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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 ---- ----
Coarctation of Coarctation of aortaaorta
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)
Ebstein Ebstein malformationmalformation
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)
Perimembranous Perimembranous VSDVSD
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)
Coarctation of Coarctation of aortaaorta
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)
Ebstein Ebstein malformationmalformation
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)
Perimembranous Perimembranous VSDVSD
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)
a/b labetalola/b labetalol 77 0.30.3 33 <0.<0.11
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)
AtenololAtenolol 66 0.20.2 33 <0.<0.11
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
Early UseEarly Use CasesCases ControlsControls OR (CI)OR (CI) aOR (CI)aOR (CI)
ExpExp %% ExExpp
%%
Any ClassAny Class 99 2.12.1 2525 0.60.6 3.6 (1.6-3.6 (1.6-7.7)7.7)
3.0 (1.4-3.0 (1.4-6.6)6.6)
Antiadrenergic Antiadrenergic AgentsAgents
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)
Centrally actingCentrally acting 44 0.90.9 1212 0.30.3 3.3 (1.1-3.3 (1.1-10.2)10.2)
2.9 (0.9-2.9 (0.9-9.1)9.1)
MethyldopaMethyldopa 44 0.90.9 1010 0.30.3 3.9 (1.2-3.9 (1.2-12.6)12.6)
3.5 (1.1-3.5 (1.1-11.5)11.5)
a/b labetalola/b labetalol 22 0.50.5 33 <0.<0.11
---- ----
Beta BlockerBeta Blocker 55 1.21.2 55 0.10.1 9.9 (2.8-9.9 (2.8-34.2)34.2)
8.0 (2.3-8.0 (2.3-28.4)28.4)
AtenololAtenolol 11 0.20.2 33 <0.<0.11
---- ----
Calcium Channel Calcium Channel BlockerBlocker
00 0.00.0 66 0.20.2 ---- ----
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Septal Defects and Septal Defects and Medication Class Medication Class
Early UseEarly Use CasesCases ControlsControls OR (CI)OR (CI) aOR (CI)aOR (CI)
ExpExp %% ExpExp %%
Any ClassAny Class 1818 1.71.7 2525 0.60.6 2.9 (1.5-2.9 (1.5-5.2)5.2)
2.3 (1.2-2.3 (1.2-4.3)4.3)
Antiadrenergic Antiadrenergic AgentsAgents
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)
Centrally actingCentrally acting 88 0.80.8 1212 0.30.3 2.6 (1.1-2.6 (1.1-6.5)6.5)
2.1 (0.8-2.1 (0.8-5.1)5.1)
MethyldopaMethyldopa 88 0.80.8 1010 0.30.3 3.2 (1.2-3.2 (1.2-8.0)8.0)
2.6 (1.0-2.6 (1.0-6.6)6.6)
a/b labetalola/b labetalol 44 0.40.4 33 <0.<0.11
5.3 (1.2-5.3 (1.2-23.6)23.6)
5.0 (1.1-5.0 (1.1-22.4)22.4)
Beta BlockerBeta Blocker 77 0.70.7 55 0.10.1 5.5 (1.8-5.5 (1.8-17.5)17.5)
4.7 (1.5-4.7 (1.5-15.1)15.1)
AtenololAtenolol 44 0.40.4 33 <0.<0.11
5.3 (1.2-5.3 (1.2-23.6)23.6)
4.9 (1.1-4.9 (1.1-22.2)22.2)
Calcium Channel Calcium Channel BlockerBlocker
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