The risks of congenital malformations and impact of cognitive development after foetal exposure to anti-epileptic drugs has been known for some time.

Sodium valproate is a frequently used drug for epilepsy and other disorders (including bipolar disorder and migraine). The researchers aimed to examine the link between foetal exposure and subsequent development of autism.

Methods

This was a population based study.  The sample included all children (655,615 in total) born in Denmark from 1996 to 2006. Foetal exposure was identified through the use of National prescription registers. Cox regression analysis with adjustment for a number of confounders including maternal/paternal age & psychiatric histories, birth weight & age, sex, malformations and parity was used.

Results

• 5,437 children were diagnosed with autism (of which 2,067 with childhood autism)
• 2,644 children had been exposed to antiepileptic drugs, of which 508 valproate
• Absolute risk for autism spectrum disorder after valproate exposure 4.42% (95% CI, 2.59%-7.46%) (adjusted HR 2.9 [95% Ci, 1.7-4.9])
• Absolute risk for childhood autism after valproate exposure 2.50% (95% CI, 1.30%-4.81%) (adjusted HR 5.2 [95% Ci, 2.7-10.0])
• For oxcarbazepine, lamotrigine, clonazepam and carbamazepine there appeared to be no increased risk in this study

Conclusions

The authors concluded:

Maternal use of valproate during pregnancy…significantly increased the risk of autism spectrum disorder and childhood autism in offspring… These findings must be balanced against the treatment benefits for women who require valproate for epilepsy control.

However, the absolute risk of autism spectrum disorder was less than 5%, which is important to take into account when counselling women about the use of valproate in pregnancy.

These results of this study are consistent with other findings (although slightly lower). The risks appeared higher in the first trimester, although dose did not appear to be a key factor. This reinforces the importance of providing education and contraception advice to women of child bearing age taking anti-epileptic drugs before pregnancy. It is important to note that anti-epileptic drugs can influence the effectiveness of contraceptive drugs so medical advice should always be sort.

There are a number of registers worldwide which are collecting outcome data on pregnancy and epilepsy, such as the UK Epilepsy and Pregnancy register.

This paper is fairly difficult to read understand due to the volume of statistical data. Fortunately, a short video interview with the lead author (Dr Jakob Christensen) can be found on the JAMA Network website.

Links

Jakob Christensen, PhD; Therese Koops Grønborg, MSc; Merete Juul Sørensen, PhD; Diana Schendel, PhD; Erik Thorlund Parner, PhD; Lars Henning Pedersen, PhD; Mogens Vestergaard, PhD (2013) Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood Autism JAMA;309(16):1696-1703.

JAMA Editorial on this research.

The National Autistic Society.

Sodium valproate. NHS Choices website, accessed 15th May 2013.

Epilepsy medicines and contraception. Epilepsy Action website, accessed 25th May 2013.