Role of antihypertensive therapy in mild to moderate pregnancy-induced hypertension: a prospective randomized study comparing labetalol with alpha methyldopa

Background

Pregnancy-induced hypertension (PIH) is associated with adverse fetal and maternal outcome. The role of medication to control blood pressure (BP) in mild to moderate PIH is controversial.

Aims

We conducted a prospective study to investigate whether pharmacological treatment of mild to moderate PIH is effective in improving maternal and fetal outcomes.

Methods

A total of 150 consecutive pregnant women without proteinuria and with physician-recorded systolic BP of 140–160?mmHg and/or diastolic BP of 90–105?mmHg on two occasions ≥6?h apart between 20 and 38?weeks of gestation were randomly allocated to receive either labetalol or methyldopa (50 patients each) plus standard care (treatment group) or only standard care (50 patients) (control group).

Results and conclusions

As compared to the control group, the treatment group had lower rates of severe PIH (28% vs. 10%, P?=?0.005), proteinuria (28% vs. 12%, P?=?0.016), hospitalization before term (28% vs. 14%, P?=?0.041), and delivery by cesarean section (38% vs. 22%, P?=?0.042). In a multivariable logistic regression model that adjusted for maternal age, weight, parity, previous PIH, and baseline hemoglobin, resting heart rate, and BP levels, antihypertensive therapy was associated with a lower incidence of adverse maternal events (P?=?0.011). Compared to the control group, the treatment group had lower incidence of SGA babies (40% vs. 23%, P?=?0.033), preterm birth (36% vs. 14%, P?=?0.002), and admission to neonatal unit (30% vs. 15%, P?=?0.036). After adjustment for maternal age, weight, baseline hemoglobin, resting heart rate, BP level, parity and previous history of PIH, fetal death, preterm delivery or SGA baby, antihypertensive therapy was associated with a lower incidence of adverse perinatal events (P?=?0.016). Maternal and perinatal mortality rates were not significantly different between treatment and control groups. In conclusion, pharmacological treatment of mild to moderate PIH is associated with lower rate of some maternal and fetal-neonatal non-fatal adverse events compared to no routine use of antihypertensive therapy.     

Conservative treatment of mild and moderate hypertension in pregnancy.

In a prospective study regarding conservative treatment of mild to moderate hypertension in pregnancy 5244 women were evaluated at delivery. Two hundred and fifty-eight (4.9%) were registered as hypertensive during pregnancy with a blood pressure (BP) greater than or equal to 140/90 mmHg. One hundred and ninety-six of these continued their pregnancy without medication and 96/196 were defined as preeclamptic (PE), 45/196 as chronic hypertensive (CH), and 55/196 as having gestational hypertension (GH). In 62/258 women antihypertensive treatment was initiated in the mean 6.5 (+/- 8.7) days after onset of hypertension, due to a BP greater than or equal to 150/100 mmHg. There was a later onset of hypertension in the untreated group, and BP at delivery differed in the untreated groups (p less than 0.001) with the lowest BP in women with mild GH. There was no difference in cesarean section rate in the mild hypertensive group as compared to the normal population. Birth weight and length of pregnancy were significantly lower in the untreated mild hypertensive group as compared to normal pregnant women (p less than 0.05). But in the subgroup with mild GH pregnancy length and birth weight did not differ from normal pregnancy. The conclusion from our study is that women with mild hypertension in pregnancy might refrain from antihypertensive therapy if they are closely observed during pregnancy and delivery, especially if there has been no hypertension before pregnancy and no proteinuria develops.     

Nifedipine versus expectant management in mild to moderate hypertension in pregnancy

Objective To compare the effect of routine treatment with the calcium channel blocker nifedipine in mild to moderate hypertension in pregnancy.
Design Randomised clinical trial.
Setting General and University hospitals.
Participants Pregnant women, between 12 and 34 weeks of gestation, with chronic, pregnancy-induced or unclassifiable hypertension and diastolic pressure between 90 and 110 mmHg.
Methods 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.
Results 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 041.1). 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.
Conclusions 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.     

A randomised placebo controlled trial of labetalol in the treatment of mild to moderate pregnancy induced hypertension.

OBJECTIVE: To determine the need for, and efficacy of, treatment with labetalol in women with mild-to-moderate pregnancy induced hypertension (PIH). DESIGN: Prospective double-blind randomised placebo controlled study. SETTING: Maternity units of five hospitals in the Trent Region. SUBJECTS: 144 women (86 primigravid) who developed PIH after 20 weeks gestation. INTERVENTIONS: Treatment with oral labetalol up to 600 mg daily or placebo with subsequent care of treatment failures in accordance with the attending obstetrician's practice. MAIN OUTCOME MEASURES: Number of days spent as an antenatal inpatient; the development of proteinuria; the perceived need for induction of labour or elective caesarean section; and gestation age at delivery. RESULTS: Labetalol significantly lowered the blood pressure and reduced the incidence of proteinuria. However, neither the number of days spent as an antenatal inpatient, nor the perceived need for induction of delivery or elective caesarean section, nor the gestation age at delivery differed significantly between the two treatment groups. Post-randomisation consideration of early (< or = 32 weeks) and late (> 32 weeks) onset groups showed the placebo treated early-onset group (n = 15) to have more patients with severe hypertension (> 150/110 mmHg) and a greater requirement for additional antihypertensive therapy prior to labour than the group treated with labetalol (n = 16). CONCLUSION: Anti-hypertensive intervention therapy in pregnancy induced hypertension has been examined using a placebo controlled randomised double-blind trial of labetalol in pregnancy. The maximum blood pressure prior to labour and the incidence of proteinuria was reduced in women on active therapy. However, the length of gestation was not significantly prolonged and indices of clinical outcome were not significantly altered. The appropriateness of pharmacological therapy for late-onset PIH may be questioned.     

Pregnancy outcomes of expectant management of stable mild to moderate chronic hypertension as compared with planned delivery

Objective

To compare outcomes between elective delivery at 37 weeks of pregnancy and expectant management among pregnant women with mild to moderate chronic hypertension.

Methods

In a two-center study, 76 women with mild to moderate chronic hypertension were randomly allocated to planned delivery at 37 completed weeks (group A) or expectant management for spontaneous onset of labor or reaching 41 weeks (group B) between April 2012 and October 2013. Differences were compared by t test, χ² test, or Fisher exact test. Odds ratios (ORs) with 95% confidence interval (CIs) were determined.

Results

There were no differences in superimposed pre-eclampsia (SPE), severe hypertension, preterm delivery, placental abruption, oligohydramnios, intrauterine growth restriction, or perinatal mortality between the groups. Group B had higher gestational age at delivery (P = 0.001) and birth weight (P = 0.01), but lower cesarean (OR 3.4; 95% CI, 1.2–10.3; P = 0.03) and neonatal care unit admission (OR 5.4; 95% CI, 1.4–21.0; P = 0.01) rates. More women with SPE were diagnosed before than after 37 weeks in group B (P = 0.01). Overall, patients who developed SPE had more adverse pregnancy outcomes than those who did not.

Conclusion

Mild to moderate chronic hypertension could be managed expectantly up to 41 weeks if SPE did not develop.     

Plasma volume findings in patients with mild pregnancy-induced hypertension

With the Evans blue dye-dilution technique, plasma volume was serially measured at 29 to 33 weeks' and 34 to 40 weeks' gestation in 74 pregnant women with documented mild pregnancy-induced hypertension (PIH) and 25 well-matched normotensive primigravid women. The relationship of plasma volume to clinical course, perinatal outcome, and other laboratory findings was subsequently analyzed. The patients with mild PIH were categorized into two groups based on infant outcome: appropriate for gestational age (AGA) and small for gestational age (SGA). The mean age, height, and hematocrit of the study and control patients were similar. The group of patients with mild PIH had significantly higher mean arterial blood pressures and uric acid levels (p less than 0.001). There was no difference in mean plasma volume findings between the normotensive group and the mild PIH group delivered of AGA infants. Plasma volume was reduced only in pregnancies with mild PIH with delivery of SGA infants. It is concluded that plasma volume is not reduced in most patients with mild PIH. However, plasma volume might be useful in identifying a subgroup of patients with mild PIH at risk for delivering an SGA infant.     

Calcium dobesilate lowers the blood pressure in mild to moderate midtrimester hypertension: a pilot study

To test the effects of calcium dobesilate (Doxium) in pregnancies complicated with pregnancy-induced hypertension or mild/moderate pre-eclampsia a double-blind, placebo-controlled pilot study was carried out. Primigravida patients (gestational age 相似文献   

Comparison of antihypertensive efficacy and perinatal safety of labetalol and methyldopa in the treatment of hypertension in pregnancy: a randomized controlled trial

Summary. 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 betablockade with labetalol is as safe as methyldopa for the fetus and the newborn.     

Haemodynamics of mild hypertension in pregnancy.

One hundred and sixty-three haemodynamic studies were done serially in 23 normotensive and 25 mildly hypertensive women during pregnancy. With all subjects resting in the left lateral position, heart rate, cardiac output, stroke volume, left ventricular work index, total peripheral vascular resistance and haematocrit were all significantly higher while plasma volume per unit body weight was significantly lower in the hypertensive than in the normotensive pregnant women. It is postulated that this hyperkinetic circulatory state is due to hyperactivity of the sympathetic adrenergic component of the autonomic nervous system in hypertensive pregnancy.     

Characteristics of uterine contractility during menses in women with mild to moderate endometriosis

Objective: To establish the role of uterine contractions in retrograde menstruation with subsequent abdominal implantation of endometrial tissue.

Design: Controlled prospective study.

Setting: University hospital-based study.

Patient(s): Infertile women with (n = 22) and without (n = 22) endometriosis.

Main Outcome Measure(s): Frequency, amplitude, and basal pressure tone of uterine contractions; correlation of contractions with retrograde bleeding and presence of viable endometrial cells; and dysmenorrhea before and 3 and 24 months after surgery.

Result(s): Compared with controls, patients with endometriosis had uterine contractions with higher frequency (22.73 ± 5.66 osc/10 min vs. 11.09 ± 3.26 osc/10 min), amplitude (20.83 ± 3.94 mm Hg vs. 6.77 ± 2.83 mm Hg), and basal pressure tone (50.14 ± 16.30 mm Hg vs. 24.68 ± 6.14 mm Hg). Dysmenorrhea was scored as 4.09 ± 1.44 in patients with endometriosis and 0.86 ± 1.42 in controls. Retrograde bleeding was found in 73% of patients with endometriosis vs. 9% of controls, and only 45% of patients with endometriosis had viable endometrial cells in the cul-de-sac.

Conclusion(s): Endometriosis may result from abnormal myometrial contractility through tubal transportation, dissemination, and implantation of endometrial viable cells into the abdomen.     

Comparison of analgesic activity of buprenorphine hydrochloride and morphine in patients with moderate to severe pain postoperatively

Since buprenorphine has been reported to be effectively analgesic yet free of addiction potential, two single-dose, double-blind, parallel studies were conducted to compare its analgesic activity and safety with those of morphine. The patients in each study consisted of patients experiencing moderate to severe postoperative pain. They were treated with an intramuscular injection of either 0.2 or 0.4 milligram of buprenorphine (Study I) or 0.15 or 0.30 milligram of buprenorphine (Study II) compared with 5.0 or 10.0 milligrams of morphine in both instances. Patients were interviewed prior to drug treatment and at 10, 20 and 30 minutes, and one, two, three, four, five and six hours postdose to determine pain intensity and relief. The degree of sedation, vital signs and side effects were evaluated. Buprenorphine generally appeared comparable to morphine in the onset and duration of action and in side effect liability.     

Comparative efficacy and tolerability of drotaverine 80 mg and ibuprofen 400 mg in patients with primary dysmenorrhoea--protocol DOROTA

OBJECTIVE: To compare efficacy and tolerability of drotaverine 80 mg and ibuprofen 400 mg in patients with primary dysmenorrhoea. MATERIALS AND METHODS: Nine-month, multicenter (11 study centers in Poland), randomised, double-blind, phase III study, conducted in two parallel group, included 345 women between the ages of 18 and 35, suffering from primary dysmenorrhoea with presence of moderate to severe pain in each of the last 3 cycles. Patients had regular menstrual cycles and used an adequate barrier contraception method with a negative pregnancy test before randomization. Patients were given 80 mg drotaverine or 400 mg ibuprofen and asked to assess the pain intensity rated on a 4 point categorical scale (0--none, 1--mild, 2--moderate, 3--severe) at baseline and 0.5, 1, 2, 3, 4, 5 and 6 hours after the first intake and evaluate the efficacy (excellent, good, fair, poor) at the end of the treatment period. They were also asked to asses the tolerance of the medication (excellent, good, fair, poor). RESULTS: The weighted sum of pain intensity differences over the 6-hour observation period (SPID-6) was calculated. The pain intensity before the first intake was comparable in the two groups. At the time-points, the decrease of pain was always greater in the ibuprofen 400 mg group, than in the drotaverine 80 mg group and was maximum at the 4th hour in the drotaverine 80 mg group (-1.2+/-1.18) and at the 3rd hour in the ibuprofen 400 mg group (-1.7+/-0.99). 41.8% patients treated with drotaverine and 68.6% patients treated with ibuprofen assessed drug efficacy as excellent or good. Although the patients' global assessment of tolerability was significantly better (p=0.02) with ibuprofen 400 mg (excellent or good: 86.8%), than with drotaverine 80 mg (excellent or good: 78.4%), no relevant difference between the both groups was observed for frequency, nature intensity and causality of the reported adverse events. CONCLUSIONS: After analizing the data statistically and clinically, significant differences in favour of ibuprofen 400 mg were evidenced for efficacy criteria. Ibuprofen was more efficient and the effect was faster, than drotaverine in relieving pain in dysmenorrhoea. Both drugs were well tolerated. The reported adverse events were typical drug reactions or expected events in patients suffering from dysmenorrhoea.     

A phase II study to determine the efficacy and tolerability of intravenous ZD9331 in heavily pretreated patients with ovarian cancer

OBJECTIVES: This Phase II, multicenter, open-label study was conducted to assess the efficacy and tolerability of ZD9331, a novel direct-acting thymidylate synthase inhibitor, in heavily pretreated patients with ovarian cancer. METHODS: The study recruited 44 women with ovarian cancer or primary peritoneal cancer previously treated with platinum therapy and paclitaxel and with progressive disease after, or intolerance to, topotecan administered as the most recent therapy. ZD9331 was administered as an intravenous infusion at 130 mg/m(2) on Days 1 and 8 of 3-week cycles, until objective evidence of disease progression. A cutoff date of 3 months after the last patient received the first dose was set for data collection. RESULTS: Patients received a mean of 3.3 cycles of ZD9331 and a total of 143 cycles were administered. Among the 42 patients evaluated for best overall tumor response, one achieved a complete response and two achieved a partial response, giving an objective tumor response rate of 7%. The complete response occurred at Day 15 of Cycle 2 in a patient receiving ZD9331 as her eighth-line therapy. Seven patients had stable disease, giving a disease control rate of 23%. Thirty-one patients (71%) had disease progression and the median time to progression was 53 days. Most patients (89%) experienced drug-related adverse events, most commonly nausea (73%), vomiting (48%), and neutropenia (50%). Six patients (14%) were withdrawn from treatment due to adverse events. CONCLUSIONS: The preliminary evidence of efficacy and acceptable tolerability of ZD9331 in this heavily pretreated population with ovarian cancer warrants further investigation, especially in a less heavily pretreated patient population.     

The efficacy and tolerability of Valette: a postmarketing surveillance study.

OBJECTIVES AND METHODS: A postmarketing survey was carried out to determine the efficacy and tolerability of Valette (dienogest 2.0 mg and ethinylestradiol 0.03 mg) in routine gynecological practice. RESULTS: Valette had excellent contraceptive efficacy (unadjusted Pearl index 0.14), with 11 unplanned pregnancies from a total of 92 146 cycles of exposure, of which at least four were attributable to user failure. Cycle control was good, with spotting and breakthrough bleeding, which affected 5.0% and 3.4% of women, respectively, during the first cycle, becoming less frequent thereafter. Silent menstruation, i.e. the absence of withdrawal bleeding, affected on average 2.0% of women per cycle and 5.9% within the observation period. Valette was well tolerated. The most common adverse drug reactions were mastalgia (1.46% of all users), weight gain (1.11%), headache (0.98%), nausea/vomiting (0.96%), dysmenorrhea (0.35%), decreased libido (0.31%) and depressive moods (0.28%). The dropout rate due to adverse drug reactions was only 3.2%. Only six of the 16 267 women reported events which were considered to be serious adverse drug reactions; all recovered with appropriate treatment. CONCLUSIONS: These results confirm those from previous clinical trials, and demonstrate that Valette is highly effective, very well tolerated and produces excellent cycle control in routine practice.     

Outpatient rapid 4-step desensitization for gynecologic oncology patients with mild to low-risk,moderate hypersensitivity reactions to carboplatin/cisplatin

Objective

The primary objective of this study is to assess the efficacy and safety of an outpatient, 4-step, one-solution desensitization protocol in gynecologic oncology patients with history of mild to low-risk, moderate hypersensitivity reactions (HSRs) to platinums (carboplatin and cisplatin).

Methods

This was a single institutional retrospective review. Gynecologic oncology patients with a documented history of mild or low-risk, moderate immediate HSRs to carboplatin/cisplatin and continued treatment with 4-step, one-solution desensitization protocols in the outpatient infusion center were included. Patients with delayed HSRs or immediate high-risk, moderate or severe HSRs were excluded. The primary end point was the rate of successful administrations of each course of platinums.

Results

From January 2011 to June 2013, eighteen eligible patients were evaluated for outpatient 4-step, one-solution desensitization. Thirteen patients had a history of HSRs to carboplatin and 5 with HSRs to cisplatin. All of 18 patients successfully completed 94 (98.9%) of 95 desensitization courses in the outpatient infusion center. Eight of 8 (100%) patients with initial mild HSRs completed 29/29 (100%) desensitization courses, and 9 of 10 (90%) of patients with initial moderate HSRs completed 65/66 (94%) desensitization courses. In total, 65/95 (68%) desensitizations resulted in no breakthrough reactions, and mild, moderate and severe breakthrough reactions were seen in 19%, 12% and 1% desensitizations, respectively. No patients were hospitalized during desensitization.

Conclusions

The outpatient rapid, 4-step, one-solution desensitization protocol was effective and appeared safe among gynecologic oncology patients who experienced mild to low-risk, moderate HSRs to carboplatin/cisplatin.