A comparison of the renal function biomarkers serum creatinine, pro-enkephalin and cystatin C to predict clearance of pemetrexed.

INTRODUCTION: For drugs with a narrow therapeutic window, there is a delicate balance between efficacy and toxicity, thus it is pivotal to administer the right dose from the first administration onwards. Exposure of pemetrexed, a cytotoxic drug used in lung cancer treatment, is dictated by kidney function. To facilitate optimized dosing of pemetrexed, accurate prediction of drug clearance is pivotal. Therefore, the aim of this study was to investigate the performance of the kidney function biomarkers serum creatinine, cystatin C and pro-enkephalin in terms of predicting the elimination of pemetrexed. METHODS: We performed a population pharmacokinetic analysis using a dataset from two clinical trials containing pharmacokinetic data of pemetrexed and measurements of all three biomarkers. A three-compartment model without covariates was fitted to the data and the obtained individual empirical Bayes estimates for pemetrexed clearance were considered the "true" values (Cltrue). Subsequently, the following algorithms were tested as covariates for pemetrexed clearance: the Chronic Kidney Disease Epidemiology Collaboration equation using creatinine (CKD-EPICR), cystatin C (CKD-EPICYS), a combination of both (CKD-EPICR-CYS), pro-enkephalin as an absolute value or in a combined algorithm with age and serum creatinine, and lastly, a combination of pro-enkephalin with cystatin C. RESULTS: The dataset consisted of 66 subjects with paired observations for all three kidney function biomarkers. Inclusion of CKD-EPICR-CYS as a covariate on pemetrexed clearance resulted in the best model fit, with the largest decrease in objective function (p < 0.00001) and explaining 35% of the total inter-individual variability in clearance. The predictive performance of the model to containing CKD-EPICR-CYS to predict pemetrexed clearance was good with a normalized root mean squared error and mean prediction error of 19.9% and 1.2%, respectively. CONCLUSIONS: In conclusion, this study showed that the combined CKD-EPICR-CYS performs best in terms predicting pharmacokinetics of pemetrexed. Despite the hypothesized disadvantages, creatinine remains to be a suitable and readily available marker to predict pemetrexed clearance in clinical practice.

Maternal Sepsis.

Sepsis is the second leading cause of pregnancy-related mortality in the United States. Early recognition, treatment, and escalation of care for the obstetric patient affected by sepsis mitigate the risk of mortality and improve patient outcomes. In this article, we provide an overview of maternal sepsis and address topics of maternal pathophysiology, early warning signs, diagnostic criteria, early goal-directed therapy, and contemporary critical care practices. We also present an overview of common etiologies of maternal sepsis and suggested treatment approaches.

Applying a cost-based pricing model for innovative cancer treatments subject to indication expansion: A case study for pembrolizumab and daratumumab.

BACKGROUND: Expanding the indication of already approved immuno-oncology drugs presents treatment opportunities for patients but also strains healthcare systems. Cost-based pricing models are discussed as a possibility for cost containment. This study focuses on two drugs, pembrolizumab (Keytruda) and daratumumab (Darzalex), to explore the potential effect of indication broadening on the estimated price when using the cost-based pricing (CBP) model proposed by Uyl-de Groot and Löwenberg (2018). METHODS: The model was used to calculate cumulative yearly prices, cumulative prices per indication, and non-cumulative indication-based prices using inputs such as research and development (R&D) costs, manufacturing costs, eligible patient population, and a profit margin. A deterministic stepwise analysis and scenario analysis were conducted to examine how sensitive the estimated price is to the different input assumptions. RESULTS: The yearly cumulative cost-based prices (CBPs) ranged from €52 to €885 for pembrolizumab per vial and €823 to €31,941 for daratumumab per vial. Prices were higher in initial years or indications due to smaller patient populations, decreased over time or after additional indications. Sensitivity analysis showed that the number of eligible patients had the most significant impact on the estimated price. In the scenario analysis the profit margin contributed most to a higher CBPs for both drugs. Lower estimates resulted from assumed lower R&D costs. DISCUSSION: The estimated CBPs are consistently lower than Dutch list prices for pembrolizumab (€2,861), mainly resulting from larger patient populations in registered indications. However, daratumumab's list prices fall within the range of modeled CBPs depending on the year or indication (€4,766). Both CBPs decrease over time or with additional indications. The number of eligible patients and initial R&D costs have the most significant influence on the CBPs. These findings contribute to the ongoing discussions on pharmaceutical pricing, especially concerning cancer drugs with expanding indications.

Urinary Tract Infection and Progression to Pyelonephritis: Group B Streptococcus versus E. coli.

Objective Group B Streptococcus (GBS) colonization of the lower urinary tract in pregnancy is associated with severe infections such as chorioamnionitis, endometritis, and pyelonephritis. The objective of this study was to compare rates of progression to pyelonephritis between GBS and Escherichia coli lower urinary tract infections (LUTIs), as well as compare infectious and obstetric morbidity secondary to these pathogens. Study Design Retrospective cohort of pregnant women with LUTIs (asymptomatic bacteria or acute cystitis [AC]) from a single health system between July 2013 and May 2019. Demographic, infectious, antepartum, and intrapartum data were abstracted from medical records of women with GBS or E. coli LUTI. The primary outcome was progression to pyelonephritis. Secondary outcomes included pyelonephritis-related anemia, sepsis, pyelonephritis length of stay (LOS), median gestational age (GA) at delivery, preterm delivery, and low birth weight (LBW). Logistic regression was used to calculate the adjusted odds of the primary outcome. Results Of 729 pregnant women with urinary colonization, 433 were culture positive for one of the aforementioned bacteria, with 189 (43.6%) having GBS and 244 (56.4%) having E. coli. Women with E. coli were more likely to be younger, use tobacco, have a history of AC, and have a history of preterm birth. Rates of progression to pyelonephritis were markedly higher with E. coli (15.6%) than with GBS (1.1%; p < 0.001). Median LOS for pyelonephritis and pyelonephritis-related morbidities did not differ. Median GA at delivery, preterm delivery, and LBW rates also did not differ. In adjusted analysis, controlling for history of AC, insurance status, tobacco use, prior preterm birth, primary infection type, and maternal age, women with GBS LUTI had markedly decreased odds of developing pyelonephritis in pregnancy compared with those with E. coli (adjusted odds ratio: 0.04, 95% confidence interval: 0.01-0.28). Conclusion Escherichia coli infections progress to pyelonephritis in pregnancy at markedly higher rates than GBS, although obstetric outcomes are similar.

Maternal and neonatal outcomes in patients with hepatitis C and intrahepatic cholestasis of pregnancy: The sum of the parts.

OBJECTIVE: Hepatitis C virus and intrahepatic cholestasis of pregnancy (ICP) are well-known independent risk factors for adverse outcomes in pregnancy. In addition, it is well-established that there is an association between Hepatitis C and ICP. This study's objective was to describe the impact of having both Hepatitis C and ICP on maternal and obstetric outcomes compared to patients having either Hepatitis C or ICP. METHODS: We conducted a retrospective cohort study of the Nationwide Readmissions Database, an all-payor sample of discharges from approximately 60% of US hospitalizations. Deliveries at 24-42+ weeks between 10/2015 and 12/2020 were included. Diagnosis of Hepatitis C and ICP, and outcomes related to severe maternal morbidity were identified using International Classification of Disease-10 codes. Patients were categorized based on Hepatitis C and ICP status. Weighted logistic and negative binomial regression analyses were used to evaluate the association between Hepatitis C and ICP status and outcomes, adjusting for patient and hospital characteristics. The primary outcome was any severe maternal morbidity; secondary outcomes included acute respiratory distress syndrome, acute kidney injury, sepsis, gestational diabetes, cesarean delivery, preterm birth, and hospital length of stay. We modeled interaction terms between ICP and Hepatitis C to assess whether there was a greater or lesser effect from having both conditions on outcomes than we would expect from additive combination of the individual components (i.e., synergy or antagonism). RESULTS: A total of 10,040,850 deliveries between 24-42+ weeks were identified. Of these, 45,368 had Hepatitis C only; 84,582 had ICP only; and 1,967 had both Hepatitis C and ICP. Patients with both Hepatitis C and ICP had 1.5-fold higher odds of developing severe maternal morbidity compared to having neither. There was an also an increased odds of severe maternal morbidity in patients with both Hepatitis C and ICP compared to patients with only Hepatitis C or ICP. Having both was also associated with higher odds of preterm birth and length of stay compared to having only Hepatitis C, only ICP, or neither (preterm birth: aOR 5.09, 95% CI 4.87-5.33 vs. neither; length of stay: 46% mean increase, 95% CI 35-58% vs. neither). Associations were additive-no significant interactions between hepatitis C and cholestasis were found on rates of severe maternal morbidity, acute respiratory distress syndrome, acute kidney injury, sepsis, cesarean section, or preterm birth (all p>0.05), and was minimal for gestational diabetes and length of stay. CONCLUSION: Hepatitis C and ICP are independent, additive risk factors for adverse maternal and obstetric outcomes. Despite physiologic plausibility, no evidence of a synergistic effect of these two diagnoses on outcomes was noted. These data may be useful in counseling patients regarding their increased risk of adverse outcomes when ICP presents in association with Hepatitis C versus ICP alone.

Development and validation of a bioanalytical assay for the measurement of total and unbound teicoplanin in human serum.

BACKGROUND: The glycopeptide teicoplanin is considered first-line treatment for severe infections caused by Gram-positive bacteria. Individualized treatment of teicoplanin is gaining interest. As only protein-unbound drug is pharmacologically active, a sensitive assay measuring unbound and total teicoplanin is indispensable for pharmacological research and dose optimization. OBJECTIVES: To develop and validate a UPLC-MS/MS method to quantify unbound and total teicoplanin in human serum. METHODS: The developed assay was validated according to the ICH guideline M10 on Bioanalytical Method Validation and study sample analysis. Unbound teicoplanin was obtained by ultrafiltration. The assay was cross-validated with a quantitative microsphere (QMS) immunoassay in a side-by-side comparison using 40 patient samples. RESULTS: With the developed and validated method, all main teicoplanin components (A2-1, A2-2/A2-3, A2-4/A2-5 and A3-1) can be quantified. Total run time was 5.5 min. Concentration range was 2.5-150 mg/L for total and 0.1-25 mg/L for unbound teicoplanin. Precision (coefficient of variation) and accuracy (bias) of total teicoplanin were 5.97% and 107%, respectively, and 7.17% and 108%, respectively, for unbound teicoplanin.Bland-Altman analysis showed total concentrations measured with the UPLC-MS/MS method were equivalent to the results of the QMS immunoassay. A total of 188 samples from 30 patients admitted to the ICU and haematology department were measured; total concentrations ranged between 2.92 and 98.5 mg/L, and unbound concentrations ranged between 0.37 and 30.7 mg/L. CONCLUSIONS: The developed method provided rapid, precise and accurate measurement of unbound and total teicoplanin. The developed method is now routinely applied in pharmacological research and clinical practice.

Alliance for Innovation on Maternal Health: Consensus Bundle on Sepsis in Obstetric Care.

Sepsis in obstetric care is one of the leading causes of maternal death in the United States, with Black, Asian/Pacific Islander, and American Indian/Alaska Native obstetric patients experiencing sepsis at disproportionately higher rates. State maternal mortality review committees have determined that deaths are preventable much of the time and are caused by delays in recognition, treatment, and escalation of care. The "Sepsis in Obstetric Care" patient safety bundle provides guidance for health care teams to develop coordinated, multidisciplinary care for pregnant and postpartum people by preventing infection and recognizing and treating infection early to prevent progression to sepsis. This is one of several core patient safety bundles developed by AIM (the Alliance for Innovation on Maternal Health) to provide condition- or event-specific clinical practices that should be implemented in all appropriate care settings. As with other bundles developed by AIM, the "Sepsis in Obstetric Care" patient safety bundle is organized into five domains: Readiness, Recognition and Prevention, Response, Reporting and Systems Learning, and Respectful, Equitable, and Supportive Care. The Respectful, Equitable, and Supportive Care domain provides essential best practices to support respectful, equitable, and supportive care to all patients. Further health equity considerations are integrated into the elements of each domain.

Associations between Anemia and Outcomes of Pregnant Patients with Pyelonephritis.

OBJECTIVE: This study aims to determine if pregnant patients with both pyelonephritis and anemia are at an increased risk of adverse maternal outcomes compared with those with pyelonephritis without anemia. STUDY DESIGN: We conducted a retrospective cohort study utilizing the Nationwide Readmissions Database (NRD). Patients with antepartum pyelonephritis-associated hospitalizations from October 2015 to December 2018 were included. International Classification of Diseases codes were used to identify pyelonephritis, anemia, maternal comorbidities, and severe maternal morbidities. The primary outcome was a composite of severe maternal morbidity, as defined by the Centers for Disease Control criteria. Univariate statistical methods, weighted to account for complex survey methods in the NRD, were used to assess for associations between anemia, baseline characteristics, and patient outcomes. Weighted logistic and Poisson regressions were used to assess for associations between anemia and outcomes, adjusting for clinical comorbidities and other confounding factors. RESULTS: In total, 29,296 pyelonephritis admissions were identified, corresponding to a weighted national estimate of 55,135 admissions. Of these, 11,798 (21.3%) were anemic. The rate of severe maternal morbidity was higher among anemic patients than nonanemic patients (27.8% vs. 8.9%, respectively, p < 0.001), and remained higher after adjustment (adjusted relative risk [aRR] 2.86 [95% confidence interval [CI]: 2.67, 3.06]). Rates of individual components of severe maternal morbidities, including acute respiratory distress syndrome (4.0% vs. 0.6%, aRR 3.97 [95% CI: 3.10, 5.08]), sepsis (22.5% vs. 7.9%, aRR 2.64 [95% CI: 2.45, 2.85]), shock (4.5% vs. 0.6%, aRR 5.48 [95% CI: 4.32, 6.95]), and acute renal failure (2.9% vs. 0.8%, aRR 1.99 [95% CI: 1.55, 2.55]) were all higher for anemic pyelonephritis. The mean length of stay was also longer (25% average increase, 95% CI: 22%, 28%). CONCLUSION: Among pregnant patients with pyelonephritis, those with anemia are at greater risk of severe maternal morbidity and longer hospital stay. KEY POINTS: · Anemia is associated with longer stays for pyelo.. · Anemic pyelo patients have increased morbidity.. · Anemic pyelo patients have increased sepsis risk..

Group B Streptococcus and Pregnancy: Critical Concepts and Management Nuances.

Importance: Group B Streptococcus (GBS) is a common pathogen with an effective treatment. However, it remains a significant cause of neonatal sepsis, morbidity, and mortality. The screening and management of this infection are some of the first concepts learned during medical training in obstetrics. However, effective screening and evidence-based management of GBS are nuanced with many critical caveats. Objective: The objectives of this review are to discuss the essential aspects of GBS screening and management and to highlight recent changes to recommendations and guidelines. Evidence Acquisition: Original research articles, review articles, and guidelines on GBS were reviewed. Results: The following recommendations are based on review of the evidence and professional society guidelines. Screening for GBS should occur between 36 weeks and the end of the 37th week. The culture swab should go 2 cm into the vagina and 1 cm into the anus. Patients can perform their own swabs as well. Penicillin allergy testing has been shown to be safe in pregnancy. Patients with GBS in the urine should be treated at term with antibiotic prophylaxis, independent of the colony count of the culture. Patients who are GBS-positive with preterm and prelabor rupture of membranes after 34 weeks are not candidates for expectant management, as this population has higher rates of neonatal infectious complications. Patients with a history of GBS colonization in prior pregnancy who are GBS-unknown in this current pregnancy and present with labor should receive intrapartum prophylaxis. Work on the GBS vaccine continues. Conclusions: Although all of the efforts and focus on neonatal early-onset GBS infection have led to lower rates of disease, GBS still remains a major cause of neonatal morbidity and mortality requiring continued vigilance from obstetric providers.

Preoperative cefazolin rather than clindamycin or metronidazole is associated with lower postpartum infection among women with chorioamnionitis delivering by cesarean delivery.

BACKGROUND: The optimal antibiotic regimen to prevent maternal postpartum infection among high-risk women treated for chorioamnionitis delivering by cesarean delivery remains to be defined. Emerging data suggest that cefazolin decreases the risk of cesarean surgical site infection. OBJECTIVE: To investigate whether intrapartum antibiotic therapy with cefazolin versus the current standard clindamycin or metronidazole decreases the risk of postpartum infectious morbidity among women delivering by cesarean delivery who were receiving a base regimen of ampicillin or penicillin with gentamicin for chorioamnionitis. MATERIALS AND METHODS: A secondary analysis from the Maternal-Fetal Medicine Units Network (MFMU) Cesarean Registry. We included women who delivered by cesarean delivery with presumptive chorioamnionitis (intrapartum fever >100.4°F and receipt of intrapartum antibiotics). All women received a base regimen of penicillin or ampicillin with gentamicin. We compared antibiotic therapy with cefazolin versus clindamycin or metronidazole. The primary outcome was a composite of postpartum maternal infection, including endometritis and surgical site infection. Multivariable logistic regression was used, adjusting for age, parity, race/ethnicity, insurance, body mass index at delivery, tobacco use, pregestational diabetes, American Society of Anesthesiologists classification, trial of labor prior to cesarean delivery, and postpartum antibiotics. RESULTS: Among 1105 women with presumptive chorioamnionitis who delivered by cesarean delivery, 22.0% (n = 244) received cefazolin and 77.9% (n = 861) received clindamycin or metronidazole. Most women were in labor prior to cesarean delivery (93.8%) and received postpartum antibiotics (88.4%). Almost one-tenth (9.5%) were diagnosed with a postpartum infection, most commonly endometritis (80.9%), followed by surgical site infection (20.9%) (not mutually exclusive). Women treated with cefazolin rather than clindamycin or metronidazole had lower odds of postpartum infectious morbidity (adjusted odds ratio, 0.49; 95% confidence interval, 0.26-0.90). This association held when the outcome was restricted to surgical site infection (adjusted odds ratio, 0.11; 95% confidence interval, 0.01-0.92) but not endometritis. Similar results were observed with propensity score analysis. CONCLUSION: Among women delivering by cesarean delivery who were treated for chorioamnionitis, additional antibiotic therapy with cefazolin decreased the risk of postpartum infection, primarily surgical site infection, compared to the current standard clindamycin or metronidazole.

Debunking the Myth: Do Maternal-Fetal Medicine Fellows Negatively Impact Resident Obstetrical Skills?

Objective Residency applicants often express concern that fellows negatively impact surgical opportunities, especially with less common procedures. We sought to describe the impact of maternal-fetal medicine (MFM) fellows on resident surgical opportunities. Study Design Anonymous 27-question e-survey sent to obstetrics and gynecology (OBGYN) residents in the United States and Puerto Rico in March 2018. Questions included experience as primary surgeon, for fourth year residents only, comfort performing procedures postresidency, and demographics. Residents from programs with MFM fellows (pMFM) were compared with those without (nMFM). Descriptive statistics used as appropriate. Regression was performed, controlling for significant variables. Results A total of 417 residents completed the survey; 275 (66%) from nMFM and 142 (33%) from pMFM. PMFM residents were more likely to have >7 residents/year, be from an academic residency, and less likely to be planning to practice obstetrics postresidency (all, p < 0.01). Plan to pursue MFM fellowship did not differ. NMFM residents were more likely to have been primary surgeon on a vacuum assisted delivery (77 vs. 63%, p < 0.01). No difference in primary surgeon experience was seen for forceps delivery, breech deliveries, third- or fourth-degree repairs, cerclage, or cesarean hysterectomy. With regard to comfort performing procedures postresidency, vacuum-assisted vaginal delivery (VAVD) was more likely among nMFM trainees, no other differences seen. In regression models, no differences in likelihood of comfort performing procedures postresidency for any procedures based on the presence of MFM fellows were seen. Among pMFM residents, 94% stated fellows positively impacted their learning. Conclusion MFM fellows do not appear to impact residents' perceived competency in obstetric procedures and the majority of trainees report that fellows positively impact their education.

Cumulative pemetrexed dose increases the risk of nephrotoxicity.

INTRODUCTION: Pemetrexed is a pharmacotherapeutic cornerstone in the treatment of non-small cell lung cancer. As it is primarily eliminated by renal excretion, adequate renal function is essential to prevent toxic exposure. There is growing evidence for the nephrotoxic potential of pemetrexed, which even becomes a greater issue now combined immuno-chemotherapy prolongs survival. Therefore, the aim of this study was to describe the incidence of nephrotoxicity and related treatment consequences during pemetrexed-based treatment. METHODS: A retrospective cohort study was conducted in the Jeroen Bosch Hospital, Den Bosch, the Netherlands. All patients that received at least 1 cycle of pemetrexed based therapy were included in the dataset. The primary outcome was defined as a ≥25 % reduction in eGFR. Additionally, the treatment consequences of decreased renal function were assessed. Logistic regression was used to identify risk factors for nephrotoxicity during treatment with pemetrexed. RESULTS: Of the 359 patients included in this analysis, 21 % patients had a clinically relevant decline in renal function after treatment and 8.1 % of patients discontinued treatment due to nephrotoxicity. Cumulative dose (≥10 cycles of pemetrexed based therapy) was identified as a risk factor for the primary outcome measure (adjusted OR 5.66 (CI 1.73-18.54)). CONCLUSION: This study shows that patients on pemetrexed-based treatment are at risk of developing renal impairment. Risk significantly increases with prolonged treatment. Renal impairment is expected to become an even greater issue now that pemetrexed-based immuno-chemotherapy results in longer survival and thus longer treatment duration.

Perinatal exposure of rats to the HIV drug efavirenz affects medial prefrontal cortex cytoarchitecture.

Efavirenz (EFV) is used for antiretroviral treatment of HIV infection, and successfully inhibits viral replication and mother-to-child transmission of HIV during pregnancy and childbirth. Unfortunately, the drug induces neuropsychiatric symptoms such as anxiety and depressed mood and potentially affects cognitive performance. EFV acts on, among others, the serotonin transporter and serotonin receptors that are expressed in the developing brain. Yet, how perinatal EFV exposure affects brain cytoarchitecture remains unclear. Here, we exposed pregnant and lactating rats to EFV, and examined in the medial prefrontal cortex (mPFC) of their adult offspring the effects of the maternal EFV exposure on cortical architecture. We observed a significant decrease in the number of cells, mainly mature neurons, in the infra/prelimbic and cingulate cortices of adult offspring. Next, we found an altered cortical cytoarchitecture characterized by a significant reduction in deep- and superficial-layer cells. This was accompanied by a sharp increase in programmed cell death, as we identified a significantly higher number of cleaved Caspase-3-positive cells. Finally, the serotonergic and dopaminergic innervation of the mPFC subdomains was increased. Thus, the perinatal exposure to EFV provoked in the mPFC of adult offspring cell death, significant changes in cytoarchitecture, and disturbances in serotonergic and dopaminergic innervation. Our results are important in the light of EFV treatment of HIV-positive pregnant women, and its effect on brain development and cognitive behavior.

Machine Learning and Statistical Models to Predict Postpartum Hemorrhage.

OBJECTIVE: To predict a woman's risk of postpartum hemorrhage at labor admission using machine learning and statistical models. METHODS: Predictive models were constructed and compared using data from 10 of 12 sites in the U.S. Consortium for Safe Labor Study (2002-2008) that consistently reported estimated blood loss at delivery. The outcome was postpartum hemorrhage, defined as an estimated blood loss at least 1,000 mL. Fifty-five candidate risk factors routinely available on labor admission were considered. We used logistic regression with and without lasso regularization (lasso regression) as the two statistical models, and random forest and extreme gradient boosting as the two machine learning models to predict postpartum hemorrhage. Model performance was measured by C statistics (ie, concordance index), calibration, and decision curves. Models were constructed from the first phase (2002-2006) and externally validated (ie, temporally) in the second phase (2007-2008). Further validation was performed combining both temporal and site-specific validation. RESULTS: Of the 152,279 assessed births, 7,279 (4.8%, 95% CI 4.7-4.9) had postpartum hemorrhage. All models had good-to-excellent discrimination. The extreme gradient boosting model had the best discriminative ability to predict postpartum hemorrhage (C statistic: 0.93; 95% CI 0.92-0.93), followed by random forest (C statistic: 0.92; 95% CI 0.91-0.92). The lasso regression model (C statistic: 0.87; 95% CI 0.86-0.88) and logistic regression (C statistic: 0.87; 95% CI 0.86-0.87) had lower-but-good discriminative ability. The above results held with validation across both time and sites. Decision curve analysis demonstrated that, although all models provided superior net benefit when clinical decision thresholds were between 0% and 80% predicted risk, the extreme gradient boosting model provided the greatest net benefit. CONCLUSION: Postpartum hemorrhage on labor admission can be predicted with excellent discriminative ability using machine learning and statistical models. Further clinical application is needed, which may assist health care providers to be prepared and triage at-risk women.

Chorioamnionitis and Infectious Complications after Vaginal Delivery.

OBJECTIVE: To estimate the incidence of and define risk factors for postpartum infectious complications after vaginal birth after cesarean (VBAC) complicated by chorioamnionitis. STUDY DESIGN: A secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Unit Cesarean Registry was performed. The primary outcome was a composite of postpartum infection: endometritis, sepsis, pelvic abscess, urinary tract infection, necrotizing fasciitis, and septic pelvic thrombophlebitis. Peripartum predictors were compared using parametric and nonparametric tests, as appropriate, and multivariate predictors assessed using logistic regression. RESULTS: A total of 559 subjects had chorioamnionitis in labor and a successful VBAC. Twenty-four (4.3%) subjects experienced the primary outcome, mainly due to endometritis (19/24). Significant factors included preterm delivery <32 weeks (odds ratio [OR]: 3.05, 95% confidence interval [CI]: 1.32-7.06) and body mass index (BMI) ≥40 (OR: 4.63, 95% CI: 1.25-17.14). Receipt of postpartum antibiotics was protective against postpartum infection (OR: 0.28, 95% CI: 0.12-0.65). In multivariate analysis, preterm delivery <32 weeks, BMI ≥40, and receipt of postpartum antibiotics remained associated with postpartum infection. CONCLUSION: Nearly 5% of women with chorioamnionitis had a postpartum infectious complication after vaginal delivery, with higher rates in those delivering at <32 weeks and with prepregnancy BMI ≥40. Receipt of postpartum antibiotics decreased the odds of postpartum infection markedly.

Exenatide twice-daily does not affect renal function or albuminuria compared to titrated insulin glargine in patients with type 2 diabetes mellitus: A post-hoc analysis of a 52-week randomised trial.

AIMS: To compare the effects of long-term treatment with the GLP-1RA exenatide twice-daily versus titrated insulin glargine (iGlar) on renal function and albuminuria in type 2 diabetes (T2DM) patients. METHODS: We post-hoc evaluated renal outcome-data of 54 overweight T2DM patients (mean  ±â€¯SD age 60 ±â€¯8 years, HbA1c 7.5 ±â€¯0.9%, eGFR 86 ±â€¯16 mL/min/1.73 m2, median [IQR] urinary albumin-to-creatinine-ratio (UACR) 0.75 [0.44-1.29] mg/mmol) randomised to exenatide 10 µg twice-daily or titrated iGlar on-top-of metformin for 52-weeks. Renal efficacy endpoints were change in creatinine clearance (CrCl) and albuminuria (urinary albumin-excretion [UAE] and UACR) based on 24-h urines, collected at baseline and Week-52. eGFR and exploratory endpoints were collected throughout the intervention-period, and after a 4-week wash-out. RESULTS: HbA1c-reductions were similar with exenatide (mean ±â€¯SEM -0.80 ±â€¯0.10%) and iGlar (-0.79 ±â€¯0.14%; treatment-difference 0.02%; 95% CI -0.31 to 0.42%). Change from baseline to Week-52 in CrCl, UAE or UACR did not statistically differ; only iGlar reduced albuminuria (P < 0.05; within-group). eGFR decreased from baseline to Week-4 with exenatide (-3.9 ±â€¯2.1 mL/min/1.73 m2; P = 0.069) and iGlar (-2.7 ±â€¯1.2 mL/min/1.73 m2; P = 0.034), without treatment-differences in ensuing trajectory. Exenatide versus iGlar reduced bodyweight (-5.4 kg; 2.9-7.9; P < 0.001), but did not affect blood pressure, lipids or plasma uric acid. CONCLUSIONS: Among T2DM patients without overt nephropathy, one-year treatment with exenatide twice-daily does not affect renal function-decline or onset/progression of albuminuria compared to titrated iGlar. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT00097500.