1 antihypertensive medication use and the risk of cardiovascular malformations alissa r. caton,...

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Antihypertensive Medication Use Antihypertensive Medication Use and the Risk of Cardiovascular and the Risk of Cardiovascular

MalformationsMalformations

Alissa R. Caton, Ph.D.Alissa R. Caton, Ph.D.NYS Department of HealthNYS Department of Health

MCH Epidemiology ConferenceMCH Epidemiology Conference

December 2006December 2006

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Published Studies on Published Studies on Antihypertensive Medication Use Antihypertensive Medication Use

and Cardiovascular Malformationsand Cardiovascular MalformationsPopulationPopulation YearsYears ExposureExposure RR EstimatesRR Estimates

Collaborative Collaborative Perinatal ProjectPerinatal Project

1959-1959-19651965

DIU or DIU or CV drugCV drug

0.9 (0.3-2.1)0.9 (0.3-2.1)

Baltimore-Baltimore-Washington Washington Infant StudyInfant Study

1981-1981-19891989

AHMAHM

DIUDIU1.2 (0.7-2.1) 1.2 (0.7-2.1) unadjustedunadjusted

8.6 (2.9-24.5) AVSD 8.6 (2.9-24.5) AVSD onlyonly

Hungarian C-C Hungarian C-C StudyStudy

1980-1980-19961996

CCBCCB 1.6 (0.8-3.2)1.6 (0.8-3.2)

Swedish Health Swedish Health RegistersRegisters

1995-1995-20012001

AHMAHM

BBBB

AA& DIU AA& DIU

2.0 (1.5-2.8)2.0 (1.5-2.8)

1.9 (1.2-2.8)1.9 (1.2-2.8)

~2.0 (Obs>Exp)~2.0 (Obs>Exp)

Michigan Michigan MedicaidMedicaid

1985-1985-19921992

Classes, Classes, drugsdrugs

Observed>ExpecteObserved>Expectedd

Tennessee Tennessee MedicaidMedicaid

1985-1985-20002000

ACEIACEI

Other Other AHMAHM

3.7 (1.9-7.3)3.7 (1.9-7.3)

0.7 (0.3-1.8)0.7 (0.3-1.8)

AHM=any antihypertensive medication; AA=antiadrenergic; BB=beta blocker; CCB=calcium channel blocker; DIU=diuretic; ACEI=ACE inhibitor.

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Limitations of Published Limitations of Published StudiesStudies

Too few studies and inconsistent findingsToo few studies and inconsistent findings Small sample sizes/low power to detect Small sample sizes/low power to detect

moderate associationsmoderate associations Broad groupings of cardiovascular Broad groupings of cardiovascular

malformationsmalformations Exposure misclassificationExposure misclassification

Broad groupings of medicationsBroad groupings of medications Medication reporting inaccuracyMedication reporting inaccuracy

Inadequate control of confoundingInadequate control of confounding Too little information available for adjustmentToo little information available for adjustment Confounding by indication and severityConfounding by indication and severity

Selection biasSelection bias

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Hypertension in PregnancyHypertension in Pregnancy

Present in 6-9% of pregnanciesPresent in 6-9% of pregnancies Chronic hypertension (<1%)Chronic hypertension (<1%) Gestational hypertensionGestational hypertension PreeclampsiaPreeclampsia Chronic hypertension with superimposed Chronic hypertension with superimposed

preeclampsiapreeclampsia ↑ ↑ risk of maternal/fetal death, fetal growth risk of maternal/fetal death, fetal growth

retardation, preterm delivery, placental retardation, preterm delivery, placental abruptionabruption

Expect prevalence of hypertension in Expect prevalence of hypertension in pregnancy to ↑ pregnancy to ↑

Childbearing at older maternal agesChildbearing at older maternal ages Increasing obesity in general populationIncreasing obesity in general population

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Specific AimsSpecific Aims

1.1. Characterize patterns of Characterize patterns of antihypertensive medication useantihypertensive medication use

Examine drug class, changes, and timing of Examine drug class, changes, and timing of exposure from preconception throughout exposure from preconception throughout pregnancypregnancy

Identify maternal and infant characteristics Identify maternal and infant characteristics associated with useassociated with use

2.2. Investigate the relationship between Investigate the relationship between antihypertensive medication use during antihypertensive medication use during pregnancy and cardiovascular pregnancy and cardiovascular malformationsmalformations

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Data Source, Study Design, Data Source, Study Design, & Study Subjects& Study Subjects

National Birth Defects Prevention StudyNational Birth Defects Prevention Study October 1, 1997–December 31, 2002October 1, 1997–December 31, 2002

Multicenter, population-based, case-Multicenter, population-based, case-control study of birth defectscontrol study of birth defects

CasesCases Non-chromosomal anomaliesNon-chromosomal anomalies Strict diagnostic criteria and clinical reviewStrict diagnostic criteria and clinical review

ControlsControls Sample of live births without birth defects Sample of live births without birth defects

from birth certificates or hospital recordsfrom birth certificates or hospital records Exclusions: pre-existing diabetes and Exclusions: pre-existing diabetes and

multiple birthsmultiple births

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Simple/Isolated CVM Case Simple/Isolated CVM Case GroupsGroups

Any CVM (n=2696)Any CVM (n=2696) Conotruncal (n=641)Conotruncal (n=641)

Tetralogy of Fallot (n=310)Tetralogy of Fallot (n=310) Left obstructive (LVOTO, Left obstructive (LVOTO,

n=430)n=430) Coarctation of aorta (n=159)Coarctation of aorta (n=159)

Right obstructive (RVOTO, Right obstructive (RVOTO, n=423)n=423) Pulmonic stenosis (PVS, n=303)Pulmonic stenosis (PVS, n=303) Ebstein malformation (n=38)Ebstein malformation (n=38)

Septal (n=1043)Septal (n=1043) Perimembranous ventricular Perimembranous ventricular (n=456)(n=456)

Atrial septal, secundum (n=427)Atrial septal, secundum (n=427)

Controls (n=3955)Controls (n=3955)

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Medication Class and Medication Class and TimingTiming

Slone Drug Dictionary was used to categorize Slone Drug Dictionary was used to categorize medications into classes based on componentsmedications into classes based on components

Start and stop dates were used to assign Start and stop dates were used to assign medication use to intervals from preconception medication use to intervals from preconception through birththrough birth

RiskRisk Early Use = Any use during critical period (one month Early Use = Any use during critical period (one month

preconception through pregnancy month three)preconception through pregnancy month three) Late Use = Initiated treatment after critical periodLate Use = Initiated treatment after critical period

PatternsPatterns 3 months preconception3 months preconception Trimesters 1-3Trimesters 1-3

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Exposure CategoriesExposure Categories

Early UseEarly Use MEDICATION USE DURING CRITICAL MEDICATION USE DURING CRITICAL PERIODPERIOD

Treated chronic hypertensionTreated chronic hypertension

Late UseLate Use MEDICATION USE POST-CRITICAL PERIODMEDICATION USE POST-CRITICAL PERIOD

Treated preeclampsia, gestational Treated preeclampsia, gestational hypertension, exacerbated or late diagnosed hypertension, exacerbated or late diagnosed chronic hypertensionchronic hypertension

Untreated Untreated High Blood High Blood PressurePressure

HIGH BLOOD PRESSURE ONLYHIGH BLOOD PRESSURE ONLY

Untreated preeclampsia, gestational Untreated preeclampsia, gestational hypertension, or chronic hypertensionhypertension, or chronic hypertension

UnexposedUnexposed REFERENCE GROUPREFERENCE GROUP

No high blood pressure or medicationNo high blood pressure or medication

Users without Users without High Blood High Blood PressurePressure

EXCLUDEDEXCLUDED

Medication in other CATI module (e.g. beta Medication in other CATI module (e.g. beta blocker for migraine)blocker for migraine)

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Statistical AnalysisStatistical Analysis

Odds Ratios and 95% Confidence Odds Ratios and 95% Confidence IntervalsIntervals

Bivariate analyses to assess relationships Bivariate analyses to assess relationships between covariatesbetween covariates

Stratified analysis to assess confounding Stratified analysis to assess confounding and effect modification and effect modification

Multivariable Logistic Regression AnalysisMultivariable Logistic Regression Analysis SubanalysesSubanalyses

Varying definitions of exposure (class, timing)Varying definitions of exposure (class, timing) Exclusions (family history, preterm births)Exclusions (family history, preterm births)

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Patterns of UsePatterns of Use

4,107 nonmalformed controls4,107 nonmalformed controls 387 (9.4%) reported high blood pressure387 (9.4%) reported high blood pressure 55 (1.3%) used medication from 55 (1.3%) used medication from

preconceptionpreconceptionbirthbirth = 14.2% of women reporting high blood pressure= 14.2% of women reporting high blood pressure

Medication use increased throughout Medication use increased throughout pregnancypregnancy 0.6% preconception 0.6% preconception 1.2% 31.2% 3rdrd trimester trimester

Methyldopa most commonly used drugMethyldopa most commonly used drug Contraindicated drugs reported (ACE inhibitors, Contraindicated drugs reported (ACE inhibitors,

beta blocker atenolol)beta blocker atenolol)

Timing of Use in Timing of Use in Nonmalformed ControlsNonmalformed Controls

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

AAC a/b BB CCB DIU ACEI ARB VASO NOS

MEDICATION CLASS

%

Preconception

1st Trimester

2nd Trimester

3rd Trimester

AAC=antiadrenergic, central; a/b=alpha-beta blocker labetolol; BB=beta blocker; CCB=calcium channel blocker; DIU=diuretic; ACEI=ACE inhibitor; ARB=angiotensin II receptor blocker; VASO=vasodilator.

11stst Trimester Treatment Trimester Treatment Choices in Choices in

Nonmalformed ControlsNonmalformed Controls

0

2

4

6

8

10

12

14

16

18

20

Continued Initiated Discontinued

MEDICATION

%

AAC Methyldopa

BB excl Atenolol

a/b Labetalol

AAC Clonidine

CCB

DIU

ACE inhibitor

BB Atenolol

Unknown

AAC=antiadrenergic, central; a/b=alpha-beta blocker labetolol; BB=beta blocker; CCB=calcium channel blocker; DIU=diuretic; ACEI=ACE inhibitor.

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Factors Related to Medication Factors Related to Medication ExposureExposure

Any Early Use (n=33)Any Early Use (n=33) Pre-existing diabetesPre-existing diabetes Gestational diabetesGestational diabetes ObesityObesity Age 35+Age 35+ Fertility tx/rxFertility tx/rx Multiple birthMultiple birth NH BlackNH Black Parity 2+Parity 2+ Center (IA highest, South Center (IA highest, South

lowest)lowest) Preterm birth/Low Preterm birth/Low

birthweightbirthweight

Late Use Only (n=28)Late Use Only (n=28) Overweight/ObesityOverweight/Obesity Gestational diabetesGestational diabetes Folic acid useFolic acid use NH BlackNH Black Fertility tx/rxFertility tx/rx Age 35+Age 35+ Parity 2+Parity 2+ NonsmokersNonsmokers Center (IA highest, NE Center (IA highest, NE

lowest)lowest) Preterm birth/Low Preterm birth/Low

birthweightbirthweight

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CVMs and Early UseCVMs and Early UseCase GroupCase Group CasesCases ControlControl

ssOR (CI)OR (CI) aOR (CI)aOR (CI)

ExExpp

%% ExpExp %%

Any CVMAny CVM 3737 1.41.4 2525 0.0.66

2.2 (1.3-2.2 (1.3-3.7)3.7)

1.8 (1.1-1.8 (1.1-3.1)3.1)

ConotruncalConotruncal 44 0.60.6 2525 0.0.66

1.0 (0.3-1.0 (0.3-2.9)2.9)

0.6 (0.2-0.6 (0.2-1.9)1.9)

TOFTOF 33 1.01.0 2525 0.0.66

1.6 (0.5-1.6 (0.5-5.2)5.2)

1.1 (0.3-1.1 (0.3-3.8)3.8)

LVOTOLVOTO 44 0.90.9 2525 0.0.66

1.5 (0.5-1.5 (0.5-4.3)4.3)

1.2 (0.4-1.2 (0.4-3.6)3.6)

Coarctation of Coarctation of aortaaorta

33 1.91.9 2525 0.0.66

3.1 (0.9-3.1 (0.9-10.5)10.5)

2.4 (0.7-2.4 (0.7-8.4)8.4)

RVOTORVOTO 99 2.12.1 2525 0.0.66

3.6 (1.6-3.6 (1.6-7.7)7.7)

3.0 (1.4-3.0 (1.4-6.6)6.6)

PVSPVS 55 1.71.7 2525 0.0.66

2.8 (1.1-2.8 (1.1-7.4)7.4)

2.2 (0.8-2.2 (0.8-5.8)5.8)

Ebstein Ebstein malformationmalformation

33 7.97.9 2525 0.0.66

14.4 (4.1-14.4 (4.1-50.2)50.2)

18.0 (4.8-18.0 (4.8-67.8)67.8)

SeptalSeptal 1818 1.71.7 2525 0.0.66

2.9 (1.5-2.9 (1.5-5.2)5.2)

2.3 (1.2-2.3 (1.2-4.3)4.3)

Perimembranous Perimembranous VSDVSD

77 1.51.5 2525 0.0.66

2.5 (1.1-2.5 (1.1-5.8)5.8)

2.0 (0.8-2.0 (0.8-4.7)4.7)

ASD secundumASD secundum 1010 2.42.4 2525 0.0.66

4.1 (1.9-4.1 (1.9-8.5)8.5)

3.3 (1.6-3.3 (1.6-7.1)7.1)

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CVMs and Late Use OnlyCVMs and Late Use OnlyCase GroupCase Group CasesCases ControlsControls OR (CI)OR (CI) aOR (CI)aOR (CI)

ExpExp %% ExpExp %%

Any CVMAny CVM 3232 1.21.2 2828 0.70.7 1.7 (1.0-1.7 (1.0-2.9)2.9)

1.6 (1.0-1.6 (1.0-2.8)2.8)

ConotruncalConotruncal 66 0.90.9 2828 0.70.7 1.3 (0.6-1.3 (0.6-3.3)3.3)

1.1 (0.4-1.1 (0.4-2.9)2.9)

TOFTOF 33 1.01.0 2828 0.70.7 1.4 (0.4-1.4 (0.4-4.6)4.6)

0.8 (0.2-0.8 (0.2-3.6)3.6)

LVOTOLVOTO 22 0.50.5 2828 0.70.7 ---- ----


11 0.60.6 2828 0.70.7 ---- ----

RVOTORVOTO 66 1.41.4 2828 0.70.7 2.1 (0.9-2.1 (0.9-5.1)5.1)

2.1 (0.8-2.1 (0.8-5.1)5.1)

PVSPVS 55 1.71.7 2828 0.70.7 2.5 (1.0-2.5 (1.0-6.5)6.5)

2.4 (0.9-2.4 (0.9-6.4)6.4)


11 2.62.6 2828 0.70.7 ---- ----

SeptalSeptal 1717 1.61.6 2828 0.70.7 2.4 (1.3-2.4 (1.3-4.4)4.4)

2.1 (1.1-2.1 (1.1-4.0)4.0)


77 1.51.5 2828 0.70.7 2.2 (1.0-2.2 (1.0-5.2)5.2)

2.0 (0.9-2.0 (0.9-4.7)4.7)

ASD secundumASD secundum 88 1.91.9 2828 0.70.7 2.9 (1.3-2.9 (1.3-6.4)6.4)

2.4 (1.0-2.4 (1.0-5.6)5.6)

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CVMs and Untreated High Blood CVMs and Untreated High Blood PressurePressure

Case GroupCase Group CasesCases ControlsControls OR (CI)OR (CI) aOR (CI)aOR (CI)

ExpExp %% ExpExp %%

Any CVMAny CVM 245245 9.19.1 303303 7.77.7 1.2 (1.0-1.2 (1.0-1.5)1.5)

1.2 (1.0-1.2 (1.0-1.4)1.4)

ConotruncalConotruncal 5858 9.19.1 303303 7.77.7 1.2 (0.9-1.2 (0.9-1.6)1.6)

1.1 (0.8-1.1 (0.8-1.5)1.5)

TOFTOF 2929 9.49.4 303303 7.77.7 1.3 (0.8-1.3 (0.8-1.9)1.9)

1.2 (0.8-1.2 (0.8-1.7)1.7)

LVOTOLVOTO 3535 8.28.2 303303 7.77.7 1.1 (0.7-1.1 (0.7-1.5)1.5)

1.0 (0.7-1.0 (0.7-1.5)1.5)


1717 10.10.77

303303 7.77.7 1.5 (0.9-1.5 (0.9-2.5)2.5)

1.3 (0.8-1.3 (0.8-2.3)2.3)

RVOTORVOTO 4242 10.10.00

303303 7.77.7 1.4 (1.0-1.4 (1.0-1.9)1.9)

1.3 (1.0-1.3 (1.0-1.9)1.9)

PVSPVS 3535 11.11.66

303303 7.77.7 1.6 (1.1-1.6 (1.1-2.3)2.3)

1.6 (1.1-1.6 (1.1-2.4)2.4)


44 10.10.55

303303 7.77.7 1.6 (0.6-1.6 (0.6-4.5)4.5)

1.7 (0.6-1.7 (0.6-4.9)4.9)

SeptalSeptal 9797 9.39.3 303303 7.77.7 1.3 (1.0-1.3 (1.0-1.6)1.6)

1.2 (0.9-1.2 (0.9-1.5)1.5)


4040 8.88.8 303303 7.77.7 1.2 (0.8-1.2 (0.8-1.7)1.7)

1.1 (0.8-1.1 (0.8-1.6)1.6)

ASD secundumASD secundum 5353 12.12.55

303303 7.77.7 1.8 (1.3-1.8 (1.3-2.4)2.4)

1.6 (1.2-1.6 (1.2-2.3)2.3)

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Early Use by Medication Early Use by Medication ClassClass

ClassClass CVMsCVMs ControlsControls

ExpExp %% ExpExp %%

Antiadrenergic AgentsAntiadrenergic Agents 3131 1.11.1 1919 0.50.5

Centrally actingCentrally acting 1717 0.60.6 1212 0.30.3

MethyldopaMethyldopa 1717 0.60.6 1010 0.30.3

a/b labetalola/b labetalol 77 0.30.3 33 <0.<0.11

Beta BlockerBeta Blocker 1414 0.50.5 55 0.10.1

AtenololAtenolol 66 0.20.2 33 <0.<0.11

Calcium Channel BlockerCalcium Channel Blocker 55 0.20.2 66 0.20.2

ACE InhibitorACE Inhibitor 66 0.20.2 22 <0.<0.11

Angiotensin II Receptor Angiotensin II Receptor BlockerBlocker

11 <0.<0.11

00 0.00.0

DiureticDiuretic 55 0.20.2 11 <0.<0.11

VasodilatorVasodilator 00 0.00.0 00 0.00.0

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CVMs and Medication Class CVMs and Medication Class

Early UseEarly Use CasesCases ControlsControls OR (CI)OR (CI) aOR (CI)aOR (CI)

ExExpp

%% ExpExp %%

Any ClassAny Class 3737 1.41.4 2525 0.60.6 2.2 (1.3-2.2 (1.3-3.7)3.7)

1.8 (1.1-1.8 (1.1-3.1)3.1)

Antiadrenergic Antiadrenergic AgentsAgents

3131 1.11.1 1919 0.50.5 2.5 (1.4-2.5 (1.4-4.4)4.4)

2.1 (1.2-2.1 (1.2-3.7)3.7)

Centrally actingCentrally acting 1717 0.60.6 1212 0.30.3 2.1 (1.0-2.1 (1.0-4.5)4.5)

1.8 (0.9-1.8 (0.9-3.9)3.9)

MethyldopaMethyldopa 1717 0.60.6 1010 0.30.3 2.6 (1.2-2.6 (1.2-5.6)5.6)

2.3 (1.0-2.3 (1.0-4.9)4.9)


3.5 (0.9-3.5 (0.9-13.7)13.7)

3.0 (0.8-3.0 (0.8-11.6)11.6)

Beta BlockerBeta Blocker 1414 0.50.5 55 0.10.1 4.2 (1.5-4.2 (1.5-11.8)11.8)

3.5 (1.2-3.5 (1.2-9.7)9.7)


3.0 (0.8-3.0 (0.8-12.1)12.1)

2.5 (0.6-2.5 (0.6-10.1)10.1)

Calcium Channel Calcium Channel BlockerBlocker

55 0.20.2 66 0.20.2 1.3 (0.4-1.3 (0.4-4.1)4.1)

0.9 (0.3-0.9 (0.3-3.1)3.1)

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RVOTOs and Medication RVOTOs and Medication Class Class


ExpExp %% ExExpp

%%


3.0 (1.4-3.0 (1.4-6.6)6.6)


88 1.91.9 1919 0.50.5 4.2 (1.8-4.2 (1.8-9.6)9.6)

3.5 (1.5-3.5 (1.5-8.1)8.1)


2.9 (0.9-2.9 (0.9-9.1)9.1)


3.5 (1.1-3.5 (1.1-11.5)11.5)


---- ----


8.0 (2.3-8.0 (2.3-28.4)28.4)


---- ----


00 0.00.0 66 0.20.2 ---- ----

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Septal Defects and Septal Defects and Medication Class Medication Class


ExpExp %% ExpExp %%


2.3 (1.2-2.3 (1.2-4.3)4.3)


1616 1.51.5 1919 0.50.5 3.3 (1.7-3.3 (1.7-6.5)6.5)

2.7 (1.4-2.7 (1.4-5.4)5.4)


2.1 (0.8-2.1 (0.8-5.1)5.1)


2.6 (1.0-2.6 (1.0-6.6)6.6)


5.3 (1.2-5.3 (1.2-23.6)23.6)

5.0 (1.1-5.0 (1.1-22.4)22.4)


4.7 (1.5-4.7 (1.5-15.1)15.1)


5.3 (1.2-5.3 (1.2-23.6)23.6)

4.9 (1.1-4.9 (1.1-22.2)22.2)


33 0.30.3 66 0.20.2 2.0 (0.5-2.0 (0.5-7.9)7.9)

1.3 (0.3-1.3 (0.3-5.5)5.5)

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SummarySummary

Early UseEarly Use Doubling of risk for simple, isolated CVMDoubling of risk for simple, isolated CVM Strongest elevations detected in RVOTO and Strongest elevations detected in RVOTO and

septal defectsseptal defects Beta blockers displayed highest risksBeta blockers displayed highest risks

Late Use – moderate risk for same Late Use – moderate risk for same groupsgroups

Untreated - weak elevations of riskUntreated - weak elevations of risk Conotruncal and LVOTO defects Conotruncal and LVOTO defects notnot

associated with early use, late use, or associated with early use, late use, or untreated HBPuntreated HBP

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Results in ContextResults in Context

Our finding of ~ doubling of risk for Our finding of ~ doubling of risk for CVMs in women using medication CVMs in women using medication during early pregnancy is consistent during early pregnancy is consistent with the recent study of medication use with the recent study of medication use during pregnancy in Sweden during pregnancy in Sweden (antiadrenergic agents, beta blockers)(antiadrenergic agents, beta blockers)

We found associations of medication We found associations of medication use with CVMs, including ASD use with CVMs, including ASD secundumsecundum Multiple drug classesMultiple drug classes Not able to evaluate ACE inhibitors alone Not able to evaluate ACE inhibitors alone

due to small sample sizesdue to small sample sizes

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Strengths & LimitationsStrengths & Limitations

StrengthsStrengths Exposure assessment for medication useExposure assessment for medication use

Indication-based ascertainmentIndication-based ascertainment Collected 6-24 months after deliveryCollected 6-24 months after delivery Oral prescription medication for chronic disease taken dailyOral prescription medication for chronic disease taken daily Evaluated timing of use during critical period of Evaluated timing of use during critical period of

developmentdevelopment Some class-specific analysesSome class-specific analyses

LimitationsLimitations Exposure assessment for medication useExposure assessment for medication use

Maternal self-reportMaternal self-report Inability to separate effects of medication from the Inability to separate effects of medication from the

indication for use (confounding by indication)indication for use (confounding by indication) Inability to measure the severity of high blood pressure Inability to measure the severity of high blood pressure

(confounding by severity)(confounding by severity) Small sample sizes due to rare exposures and rare Small sample sizes due to rare exposures and rare

outcomesoutcomes

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RecommendationsRecommendations

Post-marketing surveillance and research Post-marketing surveillance and research of pregnancies exposed to of pregnancies exposed to antihypertensive medicationsantihypertensive medications

Preconception planning and prenatal care Preconception planning and prenatal care for women with chronic hypertensionfor women with chronic hypertension

Better dissemination of information on Better dissemination of information on antihypertensive medication safety to antihypertensive medication safety to clinicians who care for women of clinicians who care for women of childbearing agechildbearing age

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Research DirectionsResearch Directions

Improve exposure assessment to tease Improve exposure assessment to tease apart effects of high blood pressure apart effects of high blood pressure from antihypertensive medicationfrom antihypertensive medication

Type and severity of high blood pressureType and severity of high blood pressure Other indications for useOther indications for use Medical records review for women Medical records review for women

reporting hypertension to validate reporting hypertension to validate medication use, classify hypertension type medication use, classify hypertension type and severityand severity

Examine additional defect groups, Examine additional defect groups, medication classes, factors related to medication classes, factors related to class use, effect modificationclass use, effect modification

1 antihypertensive medication use and the risk of cardiovascular malformations alissa r. caton,...

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