Statins May Prevent Some Miscarriages in a Mouse Model

MedPage Today—October 14, 2008

Reviewed by Zalman S. Ahus, M.D., Emeritus Professor
University of Pennsylvania School of Medicine

Pregnancy loss associated with antiphospholipid antibodies might be prevented with statin drugs, said researchers here. In a mouse model of antiphospholipid syndrome, treatment with simvastatin (Zocor) and pravastatin (Pravachol) reduced miscarriage by approximately 70%, reported Guillermina Girardi, Ph.D., of Hospital for Special Surgery, and colleagues in the October issue of the Journal of Clinical Investigation.

"We postulate that statins may be a good treatment for women with antiphospholipid-induced pregnancy complications," they wrote.

But Dr. Girardi urged clinicians to await the outcome of clinical studies before prescribing them for this purpose.

Antiphospholipid antibodies are seen in 3% to 7% of women of child-bearing age. They have traditionally been associated with excessive blood coagulation and thrombosis, and treatment has typically involved anti-coagulants such as warfarin.

Excessive clotting has been thought to trigger miscarriages by creating placental infarctions, killing the fetus.

But recent studies have suggested that the coagulation dysfunction may be secondary to an inflammatory process and is not the true cause of fetal loss.

In particular, antiphospholipid antibodies appear to activate the C5a complement pathway, inducing expression of tissue factor, which has both pro-coagulant and pro-inflammatory properties.

In their study, Dr. Girardi and colleagues created different types of transgenic mice in which tissue factor's inflammatory activity was disabled but its ability to trigger coagulation was left intact.

No increase in fetal loss was seen in these mice when they were dosed with antiphospholipid antibodies, suggesting that coagulation is not the mediator of fetal death.

These and other experiments pointed to neutrophils activated by the complement-tissue factor pathway as the real cause of fetal loss in the mice.

Because statins inhibit expression of tissue factor -- in addition to their cholesterol-lowering ability -- the researchers focused on these drugs as a possible therapy.

In ordinary mice dosed with antiphospholipid antibodies, the fetal loss rate was about 40%. When they were co-treated with simvastatin or pravastatin, the loss rate declined to about 10%, the researchers found.

The drugs also reduced expression of tissue factor and its chief receptor on neutrophils.

In an accompanying editorial, Hartmut Weiler, Ph.D., of the Blood Center of Wisconsin in Milwaukee, called the research elegant, clever, and stimulating.

"Acknowledging that there are limits in transferring findings from the mouse model to humans," he wrote, "the data to date suggest that thrombosis and placental infarction seen in a subset of pregnancies in women with antiphospholipid syndrome may reflect more of a complicating epiphenomenon rather than the causative pathogenic mechanism of antiphospholipid-mediated disorders of pregnancy."

He said the study also "provides a strong rationale for further exploring the therapeutic potential of statin drugs in antiphospholipid-induced pregnancy complications."

Dr. Girardi said the study's findings could also have implications for other chronic inflammatory diseases. Such conditions as rheumatoid arthritis, sepsis, Crohn's disease, and atherosclerosis are believed to involve the tissue factor pathway.

External funding for the study came from the National Institutes of Health.

Read the full story at Medpage Today.

Hospital for Special Surgery has issued a clarification statement regarding the use of statins by pregnant women.