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International

Journal of Gynecology & Obstetrics 49 (1995) 125-130

Article

Labetalol vs. methyldopa in the treatment of pregnancy-induced

hypertension
A.M. El-Qarmalawi *, A.H. Morsy, A. Al-Fadly, A. Obeid, M. Hashem
Department of Obstetrics and Gynecology, Al-Jahra Hospital, Jahra. Kuwait

Received30 June 1994; revision received IO January 1995; accepted 24 January 1995

Abstract
Objective: To assessthe efficacy and safety of labetalol compared with methyldopa in the managementof mild and
moderate casesof pregnancy-induced hypertension (PIH). Methods: One hundred four primigravidas with PIH were
randomly allocated to receive either labetalol (group A) or methyldopa (group B). The dose of the drugs was doubled
every 48 h to maintain a mean arterial blood pressure 5 103.6mmHg. Clinico-biochemical effects and frequency of
side effects were studied. The statistical level of significance was taken at P < 0.05. Results: Ten patients in group
B (18.5%) developed significant proteinuria (> 30 mg/dl) whereas none developed proteinuria in group A. Labetalol
was quicker and more efficient at controlling blood pressure,having a beneficial effect on renal functions and causing
fewer side effects compared with methyldopa. The rate of induction of labor and rate of cesareansection for uncontrolled PIH was less in group A (48% and l%, respectively) compared with group B (63.0% and 5.6%, respectively).
Moreover a higher Bishop scoreat induction of labor was noticed in group A. Conclusions: Labetalol is better tolerated
than methyldopa, gives more efficient control of blood pressureand may have a ripening effect on the uterine cervix.
Keywords: Pregnancy-induced hypertension; Labetalol; Methyldopa

1. Introduction
Some 5% of pregnancies in Kuwait are complicated by hypertensive disorders. These disorders are the leading cause of maternal mortality
and one of the major contributing causes of peri* Correspondingauthor, Maternity Department,Al-Jahra
Hospital, P.O. Box 40206, Jahra 01753, Kuwait, Tel.: +965
4896971; Fax: +965 4575430.
0020-7292/95/$09.50 0 1995 International
SSDI 0020-7292(95)02351-C

natal mortality and morbidity, the latter being

mainly due to preterm delivery and fetal growth
retardation [l]. Current management of the majority of these cases lies in hospital bed rest with or
without antihypertensive therapy. There is evidence that hospitalization early in the course of
the disease improves maternal and perinatal outcome, but the use of antihypertensive drugs in mild
and moderate cases of pregnancy-induced hypertension (PIH) is currently under debate [2,3]. In

Federation of Gynecology and Obstetrics

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A.M. El-Qarmalawi

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Kuwait, methyldopa is the most commonly

prescribeddrug for such patients, but is sometimes
associatedwith undesirable side effects.
The aim of this study was to assessthe efficacy
and safety of labetalol compared with methyl&pa
in the treatment of PIH.
2. Materials and methods
Primigravid patients with blood pressures
120-140/95-105 mmHg and with no past history
of hypertension, renal diseaseor other illness were
recruited from the hospital antenatal clinic.
All were normotensive prior to the 20th week of
gestation. Their blood pressures were measured
twice with a mercury sphygmomanometer in the
semirecumbent position. Korotkoff sounds 1 and
4 were used as the cut-off lines for systolic and
diastolic blood pressure. The patients were then
admitted to the sameantenatal ward, given a regular hospital diet and allowed unrestricted activity.
Blood pressureswere measuredat 6-h intervals for
3 consecutive days. From the patients admitted to
hospital, the study group was selected to include
primigravidas of Arab nationality at ~26 weeks
gestation, with absenceof proteinuria, and whose
blood pressure had persisted for the previous 3
days at r 120-140/95-105 mmHg. They were then
offered entry to the study and those who agreed
gave their informed written consent. Prior to
therapy systemic lupus erythematosus and pheochromocytoma were ruled out by meansof plasma
antinuclear antibodies and 24-h catecholamines in
urine, respectively. The patients were then randomly allocated in sequenceto one of two groups:
group A, treated with labetalol 100 mg t.i.d.; and
group B, treated with methyldopa 250 mg t.i.d.
Blood pressure was measured 6 hourly in the
same way as detailed above and readings were
pooled to calculate a daily average mean arterial
blood pressure (MAP) for each patient, using the
formula MAP = (sBP + 2dBP) + 3. The dosesof
the antihypertensive drugs were doubled every 48
h to keep the MAP below 103.6 mmHg up to a
maximum dose of 900 mg labetalol and 2250 mg
methyldopa per day (triple the initial dose). All the
patients were assessedon a daily basis for the oc-

& Obstetrics 49 (1995) 125-130

currence of unwanted symptoms, changesin body

weight, and proteinuria by meansof a dipstick test
(Combur-test; Boehringer, Mannheim, Germany)
on a fresh morning sample of mid-stream urine. If
there was more than a trace of proteinuria (30
mgdl), measurementof 24-h protein in urine was
then considered. Blood was collected daily for
urea, creatinine and uric acid, twice weekly for
hemoglobin, hematocrit, platelet count, bleeding
time and fibrin degradation products, and weekly
for creatinine clearance.
All patients had a detailed ultrasound scan prior
to the 20th week of gestation, and dates were
adjusted accordingly. A second ultrasound scan
was performed on admission to the study and
subsequently every 2 weeks for assessing fetal
growth and wellbeing. Any patient with a proven
or suspectedfetal congenital abnormality was disqualified from entering the study. All patients were
kept in hospital from the time of enrolment until
48 h after delivery. The reason behind this prolonged hospitalization was to test the effect of hospital mental and physical rest on blood pressure,
to ensure accurate measurementof blood pressure
by the sameteam, to allow for daily collection of
blood for biochemical testing and record any drug
side effectsor progression of the diseaseas soon as
it occurred, and finally to exclude social environment as a possible contributing factor to the
elevated blood pressure.
Statistical analysis of the data was carried out
using Students t-test (either paired or independent), Fishers exact test, or analysis of variance
for repetitive measures. The level of significance
was P < 0.05.
3. Results
One hundred twenty patients were recruited to
the study and divided equally between the two
groups. Sixteen patients were later excluded for
failure to comply with prolonged hospitalization,
six in the methyldopa group and 10 in the labetalol
group. Further analysis will focus on the 104 patients who completed the study.
The characteristics of the two groups were
similar (Table 1) as was their MAP before initiation of therapy. None of the patients in group A

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Journal of Gynecology & Obstetrics 49 (1995) 125- I30

Table 1
Clinical characteristics of the two groups of patients treated
with antihypertensive drugs (mean [SD.])

Age (years)
Weight at booking (kg)
MAP (mmHg)
Gestational age at
enrolment (weeks)

Labetalol
(n = 54)

Methyldopa
(n = 50)

24.3 (1.7)
70.4 (4.1)
92.5 (1.3)
31.3 (0.7)

25.2 (1.7)
69.2 (3.2)
91.1 (1.4)
32.3 (0.6)

developed proteinuria, while 10 patients in group

B (18.5%) developed proteinuria that persisted
until delivery. Creatinine clearance showed a significant improvement (P < 0.025) 2 weeks after
therapy in group A. This improvement was not
observedin group B. However analysis of variance
in group B showed a significantly greater variability. With the exception of an observed drop in
platelet count (still within normal) in group A
(P < 0.05, paired test), there was no abnormality
in the other hematological findings. However, because both study groups had shown a wide
variability in platelet counts, the drop in platelet
count was not considered statistically significant,
as it may have been a manifestation of variable responseto the diseaseprocess rather than an effect
of the drug. There was a significant rise in serum
uric acid values during the 1st week of therapy in
group A, which was maintained through the subsequent weeks (P < 0.05), a change that was not
observed in group B (Table 2).

In group A, 81.4% of patients had a significant

fall (P c 0.05) in MAP to below 103.6(equivalent
to blood pressure 130190mmHg) compared with
68% in group B. Side effectswere more frequent in
group B than in group A. The duration of therapy
and gestational age at labor were similar in both
groups. However more patients in group B needed
induction of labor and emergencycesareansection
due to uncontrolled blood pressure. A higher
Bishop score at induction of labor was noticed in
group A. This may have contributed to the higher
incidence of spontaneous labor in group A (Table
3). There was one case of placental abruption,
thought to be a chanceoccurrence, in group A and
none in group B.
As regards the fetal/neonatal outcome, there
was no significant difference between the two
groups. Fetal heart changes during labor, Apgar
score, birth weight, rate of admission to the
nursery and placental weight (Table 3) were
similar. Fifty infants (100%) in group A and 46
(85.2%)in group B were reviewed at 18 months of
age. All had been developing normally, both
physically and mentally.
4. Discussion
The definition of PIH by Gant and Worly [3]
was adopted in the current study to mean hypertension developing during pregnancy in a known
normotensive, non-proteinuric woman.
Pregnancies complicated by PIH remote from
term are associatedwith an increased risk of ma-

Table 2
Laboratory changes during therapy (mean [SD.])

Duration of therapy (days)

Hematocrit (%)
Platelet count (x 109/1)
Bleeding time (min)
24-h Protein in urine @I)
Plasma uric acid (ag/l)
Creatinine clearance
(mUmin)

127

Labetalol (n = 54)

Methyldopa (n = 50)

14.1 (1.9)

13.1 (1.4)

Start of therapy

During labor

Start of therapy

During labor

32.5 (2.4)
253 (80)
6.4 (1.7)
0
300
95

32.8 (2.1)
231 (64)
6.8 (2.8)
0
400
110

32.2 (2.8)
259 (60)
6.4 (1.4)
I.7 (0.3)
210
100

35.1 (3.3)
255 (65)
6.2 (2.2)
3.2 (0.5)
310
95

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Table 3
Clinical effects of therapy

Frequency of side effects (%) (n)

Drowsiness
Headache
Nasal congestion
Postural hypotension
Dyspnea

Labetalol
(n = 54)

Methyldopa
(n = 50)

None
None
None
None
6 (3)

22.2 (12)
14.8 (8)
7.4 (4)
5.6 (3)
None

Effect on duration of pregnancy (weeks)

(mean f SD.)

36.0 f 0.3

35.8 f 0.8

Effect on labor (%) (n)

Preterm labor
Spontaneous onset of labor
Induction of labor
Cesarean section for PIH
Total no. of cesareansections

6.0 (3)
54.0 (27)
48.0 (24)
2.0 (I)
16.0(8)

5.6 (3)
22.2 (12)
63.0 (34)
5.6 (3)
13.0 (7)

30.0 (15)
8.5 zt 0.5

22.2 (12)
8.5 zt 0.5

Fetal/neonatal outcome
Abnormal CTG (%) (n)
Apgar score <5 at I min
(mean f SD.)
Admission to nursery (day)
(mean l SD.)
Birth weight (g) (mean f S.D.)
Placental weight (g)
(mean l S.D.)

2.82 f 0.15
3000 (150)
501 l 33.3

ternal and fetal mortality and morbidity. There is

evidence that such pregnancies are commonly
associatedwith reduced uteroplacental blood flow
[2]. This is thought to be due to the development
of certain pathological obstructive lesions at the
level of the spiral arterioles [4,5].
Whether treatment of hypertension in patients
with mild PIH can halt or retard progression of the
diseaseis a matter for debate. On the one hand,
PIH is clearly secondary to an intrauterine disturbance: when the pregnancy ends, the problem
resolves.On the other hand, many of the features
of preeclampsia could arise from local or
generalizedmaternal endothelial cell injury, mediated by substancesreleased by the placenta. It is
possible that mild and moderate hypertension
enhancesendothelial damage or its consequences
[6]. Its medical treatment may be palliative but can
not be expectedto cure the condition. In addition,

2.91 zt 0.18
2770 (150)
491 f 52.5

antihypertensive drugs may have potentially

beneficial actions besideslowering blood pressure.
For example, beta-adrenergic blockers (including
labetalol) may inhibit platelet and red cell aggregation [7,8]. It is also believed that vasodilating
agents may enhance placental blood flow after
relaxing uteroplacental arteries [9].
A number of oral medications are in usefor lowering blood pressure,but not all have proven to be
safe during pregnancy. Methyldopa is the oldest
drug used for PIH. It is effective and safe for both
the mother and the fetus. Drug exposure in utero
does not affect later infant growth and development [lo]. The main disadvantages are a delayed
onset of action, drowsiness, depression, fluid
retention and nasal congestion. It may also give a
positive Coombs test in 20% of patients, and may
cause hemolytic anaemia, systemic lupus erythematosus-like syndrome and hepatic damage [ 111.

A.M. El-Qarmalawi

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Journal of Gynecology

Labetalol, an alpha-beta-adrenergic blocker, is

rapidly absorbed if taken orally, to reach a peak
plasma concentration within 20-60 min. It has a
rapid action with minimal effect on maternal cardiac output [ 121. The sustained effect on blood
pressure is mainly due to lowering of the peripheral resistance.Although it tends to fall acutely
during initial administration, peripheral resistance
falls further during prolonged therapy with normalization of cardiac output and stroke volume
[13]. Tolerance does not develop during therapy
[ 141.The main side effects of labetalol are fatigue,
headache, postural hypotension, gastrointestinal
symptoms (if it is used in high doses), and it can
worsen bronchial asthma [ 151.
In the current study, we compared the efficacy
and safety of labetalol with methyldopa. The latter
has been the most common drug used in Kuwait
for the treatment of PIH for the last 20 years. In
comparison with methyldopa, labetalol was
demonstrated to have a quicker action, better control of blood pressure and a beneficial effect on
renal function. Improved renal function was evidenced by an increase in creatinine clearance and
reduction of the number of patients who
developed proteinuria. Some patients in the
labetalol group complained of dyspnea. It was not,
however, severeenough to prevent continuation of
therapy. A greater number of patients in the
methyldopa group had minor side effects.
Prolongation of pregnancy was more common
in the labetalol group than in the methyldopa
group, yet it was not statistically significant. This
finding could be explained by the mild tocolytic
effect of labetalol on the myometrium [ 161. It
could also be related to the more efficient control
of blood pressure that encouraged clinicians to
adopt a conservative attitude.
It has been previously reported that labetalol
may contribute to the initiation of labor pain
possibly by a direct effect on the cervix [ 16,171.In
the current study we observed a higher incidence
of spontaneousonset of labor and a higher Bishop
score at labor induction in the labetalol group
compared with the methyldopa group. We suggest
that labetalol may help to ripen the uterine cervix
and hence increase the rate of vaginal delivery.
How labetalol does this is still under investigation.

& Obstetrics 49 (1995) 125-130

129

Labetalol can cross the placenta and reach a

concentration of 50-100% of its concentration in
the maternal plasma [ 13,181.Previous studies have
compared the neonatal effect of labetalol and
methyldopa and have found no difference in the
rate of fetal growth retardation, perinatal death
and neonatal hypoglycemia [ 19-211. Recently,
however, a case of neonatal cardiac arrest attributed to maternal intake of labetalol was
reported [22]. Although we did not observe any
unwanted perinatal effect of labetalol, we still
strongly recommend careful fetal and neonatal
monitoring of heart rate.
5. Conclusion

PIH is one of the major causesof maternal and

fetal mortality and morbidity. Yet as long as its
cause remains unknown, its prophylaxis will be
uncertain. The use of antihypertensive agents in
mild and moderate casesof PIH is controversial.
However we do feel that they have a beneficial
effect. This study showed that labetalol is more advantageous than methyldopa in terms of better
and quicker control of blood pressure, fewer side
effects and a longer delay in the incidence of proteinuria thus allowing prolongation of pregnancy.
The chances of spontaneous onset of labor were
greater in the labetalol group than in the
methyldopa group, and those who had to have induction of labor were noted to have a better
Bishop score. For all the reasons detailed above,
the maternal and fetal outcome was better in the
labetalol group than in the methyldopa group, We
now anticipate a change in PIH protocols in
Kuwait towards a greater usage of labetalol in
preference to methyldopa.
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