Use of inhaled corticosteroids during pregnancy and risk of pregnancy
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《英国医生杂志》
1 Faculty of Pharmacy, Université de Montréal, CP 6128, Succursale Centre-ville, Montreal, QC, Canada H3C 3J7, 2 Obstetric and Gynecology Department, Faculty of Medicine, Université de Montréal, 3 Mathematics and Statistics Department, Université de Montréal, 4 Research Center, H?pital du Sacré-Coeur de Montréal, Montreal
Correspondence to: L Blais lucie.blais@umontreal.ca
Abstract
Asthma is one of the most common chronic conditions in pregnant women, with 4% to 7% of women taking drugs for asthma during pregnancy.1-3 Pregnancy induced hypertension affects 6% to 8% of pregnant women and has serious consequences for the mother and child.4 An association between asthma and pregnancy induced hypertension has been reported,2 5-10 butitis still unclear whether this was due to the drugs used to treat asthma or to the asthma itself.6 11
Oral corticosteroids during pregnancy have been linked to an increased risk of pre-eclampsia,3 5 but two studies showing a non-significant risk with use of inhaled corticosteroids were underpowered.3 12 Although inhaled corticosteroids are the cornerstone of asthma treatment,13 even during pregnancy,14 evidence of any effect on risk of pregnancy induced hypertension or pre-eclampsia is lacking. We carried out a large population based study among pregnant asthmatic women to investigate the association between inhaled corticosteroids and the risk of pregnancy induced hypertension, including gestational hypertension, pre-eclampsia, and eclampsia. We also studied the effect of inhaled corticosteroids on the risk of pre-eclampsia.
Methods
We identified 3505 asthmatic women, totalling 4593 pregnancies between 1990 and 2000. This cohort comprised 302 cases of pregnancy induced hypertension (rate 6.58%, 95% confidence interval 5.88% to 7.32%), including 128 cases of gestational hypertension, 165 cases of pre-eclampsia, and nine cases of eclampsia. For each case of pregnancy induced hypertension we selected 10 controls, except for one case that occurred at 41 weeks' gestation, restricting the pool of controls to the three other women who delivered at 41 weeks. We thus selected 3013 controls matched to the cases of pregnancy induced hypertension. Independently, we selected 10 controls for each of the 165 cases of pre-eclampsia except for one, giving 1643 matched controls.
Sociodemographic characteristics were similar between cases of pregnancy induced hypertension and controls (table 1). A higher proportion of cases than controls were prescribed inhaled corticosteroids in the year before pregnancy, were taking oral corticosteroids before and during pregnancy, and saw a respiratory specialist during pregnancy. Cases took more doses of short acting 2 agonists a week and had more visits to an emergency department and admissions for asthma than did controls. Cases were more likely to be in a first pregnancy that led to a delivery and to have multiple pregnancies. More cases than controls saw a gynaecologist or an obstetrician and cases had more prenatal visits. A greater proportion of cases than controls had diabetes mellitus and chronic hypertension.
Table 1 Characteristics of women with pregnancy induced hypertension and their matched controls. Values are numbers (percentages) unless stated otherwise
The cases of pre-eclampsia and their controls had similar characteristics to those of cases of pregnancy induced hypertension and their controls (table 2).
Table 2 Characteristics of women with pre-eclampsia and their matched controls. Values are numbers (percentages) unless stated otherwise
The use of inhaled corticosteroids was not associated with an increased risk of pregnancy induced hypertension (adjusted odds ratio 1.02, 95% confidence interval, 0.77 to 1.34; table 3). Young women (18 years or less) were at a significantly reduced risk. Markers of uncontrolled asthma were significantly associated with an increased risk of pregnancy induced hypertension. Patients were more likely to have pregnancy induced hypertension if they used more than three doses of short acting 2 agonists per week before pregnancy (37%), visited an emergency department or were admitted for asthma before pregnancy (59%), and used oral corticosteroids during pregnancy until the index date (57%). Using more than three doses of short acting 2 agonists per week during pregnancy, however, significantly reduced the risk of pregnancy induced hypertension by 33%. Being seen by at least one gynaecologist or obstetrician increased the risk of having a diagnosis of pregnancy induced hypertension by 76%, as did a higher number of prenatal visits, with a 7% increased risk of pregnancy induced hypertension for each additional visit. Chronic hypertension, diabetes, and parity were the strongest predictors of pregnancy induced hypertension.
Table 3 Multivariate analyses for use of inhaled corticosteroids (dichotomous) and risk of pregnancy induced hypertension or pre-eclampsia
Using inhaled corticosteroids during pregnancy was also not associated with a risk of pre-eclampsia (adjusted odds ratio 1.06, 95% confidence interval 0.74 to 1.53). All the predictors remaining in the pregnancy induced hypertension model also remained in the pre-eclampsia model, except for maternal age at delivery and the use of short acting 2 agonists. The magnitude of the adjusted odds ratios kept in both models was similar, with the exception of diabetes mellitus, which had a non-significant effect on pre-eclampsia. The dose of inhaled corticosteroids prescribed before conception was kept in the pre-eclampsia model but not in the pregnancy induced hypertension model.
When another set of conditional logistic regression models was used we found no dose-response relation between inhaled corticosteroids and the risk of pregnancy induced hypertension and pre-eclampsia. The covariates for both conditions in the final models also remained in these models and to the same magnitude. In table 4 we therefore only present the crude and adjusted odds ratios associated with the different dosages of inhaled corticosteroids.
Table 4 Multivariate analyses for dose of inhaled corticosteroids and risk of pregnancy induced hypertension or pre-eclampsia
Because 25% of women contributed more than one pregnancy to our analyses, we carried out supplementary analyses to investigate the potential correlation between pregnancies, including one in which only one pregnancy per woman was kept (data not shown). The results were similar to those in tables 3 and 4. The correlation therefore did not have a sizeable impact on the results obtained from the conditional logistic regression models, which are the most appropriate analyses to use with a nested case-control design.
Discussion
Olesen C, Steffensen FH, Nielsen GL, de Jong-van den Berg, Olsen J, Sorensen HT. Drug use in first pregnancy and lactation: a population-based survey among Danish women. The EUROMAP group. Eur J Clin Pharmacol 1999;55: 139-44.
Alexander S, Dodds L, Armson BA. Perinatal outcomes in women with asthma during pregnancy. Obstet Gynecol 1998;92: 435-40.
Schatz M, Zeiger RS, Harden K, Hoffman CC, Chilingar L, Petitti D. The safety of asthma and allergy medications during pregnancy. J Allergy Clin Immunol 1997;100: 301-6.
Working group report on high blood pressure in pregnancy. National high blood pressure education program report. Am J Obstet Gynecol 2000;183: S1-22.
Stenius-Aarniala B, Piirila P, Teramo K. Asthma and pregnancy: a prospective study of 198 pregnancies. Thorax 1988;43: 12-8.
Bahna SL, Bjerkedal T. The course and outcome of pregnancy in women with bronchial asthma. Acta allergol 1972;27: 397-406.
Demissie K, Breckenridge MB, Rhoads GG. Infant and maternal outcomes in the pregnancies of asthmatic women. Am J Respir Crit Care Med 1998;158: 1091-5.
Lehrer S, Stone J, Lapinski R, Lockwood CJ, Schachter BS, Berkowitz R, et al. Association between pregnancy-induced hypertension and asthma during pregnancy. Am J Obstet Gynecol 1993;168: 1463-6.
Perlow JH, Montgomery D, Morgan MA, Towers CV, Porto M. Severity of asthma and perinatal outcome. Am J Obstet Gynecol 1992;167: 963-7.
Wen SW, Demissie K, Liu S. Adverse outcomes in pregnancies of asthmatic women: results from a Canadian population. Ann Epidemiol 2001;11: 7-12.
Schatz M, Zeiger RS, Hoffman CP, Harden K, Forsythe A, Chilingar L, et al. Perinatal outcomes in the pregnancies of asthmatic women: a prospective controlled analysis. Am J Respir Crit Care Med 1995;151: 1170-4.
Dombrowski MP, Schatz M, Wise R, Thom EA, Landon M, Mabie W, et al. Randomized trial of inhaled beclomethasone dipropionate versus theophylline for moderate asthma during pregnancy. Am J Obstet Gynecol 2004;190: 737-44.
National Asthma Education and Prevention Program Expert Panel. Report 2: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health. (Report No 97-4051.)
Boulet LP, Becker A, Berube D, Beveridge R, Ernst P. Canadian asthma consensus report, 1999. Canadian Asthma Consensus Group. CMAJ 1999;161(11 suppl): S1-61.
Régie de l'assurance maladie du Québec. Statistiques annuelles. Quebec: Quebec government, 1997.
Garbe E, LeLorier J, Boivin J-F, Suissa S. Risk of ocular hypertension or open-angle glaucoma in elderly patients on oral glucocorticoids. Lancet 1997;350: 979-82.
Blais L, Desgagne A, LeLorier J. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer: a nested case-control study. Arch Intern Med 2000;160: 2363-8.
Avron J, Monette J, Lacour A, Bohn RL, Monane M, Mogun H, et al. Persistence of use of lipid-lowering medications: a cross-national study. JAMA 1998;279: 1458-62.
Tamblyn R, Lavoie G, Petrella L, Monette J. The use of prescription claims databases in pharmacoepidemiological research: the accuracy and comprehensiveness of the prescription claims database in Quebec. J Clin Epidemiol 1995;48: 999-1009.
Levy AR, Mayo NE, Grimard G. Rates of transcervical and pertrochanteric hip fractures in the province of Quebec, Canada, 1981-1992. Am J Epidemiol 1995;142: 428-36.
Lubin JH, Gail MH. Biased selection of controls for case control analyses of cohort studies. Biometrics 1984;40: 63-75.
Greenland S. Modeling and variable selection in epidemiologic analysis. Am J Public Health 1989;79: 340-9.
Duley L. Pre-eclampsia and the hypertensive disorders of pregnancy. Br Med Bull 2003;67: 161-76.
Paganini-Hill A, Ross RK. Reliability of recall of drug usage and other health-related information. Am J Epidemiol 1982;116: 114-22.
Rothman KJ, Greenland S. Precision and validity in epidemiologic studies. Modern epidemiology. Philadelphia, PA: Lippincott-Raven, 1998: 115-34.
Tilley BC, Barnes AB, Bergstralh E, Labarthe D, Noller KL, Colton T, et al. A comparison of pregnancy history recall and medical records. Implications for retrospective studies. Am J Epidemiol 1985;121: 269-81.
Van den Brandt PA, Petri H, Dorant E, Goldbohm RA, Van de CS. Comparison of questionnaire information and pharmacy data on drug use. Pharm Weekbl (Sci) 1991;13: 91-6.
West SL, Savitz DA, Koch G, Strom BL, Guess HA, Hartzema A. Recall accuracy for prescription medications: self-report compared with database information. Am J Epidemiol 1995;142: 1103-12.
De Jong van den Berg LT, Feenstra N, Sorensen HT, Cornel MC. Improvement of drug exposure data in a registration of congenital anomalies. Pilot-study: pharmacist and mother as sources for drug exposure data during pregnancy. EuroMAP Group. European Medicine and Pregnancy Group. Teratology 1999;60: 33-6.(Marie-Josée Martel, PhD student1, évelyn)
Correspondence to: L Blais lucie.blais@umontreal.ca
Abstract
Asthma is one of the most common chronic conditions in pregnant women, with 4% to 7% of women taking drugs for asthma during pregnancy.1-3 Pregnancy induced hypertension affects 6% to 8% of pregnant women and has serious consequences for the mother and child.4 An association between asthma and pregnancy induced hypertension has been reported,2 5-10 butitis still unclear whether this was due to the drugs used to treat asthma or to the asthma itself.6 11
Oral corticosteroids during pregnancy have been linked to an increased risk of pre-eclampsia,3 5 but two studies showing a non-significant risk with use of inhaled corticosteroids were underpowered.3 12 Although inhaled corticosteroids are the cornerstone of asthma treatment,13 even during pregnancy,14 evidence of any effect on risk of pregnancy induced hypertension or pre-eclampsia is lacking. We carried out a large population based study among pregnant asthmatic women to investigate the association between inhaled corticosteroids and the risk of pregnancy induced hypertension, including gestational hypertension, pre-eclampsia, and eclampsia. We also studied the effect of inhaled corticosteroids on the risk of pre-eclampsia.
Methods
We identified 3505 asthmatic women, totalling 4593 pregnancies between 1990 and 2000. This cohort comprised 302 cases of pregnancy induced hypertension (rate 6.58%, 95% confidence interval 5.88% to 7.32%), including 128 cases of gestational hypertension, 165 cases of pre-eclampsia, and nine cases of eclampsia. For each case of pregnancy induced hypertension we selected 10 controls, except for one case that occurred at 41 weeks' gestation, restricting the pool of controls to the three other women who delivered at 41 weeks. We thus selected 3013 controls matched to the cases of pregnancy induced hypertension. Independently, we selected 10 controls for each of the 165 cases of pre-eclampsia except for one, giving 1643 matched controls.
Sociodemographic characteristics were similar between cases of pregnancy induced hypertension and controls (table 1). A higher proportion of cases than controls were prescribed inhaled corticosteroids in the year before pregnancy, were taking oral corticosteroids before and during pregnancy, and saw a respiratory specialist during pregnancy. Cases took more doses of short acting 2 agonists a week and had more visits to an emergency department and admissions for asthma than did controls. Cases were more likely to be in a first pregnancy that led to a delivery and to have multiple pregnancies. More cases than controls saw a gynaecologist or an obstetrician and cases had more prenatal visits. A greater proportion of cases than controls had diabetes mellitus and chronic hypertension.
Table 1 Characteristics of women with pregnancy induced hypertension and their matched controls. Values are numbers (percentages) unless stated otherwise
The cases of pre-eclampsia and their controls had similar characteristics to those of cases of pregnancy induced hypertension and their controls (table 2).
Table 2 Characteristics of women with pre-eclampsia and their matched controls. Values are numbers (percentages) unless stated otherwise
The use of inhaled corticosteroids was not associated with an increased risk of pregnancy induced hypertension (adjusted odds ratio 1.02, 95% confidence interval, 0.77 to 1.34; table 3). Young women (18 years or less) were at a significantly reduced risk. Markers of uncontrolled asthma were significantly associated with an increased risk of pregnancy induced hypertension. Patients were more likely to have pregnancy induced hypertension if they used more than three doses of short acting 2 agonists per week before pregnancy (37%), visited an emergency department or were admitted for asthma before pregnancy (59%), and used oral corticosteroids during pregnancy until the index date (57%). Using more than three doses of short acting 2 agonists per week during pregnancy, however, significantly reduced the risk of pregnancy induced hypertension by 33%. Being seen by at least one gynaecologist or obstetrician increased the risk of having a diagnosis of pregnancy induced hypertension by 76%, as did a higher number of prenatal visits, with a 7% increased risk of pregnancy induced hypertension for each additional visit. Chronic hypertension, diabetes, and parity were the strongest predictors of pregnancy induced hypertension.
Table 3 Multivariate analyses for use of inhaled corticosteroids (dichotomous) and risk of pregnancy induced hypertension or pre-eclampsia
Using inhaled corticosteroids during pregnancy was also not associated with a risk of pre-eclampsia (adjusted odds ratio 1.06, 95% confidence interval 0.74 to 1.53). All the predictors remaining in the pregnancy induced hypertension model also remained in the pre-eclampsia model, except for maternal age at delivery and the use of short acting 2 agonists. The magnitude of the adjusted odds ratios kept in both models was similar, with the exception of diabetes mellitus, which had a non-significant effect on pre-eclampsia. The dose of inhaled corticosteroids prescribed before conception was kept in the pre-eclampsia model but not in the pregnancy induced hypertension model.
When another set of conditional logistic regression models was used we found no dose-response relation between inhaled corticosteroids and the risk of pregnancy induced hypertension and pre-eclampsia. The covariates for both conditions in the final models also remained in these models and to the same magnitude. In table 4 we therefore only present the crude and adjusted odds ratios associated with the different dosages of inhaled corticosteroids.
Table 4 Multivariate analyses for dose of inhaled corticosteroids and risk of pregnancy induced hypertension or pre-eclampsia
Because 25% of women contributed more than one pregnancy to our analyses, we carried out supplementary analyses to investigate the potential correlation between pregnancies, including one in which only one pregnancy per woman was kept (data not shown). The results were similar to those in tables 3 and 4. The correlation therefore did not have a sizeable impact on the results obtained from the conditional logistic regression models, which are the most appropriate analyses to use with a nested case-control design.
Discussion
Olesen C, Steffensen FH, Nielsen GL, de Jong-van den Berg, Olsen J, Sorensen HT. Drug use in first pregnancy and lactation: a population-based survey among Danish women. The EUROMAP group. Eur J Clin Pharmacol 1999;55: 139-44.
Alexander S, Dodds L, Armson BA. Perinatal outcomes in women with asthma during pregnancy. Obstet Gynecol 1998;92: 435-40.
Schatz M, Zeiger RS, Harden K, Hoffman CC, Chilingar L, Petitti D. The safety of asthma and allergy medications during pregnancy. J Allergy Clin Immunol 1997;100: 301-6.
Working group report on high blood pressure in pregnancy. National high blood pressure education program report. Am J Obstet Gynecol 2000;183: S1-22.
Stenius-Aarniala B, Piirila P, Teramo K. Asthma and pregnancy: a prospective study of 198 pregnancies. Thorax 1988;43: 12-8.
Bahna SL, Bjerkedal T. The course and outcome of pregnancy in women with bronchial asthma. Acta allergol 1972;27: 397-406.
Demissie K, Breckenridge MB, Rhoads GG. Infant and maternal outcomes in the pregnancies of asthmatic women. Am J Respir Crit Care Med 1998;158: 1091-5.
Lehrer S, Stone J, Lapinski R, Lockwood CJ, Schachter BS, Berkowitz R, et al. Association between pregnancy-induced hypertension and asthma during pregnancy. Am J Obstet Gynecol 1993;168: 1463-6.
Perlow JH, Montgomery D, Morgan MA, Towers CV, Porto M. Severity of asthma and perinatal outcome. Am J Obstet Gynecol 1992;167: 963-7.
Wen SW, Demissie K, Liu S. Adverse outcomes in pregnancies of asthmatic women: results from a Canadian population. Ann Epidemiol 2001;11: 7-12.
Schatz M, Zeiger RS, Hoffman CP, Harden K, Forsythe A, Chilingar L, et al. Perinatal outcomes in the pregnancies of asthmatic women: a prospective controlled analysis. Am J Respir Crit Care Med 1995;151: 1170-4.
Dombrowski MP, Schatz M, Wise R, Thom EA, Landon M, Mabie W, et al. Randomized trial of inhaled beclomethasone dipropionate versus theophylline for moderate asthma during pregnancy. Am J Obstet Gynecol 2004;190: 737-44.
National Asthma Education and Prevention Program Expert Panel. Report 2: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health. (Report No 97-4051.)
Boulet LP, Becker A, Berube D, Beveridge R, Ernst P. Canadian asthma consensus report, 1999. Canadian Asthma Consensus Group. CMAJ 1999;161(11 suppl): S1-61.
Régie de l'assurance maladie du Québec. Statistiques annuelles. Quebec: Quebec government, 1997.
Garbe E, LeLorier J, Boivin J-F, Suissa S. Risk of ocular hypertension or open-angle glaucoma in elderly patients on oral glucocorticoids. Lancet 1997;350: 979-82.
Blais L, Desgagne A, LeLorier J. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer: a nested case-control study. Arch Intern Med 2000;160: 2363-8.
Avron J, Monette J, Lacour A, Bohn RL, Monane M, Mogun H, et al. Persistence of use of lipid-lowering medications: a cross-national study. JAMA 1998;279: 1458-62.
Tamblyn R, Lavoie G, Petrella L, Monette J. The use of prescription claims databases in pharmacoepidemiological research: the accuracy and comprehensiveness of the prescription claims database in Quebec. J Clin Epidemiol 1995;48: 999-1009.
Levy AR, Mayo NE, Grimard G. Rates of transcervical and pertrochanteric hip fractures in the province of Quebec, Canada, 1981-1992. Am J Epidemiol 1995;142: 428-36.
Lubin JH, Gail MH. Biased selection of controls for case control analyses of cohort studies. Biometrics 1984;40: 63-75.
Greenland S. Modeling and variable selection in epidemiologic analysis. Am J Public Health 1989;79: 340-9.
Duley L. Pre-eclampsia and the hypertensive disorders of pregnancy. Br Med Bull 2003;67: 161-76.
Paganini-Hill A, Ross RK. Reliability of recall of drug usage and other health-related information. Am J Epidemiol 1982;116: 114-22.
Rothman KJ, Greenland S. Precision and validity in epidemiologic studies. Modern epidemiology. Philadelphia, PA: Lippincott-Raven, 1998: 115-34.
Tilley BC, Barnes AB, Bergstralh E, Labarthe D, Noller KL, Colton T, et al. A comparison of pregnancy history recall and medical records. Implications for retrospective studies. Am J Epidemiol 1985;121: 269-81.
Van den Brandt PA, Petri H, Dorant E, Goldbohm RA, Van de CS. Comparison of questionnaire information and pharmacy data on drug use. Pharm Weekbl (Sci) 1991;13: 91-6.
West SL, Savitz DA, Koch G, Strom BL, Guess HA, Hartzema A. Recall accuracy for prescription medications: self-report compared with database information. Am J Epidemiol 1995;142: 1103-12.
De Jong van den Berg LT, Feenstra N, Sorensen HT, Cornel MC. Improvement of drug exposure data in a registration of congenital anomalies. Pilot-study: pharmacist and mother as sources for drug exposure data during pregnancy. EuroMAP Group. European Medicine and Pregnancy Group. Teratology 1999;60: 33-6.(Marie-Josée Martel, PhD student1, évelyn)