Fatima-Zohra Kettani

Effect of maternal asthma on the risk of specific congenital malformations: A population-based cohort study.

BACKGROUND There is a lack of consensus in the literature about the effect of maternal asthma on the development of congenital malformations. OBJECTIVE To further examine the association between maternal asthma and the risk of congenital malformations. METHODS A cohort of 41,637 pregnancies from women with and without asthma who delivered between 1990 and 2002 was reconstructed by linking three Quebec (Canada) administrative databases. All cases of malformations were identified using either the medical services or the hospital databases. The main exposure was maternal asthma, defined by the presence of at least one asthma diagnosis and at least one prescription for an asthma medication at any time in the two years before or during pregnancy. Generalized Estimation Equation models were performed to estimate the adjusted odds ratio (OR) of congenital malformations as a function of maternal asthma. RESULTS The crude prevalences of any congenital malformation were 9.5% and 7.5% for women with and without asthma, respectively. Maternal asthma was significantly associated with an increased risk of any malformation (OR=1.30; 95% CI: 1.20-1.40) and three specific groups (at the 0.0028 level): nervous system (excluding spina bifida: OR=1.83; 1.37-2.83); respiratory system (OR=1.75; 1.21-2.53); and digestive system (OR=1.48; 1.19-1.85). CONCLUSIONS Maternal asthma increases the risk of specific groups of congenital malformations. The disease itself, through fetal oxygen impairment, is likely to play a role in this increased risk, but more research is needed to disentangle the relative effect of asthma and medications used to treat this disease.

Validity of congenital malformation diagnostic codes recorded in Québec's administrative databases

To assess the validity of the diagnostic codes of congenital malformations (CMs) recorded in two of Québecs administrative databases.

Inhaled corticosteroids vs. leukotriene-receptor antagonists and asthma exacerbations in children.

BACKGROUND Compared to inhaled corticosteroids (ICS), better use of leukotriene-receptor antagonists (LTRA) may lead to a greater reduction in exacerbations among asthmatic children in real-life settings. METHODS To test this hypothesis, we used the Quebec administrative databases and identified a cohort of 27,355 asthmatic children aged 5-15 years in whom ICS or LTRA monotherapy was initiated in 1998-2005. The primary outcome was the rate of moderate-or-severe asthma exacerbations (emergency department visit or hospitalization for asthma or a dispensed prescription of oral corticosteroids) over the subsequent year. The adjusted rate ratios (RR) of asthma exacerbations were estimated with Poisson regression models. To minimize confounding by indication, all analyses were stratified by the presence or not of an asthma exacerbation in the year before treatment initiation. We also measured the proportion of days with supply prescribed and patients adherence with the Proportion of Prescribed Days Covered (PPDC). RESULTS The risk of exacerbations was significantly higher in the ICS than the LTRA group among children with no previous exacerbation (RR = 2.3; 95% CI:1.3-4.0), but not in those with ≥1 exacerbations (RR = 1.6; 0.8-3.1). The PPDC was similar between the groups (66%) but the proportion of days with supply prescribed was significantly higher in the LTRA than the ICS group (52% vs. 34%), resulting in higher use. CONCLUSIONS While confounding by indication cannot be firmly ruled out, ICS appears to be more frequently prescribed as an intermittent than a daily controller therapy resulting in less use, which may contribute to the apparent lower effectiveness compared to LTRA.

Relationship between maternal asthma, its severity and control and abortion

STUDY QUESTION Are women with asthma, and more specifically those with severe or uncontrolled asthma, at higher risk of spontaneous and induced abortions? SUMMARY ANSWER Pregnant women with asthma, notably when uncontrolled, are at higher risk of spontaneous abortion. WHAT IS KNOWN ALREADY Only one study has examined the association between asthma and spontaneous and induced abortions and revealed a modest increase in the risk of spontaneous abortions, particularly in women with more severe asthma and those with previous exacerbations, and a marginal decrease in the risk of induced abortions. STUDY DESIGN, SIZE, DURATION A cohort of pregnancies from asthmatic (n = 15,107) and non-asthmatic (n = 34,331) women was reconstructed by linking three administrative databases from Quebec (Canada), between 1992 and 2002. The cohort included 7870 spontaneous abortions, 14,596 induced abortions and 26,972 live births. PARTICIPANTS/MATERIALS, SETTING, METHODS Pregnant women with and without asthma were analyzed. Asthma was defined by at least one asthma diagnosis and one dispensed prescription for an asthma medication in the 2 years prior to or during pregnancy. Asthma severity and control were assessed using validated indexes in the year before the 20th week of pregnancy or the termination of the pregnancy. Logistic polytomous regression models were used to estimate the relationship between asthma and asthma severity and control on the risk of abortion, while adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE The prevalence of spontaneous and induced abortions was 15.9 and 29.5%, respectively. Maternal asthma was associated with an increased risk of a spontaneous abortion [odds ratio (OR) = 1.41; 95% confidence interval (CI): 1.33-1.49] and a decreased risk of induced abortions (OR = 0.92; 0.88-0.97). No association was observed between asthma severity and abortion, while uncontrolled asthma increased the risk of a spontaneous abortion by 26% (95% CI: 14-41%) and the risk of induced abortions by 11% (95% CI: 1-21%). LIMITATIONS, REASONS FOR CAUTION It is possible that the study results were confounded by imbalances between groups in variables that are not recorded in the databases, but that are known to be associated with spontaneous abortions, such as alcohol consumption, obesity or maternal smoking. However, we performed sensitivity analyses which revealed that these factors are unlikely to explain the observed increased risk for a spontaneous abortion. It is also possible that women with asthma are more likely to have abortions recorded in the databases, because subjects with a chronic disease tend to visit a physician more often than those without asthma. Therefore, our odds estimates for these outcomes may be overestimated when asthmatic women were compared with non-asthmatic women. A further limitation of the study is that it would have been more appropriate to measure the severity and control of asthma only during the pregnancy. WIDER IMPLICATIONS OF THE FINDINGS Our cohort is less representative of women in the upper socio-economic level. This is not a threat to internal validity, but it could limit the external validity if the impact of asthma on the risk of abortion differed according to the socio-economic status of the mother. Despite the absence of supporting data, this possibility cannot be completely excluded. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the Canadian Institutes of Health Research and Genentech. L.B. received research grants from Astra-Zeneca, Pfizer, sanofi-aventis, Novartis and Merck for research projects and co-chairs the Astra-Zeneca Endowment Pharmaceutical Chair in Respiratory Health. F.Z.K and A.F. have no competing interests to declare.

Associations of maternal asthma severity and control with pregnancy complications

Abstract Objectives: To assess the associations of maternal asthma severity and control with pregnancy-induced hypertension (PIH), gestational diabetes and cesarean delivery. Methods: A cohort of 41 660 pregnancies from women with and without asthma who delivered between 1990 and 2002 was constructed by linking Québec’s administrative databases. Maternal asthma was defined by at least one asthma diagnosis and one dispensed prescription for an asthma medication in the 2 years before or during pregnancy. Asthma severity and control were assessed using validated indexes during the entire pregnancy to study cesarean delivery and 1-year prior to week 20 of gestation to study PIH and gestational diabetes. Generalized Estimation Equation models were used to obtain odds ratios (OR) for PIH, gestational diabetes and cesarean in association with maternal asthma severity and control. Results: Almost one-third of the women had uncontrolled asthma and up to 5% had severe asthma. Severe asthma increased the risk of cesarean delivery (OR = 1.35; 95% CI: 1.11–1.63) compared with mild asthma, but no association was found between asthma severity and the other outcomes. The level of asthma control was not associated with any of the outcomes, except for a near-significant increased risk of PIH among uncontrolled women (OR = 1.18; 95% CI: 0.97–1.42). Conclusions: The risk of gestational diabetes was not associated with asthma severity or control, and the risk of PIH was not associated with asthma severity. However, further studies are needed to clarify the association between asthma control and PIH. The increased risk of cesarean among women with severe asthma may be explained by the physician’s and patient’s concerns over the safety of normal delivery.

ADHERENCE TO CHOLINESTERASE INHIBITORS IN PATIENTS WITH ALZHEIMER'S DISEASE

BNP category and history of heart failure were the independent factors related to mortality. Of the 147 patients with no history of heart failure (73%), survival was significantly lower in those with plasma BNP values greater than 300 pg/mL than in those with BNP lower than 100 pg/mL or between 100 and 300 pg/mL. This study found that plasma BNP measured under stable conditions was a prognostic indicator for mortality in frail and very old patients. This relationship was found independently of a history of heart failure and in very old patietns and patients with a high prevalence of comorbidities and functional decline. These findings are in agreement with those of other studies conducted in elderly patients with chronic heart failure and in geriatric patients with no history of hospitalization for cardiac disease and no evidence of heart failure. In community-dwelling subjects with no history of hospitalization for heart failure, BNP was significantly related to 2-year morbidity and mortality. This study and two others strongly support the view that plasma BNP has a prognostic value in old individuals with no history of heart failure. In these subjects, high levels of plasma BNP might indicate subclinical heart dysfunction. In addition, high BNP levels might also indicate a pronounced effect of aging on diastolic function and heart vulnerability to hemodynamic stress, although in the current study, it was not possible to investigate these hypotheses, because echocardiography assessment was not available for all patients. In addition, it was difficult to obtain reliable information about cardiac morbidity during the follow-up and causes of death. In the current study, the threshold of 300 pg/mL was dramatically informative about prognosis. This might encourage physicians to pay special attention to elderly patients with plasma BNP levels greater than 300 pg/mL, even if they are free from heart failure. Studies have shown that management of heart failure patients targeted to lower plasma BNP levels improves the prognosis of these patients. Further studies are needed to determine whether a specific therapeutic approach can improve the prognosis of elderly patients free of heart failure with high plasma BNP levels.

Asthma exacerbations during the first trimester of pregnancy and congenital malformations: revisiting the association in a large representative cohort

Background We previously reported an increased prevalence of any congenital malformation among women experiencing moderate-to-severe asthma exacerbations during the first trimester of pregnancy, based on a study in which 90.1% of the cohort of women were social welfare recipients. This study re-examined the association between asthma exacerbations and congenital malformations in a new large representative cohort of asthmatic pregnant women. Methods A cohort of 36 587 pregnancies in asthmatic women was reconstructed from Québec Province administrative databases (1998–2009). Occurrences of asthma exacerbations during the first trimester of pregnancy were assessed and categorised into severe, moderate and no such exacerbations. For comparison, we also considered moderate and severe asthma exacerbations combined. Congenital malformations were identified using diagnoses recorded in the hospitalisation database. Generalised estimation equations were used to estimate adjusted ORs of congenital malformations. Results The prevalence of any congenital malformation was 19.1%, 11.7% and 12.0% among women with severe, moderate and no such exacerbations during the first trimester, respectively. The adjusted OR for all malformations was 1.64 (95% CI 1.02 to 2.64) when women with severe exacerbations were compared with those in the reference group, while no association was seen for moderate exacerbations. Also, no association was observed between cases of moderate and severe asthma exacerbations combined and any congenital malformation. Conclusions Only severe asthma exacerbations were found to significantly increase the risk of congenital malformations in this representative study. Previous studies possibly overestimated the risk because they were based mainly on women at a lower socioeconomic status.

Beta2-agonists use during pregnancy and perinatal outcomes: a systematic review.

BACKGROUND Short and long-acting beta2-agonists (SABA and LABA) have a crucial role in asthma management during pregnancy, as stated in the current guidelines. OBJECTIVE To systematically review the evidence on beta2-agonists use during pregnancy and adverse perinatal outcomes. DATA SOURCES AND STUDY SELECTION Six databases were searched before January 1, 2013 for beta2-agonists use during pregnancy and congenital malformations, small for gestational age, mean and low birth weight, gestational age and preterm delivery. Original English language articles were included with no cut-off date. Quality assessment and post-hoc power calculations were performed. RESULTS Twenty-one original studies were identified. Four studies reported a significant increased risk of congenital malformations with SABA, while one study reported a significant decreased risk with high doses of SABA. One study reported a significant increased risk of congenital malformations with LABA and four studies reported a significant increased risk of congenital malformations with beta2-agonists (SABA and/or LABA). One study reported a decrease in birth weight centiles among LABA users. LIMITATIONS All studies reporting significant results, except two, used non-asthmatic women as reference group, making it difficult to differentiate between the effect of the disease from the one of the beta2-agonists. Non-significant results should be interpreted with caution due to the low statistical power of several studies. CONCLUSION Methodological limitations and lack of power of several studies prevent us to conclude on the perinatal safety of beta2-agonists. Until further evidence is available, physicians should continue prescribing them as recommended in the guidelines whenever needed to attain asthma control.

Relationship Between Changes in Inhaled Corticosteroid Use and Markers of Uncontrolled Asthma During Pregnancy

To describe changes in inhaled corticosteroid use during pregnancy and markers of uncontrolled asthma, and to evaluate the association between them.

Impact of Patient Reimbursement Timing and Patient Out-of-Pocket Expenses on Medication Adherence in Patients Covered by Private Drug Insurance Plans

BACKGROUND Adherence to prescribed medications used in the treatment of chronic diseases is suboptimal, and drug insurance plans can have an impact on adherence. There is little evidence on the impact of patient reimbursement timing on medication adherence. OBJECTIVE To compare adherence to prescribed medications in privately insured patients from Quebec, Canada, with different patient reimbursement timing and levels of patient out-of-pocket expenses. METHODS A retrospective cohort was constructed by selecting privately insured patients aged 18-64 years from the reMed database (2008-2012) who filled at least 1 prescription for a medication belonging to 1 of the 10 most prescribed drug classes for chronic diseases. Patient reimbursement timing was classified as immediate (immediate patient reimbursement at the point of service of the portion of the medication cost covered by the insurer) or deferred (patient reimbursement at a later time). Patient outof-pocket expenses related to the medication under study at cohort entry (available only for the immediate patient reimbursement group), which included the deductible and the coinsurance, were categorized into 5 levels (null category and quartiles):