Recent estimates of the U.S. population (United States Department of Health and Human Services, 2007) and the prevalence of epilepsy (Hirtz et al., 2007) indicate that approximately one-half million women with epilepsy (WWE) are of childbearing age. It has also been estimated that 3–5 births per thousand will be to WWE (Yerby, 2000). Epilepsy is defined by the presence of recurrent, unprovoked seizures, and the treatment is typically a daily, long-term antiepileptic drug (AED) regimen. The majority of people with epilepsy have well-controlled seizures, are otherwise healthy, and, therefore, expect to participate fully in life experiences, including child-bearing.
This parameter and the two companion parameters are updates of the previous practice parameter from 1998 (American Academy of Neurology, 1998). They employ improved methodology for the development of practice parameters to analyze a large number of new studies informing the clinical management of WWE who are pregnant or plan pregnancy.
This parameter summarizes evidence for two broad clinical questions:
Compared to women without epilepsy, are WWE at increased risk for pregnancy-related complications, including (1) cesarean delivery; (2) preeclampsia; (3) pregnancy-induced hypertension; (4) premature contractions or premature labor and delivery; (5) bleeding complications; and (6) spontaneous abortion?
For WWE who become pregnant, what is the risk of epilepsy-related complications during pregnancy, including (1) change in seizure frequency, (2) risk of status epilepticus, and (3) chance of recurrent seizures if WWE are seizure-free for 9 months prior to pregnancy?
Description of the Analytic Process
The American Academy of Neurology (AAN) assembled a panel of experts including epileptologists, general neurologists, and doctors in pharmacy with expertise in AEDs. Panel members with expertise in obstetrics, obstetrical nursing, and teratology were also included. This effort was supported by a grant from the Milken Family Foundation.
Literature review and article selection
A literature search was performed using MEDLINE, MEDLINE-In-Process, Current Contents, Biological Abstracts, and BIOSIS previews for relevant articles published between 1985 and December 2005. An updated search was performed from December 2005 through June 2007, with manual searches on some topics through February 2008. The arbitrary cutoff date of 1985 was chosen because these relatively recent articles were thought to reflect current practice and AED usage patterns and, therefore, be more applicable and reliable for this assessment than earlier reports. The search terms used were seizures/epilepsy, catamenial epilepsy, pregnancy, anticonvulsants, antiepileptic drugs, teratogenesis, birth defects, pregnancy registry, cognitive outcome, vitamin K, folate/folic acid, breastfeeding, oral contraceptives, polycystic ovary syndrome, hormone replacement therapy, menopause, perimenopause, and fertility. The search was confined to articles using human subjects and included all languages for which there was an abstract in English. A secondary search for missed references was done by reviewing the bibliographies of review articles and meta-analyses identified in the primary search.
The literature search yielded a total of 876 abstracts. To find relevant articles, two panel members screened each of the abstracts. If either panel member thought the article was potentially relevant, the full text was obtained for review. In general, abstracts were excluded from further analysis if they related to eclampsia rather than seizures due to epilepsy, related to basic mechanisms such as teratogenesis or placental AED metabolism, or were unrelated to the questions posed by the panel.
From the abstracts, a total of 285 were selected for complete review. Four panel members reviewed the full text of the articles and identified those that were relevant to each clinical question. Articles were included in the analysis of this paper if they determined the frequency of pregnancy-related or epilepsy-related complications in a cohort of pregnant WWE. Articles relevant to the clinical questions of the companion articles were included in the appropriate article and are described there.
Study classification and measures of effect
With the exception of the question pertaining to recurrent seizures in seizure-free WWE, articles were classified according to the AAN prognostic classification of evidence scheme (see Appendix S4a). Articles regarding recurrent seizures in seizure-free WWE were classified according to the AAN screening classification-of-evidence scheme (see Appendix S4b). This scheme was chosen because the absolute risk of seizure recurrence, rather than the relative risk, was deemed most clinically relevant to this question. Articles were classified separately by four panel members. Disagreements on categorization of the articles were resolved by discussion and consensus.
For pregnancy-related complications, studies were given a lower class of evidence when they did not compare complication frequencies in pregnant WWE to pregnant women without epilepsy. For epilepsy-related complications, studies were given a lower class of evidence when they did not compare complication frequencies in pregnant WWE to nonpregnant WWE.
In addition, studies were downgraded for a lack of masked outcome assessment or if they provided insufficient information to determine relative risk (RR) or odds ratios (ORs). The requirement for masked outcome assessment was waived for obviously objective outcomes such as cesarean delivery, preeclampsia, pregnancy-induced hypertension, spontaneous abortion, and status epilepticus. Meta-analyses were not performed due to heterogeneity of the studies.
When possible, the associations between epilepsy and pregnancy-related complications or pregnancy and epilepsy-related complications were determined using ORs. If not reported in the article, the writing panel attempted to calculate the appropriate ORs. For the only Class I article (Viinikainen et al., 2006), the authors were personally contacted to provide further detail on data reported in the article. To allow calculation of the OR when one of the cells of the two-by-two table was zero, 0.5 was added to each cell (Yusuf et al., 1985).
For the purposes of this parameter, a “moderately” increased risk is defined by an OR of >1.5 and <2.0 and a “substantially” increased risk by an OR of 2.0 or greater.
The 95% confidence intervals (CIs) of the ORs were used as the measure of precision. Negative studies were judged to be sufficiently sensitive to exclude an increased risk based on the upper limit of the 95% CIs. Therefore, a study failing to show a significant increased risk of a complication based on an OR of 1.2 with 95% CIs of 0.6–1.7 would be judged to be too insensitive to exclude a moderately increased risk of the complication. The strength of the practice recommendations was linked directly to the class of evidence using the scheme described in Appendix S5.
The Milken Family Foundation contributed support for this project. The authors thank Laura Moses for assistance in the preparation of this manuscript. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Disclosure: The authors report the following conflicts of interest:
Dr. Harden has served on the scientific advisory board of Cyberonics, GlaxoSmithKline, UCB Pharma, Valeant, and SK Pharmaceuticals and on the speakers’ bureau of GlaxoSmithKline, Pfizer, UCB Pharma, and Abbott. She serves as an editor of Epilepsy Currents and receives publishing royalties from Elsevier. Dr. Harden has received research funding from Forest, UCB Pharma, Ortho McNeil, and NIH/NINDS. Dr. Harden sees women with epilepsy in her office practice.
Dr. Hopp receives royalties from UpToDate.com electronic medical journal. She has been on the speakers’ bureau of UCB Pharma and GlaxoSmithKline. Dr. Hopp has given testimony in a medico-legal case.
Dr. Ting served on the scientific advisory board of UCB Pharma and has received honoraria from the Epilepsy Foundation of America.
Dr. Pennell has served on the Expert Panel for the Keppra Pregnancy Registry sponsored by UCB Pharma. She has received funding for travel from the Northeast Regional Epilepsy Group for speaking at their 2008 Epilepsy Symposium, by the UK Research Council for speaking at the Epilepsy Research UK International Expert Workshop, by UCB Pharma for attending the Executive Panel meeting for the Pregnancy Registry, by the American Epilepsy Society for attending the Board of Directors’ Meeting, by the Epilepsy Foundation for attending the Board of Directors’ and orientation meetings, by the Long Island Jewish Hospital for lecturing at Neurology Grand Rounds, by Duke University for lecturing at Neurology Grand Rounds, by Brigham and Women’s Hospital for lecturing at the Epilepsy Research Conference, by the Milken foundation for attending Pregnancy Registry meetings, and by Massachusetts General Hospital for speaking at the Annual Teratogens Course. She has received honoraria from Journal Watch Neurology for a contributing article, paid for by Massachusetts Medical Society, NEJM, for review for the Lancet Neurology, the Northeast Regional Epilepsy group for speaking at 2008 Epilepsy Symposium, North Shore Long Island Jewish Health system, Duke University, University of Maryland, the Massachusetts General Hospital for speaking at the postgraduate course in Human Teratogens, and the AAN for speaking and directing annual courses. Dr. Pennell has served as a contributing editor for Epilepsy Currents and is on the editorial board of Epilepsia. Dr. Pennell has received research support from UCB Pharma, Marinus Pharmaceuticals, NIH, HINDS, NIMH, CDC, and Emory University Research Council.
Dr. French has served on the scientific advisory board of UCB Pharma, Johnson and Johnson, Eisai, Novartis, Valeant, Icagen, Intranasal, Sepracor, and Marinus. She has received funding for travel to present findings or give lectures from UCB Pharma, Kyowa, Eisai, Johnson and Johnson, Valeant, and GlaxoSmithKline. She has served as an associate editor for Epilepsy Currents and supplement editor for Epileptic Disorders. Dr. French is the president of the Epilepsy Study Consortium, which receives money from multiple pharmaceutical companies (including GlaxoSmithKline, UCB Pharma, Johnson and Johnson, Cyberonics, Schwarz Pharma, Ortho McNeil, Eisai, Jazz Pharmaceuticals, Ovation Pharmaceuticals, Endo Pharmaceuticals, Bial Pharmaceuticals, Neurovista, Valeant Pharmaceuticals, Icagen, Supernus, Intranasal, SK Pharmaceuticals, Taro Pharmaceuticals, Neurotherapeutics, Sepracor, and Novartis) and she consults on behalf of the consortium. Dr. French has received research funding from Johnson and Johnson, Eisai, UCB Pharma, SK Pharmaceuticals, Valeant, Pfizer, NIH, and Epilepsy Research Foundation.
Dr. Hauser has served on the scientific advisory board of Ovation and Valeant. He has served on the editorial board of Acta Neurologica Scandinavia, Neuroepidemiology, and Epilepsy Research. He has received honoraria from Cornell University Symposium on epilepsy and acted as a consultant to Pfizer. Dr. Hauser has received research support from AAMC/CDC, NIH/NINDS, FAA, Mayo Clinic, Hotchkiss Neurological Institute, and has given expert testimony in his role as an FAA consultant.
Dr. Wiebe serves on the editorial board of Neurology, Epilepsia, Epilepsy and Behavior, and Canadian Journal of Neurological Sciences.
Dr. Gronseth serves as an editor of Neurology Now and on the speakers’ bureau of Boehringer-Ingelheim. He receives compensation from the AAN for consulting work.
Dr. Thurman is an employee of the CDC.
Dr. Meador serves as a journal editor for Neurology, Journal of Clinical Neurophysiology, Cognitive and Behavioral Neurology, Epilepsy and Behavior, Epilepsy Currents, and Epilepsy.com. He has received research funding from NIH/NINDS, GlaxoSmithKline, Eisai, Marius, Myriad, Neuropace, SAM Technology, and UCB Pharma. Dr. Meador estimates that 30-40% of his clinical effort is spent on EEGs and the clinical care of patients with epilepsy.
Dr. Koppel reports no disclosures.
Dr. Kaplan has served on the speakers’ bureau of UCB Pharma, GSK, and Ortho McNeil. He serves as an associate editor for Neurophysiologie Clinique, Journal of Clinical Neurophysiology, and Epilepsia. He received royalties from Demos Publications for the books Neurological Disease in Women, Epilepsy A to Z, Imitators of Epilepsy, and Nonconvulsive Status Epilepticus. He has received speaker honoraria from Medical College of South Carolina, Duke University, and Medical College of Virginia, has received research funding from NIH, Schwarz, Ortho McNeil, and Pfizer, and has acted as a consultant for Schering-Plough and Infinite Biological Technologies.
Dr. Robinson reports no disclosures.
Dr. Gidal has served on the scientific advisory board for GlaxoSmithKline, UCB Pharma, and Abbott Labs and served as an editor for Epilepsy & Behaviour, Ann Pharmacotherapy, and Pharmacists letter. Dr. Gidal has received research support from UCB Pharma.
Dr. Hovinga estimates less than 10% of his clinical effort is spent on pharmacology consults.
Dr. Wilner has served on the scientific advisory board of and received funding for travel from GlaxoSmithKline. He receives royalties from Demos Publications for Epilepsy: 199 Answers and Epilepsy in Clinical Practice. He receives board of directors compensation from GlaxoSmithKline.
Dr. Vazquez has served on the scientific advisory board of Eisai, UCB, GSK, and Ortho McNeil. She has received honoraria from UCB, GSK, Ortho McNeil, and Eisai. Dr. Vazquez has served on a speakers’ bureau for Eisai, GSK, Ortho McNeil, UCB, and Novartis.
Dr. Holmes has received research funding from Abbott Labs, GlaxoSmithKline, Eisai, Novartis, Ortho McNeil, and Pfizer.
Dr. Krumholz has served on the Department of Transportation Expert Panel on Commercial Drivers and Epilepsy and has served on the editorial board of The Neurologist and Clinical EEG and Neuroscience. He has received honoraria from the Robert Wood Johnson Medical School for grand rounds.
Dr. Finnell has served on the scientific advisory board of the NEAD study at Emory University, the University of Houston Center for Life Sciences Technology, the NIH, and the NIEHS National Advisory Environmental Health Sciences Council. He has received funding for travel from Fundacion BBVA, NIEHS National Advisory Environmental Health Sciences Council, IKMC Steering Committee, European Epilepsy Meeting, NIH, and AES. Dr. Finnell has served as a journal editor for Birth Defects Research Part A and holds a patent on folate receptor autoantibody assay. He has received honoraria from McGill University-Montreal Neurological Institute and has received research funding from the Centers for Disease Control and Prevention for the National Birth Defects Prevention Study and the Methodist Hospital Research Institute. Dr. Finnell has given expert testimony, prepared affadavits, and acted as a witness regarding legal proceedings related to the topic of this manuscript.
Ms. Le Guen reports no disclosures.