US Centers for Disease Control
Postmarketing surveillance for angiotensin-converting enzyme
inhibitor use during the first trimester of pregnancy
Morb Mortal Weekly Rep
(Mar) 46:No. 11 1997
The full text of this report follows below, courtesy of the U.S.
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
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
Services (OTIS) in North America initiated the ACEI Registry; two members
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
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
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
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
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
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
Environmental Health, CDC.
Editorial Note: ACEIs increased in popularity during the 1980s and have
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
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
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
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
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
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.
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
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
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
* Alabama, Arizona, Arkansas, California, Connecticut, Florida, Georgia,
Illinois, Indiana, Kansas, Maryland, Massachusetts, Minnesota, Missouri,
Nebraska, New York, North Carolina, North Dakota, Pennsylvania, Texas,
Vermont, Washington, and Wisconsin.