Jurnal 3 - Husnul Aridha - Stase Obsgyn

F1000Research 2023, 11:1287 Last updated: 03 JUN 2023
RESEARCH ARTICLE
Effectiveness of nifedipine, labetalol, and hydralazine

as emergency antihypertension in severe preeclampsia: a
randomized control trial [version 2; peer review: 2 approved]
Donel S 1, Dhini Aiyulie Novri1, Yulis Hamidy 2, Maya Savira 3
1Department of Obstetrics and Gynaecology, Faculty of Medicine, Universitas Riau, Pekanbaru, 28293, Indonesia
2Department of Pharmacology, Faculty of Medicine, Universitas Riau, Pekanbaru, 28293, Indonesia
3Department of Microbiology, Faculty of Medicine, Universitas Riau, Pekanbaru, 28293, Indonesia
v2 First published: 10 Nov 2022, 11:1287 Open Peer Review

https://doi.org/10.12688/f1000research.125944.1
Latest published: 27 Apr 2023, 11:1287
https://doi.org/10.12688/f1000research.125944.2 Approval Status
1 2
Abstract
Background: Preeclampsia is a highly prevalent disease among version 2
pregnant women. In the event of hypertensive emergency, nifedipine, (revision) view view
labetalol, and hydralazine are assigned as first-line therapies in 27 Apr 2023
preeclampsia. Further studies are needed to compare the
effectiveness of these drugs to find the most cost-effective drug with
version 1
minimal side effects. This study aimed to compare the effectiveness of
10 Nov 2022 view view
these drugs in lowering blood pressure during hypertensive
emergencies in severe preeclampsia.
Methods: 60 pregnant women with severe preeclampsia were 1. Talha Bin Emran , BGC Trust University
recruited in this multiple centre double-blind randomized clinical trial Bangladesh, Chittagong, Bangladesh
from May 2021 to April 2022 in Indonesia. The patients were divided
equally into three groups and treated with three doses of nifedipine, 2. Jon Wantania, Sam Ratulangi University,
labetalol, and hydralazine, respectively within one hour with 20 Manado, Indonesia
minutes interval. The effectiveness was measured based on systolic
and diastolic blood pressures, and mean arterial pressure (MAP). The Windy Wariki , Sam Ratulangi University,
observation was carried out until five hours post-third dose Manado, Indonesia
administration.
Results: The blood pressure was reduced significantly after the Any reports and responses or comments on the
administration of the first to the third dose of each antihypertensive article can be found at the end of the article.
(p<0.05). A single dose administration, four, one, and three patients
had 20% MAP reduction in nifedipine, labetalol, and hydralazine
group. Three, seven, and one patient had a failure of reaching 20%
MAP reduction even after receiving the third dose. The effectiveness
of the drugs to achieve 20% reduction of MAP could be ranked as
follows: nifedipine>labetalol>hydralazine (57.49%, 42.13%, and
40.87%, respectively) for single dose and
hydralazine>nifedipine>labetalol (111.3%, 85.12%, and 90.04%,
respectively) for triple dose.
Conclusions: Nifedipine is the most effective drug to reduce the blood
pressure when single dose administration is used, but requires more
Page 1 of 27
doses to further reduce the blood pressure. Hydralazine is the most

effective when the drug administration is maxed up to three doses
within 60 minutes with 20 minutes interval.
Thai Clinical Trials Registry (TCTR): TCTR20221014007 (14/10/2022)
Keywords
Hypertension; gestation; systolic blood pressure; diastolic blood
pressures; mean arterial pressure; preeclampsia
Corresponding author: Donel S (donelmy@yahoo.com)

Author roles: S D: Conceptualization, Project Administration, Resources, Supervision, Validation, Writing – Review & Editing; Novri DA:
Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Software, Visualization, Writing – Original Draft
Preparation, Writing – Review & Editing; Hamidy Y: Formal Analysis, Methodology, Resources, Supervision, Validation, Visualization,
Writing – Review & Editing; Savira M: Conceptualization, Methodology, Resources, Supervision, Validation, Writing – Review & Editing
Competing interests: No competing interests were disclosed.
Grant information: The author(s) declared that no grants were involved in supporting this work.
Copyright: © 2023 S D et al. This is an open access article distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite this article: S D, Novri DA, Hamidy Y and Savira M. Effectiveness of nifedipine, labetalol, and hydralazine as emergency
antihypertension in severe preeclampsia: a randomized control trial [version 2; peer review: 2 approved] F1000Research 2023, 11
:1287 https://doi.org/10.12688/f1000research.125944.2
First published: 10 Nov 2022, 11:1287 https://doi.org/10.12688/f1000research.125944.1
Page 2 of 27
REVISED Amendments from Version 1

There are some changes made in the revised version. The title has been changed by adding “: a randomized control trial”. We
have added more information in the methods such as make it is clear who are the healthcare workers. We have corrected
some typos in the numbering related to the statistics. We have corrected the labels of the figures and now the connection
between the figures and the explanations in the text have been corrected and checked for the correctness. Table 7 was
removed.
Any further responses from the reviewers can be found at the end of the article
Introduction
Preeclampsia and eclampsia are major problems in obstetric cares. Preeclampsia is one of the main causes of maternal
morbidity and mortality in addition to infection and bleeding with the prevalence rate between 5–8% among pregnant
women.1 The main cause of preeclampsia is unknown and the disease is therefore also called the disease of theory. As a
result, the guidelines of preeclampsia management are updated and changed from time to time.2 Research continues to be
updated to find the best formulation for diagnosis and management with the main aim to provide the management with the
most optimal outcome for the mother and foetus. Termination of pregnancy is still considered the gold standard in severe
preeclampsia, but this becomes a problem when the pregnancy is still premature as it can increase the infant mortality
rate.1
High blood pressure is the main indicator in the diagnosis of preeclampsia. Treatment of severe preeclampsia requires
anticonvulsant and antihypertensive drugs. The purpose of administering antihypertensive drugs is to prevent cerebral
bleeding. The American Congress of Obstetricians and Gynaecologists (ACOG) states that pregnant women with systolic
blood pressure 160 mmHg and/or diastolic 110 mmHg that persist for 15 minutes should be considered an emergency
condition and receive antihypertensives immediately, no later than 30 minutes.2 To date, ACOG has offered nifedipine,
labetalol, or hydralazine as the antihypertensive emergency in preeclampsia.2 In June 2020, ACOG issued a statement
that women with gestational hypertension presenting with high blood pressure (severe range) should be treated as same as
severe preeclampsia.1
An indicator of a decrease in blood pressure in patients with severe preeclampsia is the mean arterial pressure (MAP).
MAP is obtained by the formula of twice the diastolic pressure plus one systolic pressure, then divided by three.3 The
target for MAP reduction in patients with severe preeclampsia is around 20–25%.3 This aims to maintain adequate
uteroplacental circulation for the foetus. If blood pressure is reduced too low, there will be a sharp decrease in placental
perfusion resulting in foetal distress, while the main goal of the management of preeclampsia is not only centred on the
mother, but also on the outcome of the baby.
Recommendations for antihypertensive drugs in preeclampsia are changing rapidly. Multiple antihypertensive drugs
have been listed as drugs of choice for the treatment of severe preeclampsia but then excluded due to inconsistent
treatment outcomes. Intravenous labetalol and intravenous hydralazine have long been considered as first-line therapy in
hypertensive emergencies, severe hypertension in pregnant women, and in the postpartum period.4 Although there is little
information regarding the use of calcium channel blockers, several studies have shown that oral nifedipine can also be
considered as first-line therapy, especially when intravenous access is difficult.2 However, further studies are needed to
compare the effectiveness of these three drugs with the aim of finding cost-effective drugs with minimal side effects, and
right on target.
Previous studies on the effectiveness of these three drugs showed mixed results.4,5 Hydralazine and labetalol are
considered to have a balanced effectiveness and side effect to achieve target blood pressure (systolic blood pressure
140–150 mmHg and diastolic blood pressure 90–100 mmHg) in preeclampsia.4,6 However, labetalol lowered blood
pressure more rapidly than hydralazine.4 Another study comparing nifedipine and labetalol showed that these two drugs
had the same effectiveness in achieving target blood pressures (systolic blood pressure 120–150 mmHg and diastolic
blood pressure 70−100 mmHg) within 6 h with no adverse outcomes; 84% women vs 77% women with p=0.05.5
However, single-use nifedipine was more effective than labetalol.5
In our preliminary study, the emergency antihypertensive drugs in severe preeclampsia that are often used in the Arifin
Achmad Hospital, Riau Province of Indonesia and the affiliated hospitals of Faculty of Medicine, Universitas Riau, are
nifedipine and methyldopa. There has never been a standardized study or observation on the safety and effectiveness of
antihypertensive drugs in Indonesian population. Therefore, this study was conducted to compare the effectiveness of
oral nifedipine, and intravenous labetalol and intravenous hydralazine as antihypertensives in severe preeclampsia.
Page 3 of 27
Methods
Study setting
This study was a double-blind, randomized clinical trial to compare the effectiveness of oral nifedipine, intravenous
labetalol, and intravenous hydralazine as antihypertensive emergency in severe preeclampsia. The multicentre study was
conducted at four hospitals at Riau Province of Indonesia, Arifin Achmad Hospital, Tengku Rafian Siak Sri Indrapura
Hospital, Dumai Hospital, and Bengkalis Hospital, from May 2021 to April 2022. These hospitals were chosen because
they are affiliated with Faculty of Medicine, Universitas Riau.
Ethical considerations and registration

The protocol of the study was approved on 28 May 2021 by the Medical and Health Research Ethics Unit, Faculty of
Medicine, Universitas Riau with the number B/045/UN19.5.1.1.8/UEPKK/2021. This clinical trial has been registered at
Thai Clinical Trials Registry (TCTR) with identification number is TCTR20221014007 (approved on 14 October 2022).
This clinical trial was registered retrospectively in TCTR since the protocol of the study has been registered locally and
this following the Indonesia law. All patients gave written informed consent before the enrolment. This study is reported
in line with the CONSORT guidelines.20
Patient recruitment and criteria

The severe preeclampsia patients were recruited consecutively from populations that met the inclusion criteria. The
minimal sample size of the study was 13 patients for each arm. This number based on calculation based on formula:

ðZα þ ZβÞS 2
n1 ¼ n2 n3 ¼ ð1 ρ Þ
ðx1 x2Þ
where α is the significance level to be measured (0.05), β is the study power (80%) and x1-x2 is the difference of the score
between groups that considered significant (10) and S is standard deviation e between groups.
However, a total of 20 severe preeclampsia patients were recruited for each group to prevent underpower due to drop-out
and therefore there were 60 patients included in this study. The severe preeclampsia was defined as pregnant women with
systolic blood pressure ≥160 mmHg or diastolic ≥110 mmHg that persisted for 15 minutes. Inclusion criteria were:
(a) severe preeclampsia patient with 28–34-week gestation; (b) had live foetus; (c) upper arm circumference 23.5–33 cm;
and (d) haemoglobin level at least 10.5 g/dL. All severe preeclampsia patients with decreased consciousness; had
complications such as eclampsia, HELLP syndrome, kidney failure, or acute pulmonary oedema; in labour; received
antihypertensive therapy in the last 12 hours; had an allergy to the trial drugs; and had asthma and heart disease were
excluded. In this study the drop-out criteria were: the mother experienced allergy symptoms, had labour, or emergency
symptoms such as placental abruption and foetal distress during the study.
Blinding and study procedure

All severe preeclampsia patients who came to the hospitals were subjected to anamnesis, physical and laboratories
examination and then selected based on predetermined inclusion criteria. Blood pressure measurements were carried out
using a digital sphygmomanometer with the Omron 7600T brand. The patient was asked to sit and rest for 10 minutes, the
measurement was conducted twice on the arm with a distance period of 15 minutes, and the data taken was the second
measurement. If the patients met the requirements, they were asked to participate in the study and all patients have to sign
the written informed consent before the enrolment. The assigned group was computerized randomized using Randomizer
software. Simple randomization was employed. In brief, 60 kits were prepared by the authors and were labelled 1 to
60 and each of kit containing three tables and three ampoules with the same sizes and colours. Kits no 1–20, 21–40 and
41–60 contained nifedipine, labetalol and hydralazine, respectively. For example, for one nifedipine kit, it contained
3 nifedipine tablets and 3 ampoules of placebo liquid. An author created the random sequence list consisting who will
receive the kit no 1 until 60 based on random sequences provided by Randomizer software. For example, if the list from
the software run was 41, 23, 4 and soon, the patient who arrived first, second and third to the hospital would be given kit no
41, 23 and 4, respectively. Each drug was administered 3 doses within 60 minutes (i.e., 20 minutes interval). Each dose of
the drug contained: oral nifedipine (20 mg), intravenous labetalol (20 mg in 10 ml of sodium chloride 0.9%) and
intravenous hydralazine (10 mg in 10 ml of sodium chloride 0.9%). Since the study consisted multiple healthcare centers,
patient enrolment was conducted in one hospital at one time based on allocated time. Therefore, there were no separation
of the sequence list between centres.
The enrolment of the patient was conducted by the doctors in each centre. The doctors have been informed about the study
and have been trained. The doctors and patients did not know the drugs contained in the kit. The doctors were instructed to
administrate one pair of drugs (i.e., one tablet and one ampoule injection; this contained one drug and one placebo) for
Page 4 of 27
each time. The blood pressure was assessed 20 minutes after each administration. If the blood pressure did not meet the
MAP target, the second pair of drugs (one tablet and one ampoule injection) was given and the blood pressure was
reassessed in 20 minutes until the third pair of the drugs. The blood pressure was re-assessed 60 min post-first dose, 2, 4
and 6 h post-first dose. Therefore, the blood pressure was measured seven times as follows: (1) minute 0 (pre-treatment);
(2) 20 min post-first dose; (3) 20 min post-second dose (i.e., 40 min post-first dose); (4) 20 min post-third dose
(i.e., 60 min post-first dose); (5) 2 h post-first dose; (6) 4 h post-first dose; and (7) 6 h post-first dose.
The technique of administering magnesium sulphate and dexamethasone was uniform in all patients. If the MAP was nor
reached after the third dose, the patient was treated with other drugs and excluded from the final analysis.
End points
The end points of this study were: (a) systolic blood pressure; (b) diastolic blood pressure; (c) MAP; and (d) side effects.
Statistical analysis
Characteristics of patients from each group were tested for normality. The normality of data was measured using the
Kolmogorov-Smirnov test. The data that had normal distribution were analysed using one-way ANOVA and followed by
post hoc analyses. The data that did not distribute normally were analysed using Kruskal-Wallis and Friedmann followed
by post hoc analyses. Comparison of the effectiveness of the three drugs was tested using N-Gain analysis. To determine
how far the differences exist, Cohen's d effect size analysis was used. Further analysis with Kaplan-Meier survival was
conducted. Statistical analysis was performed using SPSS software version 22 (Statistical Package for Social Sciences,
Chicago, IL, USA).
Results
The study was conducted on 60 patients with severe preeclampsia and they were divided into 3 groups: 20 patients in the
nifedipine group, 20 patients in the labetalol group, and 20 patients in the hydralazine group.19 Patients were recruited
from the population that met the inclusion criteria and were willing to participate in the study by signing an informed
consent. Patients were then monitored closely and periodically according to the study protocol. The number of patients for
each step of enrolment, allocation, follow-up and analysis are presented in Figure 1. Out of 60 patients, 11 patients did not
achieve the MAP target after three doses of the tested drugs and therefore were excluded for effectiveness analysis of
nifedipine, labetalol, and hydralazine to reduce the blood pressure.
Patients’ characteristics
We recruited 60 severe preeclampsia patients and were divided randomly to receive nifedipine, labetalol and hydralazine.
The characteristics of the patients including age, gravida, gestational age (gestation), upper arm circumference (UAC),
systolic, diastolic, MAP, pulse, and foetal heart rate of each group are presented in Table 1. Our data indicated that there is
uniformity of characteristics between the three groups.
Required dose for nifedipine, labetalol, and hydralazine to achieve MAP target
Data regarding the dose required for nifedipine, labetalol, and hydralazine to reach the target MAP (20% reduction)
are presented in Figure 2. The study found that 4, 1 and 3 patients of nifedipine, labetalol, and hydralazine group
achieved the MAP target with only one dose, respectively. There were 3, 7 and 1 patients were unable to achieve the
target MAP after three doses of nifedipine, labetalol, and hydralazine, respectively and these patients were excluded
from further analyses.
Effectiveness of nifedipine, labetalol, and hydralazine to reduce the blood pressure

We assessed the effectiveness of nifedipine, labetalol, and hydralazine to reduce the systolic and diastolic blood pressure
where the data were treated as numerically to provided more detailed blood pressure reduction.
Nifedipine
The effectivity of nifedipine to reduce the systolic, diastolic and MAP is presented in Table 2. Our data indicated that
nifedipine decreased the systolic pressure the most at 20 min post-first dose (difference from the first measurement to the
second measurement) as much as 13.41 mmHg with a p<0.001. Meanwhile for second dose (second third measurement),
and the next dose no longer showed a significant difference. Nifedipine also decreased diastolic pressure the most and
significantly at 20 min post-first dose as much as 16.71 mmHg with a p<0.001. Nifedipine decreased the MAP
15.61 mmHg, 6.37 mmHg and 2.90 mmHg 20 min post the first, second and the third dose of nifedipine. The MAP
reduction on 20 min post the first dose was significant statistically with p<0.001.
Page 5 of 27
Figure 1. Flowchart of patients’ enrolment, allocation, follow-up and analysis.
Table 1. Characteristics of the patients of three study groups pre-treatment.
Characteristic Nifedipine n=20 Labetalol n=20 Hydralazine n=20 p-valuea

Age (year) 30.75.8 30.35.2 30.94.2 0.148
Gravida 1.60.9 1.50.7 1.50.6 0.142
Gestation (week) 31.23.0 31.71.8 31.53.6 0.227
Upper arm circumference (mm) 30.73.3 28.62.3 28.92.4 0.588
Systolic blood pressure (mmHg) 170.711.6 177.416.0 174.213.7 0.088
Diastolic blood pressure (mmHg) 112.619.4 105.715.8 107.716.0 0.645
Mean arterial pressure (mmHg) 132.014.5 130.012.0 130.09.6 0.094
Pulse (min-1) 83.41.8 83.21.2 85.51.4 0.260
-1
Foetal heart rate (min ) 146.47 144.36.9 144.65.4 0.346
a
Analysis was conducted using ANOVA.
The changes of the mean systolic, diastolic and MAP are presented in Figure 3. The data suggested there was a sharp
decrease of systolic and diastolic after the first dose of nifedipine and the blood pressure kept decrease until 20 min after
the third dose (after 2 hours of first dose) but it started to bounce again afterward (Figure 3).
Labetalol
Labetalol decreased systolic blood pressure the most and significantly at 20 min post the first and the third dose (13.38 and
12.00 mmHg) (Table 3). The systolic blood pressure continued to decrease until 5 hours post the third dose (Figure 4). The
Page 6 of 27
Figure 2. Dose required to reach target mean arterial pressure (MAP) in patients with severe preeclampsia
treated with nifedipine, labetalol, and hydralazine.
Table 2. Effect of nifedipine to reduce the blood pressure over time in severe preeclampsia patient.
Blood Time Mean difference (I-J)a 95% CI for differenceb p-valueb

pressure comparation
Lower bound Upper bound
Systolic Pre – 20 min 13.412 7.019 19.805 <0.001*
20 min – 40 min 4.412 -4.464 13.288 1.000
40 min – 60 min 3.765 -4.857 12.387 1.000
60 min – 2 h 4.529 -14.701 23.760 1.000
2h–4h -4.176 -10.050 1.697 0.438
4h–6h -7.765 -16.654 1.124 0.131
6 h – Pre -14.176 -23.586 -4.767 0.001*
Diastolic Pre – 20 min 16.706 9.634 23.778 <0.001*
20 min – 40 min 7.353 -1.143 15.849 0.139
40 min – 60 min 2.471 -5.993 10.934 1.000
60 min – 2 h 2.118 -8.781 13.016 1.000
2h–4h -3.706 -10.410 2.999 1.000
4h–6h -7.118 -12.873 -1.362 0.008*
6 h – Pre -17.824 -31.400 -4.247 0.005*
MAP Pre – 20 min 15.608 10.391 20.825 <0.001*
20 min – 40 min 6.373 -0.925 13.670 0.131
40 min– 60 min 2.902 -5.090 10.894 1.000
60 min – 2 h 2.922 -10.434 16.277 1.000
2h–4h -3.863 -9.050 1.324 0.343
4h–6h -7.333 -12.962 -1.705 0.005*
6 h – Pre -16.608 -26.980 -6.236 0.001*
a
Based on estimated marginal means.
b
Adjustment for multiple comparisons: Bonferroni.
*The mean difference is significant at p<0.01.
pattern of the of the reduction was similar with diastolic where the reduction mainly occurred after 20 min post the first
and third dose (with reduction about 9.69 and 8.30 mmHg, respectively) (Table 3). In contrast, the diastolic blood
pressure increased after the 20 min post the third dose (Figure 4). The changes of the MAP were similar with diastolic and
the increase of diastolic and MAP were very small after the third dose (Figure 4).
Hydralazine
Effectivity of hydralazine in lowering the blood pressure has been presented in Table 4. Due to abnormal distribution
of the systolic data, Friedman's test was carried out instead. The test yielded p-value of less than 0.001. As for the diastolic
Page 7 of 27
Figure 3. Changes of systolic (A), diastolic (B) and mean arterial pressure (MAP) post nifedipine administra-
tion. The blood pressure is measured: (1) minute 0 (pre-treatment); (2) 20 min post-first dose; (3) 20 min post-second
dose; (4) 20 min post-third dose; (5) 1 h post-third dose; (6) 3 h post-third dose; and (7) 5 h post-third dose.
Table 3. Effect of labetalol to reduce the blood pressure over time in severe preeclampsia patient.
Blood Time Mean difference (I-J)a 95% CI for differenceb p-valueb

pressure comparation
Systolic Pre – 20 min 13.385 2.538 24.232 0.010**
20 min – 40 min 5.462 -8.580 19.503 1.000
40 min – 60 min 12.000 1.158 22.842 0.024*
60 min – 2 h 0.692 -6.271 7.656 1.000
2h–4h 0.538 -5.423 6.500 1.000
4h–6h 2.077 -2.097 6.251 1.000
6 h – Pre -34.154 -46.904 -21.404 <0.001**
Diastolic Pre – 20 min 9.692 3.625 15.759 0.001**
20 min – 40 min 5.462 -8.012 18.935 1.000
40 min – 60 min 8.308 2.609 14.006 0.002**
60 min – 2 h -0.846 -7.149 5.456 1.000
2h–4h -2.923 -8.335 2.489 1.000
4h–6h 0.538 -4.307 5.384 1.000
6 h – Pre -20.231 -37.391 -3.070 0.015*
MAP Pre – 20 min 10.921 4.931 16.910 <0.001**
20 min – 40 min 5.464 -5.311 16.240 1.000
40 min – 60 min 9.538 2.442 16.635 0.005**
60 min – 2 h -0.333 -6.081 5.414 1.000
2h–4h -1.769 -5.590 2.052 1.000
4h–6h 1.051 -2.347 4.450 1.000
6 h – Pre -24.872 -36.993 -12.751 <0.001**
a
b
**The mean difference is significant at p<0.01.
blood pressure and MAP, significant decreases was obtained until 20 minutes post-third dose. This can be observed in
the curve presented in Figure 5, where sharp decreases of systolic pressure were observed up to 20 minutes post-
third administration. However, in the case of systolic blood pressure, a mild rebound occurred at 1 hour post-third
administration (Figure 5).
Page 8 of 27
Figure 4. Changes of systolic (A), diastolic (B) and mean arterial pressure (MAP) post labetalol administration.
The blood pressure is measured: (1) minute 0 (pre-treatment); (2) 20 min post-first dose; (3) 20 min post-second dose;
(4) 20 min post-third dose; (5) 1 h post-third dose; (6) 3 h post-third dose; and (7) 5 h post-third dose.
Table 4. Effect of hydralazine to reduce the blood pressure over time in severe preeclampsia patients.
Blood Time Mean rank or mean 95% CI for differenceb p-valueb

pressure comparation difference (I-J)a
Systolic Pre – 20 min 6.95 <0.001c,**
20 min – 40 min 5.71
40 min 3 – 60 min 3.85
60 min – 2 h 2.84
2h–4h 3.13
4h–6h 2.92
6 h – Pre 6.95
Diastolic Pre – 20 min 12.000 3.928 20.072 0.001**
20 min – 40 min 8.579 1.175 15.983 0.014*
40 min 3 – 60 min 8.421 1.412 15.430 0.010*
60 min – 2 h 0.684 -4.275 5.643 1.000
2h–4h -0.737 -3.965 2.491 1.000
4h–6h -0.105 -4.567 4.357 1.000
6 h – Pre -28.842 -37.887 -19.798 <0.001**
MAP Pre – 20 min 11.982 4.784 19.180 <0.001**
20 min – 40 min 9.912 3.542 16.283 0.001**
40 min 3 – 60 min 7.825 2.416 13.233 0.002**
60 min – 2 h 0.281 -3.201 3.762 1.000
2h–4h 0.035 -2.152 2.222 1.000
4h–6h 0.175 -2.685 3.036 1.000
6 h – Pre -30.211 -34.932 -25.489 <0.001**
a
b
c
Analysed using Friedmann test.
Effectiveness comparisons of nifedipine, labetalol, and hydralazine after single and triple dose
administration
To compare the effectiveness among the three drugs, N-gain values were calculated based on the MAP reduction and
presented in Table 5. The results showed that nifedipine, labetalol, and hydralazine in a single dose had N-gain values of
0.575 (58%); 0.421 (42%); and 0.408 (41%), respectively. This means, according to Melzer criteria,7 these three drugs
Page 9 of 27
Figure 5. Changes of systolic (A), diastolic (B) and mean arterial pressure (MAP) post hydralazine administra-
tion. The blood pressure is measured: (1) minute 0 (pre-treatment); (2) 20 min post-first dose; (3) 20 min post-second
dose; (4) 20 min post-third dose; (5) 1 h post-third dose; (6) 3 h post-third dose; and (7) 5 h post-third dose.
Table 5. N-gain administration of one dose and triple doses of the test drug.
Dose Type of anti-hypertensive N-gain

Mean Std. Error
Single dose Nifedipine 0.574 0.062
Labetalol 0.421 0.058
Hydralazine 0.408 0.060
Triple dose Nifedipine 0.900 0.034
Labetalol 0.851 0.045
Hydralazine 1.112 0.060
had medium effectiveness in lowering blood pressure to achieve the target MAP (20%). Meanwhile, if referred to Hake
criteria,8 nifedipine is highly effective, while labetalol and hydralazine are less effective in achieving a 20% MAP
reduction. We also found significant difference of the MAP among the three drugs when administered in a single dose
with p=0.037 based on Kruskal-Wallis test (Figure 6). According to pairwise comparative analysis, only hydralazine and
nifedipine appeared to have significant difference with p=0.048 (Table 6). While the effectiveness of nifedipine was not
significantly different with that of labetalol (p=0.148), also shown by hydralazine versus labetalol (p=1.000) (Table 6).
After the administration of three doses of nifedipine, labetalol, and hydralazine within 60 minutes, the N-gain values were
calculated based on the MAP reduction (Table 5). The mean of N-gain were 0.900 (90%); 0.851 (85%); and 1.113 (111%)
for nifedipine, labetalol, and hydralazine, respectively. On the basis of both Melzer and Hake criteria,7,8 all the three drugs
had highly effective in lowering blood pressure to achieve the target MAP of 20%. Kruskal-Wallis test revealed that the
MAP reduction by all drugs were significantly different after three consecutive doses administration (p=0.009) (Figure 6).
Figure 6. Kruskal-Wallis test on MAP reduction by nifedipine, labetalol, and hydralazine when administered in
a single dose (a) and triple dose (b).
Page 10 of 27
Table 6. Pairwise comparisons of the tested anti-hypertensives at single and triple doses administration.
Dose Comparison Test statistic Std. error Std. test statistic adj. p-value
Single Hydralazine vs. labetalol 2.450 5.523 0.444 1.000
Hydralazine vs. nifedipine 13.300 5.523 2.408 0.048*
Labetalol vs. nifedipine 10.850 5.523 1.965 0.148
Triple Hydralazine vs. labetalol 5.650 5.523 1.023 0.919
Hydralazine vs. nifedipine -16.700 5.523 -3.24 0.007**
Labetalol vs. nifedipine -11.050 5.523 -2.001 0.136
Based on pairwise comparisons, there were no difference in the effectiveness between labetalol and nifedipine (p=0.919);
and between nifedipine and hydralazine (p=0.136) (Table 6). Significantly difference of MAP reduction was observed
between labetalol and hydralazine (p=0.007) (Table 6).
Secondary outcome: side effects

The presence of ten side effects (tachycardia, hypotension, foetal heart rate abnormality, nausea, vomit, dizzy, palpitation,
headache, chest pain, and tachypnoea) was assessed following the administration of all three drugs. No patients treated
with labetalol and hydralazine complained the side effect. Among patients treated with nifedipine, no side effects were
reported by the patient except tachycardia.
Discussion
To date, ACOG has recommended three types of first-line drugs that can be used as emergency management of
hypertension in pregnancy: oral nifedipine, intravenous labetalol, and intravenous hydralazine. The blood pressure
targets to be achieved in patients with hypertensive emergencies in pregnancy differ from one guideline to another.9 The
latest ACOG bulletin guidelines did not mention the target blood pressure and only mentioned the blood pressure
threshold that clinicians should to achieve. This present study was the first to report the direct comparison of the
effectiveness of nifedipine, labetalol, and hydralazine together. In our study, a 20-25% decrease in MAP from baseline
was considered the target blood pressure to be achieved. We also processed the data numerically so that a decrease of
1 mmHg was calculated and analysed to produce a detailed outcome. The blood pressure and pulse rate of the patients at
the baseline are similar to previous studies studying the severe preeclampsia.9–12 No characteristic differences were
observed among nifedipine, labetalol, and hydralazine groups in the present study.
Our data suggested that oral nifedipine and intravenous labetalol and hydralazine regimens can be used to treat
hypertensive emergencies in pregnancy. If 20-25% reduction of MAP is used as the target, where three doses was set
as the maximum, the intravenous hydralazine monotherapy had the lowest failure rate (1 patient). In contrast, intravenous
labetalol monotherapy had a failure rate 7 patients (35%, 7/20 patients). As reported previously, labetalol group had
relatively low efficacy and required cross-treatment or alternative treatment.10 It is worth noting that the target for MAP
reduction may vary across hospitals. Hence, further processing of these ordinal data was not carried out.
Based on the data of systolic pressure following post-administration time, nifedipine had maximum effectiveness by one
dose of administration, but experienced a rebound after 4 hours. As in the labetalol group, the blood pressure reduction
peaked twice; at post-20 and -60 minutes administration. Patients in hydralazine group had the lowest blood pressures at
three points of measurement: at post-20, -40, and -60 minutes administration. These findings suggest that titration dose is
required. Comparative analysis among the three drugs using a single dose yielded a statistical significance of p=0.037.
When administered with a single dose, nifedipine performed the best, followed by labetalol and hydralazine and no
significant difference of efficacy between labetalol and nifedipine. The result is similar to the finding from a previous
study10 where labetalol and nifedipine had no significant different in reduction of the blood pressure. Rapid reduction of
the blood pressure in nifedipine group in our study also similar with previous study13 where the reduction of the blood
pressure was achieved faster by nifedipine compared with hydralazine.13 Both nifedipine and hydralazine work by
resulting vasodilating effects.14,15 However, hydralazine has more effect on the arteries than veins15 while nifedipine, as a
calcium channel blocker, causes overall vasodilation, thereby leading to a decrease in peripheral vascular resistance.14
Taken altogether, nifedipine could be the most efficacious when administered at a single dose.
According to the ACOG guidelines, the maximum dose of emergency antihypertension is 3 times administration within
60 minutes. The comparative analysis revealed that hydralazine yielded the most optimum reduction of blood pressure,
Page 11 of 27
followed by nifedipine and labetalol, respectively. This could be observed through the significant reduction of blood
pressure on the first until the fourth measurements.
We did not witness any adverse effects experienced by the mothers or infants following the drug administration, in which
our data are similar to that of reported.16–18 Nonetheless, other studies reported the occurrence of nausea and vomiting as
adverse effects of labetalol (16%) or nifedipine (8%).10 In another study, patients in labetalol and nifedipine group
experienced dizziness and/or headaches (24% vs 12%), palpitations (8% vs 4%), and foetal heart rate abnormalities (4%
vs 8%).9 These different findings on side effect might be due to the maximum dose used in both foregoing studies, which
was 5 doses.9,10
The strengths of this study include the multicentred randomized controlled study design, intensive monitoring, and
repeated measurements up to seven times. However, this study is limited by the fact that some of the hospitals only used
single blinding because labetalol and hydralazine are new to some doctors. We also did not consider the circadian rhythms
in our study and this might affect the blood pressure. Some of the side effects were measured subjectively such as nausea,
vomit, dizzy, palpitation, headache and chest pain. However, the methods were exactly the same in all groups.
Conclusions
Our data suggested that nifedipine is the most effective in reducing blood pressure using a single dose administration
during hypertensive emergency in severe preeclampsia. The lowering blood pressure effect of nifedipine was not
significantly different to labetalol but was significantly superior as compared with hydralazine. Nifedipine had a
significant rebound phenomenon in blood pressure after four hours of drug administration, hence the necessity of
re-administering antihypertensives. In maintaining the low blood pressure, hydralazine was significantly more effective
than labetalol and no different effectiveness between hydralazine and nifedipine. All drugs are considered safe after triple
dose administration within one hour.
Based on the present study, in high resource settings, hydralazine is recommended to treat severe preeclampsia cases with
hypertensive emergency since it reduces the blood pressure rapidly and has no rebound phenomenon. We recommend to
use nifedipine in the low resource settings since it is cheap and easy to use and store while still has good ability to reduce
the blood pressure. However, blood pressure maintenance is required because it might rebound after approximately six
hours.
Data availability
Underlying data
Figshare: ‘Effectiveness of nifedipine, labetalol, and hydralazine as emergency antihypertension in severe preeclampsia’.
DOI: https://doi.org/10.6084/m9.figshare.20933785.19
This project contains the following underlying data:
- Master Data.xlsx [Table containing the raw data of the study].
Reporting guidelines
Figshare: CONSORT checklist for Effectiveness of nifedipine, labetalol, and hydralazine as emergency antihypertension
in severe preeclampsia. DOI: https://doi.org/10.6084/m9.figshare.21443028.20
Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).
Acknowledgements
We would like to thank you to all healthcare workers in Arifin Achmad Hospital, Tengku Rafian Siak Sri Indrapura
Hospital, Dumai Hospital, and Bengkalis Hospital who assisted in this study.
Page 12 of 27
References
1. American College of Obstetricians and Gynecologists: Gestational 12. Garovic VD, Dechend R, Easterling T, et al. : Hypertension in
Hypertension and Preeclampsia. Practice Bulletin No. 222, June pregnancy: diagnosis, blood pressure goals, and
2020. pharmacotherapy: a scientific statement from the American
2. American College of Obstetricians and Gynecologists: Emergent Heart Association. Hypertension. 2022; 79: e21–e41.
therapy for acute onset, severe hypertension during pregnancy PubMed Abstract|Publisher Full Text
and the postpartum period. Committee Opinion. Feb 2019; (767). 13. Rezaei Z, Sharbaf FR, Pourmojieb M, et al.: Comparison of the
3. Fogagnolo A: Mean Arterial Pressure and Central Venous Pressure efficacy of nifedipine and hydralazine in hypertensive crisis in
Difference as a Prognostic Tool for Postoperative Acute Kidney Injury. pregnancy. Acta Med. Iran. 2011; 49(11): 701–706.
Geneva: Euroanaesthesia; 2017; 233. PubMed Abstract
4. Patel P, Koli D, Maitra N, et al.: Comparison of Efficacy and Safety of 14. Easterling T, Mundle S, Bracken H, et al.: Oral antihypertensive
Intravenous Labetalol Versus Hydralazine for Management of regimens (nifedipine retard, labetalol, and methyldopa) for
Severe Hypertension in Pregnancy. J. Obstet. Gynaecol. India. 2018; management of severe hypertension in pregnancy: an open-
68(5): 376–381. label, randomised controlled trial. Lancet. 2019 Sep 21;
PubMed Abstract|Publisher Full Text 394(10203): 1011–1021. Epub 2019 Aug 1.
PubMed Abstract|Publisher Full Text|Free Full Text
5. Easterling T, Mudle S, Bracken H, et al.: Oral antihypertensive
regimens (nifedipine retard, labetalol, and methyldopa) for 15. Antza C, Dimou C, Doundoulakis I, et al.: The flipside of hydralazine
management of severe hypertension in pregnancy: an open- in pregnancy: A systematic review and meta-analysis. Pregnancy
label, randomised controlled trial. Lancet. 2019; 394: 1011–1021. Hypertens. 2020 Jan; 19: 177–186.
PubMed Abstract|Publisher Full Text PubMed Abstract|Publisher Full Text
6. Cunningham FG, Leveno KJ, Bloom SL, et al.: Williams Obstetrics. 16. Firoz T, Magee LA, MacDonell K, et al.: Oral antihypertensive
25th ed. New York: Mc Graw Hill; 2018. therapy for severe hypertension in pregnancy and postpartum:
a systematic review. BJOG. 2014 Sep; 121(10): 1210–1218;
7. Meltzer DE: The relationship between mathematics preparation discussion 1220.
and conceptual learning gains in physics: A possible “hidden PubMed Abstract|Publisher Full Text|Free Full Text
variable” in diagnostic pretest scores. Am. J. Phys. 2002; 70(12):
1259–1268. 17. Adebayo JA, Nwafor JI, Lawani LO, et al.: Efficacy of nifedipine
Publisher Full Text versus hydralazine in the management of severe hypertension
in pregnancy: A randomised controlled trial. Niger. Postgrad.
8. Hake RR: Analyzing change/gain scores. 1999. Med. J. 2020 Oct-Dec; 27(4): 317–324.
Reference Source PubMed Abstract|Publisher Full Text
9. Biswas SK, Raha SK, Mahbuba.: Oral Nifedipine versus 18. Aali BS, Nejad SS: Nifedipine or hydralazine as a first-line agent to
Intravenous Labetalol for Acute Blood Pressure Control in control hypertension in severe preeclampsia. Acta Obstet.
Severe Hypertension of Pregnancy: A Study at Faridpur Medical Gynecol. Scand. 2002 Jan; 81(1): 25–30.
College Hospital. Faridpur Med. Coll. J. 2021; 16(1): 25–29. PubMed Abstract|Publisher Full Text
Publisher Full Text
19. Suhaimi D: Effectiveness of nifedipine, labetalol, and hydralazine as
10. Raheem IA, Saaid R, Omar SZ, et al.: Oral nifedipine versus emergency antihypertension in severe preeclampsia. figshare.
intravenous labetalol for acute blood pressure control in [Dataset]. Journal Contribution. 2022.
hypertensive emergencies of pregnancy: a randomised trial. Publisher Full Text
BJOG. 2012 Jan; 119(1): 78–85. Epub 2011 Oct 10.
PubMed Abstract|Publisher Full Text 20. Suhaimi D: CONSORT checklist for Effectiveness of nifedipine,
labetalol, and hydralazine as emergency antihypertension in severe
11. Dhali B, Bhattacharya S, Ganguly RP, et al.: A randomized trial of preeclampsia. figshare. 2022. [Dataset]. Journal Contribution. 2022.
intravenous labetalol & oral nifedipine in severe pregnancy Publisher Full Text
induced hypertension. Int. J. Reprod. Contracept. Obstet. Gynecol.
2012; 1: 42–46.
Page 13 of 27
Open Peer Review

Current Peer Review Status:
Version 2
Reviewer Report 02 June 2023
https://doi.org/10.5256/f1000research.144510.r171164
© 2023 Wantania J et al. This is an open access peer review report distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
Jon Wantania
Department of Obstetric and Gynaecology, Maternal Foetal Medicine Division, Medical Faculty,
Sam Ratulangi University, Manado, North Sulawesi, Indonesia
Windy Wariki
Thank you for revision of your manuscript.
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: John Wantania : Maternal Fetal Medicine ; Windy Mariane Virenia
Wariki : Clinical Epidemiologist
We confirm that we have read this submission and believe that we have an appropriate level
of expertise to confirm that it is of an acceptable scientific standard.
Reviewer Report 02 May 2023
© 2023 Emran T. This is an open access peer review report distributed under the terms of the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
Talha Bin Emran

Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, Bangladesh
Authors addressed all of my comments. The revised manuscript can be accepted for indexing.
Page 14 of 27
Reviewer Expertise: Immunology, Alternative Medicine, Public Health, Bioinformatics
I confirm that I have read this submission and believe that I have an appropriate level of
expertise to confirm that it is of an acceptable scientific standard.
Version 1
Reviewer Report 02 December 2022
© 2022 Wantania J et al. This is an open access peer review report distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
Jon Wantania
1 Department of Obstetric and Gynaecology, Maternal Foetal Medicine Division, Medical Faculty,

2 Department of Obstetric and Gynaecology, Maternal Foetal Medicine Division, Medical Faculty,

Windy Wariki
1 Sam Ratulangi University, Manado, North Sulawesi, Indonesia
2 Sam Ratulangi University, Manado, North Sulawesi, Indonesia
Thank you for your hard work. As a reviewer, I appreciate the efforts of the authors. The methods
and research results presented are excellent and it hoped that great benefits obtained from this
article. However, there are still some minor issues to address, which are listed below, in general:
○This article is useful, but still there are several weaknesses that need to be considered.
○ The introduction section should describe in more depth what is the novelty and urgency of
this study.
○ The methods, and interpretations of the statistical analysis are not carefully presented.
Therefore, further consultations with biostatistician or epidemiologist may potentially
improve this article.
○ The authors may not be careful enough in writing due to some mistakes in grammar and
inconsistency in writing.
Introduction
Paragraph 4: The authors mentioned about the recommendations for antihypertension drugs in
preeclampsia and stated, “Multiple drugs are included and excluded from the list of drugs of
choice for the treatment of severe preeclampsia”. This sentence is a little unclear. Could you
please clarify exactly what you mean about multiple drugs being included and also excluded as
well? The authors should modify the sentence so that it is easier for the reader to understand.
Page 15 of 27
Paragraph 4: In the third sentence the authors explained the dosage form of hydralazine, without
writing down the dosage form of labetalol.
Paragraph 5: The authors stated: “Hydralazine and labetalol are considered to have a balanced
effectiveness and side effect in lowering blood pressure in preeclampsia”, and “Another study
comparing nifedipine and labetalol…” Here, the authors should explain if the indicator used to
measure “lowering blood pressure” were the same, for example the mean arterial pressure (MAP),
and need to confirm quantitatively how much the blood pressure declined so that the reader can
judge that they are comparable.
Paragraph 6: In the objective of this study, the authors mentioned the dosage form of nifedipine
and labetalol. The authors should consistently explain the dosage form of hydralazine as well,
bearing in mind that nifedipine and labetalol have different dosage forms.
Methods
Study setting and registration
In line with the subtitle above including registration, the authors should explain matters related to
registration in this section instead of explaining it in the ethical considerations section. However, if
the authors should explain this in ethical considerations section, can “registration” in this subtitle
be eliminated?

In the second sentence the authors stated “The minimal sample size of the study was 13 patients”.
This is different from the explanation in the Results section that the total number of samples was
60. Does it mean that the results of the minimum sample size calculation are 13 patients in each
group?
The minimum sample calculation formula used by the authors is for two groups. Considering that
this research was an unpaired numerical comparative study conducted on three groups with
measurements of seven times, it would be more appropriate if the authors calculated the number
of samples based on the above considerations.

The authors are suggested to explain in more detail about the following sentence “For example,
the patient who arrived first and second to the hospital should be given kit no 41 and 23”.
Furthermore, the authors also need to describe who are the “health workers” specifically,
mentioned in this sentence “Health workers were instructed to administrate one pair of drug….”
with reference to Peraturan Menteri Kesehatan Republik Indonesia Nomor 13 Tahun 2020.
Endpoints:
The authors stated “The blood pressure was measured seven times...” As a suggestion, this
sentence should be more suitable when explained in the subtitle “Blinding and study procedure”
above.
The authors have explained that a normality test has been carried out, therefore it is advised to
write down the name of the normality test used, for example by taking into account the number of
Page 16 of 27
samples, or other considerations or assumptions.
Results
Figure 1: In the last column of the “Analysis” section, it was written that the total number of
respondents was 49 patients, quite different from the explanation in the Results section that 60
patients were analyzed. It is suggested that the authors need to be clearer, for example, when and
for what to analyzing 60 patients, or only 49 patients.
Required time for nifedipine, labetalol, and hydralazine group achieved the MAP
The authors have explained that the results regarding the time required for the three drugs to
reach the target MAP are presented in Figure 1. However, the results shown in figure 1 are
different from this explanation.
Nifedipine (page 6)
In this section, the author has directed the reader for three times to see the results in Table 2,
even though all the data in this section are only showed in table 2. As a suggestion, it would be
better if Table 2 was written only once, for example at the beginning or end of a paragraph of the
explanation.
Sentence stating “Nifedipine decrease the MAP 15.61 mmHg, 5.46 mmHg and 12.00 mmHg 20 min
post the first…”. However, 5.46 mmHg and 12.00 mmHg are not found in Table 2. Similar with the
sentence sixth which is in Table 2 the p=0.010 and p=0.024 are not found.
Table 2
On the footnote of table 2 was written the mean difference is significant at p<0.005. But in this
table, there is no p-value less than 0.05 (p<0.05) which means that this mark (*) no need to be
mentioned in the footnote.
Page 7: The description below Figure 2 where the author wants to explain the changes of mean
systolic, diastolic and MAP. The authors are asked to be more careful in presenting the results
where the appearance of Figure 2 inconsistent from this explanation. Figure 2 is a comparison of
the three types of drugs in achieving MAP.
Figure 2:
It would be more informative and flowing if the appearance of Figure 2 and its description are in
the “Effectiveness comparisons of nifedipine, labetalol, and hydralazine” section compared to the
current view which is in the section or explanation of nifedipine.
Labetalol
The authors are advised to revise the figure number that is not in accordance with the explanation
about labetalol, which is different from what is presented in Figure 3.
Hydralazine
In Table 4, the results of the analysis to explain the decrease in systolic blood pressure were not
found. Also, Figure 4 is a description of labetalol, not hydralazine.
Page 8: Explanation of the results of Kruskal-Wallis test is not present in the Figure 5, but in Figure
6.
Page 17 of 27
Table 7: Suggestion for the authors regarding reported side effects where there was only one
namely tachycardia, it would be better if the result is presented in a narrative manner.
Discussion
Discussion section is still having major problems, addition information requested on strength and
limitation are not clearly explain.
The authors are lacking in explanation the agreements and disagreements with findings from
other studies.
Limitations
The limitation in methodological should be clearly explained and address as one of the limitations
of this study.
The authors are suggested to give specific recommendations to the reader as respond to key
findings.
Is the work clearly and accurately presented and does it cite the current literature?
Partly
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?
Partly
If applicable, is the statistical analysis and its interpretation appropriate?

I cannot comment. A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?
Yes
Are the conclusions drawn adequately supported by the results?

Partly
Reviewer Expertise: John Wantania : Maternal Fetal Medicine ; Windy Wariki : Clinical
Epidemiologist
We confirm that we have read this submission and believe that we have an appropriate level
of expertise to confirm that it is of an acceptable scientific standard, however we have
significant reservations, as outlined above.
Author Response 16 Feb 2023
Page 18 of 27
Donel S
Thank you for your hard work. As a reviewer, I appreciate the efforts of the authors. The
methods and research results presented are excellent and it hoped that great benefits
obtained from this article. However, there are still some minor issues to address, which are
listed below, in general:
This article is useful, but still there are several weaknesses that need to be considered.
The introduction section should describe in more depth what is the novelty and urgency of
this study.
The methods, and interpretations of the statistical analysis are not carefully presented.
Therefore, further consultations with biostatistician or epidemiologist may potentially
improve this article.
The authors may not be careful enough in writing due to some mistakes in grammar and
inconsistency in writing.
RESPONSES: Thank you for reviewing our manuscript. The comments and suggestions have
improved the quality of our current manuscript significantly.
We have added the required information in the methods as requested. Also, we have
corrected some typos in the numbering related to the statistics. We have corrected the
labels of the figures. The connection between the figures and the explanation texts have
been corrected and checked for the correctness.
Introduction
Paragraph 4: The authors mentioned about the recommendations for antihypertension
drugs in preeclampsia and stated, “Multiple drugs are included and excluded from the list of
drugs of choice for the treatment of severe preeclampsia”. This sentence is a little unclear.
Could you please clarify exactly what you mean about multiple drugs being included and
also excluded as well? The authors should modify the sentence so that it is easier for the
reader to understand.
RESPONSES: We have revised the sentence.
Paragraph 4: In the third sentence the authors explained the dosage form of hydralazine,
without writing down the dosage form of labetalol.
RESPONSES: Have been included: “Intravenous labetalol and intravenous hydralazine have
long been considered as first-line therapy in hypertensive emergencies, severe
hypertension in pregnant women, and in the postpartum period”.
Paragraph 5: The authors stated: “Hydralazine and labetalol are considered to have a
balanced effectiveness and side effect in lowering blood pressure in preeclampsia”, and
“Another study comparing nifedipine and labetalol…” Here, the authors should explain if the
indicator used to measure “lowering blood pressure” were the same, for example the mean
arterial pressure (MAP), and need to confirm quantitatively how much the blood pressure
declined so that the reader can judge that they are comparable.
RESPONSES: We have added more detailed of the information related to the studies.
Paragraph 6: In the objective of this study, the authors mentioned the dosage form of
nifedipine and labetalol. The authors should consistently explain the dosage form of
Page 19 of 27
hydralazine as well, bearing in mind that nifedipine and labetalol have different dosage
forms.
RESPONSES: Have been included: “Therefore, this study was conducted to compare the
effectiveness of oral nifedipine, and intravenous labetalol and intravenous hydralazine as
antihypertensives in severe preeclampsia.”
Methods
Study setting and registration
In line with the subtitle above including registration, the authors should explain matters
related to registration in this section instead of explaining it in the ethical considerations
section. However, if the authors should explain this in ethical considerations section, can
“registration” in this subtitle be eliminated?
RESPONSES: Thank you for the suggestion. We have changed the subheading to: “Study
setting” only and moved the “registration” into: “Ethical considerations and registration”

In the second sentence the authors stated “The minimal sample size of the study was 13
patients”. This is different from the explanation in the Results section that the total number
of samples was 60. Does it mean that the results of the minimum sample size calculation
are 13 patients in each group? RESPONSES: 13 patients are minimal sample size for each
group. Therefore, we have revised to: “The minimal sample size of the study was 13 patients
for each arm.”
The minimum sample calculation formula used by the authors is for two groups.
Considering that this research was an unpaired numerical comparative study conducted on
three groups with measurements of seven times, it would be more appropriate if the
authors calculated the number of samples based on the above considerations.
RESPONSES: We have checked again and we confirm that this formula also can be used for
three groups.

The authors are suggested to explain in more detail about the following sentence “For
example, the patient who arrived first and second to the hospital should be given kit no 41
and 23”.
RESPONSES: We have revised the sentence and we believe it is clear now. “For example, if
the list from the software run was 41, 23, 4 and soon, the patient who arrived first, second
and third to the hospital should be given kit no 41, 23 and 4, respectively.”
Furthermore, the authors also need to describe who are the “health workers” specifically,
mentioned in this sentence “Health workers were instructed to administrate one pair of
drug….” with reference to Peraturan Menteri Kesehatan Republik Indonesia Nomor 13
Tahun 2020.
RESPONSES: They were doctors. And the text has been revised: “The enrolment of the
patient was conducted by the doctors in each centre. The doctors have been informed
about the study and have been trained. The doctors and patients did not know the drugs
contained in the kit.”
Page 20 of 27
Endpoints:
The authors stated “The blood pressure was measured seven times...” As a suggestion, this
sentence should be more suitable when explained in the subtitle “Blinding and study
procedure” above.
RESPONSES: Thank you for the suggestion. The sentence has been moved within “Blinding
and study procedure” subheading.
The authors have explained that a normality test has been carried out, therefore it is
advised to write down the name of the normality test used, for example by taking into
account the number of samples, or other considerations or assumptions.
RESPONSES: We have added the information of the test used to measure the normality of
the data. We added: “The normality of data was measured using the Kolmogorov-Smirnov
test.”
Results
Figure 1: In the last column of the “Analysis” section, it was written that the total number of
respondents was 49 patients, quite different from the explanation in the Results section
that 60 patients were analyzed. It is suggested that the authors need to be clearer, for
example, when and for what to analyzing 60 patients, or only 49 patients.
RESPONSES: Thank you for questioning this. We have added the information related to this.
We add: “Out of 60 patients, 11 patients did not achieve the MAP target after three doses of
the tested drugs and therefore were excluded for effectiveness analysis of nifedipine,
labetalol, and hydralazine to reduce the blood pressure.”
Required time for nifedipine, labetalol, and hydralazine group achieved the MAP
The authors have explained that the results regarding the time required for the three drugs
to reach the target MAP are presented in Figure 1. However, the results shown in figure 1
are different from this explanation.
RESPONSES: Thank you pointing this mistake. It should be Figure 2. Also it has been
changed to “Required dose for nifedipine, labetalol, and hydralazine to achieve MAP target”
“Data regarding the dose required for nifedipine, labetalol, and hydralazine to reach the
target MAP (20% reduction) are presented in Figure 2.”
Nifedipine (page 6)
In this section, the author has directed the reader for three times to see the results in Table
2, even though all the data in this section are only showed in table 2. As a suggestion, it
would be better if Table 2 was written only once, for example at the beginning or end of a
paragraph of the explanation.
RESPONSES: Now it only mentioned only once in the beginning.
Sentence stating “Nifedipine decrease the MAP 15.61 mmHg, 5.46 mmHg and 12.00 mmHg
20 min post the first…”. However, 5.46 mmHg and 12.00 mmHg are not found in Table 2.
Similar with the sentence sixth which is in Table 2 the p=0.010 and p=0.024 are not found.
RESPONSES: We appreciated with this correction. We have corrected the sentences:
“Nifedipine decreased the MAP 15.61 mmHg, 6.37 mmHg and 2.90 mmHg 20 min post the
first, second and the third dose of nifedipine. The MAP reduction on 20 min post the first
Page 21 of 27
dose was significant statistically with p<0.001.”
Table 2
On the footnote of table 2 was written the mean difference is significant at p<0.005. But in
this table, there is no p-value less than 0.05 (p<0.05) which means that this mark (*) no need
to be mentioned in the footnote.
RESPONSES: Now the * has been deleted. And ** has been changed to “*The mean
difference is significant at p<0.01.” The * in the table also have been deleted. Thank you.
Page 7: The description below Figure 2 where the author wants to explain the changes of
mean systolic, diastolic and MAP. The authors are asked to be more careful in presenting
the results where the appearance of Figure 2 inconsistent from this explanation. Figure 2 is
a comparison of the three types of drugs in achieving MAP.
RESPONSES: Thank you for catch this mistake. We realized that there was a shift of the
labels of the figures. This should be Figure 3 not Figure 2. Now it has been corrected into
Figure 3. The revised texts: “The changes of the mean systolic, diastolic and MAP are
presented in Figure 3. The data suggested there was a sharp decrease of systolic and
diastolic after the first dose of nifedipine and the blood pressure kept decrease until 20 min
after the third dose (after 2 hours of first dose) but it started to bounce again afterward (
Figure 3).”
Figure 2:
It would be more informative and flowing if the appearance of Figure 2 and its description
are in the “Effectiveness comparisons of nifedipine, labetalol, and hydralazine” section
compared to the current view which is in the section or explanation of nifedipine.
RESPONSES: We agree with this suggestion because it is hard to follow the texts and the
Figure 2.
We have re-requested the layout editor to move Figure 2 directly under the subheading:
“Required dose for nifedipine, labetalol, and hydralazine to achieve MAP target”.
Labetalol
The authors are advised to revise the figure number that is not in accordance with the
explanation about labetalol, which is different from what is presented in Figure 3.
RESPONSES: As we responded previously, we realized that there was a shift of the labels of
the figures. Now all have been corrected.
Hydralazine
In Table 4, the results of the analysis to explain the decrease in systolic blood pressure were
not found. Also, Figure 4 is a description of labetalol, not hydralazine.
RESPONSES: The systolic data was not distributed normally and therefore the Friedmann
test and this analysis produced one p-value only and no 95%CI. To ensure this is clear, we
have included the information as a note under the Table 4. “c Analysed using Friedmann
test.”
As we stated previously, all labels of the figures have been rechecked and corrected.
Page 8: Explanation of the results of Kruskal-Wallis test is not present in the Figure 5, but in
Page 22 of 27
Figure 6.
RESPONSES: All labels of the figures have been rechecked and corrected.
Table 7: Suggestion for the authors regarding reported side effects where there was only
one namely tachycardia, it would be better if the result is presented in a narrative manner.
RESPONSES: Now Table 7 has been deleted as suggested and we have added “side effects”
after the secondary outcome.
Discussion
Discussion section is still having major problems, addition information requested on
strength and limitation are not clearly explain.
RESPONSES: We have provided the information related to the strengths and limitations of
the study.
The authors are lacking in explanation the agreements and disagreements with findings
from other studies.
RESPONSES: Thank you for your suggestions. Unfortunately, available studies are limited
and therefore it is not possible to compare with previous studies.
Limitations
The limitation in methodological should be clearly explained and address as one of the
limitations of this study.
The authors are suggested to give specific recommendations to the reader as respond to
key findings.
RESPONSES: We have listed all the limitations of the study. We also have added specific
recommendation from the results of the study. We added: “ Based on the present study, in
high resource settings, hydralazine is recommended to treat severe preeclampsia cases
with hypertensive emergency since it reduces the blood pressure rapidly and has no
rebound phenomenon. We recommend to use nifedipine in the low resource settings since
it is cheap and easy to use and store while still has good ability to reduce the blood
pressure. However, blood pressure maintenance is required because it might rebound after
approximately six hours.”
Reviewer Report 14 November 2022
© 2022 Emran T. This is an open access peer review report distributed under the terms of the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
Talha Bin Emran

1
Page 23 of 27
Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, Bangladesh

2 Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, Bangladesh
The study assessed the effectiveness of nifedipine, labetalol, and hydralazine as emergency
antihypertension in severe preeclampsia (SP). SP is a significantly important health problem in
both developed and developing countries. My comments:
○ The study was well-designed and conducted with balanced conclusions.
○ The title of the study is clear and balanced however the information on RCT is needed such
as: “Effectiveness of nifedipine, labetalol, and hydralazine as emergency antihypertension in
severe preeclampsia: a randomized control trial”.
○ The structured abstract contains all important information, including the registry number.
○ The introduction section provides the importance and significance of the problem as well as
the scientific gap. The aim of the study is also clearly stated.
○ The study setting is clearly stated although the justification for choosing those hospitals
might be helpful.
○ The sample size is relatively small, but the justification and calculation are provided on how
the sample was calculated.
○ Double blinding and randomization were conducted to avoid bias.
○ The procedures are explained adequately but the information on whether the healthcare
workers received the training from the researchers is important to ensure that they worked
following the guideline.
○ The Results assisted with a flowchart, and this helps the readers to understand each step of
enrolment, allocation, follow-up, and analysis.
○ The baseline of the data of the patients between the group are relatively homogeneous.
○ The comparations between drugs were conducted for each endpoint and should be
appreciated.
○ Table 7. The information in this table can basically be written in two sentences only since
there were no side effects in the labetalol and hydralazine groups. Also “Secondary
outcome” could be changed to “Side effect.”
○ Discussion and conclusion are balanced; the study's strengths and limitations are discussed.
However, some suggestions to measure soluble fms-like tyrosine kinase 1, endothelin-1,
and soluble endoglin likely do not support the data of this study.
Is the work clearly and accurately presented and does it cite the current literature?
Yes
Page 24 of 27
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?
Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?
Yes
Are the conclusions drawn adequately supported by the results?

Yes
Reviewer Expertise: Immunology, Alternative Medicine, Public Health, Bioinformatics
I confirm that I have read this submission and believe that I have an appropriate level of
expertise to confirm that it is of an acceptable scientific standard.
Author Response 16 Feb 2023

Donel S
The study assessed the effectiveness of nifedipine, labetalol, and hydralazine as emergency
antihypertension in severe preeclampsia (SP). SP is a significantly important health problem
in both developed and developing countries. My comments: The study was well-designed
and conducted with balanced conclusions.
RESPONSES: Thank you for your appreciation.
The title of the study is clear and balanced however the information on RCT is needed such
as: “Effectiveness of nifedipine, labetalol, and hydralazine as emergency antihypertension in
severe preeclampsia: a randomized control trial”.
RESPONSES: We have revised the tittle by adding: “: a randomized control trial”
The structured abstract contains all important information, including the registry number.
The introduction section provides the importance and significance of the problem as well as
the scientific gap. The aim of the study is also clearly stated.
The study setting is clearly stated although the justification for choosing those hospitals
might be helpful.
RESPONSES: The reasons have been provided: “These hospitals were chosen because they
are affiliated with Faculty of Medicine, Universitas Riau.”
The sample size is relatively small, but the justification and calculation are provided on how
Page 25 of 27
the sample was calculated.

Double blinding and randomization were conducted to avoid bias.
The procedures are explained adequately but the information on whether the healthcare
workers received the training from the researchers is important to ensure that they worked
following the guideline.
RESPONSES: We have added the information that the healthcare workers have been trained:
“The doctors have been informed about the study and have been trained.”
The Results assisted with a flowchart, and this helps the readers to understand each step of
enrolment, allocation, follow-up, and analysis.
The baseline of the data of the patients between the group are relatively homogeneous.
The comparations between drugs were conducted for each endpoint and should be
appreciated
Table 7. The information in this table can basically be written in two sentences only since
there were no side effects in the labetalol and hydralazine groups. Also “Secondary
outcome” could be changed to “Side effect.”
RESPONSES: Thank you for the suggestion. Now Table 7 has been deleted and we have
added “side effects” after the secondary outcome.
Discussion and conclusion are balanced; the study's strengths and limitations are discussed.
However, some suggestions to measure soluble fms-like tyrosine kinase 1, endothelin-1,
and soluble endoglin likely do not support the data of this study.
RESPONSE: Thank you for the suggestion. This sentence has been deleted.
Page 26 of 27
The benefits of publishing with F1000Research:
• Your article is published within days, with no editorial bias
• You can publish traditional articles, null/negative results, case reports, data notes and more
• The peer review process is transparent and collaborative
• Your article is indexed in PubMed after passing peer review
• Dedicated customer support at every stage
For pre-submission enquiries, contact research@f1000.com
Page 27 of 27

Jurnal 3 - Husnul Aridha - Stase Obsgyn

Uploaded by

Copyright:

Available Formats

You might also like

Jurnal 3 - Husnul Aridha - Stase Obsgyn

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Jurnal 3 - Husnul Aridha - Stase Obsgyn

Uploaded by

Copyright:

Available Formats

F1000Research 2023, 11:1287 Last updated: 03 JUN 2023

Effectiveness of nifedipine, labetalol, and hydralazine

v2 First published: 10 Nov 2022, 11:1287 Open Peer Review

doses to further reduce the blood pressure. Hydralazine is the most

Corresponding author: Donel S (donelmy@yahoo.com)

REVISED Amendments from Version 1

Ethical considerations and registration

Patient recruitment and criteria

Blinding and study procedure

Effectiveness of nifedipine, labetalol, and hydralazine to reduce the blood pressure

Figure 1. Flowchart of patients’ enrolment, allocation, follow-up and analysis.

Table 1. Characteristics of the patients of three study groups pre-treatment.

Characteristic Nifedipine n=20 Labetalol n=20 Hydralazine n=20 p-valuea

Blood Time Mean difference (I-J)a 95% CI for differenceb p-valueb

Blood Time Mean difference (I-J)a 95% CI for differenceb p-valueb

Blood Time Mean rank or mean 95% CI for differenceb p-valueb

Dose Type of anti-hypertensive N-gain

Secondary outcome: side effects

This project contains the following underlying data:

- Master Data.xlsx [Table containing the raw data of the study].

Open Peer Review

Reviewer Report 02 June 2023

Thank you for revision of your manuscript.

Competing Interests: No competing interests were disclosed.

Reviewer Report 02 May 2023

Talha Bin Emran

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Immunology, Alternative Medicine, Public Health, Bioinformatics

Reviewer Report 02 December 2022

Sam Ratulangi University, Manado, North Sulawesi, Indonesia

Sam Ratulangi University, Manado, North Sulawesi, Indonesia

Patient recruitment and criteria

Blinding and study procedure

samples, or other considerations or assumptions.

Is the study design appropriate and is the work technically sound?

If applicable, is the statistical analysis and its interpretation appropriate?

Are the conclusions drawn adequately supported by the results?

Competing Interests: No competing interests were disclosed.

Author Response 16 Feb 2023

Patient recruitment and criteria

Blinding and study procedure

dose was significant statistically with p<0.001.”

Competing Interests: No competing interests were disclosed.

Reviewer Report 14 November 2022

Talha Bin Emran

Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, Bangladesh

○ Double blinding and randomization were conducted to avoid bias.

Is the study design appropriate and is the work technically sound?

If applicable, is the statistical analysis and its interpretation appropriate?

Are the conclusions drawn adequately supported by the results?

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Immunology, Alternative Medicine, Public Health, Bioinformatics

Author Response 16 Feb 2023

the sample was calculated.

Competing Interests: No competing interests were disclosed.

The benefits of publishing with F1000Research:

• Your article is published within days, with no editorial bias

• The peer review process is transparent and collaborative