title: Antiepileptic drugs and intrauterine death: A prospective observational study from EURAP.
abstract: OBJECTIVE
  To compare the risk of spontaneous abortions and stillbirth associated with maternal use of different antiepileptic drugs (AEDs).
  
  
  METHODS
  The EURAP registry is an observational international cohort study primarily designed to determine the risk of major congenital malformations (MCMs) after prenatal AED exposure. Using EURAP data, we prospectively monitored pregnancies exposed to the 6 most common AED monotherapies and to polytherapy. Intrauterine death (spontaneous abortion and stillbirth combined) was the primary endpoint.
  
  
  RESULTS
  Of 7,055 pregnancies exposed to monotherapy with lamotrigine (n = 1,910), carbamazepine (n = 1,713), valproic acid (n = 1,171), levetiracetam (n = 324), oxcarbazepine (n = 262), or phenobarbital (n = 260), and to polytherapy (n = 1,415), 632 ended in intrauterine deaths (592 spontaneous abortions and 40 stillbirths). Rates of intrauterine death were similar across the different monotherapies (8.2%; 95% confidence interval [CI] 7.5%-8.9%), higher with polytherapy (12.1%; 95% CI 10.5%-13.9%), but showed no relationship with AED dose in monotherapy at conception. Multivariable analysis including 11 covariates in addition to the different AED exposures showed that the risk was greater with polytherapy vs monotherapy (risk ratio [RR] 1.38; 95% CI 1.14-1.66), parental history of MCMs (RR 1.92; 1.20-3.07), maternal age (RR 1.06; 1.04-1.07), and number of previous intrauterine deaths (RR 1.09; 1.00-1.19). The risk was greater with early enrollment and decreased with later gestational week at enrollment (RR 0.84; 0.82-0.86).
  
  
  CONCLUSIONS
  The most important risk factors for intrauterine death in pregnancies of women with epilepsy include maternal exposure to AED polytherapy and the presence of MCMs in at least one of the parents.
authors.affiliation: From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet, Stockholm, Sweden; Epilepsy Center (D.B.), Department of Neurophysiology and Experimental Epileptology, IRCCS Neurological Institute Carlo Besta Foundation, Milan; Department of Clinical Science and Community (E.B.), Section of Medical Statistics and Biometry G.A. Maccacaro, Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.J.C.), Belfast, Ireland; Department of Medical Genetics (D.L.), University Medical Center Utrecht; SEIN-Epilepsy Institute in the Netherlands Foundation (D.L.), Hoofddorp, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia, and Clinical Trial Center, C. Mondino National Neurological Institute, Pavia, Italy; The Epilepsy Clinic (A.S.), Department of Neurology, Rigshospitalet University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala, India; and Departments of Medicine and Neurology (F.V.), University of Melbourne, Royal Melbourne Hospital, Australia. torbjorn.tomson@karolinska.se.
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Tomson
authors.affiliation: From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet, Stockholm, Sweden; Epilepsy Center (D.B.), Department of Neurophysiology and Experimental Epileptology, IRCCS Neurological Institute Carlo Besta Foundation, Milan; Department of Clinical Science and Community (E.B.), Section of Medical Statistics and Biometry G.A. Maccacaro, Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.J.C.), Belfast, Ireland; Department of Medical Genetics (D.L.), University Medical Center Utrecht; SEIN-Epilepsy Institute in the Netherlands Foundation (D.L.), Hoofddorp, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia, and Clinical Trial Center, C. Mondino National Neurological Institute, Pavia, Italy; The Epilepsy Clinic (A.S.), Department of Neurology, Rigshospitalet University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala, India; and Departments of Medicine and Neurology (F.V.), University of Melbourne, Royal Melbourne Hospital, Australia.
authors.forename: Dina
authors.initials: D
authors.lastname: Battino
authors.affiliation: From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet, Stockholm, Sweden; Epilepsy Center (D.B.), Department of Neurophysiology and Experimental Epileptology, IRCCS Neurological Institute Carlo Besta Foundation, Milan; Department of Clinical Science and Community (E.B.), Section of Medical Statistics and Biometry G.A. Maccacaro, Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.J.C.), Belfast, Ireland; Department of Medical Genetics (D.L.), University Medical Center Utrecht; SEIN-Epilepsy Institute in the Netherlands Foundation (D.L.), Hoofddorp, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia, and Clinical Trial Center, C. Mondino National Neurological Institute, Pavia, Italy; The Epilepsy Clinic (A.S.), Department of Neurology, Rigshospitalet University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala, India; and Departments of Medicine and Neurology (F.V.), University of Melbourne, Royal Melbourne Hospital, Australia.
authors.forename: Erminio
authors.initials: E
authors.lastname: Bonizzoni
authors.affiliation: From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet, Stockholm, Sweden; Epilepsy Center (D.B.), Department of Neurophysiology and Experimental Epileptology, IRCCS Neurological Institute Carlo Besta Foundation, Milan; Department of Clinical Science and Community (E.B.), Section of Medical Statistics and Biometry G.A. Maccacaro, Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.J.C.), Belfast, Ireland; Department of Medical Genetics (D.L.), University Medical Center Utrecht; SEIN-Epilepsy Institute in the Netherlands Foundation (D.L.), Hoofddorp, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia, and Clinical Trial Center, C. Mondino National Neurological Institute, Pavia, Italy; The Epilepsy Clinic (A.S.), Department of Neurology, Rigshospitalet University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala, India; and Departments of Medicine and Neurology (F.V.), University of Melbourne, Royal Melbourne Hospital, Australia.
authors.forename: John J
authors.initials: JJ
authors.lastname: Craig
authors.affiliation: From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet, Stockholm, Sweden; Epilepsy Center (D.B.), Department of Neurophysiology and Experimental Epileptology, IRCCS Neurological Institute Carlo Besta Foundation, Milan; Department of Clinical Science and Community (E.B.), Section of Medical Statistics and Biometry G.A. Maccacaro, Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.J.C.), Belfast, Ireland; Department of Medical Genetics (D.L.), University Medical Center Utrecht; SEIN-Epilepsy Institute in the Netherlands Foundation (D.L.), Hoofddorp, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia, and Clinical Trial Center, C. Mondino National Neurological Institute, Pavia, Italy; The Epilepsy Clinic (A.S.), Department of Neurology, Rigshospitalet University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala, India; and Departments of Medicine and Neurology (F.V.), University of Melbourne, Royal Melbourne Hospital, Australia.
authors.forename: Dick
authors.initials: D
authors.lastname: Lindhout
authors.affiliation: From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet, Stockholm, Sweden; Epilepsy Center (D.B.), Department of Neurophysiology and Experimental Epileptology, IRCCS Neurological Institute Carlo Besta Foundation, Milan; Department of Clinical Science and Community (E.B.), Section of Medical Statistics and Biometry G.A. Maccacaro, Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.J.C.), Belfast, Ireland; Department of Medical Genetics (D.L.), University Medical Center Utrecht; SEIN-Epilepsy Institute in the Netherlands Foundation (D.L.), Hoofddorp, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia, and Clinical Trial Center, C. Mondino National Neurological Institute, Pavia, Italy; The Epilepsy Clinic (A.S.), Department of Neurology, Rigshospitalet University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala, India; and Departments of Medicine and Neurology (F.V.), University of Melbourne, Royal Melbourne Hospital, Australia.
authors.forename: Emilio
authors.initials: E
authors.lastname: Perucca
authors.affiliation: From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet, Stockholm, Sweden; Epilepsy Center (D.B.), Department of Neurophysiology and Experimental Epileptology, IRCCS Neurological Institute Carlo Besta Foundation, Milan; Department of Clinical Science and Community (E.B.), Section of Medical Statistics and Biometry G.A. Maccacaro, Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.J.C.), Belfast, Ireland; Department of Medical Genetics (D.L.), University Medical Center Utrecht; SEIN-Epilepsy Institute in the Netherlands Foundation (D.L.), Hoofddorp, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia, and Clinical Trial Center, C. Mondino National Neurological Institute, Pavia, Italy; The Epilepsy Clinic (A.S.), Department of Neurology, Rigshospitalet University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala, India; and Departments of Medicine and Neurology (F.V.), University of Melbourne, Royal Melbourne Hospital, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Sabers
authors.affiliation: From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet, Stockholm, Sweden; Epilepsy Center (D.B.), Department of Neurophysiology and Experimental Epileptology, IRCCS Neurological Institute Carlo Besta Foundation, Milan; Department of Clinical Science and Community (E.B.), Section of Medical Statistics and Biometry G.A. Maccacaro, Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.J.C.), Belfast, Ireland; Department of Medical Genetics (D.L.), University Medical Center Utrecht; SEIN-Epilepsy Institute in the Netherlands Foundation (D.L.), Hoofddorp, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia, and Clinical Trial Center, C. Mondino National Neurological Institute, Pavia, Italy; The Epilepsy Clinic (A.S.), Department of Neurology, Rigshospitalet University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala, India; and Departments of Medicine and Neurology (F.V.), University of Melbourne, Royal Melbourne Hospital, Australia.
authors.forename: Sanjeev V
authors.initials: SV
authors.lastname: Thomas
authors.affiliation: From the Department of Clinical Neuroscience (T.T.), Karolinska Institutet, Stockholm, Sweden; Epilepsy Center (D.B.), Department of Neurophysiology and Experimental Epileptology, IRCCS Neurological Institute Carlo Besta Foundation, Milan; Department of Clinical Science and Community (E.B.), Section of Medical Statistics and Biometry G.A. Maccacaro, Faculty of Medicine and Surgery, University of Milan, Italy; Belfast Health and Social Care Trust (J.J.C.), Belfast, Ireland; Department of Medical Genetics (D.L.), University Medical Center Utrecht; SEIN-Epilepsy Institute in the Netherlands Foundation (D.L.), Hoofddorp, the Netherlands; Department of Internal Medicine and Therapeutics (E.P.), University of Pavia, and Clinical Trial Center, C. Mondino National Neurological Institute, Pavia, Italy; The Epilepsy Clinic (A.S.), Department of Neurology, Rigshospitalet University State Hospital, Copenhagen, Denmark; Department of Neurology (S.V.T.), Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala, India; and Departments of Medicine and Neurology (F.V.), University of Melbourne, Royal Melbourne Hospital, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Vajda
mesh_terms: D000022:Abortion, Spontaneous / Q000139:chemically induced* / Q000453:epidemiology; D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects*; D000013:Congenital Abnormalities / Q000453:epidemiology; D004359:Drug Therapy, Combination / Q000009:adverse effects; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008875:Middle Aged; D011247:Pregnancy; D011248:Pregnancy Complications / Q000139:chemically induced* / Q000188:drug therapy*; D011446:Prospective Studies; D012042:Registries; D012307:Risk Factors; D050497:Stillbirth / Q000453:epidemiology; D055815:Young Adult
chemical_list: D000927:Anticonvulsants