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DOI: 10.1111/1471-0528.

13463

Systematic review

www.bjog.org

Oral nifedipine versus intravenous labetalol for


severe hypertension during pregnancy: a
systematic review and meta-analysis
S Shekhar,a N Gupta,b R Kirubakaran,c P Pareekd
a

Department of Obstetrics & Gynecology, All India Institute of Medical Sciences, Jodhpur, India b Department of Pediatrics, All India
Institute of Medical Sciences, Jodhpur, India c South Asian Cochrane Network, Christian Medical College Vellore, Vellore, India d Department
of Radiation Oncology, All India Institute of Medical Sciences, Jodhpur, India
Correspondence: S Shekhar, 401/4, Residential Complex, AIIMS, Jodhpur, Rajasthan 342005, India. Email longshanks28@gmail.com
Accepted 6 April 2015. Published Online 26 June 2015.

Background Oral nifedipine is recommended along with labetalol

and hydralazine for treatment of severe hypertension during


pregnancy by most authorities. Although nifedipine is cheap and
easily administered, the usage pattern among health care providers
suggests a strong preference for labetalol despite lack of evidence
for the same.
Objectives To determine the efficacy and safety of oral nifedipine

for treatment of severe hypertension of pregnancy compared with


intravenous labetalol.
Search strategy We systematically searched for articles comparing

oral nifedipine with intravenous labetalol for the treatment of


severe hypertension during pregnancy in any language, over
Medline, Cochrane Central Register of Clinical Trials and Google
Scholar from inception till February 2014.
Selection criteria We included all RCTs that compared

intravenous labetalol with oral nifedipine for treatment of severe


hypertension during pregnancy, addressing relevant efficacy and
safety outcomes.
Data collection and analysis Eligible studies were reviewed, and

data were extracted onto a standard form. We used Cochrane

review manager software for quantitative analysis. Data were


analysed using a fixed effect model.
Main results The pooled analysis of seven trials (four from
developing countries) consisting of 363 womaninfant pairs
showed that oral nifedipine was associated with less risk of
persistent hypertension (RR 0.42, 95% CI 0.180.96) and reported
maternal side effects (RR 0.57, 95% CI 0.350.94). However, on
sensitivity analysis the outcome persistent hypertension was no
longer significant. Other outcomes did not reach statistical
significance.
Conclusion Oral nifedipine is as efficacious and safe as intravenous

labetalol and may have an edge in low resource settings.


Keywords Labetalol, meta-analysis nifedipine, severe hypertension
during pregnancy, severe pre-eclampsia.
Tweetable abstract Although studies to date are few in number
and small, nifedipine shows promise for severe hypertension in
pregnancy.
Linked article This article is commented on by LA Magee, p. 48 in
this issue. To view this mini commentary visit http://dx.doi.org/
10.1111/1471-0528.13494.

Please cite this paper as: Shekhar S, Gupta N, Kirubakaran R, Pareek P. Oral nifedipine versus intravenous labetalol for severe hypertension during
pregnancy: a systematic review and meta-analysis. BJOG 2016;123:4047.

Introduction
Hypertensive disorders of pregnancy affect one of every
ten pregnant women, and are one of the leading causes of
maternal and perinatal mortality and morbidity.1,2 In
these women, blood pressure (BP) can rise acutely to
dangerous levels, posing a serious threat to the life and
wellbeing of mother and fetus by inflicting end organ
damage. Maternal and fetal risks are decreased by swift
but controlled lowering of BP to safer levels, with antihy-

40

pertensive drugs.25 Most of the authorities recommend


labetalol, hydralazine and nifedipine as first line alternatives for the treatment of severe hypertension during pregnancy.2,68 Hydralazine had been the drug of choice for a
long time; however, the faith in hydralazine has dwindled
over the past decade due to evidence of increased maternal and fetal complications associated with its use.9,10
Moreover, manufacturing shortages have made it unavailable in many parts of the world.11 Labetalol and nifedipine have fast emerged as alternative drugs and can be

2015 Royal College of Obstetricians and Gynaecologists

Nifedipine versus labetalol: meta-analysis

judged from the change in usage pattern of these drugs in


the past decade. A recent online poll among health care
providers found intravenous labetalol as the first choice
(57%) followed by hydralazine (33%) and nifedipine (9%)
(pers. comm.).12 This is in sharp contrast to the study by
Heazell et al.13 in 2004 in which 90% of the respondents
were using hydralazine and only 7% and just over 2%
were using labetalol and nifedipine, respectively. Although
nifedipine is cheap, widely available and easily administered, the usage pattern highlights a strong preference for
labetalol and reflects a trust deficit for oral nifedipine
among health care providers. Both intravenous labetalol
and nifedipine have been compared directly with many
other antihypertensive agents for hypertensive crises during pregnancy; however, their direct comparison with each
other is limited to a very few RCTs.1421 Most of these
trials suffer from small sample size or methodological
shortcomings, thus precluding any definite conclusion
regarding comparative efficacy and safety of these two
drugs. This comparison has also been attempted in the
domain of a systematic review by Cochrane collaboration;
however, the results were inconclusive.6 One study was
not identified and erroneous exclusion of another study
resulted in underpowered meta-analysis. Recently a metaanalysis of RCTs comparing intravenous labetalol and oral
nifedipine was published.22 That meta-analysis identified
and included a smaller number of studies, reducing the
power of meta-analysis. Moreover, primary outcomes
(number of doses and time taken to lower BP) studied by
Shi et al.22 are of little clinical relevance, as comparative
differences in these parameters alone cannot guide clinical
practice. More substantive outcomes that are important to
women and their babies, such as persistent hypertension,
stroke, placental abruption, fetal heart rate (FHR) abnormalities and perinatal mortality, have not been studied.
Lastly, authors have used a fixed effects model even in
the presence of very considerable heterogeneity. These
issues seriously limit the applicability of the evidence generated by this meta-analysis for use in clinical practice.
Therefore the need to generate robust evidence about the
comparative efficacy and safety of intravenous labetalol
and oral nifedipine which can be used to guide clinical
practice is greater than ever. We sought to evaluate the
efficacy and safety of oral nifedipine for treatment of
severe hypertension of pregnancy compared with intravenous labetalol in the context of outcomes which are of
importance to mothers and their babies.

Methods
The review is registered at http://www.crd.york.ac.uk/
PROSPERO/display_record.asp?ID=CRD42014008763#.U6
HCRig8v4Y

2015 Royal College of Obstetricians and Gynaecologists

Systematic search
We systematically searched the Cochrane central register of
controlled trials and Medline from inception till February
2014 as well as Google scholar. We also searched for
abstracts and proceedings of conferences including the
International Society for the Study of Hypertension in
Pregnancy. If necessary, we communicated with authors for
more information on relevant articles or abstracts. We also
searched for dissertation and relevant doctoral theses
through Shodh Ganga (a repository for Indian theses). Previous reviews, bibliographies of published trials and cross
references were also searched. We developed a search strategy using the following search terms and their associated
medical subject headings to identify all the relevant studies:
hypertensive crisis, nifedipine, labetalol, preeclampsia,
hypertension and pregnancy and severe hypertension
pregnancy. We modified the search strategy in accordance
with different electronic databases.

Study selection and data extraction


We included all randomised controlled trials (RCTs)
which compared intravenous labetalol with oral nifedipine for treatment of severe hypertension (defined as systolic BP 160 mmHg and/or diastolic BP 105 mmHg)
during pregnancy with relevant outcomes addressing
maternal, fetal and perinatal benefits or risks. Studies
published only as abstracts were included provided there
was sufficient information presented in the abstract to
demonstrate that it met the inclusion criteria and was of
an acceptable methodological standard. Studies including
both antepartum and postpartum women were to be
included provided intended outcomes were presented
separately for antepartum subjects. No language restrictions were applied, although we could not identify any
study in languages other than English. Primary maternal
outcomes for which data was extracted were: persistent
hypertension (defined either as the need for an antihypertensive drug other than the allocated treatment or as
failure to lower the BP to safe levels with the allocated
treatment), maternal hypotension (defined as systolic BP
of <90 mmHg and/or diastolic BP of <60 mmHg or low
BP causing clinical problems), and serious maternal morbidity (defined as at least one of stroke, placental abruption, disseminated intravascular coagulation, pulmonary
oedema, renal failure and need for maternal intensive
care admission). Secondary maternal outcomes studied
were; caesarean section, resurgence of hypertensive crisis,
lengthening of period of gestation, reported maternal side
effects (headache, nausea, vomiting and palpitation) and
maternal side effects specific to the drug (tachycardia or
bradycardia). Primary perinatal outcomes studied were:
fetal heart rate abnormalities while on treatment, intrauterine fetal death and neonatal death. Secondary neona-

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Shekhar et al.

tal outcomes of interest were: need for neonatal intensive


care admission and low (<7) APGAR score at 5 minutes
of life.

Study quality assessment


Two authors (SS, NG) worked independently to search
for and assess studies for their methodological quality for
inclusion in the review. Studies were assessed for the following key criteria: random sequence generation, allocation concealment, blinding of intervention, blinding of
outcome assessment, completeness of follow-up and other
biases. These were reported as yes, no or cant tell.
Data were extracted independently and in duplicate. Any
disagreement was resolved by consensus. Assessment of
methodological quality and data extraction of one study18
was done by NG and RK because one of the authors of
this review (SS) is also the author of that study. Risk of
bias for each study was assessed using the criteria
outlined in the Cochrane Handbook for Systematic
Reviews of Interventions.23 We resolved any disagreement
by consensus.

Data synthesis
We used Cochrane review manager software (REVMAN
version 5.3, The Nordic Cochrane Center, Copenhagen,
Denmark) for quantitative analysis. All the outcomes were
binary and results were presented as the summary relative
risk (RR) with 95% confidence intervals (CI). We also calculated risk difference (RD) for outcomes in which the
treatment effect was significant at the 5% level. We evaluated statistical heterogeneity using a chi-squared test to
assess for heterogeneity between trials with a P-value less
than 0.10 and the I2 statistics for quantifying the degree of
heterogeneity across studies (roughly interpreted as follows:
040%, probably not important; 3060%, may represent
moderate heterogeneity; 5090%, may represent substantial
heterogeneity; 75100%, very considerable heterogeneity).23
We analysed the data using a fixed effect model. However,
a random effects model was used when I2 was greater than
50%.

Subgroup analysis
We intended to do pre-specified subgroup analysis of primary outcomes for (1) different regimens of each drug
used and (2) patients with hypertension alone or patients
with hypertension and proteinuria.

high risk or unclear risk based on the assessment. For the


purpose of a planned sensitivity analysis, we counted the
total number of low risk scores (of seven) for each study.
Judgement of the overall quality of a study as high was
based on at least four domains having a low risk score,
with two mandatory domainssequence generation and
allocation concealment.23

Grading the quality of evidence


We graded the quality of evidence for most of the efficacy and safety outcomes using the GRADE profiler
(GRADEpro).24 GRADEpro is a computer software application to create summaries of research evidence. It presents key information about all relevant outcomes for a
given health care question, and a grade for the quality of
evidence for each outcome. This tool is intended for
authors of systematic reviews, guideline developers and
those requiring summaries of the best available evidence
for recommendations about particular courses of action
in health care.

Results
Study characteristics
Seven RCTs involving 363 womaninfant pairs met the
inclusion criteria.14,1621 Supporting Information Table S1
shows selected characteristics of included trials. Three trials14,16,20 enrolled women with pre-existing hypertension
and pregnancy-induced hypertension with or without
proteinuria and two trials18,19 enrolled only pregnancyinduced hypertension with or without proteinuria. Information regarding the formulation of nifedipine was available for five trials. Four trials1821 used a tablet form of
nifedipine and one trial16 used nifedipine capsules that
were swallowed whole. Hypotension was variably defined
as BP of <90/60 mmHg by two trials,18,19 as systolic BP
(sBP) of <80 mmHg by one trial (16) and as sBP of
<120 mmHg by another (21). Two trials included antepartum and postpartum patients;16,20 however, these trials
were included, as sufficient information about
antepartum women with their respective outcomes was
available.

Maternal outcomes: efficacy and


safety
Persistent hypertension

Sensitivity analysis
We carried out a planned sensitivity analysis to explore the
impact of study quality on effect size for primary outcomes. The Cochrane collaboration tool for assessing risk
of bias is domain-based, and addresses seven specific
domains. Each domain of the study is adjudged as low risk,

42

For this outcome, all seven trials (363 women and 21


outcome events) were included in the primary analysis.
Persistent hypertension was variably defined as sBP of
>150 mmHg, 160 mmHg, or diastolic blood pressure
(dBP) of >100 mmHg, failure to achieve 25% reduction
in mean arterial pressure after maximum dosage of drug.

2015 Royal College of Obstetricians and Gynaecologists

Nifedipine versus labetalol: meta-analysis

(A)

(B)

(C)

Figure 1. (A) Forest plotpersistent hypertension. (B) Forest plotreported maternal side effects. (C) Forest plotneonatal death.

2015 Royal College of Obstetricians and Gynaecologists

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Shekhar et al.

One trial21 defined persistent hypertension as failure to


achieve target blood pressure of 150 sBP and 95 dBP
within 1 hour. Primary analysis demonstrated that oral
nifedipine was associated with significantly reduced (58%
risk reduction) risk of persistent hypertension (RR 0.42,
95% CI 0.180.96) (Figure 1A). Results did not vary
much across studies (I2 = 25%). However, on using RD
as a summary statistic (RD 0.05, 95% CI 0.10 to
0.00) heterogeneity amongst trials rose to 61%. On
sensitivity analysis, the significance of the estimate was
lost. Subgroup analysis did not find any significant difference in efficacy between nifedipine and labetalol
amongst various dosage groups. Quality of evidence was
low (Table 1).

For comparative analysis of reported maternal side effects,


three trials (207 women) were included. Meta-analysis
demonstrated significantly fewer side effects with nifedipine
(RR 0.57, 95% CI 0.350.94). There was no heterogeneity
amongst trials (I2 = 0%). The results varied minimally
between studies (I2 = 25%) when RD was used as the summary statistic (RD 0.14, 95% CI 0.25 to 0.02). Quality
of evidence was moderate (Table 1, Figure 1B).

Serious maternal morbidity

Caesarean section

The analysis of the outcome serious maternal morbidity


was based upon five trials with 256 women. There was no
difference in the serious maternal morbidity between the
two groups (RR 0.73, 95% CI 0.281.88). Minimal heterogeneity was observed (I2 = 20%). Nifedipine and labetalol
did not differ significantly in reducing severe maternal
morbidity within various dosage regimens. Quality of evidence was moderate (Table 1).

For analysis of caesarean section (all caesarean sections),


four trials (294 women) were included. There was no significant difference in the caesarean section rates with use of
either drug (RR 0.98, 95% CI 0.75 to 1.30) and results
did not vary across studies (I2 = 5%). Quality of evidence
was moderate (Table 1).

Maternal mortality
There was only one maternal death reported in five trials
included for analysis. We could not do a quantitative
analysis for the outcomes resurgence of hypertensive crisis
or lengthening of gestation due to lack of data.

Maternal hypotension
Six trials with 243 women and one event were included for
analysis (RR 2.81, 95% CI 0.1263.83). Quality of evidence
was low (Table 1).

Reported maternal side effects

Fetal and neonatal outcomes: efficacy


and safety
FHR abnormalities
For this analysis, five trials (323 womaninfant pairs) were
included. The difference was not statistically significant (RR
0.31, 95% CI 0.091.11). Subgroup analysis did not find

Table 1. Summary of findings


Outcome

Studies

Maternal efficacy and safety


Persistent hypertension
7
Serious maternal
5
morbidity
Maternal hypotension
6
Maternal mortality
5
Reported maternal
3
side effects
Caesarean section
4
Fetal and perinatal outcome
FHR abnormalities
5
Intrauterine death
5
Neonatal death
4
Low Apgar
2
NICU admission
5

Participants

Nifedipine
events/total

Labetalol
events/total

Statistical method

Effect estimate

363
256

6/187
6/125

15/176
8/131

RR (M-H, Fixed, 95% CI)


RR (M-H, Fixed, 95% CI)

0.42 (0.18, 0.96)


0.73 (0.28, 1.88)

Low
Moderate

343
323
207

1/176
0/166
19/106

0/167
1/157
32/101

RR (M-H, Fixed, 95% CI)


RR (M-H, Fixed, 95% CI)
RR (M-H, Fixed, 95% CI)

2.81 (0.12, 63.83)


0.30 (0.01, 7.22)
0.57 (0.35, 0.94)

Low
Not done
Moderate

294

58/151

56/143

RR (M-H, Fixed, 95% CI)

0.98 (0.75, 1.30)

Moderate

323
323
221
89
323

2/166
13/121
3/116
2/45
32/166

8/157
18/157
10/105
4/44
39/157

RR
RR
RR
RR
RR

0.31
0.66
0.27
0.48
0.77

Low
Moderate
Moderate
Not done
Moderate

(M-H,
(M-H,
(M-H,
(M-H,
(M-H,

Fixed,
Fixed,
Fixed,
Fixed,
Fixed,

95%
95%
95%
95%
95%

CI)
CI)
CI)
CI)
CI)

(0.09, 1.11)
(0.35, 1.27)
(0.09, 0.87)
(0.09, 2.49)
(0.51, 1.14)

Quality of
evidence

BP, blood pressure; CI, confidence intervals; FHR, fetal heart rate; M-H, MantelHaenszel; NICU, neonatal intensive care unit; RR, relative risk.
Bold text indicates significant difference.

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2015 Royal College of Obstetricians and Gynaecologists

Nifedipine versus labetalol: meta-analysis

any difference in this outcome between nifedipine and labetalol when used in different doses. Quality of evidence was
low (Table 1).

Intrauterine fetal death and neonatal death


Five trials (323 womaninfant pairs) were included for
analyses of intrauterine fetal death and four trials were
included for the analysis of neonatal mortality. The analyses did not show a significant difference of risk for intrauterine death between nifedipine and labetalol (RR 0.66,
95% CI 0.351.27); however, the risk of neonatal death was
significantly reduced with nifedipine compared with labetalol (RR 0.27, 95% CI 0.090.87). There was no heterogeneity amongst trials. Sensitivity analysis did not change the
significance of the results. On using RD as the summary
statistic, results varied minimally between studies
(I2 = 33%). Quality of evidence was moderate (Table 1,
Figure 1C).

Low Apgar score


Two trials (89 women) were included for analysis of low
Apgar scores at 5 minutes of life. Pooled estimates did not
demonstrate significant difference with either of two drugs
(RR 0.48, 95% CI 0.092.49).

the globe from Southeast Asia19 to the Indian peninsula,14,17,18,20 Europe21 and North America.16 This review
attempted prespecified subgroup analysis for different dosage regimen within nifedipine and labetalol. Another strong
point of this review is the use of different summary statistics for significant outcomes and their effect on consistency
of results. We used RD in a secondary analysis for three
outcomes for which relative risk was statistically significant.
With the exception of persistent hypertension, the heterogeneity between trials did not increase significantly for the
other two outcomes when risk difference was used as the
summary statistic. The results of RD analyses underline the
lower variability seen in event rate between trials. Grading
of the quality of evidence also adds weight to the findings,
as the quality of evidence for most of the outcomes in our
study is moderate, with only a few of low quality.
The most important limitation is the small number of
included trials and small number of participants in each of
these trials. However, compared with previous meta-analysis comparing these two drugs,6,22 the present study has
included maximum number of trials. Because there were
fewer than ten studies, we could not use a funnel plot to
explore the possibility of publication bias. Nonetheless, the
chances of publication bias were mitigated by the fact that
not all the trials had positive results for all the outcomes.

NICU admission
Four trials (323 women) were included for this analysis.
Analysis demonstrated a favourable trend towards nifedipine (RR 0.77, 95% CI 0.511.14); however, this did not
reach statistical significance. Quality of evidence was moderate (Table 1).

Discussion
Main findings
In this review of comparative efficacy and safety of oral
nifedipine and intravenous labetalol for the treatment of
severe hypertension during pregnancy, seven RCTs involving 363 womaninfant pairs were included. Four trials were
from the Indian peninsula with total of 264 women, one
trial included 29 American women, one included 20 European women, and another included 50 Southeast Asian
women. We found that oral nifedipine was associated with
significantly reduced risk of persistent hypertension,
reported maternal side effects and neonatal death rate.
Although the beneficial effects did not reach statistical significance for rest of the outcomes, nifedipine consistently
demonstrated a favourable trend.

Strength and limitations


The most important strength of this review is that four of
seven trials were considered to have overall high quality.
The included studies represented different ethnicity across

2015 Royal College of Obstetricians and Gynaecologists

Interpretation
The Cochrane systematic review stated that due to insufficient data, no reliable conclusion could be drawn about the
comparative efficacy and safety of these two drugs.6 We
found that oral nifedipine was more efficacious in lowering
the BP to safer levels, but this must be viewed with caution, as the significance of the estimates was lost on sensitivity analysis and the heterogeneity between trials became
significant when risk difference was used as the summary
statistic. In their meta-analysis, Shi et al.22 did not study
persistent hypertension as an outcome. The use of nifedipine was associated with significantly reduced risk of neonatal death. However, this reduced risk of neonatal death
does not necessarily reflect comparative efficacy of the drug
when used as an acute intervention. Neonatal mortality is
subject to a number of factors and an important one is gestational age at the time of delivery (rather than at the time
of recruitment), which unfortunately was not reported by
any of the trials. Data from one study14 were heavily
weighted for analysis of neonatal death. This was a published abstract (limited data) from India, where neonatal
resuscitative facilities and perinatal care not just differ from
developed countries, but vary widely from region to region.
Our finding of a significantly reduced risk of reported
maternal side effects with nifedipine usage is in keeping
with the results of two previously published meta-analyses.6,22

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Shekhar et al.

Conclusion
There is a need for large, adequately powered trials comparing intravenous labetalol and oral nifedipine for treatment of severe hypertension during pregnancy. Researchers
should be careful to measure differences of relevant and
direct clinical outcomes of efficacy and safety. Future trials
should use stratified randomisation of participants based
on BP values. They should also stratify analysis of women
with hypertension alone and women hypertension with
proteinuria.
Isolated reports of circulatory collapse with parallel use of
nifedipine and magnesium sulphate 25,26 and theoretical
concerns due to uterine-relaxant abilities of nifedipine, perhaps have led to a trust deficit for use of nifedipine among
health care providers, despite numerous studies attesting to
the relative safety of nifedipine in late pregnancy.27 No serious adverse effect was reported with nifedipine in any of the
studies included in this review. This review shows that nifedipine, when used for treatment of hypertensive crises of pregnancy, is as efficacious and safe as labetalol and may be
advantageous in low resource settings. We believe that our
findings are reliable, despite the small number of studies to
date, due to the consistency of findings across trials. This
may be of particular importance for resource-poor countries
and regions where hydralazine is not available, but it is also
likely to have an important impact on all pregnant women
and neonates regardless of the setting. Until more evidence
from adequately powered trials comparing these two drugs is
generated, this meta-analysis provides a useful and comprehensive comparative analysis of efficacy and safety outcomes,
when these two agents are used to lower BP in pregnant
women with severe hypertension.

Disclosure of interests
None declared. Completed disclosure of interests form
available to view online as supporting information.

Contribution to authorship
SS designed the study, selected and reviewed studies identified by the scientific literature search, did the Cochrane risk
of bias, wrote drafts with NG and wrote the final paper.
RK contributed to the statistical analysis, data synthesis of
outcomes and grading of the evidence with SS. NG was
involved in the conception and design of the study,
reviewed abstracts to identify the core studies, extracted the
data from included studies, critically reviewed and edited
the final paper. RK was involved in the development of
search strategy and contributed to the methods writing section. PP did the planning analysis, reviewed articles selected
by SS and NG, and helped with data extraction from
selected articles.

46

Details of ethics approval


Not applicable.

Funding
None.

Acknowledgements
Many thanks to K. Patil for her generosity in supplying
unpublished data.

Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Figure S1. Flow diagram of selection of studies.
Table S1. Characteristics of included studies. &

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