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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

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
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.

what are considered congenital malformations in epilepsy studies3
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.

do maternal seizures contribute to congenital malformations
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)
contribution of seizures to pregnancy outcome is an important consideration
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?
evidence suggests a trend for the association between seizures during pregnancy and malformations
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.

seizures during pregnancy con t
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.

seizures during pregnancy con t8
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

on the other hand
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

on the other hand10
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.

seizures during pregnancy conclusions
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
malformations due to epilepsy itself no aeds no major seizures
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.

maternal effects spontaneous abortion may be a marker for epilepsy
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.

aed exposure and major malformations
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.

risk factors for malformations including aeds
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.

teratogenicity of aeds
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.

madre study international survey of malformations
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.

further evidence for aeds associating with malformations
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

joint european prospective study
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.

newer aeds and malformations
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.

newer aeds and malformations con t
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.

potential mechanisms of aed teratogenesis
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
other reasons to prevent seizures with aeds during pregnancy
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.

more reasons to prevent seizures with aeds during pregnancy
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
conclusions
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
development and cognitive outcomes in infants of mothers with epilepsy
Development and Cognitive Outcomes in Infants of Mothers with Epilepsy

Kimford J. Meador, MD

University of Florida

Gainesville, FL, USA

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

Weiss

aed teratogenicity
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)
slide30

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

Weiss

malformations rates higher in
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)

congenital malformations polytherapy in japan 1978 89
Congenital Malformations & Polytherapy in Japan 1978-89

% Malformations

Number of AEDs

Kaneko et al, 1992

congenital malformations
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%)

aed teratogenicity34
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

aed pregnancy registries
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

fetal aed syndrome
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
in utero aeds behavioral neurodevelopment in animals

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

Weiss

adult iq and in utero phenobarbital exposure
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

additional education needs in children of epilepsy women
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

retrospective study in utero aed exposure iq
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

prospective iq study
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

nead study http www neadstudy com
NEAD Studyhttp://www.neadstudy.com

25 sites: USA & UK

361 mother & child pairs enrolled

Funded by NIH/NINDS #RO1 NS 38455

interim analysis
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

serious adverse outcomes
Serious Adverse Outcomes
  • Fetal Death
  • Congenital Malformation which could be related to AED
  • Developmental Delay
fetal death
% Fetal Death

% AE for Each AED

CBZ LTG PHT VPA

congenital malformations47
% Congenital Malformations

% AE for Each AED

CBZ LTG PHT VPA

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

Types of Congenital Malformations
developmental delay
% Developmental Delay

% AE for Each AED

CBZ LTG PHT VPA

total serious adverse events
% 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

possible mechanisms of aed effects on neurodevelopment
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

aeds apoptosis in developing brain
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

pregnancy registries their utility and role in guiding clinical decision making

Pregnancy Registries: Their Utility and Role in Guiding Clinical Decision Making

W. Allen Hauser, MD

College of Physicians and SurgeonsColumbia UniversityNew York, NY

malformations in infants of mothers with epilepsy
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

Mueller-Kuepper M. Acta Paedopsychiatr. 1963.

Speidel BD, et al. Lancet. 1972.

congenital malformations increased in ime
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)
how do we choose the safest therapies
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
population based studies iceland
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%
population based studies iceland60
Population-Based Studies:Iceland
  • 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

population based studies rochester minnesota
Population-Based Studies:Rochester, 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.

population based studies rochester minnesota62
Population-Based Studies:Rochester, 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

how do we choose the safest therapies63
How Do We Choose the Safest Therapies?
  • Registries of malformations
    • Can be powerful but may be misleading
    • Little information regarding disease
    • Reasons for exposure
international database on malformations and drug exposure
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

malformation database
Malformation Database
  • Case-control methodology
  • Clefts: phenobarbital
  • Cardiac: phenobarbital, VPA, CBZ
  • Hypospadias: VPA
  • Limb reduction: VPA
  • Coarctation: VPA
  • Porencephaly: VPA

CBZ = carbamazepine; VPA = valproic acid

Arpino C, et al. Epilepsia. 2000.

malformation registries
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
record linkage systems
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.

record linkage
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.

hospital based registries
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

hospital based registries70
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

hospital based registries71
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.

hospital based registries72
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.

pregnancy registries
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
how do we choose the safest therapies74
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
international lamotrigine pregnancy registry
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%)

LTG = lamotrigine; VPA = valproic acid

Tennis P, et al. Epilepsia. 2002.

north american aed and pregnancy registry
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
north american aed and pregnancy registry77
North American AED and Pregnancy Registry
  • Prospective surveillance of AEDs in pregnancy
  • “Pure” prospective—no 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
north american aed and pregnancy registry78
North American AED and Pregnancy Registry
  • Comparison from rate of nonchromosomal congenital anomalies in 69277 births at Brigham and Women’s Hospital: 1.62%1
  • Comparison with internal “controls” and other pure prospective cases

1. Nelson K, Holmes LB. N Engl J Med. 1989.

north american aed and pregnancy registry79
North American AED and Pregnancy Registry
  • Data collected
    • Age
    • Parity
    • Smoking
    • Seizures during pregnancy
    • Folate supplementation
    • Other prenatal vitamins
    • Duration of epilepsy
north american aed and pregnancy registry80
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
north american aed and pregnancy registry81
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.

north american aed and pregnancy registry82
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
north american aed and pregnancy registry83
North American AED and Pregnancy Registry
  • Problems
    • Women predominantly Caucasian, well educated
    • Need for women to call
    • Reluctance of women to release medical data
slide84

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

slide85

http://www.massgeneral.org/aed/

To order materials, please contact the Registry at 1-888-233-2334 or send e-mail tomnambisan@partners.org

eurap
EURAP
  • 37 reporting countries with national coordinators
  • Prospective cases (before 16 weeks and without knowledge of outcome)
  • One central EURAP registry—Milan
  • Work through network of reporting physicians who also provide data
  • 1-year follow-up
eurap87
EURAP
  • As of May 2004
    • >4000 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
eurap88
EURAP

Supported by educational grants from GlaxoSmithKline:

  • Janssen-Cilag
  • Pfizer
  • Sanofi-Synthelabo
  • UCB Pharma
  • Novartis
eurap89
EURAP
  • Large number of centers but small numbers from some contributors
  • Unblinded assessment
  • Population heterogeneity
united kingdom epilepsy and pregnancy group
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
united kingdom epilepsy and pregnancy group91
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
conclusions92
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