2 Minute Medicine Rewind March 20, 2017


Association between maternal body mass index in early pregnancy and incidence of cerebral palsy

Cerebral palsy is the most common pediatric motor disorder which can result in significant lifetime disability for children. One previous small scale study suggested an association between maternal BMI and cerebral palsy however, the relationship in a large scale study has not yet been confirmed. The purpose of this study was to determine the associations between early pregnancy BMI and rates of cerebral palsy by gestational age. This retrospective cohort study obtained cases from several nation wide patient registries from 1997 to 2011. Maternal BMI was calculated from self reported height and weight measurements from initial prenatal visits. Other variables assessed in this study were maternal age, parity, cohabitation with child’s father, smoking, and length of gestation.  Of the 1,423,929 children included, 3,029 were diagnosed with cerebral palsy over a median of 7.8 years of follow-up (the risk of cerebral palsy was 2.13 per 1,000 live births). Rates of cerebral palsy increased with maternal overweight and obesity among children born at full term. Compared with children of normal weight mothers, the adjusted hazard ratio (HR) of cerebral palsy for overweight was 2.22 (95%CI, 1.11-1.13) and for obesity grade 1 was 1.28 (95%CI, 1.11-1.47), grade 2 was 1.54 (95%CI, 1.24-1.93), and grade 3 was 2.02 (95%CI, 1.46-2.79). The results were statistically significant for children born at full term who comprised 71% of all children with cerebral palsy but not for preterm infants. The study concluded that among Swedish women with singleton children, maternal overweight and obesity were significantly associated with higher rates of cerebral palsy. The association however was limited to children born at full term.

Variation in inpatient croup management and outcomes

Because croup is a clinical diagnosis, ancillary testing such as radiologic imaging or lab tests are not helpful. Given the limited inpatient-specific evidence for croup management, the authors hypothesized that there would be variability in the use of not routinely indicated resources (NRIRs). The purpose of this study was to describe the variation and predictors of variation in the use of NRIRs. This was a retrospective cohort study that used the Pediatric Health Information System database of  6236 inpatients with croup aged six months to 15 years who were admitted from January 2012 to September 2014.  The authors collected patient level information (demographics, clinical presentation, treatment, outcomes) and hospital characteristics (croup admission and annual patient census). The NRIRs analyzed included parenteral steroids, viral studied, chest and lateral neck xrays, and antibiotics. Results showed there were several variations in croup management based on hospital. For example, depending on the hospital, viral studies ranged from 1-40%, parenteral steroid use ranged from 16-88%, and use of ≥2 NRIRs ranged from 16-60% at the hospital level. Besides antibiotic use, the risk-adjusted analysis showed wide differences in the use of NRIRs across hospitals, conversely, hospital level variation in patient outcomes were not as pronounced. Based on hospital, rates of intubation ranged from 0-6%, proportion of 30 day readmission ranged from 0-3%, and rates of return to ED within one week were 0-3%. Data failed to show clear associations between NRIR use and patient outcomes. The authors concluded that there was up to a five fold difference in NRIR utilization attributable to hospital level practice variability in inpatient croup care despite differences in outcome and there remains a need for inpatient specific evidence based intervention to reduce unnecessary resource utilization and to improve patient outcomes.

Association between dietary factors and mortality from heart disease, stroke, and type 2 diabetes in the United States

Dietary habits have a clear influence on risk factors for heart disease, stroke, and type 2 diabetes. The purpose of this study was to estimate associations of intake of 10 specific dietary factors with mortality due to heart disease, stroke, and type 2 diabetes among US adults. The study utilized a comparative risk assessment model to estimate the numbers of deaths due to heart disease, stroke, type 2 diabetes associated with suboptimal intake of 10 dietary factors among US adults. The 10 factors were consumption of fruits, vegetables, nuts/seeds, whole grains, unprocessed red meats, processed meats, sugar-sweetened beverages, polyunsaturated fats, seafood omega 3-fats, and sodium. Data was obtained from National Health and Nutrition Examination Surveys from 1999-2002 and 2009-2012, and disease-specific national mortality obtained from the National Center for Health Statistics. In 2012, over 506,100 deaths occurred due to heart disease, 128,294 occurred from stroke, and 67,914 due to type 2 diabetes. Of these 318,656 (95% uncertainty interval [UI], 306,064-329,755; 45.4%) were due to suboptimal dietary consumptions such as high sodium intake (9.5% of all deaths), low nuts/seeds (8.5%), high processed meats (8.2%), low seafood omega 3-fats (7.8%), low vegetables (7.6%), low fruits (7.5%), and high sugar-sweetened beverages (7.4%). Between 2002 and 2012, population-adjusted US cardiometabolic deaths per year decreased by 26.5%. The greatest decline was associated with insufficient polyunsaturated fats (−20.8% relative change [95% UI, −18.5% to −22.8%]), nuts/seeds (−18.0% [95% UI, −14.6% to −21.0%]), and excess sugar sweetened beverages (−14.5% [95% UI, −12.0% to −16.9%]). The greatest increase was associated with unprocessed red meats (+14.4% [95% UI, 9.1%-19.5%]). The authors concluded that dietary factors were associated with substantial proportion of deaths from heart disease, stroke, and type 2 diabetes.

Pembrolizumab as second-line therapy for advanced urothelial carcinoma

It is known that patients with advanced urothelial carcinoma that progresses after receiving platinum-based chemotherapy have a poor prognosis and limited treatment options. The purpose of this study was to evaluate the effect of pembrolizumab, an antibody against programmed death 1 receptor (PD-1) compared to other second-line therapies for metastatic urothelial carcinoma that recurs after platinum-based chemotherapy. This was an open-label, international, phase 3 trial where 542 patients with advanced urothelial cancer which progressed or recurred following platinum-based chemotherapy were randomly assigned to receive pembrolizumab at a dose of 200mg every three weeks or the investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The outcomes of interest were overall survival and progression free survival.

The median duration of follow up was 14.1 months and the overall survival was significantly longer in the pembrolizumab group compared to the chemotherapy group (HR 0.73: 95%CI: 0.59 to 0.91; p=0.002).  In addition, pembrolizumab was associated with longer overall survival (HR 0.57; 95%CI: 0.37 to 0.88; p=0.005) in patients with high PD-L1 expression. Treatment response observed on imaging was also significantly higher for the pembrolizumab group (21.1% vs. 11.4%; p=0.001). Adverse events were observed in 60.9% of pembrolizumab patients and 90.2% of those treated with chemotherapy. The authors concluded that pembrolizumab was associated with significantly longer overall survival (by three months) and with lower rate of treated related adverse events than chemotherapy in platinum-refractory advanced urothelial carcinoma.

Long-term low-density lipoprotein cholesterol-lowering efficacy, persistence, and safety of evolocumab in treatment of hypercholesterolemia

Several trials have shown the efficacy of monoclonal antibodies such as evolocumab against proprotein convertase subtilisin/kexin type 9 (PCSK9-inhibitor) at decreasing low-density lipoprotein cholesterol (LDL-C) levels when statins were insufficient. However, these trials have only been studied over short periods. The purpose of this study was to determine the long term efficacy and safety during long term therapy with evolocumab and quantify whether LDL-C level reductions persist across different populations. This was an ongoing, randomized open-label extension trial (OSLER-1) conducted at 192 sites in 18 countries from October 2011 to August 2016. A total of 1324 of 1666 patients randomized into one of five 12-week double-blind phase 2 parent studies completed a parent study and chose to participate in OSLER-1. 1255 received 1 or more evolocumab dose. During year 1, patients were randomized to 420mg evolocumab, plus standard of care (SOC), or SOC alone. After year 1, all patients continuing the study received evolocumab plus SOC. The outcomes of interest were lipid levels, safety, and tolerability ever 12 weeks.  The mean age (SD) of the population was 57.1 (11.6) years with 52.9% women. The median LDL-C level was 133 mg/dL. After one year, evolocumab plus SOC was associated with a significant reduction in LDL-C level by 61% (95%CI: -63% to -60%) vs  2% (95CI: -5% to -0.2%) with SOC alone (p<0.001).  In addition, at two, three, and four years of follow up, the median LDL-C level was reduced by 59% (95% CI, −60% to −57%), 59% (95% CI, −61% to −58%), and 57% (95% CI, −59% to −55%), respectively from the study at baseline. The annualized incidence of new-onset diabetes was 4% in the SOC alone group and 2.8% in the evolocumab plus SOC group. Neurocognitive event rates were 0% (SOC alone) and 0.4% (evolocumab plus SOC).  The authors concluded in this longest clinical trial exposure to a PCSK9 inhibitor to date, evolocumab produced sustained reductions in LDL-C levels and the annual frequency of adverse events did not occur more frequently with cumulative exposure during open-label observation.

Image: PD

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