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)