1 Center of Medical Genetics in Poznań, Medical University in Poznań 2 Chair and Department of Medical Genetics, Medical University in Poznań

Archives of Perinatal Medicine 14(1), 57-60, 2008 CASE REPORT

Valproic acid and pregnancy:clinical presentation of 3 cases with valproate embryopathy

ALEKSANDER JAMSHEER1,2, ANNA MATERNA-KIRYLUK1,2, ANNA LATOS-BIELEŃSKA1,2

Abstract Fetal Valproate Syndrome (FVS) is caused by prenatal exposure to valproic acid (VPA). Clinical phenotype of FVS includes characteristicfacial dysmorphism, various congenital defects, developmental delay/mental retardation, and other neurologic deficits. The risk of congenitalmalfomation in the developing fetus is 2 or 3-fold higher (4-6%) than that of background population. In this report, we describe clinicalcharacteristics of 3 infants with the diagnosis of FVS. We summarize important issues in the management of VPA-treated women atchildbearing age. Measures that include: informed planning of pregnancy, VPA treatment optimization to the lowest effective dose, folic acidsupplementation, prenatal ultrasonographic monitoring, and maternal serum alpha-fetoprotein testing, should help to diminish the risk ofadverse pregnancy outcomes.

Key words: valproic acid, congenital malformation, fetal valproate syndrome, seizure disorder, teratogen, valproate embryopathy

Introduction

Fetal Valproate Syndrome (FVS), also known as ValproateEmbryopathy, is caused by prenatal exposure to valproic acid(VPA), one of the most common antiepileptic drugs. VPA andits derivatives are widely used in treatment of various seizuredisorders and some psychiatric conditions. The majority ofchildbearing women exposed to VPA deliver healthy infants,however, the risk of congenital malfomation in the developingfetus is 2 or 3-fold higher (4-6%) than the risk in general po-pulation (2%) [1]. First reports on possible teratogenic activityof VPA appeared in early 1980 s [2, 3]. Currently, with greatcontributions from population-based registries of congenitalmalformations, the spectrum of defects observed in FVS iswell described and established.

Clinical phenotype of FVS encompasses structural con-genital defects, various neurologic deficits, as well as characte-ristic facial appearance. Congenital malfomations include limbdefects (37%) [4], cardiac anomalies (26%), genitourinary ab-normalities (28%), oral clefts (4%), ocular and brain anomalies(10%), and spina bifida (3%) [5]. Developmental deficits/mentalretardation and hypotonia are found in 30-70% of affected indi-viduals [5, 6]. Speech delay, hyperactivity, learning difficultiesand autistic behaviour are also relatively frequent [7]. Seizuresare observed rarely (3%) [5]. Facial dysmorphism include tri-gonocephaly with prominent metopic suture, bifrontal nar-rowing, micrognathia, broad, flat nasal bridge, antevertednostrils, epicanthal folds, long and smooth philtrum, thin ver-million boarder, and mild changes of the external ears [5, 6].

The aim of this report is twofold. First, by the clinicalphenotype presentation of 3 infants with the diagnosis of FVS,we hope to draw attention of gynaecologists to the matter ofpregnancy in epileptic mothers, second, we summarize themanagement issues in VPA-treated women of childbearingage, aiming at minimization of their risk of adverse pregnancyoutcomes.

Clinical report

We report on 3 cases of FVS seen in our clinic during thelast year. All three infants were born to epileptic mothers,treated with different doses of VPA as monotherapy duringgestation. The infants presented with typical symptoms of val-proate embryopathy, including craniofacial dysmorphic fea-tures, mental retardation/developmental delay, and variousstructural congenital malformations (Table 1).

Patient 1

Infant 1, a female baby, was delivered vaginally at term toyoung, nonconsaguineous parents after the first, uneventfullpregnancy. The mother had taken valproic acid (1500 mga day) throughout the whole gestational period, with good con-trol of her seizure disorder. Pregnancy had been unplanned,

Fig. 1a. Facial dysmorphic features typical of FVS in infant 1

A. Jamsheer, A. Materna-Kiryluk, A. Latos-Bieleńska58

Table 1. Clinical characterisc of 3 infants with the diagnosis of FVS with reference to previous reports

Clinical charcteristics Patient 1 Patient 2 Patient 3FVS patients

(according to Kozma et al., 2001and Rodriguez-Pinilla et al., 2000)

Age of Parents at birth (mother/father) 20/21 33/35 22/25 –

Delivery: week of confinement Apgar score weight at birth length at birth head circumference

4210 (1’)

3210 g (25-50 c)50 cm (25-50 c)

34 cm (25 c)

3910 (1’)

3620 g (75 c)56 cm (> 97 c)35 cm (50-75 c)

4010 (1’)

3250 g (25-50 c)55 cm (> 97 c)32 cm(< 3 c)

–

Facial dysmorphism + + + 100%

Developmental deficits/ Mental retardation + + + 30%

Hypotonia – – – 10%

Failure to thrive/ Growth retardation – + – 15%

Cardiac defect – + – 26%

Limb defect + – + 37%

Genitourinary malformations – + – 28%

Neural Tube Defects – – – 3%

Brain abnormalities – + + 10%

Cleft palate + – – 4%

Fig. 1b. CT-scan of the cranium – trigonocephaly with prominentmetopic suture in infant 1

and 0.4 mg folic acid had been used from month 2, till the endof gestation. Bilateral talipes equinovarus, malformations ofthe thumbs and cleft palate were diagnosed at birth. On exa-mination at the age of 8 and 11 months, child exhibited typicalcraniofacial dysmorphic features (Fig. 1a), including trigono-cephaly (Fig. 1b), prominent metopic suture, bifrontal narro-wing, hypotelorism, broad and flat nasal bridge, and smalldownturned mouth with thin vermillion border. Postnatal

growth was normal, however, mild gross motor delay wasobserved. Ultrasound imaging of the brain and abdomen, CTscan of the brain, echocardiography, and karyotype were nor-mal (46,XX).

Patient 2

Infant 2, a male baby, was born vaginally at term to non-consaguineous parents after the third, uneventfull pregnancy.The mother was initiated on antiepileptic therapy 3 weeks

Fig. 2. Characteristic of FVS facial dysmorphismwith marked trigonocephaly – infant 2

prior to unplanned conception (800 mg VPA daily). This treat-ment was continued throughout pregnancy with adequate con-trol of her seizures. She had not received folic acid supplemen-tation. On evaluation at the age of 7 months, the child presen-

Valproic acid and pregnancy 59

ted with developmental delay, hypertonia, failure to thrive(weight 5340 g, below 3rd centile), hypospadias, as well as fa-cial dysmorphism with trigonocephaly, low-set ears, low nasalbridge, anteverted nostrils, and bilateral epicanthal fold(Fig. 2). Growth retardation was conspicuous from 4 monthsof age. Sitting was achieved at the age of 19 months. Ultra-sound imaging of the brain at 4 months of age showed mildhydrocephalus. Echocardiography revealed ASD type II. Ultra-sound scan of the abdomen was unremarkable, karyotype(46,XY) and CFTR mutation sreening were normal.

Patient 3

This 6 year old girl was referred to our clinic because ofmental retardation and craniofacial dysmorphic features. Shehad been delivered vaginally at term after the first uneventfullpregnancy of young nonconsaguineous parents. From 12 years

Fig. 3. Mild facial dysmorphism in patient 3

of age, the mother suffered from a seizure disorder and wasmaintained on VPA 1000 mg daily throughout gestation. 4 we-eks after her unplanned conception, she started 0.4 mg folicacid supplementation. The infant exhibited signs of psycho-motor delay in early childhood with independent sitting andwalking both markedly delayed (18 and 23 months respecti-vely). During the first two years of life, the patient requiredmultiple hospitalizations for recurrent respiratory infections.On physical examination at the age of 6 years, mild facial dys-morphism (Fig. 3), symptoms of cutis laxa, and clinodactyly of4th toes were noted. Weight and height were within 10-25th

centile. MRI of the brain showed cortical atrophy in the frontallobes.

Discussion

Although the majority of infants exposed to VPA in uteroare born healthy and have normal psychomotor development,the risk of congenital abnormalities is approximately three

times higher compared to the general population. VPA treat-ment of epileptic women at childbearing age often cannot beavoided, thus several prophylactic measures should be under-taken to minimize the risk of adverse pregnancy outcomes.First of all, potential mothers should be carefully informed onthe possible deleterious effects of this medication on a fetus.This might help with pregnancy planning. Since there is evi-dence for protective effect of folate consumption, folic acidsupplementation, preferably 4 or 5 mg a day 8 weeks prior toconception, is recommended [8]. Adequate seizure controlshould be achieved before conception and treatment optimizedto the lowest effective VPA dose. Teratogenicity of VPA ishighly dosage-dependent, and the risk of congenital malfor-mations starts to increase at doses of 600 mg/d, becomingmore prominent when doses exceed 1000 mg/d. One of themost severe FVS defects, spina bifida, has been associatedwith significantly higher average daily dose of VPA (1640± 136 mg/d) compared to pregnancies with normal outcome(941 ± 48 mg/d) [9]. Therefore, we recommend that beforeeach planned pregnancy referral to the neurologist, in orderto possibly minimize valproate dose, should always take place.During pregnancy, VPA-treated mothers should undergo se-rum alpha-fetoprotein testing and prenatal ultrasound scan-ning to rule out major malformations, including neural tube de-fects [8]. There is also a suggestion for genetic susceptibilityto development of FVS, as several families with 2 or moreaffected siblings have been reported [5, 10]. Therefore in thesetting of continuous maternal treatment, if the first infantsuffers from VPA embryopathy, each following pregnancyshould be regarded high risk.

Conclusions

The cases described above demonstrate that prenatal VPAexposure may have a profound effect on fetal organ develop-ment, as well as psychomotor and cognitive functioning. Wo-men of childbearing age who are treated with VPA shouldreceive comprehensive information on the increased risk offetal congenital malformations. Preventive measures, inclu-ding maternal education and careful family planning, folic acidsupplemenation 4 or 5 mg a day should be emphasized as themost effective risk reduction strategies.

References

[1] Yerby M.S. (2003) Management issues with epilepsy: neuraltube defects and folic acid supplementation. Neurology, 61(Suppl 2): S23-26.

[2] Dalens B., Raynaud E.J., Gaulme J. (1980) Teratogenicity ofvalproic acid. J. Pediatr. 97: 332-333.

[3] Gomez M.R. (1981) Possible teratogenicity of valproic acid.J. Pediatr. 98: 508-509.

[4] Rodriguez-Pinilla E., Arroyo I., Fondevilla J. et al. (2000) Pre-natal exposure to valproic acid during pregnancy and limb de-ficiencies: a case-control study. Am. J. Med. Genet. 90: 376-381.

[5] Kozma Ch. (2001) Valproic acid embryopathy: report of twosiblings with further expansion of the phenotypic abnormalitiesand a review of the literature. Am. J. Med. Genet. 98: 168-175.

A. Jamsheer, A. Materna-Kiryluk, A. Latos-Bieleńska60

[6] Ardinger H.H., Atkin J.F., Blackstone R.D. et al. (1988) Verifica-tion of the fetal valproate syndrome phenotype. Am. J. Med. Ge-net. 29: 171-185

[7] Moore S.J., Turnpenny P., Quinn A. et al. (2000) A clinicalstudy of 57 children with fetal anticonvulsant syndromes.J. Med. Genet. 37: 489-497.

[8] Genton P., Semah F., Trinka E. (2006) Valproic acid inepilepsy: pregnancy-related issues. Drug. Saf. 29: 1-21.

[9] Omtzigt J.G., Los F.J., Grobbee D.E. et al. (1992) The risk ofspina bifida aperta after first-trimester exposure to valproate ina prenatal cohort. Neurology 42(Suppl 5): 119-125.

[10] Malm H., Kajantie E., Kivirikko S. et al. (2002) Valproate em-bryopathy in three sets of siblings: further proof of hereditarysusceptibility. Neurology 59: 630-633.

J Aleksander Jamsheer

Chair and Department of Medical Genetics Medical University in Poznańul. Grunwaldzka 55 paw.15, 60-352 Poznań e-mail: jamsheer@wp.pl