A New Hope for Preeclampsia

Pravastatin, a commonly prescribed drug for cardiovascular conditions, may help to dramatically reduce the incidience of preeclampsia in pregnant women.

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By Daniel Oppenheimer
Editor, Texas Health Journal

 

The benefits of a good drug to treat or prevent preeclampsia, which complicates 5-8% of pregnancies, would be immense. The condition, which is characterized by high blood pressure during pregnancy, is a major driver of preterm delivery, maternal injury and death, and worse short- and long-term outcomes for babies.

Researchers have been working for decades, with little success, on ways to treat preeclampsia or reduce the risk of developing it. They’ve tried blood pressure medications, antioxidant vitamins, salt restriction, aspirin, fish oil, and calcium, all with little or no effect. A new drug that dramatically reduced the risks would be a unicorn under any circumstances. That the new drug might in fact be an old drug, proven safe in many studies and already sold cheaply as a generic, would be extraordinary.

“Right now, for women who already have preeclampsia, we can provide magnesium sulfate to prevent them from getting seizures, and then at some point deliver the baby and placenta early,” said Dr. Maged Costantine, Professor of Obstetrics and Gynecology at The University of Texas Medica Branch in Galveston (UTMB). “There is some evidence that low-dose aspirin can reduce the risk of getting preeclampsia a bit if given early enough. That’s about it.

Dr. Maged Costantine, Professor of Obstetrics and Gynecology

Dr. Maged Costantine, Professor of Obstetrics and Gynecology

Back in 2007, not long after starting a fellowship in the lab of UTMB professor George Saade, Costantine approached Saade about the possibility that statins might be effective for reducing the risk of preeclampsia. At that point statins, which are a class of drugs known as HMG-CoA reductase inhibitors, had already taken the pharmaceutical world by storm. They effectively lowered cholesterol, reduced mortality for various forms of cardiovascular disease, and if taken preventively reduced the risk of developing a variety of cardiovascular conditions.

They were, and are, wonder drugs for people with cardiovascular conditions or at high risk of developing them. Except for pregnant women.  Because of some evidence that some statins may increase the risk of congenital anomalies, and because statins lower cholesterol, which can impact fetal development, the whole class of drugs has been designated “category X.” Providers don’t prescribe them for pregnant women. This is the case even for Pravastatin, which is the most water-soluble statin, and which only minimally crosses into the placenta.

Costantine had surveyed the research on how statins worked in men and women who weren’t pregnant, and there were clear similarities in the pathologies of preeclampsia and of cardiovascular diseases that were known to benefit from statins. There was also evidence that women who were diagnosed with preeclampsia during pregnancy were at higher risk, later in life, for cardiovascular disease. Maybe, he hypothesized, the drugs that helped with the latter would help with the former. Saade liked the hypothesis and encouraged Costantine to test it in an animal model the lab had been working with.

Dr. George Saade, Director of the Division of Maternal-Fetal Medicine at UTMB

Dr. George Saade, Director of the Division of Maternal-Fetal Medicine at UTMB

“I was enormously fortunate to be in Dr. Saade’s lab, which had the capacity to do these initial animal studies,” said Costantine. “Without that, the work couldn’t have moved forward.”

In the animal tests, Costantine, Saade and their colleagues began with pregnant mice that were medicated to develop a mouse version of preeclampsia later in their pregnancies. Some of the mice were also given Pravastatin, which is a commonly prescribed statin. The results were striking. The mice given Pravastatin were less likely to develop a preeclampsia-like disease. Their fetuses grew better, and the balance of pro-growth hormones in utero were healthier. They then tested the mechanisms through which Pravastatin may work, and determined the long-term outcomes of pups that were exposed to the drug in-utero. Not only did the drug prove safe long term, it also prevented the pups from developing several metabolic, vascular and neurologic abnormalities associated with preeclampsia.

The results of the animal trials were sufficiently positive that Costantine and his colleagues moved on to a double-blind trial of pregnant women who had a history of severe early preeclampsia in a prior pregnancy.[1] Although the trial was too small to allow for hard conclusions about the efficacy of Pravastatin, the results were promising. Of the ten women given placebos, four developed preeclampsia and five delivered before 37 weeks. None of the 10 women who were given a daily dose of 10 mg of Pravastatin developed the condition, and only one delivered before 37 weeks. There were no differences between the 2 groups in terms of negative side effects or bad birth outcomes. A subsequent human trial, the results of which haven’t yet been published, also found a significant decline in the rates of preeclampsia and preterm delivery. In addition, both studies showed minimal transfer of the drug to the fetus (as measured in the cord blood).

“From the best evidence we have for aspirin, the drop in rates is 10-20 percent,” said Costantine. “By comparison we are finding a huge drop.”

“This is a perfect story about how to move something from the lab to the clinic,” said Saade, Director of the Division of Maternal-Fetal Medicine at UTMB. “Dr. Costantine had the idea, then developed it into a protocol in the lab. He proved it in the lab multiple times, reconfirmed it several different times, proposed a mechanism, and took it to the next step in humans. If we were in another field, this is the point at which a pharmaceutical company would come in and fund the bigger trials necessary to move it further. But in obstetrics and gynecology, that’s much less likely to happen.”

The problem, said Saade, is the cost-benefit analysis for pharmaceutical companies. When making drugs for pregnant women the legal exposure is “very high and very long,” with companies being liable not just for bad outcomes during and right after the pregnancy, but for health effects that may surface in children years or even decades later. The potential profit, on the other hand, is much less than it would be for a drug for chronic disease, since pregnant women are only going to need a useful medication for the duration of their pregnancy. In the case of an FDA-approved drug like Pravastatin, which is already available as a generic, the incentives are even weaker.

The good news is that Saade and Costantine and their colleagues have recently been funded, by the National Heart Lung and Blood Institue (NHLBI), to conduct a much larger study to determine the effects of Pravastatin on pregnant women at high risk for preeclampsia. This study will be conducted at the NICHD-Maternal Fetal Medicine Units Network. If similar results emerge from the new trial, which includes 1,550 patients, it could be the tipping point for a major change in practice among Ob-Gyns.

“If the results are positive, then what likely will happen is one of the big professional associations, like the American College of Obstetricians and Gynecologists (ACOG), will begin a review process,” said Saade. “They’ll evaluate all the evidence, not just the one trial. If results are what we expect them to be, they’ll come out with new guidelines and recommendations that women who have previously had preeclampsia should be started on statins early in their pregnancies.”

Because providers are already technically able to prescribe Pravastatin as an off-label drug for pregnant women, the FDA won’t have to formally approve the new practice. The agency could decide to step in to review its use in pregnant women, but if the evidence base is strong, and groups like ACOG and the Society for Maternal and Fetal Medicine (SMFM) are on board, the FDA is unlikely to intervene.

Costantine and Saade are hopeful not just that Pravastatin will reduce the risk of preeclampsia for women with a previous experience of the condition, but for other at-risk women. They also see benefits that would extend far beyond the United States.

“If you take it globally, it is even more important,” said Saade. “Our health care system is usually able to prevent mortality in women who develop preeclampsia, and provide excellent care for babies who are born prematurely. Globally, however, women die from conditions like this all the time. When their babies are born prematurely, they’re much more likely to die. If the results of our bigger trial are similar to the pilots, this could be a big, big deal. Pravastatin is cheap, doesn’t require refrigeration, and doesn’t require special handling, all of which is important when you’re thinking globally.”

Even if Pravastatin doesn’t produce the results they hope, Saade and Costantine see a broader principle at stake. The medical profession, and the funding bureaucracies, have to find ways to fund and conduct more research on how various drugs impact pregnancy. The risks are real, but the potential benefits are too enormous to neglect.

“As Dr. Saade always says, pregnancy is a window to future health,” said Costantine. “A lot of the long-term conditions that affect populations start in pregnancy, and may develop in the first place, or take a more severe course, because they go untreated during pregnancy. Preventing these complications in pregnancy will improve the long-term health for so many women, and for their babies.”


[1] The trial was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and conducted through the Obstetrics Fetal Pharmacology Research Centers (OPRC) Network. Dr. Gary Hankins, Chair of the department of Obstetrics and Gynecology, was the PI for OPRC’s center at UTMB.