Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy
Stephen J.Hunt, Dept of Neurology, Royal Victoria Hospital, Belfast, BT12 6BA, Northern Irelandclooney40@hotmail.com
John J. Craig, James I. Morrow
Submitted July 14, 2008
We read with interest Holmes et al.’s findings of an increased risk of oral clefts in offspring exposed to lamotrigine during pregnancy. [1] Our results from the UK Epilepsy & Pregnancy Register, another independent prospective registration and follow-up study, do not confirm this finding. Our study methods have been previously published. [2]
We had full outcome data for 1229 pregnancies exposed to lamotrigine as monotherapy resulting in 1151 live births. Twenty-eight major congenital malformations were reported [MCM rate 2.4% (95% C.I.1.7– 3.5)]. Of these, one male infant was born with nonsyndromic cleft lip and palate [0.087% (95% C.I. 0.015 – 0.49)] to a 23-year-old nonsmoker, having been exposed to 200mg/day of lamotrigine through pregnancy. Folic acid was commenced following conception.
There were no cases of isolated cleft lip or isolated cleft palate. No specific pattern of malformations has emerged in this cohort. A European network of population-based congenital anomaly registers (Eurocat) did not find any evidence of an increased risk of isolated oral clefts relative to other malformations due to first trimester exposure to lamotrigine in monotherapy. [3]
We congratulate Holmes et al. but on their work but the substantial differences between their and our findings highlights the difficulty in interpreting data from observational uncontrolled studies especially when the event rates studied are rare.
While there may be true differences for oral clefts between the populations studied in the US and the UK it is also possible that the differences reflect reporting bias. Despite all the pregnancy data available, there are still major problems in counseling women with epilepsy. Replication across different datasets is likely to be critical before we are fully able to inform women.
References
1. Holmes LB, Baldwin EJ, Smith CR, et al. Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. Neurology 2008;70:2152–2158.
2. Morrow J, Russell A, Guthrie E, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psych 2006;77:193–198.
3. Dolk H, Jentink J, Loane M, Morris J, de Jong-van den Berg LTW and the Eurocat Antiepileptic Drug Working Group. Does Lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations? Neurology (in press).
Disclosure:
The study referenced in [2] was made possible by a research grant from the Epilepsy Research Foundation and a number of educational grants from pharmaceutical companies (Glaxo-Smith-Kline, Sanofi-Aventis, UCB-Phama, Janssen-Cilag, Pfizer, Eisai.) An internet based web site detailing the aims of the UK Epilepsy and Pregnancy register was made possible by a grant from Glaxo-Smith-Kline and UCB-Pharma. SH, JC and JM have attended meetings with the support of various pharmaceutical companies, including GSK. JC and JM have given lectures at the bequest of pharmaceutical companies, including GSK, for which they have received honoraria.
We read with interest Holmes et al.’s findings of an increased risk of oral clefts in offspring exposed to lamotrigine during pregnancy. [1] Our results from the UK Epilepsy & Pregnancy Register, another independent prospective registration and follow-up study, do not confirm this finding. Our study methods have been previously published. [2]
We had full outcome data for 1229 pregnancies exposed to lamotrigine as monotherapy resulting in 1151 live births. Twenty-eight major congenital malformations were reported [MCM rate 2.4% (95% C.I.1.7– 3.5)]. Of these, one male infant was born with nonsyndromic cleft lip and palate [0.087% (95% C.I. 0.015 – 0.49)] to a 23-year-old nonsmoker, having been exposed to 200mg/day of lamotrigine through pregnancy. Folic acid was commenced following conception.
There were no cases of isolated cleft lip or isolated cleft palate. No specific pattern of malformations has emerged in this cohort. A European network of population-based congenital anomaly registers (Eurocat) did not find any evidence of an increased risk of isolated oral clefts relative to other malformations due to first trimester exposure to lamotrigine in monotherapy. [3]
We congratulate Holmes et al. but on their work but the substantial differences between their and our findings highlights the difficulty in interpreting data from observational uncontrolled studies especially when the event rates studied are rare.
While there may be true differences for oral clefts between the populations studied in the US and the UK it is also possible that the differences reflect reporting bias. Despite all the pregnancy data available, there are still major problems in counseling women with epilepsy. Replication across different datasets is likely to be critical before we are fully able to inform women.
References
1. Holmes LB, Baldwin EJ, Smith CR, et al. Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. Neurology 2008;70:2152–2158.
2. Morrow J, Russell A, Guthrie E, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psych 2006;77:193–198.
3. Dolk H, Jentink J, Loane M, Morris J, de Jong-van den Berg LTW and the Eurocat Antiepileptic Drug Working Group. Does Lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations? Neurology (in press).
Disclosure: The study referenced in [2] was made possible by a research grant from the Epilepsy Research Foundation and a number of educational grants from pharmaceutical companies (Glaxo-Smith-Kline, Sanofi-Aventis, UCB-Phama, Janssen-Cilag, Pfizer, Eisai.) An internet based web site detailing the aims of the UK Epilepsy and Pregnancy register was made possible by a grant from Glaxo-Smith-Kline and UCB-Pharma. SH, JC and JM have attended meetings with the support of various pharmaceutical companies, including GSK. JC and JM have given lectures at the bequest of pharmaceutical companies, including GSK, for which they have received honoraria.