Antiepileptic drug use and birth rate in patients with epilepsy—a population-based cohort study in Finland

Human Reproduction, Sep 2006

BACKGROUND: Antiepileptic medication use affects reproductive endocrine function, but its impact on fertility is not well known. METHODS: All epilepsy patients, who were approved as being eligible for reimbursement for antiepileptic drug (AED) costs from the Social Insurance Institution (SII) of Finland for the first time 1985–94, were identified from the SII database. A reference cohort without epilepsy was identified from the Finnish Population Register Centre. Information on AED purchases 1996–2000 was obtained from the SII database through computerized record linkage with the unique personal identification number assigned to all residents of Finland. The three AEDs included were carbamazepine, oxcarbazepine (OXC) and valproate. RESULTS: Birth rate was lower in both men and women with epilepsy on AEDs than in the reference cohort without epilepsy. However, compared with patients not using AED during the study period, the birth rate was lowered only among men on OXC [rate ratio (RR) = 0.52, 95% confidence interval (CI) = 0.32, 0.84]. CONCLUSIONS: The birth rate was lower in both women and men on any of the three AEDs compared with the reference cohort without epilepsy. However, a statistically significant difference between treated and untreated patients was only seen in men on OXC. It is unclear to what extent the differences found in this study are due to social or biological factors.

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Antiepileptic drug use and birth rate in patients with epilepsy—a population-based cohort study in Finland

Miia Artama 2 J.I.T.Isojrvi 1 3 A.Auvinen 0 2 0 Pediatric Research Centre, Tampere University Hospital , Tampere , Finland 1 Department of Neurology, University of Oulu , Oulu 2 School of Public Health, University of Tampere , Tampere 3 Address during the study: GlaxoSmithKline , Neurosciences MDC, Research Triangle Park, NC 27709 , USA BACKGROUND: Antiepileptic medication use affects reproductive endocrine function, but its impact on fertility is not well known. METHODS: All epilepsy patients, who were approved as being eligible for reimbursement for antiepileptic drug (AED) costs from the Social Insurance Institution (SII) of Finland for the first time 1985-94, were identified from the SII database. A reference cohort without epilepsy was identified from the Finnish Population Register Centre. Information on AED purchases 1996-2000 was obtained from the SII database through computerized record linkage with the unique personal identification number assigned to all residents of Finland. The three AEDs included were carbamazepine, oxcarbazepine (OXC) and valproate. RESULTS: Birth rate was lower in both men and women with epilepsy on AEDs than in the reference cohort without epilepsy. However, compared with patients not using AED during the study period, the birth rate was lowered only among men on OXC [rate ratio (RR) = 0.52, 95% confidence interval (CI) = 0.32, 0.84]. CONCLUSIONS: The birth rate was lower in both women and men on any of the three AEDs compared with the reference cohort without epilepsy. However, a statistically significant difference between treated and untreated patients was only seen in men on OXC. It is unclear to what extent the differences found in this study are due to social or biological factors. Background Birth rate is lowered in both female and male patients with epilepsy (Artama et al., 2004). This is partly explained by the decreased rate of marriages (Schupf and Ottman, 1994, 1996; Jalava and Sillanp, 1997), but birth rate is also lower in married persons with epilepsy than in the general population (Dansky et al., 1980; Schupf and Ottman, 1994, 1996; Jalava and Sillanp, 1997). Epilepsy itself, but also antiepileptic drug (AED) use, may affect reproductive endocrine function (Herzog et al., 1986a,b; Isojrvi et al., 1990, 1993; Mikkonen et al., 2004), and these alterations may be associated with reduced fertility. Among women with epilepsy, menstrual disorders reflecting ovulatory dysfunction related to, for example, polycystic ovaries, hyperandrogenism and anovulatory cycles are more common than in general population (Herzog et al., 1986a; Isojrvi et al., 1993). These conditions may reduce fertility in women with epilepsy (Isojrvi et al., 2005). In men with epilepsy, long-term use of liver enzyme inducing AEDs is associated with increased serum concentrations of sex hormone-binding globulin and reduced bioactive serum testosterone, which may affect reproductive functions (Isojrvi et al., 2005). In addition, the use of certain AEDs may reduce sperm motility, induce sperm abnormalities and decrease testicular volume (Rste et al., 2003; Isojrvi et al., 2004). Changes in sperm quality can obviously have direct effects on fertility in men. Previous population-based studies on birth rate among patients with epilepsy are few (Webber et al., 1986; Jalava and Sillanp, 1997; Olafsson et al., 1998; Wallace et al., 1998; Artama et al., 2004), and those addressing the effects of specific AEDs on birth rate have been based on small samples (Jalava and Sillanp, 1997). We conducted this populationbased study to evaluate the role of commonly used AEDs on birth rate among patients with epilepsy in a large and representative patient cohort using comprehensive information on AED purchases and live-born children. Materials and methods In Finland, all permanent residents are entitled to national health insurance, which is maintained by the state and financed by tax revenues. The national health insurance includes a drug reimbursement system, which covers fully or partially the costs of prescribed medications. This reimbursement system consists of three categories: basic, special (75% of cost) and complete (100% of cost). Epilepsy is one of the approximately 50 diseases in the complete reimbursement category. The requirement for the reimbursement of costs for AEDs is a medical certificate showing that the epilepsy diagnosis is based on clinical examination; it fulfils the international diagnostic criteria (Fisher et al., 2005) and is made by a board-certified neurologist. The medical certificate needs to include sufficient information to confirm the diagnosis of epilepsy. This information consists of medical history with description of the seizure symptomatology, the possible aetiology of epilepsy, if known, the duration of epilepsy symptoms and other relevant medical history. Data on the results of imaging studies of the brain and EEG are included, when available. AEDs that are prescribed f (...truncated)


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Miia Artama, J.I.T. Isojärvi, A. Auvinen. Antiepileptic drug use and birth rate in patients with epilepsy—a population-based cohort study in Finland, Human Reproduction, 2006, pp. 2290-2295, 21/9, DOI: 10.1093/humrep/del194