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.

Circulating Cell-Free Mitochondrial DNA as a Novel Biomarker for Intra-Amniotic Infection in Obstetrics: A Pilot Trial.

Background/Objectives: Intra-amniotic infection (IAI) is a rare but serious condition with potential complications such as preterm labor and intrauterine fetal death. Diagnosing IAI is challenging due to varied clinical signs. Oxidative stress and mitochondrial dysfunction have been hypothesized to evolve around IAI. This study focused on measuring circulating mtDNA levels, a proposed biomarker for mitochondrial dysfunction, in maternal serum and placenta of women with confirmed IAI and healthy controls. Methods: 12 women with confirmed IAI (IAI group) were enrolled following premature preterm rupture of the membranes (PPROM) and compared to 21 healthy women (control group). Maternal blood was obtained two weeks pre-partum and peripartum; furthermore, postpartum placental blood was taken. In the IAI group, maternal blood was taken once weekly until delivery as well as peripartum, as was placental blood. Circulating cell-free mtDNA was quantified by real-time quantitative PCR. Results: Upon admission, in the IAI group, mean plasma mtDNA levels were 735.8 fg/µL compared to 134.0 fg/µL in the control group (p < 0.05). After delivery, in the IAI group, mean mtDNA levels in the placenta were 3010 fg/µL versus 652.4 fg/µL (p < 0.05). Conclusions: Circulating cell-free mtDNA could serve as a valuable biomarker for IAI prediction and diagnosis. Future research should establish reference values for sensitivity in predicting IAI.

Semi-quantitative metalloproteinase-8 rapid test for the prediction of adverse pregnancy outcomes in patients with preterm premature rupture of membranes.

OBJECTIVE: We aimed to determine whether the semi-quantitative metalloproteinase-8 (MMP-8) bedside test is a worthwhile indicator in reflecting the severity of of intra-amniotic inflammation (IAI) and in predicting adverse pregnancy outcomes. STUDY DESIGN: This retrospective cohort study comprised 76 singleton-pregnant women admitted to the Seoul National University Bundang Hospital with a diagnosis of preterm premature rupture of membranes (preterm PROM) between 20 weeks 0 days and 33 weeks 6 days of gestation who underwent trans-abdominal amniocentesis to confirm intra-amniotic infection by positive results for aerobic/anaerobic bacteria, fungi, and genital mycoplasma and evaluate lung maturity. The semi-quantitative MMP-8 rapid test kit employs a colourimetric assay to quantify MMP-8 levels in amniotic fluid (AF), expressing results from 0 to 100 percent. Participants were divided into three groups: group 1, including negative MMP-8 test with colour scale of 0 % (negative, n = 17); group 2, including positive MMP-8 test with colour scale < 51 % (weak positive, n = 21); and group 3, including positive MMP-8 test with colour scale of 51 %-100 % (strong positive, n = 38). RESULTS: Approximately 78 % (59/76) of the participants showed a positive MMP-8 test result; all culture-proven AF samples (33.3 % [25/75]) yielded positive MMP-8 test, categorizing these patients into either group 2 or group 3. A significant trend was observed where the rate of positive culture-proven samples increased with the progression from group 1 (negative) to group 3 (strong positive). Both white blood cell counts in AF and maternal serum C-reactive protein levels were found to escalate with the progression of test results from negative to strong positive. This progression was associated with an increased risk of spontaneous preterm birth within 48 h, 7 days, and 14 days from amniocentesis and within 34 weeks of gestation. CONCLUSION: The more the test results progress from negative to strong positive, the shorter the interval from amniocentesis to delivery becomes, and the higher the risk of intra-amniotic infection, spontaneous preterm delivery, and other perinatal complications. This relationship highlights the critical value of the semi-quantitative MMP-8 rapid test in predicting adverse pregnancy outcomes in patients with preterm PROM.

Intra-amniotic Candida albicans Infection Treated With Liposomal Amphotericin B With a Successful Neonatal Outcome.

Intra-amniotic infection with Candida species is an uncommon but severe condition with high fetal morbimortality and no established clinical guidelines for its management. We report a Candida albicans intra-amniotic infection diagnosed in a 25-week pregnant woman, successfully treated with high-dose liposomal amphotericin B. Pregnancy was prolonged until 30 weeks, and despite persistently positive Candida cultures in amniotic fluid, a healthy newborn was delivered without evidence of systemic infection. Amphotericin concentration was determined at birth, revealing levels over 30 times higher in mother's and cord blood than in the amniotic fluid, probably explaining the clinical protection despite failure in obtaining fungal clearance.

Intra-amniotic infection and/or inflammation is associated with fetal cardiac concentric hypertrophy and diastolic dysfunction in preterm labor and preterm prelabor rupture of membranes.

BACKGROUND: Preterm delivery is associated with cardiovascular remodeling and dysfunction in children and adults. However, it is unknown whether these effects are caused by the neonatal consequences of preterm birth or if these are already present in utero. OBJECTIVE: We evaluated fetal cardiac morphology and function in fetuses of mothers admitted for preterm labor or preterm prelabor rupture of membranes and the association of these changes with the presence of intra-amniotic infection and/or inflammation. STUDY DESIGN: In this prospective cohort study, fetal echocardiography and amniocentesis were performed at admission in singleton pregnant women with preterm labor and/or preterm prelabor rupture of membranes between 24.0 and 34.0 weeks' gestation with (intra-amniotic infection and/or inflammation group, n=41) and without intra-amniotic infection and/or inflammation (non-intra-amniotic infection and/or inflammation, n=54). Controls (n=48) were outpatient pregnant women without preterm labor or preterm prelabor rupture of membranes. Intra-amniotic infection was defined by a positive amniotic fluid culture or positive 16S ribosomal RNA gene. Intra-amniotic inflammation was defined by using the amniotic fluid interleukin-6 cutoff levels previously reported by our group being >1.43 ng/mL in preterm prelabor rupture of membranes and >13.4 ng/mL in preterm labor. Fetal cardiac morphology and function was evaluated using echocardiography, and troponin-I and N-terminal pro-brain natriuretic peptide concentrations were measured in amniotic fluid from women with preterm labor or preterm prelabor rupture of membranes and compared with 20 amniotic fluid Biobank samples obtained for reasons other than preterm labor or preterm prelabor rupture of membranes or cardiac pathology. The data were adjusted for the estimated fetal weight below the 10th percentile and for preterm prelabor rupture of membranes at admission and also for gestational age at amniocentesis when amniotic fluid biomarkers were compared. RESULTS: From 2018 to 2021, 143 fetuses were included; 95 fetuses were from mothers admitted with a diagnosis of preterm labor or preterm prelabor rupture of membranes, and among those, 41 (28.7%) were in the intra-amniotic infection and/or inflammation group and 54 (37.8%) were in the non-intra-amniotic infection and/or inflammation group. A total of 48 (33.6%) fetuses were included in the control group. Fetuses with preterm labor and/or preterm prelabor rupture of membranes had signs of subclinical cardiac concentric hypertrophy (median left wall thickness of 0.93 [interquartile range, 0.72-1.16] in the intra-amniotic infection and/or inflammation group; 0.79 [0.66-0.92] in the non-intra-amniotic infection and/or inflammation group; and 0.69 [0.56-0.83] in controls; P<.001) and diastolic dysfunction (tricuspid A duration 0.23 seconds [0.21-0.25], 0.24 [0.22-0.25], and 0.21 [0.2-0.23]; P=.007). Systolic function was similar among groups. Higher values of amniotic fluid troponin I (1413 pg/mL [927-2334], 1190 [829-1636], and 841 [671-959]; P<.001) and N-terminal pro-brain natriuretic peptide were detected (35.0%, 17%, and 0%; P=.005) in fetuses with preterm labor or preterm prelabor rupture of membranes when compared with the control group. The highest N-terminal pro-brain natriuretic peptide concentrations were found in the intra-amniotic infection and/or inflammation group. CONCLUSION: Fetuses with preterm labor or preterm prelabor rupture of membranes showed signs of cardiac remodeling and subclinical dysfunction, which were more pronounced in those exposed to intra-amniotic infection and/or inflammation. These findings support that the cardiovascular effects observed in children and adults born preterm have, at least in part, a prenatal origin.

A multivariable prediction model for intra-amniotic infection in patients with preterm labor and intact membranes including a point of care system that measures amniotic fluid MMP-8.

OBJECTIVES: Among patients with preterm labor and intact membranes (PTL), those with intra-amniotic infection (IAI) present the highest risk of adverse perinatal outcomes. Current identification of IAI, based on microbiological cultures and/or polymerase chain reaction amplification of the 16S ribosomal RNA gene, delay diagnosis and, consequently, antenatal management. The aim to of the study was to assess the performance of a multivariable prediction model for diagnosing IAI in patients with PTL below 34.0 weeks using clinical, sonographic and biochemical biomarkers. METHODS: From 2019 to 2022, we prospectively included pregnant patients admitted below 34.0 weeks with diagnosis of PTL and had undergone amniocentesis to rule in/out IAI. The main outcome was IAI, defined by a positive culture and/or 16S ribosomal RNA gene in amniotic fluid. Based on the date of admission, the sample (n=98) was divided into a derivation (2019-2020, n=49) and validation cohort (2021-2022, n=49). Logistic regression models were developed for the outcomes evaluated. As predictive variables we explored ultrasound cervical length measurement at admission, maternal C-reactive protein, gestational age, and amniotic fluid glucose and matrix metalloproteinase-8 (MMP-8) levels. The model was developed in the derivation cohort and applied to the validation cohort and diagnostic performance was evaluated. Clinical management was blinded to the model results. RESULTS: During the study period, we included 98 patients admitted with a diagnosis of PTL. Of these, 10 % had IAI. The final model included MMP-8 and amniotic fluid glucose levels and showed an area under the receiver operating characteristic curve to predict the risk of IAI of 0.961 (95 % confidence interval: 0.860-0.995) with a sensitivity of 75 %, specificity of 93.3 %, positive likelihood ratio (LR) of 11.3 and negative LR of 0.27 in the validation cohort. CONCLUSIONS: In patients with PTL, a multivariable prediction model including amniotic fluid MMP-8 and glucose levels might help in the clinical management of patients undergoing amniocentesis to rule in/out IAI, providing results within a few minutes.

Analysis of gastric fluid in preterm newborns supports the view that the amniotic cavity is sterile before the onset of parturition: a retrospective cohort study.

OBJECTIVES: To compare the frequency of Ureaplasma-positive gastric fluid (GF) cultures based on the cause and mode of delivery in preterm newborns. METHODS: This retrospective cohort study included women with a singleton pregnancy who delivered prematurely (between 23+0 and 32+0 weeks of gestation, n=464) at a single university hospital in South Korea. The newborns' GF was obtained on the day of birth via nasogastric intubation. The frequency of Ureaplasma spp. in GF cultures was measured and compared according to the cause and mode of delivery. RESULTS: Ureaplasma spp. was detected in 20.3 % of the GF samples. The presence of Ureaplasma spp. was significantly higher in the spontaneous preterm birth group than in the indicated preterm birth group (30.2 vs. 3.0 %; p<0.001). Additionally, Ureaplasma spp. was more frequently found in the vaginal delivery group than in the cesarean delivery group, irrespective of the cause of preterm delivery [indicated preterm birth group (22.2 vs. 1.9 %, p=0.023); spontaneous preterm birth group (37.7 vs. 24.2 %, p=0.015)]. CONCLUSIONS: Ureaplasma spp. were found in 20.3 % of the GFs. However, only 1.9 % of newborns in the indicated preterm birth group with cesarean delivery had a Ureaplasma-positive GF culture.

Evaluation of amniotic fluid neutrophil gelatinase-associated lipocalin and L-type fatty acid-binding protein levels during pregnancy.

Objective: We aimed to examine amniotic fluid neutrophil gelatinase-associated lipocalin (NGAL) and L-type fatty acid-binding protein (L-FABP) levels during pregnancy. Study design: This study included singleton pregnancies. Amniotic fluid samples were collected at the time of vaginal delivery, cesarean section, amniocentesis, amnioreduction, and amnioinfusion. We analyzed changes of the NGAL and L-FABP levels during pregnancy and the factors affecting these values and their association with clinical outcomes. Results: Three hundred and one pregnancies were analyzed. Respective Pearson correlation coefficients for the NGAL and L-FABP levels and gestational age at inspection were - 0.351 and - 0.819 (p <0.001 and p < 0.001, respectively); weak and strong negative correlation were observed. The NGAL level was significantly higher in the intra-amniotic infection group than in the control group (p < 0.001). The L-FABP level was significantly higher in the fetal blood flow abnormalities group than in the control group (p < 0.001). The NGAL and L-FABP levels were significantly higher in the adverse outcomes group than in the control group (p = 0.019 and p < 0.001, respectively), and the respective areas under the concentration-time curve, with optimal cutoff values, for the NGAL and L-FABP levels were 0.693 (14,800 µg/gCr) and 0.864 (378 µg/gCr). Conclusions: Amniotic fluid NGAL and L-FABP levels reflect fetal and neonatal immaturity. Additionally, the NGAL level is a useful predictive factor of intra-amniotic infection, and the L-FABP level is a useful predictive factor of fetal condition and short- and long-term prognoses.

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.

Validating the performance of 3 sepsis screening tools in patients with clinical chorioamnionitis.

BACKGROUND: Maternal sepsis is a leading cause of maternal death in the United States. Approximately two-thirds of maternal deaths because of sepsis are related to delayed recognition or treatment. New early warning systems using a 2-step approach have been developed for the early recognition of sepsis in obstetrics; however, their performance has not been validated. OBJECTIVE: This study aimed to assess the performance of 3 primary screening tools introduced by the Society of Obstetric Medicine Australia and New Zealand and the California Maternal Quality Care Collaborative for use in the first step of their 2-step early warning systems. The obstetrically modified quick Sequential (sepsis-related) Organ Failure Assessment score tool, the obstetrically modified Systemic Inflammatory Response Syndrome tool, and the obstetrically modified Systemic Inflammatory Response Syndrome 1 tool were evaluated for the early detection of sepsis in patients with clinically diagnosed chorioamnionitis. STUDY DESIGN: This was a retrospective cohort study using prospectively collected clinical data at a tertiary care center and an affiliated healthcare system. The electronic health records were searched to identify and verify cases with clinically diagnosed chorioamnionitis between November 2017 and September 2022. The flow sheet for every patient was reviewed to determine when criteria were met for any of the 3 tools. The performance of these tools was analyzed using their sensitivity, specificity, positive and negative predictive values, and receiver operating characteristic curve for the identification of sepsis. RESULTS: There were 545 cases that had the requisite data for inclusion in the analysis. Of note, 11 patients met the criteria for sepsis. Both the obstetrically modified Systemic Inflammatory Response Syndrome and obstetrically modified Systemic Inflammatory Response Syndrome 1 tools had overall similar test characteristics, which were notably different from the obstetrically modified quick Sequential Organ Failure Assessment tool. The screen-positive rate of the obstetrically modified quick Sequential Organ Failure Assessment tool (1.5%; 95% confidence interval, 0.6%-2.9%) was lower than that of the obstetrically modified Systemic Inflammatory Response Syndrome tool (60.0%; 95% confidence interval, 55.7%-64.1%) and the obstetrically modified Systemic Inflammatory Response Syndrome 1 tool (50.0%; 95% confidence interval, 45.8%-54.3%). The sensitivities of the obstetrically modified Systemic Inflammatory Response Syndrome tool (100.0%; 95% confidence interval, 71.5%-100.0%) and the obstetrically modified Systemic Inflammatory Response Syndrome 1 tool (100.0%; 95% confidence interval, 71.5%-100.0%) were higher than that of the obstetrically modified quick Sequential Organ Failure Assessment tool (18.0%; 95% confidence interval, 2.3%-51.8%). All 3 tools had high negative predictive values; however, their positive predictive values were poor. CONCLUSION: This study demonstrated that all 3 tools had limitations in screening for sepsis among patients with a clinical diagnosis of chorioamnionitis. The obstetrically modified quick Sequential Organ Failure Assessment tool missed more than half of the sepsis cases and, thus, had poor performance as a primary screening tool for sepsis. Both the obstetrically modified Systemic Inflammatory Response Syndrome and obstetrically modified Systemic Inflammatory Response Syndrome 1 tools captured all sepsis cases; however, they tended to overdetect sepsis.

Association between intracervical Foley balloon and clinical chorioamnionitis among patients with group B streptococcus colonization undergoing induction with standardized labor management.

BACKGROUND: Intracervical Foley balloons are commonly used for cervical ripening, but there has been a historical concern regarding an increased risk of clinical chorioamnionitis with Foley balloon use in patients with group B streptococcus. OBJECTIVE: This study aimed to determine whether intracervical Foley balloon use in patients with group B streptococcus is associated with an increased risk of clinical chorioamnionitis. STUDY DESIGN: This was a secondary analysis of a randomized controlled trial Mechanical and Pharmacologic Methods of Labor Induction: A Randomized Controlled Trial that compared cervical ripening agents within a standardized labor protocol. Foley balloon (alone, with oxytocin, or with misoprostol) was compared with misoprostol only to evaluate the primary outcome of clinical chorioamnionitis, defined based on the American College of Obstetricians and Gynecologists guidelines. Patients with a term, singleton pregnancy with intact membranes and an unfavorable cervix (Bishop score of ≤6 and dilation ≤2 cm) and a known group B streptococcus status were included. The secondary outcomes included a composite postpartum maternal infectious outcome consisting of any occurrence of endometritis, wound infection, postpartum urinary tract infection, or maternal sepsis; additional secondary outcomes included neonatal outcomes. Binomial regression with robust error variance was used to evaluate whether group B streptococcus status modified the relationship between Foley balloon use and clinical chorioamnionitis and to adjust for confounders. RESULTS: A total of 491 patients were enrolled in the original trial. Of these patients, 467 had a known group B streptococcus status and underwent cervical ripening: 182 (39.0%) had group B streptococcus, and 285 (61.0%) did not have group B streptococcus. Moreover, 73.0% of patients received a Foley balloon, and 27.0% of patients did not receive a Foley balloon. There was no difference in the demographic or clinical characteristics between groups. The overall rate of clinical chorioamnionitis was 12.2%, with no difference between those with and without a Foley balloon (12.6% vs 11.1%, respectively; P=.66). Group B streptococcus status did not modify the association between Foley balloon use and clinical chorioamnionitis (relative risk, 0.93; 95% confidence interval, 0.50-1.72). This remained unchanged after adjusting for gestational age (adjusted relative risk, 0.87; 95% confidence interval, 0.45-1.67). Furthermore, other maternal and neonatal outcomes were similar between groups. CONCLUSION: In this secondary analysis of a large randomized trial using a standardized labor protocol, there was no increased risk of infectious morbidity with Foley balloon use in patients overall and in patients with group B streptococcus. Our findings support that a Foley balloon can be safely used for cervical ripening in patients with group B streptococcus colonization.

Amniotic fluid sludge is associated with earlier preterm delivery and raised cervicovaginal interleukin 8 concentrations.

BACKGROUND: Preterm birth is the leading cause of global neonatal mortality. Amniotic fluid sludge, thought to indicate intra-amniotic infection, may have potential as a clinical biomarker of preterm birth risk. OBJECTIVE: This study aimed to analyze whether the presence of amniotic fluid sludge in pregnant participants with a known short cervical length can help improve the understanding of the etiology and guide management choice. STUDY DESIGN: This was a retrospective cohort study analyzing the effects of amniotic fluid sludge presence on the risk of preterm birth in high-risk asymptomatic pregnant participants with a short cervical length (<25 mm) at a large tertiary referral maternity center in London. Amniotic fluid sludge was detected on a routine transvaginal ultrasound scan. RESULTS: Overall, 147 pregnant participants with a short cervical length were identified, 54 of whom had amniotic fluid sludge. Compared with pregnant participants without amniotic fluid sludge, pregnant participants with amniotic fluid sludge were more likely to have a short cervical length (19 vs 14 mm, respectively; P<.0001) and increased cervicovaginal fetal fibronectin concentrations at diagnosis (125 vs 45 ng/mL, respectively; P=.0006). Pregnant participants with amniotic fluid sludge were at increased risk of midtrimester loss and delivery before 24 weeks of gestation (relative risk, 3.4; 95% confidence interval, 1.2-10.3). Furthermore, this study showed that pregnant participants with amniotic fluid sludge have increased cervicovaginal interleukin 8 concentrations, supporting the concept of amniotic fluid sludge as an indicator of an inflammatory response to microbial invasion (P=.03). Neonatal outcomes were similar between the 2 groups. CONCLUSION: In our cohort of high-risk asymptomatic pregnant participants with a short cervical length, the presence of amniotic fluid sludge is associated with an increased risk of delivery before 24 weeks of gestation. Moreover, pregnant participants with amniotic fluid sludge were more likely to have raised fetal fibronectin levels and inflammatory cytokines, particularly interleukin 8, in the cervicovaginal fluid, supporting the concept that amniotic fluid sludge is associated with an infective or inflammatory process. Future research should aim to further establish the clinical significance of amniotic fluid sludge presence and guide subsequent management.

The MNRR1 activator nitazoxanide abrogates lipopolysaccharide-induced preterm birth in mice.

Intra-amniotic inflammation leading to preterm birth is one of the leading causes of neonatal morbidity and mortality. We recently reported that the mitochondrial levels of MNRR1 (Mitochondrial Nuclear Retrograde, Regulator 1; also called CHCHD2, AAG10, or PARK22), an important bi-organellar regulator of cellular function, are reduced in the context of inflammation and that genetic and pharmacological increases in MNRR1 levels can counter the inflammatory profile. Herein, we show that nitazoxanide, a clinically approved drug, is an activator of MNRR1 and abrogates preterm birth in a well-characterized murine model caused by intra-amniotic lipopolysaccharide (LPS) injection.

Intra-Amniotic Inflammation or Infection: Suspected and Confirmed Diagnosis of "Triple I" at Term.

Chorioamnionitis (CA) at term of pregnancy can have an infectious and/or inflammatory origin and is associated with adverse outcomes. Triple I (intrauterine inflammation, infection, or both, TI) has been proposed to reduce the overdiagnosis of infection and neonatal overtreatment. The aim of this study is to identify clinical and histological variables that could predict adverse outcomes when TI is suspected and/or confirmed. This retrospective cohort study included 404 pregnancies (gestational age ≥ 37 weeks) that were divided into 5 all-inclusive and mutually exclusive groups. TI was defined according to the NICHD definition of 2015, and it could be confirmed (TI+) or not confirmed (TI-) via histological examination. Signs of infection/inflammation that did not conform to the definition of TI were classified as "clinical suspicion" and could be supported (CS+) or not supported (CS-) by histology. Cases of histological chorioamnionitis (HCA) without clinical manifestation represented a fifth group. Whole placental involvement (WPLI) was defined as a histological inflammation involving the maternal and fetal sides. There were 113 TI+, 30 TI-, 186 CS+, 35 CS-, and 40 isolated HCA cases. WPLI was diagnosed in 133 cases (39.2%). Composite neonatal outcome (CNO) occurred in 114 cases (28.2%) while composite maternal outcome (CMO) occurred in 192 cases (47.5%). Compared with CS+, TI+ was more predictive of CNO (p = 0.001), CMO (p < 0.001), and WPLI (p = 0.005). WPLI was related both to CNO (p < 0.001) and to CMO (p = 0.046). TI+ and WPLI showed similar sensitivity but different specificity in predicting CNO. At logistic regression, CNO was independently predicted by TI+ (OR 2.21; p = 0.001) and by WPLI (OR 2.23; p = 0.001). Compared with CS, TI is a better predictor of CNO and can be useful for the identification of newborns at risk.

Impact of antimicrobial stewardship interventions on peripartum antibiotic prescribing in patients with penicillin allergy.

BACKGROUND: Beta-lactam antibiotics (eg, penicillins, cephalosporins, and carbapenems) are preferred for group B streptococcus prophylaxis, intra-amniotic infection, and cesarean surgical site infection prophylaxis. Non-beta-lactam alternatives are associated with inferior efficacy and contribute to higher rates of surgical site infection and longer lengths of stay. Most patients who report a penicillin allergy can tolerate penicillins without any adverse reaction. There are low rates of cross-reactivity between penicillins and other beta-lactams, including cephalosporins and carbapenems. Efforts to evaluate penicillin allergy and promote the use of beta-lactams are needed. OBJECTIVE: This study aimed to evaluate whether an antimicrobial stewardship intervention improved the use of first-line antibiotics for peripartum indications in patients with a reported penicillin allergy, following updates to institutional guidelines. STUDY DESIGN: This was a retrospective study of adult patients presenting for vaginal or cesarean delivery at 2 hospitals within a healthcare system. Patients received at least 1 dose of antibiotics for a peripartum indication between May 1, 2018, and October 31, 2018 (preintervention group) and May 1, 2020, to October 31, 2020 (postintervention group). The stewardship intervention bundle, which was implemented between March 2019 and April 2020, included updates to institutional antibiotic guidelines, reclassification of severe penicillin allergy, development of obstetrical prophylaxis and treatment order sets, promotion of allergy referral services, and establishment of a physician champion. The primary outcome was the composite rates of patients with reported penicillin allergy who received a preferred antibiotic for a peripartum indication. The secondary measures included maternal and neonatal outcomes. RESULTS: A total of 192 patients with a history of documented penicillin allergy were evaluated (96 patients in the preintervention group and 96 patients in the postintervention group). Hives were the most commonly reported index symptom in both groups (40/96 [41.7%] vs 39/96 [40.6%]; P=.883). After stewardship interventions, there was a significant increase in the rate of preferred antibiotic use (33/96 [34.3%] vs 81/96 [84.3%]; P<.001). The effect was the greatest in patients with nonsevere allergy (14/76 [18.4%] vs 68/82 [82.9%]; P<.001). There was no difference in the rates of postpartum endometritis, 30-day readmission, 90-day surgical site infection, or neonatal early-onset sepsis between the pre- and postintervention groups. Of note, 1 patient in the postintervention group experienced itching, and another patient developed a rash, both of which resolved with medical management. CONCLUSION: A comprehensive antibiotic stewardship intervention was associated with a 50% increase in the use of preferred antibiotics for peripartum indications in patients with penicillin allergy. Allergic reactions with first-line beta-lactams were minimal and manageable.

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.

Further Evidence that an Episode of Premature Labor Is a Pathologic State: Involvement of the Insulin-Like Growth Factor System.

INTRODUCTION: Approximately 47% of women with an episode of preterm labor deliver at term; however, their infants are at greater risk of being small for gestational age and for neurodevelopmental disorders. In these cases, a pathologic insult may disrupt the homeostatic responses sustaining pregnancy. We tested the hypothesis of an involvement of components of the insulin-like growth factor (IGF) system. METHODS: This is a cross-sectional study in which maternal plasma concentrations of pregnancy-associated plasma protease (PAPP)-A, PAPP-A2, insulin-like growth factor-binding protein 1 (IGFBP-1), and IGFBP-4 were determined in the following groups of women: (1) no episodes of preterm labor, term delivery (controls, n = 100); (2) episode of preterm labor, term delivery (n = 50); (3) episode of preterm labor, preterm delivery (n = 100); (4) pregnant women at term not in labor (n = 61); and (5) pregnant women at term in labor (n = 61). Pairwise differences in maternal plasma concentrations of PAPP-A, PAPP-A2, IGFBP-1, and IGFBP-4 among study groups were assessed by fitting linear models on log-transformed data and included adjustment for relevant covariates. Significance of the group coefficient in the linear models was assessed via t-scores, with p < 0.05 deemed a significant result. RESULTS: Compared to controls, (1) women with an episode of premature labor, regardless of a preterm or a term delivery, had higher mean plasma concentrations of PAPP-A2 and IGFBP-1 (each p < 0.05); (2) women with an episode of premature labor who delivered at term also had a higher mean concentration of PAPP-A (p < 0.05); and (3) acute histologic chorioamnionitis and spontaneous labor at term were not associated with significant changes in these analytes. CONCLUSION: An episode of preterm labor involves the IGF system, supporting the view that the premature activation of parturition is a pathologic state, even in those women who delivered at term.

Amniotic fluid CD36 in pregnancies complicated by spontaneous preterm delivery: a retrospective cohort study.

OBJECTIVE: The aim of this study was to evaluate CD36 concentrations in amniotic fluid in pregnancies complicated by spontaneous delivery with intact fetal membranes (preterm labor, PTL) and preterm prelabor rupture of membranes (PPROM) with respect to the presence of the intra-amniotic infection. METHODS: A total of 80 women with PPROM and 71 with PTL were included in the study. Amniotic fluid samples were obtained by transabdominal amniocentesis. Amniotic fluid CD36 concentrations were assessed by enzyme-linked immunosorbent assay. Microbial colonization of the amniotic cavity (MIAC) was determined by the cultivation and non-cultivation approach. Intra-amniotic inflammation (IAI) was defined as an amniotic fluid bedside interleukin-6 concentration ≥3000 pg/mL. Intra-amniotic infection was characterized by the presence of both MIAC and IAI. RESULTS: Women with PPROM with intra-amniotic infection had higher amniotic fluid CD36 concentrations than women without infection (with infection: median 346 pg/mL, IQR 262-384 vs. without infection: median 242 pg/mL, IQR 199-304; p = .006) A positive correlation between amniotic fluid CD36 concentrations and interleukin-6 concentrations was found (rho = 0.48; p < .0001). In PTL pregnancies, no statistically significant difference was found in the amniotic fluid level of CD36 between intra-amniotic infection, sterile IAI, and negative amniotic fluid. CONCLUSIONS: The presence of intra-amniotic infection is characterized by higher amniotic fluid CD36 concentrations in pregnancies complicated by PPROM. An amniotic fluid CD36 cutoff value of 252.5 pg/mL was found to be optimal for the prediction of intra-amniotic infection. In PTL pregnancies, no statistically significant change in CD36 concentration was found with respect to the presence of intra-amniotic infection.

Management of Pregnancy with Cervical Shortening: Real-Life Clinical Challenges.

Background and Objectives: Preterm birth is the leading cause of neonatal mortality worldwide and may be responsible for lifelong morbidities in the survivors. Cervical shortening is one of the common pathways to preterm birth associated with its own diagnostic and management challenges. The preventive modalities that have been tested include progesterone supplementation and cervical cerclage and pessaries. The study aimed to assess the management strategies and outcomes in a group of patients with a short cervix during pregnancy or cervical insufficiency. Materials and Methods: Seventy patients from the Riga Maternity Hospital in Riga, Latvia, were included in the prospective longitudinal cohort study between 2017 and 2021. Patients were treated with progesterone, cerclage, and/or pessaries. The signs of intra-amniotic infection/inflammation were assessed, and antibacterial therapy was given when the signs were positive. Results: The rates of PTB were 43.6% (n = 17), 45.5% (n = 5), 61.1% (n = 11), and 50.0% (n = 1) in progesterone only, cerclage, pessary, and cerclage plus pesssary groups, respectively. The progesterone therapy was associated with a reduced preterm birth risk (x2(1) = 6.937, p = 0.008)), whereas positive signs of intra-amniotic infection/inflammation significantly predicted the risk of preterm birth (p = 0.005, OR = 3.82, 95% [CI 1.31-11.11]). Conclusions: A short cervix and bulging membranes, both indicators of intra-amniotic infection/inflammation, are the key risk factors in preterm birth risk predictions. Progesterone supplementation should remain at the forefront of preterm birth prevention. Among patients with a short cervix and especially complex anamnesis, the preterm rates remain high. The successful management of patients with cervical shortening lies between the consensus-based approach for screening, follow-up, and treatment on the one side and personalising medical therapy on the other.

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.