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Practice parameter update: management issues for women with epilepsy - focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes. Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society |
Harden CL, Meador KJ, Pennell PB, Hauser WA, Gronseth GS, French JA, Wiebe S, Thurman D, Koppel BS, Kaplan PW, Robinson JN, Hopp J, Ting TY, Gidal B, Hovinga CA, Wilner AN, Vazquez B, Holmes L, Krumholz A, Finnell R, Hirtz D, Le Guen C |
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CRD summary This review concluded that valproate and anti-epileptic drug polytherapy during pregnancy first trimester should be avoided to decrease the risk of congenital malformations, and throughout pregnancy to prevent reduced cognitive outcomes; pregnancy risk stratification should incorporate risks in children of women with epilepsy taking anti-epileptic drugs. Limitations in reporting make it difficult to establish the reliability of these conclusions. Authors' objectives To assess the evidence for management issues related to the care of women with epilepsy during pregnancy. Searching Search details were reported in a related paper (see Other Publications of Related Interest), which stated that MEDLINE, Current Contents and BIOSIS Previews databases were searched from December 1985 to June 2007 for relevant studies, published in any language with an English abstract. Hand searches were conducted up to February 2008. Bibliographies of reviews and meta-analyses were also examined for relevant publications. Study selection Studies that reported the risk of neonatal death, low birthweight, low Apgar scores (neonate health assessment method) and adverse long-term outcomes in children born to women with epilepsy were included in the review. Also, studies specifically evaluating the risk of major congenital malformations associated with intrauterine exposure to anti-epileptic drugs in neonates born to women with epilepsy were included. To evaluate the specific risk of major congenital malformations due to anti-epileptic drugs in the first trimester, only studies in which women with epilepsy not taking anti-epileptic drugs served as comparators were included in the review. Studies including women who were taking anti-epileptic drugs for other reasons were eligible for other review questions.
Selected studies included prospective and retrospective cohort studies, case-control studies, prospective observational and controlled studies. Specific anti-epileptic drugs evaluated included valproate, carbamazepine, lamotrigine and phenytoin.
At least two reviewers were involved in the selection of studies for inclusion (the analytical process was reported in a related paper; see Other Publications of Related Interest). Assessment of study quality Included studies were classified (from class I to IV) according to pre-specified criteria including: study design; representativeness of study sample; definition of risk factors; methods used to minimise confounding and bias; and reporting of measures of effect.
Four reviewers independently classified the studies with disagreements resolved by discussion and consensus (the analytical process was reported in a related paper; see Other Publications of Related Interest). Data extraction Absolute risks, relative risks (RRs), and odds ratios (ORs) with related 95% confidence intervals (95% CIs) were extracted from the included studies. If not reported, these values were calculated where possible (the analytical process was reported in a related paper; see Other Publications of Related Interest). The reviewers contacted the authors of one study to obtain additional data.
The authors did not state how many reviewers performed the extraction. Methods of synthesis The studies were combined in a narrative synthesis, grouped by outcome. Only studies rated class III or higher appear to have been included in the synthesis. Results of the review Fifty-two articles (n=unclear) were identified by the literature search, of which 35 class I to class III studies were presented in data extraction tables (in supplementary online appendices).
Intrauterine first-trimester valproate exposure was associated with a higher risk of major congenital malformations compared with carbamazepine (two class I studies) and possibly compared to phenytoin (one class II study) or lamotrigine (two class III studies).
Valproate was associated to the development of major congenital malformations as part of polytherapy (one class I study) and as monotherapy (one class II study).
Anti-epileptic drug polytherapy was associated with the development of major congenital malformations and reduced cognitive outcomes relative to monotherapy regimens (one class I study).
Reduced cognitive outcomes were associated with intrauterine exposure to valproate monotherapy (two Class II studies) and to some extent with exposure to phenytoin (one class I and two class II studies) or phenobarbital monotherapy (two class III studies).
Neonates of women with epilepsy showed an increased risk of being small for gestational age (two class II studies) and an increased risk of a one-minute Agar score of less than 7 (one class II study). Authors' conclusions If possible, avoidance of valproate and anti-epileptic drug polytherapy during the first trimester of pregnancy was recommended to decrease the risk of congenital malformations, and throughout pregnancy to prevent reduced cognitive outcomes. Pregnancy risk stratification should reflect that children of women with epilepsy taking anti-epileptic drugs were probably at increased risk of being small for gestational age and possibly at increased risk of scoring below normal in the one-minute Apgar neonate health assessment method. CRD commentary The review question was defined in terms of the participants, interventions and outcomes of interest. Attempts were made to identify relevant evidence from multiple sources, regardless of language. With the exception of data extraction, the authors reported attempts to minimise bias at each stage of the review process.
Validity of studies was broadly assessed using established criteria and this assessment was incorporated into the synthesis. The use of a narrative synthesis appeared appropriate given the apparent heterogeneity of the included studies, although the precise number of studies examined was not entirely clear from the presented text and tables.
The authors conclusions appeared to follow from the evidence presented, but limitations in reporting make it difficult to establish the reliability of these conclusions. Implications of the review for practice and research Practice: The authors stated valproate and anti-epileptic drug polytherapy should be avoided during the first trimester of pregnancy to decrease the risk of congenital malformations, and throughout pregnancy to prevent reduced cognitive outcomes. They add that pregnancy risk stratification should reflect that children of women with epilepsy taking anti-epileptic drugs are probably at increased risk of being small for gestational age and possibly at increased risk of a one-minute Apgar score of less than 7.
Research: The authors stated that further research is required to clarify the dose-malformation relationship for all anti-epileptic drugs, and the adverse neonatal and long-term cognitive outcomes of children exposed to anti-epileptic drugs in utero. They added that further research on the cognitive effects of anti-epileptic drug exposure during breastfeeding should also be considered, and that future studies should evaluate metabolic systems for which medication could lower teratogenic risk. Funding The Milken Family Foundation. Bibliographic details Harden CL, Meador KJ, Pennell PB, Hauser WA, Gronseth GS, French JA, Wiebe S, Thurman D, Koppel BS, Kaplan PW, Robinson JN, Hopp J, Ting TY, Gidal B, Hovinga CA, Wilner AN, Vazquez B, Holmes L, Krumholz A, Finnell R, Hirtz D, Le Guen C. Practice parameter update: management issues for women with epilepsy - focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes. Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009; 73(2): 133-141 Other publications of related interest Harden CL, Hopp J, Ting TY, Pennell PB, French JA, Hauser WA, Wiebe S, Gronseth GS, Thurman D, Meador KJ, Koppel BS, Kaplan PW, Robinson JN, Gidal B, Hovinga CA, Wilner AN, Vazquez B, Holmes L, Krumholz A, Finnell R, Le Guen C. Practice parameter update: management issues for women with epilepsy - focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency. Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009;73(2):126-132.
Harden CL, Pennell PB, Koppel BS, Hovinga CA, Gidal B, Meador KJ, Hopp J, Ting TY, Hauser WA, Thurman D, Kaplan PW, Robinson JN, French JA, Wiebe S, Wilner AN, Vazquez B, Holmes L, Krumholz A, Finnell R, Shafer PO, Le Guen C. Practice parameter update: management issues for women with epilepsy - focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding. Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009;73(2):142-149. Indexing Status Subject indexing assigned by NLM MeSH Abnormalities, Drug-Induced /etiology; Anticonvulsants /adverse effects /contraindications /therapeutic use; Birth Weight /drug effects; Cognition Disorders /chemically induced; Drug Therapy, Combination; Epilepsy /drug therapy; Female; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications /drug therapy; Prenatal Exposure Delayed Effects; Risk; Valproic Acid /adverse effects /contraindications /therapeutic use AccessionNumber 12009107456 Date bibliographic record published 16/12/2009 Date abstract record published 15/09/2010 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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