Trends in using beta-blockers and methyldopa for hypertensive disorders during pregnancy in a Canadian population

  • Ri-hua Xie
    Affiliations
    Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Road, Guangzhou 510515, China

    OMNI Research Group, Department of Obstetrics and Gynecology, University of Ottawa, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6

    Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Canada K1H 8L6
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  • Yanfang Guo
    Affiliations
    OMNI Research Group, Department of Obstetrics and Gynecology, University of Ottawa, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6

    Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Canada K1H 8L6
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  • Daniel Krewski
    Affiliations
    McLaughlin Centre for Population Health Risk Assessment, Institute of Population Health, University of Ottawa, 1 Stewart Street, Ottawa, Ontario, Canada K1N 6N5

    Risk Sciences International, Dalhousie Street, Ottawa, Ontario, Canada K1N 7G2

    Department of Epidemiology and Community Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5
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  • Donald Mattison
    Affiliations
    McLaughlin Centre for Population Health Risk Assessment, Institute of Population Health, University of Ottawa, 1 Stewart Street, Ottawa, Ontario, Canada K1N 6N5

    Risk Sciences International, Dalhousie Street, Ottawa, Ontario, Canada K1N 7G2
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  • Kara Nerenberg
    Affiliations
    OMNI Research Group, Department of Obstetrics and Gynecology, University of Ottawa, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6

    Department of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5
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  • Mark C. Walker
    Affiliations
    OMNI Research Group, Department of Obstetrics and Gynecology, University of Ottawa, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6

    Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Canada K1H 8L6

    Department of Epidemiology and Community Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5
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  • Shi Wu Wen
    Correspondence
    Corresponding author at: OMNI Research Group, Department of Obstetrics and Gynecology, University of Ottawa, 501 Smyth Road, Box 241, Ottawa, Ontario, Canada K1H 8L6. Tel.: +1 613 737 8899x73912; fax: +1 613 739 6266.
    Affiliations
    OMNI Research Group, Department of Obstetrics and Gynecology, University of Ottawa, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6

    Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Canada K1H 8L6

    Department of Epidemiology and Community Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5

    School of Public Health, Central South University, 110 XiangYa Road, Changsha, Hunan 410078, China
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Published:October 07, 2013DOI:https://doi.org/10.1016/j.ejogrb.2013.09.032

      Abstract

      Objective

      To describe trends in and patterns of antihypertensive drug use in a general obstetric population.

      Study design

      Historical cohort study. A total of 18,117 women who gave birth in a Saskatchewan hospital between January 1, 1980 and December 31, 2005 with a diagnosis of hypertensive disorders in pregnancy were identified and included in the analysis.

      Results

      The rate of treatment with antihypertensive drugs for pregnant women with chronic hypertension rose from 19.94% in 1980–1984 to 37.63% in 2000–2005. There were similar increases in antihypertensive drug use from 1.51% to 14.47% for gestational hypertension/non-severe preeclampsia, and from 1.56% to 20.86% for severe preeclampsia/eclampsia. Methyldopa was the most frequently used drug, followed by beta-blockers, with other antihypertensive drugs accounting for about 18.43% of total uses. The use of both methyldopa and labetalol has increased in recent years while the use of other antihypertensive drugs has decreased. Other antihypertensive drugs were more commonly prescribed in earlier gestation, while methyldopa and labetalol were generally prescribed in later gestation.

      Conclusion

      The use of antihypertensive drugs in pregnancy is relatively common and is increasing, with the liberal use of methyldopa and (especially) labetalol contributing appreciably to this increase.

      Keywords

      1. Introduction

      Hypertensive disorders are common medical complications of pregnancy associated with significantly increased risks of maternal and neonatal complications [
      • Helewa M.E.
      • Burrows R.F.
      • Smith J.
      • Williams K.
      • Brain P.
      Report of the Canadian Hypertension Society Consensus Conference: 1. Definitions, evaluation and classification of hypertensive disorders in pregnancy.
      ]. Although the importance of early, aggressive blood pressure control outside pregnancy has been clearly demonstrated, the role of blood pressure control during pregnancy remains unclear [
      • Magee L.A.
      • Abalos E.
      • von Dadelszen P.
      • Sibai B.
      • Easterling T.
      • Walkinshaw S.
      CHIPS Study Group. How to manage hypertension in pregnancy effectively.
      ,
      • Podymow T.
      • August P.
      Update on the use of antihypertensive drugs in pregnancy.
      ]. Even though treatment with antihypertensive drugs for severe hypertension in pregnancy (i.e., blood pressure > 160/110 mmHg) has been recommended, the question as to whether mild-to-moderately elevated blood pressure (i.e., blood pressure ≤ 160/110 mmHg) should be treated with antihypertensive drugs remains controversial [
      • Magee L.A.
      • Abalos E.
      • von Dadelszen P.
      • Sibai B.
      • Easterling T.
      • Walkinshaw S.
      CHIPS Study Group. How to manage hypertension in pregnancy effectively.
      ,
      • Podymow T.
      • August P.
      Update on the use of antihypertensive drugs in pregnancy.
      ]. Due to the lack of data on the efficacy and safety of antihypertensive drugs in pregnancy, there exist large variations in clinical practice guidelines among different countries/jurisdictions [
      • Magee L.A.
      • Abalos E.
      • von Dadelszen P.
      • Sibai B.
      • Easterling T.
      • Walkinshaw S.
      CHIPS Study Group. How to manage hypertension in pregnancy effectively.
      ,
      • Podymow T.
      • August P.
      Update on the use of antihypertensive drugs in pregnancy.
      ].
      Alpha agonists (methyldopa) and beta-blockers (acebutolol, atenolol, labetalol, mepindolol, metoprolol, pindolol, oxprenolol, and propranolol) are among the most frequently recommended antihypertensive drugs in pregnancy, although other drugs such as calcium channel blockers (siradipine, nicardipine, nifedipine and verapamil), diuretics (hydrochlorothiazide, etc.), vasodilators (hydralazine and prazozin), ketanserin and glyceryltrinitrate have also been used [
      • Abalos E.
      • Duley L.
      • Steyn D.W.
      • Henderson-Smart D.J.
      Antihypertensive drug therapy for mild to moderate hypertension during pregnancy.
      ,
      • ACOG Practice Bulletin
      Chronic hypertension in pregnancy.
      ,
      • Chobanian A.V.
      • Bakris G.L.
      • Black H.R.
      • et al.
      National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, and Treatment of high blood pressure. The Seventh Report of the Joint Committee.
      ,
      • Magee L.
      • Helewa M.
      • MoutquinJM
      • vonDadelszen P.
      Hypertension Guideline Committee. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy.
      ]. The safety of beta-blockers (including labetalol) in pregnancy has not been well established, as some studies have reported an association between pregnancy exposure to beta-blockers and low birth weight infants [
      • Podymow T.
      • August P.
      Update on the use of antihypertensive drugs in pregnancy.
      ,
      • Magee L.A.
      • Duley L.
      Oral beta-blockers for mild to moderate hypertension during pregnancy.
      ,
      • Lydakis C.
      • Lip G.Y.
      • Beevers M.
      • Beevers D.G.
      Atenolol and fetal growth in pregnancies complicated by hypertension.
      ]. The literature on the actual use of antihypertensive drugs in routine obstetric practice is sparse [
      • Bánhidy F.
      • Acs N.
      • Puhó E.H.
      • Czeizel A.E.
      The efficacy of antihypertensive treatment in pregnant women with chronic and gestational hypertension: a population-based study.
      ,
      • Anderson G.D.
      • Carr D.B.
      Effect of pregnancy on the pharmacokinetics of antihypertensive drugs.
      ,
      • Andrade S.E.
      • Raebel M.A.
      • Brown J.
      • et al.
      Outpatient use of cardiovascular drugs during pregnancy.
      ,
      • Bateman B.T.
      • Hernandez-Diaz S.
      • Huybrechts K.F.
      • et al.
      Patterns of outpatient antihypertensive medication use during pregnancy in a Medicaid population.
      ]. The objective of the present study was to assess trends and patterns of beta-blockers and methyldopa in pregnancy in general obstetric practice, using a population-based health care database in the Canadian province of Saskatchewan.

      2. Materials and methods

      Women who were eligible for coverage by the Saskatchewan Prescription Drug Plan (out-patient prescriptions) and who delivered a singleton in Saskatchewan from January 1, 1980 to June 30, 1987 or January 1, 1990 to December 31, 2005 with a diagnosis of a hypertensive disorder in pregnancy were identified through ICD-9/ICD-10-CA codes recorded in the database. Infants born between July 1, 1987 and December 31, 1989 were excluded because information on maternal drug use during pregnancy is incomplete. The majority of pregnant women with hypertensive disorders treated with antihypertensive drugs were treated with beta-blockers and/or methyldopa, and therefore we excluded women who were treated with other antihypertensive drugs alone. The following data were abstracted from the Saskatchewan health databases: a unique identifier, number of days between drug dispensing date and infant birth date, gestational age categories (0–23 weeks, 24–29 weeks, 30–37 weeks, 38–41weeks, and more than 42 weeks), the specific name of beta-blockers and methyldopa, and women's demography. Information on prescription of antihypertensive drugs in pregnancy was ascertained for each study participant using number of days between drug dispensing date and infant birth date.
      Hypertensive disorders in pregnancy are generally classified by professional guidelines as: pre-existing hypertension (chronic hypertension predating the pregnancy or when hypertension is diagnosed before 20 weeks’ gestation); gestational hypertension (hypertension developing after 20 weeks’ gestation and urinary protein excretion < 0.3 g/day); preeclampsia (hypertension diagnosed after 20 weeks’ gestation with urinary protein excretion > 0.3 g/day); and pre-existing hypertension with superimposed preeclampsia [
      • Helewa M.E.
      • Burrows R.F.
      • Smith J.
      • Williams K.
      • Brain P.
      Report of the Canadian Hypertension Society Consensus Conference: 1. Definitions, evaluation and classification of hypertensive disorders in pregnancy.
      ]. Eclampsia is a form of severe preeclampsia resulting in maternal seizure(s). These hypertensive disorders were captured by ICD-9 and ICD-10-CA codes contained in the database. For this study, we re-grouped the hypertensive disorders in pregnancy according to their severity and clinical management regimens. The classes were as follows: (1) chronic hypertension (women with chronic hypertension with or without superimposed preeclampsia); (2) gestational hypertension (women with either gestational hypertension or non-severe preeclampsia); and (3) severe preeclampsia (women with severe preeclampsia and/or eclampsia). For the rest of the paper these groups will be used.
      We first described antihypertensive drug uses in pregnancy in the overall pregnancy and by trimesters. We then compared secular trends of treatment for the following three categories of antihypertensive drugs: (a) methyldopa, (b) labetalol, and (c) other beta-blockers. Supplementary analyses restricted to first pregnancies were also performed. All analyses were performed by SAS 9.2 (SAS Institute Inc., Cary, NC).

      3. Results

      A total of 19,003 pregnant women with a diagnosis of hypertensive disorders in pregnancy were identified from the database. Eight hundred and eighty-six women used other antihypertensive drugs alone without beta-blockers and/or methyldopa and were excluded, leaving 18,117 women for final analysis. Of them, 4229 had chronic hypertension, 13,006 had gestational hypertension/non-severe preeclampsia, and 882 had a diagnosis of severe preeclampsia.
      Detailed information on specific antihypertensive drugs used in pregnancy is described in Table 1. Methyldopa was the most frequently used drug, followed by labetalol, with other beta-blockers the least used. About 18% women received other antihypertensive drugs along with beta-blockers and/or methyldopa.
      Table 1Antihypertensive drug used in pregnant women by class of hypertensive disorders in Saskatchewan, 1980–2005.
      Data between July 1, 1987 and December 31, 1989 were unavailable.
      Drug categoryOverall n (%)Chronic hypertension
      Chronic hypertension: women with chronic hypertension with or without superimposed preeclampsia.


      n (%)
      Gestational hypertension
      Gestational hypertension: women with either gestational hypertension or non-severe preeclampsia.


      n (%)
      Severe preeclampsia
      Severe preeclampsia: women with severe preeclampsia and/or eclampsia.


      n (%)
      Beta-blockers
       Acebutolol17 (0.8)16 (1.4)1 (0.1)0 (0.0)
       Atenolol171 (8.2)139 (12.1)25 (3.0)7 (6.8)
       Labetalol449 (21.6)221 (19.2)187 (22.6)41 (39.8)
       Metoprolol30 (1.4)25 (2.2)2 (0.2)3 (2.9)
       Nadolol10 (0.5)10 (0.9)0 (0.0)0 (0.0)
       Oxprenolol4 (0.2)3 (0.3)1 (0.1)0 (0.0)
       Pindolol27 (1.3)23 (2.0)3 (0.4)1 (1.0)
       Propranolol146 (7.0)89 (7.7)53 (6.4)4 (3.9)
       Timolol19 (0.9)15 (1.3)4 (0.5)0 (0.0)
      Alpha-blockers
       Methyldopa1404 (67.4)766 (66.4)581 (70.3)57 (55.3)
      Other antihypertensives
      Along with beta-blockers and/or methyldopa.
      384 (18.4)337 (29.2)40 (4.8)7 (6.8)
      a Data between July 1, 1987 and December 31, 1989 were unavailable.
      b Along with beta-blockers and/or methyldopa.
      c Chronic hypertension: women with chronic hypertension with or without superimposed preeclampsia.
      d Gestational hypertension: women with either gestational hypertension or non-severe preeclampsia.
      e Severe preeclampsia: women with severe preeclampsia and/or eclampsia.
      Table 2 shows the use of antihypertensive drugs during different gestational periods. Methyldopa was the most frequently prescribed antihypertensive drug in the third trimester, followed by labetalol.
      Table 2Categories of antihypertensive drugs used for hypertensive disorders in pregnancy by trimester in Saskatchewan, 1980–2005.
      Data between July 1, 1987 and December 31, 1989 were unavailable.
      Drug categoryFirst trimester (N = 626)

      n (%)
      Second trimester (N = 849)

      n (%)
      Third trimester (N = 1820)

      n (%)
      Labetalol41 (6.6)99 (11.7)354 (19.5)
      Other beta-blockers144 (23.0)135 (15.9)172 (9.5)
      Methyldopa144 (23.0)320 (37.7)973 (53.5)
      Other antihypertensives
      Chronic hypertension: women with chronic hypertension with or without superimposed preeclampsia.
      297 (47.4)295 (34.8)321 (17.6)
      a Data between July 1, 1987 and December 31, 1989 were unavailable.
      b Along with beta-blockers and/or methyldopa.
      Table 3 compares secular trends of different categories of antihypertensive drugs. The use of both methyldopa and (especially) labetalol has increased in recent years, while the use of other beta-blockers has decreased.
      Table 3Categories of antihypertensive drug used for pregnant women with hypertensive disorders over time in Saskatchewan, 1980–2005.
      Data between July 1, 1987 and December 31, 1989 were unavailable.
      YearChronic hypertension
      Chronic hypertension: women with chronic hypertension with or without superimposed preeclampsia.
      Gestational hypertension
      Gestational hypertension: women with either gestational hypertension or non-severe preeclampsia.
      Severe preeclampsia
      Severe preeclampsia: women with severe preeclampsia and/or eclampsia.
      NLabetalol

      n (%)
      Other beta-blockers

      n (%)
      Methyldopa

      n (%)
      NLabetalol

      n (%)
      Other beta-blockers

      n (%)
      Methyldopa

      n (%)
      NLabetalol

      n (%)
      Other beta-blockers

      n (%)
      Methyldopa

      n (%)
      1980–19846170 (0.0)64 (10.4)68 (11.0)32490 (0.0)15 (0.5)33 (1.0)640 (0.0)0 (0.0)1 (1.6)
      1985-June 874341 (0.2)50 (11.5)52 (12.0)17910 (0.0)14 (0.8)22 (1.2)1370 (0.0)3 (2.2)3 (2.2)
      1990–199482532 (3.9)59 (7.2)120 (14.6)292915 (0.5)21 (0.7)93 (3.2)1781 (0.6)1 (0.6)5 (2.8)
      1995–1999105133 (3.1)58 (5.5)184 (17.5)243825 (1.0)20 (0.8)196 (8.0)1533 (2.0)4 (2.6)10 (6.5)
      2000–20051302155 (11.9)71 (5.5)342 (26.3)2599147 (5.7)16 (0.6)237 (9.1)35037 (10.6)6 (1.7)38 (10.9)
      a Data between July 1, 1987 and December 31, 1989 were unavailable.
      b Chronic hypertension: women with chronic hypertension with or without superimposed preeclampsia.
      c Gestational hypertension: women with either gestational hypertension or non-severe preeclampsia.
      d Severe preeclampsia: women with severe preeclampsia and/or eclampsia.
      Findings from supplementary analyses restricting to first pregnancies were similar (data available upon request).

      4. Comment

      Our large population-based study found that among pregnant women with a diagnosis of any hypertensive disorder, the overall treatment rate was 15.6% (of the 19,003 women with hypertensive disorders in pregnancy, 2,073were dispensed beta-blockers and/or methyldopa plus 886 dispensed other antihypertensive drugs alone). Methyldopa was the most frequently used drug, followed by labetalol, with other beta-blockers the least used. The use of both methyldopa and (especially) labetalol has increased in recent years, while the use of other beta-blockers has decreased.
      Our study was based on women with a diagnosis of hypertensive disorders in pregnancy in the majority of the obstetric population in the Canadian province of Saskatchewan, thereby reducing selection bias. Drug utilization information was abstracted from claim records. As a result, recall bias that might occur if the information was obtained directly from the women themselves can be avoided. Finally, the protracted study period permitted an assessment of the evolution of patterns of antihypertensive drug use during pregnancy over the course of more than two decades. These results provide novel and important information to health care providers and planners, as they can examine if similar trends/patterns exist in their own practices and jurisdictions.
      Our study has several limitations. First, drugs dispensed during hospitalizations or given as samples in physicians’ offices were not available from the Saskatchewan Prescription Drug Plan Database. These prescriptions should, however, represent only a small fraction of antihypertensive medication use. Moreover, patients who received antihypertensive medication in hospitals or as samples in physicians’ offices would be very likely to continue drug treatment, and thus later be identified using the drug the Saskatchewan Prescription Drug Plan Database. Second, there is no information on drug adherence in Saskatchewan's prescription drug file. As such, some patients who received prescription drugs from the pharmacy but did not actually consume the medications could be misclassified as “users”, leading to an over-estimate of the prevalence of use. Finally, administrative health data are prone to certain degree of coding errors [
      ]. As a result, misclassifications of diseases and drugs could occur.
      Our extensive search of the literature identified few articles reporting on the use of antihypertensive drugs in pregnancy. These articles revealed dramatically different rates of treatment, ranging from 96.4% for pregnant women with chronic hypertension in Hungary to 6.7% for pregnant women with gestational hypertension in our study [
      • Bánhidy F.
      • Acs N.
      • Puhó E.H.
      • Czeizel A.E.
      The efficacy of antihypertensive treatment in pregnant women with chronic and gestational hypertension: a population-based study.
      ,
      • Anderson G.D.
      • Carr D.B.
      Effect of pregnancy on the pharmacokinetics of antihypertensive drugs.
      ,
      • Andrade S.E.
      • Raebel M.A.
      • Brown J.
      • et al.
      Outpatient use of cardiovascular drugs during pregnancy.
      ,
      • Bateman B.T.
      • Hernandez-Diaz S.
      • Huybrechts K.F.
      • et al.
      Patterns of outpatient antihypertensive medication use during pregnancy in a Medicaid population.
      ] (Table 4). Considering only data from recent years (2000–2005), the overall treatment rate in our study population was quite similar to what was observed by Bateman et al. in the United States [
      • Bateman B.T.
      • Hernandez-Diaz S.
      • Huybrechts K.F.
      • et al.
      Patterns of outpatient antihypertensive medication use during pregnancy in a Medicaid population.
      ] but much lower than in the Hungarian population [
      • Bánhidy F.
      • Acs N.
      • Puhó E.H.
      • Czeizel A.E.
      The efficacy of antihypertensive treatment in pregnant women with chronic and gestational hypertension: a population-based study.
      ]. Different from our observation, the most common antihypertensive drugs dispensed during pregnancy in a HMO population in the United States observed by Andrade et al. were nifedipine (1219 deliveries; 1.0%), methyldopa (961 deliveries; 0.8%), atenolol (593 deliveries; 0.5%), and labetalol (576 deliveries; 0.5%) [
      • Andrade S.E.
      • Raebel M.A.
      • Brown J.
      • et al.
      Outpatient use of cardiovascular drugs during pregnancy.
      ], suggesting that dramatic variation existed not only in overall treatment rate, but also in specific drugs used for treatment.
      Table 4Prevalence of antihypertensive drug uses in pregnancy reported in the literature.
      AuthorYear of publicationStudy populationPrevalence of antihypertensive drug uses in pregnancy (all pregnancies) (%)Prevalence of antihypertensive drug uses in pregnancy (in pregnancies with hypertensive disorders) (%)
      Bánhidy
      • Bánhidy F.
      • Acs N.
      • Puhó E.H.
      • Czeizel A.E.
      The efficacy of antihypertensive treatment in pregnant women with chronic and gestational hypertension: a population-based study.
      2010Pregnant women with chronic hypertension in HungaryN/A96.4
      Bánhidy
      • Bánhidy F.
      • Acs N.
      • Puhó E.H.
      • Czeizel A.E.
      The efficacy of antihypertensive treatment in pregnant women with chronic and gestational hypertension: a population-based study.
      2010Pregnant women with gestational hypertension in HungaryN/A59.8
      Anderson and Carr
      • Anderson G.D.
      • Carr D.B.
      Effect of pregnancy on the pharmacokinetics of antihypertensive drugs.
      2008Pregnant women in the United States3.0N/A
      Andrade
      • Andrade S.E.
      • Raebel M.A.
      • Brown J.
      • et al.
      Outpatient use of cardiovascular drugs during pregnancy.
      2008Pregnant women in the United States3.1N/A
      Bateman
      • Bateman B.T.
      • Hernandez-Diaz S.
      • Huybrechts K.F.
      • et al.
      Patterns of outpatient antihypertensive medication use during pregnancy in a Medicaid population.
      2012Pregnant women in the United States4.421.9
      Estimated by the formula: assuming 50% of the antihypertensive drugs were actually prescribed to women with a hypertensive disorders during pregnancy and further assuming that the rate of hypertensive disorders in pregnancy in the Medicaid population by Bateman et al. was 10%, the prevalence of antihypertensive drug uses in pregnant women with a diagnosis of hypertensive disorders during pregnancy is: 24,226/(1,106,757*0.10)=21.9% in their cohort.
      Xie (current study)2013Women with hypertensive disorders of pregnancy in CanadaN/A15.6
      Xie (current study)2013Pregnant women with chronic hypertension in CanadaN/A27.1
      Xie (current study)2013Pregnant women with gestational hypertension in CanadaN/A6.7
      Xie et al. (current study)2013Pregnant women with severe preeclampsia in CanadaN/A8.6
      N/A, not available.
      a Estimated by the formula: assuming 50% of the antihypertensive drugs were actually prescribed to women with a hypertensive disorders during pregnancy and further assuming that the rate of hypertensive disorders in pregnancy in the Medicaid population by Bateman et al. was 10%, the prevalence of antihypertensive drug uses in pregnant women with a diagnosis of hypertensive disorders during pregnancy is: 24,226/(1,106,757 * 0.10) = 21.9% in their cohort.
      Bateman et al. also observed an increase in antihypertensive use during pregnancy from 3.5% in 2000 to 4.9% in 2007 [
      • Bateman B.T.
      • Hernandez-Diaz S.
      • Huybrechts K.F.
      • et al.
      Patterns of outpatient antihypertensive medication use during pregnancy in a Medicaid population.
      ], and attributed this to the increased rates of chronic hypertension and gestational hypertension in the population, which they considered as being secondary to increased obesity and advanced maternal age in the United States [
      • Bateman B.T.
      • Bansil P.
      • Hernandez-Diaz S.
      • Mhyre J.M.
      • Callaghan W.M.
      • Kuklina E.V.
      Prevalence, trends, and outcomes of chronic hypertension: a nationwide sample of delivery admission.
      ,
      • Kim S.Y.
      • Dietz P.M.
      • England L.
      • Morrow B.
      • Callaghan W.M.
      Trends in pre-pregnancy obesity in nine states, 1993–2003.
      ,
      • Kuklina E.V.
      • Ayala C.
      • Callaghan W.M.
      Hypertensive disorders and severe obstetric morbidity in the United States.
      ] during the study period. Both increased prevalence of hypertensive disorders of pregnancy caused by obesity and advanced maternal age and increased prescriptions for diagnosed hypertensive disorders may have led to increased maternal exposure to antihypertensive drugs. However, the magnitude of the increase caused by increased prescriptions observed in our study was much larger than the increase in prevalence of hypertensive disorders associated with increase in obesity and advanced maternal age [
      • Bateman B.T.
      • Bansil P.
      • Hernandez-Diaz S.
      • Mhyre J.M.
      • Callaghan W.M.
      • Kuklina E.V.
      Prevalence, trends, and outcomes of chronic hypertension: a nationwide sample of delivery admission.
      ,
      • Kim S.Y.
      • Dietz P.M.
      • England L.
      • Morrow B.
      • Callaghan W.M.
      Trends in pre-pregnancy obesity in nine states, 1993–2003.
      ,
      • Kuklina E.V.
      • Ayala C.
      • Callaghan W.M.
      Hypertensive disorders and severe obstetric morbidity in the United States.
      ]. Bateman et al. found that use of angiotensin-converting enzyme inhibitors, which are considered contraindicated in late pregnancy, occurred in 928 (4.9%) of antihypertensive medication users in the second trimester and in 383 (1.1%) women in the third trimester [
      • Bateman B.T.
      • Hernandez-Diaz S.
      • Huybrechts K.F.
      • et al.
      Patterns of outpatient antihypertensive medication use during pregnancy in a Medicaid population.
      ]. The use of contraindicated drugs in pregnancy is important to study, but we were unable to obtain direct information on certain types of drugs due to limitations with our dataset.
      In summary, our population-based study found that, consistent with professional guidelines, the most frequently prescribed drugs were methyldopa and labetalol. Both can effectively control maternal blood pressure with no serious side effects [
      • Podymow T.
      • August P.
      Update on the use of antihypertensive drugs in pregnancy.
      ]. However, there are still unresolved issues in the use of beta-blockers (including labetalol) in pregnancy, as several studies suggest that their use may be associated with low birth weight [
      • Podymow T.
      • August P.
      Update on the use of antihypertensive drugs in pregnancy.
      ,
      • Magee L.A.
      • Duley L.
      Oral beta-blockers for mild to moderate hypertension during pregnancy.
      ,
      • Lydakis C.
      • Lip G.Y.
      • Beevers M.
      • Beevers D.G.
      Atenolol and fetal growth in pregnancies complicated by hypertension.
      ]. Antihypertensive drugs are often given to reduce maternal blood pressure in those with severe hypertension to prevent stroke and hypertensive crises [
      • Magee L.A.
      • Abalos E.
      • von Dadelszen P.
      • Sibai B.
      • Easterling T.
      • Walkinshaw S.
      CHIPS Study Group. How to manage hypertension in pregnancy effectively.
      ,
      • Podymow T.
      • August P.
      Update on the use of antihypertensive drugs in pregnancy.
      ]. There is, however, no conclusive evidence that antihypertensive treatment is beneficial to the mother in the case of mild-to-moderate hypertension in pregnancy. Given this uncertainty, the significantly increased use of labetalol for women with either chronic or gestational hypertension observed in our study deserves further attention. Large-scale epidemiologic studies should be conducted to assess the potential benefits and adverse effects of the commonly used antihypertensive drugs during pregnancy on mothers and fetuses.

      Acknowledgements

      This study was supported partly by a grant from the Ontario Ministry of Health and Long-term Care through it Drug Innovation grant (grant # 2008-007 ) and a grant from Canadian Institutes for Health Research (CIHR ; grant # MOP 86537 ). Dr. Wen is a recipient of Mid-Career Award from CIHR's Institute for Gender-Ontario Women's Health Council. Dr. Krewski is the Natural Sciences and Engineering Research Council of Canada Chair in Risk Science at the University of Ottawa. Dr. Mark Walker is supported by a University of Ottawa Tier 1 Chair in Perinatal Epidemiology. The authors thank Dr. Xi-kuan Chen for his contribution at the early stage of this project. This study was based on de-identified data provided by the Saskatchewan Ministry of Health. The interpretation and conclusions contained herein do not necessarily represent those of the Government of Saskatchewan or the Saskatchewan Ministry of Health.

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