Malformations, Withdrawal Manifestations, and Hypoglycaemia After Exposure to Valproate in Utero
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288 Archives of Disease in Childhood 1993; 69: 288-291 Malformations, withdrawal manifestations, and hypoglycaemia after exposure to valproate in utero E Thisted, F Ebbesen Abstract that there is an association between valproate An unselected series is presented of 17 treatment during pregnancy and spina bifida in infants born to epileptic mothers and the fetus.5 6 12 Furthermore, some authors exposed to sodium valproate during have postulated the existence of a 'fetal pregnancy. Nine infants had minor abnor- valproate syndrome', in which infants have malities and of these infants five also had minor abnormalities and major malformations major malformations, described as the to a variable degree.9 14 15 18 'fetal valproate syndrome'. The most We present 17 infants born to 17 epileptic frequent malformation was congenital mothers who received sodium valproate as heart disease. Nine of the infants had monotherapy or polytherapy during pregnancy. manifestations of withdrawal, such as The purpose ofthis study is to draw attention to irritability, jitteriness, abnormalities of the high frequency of minor abnormalities and tone, seizures, and feeding problems. major malformations, the withdrawal mani- Four of these infants had an unrelated festations, and hypoglycaemia in these infants. hypoglycaemia. The frequency of with- drawal symptoms was significantly related to the dose of valproate given to Patients and methods the mothers in the third trimester, and We studied all infants born to epileptic mothers there was a tendency for both the fre- treated with valproate as monotherapy or poly- quency of the minor abnormalities and therapy during pregnancy in the North Jutland the major malformations to be related to region of Denmark between 1 January 1987 the valproate dosage in the first trimester. and 31 December 1989. During this period (Arch Dis Child 1993; 69: 288-291) 18 000 infants were born. Seventeen mothers gave birth to 17 infants. Twelve mothers had primary generalised The frequency of minor abnormalities and epilepsy and five complex partial epilepsy major malformations in infants of epileptic (table 1). Eleven mothers had valproate as mothers is increased and associated with the monotherapy, three had valproate and carba- Department of epilepsy.' In addition, phenytoin given to mazepine, two valproate and ethosuximide, Paediatrics, Aalborg pregnant women might increase the frequency and one valproate and primidone (table 1). Hospital, Denmark of abnormalities and malformations, 'the Pregnant epileptic women were seen monthly E Thisted F Ebbesen fetal hydantoin syndrome'.2 Other antiepilep- by a neurologist. The drug plasma concen- tic drugs are suspected of having a teratogenic trations were measured and future doses Correspondence to: Dr Ebbe Thisted, effect. prescribed. Doses were titrated from pre- Department of Paediatrics, The teratogenic effect of valproate was pregnancy plasma concentrations to maintain University Hospital of Hvidovre, Kettegards Alle observed in animals by Pinder et al,3 and a a constant valproate concentration and to 30, DK-2650 Denmark. possible teratogenic effect has also been ensure, as far as possible, absence of seizures. Accepted 29 April 1993 described in humans.4-18 It has been suggested Concentrations were measured as fasting Table I Maternal data Epileptic Daily dose ofantiepileptic drug(s) in g/24 hours attack (range ofplasma concentrations in itmol/l) Mother Type of during Poor No epilepsy pregnancy Medication 1st trinester 2nd tnimester 3rd tnimester conmpliance Complex partial Valproate 0.0 0-6 '0 9 (266-360) 0-9 (326-347 2 Primary generalised Valproate 0 9 (159) 1-2 (232-271) 1-2 (256-338) 3 Primary generalised Valproate 0-9 (289) 0-9-1-2 (246-384) 1 2 (270-343) 4 Primary generalised Valproate 1 0 (467) 1 0 1 0 (67) + 5 Primary generalised Valproate 1 0 (123-361) 1-0 (157-238) 1 0 (154-200) 6 Primary generalised Valproate 1-2 1-2 (217) 1 2 (221-244) 7 Primary generalised Valproate 1-5 1-5- '2-5 (329-581) 2 5 '3-0 (351-426) 8 Primary generalised + Valproate 2-0 2-0 *2-5 (33-115) 3-0 (119-201) + 9 Complex partial Valproate 2-0 (550) 2-0-2-5 (252-513) 2 5 (301-373) 10 Complex partial Valproate 2-5 (498) 2-5-3-5 (495-821) 4 0-'50 (468-580) 11 Primary generalised Valproate 3-5 (792-1132) 3-5 (523-692) 3-5 (443-520) 12 Primary generalised Valproate, 1 0 (283-519) 1-5 -'2 0 (327-717) 2-0 (452-556) carbamazepine 0 4 -03 (22) 0-2 -'0-0 0.0 13 Complex partial Valproate, 1-0 (275) 1 0 (307-309) 1-5-2-0 (222-372) carbamazepine 0-8 (25) 0-8 (17-25) 1-2 '1 6 (18-19) 14 Complex partial + Valproate, 2-7 (249) 2-7 '3-3(216-290) 33-4-2 (141-481) + carbamazepine 0 8 (22-25) 12-'16 (17-20) 2 2 '3 2 (20-29) 15 Primary generalised Valproate, 3 0 (386) 3 6 -4-8 (372-468) 5-4-6-0 (383-599) + ethosuximide 1.0 1 0 (185-260) 1-0 (234-295) 16 Primary generalised Valproate, 4-8 (408) 5-4 -6-0 (256-476) 6-0 '6-6 (352-632) ethosuximide 1 0 (355) 1 0 (300-310) 1-0 (296-319) 17 Primary generalised Valproate, 2-5 (601-776) 30 '3 5 (674-1162) 3-5-'40 (385-1140) primidone 0 125 0 125 (5-10) 0 125 (3-6) Malformations, withdrawal manifestations, and hypoglycaemia after exposure to valproate in utero 289 Table 2 Infant data Hypoglycaemia Apgar Admitted (minimum Gestational Birth score to f blood Infant age weight 1-5 neonatal Hypertonial Feeding glucose No (weeks) (g) minutes unit Iritability _itteriness Hypertonia hypotonia Seizures problems (mmol/l)) 41 3250 10-10 + + + + 2 41 4000 10-10 3 42 4020 10-10 4 37 3150 10-10 + + 5 39 2500 10-10 6 39 3640 10-10 7 40 2950 6-10 + + + + 8 42 3300 10-10 9 39 3500 8-10 + + + + + 10 39 3125 6-9 + + + + + 06 11 38 3500 6-7 + 12 38 3900 10-10 13 42 4100 9-10 + + + + + 14 40 4040 10-10 + + + + 1-1 15 39 2760 10-10 + + + + 1-7 16 42 4300 10-10 + + + + + 17 40 2840 10-10 + + + + + 1-5 values at 8-10 am; valproate, carbamazepine, Results and ethosuxcimide were measured using the Mothers' data are given in table 1. The daily fluorescence polarisation immunoassay'9 and valproate dose varied from 0 0 g to 4-8 g in the primidone cooncentration was measured using first trimester and from 0-9 to 6-6 g in the third high pressur(e liquid chromatography.20 trimester. In 13 (78%) women the valproate All womera were offered amniocentesis but it dose needed to be increased during pregnancy was performled in only eight cases. Concen- to maintain a constant plasma valproate tration of x fetoprotein in amniotic fluid concentration. This concentration measured was normal as were fetal chromosomes. No between zero and 1162 ,umol/l. Four mothers therapeutic aibortion was performed. showed poor compliance and three of them The womren totally abstained from or used had epileptic attack(s) during pregnancy. only small aamounts of alcohol during preg- Data ofthe infants are given in table 2. Their nancy. gestational ages and birth weights were Eleven of the 17 infants (65%) were admit- normal, 40 (37-42) weeks and 3500 ted to the neonatal unit and subsequently (2500-4300) g (range), respectively. The followed up in the paediatric outpatient clinic. deliveries were uncomplicated and in no case The remainiing six infants were examined in was an infant significantly asphyxiated. the maternity ward by a paediatrician. These Eleven infants (65%) were admitted to the children wer^e investigated in the clinic at the neonatal unit in the first two days of life, nine age of 1-5-3-5 years. All infants were examined because of neurological symptoms and two using the rnotor perceptual developmental because of major malformations. test,2' and olbservations made of the children's Nine of the infants (53%) had minor abnor- ability in coracentrating, mimicry, and speech. malities (table 3), such as rough curly hair, Statistical analysis was performed using the epicanthic folds, hypertelorism, a deep groove X2 test. The 1level of significance was chosen at below the lower lids, upturned nose, ante- 5%. verted nostrils, shallow philtrum, thin upper vermillion border, low set or unusually shaped ears, overlapping toes, and inguinal hernias. Table 3 Minor abnormalities Major malformations were demonstrated in five of the nine infants with minor abnormali- Infant no ties (29% of the total; table 4). The most com- 4 7 10 11 13 15 16 17 mon malformation was a congenital heart -- defect, which was present in four. Rough curly hair + Epicanthic folds + + + + + + In those cases where the mothers received a Hypertelorism + + + + + + daily valproate dose of -2-5 g, five out of six Deep groove below the lower lids + Upturned nose + + + + + + infants were born with minor abnormalities; Anteverted nostrils + + + additionally three of the infants had major Shallow philtrum + + Thin upper vermillion border + + + + malformations. In those cases where the Low set or unusually shaped ears + + + + + mothers received less than 2 5 g valproate, only Overlapping toes Inguinal hernias + + + four out of 11 infants had minor abnormalities with additional major malformations in two. Table 4 Major malformations Infant No Malformations 4 Congenital heart defect (atrial septal defect and ventricular septal defect), radial deviation of the right hand 10 Congenital heart defect (pulmonary stenosis), bilateral cataract with suspicion of blindness, severe hearing defect 11 Congenital heart defect (Fallot's tetralogy), cheilognathopalatoschisis, perineoscrotal hypospadias, bilateral undescended testes 13 Congenital heart defect (bicuspid aortic valve with mild aortic insufficiency) 17 Severe herniation of oesophagus 290 Thisted, Ebbesen Nine (53%) of the infants developed neuro- plasma valproate during pregnancy.