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1 doi: /j.ultrasmedbio Ultrasound in Med. & Biol., Vol. 37, No. 1, pp , 2011 Copyright Ó 2011 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved /$ - see front matter d Original Contribution CHANGES IN FETAL AND MATERNAL DOPPLER PARAMETERS OBSERVED DURING ACUTE SEVERE HYPERTENSION TREATMENT WITH HYDRALAZINE OR LABETALOL: A RANDOMIZED CONTROLLED TRIAL MARIA RITA F. BAGGIO,* WELLINGTON P. MARTINS,* y ANA CAROLINA S. CALDERON,* ADERSON T. BEREZOWSKI,* ALESSANDRA CRISTINA MARCOLIN,* GERALDO DUARTE,* and RICARDO C. CAVALLI* * Departamento de Ginecologia e Obstetrıcia, Faculdade de Medicina de Ribeir~ao Preto, Universidade de S~ao Paulo (DGO-FMRP-USP), Ribeir~ao Preto, S~ao Paulo, Brazil; and y Escola de Ultra-sonografia e Reciclagem Medica de Ribeir~ao Preto (EURP), Ribeir~ao Preto, S~ao Paulo, Brazil (Received 22 July 2010; revised 29 September 2010; in final form 7 October 2010) Abstract We evaluated 16 pregnant women with gestational age between 20 and 32 weeks in acute severe hypertension which were randomly allocated to receive either hydralazine or labetalol. Blood pressure and Doppler ultrasound parameters from maternal uterine and fetal middle cerebral and umbilical arteries were assessed during acute severe hypertension and after treatment. A significant reduction in systolic and diastolic blood pressure was observed in both groups. A significant change in Doppler parameters was observed only in pregnant women who received hydralazine: an increase in uterine arteries resistance index. We concluded that both drugs were highly effective in reducing blood pressure in these women. Despite the observed increase in resistance index of uterine arteries associated with hydralazine, the use of hydralazine and labetalol were not related to any significant changes in fetal Doppler, which is reassuring about the safety of these drugs when treating acute severe hypertension in pregnancy. ( wpmartins@gmail.com) Ó 2011 World Federation for Ultrasound in Medicine & Biology. Key Words: Hydralazine, Labetalol, Hypertension, Pregnancy-induced, Ultrasonography, Doppler. INTRODUCTION The hypertensive disorders affect approximately 6% of pregnant women (Povoa et al. 2008) and is one of the three leading causes of pregnancy-related deaths (Chang et al. 2003), which are embolism (20%), hemorrhage (17%) and pregnancy-induced hypertension (16%). Hypertensive disorders of pregnancy are also associated with impaired uteroplacental circulation and consequent intrauterine growth restriction (Miller et al. 2008). Hydralazine and labetalol are the most recommended drugs to control acute hypertension in pregnant women (ACOG 2002; NHBPEP 2000). Labetalol is a b-adrenergic blocker and nonselective a1 receptor blocker (Louis et al. 1984; Lund-Johansen 1984), which Address correspondence to: Wellington P. Martins, Departamento de Ginecologia e Obstetrıcia do Hospital das Clınicas - 8 andar, Faculdade de Medicina de Ribeir~ao Preto, Universidade de S~ao Paulo, Av Bandeirantes Campus da USP, Ribeir~ao Preto, S~ao Paulo, Brazil. wpmartins@gmail.com reduces the systemic vascular resistance without reducing cerebral, renal and coronary blood flow (Pearce and Wallin 1994). This drug has been used in pregnancyinduced hypertension because reduced placental transfer occurs, mainly due to low lipid solubility (Varon and Marik 2003). Hydralazine acts directly on smooth muscle, predominantly on the high resistance vessels (small arteries and arterioles) preserving the oxygenation of vital areas, such as the spleen, heart, brain and kidneys (Sato et al. 2003). However, the use of hydralazine was associated with higher rate of maternal hypotension, cesarean section, placental detachment, maternal oliguria and lower values for the 1 min Apgar compared with the use of oral nifedipine and labetalol (Magee et al. 2003) but the evidence was not sufficiently robust for clinical recommendation. The objective of treating severe hypertension is to avoid vascular damage (encephalopathy and hemorrhage) and congestive heart failure due to blood pressure elevation without causing excessive reduction in blood pressure that would critically affect uteroplacental 53

2 54 Ultrasound in Medicine and Biology Volume 37, Number 1, 2011 perfusion (Bolte et al. 2001; Vigil-De Gracia et al. 2006). In situations when uteroplacental perfusion is impaired, changes in uterine artery blood flow and subsequent adaptive changes in fetal circulation one should expect, what probably could be detected by Doppler ultrasound (Hoffman and Galan 2009). In this study we evaluate maternal blood pressure and Doppler ultrasound parameters of uterine, umbilical and middle cerebral arteries before and after acute severe hypertension treatment using either hydralazine or labetalol. METHODS Subjects Pregnant women in acute severe hypertension with gestational age between 20 and 32 weeks and body mass index #40 kg/m 2 were enrolled in this study. Acute severe hypertension was defined according to the guidelines of the National High Blood Pressure Education Program (NHBPEP): sustained high blood pressure: $160 mm Hg systolic, $105 mm Hg diastolic or both (NHBPEP 2000). We considered as sustained high blood pressure when high values were observed in two consecutive measurements at least 30 min apart. A total of 17 pregnant women who agreed to participate were randomly assigned to receive either labetalol or hydralazine but one was excluded from the study because both drugs were necessary to control blood pressure. Therefore, 16 patients were fully evaluated: eight were assigned to use hydralazine and the other eight to use labetalol. This study was approved by the local institutional review board and all subjects signed informed consent. Hypertension was classified according to the guidelines of the NHBPEP as chronic hypertension, pre-eclampsia-eclampsia, preeclampsia superimposed on chronic hypertension and gestational hypertension (NHBPEP 2000). In the labetalol group, there were four pre-eclampsia, one pre-eclampsia superimposed on chronic hypertension and three gestational hypertension; in the hydralazine group there were five pre-eclampsia, two gestational hypertension and one chronic hypertension. Sample size Considering described values for middle cerebral artery pulsatility index in women with pregnancy-induce hypertension: (Piazze et al. 2005), we need to evaluate eight women per group to have an 80% power to detect a 20% relative change in this parameter, considering a Blood pressure evaluation The maternal blood pressure was evaluated by using a standard mercury sphygmomanometer in the nondominant arm. Blood pressure was evaluated during acute severe hypertension and after labetalol or hydralazine. Treatment of acute severe hypertension Labetalol or hydralazine was used according to the American Congress of Obstetricians and Gynecologists (ACOG) guidelines (2002): Hydralazine: 5 10-mg doses intravenously every min until blood pressure lower than 150/100 mm Hg Labetalol: 20-mg intravenous bolus dose followed by 40 mg if not effective within 10 min; then, 80 mg every 10 min until blood pressure lower than 150/100 mmhg or maximum total dose of 220 mg. The fetuses were monitored by Doppler assessment of fetal heart rate each 10 min after treatment until Doppler evaluation. Ultrasonography Maternal and fetal Doppler ultrasound (US) examinations were performed in a room with controlled temperature of about 23 C and moderate lighting. Before the US examination, the pregnant women rested for 10 min with their back supported in a 45 degree position to prevent compression of the inferior vena cava (Ryo et al. 1998). Doppler US was performed using an HDI 3500 ATL (Advanced Technologies Laboratories, Bothell, WA, USA), using a 2 5 MHz broadband probe. For evaluation by Doppler US, a low filter (100 Hz) was used to prevent loss of the diastolic flow component (Gallarreta et al. 2010; Maulik 1989) and the insonation angle was always less than 60 to avoid artifacts in the spectral Doppler (Gallarreta et al. 2010). Doppler US of the maternal uterine arteries was performed with the women breathing spontaneously. After identification of the vessel on the oblique plane, the sample was positioned 1 cm distal to the point of anatomical crossing with the external iliac artery and the angle was corrected until five similar consecutive waves were obtained. Doppler analysis of the fetal umbilical artery and middle cerebral arteries was performed during periods of fetal rest in the presence of a fetal heart rate of 120 to 160 bpm. For the acquisition of the tracing of the umbilical artery, the artery was identified with color Doppler of a free loop and the 3 mm samples was positioned in such a way as to permit evaluation of both the artery and vein, with the Doppler spectrum being evaluated until five similar consecutive waves were obtained by free loop color Doppler. For the identification of the fetal middle cerebral artery, an axial section of the fetal head was obtained at the level of the thalamus and of the cavum septum pellucidum. The transducer was then moved up to the Willis polygon and the pulsation of the two middle cerebral arteries was observed. With the aid of the amplitude

3 Hypertension treatment with hydralazine or labetalol d M. R. F. BAGGIO et al. 55 Doppler it was possible to identify the artery to be studied, with the spectral Doppler being then activated. The dial was calibrated for a sample volume of 1 mm and placed on the middle cerebral artery as close as possible to the skull cap, before its bifurcation (Luzi et al. 1996). The resistance index (RI) of these waves was calculated as systolic velocity diastolic velocity/ systolic velocity using the manual mode for the middle cerebral and umbilical arteries, while the pulsatility index (PI) was determined for the uterine arteries as (systolic velocity diastolic velocity)/mean velocity. Laboratory evaluation Serum concentrations of hemoglobin, platelets, aspartate aminotransferase (AST), creatinine, total bilirubin and urea were determined in blood samples collected from pregnant women during the acute severe hypertension. Statistical analysis Statistical analysis used the software PASW 18.0 for Windows (SPSS Inc., Chicago, IL, USA). Kolmogorov- Smirnov test was used to assess normality of the evaluated parameters. We compared the values obtained for the age of pregnant women, gestational age and laboratory tests, among pregnant women who used hydralazine or labetalol, by unpaired t-test. Concerning uterine artery PI and RI, we compare the values using paired t-test. Since no significant differences were observed between right and left uterine artery PI and RI, we used the average value for all other comparisons (Manetta et al. 2008). In both groups the blood pressure, heart rate and Doppler parameters values observed during acute severe hypertension were compared with values observed after labetalol or hydralazine by using the paired t-test. The observed changes in these parameters [(value observed after labetalol or hydralazine) (value observed during acute severe hypertension)] were compared between the groups by using the unpaired t-test. Significance level was considered as p,.05. RESULTS No significant difference was observed when comparing age, gestational age and laboratory tests between pregnant women randomized to receive either hydralazine or labetalol (Table 1). When comparing blood pressure and Doppler parameters values observed during acute severe hypertension and after treatment with hydralazine or labetalol until blood pressure lower than 150/100 mm Hg we observed a significant reduction in systolic and diastolic blood pressure in both groups (Table 2). When evaluating uterine artery Doppler parameters, a significant increase in RI was observed in pregnant women who received hydralazine, while a trend to decrease in both RI and PI of uterine arteries was observed in those who received labetatol (Table 2). When comparing maternal and fetal heart rate before and after treatment no significant differences were observed in both hydralazine (maternal heart rate: bpm vs bpm, p ; fetal heart rate: bpm vs bpm, p ; pre- vs. post treatment values, respectively) and labetalol groups (maternal heart rate: bpm vs bpm, p ; fetal heart rate: bpm vs bpm, p ; pre- vs. post treatment values, respectively). When comparing changes in the evaluated parameters between pregnant women who received hydralazine or labetalol, a significant difference was observed only in uterine artery RI (p ) (Table 3). DISCUSSION Acute severe hypertension is associated with generalized arteriolar vasoconstriction and reduced flow uteroplacental and consequent deficit of oxygen supply in the areas of maternal fetal exchange, submitting the fetus to Table 1. Comparison of age, gestational age and laboratory tests between pregnant women randomized to receive either hydralazine or labetalol Hydralazine Labetalol Mean SD Mean SD p Age (years) Gestational age (weeks) Hemoglobin (g/dl) Platelets (1.000/mm 3 ) AST (IU/L) Creatinine (mg/dl) Total bilirubin (mg/dl) Urea (mg/dl) p values obtained by unpaired t-test. AST 5 aspartate aminotransferase.

4 56 Ultrasound in Medicine and Biology Volume 37, Number 1, 2011 Table 2. Comparison of blood pressure and Doppler parameters from maternal uterine arteries and fetal middle cerebral and umbilical arteries observed during acute severe hypertension (pre) with values observed after labetalol or hydralazine (post) Pre Post Hydralazine Mean SD Mean SD p Systolic blood pressure (mm Hg) ,0.01 Diastolic blood pressure (mm Hg) ,0.01 Umbilical artery PI Umbilical artery RI Middle cerebral artery PI Middle cerebral artery RI Uterine artery PI Uterine artery RI Pre Post Labetalol Mean SD Mean SD p Systolic blood pressure (mm Hg) ,0.01 Diastolic blood pressure (mm Hg) ,0.01 Umbilical artery PI Umbilical artery RI Middle cerebral artery PI Middle cerebral artery RI Uterine artery PI Uterine artery RI p values were obtained by using paired t-test. PI 5 pulsatility index; RI 5 resistance index. hypoxia (Williams and Wilson 1999). The administration of antihypertensive drugs may increase the uteroplacental flow, due to the reduction of uterine vascular resistance; however, blood pressure reduction may cause a reverse effect, reducing uteroplacental flow and worsening the intra-uterine conditions. A recent meta-analysis suggested that intravenous labetalol is as effective as and has fewer side effects than intravenous hydralazine (Magee et al. 2003). In this meta-analysis authors evaluated five trials that compared hydralazine with labetalol: hydralazine was associated with significantly higher maternal side effects and worse maternal and perinatal outcomes than labetalol. On the other hand, a more recent randomized controlled clinical trial evaluating 200 pregnant women with severe hypertension in pregnancy receiving either hydralazine or labetalol found similar maternal and neonatal outcomes between the two groups (Vigil-De Gracia et al. 2006): palpitations and tachycardia were more common in women using hydralazine, while neonatal bradycardia and hypotension were more common with labetalol; and exactly two neonatal and no maternal deaths occurred in each group. Additionally, the authors from another recent meta-analysis evaluating hypertensive drugs for very high blood pressure during pregnancy concluded that until better evidence is available, the choice of antihypertensive should depend on the clinician s experience and familiarity with a particular drug because until now there is insufficient data proving superiority of one drug over others (Duley et al. 2006). Table 3. Comparison of the observed changes in the blood pressure and Doppler parameters from maternal uterine arteries and fetal middle cerebral and umbilical arteries between pregnant women who use hydralazine or labetalol Hydralazine Labetalol Mean SD Mean SD p Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Umbilical artery PI Umbilical artery RI Middle cerebral artery PI Middle cerebral artery RI Uterine artery PI Uterine artery RI p values were obtained by using paired t-test. Change 5 [(value observed after labetalol or hydralazine) (value observed during acute severe hypertension)]. PI 5 pulsatility index; RI 5 resistance index.

5 Hypertension treatment with hydralazine or labetalol d M. R. F. BAGGIO et al. 57 In our study, both drugs were very effective in reducing blood pressure and in only one pregnant woman we needed to use both drugs to reduce blood pressure to more desirable levels. Both hydralazine and labetalol are now considered as first-line drugs in the treatment of severe hypertension (Vigil-De Gracia et al. 2006): hydralazine has been used safely in pregnant women for several decades and is, therefore, considered the treatment as the first alternative by some guidelines (ACOG 2002; NHBPEP 2000). Labetalol, an a- and b-adrenergic blocker with both immediate and prolonged effect, also proved to be very safe and is being frequently used (Caetano et al. 2004) and recommended to treat severe hypertension in pregnancy (Frias and Belfort 2003; Leeman and Fontaine 2008). Concerning Doppler evaluation, an increase in uterine arteries RI was observed in pregnant women who received hydralazine, while the use of labetalol was associated with a trend of decrease in uterine arteries PI and RI. Therefore, one should conclude that these results favor labetalol, since this drug was associated with improvement in uteroplacental blood flow, while hydralazine worsened the resistance index. The significant difference in the change of uterine artery resistance observed in pregnant women who received hydralazine might be a consequence of greater (but not significant) reduction in blood pressure observed in women using hydralazine (Table 3): the observed change in systolic blood pressure was vs , with p (hydralazine vs. labetalol, respectively) and the observed change in diastolic blood pressure was vs , with p This observation is in accordance with higher rates of maternal hypotension observed with hydralazine compared to labetalol (Magee et al. 2003) and greater reductions in blood pressure are not desirable because low blood pressure can impair uteroplacental circulation. On the other hand, in situations where fetal oxygenation is reduced, several changes in fetal hemodynamics occur in an attempt to preserve vital organs, such as central nervous system, which would be noticed by Doppler ultrasound, e.g., a resistance reduction in middle cerebral arteries (Hoffman and Galan 2009). Since the use of both drugs were not associated with significant changes in fetal Doppler ultrasound parameters, further conclusions about negative effect of hydralazine on uteroplacental circulation would be still premature. A criticism to this evidence is the small sample evaluated by this study, which does not have the sufficient power to evaluate more subtle changes (e.g.,,20% of relative change). Another interesting point was to consider that women with chronic hypertension (and longer-standing disease) may respond differently from those with hypertension occurring only during the current pregnancy; however, our sample was not sufficiently big enough to permit such stratification. In conclusion, we observed that both drugs were highly effective in reducing blood pressure of pregnant women with very high blood pressure. Although the use of hydralazine has caused worse changes in uterine arteries resistance index, the use of both drugs were not related to any significant changes in Doppler evaluation of fetal hemodynamic and this information is reassuring about the safety of these drugs in the treatment of severe acute hypertension during pregnancy. Therefore, the choice between these two drugs should be based in other criteria such as respective contraindications, costs, availability and clinician s experience. REFERENCES ACOG. ACOG practice bulletin. 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