Association Between Diabetes and Mortality Among Adult Patients Hospitalized With COVID-19: A Cohort Study of Hospitalized Adults in Ontario, Canada, and Copenhagen, Denmark.

OBJECTIVES: Diabetes has been reported to be associated with an increased risk of death among patients with COVID-19. However, the available studies lack detail on COVID-19 illness severity and measurement of relevant comorbidities. METHODS: We conducted a multicentre, retrospective cohort study of patients 18 years of age and older who were hospitalized with COVID-19 between January 1, 2020, and November 30, 2020, in Ontario, Canada, and Copenhagen, Denmark. Chart abstraction emphasizing comorbidities and disease severity was performed by trained research personnel. The association between diabetes and death was measured using Poisson regression. The main outcome measure was in-hospital 30-day risk of death. RESULTS: Our study included 1,133 hospitalized patients with COVID-19 in Ontario and 305 in Denmark, of whom 405 and 75 patients, respectively, had pre-existing diabetes. In both Ontario and Denmark, patients with diabetes were more likely to be older; have chronic kidney disease, cardiovascular disease, and higher troponin levels; and be receiving antibiotics, when compared with adults without diabetes. In Ontario, 24% (n=96) of adults with diabetes died compared with 15% (n=109) of adults without diabetes. In Denmark, 16% (n=12) of adults with diabetes died in hospital compared with 13% (n=29) of those without diabetes. In Ontario, the crude mortality ratio among patients with diabetes was 1.60 (95% confidence interval [CI], 1.24 to 2.07) and in the adjusted regression model it was 1.19 (95% CI, 0.86 to 1.66). In Denmark, the crude mortality ratio among patients with diabetes was 1.27 (95% CI, 0.68 to 2.36) and in the adjusted model it was 0.87 (95% CI, 0.49 to 1.54). Meta-analysis of the 2 rate ratios from each region resulted in a crude mortality ratio of 1.55 (95% CI, 1.22 to 1.96) and an adjusted mortality ratio of 1.11 (95% CI, 0.84 to 1.47). CONCLUSION: The presence of diabetes was not strongly associated with in-hospital COVID-19 mortality independent of illness severity and other comorbidities.

Potentially avoidable admissions to general internal medicine at an academic teaching hospital: an observational study.

BACKGROUND: Identifying potentially avoidable admissions to Canadian hospitals is an important health system goal. With general internal medicine (GIM) accounting for 40% of hospital admissions, we sought to develop a method to identify potentially avoidable admissions and characterize patient, provider and health system factors. METHODS: We conducted an observational study of GIM admissions at our institution from August 2019 to February 2020. We defined potentially avoidable admissions as admissions that could be managed in an appropriate and safe manner in the emergency department or ambulatory setting and asked staff physicians to screen admissions daily and flag candidates as potentially avoidable admissions. For each candidate, we prepared a case review and debriefed with members of the admitting team. We then reviewed each candidate with our research team, assigned an avoidability score (1 [low] to 4 [high]) and identified contributing factors for those with scores of 3 or more. RESULTS: We screened 601 total admissions and staff physicians flagged 117 (19.5%) of these as candidate potential avoidable admissions. Consensus review identified 67 candidates as potentially avoidable admissions (11.1%, 95% confidence interval 8.8%-13.9%); these patients were younger (mean age 65 yr v. 72 yr), had fewer comorbidities (Canadian Institute for Health Information Case Mix Group+ 0.42 v. 1.14), had lower resource-intensity weighting scores (0.72 v. 1.50) and shorter hospital lengths of stay (29 h v. 105 h) (p < 0.01). Common factors included diagnostic and therapeutic uncertainty, perceived need for short-term monitoring, government directive of a 4-hour limit for admission decision-making and subspecialist request to admit. INTERPRETATION: Our prospective method of screening, flagging and case review showed that 1 in 9 GIM admissions were potentially avoidable. Other institutions could consider adapting this methodology to ascertain their rate of potentially avoidable admissions and to understand contributing factors to inform improvement endeavours.

Resident physicians' perceptions of COVID-19 risk.

BACKGROUND: Resident physicians provide front-line care to coronavirus disease 2019 (COVID-19) patients, but little is known about how they perceive the risk to their own health or how this is affected by the increasing role of social media in disseminating information. This study aims to determine resident physicians' perceptions of personal COVID-19 risk during the first COVID wave and compare risk perceptions between low-average and high social media users. METHODS: We conducted a cross-sectional survey at the University of Toronto in May 2020 among resident physicians in internal medicine, emergency medicine, critical care, and anaesthesia. Participants were considered high social media users if above the median for daily social media use and low-average users if at or below the median. The primary outcome was perceived risk of hospitalization with COVID-19 within 6 months. RESULTS: A total of 98 resident physicians reported a median of 1-2 hours daily on social media, and 55.7% endorsed social media as a very or the most common source of information on COVID-19. The median overall perceived risk of hospitalization was 10% (inter-quartile range [IQR] 5-25)-7.5% for low-average social media users and 17.5% for high social media users (p = 0.10). CONCLUSIONS: Resident physicians have an elevated perception of COVID-19 risk, including a perceived risk of hospitalization 250 times greater than the local population risk. Although social media are an important source of information on COVID-19, risk perception did not significantly differ between high and low-average social media users.

HISTORIQUE: Les résidents en médecine donnent des soins de première ligne aux patients atteints de la maladie à coronavirus 2019 (COVID-19), mais on possède peu d'information au sujet de la perception de leur risque personnel ou de l'effet de la diffusion croissante d'information et de désinformation dans les réseaux sociaux sur leur perception. La présente étude vise à déterminer les perceptions du risque personnel de COVID-19 chez les résidents en médecine pendant la première vague de la pandémie et à comparer les perceptions de risque entre les utilisateurs faibles à modérés et les grands utilisateurs des réseaux sociaux. MÉTHODOLOGIE: En mai 2020, les chercheurs ont réalisé une étude transversale auprès des résidents en médecine interne, en médecine d'urgence, en soins intensifs et en anesthésie de l'Université de Toronto. Ceux qui se situaient au-dessus de la médiane d'utilisation quotidienne des réseaux sociaux étaient considérés comme de grands utilisateurs des réseaux sociaux, et ceux qui se situaient sur ou sous la médiane, comme des utilisateurs faibles ou modérés. Le résultat clinique primaire était le risque perçu d'hospitalisation à cause de la COVID-19 dans les six mois, et les résultats cliniques secondaires, le risque estimatif de contracter la COVID-19 ou d'infecter des membres de la famille, le degré d'anxiété au sujet de la COVID-19 et les répercussions perçues de l'hospitalisation. RÉSULTATS: Au total, 98 résidents en médecine ont déclaré consacrer une médiane de une à deux heures par jour aux réseaux sociaux, et 55,7 % considéraient les réseaux sociaux comme leur principale source d'information ou une source d'information très importante sur la COVID-19. Le risque médian perçu de contracter la COVID-19 s'élevait à 60 % (ratio interquartile [RIQ] 32 à 75), d'être hospitalisé, à 10 % (RIQ 5 à 25), et d'infecter des membres de la famille, à 37 % (RIQ 10,5 à 60). Le risque médian perçu d'hospitalisation s'élevait à 7,5 % pour les utilisateurs faibles ou modérés des réseaux sociaux, et à 17,5 % pour les grands utilisateurs des réseaux sociaux (p = 0,10). CONCLUSIONS: Les résidents en médecine ont une perception élevée du risque de COVID-19, y compris une perception du risque d'hospitalisation 250 fois plus élevée que celle de la population locale. Même si les médias sociaux représentent une source importante d'information sur la COVID-19 pour les résidents en médecine, la perception du risque ne différait pas de manière significative entre les grands utilisateurs et les faibles utilisateurs des réseaux sociaux.

Variation in the risk of death due to COVID-19: An international multicenter cohort study of hospitalized adults.

BACKGROUND: There is wide variation in mortality among patients hospitalized with COVID-19. Whether this is related to patient or hospital factors is unknown. OBJECTIVE: To compare the risk of mortality for patients hospitalized with COVID-19 and to determine whether the majority of that variation was explained by differences in patient characteristics across sites. DESIGN, SETTING, AND PARTICIPANTS: An international multicenter cohort study of hospitalized adults with laboratory-confirmed COVID-19 enrolled from 10 hospitals in Ontario, Canada and 8 hospitals in Copenhagen, Denmark between January 1, 2020 and November 11, 2020. MAIN OUTCOMES AND MEASURES: Inpatient mortality. We used a multivariable multilevel regression model to compare the in-hospital mortality risk across hospitals and quantify the variation attributable to patient-level factors. RESULTS: There were 1364 adults hospitalized with COVID-19 in Ontario (n = 1149) and in Denmark (n = 215). In Ontario, the absolute risk of in-hospital mortality ranged from 12.0% to 39.8% across hospitals. Ninety-eight percent of the variation in mortality in Ontario was explained by differences in the characteristics of the patients. In Denmark, the absolute risk of inpatients ranged from 13.8% to 20.6%. One hundred percent of the variation in mortality in Denmark was explained by differences in the characteristics of the inpatients. CONCLUSION: There was wide variation in inpatient COVID-19 mortality across hospitals, which was largely explained by patient-level factors, such as age and severity of presenting illness. However, hospital-level factors that could have affected care, including resource availability and capacity, were not taken into account. These findings highlight potential limitations in comparing crude mortality rates across hospitals for the purposes of reporting on the quality of care.

Prediction of personal protective equipment use in hospitals during COVID-19.

Demand for Personal Protective Equipment (PPE) such as surgical masks, gloves, and gowns has increased significantly since the onset of the COVID-19 pandemic. In hospital settings, both medical staff and patients are required to wear PPE. As these facilities resume regular operations, staff will be required to wear PPE at all times while additional PPE will be mandated during medical procedures. This will put increased pressure on hospitals which have had problems predicting PPE usage and sourcing its supply. To meet this challenge, we propose an approach to predict demand for PPE. Specifically, we model the admission of patients to a medical department using multiple independent [Formula: see text] queues. Each queue represents a class of patients with similar treatment plans and hospital length-of-stay. By estimating the total workload of each class, we derive closed-form estimates for the expected amount of PPE required over a specified time horizon using current PPE guidelines. We apply our approach to a data set of 22,039 patients admitted to the general internal medicine department at St. Michael's hospital in Toronto, Canada from April 2010 to November 2019. We find that gloves and surgical masks represent approximately 90% of predicted PPE usage. We also find that while demand for gloves is driven entirely by patient-practitioner interactions, 86% of the predicted demand for surgical masks can be attributed to the requirement that medical practitioners will need to wear them when not interacting with patients.

Major reductions in unnecessary aspartate aminotransferase and blood urea nitrogen tests with a quality improvement initiative.

BACKGROUND/CONTEXT: Unnecessary laboratory testing leads to considerable healthcare costs. Aspartate aminotransferase (AST), commonly ordered with alanine aminotransferase (ALT) and blood urea nitrogen (BUN), commonly ordered with creatinine (Cr), often add little value to patient management at significant cost. We undertook a choosing wisely based quality improvement initiative to reduce the frequency of testing. OBJECTIVES: To reduce the ratio of AST/ALT and BUN/Cr to less than 5% for all inpatient and outpatient test orders. MEASURES: Absolute number and ratio of AST/ALT and BUN/Cr; AST, ALT, BUN and Cr tests per 100 hospital days; projected annualised cost savings and monthly acute inpatient bed days. IMPROVEMENTS: We created guidelines for appropriate indications of AST and BUN testing, provided education with audit and feedback and removed AST and BUN from institutional order sets. IMPACT/RESULTS: The ratios of AST/ALT and BUN/Cr decreased significantly over the study period (0.37 to 0.14, 0.57 to 0.14, respectively), although the goal of 0.05 was not achieved due to a delay in adopting the choosing wisely strategies during the study time period by some inpatient units. The number of tests per 100 hospital days decreased from 20 to 7 AST (95% CI 19 to 20.5, 5.6 to 8.7, p<0.001) and from 72 to 17 BUN (95% CI 70 to 73.4, 16.6 to 22.9, p<0.001). The initiative resulted in a projected annualised cost savings of C$221 749. DISCUSSION: A significant decrease in the AST/ALT and BUN/Cr ratios can be achieved with a multimodal approach and will result in substantial healthcare savings.

Empiric Antibiotic Treatment Thresholds for Serious Bacterial Infections: A Scenario-based Survey Study.

BACKGROUND: Physicians face competing demands of maximizing pathogen coverage while minimizing unnecessary use of broad-spectrum antibiotics when managing sepsis. We sought to identify physicians' perceived likelihood of coverage achieved by their usual empiric antibiotic regimen, along with minimum thresholds of coverage they would be willing to accept when managing these patients. METHODS: We conducted a scenario-based survey of internal medicine physicians from across Canada using a 2 × 2 factorial design, varied by infection source (undifferentiated vs genitourinary) and severity (mild vs severe) denoted by the Quick Sequential Organ Failure Assessment (qSOFA) score. For each scenario, participants selected their preferred empiric antibiotic regimen, estimated the likelihood of coverage achieved by that regimen, and considered their minimum threshold of coverage. RESULTS: We had 238 respondents: 87 (36.6%) residents and 151 attending physicians (63.4%). The perceived likelihood of antibiotic coverage and minimum thresholds of coverage (with interquartile range) for each scenario were as follows: (1) severe undifferentiated, 90% (89.5%-95.0%) and 90% (80%-95%), respectively; (2) mild undifferentiated, 89% (80%-95%) and 80% (70%-89.5%); (3) severe genitourinary, 91% (87.3%-95.0%) and 90% (80.0%-90.0%); and (4) mild genitourinary, 90% (81.8%-91.3%) and 80% (71.8%-90%). Illness severity and infectious disease specialty predicted higher thresholds of coverage whereas less clinical experience and lower self-reported prescribing intensity predicted lower thresholds of coverage. CONCLUSIONS: Pathogen coverage of 80% and 90% are physician-acceptable thresholds for managing patients with mild and severe sepsis from bacterial infections. These data may inform clinical guidelines and decision-support tools to improve empiric antibiotic prescribing.

Cardiac stress biomarkers after red blood cell transfusion in patients at risk for transfusion-associated circulatory overload: a prospective observational study.

BACKGROUND: Transfusion-associated circulatory overload (TACO) is a leading cause of serious reactions. In regard to TACO, little is known regarding biomarkers as a predictor, their most informative timing, or thresholds of significance or differentiation from other reactions. STUDY DESIGN AND METHODS: In this study of inpatients at risk for TACO (age ≥ 50 years) receiving 1 red blood cell unit, cardiac biomarkers, brain natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP), and high-sensitivity troponin were measured at baseline, 6 to 12 hours (except troponin) posttransfusion, and 18 to 24 hours posttransfusion. Primary outcome was a critical increase in biomarkers (>1.5-fold increase and supranormal) at 18 to 24 hours. RESULTS: Fifty-one patients were analyzed; 29% had cardiovascular disease, 73% had one or more cardiac risk factors, and 50% took cardiac or antihypertensive therapies. Although eight (16%) developed an increase in systolic pressure of at least 30 mmHg and four (8%) reported dyspnea and/or cough, none had TACO. At baseline, BNP level was more than 100 ng/L in 59% and NT-proBNP was more than 300 pg/mL in 83%. A total of 25% had a BNP critical increase, 33% had a NT-proBNP critical increase, and 2% had a troponin critical increase at 18 to 24 hours. Overall, 38% had at least one biomarker critical increase and NT-proBNP/BNP concordance was 84%. An increase in the NT-proBNP (>1.5-fold increase and >300 pg/mL) at 18 to 24 hours was the commonest biomarker change. CONCLUSIONS: An increase of the NT-proBNP at 18 to 24 hours may be the preferred surrogate marker for identifying a patient experiencing physiologic difficulty in handling the volume challenge. Larger studies are needed to clarify the risk of TACO for a given pretransfusion biomarker profile and the correlation between TACO and increase in biomarkers after transfusion.

Availability of naloxone in Canadian pharmacies:a population-based survey.

BACKGROUND: Naloxone is life-saving when administered after opioid overdose. In March 2016, the Canadian government made the antidote available without prescription, but anecdotal reports suggest members of the public have difficulty in procuring it. We examined the availability of naloxone in community pharmacies across Canada. METHODS: We identified community pharmacies in Canada (n = 10 296) and randomly selected 506, stratified using proportionate allocation by population size. We excluded pharmacies in Alberta and Manitoba because these provinces released data indicating which pharmacies made naloxone available to the public during the data collection phase of the study. We contacted pharmacies by telephone during working hours and used a standardized survey to enquire about the availability of naloxone, the associated cost and the need for a prescription. When a pharmacy did not have naloxone available, we ascertained if it could be procured within 7 days. RESULTS: We contacted 429 community pharmacies. Of these, 103 (24.0%) had naloxone available. Availability was highest in British Columbia (33 of 65; 50.8%), followed by the Maritimes (12 of 35; 34.3%), Ontario (52 of 193; 26.9%) and central and northern Canada (5 of 21; 23.8%). In Quebec, 1 of 115 (0.9%) pharmacies had naloxone available. Of pharmacies without naloxone, fewer than 1 in 5 anticipated being able to provide it within 1 week (63 of 326; 19.3%). INTERPRETATION: Most community pharmacies in Canada did not have naloxone on hand and in those without naloxone available, fewer than 1 in 5 anticipated being able to provide it within 1 week. Our findings emphasize the need for increased availability of naloxone in pharmacies across Canada.

Prescription Stimulant Use and Hospitalization for Psychosis or Mania: A Population-Based Study.

Small studies suggest that prescription stimulants can precipitate psychosis and mania. We conducted a population-based case-crossover study to examine whether hospitalization for psychosis or mania was associated with initiation of stimulant therapy. Between October 1, 1999 and March 31, 2013, we studied 12,856 young people who received a stimulant prescription and were subsequently hospitalized for psychosis or mania. Of these, 183 commenced treatment during 1 of 2 prespecified 60-day intervals (defined as the "risk interval" and "control interval," respectively) prior to admission. We found that stimulant initiation was associated with an increased risk of hospitalization for psychosis or mania in the subsequent 60 days (odds ratio, 1.86; 95% confidence interval, 1.39-2.56). The risk was marginally higher in patients treated with antipsychotic drugs (odds ratio, 2.06; 95% confidence interval, 1.38-3.28), but remained in patients with no such history (odds ratio, 1.66; 95% confidence interval, 1.09-2.66). One third of subjects received another stimulant prescription after hospital discharge. Of these, 45% were readmitted with psychosis or mania shortly thereafter. We conclude that initiation of prescription stimulants is associated with an increased risk of hospitalization for psychosis or mania. Resumption of therapy is common, which may reflect a lack of awareness of the potential causative role of these drugs.

Socioeconomic status and risk of hemorrhage during warfarin therapy for atrial fibrillation: A population-based study.

BACKGROUND: Among patients taking warfarin, lower socioeconomic status is associated with poorer control of anticoagulation. However, the extent to which socioeconomic status influences the risk of hemorrhage is unknown. We examined the extent to which socioeconomic status influences the risk of hemorrhage in older individuals newly commencing warfarin therapy for atrial fibrillation. METHODS: We conducted a population-based cohort study of individuals 66 years or older with atrial fibrillation who commenced warfarin therapy between April 1, 1997, and November 30th 2011, in Ontario, Canada. We used neighborhood-level income quintiles as a measure of socioeconomic status. The primary outcome was an emergency department visit or hospitalization for hemorrhage, and the secondary outcome was fatal hemorrhage. RESULTS: We studied 166,742 older patients with atrial fibrillation who commenced warfarin therapy. Of these, 16,371 (9.8%) were hospitalized for hemorrhage during a median follow-up of 369 (interquartile range 102-865) days. After multivariable adjustment using Cox proportional hazards regression, we found that those in the lowest-income quintile faced an increased risk of hospitalization for hemorrhage relative to those in the highest quintile (adjusted hazard ratio 1.18, 95% CI 1.12-1.23). Similarly, the risk of fatal hemorrhage (n = 1,802) was increased in the lowest-income relative to the highest-income quintile (adjusted hazard ratio 1.28, 95% CI 1.11-1.48). CONCLUSIONS: Among older individuals receiving warfarin therapy for atrial fibrillation, lower socioeconomic status is a risk factor for hemorrhage and hemorrhage-related mortality. This factor should be carefully considered when initiating and monitoring warfarin therapy.

A population-based study of the drug interaction between clopidogrel and angiotensin converting enzyme inhibitors.

AIMS: Clopidogrel and angiotensin converting enzyme (ACE) inhibitors are commonly co-prescribed drugs. Clopidogrel inhibits carboxylesterase 1 (CES1), the enzyme responsible for converting prodrug ACE inhibitors (such as ramipril and perindopril) to their active metabolites. The clinical implications of this potential drug interaction are unknown. The clinical consequences of the potential drug interaction between clopidogrel and prodrug ACE inhibitors were examined. METHODS: We conducted a nested case-control study of Ontarians aged 66 years and older treated with clopidogrel between September 1 2003 and March 31 2013 following acute myocardial infarction. Cases were subjects who died or were hospitalized for reinfarction or heart failure in the subsequent year, and each was matched with up to four controls. The primary outcome was a composite of reinfarction, heart failure or death. The primary analysis examined whether use of the prodrug ACE inhibitors ramipril or perindopril was more common among cases than use of lisinopril, an active ACE inhibitor. RESULTS: Among 45 918 patients treated with clopidogrel following myocardial infarction, we identified 4203 cases and 14 964 controls. After adjustment, we found no association between the composite outcome and use of perindopril (adjusted odds ratio (aOR) 0.94, 95% confidence interval (CI) 0.76, 1.16) or ramipril (aOR 0.97, 95% CI 0.80, 1.18), relative to lisinopril. Secondary analyses of each element of the composite outcome yielded similar findings. CONCLUSIONS: Following myocardial infarction, use of clopidogrel with ACE inhibitors activated by CES1 is not associated with an increased risk of adverse cardiovascular outcomes relative to lisinopril. These findings suggest that the recently described drug interaction between clopidogrel and prodrug ACE inhibitors is of little clinical relevance.

Maternal bacterial infections impact expression of drug transporters in human placenta.

BACKGROUND: Several efflux and uptake transporters in the placenta are involved in the transmembrane transport of endogenous substrates and xenobiotics. Their expression and function may be altered in maternal complications associated with inflammation. Our objective was to examine the effect of chorioamnionitis, a bacterial intra-amniotic infection on the expression of clinically important transporters in human placenta. METHODS: Human placental samples were collected from preterm and term pregnancies diagnosed with chorioamnionitis infection and were gestational age-matched with samples from pregnancies with no obstetric complications, using predefined exclusion criteria. Transporter protein expression was quantified using Western blots while cytokine and transporter mRNA expression was measured via real-time polymerase chain reaction. RESULTS: mRNA levels of pro-inflammatory cytokines IL-6, IL-1ß and TNF-α were markedly elevated by 2.5- to 3-fold in preterm placentas with infection, relative to preterm controls (p<0.05). Expression of ABCG2 and SLCO2B1 was downregulated by 48 to 57% (p<0.05) in placentas from women with infection and preterm parturition, relative to preterm healthy controls. Protein and mRNA expression changes were generally consistent. At term, ABCG2 mRNA and SLCO2B1 protein expression levels were significantly downregulated, relative to controls. Significant changes in ABCB1 and SLCO4A1 expression were not observed, however ABCB1 transcript levels strongly correlated with IL-6, IL-1ß and TNF-α expression (p<0.001), potentially suggesting involvement of cytokine-mediated regulation. CONCLUSIONS: Collectively, these data show that maternal infections impact the expression of key drug transporters in placenta, suggesting that materno-fetal drug transport may be altered by changes in placental expression of ABC and OATP transporters.

Cocaine abuse during pregnancy.

Cocaine abuse during pregnancy is a significant public health problem but is infrequently discussed between physicians and patients. The impact of in utero cocaine exposure on pregnancy and the baby has received significant media attention in preceding decades because of fears of teratogenicity, long-term health consequences, and poor cognitive and neurodevelopmental outcomes. We sought to review the medical literature examining these phenomena. We identified risks to the pregnancy and baby in women abusing cocaine during pregnancy. These include preterm birth, placenta-associated syndromes (e.g., placental abruption, preeclampsia, and placental infarction), and impaired fetal growth. Long-term neurodevelopmental and cognitive deficits include (but are not limited to) poorer language development, learning and perceptual reasoning, behavioural problems, and adverse effects on memory and executive function. However, these results should be interpreted cautiously because cocaine abuse may be accompanied by many other maternal and sociodemographic risk factors, so it is difficult to ascertain the effect of cocaine alone. Therefore, it is critical to counsel patients about potential risk, and perhaps more importantly, to treat addiction and to better understand, and advocate for improvements to, these patients' high-risk environment.

Bien que la consommation de cocaïne pendant la grossesse constitue un problème de santé publique considérable, elle ne fait que peu fréquemment l'objet de discussions entre les médecins et leurs patientes. Les effets de l'exposition in utero à la cocaïne sur la grossesse et l'enfant se sont mérités une attention médiatique considérable au cours des dernières décennies, en raison de préoccupations au sujet de la tératogénicité de la cocaïne, de ses conséquences à long terme sur la santé et de son influence sur l'obtention de piètres issues cognitives et neurodéveloppementales. Nous avons cherché à analyser la littérature médicale examinant ces phénomènes. Nous avons identifié des risques pour la grossesse et l'enfant attribuables à la consommation de cocaïne pendant la grossesse. Parmi ces risques, on trouve l'accouchement préterme, des syndromes associés au placenta (p. ex. décollement placentaire, prééclampsie et infarctus placentaire) et l'altération de la croissance fœtale. Parmi les déficits cognitifs et neurodéveloppementaux à long terme, on trouve (entre autres) des difficultés quant au développement langagier, à l'apprentissage et au raisonnement perceptif, des problèmes comportementaux et des effets indésirables sur la mémoire et la fonction exécutive. Toutefois, ces résultats devraient être interprétés avec prudence, puisque la consommation de cocaïne pourrait s'accompagner de nombreux autres facteurs de risque maternels et sociodémographiques; il est donc difficile de déterminer l'effet qui est seulement attribuable à la cocaïne. Ainsi, il est d'une importance cruciale de conseiller les patientes au sujet des risques potentiels d'une telle pratique et, ce qui est peut-être encore plus important, d'assurer la prise en charge de l'assuétude et de mieux comprendre les conditions de vie à risque élevé de ces patientes (et de promouvoir la mise en œuvre de mesures permettant de les améliorer).

Malaria infection alters the expression of hepatobiliary and placental drug transporters in pregnant mice.

Preventing and treating malaria in pregnancy is a global health priority. However little is known regarding the impact of malaria infection on the maternal and fetal disposition of pharmaceuticals and other xenobiotics. Our objective was to characterize expression of key determinants of drug-disposition in maternal and fetal tissues in a validated murine model of experimental placental malaria. Balb/c mice were infected with Plasmodium berghei at mid gestation [gestational day (GD) 13] and maternal, placental, and fetal tissues were collected at GD19. Expression of key ABC drug transporters and Cyp3a11 was examined by quantitative polymerase chain reaction. Western blotting was used to examine the protein expression of multidrug resistance protein 1 (MDR1, ABCB1). Compared with controls, placental mRNA expression of Abcb1a, Abcb1b, Abcc1, Abcc2, Abcc3, and Abcg2 were significantly downregulated in the malaria-infected group (P < 0.05), as was placental MDR1 protein (P < 0.05). Significantly decreased hepatic expression of Abcc2, Abcg2, and Abcb11 and significantly increased expression of Abcb1b, Abcc1, and Abcc3 were seen in malaria-infected dams (P < 0.05) in comparison with uninfected controls. The expression of Abcb1a and Abcg2 was significantly decreased in fetal liver of infected dams, whereas levels of Abcb1b were increased (P < 0.05). Maternal and fetal hepatic expression of Cyp3a11 was significantly downregulated in the malaria group (P < 0.05). Together, malaria-induced alterations in the expression of transporters and drug-metabolizing enzymes in maternal and fetal tissues may alter the disposition of endogenous and therapeutic substrates, potentially impacting maternal and fetal outcomes.

Breast milk and cognitive development--the role of confounders: a systematic review.

OBJECTIVES: The association between breastfeeding and child cognitive development is conflicted by studies reporting positive and null effects. This relationship may be confounded by factors associated with breastfeeding, specifically maternal socioeconomic class and IQ. DESIGN: Systematic review of the literature. SETTING AND PARTICIPANTS: Any prospective or retrospective study, in any language, evaluating the association between breastfeeding and cognitive development using a validated method in healthy term infants, children or adults, was included. PRIMARY AND SECONDARY OUTCOME MEASURES: Extracted data included the study design, target population and sample size, breastfeeding exposure, cognitive development assessment tool used and participants' age, summary of the results prior to, and following, adjustment for confounders, and all confounders adjusted for. Study quality was assessed as well. RESULTS: 84 studies met our inclusion criteria (34 rated as high quality, 26 moderate and 24 low quality). Critical assessment of accepted studies revealed the following associations: 21 null, 28 positive, 18 null after adjusting for confounders and 17 positive-diminished after adjusting for confounders. Directionality of effect did not correlate with study quality; however, studies showing a decreased effect after multivariate analysis were of superior quality compared with other study groupings (14/17 high quality, 82%). Further, studies that showed null or diminished effect after multivariate analysis corrected for significantly more confounders (7.7±3.4) as compared with those that found no change following adjustment (5.6±4.5, p=0.04). The majority of included studies were carried out during childhood (75%) and set in high-income countries (85.5%). CONCLUSIONS: Much of the reported effect of breastfeeding on child neurodevelopment is due to confounding. It is unlikely that additional work will change the current synthesis. Future studies should attempt to rigorously control for all important confounders. Alternatively, study designs using sibling cohorts discordant for breastfeeding may yield more robust conclusions.

Maternal cocaine use during breastfeeding.

QUESTION: In my practice several patients have struggled with cocaine abuse during their pregnancies. One woman, now postpartum, wants to breastfeed her infant. Despite being abstinent for the final few months of her pregnancy, I am concerned about the potential adverse effects on her child if she happens to relapse. What is the current evidence about the risks of cocaine exposure during breastfeeding? ANSWER: Given the substantial benefits of breastfeeding for infant health and development, there is no reason for mothers who previously abused cocaine to avoid breastfeeding. It is important for the health care team to counsel patients both on the serious potential risks of cocaine exposure for babies and on the benefits of breastfeeding, to allow for an informed choice. Additionally, attempts should be made to estimate maternal commitment to breastfeeding and discontinuation of cocaine use, and to offer addiction counseling to mitigate the potential risks of infant cocaine exposure. It is paramount to minimize the risk to the infant, which would certainly include mothers ceasing use of cocaine while breastfeeding. For mothers who elect to breastfeed and use cocaine intermittently, breastfeeding should be delayed sufficiently after cocaine use to allow for drug elimination (approximately 24 hours).

Smoking cessation therapy during pregnancy.

QUESTION: Despite being highly motivated to quit, many of my patients struggle with smoking cessation during pregnancy. Can you comment on the current treatment options and discuss their safety and efficacy during pregnancy? ANSWER: Given the considerable and well-documented adverse effects of antenatal smoking on mother and fetus, pharmacotherapy for smoking cessation should be considered. Available medications include nicotine replacement therapy, sustained-release bupropion, and varenicline. Nicotine replacement therapy and bupropion do not appear to increase the risk of major malformations; however, there is currently limited evidence on the use of varenicline during pregnancy. Given that these agents are only marginally successful in smoking cessation, their use should always be accompanied by behavioural counseling and education to maximize quit rates.

Expression of ABC Efflux transporters in placenta from women with insulin-managed diabetes.

Drug efflux transporters in the placenta can significantly influence the materno-fetal transfer of a diverse array of drugs and other xenobiotics. To determine if clinically important drug efflux transporter expression is altered in pregnancies complicated by gestational diabetes mellitus (GDM-I) or type 1 diabetes mellitus (T1DM-I), we compared the expression of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2) and the breast cancer resistance protein (BCRP) via western blotting and quantitative real-time polymerase chain reaction in samples obtained from insulin-managed diabetic pregnancies to healthy term-matched controls. At the level of mRNA, we found significantly increased expression of MDR1 in the GDM-I group compared to both the T1DM-I (p<0.01) and control groups (p<0.05). Significant changes in the placental protein expression of MDR1, MRP2, and BCRP were not detected (p>0.05). Interestingly, there was a significant, positive correlation observed between plasma hemoglobin A1c levels (a retrospective marker of glycemic control) and both BCRP protein expression (r = 0.45, p<0.05) and BCRP mRNA expression (r = 0.58, p<0.01) in the insulin-managed DM groups. Collectively, the data suggest that the expression of placental efflux transporters is not altered in pregnancies complicated by diabetes when hyperglycemia is managed; however, given the relationship between BCRP expression and plasma hemoglobin A1c levels it is plausible that their expression could change in poorly managed diabetes.