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Maternal Seizures, Maternal Epilepsy, and AEDs: The Variables Associated With Congenital Malformations

Maternal Seizures, Maternal Epilepsy, and AEDs: The Variables Associated With Congenital Malformations. Cynthia L. Harden, MD Comprehensive Epilepsy Center Weill Medical College of Cornell University New York, NY. What Are Considered Congenital Malformations in Epilepsy Studies?.

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Maternal Seizures, Maternal Epilepsy, and AEDs: The Variables Associated With Congenital Malformations

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  1. Maternal Seizures, Maternal Epilepsy, and AEDs: The Variables Associated With Congenital Malformations Cynthia L. Harden, MD Comprehensive Epilepsy Center Weill Medical College of Cornell University New York, NY

  2. What Are Considered Congenital Malformations in Epilepsy Studies? • Major malformations are structural abnormalities with surgical, medical, or cosmetic importance (identified during the first 5 days of life) • Ventricular septal defect, coarctation of the aorta, Tetralogy of Fallot, aortic valve stenosis, hypoplasia of mitral valve • Cleft lip and cleft palate • Penile hypospadias, imperforate anus • Talipes equinovarus (clubfoot), calcaneovalgus (flexible flat foot), terminal transverse limb defects, hip dysplasia, inguinal hernia Holmes LB, et al. N Engl J Med. 2001.

  3. What Are Considered Congenital Malformations in Epilepsy Studies? • AED-related “outcomes of interest” • Microcephaly • Growth retardation • Hypoplasia of midface and fingers • Physical abnormalities not considered to be major malformations • Transverse palm crease • PDA, undescended testicle, mild hydronephrosis, absence of 1 kidney Holmes LB, et al. N Engl J Med. 2001.

  4. Do Maternal Seizures Contribute to Congenital Malformations? • Recent evidence is mixed • Studies are difficult since an independent effect of seizures on pregnancy outcome is confounded by: • AED effect (important) • Maternal epilepsy syndrome (probably not so important)

  5. Contribution of Seizures to Pregnancy Outcome Is an Important Consideration • Prevention of seizures during pregnancy is considered optimal care • An important discussion point with patients regarding medication compliance during pregnancy • What evidenced-based information is available to help us advise patients?

  6. Evidence Suggests a Trend for the Association Between Seizures During Pregnancy and Malformations • In a prospective study, convulsive seizures during first trimester were associated with malformations in 7.4% (2/27) • Compared with • 7.8% in women with more minor seizures during pregnancy (22/281) • 5.7% for AED monotherapy • 8.6% for AED polytherapy • 5.2% for CBZ, 3.4% for PHT, 4.7% for PB monotherapy • Seizures add to AED rate of malformations or associate with epilepsy that requires more AEDs? CBZ = carbamazepine; PB = phenobarbital; PHT = phenytoin Holmes LB, et al. N Engl J Med. 2001.

  7. Seizures During Pregnancy (con’t.) • Historical population-based study reported that seizures during pregnancy were associated with a significant increased risk of major malformations (standard morbidity ratio 3.8 [8/95]) • No seizures during pregnancy associated with no increased risk (SMR 0.7 [1/62]) • Proportion of women taking AEDs was same in both groups • Note: seizure history not available for 40% of total study population; timing and seizure type not reported Olafsson E, et al. Epilepsia. 1999.

  8. Seizures During Pregnancy (con’t.) • Prospective study of population in Rotterdam found an increased risk of malformations if seizures occurred in the first trimester of pregnancy • 12.3% (9/73) of offspring in the seizure group and 4.0% (4/99) in the seizure-free group (P<.10) • Subject took on average 1.7 AEDs, but AEDs specific to each group were not described • Only partial seizures associated with malformations Lindhout D, et al. Neurology. 1992

  9. On the Other Hand. . . • International prospective study (Japan, Italy, Canada) found no association between seizures in the first trimester and malformations • Large study: 983 pregnancies, 83 malformed infants (8.4%) • Half of each group had seizures in first trimester Kaneko S, et al. Epilepsy Res. 1999

  10. On the Other Hand. . . • Prospective study of 970 pregnancies showed that generalized convulsive seizures in the first trimester were not associated with an increased risk of malformations (2/60)1 • Study performed in Rochester, MN also showed that seizures during pregnancy were not associated with increased risk of malformations2 1. Kaaja E, et al. Neurology. 2003. 2. Annengers JF, et al. Int J Epidemiol. 1978.

  11. Seizures During Pregnancy: Conclusions • In 6 studies of malformations in infants born to mothers with epilepsy, relationship to seizures is not consistent • 3 are negative • 2 are positive • 1 is suggestive of a relationship • Since an association between seizures and malformations is interrelated with epilepsy severity and AED treatment, can we impact pregnancy outcome by controlling seizures? • Possibly, especially with monotherapy

  12. Malformations Due to Epilepsy Itself; No AEDs, No Major Seizures • Studied indirectly in a study powered to evaluate the intelligence and physical features of children of women with epilepsy • 57 children born to mothers with epilepsy not taking AEDs during pregnancy compared to 57 controls • 11/57 mothers had minor seizures only during pregnancy • No difference in primary outcomes (to detect >7 point IQ difference) • Major malformations in 8.7% of study group and 5.3% of controls (P = 0.358) • Would higher numbers have shown an effect? Holmes LB, et al. Teratology. 2000.

  13. Maternal Effects: Spontaneous Abortion May Be a Marker for Epilepsy • Spontaneous abortion occurs more frequently in women with epilepsy compared with their siblings • History of spontaneous abortion in women with epilepsy increases the risk by 4-5 times that they will also have a child with epilepsy • Spontaneous abortion may be risk factor for epilepsy in offspring and a marker for genetic susceptibility to epilepsy in the mother Schupf N, et al. Neurology. 2001.

  14. AED Exposure and Major Malformations • North American AED Pregnancy Registry experience 1997-2002 • 3002 women, 2330 with monotherapy of self-enrolled women • 77 infants exposed to PB as monotherapy; mothers had no idea of the outcome at time of enrollment (“pure prospective”) • After 77 birth outcomes, the criteria were met for increased risk (lower end of 95% CL>2); 6.5% • 6.5% is greater than the general population at the Active Malformations Surveillance Program and Brigham and Women’s Hospital; 1.6%, relative risk 4.2, P = .001 (one-sided) • Not different from 3 other most-frequent AED monotherapy exposures (n = 796) combined; 2.9% PB = phenobarbital Holmes LB, et al. Arch Neurol. 2004.

  15. Risk Factors for Malformations Including AEDs • 979 offspring of women with epilepsy; 740 on AEDs, 239 not • Malformations occurred 28/740 (3.8%) and 2/239 (0.8%) P = .02 (local general population rate considered was 0.96%) • Logistic regression showed use of CBZ or valproate was associated with increased risk • Oxcarbazepine included in analysis but only 9 subjects; not enough for analysis • Low serum folate levels: only 11 subjects • Significant trend toward increased risk with polytherapy (P = .02) CBZ = carbamazepine Kaaja E, et al. Neurology. 2003.

  16. Teratogenicity of AEDs • Women screened in L&D suites for history of seizures and AED use • 509 women with AED exposure identified out of 128,049; infants examined without knowing group • Higher incidence of “embryopathy” in AED monotherapy group (n = 223) compared with controls (n = 508); 20.6% vs 8.5%, odds ratio 2.8 • Polytherapy (n = 93) showed increased risk; 28% vs 8.5%, odds ratio 4.21 1. Holmes LB, et al. N Engl J Med. 2001.

  17. MADRE Study: International Survey of Malformations • Data set of congenital malformations evaluated for infants who were exposed to AEDs • 8005 cases; 299 were exposed to AEDs, 241 to monotherapy • Findings: • Oral clefts associated with PB and methylphenobarbital • Cardiac malformations with PB, methobarbital, VPA, and CBZ • Spina bifida, hypospadias, porencephaly, and other brain anomalies, limb reduction deficits with VPA CBZ = carbamazepine; PB = phenobarbital; VPA = valproic acid Arpino C, et al. Epilepsia. 2000.

  18. Further Evidence for AEDs Associating With Malformations • 517 pregnancies in Milan1 • 5.3% had major malformations • Population based-study from the island-nation Iceland2 • 2.7x risk for major malformations; few obstetrical complications • AED exposure in Japan, Italy and Canada3 • 9.0% vs 3.1% (moms with epilepsy not on AEDs); dose effect of VPA >1000 mg confirmed • Prospective analysis of 983 offspring with comparison of 2 consecutive cohorts in Netherlands4 • Decreased malformations over time from 10% to 7.6%; PB decreased and VPA, CBZ increased 1. Canger R, et al. Epilepsia. 1999.2. Olafsson E, et al. Epilepsia. 1998.3. Kaneko S, et al. Epilepsy Res. 1999.4. Lindhout D, et al. Neurology. 1992. CBZ = carbamazepine; PB = phenobarbital; VPA = valproic acid

  19. Joint European Prospective Study • Pooled data from the Netherlands, Germany, and Finland • Evaluated 1221 children; used a control group for part of analysis • Increased risk of major malformations found: • VPA as monotherapy; RR = 4.9 • CBZ as monotherapy; RR = 4.9 • Both were associated with spinal bifida aperta +/- anterior neuroaxis anomalies • Doses of VPA >1000 mg/day associated with increased risk compared with lower doses CBZ = carbamazepine; VPA = valproic acid Samren EB, et al. Epilepsia. 1997.

  20. Newer AEDs and Malformations • GSK International Lamotrigine Pregnancy Registry 11-year results: 10/360 (2.8%) first trimester monotherapy exposures had major malformations; sufficient sample to detect a 1.85x increased risk with 80% power assuming a minimum risk of 3%1 • Oxcarbazepine exposures as monotherapy in 35 infants with no major or minor malformations examined at birth, 3 and 6 months of age2 1. Messenheimer, et al. [abstract] 2004. Available at: http://www.call4abstracts.com. Accessed November 16, 2004.2. Meischenguiser, et al. Epilepsy Behav. 2004.

  21. Newer AEDs and Malformations (con’t.) • Gabapentin Pregnancy Registry; no malformations in 19 infants exposed to gabapentin monotherapy early in pregnancy1 • Three cases of levetiracetam monotherapy during pregnancy; outcomes normal up to 12 months postnatally2 1. Montouris G. Epilepsy Behav. 2003.2. Long L. Epilepsy Behav. 2003.

  22. Potential Mechanisms of AED Teratogenesis • Suppression of neuronal physiology by AEDs • Decreased folic acid due to AED interference with metabolism or absorption • Altered NMDA/GABA-related mechanisms caused by AEDs (similar to fetal alcohol syndrome) • Ischemia/hypoxia due to AED effects on cardiac function • Reactive intermediates • Epoxides; but not formed in fetal tissues • Free radicals of bioactivated AEDs

  23. Other Reasons to Prevent Seizures With AEDs During Pregnancy • Seizures are a risk to the pregnancy • Trauma during pregnancy can result in abruptio placentae (20%-50% of blunt injuries), premature labor, and fetal death • Generalized convulsions have caused fetal heart rate depression, fetal hypoxia and acidosis, and intracranial hemorrhage1-3 • One case of decreased fetal heart rate after complex partial seizures4 • Status epilepticus during pregnancy is associated with high maternal and fetal mortality rate5 4. Nei M. et al. Neurology. 1998.5. Teramo K, et al. In: Epilepsy, Pregnancy and the Child. Raven Press. 1982. 1. Minkoff H, et al. Obstet Gynecol. 1985. 2. Teramo K, et al. J Perinat Med. 1979.3. Hiilesmaa VK, et al. Am J Obstet. 1985.

  24. More Reasons to Prevent Seizures With AEDs During Pregnancy • Seizures during pregnancy may be associated with • Intrauterine growth retardation • Miscarriage • Fetal loss after 20 weeks (fetal wastage) • Neurocognitive outcome

  25. Conclusions • AEDs are associated with major malformations • Evidence continues to emerge • Monotherapy poses less risk than polytherapy • Seizures may be associated with major malformations • Maternal epilepsy likely has little influence on major malformations, but larger studies needed

  26. Q & A

  27. Development and Cognitive Outcomes in Infants of Mothers with Epilepsy Kimford J. Meador, MD University of Florida Gainesville, FL, USA

  28. Children of Women with Epilepsy • Majority of the children are normal. • As a group, both somatic & functional neurodevelopment are reduced. Weiss

  29. AED Teratogenicity • 1963 Von Muller Kuppers • First report of AED malformation (mephenytoin) • 1964 Janz & Fuchs • Increased miscarriages & stillbirths (survey of 426 pregnancies) • 1965 Centra & Rasore-Quartino • First report of AED congenital heart defect (PB & PHT) • 1970 German et al. • Trimethdione induced malformations • 1972 Speidel & Meadow • First IME survey (427preg.) of increased malformation risk (X2)

  30. Malformations & mental retardation are increased in children of mothers with epilepsy, but not children of fathers with epilepsy. Weiss

  31. Malformations Rates Higher in: • AED Treated vs Untreated • Higher vs Lower ABLs • Polytherapy vs Monotherapy *Most investigators have found no relation to seizure frequency. (Exceptions: Majewski et al, 1980; Lindhout et al, 1992)

  32. Congenital Malformations & Polytherapy in Japan 1978-89 % Malformations Number of AEDs Kaneko et al, 1992

  33. Congenital Malformations Weiss • General Population 2 - 3% • Infants of Mothers with Epilepsy4 - 6% (Range = 1.25 - 18.6%) Major Malformations: Orofacial Clefts, Heart Defects, Urological & Neural Tube Defects (VPA=1.5%, CBZ=0.5%)

  34. AED Teratogenicity MonoTxPolyTxNo AEDControls Major 4.5% 8.6% 0% 1.8% Malformations N 223 93 98 508 Similar rates in 35 exposed children of mothers without epilepsy: Major malformations = 9%. 128,049 children at delivery 1986-1993 in Boston. Holmes et al. NEJM 2001

  35. AED Pregnancy Registries Prospective studies of anatomical defects and major adverse outcomes • North America • PB=6.5%, VPA=10.7% • EURAP • Australian • VPA=16%, CBZ=3.1%, PHT=5%, LTG=0% • UK • VPA=5.9%, CBZ=2.3%, LTG=2.1% • Pharmaceutical Companies Weiss

  36. Fetal AED Syndrome • Six clinical syndromes described: CBZ, PB, PHT, PRM, TRM, VPA • Dysmorphisms such as: epicanthal folds, hypertelorism, broad/flat nasal bridge, upturned nose, distal digital hypoplasia • Risk of retardation is increased with increased # of dysmorphisms

  37. Weiss In Utero AEDs & Behavioral Neurodevelopment in Animals • PB reduces brain weight, hippocampal cell #, & catecholamines, and impairs behavior in mice. • PHT can impair coordination and learning in rats; the effects are long lasting. PHT can cause hyperactivity in monkeys. • Neurobehavioral effects have also been found for trimethadione & valproate.

  38. Neurodevelopment in Children of Women with Epilepsy • Maternal seizure type • # of seizures during pregnancy • IQ & education of parents • AEDs • Other environmental factors Weiss

  39. Adult IQ and In Utero Phenobarbital Exposure NObservedPredictedP-value* VIQ33 101 108 .04 FSIQ33 100 107 .06 Low SES20 95 108 .01 Unwanted16 94 106 .01 Both10 86 106 .001 Reinisch et al, JAMA 1995

  40. Additional Education Needs in Children of Epilepsy Women ExposureN% AENOdds Ratio No drug 176 11% 1.0 Mono VPA* 56 30% 3.40 (1.63-7.10) Mono CBZ 63 3% 0.26 (0.06-1.15) Mono Other 31 6% 0.54 (0.12-2.44) Poly + VPA 37 24% 2.51 (1.04-6.07) Poly - VPA 37 16% 1.51 (0.56-4.07) *significantly greater Adab et al., J Neurol Neurosurg Psych 2001

  41. Retrospective Study: In Utero AED Exposure & IQ ExposureNVIQCI No AED 80 91 87-95 Mono VPA 41 84* 78-89 MonoTx CBZ 52 94 90-98 MonoTx PHT 21 98 91-106 PolyTx + VPA 28 87 82-93 PolyTx - VPA 21 92 92-98 *Differs fromCBZ, PHT & no AED Adab et al., J Neurol Neurosurg Psych 2004

  42. Prospective IQ Study • 61% (182 / 300) children of epilepsy mothers • 51% (141 / 278) control children • IQ testing at mean age 7 y/o (2-10) • Verbal IQ VPA Monotherapy 84+ 3.8 SEM CBZ Monotherapy 96+ 1.9 Healthy Control Group 95+ 1.2 • Differ controlling for age, education, & polytherapy • CBZ=86, VPA=13, Other=8, PolyTx=30, None=45 Gaily et al. Neurology 2004

  43. NEAD Studyhttp://www.neadstudy.com 25 sites: USA & UK 361 mother & child pairs enrolled Funded by NIH/NINDS #RO1 NS 38455

  44. Interim Analysis • 361 mother/child pairs enrolled in 4 AED monotherapy groups AED N Carbamazepine 120 Lamotrigine 108 Phenytoin 61 Valproate 72 Majority of children less than 3 years old at time of present analysis

  45. Serious Adverse Outcomes • Fetal Death • Congenital Malformation which could be related to AED • Developmental Delay

  46. % Fetal Death % AE for Each AED CBZ LTG PHT VPA

  47. % Congenital Malformations % AE for Each AED CBZ LTG PHT VPA

  48. Cardiac ASD, VSD, Hypoplastic Right Heart, Coarctation of Aorta Cerebral Agenesis of Corpus Callosum Brachycephaly Midline Defects Cleft Palate Skeletal Dysplastic Ribs, 2 Thumbs on 1 Hand Urogenital Hypospadius, Absent Kidney, Undescended Testicle Types of Congenital Malformations

  49. % Developmental Delay % AE for Each AED CBZ LTG PHT VPA

  50. % Total Serious Adverse Events P<.0001 Fisher’s exact test % SAE for Each AED CBZ LTG PHT VPA Serious Adverse Events = fetal death, major congenital malformation, or developmental delay

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