- Email: [email protected]
CAFFEINE IN PREGNANCY
1020
study showed that 1 in 10 of 800 inpatients on propranolol had adverse effects.6 Whilst we cannot comment on Jack and Kendall’s data in press, we would point out that interindividual differences in plasma levels of lipophilic &bgr;-blockers due to food, increased erythrocyte sedimentation rate, or enzyme induction are not as pronounced as those due to genetically determined drug oxidation status. In a study by Bennett et al., interindividual differences in the area-under-curve (zero hours to infinity) of metoprolol were of the order of 2600% while 15 days of treatment with rifampicin resulted in a mean change of only about 33%. This firmly underlines the considerably important role of genetic factors. We would not encourage a simple switch from a hepatically metabolised lipophilic to a renally eliminated hydrophilic (3-blocker since the latter differs significantly from the former in absorption, protein-binding, and distribution properties.8 All&bgr;-blockers are not equally effective against the currently citable fifty clinical indications for &bgr;-blocker therapy.Furthermore, it is difficult to see how Jack and Kendall propose to overcome the problems arising from variable presystemic hepatic metabolism of drugs by simple manipulation of drug release characteristics. R. R. SHAH N. S. OATES J. R. IDLE R. L. SMITH
Department of Biochemical Pharmacology, St Mary’s Hospital Medical School, London W2 IPG
UMBILICAL CORD PLASMA CAFFEINE CONCENTRATIONS
*To
convert to
mg/1 multiply by 0
. 1942.
effect on the pregnancy or baby, as judged by records of the labour, Apgar scores, and clinical examination. These findings indicate that babies may be born with large caffeine loads. In this one series at a London hospital levels of maternal caffeine ingestion and umbilical cord caffeine concentrations greater than those seen in American studies were not associated with adverse effects on pregnancy. Department of Clinical Pharmacology, Guy’s Hospital Medical School, London SE1
CAFFEINE IN PREGNANCY
SiR,-The safety of caffeine ingestion in pregnancy is controversial. In 1980 the U.S. Food and Drug Administration advised women to reduce their caffeine intake during pregnancy but Linn et al.concluded that caffeine had hardly any or no effect on pregnancy. Paediatricians have suggested the use of caffeine and 2 theophylline in the treatment of recurrent apnoea of the newborn.2 I assessed caffeine intake in fifty-two healthy pregnant British women and measured the transplacental passage of caffeine in fiftyfive healthy, full-term babies. The average caffeine content in a cup of coffee was assumed to be 83 mg, in a cup of tea or glass of cola 40 mg, and in a cup of cocoa 5 mg.3The mean caffeine intake during a typical day in the pregnancy was 290±230 mg (SD). The usual source of caffeine was tea. This is double the average caffeine intake in a study of over a thousand American pregnant women reported by
Graham.3
Umbilical cord blood caffeine levels were measured by a specific gas liquid chromatographic method (see table). The distribution of caffeine concentrations was significantly different (p<0-001, chi squared) when compared with data in the American studies of Bory et al. and Aranda et al. have reported that the minimum concentration at which caffeine stimulates respiration is between 15.4 and 20 -66 cmol/1 (3 and 4 mg/1). Of the British babies 14 (27%) had plasma caffeine concentrations than 15’4mol/1 in with 4% and these included 7 with Soyka’s series5) (compared concentrations in the therapeutic range for the treatment of recurrent apnoea The highest caffeine concentration was 62 pmol/l, which is well below the lowest level at which toxicity has been observed (260 Caffeine had no
Soyka.5
greater
WILLIAM VAN’T HOFF
HEPATIC ENCEPHALOPATHY AND GABA
SiR,-Dr Schafer and Dr Jones (Jan. 2, p. 18), in their interesting hypothesis on the pathophysiology of hepatic encephalo-
pathy, conclude that "the pattern of postsynaptic neuronal activity in hepatic encephalopathy is similar to that induced by drugs which cause GABA-ergic neural inhibition." This conclusion is based on the similarity of the changes of the visual evoked potential in acute hepatic failure and in barbiturate/benzodiazepine induced coma. This conclusion is incorrect. Evoked potentials do not permit conclusions about the underlying pattern of postsynaptic neuronal activity unless the following are known: (a) the type of postsynaptic activity involved, excitatory and inhibitory, its somadendritic location, and the spatial extent of the conductance changes; (b) the relation between the dendritic length and electronic length constants of the cellular population involved; (c) the vertical extent of dendrites as a function of the depth of the cell body in the cerebral cortex and (d) the distribution of responding cells over cortical depth.The complete data needed to interpret the visual evoked response in terms of the underlying postsynaptic neuronal activity are not available. The suggestion that "gut derived GABA contributes to the neuronal inhibition of hepatic encephalopathy neglects two important observations on the function of the CNS. An increase of inhibition at the neuronal level may cause not only a depression of
99: 665-70.
the output of the neuronal circuits of the CNS but also an excessive increase. Neuronal circuits containing an inhibition of inhibition have been described in the CNS: neuron 12 inhibits neuron II which inhibits a spontaneously active output neuron 0.2 Thus, an increase of inhibition at the neuronal level may cause hyperexcitation of the output of neuronal circuits in the CNS and not contribute to the "neural inhibition of hepatic encephalopathy". The action of ammonia on postsynaptic inhibition may counteract increases of GABA-ergic inhibition. Ammonia inactivates the extrusion of Cl from neurons,3abolishes the hyperpolarising action of postsynaptic inhibition, and thus renders GABA-ergic inhibition in the cerebral cortex ineffective at cerebral ammonia concentrations beyond 0 - 61
S, Schoenbaum SC, Monson RR, Rosner B, Stubblefield PG, Ryan KJ. No association between coffee consumption and adverse outcomes of pregnancy. N Engl
1.
(26—103jL
mol/1).
W, Silverman R, Strom J, Elkayam U, Sonnenblick E. Adverse effects: Choosing a &bgr;-adrenoreceptor blocker. Am Heart J 1979; 98: 256-62. 7. Bennett PN, John VA, Whitmarsh VB. Effect of rifampicin on metoprolol and antipyrine kinetics. Br J Clin Pharmacol 1982; 13: 387-91. 8. Cruickshank JM. The clinical importance of cardioselectivity and lipophilicity in betablockers. Am Heart J 1980; 100: 160-78. 9 Frishman W. The &bgr;-adrenoreceptor blocking drugs: a perspective. Am Heart J 1980; 6. Frishman
1. Linn
2.
J Med 1982; 306: 141-45. Aranda JV, Grondin D, Sasyniuk BI. Pharmacologic considerations in the therapy of
neonatal apnea. Pediatr Clin North Am 1981; 28: 113-33. 3 Graham DM. Caffeine: Its identity, dietary sources, intake and biologic effects. Nutr Rev 1978, 36: 97-102. 4. Bory C, Baltassat P, Porthault M, Bethenod M, Frederich A, Aranda JV. Metabolism of theophylline to caffeine in premature newborn infants. J Pediatr 1979; 94: 988-92. 5 Soyka LF. Effects of methylxanthines on the fetus. Clin Perinatol 1979, 6: 37-51.
the antidromic cortical response II: On the contribution of cell discharge and PSPs to the evoked potentials. Elecroencephalogr Clin
Humphrey DR. Re-analysis of
Neurophysiol 1968; 25: 421-42. Epilepsy and antiepileptic drugs: a speculative synthesis. In Glaser GH, Penry JK, Woodbury DM, eds. Antiepileptic drugs: Mechanisms of action. New
2. Roberts E.
York: Raven Press, 1980: 667-713. 3. Lux HD. Ammonium and chloride extrusion:
Hyperpolarizing synaptic inhibition in spinal motoneurons. Science 1971; 173: 555-57. 4. Raabe W, Gumnit RJ. Disinhibition in cat motor cortex by ammonia. J Neurophysiol 1975; 38: 347-55.
study showed that 1 in 10 of 800 inpatients on propranolol had adverse effects.6 Whilst we cannot comment on Jack and Kendall’s data in press, we would point out that interindividual differences in plasma levels of lipophilic &bgr;-blockers due to food, increased erythrocyte sedimentation rate, or enzyme induction are not as pronounced as those due to genetically determined drug oxidation status. In a study by Bennett et al., interindividual differences in the area-under-curve (zero hours to infinity) of metoprolol were of the order of 2600% while 15 days of treatment with rifampicin resulted in a mean change of only about 33%. This firmly underlines the considerably important role of genetic factors. We would not encourage a simple switch from a hepatically metabolised lipophilic to a renally eliminated hydrophilic (3-blocker since the latter differs significantly from the former in absorption, protein-binding, and distribution properties.8 All&bgr;-blockers are not equally effective against the currently citable fifty clinical indications for &bgr;-blocker therapy.Furthermore, it is difficult to see how Jack and Kendall propose to overcome the problems arising from variable presystemic hepatic metabolism of drugs by simple manipulation of drug release characteristics. R. R. SHAH N. S. OATES J. R. IDLE R. L. SMITH
Department of Biochemical Pharmacology, St Mary’s Hospital Medical School, London W2 IPG
UMBILICAL CORD PLASMA CAFFEINE CONCENTRATIONS
*To
convert to
mg/1 multiply by 0
. 1942.
effect on the pregnancy or baby, as judged by records of the labour, Apgar scores, and clinical examination. These findings indicate that babies may be born with large caffeine loads. In this one series at a London hospital levels of maternal caffeine ingestion and umbilical cord caffeine concentrations greater than those seen in American studies were not associated with adverse effects on pregnancy. Department of Clinical Pharmacology, Guy’s Hospital Medical School, London SE1
CAFFEINE IN PREGNANCY
SiR,-The safety of caffeine ingestion in pregnancy is controversial. In 1980 the U.S. Food and Drug Administration advised women to reduce their caffeine intake during pregnancy but Linn et al.concluded that caffeine had hardly any or no effect on pregnancy. Paediatricians have suggested the use of caffeine and 2 theophylline in the treatment of recurrent apnoea of the newborn.2 I assessed caffeine intake in fifty-two healthy pregnant British women and measured the transplacental passage of caffeine in fiftyfive healthy, full-term babies. The average caffeine content in a cup of coffee was assumed to be 83 mg, in a cup of tea or glass of cola 40 mg, and in a cup of cocoa 5 mg.3The mean caffeine intake during a typical day in the pregnancy was 290±230 mg (SD). The usual source of caffeine was tea. This is double the average caffeine intake in a study of over a thousand American pregnant women reported by
Graham.3
Umbilical cord blood caffeine levels were measured by a specific gas liquid chromatographic method (see table). The distribution of caffeine concentrations was significantly different (p<0-001, chi squared) when compared with data in the American studies of Bory et al. and Aranda et al. have reported that the minimum concentration at which caffeine stimulates respiration is between 15.4 and 20 -66 cmol/1 (3 and 4 mg/1). Of the British babies 14 (27%) had plasma caffeine concentrations than 15’4mol/1 in with 4% and these included 7 with Soyka’s series5) (compared concentrations in the therapeutic range for the treatment of recurrent apnoea The highest caffeine concentration was 62 pmol/l, which is well below the lowest level at which toxicity has been observed (260 Caffeine had no
Soyka.5
greater
WILLIAM VAN’T HOFF
HEPATIC ENCEPHALOPATHY AND GABA
SiR,-Dr Schafer and Dr Jones (Jan. 2, p. 18), in their interesting hypothesis on the pathophysiology of hepatic encephalo-
pathy, conclude that "the pattern of postsynaptic neuronal activity in hepatic encephalopathy is similar to that induced by drugs which cause GABA-ergic neural inhibition." This conclusion is based on the similarity of the changes of the visual evoked potential in acute hepatic failure and in barbiturate/benzodiazepine induced coma. This conclusion is incorrect. Evoked potentials do not permit conclusions about the underlying pattern of postsynaptic neuronal activity unless the following are known: (a) the type of postsynaptic activity involved, excitatory and inhibitory, its somadendritic location, and the spatial extent of the conductance changes; (b) the relation between the dendritic length and electronic length constants of the cellular population involved; (c) the vertical extent of dendrites as a function of the depth of the cell body in the cerebral cortex and (d) the distribution of responding cells over cortical depth.The complete data needed to interpret the visual evoked response in terms of the underlying postsynaptic neuronal activity are not available. The suggestion that "gut derived GABA contributes to the neuronal inhibition of hepatic encephalopathy neglects two important observations on the function of the CNS. An increase of inhibition at the neuronal level may cause not only a depression of
99: 665-70.
the output of the neuronal circuits of the CNS but also an excessive increase. Neuronal circuits containing an inhibition of inhibition have been described in the CNS: neuron 12 inhibits neuron II which inhibits a spontaneously active output neuron 0.2 Thus, an increase of inhibition at the neuronal level may cause hyperexcitation of the output of neuronal circuits in the CNS and not contribute to the "neural inhibition of hepatic encephalopathy". The action of ammonia on postsynaptic inhibition may counteract increases of GABA-ergic inhibition. Ammonia inactivates the extrusion of Cl from neurons,3abolishes the hyperpolarising action of postsynaptic inhibition, and thus renders GABA-ergic inhibition in the cerebral cortex ineffective at cerebral ammonia concentrations beyond 0 - 61
S, Schoenbaum SC, Monson RR, Rosner B, Stubblefield PG, Ryan KJ. No association between coffee consumption and adverse outcomes of pregnancy. N Engl
1.
(26—103jL
mol/1).
W, Silverman R, Strom J, Elkayam U, Sonnenblick E. Adverse effects: Choosing a &bgr;-adrenoreceptor blocker. Am Heart J 1979; 98: 256-62. 7. Bennett PN, John VA, Whitmarsh VB. Effect of rifampicin on metoprolol and antipyrine kinetics. Br J Clin Pharmacol 1982; 13: 387-91. 8. Cruickshank JM. The clinical importance of cardioselectivity and lipophilicity in betablockers. Am Heart J 1980; 100: 160-78. 9 Frishman W. The &bgr;-adrenoreceptor blocking drugs: a perspective. Am Heart J 1980; 6. Frishman
1. Linn
2.
J Med 1982; 306: 141-45. Aranda JV, Grondin D, Sasyniuk BI. Pharmacologic considerations in the therapy of
neonatal apnea. Pediatr Clin North Am 1981; 28: 113-33. 3 Graham DM. Caffeine: Its identity, dietary sources, intake and biologic effects. Nutr Rev 1978, 36: 97-102. 4. Bory C, Baltassat P, Porthault M, Bethenod M, Frederich A, Aranda JV. Metabolism of theophylline to caffeine in premature newborn infants. J Pediatr 1979; 94: 988-92. 5 Soyka LF. Effects of methylxanthines on the fetus. Clin Perinatol 1979, 6: 37-51.
the antidromic cortical response II: On the contribution of cell discharge and PSPs to the evoked potentials. Elecroencephalogr Clin
Humphrey DR. Re-analysis of
Neurophysiol 1968; 25: 421-42. Epilepsy and antiepileptic drugs: a speculative synthesis. In Glaser GH, Penry JK, Woodbury DM, eds. Antiepileptic drugs: Mechanisms of action. New
2. Roberts E.
York: Raven Press, 1980: 667-713. 3. Lux HD. Ammonium and chloride extrusion:
Hyperpolarizing synaptic inhibition in spinal motoneurons. Science 1971; 173: 555-57. 4. Raabe W, Gumnit RJ. Disinhibition in cat motor cortex by ammonia. J Neurophysiol 1975; 38: 347-55.