Mary King, MD, and Peter S. Bernstein, MD, MPH

Disclosures

November 16, 2005

Question

We are treating a pregnant patient who had a stroke 2 years ago (carotid dissection) and now is on Plavix (clopidogrel). What has been your experience with Plavix in pregnancy, and when would you stop administering it? She will be undergoing a repeat cesarean section.

Response from Mary King, MD, and Peter S. Bernstein, MD, MPH

First, the patient's underlying medical problem needs to be addressed. This is a much bigger issue than the use of clopidogrel. Close collaboration with other specialists that are caring for her is important. She should possibly be evaluated for the presence of occlusive vascular disease in either the coronary or peripheral arteries, and she should be evaluated for other risk factors for stroke, such as cardiac arrhythmia.[1] Medical therapy is recommended in some cases of carotid dissection, with anticoagulation or long-term aspirin cited as options. If the carotid dissection is related to atherosclerotic disease, recurrent dissection can occur, with an incidence of 3% at 3 years and 12% at 10 years. The recurrence most often involves a different cervical vessel. This risk of recurrence is the rationale for anticoagulation or aspirin.[2] Clopidogrel is a newer medication that is an alternative to aspirin.

Clopidogrel antagonizes platelet aggregation by preventing binding of fibrinogen to the adenosine diphosphate (ADP) receptor on platelets. This mechanism differs from that of aspirin, which functions as an irreversible inhibitor of cylco-oxygenase. Clopidogrel is used to prevent recurrent ischemic events in patients with a high-risk history or who have acute myocardial infarction (MI) or ischemic stroke, unstable or stable angina, previous MI, stroke or cerebral ischemia, peripheral vascular disease, or atrial fibrillation.

The relative effectiveness of clopidogrel and aspirin in preventing recurrent ischemic events has been the subject of numerous studies. A meta-analysis published in 2000[3] found that clopidogrel and ticlopidine, a similar drug, were modestly but significantly more effective than aspirin in preventing serious vascular events in high-risk patients. A more recent meta-analysis published in 2002[4] found that aspirin or another antiplatelet drug is protective in these patients and that clopidogrel may be more effective than aspirin; but the evidence is not yet conclusive. Aspirin has other effects on pregnancy, such as premature closure of the ductus arteriosus, that make it undesirable for use in the third trimester of pregnancy.

The use of clopidogrel during pregnancy raises 2 questions. The first involves teratogenicity. Preclinical studies reported to the United States Food and Drug Administration showed no adverse reproductive effects of the drug on pregnancy in rats and rabbits at doses 65 and 78 times the recommended human dose.[5] This information earned it a rating of pregnancy class B. However, there are only 2 case reports of use of clopidogrel in pregnancy, and experience is limited. The second issue involves whether clopidogrel needs to be discontinued later in pregnancy. As it works on a different pathway than aspirin to prevent platelet aggregation, the concern over aspirin's effect on prostaglandins is not relevant. Clopidogrel can be used throughout pregnancy.

There may be another issue related to delivery, however. The patient in question is planning to have a repeat cesarean, and there is some evidence that clopidogrel may cause more hemorrhagic complications of surgery. The literature shows increased intraoperative bleeding in nonpregnant patients when clopidogrel is continued through the perioperative period. For example, there is an increase in the number of hemorrhagic complications in patients undergoing coronary artery bypass surgery while taking clopidogrel, with more surgical re-exploration, red-blood cell transfusions, and use of cryoprecipitate.[6]

The patient may also be at risk for postoperative bleeding. In the single case report on the use of clopidogrel during pregnancy, the medication was continued through the perioperative period because of the high level of concern for the patient's cardiac status after an MI and cardiac stent placement during the pregnancy; an uncomplicated cesarean was performed. The patient then experienced occult postoperative bleeding; her hemoglobin level decreased from 11.3 g/dL to 6.3 g/dL, and she required transfusion of 4 units of packed red blood cells. This experience is consistent with the findings reported in nonpregnant surgical patients.

In addition, there are several reports of epidural hematoma attributed to clopidogrel, and regional anesthesia is generally contraindicated in patients taking this medication. If regional anesthesia is impossible for the cesarean delivery, the patient faces the increased risk of general anesthesia in pregnancy. Discontinuing clopidogrel 1 week before surgery has been suggested, but there still may still be concern about the risk of bleeding at the time of placement of the epidural or spinal anesthetic. Again, experience with this medication is very limited. The decision about whether to hold the medication 1week prior to surgery and then resume postoperatively should be made in consultation with the patient's physician who prescribed the drug.

As with many medications in pregnancy, its use requires an assessment of the risks and benefits for the particular patient.

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