British Journal of Obstetrics and Gynaecology
March 2000, V01107,pp. 299-307
REVIEW
Nifedipine in pregnancy
Introduction
Nifedipine is a dihydropyridine calcium channel
blocker that is widely used for the treatment of cardio-
vascular disorders in nonpregnant individuals. Over the
last 15 years its favourable pharmacologic characteris-
tics have resulted in its efficacy and safety being
assessed in pregnancy. Its application both as a treat-
ment for acute severe hypertension, as well as for long
term use for hypertension in pregnancy, have been
explored. The drug has been shown to have a tocolytic
effect on uterine smooth muscle and hence its use in the
prevention of preterm delivery has been investigated.
In this article, the mechanism of action of the drug, as
well as the current understanding of its metabolism and
pharmacokinetics in pregnancy, is reviewed, including
assessment of the literature on the use of nifedipine in
the management of hypertension in pregnancy and its
use in suppressing preterm labour.
A literature search of MEDLINE and the Cochrane
Library was conducted for the years 1975 to September
1997 concerning the use of nifedipine in pregnancy,
both for the treatment of hypertension and for tocolysis.
The keywords used were: nifedipine, calcium channel
blockers, pregnancy, hypertension, pre-eclampsia,
umbilical artery blood flow,uteroplacental blood flow,
teratogenicity, tocolysis, preterm labour; preterm deliv-
ery. The reference lists of all identified articles were
examined to find additional relevant studies.
Nifedipine
Nifedipine is a type 2 calcium channel blocker that
inhibits the inward flow of calcium across the L-type
slow channels of cellular membranes',2.Its effect is pri-
marily that of causing smooth muscle relaxation. Its
applications have been in vascular, uterine and bladder
smooth muscle relaxation. Unlike the type 1 agents, it
has minimal effects on the cardiac conducting system'.
The ability of nifedipine to vasodilate the systemic
and pulmonary vasculature with full reversibility on
stopping the drug and its lack of tachyphylaxis' has
resulted in it becoming a widely used agent in the treat-
ment of acute and chronic hypertension and angina pec-
tons. It causes a decrease in arterial vascular resistance
but with minimal effect on the venous system. It results
0 RCOG 2000 British Journal of Obstetrics and Gynaecology
in a 20% lowering of the systolic, diastolic and mean
arterial blood pressures'. An increase in cardiac output
results from both reflex tachycardia secondary to stimu-
lation of the sympathetic nervous system and an
increase in stroke volume. Hepatic and renal blood flow
are also in~reased'.~. This vascular relaxation, which is
marked in hypertensive patients, does not occur signifi-
cantly in normotensive patients, thus allowing the drug
to be used in its other applications'.
Nifedipine has been shown to cause relaxation of the
uterine smooth muscle and hence its use as a tocolytic
agent has been evaluated. In vitro studies have shown
the ability of nifedipine to inhibit myometrial contrac-
tion in pregnant and nonpregnant ~ o r n e n ~It- causes
~. a
reduction in basal tone and in the amplitude and fre-
quency of uterine contractions7**,whether these are
spontaneous contractions or induced by potassium, oxy-
tocin or prostaglandin and F22'".
The pharmacokinetics of the drug are well
described'.". Maximum serum concentrations of the
drug are obtained most quickly if the capsule is first bit-
ten and the drug then swallowed. With standard oral
administration the peak concentration occurs slightly
later. Sublingual administration with absorption through
the buccal mucosa is poor and Blood pres-
sure falls within five to ten minutes of a capsule being
bitten and then swallowed, and ten to thirty minutes
with oral administration. The rate of onset of action of
nifedipine is similar in pregnant and in nonpregnant
women. Metabolism occurs in the liver, 30% to 40% of
the drug being metabolised in the first pass, and the
inactive metabolites are excreted in the urine. In preg-
nancy the physiological changes in the cardiovascular
system and in hepatic function result in an increased rate
of metabolism and clearance of the drug. The peak
serum concentration (Cmax), the elimination half-life
and clearance rate in pregnancy and nonpregnancy of a
standard 10 mg oral dose are shown in Table 114-".
Due to these differences in metabolism and clearance
in pregnancy, the duration of action of nifedipine is
reduced to four to six hoursI5.Consequently higher and
more frequent doses may be required in pregnant
women to obtain adequate antihypertensive effects. The
recommended starting dose is 10 to 20 mg, six hourly.
Nifedipine crosses the placental4.The ratio of nifedip-
ine concentrations in umbilical cord blood compared
299
300 REVIEW
Table 1. Peak serum concentration, elimination half-life and
clearance rate of standard 10 mg dose in pregnancy and nonpregnant
state. Values are given as mean (SD).
Pregnancy Nonpregnancy
Peak serum concentration (nglmL) 38.6 (18) 73.48 (17.48)
Elimination half-life (h) 1.3 (0.5) 3.43 (10.6)
Elimination clearance rate (L/h/kg) 2 (0.8) 0.49 (0.09)
with maternal serum is 0-93’4,’5. The fetal liver poorly
metabolises the drug and it is excreted in the urine,
resulting in an amniotic fluid to maternal serum concen-
tration ratio of 0.5615.It does not cause any alteration in
fetal blood pressure in animals’”.”.
Hypertension in pregnancy
Hypertension in pregnancy may be chronic (essential or
secondary to underlying maternal disease) or due to pre-
eclampsia. The effect of antihypertensive agents is dif-
ferent in these conditions, which must be considered
when interpreting randomised trials of the treatment of
hypertension in pregnancy.
Normally in pregnancy there is a reduction in the sys-
temic vascular resistance, such that chronic hyperten-
sion often improves in the second trimester and early
third trimester, to be restored in late pregnancyI8.
Women with chronic hypertension have a 10% to 30%
increased risk of developing pre-eclampsia’y--21. If pre-
eclampsia does not occur the course of mild and moder-
ate essential hypertension is benign, and it is uncertain
whether antihypertensive treatment improves the out-
come of pregnan~y’”-?~.
Pre-eclampsia is a progressive systemic disease due
to inadequate trophoblastic invasion of the spiral arteri-
o l e ~It~is~associated
. with significant maternal and fetal
morbidity and mortality. In pre-eclampsia hypertension
is due to generalised arteriolar vasospasm and decreased
plasma volume26-28.The spiral arteries of the .pIacenta
maintain their muscular tone and responsiveness to
vasoactive There is associated lipid depo-
sition and acute atherosis, leading to placental
ischaemia and infarction29. Altered prostanoid
metabolism and nitric oxide production in placental
blood vessels also occurs’”’’’. The pathological pro-
cesses in the placenta result in dissemination of abnor-
mal substances throughout the circulation, leading to
disturbed endothelial function, platelet consumption,
and increased vascular resistance and hypertension”*”’.
The only definitive treatment of pre-eclampsia is deliv-
ery of the woman, but immediate delivery is not desirable
when the fetus is preterm and the pre-eclampsia is not
severe. Bed rest and antihypertensive agents14are most
commonly advised, and plasma volume expansion and
antioxidants have also been evaluated-l”-”*.The efficacy
of these treatments as regards maternal and fetal out-
come in pre-eclampsia is uncertain.
The control of severe hypertension, however, is
uncontroversial. It is well proven that mean arterial pres-
sures > 140 mmHg can result in cerebral arteriolar dam-
age. Histological changes are detectable as early as
10 minutes after the onset of severe hypertension, and
clinically apparent arteriolar damage is seen within a few
hour^",^'. Cerebral haemorrhage is the commonest cause
of maternal death in pre-eclampsia and ec1ampsia4lA3.
A number of drugs have been used in pregnancy to
treat hypertension in pregnancy. The most widely used
are methyldopa and the beta-blockers, atenolol and
labetalol. Methyldopa has been used extensively and
appears to be effective, and safe, both for mother and
f e t u ~ ’ ~Maternal
, ~ ~ . side effects include lethargy, drowsi-
ness and depression, and drug-induced hepatitis can be
confused with early HELLP syndrome4’.Although beta-
blockers are considered safe in pregnancy&,intrauterine
growth retardation has been linked to their use and side
effects of hypoglycaemia and blockade of the neonatal
cardiac conducting system have been reported4’.
Dihydralazine has been the most commonly used
drug in the acute hypertensive emergency in pregnancy,
but its side effects of headaches, palpitations and tachy-
cardia, as well as its ability to cause too rapid a fall in
blood pressure are well d e s ~ r i b e d ~ ’It, ~is~possible
. that
these hypotensive episodes may be a reflection of
underlying intravascular volume status rather than any
property of the drug itself. Sodium nitroprusside and
diazoxide are known to produce precipitous falls in
blood pressure, often with adverse effects in an already
compromised f e t u ~ ~ ~ ~ ~ ‘ ) .
The ideal drug for the treatment of pregnancy hyper-
tension continues to be sought. It should be rapidly effec-
tive and long acting, with minimal side effects to the
mother, and it should not compromise the fetus either
directly or by a reduction in placental perfusion. With an
ever increasing body of evidence describing the safety,
efficacy and minimal side effects of the calcium channel
blockers outside of pregnancy, a number of authors have
investigated their use in pregnancy. Nifedipine has been
the most commonly used of these agents.
The mode of action of nifedipine to reduce systemic
vascular resistance and its ability to improve urine out-
put by increasing renal blood flow and by inhibiting the
release of anti-diuretic hormone make it a highly appro-
priate drug for use in hypertension in pregnancy.
Nifedipine in the management of hypertensionin
pregnancy
Acknowledging the uncertainty surrounding the bene-
fits of antihypertensive treatment in mild and moderate
0 RCOG 2000 Br J Obstet Gynaecol 107,299-307

hypertension, a number of small studies have been per-
formed to evaluate the use of nifedipine in pregnancy
remote from term. It has been compared with bed rests1,
placebos2,m e t h y l d ~ p and
a ~ ~dihydralazines4and appears
to be an effective antihypertensive agent but shows no
benefit in significantly prolonging pregnancy or
improving maternal or fetal outcome. No studies have
been done to investigate the long term effects on infants
of mothers who have received nifedipine in pregnancy.
Sibai et uLsl compared bed rest with oral nifedipine in
200 women with pre-eclampsia between 26 and 36
weeks of gestation. They showed a significant reduction
in the systolic and diastolic blood pressures with
nifedipine, as well as a reduction in the number of deliv-
eries for severe hypertension. However, the mean dura-
tion of hospitalisation in the two groups was similar and
the use of nifedipine made no difference to prolongation
of pregnancy. It also did not affect renal function, uri-
nary excretion of protein or platelet count. No difference
in fetal outcome was noted between the two groups.
Abnormal fetal heart rate traces, Apgar scores, inci-
dence of suspected small for gestational age infants and
admission to the special care nursery were all similar.
Comparing nifedipine 20 mg (8 hourly) with placebo,
given in a similar regimen, Ismail et uL5*reaffirmed its
antihypertensive efficacy in pregnancy without any
adverse fetal outcome. In the 20 women given nifedip-
ine he was able to show an improvement in serum urea
and creatinine levels, as well as in 24 hour urinary pro-
tein excretion with prolonged use of nifedipine. Similar
results were found when nifedipine was compared with
placebo in the management of women with pre-eclamp-
sia in the immediate postpartum period. There was both
a significant reduction in the mean arterial pressure as
well as a mean increase in urine output of over
800 mL/24 hours. However, no difference was found in
urinary protein excretion, creatinine clearance or serum
levels of urea or uric acid.
Nifedipine has been compared with methyldopa for
the treatment of pregnancy-induced hypertension and
been shown to be comparable in its antihypertensive
action but achieved no improvement in prolongation of
pregnancy or fetal outcomes3.
Fenakel et uLS4suggested that nifedipine was superior
to hydralazine in the treatment of pre-eclampsia remote
from term. In a group of 54 women with pre-eclampsia
they were able to control the blood pressure signifi-
cantly more often with nifedipine than with hydralazine
and found that it was more predictable in its action and
did not cause precipitous falls in blood pressure. They
also noted an increase in urine output and associated
decrease in peripheral oedema in 12 of the 24 women on
this drug. No difference was found in urinary protein
excretion. Perinatal outcome was similar with the two
drugs but pregnancy was prolonged on average a week
0 RCOG 2000 Br J Obstet Gynaecol 107,299-307
REVIEW 301
longer than with hydralazine, with a resultant increase in
birthweight and reduced admission to the neonatal
intensive care unit.
In a descriptive study Constantine et uLsSinvestigated
the use of nifedipine as a second line drug in women with
hypertension in pregnancy not controlled by either
atenolol or methyldopa. They were able to control the
hypertension effectively in 20 of the 23 women by the
administration of 40 to 120 mg of slow release nifedipine
daily. However, a high rate of perinatal morbidity and
mortality was disturbing. Due to the uncontrolled nature
of the study and the different causes of the hypertension,
the contribution of the drug regimen was uncertain.
It appears that nifedipine is at least as good as dihy-
dralazine in its antihypertensive effect, but its onset of
action is less likely to be precipitous. In the short term it
may increase urine output by reduction of the resistance
of the renal arteries and by decreasing the release of anti
diuretic hormone. No improvement in outcome or
adverse effect on the fetus has been shown but it may
have a benefit by prolonging pregnancy.
Control of acute severe hypertension
Nifedipine has been used successfully in nonpregnant
women to reduce the blood pressure in acute severe
hypertension. Research using animals has confirmed its
efficacy in pregnancy without any significant effect on
placental blood flow or compromise to the fetuss6.Some
studies have described its use in human pregnancy, com-
paring it with dihydralazine as regards its efficacy and
its side
In a descriptive study of 21 pregnant women with
severe hypertension in the antepartum or postpartum
period, Walters and Redmad7 showed that nifedipine
resulted in a significant reduction in systolic and dias-
tolic blood pressure. Its action was prompt and an oral
10 mg dose resulted in control for four hours. Side
effects were minimal and there appeared to be no signif-
icant potentiation of other antihypertensiveagents.
Three randomised controlled trials have compared the
efficacy and safety of nifedipine and dihydralazine in
acute severe hypertension in Visser and
Wallenbergs8 compared the haemodynamic effects of
10 mg oral nifedipine and an intravenous hydralazine
infusion of 1 to 3 mg per hour in 20 women with severe
pre-eclampsia. They showed that both drugs had similar
ability to reduce blood pressure to acceptable levels due
to a significant reduction in systemic vascular resis-
tance, accompanied by similar increases in cardiac out-
put and heart rate. However, pulmonary capillary wedge
pressure decreased significantly less with nifedipine
than with dihydralazine. Five women treated with
hydralazine developed fetal distress, compared with
none treated by nifedipine. Similar efficacy of the two
302 R E V I E W
drugs has been shown by Jegasothy and Parathamad9 in
a group of 200 severely hypertensive women where
5 mg sublingual nifedipine was compared with 5 mg of
hydralazine given intravenously. In this trial no differ-
ence in adverse fetal outcome was found between the
two groups. In a smaller study of 33 primigravidae with
severe pre-eclampsia, Seabe et aL6' confirmed the simi-
larity of effectiveness of the two drugs but showed an
earlier onset of action with oral nifedipine. They
reported equivalent increases of maternal heart rate with
both drugs. One woman required delivery for fetal dis-
tress following a precipitous fall in blood pressure with
nifedipine; otherwise fetal outcome was similar.
The comparable efficacy, possible earlier onset of
action, minimal adverse effects and ease of administra-
tion of the oral nifedipine tablet, or of a punctured, then
swallowed capsule of nifedipine, make it a suitable
alternative to hydralazine in acute hypertensive emer-
gencies. The Canadian Hypertension Society as well as
the Australasian Society for Study of Hypertension have
now both recommended its use as one of the first line
drugs in severe hypertension in pregnancy"-".
Attenuation of the hypertensive response at
intubation
In pregnant women who are hypertensive there is an
exaggeration of the pressor response to laryngoscopy
and intubatiod3. This transient, severe hypertension has
been associated with increased intracranial pressure,
cerebral haemorrhage and cardiac failure with pul-
monary oedema. Drugs, such as magnesium sulphate
and alfentanil, have been used to attenuate this response.
Nifedipine has been used to suppress the hypertensive
response to intubation in both normotensive patients, as
well as in patients with coronary vascular disease and
found to be e f f e ~ t i v e ~Hence
~ . ~ ~its
. potential role in this
regard in pregnancy has been investigated.
Kurmer et ~ 1evaluated. ~ the ~ use of 10 mg of nifedip-
ine in 30 women with pre-eclampsia requiring caesarean
section. Nifedipine resulted in a smooth, gradual and
significant reduction in systolic, diastolic and mean
arterial pressure over the 20 minutes before the general
anaesthetic was administered. When compared with
placebo, it significantly attenuated the hypertensive
response to laryngoscopy and intubation. It did, how-
ever, result in a significant increase in maternal heart
rate prior to and with intubation. No adverse fetal effects
were noted. No controlled comparisons with other drugs
used for this purpose exist.
The use of nifedipine in tocolysis
The most commonly used agents for the treatment of
preterm labour have been the beta-sympathomimetic
drugs, magnesium sulphate and indomethacin. These
drugs appear to be effective in prolonging pregnancy in
the short term but have no effect on delaying delivery in
the long temf7-'j9.They have no effect on fetal morbidity
or mortality, and they all have significant side effectP.
There have been instances of beta-sympathomimetic
drugs being associated with pulmonary oedema, myocar-
dial ischaemia and cardiac arrhythmias7'. Their effects on
the cardiovascular system, renal function and glucose
homeostasis have made their use difficult in women with
cardiac disease and with diabetes m e l l i t ~ s ~Magne-
~~~'.
sium sulphate may cause depression of the nervous sys-
tem in both the mother and the newborn infant7'; and long
term indomethacin has been shown to cause spasm of the
ductus arteriosus and renal arteries in the fetus7'. Both the
beta-sympathomimetic drugs and magnesium sulphate
are used intravenously in preterm labour and are therefore
associated with the risks of intravenous infusions.
The action of the calcium channel blockers to inhibit
smooth muscle contractility with apparent minimal side
effects to the mother and fetus has resulted in their being
evaluated as tocolytic agents. Animal studies have shown
the ability of nifedipine to prolong pregnancy and prevent
preterm delivery in both rats7476and ewes77.Several stud-
ies in humans have evaluated the tocolytic action of
nifedipine in preterm labour. There are no published ran-
domised trials comparing nifedipine to placebo but it has
been compared with 'no treatment'78, r i t ~ d r i n e ~and
~~'
terbutalines4as well as to magnesium sulphateg5.
Nifedipine versus other tocolytic agents
The efficacy of nifedipine in suppressing pretem labour
appears to be as good as, and possibly better than, rito-
drine and t e r b ~ t a l i n e ~ " ~It' ~also
~ ~ .appears equivalent in
its ability to prolong pregnancy once the premature con-
tractions have abated79,s3,s6. The temporary effects on
contractions and the immediate delay in delivery are not
linked to an improvement in perinatal mortality.
Only one randomised trial has compared the efficacy
of nifedipine to 'no treatment'78. This trial showed that
nifedipine was superior to no treatment but, similar to
other studies, was not large enough to show an effect on
important outcomes. In this trial Reid and W e l l b allo- ~~~
cated 60 women in preterm labour with singleton preg-
nancies between 20 and 35 weeks of gestation to receive
either oral nifedipine, an intravenous infusion of rito-
drine or no treatment. Preterm labour was defined as one
contraction or more every ten minutes, with the cervix
dilated < 5 cm. Thirty milligrammes of nifedipine were
given orally, followed by 20 mg every eight hours. The
primary outcomes were suppression of contractions for
48 hours, and no further dilatation of the cervix. There
was a significantly higher success rate with nifedipine,
compared with ritodrine or no treatment. They also
0 RCOG 2000 Br J Obstet Gynaecol 107,299-307

found that nifedipine significantly prolonged the time
from admission to hospital to delivery, compared with
ritodrine or no treatment: the average times were 36.3
days with nifedipine; 25.1 days with ritodrine and 19.3
days with no treatment.
Papatsonis et ~ 1randomised
. ~ ~ 185 women in pretenn
labour between 20 and 33 weeks of gestation to receive
either intravenous ritodrine or oral nifedipine. The
authors defined preterm labour as either one contraction
or more every ten minutes or prelabour rupture of the
membranes. The dosage regimen was 10 mg nifedipine
every 15 minutes for the first hour until contractions
stopped (to a maximum of 40 mg), then a daily dose of
slow-release nifedipine of 60-160 mg, depending on the
amount needed in the first hour. Significantly fewer
women taking nifedipine were delivered within
24 hours, within 48 hours and within seven days com-
pared with ritodrine. Separate analysis of the group of
women with prelabour rupture of membranes showed
that neither drug was superior in prolonging pregnancy.
Twelve women discontinued ritodrine because of side
effects, compared with none taking nifedipine. Fetal
outcome was similar, with no difference in Apgar scores
or in arterial or venous pH measurements at birth. There
were significantly fewer admissions to the neonatal
intensive care unit in the nifedipine group.
Kupferminc et ~ 1 . ’ undertook
~ a randomised trial
including 7 1 women to compare nifedipine and ritodrine,
and showed a similar prolongation of pregnancy for
48 hours, seven days and until 36 weeks79.Preterm labour
was defined as regular uterine contractions at least once
every six minutes with progressive cervical dilatation.
Nifedipine was administered in an initial dose of 30 mg
followed by a further 20 mg 90 minutes later if uterine
contractions persisted. A maintenance dose of 20 mg
nifedipine was then given orally every eight hours.
Eleven women with twin pregnancies were included in
this trial; of the six that received nifedipine, three were
delivered after 36 weeks of gestation, compared with
three of the five women who received ritodrine. These
results are in keeping with three smaller prospective trials
in the literature that have compared these two drugs in
similar dosess1-”. All have shown comparable efficacy of
nifedipine and ritodrine in suppressing pretenn delivery.
Smith and Woodlands4compared oral nifedipine with
subcutaneous terbutaline in 52 women in preterm labour
between 20 and 35 weeks of gestation. They found a sim-
ilar success rate of 68% for nifedipine and 71% for terbu-
taline in completely stopping contractions within two
hours of starting treatment. Glock and MoralesS5found
nifedipine to be as effective as magnesium sulphate in
delaying delivery for 48 hours, with success rates of 92%
and 93%, respectively. McLaughin et ~ 1 . ’showed
~ these
two drugs had similar efficacy in prolonging pregnancy
and preventing birth before 37 weeks of gestation.
0 RCOG 2000 Br J Obstet Gynaecol 107,299-307
REVIEW 303
A major advantage noted in these studies is the
reduced amount of maternal side effects reported with
the use of nifedipine compared with the other
hgs78-80,82-84,86.88 . A 1owering of blood pressure and an
increase in heart rate were noted but were less common
with nifedipine than with ritodrine or t e r b ~ t a l i n e ~ ~ . ~ ’ ~ ~
No deleterious fetal effects have been noted with the use
of nifedipine as a tocolytic agent. A systematic review in
the Cochrane Library, comparing nifedipine and the
beta-sympathomimetic drugs, showed that nifedipine
reduces the number of deliveries of newborn infants
weighing less than 2500 g, but the number of infants
admitted to the neonatal intensive care unit was
i n ~ r e a s e d There
~ ~ . was no difference in the stillbirth or
neonatal death rate. It must be noted that collectively
only a small number of women have received nifedipine
as tocolysis, and the absence of adverse fetal effects
needs further evaluation.
Drug interactions
Magnesium sulphate is commonly used in eclampsia to
prevent further seizures and in preterm labour as a
tocolytic. Concern has been raised about the concurrent
use of magnesium sulphate and nifedipine and the possi-
ble potentiation of the antihypertensive action and neuro-
muscular blockade of magnesium sulphate. In rats
nifedipine exacerbates both the antihypertensive action”
and the cardiac toxicity’” of magnesium sulphate.
Marked hypotension with magnesium sulphate and
nifedipine has been reported. Weisman et al.” reported
two women who experienced significant hypotension
after receiving 10 mg oral nifedipine while on an intra-
venous infusion of magnesium sulphate (20 g/day)”.
These women were also receiving methyldopa 2 g
daily. On stopping the magnesium sulphate the blood
pressure returned to previous levels within 30 minutes.
Ben-Ami et aL9*reported a woman with pre-eclampsia
who was receiving an intravenous infusion of magne-
sium sulphate (2 g/h) and who experienced muscle
weakness and hypotension after taking 20 mg nifedip-
ine orally9*.Her symptoms improved within 15 minutes
of receiving 1 g calcium gluconate intravenously.
Another case, reported by Snyder et al.”, described sig-
nificant muscle weakness in a woman who received an
intravenous infusion of 0-5 g/h magnesium sulphate
while taking 20 mg nifedipine 8hrly as a tocolytic
agent93.Her symptoms disappeared rapidly when mag-
nesium sulphate was stopped.
Other authors have found no adverse side effects
when nifedipine and magnesium sulphate are used
simultaneously54~57. Although two drugs with negative
inotropic actions may not compromise a woman with
normal ventricular function, this may not be true in a
woman with heart disease.
304 R E V I E W
The fear of an exaggerated antihypertensive effect
when nifedipine is used with other, commonly used,
antihypertensive agents such as methyldopa and the
beta-blockers appears to be u n f o ~ n d e d ~ ~Beta-adren-
.~'.
ergic blocking drugs may reduce the tachycardia
induced by nifedipine.
Nifedipine causes an increase in blood flow to the
liver which may alter the metabolism of other drugs, and
has been shown to affect blood levels of digoxin, pheny-
toin, and theophylline. These drugs require closer moni-
toring of their blood levels if nifedipine is also taken'.
Effects on the fetus
Teratogenic effects on the fetus are a concern with
nifedipine, but there may also be adverse effects of
nifedipine on uteroplacental blood flow and also on fetal
blood flow. Nifedipine is rated as a Category C drug
with respect to its use in pregnancy94.This means that its
teratogenic potential is uncertain, and hence it is recom-
mended that it is used only where maternal benefit is
seen to outweigh potential fetal effects. No specific con-
genital defects in humans have been recorded that are
attributable to its use. However, digital abnormalities
have been noted resulting from very high doses admin-
stered to animals. The development of hyperphalangeal
bones in the fingers and toes has occurred in rats given
doses of > 150 m g / l ~ gIn~ ~rabbits,
. distal digital defects
secondary to cartilage necrosis have been recorded96.
Magee et undertook a prospective multicentre
cohort study to assess the risk of abnormalities in
fetuses after exposure to calcium channel blocking
drugs in the first trimester. Forty-four women had been
exposed to nifedipine in pregnancy, and 43 infants were
normal at birth. One woman was delivered of an infant
with multiple congenital abnormalities and develop-
mental delay; the patient had epilepsy and systemic
lupus erythematosus and was also taking carba-
mazepine, cyclophosphamide,prednisone, atenolol and
ibuprofen throughout her pregnancy.
Haemodynamic changes
Fetal growth restriction secondary to placental insuffi-
ciency commonly occurs in pregnancies complicated by
hyperten~ion~~. Any reduction in maternal blood pres-
sure may be accompanied by a decrease in uterine per-
fusion pressure which may diminish uterine blood flow
and fetal oxygen supply. This effect may be exacerbated
where there is decreased blood volume, as occurs in pre-
eclampsia. Dilatation of the uterine arteries may also
reduce the critical perfusion pressure necessary for an
adequate supply of oxygen to the fetus. Nifedipine
crosses the placenta and hence its direct effects on fetal
haemodynamics must be assessedI4.
The results of studies in animals concerning the
effects of nifedipine on uterine perfusion have been con-
tradictory. Experiments in hypertensive rats and in preg-
nant goats and ewes have not shown any significant
alteration in uterine blood flow with nifedipine, despite
a reduction in placental vascular r e s i s t a n ~ e ~ ~ ~ ~ ~ ~ ' ~ .
In research using sheep, Harake et ~ 1 . showed '~ that
when there was a significant drop in maternal blood
pressure there was a decrease in uterine blood flow.
Similar findings by Blea et ul. l7 found this decrease to be
temporary. In both of these studies it was also noted that
there was a tendency to fetal hypoxaemia and acidosis
during the infusion of nifedipine.
Where nifedipine has been used in acute severe
hypertension in pregnancy, Doppler measurements of
velocity waveforms in the uterine artery have remained
unchanged'0'~'02.Similar findings have been shown by
Moretti et al.'O3 with chronic use of the drug in pre-
eclampsia. Using radio isotopes Lindow et al.'04 were
also unable to show any significant change in uteropla-
cental blood flow after a single dose of nifedipine.
In vitro studies have shown nifedipine has a vasodila-
tory effect on umbilical and chorionic plate vessels, sug-
gesting that nifedipine reduces vascular resistance in the
fetal placental In humans, there have
been no changes shown in umbilical artery
flowS2,82,101 ,103,106,l07
or in the fetal descending aorta or
internal carotid artery f l o ~ ' ~ with ~ ~ . nifedipine,
' ~
whether used to treat severe hypertension or preterm
labour.
Acute hypotension may be associated with fetal dis-
tress, and this may occur with nifedipine. Impey''' has
reported a case of acute fetal distress in a woman with
pregnancy induced hypertension who became
hypotensive after receiving 10 mg of nifedipine sublin-
gually. Hata et u1.'09 have also recorded a case of fetal
distress at 32 weeks of gestation in a pregnancy with
severe hypertension following the administration of
sublingual nifedipine: the woman's blood pressure fell
from 208/122 mmHg to 136196 mmHg, and was
accompanied by severe variable and late decelerations.
The fetus had intrauterine growth retardation and
abnormal flow velocity waveforms. When compared
with dihydralazine however, nifedipine is associated
with fewer episodes of acute fetal distress, as sug-
gested by nonreassuring fetal heart rate changes in
pregnancies ~ i t h ~ and ~ , 'without
'~ intrauterine growth
restriction54.5"101, I 03.110
A number of studies have investigatedthe cardiovascu-
lar effects of nifedipine in women whose blood pressure
is normal. Mari et al."' studied women receiving nifedip-
ine for preterm labour and found no change in the uterine
artery pulsatility index"'. Pirhonen et aZ.IWhowever,
found a significant reduction in the systolic to diastolic
ratio in the uterine artery of normotensive women, but
0 RCOG 2000 Br J Obstet Gynaecol 107,299-307

this decrease in vascular resistance did not extend to the
arcuate artery. In neither of these studies were any
adverse effects on fetal heart rate patterns noted, and
fetal umbilical, middle cerebral and renal artery veloc-
ity waveforms remained normal. No alteration was
found in fetal cardiac output’” or fetal heart rate. A
review of all women who had received nifedipine for
tocolysis at St Josephs Hospital, Denver, Colorado, was
undertaken by Murray et al. in 1992@.One hundred and
two women had taken nifedipine, and there were 265
nonstress test or biophysical profiles performed during
nifedipine therapy. There was only one abnormal test
and one neonatal death of a child with a congenital
abnormality and intrauterine growth restriction.
In summary, nifedipine is an effective tocolytic
drug, has fewer maternal side effects than the currently
used drugs, and appears to have no adverse fetal
effects, but the studies are small and further research is
required in this area.
Maternal side effects
Maternal side effects with nifedipine seldom occur,
and there is rarely a need to stop the drug as a result of
these. Side effects are related to the dose and include
flushing, headaches, and sweaty palms1s~54~57~58~78~79~88;
rarely, constipation, diarrhoea, heartburn, dyspnoea,
and chest pain have been described. Tachycardia
occurs commonly but is seldom associated with palpi-
tations and appears to have no adverse effect^',^'.^^.^^,^^.
A reduction in blood pressure in normotensive women
in whom the drug is being used for tocolysis generally
occurs but is asymptomatic and appears to be clinically
insignifi~ant”.~~.~’~~~.
Conclusions
Nifedipine is an effective drug to treat severe hyperten-
sion in pregnancy and preterm labour. Because it is given
in a tablet or capsule by mouth, it is easier to use than
intravenous drugs. The described side effects of nifedip-
ine to the pregnant woman and her infant appear minimal.
However, the studies of nifedipine are small and
larger randomised trials are required before any recom-
mendations can be made about the use of nifedipine in
routine clinical practice.
Acknowledgements
The authors would like to acknowledge the financial
support of Bayer Pharmaceuticals for departmental
research into preterm labour. The clinical trials of P. S.
and R. J. were supported by a grant from the NHS(E)
West Midlands R & D Programme.
0 RCOG 2000 Br J Obstet Gynaecol 107,299-307
REVIEW 305
Patricia Smith, Consultant (Obstetrics)
McMaster Universiv, Hamilton, Ontario, Canada
John Anthony, Consultant (Obstetrics)
Cape Town University Hospital, South Africa
Richard Johanson, Consultant (Obstetrics)
North Staffordshire Hospital, Stoke on Trent, UK
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