Amélie Forget

Use of inhaled corticosteroids during pregnancy and risk of pregnancy induced hypertension: nested case-control study

Abstract Objective To determine whether the use of inhaled corticosteroids during pregnancy increases the risk of pregnancy induced hypertension and pre-eclampsia among asthmatic women. Design Nested case-control study. Setting Three administrative health databases from Quebec: RAMQ, MED-ECHO, and Fichier des événements démographiques. Participants 3505 women with asthma, totalling 4593 pregnancies, between 1990 and 2000. Main outcome measuresPregnancy induced hypertension and pre-eclampsia. Results 302 cases of pregnancy induced hypertension and 165 cases of pre-eclampsia were identified. Use of inhaled corticosteroids from conception until date of outcome was not associated with an increased risk of pregnancy induced hypertension (adjusted odds ratio 1.02, 95% confidence interval 0.77 to 1.34) or pre-eclampsia (1.06, 0.74 to 1.53). No significant dose-response relation was observed between inhaled corticosteroids and pregnancy induced hypertension or pre-eclampsia. Oral corticosteroids were significantly associated with the risk of pregnancy induced hypertension (adjusted odds ratio 1.57, 1.02 to 2.41), and a trend was seen for pre-eclampsia (1.72, 0.98 to 3.02). Conclusion No significant increase of the risk of pregnancy induced hypertension or pre-eclampsia was detected among users of inhaled corticosteroids during pregnancy, while markers of uncontrolled and severe asthma were found to significantly increase the risks of pregnancy induced hypertension and pre—eclampsia.

Asthma exacerbations during the first trimester of pregnancy and the risk of congenital malformations among asthmatic women

BACKGROUND Uncontrolled maternal asthma during pregnancy has been hypothesized as a cause of congenital malformation, but literature is scare on this topic. OBJECTIVE The aim of this study was to investigate whether asthmatic women who had an exacerbation during the first trimester of pregnancy were more at risk of having a baby with a congenital malformation. METHODS From the linkage of 3 Canadian administrative databases, we reconstructed a cohort of 4344 pregnancies of asthmatic women. Asthma exacerbations were assessed during the first trimester of pregnancy and were defined as a filled prescription for oral corticosteroids, an emergency department visit, or a hospitalization for asthma. Congenital malformations were assessed at birth and during the first year of life of the newborn by using diagnoses recorded in the databases. Generalized estimating equation models were used to estimate adjusted odds ratios of congenital malformations in association with asthma exacerbations. RESULTS In the cohort we identified 398 (9.2%) babies with at least 1 malformation and 261 (6.0%) with a major malformation. The crude prevalences of malformations were 12.8% and 8.9%, respectively, for women who had and those who did not have an exacerbation. The adjusted odds ratio for all malformations was 1.48 (95% CI, 1.04-2.09) when comparing women who had and those who did not have an exacerbation. The corresponding figures were 1.32 (95% CI, 0.86-2.04) for major malformations. CONCLUSION Asthma exacerbations during the first trimester of pregnancy were found to significantly increase the risk of a congenital malformation.

Use of inhaled corticosteroids during the first trimester of pregnancy and the risk of congenital malformations among women with asthma

Aim: To investigate whether the maternal use of different doses of inhaled corticosteroids (ICSs) during the first trimester of pregnancy for the treatment of asthma increases the risk of congenital malformations in the offspring. Methods: From the linkage of three administrative Canadian databases, a cohort of 4561 pregnancies from women with asthma who delivered between 1990 and 2000 was reconstructed. A two-stage sampling cohort design was used to acquire additional data from the woman’s medical chart. Cases of congenital malformation were identified from the medical services database or the hospital database. Using refill patterns of medications, the average daily dose of ICSs used during the first trimester was calculated and categorised as follows: 0, 1–500, 500–1000 and >1000 μg/day in beclomethasone–chlorofluorocarbon equivalent. A Generalized Estimation Equation model was used to estimate the adjusted odds ratio of congenital malformation as a function of ICS daily dose. All analyses were performed for all malformations and major malformations separately. Results: Within the cohort 418 babies were identified with a congenital malformation (9.2%), 278 of which had a major malformation. About 40% of women used ICSs during the first trimester, but only 5.3% of women used >500 μg/day. The adjusted odds ratio (95% CI) for all malformations associated with the use of ICSs during the first trimester was: 0.77 (0.53 to 1.13) for 1–500, 0.41 (0.19 to 0.92) for 501–1000 and 1.00 (0.42 to 2.36) for >1000 μg/day. The corresponding figures for major malformations were 0.90 (0.64 to 1.24), 0.56 (0.22 to 1.43) and 1.67 (0.56 to 5.03). Conclusion: This study adds evidence to the safety of ICSs for the treatment of asthma during pregnancy, with regard to the likelihood of congenital malformation.

Agreement between administrative databases and medical charts for pregnancy-related variables among asthmatic women†

To determine the validity of pregnancy variables recorded in administrative databases of Quebec using patient medical charts as the gold standard among asthmatic pregnant women.

Risk of perinatal mortality associated with asthma during pregnancy

Background: Thirteen studies investigating the association between asthma during pregnancy and perinatal mortality reported generally no increased risk. Most of these studies should be interpreted with caution because they were limited in terms of statistical power. A study was therefore undertaken to evaluate whether maternal asthma during pregnancy increases the risk of perinatal mortality. Methods: Through three administrative databases from Québec (Canada), a cohort of women with and without asthma who had at least one pregnancy between 1990 and 2002 was formed. Perinatal mortality was identified by diagnostic codes. The adjusted odds ratio (OR) of perinatal mortality in women with and without asthma was compared using Generalised Estimation Equation (GEE) models. The first model included all potential confounders (except small for gestational age, SGA), the second model excluded birth weight, gestational age at birth and SGA and the third model excluded birth weight, gestational age at birth but included only SGA. This analysis was also stratified for birth weight and gestational age at birth. Results: The cohort was formed of 13 100 and 28 042 single pregnancies in women with and without asthma. The crude OR of perinatal mortality was 1.35 (95% CI 1.08 to 1.67), which decreased to 0.93 (95% CI 0.75 to 1.17) after adjustment for birth weight and gestational age at birth. Women with asthma had a higher rate of low birthweight babies and preterm delivery than those without asthma. Conclusion: The increased risk of low birthweight babies and premature delivery in women with asthma may partly explain the association between maternal asthma and the increased risk of perinatal mortality.

Nuclear Shuttling of She2p Couples ASH1 mRNA Localization to its Translational Repression by Recruiting Loc1p and Puf6p

The transport and localization of mRNAs results in the asymmetric synthesis of specific proteins. In yeast, the nucleocytoplasmic shuttling protein She2 binds the ASH1 mRNA and targets it for localization at the bud tip by recruiting the She3p-Myo4p complex. Although the cytoplasmic role of She2p in mRNA localization is well characterized, its nuclear function is still unclear. Here, we show that She2p contains a nonclassical nuclear localization signal (NLS) that is essential for its nuclear import via the importin alpha Srp1p. Exclusion of She2p from the nucleus by mutagenesis of its NLS leads to defective ASH1 mRNA localization and Ash1p sorting. Interestingly, these phenotypes mimic knockouts of LOC1 and PUF6, which encode for nuclear RNA-binding proteins that bind the ASH1 mRNA and control its translation. We find that She2p interacts with both Loc1p and Puf6p and that excluding She2p from the nucleus decreases this interaction. Absence of nuclear She2p disrupts the binding of Loc1p and Puf6p to the ASH1 mRNA, suggesting that nuclear import of She2p is necessary to recruit both factors to the ASH1 transcript. This study reveals that a direct coupling between localization and translation regulation factors in the nucleus is required for proper cytoplasmic localization of mRNAs.

Development and validation of database indexes of asthma severity and control.

Background: The use of administrative databases to perform epidemiological studies in asthma has increased in recent years. The absence of clinical parameters to measure the level of asthma severity and control is a major limitation of database studies. A study was undertaken to develop and validate two database indexes to measure the control and severity of asthma. Methods: Database indexes of asthma severity and control were derived from definitions in the Canadian Asthma Consensus Guidelines based on dispensed prescriptions and on medical services recorded in two large administrative databases from the Canadian province of Québec (Régie de l’Assurance Maladie du Québec (RAMQ) and MED-ECHO) over 12 months. The database indexes of asthma severity and control were validated against the pulmonary function test results of 71 patients with asthma randomly selected from two asthma clinics, and they were also applied to a cohort of patients with asthma followed up for 139 283 person-years selected from the RAMQ and MED-ECHO databases between 1 January 1997 and 31 December 2004. Results: According to the database indexes, 49.3%, 29.6% and 21.1% of patients recruited at the asthma clinics were found to have mild, moderate and severe asthma, respectively, while 53.5% were found to have controlled asthma. The mean predicted value of the forced expiratory volume in 1 s (FEV1) ranged from 89.8% for mild asthma to 61.5% for severe asthma (p<0.001), whereas the range from controlled to uncontrolled asthma was 89.5% to 67.3% (p<0.001). The ratio of the FEV1 to the forced vital capacity (FEV1/FVC ratio) measured in 56 patients ranged from 75.8% for mild asthma to 61.8% for severe asthma (p = 0.030), whereas the range from controlled to uncontrolled asthma was 75.3% to 65.7% (p<0.001). Conclusion: In the absence of clinical data, these database indexes could be used in epidemiological studies to assess the severity and control of asthma.

Effect of maternal moderate to severe asthma on perinatal outcomes

BACKGROUND/OBJECTIVES It has been reported that adverse fetal outcomes are more prevalent in pregnant women with asthma than they are in women without asthma. In our study, we investigated the effect that the severity of asthma during pregnancy has on the risk of a small for gestational age (SGA) infant, low birth weight (LBW), and preterm birth. METHODS A population-based cohort of 13,007 pregnancies from asthmatic women was reconstructed through the linking of three of Quebecs (Canada) administrative databases covering the period between 1990 and 2002. A two-stage sampling cohort design was used to collect additional information on the selected womens life-style habits via a mailed questionnaire. Asthma severity during pregnancy was measured with a validated database index. A logistic regression model was used to obtain the adjusted odds ratios of SGA, LBW and preterm birth as a function of the level of asthma severity. RESULTS The proportions of women with mild, moderate and severe asthma were 82.5%, 12.5% and 5.0%, respectively. We sent 3,168 questionnaires to selected women, with a 40.2% (n=1274) response rate. Final estimates showed that the risk of SGA was significantly higher among severe (OR:1.48, 95%CI: 1.15-1.91) and moderate asthmatic women (OR: 1.30, 95%CI:1.10-1.55) than mild asthmatic women. No significant associations were found between asthma severity, preterm birth and LBW. CONCLUSIONS Mothers with severe and moderate asthma during pregnancy have a higher risk of SGA babies than those with mild asthma.

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.

Impact of maternal use of asthma-controller therapy on perinatal outcomes

Background Asthma during pregnancy usually requires treatment with controller medications about which more safety information is needed. The objectives are to assess the impact of the use of long-acting β2-agonists (LABAs) and the dose of inhaled corticosteroids (ICSs) during pregnancy on the prevalence of low birth weight (LBW), preterm birth (PB) and small for gestational age (SGA). Methods A cohort of women with asthma giving birth from 1998 to 2008 was constructed from Québec (Canada) administrative databases. LBW was defined as weight <2500 g, PB as delivery before 37 weeks’ gestation and SGA as a birth weight below the 10th percentile. The impact of the use of LABAs and the dose of ICSs during pregnancy on the outcomes was determined with generalised-estimating-equation models. Results The cohort included 7376 pregnancies: 8.8% exposed to LABAs and 56.9% exposed to ICSs. All LABA users also received ICSs. The prevalence of LBW, PB and SGA was 7.7%, 9.5% and 13.5%, respectively. LABA use was not found to be associated with increased prevalence of LBW (OR 0.81; 95% CI 0.58 to 1.12), PB (OR 0.84; 95% CI 0.61 to 1.15) or SGA (OR 0.92; 95% CI 0.70 to 1.20). Mean ICSs doses >125 μg/day (fluticasone-equivalent) were associated with a non-significant trend of increased LBW, PB and SGA. Conclusions Despite the possibility of residual confounding due to uncontrolled or more severe asthma or smoking status, the use of LABA and low to moderate doses of ICSs were not associated with increased prevalence of perinatal outcomes. Additional research on higher ICSs doses is required to better evaluate their safety during pregnancy.