Final results from 18 years of the International Lamotrigine Pregnancy Registry.

OBJECTIVE: To monitor for a signal for major teratogenicity following in utero lamotrigine exposure. METHODS: Health care providers reported lamotrigine exposure during pregnancy, and subsequent outcomes, on a voluntary basis. Prospective reporting early in pregnancy was encouraged. Major congenital malformations (MCMs) were classified according to the Centers for Disease Control and Prevention (CDC) criteria and were reviewed by a pediatrician on the Registry's Scientific Advisory Committee. The proportion of infants with MCMs was calculated by trimester and therapy type and descriptively compared to population-based reference estimates. RESULTS: Over an 18-year period, 35 infants with MCMs were observed among 1,558 first-trimester monotherapy exposures: 2.2%(95% confidence interval [CI] 1.6%-3.1%). This was similar to estimates from general population-based cohorts. The observed proportion of infants with MCMs among 150 lamotrigine/valproate polytherapy exposures was 10.7% (95% CI 6.4%-17.0%) and was 2.8% (95% CI 1.5%-5.0%) among 430 infants exposed to lamotrigine polytherapy without valproate. No consistent pattern of malformation type, or malformation frequency by dose, was observed. DISCUSSION: The Registry did not detect an appreciable increase in MCM frequency following first-trimester lamotrigine monotherapy exposure. With over 1,500 first-trimester monotherapy exposures, the Registry was powered to detect major teratogenicity. The proportion of infants with MCMs following lamotrigine/valproate polytherapy exposure was high, but similar to that previously reported with valproate monotherapy. The Registry failed to observe an increased MCM frequency with increasing lamotrigine dose. Monitoring of specific malformations among lamotrigine-exposed pregnancies will continue through case-control surveillance in the European Congenital Anomalies and Twins Registers network.

The association between exposure to COX-2 inhibitors and schizophrenia deterioration. A nested case-control study.

BACKGROUND: COX-2 inhibitors (COX-2i) have been reported to have beneficial effects on schizophrenia. This observational study assesses the association between exposure to COX-2i or/and NSAIDs and schizophrenia deterioration. METHODS: We conducted a case-control study within a cohort (n=3,485) of antipsychotic users with a schizophrenia diagnosis (ICD-9=295.x) in IMS-Lifelink, a US claims database. Case events indicating exacerbation of schizophrenia were: switching antipsychotic medication, starting combination therapy, using parenteral antipsychotics or an increasing dose. For each case one control was selected. Exposure to COX-2i/NSAIDs (current/recent/none) and cumulative exposure in Defined Daily Doses 90 days before the index/event date were assessed. Age, sex and co-medication were evaluated as confounders. Logistic regression analysis was used to assess the association. RESULTS: 1,443 case events occurred. For current use, no benefit on schizophrenia case events from exposure to COX-2i was found (adjusted OR 1.16; 95% CI 0.83-1.62). Instead, recent COX2i use with a duration of 0 to 93 days was associated with an increased risk for schizophrenia deterioration (adjusted OR 2.56; 95% CI 1.35-4.87). This association was strongest in rofecoxib. No relation was found for NSAIDs. CONCLUSION: The use of COX-2i was not associated with a decreased risk for schizophrenia deterioration in this population.

Use of antiepileptic drugs and risk of fractures: case-control study among patients with epilepsy.

OBJECTIVE: To study the association between use of antiepileptic drugs (AEDs) and risk of fractures. METHODS: The authors obtained data from the General Practice Research Database (GPRD). A case-control study was nested within a cohort of patients with active epilepsy. Cases were patients with a first fracture after cohort entry. Up to four controls were matched to each case by practice, sex, year of birth, timing of first epilepsy diagnosis, index date, and duration of GPRD history. Cumulative exposure to AEDs was assessed by summing the duration of all AED prescriptions. A distinction was made between AEDs that induce the hepatic cytochrome P-450 enzyme system and AEDs that do not. Medical conditions and drugs known to be associated with bone metabolism or falls were evaluated as potential confounders. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% CIs. RESULTS: The study population comprised 1,018 cases and 1,842 matched controls. The risk of fractures increased with cumulative duration of exposure (p for trend < 0.001), with the strongest association for greater than 12 years of use: adjusted OR 4.15 (95% CI 2.71 to 6.34). Risk estimates were higher in women than in men. There was no difference between users of AEDs that induce and AEDs that do not induce the hepatic cytochrome P-450 system. CONCLUSIONS: Long-term use of AEDs was associated with an increased risk of fractures, especially in women. More research on mechanisms of AED-induced bone breakdown and female vulnerability to the effects of AEDs on bone health is warranted.