Does lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations?
OBJECTIVE
To investigate whether first trimester exposure to lamotrigine (LTG) monotherapy is specifically associated with an increased risk of orofacial clefts (OCs) relative to other malformations, in response to a signal regarding increased OC risk.


METHODS
Population-based case-control study with malformed controls based on EUROCAT congenital anomaly registers. The study population covered 3.9 million births from 19 registries 1995-2005. Registrations included congenital anomaly among livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. Cases were 5,511 nonsyndromic OC registrations, of whom 4,571 were isolated, 1,969 were cleft palate (CP), and 1,532 were isolated CP. Controls were 80,052 nonchromosomal, non-OC registrations. We compared first trimester LTG and antiepileptic drug (AED) use vs nonepileptic non-AED use, for mono and polytherapy, adjusting for maternal age. An additional exploratory analysis compared the observed and expected distribution of malformation types associated with LTG use.


RESULTS
There were 72 LTG exposed (40 mono- and 32 polytherapy) registrations. The ORs for LTG monotherapy vs no AED use were 0.67 (95% CI 0.10-2.34) for OC relative to other malformations, 0.80 (95% CI 0.11-2.85) for isolated OC, 0.79 (95% CI 0.03-4.35) for CP, and 1.01 (95% CI 0.03-5.57) for isolated CP. ORs for any AED use vs no AED use were 1.43 (95% CI 1.03-1.93) for OC, 1.21 (95% CI 0.82-1.72) for isolated OC, 2.37 (95% CI 1.54-3.43) for CP, and 1.86 (95% CI 1.07-2.94) for isolated CP. The distribution of other nonchromosomal malformation types with LTG exposure was similar to non-AED exposed.


CONCLUSIONS
We find no evidence of a specific increased risk of isolated orofacial clefts relative to other malformations due to lamotrigine (LTG) monotherapy. Our study is not designed to assess whether there is a generalized increased risk of malformations with LTG exposure.
Dolk
H
H
Social Pharmacy, Pharmacoepidemiology and Pharmacotherapy, Groningen University Institute for Drug Exploration (GUIDE), University of Groningen, The Netherlands, Ant. Deusinglaan 1, 9713 AV Groningen The Netherlands. l.t.w.de.jong-van.den.berg@rug.nl
Jentink
J
J
Loane
M
M
Morris
J
J
de Jong-van den Berg
L T W
LT
D000293:Adolescent; D018692:Antimanic Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002971:Cleft Lip / Q000139:chemically induced* / Q000453:epidemiology; D018672:Community Health Planning; D016001:Confidence Intervals; D000013:Congenital Abnormalities / Q000453:epidemiology / Q000209:etiology*; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D016017:Odds Ratio; D011247:Pregnancy; D011248:Pregnancy Complications / Q000139:chemically induced*; D011297:Prenatal Exposure Delayed Effects; D012042:Registries; D012189:Retrospective Studies; D012306:Risk; D012307:Risk Factors; D014227:Triazines / Q000009:adverse effects*
D018692:Antimanic Agents; D014227:Triazines; D000077213:Lamotrigine