Pregnancy Outcome Following Exposure to

Angiotensin-Converting Enzyme Inhibitors or Angiotensin

Receptor Antagonists
A Systematic Review
Marina Bullo; Sibylle Tschumi; Barbara S. Bucher; Mario G. Bianchetti; Giacomo D. Simonetti

Abstract—The objective was to analyze the outcome following prenatal exposure to angiotensin-converting enzyme
inhibitors (ACE-Is) or angiotensin receptor antagonists (ARBs). For this purpose, a systematic review of published case
reports and case series dealing with intrauterine exposure to ACE-Is or to ARBs using Medline as the source of data
was performed. The publications retained for analysis included patients who were described individually, revealing, at
minimum, the gestational age, substance used, period of medication intake, and the outcome. In total, 72 reports were
included; 37 articles (118 well-documented cases) described the prenatal exposure to ACE-Is; and 35 articles (68 cases)
described the prenatal exposure to ARBs. Overall, 52% of the newborns exposed to ACE-Is and 13% of the newborns
exposed to ARBs did not exhibit any complications (P⬍0.0001). Neonatal complications were more frequent following
exposure to ARBs and included renal failure, oligohydramnios, death, arterial hypotension, intrauterine growth
retardation, respiratory distress syndrome, pulmonary hypoplasia, hypocalvaria, limb defects, persistent patent ductus
arteriosus, or cerebral complications. The long-term outcome is described as positive in only 50% of the exposed
children. Fetopathy caused by exposure to ACE-Is or ARBs has relevant neonatal and long-term complications. The outcome
is poorer following exposure to ARBs. We propose the term “fetal renin-angiotensin system blockade syndrome” to describe
the related clinical findings. Thirty years after the first description of ACE-I fetopathy, relevant complications are, at present,
regularly described, indicating that the awareness of the deleterious effect of prenatal exposure to drugs inhibiting the
renin-angiotensin system should be improved. (Hypertension. 2012;60:444-450.) ● Online Data Supplement
Downloaded from http://ahajournals.org by on September 18, 2019

Key Words: pregnancy 䡲 angiotensin-converting enzyme inhibitors 䡲 angiotensin receptor blockers

䡲 fetopathy 䡲 prenatal exposure 䡲 systematic review

A n undamaged renin-angiotensin system (RAS) is a

prerequisite for normal prenatal renal development.
Loss of function mutations in the genes encoding the RAS
present with a disturbed renal development, characterized by
reduced fetal diuresis, leading to oligohydramnios and, occa-
sionally, skull-ossification defects. At birth, blood pressure is
low, and death occurs in most cases.1 This clinical scenario
resembles the findings, first reported by Guignard et al2 and
Duminy et al3 in 1981, in infants exposed during pregnancy
to drugs that block the RAS. This condition, which occurs
following maternal treatment with either angiotensin-
converting enzyme inhibitors (ACE-Is) or angiotensin recep-
tor antagonists (ARBs), is usually termed fetal renin-
angiotensin system blockade syndrome (fetal RAS-blockade
syndrome). Some data also indicate a possible association
between the use of these drugs during the first trimester of
pregnancy and congenital malformations.
Because the adverse effects of drugs that block the RAS in
the unborn child have been described only in single-case
reports or in small case series, we performed a formal
systematic analysis of the literature that addresses the
intrauterine exposure to ACE-Is or ARBs. Our purposes in
conducting this study were as follows: (1) provide a more
rational foundation for the outcome and management of
exposed children; (2) describe the evolution of the aware-
ness of this syndrome during the last 30 years; (3) find a
rational correlation between the time of intake (trimester)
and the outcome; and (4) describe the differences in
presentation and outcomes between intrauterine exposure
to ACE-Is and ARBs.
Methods
Between April 2010 and August 2011, we performed a thorough
computer-based search of the terms angiotensin receptor blocker,

Received April 2, 2012; first decision April 20, 2012; revision accepted June 2, 2012.
From the Department of Pediatrics and Division of Pediatric Nephrology, University Hospital (Inselspital), Berne, Switzerland (M.B., S.T., B.S.B.,
G.D.S.); Division of Pediatrics, Hospitals Bellinzona and Mendrisio, Bellinzona, Switzerland (M.G.B.).
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.
112.196352/-/DC1.
Correspondence to Giacomo D. Simonetti, Department of Pediatrics and Division of Pediatric Nephrology, University Children’s Hospital (Inselspital),
Berne, Switzerland. E-mail giacomo.simonetti@insel.ch
© 2012 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.112.196352

444
 Bullo et al
100
*§
% Infants with complications
80 † system blockade syndrome related to a period
† inhibitors or angiotensin receptor blockers. The
60
* enzyme inhibitors; gray bar, angiotensin recep-
40
20
32 18 11 1 18 3 15 18
0 to ACE-I during the third trimester; and §
First Second Third First +
Trimester Trimester Trimester Second
Trimester
Angiotensin converting enzyme inhibitors
Angiotensin receptor blockers
angiotensin receptor antagonist, angiotensin converting enzyme
inhibitor, ARB, ACE-I, or sartan, each combined with pregnancy,
fetopathy, fetus, newborn, teratogen, fetal exposure, prenatal expo-
sure, or toxicity in the US National Library of Medicine (Medline)
for the period January 1980 through August 2011 as sources of data,
using the Prisma Guidelines.4
Study Selection and Validity Assessment
Publications available as a full-length article or a letter in English,
German, French, Portuguese, Spanish, or Italian, including patients
who were described individually, were retained for analysis if the
publication described, at minimum, the gestational age, substance
used, period of medication intake (gestational trimester), and out-
Downloaded from http://ahajournals.org by on September 18, 2019
come of the single cases. If the same case was present in different
publications, we retained the most complete description. Two au-
thors (M.B. and G.D.S.) scanned the titles and abstracts for the initial
selection. The selected articles were reviewed in full and indepen-
dently assessed for eligibility by the same 2 reviewers.
Outcome Measures
Outcomes were neonatal and long-term (defined as present after 6
months of life) complications, following the exposure to medications
inhibiting the RAS.
Data Extraction and Synthesis
From each case of prenatal exposure to medications blocking the
RAS, we extracted the patients’ clinical characteristics, including
information concerning the underlying cause of the antihypertensive
treatment of the mother, maternal age, period of prenatal exposure
(gestational trimester), gestational age at birth, birth weight, neonatal
complications, and the period of follow-up with long-term
consequences.
Statistical Analyses
The analyzed data were all extrapolated from case reports and case
series and were homogenous in view of the clinical context;
moreover, all of the retained studies presented the data of the single
cases similarly, therefore, permitting estimation of the outcomes and
comparison between the ACE-I and ARB subgroups. Continuous
data are presented as the mean values with standard deviations
(SDs), and categorical data are presented as frequencies and percent-
ages calculated from the results reported in the original publications.
The Fisher exact test was used to compare dichotomous variables,
and the Student t test or the Mann-Whitney–Wilcoxon rank-sum test
was used to compare continuous variables, as appropriate. All of the
statistical analyses were performed with GraphPad Prism, version
5.01 for Windows (GraphPad Software). Statistical significance was
assigned at P⬍0.05.
Fetal Renin-Angiotensin System Blockade Syndrome 445
*§
Figure 1. Prevalence of fetal renin-angiotensin
of exposure to angiotensin-converting enzyme
† black bar indicates angiotensin-converting
tor blockers. The number in the columns refers
to the total number of the considered new-
‡ borns in a given period. * denotes a significant
difference between the 2 groups; † denotes a
†
significant difference to the newborn exposed
to ACE-I during the first trimester; ‡ denotes a
significant difference to the newborn exposed
11 2 31 26
Second + Entire denotes a significant difference to the newborn
Third Pregnancy exposed to ARB during the first trimester
Trimester
(P⬍0.05).
Results
Search Results
The initial search revealed 3639 publications, of which 1685
remained after excluding duplicates (ie, the same publications
were found with different search terms). One hundred and
seventeen of them were reviewed in detail, and 61 reports
were retained for the final analysis (see online-only Data
Supplement Figure S1). Eleven further pertinent reports were
found in the references of the mentioned 117 reports. Hence,
a total of 72 reports (64 in English, 6 in French, 1 in
Portuguese, and 1 in Spanish) were used for the final analysis.
The reports document 186 cases.2,5–75 Thirty-seven reports
documented the prenatal exposure to ACE-Is, for a total of
118 well-documented cases (captopril: N⫽59; enalapril:
N⫽42; lisinopril: N⫽11; ramipril: N⫽3; benazepril: N⫽2;
quinapril: N⫽1), and 35 reports documented the prenatal
exposure to ARBs, for a total of 68 cases (losartan: N⫽20;
candesartan: N⫽17; valsartan: N⫽17; irbesartan: N⫽7, olm-
esartan: N⫽6; telmisartan: N⫽1).
Six articles were excluded from the analysis because the
listed cases were not described in detail76–81; however, these
reports were further explored for the description of the
prevalence and general aspects of fetal RAS-blockade syn-
drome (see the online-only Data Supplement Expanded Re-
sults section with Figure S2) and the analysis of the preva-
lence of major congenital malformations.
Intrauterine Exposure to ACE-Is
The mean maternal age of the 118 well-documented cases of
intrauterine exposure to ACE-Is was 31.3⫾6.6 years. ACE-Is
were generally taken by the mother only during the first
trimester of the pregnancy (32 cases); however, occasionally,
the medication was taken only during the second trimester
(11 cases) or only during the third trimester (18 cases). In 15
cases, ACE-Is were taken during the first and second trimes-
ters; in 11 cases, they were taken during the second and third
trimesters; and in 31 cases, they were taken during the entire
pregnancy (Figure 1).
The children were born at a mean gestational age of
34.7⫾3.7 weeks, with a mean birth weight of 2121⫾877 g.
 446 Hypertension August 2012
Death, miscarriage or intrauterine fetal death
Cerebral complications
Intrauterine growth retardation
Limbs defects
Hypocalvaria
Persistent patent ductus arteriosus Botalli
Respiratory distress syndrome
Pulmonary hypoplasia
Arterial hypotension
Renal failure or need for dialysis
Anuria
Oligohydramnios
newborns without any complication
0 10
Angiotensin converting enzyme inhibitors
Angiotensin receptor blockers
Figure 2. The complications observed following exposure during pregnancy to drugs that inhibit the renin-angiotensin system
(expressed as percentages). The black bar indicates angiotensin-converting enzyme inhibitors: gray bar, angiotensin receptor blockers.
*denotes a significant difference between the 2 groups (P⬍0.05).
Sixty-one newborns (52%) were described as not having
Downloaded from http://ahajournals.org by on September 18, 2019
fetal RAS-blockade syndrome (Figure 2, online-only Data
Supplement Table S1). Significantly more newborns without
fetal RAS-blockade syndrome were exposed at the beginning
of the pregnancy only (P⬍0.05, online-only Data Supplement
Table S1). Thirty-six of these 61 newborns (59%) were
exposed to captopril, 17 (28%) to enalapril, 6 (10%) to
lisinopril, and 1 each (1.5%) to quinapril and ramipril.
Interestingly, 24 of the 25 newborns who experienced no
complications and were exposed at the end of the pregnancy
or during the entire pregnancy had been exposed to captopril,
a drug with a short elimination half-life. The remaining
healthy newborns had been exposed to enalapril.
The most commonly observed complications were as
follows: renal failure or need for dialysis (23%), anuria
(20%), oligohydramnios (19%), death (intrauterine or after
birth) or miscarriage (18%), arterial hypotension (17%),
intrauterine growth retardation (15%), respiratory distress
syndrome (14%), hypocalvaria (8%), limb defects (8%),
persistent patent ductus arteriosus (6%), pulmonary hypopla-
sia (5%), or cerebral complications (4%), as depicted in
Figure 2. These complications were more frequent if the
ACE-Is were taken during the entire pregnancy or during the
second and third trimesters (Figure 1, online-only Data
Supplement Table S1; P⬍0.05). Five cases were character-
ized by miscarriage, 1 case by voluntary abortion, 6 cases by
intrauterine death (ie, after the 18th gestational week), 9 by
postpartum death (8 preterm newborns and 1 term newborn),
and 57 cases were characterized by premature births. In 40
cases, the neonates born at term were described as alive.
*
*
*
*
*
*
*
*
*
20 30 40 50 60 70
% Infants with complication
Intrauterine Exposure to ARBs
The mean maternal age of the 68 well-documented cases of
intrauterine exposure to ARBs was 36.1⫾5.8 years. ARBs
were generally taken by the mother during the entire preg-
nancy (26 cases). In each of 18 cases, the medication was
taken exclusively during the first trimester of pregnancy or
during the first and second trimesters; however, the medica-
tion was rarely taken exclusively during the second trimester
(1 case) or only during the third trimester (3 cases). In 2 cases,
ARBs were taken during the second and third trimesters
(Figure 1).
The children were born at a mean gestational age of
33.5⫾3.9 weeks, with a mean body weight of 2140⫾769 g.
Nine newborns (13%) were described as not having fetal
RAS-blockade syndrome (Figure 2, online-only Data Supple-
ment Table S1); 8 of these newborns had been exposed only
during the first trimester, and 1 newborn had been exposed
during the first and second trimesters. Five of these 9
newborns (56%) were exposed to losartan, 2 (22%) to
valsartan, and 1 each (11%) to candesartan and irbesartan.
The most commonly observed complications included the
following: oligohydramnios (63%), renal failure or need for
dialysis (51%), anuria (40%), respiratory distress syndrome
(37%), death (intrauterine or after birth) or miscarriage
(37%), hypocalvaria (32%), limb defects (32%), intrauterine
growth retardation (16%), pulmonary hypoplasia (16%), ar-
terial hypotension (15%), cerebral complications (10%), or
persistent patent ductus arteriosus (9%), as depicted in Figure
2. These complications were more frequent if the ARB had
been taken during the entire pregnancy (Figure 1, online-only
Data Supplement Table S1; P⬍0.05).
 Bullo et al
Two cases were characterized by miscarriage, 4 cases by
voluntary abortion, 5 cases by intrauterine death, and 14 cases
were characterized by postpartum death (13 preterm and 1
term newborn). Twenty-eight premature neonates and 15
neonates born at term were described as alive.
Comparison Between Intrauterine Exposure to
ACE-Is and ARBs
The mothers treated with ARBs were older by 4.8 years
compared with the mothers treated with ACE-Is (P⬍0.0001).
Pregnancy-induced hypertension was less frequently the in-
dication for therapy in mothers treated with ARBs (P⫽0.02),
and the gestational age of infants born alive was younger in
newborns prenatally exposed to ARBs (P⫽0.04). Newborns
prenatally exposed to ACE-Is were more frequently born
without fetal RAS-blockade syndrome compared with the
group of newborns exposed to ARBs (P⬍0.0001), indepen-
dent of the exposure period (Figure 2, online-only Data
Supplement Table S1). Moreover, preterm newborns exposed
to ARBs more frequently died postnatally compared with the
preterm newborns exposed to ACE-Is (P⫽0.02); this differ-
ence was not significant for newborns born at term. The
prevalence of miscarriage or intrauterine death was not
different between the groups.
In general, complications were more frequent in children
prenatally exposed to ARBs when compared with children
exposed to ACE-Is (Figure 1, Figure 2, and online-only Data
Supplement Table S1). Moreover, if the children were ex-
posed only at the beginning of pregnancy, oligohydramnios,
renal failure, hypocalvaria, and limb defects were also more
Downloaded from http://ahajournals.org by on September 18, 2019
frequently observed in children prenatally exposed to ARBs
(Figure 1, online-only Data Supplement Table S1).
Follow-Up at 6 or More Months
Long-term outcomes with a follow-up of ⬎6 months
were only available for a total of 26 chil-
dren.7–8,10,17,21,23,25,27,29,30,34,37,38,44,48,54,60,61,63,65,69 The
mean age of the children described was 3.3⫾4.5 (range: 0.5
to 18) years. Fourteen children had prenatally been exposed
to ACE-Is, and 12 had been exposed to ARBs. Four children
were exposed only during the first or second trimesters (1,
ACE-I; and 3, ARBs), and 22 were exposed during the
second and third trimesters or during the entire pregnancy
(13, ACE-Is; and 9, ARBs). The most frequently described
complications of fetal RAS-blockade syndrome are depicted
in Table. Complications were similar if the children had been
exposed to ACE-Is or ARBs. In the 4 children exposed
exclusively during the first or second trimester, the general
outcome was good (ie, normal development and kidney
function) in 3 and mild in 1 (ie, mild renal insufficiency,
arterial hypertension, proteinuria, or developmental delay),
whereas, in the 22 children exposed at the end or during
the entire pregnancy, the outcome was good in 10, mild in
10, and bad in 2 (ie, need for dialysis or transplantation).
Permanent Congenital Malformations, Other Than
Those Described Above, Following Prenatal
Exposure to Drugs Inhibiting the
Renin-Angiotensin System
Major permanent congenital malformations following prena-
tal exposure to drugs inhibiting the RAS has been debated in
Fetal Renin-Angiotensin System Blockade Syndrome 447
Table. Outcome of Fetal RAS-Blockade Syndrome After a
Follow-Up of >6 Months in 26 Well-Described Children
Complications Total 26 Children (%)
Renal failure 6 (23%)
Dialysis 2 (8%)
Arterial hypertension 4 (15%)
Proteinuria 4 (15%)
Acidosis 2 (8%)
Polyuria 3 (12%)
Small or hyperechogenic kidneys on ultrasound 4 (15%)
Polycythemia 2 (8%)
Growth retardation or failure to thrive 4 (15%)
Neurodevelopmental delay 3 (12%)
Outcome
Normal 13 (50%)
Mild 11 (42%)
Bad 2 (8%)
Long-term complications were similar if the children were exposed to
angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers.
RAS indicates renin-angiotensin system.
several studies. The analysis performed by Cooper et al
demonstrates that exposure to ACE-Is during the first trimes-
ter of pregnancy is a risk factor for major congenital malfor-
mations.76 Other reports could not confirm these results and
suggest that ACE-Is or ARBs are not major teratogens when
used in the first trimester only.79–81
Discussion
Drugs that block the RAS, either ACE-Is or ARBs, are
effective agents, with few side effects, which are often
prescribed to women of reproductive age.82 This systematic
review confirms that fetal RAS-blockade syndrome is fre-
quent. Moreover, this survey demonstrates that fetal RAS-
blockade syndrome also occurs following first-trimester ex-
posure to ACE-Is or ARBs, although it occurs significantly
less frequently when compared with exposure during the
second and third trimesters of pregnancy or during the entire
pregnancy. Finally, the review surprisingly demonstrates that
fetal RAS-blockade syndrome is more frequent and severe in
newborns exposed to ARBs than in newborns prenatally
exposed to ACE-Is. This review largely supports the current
recommendations stating that women of childbearing age
should be treated with ACE-Is or ARBs only if absolutely
indicated; women taking these drugs should be warned about
the consequences of prenatal exposure, and effective
contraception must be assured. These warnings are impor-
tant because 5% of the women of childbearing age have to be
treated with antihypertensive medication.83 Furthermore,
ACE-Is or ARBs should never be started during pregnancy.
The RAS promotes cellular proliferation and cellular
growth via angiotensin II and the angiotensin II type 1
receptor, which is blocked by ARBs. Angiotensin II is crucial
for fetal kidney development, especially at the end of preg-
nancy, and is less important at the beginning of fetal devel-
opment. This finding may explain the better outcomes in
newborns exposed only during the first trimester of preg-
 448 Hypertension August 2012
nancy.84–87 Moreover, angiotensin II maintains adequate
renal perfusion and glomerular filtration in the low-perfusion
pressure system of the fetal kidney. The consequences of the
inhibition of the RAS are renal hypoperfusion and ischemia,
leading to reduced glomerular filtration (and oligohydram-
nios) and impaired tubular development.
There exists some difference between ACE-Is and ARBs in
their mechanism of action that could explain the diverse
outcomes following in utero exposure to these drugs. By
decreasing angiotensin II production, ACE-Is reduce the
activation of both type 1 and type 2 angiotensin II receptors,
whereas only the former is inhibited by the ARBs. Further-
more, in some tissues, the production of angiotensin II is
catalyzed by enzymes other than angiotensin-converting en-
zymes, an effect that can be inhibited by ARBs but not by
ACE-Is. Finally, ARBs usually have a longer elimination
half-life than ACE-Is. Taken together, these data suggest that
the less favorable outcomes following in utero exposure to
ARBs compared with ACE-Is might result from a more
profound and longer blockade of the angiotensin II action on
its type 1 receptor. This hypothesis is supported by Hanssens
et al.88 These authors noted a better outcome following in
utero exposure to captopril, an ACE-I with a very short
elimination half-time, compared with enalapril, an ACE-I
with a slightly longer elimination half-time.
Few reports address the long-term follow-up after fetal
exposure to drugs inhibiting the RAS. Renal complications
were the most frequently encountered long-term complica-
tions of fetal RAS-blockade syndrome, followed by neurode-
Downloaded from http://ahajournals.org by on September 18, 2019
velopmental delay and failure to thrive. Approximately half
of the children exposed to RAS inhibitors had favorable
long-term outcomes without sequelae, and half of the children
developed some chronic condition. Ten percent of children
exposed experienced a bad outcome, such as end-stage renal
disease. Long-term multidisciplinary follow-up is indicated in
these children.
Major permanent congenital malformations following ex-
posure to drugs inhibiting the RAS during the first trimester
of pregnancy is a matter of discussion, and the results of
differently designed surveys are not uniform.76,79–81 It is
worthy of mention that the congenital malformations that
occur following in utero exposure to a blocker of the RAS
may result either directly from the drug as well as from the
underlying maternal illness. It is well-recognized, for exam-
ple, that pregestational diabetes mellitus is associated with a
2- to 3-fold increase in risk of malformations.
Our analysis demonstrates that, despite the first warnings
in 1980 (animal data presented by Broughton-Pipkin et al89)
and 1981 (human data reported by Guignard et al2 and
Duminy et al3), several cases of fetal exposure to ACE-Is and
ARBs have been reported thereafter without any decrease of
the reported cases. The reasons for this trend are most likely
multifactorial: The ignorance of the treating physicians
and the scarce information available to the women of a
childbearing age who consequently do not discontinue the
chronic antihypertensive therapy during pregnancy or be-
cause self-medication was not communicated to the treat-
ing obstetrician.71
With the development of aliskiren, a drug that directly
inhibits the activity of renin, blockade of the RAS at a third
level has become a reality. No information concerning its
teratogenicity is currently available. Nonetheless, similar to
ACE-Is and ARBs, aliskiren should not be used during
pregnancy.
The results of this systematic review must be viewed with
an understanding of the inherent limitations of the analysis
process, which incorporated data exclusively from single-
case reports or case series published between 1981 and 2011,
permitting comparison between groups only as estimates.
Perspectives
Fetal exposure to ACE-Is or ARBs has relevant neonatal and
long-term complications. The neonatal outcome appear to be
poorer following prenatal exposure to ARBs compared with
ACE-Is. Thirty years after the first description of ACE-I
fetopathy, relevant complications are regularly described,
indicating that the awareness of the deleterious effects of
prenatal exposure to drugs inhibiting the RAS should be
addressed.
Disclosures
None.
References
1. Gubler MC, Antignac C. Renin-angiotensin system in kidney devel-
opment: renal tubular dysgenesis. Kidney Int. 2010;77:400–406.
2. Guignard J, Burgener F, Cálame A. Persistent anuria in a neonatë: a side
effect of captopril. Int J Pediatr Nephrol. 1981;2:133.
3. Duminy PC, Burger PD. Fetal abnormality associated with the use of
captopril during pregnancy. S Afr Med J. 1981;60:805.
4. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP,
Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement
for reporting systematic reviews and meta-analyses of studies that
evaluate healthcare interventions: explanation and elaboration. BMJ.
2009;339:b2700.
5. Baethge BA, Wolf RE. Successful pregnancy with scleroderma renal
disease and pulmonary hypertension in a patient using angiotensin con-
verting enzyme inhibitors. Ann Rheum Dis. 1989;48:776–778.
6. Bald M, Holder M, Zieger M, Vochem M, Leichter HE. Increased renal
echogenicity in a preterm neonate. Kidneys with tubular dysplasia due to
exposure to candesartan during pregnancy. Pediatr Nephrol. 2005;20:
1664–1665, 1666 –1668.
7. Bass JK, Faix RG. Gestational therapy with an angiotensin II receptor
antagonist and transient renal failure in a premature infant. Am J
Perinatol. 2006;23:313–317.
8. Berkane N, Carlier P, Verstraete L, Mathieu E, Heim N, Uzan S. Fetal
toxicity of valsartan and possible reversible adverse side effects. Birth
Defects Res A Clin Mol Teratol. 2004;70:547–549.
9. Boix E, Zapater P, Pico A, Moreno O. Teratogenicity with angiotensin II
receptor antagonists in pregnancy. J Endocrinol Invest. 2005;28:
1029–1031.
10. Bos-Thompson MA, Hillaire-Buys D, Muller F, Dechaud H, Mazurier E,
Boulot P, Morin D. Fetal toxic effects of angiotensin II receptor antag-
onists: case report and follow-up after birth. Ann Pharmacother. 2005;
39:157–161.
11. Boutroy MJ, Vert P, Hurault de Ligny B, Miton A. Captopril adminis-
tration in pregnancy impairs fetal angiotensin converting enzyme activity
and neonatal adaptation. Lancet. 1984;2:935–936.
12. Briggs GG, Nageotte MP. Fatal fetal outcome with the combined use of
valsartan and atenolol. Ann Pharmacother. 2001;35:859–861.
13. Caraman PL, Miton A, Hurault de Ligny B, Kessler M, Boutroy MJ,
Schweitzer M, Brocard O, Ragage JP, Netter P. [Pregnancy under cap-
topril]. Therapie. 1984;39:59–62.
14. Celentano C, Prefumo F, di Vera E, Iannicco A, Gallo DP, Liberati M.
Reversible acute fetal renal failure due to maternal exposure to angio-
tensin receptor blocker. Pediatr Nephrol. 2008;23:333–334.
 Bullo et al
15. Chisholm CA, Chescheir NC, Kennedy M. Reversible oligohydramnios
in a pregnancy with angiotensin-converting enzyme inhibitor exposure.
Am J Perinatol. 1997;14:511–513.
16. Chung NA, Lip GY, Beevers M, Beevers DG. Angiotensin-II-receptor
inhibitors in pregnancy. Lancet. 2001;357:1620–1621.
17. Coen G, Cugini P, Gerlini G, Finistauri D, Cinotti GA. Successful
treatment of long-lasting severe hypertension with captopril during a twin
pregnancy. Nephron. 1985;40:498–500.
18. Cox RM, Anderson JM, Cox P. Defective embryogenesis with angio-
tensin II receptor antagonists in pregnancy. BJOG. 2003;110:1038.
19. Cunniff C, Jones KL, Phillipson J, Benirschke K, Short S, Wujek J.
Oligohydramnios sequence and renal tubular malformation associated
with maternal enalapril use. Am J Obstet Gynecol. 1990;162:187–189.
20. Daikha-Dahmane F, Levy-Beff E, Jugie M, Lenclen R. Foetal kidney
maldevelopment in maternal use of angiotensin II type I receptor antag-
onists. Pediatr Nephrol. 2006;21:729–732.
21. Ducret F, Pointet P, Lauvergeon B, Jacoulet C, Gagnaire J. [Pregnancy
under converting enzyme inhibitor]. Presse Med. 1985;14:897.
22. Easterling TR, Carr DB, Davis C, Diederichs C, Brateng DA, Schmucker
B. Low-dose, short-acting, angiotensin-converting enzyme inhibitors as
rescue therapy in pregnancy. Obstet Gynecol. 2000;96:956–961.
23. Filler G, Wong H, Condello AS, Charbonneau C, Sinclair B, Kovesi T,
Hutchison J. Early dialysis in a neonate with intrauterine lisinopril
exposure. Arch Dis Child Fetal Neonatal Ed. 2003;88:F154–F156.
24. Fiocchi R, Lijnen P, Fagard R, Staessen J, Amery A, Van Assche F, Spitz
B, Rademaker M. Captopril during pregnancy. Lancet. 1984;2:1153.
25. Georgaki-Angelaki E, Stergiou N, Naoum E, Papassotiriou I, Anag-
nostakou M. Olmesartan medoxomil-induced acute renal failure in a
premature newborn following maternal exposure during pregnancy: a
case report and review of the literature. Nephrol Dial Transplant Plus.
2009;2:295–297.
26. Gersak K, Cvijic M, Cerar LK. Angiotensin II receptor blockers in
pregnancy: a report of five cases. Reprod Toxicol. 2009;28:109–112.
27. Guron G, Molne J, Swerkersson S, Friberg P, Hansson S. A 14-year-old
girl with renal abnormalities after brief intrauterine exposure to enalapril
during late gestation. Nephrol Dial Transplant. 2006;21:522–525.
28. Hasbun HJ, Valdes RE, San Martin OA, Catalan MJ, Salinas QS, Parra
Downloaded from http://ahajournals.org by on September 18, 2019
CM. [Transient renal failure in a newborn due to angiotensin receptor II
antagonist use during pregnancy: report of a case]. Rev Med Chil. 2008;
136:624–630.
29. Hinsberger A, Wingen AM, Hoyer PF. Angiotensin-II-receptor inhibitors
in pregnancy. Lancet. 2001;357:1620.
30. Hulton SA, Thomson PD, Cooper PA, Rothberg AD. Angiotensin-
converting enzyme inhibitors in pregnancy may result in neonatal renal
failure. S Afr Med J. 1990;78:673–676.
31. Kaler SG, Patrinos ME, Lambert GH, Myers TF, Karlman R, Anderson
CL. Hypertrichosis and congenital anomalies associated with maternal
use of minoxidil. Pediatrics. 1987;79:434–436.
32. Kato K, Okuda M, Ishikawa H, Takahashi T, Hirahara F. Oligohy-
dramnios and pulmonary hypoplasia: a case in which involvement of an
angiotensin II receptor antagonist was suspected. J Obstet Gynaecol Res.
2008;34:242–246.
33. Knott PD, Thorpe SS, Lamont CA. Congenital renal dysgenesis possibly
due to captopril. Lancet. 1989;1:451.
34. Kolagasi O, Sari F, Akar M, Sari R. Normal pregnancy and healthy child
after continued exposure to gliclazide and ramipril during pregnancy. Ann
Pharmacother. 2009;43:147–149.
35. Kreft-Jais C, Plouin PF, Tchobroutsky C, Boutroy MJ. Angiotensin-
converting enzyme inhibitors during pregnancy: a survey of 22 patients
given captopril and nine given enalapril. Br J Obstet Gynaecol. 1988;95:
420–422.
36. Lambot MA, Vermeylen D, Noel JC. Angiotensin-II-receptor inhibitors
in pregnancy. Lancet. 2001;357:1619–1620.
37. Laube GF, Kemper MJ, Schubiger G, Neuhaus TJ. Angiotensin-
converting enzyme inhibitor fetopathy: long-term outcome. Arch Dis
Child Fetal Neonatal Ed. 2007;92:F402–F403.
38. Lavoratti G, Seracini D, Fiorini P, Cocchi C, Materassi M, Donzelli G,
Pela I. Neonatal anuria by ACE inhibitors during pregnancy. Nephron.
1997;76:235–236.
39. Lip GY, Churchill D, Beevers M, Auckett A, Beevers DG. Angiotensin-
converting-enzyme inhibitors in early pregnancy. Lancet. 1997;350:
1446–1447.
40. Mann R, Mackay F, Pearce G, Freemantle S, Wilton L. Losartan: a study
of pharmacovigilance data on 14 522 patients. J Hum Hypertens. 1999;
13:551–557.
Fetal Renin-Angiotensin System Blockade Syndrome 449
41. Martinovic J, Benachi A, Laurent N, Daikha-Dahmane F, Gubler MC.
Fetal toxic effects and angiotensin-II-receptor antagonists. Lancet. 2001;
358:241–242.
42. Mehta N, Modi N. ACE inhibitors in pregnancy. Lancet. 1989;2:96–97.
43. Millar JA, Wilson PD, Morrison N. Management of severe hypertension
in pregnancy by a combined drug regimen including captopril: case
report. N Z Med J. 1983;96:796–798.
44. Miura K, Sekine T, Iida A, Takahashi K, Igarashi T. Salt-losing neph-
rogenic diabetes insipidus caused by fetal exposure to angiotensin
receptor blocker. Pediatr Nephrol. 2009;24:1235–1238.
45. Muller PR, James A. Pregnancy with prolonged fetal exposure to an
angiotensin-converting enzyme inhibitor. J Perinatol. 2002;22:582–584.
46. Munk PS, von Brandis P, Larsen AI. Reversible fetal renal failure after
maternal treatment with Candesartan: a case report. Reprod Toxicol.
2010;29:381–382.
47. Nayar B, Singhal A, Aggarwal R, Malhotra N. Losartan induced fetal
toxicity. Indian J Pediatr. 2003;70:923–924.
48. Neves S, Santos R, Gomes C, Correia AJ. [Fetopathy associated with
exposure to angiotensin converting enzyme inhibitors]. Acta Med Port.
2010;23:697–700.
49. Payen V, Chemin A, Jonville-Bera AP, Saliba E, Cantagrel S. [Fetal
toxicity of angiotensin-II receptor antagonists]. J Gynecol Obstet Biol
Reprod (Paris). 2006;35:729–731.
50. Pietrement C, Malot L, Santerne B, Roussel B, Motte J, Morville P.
Neonatal acute renal failure secondary to maternal exposure to
telmisartan, angiotensin II receptor antagonist. J Perinatol. 2003;23:
254–255.
51. Piper JM, Ray WA, Rosa FW. Pregnancy outcome following exposure to
angiotensin-converting enzyme inhibitors. Obstet Gynecol. 1992;80:
429–432.
52. Plouin PF, Tchobroutsky C. [Inhibition of angiotensin converting enzyme
in human pregnancy. 15 cases]. Presse Med. 1985;14:2175–2178.
53. Prasad N, Gulati S, Jain M, Tewari P. An unusual case of neonatal anuria.
Indian Pediatr. 2003;40:258–260.
54. Pryde PG, Sedman AB, Nugent CE, Barr M Jr. Angiotensin-converting
enzyme inhibitor fetopathy. J Am Soc Nephrol. 1993;3:1575–1582.
55. Rhabbour M, Lenoir S, Bouissou F, Rolland M, Fournie A. [Fetal and
neonatal effects of maternal treatment with angiotensin converting
enzyme inhibitor]. Arch Pediatr. 1994;1:497–500.
56. Roger N, Popovic I, Madelenat P, Mahieu-Caputo D. [Fetal toxicity of
angiotensin-II-receptor inhibitors. Case report]. Gynecol Obstet Fertil.
2007;35:556–560.
57. Rosa FW, Bosco LA, Graham CF, Milstien JB, Dreis M, Creamer J.
Neonatal anuria with maternal angiotensin-converting enzyme inhibition.
Obstet Gynecol. 1989;74:371–374.
58. Rothberg AD, Lorenz R. Can captopril cause fetal and neonatal renal
failure? Pediatr Pharmacol (New York). 1984;4:189–192.
59. Saji H, Yamanaka M, Hagiwara A, Ijiri R. Losartan and fetal toxic
effects. Lancet. 2001;357:363.
60. Schaefer C. Angiotensin II-receptor-antagonists: further evidence of feto-
toxicity but not teratogenicity. Birth Defects Res A Clin Mol Teratol.
2003;67:591–594.
61. Schubiger G, Flury G, Nussberger J. Enalapril for pregnancy-induced
hypertension: acute renal failure in a neonate. Ann Intern Med. 1988;108:
215–216.
62. Scott AA, Purohit DM. Neonatal renal failure: a complication of maternal
antihypertensive therapy. Am J Obstet Gynecol. 1989;160:1223–1224.
63. Serreau R, Luton D, Macher MA, Delezoide AL, Garel C, Jacqz-Aigrain
E. Developmental toxicity of the angiotensin II type 1 receptor antag-
onists during human pregnancy: a report of 10 cases. BJOG. 2005;112:
710–712.
64. Shrim A, Berger H, Kingdom J, Hamoudi A, Shah PS, Koren G. Pro-
longed exposure to angiotensin-converting enzyme inhibitors during
pregnancy. Fetal toxicity could be reversible. Can Fam Physician. 2005;
51:1335–1337.
65. Simonetti GD, Baumann T, Pachlopnik JM, von Vigier RO, Bianchetti
MG. Non-lethal fetal toxicity of the angiotensin receptor blocker cande-
sartan. Pediatr Nephrol. 2006;21:1329–1330.
66. Sinelli MT, Cattarelli D, Cortinovis S, Maroccolo D, Chirico G. Severe
neonatal renal failure after maternal use of angiotensin II type I receptor
antagonists. Pediatr Med Chir. 2008;30:306–308.
67. Thorpe-Beeston JG, Armar NA, Dancy M, Cochrane GW, Ryan G,
Rodeck CH. Pregnancy and ACE inhibitors. Br J Obstet Gynaecol.
1993;100:692–693.
 450 Hypertension August 2012
68. Velazquez-Armenta EY, Han JY, Choi JS, Yang KM, Nava-Ocampo AA.
Angiotensin II receptor blockers in pregnancy: a case report and sys-
tematic review of the literature. Hypertens Pregnancy. 2007;26:51–66.
69. Vendemmia M, Garcia-Meric P, Rizzotti A, Boubred F, Lacroze V,
Liprandi A, Simeoni U. Fetal and neonatal consequences of antenatal
exposure to type 1 angiotensin II receptor-antagonists. J Matern Fetal
Neonatal Med. 2005;18:137–140.
70. Yip SK, Leung TN, Fung HY. Exposure to angiotensin-converting
enzyme inhibitors during first trimester: is it safe to fetus? Acta Obstet
Gynecol Scand. 1998;77:570–571.
71. Esposito F, Galfetti M, Lava SA, Balestra B, Bianchetti MG. Fetopathy
probably associated to self-medication with a blocker of the renin-
angiotensin system. Arch Gynecol Obstet. 2011;284:1321.
72. Hunseler C, Paneitz A, Friedrich D, Lindner U, Oberthuer A, Korber F,
Schmitt K, Welzing L, Muller A, Herkenrath P, Hoppe B, Gortner L,
Roth B, Kattner E, Schaible T. Angiotensin II receptor blocker induced
fetopathy: 7 cases. Klin Padiatr. 2011;223:10–14.
73. Morgan M, De Jong-van den Berg LT, Jordan S. Drug safety in preg-
nancy–monitoring congenital anomalies. J Nurs Manag. 2011;19:
305–310.
74. Hurault de Ligny B, Mintz P, Ryckelynck JP, Herlicoviez M, Muller G,
Levy G. [Captopril treatment of severe arterial hypertension in
pregnancy]. J Gynecol Obstet Biol Reprod (Paris). 1987;16:643–648.
75. Haaland K. Angiotensin II receptor antagonists against migraine in preg-
nancy: fatal outcome. J Headache Pain. 2010;11:167–169.
76. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S,
Gideon PS, Hall K, Ray WA. Major congenital malformations after
first-trimester exposure to ACE inhibitors. N Engl J Med. 2006;354:
2443–2451.
77. Biswas PN, Wilton LV, Shakir SW. The safety of valsartan: results of a
postmarketing surveillance study on 12 881 patients in England. J Hum
Hypertens. 2002;16:795–803.
78. Bowen ME, Ray WA, Arbogast PG, Ding H, Cooper WO. Increasing
exposure to angiotensin-converting enzyme inhibitors in pregnancy. Am J
Obstet Gynecol. 2008;198:e291–e295.
79. Diav-Citrin O, Shechtman S, Halberstadt Y, Finkel-Pekarsky V,
Wajnberg R, Arnon J, Di Gianantonio E, Clementi M, Ornoy A.
Downloaded from http://ahajournals.org by on September 18, 2019
Novelty and Significance
What Is New?
● Fetal exposure to ACE-Is or ARBs carries the risk for relevant neonatal
and long-term complications, termed fetal renin-angiotensin system
blockade syndrome.
● The neonatal outcome is poorer following prenatal exposure to ARBs.
What Is Relevant?
● The awareness of the deleterious effect of prenatal exposure to drugs
inhibiting the renin-angiotensin system should be improved.
Pregnancy outcome after in utero exposure to angiotensin converting
enzyme inhibitors or angiotensin receptor blockers. Reprod Toxicol.
2011;31:540–545.
80. Karthikeyan VJ, Ferner RE, Baghdadi S, Lane DA, Lip GY, Beevers DG.
Are angiotensin-converting enzyme inhibitors and angiotensin receptor
blockers safe in pregnancy: a report of ninety-one pregnancies.
J Hypertens. 2011;29:396–399.
81. Porta M, Hainer JW, Jansson SO, Malm A, Bilous R, Chaturvedi N,
Fuller JH, Klein R, Orchard T, Parving HH, Sjolie AK. Exposure to
candesartan during the first trimester of pregnancy in type 1 diabetes:
experience from the placebo-controlled DIabetic REtinopathy Cande-
sartan Trials. Diabetologia. 2011;54:1298–1303.
82. Krause T, Lovibond K, Caulfield M, McCormack T, Williams B. Man-
agement of hypertension: summary of NICE guidance. BMJ. 2011;343:
d4891.
83. Sibai BM. Chronic hypertension in pregnancy. Obstet Gynecol. 2002;
100:369–377.
84. Alwan S, Polifka JE, Friedman JM. Angiotensin II receptor antagonist
treatment during pregnancy. Birth Defects Res A Clin Mol Teratol. 2005;
73:123–130.
85. Sedman AB, Kershaw DB, Bunchman TE. Recognition and management
of angiotensin converting enzyme inhibitor fetopathy. Pediatr Nephrol.
1995;9:382–385.
86. Sekine T, Miura K, Takahashi K, Igarashi T. Children’s toxicology from
bench to bed–Drug-induced renal injury (1): The toxic effects of
ARB/ACEI on fetal kidney development. J Toxicol Sci. 2009;34 Suppl
2:SP245–SP250.
87. 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;96:451–456.
88. Hanssens M, Keirse MJ, Vankelecom F, Van Assche FA. Fetal and
neonatal effects of treatment with angiotensin-converting enzyme
inhibitors in pregnancy. Obstet Gynecol. 1991;78:128–135.
89. Broughton Pipkin F, Turner SR, Symonds EM. Possible risk with cap-
topril in pregnancy: some animal data. Lancet. 1980;1:1256.
Summary
Fetal exposure to ACE-Is or ARBs have relevant neonatal
and long-term complications. The neonatal outcome appears
to be poorer following prenatal exposure to ARBs compared
with ACE-Is. The awareness of the deleterious effects of
prenatal exposure to drugs inhibiting the RAS should be
addressed.