Antihypertensive Medication Use and the Risk of Cardiovascular Malformations

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Antihypertensive Medication Use and the Risk of
Cardiovascular Malformations

• Alissa R. Caton, Ph.D.
• NYS Department of Health
• MCH Epidemiology Conference
• December 2006

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Published Studies on Antihypertensive Medication
Use and Cardiovascular Malformations
AHMany antihypertensive medication
AAantiadrenergic BBbeta blocker
CCBcalcium channel blocker DIUdiuretic
ACEIACE inhibitor.
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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

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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

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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

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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

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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)

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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

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Exposure Categories
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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)

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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)

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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.
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1st Trimester Treatment Choices in Nonmalformed
Controls
AACantiadrenergic, central a/balpha-beta
blocker labetolol BBbeta blocker CCBcalcium
channel blocker DIUdiuretic ACEIACE inhibitor.
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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

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CVMs and Early Use
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CVMs and Late Use Only
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CVMs and Untreated High Blood Pressure
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Early Use by Medication Class
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CVMs and Medication Class
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RVOTOs and Medication Class
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Septal Defects and Medication Class
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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

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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

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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

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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

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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