use of ace inhibitors in pregnant women and the risk of congenital heart defects de-kun li, md, phd...

Use of ACE Inhibitors in Pregnant Women Use of ACE Inhibitors in Pregnant Women and the Risk of Congenital Heart Defectsand the Risk of Congenital Heart Defects

De-Kun Li, MD, PhDDe-Kun Li, MD, PhD

Division of ResearchDivision of ResearchKaiser Permanente Northern CaliforniaKaiser Permanente Northern California

Oakland, CaliforniaOakland, California

Sponsored by AHRQ DEcIDE Sponsored by AHRQ DEcIDE TO TO HHSA290-2005-0033-I -TO3-WA1HHSA290-2005-0033-I -TO3-WA1

BackgroundBackground

Angiotensin-converting enzyme inhibitors (ACEIs): a class of antihypertensive (ACEIs): a class of antihypertensive medicationsmedications

Widely used for hypertension treatment Widely used for hypertension treatment

Hypertension in pregnancy: 5-10%


Fetal toxicity for use of ACEIs in the 2Fetal toxicity for use of ACEIs in the 2ndnd or 3 or 3rdrd trimester trimester

– Oligohydramnios– Fetal growth retardation– Pulmonary hypoplasia– Hypocalvaria – Neonatal hypotension– Renal failure– High mortality

Hypotension related


A new study linked ACEI use in the 1A new study linked ACEI use in the 1stst trimester to birth defects (BD) trimester to birth defects (BD)

– Increased risk of BDs with ACEI use (RR: Increased risk of BDs with ACEI use (RR: 2.7 to 4.4)2.7 to 4.4)

– No increased risk of BDs with use of other No increased risk of BDs with use of other antihypertensives (RR: 0.6 to 0.9) antihypertensives (RR: 0.6 to 0.9)

– Compared to all non-usersCompared to all non-users– The increased risk unique to ACEI usersThe increased risk unique to ACEI users

Study ObjectivesStudy ObjectivesTo replicate the new study finding in a To replicate the new study finding in a larger and diverse populationlarger and diverse population

Does use of ACEIs during 1Does use of ACEIs during 1stst trimester trimester increase the risk of birth defects, increase the risk of birth defects, especially heart defects and NTDs?especially heart defects and NTDs?

Does timing of the exposure matter?Does timing of the exposure matter?

Is the association unique to ACEI use or to Is the association unique to ACEI use or to all antihypertensive medications?all antihypertensive medications?

Is the medication or hypertension?Is the medication or hypertension?

Study Population: Kaiser Permanente Study Population: Kaiser Permanente Northern California (KPNC)Northern California (KPNC)

3.2 million members3.2 million members

Diverse, representative populationDiverse, representative population

Annual births: 32,000-34,000Annual births: 32,000-34,000– Gestational age recordedGestational age recorded– Able to determine gestational age at drug useAble to determine gestational age at drug use– Identify pregnancy and labor complications Identify pregnancy and labor complications

(e.g., PE, PROM, diabetes, infections, fetal (e.g., PE, PROM, diabetes, infections, fetal distress, placenta previa, abruptio placenta, and distress, placenta previa, abruptio placenta, and seizure)seizure)

KPNC Pregnancy & Birth DataKPNC Pregnancy & Birth Data

Diabetes registryDiabetes registry

Diagnosis of birth defects and other medical Diagnosis of birth defects and other medical conditions in newbornsconditions in newborns

Regionwide data going back to 1995Regionwide data going back to 1995

KPNC: Drug Exposure DataKPNC: Drug Exposure Data

All ordered and dispensed ambulatory All ordered and dispensed ambulatory prescription medications since 1995prescription medications since 1995

Information on estimated days supply and Information on estimated days supply and refill dates/patternsrefill dates/patterns

Some OTC medicationsSome OTC medications

KPNC: Clinical and Admin KPNC: Clinical and Admin DatabasesDatabases

Indications and other confoundersIndications and other confounders– Clinical diagnoses (inpatient and ambulatory)Clinical diagnoses (inpatient and ambulatory)– Laboratory test resultsLaboratory test results– Multiple, validated disease registries: diabetes Multiple, validated disease registries: diabetes

registry, asthma registry, cancer registry, etcregistry, asthma registry, cancer registry, etc– Ability to link to birth certificate infoAbility to link to birth certificate info– Access to maternal weight or BMIAccess to maternal weight or BMI

EMR in recent yearsEMR in recent years

Study DesignStudy Design

Population-based cohort study of pregnant Population-based cohort study of pregnant womenwomen

Linkage across clinical diagnosis data, Linkage across clinical diagnosis data, outpatient pharmacy data, laboratory outpatient pharmacy data, laboratory results, and birth certificate dataresults, and birth certificate data

Exposed Cohort Exposed Cohort

Pregnant women exposed to ACE Pregnant women exposed to ACE inhibitorsinhibitors– Any time during pregnancyAny time during pregnancy– During the first trimesterDuring the first trimester– During the second and third trimestersDuring the second and third trimesters– During multiple trimestersDuring multiple trimesters

Unexposed CohortsUnexposed Cohorts

Three types of comparison groups (controls)Three types of comparison groups (controls)– Users of other antihypertensive medications Users of other antihypertensive medications

during pregnancyduring pregnancy– Pregnant women with a diagnosis of Pregnant women with a diagnosis of

hypertension, but no use of antihypertensiveshypertension, but no use of antihypertensives– Pregnant women without a diagnosis of Pregnant women without a diagnosis of

hypertension and use of any antihypertensive hypertension and use of any antihypertensive medications during pregnancymedications during pregnancy

Primary Outcome MeasuresPrimary Outcome Measures

Live birthLive birth– Birth defectsBirth defects

Overall birth defectsOverall birth defects

Congenital heart defectsCongenital heart defects

Neural tube defectsNeural tube defects

Linkage Process (1): All livebirthsLinkage Process (1): All livebirths

Identify all live births (birth cohort)Identify all live births (birth cohort)

Determine their gestational ageDetermine their gestational age

Determine birth type (live vs. still birth)Determine birth type (live vs. still birth)

Linkage Process (2): Identifying Women Linkage Process (2): Identifying Women Exposed to ACEIs and Other drugsExposed to ACEIs and Other drugs

Determine a cohort of medication usersDetermine a cohort of medication users– Identify female users of ACEIs during the study Identify female users of ACEIs during the study

period (1995-2008)period (1995-2008)

– Identify female users of other antihypertensive Identify female users of other antihypertensive medications during the same study periodmedications during the same study period

Linkage Process (3): Characterizing Drug Linkage Process (3): Characterizing Drug Exposure among Mothers of livebornsExposure among Mothers of liveborns

Linkage between birth cohort and the Linkage between birth cohort and the cohort of medication userscohort of medication users

Determine use of ACEI during pregnancyDetermine use of ACEI during pregnancy

Determine the timing of ACEI exposureDetermine the timing of ACEI exposure

Determine use of other antihypertensive Determine use of other antihypertensive medicationsmedications

Linkage Process (4): Identifying Linkage Process (4): Identifying Potential Confounders Potential Confounders

Linkage to other data sources Linkage to other data sources – Birth CertificatesBirth Certificates– Other maternal clinical data for weight or BMIOther maternal clinical data for weight or BMI– Gestational Diabetes RegistryGestational Diabetes Registry– Clinical data for diagnosis of hypertensionClinical data for diagnosis of hypertension

Linkage Process (5): Identifying Birth Linkage Process (5): Identifying Birth Defects in Pregnancies >20 WeeksDefects in Pregnancies >20 Weeks

Identify birth defects up to 13 years of ageIdentify birth defects up to 13 years of age

Verify diagnoses of birth defects among a Verify diagnoses of birth defects among a random sample of those with birth defects random sample of those with birth defects – Over-sample those with exposure to ACE Over-sample those with exposure to ACE

inhibitorsinhibitors

ResultsResults

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 2nd or 3rd trimester

Prevalence of other antihypertensivePrevalence of other antihypertensive– 38/1,00 during pregnancy38/1,00 during pregnancy– 3.0/1,000 during the first trimester only3.0/1,000 during the first trimester only– 28.5/1,000 in the 2nd or 3rd trimester

Table 1. Distribution of Selected Maternal Characteristics by Fetal Exposure Status to Antihypertensive Medications during Pregnancy, Kaiser Permanente of Northern California 1995-2008.

CharacteristicsCharacteristics

Antihypertensive Medication UseAntihypertensive Medication Use

No Meds, No HTNNo Meds, No HTNa a

(N=416,218)(N=416,218)No Meds, HTNNo Meds, HTNbb

(N=31,274)(N=31,274)Other MedsOther Medscc (N=17,507)(N=17,507)

ACEI ACEI

(N=817)(N=817)

Maternal Age at Delivery (yr)Maternal Age at Delivery (yr)

<20<20 27,839 (6.7%)27,839 (6.7%) 2,019 (6.5%) 2,019 (6.5%) 899 (5.1%) 899 (5.1%) 7 (0.9%) 7 (0.9%)

20-<2520-<25 73,186 (17.6%)73,186 (17.6%) 5,210 (16.7%) 5,210 (16.7%) 2,340 (13.4%) 2,340 (13.4%) 46 (5.6%) 46 (5.6%)

25-<3025-<30 119,109 (28.6%)119,109 (28.6%) 8,124 (26.0%) 8,124 (26.0%) 4,289 (24.5%) 4,289 (24.5%) 109 (13.3%) 109 (13.3%)

30-<3530-<35 118,237 (28.4%)118,237 (28.4%) 8,648 (27.7%) 8,648 (27.7%) 5,113 (29.2%) 5,113 (29.2%) 231 (28.3%) 231 (28.3%)

35-<4035-<40 62,812 (15.1%)62,812 (15.1%) 5,554 (17.8%) 5,554 (17.8%) 3,647 (20.8%) 3,647 (20.8%) 269 (32.9%) 269 (32.9%)

40+40+ 14,523 (3.5%)14,523 (3.5%) 1,710 (5.5%) 1,710 (5.5%) 1,204 (6.9%) 1,204 (6.9%) 154 (18.9%) 154 (18.9%)

UnknownUnknown 512 (0.1%)512 (0.1%) 9 (0.0%) 9 (0.0%) 15 (0.1%) 15 (0.1%) 1 (0.1%) 1 (0.1%)

Maternal Race/EthnicityMaternal Race/Ethnicity

WhiteWhite 185,778 (44.6%) 185,778 (44.6%) 15,286 (48.9%) 15,286 (48.9%) 8,139 (46.5%) 8,139 (46.5%) 282 (34.5%) 282 (34.5%)

African AmericanAfrican American 34,988 (8.4%) 34,988 (8.4%) 3,471 (11.1%) 3,471 (11.1%) 2,473 (14.1%) 2,473 (14.1%) 163 (20.0%) 163 (20.0%)

HispanicHispanic 89,377 (21.5%) 89,377 (21.5%) 6,179 (19.8%) 6,179 (19.8%) 2,833 (16.2%)2,833 (16.2%) 135 (16.5%) 135 (16.5%)

AsianAsian 84,594 (20.3%) 84,594 (20.3%) 5,143 (16.4%) 5,143 (16.4%) 3,286 (18.8%) 3,286 (18.8%) 175 (21.4%) 175 (21.4%)

OtherOther 3,477 (0.8%) 3,477 (0.8%) 313 (1.0%) 313 (1.0%) 195 (1.1%) 195 (1.1%) 9 (1.1%) 9 (1.1%)

UnknownUnknown 18,004 (4.3%) 18,004 (4.3%) 882 (2.8%) 882 (2.8%) 581 (3.3%) 581 (3.3%) 53 (6.5%) 53 (6.5%)

Table 1. Distribution of Selected Maternal Characteristics by Fetal Table 1. Distribution of Selected Maternal Characteristics by Fetal Exposure Status to Antihypertensive Medications during Exposure Status to Antihypertensive Medications during Pregnancy, Kaiser Permanente of Northern California 1995-2008.Pregnancy, Kaiser Permanente of Northern California 1995-2008.(Cont.)(Cont.)

CharacteristicsCharacteristics

Antihypertensive Medication UseAntihypertensive Medication Use

No Meds, No HTNNo Meds, No HTNaa (N=416,218)(N=416,218)

No Meds, HTNNo Meds, HTNb b

(N=31,274)(N=31,274)Other MedsOther Medscc (N=17,507)(N=17,507)

ACEI ACEI

(N=817)(N=817)

Parity (Previous Live Births)Parity (Previous Live Births)

00 161,182 (38.7%) 161,182 (38.7%) 15,642 (50.0%) 15,642 (50.0%) 6,319 (36.1%) 6,319 (36.1%) 213 (26.1%) 213 (26.1%)

11 135,153 (32.5%) 135,153 (32.5%) 8,560 (27.4%) 8,560 (27.4%) 5,373 (30.7%) 5,373 (30.7%) 212 (26.0%) 212 (26.0%)

22 65,195 (15.7%) 65,195 (15.7%) 3,842 (12.3%) 3,842 (12.3%) 3,046 (17.4%) 3,046 (17.4%) 181 (22.2%) 181 (22.2%)

3+3+ 35,375 (8.5%) 35,375 (8.5%) 2,227 (7.1%) 2,227 (7.1%) 1,952 (11.2%) 1,952 (11.2%) 143 (17.5%) 143 (17.5%)

UnknownUnknown 19,313 (4.6%) 19,313 (4.6%) 1,003 (3.2%) 1,003 (3.2%) 817 (4.7%) 817 (4.7%) 68 (8.3%) 68 (8.3%)

Maternal WeightMaternal Weight

<90<90thth Percentile Percentile 263,013 (63.2%) 263,013 (63.2%) 17,377 (55.6%) 17,377 (55.6%) 10,220 (58.4%) 10,220 (58.4%) 350 (42.8%) 350 (42.8%)

≥≥9090thth Percentile (207 lbs) Percentile (207 lbs) 25,723 (6.2%) 25,723 (6.2%) 5,736 (18.3%) 5,736 (18.3%) 2,229 (12.7%) 2,229 (12.7%) 235 (28.8%) 235 (28.8%)

UnknownUnknown 127,482 (30.6%) 127,482 (30.6%) 8,161 (26.1%) 8,161 (26.1%) 5,058 (28.9%) 5,058 (28.9%) 232 (28.4%) 232 (28.4%)

Pre-existing DiabetesPre-existing Diabetes

YesYes 1,651 (0.4%) 1,651 (0.4%) 689 (2.2%) 689 (2.2%) 470 (2.7%) 470 (2.7%) 316 (38.7%) 316 (38.7%)

NoNo 414,567 (99.6%) 414,567 (99.6%) 30,585 (97.8%) 30,585 (97.8%) 17,037 (97.3%) 17,037 (97.3%) 501 (61.3%) 501 (61.3%)

a.a. No use of anti-hypertensive medications during pregnancy and no diagnosis of hypertensionNo 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 hypertensionb. No use of anti-hypertensive medications during pregnancy, but with a diagnosis of hypertension

c. Anti-hypertensive medications other than ACE inhibitors (ACEI)c. Anti-hypertensive medications other than ACE inhibitors (ACEI)

Table 2. Fetal Exposure to Antihypertensive Medications and the Risk of Table 2. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, Kaiser Permanente, Northern California Major Malformations, Kaiser Permanente, Northern California 1995-20081995-2008

Medication use Birth DefectsBirth Defects NoNoa a n (%)n (%) Yes n (%)Yes n (%) Odds Ratio*Odds Ratio*

11stst Trimester Only Trimester Only

Any MalformationsAny Malformations

No MedsNo Meds,, No HTN No HTN 393,789 (94.6) 393,789 (94.6) 22,429 (5.4) 22,429 (5.4) Reference Reference

No Meds, With HTNNo Meds, With HTN 29,027 (92.8) 29,027 (92.8) 2,247 (7.2) 2,247 (7.2) 1.25 (1.19 – 1.31) 1.25 (1.19 – 1.31)

Other Meds OnlyOther Meds Only 1,062 (93.1) 1,062 (93.1) 79 (6.9) 79 (6.9) 1.22 (0.97 – 1.54) 1.22 (0.97 – 1.54)

ACEI AnyACEI Any 393 (91.6) 393 (91.6) 36 (8.4) 36 (8.4) 1.19 (0.84 – 1.68) 1.19 (0.84 – 1.68)

Congenital Heart Defects (CHD)Congenital Heart Defects (CHD)

No Meds, No HTNNo Meds, No HTN 393,789 (98.4) 393,789 (98.4) 6,232 (1.6) 6,232 (1.6) Reference Reference

No Meds, With HTNNo Meds, With HTN 29,027 (97.6) 29,027 (97.6) 708 (2.4) 1.41 (1.30 – 1.53) 1.41 (1.30 – 1.53)

Other Meds Only Other Meds Only 1,062 (97.4) 1,062 (97.4) 28 (2.6) 28 (2.6) 1.52 (1.04 – 2.21) 1.52 (1.04 – 2.21)

ACEI AnyACEI Any 393 (96.1) 393 (96.1) 16 (3.9) 16 (3.9) 1.52 (0.91 – 2.55) 1.52 (0.91 – 2.55)

Neural Tube Defects (NTD)Neural Tube Defects (NTD)

No Meds, No HTNNo Meds, No HTN 393,789 (99.4) 393,789 (99.4) 2,447 (0.6) 2,447 (0.6) ReferenceReference

No Meds, With HTNNo Meds, With HTN 29,027 (99.0) 29,027 (99.0) 281 (1.0) 281 (1.0) 1.43 (1.26 – 1.62) 1.43 (1.26 – 1.62)


ACEI AnyACEI Any 393 (99.5) 393 (99.5) 2 (0.5) 2 (0.5) 0.55 (0.14 – 2.23) 0.55 (0.14 – 2.23)

Table 2. Fetal Exposure to Antihypertensive Medications and the Table 2. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, Kaiser Permanente, Northern Risk of Major Malformations, Kaiser Permanente, Northern California 1995-2008 (Cont.) California 1995-2008 (Cont.)

Medication UseMedication Use Birth DefectsBirth Defects NoNoa a n (%)n (%) Yes n (%)Yes n (%) Odds Ratio*Odds Ratio*

Other Periods During PregnancyOther Periods During Pregnancy

11stst Trimester Ever Trimester Ever





ACEI AnyACEI Any 701 (92.1) 701 (92.1) 60 (7.9) 60 (7.9) 1.10 (0.83 – 1.44) 1.10 (0.83 – 1.44)





ACEI AnyACEI Any 701 (96.6) 701 (96.6) 25 (3.4) 25 (3.4) 1.33 (0.87 – 2.02) 1.33 (0.87 – 2.02)





ACEI AnyACEI Any 701 (99.2) 701 (99.2) 6 (0.9) 6 (0.9) 0.95 (0.42 – 2.17) 0.95 (0.42 – 2.17)

Table 2. Fetal Exposure to Antihypertensive Medications and the Table 2. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, Kaiser Permanente, Northern Risk of Major Malformations, Kaiser Permanente, Northern California 1995-2008 (Cont.) California 1995-2008 (Cont.)

Medication UseMedication Use Birth DefectsBirth Defects NoNoa a n(%)n(%) Yes n (%)Yes n (%) Odds Ratio*Odds Ratio*


22ndnd/3/3rdrd Trimester Only Trimester Only




Other Meds OnlyOther Meds Only 11,783 (89.8) 11,783 (89.8) 1,334 (10.2) 1,334 (10.2) 1.94 (1.83 – 2.05) 1.94 (1.83 – 2.05)

ACEI AnyACEI Any 48 (85.7) 48 (85.7) 8 (14.3) 8 (14.3) 2.51 (1.18 – 5.34) 2.51 (1.18 – 5.34)


No Meds, No HTNNo Meds, No HTN 393,789 (98.4) ) 393,789 (98.4) ) 6,232 (1.6) 6,232 (1.6) Reference Reference



ACEI AnyACEI Any 48 (90.6) 48 (90.6) 5 (9.4) 5 (9.4) 5.03 (1.99 – 12.74) 5.03 (1.99 – 12.74)




Other Meds OnlyOther Meds Only 11,783 (98.4) 11,783 (98.4) 193 (1.6) 193 (1.6) 2.51 (2.16 – 2.91)2.51 (2.16 – 2.91)

ACEI AnyACEI Any 48 (96.0) 48 (96.0) 2 (4.0) 2 (4.0) 5.05 (1.22 – 20.94) 5.05 (1.22 – 20.94)

* Adjusted for preexisting diabetes, maternal age, race/ethnicity, parity and maternal weight.* Adjusted for preexisting diabetes, maternal age, race/ethnicity, parity and maternal weight.

a. No any birth defecta. No any birth defect

b. Anti-hypertensive medicationsb. Anti-hypertensive medications

c. Hypertensionc. Hypertension

Table 3. Fetal Exposure to Antihypertensive Medications and the Table 3. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, Among Mothers Risk of Major Malformations, Among Mothers without Preexisting without Preexisting DiabetesDiabetes, Kaiser Permanente Northern California 1995-2008, Kaiser Permanente Northern California 1995-2008




No MedsNo Medsbb, No HTN, No HTNcc 392,290 (94.6) 392,290 (94.6) 222,77 (5.4) 222,77 (5.4) Reference Reference



ACEI AnyACEI Any 251 (94.4) 251 (94.4) 15 (5.6) 15 (5.6) 1.00 (0.59 – 1.68) 1.00 (0.59 – 1.68)





ACEI AnyACEI Any 251 (96.9) 251 (96.9) 8 (3.1) 8 (3.1) 1.85 (0.91 – 3.74) 1.85 (0.91 – 3.74)





ACEI AnyACEI Any 251 (99.2) 251 (99.2) 2 (0.8) 2 (0.8) 1.20 (0.30 – 4.85) 1.20 (0.30 – 4.85)

Table 3. Fetal Exposure to Antihypertensive Medications and the Risk of Table 3. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, Among Mothers Major Malformations, Among Mothers without Preexisting without Preexisting DiabetesDiabetes, Kaiser Permanente Northern California 1995-2008 , Kaiser Permanente Northern California 1995-2008 (Cont.)(Cont.)



11stst Trimester Ever Trimester Ever





ACEI AnyACEI Any 429 (94.5) 429 (94.5) 25 (5.5) 25 (5.5) 0.98 (0.65 – 1.46) 0.98 (0.65 – 1.46)





ACEI AnyACEI Any 429 (97.3) 429 (97.3) 12 (2.7) 12 (2.7) 1.61 (0.90 – 2.86) 1.61 (0.90 – 2.86)





ACEI AnyACEI Any 429 (98.6) 429 (98.6) 6 (1.4) 6 (1.4) 2.09 (0.93 – 4.69) 2.09 (0.93 – 4.69)

Table 3. Fetal Exposure to Antihypertensive Medications and the Risk of Table 3. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, Among Mothers Major Malformations, Among Mothers without Preexisting without Preexisting DiabetesDiabetes, Kaiser Permanente Northern California 1995-2008 , Kaiser Permanente Northern California 1995-2008 (Cont.)(Cont.)



22ndnd/3/3rdrdTrimester OnlyTrimester Only




Other Meds OnlyOther Meds Only 11,540 (89.9) 11,540 (89.9) 1,299 (10.1) 1,299 (10.1) 1.95 (1.84 – 2.07) 1.95 (1.84 – 2.07)

ACEI AnyACEI Any 40 (85.1) 40 (85.1) 7 (14.9) 7 (14.9) 2.98 (1.33 – 6.65) 2.98 (1.33 – 6.65)





ACEI AnyACEI Any 40 (88.9) 40 (88.9) 5 (11.1) 5 (11.1) 7.24 (2.85 – 18.36) 7.24 (2.85 – 18.36)





ACEI AnyACEI Any 40 (95.2) 40 (95.2) 2 (4.8) 2 (4.8) 7.18 (1.73 – 29.80) 7.18 (1.73 – 29.80)

* Adjusted for preexisting diabetes, maternal age, race/ethnicity, parity and maternal weight.* Adjusted for preexisting diabetes, maternal age, race/ethnicity, parity and maternal weight.



c. Hypertension c. Hypertension

Table 4. Fetal Exposure to Antihypertensive Medications and the Risk of Table 4. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, among Mothers Major Malformations, among Mothers without Preexisting without Preexisting DiabetesDiabetes, by an underlying diagnosis of hypertension, Kaiser , by an underlying diagnosis of hypertension, Kaiser Permanente, Northern California 1995-2008 Permanente, Northern California 1995-2008




No MedsNo Meds,, No HTN No HTN 392,290 (94.6) 392,290 (94.6) 22,277 (5.4) 22,277 (5.4) Reference Reference


Other Meds Only, No HTNOther Meds Only, No HTN 680 (92.8) 680 (92.8) 53 (7.2) 53 (7.2) 1.32 (1.00 – 1.75) 1.32 (1.00 – 1.75)

Other Meds Only, With HTNOther Meds Only, With HTN 357 (94.4) 357 (94.4) 21 (5.6) 21 (5.6) 0.96 (0.62 – 1.50) 0.96 (0.62 – 1.50)

ACEI Any, No HTNACEI Any, No HTN 22 (100.0) 22 (100.0) 0 (0.0) 0 (0.0) NA NA

ACEI Any, With HTNACEI Any, With HTN 229 (93.9) 229 (93.9) 15 (6.2) 15 (6.2) 1.08 (0.64 – 1.83) 1.08 (0.64 – 1.83)




Other Meds Only, No HTNOther Meds Only, No HTN 680 (97.6) 680 (97.6) 17 (2.4) 17 (2.4) 1.53 (0.95 – 2.48) 1.53 (0.95 – 2.48)

Other Meds Only, With HTN Other Meds Only, With HTN 357 (97.5) 357 (97.5) 9 (2.5) 9 (2.5) 1.43 (0.74 – 2.78) 1.43 (0.74 – 2.78)



Table 4. Fetal Exposure to Antihypertensive Medications and the Risk of Table 4. Fetal Exposure to Antihypertensive Medications and the Risk of Major Malformations, among Mothers Major Malformations, among Mothers without Preexisting without Preexisting DiabetesDiabetes, by an underlying diagnosis of hypertension, Kaiser , by an underlying diagnosis of hypertension, Kaiser Permanente, Northern California 1995-2008 (Cont.) Permanente, Northern California 1995-2008 (Cont.)






Other Meds Only, No HTNOther Meds Only, No HTN 680 (99.3) 680 (99.3) 5 (0.7) 5 (0.7) 1.15 (0.48 - 2.77) 1.15 (0.48 - 2.77)

Other Meds Only, With HTNOther Meds Only, With HTN 357 (98.9) 357 (98.9) 4 (1.1) 4 (1.1) 1.66 (0.62 – 4.46) 1.66 (0.62 – 4.46)



* * Adjusted for maternal age, race/ethnicity, parity and maternal weightAdjusted for maternal age, race/ethnicity, parity and maternal weight



c. Hypertension c. Hypertension

LimitationsLimitations

Low frequency of ACEI use during Low frequency of ACEI use during pregnancypregnancy

No information on complianceNo information on compliance

Limited information on confoundersLimited information on confounders

Inability to study individual defectsInability to study individual defects

StrengthsStrengths

Large study population (almost a half Large study population (almost a half million maternal-infant pairs)million maternal-infant pairs)

Population-based (every live-birth)Population-based (every live-birth)

Control for underlying indication Control for underlying indication (hypertension)(hypertension)

Three types of controlsThree types of controls

Confirmation from other studiesConfirmation from other studies

Swedish studySwedish study– A cohort studyA cohort study– Both ACEI and other antihypertensive Both ACEI and other antihypertensive

medications had similarly increased risk of BDsmedications had similarly increased risk of BDs

CDC studyCDC study– A case-control studyA case-control study– A similar association for both ACEI and other A similar association for both ACEI and other

antihypertensive medications antihypertensive medications – Hypertension also increases the riskHypertension also increases the risk

ConclusionsConclusions

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

ConclusionsConclusions

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

Important issues in drug safety researchImportant issues in drug safety research

Unlikely to do RCT type studiesUnlikely to do RCT type studies– Ethical considerationEthical consideration

PregnancyPregnancy– Effect on motherEffect on mother– Effect on fetusEffect on fetus

Example: antidepressants to PPDExample: antidepressants to PPD

– Long-term safety issuesLong-term safety issues


Observational studiesObservational studies– Based on existing automated dataBased on existing automated data

Claim dataClaim data

Clinical dataClinical data

EMREMR

– Collect original dataCollect original dataCohort studies: Cohort studies:

– ExpensiveExpensive– Long-term follow upLong-term follow up

Case-control studiesCase-control studies– EfficientEfficient– Recall issue (errors or biases)Recall issue (errors or biases)


Issues related to studies using automated Issues related to studies using automated datadata

Control underlying indication: separate controlsControl underlying indication: separate controls

Incomplete ascertainment of exposed womenIncomplete ascertainment of exposed women– Drug coverage (outside the system)Drug coverage (outside the system)– Mixed in other drug categoriesMixed in other drug categories– Sample size issue when exposure is rare, misclassified Sample size issue when exposure is rare, misclassified

as non-user, rather than biasas non-user, rather than bias

Compliance: can be a problem for rare drug Compliance: can be a problem for rare drug exposure (dilute exposed group) depending on exposure (dilute exposed group) depending on seriousness of underlying conditions. seriousness of underlying conditions.


Issues related to studies using automated Issues related to studies using automated datadata

Limited information on confoundersLimited information on confounders

Potential biased ascertainment of conditions with Potential biased ascertainment of conditions with significant under-diagnosis (e.g., depression, significant under-diagnosis (e.g., depression, ADHD, etc.), users being examined more carefullyADHD, etc.), users being examined more carefully

Issues related to studies collecting original Issues related to studies collecting original datadata– Same principles for cohort and case-control Same principles for cohort and case-control

studiesstudies– Key: select correct controls. Key: select correct controls.

use of ace inhibitors in pregnant women and the risk of congenital heart defects de-kun li, md, phd...

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