of severe ROP. A strong association was found in infants who needed oxygen supplementation at 36 weeks and those who required steroids or platelets in the postnatal period.

Expression of inflammatory, angiogenic, and extracellular matrix-related mediators in the cervicovaginal fluid of women with preterm premature rupture of membranes: Relationship with acute histological chorioamnionitis.

PROBLEM: To investigate whether altered expression of various inflammation-, angiogenesis-, and extracellular matrix-related mediators in cervicovaginal fluid (CVF) could be independently associated with acute histological chorioamnionitis (HCA), microbial-associated HCA, and funisitis in women with preterm premature rupture of membranes (PPROM). METHOD OF STUDY: Clinical data of 102 consecutive singleton pregnant women with PPROM at 23+0 to 34+0 weeks were retrospectively analyzed. CVF samples were collected upon admission. Levels of APRIL, DKK-3, IGFBP-1/2, IL-6/8, lipocalin-2, M-CSF, MIP-1α, MMP-8/9, S100A8A9, TGFBI, TIMP-1, TNFR2, uPA, and VDBP were determined by ELISA. Placentas were histologically examined after birth. RESULTS: Multivariate logistic regression analyses showed that: (1) elevated CVF levels of IL-8 and TNFR2 were independently associated with acute HCA; (2) elevated CVF levels of IL-6, IL-8, M-CSF, MMP-8, and TNFR2 were independently associated with microbial-associated HCA; and (3) elevated CVF IL-8 and MMP-8 levels were independently associated with funisitis when adjusted for gestational age. Areas under the curves of the aforementioned CVF biomarkers ranged within 0.61-0.77, thereby demonstrating poor to fair diagnostic capacity for these clinical endpoints. HCA risk significantly increased as the CVF levels of each inflammatory mediator increased (P for trend < 0.05). CONCLUSIONS: Herein, we identified several inflammatory biomarkers (IL-6/8, M-CSF, MMP-8, and TNFR2) in the CVF that are independently associated with acute HCA, microbial-associated HCA, and funisitis in women with PPROM. Furthermore, the degree of inflammatory response in the CVF, based on the levels of these proteins, demonstrated a direct relationship with HCA risk (especially risk severity).

Changing Laboratory Practice for Early Detection of a Fetal Inflammatory Response: A Contemporary Approach.

Neonates born with the fetal inflammatory response (FIR) are at risk of complications such as early-onset neonatal sepsis, meningitis, and pneumonia. Providing an early histopathological diagnosis of FIR is important to guide management but can be a challenge in busy laboratories. This is a retrospective cross-sectional study over a four-month duration recruiting all placental cases with histological chorioamnionitis in our institution. The diagnostic performance of the umbilical cord (UC) section in identifying FIR, relative to the corresponding subsequent placental sections, was assessed. Clinical predictors of umbilical cord FIR were also investigated. A total of 390 UC sections were analyzed, of which 206 (52.8%) were found positive for FIR: 111 cases (53.9%) stage 1, 87 (42.2%) stage 2, and 8 (3.9%) stage 3. Our data revealed a good diagnostic sensitivity, specificity, positive predictive value, and accuracy of 76.2% (95%CI: 68.6-82.7%), 82.4% (95%CI: 65.5-93.2%), 95.0% (95%CI: 90.2-97.6%), and 77.3% (95%CI: 70.6-83.1%) respectively, in cases when clinical chorioamnionitis, fever and/or prolonged rupture of membrane (PROM) were suspected, with the area under the curve of 0.793. A maternal inflammatory response (MIR) was correlated with FIR (p < 0.001). Multivariate logistic regression analysis indicated that the higher the gestational age, clinical suspicion of chorioamnionitis, fever, and/or PROM, and the higher the stage of MIR significantly increased the odds of FIR (p < 0.001). UC section diagnosis of FIR is reasonably accurate in cases with clinical chorioamnionitis, fever, and/or PROM. Changing current laboratory practice to rapid processing of UC ahead of the rest of the other placental sections can be recommended in busy pathology departments.

Association of Funisitis with Short-Term Outcomes of Prematurity: A Frequentist and Bayesian Meta-Analysis.

The fetal systemic inflammatory response associated with intra-amniotic inflammation may play a key role in the pathogenesis of complications of preterm birth. Funisitis is the histologic equivalent of the fetal inflammatory response, whereas chorioamnionitis represents a maternal inflammatory response. We conducted a frequentist and Bayesian model average (BMA) meta-analysis of studies investigating the effects of funisitis on short-term outcomes of prematurity. Thirty-three studies (12,237 infants with gestational age ≤ 34 weeks) were included. Frequentist meta-analysis showed that funisitis was associated with an increased risk of any bronchopulmonary dysplasia (BPD), moderate/severe BPD, retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), any sepsis, early-onset sepsis (EOS), and mortality. However, Bayesian meta-analysis showed that the evidence in favor of the alternative hypothesis (i.e., funisitis is associated with an increased risk of developing the outcome) was strong for any IVH, moderate for severe IVH and EOS, and weak for the other outcomes. When the control group was restricted to infants having chorioamnionitis without funisitis, the only outcome associated with funisitis was any IVH. In conclusion, our data suggest that the presence of funisitis does not add an additional risk to preterm birth when compared to chorioamnionitis in the absence of fetal inflammatory response.

Prediction scores based on neonatal inflammatory markers for chorioamnionitis and funisitis in extremely low gestational age neonates.

AIM: The aim of the study was to examine the predictive value of inflammatory markers for chorioamnionitis and funisitis in extremely low gestational age neonates. METHODS: According to the Redline histopathological classification, extremely low gestational age neonates were classified into: (1) maternal inflammatory response ≤1 or ≥2, based on inflammatory findings of the placenta and (2) foetal inflammatory response ≤1 or ≥2, based on inflammatory findings of the umbilical cord. On admission and 12-36 h postnatally, procalcitonin and high-sensitivity C-reactive protein levels and white blood cell and neutrophil counts were compared. For both maternal and foetal inflammatory responses ≥2, the predictive value of each inflammatory marker was calculated. RESULTS: On admission, procalcitonin had the best predictive value for maternal and foetal inflammatory response ≥2. The maternal inflammatory response ≥2 prediction score includes procalcitonin level on admission, high-sensitivity C-reactive protein level and white blood cell count at 12-36 h postnatally. Foetal inflammatory response ≥2 prediction score includes procalcitonin level and white blood cell count on admission and 12-36 h postnatally. The sensitivities were 96.4% and 96.3%, respectively. CONCLUSION: Procalcitonin, high-sensitivity C-reactive protein levels and white blood cell count provide highly sensitive prediction scores for chorioamnionitis and funisitis in extremely low gestational age neonates.

Placental pathology is necessary to understand common pregnancy complications and achieve an improved taxonomy of obstetrical disease.

The importance of a fully functioning placenta for a good pregnancy outcome is unquestioned. Loss of function can lead to pregnancy complications and is often detected by a thorough placental pathologic examination. Placental pathology has advanced the science and practice of obstetrics and neonatal-perinatal medicine by classifying diseases according to underlying biology and specific patterns of injury. Many past obstacles have limited the incorporation of placental findings into both clinical studies and day-to-day practice. Limitations have included variability in the nomenclature used to describe placental lesions, a shortage of perinatal pathologists fully competent to analyze placental specimens, and a troubling lack of understanding of placental diagnoses by clinicians. However, the potential use of placental pathology for phenotypic classification, improved understanding of the biology of adverse pregnancy outcomes, the development of treatment and prevention, and patient counseling has never been greater. This review, written partly in response to a recent critique published in a major obstetrics-gynecology journal, reexamines the role of placental pathology by reviewing current concepts of biology; explaining the most recent terminology; emphasizing the usefulness of specific diagnoses for obstetrician-gynecologists, neonatologists, and patients; previewing upcoming changes in recommendations for placental submission; and suggesting future improvements. These improvements should include further consideration of overall healthcare costs, cost-effectiveness, the clinical value added of placental assessment, improvements in placental pathology education and practice, and leveraging of placental pathology to identify new biomarkers of disease and evaluate novel therapies tailored to specific clinicopathologic phenotypes of both women and infants.

Does acute funisitis predict worse neonatal outcomes among term newborns?

BACKGROUND: Acute funisitis-the histologic diagnosis of inflammation within the umbilical cord-represents a fetal inflammatory response to infection. Although acute funisitis has been associated with an increased risk of adverse outcomes among preterm neonates, there are limited and conflicting data with term deliveries. OBJECTIVE: This study aimed to evaluate the association between acute funisitis and neonatal morbidity in neonates born at term to pregnant patients with a clinical diagnosis of intraamniotic infection. STUDY DESIGN: This was a retrospective cohort study of pregnant patients who had clinically diagnosed intraamniotic infection at term, delivered vaginally at a single tertiary institution from 2013 to 2019, and had histologic chorioamnionitis on placental pathology. Patients with intrauterine fetal demise or missing neonatal/placental pathology data were excluded. The primary outcome was a neonatal sepsis composite, defined as culture-positive bacteremia, neutropenia (absolute neutrophil count<3500/µL), or immature-to-total neutrophil ratio>0.2. The secondary outcomes included composite neonatal morbidity, defined as neonatal intensive care unit admission, 5-minute Apgar score <7, bacteremia, endotracheal intubation or need for continuous positive airway pressure, intraventricular hemorrhage (grade 3 or 4), necrotizing enterocolitis (stage 3 or 4), umbilical artery pH<7.1, umbilical artery base excess>12, and neonatal mortality. The components of these composites, neonatal intensive care unit length of stay, and Kaiser early-onset sepsis score were also measured. Neonates with acute funisitis on pathology were compared with those without acute funisitis using bivariate statistics. Regression was used to estimate the relative risk of outcomes. RESULTS: Of 184 neonates with deliveries complicated by intraamniotic infection, acute funisitis was present in 109 (59%) placental specimens. Composite neonatal sepsis was significantly higher among neonates with acute funisitis (relative risk, 1.85; 95% confidence interval, 1.13-3.03) than in those without acute funisitis. As a marker for sepsis, acute funisitis has a sensitivity of 39.4%, negative predictive value of 47.2%, specificity of 78.7%, and positive predictive value of 72.9%. An immature-to-total neutrophil ratio>0.2 (relative risk, 1.83; 95% confidence interval, 1.09-3.08) was also significantly associated with acute funisitis. Neonatal morbidity composite, intraventricular hemorrhage, necrotizing enterocolitis, neonatal intensive care unit admission, higher Kaiser early-onset sepsis scores, and other examined outcomes were not statistically associated with acute funisitis. CONCLUSION: In term deliveries complicated by intraamniotic infection, acute funisitis was associated with increased neonatal sepsis. Current approaches for estimating neonatal sepsis risk are limited by their reliance on indirect maternal factors such as maximum maternal temperature and intrapartum antibiotic use. This study suggests that acute funisitis may serve as a marker that could be utilized to augment risk stratification at birth if a protocol for evaluating the umbilical cord in real-time were widely adopted.

The role of intraamniotic inflammation in threatened midtrimester miscarriage.

BACKGROUND: The assessment and management of patients with threatened midtrimester miscarriage is a clinical challenge because the etiology of this condition is poorly understood. OBJECTIVE: This study aimed to examine the frequency of intraamniotic infection or inflammation and the effect of antibiotics in patients presenting with regular uterine contractions and intact membranes before 20 weeks of gestation. STUDY DESIGN: This retrospective study comprised patients who met the following criteria: (1) singleton gestation, (2) gestational age before 20 weeks, (3) the presence of regular uterine contractions confirmed by a tocodynamometer (8 or more contractions in 60 minutes), (4) intact amniotic membranes, and (5) transabdominal amniocentesis performed for the evaluation of the microbiologic and inflammatory status of the amniotic cavity. Samples of amniotic fluid were cultured for aerobic and anaerobic bacteria and genital mycoplasmas, and polymerase chain reaction was performed to detect Ureaplasma species. Amniotic fluid was tested for white blood cell counts and matrix metalloproteinase-8 concentrations to diagnose intraamniotic inflammation. Patients with intraamniotic inflammation, or intraamniotic infection, were treated with antibiotics (a combination of ceftriaxone, clarithromycin, and metronidazole). Treatment success was defined as the resolution of intraamniotic infection/inflammation at the follow-up amniocentesis or delivery after 34 weeks of gestation. RESULTS: 1) Intraamniotic inflammation was present in 88% (15/17) of patients, whereas infection was detectable in only 2 cases; 2) objective evidence of resolution of intraamniotic inflammation after antibiotic treatment was demonstrated in 100% (4/4) of patients who underwent a follow-up amniocentesis; 3) 30% (5/15) of women receiving antibiotics delivered after 34 weeks of gestation (3 of the 5 patients had a negative follow-up amniocentesis, and 2 of the women were without a follow-up amniocentesis); 4) the overall treatment success of antibiotics was 40% (6/15; 4 cases of objective evidence of resolution of intra-amniotic inflammation and 5 cases of delivery after 34 weeks of gestation). CONCLUSION: The prevalence of intraamniotic inflammation in patients who presented with a threatened midtrimester miscarriage was 88% (15/17), and, in most cases, microorganisms could not be detected. Antibiotic treatment, administered to patients with intraamniotic inflammation, was associated with either objective resolution of intraamniotic inflammation or delivery after 34 weeks of gestation in 40% (6/15) of the cases.