Pregnancy Hypertension 17 (2019) 54–58

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Pregnancy Hypertension
journal homepage: www.elsevier.com/locate/preghy

Methyldopa versus nifedipine or no medication for treatment of chronic T

hypertension during pregnancy: A multicenter randomized clinical trial
⁎
Mohamed Salamaa, Mohamed Rezka, , Wael Gabera, Haitham Hamzaa, Hala Marawanb,
Awni Gamalc, Sameh Abdallahd
a
Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufia University, Egypt
b
Department of Community Medicine and Public Health, Faculty of Medicine, Menoufia University, Egypt
c
Department of Cardiology, Faculty of Medicine, Menoufia University, Egypt
d
Department of Pediatrics, Faculty of Medicine, Menoufia University, Egypt

A R T I C LE I N FO A B S T R A C T

Keywords: Objective: To assess the maternal and fetal outcome in women with mild to moderate chronic hypertension on
Chronic hypertension antihypertensive drug (methyldopa or nifedipine) therapy compared to no medication.
Methyldopa Methods: This multicenter randomized clinical trial was conducted at Menoufia University hospital, Shibin El-
Nifedipine kom Teaching hospital and 11 Central hospitals at Menoufia governorate, Egypt.490 pregnant women with mild
Maternal outcome
to moderate chronic hypertension were randomized into three groups; methyldopa group (n = 166), nifedipine
Fetal outcome
group (n = 160) and control or no medication group (n = 164) who were followed from the beginning of
pregnancy till the end of puerperium to record maternal and fetal outcome.
Results: Mothers in the control (no medication) group were more prone for the development of severe hy-
pertension, preeclampsia, renal impairment, ECG changes, placental abruption and repeated hospital admissions
(p < 0.001) when compared to mothers in both treatment groups (methyldopa and nifedipine). Neonates in the
control (no medication) group were more prone for prematurity and admission to neonatal ICU (p < 0.001).
Conclusion: Antihypertensive drug therapy is advisable in mild to moderate chronic hypertension during preg-
nancy to decrease maternal and fetal morbidity. When considering which agents to use for treatment, oral
methyldopa and nifedipine are valid options.

1. Introduction terms of the development of severe hypertension, renal impairment,

ECG changes, placental abruption, repeated hospital admissions for
Chronic hypertension affects about 1–5% of women during the re- blood pressure control, preterm delivery and neonatal ICU admission
productive years in different populations. Women with chronic hy- [6].
pertension are at significant risk for maternal morbidity and mortality, The aim of this study was to assess the maternal and fetal outcome
in terms of development of severe hypertension with its squeal; yet it in women with mild to moderate chronic hypertension on anti-
remains unclear whether antihypertensive treatment during pregnancy hypertensive drug (methyldopa or nifedipine) therapy compared to no
lowers these risks or not [1–3]. medication.
Lowering the blood pressure by antihypertensive drugs in women
with mild to moderate chronic hypertension has no significant effect on 2. Materials and methods
the risk of small for gestational age (SGA) and preeclampsia as recently
reported [4] while another recent study concluded an increased risk of This multicenter randomized clinical trial was conducted at the
severe maternal hypertension (adjusted odds ratio, 1.8) when blood departments of Obstetrics and Gynecology at Menoufia University
pressure was not tightly controlled during pregnancy [5]. hospital, Shibin El-kom Teaching hospital and 11 Central hospitals at
A recent four-year observational study at our institution revealed Menoufia governorate, Egypt in collaboration with the Community
increased maternal and fetal morbidity following discontinuation of Medicine and Public Health, Cardiology and Pediatrics departments at
antihypertensive drugs in mild to moderate chronic hypertension in the respective hospitals during the period between the beginning of

⁎
Corresponding author.
E-mail address: [email protected]fia.edu.eg (M. Rezk).

https://doi.org/10.1016/j.preghy.2019.05.009
Received 11 February 2019; Received in revised form 27 March 2019; Accepted 8 May 2019
Available online 09 May 2019
2210-7789/ © 2019 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.
M. Salama, et al. Pregnancy Hypertension 17 (2019) 54–58

August 2017 and the end of August 2018 which is the last day of follow possible drop out cases. Fig. 1 revealed the flow diagram.
up of the last recruited participant. Randomization was performed using computer-generated simple
The study protocol was formally reviewed and approved at random tables with patients randomly allocated into three groups in the
Menoufia faculty of Medicine with Ethical clearance letter number ratio of 1:1:1 as follows:
426H/2017 in 17 July 2017 with similar approval obtained from the Group 1 (Methyldopa group): included 166 patients who received
Ministry of Health (MOH letter number 1436). All study participants methyl dopa tablets 1–2 gm per day in divided doses for blood pressure
signed an informed consent form after thorough explanation of the control. (Aldomet, 250 mg tablet Kahira Pharma. & chem. ind. co.
study objectives. Egypt).
Pregnant women diagnosed with mild to moderate chronic hy- Group 2 (Nifedipine group): included 160 patients who received
pertension without medication and without features of end organ af- Nifedipine tablets 20–40 mg per day in divided doses for blood pressure
fection as renal or hepatic impairment, fundal changes; with systolic control. (Epilat retard 20 mg tablets, EIPICO pharmaceuticals, Egypt).
blood pressure of 140–159 mmHg or diastolic blood pressure of Group 3 (no medication group): included 164 patients who re-
90–109 mmHg, at the beginning of pregnancy (between 6 and ceived placebo tablets (vitamin-C tablets). (Cevarol tablet 500 mg,
10 weeks) were included in the study after thorough history taking, Memphis pharmaceuticals, Egypt).
clinical examination, laboratory investigations included complete blood Patients in the three groups received low dose aspirin from the 12th
count, kidney and liver function tests, fundus examination, ECG and week through 36th weeks of pregnancy (Aspirin 81 mg, European
Obstetric Ultrasound. Egyptian Pharm.ind. Egypt) to decrease the risk of development of
Women with multiple pregnancies, proteinuria at less than preeclampsia.
20 weeks’ gestation, having other associated medical disorders as dia- Serial blood pressure (BP) measurements were taken during the
betes mellitus, bronchial asthma & epilepsy as well as pregnancies antenatal care visits which were assigned regularly every 2–4 weeks
complicated by fetal malformations; were excluded from the study. based on previous BP readings. The dosage was adjusted according to
Based on the result of previous study [6] with 40% difference be- BP readings with management of adverse effects if raised by the par-
tween treatment and non-treatment groups of mild to moderate chronic ticipants. Patients who developed severe hypertension were managed
hypertension regarding the development of severe hypertension, 145 by the addition of another antihypertensive agent if they already re-
patients were needed in every single group for the study to have 90% ceived the maximal dosage of the particular antihypertensive drug.
power to detect 10% difference between the three groups (p = 0.05, Randomization was accomplished using cards. 504 sequentially
two-sided) with inclusion of extra 15% patients to compensate for numbered, opaque, sealed envelopes were used, containing 168 cards

Assessed for eligibility (n=520)

Enrollment

Excluded (n=16)

-Not meeting inclusion

criteria (n=10).

-Declined to participate
(n=6).

Randomized (n=504)
Allocation

Received Received Received no

Methyldopa Nifedipine medication
(n=168) (n=168) (n=168)
Follow up

Lost follow up Lost follow up

Lost follow up
(n=8) (n=4)
(n=2)
Analysis

Analyzed (n=166) Analyzed (n=160) Analyzed (n=164)

Fig. 1. The CONSORT Flow Diagram.

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M. Salama, et al. Pregnancy Hypertension 17 (2019) 54–58

Table 1
Maternal characteristics.
Methyldopa group (n = 166) Nifedipine group (n = 160) Control group (n = 164) Chi square test P-value

Age (years): 0.34 > 0.05

20–30 80 (48.2%) 72 (45%) 76 (46.3%)
31–40 86 (51.8%) 88 (55%) 88 (53.7%)
Parity: 0.26 > 0.05
P1-2 70 (42.2%) 64 (40%) 66 (40.2%)
≥P3 96 (57.8%) 96 (60%) 98 (59.8%)
Body mass index (Kg/m2): 0.22 > 0.05
18–25 80 (48.2%) 76 (47.5%) 78 (47.6%)
25.1–29.9 56 (33.7%) 52 (32.5%) 54 (32.9%)
≥30 30 (18.1%) 32 (20%) 32 (19.5%)
SBP at enrollment (mmHg) 150.52 ± 5.97 151.11 ± 5.21 151.2 ± 5.36 0.31* > 0.05
DBP at enrollment (mmHg) 98.3 ± 4.23 98.51 ± 4.11 98.22 ± 4.36 0.34* > 0.05
Gestational age at enrollment (Weeks) 8.22 ± 1.68 8.12 ± 1.77 8.24 ± 1.45 0.28* > 0.05
Duration of hypertension (years) 3.43 ± 1.81 3.92 ± 1.32 3.62 ± 1.74 0.864* > 0.05
Past history of adverse obstetric outcome† 52 (31.3%) 48 (30%) 58 (35.4%) 1.16 > 0.05

* †
Student t-test, SBP = Systolic blood pressure, DBP = Diastolic blood pressure, Adverse outcome included preeclampsia, small for gestational age, placental
abruption and perinatal mortality.

Table 2
Maternal outcome.
Methyldopa group (n = 166) Nifedipine group (n = 160) Control group (n = 164) Chi square test P-value OR at 95% CI

Severe hypertension 38 (22.9%) 36(22.5%) 88 (53.6%) 47.26 < 0.001 0.26 (0.16–0.41)†
0.25 (0.15–0.41)*
1.02(0.61–1.72)‡
Preeclampsia (PE) 44 (26.5%) 46 (28.7%) 80 (48.8%) 22.79 < 0.001 0.37(0.23–0.59)†
0.41(0.26–0.66)*
0.89(0.55–1.45)‡
Renal impairment 32 (19.3%) 34 (21.3%) 88 (53.6%) 56.67 < 0.001 0.21 (0.13–0.34)†
0.23 (0.14–0.38)*
0.88 (0.52–1.52)‡
Hepatic impairment 36 (21.7%) 38 (23.8%) 48 (29.3%) 2.70 > 0.05 –
ECG changes 36 (21.7%) 40 (25%) 92 (56.1%) 52.45 < 0.001 0.22 (0.13–0.35)†
0.26 (0.16–0.42)*
0.83 (0.50–1.39)‡
Placental abruption 10 (6.02%) 12 (7.5%) 38 (23.2%) 27.55 < 0.001 0.21 (0.10–0.44)†
0.27 (0.13–0.54)*
0.79 (0.33–1.88)‡
Hospital admissions 32 (19.3%) 34 (21.3%) 72 (43.9%) 30.34 < 0.001 0.31 (0.19–0.50)†
0.34 (0.21–0.56)*
0.88 (0.52–1.52) ‡
Venous thromboembolism 4 (2.4%) 4 (2.5%) 6 (3.7%) 0.57 > 0.05 –
Cesarean Delivery 52 (31.3%) 48 (30%) 58 (35.4%) 1.16 > 0.05 –
Maternal mortality 0 0 0 – – –

† * ‡
OR at 95% CI = Odd’s ratio at 95% Confidence interval, OR between Methyldopa and Control group, OR between Nifedipine and Control group, OR between
Methyldopa and Nifedipine group.

labelled as ‘methyldopa’, 168 cards labeled as ‘nifedipine’ and 168 eclampsia (generalized convulsions), renal impairment (elevated serum
cards as ‘vitamin-C’. All of the envelopes were mixed together and creatinine > 1.1 mg/dl), liver impairment (elevated liver enzymes
placed in a box. The envelops were further divided into two equal parts twice the normal values), ECG changes (left ventricular heave and/or
to be kept at the Pharmacy of Menoufia University hospital while the strain pattern), placental abruption based on clinical presentation and
other was kept at the main Insurance Pharmacy of the MOH. When the confirmed by ultrasound, mode of delivery, hospital admissions for
Obstetrician at the antenatal care clinic in the included hospitals pre- blood pressure control twice or more during pregnancy, venous
scribed an antihypertensive drug, the pharmacist in charge selected a thromboembolism (VTE) and maternal mortality. Indications of de-
random envelope from the box. The three drugs are rounded, white livery were based primarily upon clinical presentation and gestational
tablets of nearly the same size; accordingly, the three drugs were in- age e.g. patients who developed severe preeclampsia or eclampsia at
distinguishable to the participants. any gestational age were managed by termination of pregnancy ac-
Follow up of participants via regular ANC visits till delivery and cording to our hospital policy, patients who developed severe FGR …etc
throughout the puerperium to record the obstetric outcome. Fetal-neonatal outcome: small for gestational age (SGA) defined
as a birth weight < 10th percentile, birth weight, 5 min Apgar score,
2.1. Outcome measures preterm labour (delivery < 37 weeks), gestational age at delivery, in-
trauterine fetal demise (IUFD), admission to neonatal intensive care
Maternal outcome: development of severe hypertension (systolic unit (NICU) and neonatal death (defined as death during the first four
blood pressure ≥160 mmHg and/or diatolic blood pressure weeks after delivery).
≥110 mmHg) at ANC visits or if they sought the Emergency depart-
ment, superimposed preeclampsia (a new onset proteinuria with 0.3 g
of protein or more in a 24-h urine specimen after 20 weeks’ gestation),

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M. Salama, et al. Pregnancy Hypertension 17 (2019) 54–58

Table 3
Fetal and neonatal outcome.
Methyldopa group (n = 166) Nifedipine group (n = 160) Control group (n = 164) Chi square test P-value OR at 95% CI

Small for gestational age 38 (22.9%) 40 (25%) 32 (19.5%) 1.43 > 0.05 –
Intrauterine fetal demise 4 (2.4%) 4 (2.5%) 6 (3.7%) 0.57 > 0.05 –
Prematurity 30 (18.1%) 42 (26.3%) 50 (30.5%) 7.03 0.029 0.50 (0.30–0.84)†
0.81 (0.50–1.32)*
0.62 (0.36–1.05)‡
Gestational age at delivery (Weeks) 35.6 ± 2.62 35.42 ± 2.44 35.56 ± 2.5 0.89 > 0.05# –
Birth weight (Kg) 2.24 ± 0.62 2.26 ± 0.66 2.25 ± 0.6 0.56 > 0.05# –
Apgar score < 7 at 5 min 10(6.02%) 12 (7.5%) 38 (23.2%) 27.55 < 0.001 0.21 (0.10–0.44)†
0.27 (0.13–0.54)*
0.79 (0.33–1.88)‡
Prematurity 30 (18.1%) 42 (26.3%) 50 (30.5%) 7.03 0.029 0.50 (0.30–0.84)†
0.81 (0.50–1.32)*
0.62 (0.36–1.05)‡
Admission to NICU 22 (13.3%) 26 (16.3%) 48 (29.3%) 15.12 < 0.001 0.37 (0.21–0.65)†
0.47 (0.27–0.80)*
0.79 (0.43–1.46)‡
Neonatal mortality 6 (3.6%) 8 (5%) 12 (7.3%) 2.30 > 0.05 –

#
Student t-test, OR at 95% CI = Odd’s ratio at 95% Confidence interval, † OR between Methyldopa and Control group, * OR between Nifedipine and Control group, ‡
OR between Methyldopa and Nifedipine group.

2.2. Statistical analysis were allocated to receive calcium channel blockers plus low-dosage
aspirin and vitamin C throughout pregnancy. None of them developed
The data collected were tabulated & analyzed by SPSS (Statistical severe preeclampsia or eclampsia [7].
Package for the Social Science software, Chicago, IL, USA) version 22 A recent prospective study of 586 women with pre-pregnancy
and the analysis of the results was per protocol analysis. Chi square and chronic hypertension, in the absence of renal or liver disease who were
Fischer’s exact tests as appropriate. P-value less than 0.05 considered divided into three groups; group 1 (n = 199), blood pressure
statistically significant and less than 0.001 was highly significant. (BP) < 140/90 mm Hg without antihypertensive medication; group 2
(n = 220), BP < 140/90 mm Hg with antihypertensive medication; and
3. Results group 3 (n = 167), systolic BP ≥140 mm Hg and/or diastolic BP
≥90 mm Hg, despite antihypertensive medication; was designated to
There was no significant difference between the three groups re- control the blood pressure with antihypertensive drugs; There was a
garding maternal demographic data in terms of age, parity and body significant increase from group 1 to group 3 in the incidence of severe
mass index, systolic and diastolic blood pressure at enrollment, gesta- hypertension (10.6%, 22.2%, and 52.1%), preterm preeclampsia with
tional age at enrollment, duration of chronic hypertension and past onset at < 37 weeks of gestation (7.0%, 15.9%, and 20.4%), and small
history of adverse obstetric outcome (p > 0.05) as depicted in Table 1. for gestational age (13.1%, 17.7%, and 21.1%)in patients with delayed
Mothers in the control (no medication) group were more prone for initiation of drug therapy during the first trimester [8].
the development of severe hypertension, preeclampsia, renal impair- Methyldopa was associated with better obstetric outcome when
ment, ECG changes, placental abruption and repeated hospital admis- used to control blood pressure during pregnancy particularly in women
sions (p < 0.001) when compared to mothers in both treatment groups with pre-existing hypertension [9].
(methyldopa and nifedipine). There was no significant difference be- Calcium channel blockers inhibit the L-type calcium channels in the
tween the three groups regarding the development of hepatic impair- cardiac and vascular smooth muscle cells, which exerts negative in-
ment, venous thromboembolism and cesarean delivery (p > 0.05) as otropic effects on the heart and causes vasodilation, leading to de-
revealed in Table 2. creased systemic vascular resistance [10].
Neonates in the control (no medication) group were more prone for Nifedipine was found to be comparable to intravenous hydralazine,
prematurity, low Apgar score < 7 at 5 min and admission to neonatal oral and intravenous labetalol for treatment of severe hypertensive
ICU (p < 0.001) with no differences in the rates of small for gestational emergencies during pregnancy as well as to control blood pressure in
age, birth weight, gestational age at delivery, intrauterine fetal demise chronic hypertension [11–15].
and neonatal death (p > 0.05) when compared to their counterparts in The increased morbidity related to hypertensive disorders of preg-
the treatment groups as shown in Table 3. nancy is presumed to be associated with the development of severe
hypertension which could be brought down by decreasing its incidence
via antihypertensive drug therapy.
4. Discussion
A recent retrospective cohort study of 2252 women with acute se-
vere intrapartum hypertension and 93,650 women without severe hy-
The present study confirmed the beneficial use of antihypertensive
pertension delivering between July 2012 and August 2014 at 15 hos-
drugs in patients with mild to moderate chronic hypertension with
pitals in United States; revealed a significantly higher risk of severe
significant reduction in the rates of severe hypertension, preeclampsia,
maternal morbidity in women with acute severe intrapartum hy-
renal impairment, ECG changes, placental abruption and repeated
pertension with oral nifedipine being the most effective first-line
hospital admissions as well as prematurity and admission to neonatal
medication followed by intravenous labetalol and intravenous hy-
ICU.
dralazine [16].
Although a recent systematic review and meta-analysis suggested
The perinatal mortality rate was not significantly different among
that lowering the blood pressure by antihypertensive drugs in women
the treatment and control groups which could be attributed to the use of
with mild to moderate chronic hypertension has no significant effect on
low dose aspirin in all participants.
the risk of small for gestational age (SGA) and preeclampsia [4]. Other
Previous systematic review confirmed that aspirin reduces the risk
trials refuted this conclusion [7,8].
of perinatal mortality and preeclampsia in women with historical risk
Thirty three patients with mild to moderate chronic hypertension

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M. Salama, et al. Pregnancy Hypertension 17 (2019) 54–58

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