Can the use of azithromycin during labour reduce the incidence of infection among puerperae and newborns? A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: This systematic review and meta-analysis investigated whether the use of azithromycin during labour or caesarean section reduces the incidence of sepsis and infection among mothers and newborns. DATA SOURCES: We independently searched the PubMed, Web of Science, Cochrane Library and EMBASE databases for relevant studies published before February, 2024. METHODS: We included RCTs that evaluated the effect of prenatal oral or intravenous azithromycin or placebo on intrapartum or postpartum infection incidence. We included studies evaluating women who had vaginal births as well as caesarean sections. Studies reporting maternal and neonatal infections were included in the current analysis. Review Manager 5.4 was used to analyse 6 randomized clinical trials involving 44,448 mothers and 44,820 newborns. The risk of bias of each included study was assessed using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions.Primary outcomes included the incidence of maternal sepsis and all-cause mortality and neonatal sepsis and all-cause mortality; secondary outcomes included maternal (endometritis, wound and surgical site infections, chorioamnionitis, and urinary tract infections) and neonatal outcomes (infections of the eyes, ears and skin). A random-effects model was used to test for overall effects and heterogeneity. RESULTS: The pooled odds ratios (ORs) were as follows: 0.65 for maternal sepsis (95% CI, 0.55-0.77; I2, 0%; P < .00001); 0.62 for endometritis (95% CI, 0.52-0.74; I2, 2%; P < .00001); and 0.43 for maternal wound or surgical site infection (95% CI, 0.24-0.78; P < .005); however, there was great heterogeneity among the studies (I2, 75%). The pooled OR for pyelonephritis and urinary tract infections was 0.3 (95% CI, 0.17-0.52; I2, 0%; P < .0001), and that for neonatal skin infections was 0.48 (95% CI, 0.35-0.65; I2, 0%, P < .00001). There was no significant difference in maternal all-cause mortality or incidence of chorioamnionitis between the two groups. No significant differences were observed in the incidence of neonatal sepsis or suspected sepsis, all-cause mortality, or infections of the eyes or ears. CONCLUSION: In this meta-analysis, azithromycin use during labour reduced the incidence of maternal sepsis, endometritis, incisional infections and urinary tract infections but did not reduce the incidence of neonatal-associated infections, except for neonatal skin infections. These findings indicate that azithromycin may be potentially beneficial for maternal postpartum infections, but its effect on neonatal prognosis remains unclear. Azithromycin should be used antenatally only if the clinical indication is clear and the potential benefits outweigh the harms.

Intrapartum azithromycin to prevent maternal and neonatal sepsis and deaths: A systematic review with meta-analysis.

OBJECTIVES: A systematic review with met-analysis was performed to summarise the evidence on the effect of intrapartum azithromycin on maternal and neonatal infections and deaths. SEARCH STRATEGY: PubMed, Scopus and Web of Science databases were searched in March 2023. SELECTION CRITERIA: Randomised controlled trials comparing intrapartum single-dose of azithromycin with placebo. DATA COLLECTION AND ANALYSIS: Maternal infections, maternal mortality, neonatal sepsis, neonatal mortality. We used the random-effects Mantel-Haenszel method to calculate risk ratios (RR) with 95% confidence intervals (95% CI). We assessed risk of bias of the included studies and estimated the evidence certainty using the GRADE approach. MAIN RESULTS: After screening 410 abstracts, five studies with 44 190 women and 44 565 neonates were included. The risk of bias was low in four and had some concerns in one of the studies. The risk of endometritis was 1.5% in the azithromycin group and 2.3% in the placebo group (RR 0.64, 95% CI 0.55-0.75), and the evidence certainty was high. The respective risk for chorioamnionitis was 0.05% and 0.1% (RR 0.50, 95% CI 0.22-1.18; evidence certainty moderate). The wound infection rate was lower in the azithromycin group (1.6%) than in the placebo group (2.5%), RR 0.52 (95% CI 0.30-0.89; moderate certainty evidence). The maternal sepsis rate was 1.1% in the azithromycin group and 1.7% in the placebo group (RR 0.66, 95% CI 0.56-0.77; evidence certainty high). Mortality rates did not show evidence of a difference (0.09% versus 0.08%; RR 1.26, 95% CI 0.65-2.42; moderate certainty evidence). The neonatal mortality rate was 0.7% in the azithromycin group and 0.8% in the placebo group (RR 0.94, 95% CI 0.76-1.16; moderate certainty evidence). The neonatal sepsis rate was 7.6% in the azithromycin group and 7.4% in the placebo group (RR 1.02, 95% CI 0.96-1.09; moderate certainty evidence). CONCLUSIONS: Intrapartum administration of azithromycin to the mother reduces maternal postpartum infections, including sepsis. Impact on maternal mortality remains undecided. Azithromycin does not reduce neonatal sepsis or mortality rates.

Efficacy of prophylactic antibiotics for preterm premature rupture of membranes: a systematic review and network meta-analysis.

OBJECTIVE: Various prophylactic antibiotic regimens are used in the management of preterm premature rupture of membranes. We investigated the efficacy and safety of these regimens in terms of maternal and neonatal outcomes. DATA SOURCES: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to July 20, 2021. STUDY ELIGIBILITY CRITERIA: We included randomized controlled trials involving pregnant women with preterm premature rupture of membranes before 37 weeks of gestation and a comparison of ≥2 of the following 10 antibiotic regimens: control/placebo, erythromycin, clindamycin, clindamycin plus gentamicin, penicillins, cephalosporins, co-amoxiclav, co-amoxiclav plus erythromycin, aminopenicillins plus macrolides, and cephalosporins plus macrolides. METHODS: Two investigators independently extracted published data and assessed the risk of bias with a standard procedure following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Network meta-analysis was conducted using the random-effects model. RESULTS: A total of 23 studies that recruited a total of 7671 pregnant women were included. Only penicillins (odds ratio, 0.46; 95% confidence interval, 0.27-0.77) had significantly superior effectiveness for maternal chorioamnionitis. Clindamycin plus gentamicin reduced the risk of clinical chorioamnionitis, with borderline significance (odds ratio, 0.16; 95% confidence interval, 0.03-1.00). By contrast, clindamycin alone increased the risk of maternal infection. For cesarean delivery, no significant differences were noted among these regimens. CONCLUSION: Penicillins remain the recommended antibiotic regimen for reducing maternal clinical chorioamnionitis. The alternative regimen includes clindamycin plus gentamicin. Clindamycin should not be used alone.

Role of lactoferrin in preventing preterm birth and pregnancy complications: a systematic review and meta-analysis.

INTRODUCTION: The aim of this systematic review was to report the role of lactoferrin supplementation for the prevention of preterm birth (PTB) in women at risk. EVIDENCE ACQUISITION: PubMed and Embase databases were searched. Inclusion criteria were studies exploring maternal and perinatal outcomes in women at high-risk for preterm birth receiving compared to those not receiving lactoferrin during pregnancy. The primary outcome was preterm PTB<37 weeks; the secondary outcomes were gestational age at birth, PTB<34 and 28 weeks, preterm premature rupture of the membranes (PPROM), chorioamnionitis and admission to Neonatal Intensive Care Unit. Random effect meta-analyses were used to analyze the data. EVIDENCE SYNTHESIS: Six studies (333 pregnancies) were included. Overall, women taking lactoferrin had a lower risk of PTB<37 weeks of gestation with an OR of 0.43 (95% CI: 0.2-0.9). Likewise, gestational age at delivery was higher in women-taking compared to those not-taking lactoferrin (MD=0.46 weeks, SD=0.17, P=0.006). The other included studies explored the role of lactoferrin in affecting the inflammatory profile in the amniotic fluid of women undergoing invasive test, without reporting its actual role in preventing PTB. CONCLUSIONS: Prophylactic administration of lactoferrin can reduce the risk of PTB in women at risk. Further large and adequately powered randomized trial are needed in order to elucidate the actual role of lactoferrin in reducing the risk of preterm birth and in affecting perinatal outcomes in women at risk.

Partial protective effects of melatonin on developing brain in a rat model of chorioamnionitis.

Melatonin has shown promising neuroprotective effects due to its anti-oxidant, anti-inflammatory and anti-apoptotic properties, making it a candidate drug for translation to humans in conditions that compromise the developing brain. Our study aimed to explore the impact of prenatal melatonin in an inflammatory/infectious context on GABAergic neurons and on oligodendrocytes (OLs), key cells involved in the encephalopathy of prematurity. An inflammatory/infectious agent (LPS, 300 µg/kg) was injected intraperitoneally (i.p.) to pregnant Wistar rats at gestational day 19 and 20. Melatonin (5 mg/kg) was injected i.p. following the same schedule. Immunostainings focusing on GABAergic neurons, OL lineage and myelination were performed on pup brain sections. Melatonin succeeded in preventing the LPS-induced decrease of GABAergic neurons within the retrospenial cortex, and sustainably promoted GABAergic neurons within the dentate gyrus in the inflammatory/infectious context. However, melatonin did not effectively prevent the LPS-induced alterations on OLs and myelination. Therefore, we demonstrated that melatonin partially prevented the deleterious effects of LPS according to the cell type. The timing of exposure related to the cell maturation stage is likely to be critical to achieve an efficient action of melatonin. Furthermore, it can be speculated that melatonin exerts a modest protective effect on extremely preterm infant brains.

Single Dose of Oral Azithromycin With or Without Amoxicillin to Prevent Peripartum Infection in Laboring, High-Risk Women in Cameroon: A Randomized Controlled Trial.

OBJECTIVE: To compare the effectiveness of single-dose azithromycin, with or without amoxicillin, with placebo to prevent peripartum infection in laboring women. METHODS: We conducted a multicenter, three-group, double-blind randomized controlled trial of women with viable term nonanomalous pregnancies with either prolonged labor of 18 hours or longer or rupture of membranes for 8 hours or longer in Cameroon. Women with chorioamnionitis before randomization, study drug contraindications, or planned cesarean births were excluded. Women were randomized to oral azithromycin 1 g-placebo (group 1), oral azithromycin 1 g-oral amoxicillin 2 g (group 2), or placebo-placebo (group 3). All groups received usual care, including antibiotics given at the health care professional's discretion. The primary outcome was a composite of maternal peripartum infection or death from any cause up to 6 weeks postpartum. Two primary comparisons (group 1 vs group 3 and group 2 vs group 3) were planned. We estimated that 241 women per group (planning for 750 total) would provide 80% power at two-sided α=0.05 (0.025 per comparison) to detect a 50% effect size assuming 20% baseline composite infection rate. RESULTS: From January 6, 2018, to May 15, 2020, 6,531 women were screened, and 756 (253 in group 1, 253 in group 2, and 250 in group 3) were randomized. Baseline characteristics (including body mass index, duration of rupture of membranes or labor, and parity) were balanced across groups, except for maternal age. More than 60% of women in each group received usual-care antibiotics: more than 90% penicillin and approximately 50% for prolonged rupture of membranes across all study groups. Composite outcome incidences were similar in antibiotic groups 1 (6%) and 2 (7%) compared with placebo group 3 (10%) (RR 0.6, 95% CI 0.3-1.2; 0.7, 95% CI 0.4-1.3, respectively). Chorioamnionitis and wound infection were significantly lower in group 2 (3.2% vs 0.4% and 4% vs 0.8% respectively, both P=.02) compared with group 3. There were no differences in other maternal or neonatal outcomes including neonatal infection. CONCLUSION: A single dose of oral azithromycin with or without amoxicillin for prolonged labor or rupture of membranes at term did not reduce maternal peripartum or neonatal infection. Observed lower than expected infection rates and frequent usual-care antibiotic use may have contributed to these findings. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03248297. FUNDING SOURCE: Merck for Mothers Investigator Studies Program grant.

Beneficios de los antibióticos en la rotura prematura de membranas de pretérmino y factores que intervienen en la eficacia del tratamiento: revisión narrativa / Benefits of antibiotics in preterm premature rupture of membranes and factors involved in the efficacy of the treatment: narrative review

Resumen El parto prematuro es la principal causa de morbilidad y de mortalidad perinatal, y hasta un tercio de los casos presentan rotura prematura de membranas. La infección intrauterina que asciende desde la vagina es su principal causa en un hospital público de Chile. Esta revisión narrativa mediante búsqueda en PubMed, Cochrane, Embase, Scielo, Science Direct y Wiley Online Library incluye estudios publicados sobre los diferentes factores infecciosos que intervienen en el resultado adverso perinatal y la eficacia de los antibióticos en la rotura prematura de membranas de pretérmino. Además, contiene recomendaciones de sociedades científicas sobre el uso de antibióticos en estos casos. Los ensayos concluyen que los antimicrobianos prolongan el embarazo, disminuyen la corioamnionitis clínica y reducen variadas morbilidades neonatales, pero no reducen la mortalidad perinatal ni las secuelas tardías en la infancia. Los resultados adversos obstétricos, especialmente los neonatales, y las secuelas dependen de la existencia de invasión microbiana de la cavidad amniótica o de infección cérvico-vaginal, de la virulencia de los microorganismos aislados, del compromiso inflamatorio/infeccioso de la placenta (corioamnionitis histológica, funisitis) y de la respuesta inflamatoria fetal. Para mejorar los resultados adversos obstétricos neonatales en la rotura prematura de membranas de pretérmino, los esquemas de antibióticos deben ser eficaces, cubriendo el amplio espectro microbiológico existente y actuando sobre los factores infecciosos implicados en la gravedad de la infección. Además, deben administrarse de manera intensiva y prolongada hasta el parto.

Abstract Preterm birth is the leading cause of perinatal morbidity and mortality, and up to a third of them have premature rupture of membranes. Intrauterine infection that rises from the vagina is its main cause in a public hospital in Chile. This narrative review by searching PubMed, Cochrane, Embase, Scielo, Science Direct and Wiley Online Library includes published studies of the different infectious factors involved in perinatal adverse outcome and of the efficacy of antibiotics in preterm premature rupture of membranes. It also contains recommendations from scientific societies on the use of antibiotics in these cases. These trials conclude that antimicrobials prolong pregnancy, decrease clinical chorioamnionitis, and reduce various neonatal morbidities, but do not reduce perinatal mortality or infant sequelae. Obstetric and especially neonatal adverse outcomes in these patients depend on the existence of microbial invasion of the amniotic cavity and/or cervicovaginal infection, of the virulence of the isolated microorganisms, of inflammatory/infectious involvement of the placenta (histological chorioamnionitis, funisitis) and fetal inflammatory response. To improve adverse neonatal obstetric outcomes in preterm premature rupture of membranes, antibiotic regimens must be effective, covering the wide existing microbiological spectrum and acting on infectious factors responsible for the severity of the infection. In addition, they must be administered aggressively and for a long time until delivery.

Chorioamnionitis after premature rupture of membranes in nulliparas undergoing labor induction: prostaglandin E2 vs. oxytocin.

OBJECTIVES: To assess the risk of chorioamnionitis in nulliparous, term, singleton, vertex (NTSV) pregnancies with premature rupture of membranes (PROM) and an unfavorable cervix undergoing labor induction with either prostaglandin E2 (PGE2) or oxytocin only. METHODS: Retrospective cohort of NTSV pregnancies presenting with PROM who underwent labor induction with either PGE2 (n=94) or oxytocin (n=181) between October 2015 and March 2019. The primary outcome of chorioamnionitis was compared between the two groups. Statistical analysis included Chi-squared and Wilcoxon rank-sum tests, as well as logistic regression. For time to delivery, a Cox proportional hazard regression was used to determine the hazard ratio (HR) and adjusted HR (aHR). RESULTS: Baseline characteristics were similar between the two groups. Cervical ripening with PGE2 was associated with an increased rate of chorioamnionitis (18.1 vs. 6.1%; aOR 4.14, p=0.001), increased neonatal intensive care unit admissions (20.2 vs. 9.9%; aOR 2.4, p=0.02), longer time interval from PROM to delivery (24.4 vs. 17.9 h; aHR 0.56, p=<0.0001), and lower incidence of meconium (7.4 vs. 14.4%; aOR 0.26, p=0.01), compared to the oxytocin group. CONCLUSIONS: Based on our data, the use of oxytocin appears both superior and safer compared to PGE2 in NTSV pregnancies with PROM undergoing labor induction.

Immunohistochemical analysis of protective effects of maternal fingolimod on the placenta and fetal lung and brain in chorioamnionitis-induced preterm birth rat model.

OBJECTIVES: Fingolimod (FIN) is used for multiple sclerosis treatment and has potential antiapoptotic and anti-inflammatory effects. We aimed at expanding our knowledge on various immunohistochemical markers for elucidating the possible mechanisms of action of fingolimod in the placenta and fetal lung and brain. METHODS: Sixteen pregnant rats were divided into four groups. On gestational day 17, lipopolysaccharide (LPS) was injected intraperitoneally to induce preterm fetal injury followed by intraperitoneal injection of fingolimod. Hysterotomy for preterm delivery was performed 6 h after fingolimod was injected. The study groups included (1) control, (2) LPS (1 mg/kg), (3) FIN (4 mg/kg), and (4) FIN + LPS. Fetal brain and lung and placenta samples were collected for histopathological examination. Moreover, fetal lungs (surfactant protein-A (SP-A), SP-B, SP-D, caspase-3, and caspase-8), fetal brains (interleukin-10, interleukin-1ß, TNF-α, caspase-8, glial fibrillary acidic protein, vimentin, myelin basic protein, and receptor activator of nuclear factor kappa), and placenta tissues (interleukin-10, interleukin-1ß, TNF-α, caspase-3, and caspase-8) were immunohistochemically evaluated. RESULTS: Maternal fingolimod treatment led to attenuation of LPS-induced fetal brain, lung, and placental injury, as indicated by lower immunoexpression of inflammatory markers compared to LPS group (p < .0001 for all comparisons). CONCLUSION: The findings of the present study confirm the neuroprotective effects of antenatally administered fingolimod, which also significantly improved preterm fetal lung injury and placental inflammation in LPS-exposed preterm pregnancies by possible antiapoptotic and anti-inflammatory effects.

Azithromycin in the Treatment of Preterm Prelabor Rupture of Membranes Demonstrates a Lower Risk of Chorioamnionitis and Postpartum Endometritis with an Equivalent Latency Period Compared with Erythromycin Antibiotic Regimens.

Objective: To determine if antibiotic regimens including azithromycin versus erythromycin has an impact on pregnancy latency and development of clinical chorioamnionitis in the context of preterm prelabor rupture of membranes. Study Design. We conducted a prospective observational cohort study and followed all women receiving antibiotic regimens including either azithromycin or erythromycin in the context of preterm prelabor rupture of membranes. Primary outcomes were the duration of pregnancy latency period and development of chorioamnionitis. Secondary outcomes included neonatal sepsis with positive blood culture, cesarean delivery, postpartum endometritis, and meconium-stained amniotic fluid. Results: This study included 310 patients, with 142 receiving the azithromycin regimen and 168 receiving the erythromycin regimen. Patients receiving the azithromycin regimen had a statistically significant advantage in overall rates of clinical chorioamnionitis (13.4% versus 25%, p = 0.010), neonatal sepsis (4.9% versus 14.9%, p = 0.004), and postpartum endometritis (14.8% versus 31%, p = 0.001). In crude and adjusted models, when comparing the azithromycin group with the erythromycin group, a decreased risk was noted for the development of clinical chorioamnionitis, neonatal sepsis, and postpartum endometritis. Pregnancy latency by regimen was not significantly different in crude and adjusted models. Conclusion: Our study suggests that latency antibiotic regimens substituting azithromycin for erythromycin have lower rates and decreased risk of clinical chorioamnionitis, neonatal sepsis, and postpartum endometritis with no difference in pregnancy latency.

Intra-Amniotic Infection with Ureaplasma parvum Causes Preterm Birth and Neonatal Mortality That Are Prevented by Treatment with Clarithromycin.

Intra-amniotic infection is strongly associated with adverse pregnancy and neonatal outcomes. Most intra-amniotic infections are due to Ureaplasma species; however, the pathogenic potency of these genital mycoplasmas to induce preterm birth is still controversial. Here, we first laid out a taxonomic characterization of Ureaplasma isolates from women with intra-amniotic infection, which revealed that Ureaplasma parvum is the most common bacterium found in this clinical condition. Next, using animal models, we provided a causal link between intra-amniotic inoculation with Ureaplasma species and preterm birth. Importantly, the intra-amniotic inoculation of Ureaplasma species induced high rates of mortality in both preterm and term neonates. The in vivo potency of U. parvum to induce preterm birth was not associated with known virulence factors. However, term-derived and preterm-derived U. parvum isolates were capable of inducing an intra-amniotic inflammatory response. Both U. parvum isolates invaded several fetal tissues, primarily the fetal lung, and caused fetal inflammatory response syndrome. This bacterium was also detected in the placenta, reproductive tissues, and most severely in the fetal membranes, inducing a local inflammatory response that was replicated in an in vitro model. Importantly, treatment with clarithromycin, a recently recommended yet not widely utilized antibiotic, prevented the adverse pregnancy and neonatal outcomes induced by U. parvum These findings shed light on the maternal-fetal immunobiology of intra-amniotic infection.IMPORTANCE Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Multiple etiologies are associated with preterm birth; however, 25% of preterm infants are born to a mother with intra-amniotic infection, most commonly due to invasion of the amniotic cavity by Ureaplasma species. Much research has focused on establishing a link between Ureaplasma species and adverse pregnancy/neonatal outcomes; however, little is known about the taxonomy of and host response against Ureaplasma species. Here, we applied a multifaceted approach, including human samples, in vivo models, and in vitro manipulations, to study the maternal-fetal immunobiology of Ureaplasma infection during pregnancy. Furthermore, we investigated the use of clarithromycin as a treatment for this infection. Our research provides translational knowledge that bolsters scientific understanding of Ureaplasma species as a cause of adverse pregnancy/neonatal outcomes and gives strong evidence for the use of clarithromycin as the recommended treatment for women intra-amniotically infected with Ureaplasma species.

Antibiotic administration reduces the rate of intraamniotic inflammation in preterm prelabor rupture of the membranes.

BACKGROUND: Preterm prelabor rupture of the membranes (PPROM) is frequently complicated by intraamniotic inflammatory processes such as intraamniotic infection and sterile intraamniotic inflammation. Antibiotic therapy is recommended to patients with PPROM to prolong the interval between this complication and delivery (latency period), reduce the risk of clinical chorioamnionitis, and improve neonatal outcome. However, there is a lack of information regarding whether the administration of antibiotics can reduce the intensity of the intraamniotic inflammatory response or eradicate microorganisms in patients with PPROM. OBJECTIVE: The first aim of the study was to determine whether antimicrobial agents can reduce the magnitude of the intraamniotic inflammatory response in patients with PPROM by assessing the concentrations of interleukin-6 in amniotic fluid before and after antibiotic treatment. The second aim was to determine whether treatment with intravenous clarithromycin changes the microbial load of Ureaplasma spp DNA in amniotic fluid. STUDY DESIGN: A retrospective cohort study included patients who had (1) a singleton gestation, (2) PPROM between 24+0 and 33+6 weeks, (3) a transabdominal amniocentesis at the time of admission, and (4) intravenous antibiotic treatment (clarithromycin for patients with intraamniotic inflammation and benzylpenicillin/clindamycin in the cases of allergy in patients without intraamniotic inflammation) for 7 days. Follow-up amniocenteses (7th day after admission) were performed in the subset of patients with a latency period lasting longer than 7 days. Concentrations of interleukin-6 were measured in the samples of amniotic fluid with a bedside test, and the presence of microbial invasion of the amniotic cavity was assessed with culture and molecular microbiological methods. Intraamniotic inflammation was defined as a bedside interleukin-6 concentration ≥745 pg/mL in the samples of amniotic fluid. Intraamniotic infection was defined as the presence of both microbial invasion of the amniotic cavity and intraamniotic inflammation; sterile intraamniotic inflammation was defined as the presence of intraamniotic inflammation without microbial invasion of the amniotic cavity. RESULTS: A total of 270 patients with PPROM were included in this study: 207 patients delivered within 7 days and 63 patients delivered after 7 days of admission. Of the 63 patients who delivered after 7 days following the initial amniocentesis, 40 underwent a follow-up amniocentesis. Patients with intraamniotic infection (n = 7) and sterile intraamniotic inflammation (n = 7) were treated with intravenous clarithromycin. Patients without either microbial invasion of the amniotic cavity or intraamniotic inflammation (n = 26) were treated with benzylpenicillin or clindamycin. Treatment with clarithromycin decreased the interleukin-6 concentration in amniotic fluid at the follow-up amniocentesis compared to the initial amniocentesis in patients with intraamniotic infection (follow-up: median, 295 pg/mL, interquartile range [IQR], 72-673 vs initial: median, 2973 pg/mL, IQR, 1750-6296; P = .02) and in those with sterile intraamniotic inflammation (follow-up: median, 221 pg/mL, IQR 118-366 pg/mL vs initial: median, 1446 pg/mL, IQR, 1300-2941; P = .02). Samples of amniotic fluid with Ureaplasma spp DNA had a lower microbial load at the time of follow-up amniocentesis compared to the initial amniocentesis (follow-up: median, 1.8 × 104 copies DNA/mL, 2.9 × 104 to 6.7 × 108 vs initial: median, 4.7 × 107 copies DNA/mL, interquartile range, 2.9 × 103 to 3.6 × 107; P = .03). CONCLUSION: Intravenous therapy with clarithromycin was associated with a reduction in the intensity of the intraamniotic inflammatory response in patients with PPROM with either intraamniotic infection or sterile intraamniotic inflammation. Moreover, treatment with clarithromycin was related to a reduction in the load of Ureaplasma spp DNA in the amniotic fluid of patients with PPROM <34 weeks of gestation.

Protection of the Ovine Fetal Gut against Ureaplasma-Induced Chorioamnionitis: A Potential Role for Plant Sterols.

Chorioamnionitis, clinically most frequently associated with Ureaplasma, is linked to intestinal inflammation and subsequent gut injury. No treatment is available to prevent chorioamnionitis-driven adverse intestinal outcomes. Evidence is increasing that plant sterols possess immune-modulatory properties. Therefore, we investigated the potential therapeutic effects of plant sterols in lambs intra-amniotically (IA) exposed to Ureaplasma. Fetal lambs were IA exposed to Ureaplasma parvum (U. parvum, UP) for six days from 127 d-133 d of gestational age (GA). The plant sterols ß-sitosterol and campesterol, dissolved with ß-cyclodextrin (carrier), were given IA every two days from 122 d-131 d GA. Fetal circulatory cytokine levels, gut inflammation, intestinal injury, enterocyte maturation, and mucosal phospholipid and bile acid profiles were measured at 133 d GA (term 150 d). IA plant sterol administration blocked a fetal inflammatory response syndrome. Plant sterols reduced intestinal accumulation of proinflammatory phospholipids and tended to prevent mucosal myeloperoxidase-positive (MPO) cell influx, indicating an inhibition of gut inflammation. IA administration of plant sterols and carrier diminished intestinal mucosal damage, stimulated maturation of the immature epithelium, and partially prevented U. parvum-driven reduction of mucosal bile acids. In conclusion, we show that ß-sitosterol and campesterol administration protected the fetus against adverse gut outcomes following UP-driven chorioamnionitis by preventing intestinal and systemic inflammation.

Induction of Labor versus Scheduled Cesarean in Morbidly Obese Women: A Cost-Effectiveness Analysis.

OBJECTIVE: To assess the costs, complication rates, and harm-benefit tradeoffs of induction of labor (IOL) compared to scheduled cesarean delivery (CD) in women with class III obesity. STUDY DESIGN: We conducted a cost analysis of IOL versus scheduled CD in nulliparous morbidly obese women. Primary outcomes were surgical site infection (SSI), chorioamnionitis, venous thromboembolism, blood transfusion, and readmission. Model outcomes were mean cost of each strategy, cost per complication avoided, and complication tradeoffs. We assessed the costs, complication rates, and harm-benefit tradeoffs of IOL compared with scheduled CD in women with class III obesity. RESULTS: A total of 110 patients underwent scheduled CD and 114 underwent IOL, of whom 61 (54%) delivered via cesarean. The group delivering vaginally experienced fewer complications. SSI occurred in 0% in the vaginal delivery group, 13% following scheduled cesarean, and 16% following induction then cesarean. In the decision model, the mean cost of induction was $13,349 compared with $14,575 for scheduled CD. Scheduled CD costs $9,699 per case of chorioamnionitis avoided, resulted in 18 cases of chorioamnionitis avoided per additional SSI and 3 cases of chorioamnionitis avoided per additional hospital readmission. In sensitivity analysis, IOL is cost saving compared with scheduled CD unless the cesarean rate following induction exceeds 70%. CONCLUSION: In morbidly obese women, induction of labor remains cost-saving until the rate of cesarean following induction exceeds 70%.

Evidence-based interventions to reduce obstetric-related infections at an army training facility.

BACKGROUND: OBJECTIVE: Obstetric-related infections are a major cause of maternal morbidity and mortality worldwide. Our team implemented an evidence-based infection control bundle aimed at reducing obstetric-related infections at our facility. METHODS: A multidisciplinary team at Tripler Army Medical Center developed, implemented, and evaluated an evidence-based maternal safety infection control bundle (MSICB) on labor and delivery aimed at reducing the incidence of surgical site infections (SSI) and chorioamnionitis. Adenosine triphosphate testing of patient care-related surfaces was performed while behavioral and environmental interventions were implemented. Incidence rates for chorioamnionitis, SSI, and endometritis were compared between pre- and during-MSICB implementation using Fisher exact test and Poisson regression, adjusting for year and quarter. The decision science analysts at US Army Medical Command, Fort Sam Houston, Texas responsible for our facility utilized diagnosis-related group and ICD-10 Procedure Coding to determine infection-related costs. RESULTS: Prior to implementation of the MSICB, the rates of chorioamnionitis, SSI, and endometritis in the first half of 2016 were 6.3%, 3.4%, and 0.4%, respectively. After implementation of the MSICB, in the first 6 months of 2017, the rates of chorioamnionitis and SSI decreased to 1.7% and 1.0%, respectively, with no change in the rate of endometritis. The rate was significantly lower after implementation for chorioamnionitis (P < .001), and there was a statistically nonsignificant decrease for SSI (P = .060) and no difference for postpartum endometritis (P = 1.00). These reductions resulted in an estimated net cost savings of $671,218. CONCLUSIONS: A multidisciplinary approach with evidence-based strategies resulted in a significant decrease (P < .001) in chorioamnionitis and a statistically nonsignificant decrease (P = .060) in the SSI rate, which resulted in a significant cost savings for the hospital. There was no change in our postpartum endometritis rate.

Antenatal Vitamin D Preserves Placental Vascular and Fetal Growth in Experimental Chorioamnionitis Due to Intra-amniotic Endotoxin Exposure.

BACKGROUND: Chorioamnionitis (CA) is associated with a high risk for the development of bronchopulmonary dysplasia (BPD) after preterm birth, but mechanisms that increase susceptibility for BPD and strategies to prevent BPD are uncertain. As a model of CA, antenatal intra-amniotic (IA) endotoxin (ETX) exposure alters placental structure, causes fetal growth restriction, increases perinatal mortality, and causes sustained cardiorespiratory abnormalities throughout infancy. Vitamin D (Vit D) has been shown to have both anti-inflammatory and proangiogenic properties. Antenatal IA treatment with Vit D (1,25-(OH)2D3) during IA ETX exposure improves survival and increases vascular and alveolar growth in infant rats. Whether IA ETX causes decreased placental vascular development and if the protective effects of prenatal Vit D treatment are due to direct effects on the fetus or to improved placental vascular development remain unknown. OBJECTIVE: The objective of this study was to determine if IA ETX impairs placental vascular development and Vit D metabolism, and whether 1,25-(OH)2D3 treatment improves placental vascularity after IA ETX exposure during late gestation in pregnant rats. DESIGN/METHODS: Fetal rats were exposed to ETX (10 mg), ETX + 1,25-(OH)2D3 (1 ng/mL), 1,25-(OH)2D3 (1 ng/mL), or saline (control) via IA injection at E20 and delivered 2 days later. To assess placental vascular development, histologic sections from the placenta were stained for CD31 and vessel density per high power field (HPF) was determined and analyzed using Matlab software. To determine the effects of ETX on placental Vit D metabolism, Vit D receptor (VDR) and activity of the Vit D conversion enzyme, CYP27B1, were assayed from placental homogenates. Angiogenic mediators were measured by reverse transcription polymerase chain reaction by RNA extracted from placental tissue. RESULTS: IA ETX reduced placenta and newborn birth weights by 22 and 20%, respectively, when compared with controls (placental weight: 0.60 vs. 0.47 g; p < 0.0001; birth weight: 4.68 vs. 5.88 g; p < 0.0001). IA 1,25-(OH)2D3 treatment increased birth weight by 12% in ETX-exposed pups (5.25 vs. 4.68 g; p < 0.001). IA ETX decreased placental vessel density by 24% in comparison with controls (1,114 vs. 848 vessels per HPF; p < 0.05). Treatment with IA 1,25-(OH)2D3 increased placenta vessel density twofold after ETX exposure (1,739 vs. 848); p < 0.0001), and increased vessel density compared with saline controls by 56% (1,739 vs. 1,114; p < 0.0001). IA ETX decreased both VDR and CYP27B1 expression by 83 and 35%, respectively (p < 0.01). CONCLUSION: IA ETX decreases placental growth and vessel density and decreases placental VDR and CYP27B1 protein expression, and that antenatal 1,25-(OH)2D3 restores placental weight and vessel density, as well as birth weight. We speculate that 1,25-(OH)2D3 treatment preserves placental function in experimental CA and that these effects may be mediated by increased vascular growth.

The Effects of Magnesium Sulfate on the Inflammatory Response of Placentas Perfused With Lipopolysaccharide: Using the Ex Vivo Dual-Perfused Human Single-Cotyledon Model.

OBJECTIVES: Multiple mechanisms have been proposed for the neuroprotective effects of magnesium sulfate (MgSO4). We aimed to examine the effects of lipopolysaccharide (LPS) and MgSO4 on the placental expression of nuclear factor κ light chain enhancer of activated B cells (NF-κB), interleukin (IL) 6, adrenocorticotropic hormone (ACTH), and nitric oxide synthase (NOS); all known to participate in the inflammatory cascade. METHODS: Placentas were obtained and selected cotyledons cannulated and dually perfused ex vivo. Placentas were perfused with 4 perfusion protocols: culture medium (M-199; controls), LPS (1 µg/mL), MgSO4 (6 g/dL), and LPS + MgSO4. Each perfusion experiment continued for 3 hours. Sixteen perfusion experiments were analyzed, 4 separate placentas were studied for each protocol. The protein levels in the perfused cotyledons were studied by Western blot analysis and compared between the groups. Interleukin 6 levels were studied in the maternal and fetal perfusate. RESULTS: The expression of NF-κB p65, IL-6, ACTH, and NOS proteins levels were significantly increased in placentas perfused with LPS as compared to placentas perfused with M-199, MgSO4 ( P < .01 for all). Placentas perfused with LPS+ MgSO4 had similar proteins levels as in the controls and MgSO4 groups. Lipopolysaccharide significantly increased IL-6 levels in maternal perfusate. CONCLUSIONS: In the human placenta, MgSO4 blocks the increase in the proteins levels of NF-κB, IL-6, ACTH, and NOS in response to inflammatory stimuli. Magnesium sulfate attenuates excessive placental inflammatory response. The decrease in placental ACTH levels following perfusion with MgSO4 may point to an additional non-anti-inflammatory mechanism of MgSO4.

Maternal Glucose Supplementation in a Murine Model of Chorioamnionitis Alleviates Dysregulation of Autophagy in Fetal Brain.

Fetal brain injury induced by intrauterine inflammation is a major risk factor for adverse neurological outcomes, including cerebral palsy, cognitive dysfunction, and behavioral disabilities. There are no adequate therapies for neuronal protection to reduce fetal brain injury, especially new strategies that may apply promptly and conveniently. In this study, we explored the effect of maternal glucose administration in a mouse model of intrauterine inflammation at term. Our results demonstrated that maternal glucose supplementation significantly increased survival birth rate and improved the neurobehavioral performance of pups exposed to intrauterine inflammation. Furthermore, we demonstrated that maternal glucose administration improved myelination and oligodendrocyte development in offspring exposed to intrauterine inflammation. Though the maternal blood glucose concentration was temporally prevented from decrease induced by intrauterine inflammation, the glucose concentration in fetal brain was not recovered by maternal glucose supplementation. The adenosine triphosphate (ATP) level and autophagy in fetal brain were regulated by maternal glucose supplementation, which may prevent dysregulation of cellular metabolism. Our study is the first to provide evidence for the role of maternal glucose supplementation in the cell survival of fetal brain during intrauterine inflammation and further support the possible medication with maternal glucose treatment.

Treatment of Preterm Premature Rupture of Membranes with Oligo-/Anhydramnion Colonized by Multiresistant Bacteria with Continuous Amnioinfusion and Antibiotic Administrations through a Subcutaneously Implanted Intrauterine Port System: A Case Report.

Bacterial infection is one of the main causes of preterm premature rupture of membranes (PPROM) leading to preterm delivery, pulmonary hypoplasia, sepsis and joint deformities. Expectant management, broad-spectrum antibiotics and antenatal corticosteroids are routinely used in this condition with very limited success to prevent bacteremia, chorioamnionitis, funisitis and intra-amniotic infection syndrome. Here, we report a case in which we attempted to treat PPROM at 26+3 weeks of gestation with anhydramnion colonized by multiresistant Klebsiella. A perinatal port system was implanted subcutaneously at 28+0 weeks of gestation, enabling long-term continuous lavage of the amniotic cavity with a hypotonic aqueous composition similar to human amniotic fluid combined with intra-amniotic antibiotic application. The patient gave birth to a preterm female infant at 31+1 weeks without any signs of infection. The girl was discharged with a weight of 2,730 g in very good condition. In the follow-up examinations at 5 months and 1 year of age, there was no apparent neurological disturbance, developmental delay or Klebsiella colonization.

Role of cervical cerclage and prolonged antibiotic therapy with azithromycin in patients with previous perinatal loss amnionitis.

In the group of 35 patients with cerclage, intermediate fetal mortality was reduced from 37.1% to 0 (p < 0.001); late fetal mortality rate from 8.5% to 2.8% (p = 0.606); prematurity from 65.7% to 5.7% (p < 0.001); newborn underweight from 11.4% to 5.7% (p = 0.671); newborns with very low weight from 34.2% to 0 (p < 0.001) and the abortion rate from 8.5% to 0 ( p < 0.001). In the group of 19 patients without buckling, intermediate fetal mortality was reduced from 26.3% to 10.5% (p = 402); late fetal mortality from 63.1% to 0 (p < 0.001); prematurity 78.9% to 31.5% (p < 0.009); the newborn of low weight from 31.5% to 10.5% (p = 0.234); newborns with very low weight from 68.4% to 15.7% (p < 0.003) and the abortion rate from 36.8 to 0 (p < 0.001). In conclusion, we believe the results of this study demonstrate the effectiveness of therapeutic and prophylactic cervical cerclage associated with prolonged antibiotic therapy.