A Comparative Study on Effectiveness of Oral Labetalol Versus Oral Nifedipine Used in the Treatment of Gestational Hypertension in a Tertiary Care Teaching Hospital

Introduction

Hypertension in pregnancy is a common clinical condition which affects 10-22% pregnancies. Hypertensive disorders of pregnancy represents spectrum of diseases ranging from chronic andgestational hypertension to eclampsia. These are associated with complications with an increased risk for adverse maternal and fetal outcomes.¹ These are classified into four conditions based on etiology and pregnancy outcomes, namely:

• Chronic hypertension

• Gestational hypertension

• Preeclampsia-eclampsia

• Preeclampsia superimposed on chronic hypertension¹

Chronic hypertension: Hypertension in pregnancy is considered to be chronic if it is diagnosed before 20 weeks of gestation, where systolic blood pressure is >140 mmHg and diastolic blood pressure is >90 mmHg.¹

Gestational hypertension: Onset of hypertension after 20 weeks of gestation is considered as gestational hypertension,1 where systolic blood pressure is ≥140 mmHg or diastolic blood pressure is ≥90 mmHg or both, recorded at least twice within four hours without features of preeclampsia. It is considered to be severe if systolic blood pressure is ≥160 mmHg or diastolic blood pressure reaches ≥110 mmHg or both. Approximately 50% women with gestational hypertension eventually develop proteinuria or other end-organ dysfunctions.¹

Pre-eclampsia and eclampsia: Pre-eclampsia is considered as an important complication of pregnancy which is significantly dangerous than gestational or chronic hypertension, characterized by hypertension, proteinuria (≥0.3 g/24 hours) and edema after the 20th week of gestation. Eclampsia is characterized by appearance of generalized convulsions along with manifestations of pre-eclampsia or their occurrence within seven days of postpartum without clinical history of epilepsy or any other convulsive disorders. 

Pre-eclampsia super imposed on chronic hypertension: It is a condition of chronic hypertension with the onset of proteinuria along with other manifestations of pre-eclampsia. Causes, as well as complications, are similar to pre-eclampsia along with the treatment regimen.

Profiles of recommended drug therapy

The national high blood pressure education program (NHBPEP) has considered certain antihypertensive drugs to be appropriate for the treatment of gestational hypertension and similar pregnancyinduced hypertension (PIH) disorders, which include methyldopa, beta-blockers except atenolol, labetalol, slow-release nifedipine and hydralazine. Drugs other than angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), which were used to control blood pressure before pregnancy may be continued even during pregnancy. Methyldopa and labetalol are considered to be effective first-line agents in restarting drug therapy in women with chronic hypertension with the exceptions of beta-blockers and ACE inhibitors according to American College of Obstetricians and Gynecologists (ACOG) Practice Bulletins.²

This study focused on comparison of two drugs, namely nifedipine (Calcium channel blockers) and labetalol (Beta-blockers), which are prescribed as first-line treatment for gestational hypertension at the study site.

Labetalol

Labetalol is a reversible α- and β-adrenoreceptor blocker used in treating hypertensive urgencies and emergencies. It acts as a non-selective competitive antagonist at β-adrenoreceptors as well as competitive antagonist at postsynaptic α-receptors. Β-blockers like labetalol are used in initial treatment of angina pectoris for long-term and also in treatment of hypertension and phaeochromocytoma due to its combined α- and βblocking activity. They are equally effective for relief from angina pectoris with or sans hypertension due to vasoconstriction as a response to various influences. Labetalol also mitigates increased coronary vascular resistance, thus improving coronary hemodynamics which is seen especially in stressed patients, in a way that is favorable in myocardial ischemic conditions. It belongs to category C in pregnancy.³

Nifedipine

Nifedipine was first among dihydropyridine class of calcium channel blockers permitted for use. It was initially developed by Bayer in 1970s, and studies had shown that short acting formulations of Nifedipine were effective in controlling blood pressure. However, due to such a rapid decrease in blood pressure, it caused significant side effects. It is a cheap and viable medication for oral administration which is primarily suggested for control of moderate to severe variations in blood pressure and particularly valuable in treatment of hypertensive disorders of pregnancy which are more commonly seen in women with diabetes. It belongs to category C in pregnancy.⁴

Adverse maternal and fetal outcomes usually observed with gestational hypertension include:

Maternal Outcomes

• Abruptio placenta

• Disseminated Intravascular Coagulation (DIC)

• HELLP Syndrome

• Post-Partum Hemorrhage (PPH)

• Preterm delivery

• Death

Fetal Outcomes

• Low Birth Weight (LBW)

• Intrauterine Growth Retardation (IUGR)

• NICU admission

• Intrauterine Fetal Demise (IUFD)

• Neonatal death

Pregnancy is a condition where more than one life is to be considered during treatment. Gestational hypertension is associated with increased risk of both adverse maternal and fetal outcomes. Since clinical management is challenging in pregnant women, care must be taken regarding the teratogenecity of medications prescribed for hypertensive disorders of pregnancy. As pregnancy progresses, the severity of drug impact on fetus increases due to increased blood flow and placental perfusion, though the medications are non-teratogenic. Drug treatment is generally reserved for moderate or severe cases of gestational hypertension. There is limited data regarding the safety of various antihypertensive drugs during pregnancy.⁵

Objectives

Primary objectives

• To compare the efficacy of oral labetalol and oral nifedipine in treatment of gestational hypertension

• To compare the safety profile of oral labetalol and oral nifedipine in treatment of gestational hypertension

• To compare the availability and cost-effectiveness of treatment

• To find the drug (either nifedipine or labetalol) used most in the subjects Secondary objectives

• To pursue knowledge about drugs used in the treatment of hypertensive disorders of pregnancy

• To counsel the patients for appropriate medication adherence

• To study the incidence of gestational hypertension

• To evaluate the gravidity and age distribution pattern among patients with hypertensive disorders during pregnancy

Materials and Methods

The present study was conducted in Chigateri District Hospital, Davanagere (Tertiary care teaching hospital). This prospective, observational study was conducted for a period of six months. Around 123 case sheets of inpatients in the Obstetrics and Gynecology (OBG) department of the hospital were considered for the study.

The required data were collected from prospective series of patients who were admitted in Obstetrics and Gynecology ward.

Study criteria

The study was carried out considering the following inclusion and exclusion criteria. Inpatients of obstetrics ward aged more than 18 years with <20 week gestation period (BP ≥140/90 mmHg) and patients willing to co-operate and show acceptance in accordance to the need of study were included. The patients with chronic hypertension (BP ≥140/90 mmHg before pregnancy or diagnosed before 20 weeks), patients with k/c/o cardiovascular diseases, renal diseases, epilepsy and patients with missing and insufficient data in case sheets were excluded from the study.

Method of data collection

• A six-month hospital based prospective observational study was conducted among the inpatients of Obstetrics and Gynecology ward at a tertiary care hospital.

• The subjects for the study were selected according to the inclusion and exclusion criteria.

• The data required for the study was collected from patient case sheets, laboratory investigation reports and from medical staff.

• Demographic details, chief complaints, medical and medication history, laboratory reports, dose route and frequency of medications given, along with follow-up of both newborn and mother was recorded in a properly designed data collection form.

• All data meeting the inclusion criteria was accessed for the study along with feto-maternal outcomes and the results were analyzed using Microsoft Excel.

• In the hospital, only Nicardia retard (brand of nifedipine) and Labebet (brand of labetalol) were highly prescribed. No generic tablets of particular contents were taken by the patients. Therefore in the study, only the above mentioned brands of nifedipine and labetalol were compared for their efficiency.

• Herein this study nifedipine name denotes nifedipine retard

Results

Prescribing pattern of anti-hypertensives according to stage of pregnancy

A total of 59 patients were prescribed antihypertensive drugs pre-natally, among which labetalol 100 was prescribed to ten patients, labetalol 200 to four patients, nifedipine 10 to 39 patients and nifedipine 20 to six patients. A total of 123 patients were prescribed antihypertensive drugs post-natally, among which 23 were prescribed labetalol 100, ten were prescribed labetalol 200, 65 were prescribed nifedipine 10 and 25 were prescribed nifedipine 20.

Prescribing pattern of antihypertensive drugs according to age group

In a total of 59 pre-term patients, 45 patients were prescribed nifedipine, out of which 23 were in the age range of 18-25 years, 21 were between 26-31 years, while only one patient was above 35 years. A total of 14 patients were prescribed labetalol among which seven were in the age range of 18-25 years, seven were between 26-35 years, while none of them were above 35 years of age

In a total of 123 post-term patients, 89 patients were given nifedipine, out of which 50 were in the age group of 18-25 years, 37 were in the age group of 26-31 years, while two patients were above 35 years. A total of 34 patients were given labetalol among which 19 were in the age group of 18-25 years, 15 were in the age group of 26-35 years, while none of the patients were above 35 years of age.

Maternal outcomes in gestational hypertension

Out of 123 patients, 34 patients prescribed with antihypertensive drugs exhibited adverse maternal effects. Among them, 25 were given nifedipine and nine were given labetalol. In case of nifedipine, preterm delivery was noted in 23 patients, two showed premature rupture of membranes (PROM), while none showed placental abruption. In case of labetalol, seven patients experienced preterm delivery, while PROM and placental abruption were noted in one patient each.

Fetal outcomes in gestational hypertension

In a total of 59 patients, 45 patients were prescribed nifedipine pre-term, among which 23 neonates were born preterm and four showed post-term birth. Forty neonates showed LBW, 20 showed Intrauterine growth restriction (IUGR), and 41 were admitted to neonatal intensive care unit (NICU), while four were stillborn. None showed Intrauterine fetal death (IUFD) or neonatal death. Among 14 patients prescribed with labetalol preterm, preterm birth was noted in seven neonates and none showed post-term birth. Seven neonates showed LBW, two showed IUGR and 13 were admitted to NICU, while one was stillborn. There were no cases of post-term birth, IUFD or neonatal death.

Efficacy of drugs in gestational hypertension

Out of 123 patients, a total of 105 patients exhibited desired therapeutic range on administration of antihypertensive drugs. Around 64 of these patients were given nifedipine 10, 16 were given nifedipine 20, 17 were given labetalol 100 and eight were given labetalol 200. 

Availability of prescribed drugs

On inquiry, both the drugs in both the available doses were found to be readily available, except in hospital pharmacy. The inquiry was done at the hospital pharmacy, nearest generic drug store, online chemist shop and a private chemist shop.

Cost effectiveness of prescribed drugs

With respect to cost-effectiveness of prescribed antihypertensive drugs, the price of a highly-prescribed brand and the generic drug were compared. In the highly-prescribed brand, nifedipine 10 was listed to be costing Rs. 24.7, nifedipine 20 was costing Rs. 33.04, labetalol 100 was Rs. 171, while labetalol 200 was costing Rs. 250.65. Generic drugs were listed to be Rs.12 for nifedipine 10, Rs. 21.42 for nifedipine 20, Rs. 60 for labetalol 100 and Rs. 25 for labetalol 200.

• Nifedipine highly-prescribed brand: Nicardia retard

• Labetalol highly prescribed brand: Lababet

• Generic Nifedipine: Adalat retard

• Generic labetalol: Normadate

Discussion

This was a prospective observational study conducted in the department of Obstetrics and Gynecology, C.G. Hospital, Davanagere for a period of six months. More than 150 case data were collected through case-sheets and verbal communication, among which 27 were omitted due to insufficient data. A similar study was conducted in 2019 by Kanika Agarwal et al. in Rajashree Medical Research Institute, Bareilly, Uttar Pradesh, India published in the Journal of Advanced Medical and Dental Research, where two groups consisting of equal number of subjects were given oral labetalol and oral nifedipine, respectively.⁶ In our study, subjects were selected arbitrarily. Our main aim was to investigate the effective drug among oral labetalol and oral nifedipine in terms of cost, prescribing pattern (pre-natal and postnatal), age group, maternal and fetal adverse effects, efficacy, as well as availability.

Regarding the prescribing pattern, out of a total of 123 subjects, 89 (72.3%) were prescribed oral nifedipine while 34 (27.6%) were prescribed oral labetalol postpartum only. Only 59 subjects (47.9%) among 123 were diagnosed with gestational hypertension in the initial stages and were prescribed drugs; 45 (76.2 %) were prescribed nifedipine and the rest were given labetalol. This shows that nifedipine was the preferred drug over labetalol for the management of gestational hypertension. Our result contradicts the findings of Kannan Sridharan et al. where both nifedipine and labetalol were reported to show similar efficacy with subtle differences in their safety profiles.⁷

In post-natal studies, when age of the patients was considered, 50 subjects were administered with nifedipine and 19 were administered with labetalol in the age group of 18-25 years. Similarly in the age group of 26-35 years, 37 were given nifedipine and 15 were given labetalol. Only two subjects of more than 35 years of age were prescribed with nifedipine. In pre-natal studies, nifedipine was highly prescribed in all age groups.

Both nifedipine and labetalol belongs to category-C, so care should be taken while administration of these drugs to patients. These drugs should be given only when benefit outweighs the risk. In our study, 59 cases were identified where the anti-hypertensives were prescribed in pre-natal stage and exhibited adverse effects in neonates. Among 45 subjects treated with nifedipine, 40 (88.8%) showed LBW, 20 (44.4%) showed IUGR, 41 (91.1%) showed NICU admission, 4 (8.8%) were stillborn, 23 (51.1%) had preterm deliveries and 4 (8.8%) had post-term deliveries. This shows that nifedipine is not recommended in pre-natal stage. Compared to nifedipine, labetalol is preferred.

On considering the maternal outcomes, among 45 subjects treated with nifedipine, 23 (51.1%) experienced preterm deliveries, 2 (4.4%) showed PROM. Among 14 subjects treated with labetalol, seven (15.5%) experienced preterm deliveries, 1 (2.2 %) showed abruption of placenta and 1 (2.2 %) showed PROM. This shows that both labetalol and nifedipine have similar incidence rates of maternal adverse effects. To compare the efficacy of drugs, we considered that the drug given in post-natal stage should fulfill the criteria of therapeutic goal management within one day of treatment. We observed that among 89 subjects treated with nifedipine, 64 (71.9%) reached desired therapeutic outcome and among 34 treated with labetalol, 25 (73.5%) reached desired therapeutic outcome. This indicates  that nifedipine showed better therapeutic efficacy when compared to labetalol, which is similar to the findings of the study conducted by Padmaja A Havle et al. ⁸ Both drugs were available in outdoor private pharmacies, online stores, but were not available in the government hospital pharmacy and were not easily available in generic pharmacies. Cost minimization plays a vital role in store management which is indirectly helpful in hospital management. Cost of generic medicines was low when compared to highly prescribed brands. However, the generic drugs for pregnancy patients are not being commonly prescribed and also the availability is very less.

Conclusion

Labetalol can be recommended prenatally for gestational hypertension condition as it is associated with less maternal and fetal adverse outcomes compared to Nefidepine. Nifedipine can be prescribed more postnatally compared to labetalol. Even though generic drugs are considered to be bioequivalent to branded drugs, they are not being commonly prescribed to pregnancy patients.

Author Contributions

Authors Aswin Santosh Nair, Mohankumar L, Mohsin Ahmed, Suraj Prabhakar Shetty contributed equally to the manuscript.

Conflicts of Interest

Nil