Published: 15 December 2014
Publications
Use of Sodium Valproate in Pregnancy
Prescriber Update 35(4): 46-48
December 2014
Sodium valproate (Epilim) was first introduced as an anti-epileptic in 19641. It is currently indicated for treatment of primary generalised epilepsy, partial (focal) epilepsy, and bipolar disease.
Epilim is contraindicated in pregnancy due to the risk of congenital malformations and developmental effects. The data sheet also recommends that Epilim should not be used in women of child-bearing potential unless other treatments are ineffective or not tolerated. Women who could become pregnant should be given medical advice on the benefits and risks of treatment before Epilim is prescribed.
Congenital malformations
The first report of teratogenic effects of valproate was published in 1980. The term fetal valproate syndrome (FVS) was suggested in 19841. A number of different anomalies have been associated with valproate exposure (see table), the clinical presentation varies between affected infants. The variability in clinical presentation may be influenced by a number of factors such as maternal seizures during pregnancy, folic acid intake, dose and timing of exposure of valproate, genetic susceptibility and parental factors such as IQ and socioeconomic status1.
Table 1. Anomalies most commonly associated with valproate exposure
| Neural tube defects | Spina bifida | Anencephaly |
| Congenital heart defects | Ventricular septal defect Atrial septal defect |
Aortic stenosis Patent ductus arteriosus |
| Limb defects | Radial ray defect Polydactyly Split hand |
Overlapping toes Camptodactyly |
| Genitourinary defects | Hypospadias | |
| Skin abnormalities | Capillary haemangioma | |
| Dysmorphic features | Trigonocephaly Prominent metopic ridge Thin arched eyebrows Epicanthic folds Infraorbital grooves |
Broad nasal bridge Short anteverted nose Long philtrum Thin upper lip |
The risk of congenital malformations following in utero exposure
to valproate is higher than the background rate of 2-3%1.
Data from pregnancy registries have found the following regarding the risk of congenital malformations in infants exposed to anti-epileptic drugs in utero:
- UK and Ireland Epilepsy and pregnancy registers (includes 1/3 of relevant pregnancies) estimate a rate of 6.7%1.
- North American Anti-Epileptic Drug Pregnancy Registry rate estimate is 9.3%2.
- International Registry of antiepileptic drugs and pregnancy rate estimate is 9.7%2.
- Australian Pregnancy Registry (includes 1/12 of all relevant pregnancies) the rate estimate is 12.4%3.
In contrast the risk of malformations associated with carbamazepine was 2.6% (1.9-3.5%) and 2.3% (1.8-3.1%) with lamotrigine in the UK and Ireland Registries2.
Valproate exposure has also been associated with a risk of spina bifida estimated at 1-2%; the background rate is 0.2-0.5%. The risk associated with carbamazepine exposure has been estimated at 0.5-1%1.
Some registries show a dose-dependent effect with valproate exposure in utero2,3. In general, a dose of greater than 1000mg/day has been associated with a higher risk for the abnormalities described above1. Data from the Australian, UK and Ireland Registries show that mean maternal valproate doses of greater than 1000mg/day were associated with fetal malformations. The data also showed that in pregnancies that were unaffected, the mean maternal dose of valproate was between 850-900mg/day. The dose of maternal valproate has been decreasing in Australia over the last 5 years which has been paralleled by a significant decrease in the rate of spina bifida and hypospadias3.
The risk of a congenital malformation is increased when women require polytherapy1.
Other antiepileptics have also been associated with malformations, for example microcephaly has been associated with carbamazepine exposure in utero1.
CARM Reports
The Centre for Adverse Reactions Monitoring (CARM) has received 13 reports of fetal valproate syndrome; the first report was received in 1997 and the most recent report in 2014. The mother's dose of valproate was only available in two reports and was greater than 1000mg/day. The majority of the reports were made at least one year after the birth of the affected child and none of the reports mentioned whether folate was taken at conception.
Other birth outcomes
The occurrence of generalised tonic-clonic seizures in pregnancy is associated with shorter gestational age and reduced birthweight. However, the majority of babies exposed to valproate in utero are of normal weight 1.
A recent study found no association between the use of anti-epileptic medicines in pregnancy and the risk of spontaneous abortion or stillbirth4.
Babies exposed to valproate in utero may exhibit withdrawal symptoms at birth such as feeding difficulties, hypoglycaemia, jitteriness, irritability and hypothermia1.
Cognitive impairment and behavioural issues
Children with FVS have also been noted to have cognitive impairment. Global developmental delay has been noted in children with severe FVS. The most frequently affected developmental aspects are speech and language 1. The average full-scale IQ of a child with FVS is in the 80-90 range. However, the verbal IQ is significantly lower1.
Autism, Asperger's syndrome and autistic spectrum disorder have been diagnosed and reported more frequently in FVS but are also seen in valproate exposed children without FVS1.
A population-based study in Denmark investigated the risk of autism spectrum disorder and autism 5. Children exposed to valproate in utero were compared with the whole population and a cohort of children born to women with epilepsy.
The study showed the following for autism spectrum disorder:
- For the whole population, the absolute risk of autism spectrum disorder in children exposed to valproate was 4.4%. The absolute risk in the total population was 1.2%.
- For children who were born to women with epilepsy, the absolute risk of autism spectrum disorder in children exposed to valproate was 4.2%. The risk for children who were not exposed to valproate was 2.4%.
The study showed the following for autism:
- For the whole population, the absolute risk of autism in children exposed to valproate was 2.5%. The absolute risk in the total population was 0.5%.
- For children who were born to women with epilepsy, the absolute risk of autism in children exposed to valproate was 3%. The risk for children who were not exposed to valproate was 1%.
The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study found a significant dose related performance decline in parental ratings of adaptive functioning in children exposed in utero to valproate or phenytoin. Children of mothers who took valproate during pregnancy were at a greater risk for a diagnosis of Attention Deficit Hyperactivity Disorder (ADHD)6.
Measurement of IQ in the NEAD study showed that the mean IQ of children (aged 6 years) exposed to valproate was in the normal range but lower than in children exposed to other anti-epileptics: 97 (95% CI 94-101) compared to 108 (105-110) for lamotrigine7.
Management
Under the Health and Disability Code of Rights women requiring valproate treatment during pregnancy must be informed about the benefits and risks of treatment and this information must be provided in writing if requested (Consumer Medicine Information is available: www.medsafe.govt.nz/consumers/CMI/e/Epilim.pdf).
It is important to note that none of the anti-epileptic medicines available are completely safe during pregnancy 1. Seizures during pregnancy are also associated with poorer developmental outcomes.
For women requiring valproate treatment the risk of malformations is reduced when the daily dose is below 1000mg. However, any dose adjustments should be made well in advance of pregnancy to ensure that seizures are still controlled 1.
High dose folic acid is recommended, starting at least six weeks pre-conception1. Periconceptional use of folic acid has generally been associated with a reduced risk of autism1. The NEAD study results provide some support for use of preconception folate. Parents reporting maternal folate use noted fewer physical complaints and atypical behaviours in their children, and teachers endorsed lower levels of anxiety in these children6. IQ was also higher in children whose mothers had taken folate 7.
The UK and Ireland Pregnancy Registries showed that neural tube defects were slightly less frequent in infants whose mothers had folic acid supplementation periconceptually and during pregnancy2.
Women should also be encouraged to address any other risk factors for adverse pregnancy outcomes.
References
- Kini U (2006) 'Fetal valproate syndrome: a review' Paediatric and Perinatal Drug Therapy 7: 123-130.
- Campbell E, Kennedy F, Russell A et al (2014) 'Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers' J Neurol Neuosurg Psychiatry 85: 1029-1034.
- Vajda FJ, O'Brien TJ, Graham JE (2013) 'Dose dependence of fetal malformations associated with valproate' Neurology 81: 999-1003.
- Bech BH, Kjaersgaard MIS, Pedersen HS et al (2014) 'Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth: population based cohort study' BMJ 349: g5159.
- Christensen J, Grønborg TK, Sørensen MJ et al (2013) 'Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism' JAMA 309: 1696-1703.
- Cohen MJ, Meador KJ, Browning N et al (2013) 'Fetal antiepileptic drug exposure: adaptive and emotional/behavioural functioning at age 6 years' Epilepsy & behaviour 29: 308-315.
- Meador KJ, Baker GA, Browning N et al (2013) 'Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study' Lancet Neurol 12: 244-52
