Antenatal creatine supplementation reduces persistent fetal lung inflammation and oxidative stress in an ovine model of chorioamnionitis.

Chorioamnionitis is a common antecedent of preterm birth and induces inflammation and oxidative stress in the fetal lungs. Reducing inflammation and oxidative stress in the fetal lungs may improve respiratory outcomes in preterm infants. Creatine is an organic acid with known anti-inflammatory and antioxidant properties. The objective of the study was to evaluate the efficacy of direct fetal creatine supplementation to reduce inflammation and oxidative stress in fetal lungs arising from an in utero proinflammatory stimulus. Fetal lambs (n = 51) were instrumented at 90 days gestation to receive a continuous infusion of creatine monohydrate (6 mg·kg-1·h-1) or saline for 17 days. Maternal chorioamnionitis was induced with intra-amniotic lipopolysaccharide (LPS; 1 mg, O55:H6) or saline 7 days before delivery at 110 days gestation. Tissue creatine content was assessed with capillary electrophoresis, and inflammatory markers were analyzed with Luminex Magpix and immunohistochemistry. Oxidative stress was measured as the level of protein thiol oxidation. The effects of LPS and creatine were analyzed using a two-way ANOVA. Fetal creatine supplementation increased lung creatine content by 149% (PCr < 0.0001) and had no adverse effects on lung morphology. LPS-exposed groups showed increased levels of interleukin-8 in the bronchoalveolar lavage (PLPS < 0.0001) and increased levels of CD45+ leukocytes (PLPS < 0.0001) and MPO+ (PLPS < 0.0001) cells in the lung parenchyma. Creatine supplementation significantly reduced the levels of CD45+ (PCr = 0.045) and MPO+ cells (PCr = 0.012) in the lungs and reduced thiol oxidation in plasma (PCr < 0.01) and lung tissue (PCr = 0.02). In conclusion, fetal creatine supplementation reduced markers of inflammation and oxidative stress in the fetal lungs arising from chorioamnionitis.NEW & NOTEWORTHY We evaluated the effect of antenatal creatine supplementation to reduce pulmonary inflammation and oxidative stress in the fetal lamb lungs arising from lipopolysaccharide (LPS)-induced chorioamnionitis. Fetal creatine supplementation increased lung creatine content and had no adverse effects on systemic fetal physiology and overall lung architecture. Importantly, fetuses that received creatine had significantly lower levels of inflammation and oxidative stress in the lungs, suggesting an anti-inflammatory and antioxidant benefit of creatine.

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.

Latency Antibiotics in Preterm Prelabor Rupture of Membranes: A Comparison of Azithromycin Regimens.

BACKGROUND: Treatment with antibiotics at the time of preterm prelabor rupture of membranes (PPROM) has been shown to prolong pregnancy. Due to the recurrent shortage of erythromycin, azithromycin has been substituted in the traditional regimen; however, there are little data on optimal dosing. OBJECTIVE: The objective of this study was to determine whether there is a difference in latency from onset of PPROM to delivery in patients who received a single dose of azithromycin compared with a 5-day course. METHODS: This was a single-center, multisite, retrospective, IRB approved analysis of patients admitted with a diagnosis of PPROM. Patients were included if rupture occurred between 22 0/7 and 33 6/7 weeks of gestation and received either a single dose or a 5-day course of azithromycin along with a beta lactam. RESULTS: A total of 376 patients were reviewed with 296 patients included in the final analysis. There was no statistical difference in the primary outcome of latency days in patients who received the 5-day versus the single-dose course (4 vs 5 days, P = 0.641). There was a significantly higher rate of histologic chorioamnionitis in the single-dose course of azithromycin (46.4% vs 62.6%, P = 0.006). CONCLUSIONS AND RELEVANCE: There was no difference in latency for patients who received a 5-day course of azithromycin versus a single dose for the treatment of PPROM. A higher rate of histologic chorioamnionitis was observed in those who received the single-day course. Prospective follow-up studies are needed to confirm these findings.

Group B Streptococcus and Intraamniotic Inflammation and Infection.

Intraamniotic inflammation and infection complicate 2% to 5% of term deliveries. Group B Streptococcus (GBS) is a common cause of intraamniotic infection associated with invasive neonatal disease and maternal morbidity. Universal vaginal-rectal screening for GBS colonization is recommended between 36 and 37 weeks. Intrapartum antibiotic prophylaxis is recommended for individuals with positive GBS screens and other risk factors. Intravenous penicillin is the preferred antimicrobial agent. Individuals with penicillin allergies may receive cefazolin for low-risk allergies and either clindamycin or vancomycin for high-risk allergies, depending on their antimicrobial susceptibilities. Clinical trials are underway to evaluate the safety and immunogenicity of maternal anti-GBS vaccine candidates.

Anti-infectious and anti-inflammatory effect of amniopatch in the treatment of spontaneous previable rupture of membranes.

Spontaneous previable rupture of membranes complicates approximately 0.4-0.7% of pregnancies and is associated with severe maternal and neonatal morbidity and mortality. Intra-amniotic inflammation is present in up to 94.4% of cases, most often caused by a bacterial infection. In comparison, the effectiveness of antibiotic therapy in its eradication reaches less than 17%. Inflammatory activity in the amniotic cavity disrupts the physiological development of the fetus with an increase in maternal, fetal, and neonatal inflammatory morbidity through the development of fetal inflammatory response syndrome, maternal chorioamnionitis, and neonatal sepsis. Amniopatch is an invasive therapeutic technique based on intra-amniotic administration of maternal hemoderivates in the form of thromboconcentrate and plasma cryoprecipitate to provide the temporary closure of the fetal membranes defect and secondary restitution of normohydramnios with correction of pressure-volume ratios. The supposed basis of this physical-mechanical action is the aggregation of coagulant components of amniopatch in the area of the defect with the formation of a valve cap. The background for the formulation of the hypothesis on the potential anti-infectious and anti-inflammatory action of non-coagulant components of amniopatch involved: i) clinical-academic and publishing outputs of the authors based on their many years' experience with amniopatch application in the treatment of spontaneous previable rupture of membranes (2008-2019), ii) the documented absence of clinically manifested chorioamnionitis in patients treated this way with a simultaneously reduced incidence of neonatal respiratory distress syndrome compared to expectant management (tocolysis, corticotherapy, antibiotic therapy). The non-coagulant components of plasma cryoprecipitate include mainly naturally occurring isohemagglutinins, albumin, and soluble plasma fibrinogen. Although these components of the amniopatch have not been attributed a significant therapeutic role, the authors assume that due to their opsonizing and aggregative properties, they can significantly participate in optimizing the intrauterine environment through the reduction in bacterial and cytokine charge in the amniotic fluid. The authors think these facts constitute a vital stimulus to future research-academic activity and, at the same time, an idea for reconsidering the therapeutic role of amniopatch as a tool for improving perinatal results of spontaneous previable ruptures of membranes.

Antibiotic Stewardship in Chorioamnionitis Exposed Neonates, A Quality Improvement Project.

BACKGROUND: Rates of neonatal early onset sepsis (EOS) in term infants have recently decreased. The 2018 AAP guidelines for the management of infants at risk for early onset sepsis allows for using a multivariate risk assessment to determine need for empiric antibiotics in infants 35 weeks or greater, including those exposed to chorioamnionitis. METHODS: A quality improvement (QI) project was undertaken to implement use of EOS calculator in chorioamnionitis exposed infants with an aim to safely decrease antibiotic exposure. Multiple Plan-Do-Study-Act (PDSA) cycles occurred to implement the change. Data regarding antibiotics, labs, length of stay and safety metrics were collected. RESULTS: Implementing the EOS calculator's use in chorioamnionitis exposed neonates decreased antibiotic exposure from 100% to 75%, and decreased average duration of antibiotics from 68 to 40 hours. Implementation decreased prolonged courses of antibiotics, lumbar punctures, length of stay and laboratory tests. No cases of early culture confirmed EOS were missed, and none occurred in this well appearing population. CONCLUSIONS: Quality improvement initiatives to implement evidence-based tools can safely and appropriately decrease antibiotic exposure in neonates.

Genomic analysis of Enterococcus faecium strain RAOG174 associated with acute chorioamnionitis carried antibiotic resistance gene: is it time for precise microbiological identification for appropriate antibiotic use?

BACKGROUND: Preterm labor syndrome is associated with high perinatal morbidity and mortality, and intra-amniotic infection is a cause of preterm labor. The standard identification of causative microorganisms is based on the use of biochemical phenotypes, together with broth dilution-based antibiotic susceptibility from organisms grown in culture. However, such methods could not provide an accurate epidemiological aspect and a genetic basis of antimicrobial resistance leading to an inappropriate antibiotic administration. Hybrid genome assembly is a combination of short- and long-read sequencing, which provides better genomic resolution and completeness for genotypic identification and characterization. Herein, we performed a hybrid whole genome assembly sequencing of a pathogen associated with acute histologic chorioamnionitis in women presenting with PPROM. RESULTS: We identified Enterococcus faecium, namely E. faecium strain RAOG174, with several antibiotic resistance genes, including vancomycin and aminoglycoside. Virulence-associated genes and potential bacteriophage were also identified in this genome. CONCLUSION: We report herein the first study demonstrating the use of hybrid genome assembly and genomic analysis to identify E. faecium ST17 as a pathogen associated with acute histologic chorioamnionitis. The analysis provided several antibiotic resistance-associated genes/mutations and mobile genetic elements. The occurrence of E. faecium ST17 raised the awareness of the colonization of clinically relevant E. faecium and the carrying of antibiotic resistance. This finding has brought the advantages of genomic approach in the identification of the bacterial species and antibiotic resistance gene for E. faecium for appropriate antibiotic use to improve maternal and neonatal care.

Association between intrapartum antibiotic prophylaxis for Group B Streptococcus colonization and clinical chorioamnionitis among patients undergoing induction of labor at term.

BACKGROUND: Rectovaginal colonization with Group B Streptococcus during pregnancy has historically been shown to be associated with an increased risk of clinical chorioamnionitis and peripartum infectious morbidity. OBJECTIVE: Newer observational data in the era of intrapartum antibiotic prophylaxis suggest a possible reversal of this association; however, it is unclear if this is related to differences in labor management for those with and without Group B Streptococcus colonization. We therefore sought to assess the association between intrapartum antibiotic prophylaxis for Group B Streptococcus colonization and clinical chorioamnionitis within the context of a randomized induction of labor trial with a standardized labor protocol. STUDY DESIGN: We performed an exploratory secondary analysis of a randomized trial of patients undergoing term induction at a tertiary care center. Patients received third trimester Group B Streptococcus screening and intrapartum antibiotic prophylaxis as routine care. Group B Streptococcus detection was performed using a carrot broth-enhanced subculture to Group B Streptococcus Detect approach (Hardy Diagnostics, Santa Maria, CA). Labor management was protocolized per the trial. Patients with unknown Group B Streptococcus status or who did not receive intrapartum antibiotic prophylaxis, if indicated, were excluded. The primary outcome was diagnosis of clinical chorioamnionitis, compared between patients who received intrapartum antibiotic prophylaxis for known Group B Streptococcus positive status (by culture, history, or Group B Streptococcus bacteriuria) and those who were Group B Streptococcus negative and did not receive intrapartum antibiotic prophylaxis. Secondary outcomes included postpartum endometritis, wound infection, a composite maternal peripartum infectious morbidity, and neonatal outcomes. RESULTS: A total of 491 patients were enrolled in the trial. Of these, 466 had a known Group B Streptococcus status and received or did not receive intrapartum antibiotic prophylaxis accordingly and were included in this analysis: 292 (62.7%) were Group B Streptococcus negative and did not receive intrapartum antibiotic prophylaxis, and 174 (37.3%) were Group B Streptococcus positive and received intrapartum antibiotic prophylaxis. The majority of patients were Non-Hispanic Black (78.1%) and nulliparous (59.7%). There were no differences in demographic, clinical, induction or labor characteristics between groups. Patients who were Group B Streptococcus positive had a 49% lower rate of clinical chorioamnionitis (8.1% vs 14.7%, odds ratio, 0.51; P=.03) and a lower rate of peripartum infectious morbidity (8.1% vs 15.8%, odds ratio, 0.47; P=.02) compared to those who were Group B Streptococcus negative. Infants born to patients who were Group B Streptococcus positive were significantly less likely to be admitted to the neonatal intensive care unit (3.4% vs 15.1%, P<.001). CONCLUSION: Although Group B Streptococcus colonization has historically been considered a risk factor for clinical chorioamnionitis, in the era of universal antibiotic prophylaxis for Group B Streptococcus positive patients, our findings support the point that intrapartum antibiotic prophylaxis for Group B Streptococcus positivity is associated with lower rates of clinical chorioamnionitis and peripartum infectious morbidity among patients undergoing induction with protocolized labor management. These findings demonstrate that intrapartum antibiotic prophylaxis for Group B Streptococcus may protect against perinatal infectious morbidity, a phenomenon that warrants further investigation.

Antibiotic treatment of women with isolated intrapartum fever vs clinical chorioamnionitis: maternal and neonatal outcomes.

BACKGROUND: Clinical chorioamnionitis refers to the presence of maternal fever (≥38°C) and at least 2 clinical signs: (1) maternal tachycardia (>100 bpm), (2) fetal tachycardia (>160 bpm), (3) maternal leukocytosis >15,000/mm2, (4) purulent vaginal discharge, and (5) uterine tenderness. Few data exist to guide the appropriate management of women with isolated intrapartum fever in the absence of other clinical signs suggesting chorioamnionitis. OBJECTIVE: This study compared maternal and neonatal infectious outcomes and microbiological outcomes between women with isolated intrapartum fever and women with clinical chorioamnionitis. STUDY DESIGN: This 10-year retrospective study included all the laboring women at our institution, at ≥34 weeks of gestation, with a singleton pregnancy and body temperature of ≥38.0°C, with or without other evidences of infection. According to our department protocol, women with isolated intrapartum fever received intravenous ampicillin, whereas women with clinical chorioamnionitis received intravenous ampicillin plus gentamicin. The primary outcome was puerperal endometritis, compared between women with isolated intrapartum fever (treated with ampicillin) and women with clinical chorioamnionitis (treated with ampicillin plus gentamicin). The secondary maternal outcomes consisted of (1) maternal clinical outcomes, such as cesarean delivery, surgical site infection, postpartum hemorrhage, and postpartum length of stay, and (2) microbiological studies, including positive chorioamniotic membrane swabs and blood culture. Among the secondary neonatal outcomes were early-onset sepsis, neonatal intensive care unit admission, and length of stay. Of note, 2 multivariate logistic regression models were created. A model aimed to predict puerperal endometritis controlled for gestational age of >41 weeks, diabetes mellitus, obesity, positive group B streptococcus status, rupture of membrane ≥18 hours, meconium staining, positive chorioamniotic membrane swabs, cesarean delivery, and empiric postdelivery antibiotic administration. A model aimed to predict neonatal early-onset sepsis controlled for gestational age of 34 to 37 weeks, positive group B streptococcus status, rupture of membrane ≥18 hours, and positive chorioamniotic membrane swabs. RESULTS: Overall, 458 women met the inclusion criteria. Compared with women with clinical chorioamnionitis (n=231), women with isolated intrapartum fever (n=227) had higher rates of puerperal endometritis (3.9% vs 8.8%; P=.03), early-onset sepsis (0.4% vs 4.4%; P=.005), positive chorioamniotic membrane swabs (46.3% vs 63.9%; P<.001), and ampicillin-resistant Escherichia coli (35.5% vs 48.9%; P=.033). The rate of group B streptococcus-positive chorioamniotic membrane swabs was similar between the groups. In a subanalysis of women with negative or unknown group B streptococcus status, the puerperal endometritis and neonatal early-onset sepsis rates were higher among women with isolated intrapartum fever than women with suspected chorioamnionitis (8.7% vs 3.3% [P=.041] and 4.1% vs 0% [P<.001], respectively). In 2 multivariate analysis models, among women with isolated intrapartum fever treated with ampicillin compared with those with clinical chorioamnionitis treated with ampicillin and gentamicin, the odds ratio of antibiotic treatment of endometritis was 2.65 (95% confidence interval, 1.06-6.62; P=.036), and the odds ratio of neonatal early-onset sepsis was 8.33 (95% confidence interval, 1.04-60.60; P=.045). CONCLUSION: Women with intrapartum fever, with or without other signs of infection, were at increased risk of maternal and neonatal complications. The use of ampicillin as a sole agent in isolated intrapartum fever might promote ampicillin-resistant E coli growth in the chorioamniotic membranes and consequently lead to puerperal endometritis and early-onset sepsis. In this context, a broad-range antibiotic should be considered.

Postnatal corticosteroid response in neonates < 32 weeks and relation with placental pathology.

Acute chorioamnionitis and maternal vascular malperfusion are associated with an increased risk of bronchopulmonary dysplasia. To prevent bronchopulmonary dysplasia, postnatal corticosteroids are given to preterm neonates. Clinical observations indicate not all neonates respond to corticosteroids, the so-called non-responders. This study aimed to investigate the association between placental pathology and short-term response to postnatal corticosteroids in neonates < 32 weeks postconceptional age at risk for bronchopulmonary dysplasia. All neonates < 32 weeks born between 2009 and 2016, receiving corticosteroids in the course of BPD, were included. The preterm neonates were divided into three groups depending on placental histology: acute chorioamnionitis, maternal vascular malperfusion, or no placental pathology. Respiratory support was assessed prior to treatment and at days 4 and 7. A responder was defined as extubation within 7 days after starting corticosteroid treatment. In total, 52% of the chorioamnionitis neonates, 67% of the maternal vascular malperfusion neonates, and 58% of neonates in the no pathology group were responders. The odds ratio for extubation was 0.53 (0.18-1.55) at day 4 and 0.66 (0.23-1.97) at day 7, in the chorioamnionitis group compared to the maternal vascular malperfusion. CONCLUSION: Short-term response to postnatal corticosteroids did not significantly differ between premature neonates born after acute chorioamnionitis, maternal vascular malperfusion, or no placenta pathology. However, a trend of better corticosteroid response in maternal vascular malperfusion neonates was found, potentially due to differences in prenatal pulmonary development and postnatal cortisol. WHAT IS KNOWN: • Bronchopulmonary dysplasia is related to chorioamnionitis and maternal vascular malperfusion. • Corticosteroids remain an important treatment in the course of bronchopulmonary dysplasia despite conflicting results and non-responsiveness in some preterm neonates. WHAT IS NEW: • Non-responsiveness might be related to differences in pulmonary inflammation and systemic cortisol due to predispositions triggered by chorioamnionitis or maternal vascular malperfusion. • Neonates born after maternal vascular malperfusion seem to respond better to postnatal corticosteroid treatment.

Azithromycin treatment for short cervix with or without amniotic fluid sludge: A matched cohort study.

BACKGROUND: Preterm birth (PTB) is one of the leading causes of neonatal mortality and morbidity worldwide. A shortened cervix is a recognised risk factor for PTB, and amniotic fluid sludge (AFS) diagnosed on ultrasound may be suggestive of underlying inflammation or infection. AIMS: The aim is to determine if azithromycin, administered in cases of a shortened cervix, results in prolongation of gestation with improvements in neonatal outcomes. MATERIALS AND METHODS: We performed a retrospective cohort study at three tertiary maternity services in Melbourne, Australia, between 2015 and 2020. Women with a singleton pregnancy were included if they had a cervical length of 15 mm or less at 13-24 weeks' gestation, with or without AFS. Exclusion criteria comprised multiple pregnancy, major fetal congenital anomaly, placenta praevia, prelabour premature rupture of membranes, vaginal bleeding and/or clinical signs suggestive of chorioamnionitis at the time of diagnosis of the short cervix. The results of antibiotic treatment with azithromycin were compared to those of no antibiotic treatment. The outcomes of interest were PTB, prelabour premature rupture of membranes (PPROM), chorioamnionitis and neonatal morbidity. RESULTS: A total of 374 women were included in the study, of whom 129 received azithromycin and 245 received no antibiotics. When adjusting for potential confounders, the adjusted risk of PTB overall was higher in the treatment group (adjusted hazard ratio 1.36 (95% confidence interval 1.04-1.77) P = 0.023) with no differences found for PPROM, chorioamnionitis or neonatal morbidity. CONCLUSION: These data do not support the routine use of azithromycin in women with a short cervix, including those with AFS detected on ultrasound.

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.

Erythromycin vs azithromycin for treatment of preterm prelabor rupture of membranes: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to estimate the effect of erythromycin vs azithromycin on the duration of latency and the rate of clinical chorioamnionitis in women with preterm prelabor rupture of membranes by performing a systematic review and meta-analysis of the existing literature. DATA SOURCES: From inception to October 2021, we explored MEDLINE, Scopus, Embase, CINAHL, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials. STUDY ELIGIBILITY CRITERIA: Studies comparing the duration of latency and the rate of clinical chorioamnionitis between women with preterm prelabor rupture of membranes who were treated with erythromycin and those who were treated with azithromycin at the time of diagnosis were included. METHODS: Here, 2 reviewers separately ascertained studies, obtained data, and gauged study quality. The mean length of latency and the rate of clinical chorioamnionitis were compared and mean differences and odds ratios with 95% confidence intervals were estimated. RESULTS: A total of 5 studies with 1289 women were identified. The mean length of latency in women with preterm prelabor rupture of membranes was similar between individuals treated with erythromycin and those treated with azithromycin: 6.6 days vs 6.7 days (mean difference, 0.07 days; 95% confidence interval, -0.45 to 0.60; I2, 0%). The median point prevalence rates of clinical chorioamnionitis were 25% (95% confidence interval, 12-32) in women treated with erythromycin and 14% (95% confidence interval, 9-24) in women treated with azithromycin. The overall clinical chorioamnionitis rate in women treated with azithromycin was lower than women treated with erythromycin (pooled odds ratio, 0.53; 95% confidence interval, 0.39-0.71; I2, 0%). CONCLUSION: The administration of azithromycin in women with preterm prelabor rupture of membranes was associated with a similar latency period but a lower rate of clinical chorioamnionitis than the administration of erythromycin.

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.

Individualized treatment of preterm premature rupture of membranes to prolong the latency period, reduce the rate of preterm birth, and improve neonatal outcomes.

BACKGROUND: Preterm premature rupture of membranes complicates approximately 3% of pregnancies. Currently, in the absence of chorioamnionitis or placental abruption, expectant management, including antenatal steroids for lung maturation and prophylactic antibiotic treatment, is recommended. The benefits of individualized management have not been adequately explored. OBJECTIVE: This study aimed to compare the impact of 2 different management strategies of preterm premature rupture of membranes in 2 tertiary obstetrical centers on latency of >7 days, latency to birth, chorioamnionitis, funisitis, and short-term adverse maternal and neonatal outcomes. STUDY DESIGN: This was a multicenter retrospective study of women with singleton pregnancies with preterm premature rupture of membranes from 23 0/7 to 33 6/7 weeks of gestation between 2014 and 2018 and undelivered within 24 hours after hospital admission managed at Sunnybrook Health Sciences Center, Toronto, Canada (standard management group), and BCNatal (Hospital Clínic of Barcelona and Hospital Sant Joan de Déu Barcelona), Barcelona, Spain (individualized management group), following local protocols. The standard management group received similar management for all patients, which included a standard antibiotic regimen and routine maternal and fetal surveillance, whereas the individualized management group received personalized management on the basis of amniocentesis at hospital admission (if possible), to rule out microbial invasion of the amniotic cavity and targeted treatment. The exclusion criteria were cervical dilatation >2 cm, active labor, contraindications to expectant management (acute chorioamnionitis, placental abruption, or abnormal fetal tracing), and major fetal anomalies. The primary outcome was latency of >7 days, and the secondary outcomes included latency to birth, chorioamnionitis, and short-term adverse maternal and neonatal outcomes. Statistical comparisons between groups were conducted with propensity score weighting. RESULTS: A total of 513 pregnancies with preterm premature rupture of membranes were included in this study: 324 patients received standard management, and 189 patients received individualized management, wherein amniocentesis was performed in 112 cases (59.3%). After propensity score weighting, patients receiving individualized management had a higher latency of >7 days (76.0% vs 41.6%; P<.001) and latency to birth (18.1±14.7 vs 9.7±9.7 days; P<.001). Although a higher rate of clinical chorioamnionitis was suspected in the individualized management group than the standard group (34.5% vs 22.0%; P<.01), there was no difference between the groups in terms of histologic chorioamnionitis (67.2% vs 73.4%; P=.16), funisitis (57.6% vs 58.1%; P=.92), or composite infectious maternal outcomes (9.1% vs 7.9%; P=.64). Prolonged latency in the individualized management group was associated with a significant reduction of preterm birth at <32 weeks of gestation (72.1% vs 90.5%; P<.001), neonatal intensive care unit admission (75.6% vs 83.0%; P=.046), and neonatal respiratory support at 28 days of life (16.1% vs 26.1%; P<.01) compared with that in the standard management group. Moreover, prolonged latency was not associated with neonatal severe morbidity at discharge (survival without severe morbidity, 80.4% vs 73.5%; P=.09). CONCLUSION: Individualized management of preterm premature rupture of membranes may prolong pregnancy and reduce preterm birth at <32 weeks of gestation, the need for neonatal support, and neonatal intensive care unit admissions, without an increase in histologic chorioamnionitis, funisitis, neonatal infection-related morbidity, and short-term adverse maternal and neonatal outcomes.

Reducing antibiotic use in asymptomatic term infants exposed to maternal chorioamnionitis: Predictive role of sepsis risk calculator.

AIM: The sepsis risk calculator (SRC) has been shown to reduce empirical antibiotic usage in neonates at risk of early-onset sepsis without increasing adverse clinical outcomes. However, its use for categorising and improving identification of at-risk neonates exposed to chorioamnionitis in the local population has not been reported. This study compares the management guided by the SRC to our unit's clinical practice of administering empirical antibiotics to all term neonates (born ≥37 weeks gestation), symptomatic and asymptomatic, who were exposed to chorioamnionitis, and evaluates the performance of the SRC in managing asymptomatic term neonates exposed to chorioamnionitis. METHODS: This single-centre retrospective study identified 178 eligible term neonates exposed to chorioamnionitis over a 17-month study period. Relevant demographic and clinical information on the mother-infant dyad was collected. The SRC was executed retrospectively in the study cohort. Descriptive statistics were used for reporting the findings. RESULTS: The mean gestational age was 39 (standard deviation, SD 1) weeks, and the mean birth weight was 3472 (SD 482) g. Of the 178 neonates, 136 (76%) were asymptomatic and received empirical antibiotic therapy for 2 days (mean). Based on management recommendations from the SRC, empirical antibiotic therapy could have been avoided in 98% of asymptomatic neonates; 88% could have been managed by observation alone, avoiding mother-infant separation. No neonate died or had a positive blood culture result. CONCLUSIONS: The SRC could reduce antibiotic exposure in asymptomatic neonates exposed to chorioamnionitis. It could assist clinicians to categorise risk in neonates exposed to chorioamnionitis.

A Survey on Variation in Diagnosis and Treatment of Chorioamnionitis in Tertiary Centres in Canada.

OBJECTIVE: Clinical detection and management of chorioamnionitis is challenging given the gold-standard for diagnosis remains placental pathology, the results of which are only available after delivery. Moreover, recommended diagnostic criteria for clinical chorioamnionitis have evolved over time. The goal of this study was to describe trends and differences in chorioamnionitis diagnostic and management practices in Canada. METHODS: We surveyed obstetric care providers participating in the Canadian Preterm Birth Network. Questionnaires were distributed electronically to all 29 sites and completed by 1 maternal-fetal medicine investigator at each site. RESULTS: The response rate was 82.8% (n = 24). There was considerable variation in the clinical criteria used to diagnose chorioamnionitis with 9 of 22 sites stating this occurs "frequently" or "very frequently." Isolated fever was "always" or "most of the time" used as an indication to start empiric antibiotic therapy in 14 of 24 sites, and 21 of 23 sites used the same diagnostic criteria for term and preterm deliveries. Placental histology (15 sites) and white blood cell count (14 sites) were the most common clinical tests performed to confirm chorioamnionitis. A combination of ampicillin and aminoglycoside antibiotics was used at 12 sites. Another frequently used antibiotic therapy was cefazolin and metronidazole (4 sites). CONCLUSION: There is a wide variation in practices for the diagnosis and management of chorioamnionitis across Canada. The results of this study will guide efforts to improve and standardize the management of this condition.

Management of Isolated Fever in Labour Compared with Clinical Chorioamnionitis in a Quaternary Centre.

OBJECTIVES: To investigate treatment patterns of women with isolated fever in labour and evaluate if variables in the sepsis in obstetrics score (SOS) or fetal tachycardia are associated with treatment differences. Our secondary objective was to compare women with isolated fever in labour with women with clinical chorioamnionitis to identify any clinicodemographic differences. METHODS: A retrospective cohort study of 473 patients at BC Women's Hospital who presented with isolated fever in labour between January 2011 and April 2016 compared with a dataset of 1135 women with clinical chorioamnionitis from 2011 to 2016 in the same institution. RESULTS: In our cohort of isolated fever in labour, antibiotics were given 74.2 % of the time, and the majority received cefazolin and metronidazole (80.9%, of those who received antibiotics). Higher maternal temperature and heart rate at time of first fever and fetal tachycardia were associated with more antibiotic use. Slightly higher maternal temperature was associated with use of a saline bolus and blood cultures. The proportion of women with a SOS greater than 5 increased 4.5-fold from time of first fever to time of maximum SOS. There were fewer cesarean deliveries in the isolated fever in labour group compared with the clinical chorioamnionitis group (22.4% vs. 54.0%; P < 0.0001). CONCLUSIONS: Slightly higher maternal temperature was associated with increased treatment, including antibiotic use, saline bolus administration, and blood cultures. As evidenced by the higher proportion of women with an SOS over 5, women with isolated fever in labour may have a propensity to deteriorate clinically.

Management of neonates with 35 weeks of gestational age or more with infectious risk factors at birth: opportunities for improvement.

OBJECTIVES: The Northern California Kaiser-Permanente Neonatal Sepsis Risk Calculator (SRC) has proved to be safe and effective in reducing laboratory tests, hospital admissions, and administration of antibiotics to patients at risk of early-onset neonatal sepsis (EONS). Many studies have focused on maternal chorioamnionitis as the principal risk factor for EONS. We wanted to know if the use of the SRC could be equally efficient in the context of several other infectious risk factors (IRF), in addition to chorioamnionitis, such as intrapartum maternal fever, GBS colonization and/or prolonged rupture of membranes (PROM). METHODS: Systematic study of neonates with ≥35 weeks gestational age (GA), born in our tertiary university hospital during a period of 18 months. Patients were retrospectively assessed with the SRC and its recommendations were compared with the actual management. A bivariate analysis of perinatal interventions, and outcomes was performed. RESULTS: A total of 5,885 newborns were born during the study period and 1783 mothers (31%) had at least one IRF. The incidence of culture-proven EONS was 0.5‰. The use of the SRC would have reduced laboratory evaluations (CBC and CRP) from 56.2 to 23.3%, and blood cultures, hospital admissions and antibiotic therapy from 22.9 to 15.5%, 17.8 and 7.6%, respectively. The management based on patients' symptoms would have shown a reduction to 7.5% in all the outcomes of interest. CONCLUSIONS: Both, the SRC and the management based on clinical findings, are safe and efficient to reduce the number of analytical studies, hospital admissions and administration of antibiotics to neonates with IRF.

Maternal Origins of Neonatal Infections: What Do Obstetrician-Gynecologist Should/Could Do?

Neonatal infections are responsible for 20% of neonatal deaths yearly. In this review, we focused on the origins of the commoner neonatal infections, and we define the role of obstetricians. Regarding group B Streptococcus, a key measure for the prevention of neonatal infection is the vaginal-rectal culture screening at term pregnancy. Intravenous penicillin is the first-line prophylaxis at the start of labor, with intravenous ampicillin as an alternative. First-generation cephalosporins or clindamycin are recommended in case of penicillin allergy. Concerning urinary tract infections (UTIs), guidelines recommend complete urinalysis and urine culture in the first trimester of pregnancy for the screening of asymptomatic bacteriuria. For lower UTIs, guidelines recommend nitrofurantoin as first-choice antibiotic. Amoxicillin or cefalexin are second-line antibiotics. For upper UTIs, guidelines recommend cephalexin per os as first line. Candida spp. colonization affects 20% of pregnant women; however, congenital fetal candidosis and Candida amnionitis are rare. First-line treatment in case of symptomatic vaginitis during pregnancy or asymptomatic colonization during the third trimester is vaginal clotrimazole. Fluconazole is not approved in pregnancy, especially during the first trimester. Genital mycoplasmas colonization during pregnancy is usually asymptomatic and associated with bacterial vaginosis. Colonization is related to neonatal respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), pneumonia, chorioamnionitis, and sepsis. Macrolides are the first-line treatment along with lactobacillus supplementation. In cases of preterm premature rupture of membranes or preterm labor, ceftriaxone, clarithromycin, and metronidazole are required to prevent intra-amniotic infection. Intra-amniotic infection affects 1 to 5% of deliveries at term and one-third of preterm ones and is associated with perinatal death, early-onset neonatal sepsis, RDS, BPD, pneumonia, meningitis, and prematurity-related diseases. Guidelines recommend a combination of ampicillin and gentamicin, and in case of caesarean section, an additional dose of clindamycin or metronidazole is required. In conclusion, obstetricians should be aware that the treatment of maternal infection during pregnancy can prevent potentially lethal infections in the newborn. KEY POINTS: · Part of neonatal infections starts from maternal infections that must be treated during pregnancy.. · Streptococcus group B and asymptomatic bacteriuria should be investigated in pregnancy and treated.. · Mycoplasma and ureaplasma vaginal colonization during pregnancy is related to negative neonatal outcomes..