Abstract
We summarize information presented at recent international meetings, of the Australian Pregnancy Registry for Women on Antiepileptic Medications, based at Melbourne University [1–4].
The relevance of psychiatrists arises because antiepileptic drugs (AEDs) are increasingly employed in treating bipolar disorder and depression. A few psychiatric patients are enrolled in the Registry and they may not be aware of the risks associated with a high dose of valproate (VPA) (doses above 1100 mg day−1).
Over 800 women are represented in the Registry, of which 565 have completed their pregnancy. The fetal malformations (FMs) rate for infants was significantly higher for the VPA than for any other AEDs.
It has been suggested that polytherapy was more detrimental in causing FMs than monotherapy. It may be that the VPA component of polytherapy is the main factor causing FMs, rather than polytherapy itself.
Lamotrigine (LTG) monotherapy (n = 62) was not associated with a single FM compared to those patients taking VPA monotherapy (n = 115, FMs = 19). Even in LTG polytherapy only four patients had outcomes with FMs. In these cases, a high-dose VPA component could be identified.
Lamotrigine has been approved for treating bipolar disorders and from the fetal safety point of view, it may represent a suitable option.
The relative safety of the four most commonly used drugs in pregnancy indicates the risks of high dose VPA. Monotherapy figures show a risk with carbamazepine (3.8%), phenytoin (5.9%) not significantly different from untreated women (2.5%), no malformations noted at this stage with LTG-and VPA-related risks, all doses were 16.5.% (p< 0.04).
With doses of VPAof 1100 mg day−1, there was a statistically high significant increase in the risk of a fetal outcome with a malformation (15/39, 30.5%), compared to that in untreated women (1/40) (p < 0.0002). This was not noted at doses below 1100 mg day−1.
In terms of efficacy against seizures, the safety of LTG is not matched by effectiveness in pregnancy. Although the Registry is not a formal randomized trial, seizures were statistically significantly more frequent in patients treated with LTG monotherapy than with VPA. A selection bias and small numbers may affect this result. Underdosing due to a fall in LTG plasma levels in each trimester and induction to LTG metabolism by hormones associated with pregnancy are likely. It is possible, however, that in bipolar disorder, efficacy of LTG in pregnancy may be less than that of VPA.
Lamotrigine plasma levels may need to be monitored. Lamotrigine takes 6 weeks after introduction to reach recommended doses and plasma concentrations.
At present the use of these two drugs pose a dilemma for doctors using VPA and LTG.
If a change was to be made on the grounds of fetal safety, the replacement of VPA with LTG may require individual planning before conception, to get the best results in bipolar disorder.