Hum. Reprod. Advance Access originally published online on June 3, 2006
Human Reproduction 2006 21(9):2290-2295; doi:10.1093/humrep/del194
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Antiepileptic drug use and birth rate in patients with epilepsy—a population-based cohort study in Finland
1 School of Public Health, University of Tampere, Tampere 2 Department of Neurology, University of Oulu, Oulu and 3 Pediatric Research Centre, Tampere University Hospital, Tampere, Finland
4 To whom correspondence should be addressed at: Tampere School of Public Health, University of Tampere, Tampere 33014, Finland. E-mail: miia.artama{at}uta.fi
5 Address during the study: GlaxoSmithKline, Neurosciences MDC, Research Triangle Park, NC 27709, USA
 |
Abstract |
|---|
 Top Abstract BackgroundMaterials and methodsResultsDiscussionConclusionsAcknowledgementsReferences |
|---|
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.
Key words: antiepileptic drug/birth rate/cohort study/epilepsy
|
Background |
|---|
|
TopAbstractBackgroundMaterials and methodsResultsDiscussionConclusionsAcknowledgementsReferences |
|---|
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 Sillanpää, 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 Sillanpää, 1997).
Epilepsy itself, but also antiepileptic drug (AED) use, may affect reproductive endocrine function (Herzog et al., 1986a,b; Isojärvi 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; Isojärvi et al., 1993). These conditions may reduce fertility in women with epilepsy (Isojärvi 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 (Isojärvi et al., 2005). In addition, the use of certain AEDs may reduce sperm motility, induce sperm abnormalities and decrease testicular volume (Røste et al., 2003; Isojärvi 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 Sillanpää, 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 Sillanpää, 1997). We conducted this population-based 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 |
|---|
|
TopAbstractBackgroundMaterials and methodsResultsDiscussionConclusionsAcknowledgementsReferences |
|---|
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 for indications other than epilepsy are recorded under other disease categories. The study cohort consisted of all epilepsy patients who were approved for complete reimbursement for antiepileptic medication purchases from the Social Insurance Institution (SII) of Finland for the first time in life between 1 January 1985 and 31 December 1994 and were alive on 1 January 1990. Because persons who had died before 1 January 1990 were eliminated from the SII database, we did not have information on them. Information obtained from SII included personal identification number and the date of eligibility approval.
The reference cohort without epilepsy was identified through the Finnish Population Register Centre with frequency matching to the patient cohort on year of birth (5-year age groups). The cohort comprised of a stratified random sample of all persons who were alive and residing in Finland on 1 January 1990.
Information on AED purchases for epilepsy from 1 January 1996 to 31 December 2000 was obtained from SII. Information covered personal identification number, anatomic therapeutic chemical (ATC) code of the drug (from N03AA to N03AX) and the date of purchase. Information was obtained on all AED purchases under AED category (ATC:N03).
Information on live-born children and vital status was obtained from the Population Registry for both epilepsy patients and reference persons without epilepsy. The information covered personal identification number, possible birth dates of children, date of first marriage, current marital status, vital status, date of emigration and date of death. Information was available up until 28 March 2001.
Study subjects contributed person-years to the analyses only during fertile ages (15–49 years). In patients with AED use, the start of follow-up was the first purchase of the AED, because all the patients were >15 years at the start of follow-up. As the follow-up time varied by type of AED and type of AED use, we defined the start of follow-up for untreated patients and reference cohort without epilepsy separately for each AED. The start of follow-up for untreated patients and reference persons was assigned as the mean starting date of the AED use among the patients with that medication in the corresponding 5-year age group.
In Finland, the prescription of reimbursed drugs is regulated in 3-month batches. Therefore, the end of medication exposure was defined as 3 months after the last purchasing date. In patients on AEDs, the closing date was the end of medication exposure, 50th birthday, emigration, death, the common closing date (28 March 2001) or the first pregnancy, whichever was earliest. Because we did not have information on the start of the first pregnancy, it was estimated by subtracting 9 months from the birth date of the first live-born child. In patients without AED use and in the reference cohort without epilepsy, the closing date was the 50th birthday, emigration, death, the common closing date (28 March 2001) or the first pregnancy, whichever was earliest.
Persons who used more than one AED during the follow-up (at subsequent periods as monotherapy or simultaneously as polytherapy) contributed person-years to each of the type of AED treatment (monotherapy/polytherapy). Persons who did not use any AEDs during the entire follow-up were used as the untreated epilepsy patient group (no medication at any time during the study period).
Separate comparisons for the first live-born child were performed between patients with AED use and reference persons without epilepsy and between epilepsy patients with AED use and epilepsy patients without any AED use during the study period. Only childless persons were included in the analyses. Analyses by type of medication were conducted pertaining to use of carbamazepine (CBZ), oxcarbazepine (OXC) and valproate (VPA). For other AEDs, the number of subjects was too small to conduct meaningful analysis. Analyses were conducted separately for monotherapies (use of CBZ, OXC or VPA with no other AEDs in use simultaneously). There were 422 patients on polytherapy including VPA + CBZ, 236 patients on polytherapy including VPA + OXC and 98 patients on CBZ + OXC polytherapy.
Data analyses were performed using Poisson regression modelling with the first live-born child as the outcome. Persons with any children before the start of the follow-up (1 January 1996) were excluded from the analyses. Statistical analyses were performed using STATA 8.2 (Stata 8.0). In the analyses, the factors considered potential confounders were age and marital status at the start of the follow-up.
The study protocol was approved by the ethical review committee of the Pirkanmaa Hospital District. Record linkages were conducted with permission from the National Centre for Research and Development in Health and Welfare and the SII of Finland.
|
Results |
|---|
|
TopAbstractBackgroundMaterials and methodsResultsDiscussionConclusionsAcknowledgementsReferences |
|---|
The number of patients on antiepileptic medication varied by type of medication (CBZ overall, n = 2689, monotherapy, n = 2365; OXC overall, n = 832, monotherapy, n = 631; VPA overall, n = 1546, monotherapy, n = 1116). Because the follow-up time for patients in each AED treatment group varied by AED and type of the therapy, the beginning of the follow-up was defined for untreated patients and the reference persons without epilepsy separately in each analysis by specific AED. Therefore, the number of untreated epilepsy patients ranged between 2714 and 2785, and the number of reference persons without epilepsy was between 13 378 and 13 689, depending on the type of AED and mode of therapy (all users/monotherapy).
The mean follow-up times varied slightly between patients with AED use, untreated patients and the reference cohort, depending on AED (CBZ: 3.39–3.86 years, monotherapy: 3.09–3.80 years; OXC: 3.05–3.60 years, monotherapy: 2.44–3.59 years; VPA: 3.20–3.68 years, monotherapy: 2.79–3.63 years) (Table I).
|
Overall, birth rate was lower among both men and women with epilepsy than in persons without epilepsy (Table II). Birth rate was decreased both among epilepsy patients on AEDs and untreated epilepsy patients in relation to the reference cohort without epilepsy in both sexes. The birth rates were lower among men than among women on CBZ and OXC (interaction CBZ overall, P = 0.02; CBZ monotherapy, P = 0.02; OXC overall, P = 0.05; OXC monotherapy, P = 0.03) in relation to reference persons without epilepsy. No interaction was found for VPA. CBZ and OXC were associated with lower birth rates than VPA in both sexes. The findings were similar in patients on monotherapy and in all users with the three most commonly used AEDs.
|
In the regression analyses, both women and men on AED had significantly lower birth rates than the reference group without epilepsy (Table III). In comparison with the untreated patients, women on any of the three AEDs had non-significantly lower birth rates. Analyses of patients on monotherapy gave similar results. Among men, birth rate was decreased in those on OXC but was not clearly lower among those on CBZ or VPA when compared with untreated patients. In men on OXC, birth rate was lower among men on monotherapy than among all males on OXC.
|
Adjustment for marital status and age at the start of the follow-up was used, because it decreased the effect of CBZ in relation to the untreated patients in both men [unadjusted rate ratio (RR) 0.70, 95% confidence interval (CI) = 0.54, 0.90; adjusted RR 0.86, 95% CI = 0.66, 1.13] and women (unadjusted RR 0.81, 95% CI = 0.65, 1.01; adjusted RR 1.01, 95% CI = 0.80, 1.27), even though it did not affect other results than CBZ.
|
Discussion |
|---|
|
TopAbstractBackgroundMaterials and methodsResultsDiscussionConclusionsAcknowledgementsReferences |
|---|
In our study, birth rate was lower in both women and men with epilepsy than in persons without epilepsy. The birth rate in both women and men treated for epilepsy was closer to the untreated patients than to the reference cohort without epilepsy. The birth rates were lower in both women and men on any of the three AEDs when compared with the reference cohort without epilepsy. However, a statistically significant difference between treated and untreated patients was seen only in men on OXC.
Few previous population-based studies on birth rate in patients with epilepsy have been published. Most of the studies have been based on small samples and lacked comparison between treated and untreated patients, as well as reference group without epilepsy (Dansky et al., 1980; Jalava and Sillanpää, 1997; Olafsson et al., 1998). Furthermore, few studies have estimated birth rate by type of AED (Webber et al., 1986; Schupf and Ottman, 1994, 1996; Olafsson et al., 1998; Wallace et al., 1998). In our register-based study, large study population and comprehensive information on live births and AED purchases enabled us to evaluate the effect of specific AEDs (CBZ, OXC and VPA) on birth rate in a representative patient cohort with epilepsy.
Some of the previous studies have suggested that birth rate is lower in men than in women with epilepsy (Webber et al., 1986; Schupf and Ottman, 1996; Artama et al., 2004). Consistent with this, birth rate was clearly decreased among men with epilepsy but less affected among female epilepsy patients in this study. The birth rates were lower in both women and men on any of the three AEDs when compared with the reference cohort. Nevertheless, a statistically significant difference between treated and untreated patients was only seen in men on OXC.
In this study, the birth rate was decreased in both treated and untreated women with epilepsy. This suggests that in women, epilepsy itself substantially contributes to the reproductive dysfunction, which is consistent with previous reports of high prevalence of reproductive endocrine disorders in women with epilepsy (Herzog et al., 1986a). On the contrary, there were no significant differences in the birth rates of women on different AEDs. This is surprising, because many studies have shown that VPA is more commonly associated with reproductive endocrine disorders characterized by anovulatory dysfunction than some other AEDs (Morrell et al., 2002; Betts et al., 2003). There are no data on the effects of OXC on reproduction in women with epilepsy, but one animal study found decreased birth rate in female monkeys treated with OXC (Lockard et al., 2000).
Previous studies have suggested that endocrine dysfunction is more common in men with epilepsy treated with AEDs than in the general population (Herzog et al., 1986b; Isojärvi et al., 1990, 1995; Rättyä et al., 2001). Sperm abnormalities have also been common among men on CBZ, OXC or VPA (Isojärvi et al., 2004). Consistent with this, birth rate was lower in men on any of these drugs than in the reference cohort in our study. However, compared with untreated men with epilepsy, birth rate was significantly reduced only among men on OXC.
The outcome in our study was the birth rate, which is a crude measure of fertility. We did not have information on semen quality or female fecundity. Similarly, information on intention to conceive and contraceptive use was not available because of register-based approach. Our findings need therefore supporting evidence from more detailed studies addressing these factors. Our patient cohort consists of patients who were eligible for reimbursement for the cost of AEDs. Information on institutionalized patients with epilepsy is not included in the SII database. These patients are probably underrepresented in our study. Also, patients who did not want the reimbursement are not included in our cohort. Few patients decline reimbursement for AEDs, because the costs of AEDs are high in Finland. Therefore, our material is likely to be highly representative of all non-institutionalized epilepsy patients in Finland.
We were able to evaluate the effect of AED usage based on the information on AED purchases. Therefore, actual drug compliance could not be evaluated in our study. Pregnant women with epilepsy may discontinue AEDs because of potential side effects (Chang and McAuley, 1998; Williams et al., 2002). We evaluated the effect of AED exposure before conception. Thus, potential non-compliance may have biased our results only if it differs between the AED groups.
In Finland, the prescription of reimbursed drugs is regulated in 3-month batches. Therefore, the end of medication exposure was defined as 3 months after the last purchasing date during the follow-up. In most of the patients on CBZ + OXC polytherapy, the overlapping period of different AED usage was very short (from few days to few weeks). Probably these patients were not in polytherapy, but their antiepileptic medication was changed from CBZ to OXC or vice versa. Similar overlapping was also found between other AEDs. This possible misclassification of AED exposure has not affected our results. We did not conduct separate analyses on polytherapy combinations, because we did not know the actual drug intake. We analysed monotherapy periods separately, because it allowed the identification of the effects of a single pharmaceutical agent.
We obtained information on all live births and used it as a measure of fertility. Yet, we were not able to assess the time of conception, because the ‘intention to conceive’ was not available. Women with epilepsy may have an increased risk for spontaneous abortions (Nakane et al., 1980; Yerby and Cawthon, 1996; Schupf and Ottman, 1997). The use of certain AEDs increases the risk for spina bifida in the offspring (Koren et al., 1998; Hernandez-Diaz et al., 2000; Matalon et al., 2002), and severe spina bifida is an indication for induced abortion (Botto et al., 1999). In a Finnish study (Kaaja et al., 2003), 0.6% of pregnancies in patients with epilepsy were terminated because of fetal congenital structural anomalies. The corresponding proportion was 0.2% in the general Finnish female population in 1999 (Gissler et al., 2000). We did not have information on spontaneous or induced abortions. Hence, we could not estimate the impact of these factors on decreased birth rate in patients with epilepsy. However, this is not likely to affect our results, because the number of terminations due to fetal congenital structural anomalies is overall small.
Maternal use of AEDs can seldom be discontinued before pregnancy because of increased risk for seizures (Sabers et al., 1998). The use of certain AEDs during pregnancy increases the risk for specific congenital malformations in the offspring (Arpino et al., 2000; Barrett and Richens, 2003; Artama et al., 2005). Furthermore, pregnancy complications are more common among women with epilepsy than in other female population (Fonager et al., 2000). In some epilepsy patients, these risks may affect the decision to have children. We could not estimate the effect of psychosocial aspects on reproduction in our patient cohort.
When antiepileptic medication is started after epilepsy diagnosis, 
60% of patients become seizure-free (Kwan and Brodie, 2000). For among 50–60% of these patients, antiepileptic medication can be discontinued successfully at some point. If there are no specific risks and the patient is compliant, antiepileptic medication is usually discontinued from 4 to 5 years after the latest seizure. Untreated epilepsy patients are a heterogeneous group including also patients who are not compliant with AED treatment.
Most patients on CBZ or OXC have partial epilepsy, whereas VPA is used mainly for generalized epilepsy. That is, patients on different AEDs or patients without AEDs may also differ in terms of epilepsy type (including aetiology, seizure characteristics and age at onset), treatment response (disease duration and seizure frequency) and comorbidity. It is unclear, if and which of these factors affect social relationships and role performance and thereby fertility in different types of epilepsy. As we did not have information on epilepsy type, we could not distinguish the effect of epilepsy and antiepileptic medication on fertility, that is, confounding by indication is possible. Therefore, our findings should be interpreted with caution.
|
Conclusions |
|---|
|
TopAbstractBackgroundMaterials and methodsResultsDiscussionConclusionsAcknowledgementsReferences |
|---|
Our results suggest that birth rate is decreased among patients with epilepsy on AEDs, more so in men. Among male patients with epilepsy, CBZ, OXC and VPA all were associated with low birth rate in relation to men without epilepsy. However, only OXC was related to reduced birth rate compared with untreated patients. Among women on any of the three AEDs (CBZ, OXC and VPA) for epilepsy, birth rate is decreased in relation to reference persons without epilepsy but not compared to untreated patients.
|
Acknowledgements |
|---|
|
TopAbstractBackgroundMaterials and methodsResultsDiscussionConclusionsAcknowledgementsReferences |
|---|
We thank Dr Ville Hiilesmaa, MD, PhD, for his reconstructive comments on earlier versions of the manuscript. The work of Miia Artama was supported by grants from the Finnish Cultural Foundation and University of Tampere.
|
References |
|---|
|
TopAbstractBackgroundMaterials and methodsResultsDiscussionConclusionsAcknowledgementsReferences |
|---|
Arpino C, Brescianini S, Robert E, Castilla EE, Cocchi G, Cornel MC, de Vigan C, Lancaster PA, Merlob P, Sumiyoshi Y, et al. (2000) Teratogenic effects of antiepileptic drugs: use of an International Database on Malformations and Drug Exposure (MADRE). Epilepsia 11:1436–1443.
Artama M, Isojärvi J, Raitanen J, Auvinen A. (2004) Birth rate among patients with epilepsy: a nationwide population-based cohort study in Finland. Am J Epidemiol 159:1057–1063.
Artama M, Auvinen A, Raudaskoski T, Isojärvi I, Isojärvi J. (2005) Antiepileptic drug use of women with epilepsy and congenital malformations in offspring. Neurology 64:1874–1878.
Barrett C and Richens A. (2003) Epilepsy and pregnancy: report of an Epilepsy Research Foundation Workshop. Epilepsy Res 52:147–187.[CrossRef][Medline]
Betts T, Yarrow H, Dutton N, Greenhill L, Rolfe T. (2003) A study of anticonvulsant medication on ovarian function in a group of women with epilepsy who have only ever taken one anticonvulsant compared with a group of women without epilepsy. Seizure 12:323–329.[CrossRef][ISI][Medline]
Botto LD, Moore CA, Khoury MJ, Erickson JD. (1999) Neural-tube defects. N Engl J Med 341:1509–1519.
Chang S-I and McAuley JW. (1998) Pharmacotherapeutic issues for women of childbearing age with epilepsy. Ann Pharmacother 32:794–801.[Abstract]
Dansky LV, Andermann E, Andermann F. (1980) Marriage and fertility in epileptic patients. Epilepsia 21:261–271.[ISI][Medline]
Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, Engel J Jr. (2005) Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 46:470–472.[CrossRef][ISI][Medline]
Fonager K, Larsen H, Pedersen L, Sørensen HT. (2000) Birth outcomes in women exposed to anticonvulsant drugs. Acta Neurol Scand 101:289–294.[CrossRef][ISI][Medline]
Gissler M, Rasimus A, Ritvanen A. (2000) Births, abortions, sterilisations and congenital anomalies 1999 – data supplier feedback 14/2000. (National Research and Development Centre for Welfare and Health, Helsinki) (http://www.stakes.info/2/1/2,1,2.asp) (accessed 15 November 2005).
Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. (2000) Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 343:1608–1614.
Herzog AG, Seibel MM, Schomer DL, Vaitukaitis JL, Geschwind N. (1986a) Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch Neurol 43:341–346.[Abstract]
Herzog AG, Seibel MM, Schomer DL, Vaitukaitis JL, Geschwind N. (1986b) Reproductive endocrine disorders in men with partial seizures of temporal lobe origin. Arch Neurol 43:347–350.[Abstract]
Isojärvi JIT, Pakarinen AJ, Ylipalosaari PJ, Myllylä VV. (1990) Serum hormones in male epileptic patients receiving anticonvulsant medication. Arch Neurol 47:670–676.[Abstract]
Isojärvi JIT, Laatikainen TJ, Pakarinen AJ, Juntunen KTS, Myllylä VV. (1993) Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 329:1383–1388.
Isojärvi JIT, Repo M, Pakarinen AJ, Lukkarinen O, Myllylä VV. (1995) Carbamazepine, phenytoin, sex hormones, and sexual function in men with epilepsy. Epilepsia 36:366–370.[CrossRef][Medline]
Isojärvi JIT, Löfgren E, Juntunen KST, Pakarinen AJ, Päivänsalo M, Rautakorpi I, Tuomivaara L. (2004) Effect of epilepsy and antiepileptic drugs on male reproductive health. Neurology 62:247–253.
Isojärvi JIT, Taubøll E, Herzog AG. (2005) Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy. CNS Drugs 19:207–223.[CrossRef][ISI][Medline]
Jalava M and Sillanpää M. (1997) Reproductive activity and offspring health of young adults with childhood-onset epilepsy: a controlled study. Epilepsia 38:532–540.[CrossRef][ISI][Medline]
Kaaja E, Kaaja R, Hiilesmaa V. (2003) Major malformations in offspring of women with epilepsy. Neurology 60:575–579.
Koren G, Pastuszak A, Ito S. (1998) Drugs in pregnancy. N Engl J Med 338:1128–1137.
Kwan P and Brodie MJ. (2000) Early identification of refractory epilepsy. New Engl J Med 342:314–319.
Lockard JS, Burkhead-Potter TM, Phillips NK, Congdon WC. (2000) Is oxcarbazepine (OCBZ) a contraceptive? Pregnancy rate compared to carbamazepine (CBZ), synthetic CBZ 10-11 epoxide (CBZE), and placebo in monkey. Epilepsia 41:(Suppl 7), 97–S–98S.
Matalon S, Schechtman S, Goldweig G, Ornoy A. (2002) The teratogenic effect of carbamazepine: a meta-analysis of 1255 exposures. Reprod Toxicol 16:9–17.[CrossRef][ISI][Medline]
Mikkonen K, Vainionpää LK, Pakarinen AJ, Järvelä IY, Tapanainen JS, Isojärvi JI. (2004) Long-term reproductive endocrine health in young women with epilepsy during puberty. Neurology 62:445–450.
Morrell MJ, Giudice L, Flynn KL, Cairn GS, Paulson AJ, Doñe S, Flaster E, Ferin M, Sauer MV. (2002) Predictors of ovulatory failure in women with epilepsy. Ann Neurol 52:704–711.[CrossRef][ISI][Medline]
Nakane Y, Okuma T, Takahashi R, Sato Y, Wada T, Sato T, Fukushima Y, Kumashiro H, Ono T, Takahashi T, et al. (1980) Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs: a report of a collaborative study group in Japan. Epilepsia 21:663–680.[ISI][Medline]
Olafsson E, Hauser WA, Gudmundsson G. (1998) Fertility in patients with epilepsy. Neurology 51:71–73.
Rättyä J, Turkka J, Pakarinen AJ, Knip M, Kotila MA, Lukkarinen O, Myllylä VV, Isojärvi JIT. (2001) Reproductive effects of valproate, carbamazepine and oxcarbazepine in men with epilepsy. Neurology 56:31–36.
Røste LS, Taubøll E, Haugen TB, Bjørnenak T, Sætre ER, Gjerstad L. (2003) Alterations in semen parameters in men with epilepsy treated with valproate or carbamazepine monotherapy. Eur J Neurol 10:501–506.[CrossRef][ISI][Medline]
Sabers A, Rogvi-Hansen B, Dam M, Fisher-Rasmussen W, Gram L, Hansen M, Moller A, Winkel H. (1998) Pregnancy and epilepsy: a retrospective study of 151 pregnancies. Acta Neurol Scand 97:164–170.[ISI][Medline]
Schupf N and Ottman R. (1994) Likelihood of pregnancy in individuals with idiopathic/cryptogenic epilepsy: social and biological influences. Epilepsia 35:750–756.[CrossRef][ISI][Medline]
Schupf N and Ottman R. (1996) Reproduction among individuals with idiopathic/cryptogenic epilepsy: risk factors for reduced fertility in marriage. Epilepsia 37:833–840.[CrossRef][ISI][Medline]
Schupf N and Ottman R. (1997) Reproduction among individuals with idiopathic/cryptogenic epilepsy: risk factors for spontaneous abortion. Epilepsia 38:824–829.[CrossRef][ISI][Medline]
Stata 8.0. Stata Corporation, College Station, TX 77845, USA.
Wallace H, Shorvon S, Tallis R. (1998) Age-specific incidence and prevalence rates of treated epilepsy in an unselected population of 2 052 922 and age specific fertility rates of women with epilepsy. Lancet 352:1970–1973.[CrossRef][ISI][Medline]
Webber MP, Hauser WA, Ottman R, Annegers JF. (1986) Fertility in persons with epilepsy: 1935–1974. Epilepsia 27:746–752.[ISI][Medline]
Williams J, Myson V, Steward S, Jones G, Wilson JF, Kerr MP, Smith PEM. (2002) Self-discontinuation of antiepileptic medication in pregnancy: detection by hair analysis. Epilepsia 43:824–831.[CrossRef][ISI][Medline]
Yerby M and Cawthon M. (1996) Fetal death, malformations and infant mortality in infants of mothers with epilepsy. Epilepsia 37:Suppl 5, 98 Abstract.[ISI][Medline]
Submitted on November 16, 2005; resubmitted on February 13, 2006; resubmitted on April 27, 2006; accepted on May 5, 2006.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. A. Krusche, A. J. Vloet, I. Classen-Linke, U. von Rango, H. M. Beier, and J. Alfer Class I histone deacetylase expression in the human cyclic endometrium and endometrial adenocarcinomas Hum. Reprod., November 1, 2007; 22(11): 2956 - 2966. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||