1 Tampere School of Public Health, University of Tampere, Tampere, Finland.
2 Department of Neurology, University of Oulu, Oulu, Finland.
Received for publication November 7, 2002; accepted for publication December 12, 2003.
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ABSTRACT |
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birth rate; cohort studies; epilepsy; Finland
Abbreviations: Abbreviations: CI, confidence interval; HR, hazard ratio; KELA, Social Insurance Institution of Finland.
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INTRODUCTION |
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Epilepsy (4, 5) and use of antiepileptic medication (6, 7) may affect reproductive endocrine function, and reproductive endocrine disorders are more common in patients with epilepsy than in the general population (46). Hence, both male (5, 7) and female (4, 6) epilepsy patients may be more susceptible to a reduced birth rate than the rest of the population.
Epilepsy may also have negative social and psychological implications. The frequency of marriage is decreased among patients with epilepsy (1, 2, 8), but the birth rate is also decreased among married epilepsy patients (1, 2, 8, 9). Sexual dysfunction due to social and cognitive factors and lowered self-confidence appear to be more common in patients with epilepsy than in the rest of the population (10, 11).
During pregnancy and delivery, women who have epilepsy or use antiepileptic medication are predisposed to complications (12), and they may have an elevated risk of seizures (13). Some studies have reported that women with treated epilepsy have more miscarriages (14) and malformations (15) than women without treatment or without epilepsy. Increased risks of pregnancy complications may affect the decision to have children in some patients with epilepsy.
Most previous studies of birth rate in patients with epilepsy have been based on small samples and selective clinical materials. Therefore, we conducted this population-based study to obtain valid and accurate estimates of birth rate in patients with epilepsy based on a large and representative patient cohort.
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MATERIALS AND METHODS |
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The epilepsy patients included in this study were identified through the Social Insurance Institution of Finland (KELA). The patient cohort (n = 14,077) consisted of all patients with epilepsy who were approved as eligible for reimbursement for the purchase of antiepileptic medication from KELA for the first time between January 1, 1985, and December 31, 1994, who were alive on January 1, 1990, and in the fertile age group (1549 years) during the study period. The information obtained from KELA included full name, personal identification number, and date of eligibility approval. Persons who had died before January 1, 1990, were excluded from the KELA database; information on them was not available. Information on type of epilepsy or antiepileptic medication was not available either.
The reference cohort (n = 29,828) was formed as a stratified random sample of all persons who were alive and resident in Finland on January 1, 1990. These persons were identified through the Finnish Population Register Center, with frequency-matching to the patient cohort by 5-year age group.
Rates of livebirth were estimated using information obtained from the population registry. The information covered number and dates of birth of liveborn children, date of first marriage, marital status, vital status, date of emigration, and date of death. Information was obtained through computerized record linkage with the unique personal identification number assigned to all residents of Finland. Information on stillbirths or miscarriages was not available.
Only persons aged 1549 years during follow-up contributed person-years to the analysis. For the epilepsy patients, follow-up started at the start of reimbursement or the 15th birthday, whichever was later. For the reference cohort, the beginning of follow-up was the 15th birthday or the mean starting date of reimbursement among patients with epilepsy in that 5-year age group. The closing date was livebirth, the 50th birthday, emigration, death, or the common closing date (March 28, 2001), whichever was earliest. Follow-up was complete.
In the analyses carried out by start of reimbursement, the start of follow-up was divided into two periods for the epilepsy patients: 19851989 and 19901994. Follow-up for the reference cohort was subdivided into two groups regarding the start of reimbursement for the patients in every 5-year age group. The starting date of follow-up was July 1, 1987, or July 1, 1992.
Primary analyses were performed for the first liveborn child born after the start of follow-up (including all subjects). Separate analyses were performed for the first liveborn child (including only subjects without previous children), for the second liveborn child (including only subjects with one previous child at the start of follow-up), for the third liveborn child (including only subjects with two previous children at the start of follow-up), and for the fourth or subsequent liveborn child (including only subjects with three or more previous children at the start of follow-up).
Similar analyses were performed for the 5 years preceding the index date, which was defined in the patient cohort as the starting date of reimbursement for antiepileptic medication and in the reference cohort as the mean starting date of reimbursement among patients with epilepsy in that 5-year age group. The analyses were performed separately for each of the 5 years preceding the index date, with the start of follow-up at the date 15 years before the index date (or the 15th birthday if it was later). As in other analyses, only person-years accrued between the ages of 15 and 49 years were included in the analyses. The closing date was the birth of a liveborn child, the 50th birthday, emigration or death within each year, or the end of the year, whichever was earlier.
Since information was available on date of first marriage but not on dates of divorces and bereavements, marital status was classified as never married versus ever married. Information on date of marriage was missing for 44 persons (0.1 percent of subjects). Of those persons, the year of marriage was known for 17, and their marriage date was imputed as July 1 of that year. Persons with an unknown year of marriage (n = 18) or an unknown marital status (n = 9) were treated as having missing values.
The study protocol was approved by the ethical review committee of the Pirkanmaa Hospital District. Record linkage with the population registry was conducted with permission from the National Center for Research and Development in Health and Welfare. Because the study subjects were not contacted, informed consent to participate was not required.
In the statistical analysis, factors considered potential confounders and modifiers were sex, age, marital status, and previous livebirths. Analyses were conducted separately for men and women and were stratified according to age at start of follow-up, age at observation, year of start of follow-up, follow-up period, marital status, and number of previous children at start of follow-up. The analyses were performed using the Cox proportional hazards model, and the outcome was the birth of a liveborn child.
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RESULTS |
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Among men with epilepsy, the birth rate was decreased regardless of previous livebirths. In female patients, the birth rate was slightly reduced for the first livebirth (HR = 0.84, 95 percent CI: 0.79, 0.90) and for the second livebirth (HR = 0.89, 95 percent CI: 0.76, 1.04) but not for the third or subsequent livebirths.
Before epilepsy diagnosis, birth rates for the first liveborn child were also reduced in both men with epilepsy (HR = 0.76, 95 percent CI: 0.72, 0.80) and women with epilepsy (HR = 0.79, 95 percent CI: 0.76, 0.83) for the entire 5-year period preceding diagnosis. No clear trend by time to diagnosis was observed (table 4).
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DISCUSSION |
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Few large population-based studies of birth rate in patients with epilepsy have been conducted. Most previous studies have been based on a few hundred patients (2, 3, 8), with data collected from clinical records (2, 17) and without a population-based reference group (1, 2, 8, 9).
Our study population was unselected, since coverage of newly diagnosed patients was high and the reference cohort was population-based. In addition, the large study population and the register-based approach enabled us to obtain comprehensive information on livebirths. The age-specific birth rate for women in the reference cohort was similar to that of the general Finnish female population (18).
The results of previous studies on birth rate in patients with epilepsy have been partly conflicting. In most of the previous studies, the birth rate has been lower among epilepsy patients than in the general population. However, in a population-based study conducted in Iceland, no difference in birth rate was found between patients with epilepsy and the reference cohort (3). Several studies have suggested that the birth rate is reduced in both sexes, especially among men after diagnosis (1, 19). In addition, the birth rate has been reported to be lower among female epilepsy patients than among male patients (1, 9). In our study, the birth rate was decreased in both sexes, especially in men.
Our results regarding age at the start of follow-up were partly consistent with the previous studies. As in our study, lower fertility rates have been reported among female patients with onset at age 20 years or higher (2). In contrast to previous findings (1, 2, 9), we found no effect of epilepsy among persons diagnosed before age 10 years. Most patients with onset before age 10 years have generalized epilepsy. The prognosis for generalized epilepsy is favorable, and antiepileptic medication is often discontinued. In our study, differences in birth rates between the patients and the referents increased with age. However, the number of children was small in both groups.
Marital status strongly affects birth rate, and it can be regarded as both a potential confounder and an effect modifier in studies of epilepsy and birth rate. We did not have complete information on marital status, only information on the date of first marriage. Adjustment for marital status decreased the differences between patients with epilepsy and the reference cohort, especially when marital status was used as a time-dependent covariate. It has been reported that epilepsy patients frequently have children after marrying, but the birth rate is still lower than in the general population (1, 2, 8, 9). In our study, the effect of epilepsy did not differ between never-married persons and ever-married persons. This may be partly due to nondifferential misclassification induced by incomplete information on marital history.
Number of previous children modified the birth rate in women with epilepsy but not in men with epilepsy. Regardless of number of children, men with epilepsy had a decreased rate of livebirth. Correspondingly, female epilepsy patients without children or with one previous child had a lower birth rate than women without epilepsy.
The birth rate for a first liveborn child was reduced before the start of follow-up in both men and women with epilepsy. Three possible explanations could account for this finding. First, because the diagnosis of epilepsy requires recurrent seizures, patients may have convulsions preceding diagnosis, which could affect sexual relationships, behavior, function, and birth rate. This seems unlikely, however, since there was no trend by time to diagnosis. Second, this could be attributable to shared risk factors, that is, an external factors affecting both fertility and epilepsy, such as socioeconomic status. This is possible, but we did not have information with which to investigate this possibility. Third, this finding could be due to misclassification, that is, missing dates of the first epilepsy diagnosis. This is unlikely, since the coverage of reimbursement files in Finland is very high and we have checked the reimbursement decisions back to the 1960s.
There were some limitations in our study. Identification of patients with epilepsy may have been incomplete. Information on epilepsy patients who did not want reimbursement for the purchase of antiepileptic medication was not available. If a diagnosis of epilepsy is made for an institutionalized patient, information on reimbursement is not necessarily included in the KELA database. Those patients were probably underrepresented in our study. However, the cost of antiepileptic medication is high in Finland, and therefore few people with epilepsy refuse reimbursement for antiepileptic medication. Furthermore, the proportion of institutionalized epilepsy patients is small overall. Therefore, the exclusion of these persons is not likely to have substantially affected our results.
Information on type of epilepsy or medication was not available in this study. However, we were able to assess two modifiers of antiepileptic medication. We conducted analyses by year of diagnosis to assess the effect of possible changes in antiepileptic medication during the follow-up period. We conducted analyses by follow-up period to evaluate the effect of duration of use of antiepileptic medication on birth rate. Neither year of start of reimbursement nor follow-up period was a modifier of birth rate in patients with epilepsy. However, the most common types of antiepileptic medication in Finland are carboxamide derivates such as carbamazepine and oxcarbazepine, which are used mainly in partial epilepsies, and valproate, which is used mainly in generalized epilepsies (20).
Many patients probably discontinued use of antiepileptic medication during follow-up. Jalava and Sillanpää (8) reported that more than two thirds of their study patients achieved remission and did not require further medication. Those with active epilepsy who were taking two or more antiepileptic drugs had a fourfold increased risk of childlessness (95 percent CI: 1.3, 12.5) relative to the control group. Patients in remission were at similar risk as the control group. Patients with a long follow-up period are less likely to use antiepileptic medication, and they should have a birth rate similar to that of the reference cohort. However, in this study, there was a substantial difference between the patients with a long follow-up period and the reference cohort in terms of birth rate.
There are several possible explanations for the persisting differences. Decreased fertility may not be attributable to antiepileptic medication. Our follow-up time was twice as long as in most previous studies. Therefore, our follow-up time was probably sufficient to evaluate the effect of changes in or duration of use of antiepileptic medication. In addition, there may be maternal epilepsy-related factors that affect fertility, including comorbidity such as mental disability or sequelae of trauma. Increased risk of congenital malformations in epilepsy may lead to induced abortions and a decreased rate of livebirth.
Socioeconomic factors may also influence birth rate. Epilepsy may affect peoples ability to obtain education and to work, although Schupf and Ottman (9) did not find any difference in educational background between female patients and their unaffected siblings. Generally, the number of children is lower among persons with higher education than among others; therefore, it is unlikely that epilepsy-related socioeconomic factors would have influenced the observed low birth rate in persons with epilepsy. We did not have information on socioeconomic factors.
Several studies have shown that stillbirths and spontaneous abortions are more common among patients with epilepsy than in the general population. Information on stillbirths or abortions was not available in this study. Therefore, we could not estimate the contribution of these events to the decreased birth rate. Furthermore, we were not able to assess whether the reduced birth rate among patients with epilepsy was voluntary or due to a reduced capability to conceive.
In conclusion, our results suggest that birth rate is decreased in patients with epilepsy, especially among men and persons aged 20 years or more.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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