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Antihypertensive Medication Use and the Risk of Cardiovascular Malformations

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Examine drug class, changes, and timing of exposure from preconception throughout pregnancy ... 55 (1.3%) used medication from preconception ... – PowerPoint PPT presentation

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Title: Antihypertensive Medication Use and the Risk of Cardiovascular Malformations


1
Antihypertensive Medication Use and the Risk of
Cardiovascular Malformations
  • Alissa R. Caton, Ph.D.
  • NYS Department of Health
  • MCH Epidemiology Conference
  • December 2006

2
Published Studies on Antihypertensive Medication
Use and Cardiovascular Malformations
AHMany antihypertensive medication
AAantiadrenergic BBbeta blocker
CCBcalcium channel blocker DIUdiuretic
ACEIACE inhibitor.
3
Limitations of Published Studies
  • Too few studies and inconsistent findings
  • Small sample sizes/low power to detect moderate
    associations
  • Broad groupings of cardiovascular malformations
  • Exposure misclassification
  • Broad groupings of medications
  • Medication reporting inaccuracy
  • Inadequate control of confounding
  • Too little information available for adjustment
  • Confounding by indication and severity
  • Selection bias

4
Hypertension in Pregnancy
  • Present in 6-9 of pregnancies
  • Chronic hypertension (lt1)
  • Gestational hypertension
  • Preeclampsia
  • Chronic hypertension with superimposed
    preeclampsia
  • ? risk of maternal/fetal death, fetal growth
    retardation, preterm delivery, placental
    abruption
  • Expect prevalence of hypertension in pregnancy to
    ?
  • Childbearing at older maternal ages
  • Increasing obesity in general population

5
Specific Aims
  • Characterize patterns of antihypertensive
    medication use
  • Examine drug class, changes, and timing of
    exposure from preconception throughout pregnancy
  • Identify maternal and infant characteristics
    associated with use
  • Investigate the relationship between
    antihypertensive medication use during pregnancy
    and cardiovascular malformations

6
Data Source, Study Design, Study Subjects
  • National Birth Defects Prevention Study
  • October 1, 1997December 31, 2002
  • Multicenter, population-based, case-control study
    of birth defects
  • Cases
  • Non-chromosomal anomalies
  • Strict diagnostic criteria and clinical review
  • Controls
  • Sample of live births without birth defects from
    birth certificates or hospital records
  • Exclusions pre-existing diabetes and multiple
    births

7
Simple/Isolated CVM Case Groups
  • Any CVM (n2696)
  • Conotruncal (n641)
  • Tetralogy of Fallot (n310)
  • Left obstructive (LVOTO, n430)
  • Coarctation of aorta (n159)
  • Right obstructive (RVOTO, n423)
  • Pulmonic stenosis (PVS, n303)
  • Ebstein malformation (n38)
  • Septal (n1043)
  • Perimembranous ventricular (n456)
  • Atrial septal, secundum (n427)
  • Controls (n3955)

8
Medication Class and Timing
  • Slone Drug Dictionary was used to categorize
    medications into classes based on components
  • Start and stop dates were used to assign
    medication use to intervals from preconception
    through birth
  • Risk
  • Early Use Any use during critical period (one
    month preconception through pregnancy month
    three)
  • Late Use Initiated treatment after critical
    period
  • Patterns
  • 3 months preconception
  • Trimesters 1-3

9
Exposure Categories
10
Statistical Analysis
  • Odds Ratios and 95 Confidence Intervals
  • Bivariate analyses to assess relationships
    between covariates
  • Stratified analysis to assess confounding and
    effect modification
  • Multivariable Logistic Regression Analysis
  • Subanalyses
  • Varying definitions of exposure (class, timing)
  • Exclusions (family history, preterm births)

11
Patterns of Use
  • 4,107 nonmalformed controls
  • 387 (9.4) reported high blood pressure
  • 55 (1.3) used medication from preconception?birth
  • 14.2 of women reporting high blood pressure
  • Medication use increased throughout pregnancy
  • 0.6 preconception ?1.2 3rd trimester
  • Methyldopa most commonly used drug
  • Contraindicated drugs reported (ACE inhibitors,
    beta blocker atenolol)

12
Timing of Use in Nonmalformed Controls
AACantiadrenergic, central a/balpha-beta
blocker labetolol BBbeta blocker CCBcalcium
channel blocker DIUdiuretic ACEIACE
inhibitor ARBangiotensin II receptor blocker
VASOvasodilator.
13
1st Trimester Treatment Choices in Nonmalformed
Controls
AACantiadrenergic, central a/balpha-beta
blocker labetolol BBbeta blocker CCBcalcium
channel blocker DIUdiuretic ACEIACE inhibitor.
14
Factors Related to Medication Exposure
  • Any Early Use (n33)
  • Pre-existing diabetes
  • Gestational diabetes
  • Obesity
  • Age 35
  • Fertility tx/rx
  • Multiple birth
  • NH Black
  • Parity 2
  • Center (IA highest, South lowest)
  • Preterm birth/Low birthweight
  • Late Use Only (n28)
  • Overweight/Obesity
  • Gestational diabetes
  • Folic acid use
  • NH Black
  • Fertility tx/rx
  • Age 35
  • Parity 2
  • Nonsmokers
  • Center (IA highest, NE lowest)
  • Preterm birth/Low birthweight

15
CVMs and Early Use
16
CVMs and Late Use Only
17
CVMs and Untreated High Blood Pressure
18
Early Use by Medication Class
19
CVMs and Medication Class
20
RVOTOs and Medication Class
21
Septal Defects and Medication Class
22
Summary
  • Early Use
  • Doubling of risk for simple, isolated CVM
  • Strongest elevations detected in RVOTO and septal
    defects
  • Beta blockers displayed highest risks
  • Late Use moderate risk for same groups
  • Untreated - weak elevations of risk
  • Conotruncal and LVOTO defects not associated with
    early use, late use, or untreated HBP

23
Results in Context
  • Our finding of doubling of risk for CVMs in
    women using medication during early pregnancy is
    consistent with the recent study of medication
    use during pregnancy in Sweden (antiadrenergic
    agents, beta blockers)
  • We found associations of medication use with
    CVMs, including ASD secundum
  • Multiple drug classes
  • Not able to evaluate ACE inhibitors alone due to
    small sample sizes

24
Strengths Limitations
  • Strengths
  • Exposure assessment for medication use
  • Indication-based ascertainment
  • Collected 6-24 months after delivery
  • Oral prescription medication for chronic disease
    taken daily
  • Evaluated timing of use during critical period of
    development
  • Some class-specific analyses
  • Limitations
  • Exposure assessment for medication use
  • Maternal self-report
  • Inability to separate effects of medication from
    the indication for use (confounding by
    indication)
  • Inability to measure the severity of high blood
    pressure (confounding by severity)
  • Small sample sizes due to rare exposures and rare
    outcomes

25
Recommendations
  • Post-marketing surveillance and research of
    pregnancies exposed to antihypertensive
    medications
  • Preconception planning and prenatal care for
    women with chronic hypertension
  • Better dissemination of information on
    antihypertensive medication safety to clinicians
    who care for women of childbearing age

26
Research Directions
  • Improve exposure assessment to tease apart
    effects of high blood pressure from
    antihypertensive medication
  • Type and severity of high blood pressure
  • Other indications for use
  • Medical records review for women reporting
    hypertension to validate medication use, classify
    hypertension type and severity
  • Examine additional defect groups, medication
    classes, factors related to class use, effect
    modification
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