1. 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. 2 Published Studies on Antihypertensive Medication Use and Cardiovascular Malformations PopulationYearsExposure RR Estimates Collaborative Perinatal Project 1959-1965 DIU or CV drug 0.9 (0.3-2.1) Baltimore-Washington Infant Study 1981-1989AHMDIU 1.2 (0.7-2.1) unadjusted 8.6 (2.9-24.5) AVSD only Hungarian C-C Study 1980-1996CCB 1.6 (0.8-3.2) Swedish Health Registers 1995-2001AHMBB AA& DIU 2.0 (1.5-2.8) 1.9 (1.2-2.8) ~2.0 (Obs>Exp) Michigan Medicaid 1985-1992 Classes, drugs Observed>Expected Tennessee Medicaid 1985-2000ACEI Other AHM 3.7 (1.9-7.3) 0.7 (0.3-1.8) AHM=any antihypertensive medication; AA=antiadrenergic; BB=beta blocker; CCB=calcium channel blocker; DIU=diuretic; ACEI=ACE inhibitor.

3. 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. 4 Hypertension in Pregnancy  Present in 6-9% of pregnancies  Chronic hypertension (<1%)  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. 5 Specific Aims 1. 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 2. Investigate the relationship between antihypertensive medication use during pregnancy and cardiovascular malformations

6. 6 Data Source, Study Design, & Study Subjects  National Birth Defects Prevention Study  October 1, 1997–December 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. 7 Simple/Isolated CVM Case Groups  Any CVM (n=2696)  Conotruncal (n=641)  Tetralogy of Fallot (n=310)  Left obstructive (LVOTO, n=430)  Coarctation of aorta (n=159)  Right obstructive (RVOTO, n=423)  Pulmonic stenosis (PVS, n=303)  Ebstein malformation (n=38)  Septal (n=1043)  Perimembranous ventricular (n=456)  Atrial septal, secundum (n=427)  Controls (n=3955)

8. 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. 9 Exposure Categories Early Use MEDICATION USE DURING CRITICAL PERIOD Treated chronic hypertension Late Use MEDICATION USE POST-CRITICAL PERIOD Treated preeclampsia, gestational hypertension, exacerbated or late diagnosed chronic hypertension Untreated High Blood Pressure HIGH BLOOD PRESSURE ONLY Untreated preeclampsia, gestational hypertension, or chronic hypertension Unexposed REFERENCE GROUP No high blood pressure or medication Users without High Blood Pressure EXCLUDED Medication in other CATI module (e.g. beta blocker for migraine)

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

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

12. Timing of Use in Nonmalformed Controls 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.

13. 1 st Trimester Treatment Choices in Nonmalformed Controls AAC=antiadrenergic, central; a/b=alpha-beta blocker labetolol; BB=beta blocker; CCB=calcium channel blocker; DIU=diuretic; ACEI=ACE inhibitor.

14. 14 Factors Related to Medication Exposure Any Early Use (n=33) Any Early Use (n=33) Pre-existing diabetes Pre-existing diabetes Gestational diabetes Gestational diabetes Obesity Obesity Age 35+ Age 35+ Fertility tx/rx Fertility tx/rx Multiple birth Multiple birth NH Black NH Black Parity 2+ Parity 2+ Center (IA highest, South lowest) Center (IA highest, South lowest) Preterm birth/Low birthweight Preterm birth/Low birthweight Late Use Only (n=28) 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. 15 CVMs and Early Use Case Group CasesControls OR (CI) aOR (CI) Exp%Exp% Any CVM 371.4250.6 2.2 (1.3-3.7) 1.8 (1.1-3.1) Conotruncal40.6250.6 1.0 (0.3-2.9) 0.6 (0.2-1.9) TOF TOF31.0250.6 1.6 (0.5-5.2) 1.1 (0.3-3.8) LVOTO40.9250.6 1.5 (0.5-4.3) 1.2 (0.4-3.6) Coarctation of aorta Coarctation of aorta31.9250.6 3.1 (0.9-10.5) 2.4 (0.7-8.4) RVOTO92.1250.6 3.6 (1.6-7.7) 3.0 (1.4-6.6) PVS PVS51.7250.6 2.8 (1.1-7.4) 2.2 (0.8-5.8) Ebstein malformation Ebstein malformation37.9250.6 14.4 (4.1-50.2) 18.0 (4.8-67.8) Septal181.7250.6 2.9 (1.5-5.2) 2.3 (1.2-4.3) Perimembranous VSD Perimembranous VSD71.5250.6 2.5 (1.1-5.8) 2.0 (0.8-4.7) ASD secundum ASD secundum102.4250.6 4.1 (1.9-8.5) 3.3 (1.6-7.1)

16. 16 CVMs and Late Use Only Case Group CasesControls OR (CI) aOR (CI) Exp%Exp% Any CVM 321.2280.7 1.7 (1.0-2.9) 1.6 (1.0-2.8) Conotruncal60.9280.7 1.3 (0.6-3.3) 1.1 (0.4-2.9) TOF TOF31.0280.7 1.4 (0.4-4.6) 0.8 (0.2-3.6) LVOTO20.5280.7---- Coarctation of aorta Coarctation of aorta10.6280.7---- RVOTO61.4280.7 2.1 (0.9-5.1) 2.1 (0.8-5.1) PVS PVS51.7280.7 2.5 (1.0-6.5) 2.4 (0.9-6.4) Ebstein malformation Ebstein malformation12.6280.7---- Septal171.6280.7 2.4 (1.3-4.4) 2.1 (1.1-4.0) Perimembranous VSD Perimembranous VSD71.5280.7 2.2 (1.0-5.2) 2.0 (0.9-4.7) ASD secundum ASD secundum81.9280.7 2.9 (1.3-6.4) 2.4 (1.0-5.6)

17. 17 CVMs and Untreated High Blood Pressure Case Group CasesControls OR (CI) aOR (CI) Exp%Exp% Any CVM 2459.13037.7 1.2 (1.0-1.5) 1.2 (1.0-1.4) Conotruncal589.13037.7 1.2 (0.9-1.6) 1.1 (0.8-1.5) TOF TOF299.43037.7 1.3 (0.8-1.9) 1.2 (0.8-1.7) LVOTO358.23037.7 1.1 (0.7-1.5) 1.0 (0.7-1.5) Coarctation of aorta Coarctation of aorta1710.73037.7 1.5 (0.9-2.5) 1.3 (0.8-2.3) RVOTO4210.03037.7 1.4 (1.0-1.9) 1.3 (1.0-1.9) PVS PVS3511.63037.7 1.6 (1.1-2.3) 1.6 (1.1-2.4) Ebstein malformation Ebstein malformation410.53037.7 1.6 (0.6-4.5) 1.7 (0.6-4.9) Septal979.33037.7 1.3 (1.0-1.6) 1.2 (0.9-1.5) Perimembranous VSD Perimembranous VSD408.83037.7 1.2 (0.8-1.7) 1.1 (0.8-1.6) ASD secundum ASD secundum5312.53037.7 1.8 (1.3-2.4) 1.6 (1.2-2.3)

18. 18 Early Use by Medication Class ClassCVMsControls Exp%Exp% Antiadrenergic Agents 311.1190.5 Centrally acting Centrally acting170.6120.3 Methyldopa Methyldopa170.6100.3 a/b labetalol a/b labetalol70.33<0.1 Beta Blocker Beta Blocker140.550.1 Atenolol Atenolol60.23<0.1 Calcium Channel Blocker 50.260.2 ACE Inhibitor 60.22<0.1 Angiotensin II Receptor Blocker 1<0.100.0 Diuretic50.21<0.1 Vasodilator00.000.0

19. 19 CVMs and Medication Class Early Use CasesControls OR (CI) aOR (CI) Exp%Exp% Any Class 371.4250.6 2.2 (1.3-3.7) 1.8 (1.1-3.1) Antiadrenergic Agents 311.1190.5 2.5 (1.4-4.4) 2.1 (1.2-3.7) Centrally acting Centrally acting170.6120.3 2.1 (1.0-4.5) 1.8 (0.9-3.9) Methyldopa Methyldopa170.6100.3 2.6 (1.2-5.6) 2.3 (1.0-4.9) a/b labetalol a/b labetalol70.33<0.1 3.5 (0.9-13.7) 3.0 (0.8-11.6) Beta Blocker Beta Blocker140.550.1 4.2 (1.5-11.8) 3.5 (1.2-9.7) Atenolol Atenolol60.23<0.1 3.0 (0.8-12.1) 2.5 (0.6-10.1) Calcium Channel Blocker 50.260.2 1.3 (0.4-4.1) 0.9 (0.3-3.1)

20. 20 RVOTOs and Medication Class Early Use CasesControls OR (CI) aOR (CI) Exp%Exp% Any Class 92.1250.6 3.6 (1.6-7.7) 3.0 (1.4-6.6) Antiadrenergic Agents 81.9190.5 4.2 (1.8-9.6) 3.5 (1.5-8.1) Centrally acting Centrally acting40.9120.3 3.3 (1.1-10.2) 2.9 (0.9-9.1) Methyldopa Methyldopa40.9100.3 3.9 (1.2-12.6) 3.5 (1.1-11.5) a/b labetalol a/b labetalol20.53<0.1---- Beta Blocker Beta Blocker51.250.1 9.9 (2.8-34.2) 8.0 (2.3-28.4) Atenolol Atenolol10.23<0.1---- Calcium Channel Blocker 00.060.2----

21. 21 Septal Defects and Medication Class Early Use CasesControls OR (CI) aOR (CI) Exp%Exp% Any Class 181.7250.6 2.9 (1.5-5.2) 2.3 (1.2-4.3) Antiadrenergic Agents 161.5190.5 3.3 (1.7-6.5) 2.7 (1.4-5.4) Centrally acting Centrally acting80.8120.3 2.6 (1.1-6.5) 2.1 (0.8-5.1) Methyldopa Methyldopa80.8100.3 3.2 (1.2-8.0) 2.6 (1.0-6.6) a/b labetalol a/b labetalol40.43<0.1 5.3 (1.2-23.6) 5.0 (1.1-22.4) Beta Blocker Beta Blocker70.750.1 5.5 (1.8-17.5) 4.7 (1.5-15.1) Atenolol Atenolol40.43<0.1 5.3 (1.2-23.6) 4.9 (1.1-22.2) Calcium Channel Blocker 30.360.2 2.0 (0.5-7.9) 1.3 (0.3-5.5)

22. 22 Summary Early Use Early Use Doubling of risk for simple, isolated CVM Doubling of risk for simple, isolated CVM Strongest elevations detected in RVOTO and septal defects Strongest elevations detected in RVOTO and septal defects Beta blockers displayed highest risks Beta blockers displayed highest risks Late Use – moderate risk for same groups Late Use – moderate risk for same groups Untreated - weak elevations of risk Untreated - weak elevations of risk Conotruncal and LVOTO defects not associated with early use, late use, or untreated HBP Conotruncal and LVOTO defects not associated with early use, late use, or untreated HBP

23. 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) 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 We found associations of medication use with CVMs, including ASD secundum Multiple drug classes Multiple drug classes Not able to evaluate ACE inhibitors alone due to small sample sizes Not able to evaluate ACE inhibitors alone due to small sample sizes

24. 24 Strengths & Limitations Strengths Strengths Exposure assessment for medication use 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 Exposure assessment for medication use Maternal self-report Maternal self-report Inability to separate effects of medication from the indication for use (confounding by indication) 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) Inability to measure the severity of high blood pressure (confounding by severity) Small sample sizes due to rare exposures and rare outcomes Small sample sizes due to rare exposures and rare outcomes

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

26. 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