A prospective controlled trial of metoprolol-hydralazine treatment in hypertension during pregnancy. Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial. A randomized comparison of early with conservative use of antihypertensive drugs in the management of pregnancy-induced hypertension. Comparison of antihypertensive efficacy and perinatal safety of labetalol and methyldopa in the treatment of hypertension in pregnancy: a randomized controlled trial. Ephedrine and phenylephrine for avoiding maternal hypotension due to spinal anaesthesia for caesarean section. Effects on uteroplacental and fetal haemodynamics. Behavioral and physiological effects of a beta blocker and relaxation therapy on mild hypertensives. Beta-adrenergic blocking agents in the treatment of pregnancy-induced hypertension. [Management of severe pre-eclampsia/eclampsia. Comparison between nifedipine and hydralazine as antihypertensive agents]. Placebo-controlled trial of atenolol in treatment of pregnancy-associated hypertension. Nutritional factors and rest reduce pregnancy-induced hypertension and pre-eclampsia in positive roll-over test primigravidas. The fetal outcome in a randomized double-blind controlled trial of labetalol versus placebo in pregnancy-induced hypertension. Nifedipine or hydralazine as a first-line agent to control hypertension in severe preeclampsia. Nifedipine versus expectant management in mild to moderate hypertension in pregnancy. Gruppo di Studio Ipertensione in Gravidanza. Comparison of a chronotherapeutically administered beta blocker vs. a traditionally administered beta blocker in patients with hypertension. Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: the International Prospective Primary Prevention Study in Hypertension (IPPPSH). The IPPPSH Collaborative Group. Comparison of labetalol and dihydralazine in hypertensive emergencies of pregnancy. A randomized trial of tight vs. less tight control of mild essential and gestational hypertension in pregnancy. Effect of low-dose aspirin on vascular refractoriness in angiotensin-sensitive primigravid women. Treatment of severe preeclampsia with antithrombin concentrate: results of a prospective feasibility study.
In an open, controlled trial, treatment with a combination of metoprolol and hydralazine was compared with non-pharmacological management of mild and moderate hypertension in pregnancy. One hundred and sixty-one women participated in the study. The drug-treated group showed significantly better blood pressure control than the group not given antihypertensives. Induction of labor before term, because of maternal or fetal complications, was somewhat more frequent in the control group. Nine women in the treatment group and 5 in the control group developed albuminuria. Three infants in the drug-treated group died perinatally, and one in the control group. The outcome for the newborns was similar in both groups concerning birth weight, head circumference and Apgar score and in the frequencies of respiratory distress, bradycardia and hypoglycemia. The better blood pressure control achieved with these drugs makes it possible to treat the patient at home and reduce the risk of emergency delivery, but treatment does not seem to be mandatory for a good outcome of the pregnancy in cases of mild and moderate hypertension during pregnancy. Men aged 40-64 years with mild to moderate hypertension [diastolic blood pressure (DBP) 100-130 mmHg] were randomized to treatment with a diuretic (n = 3272) or a beta-blocker (n = 3297), with additional drugs if necessary, to determine whether a beta-blocker based treatment differs from thiazide diuretic based treatment with regard to the prevention of coronary heart disease (CHD) events and death. Patients with previous CHD, stroke or other serious diseases, or with contraindications to diuretics or beta-blockers were excluded. If normotension (DBP less than 95 mmHg) was not achieved by monotherapy, other antihypertensive drugs were added, but the two basic drugs were not crossed over. Patients were assessed at 6-monthly intervals. The mean follow-up for end-points was 45.1 months. Blood pressure (BP) side effects and end-points were recorded in a standardized manner. Entry characteristics and the BP reduction achieved were very similar in both treatment groups. All analyses were made on an intention-to-treat basis. The incidence of CHD did not differ between the two treatment groups. The incidence of fatal stroke tended to be lower in the beta-blocker treated group than in the diuretic treated group. Total mortality and the total number of end-points were similar in both groups. The percentage of patients withdrawn due to side effects was similar, whereas the number of reported symptoms, according to a questionnaire, was higher for patients on beta-blockers. The incidence of diabetes did not differ between the two groups. Subgroup analyses did not detect a difference in the effect of beta-blockers compared with diuretics in smokers as opposed to non-smokers, and beta-blockers also had the same effects as diuretics in the quartile with the highest predicted risk for CHD. Beta-blockers and thiazide diuretics were approximately equally well tolerated. The two drugs had a similar BP reducing effect although additional drugs had to be given more often in the diuretic group. Antihypertensive treatment based on a beta-blocker or on a thiazide diuretic could not be shown to affect the prevention of hypertensive complications, including CHD, to a different extent. Two treatment strategies were compared in 155 women with pregnancy-induced hypertension who were also given comprehensive non-pharmacological care. The mean gestation at entry was 28 weeks. As long as the diastolic blood pressure (DBP) remained below 106 mmHg, oxprenolol, or oxprenolol plus dihydralazine, were given to the early treatment group, and matching placebos to the control group. Open antihypertensive treatment was provided for patients whose DBP rose above 105 mmHg. Proteinuria occurred in seven women in each group. In the early treatment group, 13 of the 78 women were delivered by caesarean section; the corresponding numbers in the control group were 27 of 76 (17 vs 36%, 95% confidence interval (CI) of difference: 5-33%); the sections included seven and 16 in the early treatment and control groups, respectively, for severe hypertension and/or fetal distress. There were five perinatal deaths, two in the early treatment group and three in the control group. Early treatment did not influence gestational age at birth or birthweight. Respiratory distress syndrome occurred in four infants in the early treated group and in 10 in the control group; 14 infants in the former group and 26 in the latter were in hospital for more than 10 days (18 vs 35%; 95% CI of difference 4-32%). These results indicate that early antihypertensive treatment with oxprenolol is safe for the fetus and newborn in pregnancy-induced hypertension, but has no advantage over non-pharmacological care in terms of fetal growth. However, it may prevent acute hypertension in late pregnancy and associated fetal distress, and thus reduce the number of caesarean sections. Labetalol was compared with methyldopa in a randomized controlled trial involving 176 pregnant women with mild to moderate hypertension. Diastolic blood pressure below 86 mmHg was obtained in a similar proportion of women given labetalol or methyldopa. Intrauterine death occurred in four women treated with methyldopa, and the one neonatal death on day 1 occurred in the labetalol group. The average birthweight and the proportion of preterm or small-for-gestational-age babies were similar in both groups. Heart rate, blood pressure, blood glucose, respiratory rate, and Silverman score of the babies did not differ between the two treatment groups, whether the comparison was made for all the infants, or only for those that were preterm or small-for-gestational-age. These data indicate that maternal beta-blockade with labetalol is as safe as methyldopa for the fetus and the newborn. The effects of i.v. vasopressors on Doppler velocimetry of the maternal uterine and placental arcuate arteries and the fetal umbilical, renal and middle cerebral arteries were studied during spinal anaesthesia in 19 healthy parturients undergoing elective caesarean section. Fetal myocardial function was investigated at the same time by M-mode echocardiography. The patients were randomized into two groups, to be given either ephedrine or phenylephrine as a prophylactic infusion supplemented with minor boluses if systolic arterial pressure decreased by more than 10 mmHg from the control value. Both the vasopressors restored maternal arterial pressure effectively. The ephedrine group showed no significant differences in any of the Doppler velocimetry recordings relative to the baseline values, but during the phenylephrine infusion the blood flow velocity waveform indices for the uterine and placental arcuate arteries increased significantly and vascular resistance decreased significantly in the fetal renal arteries. Healthy fetuses seem to tolerate these changes in uteroplacental circulation well, however, since the Apgar scores for the newborns and the acid-base values in the umbilical cord were within the normal range in both groups. The results suggest that some caution is required when selecting the specific vasopressor agent, the dosage and the mode of administration for the treatment of maternal hypotension secondary to spinal anaesthesia for caesarean section. In this industrial-based study we compared the blood pressure (BP)-lowering effectiveness of relaxation, a beta blocker, and the combined use of these two treatments in 47 untreated, mildly hypertensive blue collar steel workers. Using a randomized two by two factorial design, patients received either nadolol or placebo drug daily, and either a relaxation training or an education program, each lasting 8 weeks. A pre-intervention and post-intervention stress test measured response of heart rate and BP to mental and physical tasks. BP assessments were done at baseline, post-intervention, 1 month, and 3 month follow-up. Change in several self-report measures was determined. Results showed that beta blocker was more effective in lowering BP than placebo, but relaxation was not more effective in lowering BP than health education. The combined effect of beta blocker and relaxation was not superior to beta blocker alone. Compliance with relaxation practice was not superior to compliance with medication. We conclude that pharmacologic treatment is superior to the relaxation therapy tested. Fifty-one women with pregnancy-induced hypertension (PIH) were randomly allocated to one of three treatment groups: A: hydralazine (13); B: hydralazine and propranolol (17); and C: hydralazine and pindolol (19). All women fulfilled the pretreatment criteria and were of similar age, numbers of previous pregnancies and had systolic blood pressure (SBP) of between 140 and 160 mmHg and diastolic blood pressure (DBP) of between 95 and 110 mmHg. Hypertension was treated equally well by all three regimens (mean SBP was 133.6, 130 and 134 mmHg, respectively). Heart rate was significantly higher than baseline in group A and lower in groups B and C, as is to be expected with beta-blocker treatment. Side-effects were more frequent in group A than in groups B and C, 62% of the patients on hydralazine monotherapy complained of palpitations compared to 35% on combination treatment. Fetal outcome differed in the various groups. Birth weight was significantly lower in group B, where regimen included propranolol, compared to that of group C, for whom the regimen included pindolol (3,044.7 +/- 443.8 and 2,709.6 +/- 485.5 gm, p < 0.05). Mean blood glucose of the newborns were similar in groups A and C (76.5 +/- 16.5 and 78.6 +/- 15 gm%) and significantly lower in group B (62.6 +/- 14 gm%, p < 0.02). In conclusion, blood pressure was equally well treated in all three treatment groups. However, more maternal side-effects occurred in group A, the group treated with hydralazine monotherapy, while propranolol in combination with hydrazaline (group B) had some negative effects on fetal development which did not occur in pindolol/hydrazaline combination. The objective was to compare the fetal and maternal effects between parenteral hydralazine and sublingual nifedipine used like antihypertensive drugs in the management of severe preeclampsia. Study design was prospective, comparative, longitudinal, randomized clinical trial. It was carried out at Centro Medico Nacional IMSS Torreon, Coah. Gynecology and Obstetrics Department. The patients were women in the last trimester of pregnancy with severe preeclampsia were randomized to receive parenteral hydralazine or sublingual nifedipine as antihypertensive drugs. The only difference observed in this study was the Apgar of neonates whose mothers received hydralazine, that was significatively lesser than the Apgar of neonates whose mothers received nifedipine. Both medicaments are a good alternative as antihypertensive drugs in severe preeclampsia. Neonates whose mothers received Nifedipine had a higher Apgar. Atenolol was compared with placebo in a randomised and double-blind prospective study of 120 women with mild to moderate pregnancy-associated hypertension who were also initially managed conventionally by bed rest. Atenolol given once daily significantly reduced blood-pressure, prevented proteinuria, and reduced the number of hospital admissions. Loss of blood-pressure control leading to withdrawal from the study was commoner among the placebo group, whose babies had a high morbidity. Respiratory distress syndrome occurred only in the placebo group. Intrauterine growth retardation, neonatal hypoglycaemia, and hyperbilirubinaemia occurred with the same frequency in the two groups. Neonatal bradycardia was more common after atenolol but the systolic blood-pressure of the babies was the same in both groups. There was no difference between the groups in maternal symptoms which could have been attributed to beta-blocker therapy. Thus atenolol is more effective than conventional obstetric management in this form of hypertension and does not adversely affect mother or baby. The possibility of reducing pregnancy-induced hypertension and preeclampsia in primigravidas with low doses of nutritional factors and relative rest in the left lateral position was investigated in a randomized controlled, double-blind trial.
                Seventy-four normotensive women at 28-29 weeks' gestation, judged to be at risk of PIH or pre-eclampsia because they presented with a mean blood pressure of 80 mmHg or higher and a positive roll-over test, were studied. The treatment protocol was received by 37 women and the other 37 women received standard antenatal control until delivery.
                Twenty-nine (78.3%) women in the control group developed PIH and/or pre-eclampsia, as opposed to only 4 (10.8%) cases in the treatment group (P < 0.001). There were no adverse effects of treatment in mothers or in infants.
                This protocol reduces PIH and pre-eclampsia in primigravidas judged to be at risk of hypertension. Further studies are required to evaluate prostacyclin and prostaglandin E2 changes. The effects of labetalol were compared with those of placebo in a multicentre randomized double-blind and prospective study of 152 patients with mild to moderate, non-proteinuric pregnancy-induced hypertension. Labetalol in a dose of 100 mg three times daily, increasing to 200 mg three times daily where required, significantly reduced maternal mean arterial pressure. There was some reduction in preterm delivery, neonatal respiratory distress syndrome and jaundice in the labetalol-treated group. Intrauterine growth retardation and neonatal hypoglycaemia occurred with the same frequency in both groups. There were no perinatal deaths. Labetalol appears to be an effective agent in the management of mild to moderate pregnancy-induced hypertension. The data from this study suggest possible advantages and no apparent disadvantages for the fetus during its use. Pre-eclampsia is one of the most serious and common complications of pregnancy. Nifedipine, a calcium channel blocker, and the vasodilator hydralazine have both been used as antihypertensive agents in this condition. The aim of this study was to determine which of these two agents is the most appropriate antihypertensive in the management of severe pre-eclampsia.
                One hundred and twenty-six pre-eclamptic patients with a gestational age of more than 20 weeks were randomized to receive either 8 mg nifedipine sublingually or 5-10 mg intravenous hydralazine. Women with a history of heart failure and women receiving antihypertensive treatment during the course of the current pregnancy were excluded. For each patient the following data were recorded; the number of drug administrations, the time needed to control blood pressure, mean urinary output, the time interval between effective control and a new hypertensive crisis after each drug administration and relevant adverse effects in mother or fetus.
                Effective control of blood pressure was achieved in both treatment arms. Data analysis indicated significantly fewer drug administrations in the nifedipine arm of the study. The time interval before a new hypertensive crisis following initial effective control of blood pressure was significantly longer in the nifedipine group when compared with hydralazine. Effective control of blood pressure was achieved more rapidly in multiparous patients receiving nifedipine (p=0.026). Mean urinary output before and after delivery was greater in the nifedipine arm of the study. There were no significant differences between the two groups in other variables. In addition, in neither group were there any serious adverse effects in mother or fetus.
                Nifedipine is safe and more effective than hydralazine in controlling blood pressure in severe pre-eclampsia. It has the added advantage of being cheaper and more widely available than the latter and is easily administered. To compare the effect of routine treatment with the calcium channel blocker nifedipine in mild to moderate hypertension in pregnancy.
                Randomised clinical trial.
                General and University hospitals.
                Pregnant women, between 12 and 34 weeks of gestation, with chronic, pregnancy-induced or unclassifiable hypertension and diastolic pressure between 90 and 110 mmHg.
                Eligible women were randomly assigned treatment with slow-release nifedipine, 10 mg twice daily until delivery, or no treatment. In the no treatment group nifedipine was given if the diastolic pressure exceeded 110 mmHg. A total of 145 women were assigned nifedipine and 138 no treatment.
                In the nifedipine group 45.0% of women were delivered before term, compared with 37.0% in the no treatment group; the difference was not significant. In all, 56.3% of women allocated nifedipine and 62.1% allocated no treatment underwent caesarean section; the difference was not statistically different (OR 0.7, 95% CI 0.4-1.1). There was no significant difference between the two groups in the percentage of babies weighing less than the 10th centile (OR 0.8; 95% CI 0.4-1.4) or in the mean birthweight. The frequency of admission of infants to the neonatal intensive care unit was not affected by treatment.
                This trial found no benefit on pregnancy outcome of routine treatment with nifedipine. In clinical practice, the treatment of hypertension in pregnancy may be delayed until the hypertension becomes severe. Increasing systolic blood pressure and heart rate during the early morning results in increased myocardial oxygen demand. The use of beta blockers during this period may decrease cardiac workload, particularly in beta-blocker sensitive patients. The impact of a new chronotherapeutic beta blocker was assessed in 44 hypertensive patients. Patients were randomized to delayed-release propranolol (INP) dosed at 10 p.m. or to traditionally dosed propranolol (ILA) dosed at 8 a.m. for 4 weeks, following which they were switched to the alternative formulation for 4 weeks. Thirty-four-hour ambulatory blood pressure monitoring and pharmacokinetic measurements were obtained. INP and ILA resulted in significant reductions in mean 24-hour blood pressure (-9.0/-6.9 mm Hg and -10.4/-7.7 mm Hg, respectively). The top 25% of responders to high-dose propranolol (sensitive patients) were compared on each formulation. Mean trough reductions were -8.0/-6.7 mm Hg and -7.6/-5.8 mm Hg, respectively. Mean blood pressure reductions in the beta-blocker sensitive patients (n = 11) between 6 a.m. and noon were -15.2/-11.9 mm Hg on INP and -8.0/-4.6 mm Hg on ILA. Heart rate reduction was -14.1 bpm and double product reduction was -3319 in the INP patients between 6 a.m. and 12 noon compared with -10.5 and -2209 in the ILA patients. This study suggests that INP and ILA are effective once-a-day beta blockers, but the use of delayed-release propanolol results in a greater reduction in double product between 6 a.m. and noon in beta-blocker sensitive patients than does traditionally dosed propranolol. Myocardial infarction, sudden cardiac death, cerebrovascular accidents, blood pressure control and treatment tolerability were studied in a randomized double-blind trial conducted in 6357 men and women aged 40-64 years with uncomplicated essential hypertension (diastolic blood pressures 100-125 mmHg). At the start of the trial 3185 patients received treatment based on a beta-blocker (oxprenolol), while in the remaining 3172 placebo replaced oxprenolol. Supplementary drugs, excluding beta-blockers, were used as necessary in both treatment groups, with the aim of reducing diastolic pressure to 95 mmHg or less. Patients were followed for 3-5 years, a total of 25 651 patient years at risk. In most respects the two groups fared equally well; sudden death (relative risk [RR] 1.08; 95% confidence interval [Cl] 0.68 and 1.72), myocardial infarction (RR 0.83; Cl 0.59 and 1.16) and cerebrovascular accident (RR 0.97; Cl 0.64 and 1.47) rates were similar. Beta-blocker based therapy was associated with significantly lower average blood pressures, earlier ECG normalization, less hypokalaemia and fewer withdrawals from double-blind treatment for uncontrolled hypertension. Doctor-elicited and patient-assessed unwanted effects demonstrated overall good tolerability. In smokers the cardiac event rate was doubled. We propose that beta-blocker treatment effects depend on smoking status, with a significant interaction benefiting non-smoking men. Lower blood pressures during treatment were associated with substantially lower rates for cardiac as well as cerebrovascular events. Proportional hazards analysis also underlines the importance of other cardiovascular risk factors. The IPPPSH stresses the need for a comprehensive approach to the management of blood pressure and other risk factors in hypertensive patients. Labetalol (Trandate; Allen & Hanburys), a combined alpha- and beta-adrenergic blocking agent, was compared with the more commonly used peripheral vasodilator, dihydrallazine (Nepresol; Ciba), each administered as an infusion, in the treatment of severe hypertension in 20 primigravidas at greater than or equal to 32 weeks' gestation. With the dosage regimen used in this study there was a tendency towards more effective blood pressure control with dihydrallazine. The pulse rate was unaffected by labetalol therapy and there were no harmful effects on the neonate or fetus directly attributable to either drug. To assess the effects of applying a tight vs. a less tight control of mild chronic essential or gestational non-proteinuric hypertension in pregnancy.
                A randomized trial was conducted in 2006-2007 in the University of Ain Shams, Egypt. Eligible participants (n=125) were randomly assigned to either tight or less tight control of mild chronic (essential) or gestational (non-proteinuric) hypertension. The primary outcome measure was the development of severe hypertension during follow-up. Analysis was by intention-to-treat.
                In the tight target group, adjustment of the dose with an increment of 191 mg yielded a mean dose of methyldopa of 1267+/-406 mg. Both systolic and diastolic BP levels were significantly less than in the tight target group. More women in the less tight group had severe hypertension during follow up (RR 3.167 and 95% CI 1.36-7.37). The rate of antenatal hospitalization was significantly higher in the less tight target group with a relative risk of 2.57 and 95% CI 1.16-5.70. The gestational age at delivery was significantly better in the tight target group. Preterm delivery and birth weight were not significantly different between the study groups.
                Tight control of blood pressure reduces the rate of antenatal hospitalization and does not adversely affect perinatal outcomes in women with mild essential or gestational hypertension. The hypothesis that an enhanced vasopressor response to angiotensin II in pregnancy may be corrected by suppressing production of platelet thromboxane A2 with low-dose aspirin was tested in a randomized, placebo-controlled, double-blind trial. We studied 36 normotensive primigravid women with an elevated blood pressure response to intravenously infused angiotensin II at 28 weeks' gestation; 18 women received 60 mg of aspirin daily and the same number received matched placebo until 34 weeks' gestation, when angiotensin-sensitivity was again determined. In women taking aspirin, values of thrombin-induced platelet malondialdehyde production were approximately 10% of those determined in the placebo group, indicating marked suppression of thromboxane A2 synthesis. In the aspirin group vascular refractoriness to angiotensin II was restored in 14 of 17 treated women, by comparison with 5 of 15 women in the placebo group who had remained normotensive. These results support the hypothesis that prostacyclin/thromboxane imbalance is an important pathophysiologic factor in the development of the enhanced angiotensin-sensitivity associated with pregnancy-induced hypertensive disorders. The prospective feasibility study was designed to determine whether treatment with antithrombin (AT) concentrates could be used for patients with severe preeclampsia to provide clinical efficacy without the full systemic antihypertensive drug. Twenty-nine severe preeclamptic patients (24 to 36 weeks of gestation, gestosis index [GI] >/= 6 points) were randomized to receive AT (1500 U/day) or not. AT was given intravenously once daily for 7 consecutive days. Twenty-four hours of continuous infusion of 5000 U/day of unfractionated heparin was given simultaneously in both groups. There were no statistical differences in the clinical profiles of the two groups. Maternal symptoms were evaluated from the difference of GI before and after treatment, and fetal findings were evaluated from the changes of the biophysical profile score. Improvement was significantly greater in the AT group for both the GI ( P = 0.046) and the biophysical profile score ( P = 0.022). The improvement of coagulation parameters was also evaluated. The improvement of plasmin-plasmin inhibitor complex (PPIC), D-dimer levels, and platelet counts was observed in the AT group compared with the non-AT group. The coagulation index as a composite coagulation test parameter showed a significantly improvement in the AT group. No adverse events related to AT were observed. Given that AT plus heparin was significantly better than treatment with heparin alone for improvement of both GI and biophysical profile of infant, it is suggested that therapy with AT alone might be effective enough for severe preeclampsia.
Improvement in control of maternal blood pressure with use of beta-blockers would be worthwhile only if it were reflected in substantive benefits for mother and/or baby, and none have been clearly demonstrated. The effect of beta-blockers on perinatal outcome is uncertain; the worrying trend to an increase in SGA infants is partly dependent on one small outlying trial. Large randomised trials are needed to determine whether antihypertensive therapy in general (rather than beta-blocker therapy specifically) results in greater benefit than risk, for treatment of mild-moderate pregnancy hypertension. If so, then it would be appropriate to consider which antihypertensive is best, and beta-blockers should be evaluated.
[Note: the seventeen reports in the awaiting classification section of the review may alter the conclusions of the review once assessed.]