Journal of Clinical Pharmacy and Therapeutics, 2016
12439
Oral nifedipine vs. intravenous labetalol for treatment of pregnancy-induced
severe pre-eclampsia
D.-D. Shi1 MD, F.-Z. Yang1 MD, L. Zhou MD and N. Wang MD
Cangzhou Central Hospital, Cangzhou City, Hebei Province, China
Received 7 June 2016, Accepted 29 July 2016
Keywords: labetalol, nifedipine, pre-eclampsia, pregnancy
SUMMARY
What is known and objective: Pre-eclampsia is one of the most
challenging diseases of pregnancy. Both nifedipine and labeta-
lol have been used for treatment of pregnancy-induced severe
pre-eclampsia.
Methods: In the present study, the efficacy and safety of oral
nifedipine and intravenous labetalol for severe pre-eclampsia
therapy were compared. Eligible pregnant women with severe
pre-eclampsia (n = 147) were allocated to receive either oral
nifedipine or intravenous labetalol. The primary endpoint of the
study was the time needed to achieve target blood pressure.
Secondary outcomes were the time interval before a new
hypertensive crisis following effective blood pressure control,
number of doses and adverse effects.
Results and discussion: We found that the time taken to achieve
effective blood pressure control was 35 vs. 42 min for oral
nifedipine and intravenous labetalol, respectively (P = 0
37).
Compared with labetalol group, no significant difference was
observed regarding time interval and drug dosages in nifedipine
arm. Moreover, no serious side effects on maternal or perinatal
were observed in either group.
What is new and conclusions: These findings suggest that both
oral nifedipine and intravenous labetalol are effective for safely
reducing blood pressure to target levels in patients with severe
pre-eclampsia.
WHAT IS KNOWN AND OBJECTIVE
Pre-eclampsia remains a major cause of maternal morbidity and
mortality in worldwide,1 which is primarily caused by complica-
tions from severe hypertension of pregnant women. Therefore, the
need for controlling blood pressure in pregnant women with severe
hypertension is accepted.2,3 Pre-eclampsia is unique to pregnancy
and is a multisystem disorder that is usually correlated with raised
blood pressure and proteinuria. It rarely shows before 20-week
gestation. Eclampsia is one or more convulsions in association with
the syndrome of pre-eclampsia. Pregnancy-induced hypertension is
a rise in blood pressure, without proteinuria, during the second half
of pregnancy.4 Administration of antihypertensive agents is an
important part of management protocol when hypertension is
severe, that is blood pressure ≥160/110.5 The ideal agent for this
Correspondence: N. Wang, Cangzhou Central Hospital, No. 16 Xin-
hua Western Road, Cangzhou City 061000, Hebei Province, China.
Tel.:+86 18531702923; fax: +86 3172169019; e-mail: wangna1986
0101@163.com
1
Contributed equally.
© 2016 John Wiley & Sons Ltd
doi: 10.1111/jcpt.
purpose should work quickly, without causing maternal or perinatal
side effects. Currently, many authorities recommend nifedipine and
labetalol as the first-line alternatives for severe hypertension therapy
during pregnancy.3,6
Nifedipine is a calcium channel blocker agent and is a treatment
option for severe pre-eclampsia.7 The ability of nifedipine to
reduce vascular resistance and increase urine output by increasing
renal blood flow and by inhibiting the release of antidiuretic
hormone makes it an appropriate drug for controlling hyperten-
sion in pregnant women.8 No serious adverse effects on foetal
or maternal were reported as long as an effective blood pressure
control can be maintained.9 In addition, the use of nifedipine in
the treatment of preterm labour of pregnancy has not been
connected with adverse perinatal effect.10 Moreover, beneficial
effects on arterial pressure and urine output in pregnant women
with severe pre-eclampsia have been reported treatment with
nifedipine during the immediate puerperium.11 Nifedipine has
been more used in the third trimester than in the first and second
trimesters.12 There are three oral nifedipine formulations: (i) a
short-acting capsule with peak effect in 30 min, used for severe
hypertension therapy; (ii) a prolonged action tablet with peak
within hours and used for moderate-to-severe hypertension
therapy; and (iii) a slow release formulation that releases nifedip-
ine over 24 h and for treatment of non-severe hypertension.8,13
Immediate-release nifedipine is associated with ischaemic events
as dihydropyridines produce a reflex increase in sympathetic
tone.13 Therefore, it is not used in pregnancy. The recommended
oral dose of the prolonged action tablet is 10–20 mg, 2–3 times
daily (max = 180 mg/day).14
Labetalol is an antihypertensive drug with a- and b-blocking
properties and is recommended for hypertension treatment during
pregnancy by many professional associations/societies.3,15,16 In
many countries, nifedipine, labetalol and intravenous hydralazine
have been recommended as the first-line alternative for pregnancy
with severe hypertension.17 Moreover, previous study provides
evidence that intravenous labetalol is suitable first-line antihyper-
tensives for hypertensive emergencies of pregnancy.18 Currently,
the decision of drug using depends on the clinician’s experience or
familiarity with the agent. In addition, the decision is also
influenced by the cost of the drug, convenience and the adverse
effects.19 Due to the limitation of data, there is no reliable evidence
that one drug is better than the others.20 Although a number of
trials have compared hydralazine with either labetalol or nifedip-
ine, there are few studies comparing oral nifedipine and intra-
venous labetalol for control of hypertension in patients with
severe pre-eclampsia. It is still unclear whether oral nifedipine can
be an alternative to intravenous labetalol for lowering blood
pressure during pre-eclampsia.
1
Oral nifedipine vs. intravenous labetalol for severe pre-eclampsia D.-D. Shi et al.

Therefore, in the present study, we designed a randomized trial groups were assessed. Chi-square for trend, Student’s t-test and
to compare the efficacy and safety of oral nifedipine with Pearson chi-square test were applied to test differences between
intravenous labetalol in pregnancy with severe pre-eclampsia. the two treatment groups. All tests were two sided and a P value
<0
05 was considered statistically significant.
METHODS
RESULTS AND DISCUSSION
Trial design
We performed a double-blind randomized controlled study for 147 Characteristics of the participants
participants with severe pre-eclampsia in Cangzhou Central
A total of 147 participants enrolled in the trial. Seventy-four
Hospital. The gestational age of the participants is more than
participants were randomly allocated for receiving oral nifedipine
30 weeks. Pregnant women with severe pre-eclampsia who need
and 73 participants receiving intravenous labetalol. All partici-
blood pressure control were admitted to treat with antihyperten-
pants were analysed for the primary outcome. The flow chart of
sive drug. The recruitment took place from February to November
participants through the study process is shown in Fig. 1. There
2015. The latest blood pressure before to enrolment must fulfil the
were no losses and no exclusions after randomization and all
criteria of severe pre-eclampsia (blood pressure ≥160/110).21
participants were started on their allocated treatment. Table 1
Excluding criteria were a history of treatment with an antihyper-
shows characteristics of participants, and no significant differences
tensive drug and a history of heart failure during the course of the
were found between the two groups of maternal age, gestational
pregnancy. All participants provided written informed consent.
age, systolic and diastolic blood pressure, heart rate and body
This study was approved by the medical ethics committee of
mass index.
Cangzhou Central Hospital.
The participants were randomized into two treatment groups after
giving informed consent. According to previous reports14,18, seventy- Outcomes of nifedipine and labetalol in controlling of
four participants were allocated to receive oral nifedipine (10 mg hypertension in patients with severe pre-eclampsia
tablet, up to five dosages) or intravenous labetalol (in a dose regimen
The outcomes of oral nifedipine vs. intravenous labetalol for
of 20, 40 and 80 mg) every 15 min until achieved the effective blood
hypertension control are shown in Table 2. For the main
pressure control (≤150/100 mmHg). The crossover treatment was
outcome of time needed to achieve the effective blood pressure
needed if the initial treatment was not successful. Blood pressure was
control, the time taken was 35 min for oral nifedipine and
measured with a mercury sphygmomanometer. The blood pressure
42 min for intravenous labetalol, no significant difference was
was measured quarter-hourly for at least 60 min or longer until
found (P = 0
37). Both oral nifedipine and intravenous labetalol
control blood pressure was achieved. When blood pressure was
are rapidly effective, with the effective blood pressure control
≤150/100 mmHg, no further trial treatment was given. The nurse
achieved in more than 90% of cases within four dosages or
who measured blood pressure was blind to the treatment.
within 80 min of initial treatment. The time interval before a
The foetus was monitored electronically on a continuous basis
new hypertensive crisis coming after effective blood pressure
during the course of treatment with trial drugs. The maternal heart
control was similar in the oral nifedipine arm with the
rate was also measured during blood pressure measurement. In
intravenous labetalol arm (3
4 h for oral nifedipine vs. 3
1 h
the event of non-reassuring foetal or maternal status, the trial
for intravenous labetalol). Moreover, the number of dosages of
should be abandoned and appropriate measures according to the
medication needed to achieve target blood pressure was also not
provider’s judgment. When finishing the trial protocol, patients
different.
were asked to yes or no answers on the symptoms of dizziness,
vomiting, nausea, maternal tachycardia, headache, hypotension,
shortness of breath and chest pain experienced during the trial.
Data collected on every participant included chronic hypertension,
parity, age, gestational age and Apgar scores of newborns. The
following outcomes were considered as the endpoint of the trial: (i)
the time needed to achieve the effective blood pressure control
(≤150/100 mmHg), (ii)the time interval before a new hypertensive
crisis following effective blood pressure control, (iii)the number of
drug administrations and (iv) adverse effects.

Randomized technique, blinding and safety

Participants were allocated using block randomized technique.
Trial medication was prepared by the hospital pharmacy in a
double-blinded way and the randomization codes were kept by
the pharmacy. In event of suspicion of severe adverse effects by
medical personal, the trial will be stopped and the data will be
presented to the safety committee.

Statistical analysis
SPSS software packages were used to analyse data. The variables Fig. 1. Flow chart of randomized trial of nifedipine vs. labetalol in
were described and the differences between the two treatment patients with severe pre-eclampsia.

© 2016 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2016
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Oral nifedipine vs. intravenous labetalol for severe pre-eclampsia D.-D. Shi et al.

Table 1. Characteristics of participants

Characteristic Nifedipine (n = 74) Labetalol (n = 73) P value

Age (years) 28
3 (20–40) 29
1 (21–40) 0
62

Gestation (weeks) 37
6 (35
2–39
5) 37
1 (34
4–38
9) 0
72
Systolic blood pressure (mmHg)a 172
5 (168–182) 176
4 (171–185) 0
54
Diastolic blood pressure (mmHg)a 109
2 (103–114) 112
7 (105–117) 0
32
Heart rate (beats/min) 89
7 (69–101) 86
3 (65–107) 0
41
BMI (kg/m2)b 24
1 (21
2–27
5) 23
7 (20
4–26
9) 0
53

a
Systolic and diastolic blood pressure at randomization prior to starting treatment.
b
BMI, body mass index.

Table 2. Efficacy parameters of nifedipine and labetalol in con- Table 3. Short-term adverse effect and neonatal outcomes
trolling of blood pressure in patients with severe pre-eclampsia
Nifedipine Labetalol
Nifedipine Labetalol (n = 74) (n = 73) RRa (95% CI)
(n = 74) (n = 73) P value

No adverse effect 63 (85
1%) 59 (80
8%) 1
04 (0
51–2
46)

Needed time to achieve 35 (24
6–71
3) 42 (28
5–68
4) 0
37 Adverse effect 11 (14
9%) 14 (19
3%)
effective blood pressure Nausea 1 (1
4%) 3 (4
1%)
control (minutes) Vomiting 1 (1
4%) 2 (2
7%)
Time interval for a new 3
4 (1–8) 3
1 (1–8) 0
58 Maternal tachycardia 3 (4
1%) 4 (5
5%)
hypertensive crisis Headache (mild) 4 (5
4%) 2 (2
7%)
following effective blood Dizziness 2 (2
7%) 3 (4
1%)
pressure control (hours) Chest pain 0 (0) 0 (0)
Number of antihypertensive doses to achieve effective blood pressure Hypotension 0 (0) 0 (0)
control Shortness of breath 0 (0) 0 (0)
1 12 (16
2%) 10 (13
5%) Apgar score
2 30 (40
5%) 26 (35
1%) >6 64 (86
5%) 61 (83
6%)
3 26 (35
1%) 23 (31
1%) 4–6 10 (13
5%) 12 (16
4%)
4 4 (5
4%) 10 (13
5%) Birthweight (g) 3118
2  575
1 2973
6  641
5
5 2 (2
7%) 4 (5
4%)
Mean (SD) 2
4 (0
43) 2
6 (0
33) 0
46 a
RR, risk ratio of any kind of adverse effect in nifedipine vs. labetalol group.

a new hypertensive crisis coming after initial effective blood

Adverse effects on maternal or foetal
All mothers and babies were discharged alive after delivery. As
shown in Table 3. No severe adverse effects on maternal or foetal
were reported, and the response to drugs was also similar in two
treatment groups. No cardiotocographic abnormalities were
recorded. The neonatal outcomes are also shown in Table 3. No
significant difference of newborn’s Apgar scores was found
between the two groups. Ten (13
5%) newborns in the oral
nifedipine group and 12 (16
4%) in the intravenous labetalol group
had Apgar scores of 4–6. There was also no significant difference in
birthweight.
Pre-eclampsia is primarily caused by severe hypertension.22
Normally, pregnancy with severe hypertension should receive
antihypertensive agent to control their pressure.19 The maternal
and foetal risks are decreased by lowering of blood pressure to safe
levels with antihypertensive agents.23,24 The Cochrane review on
agents for severe hypertension therapy in pregnancy concluded
that until better evidence is available, the choice of antihyperten-
sive agent should depend on the clinician’s experience and
familiarity with a particular agent, and on adverse effects.17 In
the present study, our data showed that oral nifedipine and
intravenous labetalol are effective in controlling severe hyperten-
sion in patients with severe pre-eclampsia. The time interval before
pressure control in the nifedipine group was similar to the
labetalol group. Moreover, the total number of dosages of
medication needed to achieve effective blood pressure control
was not different. There were no severe adverse effects associated
with either drug treatments. Our results are consistent with
previous reports that both oral nifedipine and intravenous
labetalol are suitable antihypertensive agents for pregnancy.18,25
Nifedipine, labetalol and hydralazine have been recommend as
the first-line alternatives for severe hypertension therapy during
pregnancy by most of the authorities.3,6 There are lots of studies
comparing either nifedipine or labetalol with hydralazine. For
instance, Fenakel et al.7 demonstrated greater efficacy of nifedipine
when compared to hydralazine in achieving effective blood pressure
control in severe pre-eclampsia. Aali et al. reported that nifedipine is
more safe and effective than hydralazine in controlling hypertension
in patients with severe pre-eclampsia. Nifedipine also has the
advantage of being cheaper and more widely available than
hydralazine.21 In contrast, a Cochrane review reported that there
was no clear evidence that nifedipine or labetalol was more effective
than hydralazine.6 One recent study showed that labetalol and
hydralazine for intravenous use are equally effective in the control of
hypertension in pregnant patients with severe pre-eclampsia.26
However, there are few studies comparing nifedipine and labetalol

© 2016 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2016
3
Oral nifedipine vs. intravenous labetalol for severe pre-eclampsia D.-D. Shi et al.

in control of severe hypertension during pregnancy. In this study, cohort study including more races are needed. Future trials should
our data showed that both oral nifedipine and intravenous labetalol use stratified randomization of participants based on blood
could effectively lowering blood pressure in patients with severe pressure values and women hypertension with proteinuria.
pre-eclampsia. In agreement with previous report that oral nifedip-
ine and intravenous labetalol treatments are similarly effective in
control of severe hypertension in pregnancy.18 Although both WHAT IS NEW AND CONCLUSION
nifedipine and labetalol are rapidly effective, with the effective In conclusion, our study demonstrated that both oral nifedipine
blood pressure control achieved in more than 90% of cases within and intravenous labetalol are effective and well tolerated for the
four doses, a little fewer dosages of nifedipine were required to control of blood pressure in pregnant patients with severe pre-
achieve effective blood pressure control. Oral nifedipine was also eclampsia. Thus, oral nifedipine could be an alternative to
shown to have a little longer time effect, but the time interval for a intravenous labetalol for lowering blood pressure during severe
new hypertensive crisis was not significant longer in the oral pre-eclampsia in pregnancy.
nifedipine group than intravenous labetalol. Moreover, in the
present study, the adverse effects of both nifedipine and labetalol
were similar, and this result is consistent with the observations of ACKNOWLEDGEMENTS
previous reports.18,27 We did not observe any serious adverse
None.
maternal or neonatal effects associated with either of the trial
medications. These findings are consistent with previous studies
that oral nifedipine is as efficacious and safe as intravenous labetalol CONFLICTS OF INTEREST
in control of severe hypertension during pregnancy.19,28 However,
No conflicts of interest have been declared.
Shekhar et al.’s28 systematic review also showed that nifedipine was
associated with fewer maternal adverse effects of nausea, vomiting,
headache or palpitations. In addition, labetalol was associated with ETHICAL APPROVAL
more stillbirths [18/157 (labetalol) vs. 13/166 (nifedipine)] and more
All procedures performed in studies involving human participants
neonatal deaths [10/105 (labetalol) vs. 3/116 (nifedipine)]. There-
were in accordance with the ethical standards of the institutional
fore, oral nifedipine may be preferable because of its ease of oral
and/or national research committee and with the 1964 Helsinki
administration and low adverse effects on pregnancy outcomes.
Declaration.
There are limitations in this study, which warrant further
research. First, we recruited a relatively small number of cases.
Second, this trial included only Chinese participants; therefore, our
SOURCE OF FUNDING
findings may not fully apply to the general population. Third, this
study is a single-centre study. A larger number of multicentre None.

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