2 JMed Genet 1995;32:724-727

Syndrome of the month

Fetal valproate syndrome

J Clayton-Smith, D Donnai

There is an increased incidence of major andminor congenital abnormalities in infants bornto epileptic mothers (6 to 7% compared with2 to 3% in the general population).' Factorswhich may contribute to this include the oc-currence of seizures leading to periods ofhypoxia during pregnancy, an inherited pre-disposition to malformations owing to intrinsicmaternal factors, and the teratogenic effectsof anticonvulsants. Congenital malformationsfollowing intrauterine exposure to phenytoinare well documented,2 but more recently ateratogenic effect has been observed in humansafter maternal sodium valproate therapy.3-6 So-dium valproate is a salt of dipropyl acetic acidwhich is conjugated in the liver and has a shorthalf life. It is thought to act either by inhibitingy-aminobutyric acid metabolism or by a directeffect on mitochondria, thereby impairingcellular energy metabolism.7 It is a populardrug because of its broad range of anti-convulsant effects and relative freedom fromsedative and behavioural effects. It is 80 to90% bound to plasma proteins and may dis-place other drugs ifused in combination, givingrise to toxicity. It may also interact with otherdrugs metabolised by the liver, for example,phenobarbitone. Long term valproate therapymay lead to carnitine depletion which impairsmitochondrial fatty acid metabolism and leadsto hepatotoxicity.8 This effect is seen mainly inchildren. There is no clear relationship betweenserum concentrations and anticonvulsanteffects, and although increasing doses are re-quired during pregnancy to keep patients seiz-ure free, it is generally accepted that the lowestdose at which the patient is seizure free shouldbe used, even if this does not fall within therecommended therapeutic range of 50 to100 ,ug/ml. Valproic acid crosses the placentaand is present in a higher concentration in thefetus than in the mother.Sodium valproate was licensed for use in

1978, and the first adverse report of a fetusexposed to the drug was published in 1980.9Other reports have followed, documenting sim-ilar patterns ofminor and major malformations.Particular attention has been drawn to theoccurrence of neural tube defects in infantsexposed to valproate in utero.'0-'2 A summaryof the clinical features of the "fetal valproatesyndrome" (FVS) is documented below.

Natural historyPregnancy usually proceeds uneventfully andthere is no increased incidence of instrumentaldelivery or birth asphyxia; 10% of babies aresmall for gestational age. Withdrawal symptomsduring the neonatal period are extremely com-mon.'3 The most frequent of these are ir-ritability, jitteriness, hypotonia, and seizures,typically occurring between 12 and 48 hours.They appear to be dose related. Feeding prob-lems often ensue.Data on long term follow up of these infants

are scanty but postnatal growth appears to benormal. Microcephaly tends only to occur inthose infants also exposed to other anti-convulsants. General health is good and notall children with FVS will be drawn to theattention of the paediatrician during the firstyear of life. Ardinger et al,6 however, reviewedthe clinical features in 15 cases of FVS pre-senting with dysmorphic features and foundevidence of mild to moderate developmentaldelay or neurological abnormality in 10 (67%)on follow up. The association ofdevelopmentaldelay with valproate exposure has been con-firmed in another report3 and also correlateswith our own personal experience. Longer termeffects have not yet been documented becauseofthe relatively recent introduction ofthe drug.

Facial featuresThe facial features are listed in table 1. Incombination they give rise to a distinctive facialphenotype which was commented upon by Di-Liberti et al3 and by Winter et al.5 The patientsin figs 1 and 2 show these typical facial features,which tend to evolve with age. The nasal root

Table 1 Facial features seen in fetal valproate syndrome

TrigonocephalyTall forehead with bifrontal narrowing

Epicanthic foldsInfraorbital grooveMedial deficiency of eyebrows

Flat nasal bridgeBroad nasal rootAnteverted nares

Shallow philtrumLong upper lip with thin vermilion borderThick lower lipSmall, downturned mouth

Department ofClinical Genetics,St Mary's Hospital,Whitworth Park,Manchester M13 OJH,UKJ Clayton-SmithD Donnai

Correspondence to:Dr Clayton-Smith.

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Fetal valproate syndrome

Figure 1 Typical facial features ofFVS in an infant.Note trigonocephaly, epicanthic folds, and infraorbitalgrooves.

Table 2 Congenital malformations associated with FVS

Neural tube defectsCongenital heart diseaseCleft lip and palateGenitourinary malformationsTracheomalaciaRadial ray defectsArachnodactyly/overlapping digitsAbdominal wall defects

Figure 2 Facial features in a 3 year old with broad, flatnasal bridge, arched eyebrows, and downturned mouthwith thin vermilion border to upper lip.

Figure 3 Neural tube defects are often skin covered andusually involve the sacral region.

is broad and epicanthic folds continue inferiorlyto connect with an infraorbital crease or groove.The appearance of the mouth and upper lipare particularly characteristic and the philtralpillars are often indistinct. Many authors havecommented upon abnormal modelling of theears but there does not appear to be any specificear abnormality among the various reports.

Congenital malformationsThese are listed in table 2. The most frequentmajor congenital malformations are neural tubedefects, congenital heart defects, oral clefts,genital abnormalities, and limb defects. Otherless frequent abnormalities include abdominalwall defects, tracheomalacia, and strabismus.There has been one reported case of congenitalliver disease but this may well have been un-related to the valproate therapy."4 Neural tubedefects have been estimated to occur at around10 times the normal incidence in fetuses ex-posed to valproate and appear to be specificallyrelated to valproate therapy rather than to otheranticonvulsants.615 Most reports have been ofspina bifida rather than anencephaly and thereis a predisposition for very low lumbar or sacraldefects (fig 3) suggesting that valproate affectsprimarily the lowest closure site of the neuraltube.'6 It has been postulated that defects at thissite may be the result ofdefective canalisation ofthe neural tube rather than neurulation defects.Zinc deficiency has been suggested as a possiblecause of NTDs associated with valproate ex-posure as sodium valproate readily binds zincand NTDs have been reported both in infantsof mothers with acrodermatitis enteropathicaand in offspring of zinc deficient rats.'7 ' It isinteresting to note that the defects observed in

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Clayton-Smith, Donnai

Figure 4 Long, overlapping toes in an infant with FVS.

...ci* ./.

Figure 5 Radial ray defect in an affected neonate.

Figure 6 Bilateral radial ray defects in sib ofpatient infig 5.

FVS are often skin covered. This is significantfrom the point of view of prenatal diagnosis,as the serum AFP level is often normal so theabnormalities must be sought specifically bydetailed ultrasound scanning. Martinez-Frias'5has recently documented two cases of hydro-cephalus without spina bifida in exposed fe-tuses.

Congenital heart defects have been reportedin several patients with FVS23616 and the in-cidence of congenital heart disease is estimatedto be around four times that seen in the generalpopulation. Septal defects and valvular prob-lems have both been reported. There does notappear to be any consistent type of defect butit has been suggested that the defects may becaused by abnormal blood flow during em-bryological development.

Oral clefts have been seen five times morefrequently than expected. Published reportsoften do not distinguish between cleft lip, cleftpalate, or both, but in our personal experience,among the cases collected from clinical gen-eticists in the UK, an isolated palatal cleftis the most frequent finding. Martinez-Frias'5suggested that oral clefts were only seen whenvalproate was used in combination with otheranticonvulsants, but we know of two cases ofcleft palate occurring after exposure to val-proate alone.Limb defects and digital abnormalities of

various types are known to occur. The mostfrequently observed findings are of ar-achnodactyly with overlapping of the fingersand toes (fig 4). An underriding third toe is acommon finding. The musculature of the lowerlimbs often appears to be rather poorly de-veloped.

Other significant reports include the as-sociation of radial ray defects with FVS.419-21These have included a short or absent radius,absent or triphalangeal thumb, and preaxialpolydactyly. The radial ray defects are re-producible in animal models exposed to val-proate in utero. It has been suggested that theyonly occur in patients exposed to large dosesof valproate but the evidence for this is in-conclusive. We have personally seen a pair ofsibs born to a mother who took 1 2 g valproateper day while pregnant. This is not consideredto be a large dose during pregnancy but bothsibs were born with the typical fetal valproatefacies and radial ray defects (figs 5 and 6).Other reported limb abnormalities include tal-ipes deformity of the feet, clinodactyly, andulnar or tibial hypoplasia.

Counselling in FVSInformation regarding the incidence of fetalvalproate syndrome has mainly been derivedfrom cases reported to birth defectsregistries1722 and as such is often biased. Over-all, these studies suggest that there is a six toseven fold increase of malformations in thebabies of mothers exposed to valproate com-pared to the general population. In a morerecent study, Thisted and Ebbesen'3 studiedall infants born to epileptic mothers treatedwith valproate in the north of Denmark over a

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Fetal valproate syndrome

two year period. None of these pregnancieshad been exposed to other recognised ter-atogens such as alcohol. There were 17 preg-nancies in total: 11 of the infants requiredadmission to a special care baby unit becauseof withdrawal symptoms, nine had minor dys-morphic features consistent with FVS, and fivehad a major congenital malformation. Theeffects were dose related and were seen whenthe mothers were taking in excess of 2-5 g

valproic acid daily. Although the numbers are

not large this study suggests that the risk tofetuses exposed to valproate is significant, withthe majority showing some adverse effects.Chitayat et al 23 reported FVS in two sibs andwe have personal experience of three othersib pairs. The risk of recurrence of FVS ina subsequent pregnancy exposed to valproatewould therefore appear to be high, possiblyowing to inherent problems with the meta-bolism of valproic acid in the mothers con-

cerned. Data on the long term follow up ofexposed people remain to be collected.

1 Dieterich E, Steveling A, Lukas A, Seyfeddinpur N,Spranger J. Congenital anomalies in children of epilepticmothers and fathers. Neuropediatrics 1980;11:274-83.

2 Hanson JW, Smith DW. The fetal hydantoin syndrome.Pediatr 1975;87:285-90.

3 DiLiberti JH, Farndon PA, Dennis NR, Curry CJR. The fetalvalproate syndrome. Am Med Genet 1984;19:473-81.

4 Jager-Roman E, Deichl A, Jakob S, et al. Fetal growth,major malformations and minor anomalies in infants bornto women receiving valproic acid. Pediatr 1986;108:997-1004.

5 Winter RM, Donnai D, Burn J, Tucker SM. Fetal valproate

syndrome: is there a recognisable phenotype? J Med Genet1987;24:692-5.

6 Ardinger HH, Atkin JF, Blackston RD, et al. Verification ofthe fetal valproate syndrome phenotype. Am JT Med Genet1988;29: 171-85.

7 Brown JK. Valproate toxicity. Dev Med Child Neurol 1988;30:115-25.

8 Coulter DL. Camitine, valproate and toxicity. J Child Neurol199 1;6:7-14.

9 Dalens B, Raynaud EJ, Gaulme J. Teratogenicity of valproicacid. J Pediatr 1980;97:332-3.

10 Robert E, Guibaud P. Maternal valproic acid and congenitalneural tube defects. Lancet 1982;ii:1282-3.

11 Lindhout D, Schmidt D. In utero exposure to valproateand neural tube defects. Lancet 1986;i: 1392-3.

12 Martinez-Frias ML, Salvador J, Rodriquez-Pinilla E. Val-proate and spina bifida. Lancet 1989;i:611-12.

13 Thisted E, Ebbeson F. Malformations, withdrawal ma-nifestations and hypoglycaemia after exposure to valproatein utero. Arch Dis Child 1993;69:288-91.

14 Felding I, Rane A. Congenital liver damage after treatmentof mother with valproic acid and phenytoin? Acta PaediatrScand 1984;73:565-8.

15 Martinez-Frias ML. Clinical manifestation of prenatal ex-posure to valproic acid using case reports and ep-idemiologic information. Am J Med Genet 1990;37:277-82.

16 Van Allen MI, Kalousek DK, Chernoff GF, et al. Evidencefor multi-site closure of the neural tube in humans. Am JMed Genet 1993;47:723-43.

17 Robert E, Rosa F. Valproate and birth defects. Lancet 1983;ii:1142.

18 Hurd RW, Wilder BJ, Van Rinsvelt HA. Valproate, birthdefects and zinc. Lancet 1983;i:181.

19 Huot C, Gauthier M, Lebel M, Larbrisseau A. Congenitalmalformations associated with maternal use of valproicacid. Can _J Neurol Sci 1987;14:290-3.

20 Verloes A, Frikiche A, Gremillet C, et al. Proximal pho-comelia and radial ray aplasia in fetal valproic syndrome.EurJ3 Pediatr 1990;149:266-7.

21 Sharony R, Garber A, Viskochil D, et al. Preaxial ray re-duction defects as part of valproic acid embryofetopathy.Prenat Diagn 1993;13:909-18.

22 Mastroiacovo P, Bertolini R, Morandini S, Segni G. Ma-ternal epilepsy, valproate exposure and birth defects.Lancet 1983;ii: 1499.

23 Chitayat D, Farrell K, Anderson L, Hall JG. Congenitalabnormalities in two sibs exposed to valproic acid in utero.Am JMed Genet 1988;31:369-73.

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