Angiotensin-converting enzyme (ACE) inhibitors are some of the most frequently prescribed antihypertensives in the United States.1,2 Prior studies of ACE inhibitors demonstrated that use of these medications during the second or third trimesters of pregnancy can have direct toxic effects on the developing fetal kidney with resultant secondary complications of oligohydramnios, fetal growth restriction, skull defects, infant anuria and renal failure, and death.3-5 Thus, these agents were contraindicated during the second half of pregnancy.
Interestingly, little was known about the effects of ACE inhibitors when taken early during pregnancy. This information is important because of the timing of organ formation during gestation, which occurs primarily in the first 4 to 7 weeks after the last menstrual period.3 Because angiotensin II receptors are widely expressed in fetal tissue and could play an important role in fetal development,6,7 it is possible that first trimester exposure to ACE inhibitors increases the risk of congenital malformations. Data regarding the risk of pregnancy-related exposures came from a limited number of studies in animals and analyses of case reports, which provided only limited information on possible risks.8-12
The purpose of the ACE Inhibitors in Early Pregnancy study was to clarify the safety of the use of ACE inhibitors during pregnancy by conducting an epidemiologic study using a large Medicaid database.13 The study linked Tennessee Medicaid records of filled prescriptions and medical records of pregnant women to their infants' medical and vital records from 1985 to 2000 to identify the risk of major congenital malformations among women who filled the medications of interest as a part of their routine medical care.13 First trimester exposure to ACE inhibitors occurred in 209 children who were compared with 29,096 unexposed children and 202 children with first trimester exposure to other antihypertensives. This review describes the findings from the study and provides key clinical insights drawn from the study's conclusions.
The 29,507 study births included 411 infants who had first-trimester-only fetal exposure to antihypertensive medications. When compared with the 29,096 infants without any fetal antihypertensive exposure, the former had mothers that were older; had higher education; were more likely to be multigravid, live in rural counties, and have 1 or more chronic health conditions; and were less likely to have late prenatal care. There were 209 infants with first-trimester-only fetal exposure to ACE inhibitors and 202 infants with first-trimester-only exposure to other antihypertensive medications. The maternal characteristics for these infants were generally similar, although the ACE inhibitors-exposed infants had mothers who were slightly older and who had higher education.14
Major congenital malformations were seen among 856 infants (2.9%) in the cohort; 203 had more than 1 malformation (Table 1). Among infants with first trimester exposure to ACE inhibitors, 7.1% had any major congenital malformation. Compared with infants with no exposure to any antihypertensive medications, among whom 2.6% had any major congenital malformation, the adjusted risk of major congenital malformations was increased more than 2-fold (Table 1). The increased risk of major congenital malformations resulted primarily from increases in cardiovascular malformations and central nervous system malformations. The proportions and risk factors were adjusted for potential confounders, including maternal year of delivery, age, race, rural residence, quartile of neighborhood income, and maternal chronic illness (epilepsy, sickle cell disease, asthma, renal disease, neoplastic disease, cardiovascular disease [other than hypertension or diabetes], HIV infection, cystic fibrosis, autoimmune diseases, chronic mental illness, obesity, migraine headaches, Crohn disease, ulcerative colitis, organ transplant). The risks of any congenital malformations (occurring in 1.7% of infants) and risks of specific organ system malformations, including cardiac malformations, were not increased in infants with first trimester exposure to other antihypertensives when compared with infants with no antihypertensive exposure.
Table 2 describes the characteristics of the 18 infants with first trimester ACE inhibitor exposure. The age of the mothers ranged from 17 to 41 years, and infants had gestational ages ranging from 32 to 41 weeks. All but 1 of the infants was from a singleton pregnancy. All but 3 of the infants had been exposed to ACE inhibitors during at least 2 months of the first trimester. For 8 of 9 infants with cardiac malformations, the diagnosis was confirmed through medical record review of echocardiogram or other diagnostic test results. Seven of the infants had multiple malformations.
Key Clinical Insights
In a large population-based epidemiologic study, we found that fetal exposure to ACE inhibitors during the first trimester was associated with a risk of a major congenital malformation nearly 3 times as great as the risk with no fetal exposure to ACE inhibitors.14 Although this was an exploratory study whose findings should be confirmed, there are some important clinical insights that can be drawn from the study's conclusions.
First, despite prior clinical opinion that ACE inhibitors early in pregnancy were safe for the fetus, the findings of this study call these opinions into question. Our data suggest that such exposures are not safe and should be avoided. Healthcare providers who care for women with chronic health conditions who may be prescribed an ACE inhibitor during pregnancy should be made aware of these findings and should explore other treatment options for women. Given the fact that several other alternative medications are available to treat hypertension, these alternatives should be chosen when treating a pregnant woman with hypertension or a woman who is planning to become pregnant.
Second, women who are taking these medications should be educated about the potential risks and should take steps to prevent pregnancy. If a woman does become pregnant while taking an ACE inhibitor, she should be immediately switched to another medication to reduce the risk of adverse fetal effects.1 Detailed fetal ultrasonography and echocardiography should be offered during the second trimester (around the 18th week of gestation) to women who have taken ACE inhibitors during the first trimester. Given that the malformations found in the study were not universally life-threatening or disabling (eg, atrial and/or ventricular septal defects), the specific risks should be explored further with a woman in such a situation.
Third, these study findings highlight the relative paucity of information on pregnancy-related risks of medication exposures. For example, of the 47 other oral antihypertensive medications included in the "Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure,"15 only 8 have sufficient data to determinate the teratogenic potential of the medication.1 Despite the dearth of information, national data suggest that use of ACE inhibitors continues to rise in women of child-bearing age. Data from the National Center for Health Statistics have demonstrated that between 1995 and 2002, use of ACE inhibitors by women aged 15 to 44 years increased by 83%, such that in 2002, 2.7 million visits to a healthcare provider by women in this age range were associated with an ACE inhibitor prescription.2 Thus, further study in this area is urgently needed.
This study was one of the first large epidemiologic studies to assess the risks of pregnancy-related exposures to ACE inhibitors. The study used a nonexposed comparison group and a group of infants whose mothers took other antihypertensive medications. Several potential confounders were included in study analyses, and women with diabetes were excluded from the study cohort because of the previously described relationship between diabetes and congenital malformations.16,17 Potential outcomes were all validated through medical record review, with condition specific definitions applied for each malformation.
Limitations of the study included the fact that exposure information was recorded from filled prescriptions. It is possible that a woman may have filled a prescription but stopped taking the medication when she learned she was pregnant. This would attenuate the observed association though and thus cannot explain our findings. Although we used previously described definitions of major malformations, some of the malformations (ie, patent ductus arteriosus) may be present at birth and resolve spontaneously without long-term sequelae. In sensitivity analyses in which we excluded infants with patent ductus arteriosus, the association between exposures to ACE inhibitors and major malformations remained.
Conclusions and Future Directions
Further information on the pregnancy risks of ACE inhibitors and almost every other medication potentially used by pregnant women is needed. Thus, well-controlled studies to identify these risks should be undertaken. Until such information is available, alternative medications to ACE inhibitors should be considered in women of child-bearing age who are pregnant or who are likely to become pregnant while taking the medication.
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