Hypertension in Pregnancy-Treatment

Review Article

Austin Hypertens. 2016; 1(2): 1007.

Hypertension in Pregnancy-Treatment

Gasnier R*

Hospital De Clinicas De Porto Alegre, Federal University of Rio Grande Do Sul, Brazil

*Corresponding author: Gasnier R, Hospital De Clinicas De Porto Alegre, Federal University of Rio Grande Do Sul, Brazil

Received: September 19, 2016; Accepted: October 01, 2016; Published: October 14, 2016


Chronic hypertension complicates 3-5% of pregnancies, with 25-30% of superimposed preeclampsia. Antihypertensive medication is used for severe hypertension cases, but there is no consensus about the treatment of mild-tomoderate hypertension in pregnancy. Agents used normally include methyldopa, labetalol and nifedipine. In cases of severe hypertension, intravenous labetalol and oral nifedipine are as effective as intravenous hydralazine. The objective of the treatment is to protect the mother and to permite continuation of the pregnancy. Treatment of hypertension is not related to prevention of preeclampsia, only can previne severe hypertension development.

Keywords: Chronic hypertension; Nifedipine; Hypertension treatment; Gestational arterial hypertension

Hypertension in Pregnancy

The American College of Obstetricians and Gynecologists (ACOG) had proposed in 1972 and revised in 2000 a classification for hypertension in pregnancy, with no changes during the Task Force in 2013 [1].

1. Preeclampsia-eclampsia.

2. Arterial chronic hypertension (of any etiology).

3. Arterial chronic hypertension with superimposed preeclampsia.

4. Gestational arterial hypertension.

Chronic hypertension is diagnosed before pregnancy or in the 20 weeks of gestation, or persists more than 42 days after delivery, complicating 3-5% of pregnancies [2]. In gestational hypertension cases, occurring in 6% of pregnancies, hypertension occurs after 20 weeks of pregnancy and is not associated to proteinuria or other systemic features of preeclampsia, with normalization during the 12 weeks following delivery [3]. Preeclampsia is characterized by hypertension and proteinuria or other systemic features. Eclampsia is described as convulsions associated to preeclampsia and not caused by epilepsy or other convulsive disorders. Preeclampsia superimposed on chronic hypertension is defined as a condition of hypertension with onset of proteinuria, complicating 25% of the pregnancies with chronic hypertension [4].

Hypertension is increasingly diagnosed in the childbearing age and this mainly due to the combination of obesity and older maternal age at pregnancy. Chronic hypertension often improves in the second trimester and early third trimester because of the reduction in the systemic vascular resistance, to be restored in late pregnancy. In some cases, women with gestational hypertension remain hypertensive after delivery. They most likely have preexisting chronic hypertension masked in early pregnancy by physiological vasodilatation. After delivery blood pressure usually falls, then increases over the first 5 postpartum days. Even women whose Blood Pressure (BP) was normal during pregnancy may experience transient hypertension in the early postpartum period, reflecting a degree of vasomotor instability [5,6].

Treatment of Hypertension

The control of severe hypertension is uncontroversial, preventing complications as intracranial hemorrhage, hypertensive encephalopathy, pulmonary edema, stroke and other cardiovascular complications. In addition, it is related to pregnancy prolongation and better perinatal outcomes, avoiding fetal distress. It is important to remember that cerebral hemorrhage is the commonest cause of maternal death in preeclampsia and eclampsia. Severe hypertension in pregnancy (systolic BP 170 mm Hg, diastolic BP 110 mm Hg) represents a very serious risk, but mild-to-moderate hypertension is associated to lower risk [7]. Those with hypertensive encephalopathy, hemorrhage or eclampsia require treatment with parenteral agents to lower MAP (Mean Arterial Pressure) by 25% over minutes to hours and then lower BP to 160/110 mm Hg over subsequent hours [8], avoiding hypotension. Lower doses should be initiated in preeclampsia, because of volume depletion and attention is needed for hypotension during treatment. The velocity of BP raise may be more important than the actual level of BP. The utero-placental circulation and the cerebrovascular circulation both do not auto regulate blood flow in this setting. The basic principle is always starting low and going slow.

Most women with chronic hypertension during pregnancy present with mild essential uncomplicated hypertension and are at minimal risk for cardiovascular complications within the short time of pregnancy. Women with mild, uncomplicated chronic hypertension, without target organ damage, have good perinatal outcomes regardless of the use of antihypertensive therapy [4]. Clinical trials indicate non-consistent data concerning antihypertensive treatment on antenatal rate of hospitalization, proteinuria at delivery and preeclampsia, perinatal outcomes, preterm labor or Small for Gestational Age (SGA) [9,10]. Prevention of preeclampsia is desirable, but either specific BP targets or antihypertensive agents modify the risk. Aspirin is related to risk reduction of preeclampsia in high risk groups as chronic hypertension [11]. Antihypertensive drugs, therefore, are not related to modification in the placentation process and do not reduce chance of preeclampsia progression.

Preeclampsia is a pregnancy-specific syndrome of reduced organ perfusion secondary to vasospasm and endothelial activation, occurring in 7-10% of pregnancies and it can be associated with significant maternal and fetal morbidity-mortality. Hypertension is due to generalized arteriolar vasospasm and decreased plasma volume. The pathological process in the placenta results in dissemination of abnormal substances throughout circulation, leading to disturbed endothelial function with multiorgan systemic clinical features. Maternal and perinatal morbidities significantly increased with severe preeclampsia, causing seizures, pulmonary edema, acute renal and liver failure, Disseminated Intravascular Coagulopathy (DIC), stroke. According to the Task force in 2013, proteinuria is not a necessary feature and the emphasis is the multiorgan system involvement, as previous described by Australasian Consensus [12].

Chronic hypertension therapy can be stopped during pregnancy under close observation, or a women whose arterial pressure was well controlled before pregnancy may continue with the same agents, if not contraindicated. The National Institutes of Health recommend antihypertensive therapy for blood pressures exceeding a threshold of 150 to 160 mm Hg systolic or 100 to 110 mm Hg diastolic or in the presence of target organ damage [2,8]. In women with renal dysfunction, it is better to choose a slightly lower threshold for treatment [13]. The focus of treatment is the pregnancy, during which untreated mild-to-moderate hypertension is unlikely to lead to unfavorable long-term maternal outcomes.

There are still no definitive and complete data about safe BP treatment targets for women with hypertension in pregnancy, however guidelines and reviews generally recommend the BP values of 140-155/90-105 mm Hg [14]. In contrast to hypertension guidelines in general clinical practice, which emphasize the systolic BP, much of the obstetric literature focuses on diastolic BP, in part because of the lack of clinical trials to support one approach versus another. Review of women who suffered stroke in the setting of preeclampsia had demonstrated systolic hypertension more prevalent that diastolic hypertension (most women did not reach diastolic BP of 110 mm Hg) [15]. The literature suggests that the degree of systolic hypertension may be more associated with significant morbidity.

There are two approaches for hypertensive pregnant with Chronic Kidney Disease (CKD): the same guidelines for chronic hypertension in pregnancy or transferring the “lowest the best” approach suggested in non-pregnant CKD patients (normally BP less than 120/80 mm Hg) [16]. The effect of stricter BP control in preventing placental damage is more important in CKD with normal placentation as compared to cases in which the placenta itself is the origin of hypertension (preeclampsia superimposed on CKD). In the same way that it is possible to see different forms of preeclampsia, also there are different presentations of chronic kidney disease. Control of hypertension related to renal disease is important to prevent severe hypertension and renal damage during pregnancy, sometimes irreversible.

Antihypertensive Drugs

The question has been raised whether treatment is necessary in mild-to-moderate hypertension, especially in the absence of proteinuria. Drugs used are mainly to prevent and treat severe hypertension. One concern is that hypertension or iatrogenic hypotension might cause cardiovascular malformations and reduction of birth weight by altering perfusion in the placenta and/ or fetus [17]. Because of the circulating plasma volume contraction in preeclampsia, women may be very sensitive to relatively small doses of antihypertensive agents, risking abrupt reductions in blood pressure.

Fetal growth restriction secondary to placental insufficiency can occurs in pregnancy complicated by hypertension. Reduction in maternal BP may lead to decrease in uterine perfusion pressure and consequently in fetal oxygen supply. Decreased blood volume in preeclampsia may exacerbate this effect. In cases of mild chronic hypertension, ACOG recommends withholding or discontinuing therapy because of concern about fetal growth.

Benefits and risks of antihypertensive treatment for mild-tomoderate hypertension are not completely defined in recent reviews, including a Cochrane meta-analysis [7,18]. Antihypertensive treatments for mild-to-moderate hypertension seem to be beneficial for the mother, but without better pregnancy outcome. Treatment is based on control of severe rise in BP and the fact that arteriolar vasodilatation may help to improve organ perfusion.

International societies have differed in their recommendations for the BP which should initiate therapy. The US professional bodies recommend starting with the therapy at BP 160/105 mm Hg, not defining the target values [8]. The Canadian Hypertension Society recommends BP of 140-150/90-95 mm Hg, targeting dBP 80-89 mm Hg [19]. The Australasian professional bodies recommend BP 160/90 mm Hg and target value of 140-110/80-90 mm Hg. In cases of comorbidities as pre-gestational diabettes and renal diseases, the values should be more restrict, but is necessary to avoid excessive lower BP to prevent placental hypoperfusion and fetal growth abnormalities [20]. The National Institute of Health and Clinical Excellence recommends BP lower than 150/100 mm Hg in pregnant women with uncomplicated chronic hypertension and that lowering diastolic pressure below 80 mm Hg should be avoided. Blood pressure should be lower than 140/90 mm Hg in cases of target-organ damage.

During the Control of Hypertension in Pregnancy Study (CHIPS), comparing less-tight vs. tight control, it was shown that less-tight control was not superior to tight control for the fetus but was associated with more severe hypertension for the mother [21]. The composite primary outcome was pregnancy loss or high-level neonatal care for more than 48 hours in the first 28 days of life and the secondary serious maternal complications before 6 weeks postpartum. It is important to remember that failure to identify and treat it has been recognized as the most important failing in the care of women with pregnancy hypertension. It was a randomized trial-987 women-allocated to a target diastolic BP of 100 mm Hg or 85 mm Hg. There were few differences in key baseline characteristics between less tight versus tight control among women on either labetalol or methyldopa [22], but women who switched from labetalol or methyldopa to an agent other than these two had worse outcomes. Severe hypertension was not a primary or secondary outcome and was already a known risk associated with less-tight control. The power was insufficient to assess pregnancy outcomes that are influenced by antihypertensive therapy as SGA.

In a second analysis of this trial it was concluded that at the time that a pregnant women with chronic hypertension becomes hypertensive, or a normotensive women develops gestational hypertension, it is not possible to use maternal or pregnancy clinical characteristics including BP level to predict adverse outcomes [23]. In the same way, outcomes for less tight versus tight control were not dependent on use of methyldopa or labetalol [24]. The medications were considered at or after randomization.

Centrally acting alfa-2-adrenergic agonists

Methyldopa: It is the most common treatment for hypertension in pregnancy. There is extensively experience with the drug and longterm follow-up data regarding children whose mothers received methyldopa during pregnancy [14,25]. In a follow-up study of a large clinical trial on the effectiveness of methyldopa versus no treatment, no differences were found in the functional development of children a 4 and 7.5 years of age [26,27]. During the long term treatment, the drug does not alter cardiac output or blood flow to the uterus or kidneys [28]. BP control is gradual, over 6 to 8 hours, because of the indirect mechanism of action. It was tested in several trials compared to placebo or other hypertensive treatments.

Adverse effects are consequence of central alfa-2-agonism or decreased peripheral sympathetic tonus. These drugs act in sites in brain stem to decrease mental alertness and impair sleep, leading to fatigue, depression, poor sleep. Decreasing salivation leading to xerostomia is experienced. Elevated transaminases (5%), hepatitis and hepatic necrosis have also been reported. Some patients will develop a positive antinuclear antigen or antiglobulin (Coombs) test with chronic use and this is occasionally associated with clinical hemolytic anemia. In these cases, medications of other classes are used [29].

Clonidine: It is a selective alfa-2-agonist, acts similarly and is comparable to methyldopa with respect to safety and efficacy. Sleeping disturbances after prenatal exposure have been reported in a cohort study. It is used as third agent line for multidrug control of refractory hypertension [30].

Peripherally acting adrenergic-receptor antagonists

Beta-blockers have been used extensively in pregnancy. Small studies had suggested an association with lower Birth Weight Infants (LBW); however, in a recent meta-analysis of published data from randomized trials, the presence of SGA appeared not to be related to the antihypertensive used [31].

Labetalol: It is a non-selective beta-blocker with vascular alfa1- receptor-blocking effects and produces its hypotensive effects without compromising the maternal cardiovascular system, with immediate and prolonged effect and uteroplacental flow increase. In a trial which has included 263 patients with mild-to-moderate hypertension, randomly separated to methyldopa, labetalol and no treatment, patients with therapy had significantly lower maternal blood pressures compared to the non-medication group and were no differences among the groups concerning gestational age at delivery, birth weight, incidence of fetal growth restriction, neonatal head circumference or uteroplacental circulation [32]. In some centers methyldopa was substituted for labetalol as the first choice of treatment because of central side effects of methyldopa. Others otherwise concluded that labetalol as other beta blockers is related to fetal growth abnormalities.

It is considered safe and effective treatment, although neonatal hypoglycemia with higher doses has been reported and one placebo controlled study reported an association with fetal growth restriction in the management of preeclampsia remote from term [33]. It is used parentally to treat severe hypertension: because of a lower incidence of maternal hypotension and other adverse effects, its use now supplants that of hydralazine [34], which was previously the most commonly used agent for the treatment of severe hypertension. There is wide interpatient variability in the dose of labetalol required to control BP, an event that is not predictable by any clinical item before therapy. Another problem is the variable duration of action, particularly in patients who require higher doses. Congestive heart failure, asthma, sinus bradycardia and first-degree atrial-ventricular block contraindicate its use.

Atenolol: It is a commonly used cardio selective beta-blocker in non-pregnant patients, but its use especially in early pregnancy should be avoided. Placebo-controlled study demonstrated that atenolol in early pregnancy for chronic hypertension treatment is associated with significantly LBW and higher proportion of SGA, compared to the placebo group [35]. Bayliss concluded that LBW was associated to atenolol taken at the time of conception or during the first trimester of pregnancy [36]. Studies with atenolol in preeclampsia failed to find differences, maybe because of the late starting therapy.

In a meta-analysis and Cochrane review in 2000, individual agents were not different in their perinatal effect with the exception of atenolol, which in one small study was started at 12 to 24 weeks and resulted in significant fetal growth restriction and decreased placental weight compared to placebo: these findings were supported in subsequent retrospective review comparing atenolol with alternative therapies. Oral beta-blockers for mild-to-moderate hypertension during pregnancy have specifically been estimated in the Cochrane database [37].

Maternal outcomes are improved with the use of betablockers, with effective control of BP, decreased incidence of severe hypertension and decreased rate of preterm admission [2]. They have been found to be more effective in lowering BP compared with methyldopa in 10 trials in a recent Cochrane analysis [7].

Peripherally acting alfa-adrenergic antagonists are second line antihypertensive drugs in non-pregnant adults. Those are indicated during pregnancy in the management of hypertension because of suspected pheochromocytoma and both prazosin and phenoxybenzamine have been used, with beta-blockers used as adjunctive agents after alfa-blockade is accomplished [38]. Because there is limited experience with these drugs in pregnancy, their routine use cannot be advocated.

Methyldopa versus labetalol was associated with fewer adverse perinatal and maternal outcomes during CHIPS trial: pregnancy loss or high-level neonatal care for more than 48 hours (CHIPS primary outcome), birth weight&10th centile, severe maternal hypertension, preeclampsia and delivery at <37 weeks or <34 weeks of gestation.

Methyldopa also was of particular benefit among women with preexisting hypertension for perinatal outcomes and preterm delivery [24]. These results are consistent with a recent historical cohort from Canada: women with chronic hypertension taking methyldopa and not labetalol had fewer SGA and/or with necessity of hospitalization (respiratory distress, sepsis, seizures) [39]. The findings are not consistent with the results of previous studies: methyldopa may have had better outcomes, particularly among women with preexisting hypertension.

Severe hypertension was more common in the higher BP arm whether labetalol was the recommended drug or methyldopa was used exclusively. There is no evidence that the results of CHIPS are dependent on the choice of labetalol or methyldopa therapy used to achieve less tight or tight control of maternal BP.

Otherwise, meta-analysis of 22 trials did not find a significant difference in outcomes for methyldopa compared with beta-blockers [40]. Analyzing methyldopa versus beta-blockers and methyldopa versus calcium-channel blockers, methyldopa was associated with more adverse maternal outcomes (without impact on perinatal outcomes) with more severe hypertension (RR 1.85 95% CI 1.05- 3.33) and progression to proteinuria preeclampsia (RR 1.33 95% CI 1.01-1.85).

Calcium Channel Blockers (CCB)

Calcium channel blockers have been used to treat chronic hypertension, mild preeclampsia presenting late in gestation and urgent hypertension associated with preeclampsia. The papers have focused on the use of nifedipine. Amlodipine has been used in pregnancy but safety data are lacking. Over the last decades its favorable characteristics have resulted in its efficacy and safety being assessed in pregnancy. Its application both as a treatment for acute severe hypertension, as well as for long term use for hypertension in pregnancy, have been explored. It has minimal effect on the cardiac conducting system. It causes a decrease in arterial vascular resistance but with minimal effect on the venous system. It results in a 20% lowering of the systolic, diastolic and arterial blood pressures [41].

Due to the differences in the metabolism and clearance in pregnancy, the recommended starting dose is 10 to 20 mg, six hourly. The efficacy and safety of long acting oral nifedipine, with less risk of hypotension and fetal distress was proven for severe hypertension in pregnancy, advocating its use [42,43]. The mode of action of nifedipine reducing systemic vascular resistance and its ability to improve renal blood flow make it a highly appropriate drug for use in hypertension in pregnancy [44]. If rapid BP control is desired, the use of parenteral labetalol or hydralazine is recommended, until the desired target is achieved. The Canadian Hypertension Society as well as the Australasian Society for Study of Hypertension has both recommended its use as one of the first line drugs in severe hypertension in pregnancy.

Nifedipine also causes an increase in blood flow to the liver which may alter the metabolism of other drugs. Maternal side effects with nifedipine seldom occur and there is rarely a need to stop the drug. Side effects are related to the dose and include flushing, headaches, sweaty palms, peripheral edema [45]; rarely constipation, diarrhea, heartburn, dyspnea and chest pain have been described. Tachycardia occurs commonly but is seldom associated with palpitations and appears to have no adverse effects.

Nifedipine does not seem to cause decrease in uterine blood flow. It has been compared with methyldopa for the treatment of pregnancy-induced hypertension and been shown to be comparable in its antihypertensive action but achieved no improvement in prolongation of pregnancy or fetal outcome. It appears to be as good as hydralazine in its antihypertensive effect, but its onset of action is less likely to be precipitous. Both drugs seem to reduce blood pressure to acceptable levels due to a significant reduction in systemic vascular resistance, accompanied by similar increases in cardiac output and heart rate. Nifedipine is also associated with fewer episodes of acute fetal distress, as suggested by non-reassuring fetal heart rate changes in pregnancies with and without intrauterine growth restriction. Different units have their preferences for either parenteral labetalol or hydralazine and some use oral nifedipine.

A recent large study from the Agency for Healthcare Research and Quality-funded Health Maintenance Organization Research Network’s Center for Education and Research on Therapeutics program have concluded that third trimester exposition to calcium channel blockers was associated with markedly increased risk of neonatal seizures in term neonates, related to a decrease in fetal intracellular calcium [46]. Bateman, et al. otherwise, did not observe that increase [47].

A systematic review by Shekhar, et al. based on the results of seven trials and 363 women with severe hypertension has concluded that nifedipine is more effective that intravenous labetalol: less persistent severe hypertension 3.3% vs. 8.3% RR 0.42 95% CI 0.18-0.96 [48]. Nifedipine was associated with fewer maternal adverse effects as headache, nausea, vomiting and palpitations.

Direct vasodilators

Dihydralazine: Dihydralazine selectively relaxes arteriolar smooth muscle by an unknown mechanism. It has been commonly used in the acute emergency or as a third line agent for multidrug control of refractory hypertension. Its ability to cause too rapid a fall in blood pressure is well described, due to excessive vasodilatation or sympathetic activation. It is possible that hypotensive episodes may be a reflection of underlying intravascular volume status rather than any property of the drug itself. Also oral hydralazine it can be used for chronic hypertension in the second and third trimesters, but its use has been supplanted by agents with more favorable adverse effects [49]. Chronic use can lead in rare cases to a pyridoxineresponsive polyneurophaty or to immunologic reactions, including a drug-induced lupus syndrome. It has been used in all trimesters of pregnancy and data have not shown an association with teratogenicity, although neonatal thrombocytopenia and lupus have been reported [50] (Tables 1 & 2).

A recent meta-analysis of intravenous hydralazine for severe hypertension in pregnancy has concluded that parenteral labetalol or oral nifedipine were preferable first-line agents in accordance with association of intravenous hydralazine with more maternal and perinatal adverse effects, such as maternal hypotension, maternal oliguria, cesarean section, placental abruption, adverse effects on fetal heart rate and low Apgar scores at one minute [34,51].

Isosorbide nitrate: It is a Nitric Oxide (NO) donor, has been investigated in a small study of gestational hypertensive and preeclamptic pregnant patients. It was found that cerebral perfusion pressure is unaltered by isosorbide dinitrate, despite significant changes in maternal BP, thus decreasing the risk for ischemia and infarction when BP is lowered [52]. Besides, some papers had tested your use in form of patch medication for meliorating Doppler measurements and consequently with best pregnancy outcomes [53].

Citation:Gasnier R. Hypertension in Pregnancy-Treatment. Austin Hypertens. 2016; 1(2): 1007.