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• Re: J Morrow et al.
  John A Messenheimer
  Published on: 13 February 2006

• Published on: 13 February 2006

  Re: J Morrow et al.

  • John A Messenheimer, Neurologist
  • Other Contributors:
    • John Weil

  Dear Sir:

  In their recent report in this journal of data from the UK Epilepsy and Pregnancy Register, Morrow et al. describe a possible effect of maternal lamotri...

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  Dear Sir:

  In their recent report in this journal of data from the UK Epilepsy and Pregnancy Register, Morrow et al. describe a possible effect of maternal lamotrigine dose on the occurrence of major congenital malformations (MCM) in offspring of mothers with epilepsy.¹ This finding conflicts with results from the two other pregnancy registries that have reported on dose of lamotrigine andMCM rate including the International Lamotrigine Pregnancy Registry, for which a dose-effect analysis has recently been published as an abstract.² To contextualize the information reported by Morrow et al.¹, we summarize here the results of the dose-effect analysis of outcomes in the International Lamotrigine Pregnancy Registry and discuss them in light of findings from other registries.

   

  The analyses included all pregnancies enrolled from inception of the Lamotrigine International Pregnancy Registry in 1992 through 30 September 2005 if they had been exposed to lamotrigine monotherapy during the first trimester and had lamotrigine dosing information for the first trimester. Among the 680 first-trimester lamotrigine monotherapy exposures for which dosing data were available, the frequency of major congenital malformations was 2.8% (19/680). Numbers of exposures were sufficient to evaluate a potential dose effect up to 400 mg/day.The frequency of congenital malformations did not differ as a function of dose up to 400 mg/day by the Mantel-Haenszel statistic as shown in the following table:

  
  

  Rate of MCM in the First Trimester by Lamotrigine Monotherapy Dose Category through September 30, 2005

  Dose Category of Lamotrigine	Number of MCM/ Number of exposures during 1st Trimester	Frequency of MCMs	95% CI
  £ 200 mg/day	(10/352)	2.8%	1.4, 5.2
  >200 mg/day	9/328	2.7%	1.3, 5.2
  £300 mg/day	14/483	2.9%	1.6, 4.8
  >300 mg /day	5/197	2.5%	0.8, 5.8
  £400 mg/day	15/580	2.6%	1.4, 4.2

   

  Lamotrigine dose did not differ between outcomes with major congenital malformations (mean 250.7 mg/day; median 200 mg/day) and those without major congenital malformations (mean 281.1 mg/day; median 200 mg/day). These results, based on analyses comparable to those described in Morrow et al.’s report¹ show no evidence of an effect of maternal lamotrigine dose on the frequency of major congenital abnormalities up to a daily dose of 400 mg, above which the number of exposures was insufficient to either support or refute a dose effect of lamotrigine.

   

  This finding of a lack of a dose effect with lamotrigine is also found in recent observations from the Australian pregnancy registry, in which a dose effect for valproate was identified but no statistically significant effect of maternal lamotrigine dose, wasfound in an analysis of 128 monotherapy exposures.³We also note that Morrow et al carried out statistical analyses for mean dose but not for the data on malformation rates by the tertile dose categories presented in table 4. Using SAS Version 8.2 we carried results for exact versions of 2-sided cochrane armitage trend tests for a dose-response effect in the data in table 4: p=0.3081 for carbamazepine, p< 0.05 for valproate, p<=0.05 for lamotrigine. Although the UK, Australian, and International Lamotrigine Pregnancy registries employ different methodologies,^2,3,4 none of these differences accounts in an obvious manner for the inconsistent lamotrigine results across registries.

   

  The results from UK Registry suggest a need for further information and the discrepancy between the results reported by Morrow et al. and those from the International Lamotrigine and Australian registries highlights the need for registries to adopt a collaborative approach to understanding the potential risks of fetal AED exposure. The UK Registry data raise important questions that might best be addressed through inter-registry cooperation and sharing of information. Dose-effect analyses from other AED registries, such as the North American Anti-Epileptic Drug Registry and EURAP, could add clarity and provide clinicians with additional useful information.

   

  John A. Messenheimer, MD

  John G.Weil, MD

  GlaxoSmithKline R&D

   

  References

  1.        Morrow JI, Russell A, Gutherie E, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2005;77:193-198.

  2.        Messenheimer JA, Wiel J. Thirteen year interim results from an International Observational Study of Pregnancy Outcomes Following Exposure to Lamotrigine [abstract P01.088].58^th Annual Meeting of the AmericanAcademy of Neurology, April 1-8, 2006, San Diego, CA.

  3.        Vajda FJE, Eadie MJ. Maternal valproate dosage and foetal malformations. Acta Neurol Scand 2005;112:137-143.

  4.        Cunnington M, Tennis P, International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy. Neurology 2005;64:955-960.

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  Conflict of Interest:
  None declared.

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