Postmarketing Surveillance for Angiotensin-Converting Enzyme Inhibitor Use During the First Trimester of Pregnancy -- United States, Canada, and Israel, 1987-1995

Angiotensin-converting enzyme inhibitors (ACEIs) are effective antihypertensive drugs, but use of ACEIs during the second and third trimesters of pregnancy has been associated with a pattern of defects known as ACEI fetopathy. The predominant feature of the fetopathy is renal tubular dysplasia. Other associated conditions include hypocalvaria, intrauterine growth retardation (IUGR), and patent ductus arteriosus (PDA). These features may be related to fetal hypotension secondary to ACEI-induced decreases in fetal angiotensin or increased bradykinin (1,2). Although no adverse fetal effects have been linked to first trimester use of ACEIs, there has been no systematic evaluation of births to women with such exposures. To determine whether features of ACEI fetopathy occurred after first trimester exposure, in 1992 the Organization of Teratology Information Services (OTIS) in North America initiated the ACEI Registry; two members of the European Network of Teratology Information Services agreed to participate. This report presents findings from the ACEI Registry, which indicate that the infants of 66 women who self-reported first trimester only exposure to ACEI showed no evidence of renal tubular dysplasia.

Teratology information services (TISs) are used by pregnant women or physicians to inquire about potentially teratogenic effects of prenatal exposures. The ACEI Registry included women who directly or indirectly through physicians contacted one of seven TISs during their pregnancy about first trimester exposure to an ACEI. These women conceived during 1986-1994. All participating TISs used a standard form to report exposure details, delivery outcomes, and specific fetal or infant features associated with ACEI fetopathy. Renal function, growth retardation, and skull ossification defects were assessed.

Of 79 women enrolled, 66 (84%) had ACEI exposure limited to the first trimester of pregnancy (less than or equal to 14 weeks' gestation, as measured since the time of their last menstrual periods). These women had 48 live births from 1987 through 1995 (Table_1). The rate of spontaneous abortion among these women was 23%.

Among the 48 live births, three cases of IUGR were documented. One infant with IUGR was from twins delivered at 36 weeks' gestation; the other two were full-term. Another child had a PDA that required surgical ligation at age 18 months. That infant was born at 40 weeks' gestation to a woman who discontinued therapy with an ACEI at 71/2 weeks' gestation. She also was treated with digoxin throughout her pregnancy and with warfarin sodium for the first 5 weeks followed by heparin throughout the remainder of her pregnancy. There were no children with renal tubular dysplasia who had been exposed to ACEIs exclusively during the first trimester.

Reported by: M Feldkamp, MSPH, Pregnancy RiskLine; Organization of Teratology Information Svcs, Salt Lake City. KL Jones, MD, California Teratogen Information Svc, San Diego. A Ornoy, MD, Israel Teratology Information Svc, Jerusalem. A Pastuszak, MS, Motherisk Program, Toronto. S Rosenwasser, MEd, Massachusetts Teratogen Information Svc, Boston. B Schick, MS, Pregnancy HealthLine, Philadelphia. J Bar, MD, Beilinson Teratology Information Svc, Petah Tiqva, Jerusalem. Birth Defects and Genetic Diseases Br, Div of Birth Defects and Developmental Disabilities, National Center for Environmental Health, CDC.

Editorial Note

Editorial Note: ACEIs increased in popularity during the 1980s and have been promoted as first-line therapy for some persons with chronic hypertension and for the prevention of diabetic nephropathy, thus creating the potential for frequent ACEI exposure among women of childbearing age (1,3). In 1992, the Food and Drug Admin-istration warned physicians against prescribing ACEIs to women in their second or third trimester of pregnancy. Because only case reports exist for ACEI exposure during pregnancy, the degree of risk for ACEI fetopathy is unknown.

The findings in this report document no evidence of renal tubular dysplasia or hypocalvaria among the 48 infants born to women with exposure to ACEIs ending at less than or equal to 14 weeks. However, the number of exposures reported thus far to the registry is too small to determine conclusively that exposure to an ACEI exclusively during the first trimester is not associated with the features of ACEI fetopathy. Whenever possible, pregnant women who are using ACEIs should be changed to another antihypertensive medication to maintain normal blood pressure.

It is unknown whether first trimester exposure to ACEIs was associated with the development of IUGR in the three infants in this study because other known risk factors (i.e., multiple gestation or maternal hypertension) for IUGR were present. In addition, because no controls were included in this study, the rate of IUGR or spontaneous abortion (23%) among infants in the ACEI Registry could not be compared systematically with the rate in an unexposed cohort. Approximately 15% of all recognized pregnancies in the United States end with fetal loss, but the distinctive risk factors of women in the ACEI Registry limit comparisons to the U.S. population (4).

In previous reports of seven infants with PDAs who were exposed prenatally to ACEIs during the second and third trimester, a definite cause-and-effect relation was not established (1). Based on the possible effect of ACEIs on the fetal bradykinin-prostaglandin system, prenatal exposure to ACEIs might inhibit ductal closure. Although this may explain inhibition of ductal closure in infants whose mothers continue using the drug into the third trimester of pregnancy, it is an unlikely mechanism to explain PDA in the child reported to the ACEI Registry.

Because ascertainment of exposures among pregnant women by TIS is voluntary, data may be affected by selection bias, thus limiting the generalizability of these and other registry data. However, ongoing collection of detailed prospective exposure information combined with collection of clinical outcome data through these services can be an effective method for providing early warning of the potential teratogenic effects of drugs.

Another method of postmarketing surveillance involves using collaborating birth defect registries for case-control studies of associations between specific outcomes and drug exposures (5). This approach allows for collection of information about a wider range of exposures. CDC, in collaboration with several state-based birth defects programs, has initiated the Birth Defects Risk Factor Surveillance Program, an ongoing case-control study of a variety of birth defects and exposures. A third approach, established by the International Clearinghouse for Birth Defects Monitoring Systems (6), is a retrospective, case-only evaluation of drug exposures and birth defects (7).

OTIS member-information services operate in 24 states * and the District of Columbia. Local TIS telephone numbers for reports and consultation about ACEI and other pregnancy exposures are available on the World-Wide Web at http://orpheus.ucsd.edu/ctis/index.html, or by contacting the OTIS Information/Pregnancy RiskLine, telephone (801) 328-2229.

References

1. Barr M Jr. Teratogen update: angiotensin-converting enzyme inhibitors {Review}. Teratology 1994;50:399-409.

2. Shotan A, Widerhorn J, Hurst A, Elkayam U. Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use. Am J Med 1994;96:451-6.

3. Bakris GL. Angiotensin-converting enzyme inhibitors and progression of diabetic nephropathy. Ann Intern Med 1993;118:643-4.

4. Ventura SJ, Taffel SM, Mosher WD, Wilson JB, Henshaw S. Trends in pregnancies and pregnancy rates: estimates for the United States, 1980-92. Hyattsville, Maryland: US Department of Health and Human Services, Public Health Service, CDC, National Center for Health Statistics, 1995. (Monthly vital statistics report; vol 43, no. 11, suppl).

5. Kallen B, Mastroiacovo P, Lancaster PAL, et al. Oral contraceptives in the etiology of isolated hypospadias. Contraception 1991;44:173-82.

6. Erickson JD. The International Clearinghouse for Birth Defects Monitoring Systems: past, present and future. Int J Risk Safety Med 1991;2:239-48.

7. Robert E, Vollset SE, Botto L, et al. Malformation surveillance and maternal drug exposure: the MADRE project. Int J Risk Safety Med 1994;6:75-118.

* Alabama, Arizona, Arkansas, California, Connecticut, Florida, Georgia, Illinois, Indiana, Kansas, Maryland, Massachusetts, Minnesota, Missouri, Nebraska, New York, North Carolina, North Dakota, Pennsylvania, Texas, Utah, Vermont, Washington, and Wisconsin.

TABLE 1. Pregnancy outcome based on timing of exposure to
angiotensin-converting enzyme inhibitors (ACEIs), by week of
last exposure * -- United States, Canada, and Israel, 1987-1995
=====================================================================
                               Week of last exposure
                               ----------------------
Pregnancy outcome               <=14>14     Total
---------------------------------------------------------------------
Live-born infants                 48 +           13        61
 Major malformations               1 &            1 @       2
Spontaneous abortions             15              0        15
Induced abortions                  5              0         5

Total (mothers)                   66             13        79
---------------------------------------------------------------------
* Based on weeks following the beginning of last menstrual period.
+ Includes two sets of twins.
& Patent ductus arteriosus.
@ Renal tubular dysplasia.
=====================================================================

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