© 2005 Wiley-Liss, Inc.

Birth Defects Research (Part A) 73:123–130 (2005)

Teratogen Update

Angiotensin II Receptor Antagonist Treatment during

Pregnancy
S. Alwan,1* J.E. Polifka,2 and J.M. Friedman1
1
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
2
Department of Pediatrics, University of Washington, Seattle, Washington
Received 9 August 2004; Accepted 4 November 2004

Angiotensin II (A-II) is the main effector of the renin-angiotensin system. A-II functions by binding its type 1
(AT1) receptors to cause vasoconstriction and retention of sodium and fluid. Several AT1 receptor antago-
nists—a group of drugs collectively called “sartans”— have been marketed during the past few years for
treatment of hypertension and heart failure. At least 15 case reports describe oligohydramnios, fetal growth
retardation, pulmonary hypoplasia, limb contractures, and calvarial hypoplasia in various combinations in
association with maternal losartan, candesartan, valsartan, or telmisartan treatment during the second or third
trimester of pregnancy. Stillbirth or neonatal death is frequent in these reports, and surviving infants may
exhibit renal damage. The fetal abnormalities, which are strikingly similar to those produced by maternal
treatment with angiotensin-converting enzyme (ACE) inhibitors during the second and third trimesters of
pregnancy, are probably related to extreme sensitivity of the fetus to the hypotensive action of these drugs.
Very little information is available regarding the outcome of human pregnancies in which the mother was
treated with an AT1 receptor antagonist during the first trimester, but animal studies have not demonstrated
teratogenic effects after maternal treatment with large doses of AT1 receptor antagonists during organogenesis.
We conclude that pharmacological suppression of the fetal renin-angiotensin system through ACE inhibition or
AT1 receptor blockade seems to disrupt fetal vascular perfusion and renal function. We recommend that
maternal treatment with AT1 receptor antagonists be avoided during the second and third trimesters of
pregnancy and that women who become pregnant while taking one of these medications be changed to an
antihypertensive drug of a different class as soon as the pregnancy is recognized. Birth Defects Research (Part
A) 73:123–130, 2005. © 2005 Wiley-Liss, Inc.

INTRODUCTION
The renin-angiotensin system (RAS) is important in the
normal physiological control of blood pressure, but in
pathological states the RAS may contribute to develop-
ment of cardiovascular and renal disease. The formation of
angiotensin I (A-I) is catalyzed from its precursor, angio-
tensinogen, by the enzyme renin, an aspartyl protease
synthesized and secreted by the kidney. No significant
biological function is known for A-I, which is rapidly
converted to angiotensin II (A-II) by angiotensin convert-
ing enzyme (ACE). ACE also catalyzes the degradation of
other substrates, such as the vasodilator bradykinin, into
inactive peptides. A-II, the main effector of the RAS, acts
by inducing vasoconstriction, aldosterone secretion from
the adrenal gland, vascular smooth muscle remodeling,
and retention of sodium and fluid by the renal tubules, all
of which contribute to elevation of the blood pressure
(Bauer and Reams, 1995; Kim and Iwao, 2000). Further-
more, A-II stimulates growth and activates intracellular
signaling pathways in renal and cardiovascular cells (Kim
and Iwao, 2000).
The molecular and cellular actions of A-II are mediated
through binding to A-II type 1 (AT1) and type 2 (AT2)
*Correspondence to: Sura Alwan, Department of Medical Genetics, Room
300H, Wesbrook Building, 6174 University Boulevard, University of British
Columbia, Vancouver, British Columbia, Canada.
E-mail: alwans@interchange.ubc.ca
Published online 24 January 2005 in Wiley InterScience (www.interscience.
wiley.com).
DOI: 10.1002/bdra.20102

Birth Defects Research (Part A): Clinical and Molecular Teratology 73:123–130 (2005)
124 ALWAN ET AL.
receptors in the plasma membrane of target organs. AT1
receptors are found abundantly in many adult tissues such
as blood vessels, heart, kidney, adrenal gland, liver, brain,
and lung. The main effects of A-II in elevating arterial
pressure and vasoconstriction are mediated through AT1
receptor binding (Fig. 1) (Dzau et al., 1994; Smith and
Timmermans, 1994; Inagami, 1999; Kim and Iwao, 2000).
The function of AT2 receptors is not yet well defined, but
they may have a role in fetal growth and development.
Expression of AT2 receptors is ubiquitous in developing
fetal tissues but rapidly diminishes after birth (Grady et al.,
1991; Dzau et al., 1994; Smith and Timmermans, 1994).
Recent evidence also suggests a role for AT2 receptors in
cardiovascular remodeling and an effect opposite to that of
AT1 receptors on blood pressure regulation (Johren et al.,
2004).
Although both AT1 and AT2 receptors are present dur-
ing renal morphogenesis, the two subtypes differ in recep-
tor expression and localization as renal development and
maturation proceed (Norwood et al., 1997; Sequeira Lopez
and Gomez, 2004). Immunohistochemical studies on ro-
dent embryos have shown that at the onset of renal devel-
opment, the expression of AT2 receptors is higher than that
of AT1 receptors and localized in areas of active mesen-
chymal differentiation and newly-formed nephrons (Tu-
fro-McReddie et al., 1995; Sequeira Lopez and Gomez,
2004). Grone et al. (1992), using autoradiographic tech-
niques, found only AT2 receptors in the kidneys of 17- to
26-week-old human fetuses. On the other hand, expression
of AT1 receptors is low during the early stages of renal
development, and increases later in pregnancy in the more
mature renal tissues. In rodents, expression of AT1 recep-
tors peaks around the first week of life (Tufro-McReddie et
al., 1993; Sequeira Lopez and Gomez, 2004). AT1 and AT2
receptors accounted for 24% and 76% of A-II binding,
Birth Defects Research (Part A) 73:123–130 (2005)
Figure 1. The renin-angiotensin system
(RAS).
respectively, in the undifferentiated metanephric mesen-
chyme of 14-day-old rat embryos. By GD 17, AT1 had
increased to 40% of the receptors and was confined to
mature nephron tissues. The spatial-temporal pattern of
the AT1 and AT2 receptors suggests a regulated develop-
mental program for angiotensin II in renal development
(Norwood et al., 1997; Guron and Friberg, 2000).
ACE inhibitors are commonly used in the treatment of
hypertension (Williams, 1988), other cardiovascular dis-
ease, and renal disease (Maschio et al., 1996) and in the
prevention of myocardial infarction (Pfeffer et al., 1992;
Hansson et al., 1999). By inhibiting ACE, these drugs block
the conversion of A-I to A-II (see Fig. 1). However, A-II
formation is not suppressed entirely by ACE inhibitors
because some production occurs through ACE-indepen-
dent alternative pathways (Hollenberg et al., 1998). As a
result, a number of common adverse effects, such as dry
cough, that have been associated with ACE inhibitor treat-
ment are attributed to inhibition of bradykinin breakdown
rather than blockage of A-II formation (Linz et al., 1995).
The effectiveness, relative safety, and popularity of RAS
inhibition as an approach to the treatment of cardiovascu-
lar disease has led to the development of nonpeptide AT1
receptor antagonists, which block the RAS in a different
way (Bauer and Reams, 1995; Birkenhager and de Leeuw,
1999; Doggrell, 2002). AT1 receptor antagonists interact
with amino acids on the transmembrane domains of the
AT1 receptor, displacing, and therefore antagonizing the
action of A-II (Fig. 1). Currently, eight orally effective AT1
receptor antagonists, also referred to as “sartans,” are mar-
keted for the treatment of hypertension (Table 1). Losartan
potassium (Lo et al., 1995; Goa and Wagstaff, 1996;
Schaefer and Porter, 1996), the prototype sartan drug, was
first introduced into clinical use in 1994. Candesartan cilex-
etil (Nishikawa, 1997), eprosartan (McClellan and Balfour,
 A-II RECEPTOR ANTAGONIST TREATMENT IN PREGNANCY
Table 1
Generic and Proprietary Names of AT1 Receptor
Antagonists
Generic Proprietary
Losartan potassium Cozaar
Candesartan cilexetil Atacand
Eprosartan mesylate Teveten
Irbesartan Avapro
Telmisartan Micardis
Valsartan Diovan
Tasosartan Verdia
Olmesartan medoxomil Benicar
1998), irbesartan (Pouleur, 1997; Ruilope, 1997; Croom et
al., 2004), telmisartan (Gil-Extremera et al., 2003), valsartan
(Markham and Goa, 1997; Anonymous, 1999), tasosartan
(Maillard et al., 2002) and olmesartan medoxomil (Brousil
and Burke, 2003) have subsequently been introduced. Al-
though these compounds differ slightly in their pharma-
cological properties (Gradman, 2002), they all selectively
and competitively block the AT1 receptor and thereby
inhibit the action of A-II more effectively than the ACE
inhibitors do (Howes and Christie, 1998; Pitt and Konstam,
1998). Sartans are as effective in lowering blood pressure as
ACE inhibitors but because they do not affect metabolic
pathways outside the RAS as ACE inhibitors do, AT1
receptor antagonists have a lower frequency of side effects
(Pitt and Konstam, 1998; Mann et al., 1999; Dina and Jafari,
2000; Chung et al., 2001; Rodgers and Patterson, 2001).
ANIMAL TERATOLOGY STUDIES
Treatment of a pregnant female with a drug or other
chemical may produce various kinds of developmental
toxicity. With respect to the sartans, distinguishing be-
tween the production of malformations by interference
with embryogenesis on one hand and a pharmacological or
physiological effect of AT1 receptor blockade on the func-
tioning fetal kidney on the other is critical to understand-
ing the nature of the risks associated with maternal treat-
ment during pregnancy.
Most animal teratology studies that have been con-
ducted on sartans remain unpublished and, therefore, can-
not be independently evaluated. Published animal data on
AT1 receptor antagonists do not show treatment-related
increases in the frequency of fetal malformations, although
adverse effects on fetal growth, survival, and renal func-
tion have been reported after treatment of pregnant ro-
dents with various sartans in doses comparable to those
used therapeutically in humans.
In rats, Spence et al. (1995b), observed no adverse fetal
effects when dams were treated during organogenesis
(GDs 6 –15) with 2.5–100 times the maximum human ther-
apeutic dose of losartan on a milligram per kilogram body
weight basis, despite evidence of maternal toxicity at the
highest dose. Decreased pup body weights and a slight but
significant increase in pup deaths was seen with maternal
treatment later in pregnancy with 50 times, but not ⬍1–12
times, the maximum human therapeutic dose of losartan
(Spence et al., 1995a, 1995b). Moreover, the adverse effect
on pup weight and survival persisted with continued ma-
ternal treatment through lactation. These authors also
showed that maternal losartan treatment during GDs
125
15–20 (a period that roughly corresponds to the second
trimester of human pregnancy) induced histopathological
evidence of renal damage in the rat (Spence et al., 1995a).
Spence et al. (1996) established that the increased sensitiv-
ity of the fetus, as compared to the neonate, for losartan-
induced kidney changes is dependent on the amount of
exposure, which is related to the route of exposure (trans-
placental or through the milk). In a later study, decreased
fetal weight was observed after treatment of rats through-
out pregnancy with 20 times the maximum human dose of
losartan (Lamparter et al., 1999). No developmental toxic-
ity occurred in the offspring of rabbits treated orally be-
tween GD 6 –18 with 0 –10 times the maximum human
therapeutic dose of losartan; however, increased embry-
onic death, decreased fetal weight, and delayed ossifica-
tion were observed when the animals were treated with 20
times the maximum human therapeutic dose (Hiroyoshi et
al., 1994). This dose was also maternally toxic.
Administration of nine times the maximum human dose
of candesartan on a milligram per kilogram body weight
basis to rats during late pregnancy and lactation produced
hydronephrosis and enlargement of the renal tubules in
the pups. A similar incidence of hydronephrosis in the
pups occurred when dams were only treated during lac-
tation (Ishimura et al., 1999). The authors attributed the
hydronephrosis to treatment-induced sodium imbalance
producing an increase in urine volume during develop-
ment (Ishimura et al., 1999). In another report, hydrone-
phrosis and decreased survival occurred in rat pups after
maternal treatment with 2.8 times the maximum human
daily dose of candesartan in milligrams per kilogram body
weight (USP DI, 2004a)
In unpublished studies, no teratogenic effects are said to
have occurred when pregnant rats were treated with up to
31 times the maximum human dose of irbesartan (USP DI,
2004c) or telmisartan (USP DI, 2004d) or with six times the
maximum human dose of valsartan (USP DI, 2004e). Sim-
ilarly, no adverse effects on fetal development are said to
have occurred when pregnant mice were treated with 138
times the maximum human dose of candesartan (USP DI,
2004a) or with nine times the maximum human dose of
valsartan (USP DI, 2004e). No adverse effects on fetal de-
velopment were observed when pregnant rabbits were
treated with a dose of candesartan (USP DI, 2004a) or
eprosartan (USP DI, 2004b) within the human therapeutic
range or with 0.1 times the maximum human therapeutic
dose of valsartan (USP DI, 2004e). Maternal toxicity and
decreased fetal survival were reportedly seen when preg-
nant rabbits were treated with up to 28 times the maximum
human therapeutic dose of irbesartan (USP DI, 2004c) or
with 6.4 times the maximum human therapeutic dose of
telmisartan (USP DI, 2004d). All these comparisons are on
the basis of the body surface area or milligrams per square
meter.
Studies on sheep have shown that daily oral treatment
with 3 mg/kg of GR138950, an AT1 receptor antagonist
that has not yet been approved for clinical use, or intrave-
nous treatment with five times the maximum human ther-
apeutic daily dose of losartan late in gestation induced
changes in circulating components of the fetal RAS and
had a direct effect on the fetal cardiovascular system and
renal blood flow and function (Stevenson et al., 1996; For-
head et al., 1997).
Birth Defects Research (Part A) 73:123–130 (2005)
126 ALWAN ET AL.
These data on sartans are consistent with other studies
that support the hypothesis that the RAS in general and
A-II in particular are required for normal fetal and neona-
tal renal development. Newborn angiotensin gene knock-
out mice exhibit various renal histological abnormalities,
including a modest delay in glomerular maturation and
pronounced lesions of the renal cortex (Kim et al., 1995;
Niimura et al., 1995). The AT1 receptor gene is ubiqui-
tously expressed in the fetal kidney and developmentally
regulated in a tissue-specific manner in the rat (Tufro-
McReddie et al., 1993). The earliest appearance of renin
and AT1 gene expression in the rat fetal kidney is at GD 17
(Gomez et al., 1993), which correlates with the previously-
defined critical period for losartan-induced renal lesions
(Spence et al., 1995a, 1995b). AT1 receptors are widely
distributed in the newborn rat kidney (Grady et al., 1991),
and their blockade induces an arrest of nephrovascular
maturation and renal growth, resulting in irreversible his-
topathological abnormalities (Friberg et al., 1994; Tufro-
McReddie et al., 1995).
Blockage of AT1 receptors and inhibition of the RAS
may also interfere with early embryonic development of
the heart. AT1 receptor expression in the rat occurs in the
aorta and myocardium of the embryonic heart and is in-
volved in regulation of collagen expression in the heart
(Grady et al., 1991; Everett et al., 1997; Lamparter et al.,
1999). Reduced ventricular development and cardiac dila-
tion were produced when 9.5-day-old rat embryos were
exposed to losartan in culture medium for 48 hr at concen-
trations of 0 –100 mcg/ml (Price et al., 1997).
HUMAN DATA: FIRST-TRIMESTER
MATERNAL TREATMENT AND
MALFORMATIONS
Human data on the fetal effects of first-trimester mater-
nal sartan treatment are very limited. Major malformations
were observed in 2 (6%) of 32 infants born to women who
took one of several AT1 receptor antagonists during the
first trimester of pregnancy and were identified prospec-
tively through a teratogen information service (Schaefer,
2003). One of these pregnancies was electively terminated
because the fetus had exencephaly. The mother of this
fetus was treated with candesartan and other antihyper-
tensive agents through the 31st day of pregnancy. The
other affected child, whose mother was treated with val-
sartan and other antihypertensive drugs until the 13th
week of pregnancy, had a cleft palate, patent ductus arte-
riosus, coarctation of the aorta, and growth retardation. In
addition, one pregnancy produced a stillborn infant who
had no apparent anomalies.
In a pharmacovigilance study performed by general
practitioners in the United Kingdom (Biswas et al., 2002),
four pregnancies were reported in which the mother was
treated with valsartan during the first trimester. One preg-
nancy underwent therapeutic abortion because of hyper-
tension, and no fetal abnormalities were noted. Two preg-
nancies ended with first trimester miscarriages but no fetal
abnormalities were documented. The fourth woman had a
healthy live-born child with no abnormalities. Chung et al.
(2001) reported three apparently normal infants whose
mothers were treated with valsartan until week 18 of ges-
tation. One infant had growth retardation, which the au-
thors attribute to the underlying maternal hypertension.
Birth Defects Research (Part A) 73:123–130 (2005)
No adverse fetal effects have been associated with first-
trimester maternal treatment with ACE inhibitors, but
available data are limited to a few small studies (Barr,
1994). Larger well-controlled epidemiological studies are
needed to determine whether maternal treatment that in-
terferes with RAS function poses an increased risk of mal-
formations in the offspring.
HUMAN DATA: ADVERSE FETAL EFFECTS
ASSOCIATED WITH SECOND- AND THIRD-
TRIMESTER MATERNAL TREATMENT
Adverse fetal effects reported in human pregnancies
following maternal treatment with AT1 receptor antago-
nists during the second and third trimesters of pregnancy
include various combinations of renal failure, pulmonary
hypoplasia, skull hypoplasia, limb contractures, and fetal
or neonatal death (see Table 2). This pattern of fetal abnor-
malities is remarkably similar to that observed following
maternal treatment with ACE inhibitors during the second
or third trimester of pregnancy (Brent and Beckman, 1991;
Hanssens et al., 1991; Barr, 1994; Shotan et al., 1994; La-
voratti et al., 1997; Mastrobattista, 1997; Ratnapalan and
Koren, 2002). It appears that pharmacological suppression
of the fetal RAS by either inhibition of ACE activity or AT1
receptor blockade can severely impair fetal vascular per-
fusion and renal function under conditions that do not
cause maternal toxicity.
Renal Failure
Reduced amniotic fluid volume occurred in 14 of the 15
adverse outcomes reported after maternal treatment with
losartan, candesartan, valsartan, or telmisartan late in
pregnancy (see Table 2). Neonatal anuria was observed in
8 of the 11 infants who were born alive. In one pregnancy
complicated by oligohydramnios in which neonatal anuria
did not occur (Table 2, #12), maternal losartan treatment
was stopped at 27 weeks, and amniotic fluid volume in-
creased prior to delivery at 30 weeks of gestation (Schaefer,
2003). In another case (#7), anhydramnios resolved after
maternal valsartan treatment was withdrawn at the 24th
gestational week, but the pregnancy ended in a stillbirth at
33 weeks (Briggs and Nagoette, 2001). These observations
suggest that maternal sartan treatment in the second or
third trimester of pregnancy can suppress fetal renal func-
tion and drastically reduce urine output, thereby causing
oligohydramnios and neonatal anuria.
Enlarged and hyperechogenic kidneys were described in
eight cases on ultrasound examination, and one other case
displayed heavy kidneys on autopsy (Table 2). Histological
assessment of the kidneys was reported in five cases, all of
which revealed tubular dysgenesis with absence or poor
differentiation of the proximal tubules (Lambot et al., 2001;
Martinovic, 2001; Cox et al., 2003). Martinovic et al. (2001)
performed immunohistochemical staining in one case and
found strong renin expression in the juxtaglomerular ap-
paratus, arteriolar smooth-muscle cells, and glomerular
mesangial cells, which the authors attributed to AT1 recep-
tor blockade. These histopathological findings are similar
to those observed in the kidneys of fetuses and newborn
infants who died following maternal treatment with ACE
inhibitors late in pregnancy (Hulton et al., 1990; Shotan et
al., 1994; Lavoratti et al., 1997; Mastrobattista, 1997). The
renal changes that characterize ACE inhibitor fetopathy are
 A-II RECEPTOR ANTAGONIST TREATMENT IN PREGNANCY 127
Table 2
Adverse Fetal Outcomes Reported with Maternal AT1 Receptor An Treatment during Late Pregnancy
AT1 Treatment Gestational
receptor period age at Birth
Reference, case antagonist (gestational delivery weight Neonatal Pulmonary Skull Other
no. in text (daily dose) weeks) (weeks) Outcome (kg) Oligohydramnios anuria hypoplasia hypoplasia abnormalities

(Saji et al., 2001) Losartan 17–31 32 Stillbirth 1.59 ⫹ NA ⫹ ⫹ Limb

#1 (50 mg) contractures;
facial
deformities
(Lambot et al., Losartan 0–33 36 Died at day 4 2.18 ⫹ ⫹ ⫹ ⫺ Limb
2001) #2 contractures;
facial
deformities;
hyperechogenic
kidneys
(Hinsberger et Candesartan 0–39 39 Live birth NR ⫹ ⫹ NR ⫺ Facial palsy;
al., 2001) #3 (7 mg) enlarged
kidneys
(Martinovic et al., Valsartan 0–24 NA Termination NA ⫹ NA – ⫹ Foot and face
2001) #4 (80 mg) at 27 deformities;
weeks enlarged
kidneys
#5 Valsartan 0–28 NA Termination NA ⫹ NA – ⫹ Foot and face
at 32 deformities;
weeks enlarged
kidneys
#6 Losartan 0–34 34 Died at day 4 NR ⫹ ⫹ – ⫹ Enlarged kidneys
(50 mg)
(Briggs and Valsartan 0–24 33 Stillbirth 1.83 ⫹ NA ⫹ ⫺ Heavy kidneys
Nagoette, (80 mg)
2001) #7
(Schaefer, 2003) Candesartan 0–33 33 Died at a few 2.25 ⫹ ⫹ Suspected ⫹ Symptoms of
#8 (2 ⫻ 8 hours (infant coagulation
mg) had disorder
respiratory
distress)
#9 Valsartan 28–36 36 Live birth 2.24 ⫹ (Suspected) ⫹ NR ⫹ Limb
(80 mg) contractures;
hyperechogenic
kidneys
#10 Valsartan 0–34 34 Live birth 1.73 ⫹ ⫹ NR ⫺ ⫺
#11 Losartan 0–31 31 Live birth 1.59 ⫹ – NR ⫹ Enlarged
(50 mg) multicystic
kidneys
#12 Losartan 0–27 30 Live birth 0.96 ⫹ – Suspected ⫺ ⫺
(100 mg) (infant
had
respiratory
distress)
(Cox et al., 2003) Candesartan 0–32 32 Died at day 3 1.12 ⫹ ⫹ – ⫹ Absent right
#13 kidney and
bladder; large
left kidney
(Pietrement et al., Telmisartan 0–34 34 Live birth 2.20 ⫹ ⫹ NR ⫺ ⫺
2003) #14 (40 mg)
(Nayar et al., Losartan 0–35 35 Live birth 1.74 – – NR ⫹ ⫺
2003) #15 (25 mg)

⫹, present; –, absent; NA, not applicable; NR, not reported.

thought to result from decreased fetal renal perfusion
(Martin et al., 1992).
In normal human embryogenesis, the primitive glomer-
uli appear at approximately eight to nine weeks of gesta-
tion, and tubular function begins after the 14th week of
gestation. Nephrogenesis continues until 34 –36 weeks of
gestation (Vanderheyden et al., 2003). The fetal kidneys
begin to excrete urine into the amniotic fluid between the
eighth and 11th weeks of gestation, but prior to this time
most of the amniotic fluid is derived from maternal blood
(Moore and Persaud, 2003). The volume of amniotic fluid
progressively increases as the fetus matures, from approx-
imately 30 ml at 10 weeks to 1000 ml by 37 weeks (Moore
and Persaud, 2003). By gestational week 20, fetal urine
normally constitutes over 90% of the amniotic fluid. This is
probably why oligohydramnios has not been observed
with maternal treatment with ACE inhibitors (Martin et al.,
1992) or AT1 receptor antagonists (Chung et al., 2001;
Biswas et al., 2002; Schaefer, 2003) during the first half of
pregnancy.
Renal perfusion pressure is generally low in the devel-
oping fetus, and A-II-mediated arterial resistance is essen-
tial for regulating and maintaining the glomerular filtra-
tion rate and urine output (Hulton et al., 1990; Lavoratti et
al., 1997). Inhibition of A-II release or function through
ACE inhibitors or AT1 receptor antagonists, respectively,
may lead to fetal hypotension and renal hypoperfusion,
which ultimately cause decreased afferent glomerular
blood flow, leading to decreased glomerular filtration pres-
sure and subsequent anuria.
Pulmonary Hypoplasia
Three of the cases summarized in Table 2 were noted to
have hypoplastic lungs. Two of these infants were still-
born, and the third infant died on day four of life as a result
of severe respiratory distress (Briggs and Nagoette, 2001;
Lambot et al., 2001; Saji et al., 2001). Two other cases
reported by Schaefer (2003) were noted to have respiratory
distress. On the other hand, congested but not hypoplastic
lungs were found on autopsy in the infant reported by Cox
et al. (2003).
Adequate amniotic fluid volume is crucial for normal
fetal lung development (Laudy and Wladimiroff, 2000),

Birth Defects Research (Part A) 73:123–130 (2005)

128 ALWAN ET AL.
and pulmonary hypoplasia may occur as a result of oligo-
hydramnios of any cause, especially if it is early, pro-
longed, and severe. The mechanism by which pulmonary
hypoplasia develops is not well understood, but it has been
proposed to be due to compression of the fetal chest wall
with consequent reduction in the space for lung growth
and/or restriction of fetal breathing movements, as well as
decreased intrapulmonary pressure (Laudy and Wladimi-
roff, 2000).
The critical canalicular phase of human lung develop-
ment occurs between 16 and 28 weeks of gestation (Laudy
and Wladimiroff, 2000), and oligohydramnios may only
pose a risk for producing pulmonary hypoplasia in the
fetus during this interval (Rotschild et al., 1990). Further-
more, in pregnancies complicated by oligohydramnios, se-
verity of the amniotic fluid reduction, duration and gesta-
tional age are independent predictors of the neonatal risk
for pulmonary hypoplasia. In one study, severe oligohy-
dramnios that occurred before 25 weeks of gestation and
persisted for more than 14 days was associated with more
than 90% neonatal mortality (Kilbride et al., 1996).
Skull Hypoplasia
Hypoplastic and poorly ossified skull bones, often with
widely open sutures, were described in 9 of the 15 infants
or fetuses born to women treated with AT1 receptor an-
tagonists who had adverse outcomes (see Table 2). Hyp-
oplasia of the membranous bones of the skull is also fre-
quently observed in infants whose mothers were treated
with ACE inhibitors during the second or third trimester of
pregnancy (Barr and Cohen, 1991).
The mechanism by which maternal treatment with AT1
receptor antagonists or ACE inhibitors causes hypoplasia
of the fetal skull bones is not understood, but a combina-
tion of oligohydramnios and fetal hypotension with poor
peripheral perfusion of superficial tissues may be involved
(Brent and Beckman, 1991). Fetal membranous bones are
highly vascular and require high oxygen tension for
growth (Barr and Cohen, 1991). Decreased fetal blood flow
caused by reduced activity of the RAS may result in low
oxygen supply, which in turn may impair mineralization
and ossification of the calvarium. In addition, oligohy-
dramnios may allow the uterine musculature to exert di-
rect pressure on the developing fetal skull, which may also
interfere with calvarial ossification (Brent and Beckman,
1991; Buttar, 1997). Barr and Cohen (1991) proposed that
the vessels of the glomeruli and the calvaria might react
similarly to ACE inhibition, and Buttar (1997) suggested
that suppression of A-II activity might inhibit growth fac-
tors that are involved in membranous bone development.
Other Adverse Fetal Outcomes
The fetal effects summarized in Table 2 were quite seri-
ous—six of the fetuses or infants died, usually as a result of
severe hypotension, pulmonary hypoplasia, and/or persis-
tent anuria. In those infants who survived, renal failure
was transient and progressively improved with treatment
in three cases (#3, #11, and #14). Neonatal hypotension was
reported in two cases (#6 and #13), and only one case
confirms that blood pressure was normal in the neonate.
These observations are similar to those reported following
maternal treatment with ACE inhibitors late in pregnancy.
Limb contractures and facial deformities were also com-
monly observed among the infants and fetuses listed in
Birth Defects Research (Part A) 73:123–130 (2005)
Table 2. These anomalies are typical of the Potter sequence
(Thomas, 1974), which can be produced by decreased am-
niotic fluid volume of any cause, especially if the oligohy-
dramnios is of early onset and long duration (Christianson
et al., 1999). Features of Potter sequence have also been
reported in infants born to women who were treated with
ACE inhibitors during the second or third trimester of
pregnancy (Barr, 1994; Mastrobattista, 1997).
CONCLUSIONS AND RECOMMENDATIONS
The characteristic recurrent pattern of fetal anomalies
reported in association with maternal sartan treatment
during the second half of pregnancy, the compatibility of
these features with the known effects of RAS inhibition
produced by AT1 receptor antagonists, and the striking
similarity of this pattern with that seen after maternal
treatment with ACE inhibitors, a class of drugs that block
RAS activity by a different mechanism, leave no doubt that
maternal sartan treatment can cause fetal anomalies and
death. Because of their high affinity for AT1 receptors,
which predominate in more mature fetal renal tissues,
these adverse fetal effects are more likely to be produced
during the latter stages of pregnancy. The limited number
of cases reported and the absence of any formal epidemi-
ological analysis preclude any estimate of the magnitude
of adverse risk associated with sartan treatment late in
pregnancy in an individual patient. Similarly, no statement
can be made regarding possible differences in the fetal
risks associated with maternal treatment with different
AT1 receptor antagonists or with treatment at different
times during the second half of pregnancy. Greater dura-
tion of treatment is not necessarily associated with greater
risk because several cases with relatively mild fetal out-
comes have been reported after maternal treatment
throughout most or all of pregnancy (see cases #3, #10, #14,
and #15 in Table 2). Maternal sartan treatment that is
discontinued early in pregnancy has not been associated
with development of these characteristic fetal anomalies
(Chow and Lam, 2004). However, very little information is
available on sartan treatment limited to the first trimester,
and we do not know whether maternal AT1 receptor an-
tagonist treatment early in pregnancy is associated with a
higher than expected rate of malformations in the off-
spring.
Pregnant women are treated with an AT1 receptor an-
tagonist because they are hypertensive. Untreated hyper-
tension may result in preterm delivery, fetal growth retar-
dation, oligohydramnios, and neonatal death, adverse
outcomes that have also been reported with maternal sar-
tan treatment (Barr, 1994; Sibai, 2002). However, the asso-
ciation of these features with calvarial hypoplasia is cer-
tainly rare in the absence of maternal ACE inhibitor or AT1
receptor antagonist treatment. The histopathological
changes in the kidneys, the severity of the oligohydram-
nios, and the persistence of anuria after delivery, especially
when the fetus is not growth retarded, are also unusual in
maternal hypertension without RAS blockade. Moreover,
in two reported cases in which AT1 receptor antagonist
treatment was stopped during pregnancy, amniotic fluid
volume returned to normal, as would be expected if the
oligohydramnios were caused by the sartan treatment.
Unfortunately, there are no evidence-based guidelines
for treatment of neonates exposed to ACE inhibitors or
AT1 receptor antagonists during prenatal development. In
 A-II RECEPTOR ANTAGONIST TREATMENT IN PREGNANCY
general, it appears to be that neonatal hypotension associ-
ated with exposure to these agents does not respond well
to volume expansion or dopamine infusion (Mastrobat-
tista, 1997). Infants with severe pulmonary hypoplasia sel-
dom survive their severe respiratory distress. Infants with
renal failure may be given peritoneal dialysis. Pregnant
women who have been treated with these agents during
the second or third trimester probably should deliver in
centers with the ability to diagnose and treat neonatal
hypotension, respiratory distress, and renal failure.
AT1 receptor antagonists are effective in the treatment of
hypertension, and their side effects are relatively infre-
quent and usually mild in adults. However, use of these
drugs is contraindicated in the second and third trimester
of pregnancy because of the risk of adverse fetal effects.
Hypertensive women who become pregnant while taking
an AT1 receptor antagonist should be switched to an ef-
fective antihypertensive agent that does not impair RAS
function as soon as the pregnancy is recognized.
REFERENCES
Anonymous. 1999. Valsartan. Just a second-line antihypertensive drug. Can
Fam Physician 45:2626 –2628.
Barr M, Cohen MM. 1991. ACE inhibitor fetopathy and hypocalvaria: the
kidney-skull connection. Teratology 44:485– 495.
Barr M. 1994. Teratogen update: angiotensin-converting enzyme inhibitors.
Teratology 50:399 – 409.
Bauer JH, Reams GP. 1995. The angiotensin II type I receptor-antagonists, a
new class of antihypertensive drugs. Arch Intern Med 155:1361–1368.
Birkenhager WH, de Leeuw PW. 1999. Non-peptide angiotensin type 1
receptor antagonists in the treatment of hypertension. J Hypertens
17:873– 881.
Biswas PN, Wilton LV, Shakir SW. 2002. The safety of valsartan: results of
a postmarketing surveillance study on 12 881 patients in England. J
Hum Hypertens 16:795– 803.
Brent RL, Beckman DA. 1991. Angiotensin-converting enzyme inhibitors, an
embryopathic class of drugs with unique properties: information for
clinical teratology counselors. Teratology 43:543–546.
Briggs GG, Nagoette MP. 2001. Fatal fetal outcome with the combined use
of valsartan and atenolol. Ann Pharmacother 35:859 – 861.
Brousil JA, Burke JM. 2003. Olmesartan medoxomil: an angiotensin II-
receptor blocker. Clin Ther 25:1041–1055.
Buttar HS. 1997. An overview of the influence of ACE inhibitors on fetal-
placental circulation and perinatal development. Mol Cell Biochem
176:61–71.
Chow KM, Lam CM. 2004. Angiotensin II receptor antagonist in pregnancy.
J Perinatol 24:56 –57.
Christianson C, Huff D, McPherson E. 1999. Limb deformations in oligo-
hydramnios sequence: effects of gestational age and duration of oligo-
hydramnios. Am J Med Genet 86:430 – 433.
Chung NA, Lip GYH, Beevers M, Beevers DG. 2001. Angiotensin-II-receptor
inhibitors in pregnancy. Lancet 357:1620.
Cox RM, Anderson JM, Cox P. 2003. Defective embryogenesis with angio-
tensin II receptor antagonists in pregnancy. Br J Obstet Gynaecol 110:
1038 –1040.
Croom KF, Curran MP, Goa KL, Perry CM. 2004. Irbesartan: a review of its
use in hypertension and in the management of diabetic nephropathy.
Drugs 64:999 –1028.
Dina R, Jafari M. 2000. Angiotensin II-receptor antagonists: an overview.
Am J Health Syst Pharm 57:1231–1241.
Doggrell SA. 2002. Angiotensin AT-1 receptor antagonism: complementary
or alternative to ACE inhibition in cardiovascular and renal disease?
Expert Opin Pharmacother 3:1543–1556.
Dzau VJ, Mukoyama M, Pratt RE. 1994. Molecular biology of angiotensin
receptors: target for drug research? J Hypertens Suppl 12:S1–S5.
Everett AD, Fisher A, Tufro-McReddie A, Harris M. 1997. Developmental
regulation of angiotensin type1 and 2 receptor gene expression and
heart growth. J Mol Cell Cardiol 29:141–149.
Forhead AJ, Pipkin FB, Sutherland MF, Fowden AL. 1997. Changes in the
maternal and fetal renin-angiotensin systems in response to angioten-
sin II type 1 receptor blockade and angiotensin-converting enzyme
inhibition in pregnant sheep during late gestation. Exp Physiol 82:761–
776.
Friberg P, Sundelin B, Bohman SO, et al. 1994. Renin-angiotensin system in
129
neonatal rats: induction of a renal abnormality in response to ACE
inhibition or angiotensin II antagonism. Kidney Int 45:485– 492.
Gil-Extremera B, Ma PT, Yulde J, et al. 2003. The adjunctive effect of
telmisartan in patients with hypertension uncontrolled on current an-
tihypertensive therapy. Int J Clin Pract 57:861– 866.
Goa KL, Wagstaff AJ. 1996. Losartan potassium. A review of its pharma-
cology, clinical efficacy and tolerability in the management of hyper-
tension. Drugs 51:820 – 845.
Gomez RL, Tufro-McReddie A, Everett AD, Pentz ES. 1993. Ontogeny of
renin and AT1 receptor in the rat. Pediatr Nephrol 7:635– 638.
Gradman AH. 2002. AT(1)-receptor blockers: differences that matter. J Hum
Hypertens 16:S9 –S16.
Grady EF, Sechi LA, Griffen CA, et al. 1991. Expression of AT2 receptors in
the developing rat fetus. J Clin Invest 88:921–933.
Grone HJ, Simon M, Fuchs E. 1992. Autoradiographic characterization of
angiotensin receptor subtypes in fetal and adult human kidney. Am J
Physiol 262(Pt 2):F326 –F331.
Guron G, Friberg P. 2000. An intact renin-angiotensin system is a prereq-
uisite for normal renal development. J Hypertens 18:123–137.
Hanssens M, Keirse MJ, Vankelecom F, Van Assche FA. 1991. Fetal and
neonatal effects of treatment with angiotensin-converting enzyme in-
hibitors in pregnancy. Obstet Gynecol 78:128 –135.
Hansson L, Lindholm LH, Ekbom T, et al. 1999. Randomised trial of old and
new antihypertensive drugs in elderly patients: cardiovascular mortal-
ity and morbidity. The Swedish Trial in Old Patients with Hyperten-
sion-2 study. Lancet 354:1751–1756.
Hinsberger A, Wingen A-M, Hoyer PF. 2001. Angiotensin-II-receptor inhib-
itors in pregnancy. Lancet 357:1620.
Hiroyoshi M, Toshio N, Eydelloth RS, et al. 1994. [Toxicity studies of
losartan potassium, angiotensin II receptor antagonist (5th report)—
Oral developmental toxicity study in rabbits.]. Kiso to Rinsho 28:4043–
4051. [Jap]
Hollenberg NK, Fisher ND, Price DA. 1998. Pathways for angiotensin II
generation in intact human tissue: evidence from comparative pharma-
cological interruption of the renin system. Hypertension 32:387–392.
Howes LG, Christie N. 1998. Angiotensin receptor antagonists and ACE
inhibitors. Aust Fam Physician 27:914 –921.
Hulton SA, Thomson PD, Cooper PA, Rothberg AD. 1990. Angiotensin-
converting enzyme inhibitors in pregnancy may result in neonatal
renal failure. S Afr Med J 78:673– 676.??
Inagami T. 1999. Molecular biology and singalling of angiotensin receptors:
an overview. J Am Soc Nephrol 10:S2–S7.
Ishimura Y, Chatani F, Sato S. 1999. Characterization of hydronephrosis in
neonatal rats from dams receiving candesartan cilexetil. Int J Toxicol
18:369 –378.
Johren O, Dendorfer A, Dominiak P. 2004. Cardiovascular and renal func-
tion of angiotensin II type-2 receptors. Cardiovasc Res 62:460 – 467.
Kilbride HW, Yeast J, Thibeault DW. 1996. Defining limits of survival: lethal
pulmonary hypoplasia after midtrimester premature rupture of mem-
branes. Am J Obstet Gynecol 175:675– 681.
Kim S, Iwao H. 2000. Molecular and cellular mechanisms of angiotensin
II-mediated cardiovascular and renal diseases. Pharmacol Rev 52:11–
34.
Kim S, Krege JH, Kluckman KD, et al. 1995. Genetic control of blood
pressure and the angiotensinogen locus. Proc Natl Acad Sci USA
92:2735–2739.
Lambot M-A, Vermeylen D, Noel J-C. 2001. Angiotensin-II-receptor inhib-
itors in pregnancy. Lancet 357:1619 –1620.
Lamparter S, Sun Y, Weber KT. 1999. Angiotensin II receptor blockade
during gestation attenuates collagen formation in the developing rat
heart. Cardiovasc Res 43:165–172.
Laudy JA, Wladimiroff JW. 2000. The fetal lung. 1: Developmental aspects.
Ultrasound Obstet Gynecol 16:284 –290.
Lavoratti G, Seracini D, Fiorini P, et al. 1997. Neonatal anuria by ACE
inhibitors during pregnancy. Nephron 76:235–236.
Linz W, Wiemer G, Gohlke P, et al. 1995. Contribution of kinins to the
cardiovascular actions of angiotensin-converting enzyme inhibitors.
Pharmacol Rev 47:25– 49.
Lo MW, Goldberg MR, McCrea JB, et al. 1995. Pharmacokinetics of losartan,
an angiotensin II receptor antagonist, and its active metabolite EXP3174
in humans. Clin Pharmacol Ther 58:641– 649.
Maillard MP, Rossat J, Brunner HR, Burnier M. 2002. Tasosartan, enoltaso-
sartan, and angiotensin II receptor blockade: the confounding role of
protein binding. J Pharmacol Exp Ther 295:649 – 654.
Mann RD, Mackay F, Pearce G, et al. 1999. Losartan: a study of pharmaco-
vigilance data on 14 522 patients. J Hum Hypertens 13:551–557.
Markham A, Goa KL. 1997. Valsartan. A review of its pharmacology and
therapeutic use in essential hypertension. Drugs 54:299 –311.
Martin RA, Jones KL, Mendoza A, et al. 1992. Effect of ACE inhibition on the
fetal kidney: decreased renal blood flow. Teratology 46:317–321.
Birth Defects Research (Part A) 73:123–130 (2005)
130 ALWAN ET AL.
Martinovic J, Benachi A, Laurent N, et al. 2001. Fetal toxic effects and
angiotensin-II-receptor antagonists. Lancet 358:241–242.
Maschio G, Alberti D, Janin G. 1996. Effect of the angiotensin-converting-
enzyme inhibitor benazepril on the progression of chronic renal insuf-
ficiency. N Engl J Med 334:939 –945.
Mastrobattista JM. 1997. Angiotensin converting enzyme inhibitors in preg-
nancy. Semin Perinatol 21:124 –134.
McClellan KJ, Balfour JA. 1998. Eprosartan. Drugs 55:713–718.
Moore KL, Persaud PVN. 2003. The developing human: clinically oriented
embryology. Philadelphia: W.B. Saunders.
Nayar B, Singhal A, Aggarwal R, Malhotra N. 2003. Losartan induced fetal
toxicity. Indian J Pediatr 70:138 –142.
Niimura F, Labosky PA, Kakuchi J, et al. 1995. Gene targeting in mice
reveals a requirement for angiotensin in the development and mainte-
nance of kidney morphology and growth factor regulation. J Clin
Invest 96:2947–2954.
Nishikawa K, Naka T, Chatani F, Yoshimura Y. 1997. Candesartan cilexetil:
a review of its preclinical pharmacology. J Hum Hypertens 11(Suppl
2):S9 –S17.
Norwood VF, Craig MR, Mansel HJ, Gomez RA. 1997. Differential expres-
sion of angiotensin II receptors during early renal morphogenesis. Am J
Physiol 272(Pt 2):R662–R668.
Pfeffer MA, Braunwald E, Moye LA, et al. 1992. Effect of captopril on
mortality and morbidity in patients with left ventricular dysfunction
after myocardial infarction. Results of the survival and ventricular
enlargement trial. The SAVE Investigators. N Engl J Med 327:669 – 677.
Pietrement C, Malot L, Santerne B, et al. 2003. Neonatal acute renal failure
secondary to maternal exposure to telmisartan, angiotensin II receptor
antagonist. J Perinatol 23:254 –255.
Pitt B, Konstam MA. 1998. Overview of angiotensin II-receptor antagonists.
Am J Cardiol 82:47S– 49S.
Pouleur HG. 1997. Clinical overview of irbesartan: a new angiotensin II
receptor antagonist. Am J Hypertens 10:318S–324S.
Price RL, Carver W, Simpson DG, et al. 1997. The effects of angiotensin II
and specific angiotensin receptor blockers on embryonic cardiac devel-
opment and looping patterns. Dev Biol 192:572–584.
Ratnapalan S, Koren G. 2002. Taking ACE inhibitors during pregnancy. Is it
safe? Can Fam Physician 48:1047–1049.
Rodgers JE, Patterson JH. 2001. Angiotensin II-receptor blockers: clinical
relevance and therapeutic role. Am J Health Syst Pharm 58:671– 683.
Rotschild A, Ling EW, Puterman ML, Farquharson D. 1990. Neonatal out-
come after prolonged preterm rupture of the membranes. Am J Obstet
Gynecol 162:46 –52.
Ruilope L. 1997. Human pharmacokinetic/pharmacodynamic profile of
irbesartan: a new potent angiotensin II receptor antagonist. J Hypertens
Suppl 15:S15–S20.
Saji H, Yamanaka M, Hagiwara A, Ijiri R. 2001. Losartan and fetal toxic
effects. Lancet 357:363.
Schaefer KL, Porter JA. 1996. Angiotensin II receptor antagonists: the pro-
totype losartan. Ann Pharmacother 30:625– 636.
Schaefer C. 2003. Angiotensin II-receptor-antagonists: further evidence of
fetotoxicity but not teratogenicity. Birth Defects Res Part A Clin Mol
Teratol 67:591–594.
Sequeira Lopez MLS, Gomez RA. 2004. The role of angiotensin II in kidney
Birth Defects Research (Part A) 73:123–130 (2005)
embryogenesis and kidney abnormalities. Curr Opin Nephrol Hyper-
tens 13:117–122.
Shotan A, Widerhorn J, Hurst A, Elkayarn U. 1994. Risks of angiotensin-
converting enzyme inhibition during pregnancy: experimental and
clinical evidence, potential mechanisms, and recommendations for use.
Am J Med 96:451– 456.
Sibai BM. 2002. Chronic hypertension in pregnancy. Obstet Gynecol 100:
369 –377.
Smith RD, Timmermans PB. 1994. Human angiotensin receptor subtypes.
Curr Opin Nephrol Hypertens 3:112–122.
Spence SG, Allen HL, Cukierski MA, et al. 1995a. Defining the susceptible
period of developmental toxicity for the AT1-selective angiotensin II
receptor antagonist losartan in rats. Teratology 51:367–382.
Spence SG, Cukierski MA, Manson JM, et al. 1995b. Evaluation of the
reproductive and developmental toxicity of the AT1-selective angioten-
sin II receptor antagonist losartan in rats. Teratology 51:383–397.
Spence SG, Zacchei AG, Lee LL, et al. 1996. Toxicokinetic analysis of
losartan during gestation and lactation in the rat. Teratology 53:245–
252.
Stevenson KM, Gibson KJ, Lumbers ER. 1996. Effects of losartan on the
cardiovascular system, renal haemodynamics and function and lung
liquid flow in fetal sheep. Clin Exp Pharmacol Physiol 23:125–133.??
Thomas IT. 1974. Oligohydramnios, cause of the nonrenal features of Potter
syndrome, including pulmonary hypoplasia. J Pediatr 84:811– 814.
Tufro-McReddie A, Harrison JK, Everett AD, Gomez RA. 1993. Ontogeny of
type 1 angiotensin II receptor gene expression in the rat. J Clin Invest
91:530 –537.
Tufro-McReddie A, Romano LM, Harris JM, et al. 1995. Angiotensin II
regulates nephrogenesis and renal vascular development. Am J Physiol
269:F110 –F115.
USP DI. 2004a. Candesartan. Precautions to consider: Pregnancy/Repro-
duction In: USP DI (USP dispensing information). Vol I. Drug Infor-
mation for the health care professional. 24th ed. Taunton, MA: Mi-
cromedex, Inc.
USP DI. 2004b. Eprosartan. Precautions to consider: Pregnancy/Reproduc-
tion In: USP DI (USP dispensing information). Vol I. Drug Information
for the health care professional. 24th ed. Taunton, MA: Micromedex,
Inc.
USP DI. 2004c. Irbesartan. Precautions to consider: Pregnancy/Reproduc-
tion In: USP DI (USP dispensing information). Vol I. Drug Information
for the health care professional. 24th ed. Taunton, MA: Micromedex,
Inc.
USP DI. 2004d. Telmisartan. Precautions to consider: Pregnancy/Reproduc-
tion In: USP DI (USP dispensing information). Vol I. Drug Information
for the health care professional. 24th ed. Taunton, MA: Micromedex,
Inc.
USP DI. 2004e. Valsartan. Precautions to consider: Pregnancy/Reproduc-
tion In: USP DI (USP dispensing information). Vol I. Drug Information
for the health care professional. 24th ed. Taunton, MA: Micromedex,
Inc.
Vanderheyden T, Kumar S, Fisk NM. 2003. Fetal renal impairment. Semin
Neonatol 8:279 –289.
Williams GH. 1988. Converting-enzyme inhibitors in the treatment of hy-
pertension. N Engl J Med 319:1517–1525.