Prevention of preeclampsia Jim Roberts. Introduction The NICHD/NHLBI will soon begin a very large (9 to 12,000 women) and very expensive study of antioxidant

Prevention of Prevention of preeclampsiapreeclampsia

Jim Roberts

IntroductionIntroduction

The NICHD/NHLBI will soon begin a very large (9 to 12,000 women) and very expensive study of antioxidant therapy to attempt to prevent the pregnancy complication, preeclampsia.

What background data and principles should guide such a study?

GoalsGoals

What is preeclampsia?Prior attempts to prevent

preeclampsia• What can we learn?

Principles to guide preventive therapyRationale for antioxidant therapy Skeleton of study design (work in

progress)

PreeclampsiaPreeclampsia

Clinical (pregnancy specific syndrome)HypertensionProteinuria

ImpactLeading cause of maternal mortality5 fold increase in perinatal mortality15% of preterm births

Treatment of Treatment of PreeclampsiaPreeclampsia

Delivery!Delivery!

Usually prevents maternal mortality.

Does not prevent maternal morbidity.

Can result in iatrogenic prematurity.

Treatment of Treatment of PreeclampsiaPreeclampsia

The best treatment is prevention!

Preeclampsia Preeclampsia ProphylaxisProphylaxis

HistoryHistory• Salt restriction• Salt supplementation• Protein restriction• Protein

supplementation• Eat less• Eat more• Rest less• Rest more• etc., etc., etc. ...

Principles of Principles of ProphylaxisProphylaxis

• Successful preventive therapy requires:–Sufficient understanding of the disease to direct strategy

–The ability to identify patients at enough risk to justify prophylaxis

• “Prophylactic” treatment may actually be early therapy.

• Preventive therapy must prevent the disease and not merely the diagnosis of the disease.

““Decreasing the Diagnosis”Decreasing the Diagnosis”

Preeclampsia is diagnosed by:• increased blood pressure• proteinuriaThese are not important pathophysiological features!

Drugs which lower BP or prevents proteinuria will reduce the dx.

Have not prevented the disorder only the diagnosis.

Calcium Calcium SupplementationSupplementation

RationaleRationaleHypocalcuria in preeclampsia

? antedates disease Increased intracytoplasmic calcium

platelets: basal yes/nostimulated yes/no

Epidemiologylow calcium diets => more preeclampsia(South and Central America and Africa)

Calcium SupplementationCalcium SupplementationClinical trials and meta-analysisClinical trials and meta-analysis

OR for developing preeclampsia

Marya 1987 Villar 1987 Lopez-Jaramillo 1989 Lopez-Jaramillo 1989 Montanaro 1990 Villar 1990 Beilzan 1991 Cong 1993 Sanchez- Ramos 1994 Pooled Estimate

Favors Calcium Favors Control

0.001 0.01 0.1 1 10


Clinical trials and meta-analysisClinical trials and meta-analysis

Summary:• Preeclampsia reduced (OR = 0.38)• “PIH” reduced (OR = 0.3)• Blood pressure reduced (5.4 /

3.44)

“The minimal expense and negligible risk ... may justify administration of calcium to even the low risk cohort.”


NIH trialNIH trial

Design• 4600 low risk nulliparous women• Randomized to 2 gms Ca++ or placebo• Assess calcium intake predelivery• Assess urinary calcium in a subset


NIH trialNIH trial

Ca++(2295)

Placebo(2294)

RR(95% CI)

Preeclampsia 6.9% 7.3% 0.94(0.76, 1.16)

mild 4.7% 4.8% 0.99(0.76, 1.28)

severe 2.2% 2.6% 0.85(0.78, 1.01)

transient BP a 15.3% 17.3% 0.88(.78, 1.01)

all BP a 22.2% 26.4% 0.9(0.81, 1.00)

Why the Discrepancies?Why the Discrepancies?Calcium Trial SpecificCalcium Trial Specific

Wrong amount of calcium? • not likely

Compliance?

Poor definitions in the meta-analysis?

Supplement ≠ dietary calcium

Different populations?• much more Ca++ deficient

Aspirin for Aspirin for PreeclampsiaPreeclampsia

RationaleRationale“Prostacyclin thromboxane imbalance”

Prostacyclinvasodilator inhibits platelet aggregationmade by endothelium

Thromboxanevasoconstrictor aggregates plateletsmade by platelets


RationaleRationale“Prostacyclin thromboxane

imbalance”

In preeclampsia the ratio of prostacyclin to thromboxane is reduced (as predicted by the hypothesis)

But ...These agents have very short half

lives (i.e. they do not function as hormones)


RationaleRationale

“Prostacyclin thromboxane imbalance”

Aspirin given daily, in low doses, preferentially inhibits

thromboxane synthesis.


Clinical TrialsClinical TrialsIn the mid 1980’s several trials

suggested benefit (less preeclampsia, reduced IUGR, fewer C-sections) in high risk patients.

Quality of trials varied (e.g. historical controls, non-blind etc.)

There were, however, several controlled trials suggesting benefits.


Meta-analysisMeta-analysisIn 1991 metaanalysis of 6 highest

quality studies (= 394)concluded that ASA:

1. Reduced the incidence of preeclampsia

RR = 0.35 (0.22 - 0.55)2. Reduced the risk of IUGR

RR = 0.56 (0.36 - 0.88)3. Reduced the risk of C-section

RR = 0.34 (0.25 - 0.48)

Aspirin for Aspirin for PreeclampsiaPreeclampsiaLow Risk StudiesLow Risk Studies

Preeclampsia (%)Study Patients Mild Severe Total

NICHD Placebo 1500 3.3 3.0 6.3ASA 1485 2.0 2.0 4.6

Hauth Placebo 302 3.6 1.9 5.6et al ASA 302 1.3 0.33 1.7

CLASP* Placebo 3982 7.6ASA 3992 6.7

*CLASP study patients are of "intermediate risk". 75% were entered because of a previous history of preeclampsia


The NIH High Risk StudyThe NIH High Risk StudyIncidence of

Preeclampsia %Risk Group n ASA PlaceboPregestationalDiabetes

462 18 22

Hypertension 763 26 25Multifetalgestation

678 12 16

Previouspreeclampsia

600 17 19

All groups 2503 18 20


Cochranne MetanalysisCochranne Metanalysis35,000 women have taken ASA in RCT!

reduced preterm birthreduced perinatal mortalitystatisticaly but ? Clinically significant

Why so small an effect?Subsets?Wrong dose?Wrong time in gestation?Wrong time of day?

Why the Discrepancies?Why the Discrepancies?General metaanalysis vs. trialGeneral metaanalysis vs. trial

GIGO (garbage in = garbage out)

Publication bias• small negative trials do not get published (or submitted)

(at time of CLASP there were as many patients in unpublished studies as there were in the

positive trials cited in the 1991 meta-analysis)

Why the Discrepancies?Why the Discrepancies?General meta-analysis vs. trialGeneral meta-analysis vs. trial

Although the limitations of metaanalysis likely explain discrepancy, a caution is necessary.

• In large trials population is much less homogeneous than single center trials.

• Preeclampsia is heterogeneous.

• Perhaps only certain subsets benefit from a specific therapy.

What have we learned?What have we learned?

Meta-analysis is not a substitute for large clinical trials.

In testing preventive therapy for preeclampsia some marker of perinatal well being is the appropriate outcome.

It may be necessary to identify subsets of preeclamptic patients for effective early therapy.

Future DirectionsFuture Directions Identifying targets for therapyIdentifying targets for therapy

Preeclampsia:• manifests many pathophysiological

changes?cause or effect?

• is present before evident disease

• ends when pregnancy ends

• is likely the convergence of several pathways with a common

endpoint

Future DirectionsFuture Directions Identifying targets for therapyIdentifying targets for therapy

Future trials should be guided by well established pathophysiological features.

• Biologically plausible antecedent of maternal/perinatal mortality/morbidity

• Present before disease• Returns to normal after

pregnancy

• May only be pertinent to a subset of preeclamptic women

Future DirectionsFuture DirectionsEffects on perinatal outcomeEffects on perinatal outcome

Signs of preeclampsia are not an important part of physiology.

As an inherited disease, predicts survival value of the disorder.

It is possible to mask the diagnosis without affecting relevant pathophysiology.


Future clinical trials:• must be large enough to detect adverse

fetal/neonatal outcome

• should have as primary outcome an endpoint relevant to neonatal well-being


Future clinical trials:• must be large enough to detect adverse

fetal/neonatal outcome

• should have as primary outcome an endpoint relevant to neonatal well-being

• Admit our knowledge is limited and also collect mechanistic data (without compromising trial)

Documents

Prevention of preeclampsia Jim Roberts. Introduction The NICHD/NHLBI will soon begin a very large (9 to 12,000 women) and very expensive study of antioxidant