Arch Gynecol Obstet (2012) 286:637642
DOI 10.1007/s00404-012-2371-x
MATERNAL-FETAL MEDICINE
Nifedipine versus labetalol in the treatment of hypertensive
disorders of pregnancy
Stefano R. Giannubilo Valeria Bezzeccheri
Stefano Cecchi Beatrice Landi Giovanna I. Battistoni
Paola Vitali Lucia Cecchi Andrea L. Tranquilli
Received: 21 January 2012 / Accepted: 26 April 2012 / Published online: 12 May 2012
Springer-Verlag 2012
Abstract
Purpose To assess the maternal and fetal outcomes of
pregnancies affected by hypertensive disorders treated with
nifedipine versus labetalol.
Methods A retrospective study in hypertensive patients
treated during pregnancy with nifedipine or labetalol was
conducted. After the charts review the patients were divi-
ded in the four groups: gestational hypertension (113
patients); mild preeclampsia (77 patients); severe pre-
eclampsia (31 patients); HELLP syndrome (21 patients).
The pregnancy and neonatal records were analyzed by
paired and unpaired t test.
Results We found that there was an higher rate of intra-
uterine growth restriction infants among women treated
with labetalol compared with those treated with nifedipine
(38.8 vs. 15.5 %; p \ 0.05), but only in the subgroup of
women affected by Gestational Hypertension and Mild
Preeclampsia. In this group was also higher the rate of fetal
worsening assessed by fetal heart rate tracing (33.3 vs.
14.2 %; p \ 0.05). No neonatal malformations and no
differences in the rate of adverse side effects were
observed.
Conclusions Antihypertensive therapy in pregnancy with
Labetalol may have the potential to impair fetal behavior in
low degrees hypertensive diseases of pregnancy. Optimal
care must balance the potentially conflicting risks and
benefits to mother and fetus.
S. R. Giannubilo (&)
V. Bezzeccheri
S. Cecchi
B. Landi

G. I. Battistoni
P. Vitali
L. Cecchi
A. L. Tranquilli
Department of Clinical Sciences, Polytechnic University
of Marche, G. Salesi Hospital via F. Corridoni 11,
60123 Ancona, Italy
e-mail: s.giannubilo@univpm.it
Keywords Nifedipine
Labetalol
Pregnancy

Hypertension
Introduction
Hypertensive disorders are the most common medical
disorders during pregnancy and are a major cause of
maternal and perinatal mortality and morbidity worldwide.
The reported rate of hypertension in pregnancy is 6 % [1].
Hypertension in pregnancy is a special condition because
the duration of therapy is shorter, the benefits to the mother
may not be obvious during the short time of treatment and
the exposure to drugs regards both mother and fetus. Even
if delivery is the only treatment and it leads to the disap-
pearance of the disease, this is usually problematic below
28 weeks of gestation when the baby can be expected to be
extremely immature. The induction of labour is also rec-
ommended for pregnancies of less than 24 weeks when the
likelihood of a viable fetus is minimal. In addition, the
pathophysiology of the hypertensive disorders in preg-
nancy will have different effects on the pharmacokinetics
as well as the pharmacodynamics of the drugs used [2].
Consequently, there are little to no data about the phar-
macokinetics, disposition, and pharmacodynamics effects,
including the proper dosing regimens of the current anti-
hypertensive drugs being used to treat the various hyper-
tensive disorders in pregnancy.
The role of antihypertensive therapy in pregnancy has
been recently reviewed by the Cochrane collaboration [3],
the risk of severe hypertension associated with the use of
antihypertensive drugs was halved, but little evidence
showed a difference in the risk of preeclampsia. Although
the use of antihypertensive drugs in women with high
blood pressure has been shown to prevent cerebrovascular
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638
problems, such treatment seemed not to prevent or alter the
natural course of the disease. The treatment of acute
hypertension should prevent potential cerebrovascular and
cardiovascular complications, which are the most common
cause of maternal mortality and morbidity in developed
countries [4]. Antihypertensive treatment is recommended
for values of systolic blood pressure of at least 160 mmHg
and for diastolic values of at least 110 mmHg [5, 6]. Even
if the evaluation and treatment of pregnant women with
severe hypertension do not differ from treatment of
hypertensive urgency/emergency, there is no consensus as
to how mild-to-moderate pregnancy hypertension (regard-
less of type) should be managed to optimize pregnancy
outcome [5, 7].
Clinicians vary in their choice of treatment for hyper-
tension in pregnancy and there is uncertainty regarding
potential benefits and harms of using antihypertensive
drugs in pregnancy. On the other hand women can be
reassured that only few categories of antihypertensive
agents have been proven to be teratogenic, in fact only
ACE inhibitors and angiotensin-receptor antagonists are
contraindicated for ongoing use in pregnancy [810]. The
evidence to date is scant and provides little direction to
clinicians taking care of these women. The Food and Drug
Administration reviews human and animal data to assign
letter grades corresponding with risk of fetal exposure in
pregnancy. Most antihypertensive agents used in preg-
nancy are designated as category C, which states that
human studies are lacking, animal studies are either posi-
tive for fetal risk or are lacking, and the drug should be
given only if potential benefits justify potential risks to the
fetus [11]. Pregnancy outcome data in humans after
exposure to calcium channel blockers are not adequate to
assess risk [12] but the largest randomized trial to date
demonstrated no significant risk [13, 14]. Beta-blockers,
especially labetalol, compare favorably with other antihy-
pertensives for use during pregnancy [15] and do not
appear to be teratogenic on the basis of limited data in
human pregnancy [16]. Selective beta-blockade agents are
considered safe, but because they have less vasodilatory
activity there is a higher risk of bradycardia.
The aim of this retrospective study was to assess the
efficacy and the outcomes of the treatment with nifedipine
compared with labetalol in different degrees of hyperten-
sive disorders of pregnancy.
Materials and methods
Charts of 242 women who delivered between January 2005
and December 2011 at the Department of Obstetrics and
Gynecology of Polytechnic University of Marche at Salesi
Hospital (Ancona, Italy) were retrospectively reviewed. All
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Arch Gynecol Obstet (2012) 286:637642
women were affected by pregnancy-induced hypertension
defined, according to internationally approved criteria [17],
as an elevated blood pressure ([140/90 mmHg) for at least
two consecutive readings 6 or more hours apart, occurring
at a gestational age greater than 20 weeks. Gestational age
was established on the basis of the last menstrual period
and confirmed by ultrasonographic examination before
20 weeks of gestation. Exclusion criteria were: multiparity,
twin pregnancy, a history of liver disorders, thrombocyto-
penia, previous chronic hypertension, renal disease, cardiac
disease, diabetes mellitus, immune disorders, evidence of
chromosomal and other fetal anomalies, significant anemia
(hemoglobin 9 g/dL or less). Ethics approval was received
by the Local Research Ethics Committee.
All patients were divided into hypertensive groups as
follows: gestational hypertension (113 patients) defined as
hypertension without significant proteinuria ([300 mg/
24 h) or other clinical anomalies; mild hypertension with
significant proteinuria (77 patients) defined as hypertension
with significant proteinuria ([300 mg in a 24-h urine
specimen) [18]; severe preeclampsia (31 patients) defined
as blood pressure of 160 mmHg systolic or higher or
110 mmHg diastolic or higher on two occasions at least 6 h
apart with proteinuria of 5 g or higher in a 24-h urine
specimen [18]; HELLP syndrome (21 patients) defined as
new onset of severe hypertension (systolic blood pressure
[160 mmHg and/or diastolic blood pressure[110 mmHg)
with platelet count of \100,000 cells/mm3, aspartate ami-
notransferase activity [70 U/L, and lactate dehydrogenase
activity of [600 U/L [19]. During recovery, ultrasono-
graphic investigation was done to preclude fetal growth
restriction (IUGR) defined as ultrasound measurement of
the fetal abdominal circumference below the 10th centile or
birthweight below the 10th centile according to our birth-
weight references values [20].
Inclusion criteria included: treatment with anti-hyper-
tensive therapy between 20 and 24 weeks of gestation with
nifedipine 20 mg or labetalol 100 mg orally given twice
daily to 12 h apart and continuation of the same drug
without overlaps with others medications until delivery.
The antihypertensive treatment was started for values of
systolic blood pressure of at least 160 mmHg and for
diastolic values of at least 110 mmHg. The choice of
antihypertensive therapy was based, at recovery, only on
clinicians expertise and/or experience in a Department with
20 medical shift workers.
The obstetric data that was recorded included: mean
arterial pressure at first control, need of cesarean section,
maternal uncontrolled hypertension and/or complications,
fetal heart rate tracing alteration, intrauterine fetal growth
restriction (IUGR), weeks of treatment, gestational age at
delivery, birthweight and admission to neonatal intensive
care unit. The Student t test for unpaired observations, or
Arch Gynecol Obstet (2012) 286:637642 639

the Chi-square test when appropriate, were used for sta- Table 1 Characteristics of the groups studied
tistical calculations between the two groups, and within Hypertensive patients Nifedipine Labetalol p\
each group Student t test for paired observations was used. (n = 242) (n = 178) (n = 64)
For these calculations a computer with a StatView (version
Gestational 92 (51.7) 21 (32.8)
4.02, Abacus Concepts, Inc., Berkeley, CA, USA) program
hypertension, No. (%)
was used; p values \0.05 were considered significant.
Mild preeclampsia, 62 (34.8) 15 (23.4)
No. (%)
Severe preeclampsia, 14 (7.8) 17 (26.6)
Results No. (%)
HELLP syndrome, 10 (5.7) 11 (17.2)
Maternal and fetal/neonatal characteristics as summarized No. (%)
in Table 1. The majority of patients were managed with Obstetrics outcomes
nifedipine (n = 178), the others (n = 64) with labetalol, No. of smoker, 12 (6.7) 3 (4.6) N.S.
approximately 46 % had gestational hypertension, 32 % No. (%)
had mild preeclampsia, 12 % had severe preeclampsia and Inheritance for 42 (23.5) 13 (20.3) N.S.
hypertension, No. (%)
8 % had HELLP syndrome. No neonatal malformations
Body mass index 23.9 3.8 24.2 2.9 N.S.
were observed, the rate of side effects is reported in
(kg/m2)
Table 1. The statistical analysis did not indicate that the
Need of cesarean 117 (65.8) 45 (70.3) N.S.
differences concerning maternal characteristics and history section, No. (%)
might bear any relevant influence on the studys results. Maternal worsening, 37 (20.7) 18 (28.1) N.S.
When comparing the group treated with nifedipine and the No. (%)
group treated with labetalol no significant differences were Fetal worsening, 43 (24.1) 17 (26.5) N.S.
found in maternal fetal/neonatal outcomes (Table 1). In a No. (%)
second step analysis the patients were divided into two Intrauterine fetal 56 (31.4) 24 (37.5) N.S.
subgroups: with gestational hypertension and mild pre- growth restriction,
No. (%)
eclampsia and with severe preeclampsia and HELLP syn-
Weeks of treatment, 12.1 1.9 13.2 2.5 N.S.
drome. In this way, when comparing the group treated with mean SD
nifedipine and those treated with labetalol differences were Gestational age at 35.9 4.4 35.1 4.1 N.S.
found in the rate of fetal worsening (nifedipine: 14.2 % vs. delivery, mean SD
labetalol: 33.3 %; p \ 0.05) and in the rate of intrauterine (weeks)
fetal growth restriction (nifedipine: 15.5 % vs. labetalol: Birthweight, 2,415.1 988.8 2,427.5 976.2 N.S.
38.8 %; p \ 0.05), but only in the subgroup of patients mean SD (g)
affected by gestational hypertension and mild preeclampsia Admission to neonatal 41 (23.0) 22 (34.3) N.S.
intensive care unit,
(Tables 2, 3).
No. (%)
Side effects
Headache, No. (%) 27 (15.1) 12 (18.7) N.S.
Discussion
Nausea, No. (%) 13 (7.3) 3 (4.6) N.S.
Breathlessness, 3 (1.6) 0
By actual data it remains unclear whether antihypertensive No. (%)
drug therapy for mild to moderate hypertension during Heartburn, No. (%) 0 0
pregnancy is worthwhile [3], and given the need to indi-
vidualize therapy and adjust therapy over time, the incon- N.S. not significant
sistent results of trials based on uniform monotherapy are
not surprising. In our series the rate of intrauterine fetal pharmacological effect, affecting metabolism within the
growth restriction in the group treated with labetalol was feto-placental unit or the transfer of nutrients across the
clearly higher than in the group treated with nifedipine, but placenta. Reduced perfusion pressure within the intervillous
only in patients affected by gestational hypertension and space could similarly affect both the placenta and the fetus
mild preeclampsia. In the same way in the group treated symmetrically, or, in the face of abnormal placentation,
with labetalol the rate of fetal worsening was higher indi- differentially. A reduction in intervillous perfusion may
cated by abnormal fetal heart tracing. The causes of this also cause sufficient stress to induce fetal heart rate anom-
association between births may be intrinsic to the mother alies. The molecule of labetalol contains two optical centers
and her pregnancies or associated with a particular therapy. and the drug is prescribed as a mixture of the four diaste-
The effect on fetal growth could be a directly toxic reoisomers. These isomers have different pharmacological

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640 Arch Gynecol Obstet (2012) 286:637642

Table 2 Characteristics of low degree pregnancy hypertension group properties. As a mixture, they act as competitive antagonists
Gestational Nifedipine Labetalol p\
at the a1-adrenoceptor, the b1-adrenoceptor and the b2-
hypertension mild (n = 154) (n = 36) adrenoceptor. The mixture also has some partial agonist
preeclampsia activity at b2-adrenoceptors and inhibits the neuronal
(n = 190) uptake of norepinephrine. The potency of labetalol as an
Mean arterial pressure 89.8 9.3 88.1 10.7 N.S. antagonist at b-adrenoceptors is approximately ten times
at first control, greater than its potency as an antagonist at a-adrenoceptors.
mean SD (mmHg) The hypotensive effect of labetalol results from vasodila-
Need of cesarean 58 (37.6) 16 (44.4) N.S. tation induced by blockade of a1-adrenoceptors and by
section, No. (%) activation of b2-adrenoceptors on vascular smooth muscle.
Maternal worsening, 10 (6.49) 2 (5.5) N.S. Blockade of b1-adrenoceptors in the heart also contributes
No. (%)
to the hypotensive effect by minimizing any reflex increase
Fetal worsening, No. 22 (14.2) 12 (33.3) \0.05
(%) in cardiac output.
Intrauterine fetal 24 (15.5) 14 (38.8) \0.05
Clinical studies of beta-blockers in pregnancy have
growth restriction, produced conflicting results with different agents, making
No. (%) it difficult to generalize for the group as a whole. In two
Weeks of treatment, 10.1 2.5 11.6 1.8 N.S. randomized studies of metoprolol in the treatment of
mean SD hypertension in pregnancy, there was no difference in birth
Gestational age at 36.3 3.4 36 3.7 N.S. weight between the active treatment and placebo groups
delivery,
[21], but metoprolol was in fact associated with higher fetal
mean SD (weeks)
survival when compared to hydralazine [22]. Oxprenolol
Birthweight, 2,597.3 718.1 2,525.7 453.6 N.S.
mean SD (g) has also been found to be either superior [23] or equal [24]
Admission to neonatal 24 (15.5) 4 (11.1) N.S. to methyldopa with respect to birth weight, fewer cesarean
intensive care unit, sections, and less prolonged neonatal care when compared
No. (%) to hydralazine [25].
N.S. not significant When labetalol plus hospitalization was compared with
hospitalization alone in the management of preeclampsia,
there was a trend for higher growth restriction in the
Table 3 Characteristics of high degree pregnancy hypertension
group
labetalol group [26]. There is mounting evidence that
atenolol, in particular, may increase the risk of intrauterine
Severe preeclampsia Nifedipine Labetalol p\ growth restriction [27]. One clinical trial of long-term
HELLP syndrome (n = 24) (n = 28)
(n = 52) atenolol for chronic hypertension in pregnancy found a
dramatic increase in small for gestational age infants
Mean arterial pressure at 92.6 12.3 93.1 11.1 N.S. among the atenolol-treated pregnancies [28]. Observational
first control,
mean SD (mmHg)
data also suggest such an effect, [2931]. Of six RCTs of
Need of cesarean 24 (100) 24 (85.7) N.S.
labetalol [3235] only one reported an increase in the rate
section, No. (%) of IUGR among women with severe proteinuric hyper-
Maternal worsening, 12 (50) 16 (57.1) N.S. tension with the use of labetalol [26]. A reduction in
No. (%) plasma volume was reported with the use of diuretics [36]
Fetal worsening, No. 12 (50) 8 (28.5) N.S. which could potentially interfere with fetal growth. An
(%) increase in the incidence of low birth weight (below the
Intrauterine fetal growth 20 (83.3) 24 (85.7) N.S. 25th percentile) was reported in one study in which
restriction, No. (%) diuretics were given to women with excessive weight gain
Weeks of treatment, 8.3 2.6 9.3 3.2 N.S. (with no significant decrease in plasma volume) [37].
mean SD
Respect to time of therapy Easterling et al. [38]
Gestational age at 33.1 3.5 32.9 3.6 N.S.
delivery, mean SD observed that after an initial fall in cardiac output attrib-
(weeks) utable to the pharmacological action of beta-blockers, a
Birthweight, 1,457.2 427.3 1,386.4 407.6 N.S. secondary fall was observed 68 weeks after the initiation
mean SD (g) of therapy. These secondary changes may represent an
Admission to neonatal 17 (70.8) 18 (64.2) N.S. improvement in the underlying physiology of hypertension,
intensive care unit, No a down regulation of disease. On the other hand the mode
(%)
of action of nifedipine to reduce systemic vascular resis-
N.S. not significant tance and its ability to improve urine output by increasing

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Arch Gynecol Obstet (2012) 286:637642
renal blood flow and by inhibiting the release of anti-
diuretic hormone make it a highly appropriate drug for use
in hypertension in pregnancy. Orally administered calcium
channel blockers, particularly nifedipine, which has been
best studied, do not appear to represent a major teratogenic
risk [39]. By our observation, even if the mean of treatment
weeks was not different, only in patients affected by ges-
tational hypertension and mild preeclampsia a difference in
fetal outcomes was observed. These degrees of disease,
such as gestational hypertension and mild preeclampsia,
may have different pathophysiological bases than severe
preeclampsia or HELLP syndrome. This may affect the
natural history of disease and also the response to medical
therapy. Because the present study was a retrospective and
not randomized cohort study of unselected consecutive
patients referred to a single center with 20 clinicians
choosing medications for the patients, this opens it to the
limitations of referral and treatment biases. Given the small
maternal benefits that are likely to be derived from therapy,
new data are urgently needed to elucidate the relative
maternal and fetal benefits and risks of oral antihypertensive
drug treatment of mild-to-moderate pregnancy hyperten-
sion. To date therapy that may benefit the mother and permit
her to prolong a hypertensive pregnancy further into ges-
tation may have the potential to impair fetal growth. Opti-
mal care balances the potentially conflicting risks and
benefits to mother and fetus. Changes in maternal and fetal
condition in the context of advancing gestational age will
result in a shift in that balance and therefore the optimal
treatment over the course of an individual pregnancy.
In conclusion, by our observation, labetalol treatment
may be associated to more frequent abnormal fetal heart
tracing versus Nifedipine, in women affected by gestational
hypertension and mild preeclampsia. Further research is
needed to evaluate the effect of prolonged antihypertensive
therapy, and whether different antihypertensive drugs have
differential effects on maternal and fetal outcomes.
Conflict of interest The authors report no conflicts of interest.
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