Efficacy of Nifedipine Versus Hydralazine in Management of Severe Hypertension in Pregnancy - A Randomised Controlled Trial

Introduction Hypertension is the commonest medical complication of pregnancy. It is associated with high maternal and perinatal mortality, especially when severe. Hypertensive disorders of pregnancy constitute one of the five major causes of maternal morbidity and mortality in obstetric practice, accounting for approximately 63,000 maternal deaths worldwide annually. It has been noted to complicate about 6-12% of pregnancies; with preeclampsia accounting for about half of these cases, while the relatively benign chronic hypertension and gestational hypertension constitute the rest. Hypertension is defined as systolic blood pressure equal to or above 140 mmHg and diastolic blood pressure equal to or above 90 mmHg, measured on two or more occasions, at least four to six hours apart. It is said to be severe when the systolic blood pressure is equal to or greater than 160 mmHg and/or the diastolic blood pressure is equal to or greater than 110 mmHg.

Hypertension in pregnancy is most worrisome when it is severe because of the associated maternal end organ damage, with associated maternal morbidity and mortality, as well as fetal complications. The end organ damage associated with severe hypertension includes renal impairment, heart failure, liver damage, pulmonary edema and cerebral injury. Though any of these complications may eventually lead to patient's demise, the most common cause of death in patients with severe hypertension is cerebro-vascular accident, resulting from disruption of cerebral auto-regulatory mechanism and increased perfusion pressure. There is also increased vascular permeability, leading to hemo-concentration, which predisposes the patient to cerebral thrombosis as well as the vasospasm associated with convulsion. Other complications include placenta abruption, preterm delivery and increased risk of cesarean delivery. In order to reduce the maternal complications associated with severe hypertension in pregnancy, there is the need for immediate treatment to lower the severely elevated blood pressure. However, due to the fact that the placenta functions as a low resistance shunt without auto-regulation, lowering the blood pressure too fast or too far may lead to reduced utero-placental perfusion, which is detrimental to the fetus. Therefore the reduction in blood pressure, though prompt, should be controlled, with a target of 140-150 mmHg systolic and 90-100 mmHg diastolic. The primary purpose of this treatment is not to change the course of the disease but to prevent cerebral hemorrhage and hypertensive encephalopathy associated with such severely elevated blood pressure. Thus the initial focus of the treatment is directed towards the safety of the mother, which is necessary to ensure that of the fetus.

The most commonly used anti-hypertensive drugs for the control of severe hypertension in pregnancy are nifedipine, labetalol and hydralazine. Nifedipine is a calcium channel blocker which blocks the L-type calcium channels in both the cardiac and vascular smooth muscle cells, thereby exerting negative inotropic effects on the heart and causing vascular dilatation which results in decreased systemic vascular resistance. It is available in tablet and capsule forms. Labetalol is a non-selective α1, β1, and β2 adrenergic receptors antagonist. It acts by dilating arterioles, thereby decreasing vascular resistance without significantly lowering the cardiac output. It may be administered orally (tablet) or intravenously. Hydralazine also lowers blood pressure by decreasing systemic vascular resistance through direct dilatation of arterioles. It is administered both intravenously and orally. These drugs have been compared with each other in different randomized controlled trials. While it is generally accepted that the three drugs are effective in controlling severe hypertension, different trials have recommended labetalol, hydralazine or nifedipine as the first line agent; and the others (as the case may be), as alternatives, depending on the prevailing circumstances and considerations of the trials.

As a result of the differences in the outcomes of randomized controlled trials on efficacy and safety of anti-hypertensive use in pregnancy, there is no consensus on which agent is the safest and most effective. A recent Cochrane review on 'drugs for treatment of very high blood pressure during pregnancy' concluded that, until better evidence was available, the choice of anti-hypertensive drugs should depend on the clinician's experience with the particular drug, on what was known about the side effects, as well as the women's preferences. Other factors that determine anti-hypertensive choice are availability, cost, fetal and maternal condition at admission. This leaves the choice of drugs to the physician's discretion which is very subjective. In Nigeria, there has been no clinical data specifying the preferred anti-hypertensive agent (among the three earlier stated) in the management of severe hypertension in pregnancy. Drug use in such circumstances has generally been based on studies done in America and Europe.

Intravenous hydralazine is the most commonly used anti-hypertensive drug in severe hypertension because of its long term established safety, efficacy, availability and cost-effectiveness. However, its administration requires more resources in terms of equipment (i.e. syringes and needles as well as intravenous cannula) and personnel (administered usually by doctors or occasionally, nurses) than that of oral agents. Its common side effects, such as headache, nausea, and vomiting may mimic symptoms of deteriorating preeclampsia and thereby create confusion during management. Also, maternal hypotension is common with parenteral hydralazine, which has been shown to be associated with an excess of caesarean sections, placental abruptions, and low Apgar scores (< 7) at five minutes compared to labetalol and nifedipine. In view of these limitations of hydralazine, there is a need to find alternative drugs with equal efficacy in controlling severe hypertension but with fewer side effects. Nifedipine is cheap, easy to administer, widely available and has less tendency to cause maternal hypotension resulting in fetal compromise. As a result of these qualities and the peculiarity of our society in terms of availability of skilled man-power, it is necessary to know if it is comparable with hydralazine in terms of efficacy and safety, with the hope of recommending its use in treatment of severe hypertension in pregnancy in Nigeria.