TABLE 2.

Valproate Dose Effects across Recent Studies

Australia Registry

Significant

34.5% malformations >1,400 mg/day vs 5.5% at ≤1,400 mg/day

Reference: Vajda et al. (11)

Finish Birth Registry

Significant

23.8% for doses >1,500 mg/day vs 9.5% for doses ≤1,500 mg/day

Reference: Artama et al. (12)

Finish Cognition Study

Significant

Reduce VIQ 20 points >1,500 mg/day, 16.6 at 800–1,500 mg/day, 4.2 <800 mg/day

Reference: Gaily et al. (29)

Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study

Significant for both birth defects and 2 y/o cognitive outcomes

24.2% malformations for doses ≥900 mg/day vs 9.1% <900 mg/day

References: Meador et al. (14, 20)

North America Registry

Not significant

1033 mg/day (±434) with malformations vs 983 mg/day (±431) without

Reference: Wyszynski et al. (15)

UK Registry

Significant (reanalyzed by Cochran-Armitage Trend Test)

9.1% >1,000 mg/day, 6.1% 600–1,000 mg/day, 4.1% <600 mg/day

[UK Registry reported no significant effect of valproate but reanalyzed by Cochran-Armitage Trend Test is significant. UK Registry found significant dose effect for lamotrigine, but the International Lamotrigine Registry (see below) did not.]

Reference: Morrow et al. (17)

UK Cognition Study

Significant

Reduce VIQ 15 points >1,500 mg/day, 9.9 at 801–1,500 mg/day, 2.2 ≤800 mg/day

Reference: Adab et al. (4)

International Lamotrigine Registry and Swedish Birth Registry

Not analyzed for valproate dose effect.

References: Cunnington et al. (13); Wide et al. (16)