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SODIUM VALPROATE AND ENURESIS
1276 MALFORMATION OF FETUS CONCEIVED 4 MONTHS AFTER TERMINATION OF MATERNAL ETRETINATE TREATMENT
SiR,-Since etretinate (’Tigason’) is teratogenic contraception is women of childbearing potential not only during treatment but also for 24 months after discontinuation (after long-
required for term
administration the
drug’s
elimination half-life is 120
days or
morel,2). Some cases of skeletal and craniofacial disorders in fetuses from women receiving etretinate have been reported, though other
have had normal children.2So far, no malformations have been reported in children whose mothers had become pregnant within 2 years of cessation of etretinate therapy. 1,3 We have observed skeletal deformations in a fetus conceived 4 months after the last dose of etretinate. A 22-year-old woman with Darier’s disease (dyskeratosis follicularis) since the age of 17 had been treated intermittently with etretinate; the last 5-month treatment with 30 mg daily ended 4 months before conception. In her 8th week of pregnancy, the patient sought genetic counselling and a medically indicated termination was decided on. She consented to chorion biopsy and to amniotic fluid investigation. A normal female karyotype was diagnosed from chromosome analysis. Serum concentrations of etretinate and its major metabolite, the carboxylic acid derivative Ro 10-1670, were 7 ng/ml and 8 ng/ml, respectively (therapeutic levels 100-500 ng/mI4,5). The pregnancy was terminated in the 10th week. The fetus (2 -2 cm long) had one lower limb much shorter than the other (5 mm left, 10 mm right). The distal left leg was rudimentary; only one toe was present, the tibia and fibula were missing, and the femur was hypoplastic. No further abnormalities were detected. Craniofacial malformations could not be assessed because the head was badly deformed by the termination. The one sidedness of skeletal deformation and its nature are consistent with an exogenous cause, probably etretinate taken by the mother before women
conception. This case emphasises the need for strict contraception to continue for 2 years after etretinate therapy. This unusual recommendation by the manufacturer is well justified. We thank Hoffmann-La Roche,
Grenzach-Wyhlen
for
measuring
serum
drug concentrations. W. GROTE D. HARMS Departments of Human Genetics, Paediatric Pathology, Dermatology, and Pharmacology, University of Kiel, 2300 Kiel, West Germany 1. 2. 3.
4. 5.
U. JÄNIG H. KIETZMANN U. RAVENS I. SCHWARZE
Bounameaux Y, Fisch T. Teratogene Wirkung von Etretinat beim Menschen. Deutsche Med Wochenschr 1984; 109: 1476-80. Cordero AA, Allevato MA, Donatti L. Ro-10-9359 and pregnancy. In: Retinoids: Advances in basic research and therapy. Berlin: Springer, 1981: 501. Rüther TH, Kietzmann H. Schwangerschaft nach Therapie mit Etretinat (Tigason). Akt Dermatol 1984, 10: 62-63. Paravicini U. Pharmacokinetics and metabolism of oral aromatic retinoids. In: Retinoids: Advances in basic research and therapy. Berlin: Springer, 1981: 13-20. Ward A, Brogden RN, Heel RC, Speight TM, Avery GS. Etretinate. A review of its pharmacological properties and therapeutic efficacy in psoriasis and other skin disorders. Drug 1983; 26: 9-43.
Happle R, Traupe H,
LIMB REDUCTION DEFORMITIES IN CHILD EXPOSED TO ISOTRETINOIN IN UTERO ON GESTATION DAYS 26-40 ONLY
SlR,-I recently saw a child with reduction deformities of the limbs, the mother having taken isotretinoin (’Accutane’) in, pregnancy. She was 26 days’ pregnant when treatment began. A urinary pregnancy test using anti-hCG serum confirmed the
mg/day for the next 14 days until the 40th day of gestation (the half-life of the drug is about 20 h). pregnancy. She took 40
The male child had reduction deformities of all four limbs. The carpals, metacarpals, and the phalanges of the thumbs of both hands were unaffected. The fingers of the left hand were represented by rudimentary proximal phalanges. There were no fingers on the right hand. The femur and upper third of the tibia and fibula were present in the right leg, the tibia and fibula were tapered at the ends.
The left
leg was normal apart from absence of the second and third
phalanges of the second toe. Limb development in man occurs from the 25th to the 42nd days of gestation beginning at stages 12 (upper limb buds) and 13 (lower limb buds). The apical ectodermal ridge (AER) is found during a period of about 10 days and is recognisable until at last digital rays have appeared (stage 17 in the upper limb, stage 18 in the lower limb).Since the limbs were developing at the time of maternal drug ingestion isotretinoin probably caused the malformations. All limbs were affected, to varying degrees, so the mechanism may have been drug damage to the AER. Both thumbs were normal; in the thalidomide syndrome the thumbs were almost always affected. In most cases of malformations reported after ingestion of retinoic acid derivatives the woman has conceived while already on treatment. In this case treatment began on the 26th day of pregnancy, which may explain the normal head, ears, and, possibly, heart in this child. The time frame of exposure to a teratogen will determine the pattern of malformation produced. Foundation 41, Sydney, New South Wales 2010, Australia 1.
W. G. MCBRIDE
R The development and classification of anomalies of the limbs in the human. In: Marius M, ed Prevention of physical and mental congenital defects: Part C. New York: Alan R. Liss, 1985: 85-90.
O’Rahilly
SODIUM VALPROATE AND ENURESIS p 980) is incorrect to that an association between sodium valproate and enuresis has not been previously described. Several studies of valproate in children 1-5 have recorded enuresis as a side-effect, the frequency being 1-7%. The two most likely explanations are that the enuresis is secondary to a central effect on the thirst centre, resulting in polydipsia, or is a consequence of the increased depth of sleep commonly associated with valproate.l Increased thirst has been demonstrated in several studies with valproate.3,5,6
SiR,-Dr Panayiotopoulos (April 27,
state
Department of Pharmacology and Therapeutics, New Medical Building, Ashton Street, PO Box 147, Liverpool L69 3BX
I. A. CHOONARA
1. Heathfield K, Dunlop D, Karanjia P, Retsas S. The long-term results oftreatingthtrtysix patients with intractable epilepsy with sodium valproate (Epilim). In: Legg NJ, ed. Clinical and pharmacological aspects of sodium valproate (Epilim) in the treatment of epilepsy. Kent: MCS Consultants, 1976: 165-70. 2. Egger J, Brett EM. Effects of sodium valproate in 100 children with special reference to weight. Br MedJ 1981,283: 577-81. 3. Herranz JL, Arteaga R, Armijo JA. Side effects of sodium valproate in monotherapy controlled by plasma levels: a study in 88 pediatric patients, EpzlepslQ ] 982; 23: 203-14. 4 Muddiman MJ, Rolles CJ. Epilepsy in general paediatric practice. Br Chn Pract 1983 (suppl 27): 99-104. 5. Herranz JL, Armijo JA, Arteaga R. Effectiveness and toxicity of phenobarbital, pnmidone, and sodium valproate in the prevention of febrile convulsions, controlled by plasma levels. EpzlepSla 1984; 25: 89-95. 6. Dinesen H, Gram L, Andersen T, Dam M. Weight gain during treatment with valproate. Acta Neurol Scand 1984; 69: 65-69.
INDUCTION OF VIBRIO CHOLERAE SPECIFIC BILIARY ANTIBODIES AFTER ORAL IMMUNISATION WITH A CHOLERA CELL-WALL FRACTION
SIR,-In cholera the profuse secretion by the enterocytes is stimulated by the toxin, or rather the "tonin", liberated by the bacteria during lysis. The first step in this process is colonisation of the gastrointestinal tract following bacterium-enterocyte interaction. The classical killed whole-cell vaccine protects 7007o of the immunised population for 5 to 6 months. Several other live attenuated and toxoid vaccines are being tested.1,2 One new oral cholera vaccine produced at Institut Pasteur and now at the end stage of clinical trial consists of CH1+2,3 a purified specific polysaccharide-containing traction derived from the Vibrio clzolaai cell-wall. It does not contain any toxin; the aim is protection from bacterial colonisation by local immunization.Direct proof that 11 results in the presence of specific antibodies m the gastrointestinal tract is still lacking.
SiR,-Since etretinate (’Tigason’) is teratogenic contraception is women of childbearing potential not only during treatment but also for 24 months after discontinuation (after long-
required for term
administration the
drug’s
elimination half-life is 120
days or
morel,2). Some cases of skeletal and craniofacial disorders in fetuses from women receiving etretinate have been reported, though other
have had normal children.2So far, no malformations have been reported in children whose mothers had become pregnant within 2 years of cessation of etretinate therapy. 1,3 We have observed skeletal deformations in a fetus conceived 4 months after the last dose of etretinate. A 22-year-old woman with Darier’s disease (dyskeratosis follicularis) since the age of 17 had been treated intermittently with etretinate; the last 5-month treatment with 30 mg daily ended 4 months before conception. In her 8th week of pregnancy, the patient sought genetic counselling and a medically indicated termination was decided on. She consented to chorion biopsy and to amniotic fluid investigation. A normal female karyotype was diagnosed from chromosome analysis. Serum concentrations of etretinate and its major metabolite, the carboxylic acid derivative Ro 10-1670, were 7 ng/ml and 8 ng/ml, respectively (therapeutic levels 100-500 ng/mI4,5). The pregnancy was terminated in the 10th week. The fetus (2 -2 cm long) had one lower limb much shorter than the other (5 mm left, 10 mm right). The distal left leg was rudimentary; only one toe was present, the tibia and fibula were missing, and the femur was hypoplastic. No further abnormalities were detected. Craniofacial malformations could not be assessed because the head was badly deformed by the termination. The one sidedness of skeletal deformation and its nature are consistent with an exogenous cause, probably etretinate taken by the mother before women
conception. This case emphasises the need for strict contraception to continue for 2 years after etretinate therapy. This unusual recommendation by the manufacturer is well justified. We thank Hoffmann-La Roche,
Grenzach-Wyhlen
for
measuring
serum
drug concentrations. W. GROTE D. HARMS Departments of Human Genetics, Paediatric Pathology, Dermatology, and Pharmacology, University of Kiel, 2300 Kiel, West Germany 1. 2. 3.
4. 5.
U. JÄNIG H. KIETZMANN U. RAVENS I. SCHWARZE
Bounameaux Y, Fisch T. Teratogene Wirkung von Etretinat beim Menschen. Deutsche Med Wochenschr 1984; 109: 1476-80. Cordero AA, Allevato MA, Donatti L. Ro-10-9359 and pregnancy. In: Retinoids: Advances in basic research and therapy. Berlin: Springer, 1981: 501. Rüther TH, Kietzmann H. Schwangerschaft nach Therapie mit Etretinat (Tigason). Akt Dermatol 1984, 10: 62-63. Paravicini U. Pharmacokinetics and metabolism of oral aromatic retinoids. In: Retinoids: Advances in basic research and therapy. Berlin: Springer, 1981: 13-20. Ward A, Brogden RN, Heel RC, Speight TM, Avery GS. Etretinate. A review of its pharmacological properties and therapeutic efficacy in psoriasis and other skin disorders. Drug 1983; 26: 9-43.
Happle R, Traupe H,
LIMB REDUCTION DEFORMITIES IN CHILD EXPOSED TO ISOTRETINOIN IN UTERO ON GESTATION DAYS 26-40 ONLY
SlR,-I recently saw a child with reduction deformities of the limbs, the mother having taken isotretinoin (’Accutane’) in, pregnancy. She was 26 days’ pregnant when treatment began. A urinary pregnancy test using anti-hCG serum confirmed the
mg/day for the next 14 days until the 40th day of gestation (the half-life of the drug is about 20 h). pregnancy. She took 40
The male child had reduction deformities of all four limbs. The carpals, metacarpals, and the phalanges of the thumbs of both hands were unaffected. The fingers of the left hand were represented by rudimentary proximal phalanges. There were no fingers on the right hand. The femur and upper third of the tibia and fibula were present in the right leg, the tibia and fibula were tapered at the ends.
The left
leg was normal apart from absence of the second and third
phalanges of the second toe. Limb development in man occurs from the 25th to the 42nd days of gestation beginning at stages 12 (upper limb buds) and 13 (lower limb buds). The apical ectodermal ridge (AER) is found during a period of about 10 days and is recognisable until at last digital rays have appeared (stage 17 in the upper limb, stage 18 in the lower limb).Since the limbs were developing at the time of maternal drug ingestion isotretinoin probably caused the malformations. All limbs were affected, to varying degrees, so the mechanism may have been drug damage to the AER. Both thumbs were normal; in the thalidomide syndrome the thumbs were almost always affected. In most cases of malformations reported after ingestion of retinoic acid derivatives the woman has conceived while already on treatment. In this case treatment began on the 26th day of pregnancy, which may explain the normal head, ears, and, possibly, heart in this child. The time frame of exposure to a teratogen will determine the pattern of malformation produced. Foundation 41, Sydney, New South Wales 2010, Australia 1.
W. G. MCBRIDE
R The development and classification of anomalies of the limbs in the human. In: Marius M, ed Prevention of physical and mental congenital defects: Part C. New York: Alan R. Liss, 1985: 85-90.
O’Rahilly
SODIUM VALPROATE AND ENURESIS p 980) is incorrect to that an association between sodium valproate and enuresis has not been previously described. Several studies of valproate in children 1-5 have recorded enuresis as a side-effect, the frequency being 1-7%. The two most likely explanations are that the enuresis is secondary to a central effect on the thirst centre, resulting in polydipsia, or is a consequence of the increased depth of sleep commonly associated with valproate.l Increased thirst has been demonstrated in several studies with valproate.3,5,6
SiR,-Dr Panayiotopoulos (April 27,
state
Department of Pharmacology and Therapeutics, New Medical Building, Ashton Street, PO Box 147, Liverpool L69 3BX
I. A. CHOONARA
1. Heathfield K, Dunlop D, Karanjia P, Retsas S. The long-term results oftreatingthtrtysix patients with intractable epilepsy with sodium valproate (Epilim). In: Legg NJ, ed. Clinical and pharmacological aspects of sodium valproate (Epilim) in the treatment of epilepsy. Kent: MCS Consultants, 1976: 165-70. 2. Egger J, Brett EM. Effects of sodium valproate in 100 children with special reference to weight. Br MedJ 1981,283: 577-81. 3. Herranz JL, Arteaga R, Armijo JA. Side effects of sodium valproate in monotherapy controlled by plasma levels: a study in 88 pediatric patients, EpzlepslQ ] 982; 23: 203-14. 4 Muddiman MJ, Rolles CJ. Epilepsy in general paediatric practice. Br Chn Pract 1983 (suppl 27): 99-104. 5. Herranz JL, Armijo JA, Arteaga R. Effectiveness and toxicity of phenobarbital, pnmidone, and sodium valproate in the prevention of febrile convulsions, controlled by plasma levels. EpzlepSla 1984; 25: 89-95. 6. Dinesen H, Gram L, Andersen T, Dam M. Weight gain during treatment with valproate. Acta Neurol Scand 1984; 69: 65-69.
INDUCTION OF VIBRIO CHOLERAE SPECIFIC BILIARY ANTIBODIES AFTER ORAL IMMUNISATION WITH A CHOLERA CELL-WALL FRACTION
SIR,-In cholera the profuse secretion by the enterocytes is stimulated by the toxin, or rather the "tonin", liberated by the bacteria during lysis. The first step in this process is colonisation of the gastrointestinal tract following bacterium-enterocyte interaction. The classical killed whole-cell vaccine protects 7007o of the immunised population for 5 to 6 months. Several other live attenuated and toxoid vaccines are being tested.1,2 One new oral cholera vaccine produced at Institut Pasteur and now at the end stage of clinical trial consists of CH1+2,3 a purified specific polysaccharide-containing traction derived from the Vibrio clzolaai cell-wall. It does not contain any toxin; the aim is protection from bacterial colonisation by local immunization.Direct proof that 11 results in the presence of specific antibodies m the gastrointestinal tract is still lacking.