No Excuse for Marketing Ace Inhibitors to Pregnant Women

Evelyn Pringle October 20, 2006

In the wake of a study published in June 2006, in The New England Journal of Medicine found a higher rate of birth defects in infants born to mothers who filled prescriptions for Angiotensin-Converting Enzyme Inhibitors (ACE inhibitors), during the first trimester of pregnancy.

The FDA advised women to reconsider the use of those drugs before becoming pregnant.

“These are preliminary data,” Sandra Kweder, MD, deputy director of the FDA’s Office of New Drugs at the Center for Drug Evaluation and Research, told reporters in a teleconference when discussing the study. “But nonetheless,” she said, “women should seek to change their medicine as soon as they become pregnant.”

“I think what’s most important about the study,” Dr Kweder stated, “is that it just brings to light the importance of women carefully reviewing medication information with their health care providers before becoming pregnant or as soon as they become pregnant, and being aware of the potential risks of certain medicines.”

Drugs used in the treatment of hypertension are real money makers for the pharmaceutical industry because they need to be taken for life, once a patient is diagnosed with the condition and ACE inhibitors are the most commonly prescribed.

According to Web MD, there are currently 10 ACE inhibitors marketed in the US. In 2005, they collectively brought in $5 billion in sales, up 13% from 2004, according to the pharmaceutical market research firm IMS Health. They are the second most commonly prescribed class of drugs, and 149 million prescriptions for ACE inhibitors were written in 2005. The top three sellers are Lotrel, Altace, and Lisinopril.

Women typically represent a considerable portion of the hypertension market. A national survey reported by MSNBC, found that the number of ACE inhibitor prescriptions written for women of childbearing age rose from 1.4 million in 1995, to 2.7 million in 2002.

The American Heart Association defines high blood pressure as:

“Blood pressure is the force in the arteries when the heart beats (systolic pressure) and when the heart is at rest (diastolic pressure). It’s measured in millimeters of mercury (mm Hg). High blood pressure (or hypertension) is defined in an adult as a blood pressure greater than or equal to 140 mm Hg systolic pressure or greater than or equal to 90 mm Hg diastolic pressure.”

Blood pressure is regulated by the kidneys which act as filters to make sure that the body’s nutrients and water are in balance and that harmful chemicals are filtered out. The kidneys release hormones which tighten or widen arteries as needed to keep that balance in tact.

When blood vessels tighten, high blood pressure results and the heart has to work harder to keep blood flowing at the correct rate. High blood pressure also puts a strain on the blood vessels and kidneys, and persistent high pressure eventually weakens the entire cardiovascular system.

According to WebMD, ACE inhibitors widen or dilate blood vessels to improve the amount of blood the heart pumps and lower blood pressure.

The October 7, 2006 article “High Blood Pressure – Type of Medications,” in Market Day Word News, defines the other classes of drugs available for the treatment of hypertension and discusses their functions.

Diuretics, it says, are sometimes called “water pills” because they work in the kidney and flush excess water and sodium from the body.

Beta-blockers reduce nerve impulses to the heart and blood vessels which makes the heart beat slower and with less force so that blood pressure drops and the heart works less hard.

Angiotensin antagonists shield blood vessels from angiotensin II and as a result, the vessels become wider and blood pressure goes down.

Calcium channel blockers, the article explains, keep calcium from entering the muscle cells of the heart and blood vessels which causes the blood vessels to relax and pressure goes down.

Alpha-blockers reduce nerve impulses to blood vessels, which allows blood to pass more easily, causing blood pressure to go down.

Alpha-beta-blockers work the same way as alpha-blockers, it notes, but also slow the heartbeat, as beta-blockers do so that less blood is pumped through the vessels and the blood pressure goes down.

Nervous system inhibitors relax blood vessels by controlling nerve impulses which causes the blood vessels to become wider and the blood pressure to go down.

Vasodilators, it says, directly open blood vessels by relaxing the muscle in the vessel walls and cause the blood pressure to go down.

Medical professionals agree that untreated hypertension can lead to serious health problems for expectant mothers and their unborn infants. During pregnancy, according to experts at the Mayo Clinic, high blood pressure can decrease blood flow to the placenta, which affects a baby’s supply of oxygen and nutrients. This may slow the baby’s growth and increase the risk of preterm delivery. High blood pressure also increases the risk of placental abruption, in which the placenta prematurely separates from the uterus, the Mayo Clinic’s web site advises.

Preeclampsia, sometimes referred to as toxaemia, is the most common of the serious complications of pregnancy related to hypertension. The condition is characterized by increased blood pressure and protein in the urine, which is a sign of kidney problems.

According to the Mayo Clinic, it “is potentially life-threatening to mother and baby if allowed to develop and progress undetected.”

Even before the June 2006 study, ACE inhibitors already carried a “black box” warning, the strongest available, about birth defects when infants were exposed to the drugs during the second and third trimester of pregnancy.

“The reason for that is that we’ve known for at least a decade, if not longer,” Dr Kweder said, “that these drugs, when exposure occurs in the second half of pregnancy, are associated with abnormal kidney functions in infants, as well as sometimes abnormalities of the kidney anatomy itself.”

The warning was added in the early 1990s, after the FDA received numerous reports on babies with birth defects associated with the drugs. The label warned that ACE inhibitors could cause skull deformities, kidney failure, lung problems and even fetal death when taken in the last two-thirds of pregnancy.

The warning did not mention the first trimester, but it stated that use of ACE inhibitors should be stopped or discontinued as soon as possible when pregnancy is detected.

In light of the more than a decade old black box warning, critics say, there was no excuse for the drug makers marketing or doctors prescribing ACE inhibitors to pregnant women because another class of drugs was known to be as effective or better in treating hypertension.

According to an April 25, 2005 analysis, in the Archives of Internal Medicine, of the “Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial,” the much cheaper diuretics work as well or better in protecting against heart attacks, than the expensive ACE inhibitors, and in fact the analysis showed that diuretics offered more protection against congestive heart failure.

The study first reported in 2002, said that diuretics were more beneficial as initial treatment for high blood pressure for protecting against adverse cardiovascular outcomes.

This latest analysis showed that even among diabetics, and those with mildly elevated fasting glucose, which is a sign of pre-diabetes, diuretics were at least as effective, and possibly even more beneficial for some patients.

This ten-year study was the largest ever conducted to compare the different classes of drugs used to treat high blood pressure. The study was led by Jeffrey Cutler, a senior adviser at the National Institute of Health’s National Hear, Lung and Blood Institute. Based on the results of the analysis, the National Institute of Health announced that it intended to use about 600 medical professionals to spread the word to doctors that diuretics should be the first line of treatment for hypertension.

The latest birth defect study was conducted at Vanderbilt University in Nashville by Dr William Cooper, MD, MPH, and colleagues. The team studied the records for 29,507 infants who were enrolled in Tennessee’s Medicaid program and born between 1985 and 2000.

The researchers first identified mothers who filled prescriptions during the first trimester of pregnancy for ACE inhibitors or other high blood pressure medications and then checked the babies’ records for major birth defects not linked to genetics.

By reviewing the files, the researchers found 411 infants who were exposed to high blood pressure drugs during the first trimester of pregnancy only, and of those babies, 209 were exposed to ACE inhibitors. Of the 209 babies in the Ace inhibitor group, the researchers found that 18, or about 7%, were born with birth defects.

That number represents more than twice the rate of birth defects in babies born to mothers who did not use any kind of high blood pressure medication.

“We found that fetal exposure to ACE inhibitors restricted to the first trimester of pregnancy,” Dr Cooper wrote in the study, “an exposure that was previously considered to be safe, was associated with a risk of a major congenital malformation that was 2.7 times as great as the risk with no fetal exposure to ACE inhibitors or other antihypertensive medications.”

The mothers in the study ranged in age from 17 to 41, and the infants were born between 32 and 41 weeks of gestation. Some of the details on the birth defects seen in newborns exposed to ACE inhibitors during the first trimester included:

1. Cardiovascular malformations were the most common, affecting 9 infants;

2. Malformations of the central nervous system were the second most common in 3 babies; and

3. 7 infants had more than one malformation.

“We knew ACE inhibitors were a possible cause of adverse fetal outcomes when exposure occurred later in pregnancy,” Dr Copper said, “but it has not been well studied in the first trimester.”

“We were very surprised that even after controlling for other risk factors,” he noted, “the TennCare records we examined showed a clear increase in a broad range of birth defects following first-trimester-only exposures.”

The alternatives to ACE inhibitors that doctors should consider when treating pregnant women with high blood pressure, are diuretics, alpha-methyldopa, some beta-blockers, and the calcium-channel blocker nifedipine, according to the FDA.

In the meantime, the pharmaceutical companies, along with the doctors who helped them peddle the highly profitable ACE inhibitors to pregnant women, should be held accountable for the life-time care of any infants born with birth defects after the FDA added the black box warning to the drugs in March 1992.

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