Management of childbearing with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders: A scoping review and expert co-creation of evidence-based clinical guidelines.

OBJECTIVE: To co-create expert guidelines for the management of pregnancy, birth, and postpartum recovery in the context of hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). DESIGN: Scoping Review and Expert Co-creation. SETTING: United Kingdom, United States of America, Canada, France, Sweden, Luxembourg, Germany, Italy, and the Netherlands. SAMPLE: Co-creators (n = 15) included expertise from patients and clinicians from the International Consortium on the Ehlers-Danlos syndromes and Hypermobility Spectrum Disorders, facilitated by the Ehlers-Danlos Society. METHODS: A scoping review using Embase, Medline, the Cochrane Central Register of Controlled Trials and CINHAL was conducted from May 2022 to September 2023. Articles were included if they reported primary research findings in relation to childbearing with hEDS/HSD, including case reports. No language limitations were placed on our search, and our team had the ability to translate and screen articles retrieved in English, French, Spanish, Italian, Russian, Swedish, Norwegian, Dutch, Danish, German, and Portuguese. The Mixed Methods Appraisal Tool was used to assess bias and quality appraise articles selected. The co-creation of guidelines was based on descriptive evidence synthesis along with practical and clinical experience supported by patient and public involvement activities. RESULTS: Primary research studies (n = 14) and case studies (n = 21) including a total of 1,260,317 participants informed the co-creation of guidelines in four overarching categories: 1) Preconceptual: conception and screening, 2) Antenatal: risk assessment, management of miscarriage and termination of pregnancy, gastrointestinal issues and mobility, 3) Intrapartum: risk assessment, birth choices (mode of birth and intended place of birth), mobility in labor and anesthesia, and 4) Postpartum: wound healing, pelvic health, care of the newborn and infant feeding. Guidelines were also included in relation to pain management, mental health, nutrition and the common co-morbidities of postural orthostatic tachycardia syndrome, other forms of dysautonomia, and mast cell diseases. CONCLUSIONS: There is limited high quality evidence available. Individualized strategies are proposed for the management of childbearing people with hEDS/HSD throughout pregnancy, birth, and the postpartum period. A multidisciplinary approach is advised to address frequently seen issues in this population such as tissue fragility, joint hypermobility, and pain, as well as common comorbidities, including dysautonomia and mast cell diseases.

Early skin-to-skin contact and risk of late-onset-sepsis in very and extremely preterm infants.

BACKGROUND: To evaluate the association between exposure to early skin-to-skin contact (SSC) and incidence of late-onset sepsis (LOS) in extremely and very preterm infants. METHODS: Observational study using the national population-based EPIPAGE-2 cohort in 2011. A propensity score for SSC exposure was used to match infants with and without exposure to SSC before day 4 of life and binomial log regression used to estimate risk ratios and CIs in the matched cohort. The primary outcome was at least one episode of LOS during hospitalization. Secondary outcomes were the occurrence of any late-onset neonatal infection (LONI), LOS with Staphylococcus or Staphylococcus aureus, incidence of LOS and LONI per 1000 central venous catheter days. RESULTS: Among the 3422 included infants, 919 were exposed to early SSC. The risk ratio (RR) for LOS was 0.86 (95% CI, 0.67-1.10), for LONI was 1.00 (95% CI, 0.83-1.21), and for LOS with Coagulase-negative Staphylococcus or Staphylococcus aureus infection was 0.91 (95% CI, 0.68-1.21) and 0.77 (95% CI, 0.31-1.87). The incidence RR for LOS per-catheter day was 0.87 (95% CI, 0.64-1.18). CONCLUSION: Early SSC exposure was not associated with LOS or LONI risk. Thus, their prevention should not be a barrier to a wider use of SSC. IMPACT: Kangaroo Mother Care decreased neonatal infection rates in middle-income countries. Skin-to-skin contact is beneficial for vulnerable preterm infants but barriers exist to its implementation. In a large population-based study using a propensity score methods, we found that skin-to-skin contact before day 4 of life was not associated with a decreased risk of late-onset-sepsis in very and extremely preterm infants. Early skin-to-skin contact was not associated with an increased risk of any late-onset-neonatal-infection, in particular with staphylococcus. The fear of neonatal infection should not be a barrier to a wider use of early skin-to-skin contact in this population.

Changes of Infant- and Family-Centered Care Practices Administered to Extremely Preterm Infants During Implementation of the NIDCAP Program.

Introduction: Many studies have evaluated the Neonatal Individualized Developmental Care and Assessment Program (NIDCAP), but few studies have assessed changes in infant- and family-centered developmental care (IFCDC) practices during its implementation. Objectives: The primary objective of this single center study was to investigate the impact of the implementation of the NIDCAP program on IFCDC practices used for management of extremely preterm infants (EPIs). The secondary objective was to determine during implementation the impact of this program on the short-term medical outcomes of all EPIs hospitalized at our center. Methods: All EPIs (<28 weeks gestational age) who were hospitalized at Strasbourg University Hospital from 2007 to 2014 were initially included. Outborn infants were excluded. The data of EPIs were compared for three time periods: 2007 to 2008 (pre-NIDCAP), 2010 to 2011, and 2013 to 2014 (during-NIDCAP implementation) using appropriate statistical tests. The clinical and caring procedures used during the first 14 days of life were analyzed, with a focus on components of individualized developmental care (NIDCAP observations), infant pain management (number of painful procedures, clinical pain assessment), skin-to-skin contact (SSC; frequency, day of initiation, and duration), and family access and involvement in the care of their children (duration of parental presence, parental participation in care). The short-term mortality and morbidity at discharge were evaluated. Results: We examined 228 EPIs who received care during the three time periods. Over time, painful procedures decreased, but pain evaluations, parental involvement in care, individualized observations, and SSC increased (all p < 0.01). In addition, the first SSC was performed earlier (p = 0.03) and lasted longer (p < 0.01). There were no differences in mortality and morbidity, but there were reductions in the duration of mechanical ventilation (p = 0.02) and the time from birth to first extubation (p = 0.02), and an increase of weight gain at discharge (p = 0.02). Conclusion: NIDCAP implementation was accompanied by progressive, measurable, and significant changes in IFCDC strategies. There were, concomitantly, moderate but statistically significant improvements in multiple important outcome measures of all hospitalized EPI.

Preeclampsia Prevalence, Risk Factors, and Pregnancy Outcomes in Sweden and China.

Importance: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality worldwide. Within-country studies have reported racial differences in the presentation and outcome, but little is known about differences between countries. Objective: To compare preeclampsia prevalence, risk factors, and pregnancy outcomes between the Swedish and Chinese populations. Design, Setting, and Participants: This cross-sectional study compared deliveries from the Swedish national Medical Birth Register (2007-2012) and the China Labor and Delivery Survey (2015-2016). The Swedish Medical Birth Register records maternal, pregnancy, and neonatal information for nearly all deliveries in Sweden. The China Labor and Delivery Survey was conducted throughout China, and these data were reweighted to enable national comparisons. Participants included 555 446 deliveries from Sweden and 79 243 deliveries from China. Data management and analysis was conducted from November 2018 to August 2020 and revised in February to March 2021. Exposures: Maternal characteristics, parity, multiple gestation, chronic and gestational diabetes, cesarean delivery. Main Outcomes and Measures: Preeclampsia prevalence and risk factors, overall and for mild and severe forms and rates of adverse neonatal outcomes compared with pregnancies with no gestational hypertension. Results: The 555 446 Swedish pregnancies and 79 243 Chinese pregnancies had mean (SD) maternal age of 30.9 (5.3) years and 28.6 (4.6) years, respectively. The overall prevalence of preeclampsia was similar in Sweden and China, 16 068 (2.9%) and 1803 (2.3%), respectively, but with 5222 cases (32.5%) considered severe in Sweden and 1228 cases (68.1%) considered severe in China. Obesity (defined as BMI ≥28 in China and BMI ≥30 in Sweden) was a stronger risk factor in China compared with Sweden (China: odds ratio [OR], 5.12; 95% CI, 3.82-6.86; Sweden: OR, 3.49; 95% CI, 3.31-3.67). Nulliparity had a much stronger association with severe preeclampsia in Sweden compared with China (Sweden: OR, 3.91; 95% CI, 3.65-4.18; China: OR, 1.65; 95% CI, 1.20-2.25). The overall stillbirth rate for singleton in China was more than 3-fold higher than in Sweden (846/77 512[1.1%] vs 1753/547 219 [0.3%], P < .001), and 10-fold higher among women with preeclampsia (66/1652 [4.6%] vs 60/14 499[0.4%], P < .001). Conclusions and Relevance: In this study, the prevalence rates of preeclampsia in Sweden and China were similar, but women in China had more severe disease and worse pregnancy outcomes than women in Sweden. The associations of obesity and nulliparity with preeclampsia suggest a role for lifestyle and health care factors but may reflect some differences in pathophysiology. These findings have relevance for current efforts to identify high-risk pregnancies and early serum markers because the value of risk prediction models and biomarkers may be population specific.

Neonatal jaundice, attention deficit hyperactivity disorder and familial effects: A Swedish register study with sibling analysis.

AIM: Neonatal jaundice is associated with higher risk of attention deficit hyperactivity disorder (ADHD), but it is unclear if the association is influenced by genetic and other familial factors. In this large population-based study, we investigated the association between neonatal jaundice and ADHD while adjusting for familial factors. METHODS: We linked several Swedish registers to identify all singleton births without congenital malformations between 1992 and 2000 (n = 814 420, including 384 290 full siblings) and followed them up until 2009. We calculated hazard ratios (HRs) for the association between neonatal jaundice and ADHD, adjusting for pregnancy, delivery and neonatal characteristics including prematurity, and parental age and education. We repeated the analyses among siblings to adjust for shared familial factors. RESULTS: At a population level, children treated for neonatal jaundice had an increased risk of ADHD (adjusted HR (aHR): 1.13, 95% CI: 1.05-1.22). In the sibling comparisons, there was no clear association between neonatal jaundice and ADHD (aHR: 1.03, 95% CI: 0.82-1.29). CONCLUSION: We found no evidence of an independent association between neonatal jaundice and ADHD within siblings in this large population-based study, suggesting that the association is probably influenced by shared familial factors, such as parental genetic and/or lifestyle effects.

Planned delivery route and outcomes of cephalic singletons born spontaneously at 24-31 weeks' gestation: The EPIPAGE-2 cohort study.

INTRODUCTION: The objective of this study was to investigate the association between planned mode of delivery and neonatal outcomes with spontaneous very preterm birth among singletons in cephalic presentation. MATERIAL AND METHODS: Etude Epidémiologique sur les Petits Ages Gestationnels 2 is a French national, prospective, population-based cohort study of preterm infants. For this study, we included women with a singleton cephalic pregnancy and spontaneous preterm labor or preterm premature rupture of membranes at 24-31 weeks' gestation. The main exposure was the planned mode of delivery (ie planned vaginal delivery or planned cesarean delivery at the initiation of labor). The primary outcome was survival at discharge and secondary outcome survival at discharge without severe morbidity. Propensity scores were used to minimize indication bias in estimating the association. RESULTS: The study population consisted of 1008 women: 206 (20.4%) had planned cesarean delivery and 802 (79.6%) planned vaginal delivery. In all, 723 (90.2%) finally had a vaginal delivery. Overall, 187 (92.0%) and 681 (87.0%) neonates in the planned cesarean delivery and planned vaginal delivery groups were discharged alive, and 156 (77.6%) and 590 (76.3%) were discharged alive without severe morbidity. After matching on propensity score, planned cesarean delivery was not associated with survival (adjusted odds ratio [aOR] 1.05, 95% confidence interval [CI] 0.48-2.28) or survival without severe morbidity (aOR 0.64, 95% CI 0.36-1.16). CONCLUSIONS: Planned cesarean delivery for cephalic presentation at 24-31 weeks' gestation after preterm labor or preterm premature rupture of membranes does not improve neonatal outcomes.

Association of blood group and red blood cell transfusion with the incidence of antepartum, peripartum and postpartum venous thromboembolism.

The increased risk of venous thromboembolism (VTE) associated with pregnancy is well-known and prophylaxis guidelines consider a number of risk factors. Although non-O blood group and red blood cell (RBC) transfusion are known to be associated with VTE risk, their contribution to pregnancy-associated VTE has received little attention. This study was conducted in a population-based cohort of 1,000,997 deliveries to women with no prior history of VTE or thrombophilia. The independent contributions of ABO blood type and RBC transfusion to the risks of antepartum, peripartum and postpartum VTE are reported as odds ratios adjusted for risk factors that are considered in current prophylaxis guidelines and other potential confounders. Compared with type O, A and B blood types have higher risk of antepartum and postpartum VTE, with odds ratios between 1.4 and 1.8. Transfusion around delivery has the largest increased risks and a dose-response effect, with adjusted odds ratios from 2.60 (1.71-3.97) for 1-2 units to 3.55 (1.32-9.55) for more than 5 units. ABO blood type and RBC transfusion were found to be independent risk factors for pregnancy-associated VTE. Further research is required to understand the underlying mechanisms and to conduct a risk-benefit assessment of the small volumes of RBCs transfused around delivery.

Evaluation of a Decision Tree for Efficient Antenatal Red Blood Cell Antibody Screening.

BACKGROUND: Hemolytic disease of the fetus and newborn due to maternal red blood cell alloimmunization can have serious consequences. Because early detection enables careful monitoring of affected pregnancies, programs to routinely screen all pregnant women have been widely adopted. Due to the low prevalence of alloimmunization, these require large investments of resources to detect a small number of cases. METHODS: We conducted a validation study of a decision tree developed in the Netherlands for determining whether to screen for alloimmunization. In a Swedish cohort, we compared the performance of that decision tree to two alternative models that used maternal characteristics, obstetric history, and transfusion history to identify high-risk women for screening or low-risk women who might be exempt from screening. The models were compared for predictive ability and potential reduction in the volume of screening. RESULTS: The decision tree applied to our study population identified 89% of alloimmunized women with a negative predictive value (NPV) of 99.7% by screening 62% of the population. To achieve the same NPV, our model exempting low-risk women captured 90% of alloimmunizations by screening 63% of the population. In contrast, the model identifying high-risk women for screening while maintaining a similar NPV captured 63% of alloimmunized women by screening 20% of the population. CONCLUSIONS: We validated that an existing decision tree for selecting women for maternal screening performed well in our population, identifying a large proportion of women who became alloimmunized, with a predictive performance almost identical to that of a more elaborate model.

NAITRE study on the impact of conditional cash transfer on poor pregnancy outcomes in underprivileged women: protocol for a nationwide pragmatic cluster-randomised superiority clinical trial in France.

INTRODUCTION: Prenatal care is recommended during pregnancy to improve neonatal and maternal outcomes. Women of lower socioeconomic status (SES) are less compliant to recommended prenatal care and suffer a higher risk of adverse perinatal outcomes. Several attempts to encourage optimal pregnancy follow-up have shown controversial results, particularly in high-income countries. Few studies have assessed financial incentives to encourage prenatal care, and none reported materno-fetal events as the primary outcome. Our study aims to determine whether financial incentives could improve pregnancy outcomes in women with low SES in a high-income country. METHODS AND ANALYSIS: This pragmatic cluster-randomised clinical trial includes pregnant women with the following criteria: (1) age above 18 years, (2) first pregnancy visit before 26 weeks of gestation and (3) belonging to a socioeconomically disadvantaged group. The intervention consists in offering financial incentives conditional on attending scheduled pregnancy follow-up consultations. Clusters are 2-month periods with random turnover across centres. A composite outcome of maternal and neonatal morbidity and mortality is the primary endpoint. Secondary endpoints include maternal or neonatal outcomes assessed separately, qualitative assessment of the perception of the intervention and cost-effectiveness analysis for which children will be followed to the end of their first year through the French health insurance database. The study started in June 2016, and based on an expected decrease in the primary endpoint from 18% to 14% in the intervention group, we plan to include 2000 women in each group. ETHICS AND DISSEMINATION: Ethics approval was first gained on 28 September 2014. An independent data security and monitoring committee has been established. Results of the main trial and each of the secondary analyses will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02402855; pre-results.

Rivaroxaban versus standard anticoagulation for symptomatic venous thromboembolism (REMOTEV observational study): Analysis of 6-month outcomes.

BACKGROUND: This study aimed to provide safety and efficacy data of rivaroxaban in routine patient care in a non-selected symptomatic venous thromboembolism (VTE) population. METHODS AND RESULTS: REMOTEV is a prospective, non-interventional study of patients with acute symptomatic VTE, treated with oral rivaroxaban, VKA or parenteral heparin/fondaparinux alone for at least 3months and who are followed up for 6months. From Nov. 2013 to July 2015, 499 consecutive patients were retained for baseline analysis and 445 for safety analysis. The mean age was 65.1years, 7.6% had previously known active cancer, 18.6% had creatinine clearance 30≤CrCl<60mL/min, and 87.8% had pulmonary embolism with or without deep venous thrombosis. The major and clinically relevant bleeding rate was 5.4% (15/280) in the rivaroxaban group, 9.4%/(9/96) in the VKA group and 7.2% (5/69) in the heparin/fondaparinux group. The recurrent VTE rate was 1.4% (4/280) in the rivaroxaban group, 3.1% (3/96) in the VKA group and 11.6% (8/69) in the heparin/fondaparinux group. In the propensity score-adjusted samples, major and clinically relevant non-major bleeding (HR 0.37 [95% CI, 0.15 to 0.93], p<0.05), all-cause death (HR 0.21 [95% CI, 0.06 to 0.66], p<0.01) and the composite of recurrent VTE, major and clinically relevant non-major bleeding and all-cause mortality (HR 0.35 [95% CI, 0.17 to 0.71], p<0.01), were significantly lower in the rivaroxaban group compared to the VKA group. CONCLUSION: In REMOTEV 6-month outcomes are consistent with the findings of the phase 3 randomized trials and post-marketing data, with low rates of major bleeding and symptomatic recurrent VTE.

Haemolytic and nonhaemolytic neonatal jaundice have different risk factor profiles.

AIM: This study examined maternal and pregnancy risk factors for haemolytic and nonhaemolytic neonatal jaundice in a large population-based cohort study. METHODS: We conducted a cohort study of 1 019 220 singleton live births from the Swedish medical birth register from 1987 to 2002, using information on neonatal jaundice and maternal and pregnancy characteristics. Diagnoses of gestational hypertensive disorders were obtained by linkage to the national inpatient register. Multivariate logistic regression analysis provided odds ratios for the risk factors of both forms of jaundice. RESULTS: A total of 6057 (0.6%) births were affected by haemolytic jaundice and 36 869 (3.6%) by nonhaemolytic jaundice. The strongest risk factors for haemolytic jaundice were maternal alloimmunisation, blood group O and neonatal jaundice in older siblings. For nonhaemolytic jaundice, the strongest risk factors were preterm birth, neonatal jaundice in older siblings, maternal origin from East or South-East Asia and maternal obesity. We estimated that 13% of haemolytic jaundice was attributable to alloimmunisation and 39% of nonhaemolytic jaundice was attributable to preterm birth. CONCLUSION: Haemolytic and nonhaemolytic neonatal jaundice had different risk factor profiles. Interventions to reduce maternal alloimmunisation, preterm birth and maternal obesity may lower the prevalence of neonatal jaundice and the risk of consequent neurological complications.

Changes in maternal blood inflammatory markers as a predictor of chorioamnionitis: a prospective multicenter study.

PROBLEM: To evaluate the inflammatory pattern in maternal circulation from women with preterm premature rupture of membranes (PPROM) considering the occurrence of histologically confirmed chorioamnionitis (HCA). METHOD OF STUDY: A prospective study was conducted in 121 women with PPROM between 24 and 34 + 0 weeks of gestation. Association between white blood cells (WBC) count, plasma CRP, IL-6, MCP-1 and IP-10 levels, and HCA was assessed. RESULTS: The rate of HCA was 44.7% (54/121). During the 5 days preceding delivery, median CRP, WBC, and IL-6 levels were significantly higher in the HCA than in no-HCA group (P < 0.001). Variations in IL-6, IP-10 levels, during the 24-72 hr before delivery, were predictors of the occurrence of HCA, but the diagnostic accuracy was low [Receiver Operating Characterictic (ROC) curve, area under the curve (AUC) = 0.56]. CONCLUSION: An increase in IL-6, CRP, IP-10 maternal plasma levels was confirmed in PPROM women with HCA. Longitudinal follow-up of these markers did not add valuable information regarding HCA.

Pharmacokinetic evaluation of esomeprazole for the treatment of gastroesophageal reflux disease.

INTRODUCTION: Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases such as gastroesophageal reflux disease (GERD). They are recommended by the American College of Gastroenterology for healing erosive esophagitis (EO) and as long-term treatment in patients with healed EO. The available PPIs differ somewhat in their pharmacokinetics and clinical properties, but whether these differences are of clinical relevance is a matter of debate. Some safety concerns have been raised with the use of PPIs, mostly an increased incidence of infectious diseases such as community-acquired pneumonia or Clostridium difficile diarrhea. AREAS COVERED: This article explores the results of clinical studies on the pharmacokinetics and pharmacodynamics of esomeprazole , as well as on its clinical efficacy to manage patients with GERD. EXPERT OPINION: GERD is a public health concern as its worldwide incidence and associated complications are increasing alongside the exponentially increasing problem of obesity. PPIs are the first pharmacological option because of their efficacy and overall positive risk-to-benefit ratio. Improved efficacy with the use of stereospecific isomers of PPIs, such as esomeprazole, has not yet been convincingly demonstrated. Nevertheless, because of individual experience with former treatment, some patients may report better symptom control when treated with a specific PPI rather than with others.

Treatment of pancreatic cancer: A narrative review of cost-effectiveness studies.

Cancer of the pancreas is the second most frequent digestive cancer in the US, accounting for about 44,000 new cases per year. In Europe, it is the sixth most frequent cancer, accounting for 2.8% of cancers in men and 3.2% in women. With a five-year survival of less than 10%, it is the fifth leading cause of cancer-related death. The majority of cases are diagnosed above the age of 65 and in about 60% of cases at an advanced stage, explaining that little improvement has been observed in survival over the past 30 years. Radical surgery offers the only curative treatment of pancreatic cancer. Alternative or combined therapeutic options in particular consist of adjuvant or neoadjuvant chemotherapy, with or without radiotherapy. Palliative treatment for locally advanced disease may benefit patient's health status and quality of life. Limitations in healthcare resources, burden of treatment, and uncertainty of the net clinical benefit of adjuvant therapy, underline the need to identify the cost-effectiveness of different therapeutic approaches, as well as a need to establish patient groups who benefit most from these treatments. The present paper reviews cost-effectiveness studies published on pancreatic cancer treatment.

Effects of leptin on lipopolysaccharide-induced remodeling in an in vitro model of human myometrial inflammation.

Reorganization of myometrial extracellular matrix (ECM) is essential for the uterus to achieve powerful synchronous contractions during labor. Remodeling of the ECM has been implicated in membrane rupture and cervical ripening. Because maternal obesity is associated with both delivery disorders and elevated circulating leptin levels, this study aimed to assess the ability of leptin to interfere with lipopolysaccharide (LPS)-induced myometrial ECM remodeling. Myometrial biopsy samples were obtained from women undergoing cesarean delivery before labor onset. Myometrial explants were incubated for 48 h with LPS and leptin. LPS challenge was associated with a marked decrease in collagen content and in heat shock protein (HSP) 47 expression, reflecting a disruption in collagen synthesis and an increase in matrix metalloproteinase (MMP) 2 and MMP9 activity and in MMP2, MMP9, and MMP13 expression. Leptin prevented an LPS-induced decrease in myometrial collagen content in a concentration-dependent manner. This effect was associated with an increase in HSP47 expression and a decrease in MMP2 and MMP9 activity and expression. These results show that leptin prevents LPS-induced myometrial remodeling through collagen synthesis stimulation and inhibition of MMP2 and MMP9. Our study strengthens the hypothesis that leptin plays a role in the development of obesity-related delivery disorders.

Failure to renew prescriptions for gastroprotective agents to patients on continuous nonsteroidal anti-inflammatory drugs increases rate of upper gastrointestinal injury.

BACKGROUND & AIMS: Patients with risk factors for gastrointestinal (GI) disorders who continuously use nonsteroidal anti-inflammatory drugs (NSAIDs) also should take gastroprotective agents (GPAs), such as proton pump inhibitors (PPIs). However, it is not clear how many physicians continue to prescribe GPAs to these patients, and whether stopping the GPA prescription increases GI complications. METHODS: We performed a retrospective, observational, longitudinal study using a validated electronic database of representative general practitioners in France. We analyzed data for 1856 patients at risk for GI events (>65 y, past history of GI ulcer, or receiving antiplatelet agents) who received prescriptions for an NSAID and PPI from 2007 to 2009. Kaplan-Meier curves were used to determine the probability of still being prescribed a GPA at 12 and 24 months after the first prescription. Multivariate logistic regression analysis was used to identify factors associated with nonpersistence. GI complication rates were compared using the Student t test. RESULTS: The probability of still being prescribed a PPI along with an NSAID 1 year after the study began was 77.5% (95% confidence interval [CI], 75.6%-79.4%) and 68.3% after 2 years (95% CI, 66.1%-70.4%). Risk factors for no longer receiving a prescription for a PPI included switching to a cyclooxygenase-2-selective inhibitor (hazard ratio [HR], 2.50; 95% CI, 1.91-3.28; P < .001) or to a nonselective NSAID (HR, 1.63; 95% CI, 1.33-1.99; P < .001), and female sex (HR, 1.25; 95% CI, 1.05-1.45; P < .05). In 50% of these cases, the PPI was reintroduced within 6 months, without a specific reason in 70% of the cases. The risk for upper GI injury was higher among patients with discontinued prescriptions for PPIs (odds ratio, 1.45; 95% CI, 1.06-2.09; P = .02). CONCLUSIONS: Within 2 years after prescribing a PPI, physicians do not renew this prescription for approximately 33% of patients receiving continuous NSAIDs. This increases the risk for GI adverse events among these patients.

Pharmacokinetic and clinical evaluation of esomeprazole and ASA for the prevention of gastroduodenal ulcers in cardiovascular patients.

INTRODUCTION: Low-dose aspirin (ASA, 75 - 325 mg/day) is widely used for the primary and secondary prevention of cardiovascular (CV) diseases. However, the value of primary prevention ASA is uncertain as the reduction in occlusive events needs to be weighed against the significant increase in major bleedings. Prevention with antisecretory drugs has been proposed to reduce the incidence of ASA-induced gastrointestinal (GI) bleedings, but non-adherence to gastro-protection is of concern, as it significantly increases the risk of upper GI adverse events. Beside patients and physicians education, one approach to overcome non-adherence is the development of fixed-dose combination. AREA COVERED: This review explores the results of clinical studies on the influence of the combination esomeprazole (ESA) and ASA on pharmacokinetic (PK) parameters, and the role for such combination in prevention of CV events in patients at risk of gastric ulcers. EXPERT OPINION: Patients at risk of ASA-induced gastroduodenal ulcer might benefit from a fixed ASA and proton pump inhibitor (PPI) combination. PK and PD parameters suggest there is no significant interaction between these drugs. Nevertheless, attention must be paid on the appropriate use of such combination, that is, still balancing the risk:benefit ratio in a real-life setting, and any increase in the proportion of patients receiving ASA and PPI should be considered as a warning signal.

Local estrogen therapy and risk of breast cancer recurrence among hormone-treated patients: a nested case-control study.

Women with estrogen-positive breast cancers receive endocrine treatment such as tamoxifen and aromatase inhibitors (AI) for 5-10 years. An important side effect of these drugs is vaginal dryness for which local hormonal therapy (LHT) represents the most effective treatment but is theoretically contraindicated. This study aimed to assess whether the use of LHT increases the risk of breast cancer recurrence among women receiving endocrine treatment. We conducted a cohort study with nested case-control analysis using the United Kingdom General Practice Research Database (GPRD). The cohort included female patients at least 18 years of age, newly diagnosed with breast cancer who received at least one AI or tamoxifen prescription between January 1, 1998 and June 30, 2008. Cases, who were patients experiencing a breast cancer recurrence during follow-up, were each matched with up to 10 controls based on age, date of cohort entry, type of endocrine treatment received, and duration of follow-up. Conditional logistic regression was used to estimate rate ratios (RR), and 95 % confidence intervals. A total of 13,479 women were included in the study, of which 2,673 received AIs, 10,806 received tamoxifen, and 271 received LHT. Mean (SD) age at cohort entry was 63.7 (14.1) years, and mean follow-up was 3.5 (2.6) years. The crude recurrence rate 25.9 per 1,000 per year. Overall, the use of LHT was not associated with an increased risk of recurrence (RR: 0.78, 95 % CI 0.48-1.25) compared with non-use. In stratified analyses, LHT did not increase the risk of recurrence among tamoxifen-treated patients (RR: 0.83, 95 % CI 0.51-1.34), while the risk was not estimable among AI-treated patients since no patients receiving LHT experienced a recurrence. The use of LHT is not associated with an increase in breast cancer recurrence among women receiving a hormone therapy.

Diagnosis and management of nonvariceal upper gastrointestinal bleeding.

Nonvariceal upper gastrointestinal bleeding (UGIB) is a major cause of morbidity and mortality worldwide. Despite the improvements in the management of this condition in western countries, mortality rates have remained at 5-10% over the past decade. This article presents the main recommendations for the management of UGIB. Pre-endoscopic management (including use of scoring scales, nasogastric tube placement and blood pressure stabilization) is crucial for triage and optimal resuscitation of patients, and should include a multidisciplinary approach at an early stage. Unless the patient has specific comorbidities, transfusion should only be considered if their hemoglobin level is ≤70 g/l. Endoscopic therapy, the cornerstone of therapeutic management of high-risk lesions, should not be delayed for more than 24 h following admission. Several endoscopic techniques, mostly using clips or thermal methods, are available and new approaches are emerging. When endoscopy fails, surgery or arterial embolization should be considered. Although the efficacy of prokinetics and high-dose intravenous PPI prior to endoscopy is controversial, the use of an intravenous PPI following endoscopy is strongly recommended. Antiplatelet therapy should be suspended and resumed in 3-5 days. Finally, all patients should be tested for Helicobacter pylori by serology in the acute setting.