Increasing exposure to angiotensin-converting enzyme inhibitors in pregnancy

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Increasing exposure to angiotensin-converting enzyme inhibitors in pregnancy Michael E. Bowen, MD, MPH; Wayne A. Ray, PhD; Patrick G. Arbogast, PhD; Hua Ding, MS; William O. Cooper, MD, MPH OBJECTIVE: The objective of the study was to identify angiotensinconverting enzyme (ACE) inhibitor prescription-filling trends in pregnant women. STUDY DESIGN: This was a retrospective cohort study in women con-

tinuously enrolled in Tennessee Medicaid during pregnancy who delivered a live infant or had a fetal death between 1986-2003 (n ⫽ 262,179). RESULTS: ACE inhibitor exposures increased more than 4-fold: from

11.2 per 10,000 pregnancies in 1986-1988 to 58.9 per 10,000 pregnancies by 2003 (adjusted risk ratio [RR], 4.49; 95% confidence interval [CI], 2.78-7.25). Exposures in the second and third trimesters

nearly tripled (RR, 2.88; 95% CI, 1.45-5.75) and did not decrease following a US Food and Drug Administration black box warning against such use in 1992. Exposures were most common among women 35 years of age or older. CONCLUSION: Despite evidence of fetal complications associated with ACE inhibitor use during pregnancy, the number of pregnant women with pregnancy-related ACE inhibitor exposures increased steadily between 1986-2003. Better methods are needed to reduce fetal exposure to potentially teratogenic prescribed medications.

Key words: angiotensin-converting enzyme inhibitor, pregnancy, prescription, teratogen

Cite this article as: Bowen ME, Ray WA, Arbogast PG, et al. Increasing exposure to angiotensin-converting enzyme inhibitors in pregnancy. Am J Obstet Gynecol 2008;198:291.e1-291.e5.

A

lthough angiotensin-converting enzyme (ACE) inhibitors are effective and relatively well-tolerated antihypertensives, their use during the second and third trimesters of pregnancy is contra-

From the Departments of Pediatrics (Drs Bowen and Cooper), Preventive Medicine (Dr Ray), and Biostatistics (Dr Arbogast and Ms Ding), Vanderbilt University School of Medicine, Nashville, TN. Presented at the International Society for Pharmacoepidemiology, Nashville, TN, Aug. 21-24, 2005. Received March 13, 2007; revised July 5, 2007; accepted Sept. 7, 2007. Reprints: William O. Cooper, MD, MPH, Child and Adolescent Health Research Unit, Vanderbilt Children’s Hospital, AA-0216 MCN, Nashville, TN 37232-8555; [email protected] This work was supported in part by the US Food and Drug Administration Contract 22302-3003; National Institute of Diabetes, Digestive, and Kidney Diseases Training Grant DK020593; and Agency for Healthcare Research and Quality Centers for Education and Research on Therapeutics Grant HS10384. 0002-9378/$34.00 © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2007.09.009

indicated. Fetal exposure during this period increases the risk of ACE inhibitor fetopathy, a constellation of findings that includes fetal hypotension, anuriaoligohydramnios, renal tubule dysplasia, hypocalvaria, and death.1-5 As a result, in 1992, the US Food and Drug Administration (FDA) issued a black box warning against the use of ACE inhibitors during the second and third trimesters of pregnancy.6 A recent study7 reported that first trimester– only exposure to ACE inhibitors, previously thought to be safe,8-11 was associated with a nearly 3-fold increased risk of major congenital malformations, including a nearly 3-fold increased risk of cardiovascular malformations and a nearly 4-fold increased risk for central nervous system malformations. Thus, the safety of ACE inhibitors at any time during pregnancy must be questioned, particularly given the availability of alternative medications to treat hypertension.1,3,12-15 Given the potential dangers of fetal ACE inhibitor exposure, it is important to document the magnitude of such exposure. However, there is little population-based information on the use of ACE inhibitors during pregnancy. Most

studies of this question have been case reports or case series or did not include more recent data. Thus, we conducted a large, retrospective cohort study in Tennessee Medicaid enrollees to describe trends of ACE inhibitor exposures during pregnancy.

M ATERIALS AND M ETHODS The study was conducted using Tennessee Medicaid data, for which computerized records of filled prescriptions provide a good record of maternal medication use. Links to vital records (birth, death, and fetal death certificates) files16 and medical records permitted identification of pregnant women, including estimated conception dates.17,18 Vital records and Medicaid enrollment files provided information on maternal and infant factors, including maternal age, race (from self-report on birth certificate), and county of residence. The date of the last menstrual period (LMP) was taken from the birth certificate when available (89.3% of all births) or estimated from birthweight using the raceand calendar year–specific distributions of gestational age for births with known LMP.19 In a previous study using the

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TABLE 1

Women giving birth and enrolled in Tennessee Medicaid throughout pregnancy, 1986-2003 Age 30 y or older, %

Enrolled because of disability, %

5964

10.8

6.4

1989-1990

8398

11.3

6.4

1991-1992

10,923

11.4

5.9

1993-1994

11,876

12.4

7.5

1995-1996

18,494

13.3

5.9

1997-1998

19,270

12.7

6.6

1999-2000

21,123

12.6

6.2

2001-2002

22,134

13.0

5.7

2003

19,853

12.6

6.9

Year

Women/year, n

1986-1988

.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................

Bowen. Increasing exposure to ACE inhibitors in pregnancy. Am J Obstet Gynecol 2008.

same databases,7 the birth certificate LMP was within 2 weeks of the LMP found in the medical record 94% of the time. The maternal use of prescribed medications was identified from Medicaid pharmacy files, which included the date that the prescription was filled and the prescribed days of medication supply up to a maximum of 31 days as limited by Tennessee Medicaid. Computerized pharmacy records have been shown to be an accurate source of medication data16 and have high concordance with patient self-report of medication use.7,16,20,21 Fetal medication exposure during a given trimester was defined as presence of 1 or more days of supply during the period. The first trimester was defined as the date of the LMP through the following 90 days, the second and third trimesters as the remainder of the pregnancy. Pregnancies were included in the study if the date of delivery was between Jan. 1, 1986-Dec. 31, 2003, and the mother was a Tennessee resident with complete information on the birth certificate for maternal age, date of delivery, maternal race, education, and county of residence. Pregnancies were further restricted to those in which the mother was enrolled in the Medicaid program from 30 days before the date of the LMP through the date of delivery or fetal death with no gaps in enrollment lasting longer than 30 days. There were 1,422,212 live births and 7909 fetal 291.e2

deaths in Tennessee between 1986-2003. Of the pregnancies resulting in these live births and fetal deaths, 624,574 were to women enrolled in Tennessee Medicaid at the time of delivery or fetal death. Of these pregnancies, 262,179 (41.9%) were in women who met enrollment criteria for the study. The study outcome was exposure to an ACE inhibitor during pregnancy, alone or in combination with another medication. The ACE inhibitors available during the study period included captopril, enalapril, lisinopril, ramapril, fosinopril, benazepril, quinapril, moexipril, trandolapril, perindopril, enalaprilat, captoprilhydrochlorothiazide, enalapril-hydrochlorothiazide, lisinopril-hydrochlorothiazide, moexipril-hydrochlorothiazide, fosinoprilhydrochlorothiazide, quinapril-hydrochlorothiazide, enalapril-felodipine, enalaprildiltiazem, benazepril-amlodipine, and trandolapril-verapamil. The mean duration of ACE inhibitor prescription supply was 29.3 ⫾ 3.2 days. Mothers who filled prescriptions for angiotensin II receptor blockers (n ⫽ 49) were not considered to have ACE inhibitor exposure. During the study years, we calculated the proportion of women with ACE inhibitor exposures during pregnancy for 2-year intervals, with 2 exceptions. Because of the limited sample size, we used a 3-year interval at the beginning of the study. To provide the most timely description of current practice, we calculated these proportions separately for

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2003, the last study year. For the same reason, some of the analyses are restricted to 2003 data. The proportions of pregnancies with ACE inhibitor exposure were adjusted for potential changes in maternal characteristics over time using the method of marginal prediction.22,23 Because such exposure was relatively infrequent (⬍10%), multiple Poisson regression was used to calculate estimated risk ratios (RRs). The regression models adjusted for maternal age, race, Medicaid enrollment category (which included participation in the Supplemental Social Security Income program, a marker for disability), and residence in a standard metropolitan statistical area. The unit of analysis was the individual pregnancy. To account for correlation because of a woman having multiple pregnancies during the study period, robust variance estimators were used to provide correct SEs and confidence intervals of the estimated risk ratios.24 All regressions were performed with SAS (v 9.1; SAS Institute, Cary, NC). Permission to perform the study and waiver of informed consent were obtained from the Vanderbilt University Institutional Review Board, the State of Tennessee Health Department, the TennCare Bureau, and the hospitals in which medical records were reviewed.

R ESULTS During the study period, the number of women giving birth who were enrolled in Tennessee Medicaid throughout pregnancy increased from 5964 per year (1986-1988) to 19,853 per year (2003; Table 1). The increase in pregnancies reflected the nationwide Medicaid expansions during the late 1980s and early 1990s25 and the introduction in 1994 of TennCare, Tennessee’s expanded Medicaid program.26 To determine whether the characteristics of the study population changed in ways that might alter the use of antihypertensive agents, we assessed trends in maternal age and serious chronic illness. The proportion of mothers who were older than 30 years of age changed little, with minor variation between 11-13%

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www.AJOG.org during the study period. Similarly, the proportion of mothers enrolled in the program because of disability, an important indicator of chronic disease in younger populations, was relatively stable throughout the study period, ranging between 6-7%. Exposures to ACE inhibitors during pregnancy increased more than 4-fold during the study period (Figure 1). There were 11.2 exposures per 10,000 pregnancies in 1986-1988; by 2003, the proportion of pregnancies with ACE inhibitor exposure had increased to 58.9 of 10,000 (RR, 4.49; 95% confidence interval [CI], 2.78-7.25). Exposures in the first trimester increased from 8.4 of 10,000 pregnancies in 1986-1988 to 54.4 of 10,000 pregnancies in 2003 (RR, 5.44; 95% CI, 3.16-9.36). Exposures in the second and third trimesters increased from 6.1 of 10,000 pregnancies in 1986-1988 to 17.6 of 10,000 pregnancies in 2003 (RR, 2.88; 95% CI, 1.45-5.75). There was no decrease in second- and third-trimester exposures following the FDA’s black box warning in 1992 (RR, 1.52; 95% CI, 0.95-2.44). Increased maternal age was strongly associated with exposure to ACE inhibitors during pregnancy (Figure 2). In 2003, the final study year, mothers younger than 25 years of age had 24.2 exposures per 10,000 pregnancies, whereas those 35 years of age or older had 255.77 of 10,000 pregnancies (RR 10.55; 95% CI, 6.12-18.21). For women giving birth during 2003, we assessed the exposure to ACE inhibitors according to the specific month of pregnancy (Table 2). Among the 117 exposed women, 84.6% had exposure during the first month, 77.8% had exposure during the second month, and 38.4% had exposure during the third month (Table 2). Thirty-five women (29.9%) had ACE inhibitor exposures during the second or third trimesters after clinical signs or pregnancy tests should have indicated pregnancy.

C OMMENT In the Tennessee Medicaid population, there was a strong secular trend of increased use of ACE inhibitors in preg-

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FIGURE 1

Pregnancy-related ACE inhibitor exposure

Pregnancy-related ACE inhibitor exposure among women enrolled in Tennessee Medicaid, 19862003 for any exposure during pregnancy, exposure during the first trimester, or exposure during the second or third trimesters. Proportions are adjusted for maternal age, reason for enrollment, residence in a standard metropolitan statistical area, and race. Bowen. Increasing exposure to ACE inhibitors in pregnancy. Am J Obstet Gynecol 2008.

nancy during the 18-year study period. By 2003, exposures to ACE inhibitors occurred in almost 60 of 10,000 pregnancies, substantially greater than the most recent published data by Andrade et al,27 reporting exposures in 7 of 10,000 pregnancies from 1996-2000. For women older than 35 years of age, exposures occurred in 3.9% of pregnancies. Exposures to ACE inhibitors during the second and third trimesters of pregnancy nearly tripled during the study period and did not decrease following the FDA’s 1992 black box warning. Could these findings simply reflect the unique nature of the Tennessee Medicaid population? The primary change that occurred during the study period was the increased number of women each year who were enrolled in Medicaid during pregnancy, which was due to both national expansions of Medicaid maternal coverage28 and the TennCare program,26 which extended Medicaid cover-

age in Tennessee to uninsured women. However, despite this population growth, maternal age, an important predictor of the risk of hypertension, and enrollment because of disability, a marker of serious chronic disease in younger populations, were relatively constant during the study years. Furthermore, the statistical analysis controlled for these factors. Additional evidence of the broader applicability of the study findings comes from national survey data showing that between 1995-2002, the prevalence of use of ACE inhibitors among women 15-44 years of age increased from 2.0% to 4.4%, such that by 2002, there were 2.7 million visits by 1544-year-old women in the United States associated with an ACE inhibitor prescription.7,29 Utilization of Medicaid pharmacy files minimizes concerns of selection bias, recall bias, and differential misclassification that may be associated with retro-

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FIGURE 2

Pregnancy-related ACE inhibitor exposure per 10,000 pregnancies with delivery of an infant during 2003

Pregnancy-related ACE inhibitor exposure per 10,000 pregnancies among women enrolled in Tennessee Medicaid who delivered an infant during 2003, according to maternal age. The proportions of pregnancies with ACE inhibitor exposure are adjusted for maternal age, reason for enrollment, residence in a standard metropolitan statistical area, and race using the method of marginal prediction. Error bars denote 95% confidence intervals. Bowen. Increasing exposure to ACE inhibitors in pregnancy. Am J Obstet Gynecol 2008.

spective assessment of medication exposures.20,30,31 However, these files have certain limitations. The prescription files indicate that a woman filled an ACE Inhibitor prescription during pregnancy, but the files cannot detect whether the prescription was taken as prescribed. It is possible that women may have stopped medication use after the pregnancy was diagnosed, but in many cases, women continued to fill ACE inhibitor prescriptions into the second and third trimesters of pregnancy. We believe that the increased use of ACE inhibitors in pregnancy reflects 2 factors.

First, the indications for these medications have expanded. A growing body of literature has supported the use of ACE inhibitors in both hypertensive30 and diabetic patients. In 1994, the guidelines recommending the use of ACE inhibitors to prevent diabetic nephropathy were released.31 Second, the growing population of women delaying childbirth until after age 35 years32 and the earlier onset of type 2 diabetes mellitus33 has resulted in an increased prevalence of hypertension and diabetes among women who become pregnant,34 thus increasing the likelihood of fetal ACE inhibitor exposure.

TABLE 2

ACE inhibitor exposure by month of pregnancy for women enrolled in Tennessee Medicaid during the final study year (2003) Month of pregnancy

Exposed, n

1

2

3

4

5

6

7

8

9

99

91

45

26

18

15

8

9

7

..............................................................................................................................................................................................................................................

Exposures per 10,000 pregnancies 49.9 45.8 22.7 13.1

9.1

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7.6 4.0 4.5 3.5

Recent recommendations from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure30 now suggest ACE inhibitors as first-line antihypertensive therapy in hypertensive diabetic patients. Consequently, the number of women of reproductive age exposed to ACE inhibitors is likely to continue to increase. Thus, without effective measures to limit ACE inhibitor use during pregnancy, the trend of increased fetal exposure is also likely to continue. The growing number of women of older age and with chronic illness who become pregnant will require better methods to protect fetal health. Medications that may adversely affect the developing fetus are likely to be prescribed for many of these women. However, given that nearly half of all pregnancies are unplanned,35 there are formidable practical difficulties in avoiding first-trimester exposures. Although women in this study may have filled a prescription during pregnancy prior to having their first prenatal visit, previous studies utilizing a similar TennCare population showed that only 6.7% of women exposed to ACE inhibitors during pregnancy had prenatal care beginning after 4 months of pregnancy.7 Efforts to reduce exposures to ACE inhibitors during pregnancy should include both physician and patient education about the use of ACE inhibitors in women of child-bearing age. Appropriate counseling on the risks and benefits of these medications should be performed at the initiation of ACE inhibitor therapy. Only recently has information regarding the dangers of first-trimester use of ACE inhibitors been published7, and the impact of these findings was not reflected in the current study. It is not trivial to assure the safety of medication use in later pregnancy exposures, as is underscored by our finding of persistent and increasing late-pregnancy exposure to ACE inhibitors, despite an FDA black box warning. Despite the large study population, the current study was not adequately powered to detect differences in fetal or neonatal death related to ACE inhibitor exposure. In addition, the du-

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www.AJOG.org ration of treatment and dose effect of exposure to ACE inhibitors were not assessed in the current study; however, future study of these issues will be important. In conclusion, despite the evidence of fetal complications associated with ACE inhibitor use during pregnancy, the number of pregnant women enrolled in Tennessee Medicaid with pregnancy-related ACE inhibitor exposures increased steadily between 1986-2003. The FDA black box warning did not appear to be effective at reducing second- and thirdtrimester use. Thus, there is an urgent need for better methods to reduce fetal exposure to potentially teratogenic prescribed medications. f ACKNOWLEDGMENTS Funding was provided by FDA (Contract 22302-3003) for the design and conduct of the study, data collection, and management. The National Institute of Diabetes, Digestive, and Kidney Diseases (training grant DK020593) provided salary support for study design, data interpretation, and manuscript preparation. The Agency for Healthcare Research and Quality Centers for Education on Research and Therapeutics (HS-10384) provided support for the design and conduct of the study, data analysis, and management. Vital records data were provided by the State of Tennessee Department of Health. TennCare data were provided by the TennCare Bureau. Michael E. Bowen, MD, MPH, had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. Drs Arbogast and Ray report receiving grant support from Pfizer for a study unrelated to the study reported in this manuscript. Dr Ray reports having received consulting fees from Pfizer for work unrelated to the study reported in this manuscript.

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