Preventıon of preeclmpsıa

Preeclampsia-eclampsia is the largest single cause of perinatal mortality and maternal death in most developed and developing countries. The ultimate goal in the management of preeclampsia is to be able to detect the disease in the early stages and have an available therapy that either cures il or at least ameliorates its progression in an attempt to achieve fetal maturity. The term "preventîon" not only points at averting the occurrence of disease (primary prevention), but also at breaking off the disease process before the emergence of clinically recognizable disease (secondarv prevention), and at prevention of complications caused by the disease process (tertiary prevention). This preseniation concems secondary preventîon of preeaclampsia.
Whether the endothelial celi injury in preeclampsia causes primarily a decrease in prostacyclin synthesis or a decrease in for example EDRF platelets play a central role in the disease process. Redman stated "preeclampsia is a trophoblast-dependent process mediated by platelet dysfunction and prevented at least in part by antiplatelet agents". On the virtually non-endolhelialized surface of the spiral arteries in the absence of an adequate production of antiaggregatory prostacyclin and/or EDRF by the uteroplacental vasculature and/or cndovascular trophoblast, surface mediated platelet activation may be expected to occur. Platelets will adhere and release alpha and dense granule constituents. Thromboxane A2 and serolonin will be generated, contributîng to platelet aggregation and inducing the fotmation of fibrin to stabilize the platelet thrombus that may occlude maternal blood flow to a placental cotyledon, thus leading to placental infarction. Based on the hypothesis that preeclampsia is at least partially caused by an irtcrease in platelet-derived thromboxane-A2, several investigators have attempted to correct this pathology by plıarmacologic manipulation with low-dose Aspirin.
Acetylsalicylic acid (Aspirin) as an antiplatelet agent: Aspirin prolongs the bleeding time through its inhibition of platelet cyclo-oxygenase activity and the resultant platelet secretory reaction. Aspirin acetylates the alanine residue at the active site of the cyclo-oxygenase enzyme. Because the acetyl group of Aspirin is covalentiy bound to the active size of cyclo-oxygenase, the inhibition of the enzyme is irreversible. Platelets lack nuclei and are unable to resynthe-size cyclo-oxygenase. Therefore, following Aspirin administration, thromboxane A2 synthesis in platelets remains impaired for the duration of their lifespan. The optimal antithrombotic dose of Aspirin remains disputed. Doses as high as 3.5 g/day and as low as 20-40 mg/day have been reported to be effective in preventing thrombotic events. İn the case of Aspirin, it is of particular importance to use the lowest effective dose, because of its concomitant effect on vessel-wall cyclo-oxygenase. Aspirin inhibits endotheiial cyclo-oxygenase, but the vesse] wall may be less sensitive and has the capacity to synthesize new cyclo-oxygenase when Aspirin is removed from the system. Another majör mechanisms involved in the causation of the "paradoxical" selectivity of low-dose Aspirin on platelet cyclo-oxygenase is based on the pharmacokinetic characterîstics of this drug. Platelets passing though the gut capillaries, while an oral dose of Aspirin is undergoing presystemic hydrolysis, are exposed to sîgnificantly higher concentrations of Aspirin than platelets in the peripheral circulation. Absorptkm of a Iow oral dose of Aspirin causes relatively high concentrations in the portal circulation leading to a cumulative inhibition of cyclo-oxygenase in platelets passing through the gut capîllaries, whereas the concentration in the peripheral circulation (after deacetylalion of Aspirin in the liver) remains too low to affect endothelial cyclo-oxygenase.
Safety aspects: The current literatüre suggests that the use of low-dose Aspirin during pregnancy is safe with regard to congenital anomalies and fetal, neonatal, and maternal cardiovascular physiology and hemostasis. Secondary prevention of preeclampsia with low-dose Aspirin: Up to the 8Ih World Congress for the Study on Hypertension in Pregnancy in November '92 in Buenos Aires the results of low-dose Aspirin in randomized trials, ali concerning small groups of selected high-risk patients, demonstrated, 30 % reduction in the incidence of gestational hypertension, 85 % reduction in the incidence of preeclampsia, and a significant reduction in the incidence of adverse perinatal outcome in the Aspirin treated group as compared to the placebo-group. The results of the more recent Italian Aspirin study, the N.I.H study, the Birmingham study and the results of the CLASP study will be discussed in some detail during the congress.
The results of the K.Î.H study, reported by Sibai et al in January '93 at the Society of perinatal Obstetricians in San Francisco, and the results of the CLASP study reported by Clıris Redman at the IXth ISSHP World Congress in March of this year suggest that low-dose Aspirin should not be adopten in routine prenatal çare. Över ali the effect of low-dose Aspirin appears to be modest. The majör benifit of lovv-dose Aspirin appears to be delaying the onset of severe preeclampsia. Hovvever, because perinatal mortality or serious morbidity is mainly associated vvith early-onset preeclampsia, this effect of low-dose Aspirin makes the use of Ihis safe antiplatelet clurg worthwhile in high-risk pa-tients. Based on the avaiiable literatüre and an 8 year personal experience vvith low-dose Aspirin I advocate the use of low-dose Aspirin only in vvomen considered at high-risk of developing preeclampsia and/or fetal growth retarclation. Because of the reported high recurrence rates of preeclampsia, we recomnıend use of low-dose Aspirin in ali patients with severe early-onset preeclampsia in the previous pregnancy. Other indications for the use of low-dose Aspirin will be discussed during thc congress. The optîrrtal time to initiate low-dose Aspirin is 10-14 weeks amenorrhea.
Low-dose Aspirin has been demonstrated not to influence the clinical course and perinatal outcome of vvomen vvith mild pregnancy-induced hypertensive dısorders (tertiary prevention). Low-dose Aspirin is not curative, but is essentially a preventive treatment vvhich, in order to be effective, should be started weeks before clinical signs of preeclampsia are present.

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