AJH
1991;
4:200S-202S
Influence of Isradipine on the Maternal and Fetal Cardiovascular System in Hypertensive Disorders in Pregnancy Andreas Feiks, Werner Griinberger, and Wolfgang
Meisner
N i n e p r e g n a n t w o m e n (aged 28.7 ± 6.9 years) w h o h a d d e v e l o p e d h y p e r t e n s i o n (blood p r e s s u r e > 1 4 0 / 90 m m Hg) t o o k p a r t i n a n o p e n p i l o t s t u d y w i t h the n e w calcium antagonist isradipine. Dosage was s t a r t e d w i t h 1.25 m g t w i c e d a i l y a n d w a s i n c r e a s e d w e e k l y to 2.5 m g a n d 5 m g t w i c e d a i l y u n t i l a d i a stolic b l o o d p r e s s u r e of ^ 80 m m H g w a s a c h i e v e d . By t h e t i m e of t h e last visit b e f o r e t e r m , b l o o d p r e s s u r e w a s significantly r e d u c e d to 129/79 m m H g a n d heart rate had not altered. External cardiotoc o g r a p h y i n d i c a t e d fetal w e l l - b e i n g t h r o u g h o u t t h e
e n t i r e s t u d y . D o p p l e r flow m e a s u r e m e n t s s h o w e d n o d e t e r i o r a t i o n i n A : Β ratio, r e s i s t a n c e i n d e x , a n d pulsatile index. All measurements in the n e w b o r n were w i t h i n n o r m a l ranges. In conclusion, isradi p i n e is a safe a n d effective d r u g for p r e g n a n t w o m e n a n d t h e i r fetuses i n t h e m a n a g e m e n t of h y pertensive disorders in pregnancy. A m J Hypertens 1990;4:200S-202S
U
used m o r e a n d m o r e frequently in this area, can lead to a decline of the uteroplacental blood flow a n d m a y h a v e adverse effects on uterine activity. Furthermore, as ßblockers are able to cross the placenta, the possibility of harmful effects on the fetus m u s t also be considered. With hydralazine, vasodilatation is followed by a subsequent rise in the circulatory v o l u m e a n d a n in crease in heart rate, w h i c h is likely to cancel out m u c h of the antihypertensive effect a n d reduce tolerability. Isra dipine is a n e w dihydropyridine calcium antagonist that h a s a high specific affinity a n d low nonspecific affinity to the dihydropyridine binding sites, together with m i n imal cardiodepressant effects. So far, it h a s not revealed a n y teratogenicity a n d therefore a p p e a r s suitable for the treatment of H D P . The objective of the present pilot study w a s to inves tigate the maternal a n d fetal circulatory effects of isradi pine in w o m e n with hypertension in pregnancy.
ntreated hypertensive disorders in pregnancy (HDP) markedly increase the risk to the fetus a n d of perinatal mortality if the maternal dia stolic blood pressure (DBP) rises above 85 to 90 m m H g . In addition, the welfare of the m o t h e r is threatened by an increased risk of eclampsia, dissemi n a t e d intravascular coagulation, lung edema, liver bleeding, a n d acute renal failure. Thus, in cases of H D P , it is essential to reduce DBP to levels below 80 m m H g . In addition to general measures, such as rest a n d relax ation, moderation of salt intake, a n d isotonic exercises, d r u g treatment should be initiated w i t h o u t delay in cases of prolonged blood pressure elevation. However, pharmacologic treatment of H D P remains a subject of dispute. While it is clear that the m o t h e r benefits from such therapy, the benefits to the fetus h a v e b e e n less obvious. /?-Blockers, w h i c h are being 1
2
From the Department of Gynecology, Krankenanstalt Rudolfstif tung; Department of Internal Medicine I, Policlinic; Vienna, Austria. Address correspondence and reprint requests to Andreas Feiks, MD, Krankenanstalt Rudolfstiftung, Gynäkologische Abteilung, Juchgasse 25, A - 1 0 3 0 Wien, Austria.
© 1991 by the American Journal of Hypertension,
Inc.
KEY WORDS: H y p e r t e n s i o n , p r e g n a n c y , u t e r o p l a c e n tal flow, c a l c i u m a n t a g o n i s t , i s r a d i p i n e .
3
PATIENTS A N D METHODS After obtaining informed consent to the study protocol, nine p r e g n a n t w o m e n w h o h a d developed h y p e r t e n sion (blood pressure > 1 4 0 / 9 0 m m Hg) b e t w e e n the
0895-7061/'91/'$3.50
AJH-FEBRUARY
1991-VOL
4, NO. 2, PART 2
twenty-sixth a n d thirty-third weeks of gestation, b u t w h o were otherwise healthy, were entered into a n o p e n pilot trial of isradipine. In the dose-titration period, isra dipine w a s started at a dose of 1.25 m g twice daily. This was increased weekly to 2.5 m g a n d 5 m g twice daily until a DBP of ^ 80 m m H g w a s achieved. The patients were treated with this optimal dose until delivery. Blood pressure w a s m e a s u r e d at each weekly visit in the m o r n ing after sitting for 5 min. A s t a n d a r d s p h y g m o m a n o m e ter with the appropriate cuff w a s used a n d always o n the a r m giving the higher blood pressure reading before treatment. The heart rate w a s m e a s u r e d by counting the n u m b e r of pulse beats in 60 sec. Before d r u g treatment, the fetal biophysical profile was performed using ultrasound scanning. Fetal heart rate a n d uterine activity were evaluated at each visit before a n d during active treatment by external cardiotocography, using the Fisher score. M e a s u r e m e n t s of blood velocity in the umbilical artery w e r e assessed using pulsed Doppler ultrasound before a n d at each visit after the dose-titration period. The A : Β ratio, resist ance index, a n d pulsatile index were calculated to esti mate uteroplacental blood flow. Prior to inclusion in the study a n d at delivery, the clinical evaluation also in cluded a complete physical examination, a 12-lead elec trocardiographic (ECG) examination, a n d routine labo ratory analysis. After delivery, routine m e a s u r e m e n t s of the n e w b o r n , including the Apgar score, w e r e per formed. Side effects (by o p e n questioning) a n d b o d y weight were evaluated at each visit. All values are ex pressed as m e a n values ± SD. Statistical analysis w a s performed using Student's paired t test. A value of Ρ = .05 w a s considered to be significant. RESULTS Nine white p r e g n a n t w o m e n (aged 28.7 ± 6.9 years, height 165.3 ± 4.3 cm, weight 86.7 ± 12.9 kg) entered the study. Three of these w o m e n were nulliparous. The m e a n gestational age at admission w a s 28.8 ± 5.9 weeks. Three w o m e n were k n o w n to h a v e hypertension while the remaining six w o m e n developed h y p e r t e n sion because of their pregnancy. The m e a n daily dose of isradipine at the e n d of the study w a s 6.7 ± 3.3 m g / d a y . By the time of the last visit before term, blood pressure h a d b e e n significantly low ered from 153 ± 1 2 / 9 6 ± 6 to 129 ± 1 7 / 7 9 ± 6 m m Hg (P < .01). Maternal heart rate w a s slightly, b u t not significantly, increased from 8 1 ± 6 to 8 7 ± 4 b e a t s / min (Figure 1). M e a n fetal heart rate w a s also essentially u n c h a n g e d (from 1 3 7 ± 8 t o l 4 2 ± 5 b e a t s / m i n ) , a n d the Fisher score (from 9.8 ± 0.4 to 9.8 ± 0.5) indicated fetal well-being. Accordingly, the uteroplacental blood flow, estimated by the Doppler technique, s h o w e d n o deterioration in A : B ratio (from 2.67 ± 0.83 to 2.17 ± 0.32),resistanceindex(from0.67 ± 0 . 2 8 t o 0 . 5 3 ± 0.08), or pulsatile index (from 0.88 ± 0.28 to 0.95 ± 0.30).
ISRADIPINE DURING PREGNANCY
mm Hg
beat/min
180 160
201S
SBP
140 120 100
DBP
I 150
80 100
60 40 I
50
20 BL
ET
0
FIGURE 1. Course of systolic (SBP) and diastolic (DBP) blood pressure, and heart rate (HR) during treatment with isradipine (mean ± SD).BL,baseline;ET,endtitration;T,treatments,delivery, **P < .01; ns, not significant ν baseline values.
The m e a n duration of labor w a s 7.2 ± 5.4 h. Placen tal weight w a s 537.7 ± 75.7 g, the weight of the n e w b o r n w a s 3366.6 ± 394.4 g, a n d Apgar scores after 1 a n d 5 m i n w e r e 9.0 ± 0.5 a n d 9.8 ± 0.3, respectively. N o malformations w e r e detected in the n e w b o r n . There were n o significant alterations in laboratory parameters nor in the results of ECG examination. During the dose-titration period, three w o m e n re p o r t e d side effects (diuresis, flushing, a n d fatigue). These w e r e m o d e r a t e a n d disappeared during the course of the study. DISCUSSION Antihypertensive d r u g t h e r a p y in p r e g n a n c y is a n area of controversy. Agents such as selective ^-blockers or m e t h y l d o p a s h o u l d b e r e c o m m e n d e d with caution. Di uretics, reserpine, Captopril, nonselective /^-blockers, a n d nifedipine are contraindicated in pregnancy. Nife dipine h a s embryotoxic effects while diuretics decrease uteroplacental circulation, leading to low birth-weight infants. Nonselective ^-blockers increase uterine activ ity a n d m a y interfere w i t h efforts to suppress p r e t e r m labor. Captopril h a s b e e n s h o w n to increase fetal mortal ity in a n i m a l s . In theory, calcium antagonists w o u l d a p p e a r to be a d v a n t a g e o u s in the treatment of H D P by maintaining uteroplacental flow t h r o u g h vasodilatation w i t h o u t fluid retention while p r o m o t i n g mild natriuretic a n d diuretic effects. They also d o not increase m y o m e trial a c t i v i t y . In this present study, isradipine lowered high blood pressure significantly during pregnancy. Doppler flow m e a s u r e m e n t s of t h e umbilical blood flow during ther a p y w e r e of primary interest a n d indicated n o deteriora tion of uteroplacental perfusion. These data are con firmed by the n o r m a l birth weights a n d high Apgar 4
5-8
202S
FEIKS ET AL
AJH-FEBRUARY
scores of the infants. The side effects with the d r u g were m o d e r a t e a n d transient. In conclusion, isradipine appears to be safe a n d effec tive for p r e g n a n t w o m e n as well as their fetuses in the m a n a g e m e n t of hypertensive disorders in pregnancy.
Friedman EA: Hypertension-hypotension in pregnancy. Correlation with fetal outcome. JAMA 1978,239:22492251.
2.
Lübbe WF: Hypertension in pregnancy: pathophysiology and management. Drugs 1984;28:170-188.
3.
Hof RP, Rüegg UT: Pharmacology of the new calcium antagonist isradipine and its metabolites. Am J Med 1988;84(suppl 3B):13-17.
4, NO. 2, PART 2
4.
Girndt J: Therapy of hypertension in pregnancy. Dtsch Med Wochenschr 1985;110:1579-1580.
5.
Read MD, Wellby DE: The use of a calcium antagonist (nifedipine) to suppress preterm labor. Br J Obstet Gynae col 1986;93(9):933-937.
6.
Cicero GL, Cellina G, Binaghi Ρ, Limonta A: Effect of nifedipine on the cardiovascular pattern in pregnancyinduced hypertension (abst). Eur J Clin Invest 1984; 14(2 part 2):4(abstr 19).
7.
Ulms ten U: Treatment of normotensive and hypertensive patients with preterm labor using oral nifedipine, a cal cium antagonist. Arch Gynecol 1984;236:69-72.
8.
Walters BNJ, Redman CWG: Control of severe hyperten sion in pregnancy with nifedipine. Proceedings of the 3rd Congress of the International Society of Hypertension in Pregnancy, Dallas, Texas, 1982, ρ 196.
REFERENCES 1.
1991-VOL
1991;
4:200S-202S
Influence of Isradipine on the Maternal and Fetal Cardiovascular System in Hypertensive Disorders in Pregnancy Andreas Feiks, Werner Griinberger, and Wolfgang
Meisner
N i n e p r e g n a n t w o m e n (aged 28.7 ± 6.9 years) w h o h a d d e v e l o p e d h y p e r t e n s i o n (blood p r e s s u r e > 1 4 0 / 90 m m Hg) t o o k p a r t i n a n o p e n p i l o t s t u d y w i t h the n e w calcium antagonist isradipine. Dosage was s t a r t e d w i t h 1.25 m g t w i c e d a i l y a n d w a s i n c r e a s e d w e e k l y to 2.5 m g a n d 5 m g t w i c e d a i l y u n t i l a d i a stolic b l o o d p r e s s u r e of ^ 80 m m H g w a s a c h i e v e d . By t h e t i m e of t h e last visit b e f o r e t e r m , b l o o d p r e s s u r e w a s significantly r e d u c e d to 129/79 m m H g a n d heart rate had not altered. External cardiotoc o g r a p h y i n d i c a t e d fetal w e l l - b e i n g t h r o u g h o u t t h e
e n t i r e s t u d y . D o p p l e r flow m e a s u r e m e n t s s h o w e d n o d e t e r i o r a t i o n i n A : Β ratio, r e s i s t a n c e i n d e x , a n d pulsatile index. All measurements in the n e w b o r n were w i t h i n n o r m a l ranges. In conclusion, isradi p i n e is a safe a n d effective d r u g for p r e g n a n t w o m e n a n d t h e i r fetuses i n t h e m a n a g e m e n t of h y pertensive disorders in pregnancy. A m J Hypertens 1990;4:200S-202S
U
used m o r e a n d m o r e frequently in this area, can lead to a decline of the uteroplacental blood flow a n d m a y h a v e adverse effects on uterine activity. Furthermore, as ßblockers are able to cross the placenta, the possibility of harmful effects on the fetus m u s t also be considered. With hydralazine, vasodilatation is followed by a subsequent rise in the circulatory v o l u m e a n d a n in crease in heart rate, w h i c h is likely to cancel out m u c h of the antihypertensive effect a n d reduce tolerability. Isra dipine is a n e w dihydropyridine calcium antagonist that h a s a high specific affinity a n d low nonspecific affinity to the dihydropyridine binding sites, together with m i n imal cardiodepressant effects. So far, it h a s not revealed a n y teratogenicity a n d therefore a p p e a r s suitable for the treatment of H D P . The objective of the present pilot study w a s to inves tigate the maternal a n d fetal circulatory effects of isradi pine in w o m e n with hypertension in pregnancy.
ntreated hypertensive disorders in pregnancy (HDP) markedly increase the risk to the fetus a n d of perinatal mortality if the maternal dia stolic blood pressure (DBP) rises above 85 to 90 m m H g . In addition, the welfare of the m o t h e r is threatened by an increased risk of eclampsia, dissemi n a t e d intravascular coagulation, lung edema, liver bleeding, a n d acute renal failure. Thus, in cases of H D P , it is essential to reduce DBP to levels below 80 m m H g . In addition to general measures, such as rest a n d relax ation, moderation of salt intake, a n d isotonic exercises, d r u g treatment should be initiated w i t h o u t delay in cases of prolonged blood pressure elevation. However, pharmacologic treatment of H D P remains a subject of dispute. While it is clear that the m o t h e r benefits from such therapy, the benefits to the fetus h a v e b e e n less obvious. /?-Blockers, w h i c h are being 1
2
From the Department of Gynecology, Krankenanstalt Rudolfstif tung; Department of Internal Medicine I, Policlinic; Vienna, Austria. Address correspondence and reprint requests to Andreas Feiks, MD, Krankenanstalt Rudolfstiftung, Gynäkologische Abteilung, Juchgasse 25, A - 1 0 3 0 Wien, Austria.
© 1991 by the American Journal of Hypertension,
Inc.
KEY WORDS: H y p e r t e n s i o n , p r e g n a n c y , u t e r o p l a c e n tal flow, c a l c i u m a n t a g o n i s t , i s r a d i p i n e .
3
PATIENTS A N D METHODS After obtaining informed consent to the study protocol, nine p r e g n a n t w o m e n w h o h a d developed h y p e r t e n sion (blood pressure > 1 4 0 / 9 0 m m Hg) b e t w e e n the
0895-7061/'91/'$3.50
AJH-FEBRUARY
1991-VOL
4, NO. 2, PART 2
twenty-sixth a n d thirty-third weeks of gestation, b u t w h o were otherwise healthy, were entered into a n o p e n pilot trial of isradipine. In the dose-titration period, isra dipine w a s started at a dose of 1.25 m g twice daily. This was increased weekly to 2.5 m g a n d 5 m g twice daily until a DBP of ^ 80 m m H g w a s achieved. The patients were treated with this optimal dose until delivery. Blood pressure w a s m e a s u r e d at each weekly visit in the m o r n ing after sitting for 5 min. A s t a n d a r d s p h y g m o m a n o m e ter with the appropriate cuff w a s used a n d always o n the a r m giving the higher blood pressure reading before treatment. The heart rate w a s m e a s u r e d by counting the n u m b e r of pulse beats in 60 sec. Before d r u g treatment, the fetal biophysical profile was performed using ultrasound scanning. Fetal heart rate a n d uterine activity were evaluated at each visit before a n d during active treatment by external cardiotocography, using the Fisher score. M e a s u r e m e n t s of blood velocity in the umbilical artery w e r e assessed using pulsed Doppler ultrasound before a n d at each visit after the dose-titration period. The A : Β ratio, resist ance index, a n d pulsatile index were calculated to esti mate uteroplacental blood flow. Prior to inclusion in the study a n d at delivery, the clinical evaluation also in cluded a complete physical examination, a 12-lead elec trocardiographic (ECG) examination, a n d routine labo ratory analysis. After delivery, routine m e a s u r e m e n t s of the n e w b o r n , including the Apgar score, w e r e per formed. Side effects (by o p e n questioning) a n d b o d y weight were evaluated at each visit. All values are ex pressed as m e a n values ± SD. Statistical analysis w a s performed using Student's paired t test. A value of Ρ = .05 w a s considered to be significant. RESULTS Nine white p r e g n a n t w o m e n (aged 28.7 ± 6.9 years, height 165.3 ± 4.3 cm, weight 86.7 ± 12.9 kg) entered the study. Three of these w o m e n were nulliparous. The m e a n gestational age at admission w a s 28.8 ± 5.9 weeks. Three w o m e n were k n o w n to h a v e hypertension while the remaining six w o m e n developed h y p e r t e n sion because of their pregnancy. The m e a n daily dose of isradipine at the e n d of the study w a s 6.7 ± 3.3 m g / d a y . By the time of the last visit before term, blood pressure h a d b e e n significantly low ered from 153 ± 1 2 / 9 6 ± 6 to 129 ± 1 7 / 7 9 ± 6 m m Hg (P < .01). Maternal heart rate w a s slightly, b u t not significantly, increased from 8 1 ± 6 to 8 7 ± 4 b e a t s / min (Figure 1). M e a n fetal heart rate w a s also essentially u n c h a n g e d (from 1 3 7 ± 8 t o l 4 2 ± 5 b e a t s / m i n ) , a n d the Fisher score (from 9.8 ± 0.4 to 9.8 ± 0.5) indicated fetal well-being. Accordingly, the uteroplacental blood flow, estimated by the Doppler technique, s h o w e d n o deterioration in A : B ratio (from 2.67 ± 0.83 to 2.17 ± 0.32),resistanceindex(from0.67 ± 0 . 2 8 t o 0 . 5 3 ± 0.08), or pulsatile index (from 0.88 ± 0.28 to 0.95 ± 0.30).
ISRADIPINE DURING PREGNANCY
mm Hg
beat/min
180 160
201S
SBP
140 120 100
DBP
I 150
80 100
60 40 I
50
20 BL
ET
0
FIGURE 1. Course of systolic (SBP) and diastolic (DBP) blood pressure, and heart rate (HR) during treatment with isradipine (mean ± SD).BL,baseline;ET,endtitration;T,treatments,delivery, **P < .01; ns, not significant ν baseline values.
The m e a n duration of labor w a s 7.2 ± 5.4 h. Placen tal weight w a s 537.7 ± 75.7 g, the weight of the n e w b o r n w a s 3366.6 ± 394.4 g, a n d Apgar scores after 1 a n d 5 m i n w e r e 9.0 ± 0.5 a n d 9.8 ± 0.3, respectively. N o malformations w e r e detected in the n e w b o r n . There were n o significant alterations in laboratory parameters nor in the results of ECG examination. During the dose-titration period, three w o m e n re p o r t e d side effects (diuresis, flushing, a n d fatigue). These w e r e m o d e r a t e a n d disappeared during the course of the study. DISCUSSION Antihypertensive d r u g t h e r a p y in p r e g n a n c y is a n area of controversy. Agents such as selective ^-blockers or m e t h y l d o p a s h o u l d b e r e c o m m e n d e d with caution. Di uretics, reserpine, Captopril, nonselective /^-blockers, a n d nifedipine are contraindicated in pregnancy. Nife dipine h a s embryotoxic effects while diuretics decrease uteroplacental circulation, leading to low birth-weight infants. Nonselective ^-blockers increase uterine activ ity a n d m a y interfere w i t h efforts to suppress p r e t e r m labor. Captopril h a s b e e n s h o w n to increase fetal mortal ity in a n i m a l s . In theory, calcium antagonists w o u l d a p p e a r to be a d v a n t a g e o u s in the treatment of H D P by maintaining uteroplacental flow t h r o u g h vasodilatation w i t h o u t fluid retention while p r o m o t i n g mild natriuretic a n d diuretic effects. They also d o not increase m y o m e trial a c t i v i t y . In this present study, isradipine lowered high blood pressure significantly during pregnancy. Doppler flow m e a s u r e m e n t s of t h e umbilical blood flow during ther a p y w e r e of primary interest a n d indicated n o deteriora tion of uteroplacental perfusion. These data are con firmed by the n o r m a l birth weights a n d high Apgar 4
5-8
202S
FEIKS ET AL
AJH-FEBRUARY
scores of the infants. The side effects with the d r u g were m o d e r a t e a n d transient. In conclusion, isradipine appears to be safe a n d effec tive for p r e g n a n t w o m e n as well as their fetuses in the m a n a g e m e n t of hypertensive disorders in pregnancy.
Friedman EA: Hypertension-hypotension in pregnancy. Correlation with fetal outcome. JAMA 1978,239:22492251.
2.
Lübbe WF: Hypertension in pregnancy: pathophysiology and management. Drugs 1984;28:170-188.
3.
Hof RP, Rüegg UT: Pharmacology of the new calcium antagonist isradipine and its metabolites. Am J Med 1988;84(suppl 3B):13-17.
4, NO. 2, PART 2
4.
Girndt J: Therapy of hypertension in pregnancy. Dtsch Med Wochenschr 1985;110:1579-1580.
5.
Read MD, Wellby DE: The use of a calcium antagonist (nifedipine) to suppress preterm labor. Br J Obstet Gynae col 1986;93(9):933-937.
6.
Cicero GL, Cellina G, Binaghi Ρ, Limonta A: Effect of nifedipine on the cardiovascular pattern in pregnancyinduced hypertension (abst). Eur J Clin Invest 1984; 14(2 part 2):4(abstr 19).
7.
Ulms ten U: Treatment of normotensive and hypertensive patients with preterm labor using oral nifedipine, a cal cium antagonist. Arch Gynecol 1984;236:69-72.
8.
Walters BNJ, Redman CWG: Control of severe hyperten sion in pregnancy with nifedipine. Proceedings of the 3rd Congress of the International Society of Hypertension in Pregnancy, Dallas, Texas, 1982, ρ 196.
REFERENCES 1.
1991-VOL
