Fetal valproate syndrome
http://www.100md.com
《美国医学杂志》
Department of pediatrics, JJM Medical College, Davangere, Karnataka, India
Abstract
Fetal Valproate Syndrome results from prenatal exposure to valproic acid. It is characterized by distinctive facial appearance, a cluster of minor and major anomalies and central nervous system dysfunction. Here we report a 4-year-old boy with typical facial features of Fetal Valproate Syndrome.
Keywords: Fetal valproate syndrome; Valproic acid
Anticonvulsants taken during pregnancy are associated with an increased risk of malformations and developmental delay. Sodium valproate is a widely used antiepileptic drug and mood stabilizer. It was licensed to use in 1978 and the first adverse report of fetus exposed to this drug was published in 1980.[1] Since then the potential teratogenic and dysmorphogenic effect of valproic acid have been emphasized.
Here we report a 4-year-old boy with dysmorphic features suggestive of Fetal Valproate Syndrome and also review the literature.
Case report
A 4-year-old boy was brought to our out patient department for evaluation of hypospadiasis. He was the only child born to a non-consanguineously married couple. Mother was on anticonvulsant sodium valproate monotherapy since 22 years. She continued the dose of 900 mg/day throughout her pregnancy. Delivery was by emergency LSCS, indication being fetal distress. His birth weight was 2.8 kg. Baby did not cry immediately after birth. Apgar score was not known. He was admitted to NICU for 3 days. Except for mild motor developmental delay his growth was normal.
Now at the age of 4 years, on examination, he had flat occiput, low set ears, slanting forehead, broad nasal bridge, hypertelorism, epicanthal folds, depressed nasal bridge, long philtrum, upturned nose, thin upperlip, small mouth. Figure1 Broad hands and feet, broad thumb deep set nails, loose skin, hypospadiasis Figure2 were other features.
His intelligence quotient was 70, with mild motor developmental delay. His weight was 18 Kg and height 104 cm (on 25th centile, NCHS). His neonatal follow-up record showed the presence of secundum ASD, but now cardiovascular system was completely normal. Echocardiogram showed normal heart without ASD. Ultrasound abdomen and CT of head did not show any abnormality. With maternal history of intake of sodium valproate throughout pregnancy and dysmorphic features typical of Fetal Valproate Syndrome, a diagnosis of FVS was made.
Discussion
Sodium valproate is a widely used antiepileptic drug and is also increasingly used for managing bipolar and other affective disorders. It is a salt of dipropyl acetic acid. It is thought to act either by inhibiting GABA metabolism or by a direct effect on mitochondria, thereby impairing cellular energy metabolism.[2] It is 80-90% bound to plasma proteins and may displace other drugs if used in combinations giving rise to toxicity. Long term valproate therapy may lead to carnitine depletion, which impairs mitochondrial fatty metabolism and leads to hepatotoxicity.
Various factors contribute to the teratogenecity of valproic acid. These include the number of drugs that are coadministered, drug dosage, differences in maternal and / or infant metabolism, the gestational age of the fetus at exposure. Valproic acid crosses the placenta and is present in a higher concentration in the fetus than in the mother.[3],[4] Various congenital malformations are associated with FVS. There is 6 to 7 times increase of malformations in babies of mothers exposed to valproate. The most frequent major congenital malformation are neural tube defects, congenital heart defects, oral clefts, genital abnormalities and limb defects. Other less frequent abnormalities include inguinal and umblical hernia, supernumerary nipple, postaxial polydactyly, bifid ribs, preaxial defect of feet.[5]
The occurrence of major malformations and number of minor anomalies may be dose related.[4] Zinc deficiency has been suggested as a possible cause of neural tube defects associated with valproate exposure as sodium valproate readily binds to zinc.[6] It has been suggested that cardiac defects could result from disordered neural crest migration.[7] Recurrence of FVS in a subsequent pregnancy exposed to valproate is high, possibly owing to inherent problems with metabolism of valproic acid in the mothers concerned.[3],[8]
Distinctive facial phenotype of fetal valproate syndrome has been described.[9],[10] The patients have typical facial features which tend to evolve with age. The facial features seen in FVS are trigonocephaly, tall forehead with bifrontal narrowing, epicanthic folds, infraorbital groove, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, antiverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip, small downturned mouth.[3]
Our case had the typical facial features, hypospadias, perinatal asphyxia, developmental delay, ostium secundum ASD at birth which closed spontaneously, although no major organ anomalies were found.
Neural tube defects have been estimated to occur at around 10 times the normal incidence in fetuses exposed to valproate and appears to be specifically related to valproate therapy, rather than to other anticonvulsants.[3] Many reports have been of spina bifida rather than anencephaly and there is predisposition for very low lumbar or sacral defects suggesting that valproate affects primarily lowest closure site of the neural tube.[11]
Congenital heart defects have been reported in several patients with FVS.[7],[12] and the incidence of congenital heart disease is estimated to be around 4 times than that seen in general population.[3] Septal defects and valvular problems have both been reported. Aortic valve stenosis, interrupted aortic arch, secundum ASD, pulmonary atresia without VSD, perimembranous VSD, hypoplastic left heart syndrome are known to occur.[5] Our case had ostium secundum ASD at birth, which closed spontaneously.
Oral clefts are 5 times more frequent than expected. Limb defects and digital abnormalities of various types are known to occur.[3] Ardinger et al[13] reviewed clinical features of 15 cases of FVS presenting with dysmorphic features and found evidence of mild to moderate developmental delay in 10 (67%) on follow-up. The association of developmental delay with valproate exposure has been confirmed in many reports.[3],[13],[14]
Pregnancy usually proceeds uneventfully and 10% of babies are small for gestational age.[3] Low apgar score[4] and withdrawal symptoms[3],[15] during the neonatal period are extremely common. The most frequent of withdrawal symptoms are irritability, jitteriness, hypotonia and seizures, which typically occur between 12 and 48 hours of life. These are dose related.[3],[15]
Postnatal growth appears to be normal and general health is good.[3] Microcephaly tends to occur only in the infants who are also exposed to other anticonvulsants.
In a recent study by Kozma[16], of the total 69 cases of FVS, majority of the patients had musculoskeletal abnormalities (62%), others had minor skin defects (30%), cardiovascular abnormalities (26%), genital (22%), and pulmonary abnormalities (16%) and neural tube defects (3%). Anomalies of brain, eye, kidney and hearing defects were found less frequently. 15% of patients had growth retardation. 12% of affected children died in infancy and 29% of surviving patients had developmental defects/mental retardation.
Prenatal diagnosis is focused on the detection of neural tube defects (NTD), as they are the proven major malformations. Estimation of maternal serum alfafetoprotein (AFP) can be used as a screening test for the presence of open NTD. As the skin covered lesions might not be associated with raised AFP levels, prenatal evaluation of valproic acid exposed fetuses must include targeted ultrasound examination particularly of the caudal spine even when AFP levels are normal.
Women taking valproic acid should be counselled and strongly encouraged to plan their pregnancies, so that periconceptional high dose folic acid that is 5 mg/day can be taken. Whenever the use of antiepileptic drug is inevitable during pregnancy, they should be administered as monotherapy, in the lowest possible dose with constant monitoring of serum concentration of antiepileptic drugs.
References
1. Dalens B, Raynaud EJ, Gaulme J. Teratogenicity of valproic acid. J Pediatr 1980; 97: 332-333.
2. Brown JK. Valproate toxicity. Dev Med Child Neurology 1988; 80: 115-125.
3. Clayton Smith J, Donnai D. Fetal valproate syndrome. J Med Genet 1995; 32: 724-727.
4. Jager-Roman E, Deichl A, Jakob S, Koch S, Rating D, Steldinger R et al. Fetal growth, major malformation and minor anomalies in infants born to women receiving valproic acid. J Pediatr 1986; 108 : 997-1004.
5. Jones KL(ed). Smith's recognizable patterns of human malformation, fifth edition, Philadelphia; WB Saunders Company 1997; 566-567.
6. Hurd RW, Wildes BJ, Van Rinovelt HA. Valproate, birth defects and zinc. Lancet 1983; 1: 181.
7. MQ CN, Ladusans EJ. Anomalous right pulmonary artery origins in association with the fetal valproate syndrome. J Med Genet 1999; 36 : 83-84.
8. Chitayat D, Farrell K, Anderson L, Hall JG. Congenital abnormalities in two sibs exposed to valproic acid in utero. Am J Med Genet 1988; 31: 369-373.
9. Dilberti JH, Farndon PA, Dennis NR, Curry CJR. The fetal valproate syndrome. Am J Med Genet 1984; 19 : 473-381.
10. Winter RM, Donnai D, Burn J, Tucker SM. Fetal valproate syndrome : is there a recognisable phenotype J Med Genet 1987; 24: 692-695.
11. Van Allen MI, Kalousek DK, Chernoff GF. Evidence for multi-site closure of neural tube in humans. Am J Med Genet 1993; 47: 723-743.
12. Praveena S, Banani P, Veena P. Fatal cardiac malformation in fetal valproate syndrome. Indian J Pediatr 2001; 68: 989-990.
13. Ardinger HH, Arkin JF, Blackston RD. Verification of the fetal valproate syndrome phenotype. Am J Med Genet 1988; 29: 171-185.
14. Christianson AL, Cheslar N, Kromber JG. Fetal valproate syndrome : clinical and neuro-develpmental features in two sibling pairs. Dev Med Child Neuro 1994; 36: 361-369.
15. Thisted B, Ebbeson F. Malformation, withdrawal manifestations and hypoglycemia after exposure to valproate in utero. Arch Dis Child 1993; 69: 288-291.
16. Kozma C. Valproic acid embryopathy : report of two siblings with further expansion of the phenotypic abnormalities and review of the literature. Am J Med Genet 2001; 98: 168-175.(Kulkarni ML, Zaheeruddin )
Abstract
Fetal Valproate Syndrome results from prenatal exposure to valproic acid. It is characterized by distinctive facial appearance, a cluster of minor and major anomalies and central nervous system dysfunction. Here we report a 4-year-old boy with typical facial features of Fetal Valproate Syndrome.
Keywords: Fetal valproate syndrome; Valproic acid
Anticonvulsants taken during pregnancy are associated with an increased risk of malformations and developmental delay. Sodium valproate is a widely used antiepileptic drug and mood stabilizer. It was licensed to use in 1978 and the first adverse report of fetus exposed to this drug was published in 1980.[1] Since then the potential teratogenic and dysmorphogenic effect of valproic acid have been emphasized.
Here we report a 4-year-old boy with dysmorphic features suggestive of Fetal Valproate Syndrome and also review the literature.
Case report
A 4-year-old boy was brought to our out patient department for evaluation of hypospadiasis. He was the only child born to a non-consanguineously married couple. Mother was on anticonvulsant sodium valproate monotherapy since 22 years. She continued the dose of 900 mg/day throughout her pregnancy. Delivery was by emergency LSCS, indication being fetal distress. His birth weight was 2.8 kg. Baby did not cry immediately after birth. Apgar score was not known. He was admitted to NICU for 3 days. Except for mild motor developmental delay his growth was normal.
Now at the age of 4 years, on examination, he had flat occiput, low set ears, slanting forehead, broad nasal bridge, hypertelorism, epicanthal folds, depressed nasal bridge, long philtrum, upturned nose, thin upperlip, small mouth. Figure1 Broad hands and feet, broad thumb deep set nails, loose skin, hypospadiasis Figure2 were other features.
His intelligence quotient was 70, with mild motor developmental delay. His weight was 18 Kg and height 104 cm (on 25th centile, NCHS). His neonatal follow-up record showed the presence of secundum ASD, but now cardiovascular system was completely normal. Echocardiogram showed normal heart without ASD. Ultrasound abdomen and CT of head did not show any abnormality. With maternal history of intake of sodium valproate throughout pregnancy and dysmorphic features typical of Fetal Valproate Syndrome, a diagnosis of FVS was made.
Discussion
Sodium valproate is a widely used antiepileptic drug and is also increasingly used for managing bipolar and other affective disorders. It is a salt of dipropyl acetic acid. It is thought to act either by inhibiting GABA metabolism or by a direct effect on mitochondria, thereby impairing cellular energy metabolism.[2] It is 80-90% bound to plasma proteins and may displace other drugs if used in combinations giving rise to toxicity. Long term valproate therapy may lead to carnitine depletion, which impairs mitochondrial fatty metabolism and leads to hepatotoxicity.
Various factors contribute to the teratogenecity of valproic acid. These include the number of drugs that are coadministered, drug dosage, differences in maternal and / or infant metabolism, the gestational age of the fetus at exposure. Valproic acid crosses the placenta and is present in a higher concentration in the fetus than in the mother.[3],[4] Various congenital malformations are associated with FVS. There is 6 to 7 times increase of malformations in babies of mothers exposed to valproate. The most frequent major congenital malformation are neural tube defects, congenital heart defects, oral clefts, genital abnormalities and limb defects. Other less frequent abnormalities include inguinal and umblical hernia, supernumerary nipple, postaxial polydactyly, bifid ribs, preaxial defect of feet.[5]
The occurrence of major malformations and number of minor anomalies may be dose related.[4] Zinc deficiency has been suggested as a possible cause of neural tube defects associated with valproate exposure as sodium valproate readily binds to zinc.[6] It has been suggested that cardiac defects could result from disordered neural crest migration.[7] Recurrence of FVS in a subsequent pregnancy exposed to valproate is high, possibly owing to inherent problems with metabolism of valproic acid in the mothers concerned.[3],[8]
Distinctive facial phenotype of fetal valproate syndrome has been described.[9],[10] The patients have typical facial features which tend to evolve with age. The facial features seen in FVS are trigonocephaly, tall forehead with bifrontal narrowing, epicanthic folds, infraorbital groove, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, antiverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip, small downturned mouth.[3]
Our case had the typical facial features, hypospadias, perinatal asphyxia, developmental delay, ostium secundum ASD at birth which closed spontaneously, although no major organ anomalies were found.
Neural tube defects have been estimated to occur at around 10 times the normal incidence in fetuses exposed to valproate and appears to be specifically related to valproate therapy, rather than to other anticonvulsants.[3] Many reports have been of spina bifida rather than anencephaly and there is predisposition for very low lumbar or sacral defects suggesting that valproate affects primarily lowest closure site of the neural tube.[11]
Congenital heart defects have been reported in several patients with FVS.[7],[12] and the incidence of congenital heart disease is estimated to be around 4 times than that seen in general population.[3] Septal defects and valvular problems have both been reported. Aortic valve stenosis, interrupted aortic arch, secundum ASD, pulmonary atresia without VSD, perimembranous VSD, hypoplastic left heart syndrome are known to occur.[5] Our case had ostium secundum ASD at birth, which closed spontaneously.
Oral clefts are 5 times more frequent than expected. Limb defects and digital abnormalities of various types are known to occur.[3] Ardinger et al[13] reviewed clinical features of 15 cases of FVS presenting with dysmorphic features and found evidence of mild to moderate developmental delay in 10 (67%) on follow-up. The association of developmental delay with valproate exposure has been confirmed in many reports.[3],[13],[14]
Pregnancy usually proceeds uneventfully and 10% of babies are small for gestational age.[3] Low apgar score[4] and withdrawal symptoms[3],[15] during the neonatal period are extremely common. The most frequent of withdrawal symptoms are irritability, jitteriness, hypotonia and seizures, which typically occur between 12 and 48 hours of life. These are dose related.[3],[15]
Postnatal growth appears to be normal and general health is good.[3] Microcephaly tends to occur only in the infants who are also exposed to other anticonvulsants.
In a recent study by Kozma[16], of the total 69 cases of FVS, majority of the patients had musculoskeletal abnormalities (62%), others had minor skin defects (30%), cardiovascular abnormalities (26%), genital (22%), and pulmonary abnormalities (16%) and neural tube defects (3%). Anomalies of brain, eye, kidney and hearing defects were found less frequently. 15% of patients had growth retardation. 12% of affected children died in infancy and 29% of surviving patients had developmental defects/mental retardation.
Prenatal diagnosis is focused on the detection of neural tube defects (NTD), as they are the proven major malformations. Estimation of maternal serum alfafetoprotein (AFP) can be used as a screening test for the presence of open NTD. As the skin covered lesions might not be associated with raised AFP levels, prenatal evaluation of valproic acid exposed fetuses must include targeted ultrasound examination particularly of the caudal spine even when AFP levels are normal.
Women taking valproic acid should be counselled and strongly encouraged to plan their pregnancies, so that periconceptional high dose folic acid that is 5 mg/day can be taken. Whenever the use of antiepileptic drug is inevitable during pregnancy, they should be administered as monotherapy, in the lowest possible dose with constant monitoring of serum concentration of antiepileptic drugs.
References
1. Dalens B, Raynaud EJ, Gaulme J. Teratogenicity of valproic acid. J Pediatr 1980; 97: 332-333.
2. Brown JK. Valproate toxicity. Dev Med Child Neurology 1988; 80: 115-125.
3. Clayton Smith J, Donnai D. Fetal valproate syndrome. J Med Genet 1995; 32: 724-727.
4. Jager-Roman E, Deichl A, Jakob S, Koch S, Rating D, Steldinger R et al. Fetal growth, major malformation and minor anomalies in infants born to women receiving valproic acid. J Pediatr 1986; 108 : 997-1004.
5. Jones KL(ed). Smith's recognizable patterns of human malformation, fifth edition, Philadelphia; WB Saunders Company 1997; 566-567.
6. Hurd RW, Wildes BJ, Van Rinovelt HA. Valproate, birth defects and zinc. Lancet 1983; 1: 181.
7. MQ CN, Ladusans EJ. Anomalous right pulmonary artery origins in association with the fetal valproate syndrome. J Med Genet 1999; 36 : 83-84.
8. Chitayat D, Farrell K, Anderson L, Hall JG. Congenital abnormalities in two sibs exposed to valproic acid in utero. Am J Med Genet 1988; 31: 369-373.
9. Dilberti JH, Farndon PA, Dennis NR, Curry CJR. The fetal valproate syndrome. Am J Med Genet 1984; 19 : 473-381.
10. Winter RM, Donnai D, Burn J, Tucker SM. Fetal valproate syndrome : is there a recognisable phenotype J Med Genet 1987; 24: 692-695.
11. Van Allen MI, Kalousek DK, Chernoff GF. Evidence for multi-site closure of neural tube in humans. Am J Med Genet 1993; 47: 723-743.
12. Praveena S, Banani P, Veena P. Fatal cardiac malformation in fetal valproate syndrome. Indian J Pediatr 2001; 68: 989-990.
13. Ardinger HH, Arkin JF, Blackston RD. Verification of the fetal valproate syndrome phenotype. Am J Med Genet 1988; 29: 171-185.
14. Christianson AL, Cheslar N, Kromber JG. Fetal valproate syndrome : clinical and neuro-develpmental features in two sibling pairs. Dev Med Child Neuro 1994; 36: 361-369.
15. Thisted B, Ebbeson F. Malformation, withdrawal manifestations and hypoglycemia after exposure to valproate in utero. Arch Dis Child 1993; 69: 288-291.
16. Kozma C. Valproic acid embryopathy : report of two siblings with further expansion of the phenotypic abnormalities and review of the literature. Am J Med Genet 2001; 98: 168-175.(Kulkarni ML, Zaheeruddin )