converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are contraindicated in pregnancy due to their association with an increased risk of fetopathy.134-136 Women who are treated with an ACE or ARB before conception should be advised to avoid exposure to these drugs during pregnancy by replacing them with a different antihypertensive drug as soon as pregnancy is confirmed.128 Studies of pregnant women who received the above classes of drugs and animal experimental studies showed increased risk of fetal hypotension, decreased glo- merular perfusion pressure, impaired renal tubular development, reduced fetal urine output or complete anuria and oligohydramnios, limb contractures, pul- monary hypoplasia, cranio-facial deformation and impaired ossification, intrauterine growth restriction and decreased placental and umbilical perfusion. Epidemiological studies demonstrated an increased risk of congenital malformations among neonates of mothers who received ACEIs and ARBs during pregnancy compared to controls.137
Several RCTs compared different antihypertensive drugs in pregnancy. A Cochrane systematic review included 24 RCTs that compared at least two anti- hypertensive drugs.138 The review did not come to a clear conclusion due to insufficient data. Hydralazine as compared to nifedipine and isradipine was seen to be less effective as regards persistent high blood pressure. No difference was detected between hy- dralazine and prostacyclin. Ketanserin is a selective S2-serotoninergic antagonist exerting alpha-1 receptor antagonistic action, especially with higher doses of the drug. It inhibits the vasoconstriction and platelet aggregation induced by serotonin.139
Hydralazine was associated with lower risk for per- sistent high blood pressure as compared to ketanserin but with increased rate of adverse effects. Urapidil is an alpha-1 receptor antagonist with agonistic action at serotonin 5-HT1A receptors. It also has a central sympatholytic effect mediated via stimulation of sero- tonin 5HT1A receptors in the central nervous system. It reduces blood pressure by decreasing peripheral vascular resistance.140 Studies comparing hydralazine to urapidil provided insufficient data. One prospective study of 100 women with severe PIH showed that urapidil was effective in 80% of cases.141
Data were also insufficient as regards the com-
parison of labetalol to hydralazine, methyldopa and nicardipine. Labetalol was associated with marginally less hypotension and caesarian section rate compared to diazoxide. MgSO4 had a higher risk of persistent high blood pressure, of maternal respiratory distress and of postpartum haemorrhage but a lower risk of eclampsia compared to nimodipine. Isosorbide was associated with lower frequency of caesarian section than MgSO4.
An RCT of 200 pregnant women who were treated with hydralazine IV or labetalol for severe PIH re- sulted in a significantly higher rate of palpitations and maternal tachycardia in the hydralazine-treated group and higher rate of hypotension and bradycardia in the labetalol-treated group.142 Another smaller (n=16) trial of hydralazine or labetalol in acute severe PIH revealed the high effectiveness of both drugs, with no effect of either of them on fetal Doppler.143 In contrast, the group that received hydralazine had a significant increase in uterine arteries resistance. Hydralazine IV as compared to mini bolus diazoxide resulted in a significantly higher rate of persistent hypertension.144 The latter was also observed in a trial of hydralazine IV or nifedipine per os in hypertensive crisis. Another smaller study of dihydralazine and urapidil found no difference as regards effectiveness between the two drugs.145 Treatment with nitroglycerine IV plus plasma volume expansion and MgSO4 as compared to sublingual nifedipine plus plasma volume expansion and MgSO4 showed no difference in effectiveness or maternal and fetal-neonatal adverse effects.146 Finally, a double-blind RCT of nifedipine per os versus labetalol IV resulted in no significant difference in the time needed to achieve the therapeutic goal or the overall efficacy between the two drugs.147
Acute severe hypertension in pregnancy is consid- ered a medical emergency and requires hospitaliza- tion. Labetalol, hydralazine and nifedipine are used as first line treatment.148 A double-blind randomized trial compared the effectiveness of oral nifedipine and intravenous labetalol in pregnant women with gestational hypertension and BP ≥160/110 mmHg. No significant difference in BP decrease was found between the two groups.149 Intravenous nitroglycerin, oral methyldopa or oral clonidine can be used as second line treatment.148 Magnesium sulfate can be used in combination with an antihypertensive agent