1. Prevention of preeclampsia Jim Roberts

2. Introduction 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?

3. Goals What is preeclampsia? Prior attempts to prevent preeclampsia What can we learn? Principles to guide preventive therapy Rationale for antioxidant therapy Skeleton of study design (work in progress)

4. Preeclampsia Clinical (pregnancy specific syndrome) Hypertension Proteinuria Impact Leading cause of maternal mortality 5 fold increase in perinatal mortality 15% of preterm births

5. Treatment of Preeclampsia Delivery! Usually prevents maternal mortality. Does not prevent maternal morbidity. Can result in iatrogenic prematurity.

6. Treatment of Preeclampsia The best treatment is prevention!

7. Preeclampsia Prophylaxis History Salt restriction Salt supplementation Protein restriction Protein supplementation Eat less Eat more Rest less Rest more etc., etc., etc....

8. Principles of Prophylaxis 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.

9. “Decreasing the Diagnosis” Preeclampsia is diagnosed by: increased blood pressure proteinuria These are not important pathophysiological features! Drugs which lower BP or prevents proteinuria will reduce the dx. Have not prevented the disorder only the diagnosis.

10. Calcium Supplementation Rationale Hypocalcuria in preeclampsia ? antedates disease Increased intracytoplasmic calcium platelets: basal yes/no stimulated yes/no Epidemiology low calcium diets => more preeclampsia (South and Central America and Africa)

11. Calcium Supplementation Clinical trials and meta-analysis OR for developing preeclampsia

12. Calcium Supplementation Clinical 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.”

13. Calcium Supplementation NIH trial Design 4600 low risk nulliparous women Randomized to 2 gms Ca++ or placebo Assess calcium intake predelivery Assess urinary calcium in a subset

14. Calcium Supplementation NIH trial

15. Why the Discrepancies? Calcium Trial Specific Wrong amount of calcium? not likely Compliance? Poor definitions in the meta- analysis? Supplement ≠ dietary calcium Different populations? much more Ca ++ deficient

16. Aspirin for Preeclampsia Rationale “Prostacyclin thromboxane imbalance” Prostacyclin vasodilator inhibits platelet aggregation made by endothelium Thromboxane vasoconstrictor aggregates platelets made by platelets

17. Aspirin for Preeclampsia Rationale “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)

18. Aspirin for Preeclampsia Rationale “Prostacyclin thromboxane imbalance” Aspirin given daily, in low doses, preferentially inhibits thromboxane synthesis.

19. Aspirin for Preeclampsia Clinical Trials In 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.

20. Aspirin for Preeclampsia Meta-analysis In 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)

21. Aspirin for Preeclampsia Low Risk Studies *CLASP study patients are of "intermediate risk". 75% were entered because of a previous history of preeclampsia

22. Aspirin for Preeclampsia The NIH High Risk Study

23. Aspirin for Preeclampsia Cochranne Metanalysis 35,000 women have taken ASA in RCT! reduced preterm birth reduced perinatal mortality statisticaly but ? Clinically significant Why so small an effect? Subsets? Wrong dose? Wrong time in gestation? Wrong time of day?

24. Why the Discrepancies? General 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)

25. Why the Discrepancies? General 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.

26. 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.

27. Future Directions Identifying 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

28. Future Directions Identifying 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

29. Future Directions Effects 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.

30. Future Directions Effects on perinatal outcome 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

31. Future Directions Effects on perinatal outcome 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)