MANAGEMENT OF HYPERTENSION IN WOMEN AND PREGNANCY - PowerPoint PPT Presentation


Title: MANAGEMENT OF HYPERTENSION IN WOMEN AND PREGNANCY


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MANAGEMENT OF HYPERTENSION IN WOMEN AND PREGNANCY
  • Suzanne Oparil, M.D.
  • Professor of Medicine, and Physiology
    Biophysics
  • Director, Vascular Biology and Hypertension
    Program
  • Division of Cardiovascular Disease
  • Department of Medicine
  • University of Alabama at Birmingham
  • Birmingham, AL
  • Atlanta, GA
  • March 30, 2005

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Systolic Blood Pressure levels for the 90th and
95th percentiles of blood pressure for boys and
girls age 1 to 17 years at 95th percentile of
height
http//hin.nhlbi.nih.gov/nhbpep_slds/ped/pedp1_1.h
tm
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TREATMENT
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THE WOMENS HEALTH INITIATIVE- PREVALENCE AND
TREATMENT STATUS BY RACE/ ETHNICITY
WHITE
76
80
BLACK
63
63
HISPANIC
59
60
60
OTHER
44
41
36
36
40
PERCENT OF COHORT
33
32
30
20
0
HYPERTENSIVE
TREATED
CONTROLLED
Wassertheil-Smoller et al. Hypertension
200036780-789
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THE WOMENS HEALTH INITIATIVE- PREVALENCE AND
TREATMENT STATUS BY AGE
80
AGE 50-59
70
65
AGE 60-69
64
63
AGE 70-79
60
53
50
41
41
PERCENT OF COHORT
37
40
29
27
30
20
10
0
HYPERTENSIVE
TREATED
CONTROLLED
Wassertheil-Smoller et al. Hypertension
200036780-789
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THE WOMENS HEALTH INITIATIVE-ANSWERS TO
QUESTIONS ABOUT BP
  • Hypertension is most prevalent in the oldest
    women and in blacks.
  • Hypertension is undertreated in postmenopausal
    women 65 treatment rates- despite documented
    physicians visits.
  • BP control is inadequate in postmenopausal women-
    worst (29) in the oldest women- independent of
    drug class.

Wassertheil-Smoller et al. Hypertension
200036780-789
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Major Outcomes in High Risk Hypertensive Patients
Randomized to Angiotensin-Converting Enzyme
Inhibitor or Calcium Channel Blocker vs Diuretic
  • The Antihypertensive and Lipid-Lowering Treatment
    to Prevent Heart Attack Trial (ALLHAT)

The ALLHAT Collaborative Research Group Sponsored
by the National Heart, Lung, and Blood Institute
(NHLBI)
JAMA. 20022882981-2997
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AntihypertensiveTrial Design
  • Randomized, double-blind, multi-center clinical
    trial
  • Determine whether occurrence of fatal CHD or
    nonfatal MI is lower for high-risk hypertensive
    patients treated with newer agents (CCB, ACEI,
    alpha-blocker) compared with a diuretic
  • 42,418 high-risk hypertensive patients 55 years

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Nonfatal MI CHD Death Subgroup Comparisons
RR (95 CI)
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  • The Losartan Intervention For Endpoint
    Reductionin Hypertension Study

An investigator initiated community-based study
in945 sites in 7 countries enrolling 9193
patients Steering Committee Chair/Vice-Chair B.
Dahlöf, D. Devereux European/US
Coordinators S.E. Kjeldsen, S. Julius Data and
Safety Monitoring Committee Chair J.
Kjekshus Clinical Endpoint Classification
Committee D. Levy, K. Thygesen
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Demographic Subgroup ResultsPrimary Endpoint
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TREATMENT EFFECT BY GENDER
Gueyffier et al. Ann Intern Med 1997126761-67
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Antihypertensive TrialImplications
  • Diuretics should be the drug of choice for first
    step therapy of hypertension
  • For the patient who cannot take a diuretic (which
    should be an unusual circumstance), CCBs and
    ACEIs may be considered.
  • Most hypertensive patients require more than one
    drug. Diuretics should generally be part of the
    antihypertensive regimen. Lifestyle advice
    should also be provided.

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Algorithm for Treatment of Hypertension
Lifestyle Modifications
Not at Goal Blood Pressure (lt140/90 mmHg)
(lt130/80 mmHg for those with diabetes or chronic
kidney disease)
Initial Drug Choices
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SELECTIVE ANTIHYPERTENSIVE THERAPY FOR WOMEN
  • No evidence to suggest that women respond
    differently to antihypertensive therapy than men
  • Diuretics may be particularly useful
  • Adverse effects are more troublesome
  • ACE inhibitor cough 3 times more common
  • Dihydropyridine CCB edema more common
  • Hirsutism with minoxidil intolerable
  • Treatment outcomes are probably similar

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HYPERTENSION IN PREGNANCY
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Classification
  • Preeclampsia-eclampsia
  • Chronic hypertension
  • Preeclampsia superimposed upon chronic
    hypertension
  • Gestational hypertension (only during pregnancy)
  • Transient hypertension (only after pregnancy)

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CLASSIFICATION OF HYPERTENSION IN PREGNANCY
Chronic hypertension
BP
CHRONIC HYPERTENSION BP140 mmHg systolic or 90 mmHg diastolic prior to pregnancy or before 20 weeks gestation Persists gt12 weeks postpartum
PREECLAMPSIA BP 140 mm Hg systolic or 90 mm Hg diastolic with proteinuria (gt300 mg/24 hr) after 20 weeks gestation Can progress to eclampsia (seizures) More common in nulliparous women, multiple gestation, women with hypertension for 4 years, family history of preeclampsia, hypertension in previous pregnancy, renal disease
CHRONIC HYPERTENSION WITH SUPERIMPOSED PREECLAMPSIA New onset after 20 weeks in a woman with hypertension In a woman with hypertension and proteinuria prior to 20 weeks gestation Sudden 2- to 3-fold increase in proteinuria Sudden increase in BP Thrombocytopenia Elevated AST or ALT
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CLASSIFICATION OF HYPERTENSION IN PREGNANCY
Chronic hypertension
BP
GESTATIONAL HYPERTENSION Hypertension without proteinuria occurring after 20 weeks gestation Temporary diagnosis (only during pregnancy) May represent pre-proteinuric phase of preeclampsia or recurrence of chronic hypertension abated in midpregnancy May evolve to preeclampsia If severe, may result in higher rates of premature delivery and growth retardation than mild preeclampsia
TRANSIENT HYPERTENSION Retrospective diagnosis (only after pregnancy) BP normal by 12 weeks postpartum May recur in subsequent pregnancies Predictive of future essential hypertension
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Clinical Implications of Preeclampsia
  • Preeclampsia ranges from mild to severe.
  • Progression may be slow or rapid hours to days
    to weeks.
  • For clinical management, preeclampsia should be
    overdiagnosed to prevent maternal and perinatal
    morbidity and mortality primarily through
    timing of delivery.

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Classification of Preeclampsia-Eclampsia (cont.)
  • The following are more ominous signs and increase
    certainty of diagnosis
  • SBP gt 160 mm Hg or DBP gt 110 mm Hg
  • Proteinuria gt 2.0 g in 24 hours (2 or 3
    dipstick)
  • Increased serum creatinine
  • Platelet count lt 100,000 cells/mm3 and/or
    evidence of microangiopathic hemolytic anemia
    with increased LDH
  • Elevated ALT or AST
  • Persistent headache or other cerebral or visual
    disturbances
  • Persistent epigastric pain

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MATERNAL RISK FACTORS FOR PREECLAMPSIA
Primigravida Positive family history (maternal or
paternal) Multiple gestations Diabetes
mellitus Insulin resistance/obesity Chronic
hypertension Preexisting renal disease Extremes
of reproductive age Hydatidiform disease History
of severe early preeclampsia in a prior
pregnancy Collagen vascular disease Black
race Increased circulating testosterone Thrombophi
lias
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Hypothetical cause and pathogenesis of
pre-eclampsia. TGFtransforming growth factor.
IFNinterferon. VEGFvascular endothelial growth
factor. PIGFplacental growth factor.
ANGIOangiopoietin 2.
Sibai et al. Lancet 365785-99, 2005.
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Levels of evidence (IIV) as outlined by the US
Preventive Task Force
Sibai et al. Lancet 365785-99, 2005.
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Preeclampsia
  • Maternal Evaluation
  • Early recognition of preeclampsia
  • Observe progression, both to prevent maternal
    complications and protect well-being of fetus.
    Early signs
  • BP rises in late second and early third
    trimesters.
  • Initial appearance of proteinuria is important.

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Preeclampsia (cont.)
  • Maternal Evaluation (cont.)
  • Often, hospitalization recommended with new-onset
    preeclampsia to assess maternal and fetal
    conditions.
  • Hospitalization for duration of pregnancy
    indicated for preterm onset of severe
    gestational hypertension or preeclampsia.
  • Ambulatory management at home or at day-care unit
    may be considered with mild gestational
    hypertension or preeclampsia remote from term.

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Preeclampsia (cont.)
  • Antepartum Management of Preeclampsia
  • Little to suggest therapy alters the underlying
    pathophysiology of preeclampsia.
  • Restricted activity may be reasonable.
  • Sodium restriction and diuretic therapy appear
    to have no positive effect.

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Preeclampsia (cont.)
  • Indications for Delivery in Preeclampsia -
    Maternal
  • Gestational age 38 weeks
  • Platelet count lt 100,000 cells/mm3
  • Progressive deterioration in liver and renal
    function
  • Suspected abruptio placentae
  • Persistent severe headaches, visual changes,
    nausea, epigastric pain, or vomiting
  • Delivery should be based on maternal and fetal
    conditions as well as gestational age.

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Preeclampsia (cont.)
  • Indications for Delivery in Preeclampsia - Fetal
  • Severe fetal growth restriction
  • Nonreassuring fetal testing results
  • Oligohydramnios
  • Delivery should be based on maternal and fetal
    conditions
  • as well as gestational age.

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Preeclampsia (cont.)
  • Route of Delivery
  • Vaginal delivery is preferable.
  • Aggressive labor induction (within 24 hours).
  • Neuraxial (epidural, spinal, and combined
    spinal-epidural) techniques offer advantages.
  • Hydralazine, nitroglycerin, or labetalol may be
    used as pretreatment to reduce significant
    hypertension during delivery.

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Preeclampsia (cont.)
  • Anticonvulsive Therapy
  • Indicated to prevent recurrent convulsions in
    women with eclampsia or to prevent convulsions in
    women with preeclampsia.
  • Parenteral magnesium sulfate reduces the
    frequency of eclampsia. (Caution in renal
    failure.)

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Treatment of Acute Severe Hypertension in
Pregnancy
  • SBP gt 160 mm Hg and/or DBP gt 105 mm Hg
  • Parenteral hydralazine is most commonly used.
  • Parenteral labetalol is second-line drug (avoid
    in women with asthma and
    CHF.)
  • Oral nifedipine used with caution.
    (Short-acting nifedipine is not approved by FDA
    for managing hypertension.)
  • Sodium nitroprusside may be used in rare cases.

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ACUTE TREATMENT OF HYPERTENSION IN PREGNANCY
AGENT DOSAGE
Hydralazine(preferred) 5 mg iv bolus, then 10 mg every 20 to 30 minutes to a maximum of 25 mg, repeat in several hours as necessary
Labetalol(second line) 20 mg iv bolus, then 40 mg 10 minutes later, 80 mg every 10 minutes for 2 additional doses to a maximum of 220 mg
Nifedipine(controversial) 10 mg po, repeat every 20 minutes to a maximum of 30 mgCautious use with magnesium sulfate, can see precipitous blood pressure drop Short acting nifedipine is not approved by FDA for managing hypertension
Sodium nitroprusside (rarely when others fail) 0.5 ug/kg/min to a maximum of 5 ug/kg/min Fetal cyanide poisoning may occur if used for more than 4 hour
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CLINICAL CHARACTERISTICS AND LABORATORY TESTS
USED TO DISCRIMINATE PREECLAMPSIA FROM CHRONIC
HYPERTENSION
PREECLAMPSIA CHRONIC HYPERTENSION
Age Extremes of age Older (30 years)
Parity Nulliparous Often multiparous
Time of diagnosis of hypertension After 20 weeks Before 20 weeks
Maternal risk factors for preeclampsia Yes No
Hypertension/preeclampsia in prior pregnancies Yes Yes
Proteinuria (gt300 mg/24hrs) Yes No
Serum uric acid Elevated (5.5 mg/dl) Normal to low
Elevated liver enzymes Yes No
Thrombocytopenia Yes No
Headache, blurred vision, epigastric abdominal pain Yes No
Persistent hypertension gt12 weeks postpartum No Yes
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MANAGEMENT OF CHRONIC HYPERTENSION IN PREGNANCY
Chronic hypertension
BP
BEFORE CONCEPTION
Evaluation for secondary hypertension Pheochromocytoma Other causes if severe
Evaluation for target organ damage Cardiac function, LVH (echocardiography) Renal disease (serum creatinine, proteinuria)
Change to medications safe for pregnancy Taper early Titrate later
Lifestyle planning Restrict aerobic exercise Avoid weight reduction Moderate sodium intake Avoid all alcohol and tobacco
Baseline laboratory testing Hematocrit, hemoglobin, platelet count, serum creatinine, uric acid, urinalysis
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Chronic Hypertension in Pregnancy
  • Prepregnancy counseling
  • Evaluate using JNC7 criteria
  • Discontinue use of ACE inhibitors and ARBs
  • Evaluate for target organ damage in women with
    longstanding hypertension
  • Discontinue use of tobacco and/or alcohol, even
    if not hypertensive
  • Discuss lifestyle changes, if applicable

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MANAGEMENT OF CHRONIC HYPERTENSION IN PREGNANCY
Chronic hypertension
BP
DURING PREGNANCY
Selection of medications safe for pregnancy
Thresholds for treatment 150-160 mmHg systolic 100-110 mmHg diastolic
Laboratory Monitoring Hematocrit, hemoglobin, platelet count, serum creatinine, uric acid, AST, ALT, quantification of urine protein, serum albumin, LDH, peripheral blood smear, coagulation studies
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Treatment of Chronic Hypertension in Pregnancy
  • Most women with stage 1 to 2 chronic hypertension
    are candidates for nondrug therapy, absent
    evidence of target organ damage.
  • Most of the increased risk associated with
    chronic hypertension occurs with superimposed
    preeclampsia.
  • End points for reinstituting treatment include
    SBP gt 150-160 or DBP gt 100-110 or evidence of
    target organ damage.

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Antihypertensive Drug Selection
  • ACEI and ARB are contraindicated in pregnancy.
  • Methyldopa preferred first-line therapy
    labetalol if methyldopa not tolerated.
  • Alternatives to methyldopa can be substituted
    based on rational mechanisms of action.
  • Long-term studies of most other agents are
    lacking in pregnant women.
  • Diuretics not used as first-line agents but are
    not contraindicated except in cases of reduced
    uteroplacental perfusion.

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ORAL TREATMENT OF HYPERTENSION IN PREGNANCY
AGENT COMMENTS
Methyldopa Preferred based on long term studies of child development and uteroplacental blood flow
Beta Blockers Reports of intrauterine growth retardation, particularly for atenolol exposure at conception or in the first trimester generally safe
Labetalol Increasingly preferred for efficacy and few side effects
Clonidine Limited data
Calcium Channel Blockers Limited data Most experience with nifedipine and isradipine No increase in major teratogenicity with exposure
Diuretics Not first line agents, probably safe
Angiotensin Converting Enzyme Inhibitors Contraindicated, reports of fetal toxicity and death
Angiotensin Receptor Blockers Contraindicated, reports of fetal toxicity and death
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Fetal Assessment in Chronic Hypertension
  • Efforts directed at early detection of
    superimposed preeclampsia and possible fetal
    growth restriction.
  • Initial sonogram at 18 to 20 weeks gestation.
  • Fetal growth carefully assessed thereafter.
  • If growth restriction, assess by nonstress tests
    or biophysical profiles.

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MANAGEMENT OF CHRONIC HYPERTENSION IN PREGNANCY
Chronic hypertension
BP
DELIVERY
Maternal indications Gestational age 38 weeks Platelet count lt100,000 cells/mm3 Deterioration in hepatic or renal function Suspected placental abruption Severe headache or visual changes Sever epigastric pain, nausea or vomiting
Fetal indications Severe fetal growth restriction Concerning fetal testing results Olugohydramnios
Acute/parenteral therapy
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MANAGEMENT OF CHRONIC HYPERTENSION IN PREGNANCY
Chronic hypertension
BP
POSTPARTUM
Lactation Withhold antihypertensive medication Taper medication dosage Selection of safe medications Close monitoring for adverse effects
LATE ISSUES AFTER HYPERTENSIVE PREGNANCY
Persistent hypertension Evaluation for secondary causes Change medication
Long-term risk Monitor blood pressure for future hypertension Treat cardiovascular risk factors
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Treating Hypertension During Lactation
  • Breastfeeding encouraged (with limits).
  • Little information on excretion of agents in
    breast milk or long-term effects on exposed
    infants.
  • No short-term adverse effects reported with
    methyldopa or hydralazine.
  • Beta-blockers propanolol labetalol
    recommended.
  • No data on calcium antagonists.
  • Diuretics may reduce milk volume/suppress
    lactation.
  • ACEI and ARB should be avoided.

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Postpartum Counseling and Followup
  • Counseling for Future Pregnancies
  • Risk of recurrent preeclampsia increases with
  • Preeclampsia before 30 weeks (40)
  • Multiparas as compared with nulliparas or new
    father
  • Risk of recurrent preeclampsia may be
    substantially greater in African Americans.

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RISK FACTORS FOR RECURRENT HYPERTENSION IN
PREGNANCY
Early onset of hypertension in a prior
pregnancy Chronic hypertension Persistent
hypertension beyond 5 weeks postpartum High
baseline blood pressure early in pregnancy
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Pregnancy, Hypertension, and Renal Disease
  • Renal insufficiency may progress and jeopardize
    fetal survival.
  • As renal failure progresses, consider sodium
    restriction, use of loop diuretics, or dialysis.
  • Magnesium sulfate is hazardous in women with
    severe renal failure doses should be reduced and
    guided by plasma magnesium determinations.
    Phenytoin may be an alternative.
  • Significant maternal morbidity associated with
    chronic dialysis during pregnancy conception
    should be discouraged.

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Remote Prognosis
  • Preeclampsia-Eclampsia
  • The more certain the diagnosis of preeclampsia,
    the lower the prevalence of remote cardiovascular
    disorders.
  • Preeclampsia-eclampsia in subsequent pregnancies
    helps define future risk.
  • Gestational hypertension in any pregnancy
    increases remote cardiovascular risk.

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In summary, the implications of the observed
impact of the treatment-induced fall in blood
pressure on fetal growth must be considered
seriously. Women are unlikely to suffer either
acute or chronic deleterious effects, over the 9
months of pregnancy, from blood pressures that
are below 170/110 mmHg. At present, we cannot
be sure of the impact that anti-hypertensive
treatment for mild-to-moderate pregnancy
hypertension may have on perinatal outcomes.
New data from clinical trials are needed.
Von Dadelszen P et al Fall in mean arterial
pressure and fetal growth restriction in
pregnancy hypertension A meta-analysis Lancet
2000355 (Jan 8)87-92.
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Management of pre-eclampsia
Sibai et al. Lancet 365785-99, 2005.
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Alphamethyldopa in Pregnancy
  • Rarely used in non-pregnant women
  • Suggested as drug of choice in pregnancy
  • Limited pharmacokinetic data in pregnancy
  • No adverse fetal-neonatal effects
  • Birth weight
  • Doppler flow studies
  • Infant follow-up to 7.5 years
  • Adverse maternal effects
  • Severe hepatitis
  • Death
  • Liver transplant

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Indications of Antihypertensive Drugs in
Pregnancy
  • Severe hypertension in labor and postpartum
  • Expectant management of severe gestational
    hypertension or preeclampsia lt 34 weeks
  • Mild chronic hypertension in pregnancy
  • Mild gestational hypertension or preeclampsia
    lt 37 weeks

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Drugs Used for Acute Severe Hypertension in
Pregnancy-Postpartum
  • IV Hydralazine
  • IV Labetalol
  • Bolus doses
  • Continuous infusion
  • Oral nifedipine
  • IV Ketanserin

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Atenolol in Pregnancy
  • Limited pharmacokinetic/dynamic data
  • Used to treat all forms of hypertension
  • Adverse fetal-neonatal effects when used lt 20
    weeks
  • Abnormal Doppler umbilical flow
  • Reduced placental weight
  • Severe reduction in fetal weight
  • Increased stillbirths
  • Infant follow-up until age 1 year
  • Only when used in 3rd trimester

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Labetalol in Pregnancy
  • Usually used to treat third trimester
    hypertension
  • Pharmacokinetics described in few reports
  • No adverse fetal-neonatal effects
  • Umbilical Doppler studies
  • Neonatal outcome
  • No infant follow-up data

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Are Particular Antihypertensives More Effective
or Harmful Than Others in Hypertension in
Pregnancy?
  • Existing data is inadequate
  • Methyldopa and thiazide diuretics appear to be
    safe?
  • Avoid ACE inhibitors and receptor blockers
  • ? Safety of atenolol in chronic hypertension

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Limitations of Surveillance Programs and Case
Reports
  • Inability to calculate rates of adverse events
  • Total of women exposed is unknown
  • No control group
  • Dependent on clinical providers
  • underreporting ( 1 in 100 to 4600)
  • Lack of previous exposure data
  • Effects of disease and multiple drugs
  • Lack of rechallenge testing

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Is Pharmacological Treatment of Hypertension in
Pregnancy Harmful to Mother, Fetus, or Infant?
  • Potential adverse effects are either poorly
    established or unclearly quantified
  • Selection bias in reporting
  • Mostly case reports
  • Pre-marketing clinical studies excluded women
    of childbearing age
  • Little data from post-marketing surveillance
    programs

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What Are the Benefits of Treating Mild
Hypertension in Pregnancy?
  • Data are insufficient to either prove or
    disprove effects in perinatal outcome
  • All trials had inadequate sample size
  • Most were unblinded
  • Few women enrolled in first trimester
  • 15 different drugs or combinations were
    studied
  • Definite need for multicenter trials

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What is the Proper Management of Young Women with
Hypertension?
  • No report that addressed the effect of blood
    pressure control before conception on fetal
    outcomes
  • Women of reproductive age are excluded from
    randomized trials
  • Only 3 trials in women aged 30-54 years
  • 8,565 studied
  • Little data in women lt 40 years

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Small-for-Gestational Age Results of Trials Given
as Risk Differences Between Antihypertensive
Treatment Groups Versus Control Groups
Arias 1979 Welt 1981 hydralazine Welt
1981 methyldopa Sibai 1984 Hogstedt
1985 Butters 1990 Sibai 1990
labetalol Sibai 1990 methyldopa Steyn
1997
-.25 0 .25 .5 . 75
Favors Antihypertensive Favors Control
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Preeclampsia Results of Trials Given as Risk
Differences Between Antihypertensive Treatment
Groups Versus Control Groups
Sibai 1984 diuretics Weitz 1987
methyldopa Sibai 1990 labetalol Sibai
1990 methyldopa Steyn 1997 ketanserian
-.5 -.25 0 .25 .5
Favors Antihypertensive Favors Control
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Perinatal Death Results of Trials Given as Risk
Differences Between Antihypertensive Treatment
Groups and Control Groups
Leather 1968 Redman 1976 Arias
1979 Welt 1981 hydralazine Welt 1981
methyldopa Sibai 1984 ketanserian
Weitz 1987 Butters 1990 Sibai 1990
labetalol Sibai 1990 methyldopa Steyn
1997
-.25 0 .25
Favors Antihypertensive Favors Control
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Antihypertensive Treatment Versus No Treatment
for Mild Chronic Hypertension in Pregnancy
Maternal
Severe hypertension 0.27 (0.14 -
0.53) 3 Additional antihypertensives 0.36 (0.23
- 0.57) 5 Admission before delivery 0.23 (0.07
- 0.70) 1 Proteinuria 0.70 (0.4 -
1.08) 6 Caesarean section 1.22 (0.8 - 1.82)
4 Abruption 0.42 (0.15 - 1.22) 3 Changed
drugs due to side effects 2.79
(0.39-20.04) 2 Perinatal Perinatal mortality
0.40 (0.12 1.32) 7 Prematurity 0.27 (0.14 -
0.53) 3 Small for gestational age infants 0.27
(0.14 - 0.53) 6 Neonatal hypoglycemia 0.27
(0.14 - 0.53) 2 Low Apgar score (5 minutes lt7)
0.27 (0.14 - 0.53) 3
0.1 0.2 1 5 10
Favors Treatment Favors Control
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Antihypertension Treatment Versus No Treatment in
Late Pregnancy
Peto odds ratio (95 CI)
Maternal Severe hypertension 0.36 (0.36
0.49) 6 Additional antihypertensives 0.39
(0.26 0.59) 13 Admission before delivery 0.45
(0.30 0.67) 4 Proteinuria at delivery 0.67
(0.51 0.89) 12 Caesarean section 0.95
(0.87 1.20) 4 Abruption 2.50 (0.76 -
8..21) 7 Changed drugs due to side effects
2.59 (0.93 7.20) 8 Maternal mortality 7.20
(0.14 363.1) 3 Perinatal Perinatal
mortality 0.68 (0.36 1.25) 15
Prematurity 0.97 (0.72 0 - 1.31) 7 Small for
gestational age infants 1.35 (0.96 1.88 9
Admission to special care baby unit 1.04 (0.77
1.40) 7 Neonatal jaundice 0.53 (0.33
1.28) 3 Neonatal hypoglycemia 0.76 (0.47
2.57 3 Neonatal bradycardia 2.14 (1.09
4.20) 3 Low Apgar score (5 minutes lt7) 0.56
(0.17 1.87) 3 Respiratory distress syndrome
0.27 (0.13 0.54) 5
0.1 0.2 1
5 10
Favors Treatment Favors Control
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Antihypertension Treatment Versus No Treatment in
Late Pregnancy
Peto odds ratio of Outcome
( 95 CI) Trials Maternal Severe
hypertension 0.36 (0.36 0.49) 6 Additional
antihypertensives 0.39 (0.26 0.59) 13
Admission before delivery 0.45 (0.30 0.67) 4
Proteinuria at delivery 0.67 (0.51 0.89) 12
Caesarean section 0.95 (0.87 1.20) 4
Abruption 2.50 (0.76 - 8..21) 7 Changed
drugs due to side effects 2.59 (0.93
7.20) 8 Maternal mortality 7.20 (0.14
363.1) 3 Perinatal Perinatal mortality 0.68
(0.36 1.25) 15 Prematurity 0.97 (0.72 0 -
1.31) 7 Small for gestational age infants 1.35
(0.96 1.88) 9 Admission to special care baby
unit 1.04 (0.77 1.40) 7 Neonatal jaundice
0.53 (0.33 1.28) 3 Neonatal hypoglycemia 0.76
(0.47 2.57) 3 Neonatal bradycardia 2.14
(1.09 4.20) 3 Low Apgar score (5 minutes
lt7) 0.56 (0.17 1.87) 3 Respiratory distress
syndrome 0.27 (0.13 0.54) 5
Peto odds ratio (95 CI)
0.1 0.2 1 5
10
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Summary Odds Ratios (95 Confidence Intervals)
For More Versus Less Activity in Women with
Mild Pregnancy-Induced Hypertension in Six Trials
Peto odds ratio of Outcome
( 95 CI) Trials Maternal Severe
hypertension 1.08 (0.71 - 1.66) 3 Additional
antihypertensives 0.80 (0.05 -
13.28) 1 Admission before delivery 0.08 (0.06
- 0.13) 4 Proteinuria 1.19 (0.76 -
1.87) 4 Preeclampsia 0.15 (0.00 - 7.57)
4 Caesarean section 0.70 (0.39 -
1.27) 3 Abruption 0.71 (0.12 -
4.23) 2 Perinatal Perinatal mortality 0.77
(0.37 - 1.61) 6 Prematurity 1.09 (0.66 -
1.79) 3 Small for gestational age infants 0.87
(0.53 - 1.41) 3 Admission to special care baby
unit 1.49 (0.84 - 2.65) 4 Low Apgar score (5
minutes lt7) 0.56 (0.06 - 5.54) 2
Peto odds ratio (95 CI)
0.01 0.1 1
10 100
Ambulation with/without admission to hospital
Favors Treatment Favors Control
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Antihypertension Treatment Versus Other
Antihypertensives in Late Pregnancy
Peto odds ratio (95 CI)
Maternal Severe hypertension 1.22 (0.70
2.10) 7 Additional antihypertensives 1.18 (0.87
1.59) 14 Admission before delivery 0.93 (0.56
1.54) 2 Proteinuria 0.87 (0.61
1.23) 15 Preeclampsia 0.95 (0.73 1.24)
16 Caesarean section 0.93 (0.06
15.02) 1 Abruption 2.66 (0.65
10.86) 10 Perinatal Perinatal mortality 0.59
(0.28 1.23) 22 Prematurity 1.07 (0.37
2.85) 7 Small for gestational age infants 0.89
(0.58 1.38) 8 Admission to special care baby
unit 0.87 (0.59 1.29) 6 Neonatal jaundice
1.55 (0.49 4.85) 2 Neonatal hypoglycemia 0.97
(0.42 2.22) 5 Neonatal bradycardia 0.49 (0.11
2.25) 1 Low Apgar score (5 minutes lt7) 1.07
(0.53 2.16) 7 Respiratory distress syndrome
0.60 (0.14 2.51) 2
0.1 0.2 1 5
10
Favors Treatment Favors Control
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MANAGEMENT OF HYPERTENSION IN WOMEN AND PREGNANCY

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Title: MANAGEMENT OF HYPERTENSION IN WOMEN AND PREGNANCY


1
MANAGEMENT OF HYPERTENSION IN WOMEN AND PREGNANCY
  • Suzanne Oparil, M.D.
  • Professor of Medicine, and Physiology
    Biophysics
  • Director, Vascular Biology and Hypertension
    Program
  • Division of Cardiovascular Disease
  • Department of Medicine
  • University of Alabama at Birmingham
  • Birmingham, AL
  • Atlanta, GA
  • March 30, 2005

2
Systolic Blood Pressure levels for the 90th and
95th percentiles of blood pressure for boys and
girls age 1 to 17 years at 95th percentile of
height
http//hin.nhlbi.nih.gov/nhbpep_slds/ped/pedp1_1.h
tm
3
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4
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5
TREATMENT
6
THE WOMENS HEALTH INITIATIVE- PREVALENCE AND
TREATMENT STATUS BY RACE/ ETHNICITY
WHITE
76
80
BLACK
63
63
HISPANIC
59
60
60
OTHER
44
41
36
36
40
PERCENT OF COHORT
33
32
30
20
0
HYPERTENSIVE
TREATED
CONTROLLED
Wassertheil-Smoller et al. Hypertension
200036780-789
7
THE WOMENS HEALTH INITIATIVE- PREVALENCE AND
TREATMENT STATUS BY AGE
80
AGE 50-59
70
65
AGE 60-69
64
63
AGE 70-79
60
53
50
41
41
PERCENT OF COHORT
37
40
29
27
30
20
10
0
HYPERTENSIVE
TREATED
CONTROLLED
Wassertheil-Smoller et al. Hypertension
200036780-789
8
THE WOMENS HEALTH INITIATIVE-ANSWERS TO
QUESTIONS ABOUT BP
  • Hypertension is most prevalent in the oldest
    women and in blacks.
  • Hypertension is undertreated in postmenopausal
    women 65 treatment rates- despite documented
    physicians visits.
  • BP control is inadequate in postmenopausal women-
    worst (29) in the oldest women- independent of
    drug class.

Wassertheil-Smoller et al. Hypertension
200036780-789
9
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10
Major Outcomes in High Risk Hypertensive Patients
Randomized to Angiotensin-Converting Enzyme
Inhibitor or Calcium Channel Blocker vs Diuretic
  • The Antihypertensive and Lipid-Lowering Treatment
    to Prevent Heart Attack Trial (ALLHAT)

The ALLHAT Collaborative Research Group Sponsored
by the National Heart, Lung, and Blood Institute
(NHLBI)
JAMA. 20022882981-2997
11
AntihypertensiveTrial Design
  • Randomized, double-blind, multi-center clinical
    trial
  • Determine whether occurrence of fatal CHD or
    nonfatal MI is lower for high-risk hypertensive
    patients treated with newer agents (CCB, ACEI,
    alpha-blocker) compared with a diuretic
  • 42,418 high-risk hypertensive patients 55 years

12
Nonfatal MI CHD Death Subgroup Comparisons
RR (95 CI)
13
  • The Losartan Intervention For Endpoint
    Reductionin Hypertension Study

An investigator initiated community-based study
in945 sites in 7 countries enrolling 9193
patients Steering Committee Chair/Vice-Chair B.
Dahlöf, D. Devereux European/US
Coordinators S.E. Kjeldsen, S. Julius Data and
Safety Monitoring Committee Chair J.
Kjekshus Clinical Endpoint Classification
Committee D. Levy, K. Thygesen
14
Demographic Subgroup ResultsPrimary Endpoint
15
TREATMENT EFFECT BY GENDER
Gueyffier et al. Ann Intern Med 1997126761-67
16
Antihypertensive TrialImplications
  • Diuretics should be the drug of choice for first
    step therapy of hypertension
  • For the patient who cannot take a diuretic (which
    should be an unusual circumstance), CCBs and
    ACEIs may be considered.
  • Most hypertensive patients require more than one
    drug. Diuretics should generally be part of the
    antihypertensive regimen. Lifestyle advice
    should also be provided.

17
Algorithm for Treatment of Hypertension
Lifestyle Modifications
Not at Goal Blood Pressure (lt140/90 mmHg)
(lt130/80 mmHg for those with diabetes or chronic
kidney disease)
Initial Drug Choices
18
SELECTIVE ANTIHYPERTENSIVE THERAPY FOR WOMEN
  • No evidence to suggest that women respond
    differently to antihypertensive therapy than men
  • Diuretics may be particularly useful
  • Adverse effects are more troublesome
  • ACE inhibitor cough 3 times more common
  • Dihydropyridine CCB edema more common
  • Hirsutism with minoxidil intolerable
  • Treatment outcomes are probably similar

19
HYPERTENSION IN PREGNANCY
20
Classification
  • Preeclampsia-eclampsia
  • Chronic hypertension
  • Preeclampsia superimposed upon chronic
    hypertension
  • Gestational hypertension (only during pregnancy)
  • Transient hypertension (only after pregnancy)

21
CLASSIFICATION OF HYPERTENSION IN PREGNANCY
Chronic hypertension
BP
CHRONIC HYPERTENSION BP140 mmHg systolic or 90 mmHg diastolic prior to pregnancy or before 20 weeks gestation Persists gt12 weeks postpartum
PREECLAMPSIA BP 140 mm Hg systolic or 90 mm Hg diastolic with proteinuria (gt300 mg/24 hr) after 20 weeks gestation Can progress to eclampsia (seizures) More common in nulliparous women, multiple gestation, women with hypertension for 4 years, family history of preeclampsia, hypertension in previous pregnancy, renal disease
CHRONIC HYPERTENSION WITH SUPERIMPOSED PREECLAMPSIA New onset after 20 weeks in a woman with hypertension In a woman with hypertension and proteinuria prior to 20 weeks gestation Sudden 2- to 3-fold increase in proteinuria Sudden increase in BP Thrombocytopenia Elevated AST or ALT
22
CLASSIFICATION OF HYPERTENSION IN PREGNANCY
Chronic hypertension
BP
GESTATIONAL HYPERTENSION Hypertension without proteinuria occurring after 20 weeks gestation Temporary diagnosis (only during pregnancy) May represent pre-proteinuric phase of preeclampsia or recurrence of chronic hypertension abated in midpregnancy May evolve to preeclampsia If severe, may result in higher rates of premature delivery and growth retardation than mild preeclampsia
TRANSIENT HYPERTENSION Retrospective diagnosis (only after pregnancy) BP normal by 12 weeks postpartum May recur in subsequent pregnancies Predictive of future essential hypertension
23
Clinical Implications of Preeclampsia
  • Preeclampsia ranges from mild to severe.
  • Progression may be slow or rapid hours to days
    to weeks.
  • For clinical management, preeclampsia should be
    overdiagnosed to prevent maternal and perinatal
    morbidity and mortality primarily through
    timing of delivery.

24
Classification of Preeclampsia-Eclampsia (cont.)
  • The following are more ominous signs and increase
    certainty of diagnosis
  • SBP gt 160 mm Hg or DBP gt 110 mm Hg
  • Proteinuria gt 2.0 g in 24 hours (2 or 3
    dipstick)
  • Increased serum creatinine
  • Platelet count lt 100,000 cells/mm3 and/or
    evidence of microangiopathic hemolytic anemia
    with increased LDH
  • Elevated ALT or AST
  • Persistent headache or other cerebral or visual
    disturbances
  • Persistent epigastric pain

25
MATERNAL RISK FACTORS FOR PREECLAMPSIA
Primigravida Positive family history (maternal or
paternal) Multiple gestations Diabetes
mellitus Insulin resistance/obesity Chronic
hypertension Preexisting renal disease Extremes
of reproductive age Hydatidiform disease History
of severe early preeclampsia in a prior
pregnancy Collagen vascular disease Black
race Increased circulating testosterone Thrombophi
lias
26
Hypothetical cause and pathogenesis of
pre-eclampsia. TGFtransforming growth factor.
IFNinterferon. VEGFvascular endothelial growth
factor. PIGFplacental growth factor.
ANGIOangiopoietin 2.
Sibai et al. Lancet 365785-99, 2005.
27
Levels of evidence (IIV) as outlined by the US
Preventive Task Force
Sibai et al. Lancet 365785-99, 2005.
28
Preeclampsia
  • Maternal Evaluation
  • Early recognition of preeclampsia
  • Observe progression, both to prevent maternal
    complications and protect well-being of fetus.
    Early signs
  • BP rises in late second and early third
    trimesters.
  • Initial appearance of proteinuria is important.

29
Preeclampsia (cont.)
  • Maternal Evaluation (cont.)
  • Often, hospitalization recommended with new-onset
    preeclampsia to assess maternal and fetal
    conditions.
  • Hospitalization for duration of pregnancy
    indicated for preterm onset of severe
    gestational hypertension or preeclampsia.
  • Ambulatory management at home or at day-care unit
    may be considered with mild gestational
    hypertension or preeclampsia remote from term.

30
Preeclampsia (cont.)
  • Antepartum Management of Preeclampsia
  • Little to suggest therapy alters the underlying
    pathophysiology of preeclampsia.
  • Restricted activity may be reasonable.
  • Sodium restriction and diuretic therapy appear
    to have no positive effect.

31
Preeclampsia (cont.)
  • Indications for Delivery in Preeclampsia -
    Maternal
  • Gestational age 38 weeks
  • Platelet count lt 100,000 cells/mm3
  • Progressive deterioration in liver and renal
    function
  • Suspected abruptio placentae
  • Persistent severe headaches, visual changes,
    nausea, epigastric pain, or vomiting
  • Delivery should be based on maternal and fetal
    conditions as well as gestational age.

32
Preeclampsia (cont.)
  • Indications for Delivery in Preeclampsia - Fetal
  • Severe fetal growth restriction
  • Nonreassuring fetal testing results
  • Oligohydramnios
  • Delivery should be based on maternal and fetal
    conditions
  • as well as gestational age.

33
Preeclampsia (cont.)
  • Route of Delivery
  • Vaginal delivery is preferable.
  • Aggressive labor induction (within 24 hours).
  • Neuraxial (epidural, spinal, and combined
    spinal-epidural) techniques offer advantages.
  • Hydralazine, nitroglycerin, or labetalol may be
    used as pretreatment to reduce significant
    hypertension during delivery.

34
Preeclampsia (cont.)
  • Anticonvulsive Therapy
  • Indicated to prevent recurrent convulsions in
    women with eclampsia or to prevent convulsions in
    women with preeclampsia.
  • Parenteral magnesium sulfate reduces the
    frequency of eclampsia. (Caution in renal
    failure.)

35
Treatment of Acute Severe Hypertension in
Pregnancy
  • SBP gt 160 mm Hg and/or DBP gt 105 mm Hg
  • Parenteral hydralazine is most commonly used.
  • Parenteral labetalol is second-line drug (avoid
    in women with asthma and
    CHF.)
  • Oral nifedipine used with caution.
    (Short-acting nifedipine is not approved by FDA
    for managing hypertension.)
  • Sodium nitroprusside may be used in rare cases.

36
ACUTE TREATMENT OF HYPERTENSION IN PREGNANCY
AGENT DOSAGE
Hydralazine(preferred) 5 mg iv bolus, then 10 mg every 20 to 30 minutes to a maximum of 25 mg, repeat in several hours as necessary
Labetalol(second line) 20 mg iv bolus, then 40 mg 10 minutes later, 80 mg every 10 minutes for 2 additional doses to a maximum of 220 mg
Nifedipine(controversial) 10 mg po, repeat every 20 minutes to a maximum of 30 mgCautious use with magnesium sulfate, can see precipitous blood pressure drop Short acting nifedipine is not approved by FDA for managing hypertension
Sodium nitroprusside (rarely when others fail) 0.5 ug/kg/min to a maximum of 5 ug/kg/min Fetal cyanide poisoning may occur if used for more than 4 hour
37
CLINICAL CHARACTERISTICS AND LABORATORY TESTS
USED TO DISCRIMINATE PREECLAMPSIA FROM CHRONIC
HYPERTENSION
PREECLAMPSIA CHRONIC HYPERTENSION
Age Extremes of age Older (30 years)
Parity Nulliparous Often multiparous
Time of diagnosis of hypertension After 20 weeks Before 20 weeks
Maternal risk factors for preeclampsia Yes No
Hypertension/preeclampsia in prior pregnancies Yes Yes
Proteinuria (gt300 mg/24hrs) Yes No
Serum uric acid Elevated (5.5 mg/dl) Normal to low
Elevated liver enzymes Yes No
Thrombocytopenia Yes No
Headache, blurred vision, epigastric abdominal pain Yes No
Persistent hypertension gt12 weeks postpartum No Yes
38
MANAGEMENT OF CHRONIC HYPERTENSION IN PREGNANCY
Chronic hypertension
BP
BEFORE CONCEPTION
Evaluation for secondary hypertension Pheochromocytoma Other causes if severe
Evaluation for target organ damage Cardiac function, LVH (echocardiography) Renal disease (serum creatinine, proteinuria)
Change to medications safe for pregnancy Taper early Titrate later
Lifestyle planning Restrict aerobic exercise Avoid weight reduction Moderate sodium intake Avoid all alcohol and tobacco
Baseline laboratory testing Hematocrit, hemoglobin, platelet count, serum creatinine, uric acid, urinalysis
39
Chronic Hypertension in Pregnancy
  • Prepregnancy counseling
  • Evaluate using JNC7 criteria
  • Discontinue use of ACE inhibitors and ARBs
  • Evaluate for target organ damage in women with
    longstanding hypertension
  • Discontinue use of tobacco and/or alcohol, even
    if not hypertensive
  • Discuss lifestyle changes, if applicable

40
MANAGEMENT OF CHRONIC HYPERTENSION IN PREGNANCY
Chronic hypertension
BP
DURING PREGNANCY
Selection of medications safe for pregnancy
Thresholds for treatment 150-160 mmHg systolic 100-110 mmHg diastolic
Laboratory Monitoring Hematocrit, hemoglobin, platelet count, serum creatinine, uric acid, AST, ALT, quantification of urine protein, serum albumin, LDH, peripheral blood smear, coagulation studies
41
Treatment of Chronic Hypertension in Pregnancy
  • Most women with stage 1 to 2 chronic hypertension
    are candidates for nondrug therapy, absent
    evidence of target organ damage.
  • Most of the increased risk associated with
    chronic hypertension occurs with superimposed
    preeclampsia.
  • End points for reinstituting treatment include
    SBP gt 150-160 or DBP gt 100-110 or evidence of
    target organ damage.

42
Antihypertensive Drug Selection
  • ACEI and ARB are contraindicated in pregnancy.
  • Methyldopa preferred first-line therapy
    labetalol if methyldopa not tolerated.
  • Alternatives to methyldopa can be substituted
    based on rational mechanisms of action.
  • Long-term studies of most other agents are
    lacking in pregnant women.
  • Diuretics not used as first-line agents but are
    not contraindicated except in cases of reduced
    uteroplacental perfusion.

43
ORAL TREATMENT OF HYPERTENSION IN PREGNANCY
AGENT COMMENTS
Methyldopa Preferred based on long term studies of child development and uteroplacental blood flow
Beta Blockers Reports of intrauterine growth retardation, particularly for atenolol exposure at conception or in the first trimester generally safe
Labetalol Increasingly preferred for efficacy and few side effects
Clonidine Limited data
Calcium Channel Blockers Limited data Most experience with nifedipine and isradipine No increase in major teratogenicity with exposure
Diuretics Not first line agents, probably safe
Angiotensin Converting Enzyme Inhibitors Contraindicated, reports of fetal toxicity and death
Angiotensin Receptor Blockers Contraindicated, reports of fetal toxicity and death
44
Fetal Assessment in Chronic Hypertension
  • Efforts directed at early detection of
    superimposed preeclampsia and possible fetal
    growth restriction.
  • Initial sonogram at 18 to 20 weeks gestation.
  • Fetal growth carefully assessed thereafter.
  • If growth restriction, assess by nonstress tests
    or biophysical profiles.

45
MANAGEMENT OF CHRONIC HYPERTENSION IN PREGNANCY
Chronic hypertension
BP
DELIVERY
Maternal indications Gestational age 38 weeks Platelet count lt100,000 cells/mm3 Deterioration in hepatic or renal function Suspected placental abruption Severe headache or visual changes Sever epigastric pain, nausea or vomiting
Fetal indications Severe fetal growth restriction Concerning fetal testing results Olugohydramnios
Acute/parenteral therapy
46
MANAGEMENT OF CHRONIC HYPERTENSION IN PREGNANCY
Chronic hypertension
BP
POSTPARTUM
Lactation Withhold antihypertensive medication Taper medication dosage Selection of safe medications Close monitoring for adverse effects
LATE ISSUES AFTER HYPERTENSIVE PREGNANCY
Persistent hypertension Evaluation for secondary causes Change medication
Long-term risk Monitor blood pressure for future hypertension Treat cardiovascular risk factors
47
Treating Hypertension During Lactation
  • Breastfeeding encouraged (with limits).
  • Little information on excretion of agents in
    breast milk or long-term effects on exposed
    infants.
  • No short-term adverse effects reported with
    methyldopa or hydralazine.
  • Beta-blockers propanolol labetalol
    recommended.
  • No data on calcium antagonists.
  • Diuretics may reduce milk volume/suppress
    lactation.
  • ACEI and ARB should be avoided.

48
Postpartum Counseling and Followup
  • Counseling for Future Pregnancies
  • Risk of recurrent preeclampsia increases with
  • Preeclampsia before 30 weeks (40)
  • Multiparas as compared with nulliparas or new
    father
  • Risk of recurrent preeclampsia may be
    substantially greater in African Americans.

49
RISK FACTORS FOR RECURRENT HYPERTENSION IN
PREGNANCY
Early onset of hypertension in a prior
pregnancy Chronic hypertension Persistent
hypertension beyond 5 weeks postpartum High
baseline blood pressure early in pregnancy
50
Pregnancy, Hypertension, and Renal Disease
  • Renal insufficiency may progress and jeopardize
    fetal survival.
  • As renal failure progresses, consider sodium
    restriction, use of loop diuretics, or dialysis.
  • Magnesium sulfate is hazardous in women with
    severe renal failure doses should be reduced and
    guided by plasma magnesium determinations.
    Phenytoin may be an alternative.
  • Significant maternal morbidity associated with
    chronic dialysis during pregnancy conception
    should be discouraged.

51
Remote Prognosis
  • Preeclampsia-Eclampsia
  • The more certain the diagnosis of preeclampsia,
    the lower the prevalence of remote cardiovascular
    disorders.
  • Preeclampsia-eclampsia in subsequent pregnancies
    helps define future risk.
  • Gestational hypertension in any pregnancy
    increases remote cardiovascular risk.

52
In summary, the implications of the observed
impact of the treatment-induced fall in blood
pressure on fetal growth must be considered
seriously. Women are unlikely to suffer either
acute or chronic deleterious effects, over the 9
months of pregnancy, from blood pressures that
are below 170/110 mmHg. At present, we cannot
be sure of the impact that anti-hypertensive
treatment for mild-to-moderate pregnancy
hypertension may have on perinatal outcomes.
New data from clinical trials are needed.
Von Dadelszen P et al Fall in mean arterial
pressure and fetal growth restriction in
pregnancy hypertension A meta-analysis Lancet
2000355 (Jan 8)87-92.
53
Management of pre-eclampsia
Sibai et al. Lancet 365785-99, 2005.
54
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55
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56
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57
Alphamethyldopa in Pregnancy
  • Rarely used in non-pregnant women
  • Suggested as drug of choice in pregnancy
  • Limited pharmacokinetic data in pregnancy
  • No adverse fetal-neonatal effects
  • Birth weight
  • Doppler flow studies
  • Infant follow-up to 7.5 years
  • Adverse maternal effects
  • Severe hepatitis
  • Death
  • Liver transplant

58
Indications of Antihypertensive Drugs in
Pregnancy
  • Severe hypertension in labor and postpartum
  • Expectant management of severe gestational
    hypertension or preeclampsia lt 34 weeks
  • Mild chronic hypertension in pregnancy
  • Mild gestational hypertension or preeclampsia
    lt 37 weeks

59
Drugs Used for Acute Severe Hypertension in
Pregnancy-Postpartum
  • IV Hydralazine
  • IV Labetalol
  • Bolus doses
  • Continuous infusion
  • Oral nifedipine
  • IV Ketanserin

60
Atenolol in Pregnancy
  • Limited pharmacokinetic/dynamic data
  • Used to treat all forms of hypertension
  • Adverse fetal-neonatal effects when used lt 20
    weeks
  • Abnormal Doppler umbilical flow
  • Reduced placental weight
  • Severe reduction in fetal weight
  • Increased stillbirths
  • Infant follow-up until age 1 year
  • Only when used in 3rd trimester

61
Labetalol in Pregnancy
  • Usually used to treat third trimester
    hypertension
  • Pharmacokinetics described in few reports
  • No adverse fetal-neonatal effects
  • Umbilical Doppler studies
  • Neonatal outcome
  • No infant follow-up data

62
Are Particular Antihypertensives More Effective
or Harmful Than Others in Hypertension in
Pregnancy?
  • Existing data is inadequate
  • Methyldopa and thiazide diuretics appear to be
    safe?
  • Avoid ACE inhibitors and receptor blockers
  • ? Safety of atenolol in chronic hypertension

63
Limitations of Surveillance Programs and Case
Reports
  • Inability to calculate rates of adverse events
  • Total of women exposed is unknown
  • No control group
  • Dependent on clinical providers
  • underreporting ( 1 in 100 to 4600)
  • Lack of previous exposure data
  • Effects of disease and multiple drugs
  • Lack of rechallenge testing

64
Is Pharmacological Treatment of Hypertension in
Pregnancy Harmful to Mother, Fetus, or Infant?
  • Potential adverse effects are either poorly
    established or unclearly quantified
  • Selection bias in reporting
  • Mostly case reports
  • Pre-marketing clinical studies excluded women
    of childbearing age
  • Little data from post-marketing surveillance
    programs

65
What Are the Benefits of Treating Mild
Hypertension in Pregnancy?
  • Data are insufficient to either prove or
    disprove effects in perinatal outcome
  • All trials had inadequate sample size
  • Most were unblinded
  • Few women enrolled in first trimester
  • 15 different drugs or combinations were
    studied
  • Definite need for multicenter trials

66
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67
What is the Proper Management of Young Women with
Hypertension?
  • No report that addressed the effect of blood
    pressure control before conception on fetal
    outcomes
  • Women of reproductive age are excluded from
    randomized trials
  • Only 3 trials in women aged 30-54 years
  • 8,565 studied
  • Little data in women lt 40 years

68
Small-for-Gestational Age Results of Trials Given
as Risk Differences Between Antihypertensive
Treatment Groups Versus Control Groups
Arias 1979 Welt 1981 hydralazine Welt
1981 methyldopa Sibai 1984 Hogstedt
1985 Butters 1990 Sibai 1990
labetalol Sibai 1990 methyldopa Steyn
1997
-.25 0 .25 .5 . 75
Favors Antihypertensive Favors Control
69
Preeclampsia Results of Trials Given as Risk
Differences Between Antihypertensive Treatment
Groups Versus Control Groups
Sibai 1984 diuretics Weitz 1987
methyldopa Sibai 1990 labetalol Sibai
1990 methyldopa Steyn 1997 ketanserian
-.5 -.25 0 .25 .5
Favors Antihypertensive Favors Control
70
Perinatal Death Results of Trials Given as Risk
Differences Between Antihypertensive Treatment
Groups and Control Groups
Leather 1968 Redman 1976 Arias
1979 Welt 1981 hydralazine Welt 1981
methyldopa Sibai 1984 ketanserian
Weitz 1987 Butters 1990 Sibai 1990
labetalol Sibai 1990 methyldopa Steyn
1997
-.25 0 .25
Favors Antihypertensive Favors Control
71
Antihypertensive Treatment Versus No Treatment
for Mild Chronic Hypertension in Pregnancy
Maternal
Severe hypertension 0.27 (0.14 -
0.53) 3 Additional antihypertensives 0.36 (0.23
- 0.57) 5 Admission before delivery 0.23 (0.07
- 0.70) 1 Proteinuria 0.70 (0.4 -
1.08) 6 Caesarean section 1.22 (0.8 - 1.82)
4 Abruption 0.42 (0.15 - 1.22) 3 Changed
drugs due to side effects 2.79
(0.39-20.04) 2 Perinatal Perinatal mortality
0.40 (0.12 1.32) 7 Prematurity 0.27 (0.14 -
0.53) 3 Small for gestational age infants 0.27
(0.14 - 0.53) 6 Neonatal hypoglycemia 0.27
(0.14 - 0.53) 2 Low Apgar score (5 minutes lt7)
0.27 (0.14 - 0.53) 3
0.1 0.2 1 5 10
Favors Treatment Favors Control
72
Antihypertension Treatment Versus No Treatment in
Late Pregnancy
Peto odds ratio (95 CI)
Maternal Severe hypertension 0.36 (0.36
0.49) 6 Additional antihypertensives 0.39
(0.26 0.59) 13 Admission before delivery 0.45
(0.30 0.67) 4 Proteinuria at delivery 0.67
(0.51 0.89) 12 Caesarean section 0.95
(0.87 1.20) 4 Abruption 2.50 (0.76 -
8..21) 7 Changed drugs due to side effects
2.59 (0.93 7.20) 8 Maternal mortality 7.20
(0.14 363.1) 3 Perinatal Perinatal
mortality 0.68 (0.36 1.25) 15
Prematurity 0.97 (0.72 0 - 1.31) 7 Small for
gestational age infants 1.35 (0.96 1.88 9
Admission to special care baby unit 1.04 (0.77
1.40) 7 Neonatal jaundice 0.53 (0.33
1.28) 3 Neonatal hypoglycemia 0.76 (0.47
2.57 3 Neonatal bradycardia 2.14 (1.09
4.20) 3 Low Apgar score (5 minutes lt7) 0.56
(0.17 1.87) 3 Respiratory distress syndrome
0.27 (0.13 0.54) 5
0.1 0.2 1
5 10
Favors Treatment Favors Control
73
Antihypertension Treatment Versus No Treatment in
Late Pregnancy
Peto odds ratio of Outcome
( 95 CI) Trials Maternal Severe
hypertension 0.36 (0.36 0.49) 6 Additional
antihypertensives 0.39 (0.26 0.59) 13
Admission before delivery 0.45 (0.30 0.67) 4
Proteinuria at delivery 0.67 (0.51 0.89) 12
Caesarean section 0.95 (0.87 1.20) 4
Abruption 2.50 (0.76 - 8..21) 7 Changed
drugs due to side effects 2.59 (0.93
7.20) 8 Maternal mortality 7.20 (0.14
363.1) 3 Perinatal Perinatal mortality 0.68
(0.36 1.25) 15 Prematurity 0.97 (0.72 0 -
1.31) 7 Small for gestational age infants 1.35
(0.96 1.88) 9 Admission to special care baby
unit 1.04 (0.77 1.40) 7 Neonatal jaundice
0.53 (0.33 1.28) 3 Neonatal hypoglycemia 0.76
(0.47 2.57) 3 Neonatal bradycardia 2.14
(1.09 4.20) 3 Low Apgar score (5 minutes
lt7) 0.56 (0.17 1.87) 3 Respiratory distress
syndrome 0.27 (0.13 0.54) 5
Peto odds ratio (95 CI)
0.1 0.2 1 5
10
74
Summary Odds Ratios (95 Confidence Intervals)
For More Versus Less Activity in Women with
Mild Pregnancy-Induced Hypertension in Six Trials
Peto odds ratio of Outcome
( 95 CI) Trials Maternal Severe
hypertension 1.08 (0.71 - 1.66) 3 Additional
antihypertensives 0.80 (0.05 -
13.28) 1 Admission before delivery 0.08 (0.06
- 0.13) 4 Proteinuria 1.19 (0.76 -
1.87) 4 Preeclampsia 0.15 (0.00 - 7.57)
4 Caesarean section 0.70 (0.39 -
1.27) 3 Abruption 0.71 (0.12 -
4.23) 2 Perinatal Perinatal mortality 0.77
(0.37 - 1.61) 6 Prematurity 1.09 (0.66 -
1.79) 3 Small for gestational age infants 0.87
(0.53 - 1.41) 3 Admission to special care baby
unit 1.49 (0.84 - 2.65) 4 Low Apgar score (5
minutes lt7) 0.56 (0.06 - 5.54) 2
Peto odds ratio (95 CI)
0.01 0.1 1
10 100
Ambulation with/without admission to hospital
Favors Treatment Favors Control
75
Antihypertension Treatment Versus Other
Antihypertensives in Late Pregnancy
Peto odds ratio (95 CI)
Maternal Severe hypertension 1.22 (0.70
2.10) 7 Additional antihypertensives 1.18 (0.87
1.59) 14 Admission before delivery 0.93 (0.56
1.54) 2 Proteinuria 0.87 (0.61
1.23) 15 Preeclampsia 0.95 (0.73 1.24)
16 Caesarean section 0.93 (0.06
15.02) 1 Abruption 2.66 (0.65
10.86) 10 Perinatal Perinatal mortality 0.59
(0.28 1.23) 22 Prematurity 1.07 (0.37
2.85) 7 Small for gestational age infants 0.89
(0.58 1.38) 8 Admission to special care baby
unit 0.87 (0.59 1.29) 6 Neonatal jaundice
1.55 (0.49 4.85) 2 Neonatal hypoglycemia 0.97
(0.42 2.22) 5 Neonatal bradycardia 0.49 (0.11
2.25) 1 Low Apgar score (5 minutes lt7) 1.07
(0.53 2.16) 7 Respiratory distress syndrome
0.60 (0.14 2.51) 2
0.1 0.2 1 5
10
Favors Treatment Favors Control
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