Labetalol in Comparison to Methyl Dopa in Treatment of Gestational Hypertension, A Randomized Trial

Randomized in to 2 groups. Group A will receive labetalol and group B will receive alpha methyldopa then measure BP.

Study group: 264 women attending Ain Shams University maternity hospital. Patients were distributed in two groups randomly. After randomization group A received labetalol 100 mg tid and group B received methyldopa 250 mg tid as starting dose. Mean Arterial pressure (MAP) was calculated.

Patients were kept in house and they were asked to come for regular follow up in the antenatal clinic in a fixed visits where Patients were monitored in the antenatal clinic after 48hrs from taking the drug and dose was assessed to control BP When there was no fall in BP even after 48 hours of drug therapy, dose of the drug was doubled. Then monitored in the antenatal clinic weekly for two weeks. Then every 2 weeks till delivery.

Auscultatory measurement with the sphygmomanometer is the most widespread method for indirect BP determination, having a high concordance level with the direct intra-arterial method.

Guidelines include:
- Seat the woman for 5-10 minutes prior to BP measurement. In semi sitting or left lateral position.
- Cuff size adequate to the patient`s arm circumference and positioned 2-3 cm above the antecubital fossa.
- Positioning of the central portion of the rubber bladder on the brachial artery.
- Positioning of the upper limb at the heart level.

Primary outcome: Control of mean arterial BP in mmHg in women with pregnancy induced hypertensions within 6 months.

➢Secondary outcome:
• Need for adding antihypertensive drugs.
• Side effect of drug used:
➢Side effect of labetalol:
• More common: nausea.
• Less common.
➢Blurred vision or other changes in vision.
➢Confusion.
➢Dizziness, fainting, light headache when getting up from lying or sitting position.
➢Side effect of alpha methyldopa:
• More common :drowsiness, dryness of mouth, headache.
• Less common: fever shortly after taking the drug.

1. Fall in mean arterial BP with labetalol/methyldopa.
2. Time required controlling BP.
3. Average dose of drugs required to control BP.
4. Side effects of drugs.

Randomization: Randomization of cases was done by computer method. 264 women with pregnancy induced hypertension were enrolled in the study and were distributed in two groups:group A and group B. The randomization allocation was 1:1.The two groups are randomly selected.

Allocation and Concealment: 264 opaque envelopes were numbered serially and in each envelope the corresponding letter which donate the allocated group was put according to randomization table then all envelops were closed and put in one box. When the first patient arrives the first envelope was opened and the women were allocated according to the letter inside.

1. Subjects
2. Investigator
3. Outcome assessor
4. Caregiver

The required sample size has been calculated using the G*Power Software (Universität Düsseldorf, Germany).

The primary outcome measure is the proportion of patients with adequate control of blood pressure at 48 hours from starting treatment, defined as systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg. The secondary outcome measure is the proportion of patients that would undergo spontaneous onset of labor.

There is at present no adequate information regarding the expected difference in the outcome measures between labetalol and methyldopa in patients with gestational hypertension. So, the present study tries to target an effective size that would be clinically relevant.

The study was conducted after approval of the ethical committee of Ain Shams University Maternity Hospital. Patients signed an informed consent to participate in the study.

Comparison between group 1 methyldopa and group 2 labetalol group (Table 1)

Comparison between the 2 groups regarding Diastolic blood pressure measurements after treatment till delivery (Figure 1)

Comparison between the 2 groups regarding mean arterial blood pressure measurements after treatment till delivery (Figure 2)

Comparison between the labetalol and methyldopa groups regarding age, parity, number of abortions and proteinuria (Table 2)

Comparison between systolic blood pressure measurements starting before treatment (baseline) overtime till delivery in methyldopa group (Table 3)

Comparison between systolic blood pressure measurements starting before treatment (baseline) overtime till delivery in methyldopa group(Figure 3)

Comparison between systolic blood pressure measurements starting before treatment (baseline) overtime till delivery in labetalol group (Table 4)

Comparison between systolic blood pressure measurements starting before treatment (baseline) overtime till delivery in labetalol group (Figure 4)

Comparison between diastolic blood pressure measurements starting before treatment (baseline) overtime till delivery in methyldopa group (Table 5)

Comparison between diastolic blood pressure measurements starting before treatment (baseline) overtime till delivery in methyldopa group (Figure 5)

Comparison between diastolic blood pressure measurements starting before treatment (baseline) overtime till delivery in labetalol group (Table 6)

Comparison between diastolic blood pressure measurements starting before treatment (baseline) overtime till delivery in labetalol group (Figure 6)

Comparison between mean arterial blood pressure measurements starting before treatment (baseline) overtime till delivery in methyldopa group (Table 7)

Comparison between mean blood pressure measurements starting before treatment (baseline) overtime till delivery in methyldopa group (Figure 7)

Comparison between mean arterial blood pressure measurements starting before treatment (baseline) overtime till delivery in labetalol group (Figure 8)

Comparison between mean arterial blood pressure measurements starting before treatment (baseline) overtime till delivery in labetalol group (Table 8)

PIH is a major cause of fetal and maternal morbidity and mortality and protection from its development is not always possible as its pathology is not completely predictable .Various medications are used in controlling hypertensive abnormalities during pregnancy [13].

In a Study made by Verma et al. denoted that adverse outcome was evidently less in the labetalol treated pregnant women compared to the methyldopa group [10].

In a study made by El-Qarmalawi et al. patients received methyldopa experienced side-effects as drowsiness (22.2%), headache (14.8%), nasal congestion (7.4%), and postural hypotension (5.6%). While 96 pregnant ladies in labetalol group complained from dyspnea, no other side-effects were documented [14].

In the present study, there is a decrease in the systolic blood pressure readings starting from a baseline which was the blood pressure before intake of the antihypertensive treatment and the measurements after 48 hours, 1, 3, 5, 7, 9 weeks after drug intake and at time of delivery in the methyldopa and labetalol group.

Verma et al. made a study and mentioned the age distribution which showed maximum patients between 19-24 years in both groups (64.44% in methyldopa group and 57.77% in labetalol group) and there was no significant difference in age distribution in both groups [13].

In the present study, there was a decrease in the diastolic blood pressure readings starting from a baseline which was the blood pressure before intake of the antihypertensive treatment and the measurements after 48 hours, 1, 3, 5, 7, 9 weeks after drug intake and at time of delivery in the methyldopa and labetalol group.

Most common age group is in contrast to the data obtained from a large database study indicate a linear relationship between age and incidence of PIH [15].

In the present study, there was a decrease in the mean arterial blood pressure readings starting from a baseline which was the blood pressure before intake of the antihypertensive treatment and the measurements after 48 hours, 1, 3, 5, 7, 9 weeks after drug intake and at time of delivery in the methyldopa and labetalol group.

In a study made by Dharwadkar MN et al. about 32.5 percent of the pregnant ladies in Methyldopa group and 37.5% in Labetalol group were primigravidae. The rest of the patients were multigravidae. However the percentage of primigravidae is greater in most other studies where the prevalence of primigravidae was 50% or above [16,17,22].

In the present study, our results show a statistically significant difference in control of blood pressure with values of systolic, diastolic and mean arterial blood pressure measurements are less in labetalol group than in methyldopa group after 48 hours, 1, 3, 5, 7, 9 weeks post drug therapy and at time of delivery with P value < 0.001 indicating a better control of blood pressure.

Labetalol is an effective antihypertensive drug which decreases both systolic and diastolic BP in pregnancy induced hypertension. About 55% of the methyldopa group received nifedepine and phenobarbitonewhere as only 22.5% of labetalol group received injections of labetalol and phenobarbitone showed that methyl dopa requires additional drugs to decrease BP than labetalol [18].

In a previous study demonstrated that labetalol is an efficient drug in decreasing blood pressure of the patients and then maintain optimal BP levels [22].

Similarly, Cruickshank et al. study revealed that Labetalol controlled the blood pressure in 45 of the 51 treated women (88%) within 24 hrs [19,20].

Marked decrease of both systolic and diastolic pressure within 24 and 48 hours from the onset of using methyldopa was observed by Hans and Kopelman [21].

Also in the present study, there was a considerable difference in pregnant women who developed proteinuria after the same dose of treatment by both drugs, as in the group of women received methyldopa there was 8 ladies developed proteinuria checked at time of delivery while in labetalol there was only one lady who had proteinuria at time of delivery with P value of 0.036 ,indicate a statistically significant value that denotes better control of arterial blood pressure and prevention of progression to preeclampsia with labetalol than with methyldopa treatment.

Future researches can be made on a larger number of pregnant women to compare various drugs used in treatment of hypertension.

The present study confirms that labetalol is an effective and safe drug for use and is more rapid in achieving adequate control of blood pressure in PIH. With a low chance of fetomaternal side-effects and this makes it appropriate to be used in PIH. Labetalol gives good control of blood pressure than methyldopa and decreases the liability for proteinuria and for progression to preeclampsia.

Labetalol has the advantage of decreasing peripheral vascular resistance with no decrease in cardiac output of the mother and heart rate and so better uteroplacental perfusion than methyldopa.

Special thanks to residents of obstetrics and Gynecology in Ain Shams Maternity Hospital, Kasralainy Obstetrics and Gynecology hospital and in National Research Centre, Egypt for their cooperation in this research.