Neurology -- Correspondence for Holmes et al., 0 (2008) 10000304

Correspondence published:

Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy: Stephen J. Hunt, John J. Craig, James I. Morrow (14 July 2008)

Reply from the authors: Lewis B. Holmes, MD, E. J. Baldwin, C. R. Smith, E. Habecker, L. Glassman, S. L. Wong, and D. F. Wyszynski (14 July 2008)

Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy 14 July 2008

Stephen J. Hunt,
Dept of Neurology, Royal Victoria Hospital
Belfast, BT12 6BA, Northern Ireland,
John J. Craig, James I. Morrow
Send Correspondence to journal:
Re: Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy

clooney40{at}hotmail.com Stephen J. Hunt, et al.

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.

Reply from the authors 14 July 2008

Lewis B. Holmes, MD,
MassGeneral Hospital for Children
175 Cambridge Street, Boston, MA 02114,
E. J. Baldwin, C. R. Smith, E. Habecker, L. Glassman, S. L. Wong, and D. F. Wyszynski
Send Correspondence to journal:
Re: Reply from the authors

holmes.lewis{at}mgh.harvard.edu Lewis B. Holmes, MD, et al.

We welcome the comments of Drs. Hunt, Craig and Morrow who examined the frequency of oral clefts in infants exposed during pregnancy to lamotrigine (LTG) as monotherapy. More information is needed to answer these concerns.
Since our findings were published in abstract form [4], we have been contacted about case reports of LTG-exposed infants with cleft lip and/or cleft palate and large databases of infants with oral clefts who had been exposed to LTG as monotherapy. We have urged each clinician to publish their findings. We also hope that large datasets of LTG-exposed pregnancies without any oral clefts will be published. From this larger experience, clinicians will be better able to establish an estimate of the absolute risk of cleft palate or cleft lip and palate in LTG-exposed pregnancies.
In addition, the LTG-exposed infants with oral clefts should be carefully examined for signs of a syndromic type of oral cleft. Do they have the mid-face and digit hypoplasia that has been identified in 25% of the infants exposed to the anticonvulsant drugs, phenytoin and Phenobarbital? [5]
Exposure to many anticonvulsant drugs during pregnancy has been shown to cause problems with specific aspects of learning or communication or deficits in IQ. The risks are different for each drug. Studies of cognitive function in LTG-exposed children are needed to determine whether any deficits are a risk. If LTG-exposed infants have digit and mid-face hypoplasia, that physical effect of fetal exposure could be a marker of associated cognitive dysfunction. [6] Pregnancy registries focus on the identification of anomalies at birth. More information is needed on the prevalence at birth of isolated cleft lip, cleft palate and cleft lip and palate in unexposed infants.
Pregnancy registries rely on the referral of eligible pregnant women by their neurologists, obstetricians, nurses and other counselors. In order for our findings in the LTG-exposed pregnancies to be based on a much larger sample, we urge all health care providers in the U.S. and Canada to encourage their pregnant patients to enroll in the Registry by calling (toll-free) 1-888-233-2334.
References
4. Holmes LB, Wyszynski DF, Baldwin EJ, Habecker E, Glassman LH, Smith CR. Increased risk for non-syndromic cleft palate among infants exposed to lamotrigine during pregnancy. Birth Def Res Part A: Clinic Molec Teratol 2006;76:318.
5. Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001;344:1132-1138.
6. Holmes LB, Coull BA, Dorfman J, Rosenberger PB. The correlation of deficits in IQ with midface and digit hypoplasia in children exposed in utero to anticonvulsant drugs. J Pediatr 2005;146:118-122.
Disclosure: Each of the authors received salary support from funds provided since 1997 by the six sponsors of the Registry. At the time this manuscript was written, the sponsors were Abbott, Eisai, GlaxoSmithKline, Novartis, Ortho-McNeil, and Pfizer.