Transcript Preeclampsia: Etiologies and Management(slide show)

Preeclampsia: Etiologies and Management
Dr. Mahmoud A. Ismail
Professor and Chief of Maternal Fetal
Medicine
Classification of the Hypertensive
Disorders Complicating Pregnancy
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Chronic Hypertension (Primary and Secondary)
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Preeclampsia/eclampsia
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Superimposed preeclampsia
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Gestational hypertension (re-designated “transient” when
pressure normalizes postpartum).
Causes of hypertension in pregnancy
superimposed
pre-eclampsia
preeclampsia
secondary
hypertension
essential
hypertension
gestational hypertension
(Brown, Buddle 1997)
Cardiovascular Adaptation in Normal
Pregnancy
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Early systemic vasodilation with increased CO
Modest decrements in BP despite large increases in ECV
Early and marked increase in arterial compliance
Marked stimulation of the renin-aldosterone systems
Refractoriness to infused vasopressors (eg, AII)
Early renal vasodilation and hyperfiltration
– no increase in PGC
– renal vasodilation appears mediated by relaxin, via the
endothelin B receptor-NO by increasing vascular MMP-9
& 2 activity (rat MMP-2 mRNA increased)
Significant Na (volume) retention; sensed as normal
BP may rise towards nonpregnant level near term
BP throughout
gestation in 6000
normal pregnancies
(white women, 25-34)
Christianson et al 1976
DEFINITIONS
Hypertension: BP > 140 systolic and/or 90 diastolic
(Severe: BP > 170 systolic and/or 110 diastolic)
probably too high
Protienuria:
Preeclampsia:
>300 mg/24h, spot Cr/Protein = 0.3,
Dipstick 1+ (high false + & -)
De Novo hypertension and proteinuria after midpregnancy
 Many
women with mild to moderate
hypertension can discontinue their
medications in early pregnancy due to
physiological gestational vasodilation
 Failure of this physiological decrease
in BP may predict poorer outcome
 Monitor pregnancy closely re: high risk
of superimposed preeclampsia (> 20%)
and likely need for antihypertensives
later in pregnancy
Why should we treat hypertension
during pregnancy?
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Will BP control prevent preeclampsia?
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Will BP control improve neonatal outcome?
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Will BP control decrease maternal morbidity?
Not just dangerous for the fetus
 BP
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of 170 systolic or 110 diastolic can
lead to cerebrovascular catastrophe in
pregnancy
 Uncontrolled hypertension often leads to
hospital admission and early delivery to
preserve maternal safety
*
Retrospective studies suggest increased cerebral accidents when systolic
levels >150 mm Hg
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Prevent: No (definitive trial needed)
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Improve neonatal outcome:
Probably…Maybe (definitive trial
needed
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Decrease maternal morbidity: Yes
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Morbidity in 2 & 3 primarily severe
hypertension
Regardless of
drug class, BP
control does not
prevent
proteinuria or
preeclampsia
Abalos et al, Cochrane 2002
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Pregnancy-specific multi-organ
syndrome
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Hypertension + proteinuria
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Over 60,000 maternal deaths
worldwide per year
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30% of premature deliveries are
consequence of PE
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Two-fold increased risk of CVD
later in life
Preeclampsia: Definition, Diagnosis
and Impact
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De novo hypertension and proteinuria presenting
after mid-pregnancy (exceptions exist)
Accounts for most, but not all, of the morbidity of
hypertension in pregnancy
May be superimposed on chronic hypertension or
renal disease, (such scenarios often severe)
Unique to human gestation, resolves with delivery
A systemic disease with multiorgan involvement
May progress to convulsive phase: eclampsia
A leading cause of maternal mortality
A leading cause of of preterm births (~15%)
Why are preeclamptic women
hypertensive?
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AII sensitivity increases even before overt preeclampsia,
and despite decreased AII, PRA and aldosterone levels
(Role of Ang I receptor autoantibodies?)
Invasive hemodynamic studies in preeclamptic women
reveal high SVRs and decreased COs
Renal vasoconstriction with greater fall in GFR than in
ERPF, suggesting afferent vasoconstriction
Sympathetic activity is increased, in parallel with BP;
whether causal or compensatory unknown
Endothelial dysfunction related (enormous literature)
Pathogenetic roles for increased AII action and impaired
VEGF signaling perhaps secondary to sFlt-1 & sEndoglin
Goravic et al, AJOG, April, 07: Preeclampsia is
also a podocyte disorder (podocyturia present)
Longitudinal changes in
cardiac output and SVR in
normal pregnancy and in
women with preeclampsia
or gestational hypertension
Bosio et al, 1999
(Vascular compliance decreased in
superimposed preeclampsia independent
of increase in blood pressures)
Hibbard et al 2005
Endoglin - overview
Endoglin or CD105 is a TGF -b1 and b3 co-receptor on endothelial
cells and syncytotrophoblasts of the placenta
• Endoglin mutations underlie Hereditary Hemorrhagic Telangiectasia-1,
characterized by AV malformations and focal loss of capillaries
• Endoglin null mice die at mid-gestation due to defective angiogenesis
and cardiovascular development
• Endoglin may be involved in the regulation of endothelial nitric oxide
synthase (eNOS) activity and the local regulation of vascular tone
An Animal Model for “severe” Preeclampsia
The simultaneous introduction of adenoviruses
encoding both sFlt1 and soluble endoglin produced
severe hypertension, heavy proteinuria, elevated
liver enzymes, and circulating schistocytes, in
essence creating a powerful model that simulates
most of the protean manifestations of preeclampsia
in humans and has obvious implications for the
study of mechanisms or therapy of the disease.
Preeclampsia: Maternal Factors: Diagnosis,
Risk, Recurrence
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Increased in women with hypertension, diabetes
mellitus, renal disease, multiple fetuses, obesity,
previous preeclampsia, insulin resistance,
hyperhomocysteinemia, or Thrombophilias
Difficult to diagnose with underlying
hypertension, renal disease, collagen vascular
disease… err in favor of diagnosis
Considerably less common in parous women
unless they have underlying risk factors
Recurrent preeclampsia predicts later
cardiovascular disease
By contrast, cardiovascular risk is lowest in
women who have been pregnant, but never
preeclamptic
WHO systematic review of screening to predict
preeclampsia
Conde-Agudelo A, et al Obstet and Gynecol 2004;104:1367-1391
87 of 7,191 articles (211,369) women met criteria.
CRITERIA
Population adequately described (by age, parity, risk)
Cut off levels; clear definitions of + or - test
Adequate blinding + results from >90% of participants
RESULTS
No clinically useful screening test to predict PE
Promising and being investigated: Combinations of
tests: e.g., Anti and pro-angiogenic factors (sFlt-1,
sEng, PlGF) (see Obstet Gynecol 109:168.07)
Levine et al N Engl J
Med 9/06
Levine et al N Engl J
Med 9/06
Preterm Preeclampsia
Levine et al N Engl J Med 9/06
Preeclampsia >37 weeks
Preeclampsia prevention/intervention trials
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Aspirin: Initially very effective in small trials, but little
effect in large subsequent trials. Meta analyses galore !
Latest (Paris collaboration) suggests small effect.
Calcium supplementation: Minimal (if any) effect on
preeclampsia, but decreases disease severity in
populations with low Ca intake (<600 mg/d).
Blood pressure control, per se: no decrease in
preeclampsia regardless of agent (diuretic, β blocker,
other) more definitive trials needed.
Fish oil, Mg supplementation appear without benefit,
Vitamin C+E: Major trials negative to-date and possibly
harmful.
Remember the Objectives of Treating
Preeclampsia
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Prevent convulsions
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Deliver a surviving child
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Prevent mortality and residual pathology in
mother and child
“Conservative Management”
in Severe Preeclampsia
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While there are studies suggesting prolongation of
pregnancy, fetal outcome is improved minimally, if at all,
while maternal morbidity increases substantially.
Temporize only as long as BP control is acceptable, and
in the absence of ominous symptoms and signs (i.e.,
headache, visual disturbance, epigastric pain,
coagulopathy or thrombocytopenia, microangiopathy,
abnormal LFTs, renal dysfunction, or fetal jeopardy) and
preferably in a tertiary care setting.
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HELLP Syndrome
Hemolysis
Elevated Liver-Enzymes
Low Platelet Count
Eclampsia: Pathophysiology and Prevention in
2006
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Noninvasive techniques suggest elevated CPP in
eclampsia, lowered by magnesium or labetalol.
Possible role for drug effects on autoregulation in
addition to systemic BP
Magnesium is drug of choice to prevent recurrent
seizures (RCTs: Mg vs diazepam or phenytoin)
24 h of Magnesium prevents seizures (without
monitoring!) in Magpie trial (>15,000 women)
Magnesium prevents seizures better than selective
cerebral vasodilator
Can occur days to weeks postpartum (Hirshfeld-Cytron et al
Obstet Gynecol Survey 61:471, 2006)
Principles of management of
hypertension in pregnancy
Most do not treat mild to moderate hypertension < BP
150-160/100-110 (except if underlying disease or
target organ damage present). All should treat BP
>150-160/100-110, 170/110 is a medical emergency
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We have no randomized trials to guide BP targets!
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Aim for vaginal delivery close to term if possible
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Monitor maternal and fetal welfare closely in these
very high risk pregnancies
 renal, hepatic, coagulation status
 fluid balance
 fetal growth, activity, cardiac reactivity
Drugs for Chronic Hypertension in
Pregnancy
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Methyldopa-B: 0.5-3 g/d 2-4 divided doses (preferred
drug of NHBPEP Working Group)
Labetalol-C: 200-1200 mg/d 2-3 divided doses
Hydralazine-C: 50-300 mg/d 2-4 divided doses (useful
only with sympatholytic agent)
β receptor blockers-C: (dose depends on agent); those
with ISA preferred by Australasian group
Nifedipine-C: 30-120 mg/d of sustained release
preparation, other CCBs seem similarly effective
Thiazide Diuretics-C: (dose depends on agent) can
cause volume depletion and electrolyte disorders, but
effective in chronic hypertensives (?salt sensitive?) as
adjunct therapy.
Drugs for Urgent Control of Severe Hypertension
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Hydralazine-C: 5mg iv/im, then 5-10 mg q 15-40 min
(or infusion of 0.5-10 mg/h)
Labetalol-C: 20 mg iv, then 20-80 mg q 20-40 min up
to max of 300 mg (or infusion of 1-2 mg/min)
Nifedipine-C: 5-10 mg po, repeat in 30 min prn, then
10-20 mg q 2-4h (noted by NHBEP working group, but
not approved by FDA for treatment of hypertension)
Nitroprusside-C: 10 µg/kg/min, agent of last resort
due to possible toxicity
Some newer (designer) ones: untested in gravid
women
Antihypertensive Selection in Nursing Mothers
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Key pharmacokinetic principles governing drug
transfer to milk include: small maternal Vd, low plasma
protein binding, high lipid solubility. Of additional
importance are neonatal oral bioavailability and safety.
Well-designed studies are pitifully few, if at all.
Atenolol and metoprolol are concentrated in milk
Diuretics can decrease milk production
CCBs and methyldopa transfer to milk, apparently with
no adverse effects
Few data on ACE inhibitors or ARBs except for
captopril which appears safe in nursing
Key Issues in Antihypertensive Selection
In spite of recent small series, there remains
NO justification for use of ACE inhibitors or
ARBs due to possible congenital malformations
and definitive fetal toxicity
 Data remain inadequate and contradictory to
choose between drug classes for maternal/fetal
risk/benefit
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– (controversy re: early β blockers vs methlydopa)
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Choose the drugs you know best from among
those commonly used in pregnancy
Summary
Pregnancy is normally a vasodilated state
which can be complicated by several
hypertensive disorders, potentially
threatening mother and fetus
 Specific diagnosis may matter
 Goals of antihypertensive therapy differ from
those in nonpregnant women
 Choice of drugs depends more on established
clinical experience than on well-designed and
adequately-powered trials in pregnant
women, which remain shamefully lacking
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Hypertension in Pregnancy: Reviews,
Guidelines, Consensus
NHBEP Working Group on Hypertension in Pregnancy: AJOG 183:S1S22, 2000
AHRQ Evidence Report on Management of Mild Chronic Hypertension in
Pregnancy: Obstet Gynecol 96:849-60, 2000
Cochrane Pregnancy and Childbirth Group: Cochrane Database of
Systematic Reviews
New Developments in Preeclampsia. Semin Nephrol 24:537-625 , 2004
(issue edited by Davison JM & Lindheimer MD)
Karumanchi S et al. Kidney Itl 67:12001-13, 2005
Redman CW, Sargent Il: Science 308:1592-4, 2004
Karumanchi SA, Lindheimer MD. Advances in the understanding of
eclampsia. Curr Hypertens Rep;10:305-12, 2008.
Lindheimer MD, Taler SJ, Cunningham FG . Hypertension in pregnancy
(invited Am Soc Hypertension position paper) Journal of the American
Society of Hypertension, (in press Nov-Dec 2008)
Special Thanks are due to:
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Professor Marshall Lindheimer, M.D. for
guidance and help in preparing this
lecture
My residents and fellows for academic
assistance
My children for technological
assistance
Novel Therapies for
Preeclampsia
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Antibodies to dioxin (digibind) or to
marinobufogenin (endogenous ouabain)
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Relaxin
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VEGF- 121
VEGF-121 therapy in experimental preeclampsia
Li et al. Hypertension 50:686. 07
Systolic BP
200
Adv-sFlt+Vehicle
Adv-sFlt+VEGF121
SBP (mmHg)
160
120
80
40
0
Naive
Null Vehicle VEGF121
Adv-sFlt
UA (ug)/Ucrea (mg)
20000
Body Weight of Fetus
Urine Albumin/Creatinine
0.7
0.6
12000
8000
4000
0
Naive
Null Vehicle VEGF121
Adv-sFlt
Body Weight per Fetus
(g/Fetus)
16000
0.5
0.4
0.3
0.2
0.1
0.0
Naive
Null Vehicle VEGF121
Adv-sFlt
Severe morbidity and mortality according to treatment
group
Calcium
n/N
Placebo
n/N
Risk
Ratio
95%
Confidenc
e
Interval
Maternal admission to intensive
care any special care unit
116/4151
138/416
1
0.85
0.75 - 0.95
Maternal admission ≥ 2 days
31/4151
37/4161
0.83
0.57-1.21
Maternal death
1/4151
6/4161
0.17
0.03 - 0.76
Severe maternal morbidity and
mortality index (*)
167/4151
209/416
1
0.80
0.70 - 0.91
Stillbirth
105/4181
113/4197
0.93
0.74 - 1.17
Neonatal mortality
37/3953
53/3956
0.70
0.56 - 0.88
(*) At least one of the following: Admission to Intensive or any special care unit, eclampsia, severe preeclampsia,
, placental abruption, HELLP, renal failure or death.
All risk ratios and 95% Confidence Intervals adjusted by centre effect. Maternal outcomes are also adjusted by
maternal body mass index.
Cumulative risk of neonatal mortality, by
treatment group
1.8
1.6
% infant died in the neonatal period
1.4
Calcium
Placebo
1.2
1.0
0.8
Cox regression model
0.6
p =0.02*
0.4
0.2
0.0
20
21
22
23
24
25
26
27
28
29
30
31
Gestational age (weeks)
Adjusted for clustering on centre
32
33
34
35
36
37
38
39
40+
Villar et al. 2006
Do not Forget!
Blood pressure decreases early in pregnancy;
thus mild chronic hypertension can be missed
and then misdiagnosed as preeclampsia or
gestational hypertension near term
 Most women with mild to moderate
hypertension require little or no drug therapy
until later in pregnancy
 As most young women are not hypertensive, we
must be aggressive in searching for secondary
causes, especially renovascular hypertension
and pheochromocytoma
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Management Continued
Roles for a laboratory data base to aid in
recognition of superimposed preeclampsia
 Role for home BP monitoring
 Hospitalization recommended for new and/or
worsening hypertension, or suspected
preeclampsia
 Severe hypertension may require continued
hospitalization for duration of pregnancy
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Preterm delivery Calcium supplementation
and maternal age
95%
Confidence
Interval
Calcium n/N
Placebo
n/N
Risk
Ratio
Preterm delivery
(<37 ws)
398/4038
436/4042
0.91
0.79 - 1.05
Early preterm delivery
(<32 ws)
106/4038
130/4042
0.82
0.71 - 0.93
Preterm delivery (<37 ws)
148/1400
180/1404
0.82
0.67 - 1.01
Early preterm delivery
(<32 ws)
34/1400
53/1404
0.64
0.42 - 0.98
Preterm delivery
(<37 ws)
250/2638
256/2638
0.97
0.83 - 1.15
Early preterm delivery
(<32 ws)
72/2638
77/2638
0.93
0.68 - 1.28
Total population
Women ≤20 years
Women >20 years
All risk ratios and 95% Confidence Intervals are adjusted by centre effect.
The denominators include multiple births.
Askie et al. Lancet 2007;369:179