RESEARCH
Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth: population based cohort study Bodil Hammer Bech,1 Maiken Ina Siegismund Kjaersgaard,2 Henrik Søndergaard Pedersen,3 Penelope P Howards,4 Merete Juul Sørensen,5 Jørn Olsen,1 Erik Thorlund Parner,2 Lars Henning Pedersen,1 6 Mogens Vestergaard,3 Jakob Christensen7 8 ЖЖEDITORIAL by Cragan 1
Section for Epidemiology, Department of Public Health, Aarhus University, DK 8000 Aarhus C, Denmark 2 Section for Biostatistics, Department of Public Health, Aarhus University, Aarhus, Denmark 3 Research Unit for General Practice and Section for General Medical Practice, Department of Public Health, Aarhus University, Aarhus, Denmark 4 Department of Epidemiology, Rollins School of Public Health, Atlanta, GA, USA 5 Regional Center of Child and Adolescent Psychiatry, Aarhus University Hospital, Risskov, Denmark 6 Department of Clinical Medicine– Obstetrics and Gynaecology, Aarhus University, Aarhus, Denmark 7 Department of Neurology, Aarhus University Hospital, Aarhus, Denmark 8 Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark Correspondence to: B H Bech [email protected] Cite this as: BMJ 2014;349:g5159 doi: 10.1136/bmj.g5159
This is a summary of a paper that was published on thebmj.com as BMJ 2014;349:g5159
thebmj.com ̻̻Clinical Review: Drug treatment of epilepsy in adults (BMJ 2014;348:g254) ̻̻Editorial: Sharper focus on uncomplicated pregnancy (BMJ 2013;347:f6470) ̻̻Letter: We must warn women about the risks of untreated, or ineffectively treated, epilepsy (BMJ 2012;344:e1430) ̻̻Editorial: Carbamazepine in pregnancy (BMJ 2010;341:c6582)
STUDY QUESTION Does the use of antiepileptic drugs during pregnancy increase the risk of spontaneous abortion and stillbirth? SUMMARY ANSWER Among women with epilepsy no overall association was found between the use of antiepileptics during pregnancy and risk of spontaneous abortion. Among women without epilepsy, however, an increased risk of spontaneous abortion could not be excluded after prenatal use of antiepileptics. We could not identify an association between antiepileptic drug use and stillbirth, but the numbers analysed were small. WHAT IS KNOWN AND WHAT THIS PAPER ADDS Little is known about the association between antiepileptic use during pregnancy and risk of spontaneous abortion and still birth. Our results suggest that women who are treated for epilepsy with antiepileptics during pregnancy may not be at increased risk of spontaneous abortion.
Participants and setting We included pregnancies identified in the Danish health registries, 1997-2008. Design, size, and duration The 983 305 pregnancies in this population based cohort were individually linked with the Danish Register of Medicinal Product Statistics for information on filled prescriptions for antiepileptics during pregnancy. Information on pregnancy outcome and diagnosis of epilepsy was obtained from health registries covering the entire population. We used binomial regression to estimate the risk ratio of spontaneous abortion and stillbirth in women who filled a prescription for antiepileptic drugs during pregnancy compared with pregnant women who did not. Main results and the role of chance Out of 983 305 pregnancies, 109 800 resulted in a spontaneous abortion (11%), 3222 in stillbirths (0.3%),
Association between antiepileptic drug use during pregnancy and spontaneous abortion stratified on epilepsy diagnosis in mother Antiepileptic use by epilepsy diagnosis
Ever diagnosis: Antiepileptics No antiepileptics Never diagnosis: Antiepileptics No antiepileptics
No of pregnancies
No of spontaneous abortions
Adjusted risk ratio* (95% CI)
2615 6645
372 978
0.98 (0.87 to 1.09) 1 (reference)
817 812 862
177 108 273
1.30 (1.14 to 1.49) 1 (reference)
*Adjusted for maternal age, cohabitation, income, education, history of severe mental disorder, and history of drug misuse.
12
and 175 694 in induced abortions (18%). We identified 4700 (0.5%) pregnancies exposed to antiepileptics. The risk of spontaneous abortion in pregnant women using antiepileptics was 16% and in pregnant women not using antiepileptics was 13%. The overall adjusted risk ratio for spontaneous abortion for women who used antiepileptics was 1.13 (95% confidence interval 1.04 to 1.24). In mothers with a diagnosis of epilepsy, we found no association between antiepileptic drug use and spontaneous abortion. In an analysis of multiple pregnancies in the same woman, we compared exposed pregnancies with unexposed pregnancies within the same woman and found no increased risk associated with use of antiepileptics (adjusted hazard ratio 0.83, 0.69 to 1.00). The unadjusted risk ratio for stillbirth was 1.29 (0.80 to 2.10). The most commonly used antiepileptics were lamotrigine (34%), valproate (13%), carbamazepine (12%), clonazepam (11%), and oxcarbazepine (11%). None of these drugs was associated with an increased risk of spontaneous abortion in women with epilepsy.
Bias, confounding, and other reasons for caution The study included all clinically recognised pregnancies in Denmark during a 12 year study period, with almost complete follow-up, thus selection bias is unlikely. Information on drug use was based on prescriptions filled for antiepileptics, and non-compliance to drug use in the exposed group could potentially attenuate the association. The analyses were adjusted for maternal age, cohabitation, income, education, and history of severe mental disorder and drug misuse. We found no association with spontaneous abortion when restricting the analyses to women with an epilepsy diagnosis, suggesting that the overall association could be explained by confounding by indication. The higher risk found among women without a diagnosis of epilepsy may be related to the underlying disorder itself or to another risk profile in these women, which we were not able to adjust for in the analyses. The study included only 18 exposed stillbirths, which were too few to do adjusted analyses. Generalisability to other populations Lamotrigine, valproate, and carbamazepine are commonly used worldwide by women with epilepsy of childbearing potential. Thus we believe that the results are generalisable globally. Study funding/potential competing interests JC received honorariums for giving lectures and serving on the scientific advisory board of UCB Nordic and Eisai, and received funding for a trip from UCB Nordic. 13 September 2014 | the bmj
Copyright of BMJ: British Medical Journal is the property of BMJ Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth: population based cohort study Bodil Hammer Bech,1 Maiken Ina Siegismund Kjaersgaard,2 Henrik Søndergaard Pedersen,3 Penelope P Howards,4 Merete Juul Sørensen,5 Jørn Olsen,1 Erik Thorlund Parner,2 Lars Henning Pedersen,1 6 Mogens Vestergaard,3 Jakob Christensen7 8 ЖЖEDITORIAL by Cragan 1
Section for Epidemiology, Department of Public Health, Aarhus University, DK 8000 Aarhus C, Denmark 2 Section for Biostatistics, Department of Public Health, Aarhus University, Aarhus, Denmark 3 Research Unit for General Practice and Section for General Medical Practice, Department of Public Health, Aarhus University, Aarhus, Denmark 4 Department of Epidemiology, Rollins School of Public Health, Atlanta, GA, USA 5 Regional Center of Child and Adolescent Psychiatry, Aarhus University Hospital, Risskov, Denmark 6 Department of Clinical Medicine– Obstetrics and Gynaecology, Aarhus University, Aarhus, Denmark 7 Department of Neurology, Aarhus University Hospital, Aarhus, Denmark 8 Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark Correspondence to: B H Bech [email protected] Cite this as: BMJ 2014;349:g5159 doi: 10.1136/bmj.g5159
This is a summary of a paper that was published on thebmj.com as BMJ 2014;349:g5159
thebmj.com ̻̻Clinical Review: Drug treatment of epilepsy in adults (BMJ 2014;348:g254) ̻̻Editorial: Sharper focus on uncomplicated pregnancy (BMJ 2013;347:f6470) ̻̻Letter: We must warn women about the risks of untreated, or ineffectively treated, epilepsy (BMJ 2012;344:e1430) ̻̻Editorial: Carbamazepine in pregnancy (BMJ 2010;341:c6582)
STUDY QUESTION Does the use of antiepileptic drugs during pregnancy increase the risk of spontaneous abortion and stillbirth? SUMMARY ANSWER Among women with epilepsy no overall association was found between the use of antiepileptics during pregnancy and risk of spontaneous abortion. Among women without epilepsy, however, an increased risk of spontaneous abortion could not be excluded after prenatal use of antiepileptics. We could not identify an association between antiepileptic drug use and stillbirth, but the numbers analysed were small. WHAT IS KNOWN AND WHAT THIS PAPER ADDS Little is known about the association between antiepileptic use during pregnancy and risk of spontaneous abortion and still birth. Our results suggest that women who are treated for epilepsy with antiepileptics during pregnancy may not be at increased risk of spontaneous abortion.
Participants and setting We included pregnancies identified in the Danish health registries, 1997-2008. Design, size, and duration The 983 305 pregnancies in this population based cohort were individually linked with the Danish Register of Medicinal Product Statistics for information on filled prescriptions for antiepileptics during pregnancy. Information on pregnancy outcome and diagnosis of epilepsy was obtained from health registries covering the entire population. We used binomial regression to estimate the risk ratio of spontaneous abortion and stillbirth in women who filled a prescription for antiepileptic drugs during pregnancy compared with pregnant women who did not. Main results and the role of chance Out of 983 305 pregnancies, 109 800 resulted in a spontaneous abortion (11%), 3222 in stillbirths (0.3%),
Association between antiepileptic drug use during pregnancy and spontaneous abortion stratified on epilepsy diagnosis in mother Antiepileptic use by epilepsy diagnosis
Ever diagnosis: Antiepileptics No antiepileptics Never diagnosis: Antiepileptics No antiepileptics
No of pregnancies
No of spontaneous abortions
Adjusted risk ratio* (95% CI)
2615 6645
372 978
0.98 (0.87 to 1.09) 1 (reference)
817 812 862
177 108 273
1.30 (1.14 to 1.49) 1 (reference)
*Adjusted for maternal age, cohabitation, income, education, history of severe mental disorder, and history of drug misuse.
12
and 175 694 in induced abortions (18%). We identified 4700 (0.5%) pregnancies exposed to antiepileptics. The risk of spontaneous abortion in pregnant women using antiepileptics was 16% and in pregnant women not using antiepileptics was 13%. The overall adjusted risk ratio for spontaneous abortion for women who used antiepileptics was 1.13 (95% confidence interval 1.04 to 1.24). In mothers with a diagnosis of epilepsy, we found no association between antiepileptic drug use and spontaneous abortion. In an analysis of multiple pregnancies in the same woman, we compared exposed pregnancies with unexposed pregnancies within the same woman and found no increased risk associated with use of antiepileptics (adjusted hazard ratio 0.83, 0.69 to 1.00). The unadjusted risk ratio for stillbirth was 1.29 (0.80 to 2.10). The most commonly used antiepileptics were lamotrigine (34%), valproate (13%), carbamazepine (12%), clonazepam (11%), and oxcarbazepine (11%). None of these drugs was associated with an increased risk of spontaneous abortion in women with epilepsy.
Bias, confounding, and other reasons for caution The study included all clinically recognised pregnancies in Denmark during a 12 year study period, with almost complete follow-up, thus selection bias is unlikely. Information on drug use was based on prescriptions filled for antiepileptics, and non-compliance to drug use in the exposed group could potentially attenuate the association. The analyses were adjusted for maternal age, cohabitation, income, education, and history of severe mental disorder and drug misuse. We found no association with spontaneous abortion when restricting the analyses to women with an epilepsy diagnosis, suggesting that the overall association could be explained by confounding by indication. The higher risk found among women without a diagnosis of epilepsy may be related to the underlying disorder itself or to another risk profile in these women, which we were not able to adjust for in the analyses. The study included only 18 exposed stillbirths, which were too few to do adjusted analyses. Generalisability to other populations Lamotrigine, valproate, and carbamazepine are commonly used worldwide by women with epilepsy of childbearing potential. Thus we believe that the results are generalisable globally. Study funding/potential competing interests JC received honorariums for giving lectures and serving on the scientific advisory board of UCB Nordic and Eisai, and received funding for a trip from UCB Nordic. 13 September 2014 | the bmj
Copyright of BMJ: British Medical Journal is the property of BMJ Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
