Beruflich Dokumente
Kultur Dokumente
13463
Systematic review
www.bjog.org
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.
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
Methods
The review is registered at http://www.crd.york.ac.uk/
PROSPERO/display_record.asp?ID=CRD42014008763#.U6
HCRig8v4Y
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.
41
Shekhar et al.
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.
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.
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
(A)
(B)
(C)
Figure 1. (A) Forest plotpersistent hypertension. (B) Forest plotreported maternal side effects. (C) Forest plotneonatal death.
43
Shekhar et al.
Caesarean section
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).
Studies
Participants
Nifedipine
events/total
Labetalol
events/total
Statistical method
Effect estimate
363
256
6/187
6/125
15/176
8/131
Low
Moderate
343
323
207
1/176
0/166
19/106
0/167
1/157
32/101
Low
Not done
Moderate
294
58/151
56/143
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.
44
any difference in this outcome between nifedipine and labetalol when used in different doses. Quality of evidence was
low (Table 1).
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.
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
45
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
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. &
References
1 Roberts JM, Pearson GD, Cutler JA, Lindheimer MD, National Heart
Lung and Blood Institute. Summary of the NHLBI working group on
research on hypertension during pregnancy. Hypertens Pregnancy
2003;22:10927.
2 National Institute of Health and Clinical Excellence. Hypertension in
pregnancy. The management of hypertensive disorders during
pregnancy. Clinical guidelines CG107. Issued: August 2010
[Internet]. [http://www.nice.org.uk/]. Accessed 20 June 2014.
3 Rey E, LeLorier J, Burgess E, Lange IR, Leduc L. Report of the
Canadian Hypertension Society Consensus Conference: 3.
pharmacologic treatment of hypertensive disorders in pregnancy.
CMAJ 1997;157:124554.
4 Report of the national high blood pressure education program
working group on high blood pressure in pregnancy. Am J Obstet
Gynecol 2000;183:S122.
5 Brown M, Hague W, Higgins J, Lowe S, McCowan L, Oats J, et al.
The detection, investigation and management of hypertension in
pregnancy: executive summary. Aust N Z J Obstet Gynaecol
2000;40:1338.
6 Duley L, Meher S, Jones L. Drugs for treatment of very high blood
pressure during pregnancy. Cochrane Database Syst Rev 2013;(7):
CD001449.
7 Magee LA, Helewa M, Moutquin J-M, von Dadelszen P, Hypertension
Guideline Committee, Strategic Training Initiative in Research in the
Reproductive Health Sciences (STIRRHS) Scholars. Diagnosis,
evaluation, and management of the hypertensive disorders of
pregnancy. J Obstet Gynaecol Can 2008;30 (Suppl 3):S148.
8 Committee on Obstetric Practice. Committee Opinion no. 514:
emergent therapy for acute-onset, severe hypertension with
preeclampsia or eclampsia. Obstet Gynecol 2011;118:14658.
9 Magee LA, Cham C, Waterman EJ, Ohlsson A, von Dadelszen P.
Hydralazine for treatment of severe hypertension in pregnancy:
meta-analysis. BMJ 2003;327:95560.
10 Magee LA, Ornstein MP, von Dadelszen P. Fortnightly review:
management of hypertension in pregnancy. BMJ 1999;318:13326.
11 Bolte AC, van Geijn HP, Dekker GA. Pharmacological treatment of
severe hypertension in pregnancy and the role of serotonin(2)receptor blockers. Eur J Obstet Gynecol Reprod Biol 2001;95:2236.
12 Anonymous. What treatment did you use in your last case of
hypertensive emergency in pregnancy? Quick Poll. Obstet Gynecol,
November 2013.
47