Journal of Human Hypertension (2002) 16, 293298

2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00

www.nature.com/jhh

REVIEW ARTICLE

The effect of antihypertensive drugs on

the fetus
T Rosenthal1 and S Oparil2
1

Chorley Hypertension Research Institute, Chaim Sheba Medical Center, Tel Hashomer and Sackler
School of Medicine, Tel Aviv University, Israel; 2Department of Medicine, Division of Cardiovascular
Disease, Vascular Biology and Hypertension Program, University of at Birmingham Alabama School of
Medicine Birmingham, AL, USA

A critical review of the literature on the effects of antihypertensive drugs on the fetus in pregnant women is
presented. The survey covers the alpha-adrenergic
receptor agonists, beta-blockers including topical eye
medications, alpha-beta blockers, calcium antagonists,
diuretics, and angiotensin-converting enzyme (ACE)
inhibitors. The lack of data on angiotensin II receptor
blockers is noted although effects are considered to be
similar to those reported with ACE inhibitors and therefore to be avoided. Analysis of the literature under-

scores that some antihypertensive drugs can be used

safely at certain stages of pregnancy, while others are
suspect and to be avoided at all costs. The lack of placebo-controlled studies on the treatment of severe
hypertension in pregnancy due to ethical considerations is discussed against the background of the
pressing need to treat these women despite the possible deleterious effects of antihypertensive drugs
Journal of Human Hypertension (2002) 16, 293298. DOI:
10.1038/sj/jhh/1001400

Keywords: hypertension in pregnancy; antihypertensive drugs and fetus; teratology and antihypertensive drugs

Introduction

Methyldopa

The use of antihypertensive drugs in pregnant

women with chronic hypertension remains controversial in light of the usual fall in blood pressure
that occurs during the first half of pregnancy,1 and
the probable deleterious effects on fetal growth and
development of antihypertensive drugs and treatment-induced blood pressure declines.2,3 Whether
or not pre-eclampsia develops, the presence of proteinuria early in pregnancy puts women with
chronic hypertension at higher risk for adverse neonatal outcomes.4 Rey and Couturier5 retrospectively
evaluated the course of 298 pregnant women with
chronic hypertension whose antihypertensive medications had been discontinued or reduced in doses
early in pregnancy. Neither superimposed preeclampsia, preterm delivery, abrupto placentae, nor
perinatal death was less frequent than in treated
women. Although placebo-controlled trials on antihypertensive drug treatment in pregnancy are lacking, considerable data have accumulated on this
topic (Table 1).

On the basis of reports of stable uteroplacental blood

flow and fetal haemodynamics,6 methyldopa has
become the preferred agent as first-line therapy and
has been used most commonly in randomised
trials.7 It is considered the safest and most efficacious antihypertensive drug for use in pregnancy
and is therefore recommended by all working
groups.8 Kirsten and colleagues9 consider it the only
acceptable drug during the first trimester of pregnancy.

Correspondence: T Rosenthal, MD, Chorley Hypertension

Research Institute, Chaim Sheba Medical Center, Tel Hashomer
52621, Israel. E-mail: trosenthsheba.health.govil

Alpha-and beta-adrenergic blocking

agents labetalol
When methyldopa causes somnolence and cannot
be tolerated, alternatives such as the alpha-betaadrenergic blocking agent, labetalol, may be used.
Clinical experience with labetalol is extensive and
it is among the most widely used antihypertensive
drugs in pregnancy.10 Blood pressure and proteinuria fell significantly in a placebo controlled
trial of labetalol in a cohort of 144 women with pregnancy-induced mild and moderate hypertension.
However, gestation was not significantly prolonged
and measures of clinical outcome were not significantly altered in these women.11 Possible advantages and no evidence of disadvantages for the fetus

Antihypertensive drugs and the fetus

T Rosenthal and S Oparil

294

Table 1 Antihypertensive therapy of chronic hypertension in

pregnancy
Drug

Dosage

Additional comments

Methyldopa

5003000 mg
Considered to be drug of choice
in 2 4 divided because of extensive experience
doses

Labetalol

2001200 mg
Similar in efficacy and safety to
in 23 divided methyldopa
doses

Beta-blockers variable

Possibility of fetal bradycardia,

lower birth weight (when used
early in pregnancy)

Calcium
channel
blockers

variable

Accumulating data support

maternal and fetal safety; may
interact with magnesium
sulfate

Alphablockers

variable

Scant data for use in pregnancy

Clonidine

0.10.8 mg in
2 4 divided
doses

Limited data

Thiazide
diuretics

variable

May be associated with

diminished volume expansion
in pregnancy; may be necessary
in salt-sensitive hypertensives
at lower doses

Angiotensinconverting
enzyme
inhibitors

contraindicated Contraindicated in pregnancy;

neonatal anuric renal failure

Angiotensin
receptor
antagonists

contraindicated Contraindicated in pregnancy;

neonatal anuria renal failure.

From: August P, Falkner B. Hypertension in pregnancy and in

children. In: Antman E (ed). Cardiovascular Therapeutics: A
Modified Companion to Braunwalds Heart Disease. W.B. Saunders Company: Philadelphia, PA, Chapter 38, 2001 (published
last week).

were reported in another trial with labetalol, this

time a double-blind controlled study in 152
women.12 Thus labetalol is generally not considered
to adversely affect the fetus during the third trimester of pregnancy, and is commonly used to treat
hypertension at that stage.10

Beta-adrenergic blocking agents

The beta-adrenergic receptor antagonists, including
metoprolol and atenolol, are also considered safe
and effective in late gestation, but have been
reported to cause some fetal problems when given in
early or mid-gestation.13,14 Beta-blockers, especially
atenolol, have been linked with fetal growth retardation when given early in pregnancy.15 A largescale retrospective study of atenolol in 78 pregnancies showed that the drug was associated with
fetal growth retardation, particularly when it was
given early in pregnancy and continued for a long
time.16 These authors urge avoiding atenolol in the
early stages of pregnancy and exercising caution at
Journal of Human Hypertension

later stages. A randomised trial in which atenolol or

placebo was given before 24 weeks of gestation to
normotensive pregnant women with high cardiac
output in an attempt to prevent pre-eclampsia
revealed similar results, namely smaller babies than
those getting placebo.17 Churchill et al,18 on the
other hand, found little difference in fetal growth
between women who began atenolol in the second
trimester, women on other antihypertensive drugs,
and those using no medication.
A basic concern of these and other authors is the
level at which blood pressure should be treated and
to which blood pressure should be lowered in pregnancy. Magee19 raises this question, noting that
many factors are likely to affect fetal growth other
than maternal blood pressure. He points to the connection between antihypertensive treatment and the
goal of best perinatal outcome, which remains to be
addressed. An international multicentre randomised
controlled trial, Control of Hypertension in Pregnancy and small for gestational age (SGA) Infants
(CHIPS), is currently being designed to answer
these questions.20
Since topical eye medications are absorbed
through the nasopharyngeal mucosa and can therefore enter the systemic circulation, beta-blocker eye
drops should be avoided in the first trimester of
pregnancy. This is especially noteworthy because
glaucoma can occur during the second to the fifth
decade of life, a time when women are at risk for
pregnancy. Indeed, Wagebvoort et al21 reported a
case in which timolol eye drops were associated
with bradycardia and arrhythmia in the fetus, a
phenomenon observed also in sheep by Van
Tetten.22 The literature on the use of other forms of
eye drops, such as betaxolol and levobunolol in
pregnant women, is lacking.23

Alpha adrenergic blocking agents

Although prazosin is rarely used in pregnancy, it
was recently reported that in the third trimester,
fetal concentrations of prazosin are 1020% of the
maternal concentrations, suggesting the possibility
that prazosin may affect the fetus.24 Prazosin has
been associated with transverse limb defects in the
fetus in a case report.25 Prazosin taken from day 7
of gestation resulted in limb defects, hypoxic renal
damage, and intrauterine death at 20 weeks. These
authors25 attributed the anomalies to drug-induced
hypotension in the mother, with resultant diminished uteroplacental blood flow, fetal hypotension
and hypoxia. This is only a speculation, and if this
were the case, we would expect to see more limb
reduction defects in the population treated with
antihypertensive drugs than we actually do. One
should be cautious about drawing conclusions concerning the adverse effects of drugs on the fetus
based on isolated case reports since fetal defects
occur in a sporadic case in the general population of

Antihypertensive drugs and the fetus

T Rosenthal and S Oparil

pregnant women independent of both hypertension

and antihypertensive therapy.

Vasodilators
The potent vasodilator minoxidil26 has been shown
to adversely affect the fetus causing hypertrichosis
of the back and extremities in a 38-week-old infant
born to a woman administered a daily regimen of
minoxidil, captopril and propranolol. Additional
pathologic features included dysmorphic facial features, bilateral fifth finger clinodactyly, and an
omphalocele containing bowel loops. The hypertrichosis was considered evidence of the transplacental effect of minoxidil, but does not necessarily
account for the other pathologic features. The congenital abnormalities might be attributable to an
interaction among the three drugs. Animal safety
studies27 of the effects of minoxidil in pregnant rats
and rabbits revealed no teratogenic effects in rats
when given at 20 and 70 times routine human doses
on gestation days 6 to 15, while rabbits given those
doses on days 618 had smaller litter sizes and
higher rates of fetal absorption.

Calcium channel blocking agents

Calcium antagonists generally constitute secondline agents, usually administered late in pregnancy.
A small multicentre prospective cohort study of first
trimester exposures to calcium channel blockers
reported no increase in major teratogenic risk.28 This
study suggests that calcium channel blockers
(especially nifedipine and verapamil) do not represent a major teratogenic risk. The prematurity and
lower birth weight that have been reported with
increased frequency among offspring of patients
treated with calcium channel blockers may be due
to the serious maternal hypertension and not to the
therapy per se. A larger multicentre study randomised 145 pregnant women with mild to moderate
hypertension to slow release nifedipine or no treatment. Neither benefit nor harm from the treatment
was reported in the 138 women who began treatment in the second trimester.29 The literature is too
sparse, however, to draw any definite conclusions
about the safety of calcium channel blockers administered early during pregnancy.

Diuretics
The known association of pre-eclampsia with
reduced plasma volume and worse fetal outcome in
women with chronic hypertension, who failed to
expand their plasma volume appropriately in pregnancy argues against use of diuretics in pregnancy.30
Indeed, plasma volume expansion was found to be
minimal in women using diuretics from early pregnancy compared with normotensive pregnant
women.31 A meta-analysis of nine randomised trials
performed by Collins et al,32 involving more than

7000 pregnant women receiving diuretics, revealed

a decrease in the tendency of the women to develop
oedema and/or hypertension. Pre-eclampsia,
appeared to have been prevented even when
oedema was not a diagnostic criterion. This may
reflect the blood pressure-lowering action of
diuretics. There was little difference in postnatal
survival between diuretic treated and untreated
groups: stillbirths were about one-third less with
treatment, but small numbers made the difference
statistically insignificant. There was no increased
incidence of adverse fetal effects.
Although data concerning the use of diuretics in
pregnant women with essential hypertension are
sparse, the Working Group Report on High Blood
Pressure in Pregnancy, 20001 concluded that gestation does not preclude use of diuretics to reduce
or control blood pressure in women whose hypertension predated conception or manifested before
mid-pregnancy. These safe and efficacious agents,
can markedly potentiate the response to other antihypertensive agents, and are not contraindicated in
pregnancy except in settings where uteroplacental
perfusion is already reduced (pre-eclampsia and
intrauterine growth restriction).

295

Angiotensin-converting enzyme
inhibitors
Animal studies have found angiotensin-converting
enzyme inhibitors (ACEIs) to be associated with
fetal anomalies. Captopril administered to two nearterm pregnant guinea pigs reduced fetal ACE
activity below levels seen in control animals,33 indicating that the drug can adversely affect blood pressure control during both fetal and neonatal life.
Administration of enalapril to ewes34 produced
unexpected fetal deaths, skeletal abnormalities, and
an unexplained stillbirth. Histological examination
of the lungs of this last fetus showed inadequate
lung expansion indicative of severe intrapartum
asphyxia and/or possibly a surfactant deficiency.
When given to lambs and rabbits late in pregnancy,35 captopril resulted in a high percentage of
stillbirths in the former and prolonged gestation in
the latter. These studies point to the rapid passage of
captopril across the placenta. Captopril in pregnant
rabbits in another study36 reduced blood pressure,
slowed uterine blood flow, and drastically decreased
uterine vein prostaglandin E (PGE). The importance
of PGE synthesis in maintaining uterine blood flow
and the survival of the fetus evidenced by these findings raises the possibility that uterine PGE synthesis is dependent on angiotensin II.
Experience with ACEIs in humans confirms much
of the data from animal studies. Fiocchi and coworkers,37 in a letter to the editor in the Lancet,
described a case in which captopril was given
throughout pregnancy to a 47-year-old hypertensive
woman with no untoward events until weeks 32
36, when there was progressive retardation in fetal
Journal of Human Hypertension

Antihypertensive drugs and the fetus

T Rosenthal and S Oparil

296

growth according to imaging and biochemical parameters. This baby was born with no abnormalities
despite continuous administration of captopril
throughout the pregnancy. With some exceptions,38
despite early case reports supporting the safety of
ACEIs in pregnancy, the literature is generally not
in favour of using ACEIs because of associated severe fetal and neonatal disease.39 A number of
reviews and reports addressed to clinical tetralogy
counsellors cited oligohydramnios and/or neonatal
anuria, pulmonary hydroplasia, mild to severe intrauterine growth retardation, and fetal death associated with ACEIs. Persistent anuria in neonates was
attributed to maternal intake of captopril40 and to a
battery of antihypertensive drugs including enalapril.41 Neonatal renal failure and some dysmorphic
features were described following captopril;42 the
death of a child from pulmonary hypoplasia was
attributed to oligohydramnios following enalapril;43
and acute renal failure was reported in a premature
newborn following enalapril.44
Two cases of bone hypocalvaria were reported by
Barr and Cohen,45 one in the fetus of a woman who
received captopril and another in a woman who
received lisinopril both fetuses had fetopathy with
renal tubular dysgenesis and severely underdeveloped calvarial bone. Other cases of underdeveloped
calvaria induced by captopril were described by
Duminy and Burger46 and Mheta and Modi.47 The
anomalies described in these casesfetal and neonatal mortality, neonatal anuria, intrauterine growth
retardation,and calvarial hypoplasiaare connected
with severe fetal hypotension during the second and
third trimester. The morphologic findings and/or
signs of fetal growth restriction attest to utero
hypotension/hypoxia.
A French group48 reported fetal death, preterm
delivery, and small-for-age newborns in women taking captopril or enalapril during pregnancy, but also
noted that in seven cases in which ACEIs were combined with diuretics, perinatal outcome was unremarkable. Brent39 considered it important to alert
physicians to the possibility of fetal and neonatal
disease following transplacental passage of captopril, especially since a report suggesting that captopril is not teratogenic49 raised the likelihood of
physicians prescribing it during pregnancy.
Although there is agreement that ACEIs can pose
a risk to the fetus,39 there is controversy over the
timing and duration of exposure in relation to fetal
risk and the magnitude of the risk during the unsafe
stages. While an editorial in The Lancet in 198950
cautioned that most of the pregnant women reported
in the various studies were also receiving other
drugs, there is no question that oligohydramnios,
fetal death, neonatal anuria, intrauterine growth
retardation and fetal calvarial hypoplasia are direct
effects of ACEIs on the fetus. ACEIs are absolutely
contraindicated in women with child-bearing potential, based on the evidence of a high degree of morbidity and mortality in fetuses or newborn infants

Journal of Human Hypertension

exposed to these drugs during pregnancy.51,52 Lip et

al53 further stated that there is no justification to
continue using ACEIs once pregnancy is documented, and recommended that they should be
stopped or changed to an alternative agent.

Angiotensin II receptor antagonists

Adverse effects of angiotensin II receptor antagonists
on fetal kidneys have been documented in rats and
sheep,5456 and recent case reports have provided
data on their effects on humans. Losartan, hydrochlorothiazide, felodipine and metoprolol given to
a 42-year-old woman from the beginning of pregnancy57 resulted in a baby with varus deformation,
of the left foot, clubbed right foot and fixed external
rotation of right knee, Potters facies, and patent
ductus arteriosus. This anuric baby died on the 4th
postnatal day. Microscopy revealed renal tubular
dysgenesis.
In another case,58 a woman on candesartan gave
birth to a baby girl with left sided facial palsy and
plexus paresis who was anuric at 24 h postpartum,
with steadily rising creatinine that dropped at 1
month of age. The authors suspect that the candesartan was responsible for the acute perinatal renal failure in this case.
Three patients59 on valsartan at the time of conception delivered babies that showed no congenital
abnormalities or evidence of renal dysfunction, one
of which had growth retardation. The authors concluded that activation of the AT1 receptor by angiotensin II plays a role in vascular development and
growth, so an AT1 antagonist should not be given to
women already pregnant or planning pregnancy.

Conclusions
The high risk of hypertension, particularly severe
hypertension, to the pregnant woman, mandates the
use of antihypertensive treatment despite possible
detrimental effects on the fetus. While antihypertensive therapy is indicated for maternal benefit, it may
also permit prolongation of the pregnancy and
thereby improve fetal maturity. However, severely
hypertensive women are usually delivered soon
after their blood pressure is controlled, since the
reduction in uteroplacental blood flow following the
quick and dramatic reduction in maternal blood
pressure adversely affects the fetus.
Diagnosing any drug-related disorder can be difficult. The relationship between a drug and an effect
can be definitively established only by withdrawal
of the suspected offending agent and rechallenge
clearly out of the question in most cases. Studies
that attempt to establish a cause and effect relationship based on clinical data are done on cohorts of
varying sizes and are usually very small. The effects
of treating severe hypertension in pregnancy have
been investigated in only a few placebo-controlled
trials. There is a pressing need for well-designed,

Antihypertensive drugs and the fetus

T Rosenthal and S Oparil

controlled studies carried out by multidisciplinary

teams of obstetricians, hypertension specialists, epidemiologists, and even geneticists. More information about the risks and safety of specific drugs,
dosages and combinations should enable the physician to be bolder in attempting to treat this condition which if left unattended, will harm both the
mother and fetus.

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