Original Articles
Oral administration of labetalol might improve not only the blood pressure but also clinical symptoms in Japanese women with gestational hypertension
2014 年 2 巻 2 号 p. 82-87
詳細
2014 年 2 巻 2 号 p. 82-87
Aim: The aim of the present study was to investigate whether oral administration of labetalol, an αβ-blocker, might be useful for managing blood pressure (BP) in women with severe pregnancy induced hypertension (PIH).
Methods: Thirty-four pregnant women with severe hypertension (≥160/110 mmHg) were enrolled (15 preeclampsia [PE] and 19 gestational hypertension [GH]). Labetalol was given orally at 300–400 mg daily, and mean arterial pressure (MAP), the numeric rating scale (NRS) for headache, the double product (DP) as a work index of cardiac function, and fetal heart monitoring were observed for 3 days.
Results: Thirty patients continued to take labetalol for 3 days. Four PE patients were dropped out. Fifteen showed a decrease of more than 10% in MAP and were considered responders, while 19 showed a decrease of less than 10% and were considered non-responders. Labetalol appeared to be more effective in GH (11/19) than in PE (4/15). The NRS was improved in both groups (6 PE and 7 GH), as was DP (13 GH and 8 PE). Unfavorable changes in fetal heart rates were seen in 3 (1 PE and 2 GH).
Conclusion: The oral administration of labetalol might control the hypertension as well as the clinical symptoms in GH.
Labetalol shows antihypertensive actions through β-receptor and selective α1-receptor blockage. It does not affect cardiac output but does slowly decrease blood pressure (BP) by reducing peripheral vascular resistance.1) Furthermore, it may decrease cerebral perfusion pressure without affecting the cerebral flow index.2)
The Japan Society for the Study of Hypertension in Pregnancy (JSSHP) Guideline 2009 for care and treatment of pregnancy induced hypertension (PIH) recommended methyldopa and hydralazine as oral antihypertensive drugs. It also stated that labetalol and calcium antagonists should only be used after obtaining informed consent.3)
In 2011, the package inserts for long-acting nifedipine and labetalol were revised as follows: long-acting nifedipine can be administered after 20 weeks of gestation, and labetalol may be used in pregnant women or in those who may be pregnant, only when the advantage of treatment is considered to exceed its risk.
The Japan Society of Hypertension (JSH) Guidelines 2014 for the Management of Hypertension state that the basic treatment for PIH is the interruption of pregnancy, and maternal protection must be the main consideration with respect to antihypertensive therapy for this disease. According to the JSSHP criteria, PIH is classified into two types. In the mild type, BP ranges from 140/ 90 to 159/109 mmHg, and in the severe type, BP is more than 160/110 mmHg. Oral administration of an antihypertensive for PIH should be started when the BP is more than 160/110 mmHg to prevent maternal organ damage (cerebrovascular, cardiac, or renal damage) by prompt antihypertensive treatment.3,4) As the BP goal, systolic BP ranges from 140 to 159 mmHg, diastolic BP ranges from 90 to 109 mmHg, and mean arterial pressure (MAP) should be decreased by 15–20%.3)
It recommended that the first-choice antihypertensive oral drugs, methyldopa, hydralazine, labetalol, and long-acting nifedipine (only after 20 weeks of gestation), should be used. For combination therapy, a combination of two drugs with different antihypertensive action mechanisms is desirable, since methyldopa and labetalol are classified as sympatholytic drugs, and hydralazine and long-acting nifedipine are classified as vasodilators. Before 20 weeks of gestation, a combination of methyldopa and hydralazine or of labetalol and hydralazine is used. After 20 weeks of gestation, combination therapy with a sympatholytic drug (either methyldopa or labetalol) and a vasodilator (either hydralazine or long-acting nifedipine) should be performed.5) Furthermore, the treatment must be switched to intravenous injection therapy, such as nicardipine or hydralazine, when a hypertensive emergency (BP ≥180/120 mmHg) occurs, and BP control by oral drugs is inappropriate. During BP control by intravenous injection, careful attention should be paid to the fetal condition, with appropriate fetal heart rate monitoring.
According to the JSSHP definition, hypertension in pregnant women is of two types: pregnant women who develop PIH, and pregnant women with hypertension that developed pre-pregnancy or prior to 20 weeks of gestation, called chronic hypertension.6) According to the JSSHP criteria of PIH, PIH occurs after 20 weeks of gestation but resolves within 12 weeks after delivery. Furthermore, it consists of preeclampsia (PE), which shows hypertension and proteinuria, and gestational hypertension (GH), which shows hypertension without proteinuria. The differences between PE and GH are well documented, with PE being more severe and difficult to manage than GH. NICE guidelines thus recommended different management strategies for each condition. The pregnant period may be more prolonged in GH than in PE due to expectant therapy. Despite these documented differences, it remains unclear how the pathophysiology of these two conditions differ.
In this retrospective study, whether oral administration of labetalol might be useful for the management of PE and GH was examined.
This retrospective study was conducted in the Department of Obstetrics and Gynecology in Nagoya City West Medical Center. The protocol of this study was approved by the Clinical Investigation Ethics Committee of Nagoya City West Medical Center.
Study populationThirty-four women with severe hypertension (systolic BP ≥160 mmHg and/or diastolic BP ≥110 mmHg) during pregnancy were enrolled. PIH was retrospectively diagnosed according to the JSSHP criteria3) 3 months after delivery.
Fifteen patients had PE, and 19 had GH according to the JSSHP definition.6) Two patients had their pregnancies interrupted within 2 days of labetalol administration, and 2 patients with PE were added another antihypertensive drug within 2 days. Thus, 30 patients (11 PE and 19 GH) were analyzed in the present study. No patient with GH developed PE. Furthermore, 2 patients (1 non-responder GH and 1 PE) developed eclampsia.
Obesity (pre-pregnant BMI >25 kg/m2) was seen in 12 cases (4 PE, 8 GH). Late childbearing (age ≥35 years) was seen in 19 (4 PE, 15 GH). Obesity with late childbearing was seen in 9 (2 PE, 7 GH) (Table 1).
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Labetalol (300–400 mg daily) was given orally to patients with severe hypertension.
Determination of BPThe changes in systolic and diastolic BPs were observed. MAP was calculated as follows: MAP (mmHg)=(systolic BP+diastolic BP×2)/3.
PIH management guidelines 2009 recommended that BP should be gradually reduced with antihypertensive drugs during pregnancy and the rate of decrease in MAP should be less than 20%. Thus, MAP was considered an adaptive index of antihypertensive drug efficacy.
Moreover, our preliminary study suggested that BP was reduced and reached a plateau within 3 days after administration of labetalol in responders (4 PE, 11 GH).
In assessing antihypertensive effects, an effective decrease in MAP was defined as more than 10% (responders), while an ineffective decrease was defined as less than 10% (non-responders) on the third day after administration.
Evaluation of other effectsHeadache was evaluated using a numeric rating scale (NRS), ranging from 0 to 10. The change in NRS was observed on the third day after the start of drug administration.
The double product (DP), as a working index of cardiac function, was calculated as follows: DP (mmHg×bpm) = systolic BP×heart rate.
Furthermore, fetal heart rates were monitored during drug administration.
Statistical analysisStatistical analysis was performed using Excel Toukei 2012 (SSRI Co., Ltd., Tokyo, Japan). The decrease in MAP with labetalol treatment was evaluated by the paired t-test in PE and GH cases. Furthermore, the hypotensive action was compared between PE and GH cases by the chi-square test, with a significance level of P<0.05.
The decrease in NRS and the change in DP were evaluated by paired t-test in PE and GH cases, with a significance level of P<0.05.
MAP decreased in both groups (GH [117±9 before vs. 107±12 mmHg after, P<0.01], PE [117±9 vs. 108±9 mmHg, P<0.01]) (Table 1, Figure 1).
Effect of labetalol on the 3rd day after starting administration.
Mean arterial pressure (MAP) decreases more in gestational hypertension (GH) than in preeclampsia (PE). Fifteen cases are responders on the third day after the start of administration. Eleven of 19 were patients with GH, while 4 of 15 were patients with PE.
** P<0.01 vs. before administration.
In 15 patients, MAP decreased more than 10% (responders), while in 19 patients it decreased less than 10% (non-responders) on the third day after the start of labetalol administration. Most responders had GH (11/19), although a few had PE (4/15). Labetalol tended to be more effective in GH than in PE (P=0.06) (Table 2). Furthermore, 2 patients with GH showed a decrease of MAP more than 20%.
| Responder (n) | Non-responder (n) | Effective rate (%) | |
|---|---|---|---|
| PE (n=15) | 4 | 11 | 27 |
| GH (n=19) | 11 | 8 | 58* |
| PIH (n=34) | 15 | 19 | 44 |
*P=0.06 vs. PE by chi-square test.
PE, preeclampsia; GH, gestational hypertension; PIH, pregnancy induced hypertension.
For headache, the NRS was improved (1.6±2.4 vs. 0.4±0.8; P=0.04) in GH (n=19). The NRS improved in both groups (6 PE and 7 GH) (Table 1 and 3).
| Before | After | |
|---|---|---|
| PE (n=11†) | 1.3±1.6 | 0.3±0.5 |
| GH (n=19) | 1.6±2.4 | 0.4±0.8* |
*P<0.05 vs. before. †Four patients were dropped out.
The headache was evaluated by numeric rating scale (NRS, ranging from 0 to 10).
PE, preeclampsia; GH, gestational hypertension.
DP decreased (12,117±1,669 vs. 11,086±962 mmHg×bpm; P=0.049) in GH (n=19). Overall, DP improved in 13 GH and 8 PE cases (Table 1 and 4).
| Before | After | |
|---|---|---|
| PE (n=11†) | 11,952±2,180 | 10,949±1,582 |
| GH (n=19) | 12,117±1,669 | 11,086±962* |
*P<0.05 vs. before. †Four patients were dropped out.
DP was calculated as systolic BP (mmHg)×heart rate (bpm).
PE, preeclampsia; GH, gestational hypertension.
Abnormal cardiotocogram findings were seen in 1 GH case and 2 PE cases during labetalol administration (Table 1).
Labetalol has both β-receptor and selective α1-receptor -adrenergic blocking activities, and it may preserve uteroplacental blood flow to a greater extent than traditional β-receptor blockers. It has a more rapid onset of action than methyldopa (within two hours versus three to six hours). In pregnant women with hypertension, this drug has been relatively commonly used in Europe and the United States, and there may be no problems regarding its safety.7,8)
Randomized trials comparing labetalol to nicardipine or methyldopa have shown that labetalol is effective and generally safe in pregnancy, although data are limited.9) A meta-analysis has shown that it was more useful than hydralazine with respect to adverse effects on the maternal condition.10)
Recently, it has become well-known that PE and GH have different pathogenetic mechanisms. The NICE guideline recommended different approaches to managing PE and GH, although oral labetalol is the first drug.11)
In PIH, especially PE, the definitive treatment of PE is delivery, which is always beneficial for the mother. As long as the pregnancy continues, the risk of complications such as seizures, placental abruption, thrombocytopenia, cerebral hemorrhage, pulmonary edema, liver hemorrhage, and acute kidney injury increases, but the risk of these complications subsides in the hours after delivery. However, delivery may not be beneficial for the fetus if it is born preterm. Although the fetus has an increased risk of fetal growth restriction and stillbirth in the preeclamptic environment, conservative management, including antihypertensive therapy, may be pursued in selected cases to gain fetal maturity.
In the present study, 4 patients with PE dropped out within 2 days of initiating labetalol treatment. Two had another antihypertensive drug added, while 2 had their pregnancies interrupted. In less than 50% (15 of 34) of patients with PIH did labetalol decrease BP effectively (i.e. MAP decreased more than 10%). However, the efficacy of labetalol was greater in patients with GH (58%) than in those with PE (27%). Furthermore, 4 patients with PE could not receive labetalol for 3 days. Thus, this ensured that labetalol would be more effective in patients with GH than in patients with PE. Patients with PE might have difficulty controlling BP and frequently need to interrupt their pregnancy within 3 days. The present study identified that labetalol might be more effective in patients with GH. Since the severity of hypertension in PE was similar to patients with GH, the difference between two might be independent of disease severity. We are currently analyzing the circadian rhythm of both PE and GH by ambulatory blood pressure measurement. Although the sample size was small (10 PE and 6 GH), our preliminary data suggested that the disappearance of circadian rhythm in pulse, indicated as possibly sympathetic nerve system was seen in PE compared with that in GH (data not shown, unpublished data). From these results, we speculated that labetalol, β- and selective α1- adrenergic receptor blocker do not effectively reduce BP in patients with PE under the pathological states of sympathetic nerve system. It needs to clarify with this in the future work.
In patients with PIH, the symptoms are severe headache, problems with vision, such as blurring or flashing before the eyes, severe pain just below the ribs, vomiting, and sudden swelling of the face, hands, or feet. If precursor symptoms for the onset of eclampsia are present, drug therapy must be initiated promptly.12)
Headache was present in 15 patients with PIH. In most patients with PIH, the oral administration of labetalol improved headache. It is well-known that labetalol might decrease cerebral perfusion pressure without affecting the cerebral flow index.10) This might be involved in the improvement of headache. In the present study, 2 patients (one was a non-responder with GH and the other had PE) developed eclampsia.
Furthermore, labetalol could improve and decrease the load on cardiac function. Labetalol as a β-receptor blocker can inhibit the increase in heart rate together with decreasing BP.
During labetalol administration, the maternal and fetal states must be carefully observed to avoid an excessive decrease in BP. Appropriate treatment is needed under conditions of maternal BP fall and/or fetal bradycardia. According to the JSSHP PIH management guidelines 2009, an excessive BP decrease occasionally causes a uteroplacental circulation disorder, especially in severe hypertension and fetal growth retardation. BP should be decreased gently, with a BP goal decrease of less than 20/10 mmHg. Furthermore, it is desirable for MAP to subsequently be maintained at less than a 20% decreased from that before the start of therapy.3)
In the present study, in 2 patients with GH, MAP fell more than 20% with labetalol administration, but no persistent or transient fetal bradycardia occurred. Thus, the hypotensive action of oral administration of labetalol is relatively weak, though it is safe for the uteroplacental circulation.
In conclusion, from the present results, oral administration of labetalol appears to inhibit hypertension in GH. Furthermore, it might improve the clinical symptoms in GH.
This work was partly supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (26462496).
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