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Propranolol administration during pregnancy: Effects on the fetus
962
June 1975 The Journal o f P E D I A T R I C S
Propranolol administration during pregnancy: Effects on the fetus The case of an Otfant born to a mother receiving continuous propranolol therapy throughout pregnancy is reported. Perinatal problems included: a small placenta, intrauterine growth retardation, fetal depression at birth, and postnatal hypoglycemia and bradycardia. These responses appeared to be the direct result of the maternal use of propranolol. Hence, infants born to mothers on continuous therapy with this agent shouM be considered at risk for developing these complications.
Gwendolyn R. Gladstone, M.D.,* Allan Hordof, M.D., and Welton M. Gersony, M.D., New York, N. Y.
P R O P R A N O L O L , a f l - a d r e n e r g i c b l o c k i n g a g e n t , is being u s e d with increasing f r e q u e n c y in the t r e a t m e n t o f h y p e r t e n s i o n , thyrotoxicosis, idiopathic hypertrophic s u b a o r t i c s t e n o s i s , a n d c a r d i a c a r r h y t h m i a s , 1 all o f which may coexist with pregnancy. Animal experiments have demonstrated that propranolol administ e r e d d u r i n g p r e g n a n c y c a n s u p p r e s s n o r m a l fetal responses to anoxia. 2 F u r t h e r m o r e , a r e c e n t case report suggests that this drug m a y h a v e caused significant d e p r e s s a n t effects in a h u m a n f e t u s ) I n t h e case reported here, h o w e v e r , the infant's course was complicated by a n u m b e r o f p r o b l e m s k n o w n to c a u s e fetal depression, so that a clear relationship b e t w e e n the materna! use o f propranolol and the neonatal distress could n o t be established. T h e p r e s e n t r e p o r t c o n c e r n s an i n f a n t b o r n to a m o t h e r who r e c e i v e d c o n t i n u o u s propranolol therapy during an otherwise u n c o m p l i c a t e d pregnancy. T h e infant had a n u m b e r o f perinatal complications w h i c h m a y b e directly attributed to the placental transfer of this agent.
From the Division of Pediatric Cardiology, Department of Pediatrics, College of Physicians and Surgeons of Columbia University, and Babies Hospital, Columbia-Presbyterian Medical Center. *Reprint address: Department of pediatrics, BHA-102, 622 West 168thSt., New York, N. E, 10032.
I1ol. 86, No. 6, pp. 962-964
CASE REPORT The patient was born after a term pregnancy to a 37-year.old mother who was taking 240 mg/day of propranolol for the management of essential hypertension at the time of conception. Other antihypertensive agents had been ineffective in decreasing the blood pressure. The dose of propranolol was decreased to I60 mg/day in the fourth month of pregnancy with good control of the hypertension; there was no albuminuria. No other medications were taken during the pregnancy. At outpatient visits, the fetal heart rate was described as "normal." Labor began spontaneously at 40 weeks. The membranes ruptured shortly after admission to the hospital, and thick, meconium-stained fluid was passed. Throughout the first stage of labor, the fetal heart rate was in the range of 120-126 beats/ minute. Since labor progressed rapidly, no analgesics were given. A local anaesthetic was administered, and the infant was delivered vaginally from the vertex position. When low outlet forceps were applied, the heart rate was found to be 60/minute. The infant was markedly depressed, with Apgar scores of 2, 1, and 4 at 1, 2, and 5 minutes, respectively. Successful resuscitation resulted in a 10-minute Apgar score of 9. The placenta, which was heavily stained with meconium , was small: it weighed 290 gm, but was otherwise grossly normal. The infant's neonatal course was complicated by: (1) polycythemja-the central hematocrit was 74% and fell to 65% after exchange transfusion; (2) hypoglycemia--the blood sugar was initially 11 mg/dl and rose to 55 mg/dl after an intravenous infusion of 10% dextrose; hypoglycemia did not recur after this episode; (3) bradycardia--the heart rate was in the range of 70-90 beats/minute during the fu~t day of life; other vital signs remained normal. With stimulation, the pulse rose transiently to
Volume 86 Number 6
120/minute. No clinical or radiologic evidence for heart failure was found; an electrocardiogram showed a sinus rhythm. Serum acid-base and calcium determinations were within normal limits. The heart rate gradually increased to a normal range over a four-day period and at discharge on the fifth day of life, the pulse rate was i 20-130/minute. At three months of age, the infant has a normal heart rate and is developing normally. DISCUSSION Bradycardia is a well-known complication of propranolol therapy, resulting primarily from the blockade of /3-receptors in the heart. Hypoglycemia, another complication of propranolol administration, is apparently caused by the drug's interference with the normal epinephrine-mediated response to a fall in blood sugar. In children, this response occurs most often during fasting. 4 A n o t h e r effect of propranolol, particularly relevant to its use during pregnancy, is the stimulation of uterine muscle, as a result of B-receptor blockade. 5 It has been p o s t u l a t e d that a s u s t a i n e d i n c r e a s e in m u s c l e tone caused by continuous administration of this drug during pregnancy could result in a small placenta and a small-for-dates infant) All of these complications were noted in the present case. It has been shown that propranolol administered intravenously to ewes causes /3-blockade in the fetus, 6 and propranolol has also been reported to cross the h u m a n placenta when given intravenously. 7 Joelsson and Barton 2 have demonstrated, in animal experiments, that the drug causes d i r e c t i m p a i r m e n t o f fetal responses to an anoxic insult. Control animals responded to anoxia with bradycardia and a transient rise in blood pressure, and when the stress was removed, an immediate tachycardia was observed. Fetuses who were administered propranolol displayed a fall in blood pressure during anoxia, and no rebound tachycardia. Studies involving the h u m a n fetus have also demonstrated that maternally administered propranolol interferes with normal autonomic responses during labor and may have a direct depressant effect on the neonate. Renou and associates 8 injected atropine Subcutaneously into the scalps of 11 fetuses during labor and then administered 10 mg of propranolol intravenously to each of the mothers. All fetuses had a sustained fall in heart rate after the maternal administration of propranoloi. F u r t h e r m o r e , e i g h t f e t u s e s w h o h a d p r e v i o u s l y responded to uterine contractions with tachycardia, no longer showed this response. Tunstall 9 reported a double-blind study of the effects of propranolol adminiStered acutely during labor. He found that four women, who were given unspecified doses o f i n t r a v e n o u s
Propranoloi administration during pregnancy
963
propranolol 30 minutes before cesarean section, gave birth to depressed infants when compared to six infants of control subjects. Most of the other reports in the literature dealing with the effects of continuous propranolol administration d u r i n g p r e g n a n c y h a v e s t r e s s e d the m o t h e r ' s course, rather than that of the fetus. 1~ 11 A recent case report, 3 however, emphasized the possible deleterious effects on the fetus. A 32-year-old woman had taken 180 mg of propranolol and 90 mg of phenobarbital per day for idiopathic r e c u r r e n t v e n t r i c u l a r t a c h y c a r d i a which had occurred in her first month o f pregnancy. A small-for-gestational-age infant was delivered at term. Perinatal problems included a drop in f~tal heart rate to 60 When low outlet forceps were applied, a tight nuchal cord, birth asphyxia with meconium-stained fluid, low Apgar scores, and a s m a l l infarcted placenta. Bradycardia and hypoglycemia were observed in the first day of life and gradually resolved over a three-day period. The possible Pole of propranolol in the causation o f these complications was discussed, although the severity o f the underlying maternal disease and the tight nuchal cord at birth undoubtedly contributed to these abnormal responses. These neonatal problems were similar to those encountered in our patient; by contrast, however, the underlying maternal disease was well controlled and there were no other etiologic factors known to cause fetal depression. Although the half-life o f propranolol in the adult is about three hours, 12 the drug may have a much longer half-life in the neonate since it is metabolized by the liver, an organ which is functionally immature in the newborn infant. This factor may account for the persistence of bradycardia and hypoglycemia b e y o n d the first day of life in involved infants. The pharmacologic actions of propranolol may have deleterious effects on the fetus and neonate. These include: impaired responses to anoxic stress; dep/'ession at birth; a small placenta; intrauterine growth retardation; a n d p o s t n a t a l b r a d y c a r d i a and h y p o g l y c e m i a . Therefore, pregnancies during which this drug is adm i n i s t e r e d m u s t b e c o n s i d e r e d " h i g h r i s k . " Both mother and fetus should be carefully monitored so that, if any o f the aforementioned complications should occur, they can be immediately recognized and treated. Successful m a n a g e m e n t of severe cases may require vigorous resuscitation, correction of hypoglycemia, and administration of atropine or isoproterenol for bradycardia. In refractory situations, it is possible that cardiac pacing may be necessary to maintain an adequate heart rate.
964
Gladstone, Hordof and Gersony
REFERENCES 1.
2.
3. 4. 5.
6.
Kosman ME: Current status of propranolol hydrochloride (InderaD JAMA 225:1380, 1973. Joelsson I, and Barton MD: The effect of blockade of the receptors of the sympathetic nervous system of the fetus, Acta Obstet Gynecol Scand 48(Suppl 3):75, 1969. Reed RL, et al: Propranolol therapy throughout pregnancy: A case report, Anaesth Analg 53:214, 1974. McBride JT, et al: Hypoglycemia associated with propranolol, Pediatrics 51:1055, 1973. Amy J J: Intrauterine administration of L-noradrenaline and propranolol during the second trimester of pregnancy, J Obstet Gynecol Br Commonw 81:75, 1974. Joelsson I, et al: The response of the unanesthetized sheep fetus to sympathomimetic amines and adrenergic agents, Am J Obstet Gynecol 114:43, 1972.
The Journal of Pediatrics June 1975
7. Barnes AB: Chronic propranolol administration during pregnancy, J Reprod Med 5:79, 1970. 8. Renou P, et al: Autonomic control of fetal heart rate, Am J Obstet Gynecol 105:949, 1969. 9. Tunstall ME: The effect of prorpanolol on the onset of breathing at birth, Br J Anaesth 41:792, 1969. 10. Jackson GL: Treatment of hyperthyroidism in pregnancy, Pa Med 76:56, 1973. 11. Turner GM, et al: Management of pregnancy complicated by hypertrophic obstructive cardiomyopathy, Br Med J 4:281, 1968. 12. Faulkner SL, et al: Time required for complete recovery from chronic propranolol therapy, N Engl J Med 289:607, 1973.
June 1975 The Journal o f P E D I A T R I C S
Propranolol administration during pregnancy: Effects on the fetus The case of an Otfant born to a mother receiving continuous propranolol therapy throughout pregnancy is reported. Perinatal problems included: a small placenta, intrauterine growth retardation, fetal depression at birth, and postnatal hypoglycemia and bradycardia. These responses appeared to be the direct result of the maternal use of propranolol. Hence, infants born to mothers on continuous therapy with this agent shouM be considered at risk for developing these complications.
Gwendolyn R. Gladstone, M.D.,* Allan Hordof, M.D., and Welton M. Gersony, M.D., New York, N. Y.
P R O P R A N O L O L , a f l - a d r e n e r g i c b l o c k i n g a g e n t , is being u s e d with increasing f r e q u e n c y in the t r e a t m e n t o f h y p e r t e n s i o n , thyrotoxicosis, idiopathic hypertrophic s u b a o r t i c s t e n o s i s , a n d c a r d i a c a r r h y t h m i a s , 1 all o f which may coexist with pregnancy. Animal experiments have demonstrated that propranolol administ e r e d d u r i n g p r e g n a n c y c a n s u p p r e s s n o r m a l fetal responses to anoxia. 2 F u r t h e r m o r e , a r e c e n t case report suggests that this drug m a y h a v e caused significant d e p r e s s a n t effects in a h u m a n f e t u s ) I n t h e case reported here, h o w e v e r , the infant's course was complicated by a n u m b e r o f p r o b l e m s k n o w n to c a u s e fetal depression, so that a clear relationship b e t w e e n the materna! use o f propranolol and the neonatal distress could n o t be established. T h e p r e s e n t r e p o r t c o n c e r n s an i n f a n t b o r n to a m o t h e r who r e c e i v e d c o n t i n u o u s propranolol therapy during an otherwise u n c o m p l i c a t e d pregnancy. T h e infant had a n u m b e r o f perinatal complications w h i c h m a y b e directly attributed to the placental transfer of this agent.
From the Division of Pediatric Cardiology, Department of Pediatrics, College of Physicians and Surgeons of Columbia University, and Babies Hospital, Columbia-Presbyterian Medical Center. *Reprint address: Department of pediatrics, BHA-102, 622 West 168thSt., New York, N. E, 10032.
I1ol. 86, No. 6, pp. 962-964
CASE REPORT The patient was born after a term pregnancy to a 37-year.old mother who was taking 240 mg/day of propranolol for the management of essential hypertension at the time of conception. Other antihypertensive agents had been ineffective in decreasing the blood pressure. The dose of propranolol was decreased to I60 mg/day in the fourth month of pregnancy with good control of the hypertension; there was no albuminuria. No other medications were taken during the pregnancy. At outpatient visits, the fetal heart rate was described as "normal." Labor began spontaneously at 40 weeks. The membranes ruptured shortly after admission to the hospital, and thick, meconium-stained fluid was passed. Throughout the first stage of labor, the fetal heart rate was in the range of 120-126 beats/ minute. Since labor progressed rapidly, no analgesics were given. A local anaesthetic was administered, and the infant was delivered vaginally from the vertex position. When low outlet forceps were applied, the heart rate was found to be 60/minute. The infant was markedly depressed, with Apgar scores of 2, 1, and 4 at 1, 2, and 5 minutes, respectively. Successful resuscitation resulted in a 10-minute Apgar score of 9. The placenta, which was heavily stained with meconium , was small: it weighed 290 gm, but was otherwise grossly normal. The infant's neonatal course was complicated by: (1) polycythemja-the central hematocrit was 74% and fell to 65% after exchange transfusion; (2) hypoglycemia--the blood sugar was initially 11 mg/dl and rose to 55 mg/dl after an intravenous infusion of 10% dextrose; hypoglycemia did not recur after this episode; (3) bradycardia--the heart rate was in the range of 70-90 beats/minute during the fu~t day of life; other vital signs remained normal. With stimulation, the pulse rose transiently to
Volume 86 Number 6
120/minute. No clinical or radiologic evidence for heart failure was found; an electrocardiogram showed a sinus rhythm. Serum acid-base and calcium determinations were within normal limits. The heart rate gradually increased to a normal range over a four-day period and at discharge on the fifth day of life, the pulse rate was i 20-130/minute. At three months of age, the infant has a normal heart rate and is developing normally. DISCUSSION Bradycardia is a well-known complication of propranolol therapy, resulting primarily from the blockade of /3-receptors in the heart. Hypoglycemia, another complication of propranolol administration, is apparently caused by the drug's interference with the normal epinephrine-mediated response to a fall in blood sugar. In children, this response occurs most often during fasting. 4 A n o t h e r effect of propranolol, particularly relevant to its use during pregnancy, is the stimulation of uterine muscle, as a result of B-receptor blockade. 5 It has been p o s t u l a t e d that a s u s t a i n e d i n c r e a s e in m u s c l e tone caused by continuous administration of this drug during pregnancy could result in a small placenta and a small-for-dates infant) All of these complications were noted in the present case. It has been shown that propranolol administered intravenously to ewes causes /3-blockade in the fetus, 6 and propranolol has also been reported to cross the h u m a n placenta when given intravenously. 7 Joelsson and Barton 2 have demonstrated, in animal experiments, that the drug causes d i r e c t i m p a i r m e n t o f fetal responses to an anoxic insult. Control animals responded to anoxia with bradycardia and a transient rise in blood pressure, and when the stress was removed, an immediate tachycardia was observed. Fetuses who were administered propranolol displayed a fall in blood pressure during anoxia, and no rebound tachycardia. Studies involving the h u m a n fetus have also demonstrated that maternally administered propranolol interferes with normal autonomic responses during labor and may have a direct depressant effect on the neonate. Renou and associates 8 injected atropine Subcutaneously into the scalps of 11 fetuses during labor and then administered 10 mg of propranolol intravenously to each of the mothers. All fetuses had a sustained fall in heart rate after the maternal administration of propranoloi. F u r t h e r m o r e , e i g h t f e t u s e s w h o h a d p r e v i o u s l y responded to uterine contractions with tachycardia, no longer showed this response. Tunstall 9 reported a double-blind study of the effects of propranolol adminiStered acutely during labor. He found that four women, who were given unspecified doses o f i n t r a v e n o u s
Propranoloi administration during pregnancy
963
propranolol 30 minutes before cesarean section, gave birth to depressed infants when compared to six infants of control subjects. Most of the other reports in the literature dealing with the effects of continuous propranolol administration d u r i n g p r e g n a n c y h a v e s t r e s s e d the m o t h e r ' s course, rather than that of the fetus. 1~ 11 A recent case report, 3 however, emphasized the possible deleterious effects on the fetus. A 32-year-old woman had taken 180 mg of propranolol and 90 mg of phenobarbital per day for idiopathic r e c u r r e n t v e n t r i c u l a r t a c h y c a r d i a which had occurred in her first month o f pregnancy. A small-for-gestational-age infant was delivered at term. Perinatal problems included a drop in f~tal heart rate to 60 When low outlet forceps were applied, a tight nuchal cord, birth asphyxia with meconium-stained fluid, low Apgar scores, and a s m a l l infarcted placenta. Bradycardia and hypoglycemia were observed in the first day of life and gradually resolved over a three-day period. The possible Pole of propranolol in the causation o f these complications was discussed, although the severity o f the underlying maternal disease and the tight nuchal cord at birth undoubtedly contributed to these abnormal responses. These neonatal problems were similar to those encountered in our patient; by contrast, however, the underlying maternal disease was well controlled and there were no other etiologic factors known to cause fetal depression. Although the half-life o f propranolol in the adult is about three hours, 12 the drug may have a much longer half-life in the neonate since it is metabolized by the liver, an organ which is functionally immature in the newborn infant. This factor may account for the persistence of bradycardia and hypoglycemia b e y o n d the first day of life in involved infants. The pharmacologic actions of propranolol may have deleterious effects on the fetus and neonate. These include: impaired responses to anoxic stress; dep/'ession at birth; a small placenta; intrauterine growth retardation; a n d p o s t n a t a l b r a d y c a r d i a and h y p o g l y c e m i a . Therefore, pregnancies during which this drug is adm i n i s t e r e d m u s t b e c o n s i d e r e d " h i g h r i s k . " Both mother and fetus should be carefully monitored so that, if any o f the aforementioned complications should occur, they can be immediately recognized and treated. Successful m a n a g e m e n t of severe cases may require vigorous resuscitation, correction of hypoglycemia, and administration of atropine or isoproterenol for bradycardia. In refractory situations, it is possible that cardiac pacing may be necessary to maintain an adequate heart rate.
964
Gladstone, Hordof and Gersony
REFERENCES 1.
2.
3. 4. 5.
6.
Kosman ME: Current status of propranolol hydrochloride (InderaD JAMA 225:1380, 1973. Joelsson I, and Barton MD: The effect of blockade of the receptors of the sympathetic nervous system of the fetus, Acta Obstet Gynecol Scand 48(Suppl 3):75, 1969. Reed RL, et al: Propranolol therapy throughout pregnancy: A case report, Anaesth Analg 53:214, 1974. McBride JT, et al: Hypoglycemia associated with propranolol, Pediatrics 51:1055, 1973. Amy J J: Intrauterine administration of L-noradrenaline and propranolol during the second trimester of pregnancy, J Obstet Gynecol Br Commonw 81:75, 1974. Joelsson I, et al: The response of the unanesthetized sheep fetus to sympathomimetic amines and adrenergic agents, Am J Obstet Gynecol 114:43, 1972.
The Journal of Pediatrics June 1975
7. Barnes AB: Chronic propranolol administration during pregnancy, J Reprod Med 5:79, 1970. 8. Renou P, et al: Autonomic control of fetal heart rate, Am J Obstet Gynecol 105:949, 1969. 9. Tunstall ME: The effect of prorpanolol on the onset of breathing at birth, Br J Anaesth 41:792, 1969. 10. Jackson GL: Treatment of hyperthyroidism in pregnancy, Pa Med 76:56, 1973. 11. Turner GM, et al: Management of pregnancy complicated by hypertrophic obstructive cardiomyopathy, Br Med J 4:281, 1968. 12. Faulkner SL, et al: Time required for complete recovery from chronic propranolol therapy, N Engl J Med 289:607, 1973.