Dolk H, Jentink J, Loane M, Morris J, de Jong-van den Berg L T W
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.
Neurology. 2008 Sep 2;71(10):714-22. doi: 10.1212/01.wnl.0000316194.98475.d8. Epub 2008 Jul 23.
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.
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.
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.
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.
鉴于有信号提示拉莫三嗪（LTG）致口面部裂隙（OC）风险增加，调查孕早期暴露于LTG单药治疗是否相较于其他畸形，会使OC风险特异性增加。
基于EUROCAT先天性异常登记系统开展以人群为基础的病例对照研究，对照为畸形对照。研究人群涵盖了1995 - 2005年来自19个登记处的390万例出生病例。登记内容包括活产、死产以及产前诊断后终止妊娠中的先天性异常。病例为5511例非综合征性OC登记病例，其中4571例为孤立性OC，1969例为腭裂（CP），1532例为孤立性CP。对照为80052例非染色体、非OC登记病例。我们比较了孕早期LTG和抗癫痫药物（AED）使用情况与非癫痫非AED使用情况，针对单药治疗和联合治疗，对产妇年龄进行了校正。另一项探索性分析比较了与LTG使用相关的畸形类型的观察分布和预期分布。
有72例暴露于LTG的登记病例（40例单药治疗和32例联合治疗）。LTG单药治疗与未使用AED相比，OC相对于其他畸形的比值比（OR）为0.67（95%可信区间[CI] 0.10 - 2.34），孤立性OC为0.80（95% CI 0.11 - 2.85），CP为0.79（95% CI 0.03 - 4.35），孤立性CP为1.01（95% CI 0.03 - 5.57）。任何AED使用与未使用AED相比，OC的OR为1.43（95% CI 1.03 - 1.93），孤立性OC为1.21（95% CI 0.82 - 1.72），CP为2.37（95% CI 1.54 - 3.43），孤立性CP为1.86（95% CI 1.07 - 2.94）。暴露于LTG的其他非染色体畸形类型的分布与暴露于非AED的情况相似。
我们没有发现证据表明LTG单药治疗相较于其他畸形会使孤立性口面部裂隙风险特异性增加。我们的研究并非旨在评估LTG暴露是否会使畸形风险普遍增加。
