Objective: To assess the relative risk of major congenital malformation (MCM) from in utero exposure to antiepileptic drug (AEDs). Methods: Prospective data collected by the UK Epilepsy and Pregnancy Register were analysed. The presence of MCMs recorded within the first three months of life was the main outcome measure. Results: Full outcome data were collected on 3607 cases. The overall MCM rate for all AED exposed cases was 4.2% (95% confidence interval (CI), 3.6% to 5.0%). The MCM rate was higher for polytherapy (6.0%) (n = 770) than for monotherapy (3.7%) (n = 2598) (crude odds ratio (OR) = 1.63 (p = 0.010), adjusted OR = 1.83 (p = 0.002)). The MCM rate for women with epilepsy who had not taken AEDs during pregnancy (n = 239) was 3.5% (1.8% to 6.8%). The MCM rate was greater for pregnancies exposed only to valproate (6.2% (95% CI, 4.6% to 8.2%) than only to carbamazepine (2.2% (1.4% to 3.4%) (OR = 2.78 (p,0.001); adjusted OR = 2.97 (p,0.001)). There were fewer MCMs for pregnancies exposed only to lamotrigine than only to valproate. A positive dose response for MCMs was found for lamotrigine (p = 0.006). Polytherapy combinations containing valproate carried a higher risk of MCM than combinations not containing valproate (OR = 2.49 (1.31 to 4.70)). Conclusions: Only 4.2% of live births to women with epilepsy had an MCM. The MCM rate for polytherapy exposure was greater than for monotherapy exposure. Polytherapy regimens containing valproate had significantly more MCMs than those not containing valproate. For monotherapy exposures, carbamazepine was associated with the lowest risk of MCM.

The number of outcomes of human pregnancies exposed to topiramate is low, but the major congenital malformation rate for topiramate polytherapy raises some concerns. Overall, the rate of oral clefts observed was 11 times the background rate. Although the present data provide new information, they should be interpreted with caution due to the sample size and wide confidence intervals.

The study supports the view that extrapolation from studies carried out in the general population to groups of women with epilepsy may be questionable. It may be that the increased risk of MCM recorded in this group occurs through mechanisms other than that of folic acid metabolism.

The serine anti-protease elafin is expressed by monocytes, alveolar macrophages, neutrophils, and at mucosal surfaces and possesses antimicrobial activity. It is also known to reduce lipopolysaccharide-induced neutrophil influx into murine alveoli as well as to abrogate lipopolysaccharide-induced production of matrix metalloprotease 9, macrophage inhibitory protein 2, and tumor necrosis factor-␣ by as-yet unidentified mechanisms. In this report we have shown that elafin inhibits the lipopolysaccharide-induced production of monocyte chemoattractant protein-1 in monocytes by inhibiting AP-1 and NF-B activation. Elafin prevented lipopolysaccharide-induced phosphorylation of AP-1, c-Jun, and JNK but had no effect on phosphorylation of p38. The lipopolysaccharide-induced degradation of IL-1R-associated kinase 1, IB␣, and IB␤ was inhibited by elafin but phosphorylation of IB␣ was unaffected. Polyubiquitinated protein including polyubiquitinated IB␣ was shown to accumulate in the presence of elafin. These results suggest that inhibition by elafin of lipopolysaccharide-induced AP-1 and NF-B activation occurs via an effect on the ubiquitinproteasome pathway.Elafin is a 6-kDa serine anti-protease initially identified in psoriatic skin scales and is also called skin-derived anti-leucoprotease. Subsequently, "elastase-specific inhibitor" was isolated from human sputum and found to have identical N-terminal sequencing as skin-derived anti-leucoprotease, and the term elafin was suggested (1). Elafin is currently known to be expressed in airways, other mucosal surfaces such as esophagus, vagina, endometrium, and coronary intima and by inflammatory cells such as monocytes, alveolar macrophages, and neutrophils.Structurally, elafin is a member of the WAP (whey acidic protein) family of proteins characterized by possessing a C-terminal core domain consisting of four disulfide bonds. Also known as trappins (transglutaminase substrate and wap domain-containing protein), these proteins also possess an N-terminal domain consisting of a variable number of repeats with the consensus sequence Gly-Gln-Asp-Pro-Val-Lys that can act as an anchoring motif by transglutaminase cross-linking (2). Pre-elafin, also known as trappin 2, is thought to undergo proteolytic cleavage, possibly by tryptase, releasing the elafin molecule (3). Elafin is a cationic protease inhibitor of human neutrophil elastase, proteinase 3, and porcine pancreatic elastase and is induced by cytokine and other stimuli including interleukin 1␤, tumor necrosis factor, human neutrophil elastase, and lipopolysaccharide (LPS) 2 (1). The gene governing elafin (and other WAP proteins) expression was cloned and sequenced on the long arm of chromosome 20. Transcriptional activation of elafin appears to be cell specific; in pulmonary epithelial cells elafin is regulated at a transcriptional level by the transcription factor nuclear factor B (NF-B) (4), whereas in mammary epithelial cells the transcription factor activating protein-1 (AP-1) mediates transcriptional activation (5). Th...