Transcript Prediction and prevention of Preeclampsia

UPDATE ON
PREDICTION & PREVENTION
OF PREECLAMPSIA
Assist. Prof. S. Rouholamin
•Prediction:
Routine urine analysis
•Prevention:
Chocolate
Outline
 Introduction
 Prediction
 Prevention
Cochrane Systematic Review
Gold Standard' for high-quality
systematic reviews
•Preeclampsia:
Hypertension
associated with
proteinuria.
•Pathogenesis:
•unknown (Barton& Sibai, 2008).
Impaired trophoblast differentiation& invasion
Placental & endothelial dysfunction
Immune maladaptation to paternal Ags
Exaggerated systemic inflam response.
•Pathogenesis:
•Differs with various risk factors:
PG Vs MG with previous PE
preexisting vas dis
preexisting DM or
multifetal gestation.
In PE:
Impaired trophoblast
differentiation &
invasion
Placental and
endothelial
dysfunction
PREDICTION OF PE
• Why prediction is important?
• The ideal screening test
• Methods
I. Preconception factors
II. Pregnancy-Related Factors
1. Risk factors
2. Markers
Why prediction is important:
1. The risk for recurrent PE can be
as high as 65% (Barton& Sibai, 2008).
2. PE is associated with substantial
maternal& perinatal
complications
The ideal Screening test:
Simple
Noninvasive
Rapid
Inexpensive
Easy to perform early in pregnancy
Highly sensitivity & predictive.
I. Preconception factors
st
1
step in the management of a
woman with a history of PE is to
conduct a detailed evaluation of
potential risk factors (Barton& Sibai, 2008).
Preconceptional Risk Factors
Rates of preeclampsia depend on: severity of underlying complications&
combinations of risk factors.
Risk factors
Risk %
Chronic hypertension/renal disease
15-40
Pre gestational DM
10-35
Connective tissue disease (lupus, rheumatoid arthritis)
10-20
Thrombophilia (acquired or congenital)
10-40
Obesity/insulin resistance
10-15
Age older than 40 y
10-20
Limited sperm exposure
10-35
Family history of preeclampsia/ cardiovascular disease
10-15
Woman born as SFGA
1.5 fold
Adverse outcome in a previous pregnancy: IUGR, ab placentae,
IUFD
2-3 fold
II. Pregnancy-Related Factors
Regular antenatal care is mandatory for the prevention & early detection
of PE.
Risk factors: Magnitude of risk depends on the number of factors
Hydrops/hydropic degeneration of the placenta
Multifetal gestation
Unexplained FGR
Gestational hypertension
UTI
Periodontal infection
Markers
Biophysical
Biochemical
Markers
Many
Based on: pathophysiological abnormalities
•SCREENING TESTS FOR PE (WHO, 2004)
I. Placental perfusion & vascular resistance dysfunction
Mean arterial blood pressure
Roll over test
Doppler ultrasound
Isometric exercise test
Intravenous infusion of angiotensin II
Platelet angiotensin II binding
Platelet calcium response to arginine vasopressin
Renin
24-hour ambulatory blood pressure monitoring
II. Fetoplacental unit dysfunction
Human chorionic gonadotropin
Alpha fetoprotein
Estriol
Inhibin A
Pregnancy-associated plasma protein A
Activin A
Corticotropin release hormone
III. Renal dysfunction
Serum uric acid
Microalbuminuria
Urinary calcium excretion
Urinary kallikrein
Microtransferrinuria
N-acetyl- glucosarninidase
IV. Endothelial& oxidant stress dysfunction
Platelet count
Platelet activation and endothelial cell
adhesion molecules
Prostacyclin
Cytokines
Isoprostanes,
Antiphospholipid antibodies,
Placenta growth factor
Hematocrit
Antithrombin Ill
Calcium
Transferrin
Atrial natriuretic peptide
Fibronectin
Endothelin
Thromboxane
Homocysteine
Serum lipids Insulin resistance
Plasminogen activator inhibitor
Leptin
Total proteins
Magnesium
Ferritin
Haptoglobin
microglobulin
Genetic markers
I. Biophysical
•Mean arterial pressure
•(2D BP+S BP)/3
•Better predictor of PE than S& D BP (BMJ
200817;336:111; Meta-analysis of 34 RCT)
2nd trimester MA BP ≥ 90 mm Hg had +ve LR 3.5
and –ve LR 0.46
•BP remains the cornerstone of early diagnosis
although it has limitations:
measurement errors associated with sphygmomanometer
effect of maternal posture on BP in pregnant women}.
•Repeated routine urinalysis
throughout pregnancy NOT useful for
predicting PE
(JAMA 2003: 12;289(10):1220)
Uterine artery Doppler ultrasound
•}impaired trophoblastic invasion of the spiral arteries:
reduction in uteroplacental blood flow}
•High pulsatility index and/or Notch in 1st & 2nd
trimesters: poor predictor of PE(Papgeorghiou & Leslie, 2007)
Uterine artery Doppler plus biochemical markers
•Promising results
•Current data do not support this combination for
routine screening for PE (Barton& Sibai, 2008).
 Diastolic Notch in
uterine artery waveform
The Roll over test
Not of value in predicting PE
II. Biochemical Markers
Angiogenic factors before & after
the onset of PE
(Barton& Sibai, 2008).
Serum placental growth factor:
reduced
Soluble fms-like tyrosine kinase:
elevated
Endoglin: elevated
Conclusion
•BP remains the cornerstone of early
diagnosis
•Markers
Reliability is inconsistent
Many suffer from poor specificity &
predictive values.
None provided a cutoff value that could
be clinically useful for the prediction of
PE
(Widmer et al, 2007).
•Currently:
There is no clinically useful
screening test to predict PE (WHO,
2004)
Prevention of PE
Primary
Secondary
Primary prevention
•Avoiding occurrence of the disease
•Obese:
achieve an ideal b wt before conception
(Villamor& Cnattingius, 2006)
No RCT
•Ch hypertension:
Control BP before conception.
No RCT
•Pregestational DM:
-Complete her family as early as possible &
before vascular complications develop
-Control DM before conception & throughout
pregnancy
Secondary
•Breaking off the disease process before emergence
of obvious clinical disease
•{Etiology of the disease is unknown}
•To correct theoretical pathophysiology
•I. Non pharmacological
II. Nutritional
III. Pharmacological
I. Non pharmacological
1. Daily Bed rest
Rest for 4-6 h/d
May reduce risk of
PE for women with normal BP
(level 2 evidence)
(Cochrane Library 2006 Issue 2:CD005939)
2. Life-style changes
•High job stress: greater risk
of PE(Sharma& Mittal, 2006)
•Reducing job stress may be
beneficial in the prevention of
PE
3. Regular prenatal exercise
•May prevent or oppose progression (Weissgerber et al, 2004)
•{Stimulation of placental growth
Reduction of oxidative stress
Reversal of maternal endothelial dysfunction}.
•Insufficient evidence
Moderate intensity regular aerobic exercise
(Cochrane Library 2006 Issue 2:CD005942)
Aerobic exercise =cardiovascular exercise=any sustained rhythmic activity that
involves large muscle groups: makes the lungs work harder as the body's need for
oxygen is increased.
•Stretching exercises are more effective at reducing the
risk of PE than walking
(University of North Carolina,2008)
Smoking:
Reduced risk for PE (Sibai et al, 2005).
{Nicotine inhibition of interleukin-2 & tumor
necrosis factor
Effects of nicotine on angiogenic proteins}.
Smoking:
abnormal fetal growth
preterm birth
Abruption
Adverse effects on maternal health.
II. Nutritional
1. Higher total dietary fiber
intake in early pregnancy may
reduce risk for PE
(level 2 evidence)
Prospective cohort study
Am J Hypertens 2008 Aug;21(8):903
2. Increasing dietary protein & energy intake
RCT: no benefit
•5 or more servings of chocolate/w in
3rd trimester:40% reduction
(Triche, 2008; Epidemiology .19:459-464), Yale University
{Chocolate, especially dark chocolate, is rich
in theobromine: stimulates the heart, relaxes
smooth muscle & dilates blood vessels, and
has been used to treat chest pain, high blood
pressure}
3. Garlic
Insufficient evidence
to recommend for
preventing PE
Cochrane Library 2006 Issue3:CD006065)
4. Dietary sodium restriction
• No significant differences
(Cochrane Library 2005 Issue 4:CD005548)
6. Fish Oil Supplementation
•Observational studies: beneficial effects
•{inhibition of platelet thromboxane A2 without affecting
prostacyclin: shifting the balance toward a reduced platelet
aggregation and increased VD}.
•RCT: No benefit
(Olsen et al, 2000)
•High doses: increase the risk of PIH
(Olafasdottir et al, 2006).
•Not recommended for the prevention of PE
5. Weight Reduction
•Although obesity is a known risk
factor, there is no evidence that limiting
wt gain during pregnancy; reduces its
occurrence.
•Wt reduction is not recommended during
pregnancy even in obese women (Kramer, 2004)
III. Pharmacological
1. Low-dose Aspirin
•{inhibits biosynthesis of platelet thromboxane A2
with little effect on vascular prostacyclin production:
altering the balance in favor of prostacyclin}.
•(50-150 mg/day)
For women with a previous history of
hypertension or PE (n=6,107):
Small to moderate benefits, safe.
level 2 evidence
(Cochrane Library 2007 Issue 2:CD004659)
2. Low-dose Aspirin/Heparin
•History of severe preterm PE &
LBW infants.
(Sergio et al, 2006)
•Lower incidence of PE (3Vs
30%)
Greater gestational age at
delivery
Higher birth wt
3. Calcium Supplementation
•Reduces the risk of PIH, particularly in
populations that have diets deficient in
calcium
level 1 evidence (Cochrane Syt review , 2006)
•The relationship between cal & risk of PIH is
inconsistent& inconclusive
The relationship between cal & the risk of PE
is highly unlikely.
Evidence-based review by FDA (2007)
4. Antihypertensive Drugs
•Mild to moderate hypertension:
Halving in the risk of developing severe
hypertension
No difference in the risk of developing PE or
proteinuria
(Cochrane syst review, 2007)
5. Diuretics
•No reduction in the incidence of PE or
perinatal mortality
•May have deleterious effects:
reduced renal & placental perfusion.
(Cochrane Library 2007 Issue 1:CD004451)
6. Antioxidant supplementation
may not affect risk of PE or
clinical outcomes
level 2 evidence
(Cochrane Library 2008 Issue
1:CD004227)
7. Concomitant Vit C& E supplementation
•{PET: imbalance of oxidant & antioxidant activity:
multiorgan endothelial dysfunction}.
•Vit C (1,000 mg/d) plus vit E (400 IU/ d)
•Did not prevent PE
level 2 evidence (Obstet Gynecol 2007 Dec;110(6):1311)
•May increases rate of LBW infants& might be
associated with higher rate of SB
level 2 evidence (Lancet 2006 Apr 8;367(9517):1145
8. Magnesium
•{Mg is beneficial for the prevention &
tt of severe PE & E
Decreased intracellular Mg in PE}
•No effect
•(365 mg& 500 mg).
Cochrane syst review, 2004
9. Folic acid& other B-vits
•{Deficiency of vit B2 may cause
biochemical changes simulating
abnormalities of PE}
•No evidence that any of B vits
can prevent PE
(Shrama& Mittal, 2006).
10. Zinc supplementation
•{Zinc concentrations are reduced in
PE}
•RCT: No benefit
(Jonsson et al, 1996)
11. Nitric oxide
Insufficient evidence for preventing
PE
Cochrane Library 2007 Issue 2:CD006490
12. Progesterone
Insufficient evidence for preventing
PE
Cochrane review, 2006
Conclusion
Regular antenatal care is mandatory for
the prevention & early detection of PE.
For prevention of PE
Bed rest
Reduction of job stress
High dietary fiber intake
Low dose aspirin
Low dose aspirin/heparin
Ca supplementation
PREECLAMPSIA
PREECLAMPSIA
 Hypertensive disorder specific to pregnancy
 affects nearly 6% of all pregnancies
 a major cause of maternal and neonatal mortality
and morbidity
 15 to 20 % of maternal mortality in developed
countries
PREECLAMPSIA
 Severity ranges from:
 a mild disorder (transient hypertension in the later
part of the pregnancy) to
 a life-threatening disorder with seizures, HELLP
syndrome, fetal hypoxia, and growth retardation
 more severe disease: 0.56 per 1000 deliveries
PREECLAMPSIA
 Predisposes women to other serious
complications:
 placental abruption
 acute renal failure
 cerebral hemorrhage
 disseminated intravascular coagulation
 circulatory collapse
PREECLAMPSIA
 The etiology is unknown
 believed to be involved:
 immune maladaptation
 placental ischemia
 oxidative stress
 genetic susceptibility
PREECLAMPSIA
 Classification of hypertension in pregnancy
 Gestational hypertension
 Preeclampsia / eclampsia
 Chronic hypertension
 Preeclampsia superimposed on chronic
hypertension
PREECLAMPSIA
 Definition of hypertension
 a systolic blood pressure of 140 mmHg or above,
 or a diastolic blood pressure of 90mmHg or above,
 on two occasions 6 hours apart
 Abnormal proteinuria
 the excretion of 300 mg or more of protein in 24
hours
PREECLAMPSIA
 Criteria for severe preeclampsia
 Blood pressure: > 160 mmHg systolic or
> 110
mm Hg diastolic
 Proteinuria: > 5 g in 24 hours
 Persistent and severe cerebral or visual
disturbances (headache, scotoma, blurred vision)
 Persistent and severe epigastric pain or right
upper quadrant pain
PREECLAMPSIA
 Criteria for severe preeclampsia
 Pulmonary edema or cyanosis
 Oliguria (< 500 mL of urine in 24 hours)
 Eclampsia (grand mal seizures)
 HELLP syndrome
PREECLAMPSIA
 Screening tests for gestational hypertension
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routine components of antepartum care trimester
early detection of vasoconstriction
early detection of altered renal function
early detection of altered hemodynamics
detection of placental hypoperfusion / ischemia
detection of endothelial activation or injury
detection of an activated coagulation / fibrinolytic
system
PREECLAMPSIA
 Prevention of preeclampsia
 women at risk: multifetal gestation, vascular or renal
disease, previous severe preeclampsia-eclampsia,
abnormal uterine artery Doppler velocimetry
 antihypertensive drugs
 magnesium
 zinc
 fish oil
 calcium
 low-dose aspirin
PREECLAMPSIA
 Mild preeclampsia - management
 < 37 weeks gestation
 inpatient or outpatient management
 worsening disease: delivery, magnesium sulfate
 > 40 weeks gestation
 delivery, magnesium sulfate
 37 - 39 weeks gestation
 inducible cervix: delivery, magnesium sulfate
 cervix not inducible: inpatient or outpatient
management
PREECLAMPSIA
 Severe preeclampsia - expectant
management
 gestational age: not recommended for < 24 weeks
or > 34 weeks gestation
 hospitalization: tertiary care center
 antenatal testing: daily
PREECLAMPSIA
 Severe preeclampsia - guidelines for
expedient delivery
 maternal indications
 eclampsia, thrombocytopenia, pulmonary edema,
acute renal failure
 persistent severe headache or visual changes
 elevated liver enzymes with persistent severe
epigastric pain or right upper quadrant tenderness
 labor or rupture of membranes
 vaginal bleeding, abruptio placenta
PREECLAMPSIA
 Severe preeclampsia - guidelines for
expedient delivery
 fetal indications
 repetitive severe variables or late decelerations
 biophysical profile < 4 on two occasions 4 hours
apart
 amniotic fluid index < 2 cm
 intrauterine growth restriction
 fetal death
 > 34 weeks gestation
PREECLAMPSIA
 Severe preeclampsia - management protocol
 admission to labor and delivery for 24 hours
 magnesium sulfate IV for 24 hours
 antihypertensives if diastolic blood pressure
110 mmHg
 meet guidelines for expedited delivery?
 yes? delivery
>
PREECLAMPSIA
 Severe preeclampsia - management protocol
 Expedited delivery? no?
 < 23 weeks: counseling for termination of pregnancy
 23-32 weeks: steroids, antihypertensive
medications, daily maternal and fetal evaluation,
delivery at 34 weeks
 32-33 weeks: amniocentesis
 immature fluid - steroids, delivery in 48 hours
PREECLAMPSIA
 HELLP syndrome - diagnosis
 10% before 27 weeks
 20% after 37 weeks
 70% between 27 and 37 weeks
 slow initial phase with accelerated final phase
versus secondary expression of sepsis, ARDS,
renal failure
PREECLAMPSIA
 HELLP syndrome
 parameters used to diagnose preeclampsia are
not reflective of disease severity
 target organ systems




liver
brain
kidneys
coagulation system
 increased maternal and perinatal risk
PREECLAMPSIA
 HELLP syndrome - diagnostic criteria
 hemolysis
 abnormal peripheral smear
 lactate dehydrogenase > 600 U/L
 elevated liver enzymes
 serum aspartate aminotransferase > 70 U/L
 lactate dehydrogenase > 600 U/L
 low platelets
 platelet count < 100,000/mm3
PREECLAMPSIA
 HELLP syndrome - differential diagnosis
 acute fatty liver of pregnancy
 appendicitis
 diabetes insipidus
 gallbladder disease
 gastroenteritis
 glomerulonephritis
 hemolytic uremic syndrome
 hepatic encephalopathy
PREECLAMPSIA
 HELLP syndrome - differential diagnosis
 idiopathic thrombocytopenia
 kidney stones
 pancreatitis
 pyelonephritis
 systemic lupus erythematosus
 thrombotic thrombocytopenia purpura
 viral hepatitis
PREECLAMPSIA
 HELLP syndrome - antepartum management
 assess and stabilize the maternal condition
 correct coagulopathy if DIC is present
 give intravenous magnesium sulfate to prevent
seizures
 provide treatment for severe hypertension to
prevent stroke
 transfer to tertiary center if appropriate
 if subcapsular hematoma of liver, computed
tomography or ultrasound of the abdomen
PREECLAMPSIA
 HELLP syndrome - antepartum management
 evaluate fetal well-being
 non stress test
 biophysical profile
 timing of delivery
 if > 34 weeks gestation, deliver
 if < 34 weeks gestation, administer corticosteroids,
then deliver in 48 hours
PREECLAMPSIA
 HELLP syndrome - management for
cesarean birth
 use general anesthesia if platelet count is
<
75,000 / mm3
 transfuse 5 to 10 units of platelets before surgery
if platelet count is < 50,000 / mm3
 leave vesicouterine peritoneum open
 install subfascial drain
PREECLAMPSIA
 HELLP syndrome - management for
cesarean birth
 schedule secondary closure of skin incision or
subcutaneous drain
 administer postoperative transfusions as needed
 perform intensive monitoring for at least 48 hours
postpartum
 consider dexamethasone (10 mg IV every 12
hours) until postpartum resolution of disease
occurs
PREECLAMPSIA
 HELLP syndrome - management of women
with a subcapsular liver hematoma
 general considerations - blood bank aware for




potential need of many units of blood
general or vascular surgeon consultation
avoid direct and indirect manipulation of liver
closely monitor hemodynamic status
management of hematoma depends on whether
it is ruptured or not
PREECLAMPSIA
 Eclampsia
 occurrence of convulsions or coma unrelated to
other associated conditions
 all new onset seizures during pregnancy eclampsia until proven otherwise
 incidence: 1 in 500 pregnancies
 3% in multiple gestations
PREECLAMPSIA
 Eclampsia
 precise cause unknown
 theories
 vasospasm
 ischemia
 edema
 multisystem organ failure
PREECLAMPSIA
 Eclampsia
 seizures usually occur without aura
 hypertension not severe in 20%
 edema absent in 30%
 proteinuria absent in 20%
 hyperreflexia is not predictive of seizure
 headache or visual changes - most common
precipitating event
PREECLAMPSIA
 Eclampsia
 80% of convulsions occur before or during the
delivery
 1/3 of cases may be not preventable
 atypical
 less than 20 weeks gestation
 more than 48 hours postpartum
PREECLAMPSIA
 Eclampsia - risk factors
 low socioeconomic status
 extremes in childbearing age
 African-American
 no prenatal care
 substance abuse
PREECLAMPSIA
 Eclampsia - management
 control convulsions
 correction of hypoxia and acidosis
 blood pressure control
 delivery after maternal stabilization
PREECLAMPSIA
 Eclampsia - anticonvulsant therapy
 magnesium sulfate
 mechanism of action - smooth muscle relaxation by
displacement of calcium
 dosage - 4-6 g intravenous loading dose, followed
by 2 g per hour
 may be given intramuscularly
PREECLAMPSIA
 Eclampsia - magnesium sulfate
 side effects:
 maternal hypotonia
 respiratory depression
 cardiac arrest
 neonatal depression
 contraindicated in myasthenia gravis
 use with caution in renal insufficiency
PREECLAMPSIA
 Eclampsia - anticonvulsant therapy
 phenytoin
 used extensively in Europe
 may be used in myasthenia gravis
 mechanism of action - may increase gamma
aminobutyric acid-mediated chloride conduction in
postsynaptic membranes
 may inhibit neurotransmitter inhibitory systems
PREECLAMPSIA
 Eclampsia - phenytoin
 dosage - 1 g loading dose over 1 hour
 cardiac monitoring during administration
 side effects
 arrhythmias with rapid administration
 hepatitis
 Steven-Johnson syndrome
PREECLAMPSIA
 Eclampsia - anticonvulsant therapy
 diazepam
 useful for status seizures
 mechanism of action - facilitate the binding of GABA
to its receptor
 benzodiazepine receptors
 dosage - 10 mg at a rate of 5 mg per min
 may be repeated at 10 to 15 minute intervals
PREECLAMPSIA
 Eclampsia - diazepam
 side effects - loss of consciousness, hypotension,
respiratory depression
 caution - may increase risk of aspiration
 causes prolonged depression of the neonate
 sodium thiopentotal
 long acting barbiturate
 used when sedation, paralysis and intubation
needed
PREECLAMPSIA
 Eclampsia - which anticonvulsant to use?
 magnesium is associated with decreased
recurrence risks of seizures when compared with
diazepam or phenytoin
 diazepam is associated with increased need for
mechanical ventilation
PREECLAMPSIA
 Eclampsia - management of fetus
 fetal bradycardia during seizure
 ~ 5 minutes after the onset of the seizure
 may be associated with rebound tachycardia
 recovery phase may show late decelerations
 monitor for uterine hypertonicity
 allow for fetal recovery
 monitor for signs of abruption
PREECLAMPSIA
 Eclampsia
 delivery is indicated regardless of gestational age
 immediate cesarean delivery is not necessary
PREECLAMPSIA
 Eclampsia - radiographic evaluation
 should be reserved for women with neurological
deficit, recurrent seizures, or atypical presentation
 abnormal CT findings - 50%
 edema, hemorrhage, infarction
 cerebral angiography has limited use
 90% of EEG evaluations may be abnormal
PREECLAMPSIA
 Eclampsia - management
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allow patient to have seizure
use bite block as needed to prevent maternal injury
establish airway
administer magnesium sulfate as soon as possible
obtain arterial blood gases
monitor urine output
control hypertension
PREECLAMPSIA
 Eclampsia - management
 rebolus with magnesium sulfate if repeat seizure
occurs
 do not intervene for fetal status while mother is
unstable
 if seizure continues, paralyze and intubate.
PREECLAMPSIA
 Counseling regarding future pregnancies -
HELLP syndrome
 information available varies
 recurrent risk of preeclampsia: 43% (19%)
 recurrent risk of HELLP syndrome: 19-27% (3%)
 If HELLP syndrome < 32 weeks
 recurrent risk of preeclampsia / eclampsia is 61%