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Antihypertensive Medication Use during Pregnancy

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Antihypertensive Medication Use during Pregnancy Alissa R. Caton, Ph.D. NYS Department of Health MCH Epidemiology Conference December 2007 Collaborators: Erin Bell ... – PowerPoint PPT presentation

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Title: Antihypertensive Medication Use during Pregnancy


1
Antihypertensive Medication Use during Pregnancy
  • Alissa R. Caton, Ph.D.
  • NYS Department of Health
  • MCH Epidemiology Conference
  • December 2007

Collaborators Erin Bell (NY), Charlotte
Druschel (NY), Martha Werler (MA), Louise-Anne
McNutt (NY), Marilyn Browne (NY), Angela Lin
(MA), Allen Mitchell (MA), Paul Romitti (IA),
Adolfo Correa (CDC), Richard Olney (CDC)
2
CDC Urgent call to public health action
  • Little experience of drugs in human pregnancy at
    time of drug marketing
  • Women and healthcare providers need current
    information about effects of medication use
    during pregnancy for the management of maternal
    conditions
  • 50 pregnancies unplanned

3
Hypertension in Pregnancy
  • Present in 5-10 of pregnancies
  • Chronic hypertension (1)
  • Gestational hypertension
  • Preeclampsia
  • Expect prevalence of hypertension in pregnancy to
    ?
  • Childbearing at older maternal ages
  • Increasing obesity in general population

4
Antihypertensive Medication Classes
  • Antiadrenergic agents
  • Centrally-acting
  • Peripherally acting (incl. beta blockers)
  • Alpha-beta blockers
  • Angiotensin converting enzyme (ACE) inhibitors
  • Angiotensin II receptor blockers
  • Calcium channel blockers
  • Direct vasodilators
  • Diuretics

5
Antihypertensive Medication Use during Pregnancy
  • Treatment Goal ? maternal blood pressure without
    compromising uteroplacental perfusion
  • Severe hypertension is treated with medication in
    the hospital
  • No consensus on treating mild-moderate forms with
    medications during pregnancy

6
Some Hypothesized Mechanisms of Teratogenicity
  • Reduced placental perfusion ? hypoxia
    ? oxidative stress
  • Altered embryonic/ fetal blood pressure

7
Treatment Guidelines in Pregnancy
  • Methyldopa antiadrenergic, centrally-acting
  • Older drug - most studied long term follow-up
    data
  • Side effects lack of energy and dizziness
  • Labetalol antiadrenergic, alpha-beta blocker
  • Lacks long term follow-up data
  • Well tolerated
  • Twice daily medications

Powrie RO, JAMA, October 3, 2007 vol 298 (13) A
30-Year-Old Woman with Chronic Hypertension
Trying to Conceive
8
Treatment Guidelines in Pregnancy
  • ACE inhibitors and angiotensin receptor blockers
    are contraindicated in the 2nd and 3rd trimesters
    due to a well known 3rd trimester fetopathy
    (kidneys, lungs, scalp)
  • Recent reports of low birth weight and
    intrauterine growth restriction with beta blocker
    use, especially atenolol and propranolol

9
Treatment Guidelines in Young Women
  • First line treatments recommended in the 7th
    Report of the Joint National Committee on
    Prevention, Detection, Evaluation, and Treatment
    of High Blood Pressure
  • Thiazide-type diuretics
  • ACE inhibitors
  • Angiotensin receptor blockers
  • Beta blockers
  • Calcium channel blockers

Powrie RO, JAMA, October 3, 2007 vol 298 (13) A
30-Year-Old Woman with Chronic Hypertension
Trying to Conceive
10
Treatment Guidelines in Young Women
  • Methyldopa and labetalol are not first line
    treatments
  • Safety concerns
  • Unplanned pregnancy - Unintentional exposure to
    contraindicated ACE inhibitors and angiotensin
    receptor blockers
  • Little information on pregnancy safety of the
    other recommended classes

Powrie RO, JAMA, October 3, 2007 vol 298 (13) A
30-Year-Old Woman with Chronic Hypertension
Trying to Conceive
11
ACE Inhibitors in the News
  • New England Journal of Medicine study based on
    Tennessee Medicaid data (Cooper et al., 2006) has
    drawn the media spotlight on the safety of 1st
    trimester ACE inhibitor use
  • 1st trimester use of ACE inhibitors associated
    with cardiovascular malformations and central
    nervous system defects
  • Authors attributed effect to the drug exposure
    because exposures to other drugs were not
    associated with increased risk

12
Published Studies on Antihypertensive Medication
Use and Congenital Heart Defects
Population (Years) Drug Class RR Estimates
Collaborative Perinatal Project (1959-65) Diuretic or cardiovascular 0.9 (0.3-2.1)
Baltimore-Washington Infant Study (1981-89) Any class Diuretic 1.2 (0.7-2.1) unadjusted 8.6 (2.9-24.5) AVSD only
Hungarian C-C Study (1980-96) Calcium channel blocker 1.6 (0.8-3.2)
Michigan Medicaid (1985-92) Classes and specific drugs ObservedgtExpected
Swedish Health Registers (1995-2001) Any class Beta blocker Antiadrenergic, diuretic 2.0 (1.5-2.8) 1.9 (1.2-2.8) 2.0 (ObsgtExp)
Tennessee Medicaid (1985-2000) ACE inhibitor 3.7 (1.9-7.3)
13
Published Studies on Antihypertensive Medication
Use and Other Birth Defects
Population (Years) Drug Class RR Estimates
Collaborative Perinatal Project (1959-65) Diuretic or cardiovascular Not significantly associated with BD
Hungarian C-C Study (1980-86) Propranolol (beta blocker) Not significantly associated with NTDs, OCs, hypospadias
Hungarian C-C Study (1980-96) Calcium channel blocker Not significantly associated with BD
Michigan Medicaid (1985-92) Classes and specific drugs ObservedgtExpected
Tennessee Medicaid (1985-2000) ACE inhibitor Other classes combined 4.4 (1.4-14.0) CNS 2.7 (1.7-4.3) BD 0.7 (0.3-1.8) BD
14
Limitations of Published Studies
  • Too few studies and inconsistent findings
  • Small sample sizes
  • Broad groupings of birth defects
  • Broad groupings of medications
  • Medication reporting inaccuracy
  • Inadequate control of confounding
  • Confounding by underlying hypertension
  • Too little information available for adjustment
  • Selection bias

15
RESEARCH DESIGN STUDY METHODS
16
Specific Aim
  • Characterize patterns of antihypertensive
    medication use
  • Examine drug class, changes, and timing of
    exposure from preconception to birth
  • Identify maternal and infant characteristics
    associated with use

17
Data Source, Study Design, Study Subjects
  • National Birth Defects Prevention Study,
    October 1, 1997Dec 31, 2003
  • 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

18
CATI Questions from High Blood Pressure Module
  • Were you ever told by a doctor that you had HBP?
  • How old were you when you were told that you had
    HBP?
  • Did you have HBP when you were pregnant with
    (NOIB)?
  • Did you take any medications or remedies for HBP
    between (-3) and (DOIB)?
  • What did you take? / Did you take anything else?
  • IF CANT RECALL, READ FROM DRUG LIST Did you
    take . . . ?
  • Between (-3) and (DOIB), when did you start using
    (MEDICINE) for this illness?
  • When did you stop using (MEDICINE)? or
  • How long did you take it?
  • How often did you use (MEDICATION)?

19
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
  • Patterns
  • 3 months preconception
  • Trimesters 1-3
  • Characteristics of Users Odds Ratios and 95
    CIs
  • Early use
  • Late initiation

20
Exposure Categories
Early Use ANY MEDICATION USE 1 MONTH PRECONCEPTION THROUGH PREGNANCY MONTH 3 Treated chronic hypertension
Late Initiation MEDICATION USE INITIATED AFTER PREGNANCY MONTH 3 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)
21
RESULTS AND DISCUSSION
22
High Blood Pressure and Medication Use
  • 4,971 nonmalformed controls
  • 463 (9.4) reported high blood pressure
  • 70 (1.4) used medication during preconception
    period and/or pregnancy
  • 15.1 of women reporting high blood pressure
  • Medication use increased throughout pregnancy
  • 0.6 preconception ?1.2 3rd trimester
  • 38 (0.8) used medications during 1st trimester
  • 31 (0.6) initiated medications after 1st
    trimester

23
Timing of Use
AACantiadrenergic, central a/balpha-beta
blocker BBbeta blocker CCBcalcium channel
blocker DIUdiuretic ACEIACE inhibitor
ARBangiotensin II receptor blocker
VASOvasodilator.
24
1st Trimester Treatment Choices in Nonmalformed
Controls
AACantiadrenergic, central a/balpha-beta
blocker labetolol BBbeta blocker CCBcalcium
channel blocker DIUdiuretic ACEIACE inhibitor.
25
Early Use
  • Methyldopa (central antiadrenergic, 14)
  • Atenolol (beta blocker, 7)
  • Labetalol (alpha-beta blocker, 3)
  • Clonidine (central antiadrenergic, 2)
  • Metoprolol (beta blocker, 2)
  • Propranolol (beta blocker, 2)
  • Amlodipine (calcium channel blocker, 2)
  • Verapamil (calcium channel blodker, 2)
  • Benazepril (ACE inhibitor, 2)
  • HCTZ combos (diuretic, 2)

26
ACE Inhibitor Use (n6)
  1. NOS - continued treatment (multiple birth)
  2. Fosinopril - started ACEI 2nd month changed to
    AAC clonidine and CCB amlodipine 3rd month
  3. Benazepril - changed to BB metoprolol 3rd month
    (diabetic)
  4. Lisinopril - changed to NOS 1st month/continued
    with diuretic (diabetic)
  5. Trandolapril - stopped treatment 3rd month
  6. Benazepril - changed to AAC methyldopa 1 month
    preconception

27
Early Use (n38)
Characteristic N OR (95 CI)
Pre-existing diabetes 4 35.2 (11.1-111.6)
Obesity 19 8.5 (3.8-19.0)
Age 35 19 5.6 (3.0-10.7)
Gestational diabetes 7 4.2 (1.8-9.7)
Multiple birth 4 4.1 (1.4-11.6)
Fertility tx/rx 5 3.8 (1.5-10.0)
NH black 12 3.3 (1.6-6.8)
Parity 2 14 2.2 (1.0-5.0)
Preterm birth 15 7.0 (3.6-13.5)
Low birth weight 15 11.7 (6.0-22.6)
28
Late Initiation (n31)
Characteristic N OR (95 CI)
Obesity 9 4.6 (1.8-11.9)
Overweight 11 3.7 (1.5-9.3)
Gestational diabetes 4 2.8 (1.0-8.0)
NH black 8 2.3 (1.0-5.4)
Fever 12 2.1 (1.0-4.4)
Preterm birth 6 2.6 (1.0-6.3)
29
Strengths Limitations
  • Strengths
  • Indication-based ascertainment of medication use
  • Collected 6-24 months after delivery
  • Oral prescription medication for chronic disease
    taken daily
  • Evaluated timing of use during pregnancy
  • Limitations
  • Maternal self-report
  • Window 3 months preconception - birth
  • Inability to measure the type or severity of
    hypertension
  • Small sample sizes due to rare exposures
  • Selection bias voluntary participants

30
Public Health Perspective
  • 4 million US births/year
  • 376,000 hypertension in pregnancy
  • 56,000 medications in pregnancy
  • 32,000 medications in 1st trimester

9.4 Hypertension, 1.4 Medications, 0.8 1st
Trimester Medication
31
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

32
Research Directions
  • Examine relationship between medication use and
    birth defects groups
  • Hypospadias (manuscript accepted)
  • Congenital heart defects (in progress)
  • Neural tube defects, oral clefts, limbs (next)
  • Examine factors related to class use
  • Reproduce analyses with Slone Birth Defects Study
    data

33
Thank you
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