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

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 (cont.)

• 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 (cont.)

• 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
  (Plt.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 gt7
  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 CLgt2) 6.5
• 6.5 is greater than the general population at
  the Active Malformations Surveillance Program and
  Brigham and Womens 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

Holmes LB, et al. Arch Neurol. 2004.
PB phenobarbital
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 LD 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 gt1000 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 gt1000 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
  31
• 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 (cont.)

• 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 Epilepsy 4 - 6
• (Range 1.25 - 18.6)
• Major Malformations
• Orofacial Clefts, Heart Defects, Urological
• Neural Tube Defects (VPA1.5, CBZ0.5)

34
AED Teratogenicity

• MonoTx PolyTx No AED Controls
• 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
• PB6.5, VPA10.7
• EURAP
• Australian
• VPA16, CBZ3.1, PHT5, LTG0
• UK
• VPA5.9, CBZ2.3, LTG2.1
• 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
In Utero AEDs Behavioral Neurodevelopment in
Animals
Weiss

• 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

• N Observed Predicted P-value
• VIQ 33 101 108 .04
• FSIQ 33 100 107 .06
• Low SES 20 95 108 .01
• Unwanted 16 94 106 .01
• Both 10 86 106 .001
• Reinisch et al, JAMA 1995

40
Additional Education Needs in Children of
Epilepsy Women

• Exposure N AEN Odds 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)

Adab et al., J Neurol Neurosurg Psych 2001
significantly greater
41
Retrospective Study In Utero AED Exposure IQ

• Exposure N VIQ CI
• 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 from CBZ, 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
• CBZ86, VPA13, Other8, PolyTx30, None45

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
Types of Congenital Malformations

• 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

49
Developmental Delay
AE for Each AED
CBZ LTG PHT VPA
50
Total Serious Adverse Events
Plt.0001 Fishers exact test
SAE for Each AED
CBZ LTG PHT VPA
Serious Adverse Events fetal death, major
congenital malformation, or developmental delay
51
Possible Mechanisms of AED Effects on
Neurodevelopment

• Neuronal Suppression
• Folate Methionine Related Mechanisms
• Ischemia Hypoxia
• Reactive Intermediates
• Free Radicals
• Arene Oxides (epoxides)
• Neuronal Apoptosis
• NMDA antagonist GABA agonist
• Antagonism of neutrophins signal proteins

Weiss
52
AEDs Apoptosis in Developing Brain

• Clonazepam, Diazepam, Phenobarbital, Phenytoin,
  Valproate, Vigabatrin
• All cause widespread neural apoptosis in rats age
  3-30 days
• Reduced expression of neutrophins extracellular
  signal proteins
• Effects prevented by ß-estradiol

Bittigau et al, Ann NY Acad Sci 2003
53
Weiss
54
Q A
55
Pregnancy Registries Their Utility and Role in
Guiding Clinical Decision Making

• W. Allen Hauser, MD
• College of Physicians and SurgeonsColumbia
  UniversityNew York, NY

56
Malformations in Infants of Mothers With Epilepsy

• First report of malformations in IME was
  published in 19631
• Microcephaly, cleft palate
• Flawed case-control study in 1972, RR 22
• No specific abnormality
• Group of characteristic anomalies
• Included the cases previously reported by the
  same authors

1. Mueller-Kuepper M. Acta Paedopsychiatr. 1963.
2. Speidel BD, et al. Lancet. 1972.

57
Congenital MalformationsIncreased in IME

• Reported with all AEDs
• RR 2.0-2.4
• 4-6 (general population 2-3)
• Most common malformations include
• Orofacial clefts
• Midline heart defects
• Skeletal defects
• Genitourinary defects (many identified late)

58
How Do We Choose the Safest Therapies?

• Population-based studies
• Advantages
• Well-characterized cases
• Excellent comparison group
• Representative of the general population
• Disadvantages
• Small numbers
• Lag in reporting

59
Population-Based Studies Iceland

• All pregnancies to women with active epilepsy
  over a 19-year period (N 163)
• Population rates major malformations at birth for
  comparison 2.2 over the same period
• WWE untreated 4.8
• WWE treated 5.9

60
Population-Based StudiesIceland

• Highest risk for diazepam (50) and sulthiame
  (40)
• Lowest risk for CBZ (1.2)
• Highest risk of standard drugs PB (8.7)
• Increased with number of drugs
• 3.4 on monotherapy
• 9 on polytherapy

Olafsson E, et al. Epilepsia. 1998.
CBZ carbamazepine PB phenobarbital
61
Population-Based StudiesRochester, Minnesota

• All births to women with epilepsy diagnosed
  between 1939 and 1976
• 0/123 births to women before diagnosis or after
  5-year remission
• 19/177 births (5.1) to women exposed in first
  trimester
• 2/82 (2.4) births to women with active epilepsy
  but no AED exposure
• 9/234 (3.8) births to wives of men with epilepsy

Annegers JF, et al. Int J Epidemiol. 1978.
Annegers JF, et al. Neurology. 1982.
62
Population-Based StudiesRochester, Minnesota

• PHT monotherapy 5/31 (16)
• Barbiturate monotherapy 5/47 (11)
• Caveat long-term follow-up, not just at birth,
  explains higher rate
• Not all answers will come from short-term
  follow-up

Annegers JF, et al. Int J Epidemiol. 1978.
Annegers JF, et al. Neurology. 1982.
PHT phenytoin
63
How Do We Choose the Safest Therapies?

• Registries of malformations
• Can be powerful but may be misleading
• Little information regarding disease
• Reasons for exposure

64
International Database on Malformations and Drug
Exposure

• 8005 malformations
• 299 exposed to AED
• n 80 VPA
• n 65 PB
• n 46 CBZ
• Case-control methodology

Arpino C, et al. Epilepsia. 2000.
CBZ carbamazepine PB phenobarbital VPA
valproic acid
65
Malformation Database

• Case-control methodology
• Clefts phenobarbital
• Cardiac phenobarbital, VPA, CBZ
• Hypospadias VPA
• Limb reduction VPA
• Coarctation VPA
• Porencephaly VPA

Arpino C, et al. Epilepsia. 2000.
CBZ carbamazepine VPA valproic acid
66
Malformation Registries

• Good points
• Include stillbirths and elective abortions
• Problems
• May underestimate risk if multiple outcomes
  possible
• May overestimate risk if perception of
  association leads to bias in reporting
• Cannot be extrapolated to population risks

67
Record Linkage Systems

• Swedish Medical Birth Registry
• Data for 7 years
• 1398 AED-exposed women
• AED OR 1.86 for malformations (95 CI 1.4-2.4)
• CBZ 28/703 (4.0)
• VPA 26/268 (9.7)
• PHT 7/103 (6.8)
• LTG 4/90 (4.4)

CBZ carbamazepine LTG lamotrigine PHT
phenytoin VPA valproic acidOR odds ratio
Wide K, et al. Acta Pediatr. 2004.
68
Record Linkage

• Problems
• Miss elective and spontaneous abortions
• Prevalence of epilepsy births 2.2/1000,
  suggesting considerable undercounting of cases
  (5-6/1000 in Iceland and in Norway)
• No detail on cases

King PB, et al. Am J Public Health.
1996.Olafsson E, et al. Epilepsia. 1998.
69
Hospital-Based Registries

• Systematic review of all births to identify
  mothers with epilepsy
• Example Boston Hospital Study
• 128,049 deliveries screened over a 7-year period
• 509 took AED, 386 as monotherapy
• 606 had history of epilepsy
• Control group

Holmes LB, et al. N Engl J Med. 2001
70
Hospital-Based Registries

• Examined 233 of 386 women on monotherapy
• n 87 PHT
• n 64 PB
• n 58 CBZ
• n 6 VPA
• PHT, PB, CBZ increased rate but not significantly
  
• All embryopathy 20, versus 8 in controls
• Highest in women taking AED for other reasons
• No major malformations in 98 WWE off meds

Holmes LB, et al. N Engl J Med. 2001
71
Hospital-Based Registries

• Despite large base population, no significant
  difference across groups
• Misses spontaneous or induced abortions
• Most but not all examined blindly, so bias may
  still be present

Harvey AS, et al. Birth Defects Res Clin Mol
Teratol. 2003.Holmes LB, et al. N Engl J Med.
2001.
72
Hospital-Based Registries

• 20-year prospective study in Milan
• 628 identified 452 provided data
• 9 some anomaly
• 5 major anomaly
• No anomaly in 25 WWE not exposed to AED
• VPA significantly greater frequency than others
  (16)

Canger R. Recenti Prog Med. 1999.
73
Pregnancy Registries

• National Regional
• EURAP
• NAREP
• Australia now merged with EURAP
• India now merged with EURAP
• United Kingdom collaborating with EURAP
• Pharmaceutical
• Lamotrigine
• Gabapentin
• Vigabatrin

74
How Do We Choose the Safest Therapies?

• Registries
• Prospective of women with epilepsy
• Hopefully identified without knowledge of outcome
• Concurrent medication information
• Large numbers needed because of low frequency
• Registries of malformations
• Can be powerful but may be misleading
• Little information regarding disease reasons for
  exposure

75
International Lamotrigine Pregnancy Registry

• Started in 1992
• Worldwide, all pregnancy exposures before
  knowledge of outcome recruited through physicians
• Follow-up to confirm adverse outcomes
• LTG monotherapy 3/168 with malformations
• (1.8, 95 CI 0.5-5.5)
• LTG polytherapy other than VPA 4/116 with
  malformations
• (4.3, 95 CI 1.6-10.35)
• LTG with VPA 5/50 with malformations
• (10, 95 CI 3.7-22.6)

Tennis P, et al. Epilepsia. 2002.
LTG lamotrigine VPA valproic acid
76
North American AED and Pregnancy Registry

• Unique collaboration between industry and
  academia
• Industry support from
• Abbott Laboratories
• Elan Pharmaceuticals
• GlaxoSmithKline
• Novartis
• Ortho-McNeil
• Pfizer Pharmaceuticals

77
North American AED and Pregnancy Registry

• Prospective surveillance of AEDs in pregnancy
• Pure prospectiveno knowledge of status of the
  fetus at enrollment
• Cases enrolled before 16th week of pregnancy
• Interviews at enrollment, 7 months, and after
  delivery
• Medical records to be obtained and reviewed

78
North American AED and Pregnancy Registry

• Comparison from rate of nonchromosomal congenital
  anomalies in 69277 births at Brigham and Womens
  Hospital 1.621
• Comparison with internal controls and other
  pure prospective cases

1. Nelson K, Holmes LB. N Engl J Med. 1989.
79
North American AED and Pregnancy Registry

• Data collected
• Age
• Parity
• Smoking
• Seizures during pregnancy
• Folate supplementation
• Other prenatal vitamins
• Duration of epilepsy

80
North American AED and Pregnancy Registry

• Committee blinded to drug status
• Release criteria established lower bound of 95
  CI greater than 2-fold increase when compared
  with the referent

81
North American AED and Pregnancy Registry

• Findings to date
• Phenobarbital1
• 6.3 pure cases with malformations
• 4.8 all exposed cases
• Valproate2
• 10.7 with malformations among exposed cases
• Malformation rate for other AEDs combined 2.9

1. Holmes LB, et al. Arch Neurol. 2004.2.
Alsdorf RM, et al. Birth Defects Res Clin Mol
Teratol. 2004.
82
North American AED and Pregnancy Registry

• Problems
• No concurrent comparison group
• No untreated epilepsy group
• Data from Iceland
• General population 2.2
• Untreated women with epilepsy 4.8
• Women with epilepsy on treatment 6
• Etiology and type of epilepsy not determined

83
North American AED and Pregnancy Registry

• Problems
• Women predominantly Caucasian, well educated
• Need for women to call
• Reluctance of women to release medical data

84
If you are pregnant and take anticonvulsant
medication for any reason, please call TOLL
FREE 1-888-233-2334 to register with the AED
Pregnancy Registry
85
http//www.massgeneral.org/aed/
To order materials, please contact the Registry
at 1-888-233-2334 or send e-mail to
mnambisan_at_partners.org
86
EURAP

• 37 reporting countries with national coordinators
• Prospective cases (before 16 weeks and without
  knowledge of outcome)
• One central EURAP registryMilan
• Work through network of reporting physicians who
  also provide data
• 1-year follow-up

87
EURAP

• As of May 2004
• gt4000 women enrolled, 2238 prospective
• Among prospective 41 generalized, 53
  localization-related
• 126 completed pregnancies (6 of total with
  3-month follow-up forms completed) have a
  definite malformation

88
EURAP

• Supported by educational grants from
  GlaxoSmithKline
• Janssen-Cilag
• Pfizer
• Sanofi-Synthelabo
• UCB Pharma
• Novartis

89
EURAP

• Large number of centers but small numbers from
  some contributors
• Unblinded assessment
• Population heterogeneity

90
United Kingdom Epilepsy and Pregnancy Group

• Women with epilepsy registered by any health care
  professional prior to information on outcome
• Women may also self-refer
• Data collected include medications used, seizure
  type, preconception folate use, other drugs,
  seizures during pregnancy
• Follow-up assessment at 3 months
• Support from Epilepsy Research Foundation

91
United Kingdom Epilepsy and Pregnancy Group

• Almost 4000 pregnancies registered
• Outcome data available on more than 3000
  pregnancies
• As of this date, no peer-reviewed publications
  available

92
Conclusions

• The need for large numbers of pregnancies
  followed to assess outcome is clear small
  numbers for most newer drugs preclude definitive
  statements regarding safety
• Prospective follow-up from early pregnancy is
  key blinded assessment important
• Comparison population needed

93
Q A