For years, doctors have known these commonly prescribed blood-pressure drugs aren't safe during the second and third trimesters due to their association with birth defects. So, physicians have routinely switched women to other medications once they find out they were pregnant. An estimated 5 percent to 8 percent of women develop high blood pressure, or hypertension, during pregnancy, according to the March of Dimes.
But the new study suggests the wisest course is to avoid ACE inhibitor (angiotensin-converting enzyme) drugs during the entire pregnancy.
"We found there was a three-fold increased [overall] risk of birth defects to infants whose mothers took ACE inhibitors the first trimester, compared to infants whose mothers took no blood-pressure medication," said study lead author Dr. William O. Cooper, associate professor of pediatrics at Vanderbilt University School of Medicine.
The study findings appear in the June 8 issue of the New England Journal of Medicine.
The study results prompted the U.S. Food and Drug Administration to hold a news briefing Tuesday afternoon. Additional research is needed before any assessment of ACE inhibitor use in early pregnancy can be made, said Drs. Robert Temple, associate director for medical policy, and Sandra L. Kweder, deputy director of the Office of New Drugs at the Center for Evaluation and Research.
"If women are thinking about becoming pregnant, they should talk to their doctors" about the most appropriate blood-pressure medication, Temple said.
The study found the risk of cardiovascular defects was nearly four times higher in children of women who took ACE inhibitors, compared with children of women who didn't take any blood-pressure medicine. In addition, central nervous system birth defects were four times higher among the children of women who took ACE inhibitors.
Fetal exposure to other blood-pressure medications during the first trimester did not produce an increased risk of birth defects, the study found.
Cooper and his colleagues studied 29,507 infants, all enrolled in Tennessee Medicaid and born between 1985 and 2000. The researchers identified 209 babies exposed to ACE inhibitors during the first trimester only; 202 exposed to other types of blood-pressure-lowering medicine during the first trimester alone; and 29,096 infants with no exposure to blood-pressure drugs during at any time during the pregnancy. Then, the researchers identified major birth defects from hospitalization claims and vital records during the first year of life.
"We adjusted for other factors known to be associated with birth defects, such as diabetes," Cooper said.
Major birth defects were found in 856 babies, or 2.9 percent; 203 had more than one defect. Problems included cardiovascular defects; musculoskeletal defects such as upper limb difficulties; gastrointestinal problems; central nervous system defects such as spina bifida; and urologic defects.
It's not known how ACE inhibitors increase the risk of birth defects, Cooper said. "ACE inhibitors inhibit an enzyme, that is how they affect blood pressure. This same enzyme is present in the fetal heart, kidney and brain during the time the organs are being formed. Interfering with that angiotensin enzyme function during the period of organ formation could interfere with the proper formation of organs," he said.
In an accompanying editorial in the journal, Dr. Jan Friedman of the University of British Columbia, Vancouver, Canada, discussed the relative lack of information on potential problems caused by ACE inhibitor use early in pregnancy. Animal studies have not found an increased risk of birth defects, but he added that "there actually has been very little information available to answer this question."
Friedman said more research is needed. Of the Cooper study, he said, "This is not the last word on the subject, but it is shocking to realize, it is almost the first."
Friedman also noted the difficulty of determining a risk-benefit profile for a mother and fetus when prescribing a drug for a pregnant patient. The risks to an unborn baby are unknown for more than 90 percent of the prescription drugs approved in the United States between 1980 and 2000, he said, citing a 2002 report in the journal Obstetrics and Gynecology.
"Women of childbearing age put on an ACE inhibitor should discuss [with their doctor] the possibility that these drugs can cause birth defects if they become pregnant," he said.
Each year in the United States, an estimated 120,000 babies are born with birth defects, such as cystic fibrosis, Down syndrome, heart defects, cleft lip and palate, and other problems. While both genetic and environmental factors, or a combination of the two, can lead to defects, the cause of about 70 percent is unknown, according to the March of Dimes.