Hypothesis The generation of pro-oxidants secondary to abnormal placental perfusion interacts with...
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Transcript of Hypothesis The generation of pro-oxidants secondary to abnormal placental perfusion interacts with...
HypothesisHypothesis
The generation of pro-oxidants secondary to abnormal placental perfusion interacts with maternal constitutional factors to generate oxidative stress.
QuestionsQuestions
Is there evidence of oxidative stress?
What is the source of oxidative stress?
Are antioxidants reduced?
Evidence of oxidative Evidence of oxidative stress in preeclampsiastress in preeclampsia
Increased circulating markersLipids (MDA, isoprostanes)Activated blood cellsAntibodies to ox-LDL
Tissue changesIncreased nitrotyrosine (NO + O) in placenta and maternal vessels
Ascorbate consumption
QuestionsQuestions
Is there evidence of oxidative stress?
What is the source of oxidative stress?
Are antioxidants reduced?
The placenta as a source The placenta as a source of oxidative stressof oxidative stress
Speculation:Uterine blood flow is reduced with uterine contractions.In addition uterine blood flow is not privileged and is decreased with posture and activity.With abnormal implantation might these physiological changes result in a hypoxia reperfusion scenario?
QuestionsQuestions
Is there evidence of oxidative stress?
What is the source of oxidative stress?
Are antioxidants reduced?
Xanthine Xanthine Oxidase/DehydrogenaseOxidase/Dehydrogenase
Xanthine Xanthine dehydrogenase (XOD)
NADH + Uric Acid
Xanthine Xanthine oxidase (XO)O + Uric Acid.
2
XOD + hypoxia XOD XO
Cytokines
XOD XO
Cytokeratin XOD
Normal 7 wks
Normal 18 wks
Normal 34 wks
Preeclampsia 28 wks
The definitive questionThe definitive question
Can preventing oxidative stress prevent endothelial activation and Stage 2 of preeclampsia?
A (small) randomized A (small) randomized controlled trial of antioxidant controlled trial of antioxidant
therapy to prevent therapy to prevent preeclampsiapreeclampsia
Chappell LC, Seed PT, Briley AL, Kelly FJ, Lee R, Hunt BJ, Parmar K, Bewley Chappell LC, Seed PT, Briley AL, Kelly FJ, Lee R, Hunt BJ, Parmar K, Bewley SJ, Shennan AH, Steer PJ, Poston L. Lancet 1999;354:810-816SJ, Shennan AH, Steer PJ, Poston L. Lancet 1999;354:810-816
High risk women identified by: doppler of uterine artery (20 and 24
weeks gestation)preeclampsia in previous pregnancychronic hypertensionprevious early onset preeclampsia
DesignDesign
positive screened women randomized at 20 weeks to 1 gm ascorbic acid and 400 IU vitamin E (n = 141) or placebo (n = 142)
If doppler not positive at 24 weeks Rx stopped
intent to treat analysisprimary outcome 30% reduction in
evidence of endothelial activation (PAI-1/PAI-2)
ResultsResults
PAI-1/PAI-2 20% with Rx (p < 0.015)
Preeclampsia (p = 0.02)Placebo 24/142Rx 11/141
Stage 2: Maternal Syndrome
Oxidative Stress
Stage 1: Reduced Placental perfusion abnormal
implantation
Maternal Constitution:
Genetic, Behavioral,
Environment
Future approachesFuture approaches
Identify women with predispositions and treat appropriately (e.g.thrombophillia, dyslipidemia)
Antioxidants?
Antioxidants for Antioxidants for preeclampsiapreeclampsia
Will they work?
Are they safe?
Antioxidant TrialAntioxidant Trial(in preparation)(in preparation)
NICHD/NHLBI/?Canada/?WHO
DesignDesign
RCT of vitamin C (1000 mg.) and Vitamin E (400 iU) vs. placebo
Prospective collection of data and biological materials
Primary outcome• severe growth restriction < 3d
centile• Infant death after 20 weeks
gestationPower analysis
p < 0.05 and power = 0.8 to detect 30% reduction in primary outcome
DesignDesign
Subjects• Nulliparous low risk women
(9000)• ? High risk women (3600)• ? Women from low C and E
intake areas (WHO)
NICHD Antioxidant NICHD Antioxidant TrialsTrials
Does it satisfy the Does it satisfy the “requirements“?“requirements“?
• Should have as primary outcome an endpoint relevant to neonatal well-being.– IUGR and death
• Must be large enough to detect adverse fetal/neonatal outcome.– At least 4500 women in each arm
NICHD Antioxidant NICHD Antioxidant TrialsTrials
Does it satisfy the Does it satisfy the “requirements“?“requirements“?• Should have as primary outcome an
endpoint relevant to neonatal well-being.– IUGR and death
• Must be large enough to detect adverse fetal/neonatal outcome.– At least 4500 women in each arm
Admits our knowledge is limited and collects mechanistic data
Preventing Preventing PreeclampsiaPreeclampsiathe “bottom line“the “bottom line“
Any future clinical trial must be guided by well established pathophysiological information
We must understand a disease before we can prevent it!
SummarySummary
Calcium and aspirin in large clinical trials did not reduce the frequency of preeclampsia
“Hints” from the aspirin trials indicate that the strategy of early treatment may be effective
Increasing data supports diverse maternal factors contributing to the pathogenesis of preeclampsia
Oxidative stress may be the convergence point
Keep your fingers crossed!
Aspirin for Aspirin for PreeclampsiaPreeclampsiaPrevention trialsPrevention trials
PreeclampsiaASA Placebo RR (95% CI)
SmallTrials
10/3193%
50/28418%
0.2 (0.1, 0.4)
Largetrials
949/139286.8%
1032/137657.5%
0.9 (0.8, 1.0)
Alltrials
959/142476.7%
1082/140497.7%
0.9 (0.8, 1.0)
After Carits et al NEJM 338:701; 1998
Aspirin for Aspirin for PreeclampsiaPreeclampsiaPrevention trialsPrevention trials
IncidenceASA Placebo RR (95% CI)
PretermDelivery
2404/1372917.5%
2540/1364518.6%
0.9 (0.9, 1.0)
PerinatalDeath
418/144072.9%
450/142533.2%
0.9 (0.8, 1.0)
After Carits et al NEJM 338:701; 1998
Why the Discrepancies?Why the Discrepancies?ASA Trial SpecificASA Trial Specific
%Preec.
%SGA
BirthWeight
“ASA” “ASA” “ASA”n + - + - + -
* *Intent to Rx 604 1.7 5.6 5.6 6.3 3249 3169
* * *Compliance 558 1.9 5.7 2.9 7.0 3314 3122
The impact of compliance
Why the Discrepancies?Why the Discrepancies?ASA Trial SpecificASA Trial Specific
Wrong dose of ASA?
Wrong timing?(*time of day and time of pregnancy)
Poor compliance?
SummarySummary
Trials of preeclampsia prevention (early treatment) have not demonstrated clinically relevant effects.
In single center trial with compliance monitoring ASA was minimally effective.
Future studies should identify a relevant target before more trials.
There may be different targets in different subsets of preeclamptic women.
Chlamydia pneumoniaeChlamydia pneumoniaeassociation with vascular diseaseassociation with vascular disease
Seropositivity is more commonCoronary artery diseaseCerebrovascular diseaseHypertension
OrganismsPresent in diseased coronariesPresent in atherosclerotic tissueTropism for vascular tissue (smooth muscle and endothelium)
Chlamydia pneumoniaeChlamydia pneumoniaeassociation with preeclampsiaassociation with preeclampsia
Adjusted(age)
%IgG
OR CI OR CI
Preeclampsia 68% 3.1 1.2,7.9
3.3 1.2,9.5
Normal 41%
No difference in I gM or I gA
Aspirin for Aspirin for PreeclampsiaPreeclampsia
The NIH High Risk StudyThe NIH High Risk Study
Incidence ofPreeclampsia %
Risk Group n ASA PlaceboPregestationalDiabetes
462 18 22
Hypertension 763 26 25Multifetalgestation
678 12 16
Previouspreeclampsia
600 17 19
All groups 2503 18 20
Oxidative stress in Oxidative stress in preeclampsiapreeclampsia
linkage of placenta and systemiclinkage of placenta and systemic
Stable products of lipid peroxidation
Activated neutrophils/monocytes
Microvillus fragments