A Comparative Study of Oral Nifedipine and Intravenous Labetalol for Acute Hypertensive Management in Pregnancy: Assessing Feto-Maternal Outcomes in a Hospital-based Randomized Control Trial

INTRODUCTION

Hypertension is one of the most common medical complications during pregnancy, and it is a leading cause of maternal mortality and morbidity.^[1] Hypertension with hemorrhage and infection forms the deadly triad that increases the risk of morbidity and mortality during pregnancy and childbirth.^[2] The incidence of hypertensive disorders in pregnancy varies between 5% and 10% contributing to 22% of perinatal and 30% of maternal deaths.^[3] The incidence of hypertensive disorders is on the rise due to factors such as women postponing their first pregnancy and an increase in pre-pregnancy weight. On the other hand, the adverse outcomes due to eclampsia are declining in industrialized and affluent societies due to better antenatal care and management of preeclampsia. Hypertensive disorders of pregnancy are classified as gestational hypertension, preeclampsia, eclampsia, chronic hypertension, and chronic hypertension with superimposed preeclampsia.

Hypertension during pregnancy is diagnosed when the systolic pressure is ≥140 mmHg and/or a diastolic pressure of ≥90 mmHg and is measured on two occasions at least 4 hours apart.^[4,5] Gestational hypertension is defined as new-onset hypertension developing after 20 weeks of gestation, during labor or in the first 24 hours postpartum, without proteinuria or any other systemic features of preeclampsia, in a previously normotensive nonproteinuric woman and the blood pressure resolves within 12 weeks postpartum. Preeclampsia is defined as hypertension associated with proteinuria greater than 0.3 g/L in a 24-hour urine collection or +1 by qualitative estimation using reagent strips, after 20 weeks of gestation. Eclampsia is defined as preeclampsia with seizure. Chronic hypertension is defined as hypertension present before the 20th week of pregnancy and persists beyond 12 weeks postpartum. Preeclampsia superimposed on chronic hypertension is diagnosed when one or more features of preeclampsia (e.g., elevated liver enzymes, low platelets, proteinuria) develop for the first time during pregnancy after 20 weeks, in a woman with pre-existing chronic hypertension.

Hypertensive disorders can result in several maternal complications including eclampsia, cerebrovascular accidents, placental abruption, HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome, pulmonary edema, acute renal failure, and microangiopathic hemolytic anemia. Hypertensive disorders also carry a risk for the baby. Preeclampsia is strongly associated with fetal growth restriction, low birth weight, spontaneous or iatrogenic preterm delivery, respiratory distress syndrome, and admission to neonatal intensive care.^[6]

For the purpose of management, preeclampsia is divided into non-severe and severe forms based on the level of blood pressure (BP) and the presence of signs and symptoms of end-organ damage. Non-severe preeclampsia is defined as BP >140/90 mmHg but <160/110 mmHg without warning signs. Severe preeclampsia is defined as BP ≥160/110 mmHg with warning signs like headache, blurring of vision, and epigastric pain.

The basic management objective for any pregnancy complicated by severe preeclampsia is the termination of pregnancy with the least possible trauma to the mother and fetus, the birth of a healthy baby, and the restoration of the health of the mother. Treating hypertension does not alter the progress of the disease, but the reduction of BP is necessary to reduce complications like placental abruption, pulmonary edema, hypertensive encephalopathy, intracranial hemorrhage, eclampsia, and end-organ damage.^[7] Several drugs are available to rapidly lower the BP in hypertensive emergencies of pregnancy. The most common drugs are nifedipine, labetalol, and hydralazine. All three of these are recommended as first-line agents.^[8] Nifedipine has now been safely used in several obstetric trials for the treatment of hypertensive emergencies.^[9-12] It is orally effective, cheap, and easy to administer and store. Nifedipine increases cardiac output and coronary blood flow and also increases urine output. Intravenous labetalol is equally effective in controlling severe hypertension in pregnancy and has the advantage of administering it in unconscious patients. An intravenous drug like injectable labetalol is mainly used to rapidly lower BP in case of acute hypertensive crisis. Injectable medications necessitate venous access and thorough fetal monitoring, which may not be feasible in resource-limited or busy settings. In contrast, oral medications can be distributed across various healthcare settings, require no cold storage, need only basic drug administration training, and are widely available in both low- and middle-income countries. Studies comparing hydralazine to labetalol and nifedipine to control BP in severe preeclampsia showed that hydralazine was associated with a higher incidence of adverse outcomes like hypotension, placental abruption, oliguria, cesarean section, adverse effect on fetal heart rate, and low Apgar score at 1 min, when compared to other hypertensives.^[13] Oral nifedipine has been proposed as a first-line alternative to IV labetalol.^[14] The purpose of this study therefore was to compare the effectiveness and safety of oral nifedipine and intravenous labetalol to normalize acute hypertension in severe preeclampsia.

METHODS

This study was conducted on 120 antenatal women admitted to the obstetrics and gynecology department at a tertiary care hospital from January 1st, 2020 to June 30th, 2021 for a period of 18 months. This was a hospital-based randomized controlled trial. The study was approved by the ethical committee of Uttar Pradesh University of Medical Science, Saifai, Etawah. This study was not registered with any clinical trial registry, as this study sample size was small and is a pilot study. This is the limitation of this study.

RESULTS

A total of 120 patients were recruited in this randomized control trial and later divided into two groups randomly by a single blinding technique. Group 1 and group 2 consisted of 60 patients each, who were managed with injection labetalol and oral nifedipine tablets, respectively. Patient characteristics are shown in Table 1. The mean age of patients was 25.85±3.10 years and 24.92±3.12 in group 1 and group 2, respectively. As well, 78.33% (47/60) and 56.67% (34/60) primigravida were found in groups 1 and 2, respectively (p=0.071). The majority of patients had a gestational age ranging from 34 to 36 weeks. The average gestational ages for group 1 and group 2 were 36.43±1.48 and 36.10±1.68, respectively. In group 1, 51.67% (31/60) of the patients were booked while in group 2, 53.33% (32/60) patients were booked (p=0.855). About 68.33% in group 1 and 66.67% in group 2 had BMI ≥30 kg/m². The mean BMI in the labetalol and nifedipine groups was 31.01±2.34 and 30.92±2.08 kg/m², respectively. The primary outcome of the study is the time taken to achieve blood pressure control is shown in Table 2. The average time taken to control the BP was 48.67±17.80 min for group 1 and 64.33±9.81 min for group 2 (p ≤ 0.0001). About 78.33% of patients in group 1 reached a target blood pressure of ≤140/90 mmHg after two doses of antihypertensive. Also, 81.67% of patients enrolled in group 2 reached the target blood pressure of ≤140/90 mmHg after three doses of antihypertensive (p-value ≤ 0.0001). A total of 81 patients comprising 66.67% of group 1 and 68.33% of group 2 were delivered vaginally. The remaining patients delivered their babies using cesarean section (p-value = 0.845). The mean birth weights of babies in group 1 and 2 were 2.41±0.46 kg and 2.36±0.53 kg, respectively. Ten percent of mothers in group 1 and 18.33% of mothers in group 2 had their newborns admitted to the intensive care unit, respectively (p = 0.191). In group 1, out of 10% of intensive care admissions, 6.67% (4/60) of the babies died. In group 2, out of 18.33% of intensive care admissions, 11.67 % (7/60) of the babies died (p = 0.342). No major adverse effects were reported in the majority of the recruited patients. In group 1, the common adverse effects were dizziness (11.67%), headache (6.67%), and nausea (5.00%). The common adverse effects in patients recruited in group 2 were nausea (10%), headache, and dizziness (8.33%). Overall, there was no significant difference in adverse effects in both groups (p-value = 0.580).

DISCUSSION

Hypertensive emergency in pregnancy is associated with morbidity and mortality in both maternal and neonatal populations. The primary aim of this study is to compare the efficacy and safety of oral nifedipine with intravenous labetalol in the control of acute hypertension in severe preeclampsia. In the present study, the mean age of the patients enrolled in this study was 25.85 and 24.92 years in the labetalol and nifedipine groups, respectively. These findings are similar to the study done by Afreen et al. (2018).^[15] In the present study, 78.33% of patients in the labetalol group and 56.67% in the nifedipine group were primigravida. A similar observation was made in the study by Duckitt et al. (2005), which showed that primiparity is one of the risk factors for preeclampsia.^[16] In the present study, 51.67% in the labetalol group and 60% in the nifedipine group belonged to gestational age of 34–36 weeks. This is similar to a study conducted by Ramprasad Dey et al. (2017).^[17] In the present study, 68.33% in the labetalol group and 66.67% in the nifedipine group have a body mass index (BMI) ≥30 kg/m². The mean BMI in the labetalol group and nifedipine group are 31.01±2.34 and 30.92±2.08 kg/m², respectively. Most of the patients enrolled in the labetalol and nifedipine groups fell under the category of obesity. These findings are similar to the study by Sibai and others (1997).^[18] In the present study, out of the 60 patients enrolled in the labetalol group, 47 patients, constituting 78.33% of the study population achieved the target blood pressure of ≤ 140/90 mmHg in 40 min of commencement of the treatment, requiring two incremental doses of intravenous labetalol. In the nifedipine group, 81.67% of the enrolled patients required three doses of oral nifedipine. On statistical analysis, there was a significant difference in the time taken for both drugs to act for reduction in systolic blood pressure. This is in contrast with a double-blind randomized trial by Raheem et al. (2012), which showed that both labetalol and nifedipine are equally efficacious in controlling blood pressure.^[19] A study conducted by Vermilion et al. (1999), showed that oral nifedipine is superior when compared to labetalol in blood pressure control.^[20] The present study’s findings were in contrast with that of Shekhar et al. (2016), which compared oral nifedipine and intravenous labetalol for severe hypertension during pregnancy. This study included 363 women and concluded that oral nifedipine is as efficacious and safe as intravenous labetalol.^[21] All the patients enrolled in the study received prophylactic magnesium sulfate therapy. None of the patients developed eclampsia in antepartum or post-partum periods. In the present study, none of the patients receiving either drug developed hypotension or neuromuscular blockade. This is similar to the Magpie trial in 2002, which recruited 10,141 women with preeclampsia and showed that there was no significant interaction between nifedipine and magnesium sulfate.^[22] All group 1 patients (injection labetalol) were given oral labetalol and all group 2 patients (oral nifedipine) were given oral nifedipine as a maintenance dose after achieving a target blood pressure of ≤140/90 mmHg. Among the patients enrolled, 66.67% delivered vaginally and 33.33% delivered by cesarean section in group 1 while in group 2, 68.33% delivered vaginally and 31.67% delivered by cesarean section.

There was no significant difference in birth weight in both groups. In the present study, 10% of the newborns from the labetalol group and 18.33% of the newborns from the nifedipine group were admitted for intensive care. A study conducted by Tayyiba Wasim et al. (2020), to compare oral nifedipine and intravenous labetalol in terms of rapidity of BP control in severe preeclampsia, showed that in the labetalol group, 22.54% of babies and in nifedipine group 29.40% of babies were admitted in neonatal intensive care unit (NICU).^[23] The causes of admission were extreme prematurity and respiratory distress syndrome. The outcome was similar in both groups. None of the newborns had neonatal hypoglycemia or hypotension after birth.

In the present study, 6.67% of the newborns from the labetalol group and 11.67% of admitted newborns from the nifedipine group died due to extreme prematurity. In a study by Tayyiba Wasim et al. (2020), 20.5% of babies in group A and 18.6% of babies in group B showed perinatal deaths.^[23]

The majority of the patients enrolled in the study did not report any notable adverse effects. The most commonly reported adverse effect in the labetalol group was dizziness and that in the nifedipine group was headache and nausea. 3.33% of the patients in the labetalol group had palpitations, though 1.67% of patients in the nifedipine group had complained of the same. 3.33% of the patients enrolled in the labetalol group complained of tremors. On the whole, there was no statistically significant difference in adverse effects between both groups. This is in comparison to the study conducted by Vermillion et al. (1999), which showed that adverse effects were infrequent.^[20]

CONCLUSION AND GLOBAL HEALTH IMPLICATIONS

Both oral nifedipine and intravenous labetalol demonstrated safety and efficacy in reducing blood pressure. None of the drugs were associated with any detrimental maternal or fetal outcomes with respect to the anti-hypertensive usage. Intravenous labetalol proved more efficacious than oral nifedipine, suggesting its suitability as a first-line treatment for hypertensive emergencies due to its rapid blood pressure-lowering effect and the need for fewer doses.