1. Use of ACE Inhibitors in Pregnant Women and the Risk of Congenital Heart Defects De-Kun Li, MD, PhD Division of Research Kaiser Permanente Northern California Oakland, California Sponsored by AHRQ DEcIDE TO HHSA290-2005-0033-I -TO3-WA1

2. Background (ACEIs): a class of antihypertensive medications Angiotensin-converting enzyme inhibitors (ACEIs): a class of antihypertensive medications Widely used for hypertension treatment Hypertension in pregnancy: 5-10%

3. Background Fetal toxicity for use of ACEIs in the 2 nd or 3 rd trimester – –Oligohydramnios – –Fetal growth retardation – –Pulmonary hypoplasia – –Hypocalvaria – –Neonatal hypotension – –Renal failure – –High mortality Hypotension related

4. Background A new study linked ACEI use in the 1 st trimester to birth defects (BD) –Increased risk of BDs with ACEI use (RR: 2.7 to 4.4) –No increased risk of BDs with use of other antihypertensives (RR: 0.6 to 0.9) –Compared to all non-users –The increased risk unique to ACEI users

5. Study Objectives To replicate the new study finding in a larger and diverse population Does use of ACEIs during 1 st trimester increase the risk of birth defects, especially heart defects and NTDs? Does timing of the exposure matter? Is the association unique to ACEI use or to all antihypertensive medications? Is the medication or hypertension?

6. Study Population: Kaiser Permanente Northern California (KPNC) 3.2 million members Diverse, representative population Annual births: 32,000-34,000 –Gestational age recorded –Able to determine gestational age at drug use –Identify pregnancy and labor complications (e.g., PE, PROM, diabetes, infections, fetal distress, placenta previa, abruptio placenta, and seizure)

7. KPNC Pregnancy & Birth Data Diabetes registry Diagnosis of birth defects and other medical conditions in newborns Regionwide data going back to 1995

8. KPNC: Drug Exposure Data All ordered and dispensed ambulatory prescription medications since 1995 Information on estimated days supply and refill dates/patterns Some OTC medications

9. KPNC: Clinical and Admin Databases Indications and other confounders –Clinical diagnoses (inpatient and ambulatory) –Laboratory test results –Multiple, validated disease registries: diabetes registry, asthma registry, cancer registry, etc –Ability to link to birth certificate info –Access to maternal weight or BMI EMR in recent years

10. Study Design Population-based cohort study of pregnant women Linkage across clinical diagnosis data, outpatient pharmacy data, laboratory results, and birth certificate data

11. Exposed Cohort Pregnant women exposed to ACE inhibitors –Any time during pregnancy –During the first trimester –During the second and third trimesters –During multiple trimesters

12. Unexposed Cohorts Three types of comparison groups (controls) –Users of other antihypertensive medications during pregnancy –Pregnant women with a diagnosis of hypertension, but no use of antihypertensives –Pregnant women without a diagnosis of hypertension and use of any antihypertensive medications during pregnancy

13. Primary Outcome Measures Live birth –Birth defects Overall birth defects Overall birth defects Congenital heart defects Congenital heart defects Neural tube defects Neural tube defects

14. Linkage Process (1): All livebirths Identify all live births (birth cohort) Determine their gestational age Determine birth type (live vs. still birth)

15. Linkage Process (2): Identifying Women Exposed to ACEIs and Other drugs Determine a cohort of medication users –Identify female users of ACEIs during the study period (1995-2008) –Identify female users of other antihypertensive medications during the same study period

16. Linkage Process (3): Characterizing Drug Exposure among Mothers of liveborns Linkage between birth cohort and the cohort of medication users Determine use of ACEI during pregnancy Determine the timing of ACEI exposure Determine use of other antihypertensive medications

17. Linkage Process (4): Identifying Potential Confounders Linkage to other data sources –Birth Certificates –Other maternal clinical data for weight or BMI –Gestational Diabetes Registry –Clinical data for diagnosis of hypertension

18. Linkage Process (5): Identifying Birth Defects in Pregnancies >20 Weeks Identify birth defects up to 13 years of age Verify diagnoses of birth defects among a random sample of those with birth defects –Over-sample those with exposure to ACE inhibitors

19. Results More than More than 465,816 mother-infant pairs Prevalence of ACEI use: – –1.8/1,000 any time during pregnancy – –1.0/1,000 during the first trimester – –0.1/1,000 in the 2 nd or 3 rd trimester Prevalence of other antihypertensive –38/1,00 during pregnancy –3.0/1,000 during the first trimester only – –28.5/1,000 in the 2 nd or 3 rd trimester

20. Table 1. Distribution of Selected Maternal Characteristics by Fetal Exposure Status to Antihypertensive Medications during Pregnancy, Kaiser Permanente of Northern California 1995-2008. Characteristics Antihypertensive Medication Use No Meds, No HTN a (N=416,218) No Meds, HTN b (N=31,274) Other Meds c (N=17,507) ACEI(N=817) Maternal Age at Delivery (yr) <20 27,839 (6.7%) 2,019 (6.5%) 899 (5.1%) 7 (0.9%) 20-<25 73,186 (17.6%) 5,210 (16.7%) 2,340 (13.4%) 46 (5.6%) 25-<30 119,109 (28.6%) 8,124 (26.0%) 4,289 (24.5%) 109 (13.3%) 30-<35 118,237 (28.4%) 8,648 (27.7%) 5,113 (29.2%) 231 (28.3%) 35-<40 62,812 (15.1%) 5,554 (17.8%) 3,647 (20.8%) 269 (32.9%) 40+ 14,523 (3.5%) 1,710 (5.5%) 1,204 (6.9%) 154 (18.9%) Unknown 512 (0.1%) 9 (0.0%) 15 (0.1%) 1 (0.1%) Maternal Race/Ethnicity White 185,778 (44.6%) 15,286 (48.9%) 8,139 (46.5%) 282 (34.5%) African American 34,988 (8.4%) 3,471 (11.1%) 2,473 (14.1%) 163 (20.0%) Hispanic 89,377 (21.5%) 6,179 (19.8%) 2,833 (16.2%) 135 (16.5%) Asian 84,594 (20.3%) 5,143 (16.4%) 3,286 (18.8%) 175 (21.4%) Other 3,477 (0.8%) 313 (1.0%) 195 (1.1%) 9 (1.1%) Unknown 18,004 (4.3%) 882 (2.8%) 581 (3.3%) 53 (6.5%)

21. Table 1. Distribution of Selected Maternal Characteristics by Fetal Exposure Status to Antihypertensive Medications during Pregnancy, Kaiser Permanente of Northern California 1995-2008. (Cont.) Characteristics Antihypertensive Medication Use No Meds, No HTN a (N=416,218) No Meds, HTN b (N=31,274) Other Meds c (N=17,507) ACEI(N=817) Parity (Previous Live Births) 0 161,182 (38.7%) 15,642 (50.0%) 6,319 (36.1%) 213 (26.1%) 1 135,153 (32.5%) 8,560 (27.4%) 5,373 (30.7%) 212 (26.0%) 2 65,195 (15.7%) 3,842 (12.3%) 3,046 (17.4%) 181 (22.2%) 3+ 35,375 (8.5%) 2,227 (7.1%) 1,952 (11.2%) 143 (17.5%) Unknown 19,313 (4.6%) 1,003 (3.2%) 817 (4.7%) 68 (8.3%) Maternal Weight <90 th Percentile 263,013 (63.2%) 17,377 (55.6%) 10,220 (58.4%) 350 (42.8%) ≥90 th Percentile (207 lbs) 25,723 (6.2%) 5,736 (18.3%) 2,229 (12.7%) 235 (28.8%) Unknown 127,482 (30.6%) 8,161 (26.1%) 5,058 (28.9%) 232 (28.4%) Pre-existing Diabetes Yes 1,651 (0.4%) 689 (2.2%) 470 (2.7%) 316 (38.7%) No 414,567 (99.6%) 30,585 (97.8%) 17,037 (97.3%) 501 (61.3%) a. No use of anti-hypertensive medications during pregnancy and no diagnosis of hypertension b. No use of anti-hypertensive medications during pregnancy, but with a diagnosis of hypertension c. Anti-hypertensive medications other than ACE inhibitors (ACEI)

22. Table 2. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, Kaiser Permanente, Northern California 1995-2008 Medication use Birth Defects No a n (%) Yes n (%) Odds Ratio* 1 st Trimester Only Any Malformations No Meds, No HTN 393,789 (94.6) 22,429 (5.4) Reference No Meds, With HTN 29,027 (92.8) 2,247 (7.2) 1.25 (1.19 – 1.31) Other Meds Only 1,062 (93.1) 79 (6.9) 1.22 (0.97 – 1.54) ACEI Any 393 (91.6) 36 (8.4) 1.19 (0.84 – 1.68) Congenital Heart Defects (CHD) No Meds, No HTN 393,789 (98.4) 6,232 (1.6) Reference No Meds, With HTN 29,027 (97.6) 708 (2.4) 1.41 (1.30 – 1.53) Other Meds Only 1,062 (97.4) 28 (2.6) 1.52 (1.04 – 2.21) ACEI Any 393 (96.1) 16 (3.9) 1.52 (0.91 – 2.55) Neural Tube Defects (NTD) No Meds, No HTN 393,789 (99.4) 2,447 (0.6) Reference No Meds, With HTN 29,027 (99.0) 281 (1.0) 1.43 (1.26 – 1.62) Other Meds Only 1,062 (99.2) 9 (0.8) 1.26 (0.65 – 2.44) ACEI Any 393 (99.5) 2 (0.5) 0.55 (0.14 – 2.23)

23. Table 2. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, Kaiser Permanente, Northern California 1995-2008 (Cont.) Medication Use Birth Defects No a n (%) Yes n (%) Odds Ratio* Other Periods During Pregnancy 1 st Trimester Ever Any Malformations No Meds, No HTN 393,789 (94.6) 22,429 (5.4) Reference No Meds, With HTN 29,027 (92.8) 2,247 (7.2) 1.25 (1.20 – 1.31) Other Meds Only 4,063 (92.6) 327 (7.5) 1.29 (1.15 – 1.45) ACEI Any 701 (92.1) 60 (7.9) 1.10 (0.83 – 1.44) Congenital Heart Defects (CHD) No Meds, No HTN 393,789 (98.4) 6,232 (1.6) Reference No Meds, With HTN 29,027 (97.6) 708 (2.4) 1.41 (1.31 – 1.53) Other Meds Only 4,063 (97.1) 123 (2.9) 1.67 (1.39 – 2.01) ACEI Any 701 (96.6) 25 (3.4) 1.33 (0.87 – 2.02) Neural Tube Defects (NTD) No Meds, No HTN 393,789 (99.4) 2,447 (0.6) Reference No Meds, With HTN 29,027 (99.0) 281 (1.0) 1.44 (1.27 – 1.63) Other Meds Only 4,063 (99.0) 41 (1.0) 1.46 (1.07 – 2.00) ACEI Any 701 (99.2) 6 (0.9) 0.95 (0.42 – 2.17)

24. Table 2. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, Kaiser Permanente, Northern California 1995-2008 (Cont.) Medication Use Birth Defects No a n(%) Yes n (%) Odds Ratio* Other Periods During Pregnancy 2 nd /3 rd Trimester Only Any Malformations No Meds, No HTN 393,789 (94.6) 22,429 (5.4) Reference No Meds, With HTN 29,027 (92.8) 2,247 (7.2) 1.26 (1.20 – 1.31) Other Meds Only 11,783 (89.8) 1,334 (10.2) 1.94 (1.83 – 2.05) ACEI Any 48 (85.7) 8 (14.3) 2.51 (1.18 – 5.34) Congenital Heart Defects (CHD) No Meds, No HTN 393,789 (98.4) ) 6,232 (1.6) Reference No Meds, With HTN 29,027 (97.6) 708 (2.4) 1.42 (1.31 – 1.54) Other Meds Only 11,783 (95.4) 566 (4.6) 2.90 (2.65 – 3.16) ACEI Any 48 (90.6) 5 (9.4) 5.03 (1.99 – 12.74) Neural Tube Defects (NTD) No Meds, No HTN 393,789 (99.4) 2,447 (0.6) Reference No Meds, With HTN 29,027 (99.0) 281 (1.0) 1.44 (1.27 – 1.63) Other Meds Only 11,783 (98.4) 193 (1.6) 2.51 (2.16 – 2.91) ACEI Any 48 (96.0) 2 (4.0) 5.05 (1.22 – 20.94) * Adjusted for preexisting diabetes, maternal age, race/ethnicity, parity and maternal weight. a. No any birth defect b. Anti-hypertensive medications c. Hypertension

25. Table 3. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, Among Mothers without Preexisting Diabetes, Kaiser Permanente Northern California 1995-2008 Medication Use Birth Defects No a n (%) Yes n (%) Odds Ratio* 1 st Trimester Only Any Malformations No Meds b, No HTN c 392,290 (94.6) 222,77 (5.4) Reference No Meds, With HTN 28,423 (92.9) 2,162 (7.1) 1.25 (1.19 – 1.31) Other Meds Only 1,037 (93.3) 74 (6.7) 1.20 (0.94 – 1.52) ACEI Any 251 (94.4) 15 (5.6) 1.00 (0.59 – 1.68) Congenital Heart Defects (CHD) No Meds, No HTN 392,290 (98.5) 6,170 (1.6) Reference No Meds, With HTN 28,423 (97.7) 669 (2.3) 1.40 (1.29 – 1.52) Other Meds Only 1,037 (97.6) 26 (2.5) 1.50 (1.01 – 2.21) ACEI Any 251 (96.9) 8 (3.1) 1.85 (0.91 – 3.74) Neural Tube Defects (NTD) No Meds, No HTN 392,290 (99.4) 2,425 (0.6) Reference No Meds, With HTN 28,423 (99.1) 268 (0.9) 1.43 (1.26 – 1.62) Other Meds Only 1,037 (99.1) 9 (0.9) 1.33 (0.69 – 2.57) ACEI Any 251 (99.2) 2 (0.8) 1.20 (0.30 – 4.85)

26. Table 3. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, Among Mothers without Preexisting Diabetes, Kaiser Permanente Northern California 1995-2008 (Cont.) Medication Use Birth Defects No a n (%) Yes n (%) Odds Ratio* Other Periods During Pregnancy 1 st Trimester Ever Any Malformations No Meds, No HTN 392,290 (94.6) 222,77 (5.4) Reference No Meds, With HTN 28,423 (92.9) 2,162 (7.1) 1.25 (1.19 – 1.31) Other Meds Only 3,890 (92.7) 308 (7.3) 1.31 (1.16 – 1.47) ACEI Any 429 (94.5) 25 (5.5) 0.98 (0.65 – 1.46) Congenital Heart Defects (CHD) No Meds, No HTN 392,290 (98.5) 6,170 (1.6) Reference No Meds, With HTN 28,423 (97.7) 669 (2.3) 1.41 (1.30 – 1.53) Other Meds Only 3,890 (97.1) 116 (2.9) 1.75 (1.45 – 2.11) ACEI Any 429 (97.3) 12 (2.7) 1.61 (0.90 – 2.86) Neural Tube Defects (NTD) No Meds, No HTN 392,290 (99.4) 2,425 (0.6) Reference No Meds, With HTN 28,423 (99.1) 268 (0.9) 1.43 (1.26 – 1.63) Other Meds Only 3,890 (99.0) 40 (1.0) 1.55 (1.13 – 2.13) ACEI Any 429 (98.6) 6 (1.4) 2.09 (0.93 – 4.69)

27. Table 3. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, Among Mothers without Preexisting Diabetes, Kaiser Permanente Northern California 1995-2008 (Cont.) Medication Use Birth Defects No a n (%) Yes n (%) Odds Ratio* Other Periods During Pregnancy 2 nd /3 rd Trimester Only Any Malformations No Meds, No HTN 392,290 (94.6) 222,77 (5.4) Reference No Meds, With HTN 28,423 (92.9) 2,162 (7.1) 1.25 (1.19 – 1.31) Other Meds Only 11,540 (89.9) 1,299 (10.1) 1.95 (1.84 – 2.07) ACEI Any 40 (85.1) 7 (14.9) 2.98 (1.33 – 6.65) Congenital Heart Defects (CHD) No Meds, No HTN 392,290 (98.5) 6,170 (1.6) Reference No Meds, With HTN 28,423 (97.7) 669 (2.3) 1.41 (1.30 – 1.53) Other Meds Only 11,540 (95.5) 549 (4.5) 2.95 (2.70 – 3.23) ACEI Any 40 (88.9) 5 (11.1) 7.24 (2.85 – 18.36) Neural Tube Defects (NTD) No Meds, No HTN 392,290 (99.4) 2,425 (0.6) Reference No Meds, With HTN 28,423 (99.1) 268 (0.9) 1.43 (1.26 – 1.63) Other Meds Only 11,540 (98.4) 185 (1.6) 2.52 (2.17 – 2.93) ACEI Any 40 (95.2) 2 (4.8) 2 (4.8) 7.18 (1.73 – 29.80) * Adjusted for preexisting diabetes, maternal age, race/ethnicity, parity and maternal weight. a. No any birth defect b. Anti-hypertensive medications c. Hypertension

28. Table 4. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, among Mothers without Preexisting Diabetes, by an underlying diagnosis of hypertension, Kaiser Permanente, Northern California 1995-2008 Medication Use Birth Defects No a n (%) Yes n (%) Odds Ratio* 1 st Trimester Only Any Malformations No Meds, No HTN 392,290 (94.6) 22,277 (5.4) Reference No Meds, With HTN 28,423 (92.9) 2,162 (7.1) 1.25 (1.19 – 1.31) Other Meds Only, No HTN 680 (92.8) 53 (7.2) 1.32 (1.00 – 1.75) Other Meds Only, With HTN 357 (94.4) 21 (5.6) 0.96 (0.62 – 1.50) ACEI Any, No HTN 22 (100.0) 0 (0.0) NA ACEI Any, With HTN 229 (93.9) 15 (6.2) 1.08 (0.64 – 1.83) Congenital Heart Defects (CHD) No Meds, No HTN 392,290 (98.5) 6,170 (1.6) Reference No Meds, With HTN 28,423 (97.7) 669 (2.3) 1.40 (1.29 – 1.52) Other Meds Only, No HTN 680 (97.6) 17 (2.4) 1.53 (0.95 – 2.48) Other Meds Only, With HTN 357 (97.5) 9 (2.5) 1.43 (0.74 – 2.78) ACEI Any, No HTN 22 (100.0) 0 (0.0) NA ACEI Any, With HTN 229 (96.6) 8 (3.4) 2.00 (0.99 – 4.06)

29. Table 4. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, among Mothers without Preexisting Diabetes, by an underlying diagnosis of hypertension, Kaiser Permanente, Northern California 1995-2008 (Cont.) Medication Use Birth Defects No a n (%) Yes n (%) Odds Ratio* 1 st Trimester Only Neural Tube Defects (NTD) No Meds, No HTN 392,290 (99.4) 2,425 (0.6) Reference No Meds, With HTN 28,423 (99.1) 268 (0.9) 1.43 (1.26 – 1.62) Other Meds Only, No HTN 680 (99.3) 5 (0.7) 1.15 (0.48 - 2.77) Other Meds Only, With HTN 357 (98.9) 4 (1.1) 1.66 (0.62 – 4.46) ACEI Any, No HTN 22 (100.0) 0 (0.0) NA ACEI Any, With HTN 229 (99.1) 2 (0.9) 1.31 (0.33 – 5.28) * Adjusted for maternal age, race/ethnicity, parity and maternal weight a. No any birth defect b. Anti-hypertensive medications c. Hypertension

30. Limitations Low frequency of ACEI use during pregnancy No information on compliance Limited information on confounders Inability to study individual defects

31. Strengths Large study population (almost a half million maternal-infant pairs) Population-based (every live-birth) Control for underlying indication (hypertension) Three types of controls

32. Confirmation from other studies Swedish study –A cohort study –Both ACEI and other antihypertensive medications had similarly increased risk of BDs CDC study –A case-control study –A similar association for both ACEI and other antihypertensive medications –Hypertension also increases the risk

33. Conclusions Maternal ACEI use in the first trimester has a risk profile similar to the use of other antihypertensive medications regarding malformations in live-born offspring Maternal ACEI use in the first trimester has a risk profile similar to underlying hypertension

34. Conclusions The apparent increased risk of malformations associated with ACEI use (and use of other antihypertensive medications) in the first trimester is likely due to the underlying hypertension rather than the medications

35. Important issues in drug safety research Unlikely to do RCT type studies –Ethical consideration Pregnancy –Effect on mother –Effect on fetus Example: antidepressants to PPD –Long-term safety issues

36. Important issues in drug safety research Observational studies –Based on existing automated data Claim data Clinical data EMR –Collect original data Cohort studies: –Expensive –Long-term follow up Case-control studies –Efficient –Recall issue (errors or biases)

37. Important issues in drug safety research Issues related to studies using automated data Control underlying indication: separate controls Incomplete ascertainment of exposed women –Drug coverage (outside the system) –Mixed in other drug categories –Sample size issue when exposure is rare, misclassified as non-user, rather than bias Compliance: can be a problem for rare drug exposure (dilute exposed group) depending on seriousness of underlying conditions.

38. Important issues in drug safety research Issues related to studies using automated data Limited information on confounders Potential biased ascertainment of conditions with significant under-diagnosis (e.g., depression, ADHD, etc.), users being examined more carefully Issues related to studies collecting original data –Same principles for cohort and case-control studies –Key: select correct controls.