Transcript Practice Parameter or Technology Assessment: TITLE (an

Practice Parameter Update: Management
issues for women with epilepsy—focus on
pregnancy (an evidence-based review)
Report of the Quality Standards Subcommittee and the
Therapeutics and Technology Assessment Subcommittee of the
American Academy of Neurology and the American Epilepsy
Society
C. L. Harden, MD; P. B. Pennell, MD; K. J. Meador, MD, FAAN; W. A. Hauser, MD,
FAAN; G. S. Gronseth, MD, FAAN; J. A. French, MD, FAAN; S. Wiebe, MD; D.
Thurman, MD, MPH; B. S. Koppel, MD, FAAN; J. Hopp, MD; T. Y. Ting, MD; C. A.
Hovinga, PharmD; B. Gidal, PharmD; P. W. Kaplan, MB, FRCP, FAAN; J. N.
Robinson, MD; A. N. Wilner, MD, FACP, FAAN; B. Vazquez, MD; L. Holmes, MD;
A. Krumholz, MD, FAAN; R. Finnell, PhD; P. O. Shafer, RN, MN; D. Hirtz, MD; C.
Le Guen
© 2009 American Academy of Neurology
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© 2009 American Academy of Neurology
Presentation Objectives
• To review the evidence on management of
women with epilepsy (WWE) who are
pregnant or plan pregnancy
- Risks of obstetrical complications, change in seizure
frequency, teratogenesis, poor perinatal outcomes,
breastfeeding, and change in blood levels
- Use of vitamin K and folic acid
• To present evidence-based
recommendations
© 2009 American Academy of Neurology
Overview
•
•
•
•
Background
Gaps in care
AAN guideline process
Analysis of evidence, conclusions,
recommendations
• Recommendations for future research
© 2009 American Academy of Neurology
Background
• Recent estimates of the U.S. population1 and the
prevalence of epilepsy2 indicate that approximately onehalf million WWE are of childbearing age.
• It has also been estimated that 3 to 5 births per thousand
will be to WWE.3
• Epilepsy is defined by the presence of recurrent,
unprovoked seizures, and the treatment is typically a
daily, long-term antiepileptic drug (AED) regimen.
• The majority of people with epilepsy have well-controlled
seizures, are otherwise healthy, and therefore expect to
participate fully in life experiences, including
childbearing.
© 2009 American Academy of Neurology
Gaps in Care
• There is a perceived need to analyze the evidence, if
any, for AEDs that have been widely prescribed over the
decade since 1998.
• Evidence was sought for maintaining seizure control
during pregnancy compared to seizure control before
conception.
• The evidence for low incidence of poor obstetrical
outcomes was not previously known before this
parameter update.
© 2009 American Academy of Neurology
AAN Guideline Process
Clinical Question
Evidence
Conclusions
Recommendations
© 2009 American Academy of Neurology
Clinical Questions
• The first step in developing guidelines is to
clearly formulate questions to be answered.
• Questions address areas of controversy,
confusion, or variation in practice.
• Questions must be answerable with data
from the literature.
• Answering the question must have the
potential to improve care/patient outcomes.
© 2009 American Academy of Neurology
Literature Search/Review
Rigorous, Comprehensive, Transparent
Complete
Search
Review abstracts
Review full text
Select articles
Relevant
© 2009 American Academy of Neurology
AAN Classification of
Evidence
• All studies rated Class I, II, III, or IV
• Five different classification systems:
– Therapeutic
• Randomization, control, blinding
– Diagnostic
• Comparison to gold standard
– Prognostic
– Screening
– Causation
© 2009 American Academy of Neurology
AAN Level of
Recommendations
• A = Established as effective, ineffective or harmful (or
established as useful/predictive or not useful/predictive)
for the given condition in the specified population.
• B = Probably effective, ineffective or harmful (or
probably useful/predictive or not useful/predictive) for the
given condition in the specified population.
• C = Possibly effective, ineffective, or harmful (or
possibly useful/predictive or not useful/predictive) for the
given condition in the specified population.
• U = Data inadequate or conflicting; given current
knowledge, treatment (test, predictor) is unproven.
Note that recommendations can be positive or negative.
© 2009 American Academy of Neurology
AAN Level of
Recommendations: Causality
• A = Risk factor is a highly probable contributor to the development
of disease or outcome. Recommendation: Risk factor should be
avoided or reduced, if possible. (Level A rating requires two or more
consistent Class I studies all showing an effect size (R.R.) ≥2 with
lower confidence limits >1. In addition, either (1) a causal inference
is coherent with known biologic mechanisms and related scientific
evidence or (2) findings clearly demonstrate that higher doses of
exposure increase likelihood of disease or outcome.)
• B = Risk factor is a probable contributor to the development of
disease or outcome. Recommendation: Risk factor avoidance or
reduction (if possible) should be considered. (Level B rating requires
at least one Class I study fulfilling other criteria above, OR two or
more consistent Class II studies, showing an effect size (R.R. or
O.R.) ≥1.5 with lower confidence limits >1.)
© 2009 American Academy of Neurology
AAN Level of
Recommendations: Causality
• C = Risk factor is a possible contributor to the development of
disease or outcome. Recommendation: Risk factor avoidance or
reduction (if possible) may be considered. (Level C rating requires 1
Class II or 2 or more Class III studies, showing effect estimate(s)
with consistent significant departure(s) from null value.)
• U = A causal relationship between the risk factor and disease or
outcome is unproven or unsupported. Recommendation: None.
(Evidence not meeting criteria for Class I – Class III.)
Note that recommendations can be positive or negative.
© 2009 American Academy of Neurology
Translating Class to
Recommendations
• A = Requires at least two consistent Class
I studies.*
• B = Requires at least one Class I study or
two consistent Class II studies.
• C = Requires at least one Class II study or
two consistent Class III studies.
• U = Studies not meeting criteria for
Class I through Class III.
© 2009 American Academy of Neurology
Translating Class to
Recommendations
* In exceptional cases, one convincing
Class I study may suffice for an “A”
recommendation if 1) all criteria are met,
2) the magnitude of effect is large (relative
rate improved outcome >5 and the lower
limit of the confidence interval is >2).
© 2009 American Academy of Neurology
Applying This Process
to the Issue
We will now turn our attention to the
guidelines.
© 2009 American Academy of Neurology
Clinical Questions
1.
2.
3.
4.
Do WWE have an increased risk of pregnancy-related
complications?
Do WWE have an increased risk of epilepsy-related
complications during pregnancy?
Do AEDs taken during the first trimester of pregnancy
increase the risk of major congenital malformations
(MCMs) in the offspring of WWE compared to the
offspring of WWE not on AEDs?
Is exposure to a specific AED during the first trimester
of pregnancy associated with an increased risk of
MCMs compared to exposure to other AEDs?
© 2009 American Academy of Neurology
Clinical Questions
5.
6.
7.
8.
9.
Is the risk of MCMs greater for AED polytherapy
compared to AED monotherapy when taken during the
first trimester of pregnancy?
Is there a relationship between AED dose and the risk
of MCMs in the offspring of WWE?
Are there specific MCMs associated with specific
AEDs?
Is cognitive outcome reduced in children of WWE who
are not exposed to AEDs in utero?
Is cognition reduced in children of WWE exposed to
AEDs in utero?
© 2009 American Academy of Neurology
Clinical Questions
10. Does AED polytherapy exposure during pregnancy
pose an increased risk for poor cognitive outcome
compared to monotherapy?
11. Is exposure to a specific AED in utero associated with
poor cognitive outcomes compared to other AEDs?
12. Is there an increased risk of small for gestational age
(SGA) outcomes in neonates born to WWE?
13. Is there an increased risk of perinatal death in
neonates born to WWE?
14. Are Apgar scores lower in neonates born to WWE?
15. Does preconceptional folic acid supplementation
reduce the risk of birth defects in neonates of WWE
taking AEDs?
© 2009 American Academy of Neurology
Clinical Questions
16. What is the risk of hemorrhagic disease in neonates
born to WWE taking AEDs?
17. Does prenatal vitamin K supplementation reduce the
risk of hemorrhagic complications in the newborns of
WWE taking AEDs?
18. Do maternally ingested AEDs cross the placenta or
penetrate into breast milk?
19. Does indirect exposure to maternally ingested AEDs
lead to symptomatic effects in the newborn?
20. For each of the AEDs, does pregnancy cause a
change in the levels of the medication or clearance of
the medication?
© 2009 American Academy of Neurology
Methods
• OVID MEDLINE, MEDLINE in Process,
Current Contents, Biological Abstracts,
and BIOSIS
– 1985 to June 2007 (with manual searches
through February 2008)
– Relevant, fully published, peer-reviewed
articles
© 2009 American Academy of Neurology
Methods
• Search terms
– seizures/epilepsy, catamenial epilepsy,
anticonvulsants, antiepileptic drugs
– pregnancy, pregnancy registry, breastfeeding,
oral contraceptives, polycystic ovary
syndrome, fertility
– teratogenesis, birth defects, cognitive
outcome, vitamin K, folate/folic acid
– hormone replacement therapy, menopause,
perimenopause
© 2009 American Academy of Neurology
Methods
• Four panelists reviewed each article for
inclusion.
• Risk of bias was determined using the
classification of evidence for each study
(Classes I–IV).
• Strength of practice recommendations were
linked directly to levels of evidence (Levels A, B,
C, and U).
• Conflicts of interest were disclosed.
© 2009 American Academy of Neurology
Literature Review
876 abstracts
285 articles
© 2009 American Academy of Neurology
Inclusion criteria:
- Relevant to the clinical
questions
- Limited to human
subjects
- Bibliographies, metaanalyses, and articles
identified by panel
members
Exclusion criteria:
- Articles relevant to
eclampsia rather than
seizures due to epilepsy
or basic mechanisms such
as teratogenesis or
placental AED metabolism
AAN Classification of Evidence
for Screening
•
Class I: A statistical, population-based sample of patients studied at a uniform point in
time (usually early) during the course of the condition. All patients undergo the
intervention of interest. The outcome, if not objective, is determined in an evaluation
that is masked to the patients’ clinical presentations.
•
Class II: A statistical, non-referral-clinic-based sample of patients studied at a uniform
point in time (usually early) during the course of the condition. Most patients undergo
the intervention of interest. The outcome, if not objective, is determined in an
evaluation that is masked to the patients’ clinical presentations.
•
Class III: A sample of patients studied during the course of the condition. Some
patients undergo the intervention of interest. The outcome, if not objective, is
determined in an evaluation by someone other than the treating physician.
•
Class IV: Studies not meeting Class I, II or III criteria including consensus, expert
opinion or a case report.
© 2009 American Academy of Neurology
AAN Classification of Evidence
for Causality
•
Class I: Prospective cohort study design that satisfies these criteria: (a) groups
studied are representative of population of interest (‘broad spectrum’); (b) risk factors
and outcomes are clearly defined with validated or generally accepted criteria, and
measured independently or objectively; (c) comparison groups are matched for
known possible confounding risk factors, or the effects of such confounders are
controlled in the study analysis; AND (d) measures of association are expressed (or
can be calculated) as rate ratios, risk ratios, relative risks (R.R.) or population
attributable risks with confidence intervals.
•
Class II: Retrospective cohort or case-control study designs that satisfy criteria (a),
(b), and (c) above, in which (d) the measure of association may also be expressed (or
can be calculated) as an odds ratio (O.R.) with confidence intervals.
•
Class III: Other cohort or case-control study designs in which groups studied
represent a narrow spectrum of the population of interest, or the measure of
association does not include an R.R. or O.R. but does include an aggregate measure
such as a correlation or group mean with standard deviation or p-value. Criterion (b)
above must still be satisfied. Obvious confounding is not evident.
© 2009 American Academy of Neurology
AAN Classification of Evidence
for Causality
•
Class IV: Studies not meeting criteria for Class I, II, or III. Specifically, studies that are
non-comparative, unrepresentative of the population of interest, with major biases or
confounding, lacking useful measures of effect, or lacking measures of effect
estimate stability.
•
Notes: In addition to the criteria above, any causal inference requires that exposure
to the risk factor precede the development of the outcome. In addition, there may be
need to allow for an induction period. In translating evidence, a requirement of two or
more studies implies that such studies should not include the same subjects.
Exploratory studies involving multiple comparisons of a variety of exposures and
outcomes may be rated lower if it is evident that the study was designed without an a
priori hypothesis or focus upon the specific exposure and outcome of interest.
Randomized clinical trials (RCTs) are equivalent to prospective cohort studies in
which the risk of confounding has been minimized. Evidence from such studies may
be considered Class I, provided it satisfies criteria (a), (b), and (d) above. Note,
however, that it is preferable to apply the AAN criteria for therapeutic studies when
classifying evidence pertaining to the experimental (treatment) variables of an RCT.
© 2009 American Academy of Neurology
AAN Classification of Evidence
for Prognosis
•
Class I: Evidence provided by a prospective study of a broad spectrum of persons
who may be at risk for developing the outcome (e.g. target disease, work status). The
study measures the predictive ability using an independent gold standard for case
definition. The predictor is measured in an evaluation that is masked to clinical
presentation and the outcome is measured in an evaluation that is masked to the
presence of the predictor. All patients have the predictor and outcome variables
measured.
•
Class II: Evidence provided by a prospective study of a narrow spectrum of persons
at risk for having the condition, or by a retrospective study of a broad spectrum of
persons with the condition compared to a broad spectrum of controls. The study
measures the prognostic accuracy of the risk factor using an acceptable independent
gold standard for case definition. The risk factor is measured in an evaluation that is
masked to the outcome.
© 2009 American Academy of Neurology
AAN Classification of Evidence
for Prognosis
•
Class III: Evidence provided by a retrospective study where either the persons with
the condition or the controls are of a narrow spectrum. The study measures the
predictive ability using an acceptable independent gold standard for case definition.
The outcome, if not objective, is determined by someone other than the person who
measured the predictor.
•
Class IV: Any design where the predictor is not applied in an independent evaluation
OR evidence provided by expert opinion or case series without controls.
© 2009 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Intervention
•
Class I: A randomized, controlled clinical trial of the intervention of interest with
masked or objective outcome assessment, in a representative population. Relevant
baseline characteristics are presented and substantially equivalent among treatment
groups or there is appropriate statistical adjustment for differences. The following are
also required**: a. concealed allocation, b. primary outcome(s) clearly defined, c.
exclusion/inclusion criteria clearly defined, d. adequate accounting for drop-outs (with
at least 80% of enrolled subjects completing the study) and cross-overs with numbers
sufficiently low to have minimal potential for bias. e. For non inferiority or equivalence
trials claiming to prove efficacy for one or both drugs, the following are also
required***: 1. The authors explicitly state the clinically meaningful difference to be
excluded by defining the threshold for equivalence or non-inferiority. 2. The standard
treatment used in the study is substantially similar to that used in previous studies
establishing efficacy of the standard treatment. (e.g. for a drug, the mode of
administration, dose and dosage adjustments are similar to those previously shown to
be effective). 3. The inclusion and exclusion criteria for patient selection and the
outcomes of patients on the standard treatment are comparable to those of previous
studies establishing efficacy of the standard treatment. 4. The interpretation of the
results of the study is based upon a per protocol analysis that takes into account
dropouts or crossovers.
© 2009 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Intervention
•
Class II: A randomized controlled clinical trial of the intervention of interest in a
representative population with masked or objective outcome assessment that lacks
one criteria a–e above or a prospective matched cohort study with masked or
objective outcome assessment in a representative population that meets b–e above.
Relevant baseline characteristics are presented and substantially equivalent among
treatment groups or there is appropriate statistical adjustment for differences.
•
Class III: All other controlled trials (including well-defined natural history controls or
patients serving as own controls) in a representative population, where outcome is
independently assessed, or independently derived by objective outcome
measurement.
•
Class IV: Studies not meeting Class I, II or III criteria including consensus or expert
opinion.
© 2009 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Intervention
•
**Note that numbers 1–3 in Class Ie are required for Class II in equivalence trials. If
any one of the three is missing, the class is automatically downgraded to Class III.
•
***Objective outcome measurement: an outcome measure that is unlikely to be
affected by an observer’s (patient, treating physician, investigator) expectation or bias
(e.g., blood tests, administrative outcome data).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 1: Do WWE have an
increased risk of pregnancy-related
complications?
© 2009 American Academy of Neurology
Conclusions
– Based on evidence from one Class I and one Class II study, it is
probable that WWE taking AEDs do not have a substantially
increased risk of Cesarean delivery. Because of the lack of
statistical precision in the Class I and Class II studies and the
evidence from multiple Class III studies, a moderately increased
risk of Cesarean delivery is possible.
– There is insufficient evidence to support or refute an increased
risk of pre-eclampsia in WWE taking AEDs.
– Based on results from two conflicting Class II studies, there is
insufficient evidence to support or refute an increased risk of
pregnancy-induced hypertension in WWE.
© 2009 American Academy of Neurology
Conclusions, cont.
– Based on evidence from one Class I study, it is probable that
WWE taking AEDs do not have a moderately increased risk of
premature contractions and premature labor and delivery during
pregnancy. However, based on evidence from one Class II
study, it is possible that WWE who smoke do have a
substantially increased risk of premature contractions and
premature labor and delivery during pregnancy compared to
women without epilepsy who smoke.
– Based on evidence from one Class I and one Class III study, it is
probable that WWE taking AEDs do not have a substantially
increased risk of late pregnancy-related bleeding complications.
However, because of a lack of statistical precision in this study, a
moderately increased risk cannot be excluded.
– Data are inadequate to support or refute an increased risk of
spontaneous abortion in WWE.
© 2009 American Academy of Neurology
Recommendations
Counseling of WWE who are pregnant or are contemplating
pregnancy should reflect that:
– there is probably no substantially increased risk (greater than 2
times expected) of Cesarean delivery for WWE taking AEDs
(Level B). However, there is possibly a moderately increased
risk (up to 1.5 times expected) of Cesarean delivery for WWE
taking AEDs (Level C).
– there is probably no substantially increased risk (greater than 2
times expected) of late pregnancy bleeding for WWE taking
AEDs (Level B).
– there is probably no moderately increased risk (greater than 1.5
times expected) of premature contractions or premature labor
and delivery for WWE taking AEDs (Level B).
© 2009 American Academy of Neurology
Recommendations, cont.
Counseling of WWE who are pregnant or are contemplating
pregnancy should reflect that:
– there is possibly a substantially increased risk of premature
contractions and premature labor and delivery during pregnancy
for WWE who smoke (Level C).
– there is insufficient evidence to support or refute an increased
risk of pre-eclampsia, pregnancy-related hypertension, or
spontaneous abortion (Level U).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 2: Do WWE have an
increased risk of epilepsy-related
complications during pregnancy?
© 2009 American Academy of Neurology
Conclusions
– There is insufficient evidence to determine the change in seizure
frequency in pregnant WWE.
– There is insufficient evidence to support or refute an increased
risk of status epilepticus in pregnant WWE.
– Two Class II articles show the rate of remaining seizure free
during pregnancy if WWE are seizure free for at least 9 months
to 1 year prior to pregnancy is probably 84 ̶ 92%.
© 2009 American Academy of Neurology
Recommendations
Counseling of WWE who are pregnant or are contemplating
pregnancy should reflect that:
– seizure freedom for at least 9 months prior to pregnancy is
probably associated with a high likelihood (84 ̶ 92%) of
remaining seizure free during pregnancy (Level B).
– there is insufficient evidence to support or refute an increased
risk of a change in seizure frequency or status epilepticus (Level
U).
© 2009 American Academy of Neurology
Clinical Context
– Some of the most important findings of this practice parameter
are what they do not demonstrate. There was no conclusive
evidence of an increased risk of many obstetrical complications
often discussed as associated with WWE during pregnancy. This
raises the possibility that there is no true difference in the rates
of obstetrical complications in WWE compared to the general
population.
– Further, the findings do not suggest high rates of seizure
increase or status epilepticus during pregnancy or an increased
risk of seizure relapse during pregnancy for WWE who are
seizure free. The data available to determine how seizure-free
WWE fare during pregnancy indicate it is likely that they will
remain seizure free, providing practitioners with another reason
to strive for seizure freedom in their patients planning pregnancy.
© 2009 American Academy of Neurology
Clinical Context
̶
It is hoped that this information will herald a new outlook about
how high (or low) the actual risk is for health complications in
WWE who become pregnant, and may serve to decrease the
anxiety and perhaps the stigma produced by this clinical
situation for both patient and practitioner.
© 2009 American Academy of Neurology
Analysis of Evidence
Question 3: Do AEDs taken during the
first trimester of pregnancy increase
the risk of MCMs in the offspring of
WWE compared to the offspring of
WWE not on AEDs?
© 2009 American Academy of Neurology
Conclusions
– AEDs taken during the first trimester probably increase the risk
of MCMs in the offspring of WWE (two adequately sensitive
Class II studies) but it cannot be determined if the increased risk
is imparted from all AEDs or from only one or some AEDs.
– Valproate (VPA) monotherapy during the first trimester possibly
increases the risk of MCMs in the offspring of WWE (one Class II
study).
– VPA used in polytherapy probably increases the risk of MCMs in
the offspring of WWE (one Class I study).
– Carbamazepine (CBZ) probably does not substantially increase
the risk of MCMs in the offspring of WWE (one Class I study).
– There is insufficient evidence to determine if lamotrigine (LTG)
(one inadequately sensitive Class I study) or other specific AEDs
(no Class III or better evidence) increase the risk of MCMs in the
offspring of WWE.
–
© 2009 American Academy of Neurology
Recommendations
– Although there is evidence that AEDs taken during the first
trimester probably increase the risk of MCMs in the offspring of
WWE, it cannot be determined if the increased risk is imparted
from all AEDs or from only one or some AEDs. Therefore, no
recommendation is made from this conclusion (Level U).
– If possible, avoidance of the use of VPA as part of polytherapy
during the first trimester of pregnancy should be considered to
decrease the risk of MCMs (Level B).
– If possible, avoidance of the use of VPA monotherapy during the
first trimester of pregnancy may be considered to decrease the
risk of MCMs (Level C).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 4: Is exposure to a specific
AED during the first trimester of
pregnancy associated with an
increased risk of MCMs compared to
exposure to other AEDs?
© 2009 American Academy of Neurology
Conclusions
– It is highly probable that taking VPA monotherapy during the first
trimester of pregnancy contributes to the development of MCMs
in the offspring of WWE compared to taking CBZ (two Class I
studies).
– VPA as part of polytherapy in the first trimester of pregnancy
probably contributes to the development of MCMs in the
offspring of WWE compared to polytherapy that does not include
VPA (one Class I and one Class II study).
– Taking VPA during the first trimester of pregnancy possibly
contributes to the development of MCMs in the offspring of WWE
compared to taking phenytoin (PHT) (one Class II study).
– Taking VPA during the first trimester of pregnancy possibly
contributes to the development of MCMs in the offspring of WWE
compared to taking lamotrigine (LTG) (one Class II study).
© 2009 American Academy of Neurology
Recommendations
– To reduce the risk of MCMs, the use of VPA during the first
trimester of pregnancy should be avoided, if possible, compared
to the use of CBZ (Level A).
– To reduce the risk of MCMs, avoidance of the use of polytherapy
with VPA during the first trimester of pregnancy, if possible,
should be considered, compared to polytherapy without VPA
(Level B).
– To reduce the risk of MCMs, avoidance of the use of VPA during
the first trimester of pregnancy, if possible, may be considered,
compared to the use of PHT or LTG (Level C).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 5: Is the risk of MCMs greater
for AED polytherapy compared to AED
monotherapy when taken during the
first trimester of pregnancy?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– Polytherapy probably contributes to the development of MCMs in
the offspring of WWE as compared to monotherapy .
Recommendation:
– To reduce the risk of MCMs, avoidance of the use of AED
polytherapy during the first trimester of pregnancy, if possible,
compared to monotherapy should be considered (Level B).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 6: Is there a relationship
between AED dose and the risk of
MCMs in the offspring of WWE?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– There is probably a relationship between the dose of VPA and
LTG and the risk of development of MCMs in the offspring of
WWE (one Class I study).
Recommendation:
– Limiting the dosage of VPA or LTG during the first trimester, if
possible, should be considered to lessen the risk of MCMs
(Level B).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 7: Are there specific MCMs
associated with specific AEDs?
© 2009 American Academy of Neurology
Conclusions
Conclusions:
– PHT exposure in utero possibly contributes to the risk of cleft
palate (one Class II study).
– CBZ exposure in utero possibly contributes to the risk of
posterior cleft palate (one Class II study).
– VPA exposure in utero probably contributes to neural tube
defects and facial clefts (one Class I study) and possibly
contributes to hypospadias (one Class II study).
– Phenobarbital (PB) exposure in utero possibly contributes to
cardiac malformations (two Class III studies).
© 2009 American Academy of Neurology
Recommendations
– Avoidance of the use of VPA, if possible, should be considered
to reduce the risk of neural tube defects and facial clefts (Level
B) and may be considered to reduce the risk of hypospadias
(Level C).
– Avoidance of PHT, CBZ, and PB, if possible, may be considered
to reduce the risk of specific MCMs: cleft palate for PHT use,
posterior cleft palate for CBZ use, and cardiac malformations for
PB use (Level C).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 8: Is cognitive outcome
reduced in children of WWE who are
not exposed to AEDs in utero?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– Cognition is probably not reduced in children of WWE who are
not exposed to AEDs in utero (two Class II studies).
Recommendation:
– Counseling of WWE who are contemplating pregnancy should
reflect that there is probably no increased risk of reduced
cognition in the offspring of WWE not taking AEDs (Level B).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 9: Is cognition reduced in
children of WWE exposed to AEDs in
utero?
© 2009 American Academy of Neurology
Conclusions
– There is insufficient evidence to determine if the children of
WWE on AEDs in general are at increased risk for reduced
cognition (conflicting Class II studies).
– CBZ probably does not increase poor cognitive outcomes
compared to unexposed controls (two Class II studies).
– VPA is probably associated with poor cognitive outcomes
compared to unexposed controls (two Class II studies).
– PHT is possibly associated with poor cognitive outcomes
compared to unexposed controls (one Class II and two Class III
studies).
– PB is possibly associated with poor cognitive outcomes in male
offspring of WWE compared to unexposed controls (two Class III
studies).
© 2009 American Academy of Neurology
Recommendations
Recommendations:
– Avoiding VPA in WWE during pregnancy, if possible, should be
considered to reduce the risk of poor cognitive outcomes (Level
B).
– Avoiding PHT in WWE during pregnancy, if possible, may be
considered to reduce the risk of poor cognitive outcomes (Level
C).
– Avoiding PB in WWE during pregnancy, if possible, may be
considered to reduce the risk of poor cognitive outcomes (Level
C).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 10: Does AED polytherapy
exposure during pregnancy pose an
increased risk for poor cognitive
outcome compared to monotherapy?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– Cognitive outcomes are probably reduced in children exposed to
AED polytherapy as compared to monotherapy in utero (three
Class II studies).
Recommendation:
– Monotherapy should be considered in place of polytherapy, if
possible, for WWE who take AEDs during pregnancy, to reduce
the risk of poor cognitive outcomes (Level B).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 11: Is exposure to a specific
AED in utero associated with poor
cognitive outcomes compared to other
AEDs?
© 2009 American Academy of Neurology
Conclusions/Recommendations
Conclusions:
– Cognitive outcomes are probably reduced in children exposed to
VPA during pregnancy compared to CBZ (two Class II studies).
– Cognitive outcomes are possibly reduced in children exposed to
VPA during pregnancy compared to PHT (one Class II study).
Recommendations:
– For WWE who are pregnant, avoidance of VPA, if possible,
should be considered, compared to CBZ to reduce the risk of
poor cognitive outcomes (Level B).
– For WWE who are pregnant, avoidance of VPA, if possible, may
be considered compared to PHT to reduce the risk of poor
cognitive outcomes (Level C).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 12: Is there an increased risk
of small for gestational age (SGA)
outcomes in neonates born to WWE?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– Neonates of WWE taking AEDs probably have an increased risk
of SGA of about twice the expected rate (two Class II studies).
Recommendation:
– Pregnancy risk stratification should reflect that the offspring of
WWE taking AEDs during pregnancy probably have an
increased risk of SGA. Further, AED use in WWE during
pregnancy should be considered in the differential diagnosis of
SGA in their offspring (Level B).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 13: Is there an increased risk
of perinatal death in neonates born to
WWE?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– There is probably no substantially increased risk of perinatal
death in neonates born to WWE (two Class II studies).
Recommendation:
– Pregnancy risk stratification should reflect that neonates born to
WWE probably do not have a substantially increased risk of
perinatal death (Level B).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 14: Are Apgar scores lower in
neonates born to WWE?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– Neonates of WWE taking AEDs possibly have an increased risk
of 1-minute Apgar scores of <7 of about twice the expected rate
(one Class II study).
Recommendation:
– Pregnancy risk stratification should reflect that the offspring of
WWE taking AEDs during pregnancy possibly have an increased
risk of 1-minute Apgar scores of <7. Further, AED use in WWE
during pregnancy may be considered in the differential diagnosis
of a 1-minute Apgar score of <7 in their offspring (Level C).
© 2009 American Academy of Neurology
Clinical Context
– This parameter focuses on the pregnancy-related risks of AEDs.
However, it does not evaluate the risks of not taking AEDs
during pregnancy. The seizure-prevention benefits of taking
AEDs are clear for the nonpregnant patient and these same
benefits apply for the pregnant patient and extend to the
protection of the fetus from maternal seizures. Although many of
the recommendations in this parameter suggest minimizing AED
exposure during pregnancy, for most WWE, discontinuing AEDs
is not a reasonable or safe option. Although the risks of seizures
during pregnancy have not been systematically studied,
discontinuing AEDs may expose the mother and fetus to
physical injury from accidents arising from partial or generalized
seizures. Decision pathways to assist in deciding when to
discontinue AEDs are available.4
© 2009 American Academy of Neurology
Clinical Context
– Based upon the evidence reviewed, it seems reasonable to
switch WWE of childbearing potential to a less teratogenic
regimen when possible. The use of VPA is a particular dilemma.
While VPA is an effective AED,5 it emerges as the AED with the
greatest number of data showing an association with risk from
in-utero exposure. If the change from VPA to another AED is
planned, it seems prudent to do this well before pregnancy to
make sure the new treatment adequately prevents seizures.
Changing to another AED during pregnancy poses risk of
allergy, other serious adverse reactions, and polytherapy
exposure. Once a patient is pregnant, changing from VPA
several weeks into gestation will not avoid the risk of MCMs,
since this phenomenon occurs very early in pregnancy. This may
also apply to cognitive teratogenesis, since the timing of
exposure related to this adverse outcome is unknown.
© 2009 American Academy of Neurology
Clinical Context
– For many AEDs, in particular the newer AEDs, there were too
few patients in the studies to make conclusions, and the
teratogenicity of these drugs is unknown.
– The finding that some MCMs occur more frequently with specific
AED exposure needs to be viewed in context. MCMs seen more
frequently with VPA, such as neural tube defects, can also be
present with exposure to other AEDs, demonstrating that this is
not an AED-specific MCM. Like other teratogens, AEDs as a
teratogenic category produce a pattern of MCMs with overlap
amongst the individual AEDs.
© 2009 American Academy of Neurology
Analysis of Evidence
Question 15: Does preconceptional
folic acid supplementation reduce the
risk of birth defects in neonates of
WWE taking AEDs?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– The risk of MCMs in the offspring of WWE is possibly decreased
by folic acid supplementation (two adequately sensitive Class III
studies).
Recommendation:
– Preconceptional folic acid supplementation in WWE may be
considered to reduce the risk of MCMs (Level C).
© 2009 American Academy of Neurology
Clinical Context
– Folic acid supplementation is generally recommended to reduce
the risk of MCMs during pregnancy,6 and although the data are
insufficient to show that it is effective in WWE, there is no
evidence of harm and no reason to suspect that it would not be
effective in this group. Therefore, the strength of this evidence
should not impact the current folic acid supplementation
recommendation that all women of childbearing potential, with or
without epilepsy, be supplemented with at least 0.4 mg of folic
acid daily prior to conception and during pregnancy.7 There was
insufficient published information to address the dosing of folic
acid and whether higher doses offer greater protective benefit to
WWE taking AEDs.
© 2009 American Academy of Neurology
Analysis of Evidence
Question 16: What is the risk of
hemorrhagic disease in neonates born
to WWE taking AEDs?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– There is insufficient evidence to determine if the risk of neonatal
hemorrhagic complications in the newborns of WWE taking
AEDs is substantially increased (one inadequately sensitive
Class II study).
Recommendation:
– Counseling of WWE who are pregnant or are contemplating
pregnancy should reflect that there is insufficient evidence to
support or refute an increased risk of hemorrhagic complications
in the newborns of WWE taking AEDs (Level U).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 17: Does prenatal vitamin K
supplementation reduce the risk of
hemorrhagic complications in the
newborns of WWE taking AEDs?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– Evidence is inadequate to determine if prenatal vitamin K
supplementation in WWE reduces neonatal hemorrhagic
complications.
Recommendation:
– There is insufficient evidence to support or refute a benefit of
prenatal vitamin K supplementation for reducing the risk of
hemorrhagic complications in the newborns of WWE (Level U).
© 2009 American Academy of Neurology
Clinical Context
– Newborns exposed to enzyme-inducing AEDs in utero routinely
receive vitamin K at delivery, as is the routine practice for all
newborns.8
© 2009 American Academy of Neurology
Analysis of Evidence
Question 18: a) Do maternally ingested
AEDs cross the placenta? b) Do
maternally ingested AEDs penetrate
into breast milk?
© 2009 American Academy of Neurology
Conclusions
– PB, primidone (PRM), PHT, CBZ, levetiracetam (LVT), and VPA
probably cross the placenta in potentially clinically important
amounts (one Class I and supporting Class II studies or two or
more Class II studies).
– Gabapentin (GBP), LTG, oxcarbazepine (OXC), and topiramate
(TPM) possibly cross the placenta in potentially clinically
important amounts (at least one Class II study for each).
– There are insufficient data to determine if ethosuximide (ESM)
crosses the placenta in clinically important amounts (one Class
III study showing significant penetration).
© 2009 American Academy of Neurology
Conclusions, cont.
– PRM and LVT probably penetrate into breast milk in potentially
clinically important amounts (one Class I study and a supporting
Class II study or two Class II studies).
– GBP, LTG, and TPM possibly penetrate into breast milk in
potentially clinically important amounts (one Class II study each).
– VPA, PB, PHT, and CBZ probably do not penetrate into breast
milk in potentially clinically important amounts (one Class I study
and a supporting Class II study or two Class II studies).
– There are insufficient data to determine if ESM penetrates breast
milk in clinically important amounts (one Class III study showing
significant transfer).
© 2009 American Academy of Neurology
Recommendations
– The fact that PB, PRM, PHT, CBZ, LVT, VPA, GBP, LTG, OXC
and TPM cross the placenta may be factored into the clinical
decision regarding the necessity of AED treatment for a woman
with epilepsy (Level B for PB, PRM, PHT, CBZ, LVT, and VPA
and Level C for GBP, LTG, OXC, and TPM).
– VPA, PB, PHT, and CBZ may be considered as not transferring
into breast milk to as great an extent as PRM, LVT, GBP, LTG,
and TPM (Level B when compared to PRM and LVT and Level
C when compared to GBP, LTG and TPM).
© 2009 American Academy of Neurology
Clinical Context
– Because of small sample size, there was no way to analyze the
potential contribution of other clinical factors, such as AED
polytherapy, on the passive transfer of AEDs to newborns of
WWE.
© 2009 American Academy of Neurology
Analysis of Evidence
Question 19: Does indirect exposure to
maternally ingested AEDs lead to
symptomatic effects in the newborn?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– There is no evidence to determine if indirect exposure to
maternally ingested AEDs has symptomatic effects on the
newborns of WWE.
Recommendation:
– No recommendation is made (Level U).
© 2009 American Academy of Neurology
Clinical Context
– Certainly many of the AEDs cross through the placenta or into
breast milk in measurable concentrations, with some meaningful
differences in AEDs, particularly for breast milk transfer. The
clinical consequences for the newborn of ingesting AEDs via
breast milk remain sorely underexplored and will continue to
produce anxiety in WWE bearing children and all who care for
these clinical dyads.
© 2009 American Academy of Neurology
Analysis of Evidence
Question 20: For each of the AEDs,
does pregnancy cause a change in the
levels of the medication or clearance of
the medication?
© 2009 American Academy of Neurology
Conclusions
– Pregnancy probably causes an increase in the clearance and a
decrease in the level of LTG during pregnancy. The decrease in
LTG level is associated with an increase in seizure frequency
(one Class I and two Class II studies).
– Pregnancy probably causes a small decrease in concentration of
CBZ (9% in second trimester and 12% in third trimester) (one
Class I study).
– Pregnancy probably causes an increase in the clearance and a
decrease in the level of PHT during pregnancy (one Class I
study).
– Pregnancy possibly causes a decrease in the level of the active
OXC metabolite, monohydroxy derivative (MHD) (two Class III
studies).
© 2009 American Academy of Neurology
Conclusions, cont.
– Pregnancy possibly causes a decrease in the level of LVT (one
Class II study).
– Evidence for a change in clearance or level of PB, VPA, PRM,
and ESM during pregnancy is inadequate to reach a conclusion.
© 2009 American Academy of Neurology
Recommendations
– Monitoring of LTG, CBZ, and PHT levels during pregnancy
should be considered (Level B).
– Monitoring of LVT and OXC (as MHD) levels during pregnancy
may be considered (Level C).
– There is insufficient evidence to support or refute a change in
PB, VPA, PRM, or ESM levels related to pregnancy (Level U),
and this lack of evidence should not discourage monitoring
levels of these AEDs during pregnancy.
© 2009 American Academy of Neurology
Clinical Context
– The studies reviewed provide some evidence supporting active
monitoring of AED levels during pregnancy. This is especially
true for LTG where changes in LTG levels were associated with
increases in seizure frequency. It seems reasonable to
individualize this monitoring for each patient with the aim of
maintaining a level near the preconceptional level, presumably at
which the woman with epilepsy was doing well with seizure
control. However, the studies reviewed fall short of determining
that adoption of an active AED monitoring program would result
in improved seizure control during pregnancy.
© 2009 American Academy of Neurology
Clinical Context
– Unfortunately, the studies reviewed provided no clear data on
the timing of the return to the prepregnancy pharmacokinetic
state after pregnancy. One study9 demonstrated that following an
empiric postpartum taper schedule of LTG reduced the
occurrence of postpartum toxicity, but more systematic
information is needed regarding the pharmacokinetic alterations
in AED metabolism postpartum for all AEDs in order to
determine the management of AED dosing in the postpartum
period.
© 2009 American Academy of Neurology
Future Research
– Stronger evidence is needed to determine if there are increased
risks of pre-eclampsia, pregnancy-induced hypertension, and
spontaneous abortion for WWE. These risks should be
evaluated in large, prospective, studies using well-matched
control groups. The effect of specific AEDs on obstetrical
outcomes also remains unexplored and deserves further study.
The existing databases for evaluating the outcomes of
pregnancies exposed to AEDs could potentially provide a source
for such information. Further evaluation for the risks of seizure
increase during pregnancy should be done, using prospective
baseline information when possible. This type of analysis would
help to reveal more information about the causes of seizure
increase during pregnancy, which may be more complicated
than AED noncompliance, decreased levels due to pregnancy
metabolism, or lack of sleep. For example, the effect of the
© 2009 American Academy of Neurology
Future Research
hormonal changes during pregnancy on seizure frequency could
be evaluated in a careful, prospective study.
– Although this parameter answers some questions, it raises
others that make this clinical situation even more challenging.
The parameter shows an increased risk of MCMs with VPA
exposure, but there is a paucity of specific information about the
absolute risk of most other AEDs. This is particularly true for the
newer AEDs, several of which are reasonable alternatives to
VPA. With ongoing data submission to AED pregnancy
registries, it is hoped that this information will soon be
forthcoming.
– The existence of an AED dose-malformation relationship needs
to be clarified for all AEDs, with the incorporation of serum levels
as well. Adverse neonatal outcomes and long-term cognitive
© 2009 American Academy of Neurology
Future Research
outcomes of children exposed to AEDs in utero for both the older
and newer AEDs need further clarification, as do the short-term
and long-term cognitive risks of AED exposure in the neonatal
and infantile periods through breastfeeding.
– In addition, future research should begin to evaluate metabolic
systems for which modification could lower teratogenic risk, such
as glutathione reductase, superoxide dismutase, epoxide
hydrolase, and other toxin-scavenging mechanisms. Further, the
interactions between AEDs and molecular targets such as
histone deacetylase and peroxisome proliferator-activated
receptors may play a role in teratogenesis. Greater
understanding of these factors may eventually permit an
individualized assessment of teratogenic risk for WWE taking
AEDs.10
© 2009 American Academy of Neurology
Future Research
– The issue of whether preconceptional folic acid supplementation
for WWE, particularly at high doses, provides additional benefit
in preventing MCMs needs to be clarified. Similarly, the risk of
hemorrhagic disease of the newborn in neonates born to WWE
taking AEDs and whether late-pregnancy vitamin K
supplementation could be beneficial need to be determined.
Studies of some commonly used AEDs were so limited that no
recommendations could be made regarding these specific
medications, such as zonisamide or TPM.
© 2009 American Academy of Neurology
Future Research
– Although many of the AEDs were shown to cross the placenta or
enter breast milk, studies were limited in duration and did not
systematically evaluate neonatal symptoms; more defined study
on acute and prolonged outcomes in exposed neonates needs to
be performed. This is particularly true for more subtle side
effects, such as cognition and general healthy neonatal
development. Information about how AED levels change during
pregnancy based on individual metabolic capacity, as well as
neonatal metabolism of AEDs consumed through breast milk, is
needed in order to guide dosing and clinical monitoring of both
mother and infant.
© 2009 American Academy of Neurology
Acknowledgments
The authors thank Andres M. Kanner, MD;
Alison M. Pack, MD; and Carmel Armon, MD,
FAAN, for their participation in the campaign to
raise awareness about the guidelines and for
their contributions to the development of
summary versions of the guidelines.
© 2009 American Academy of Neurology
References
1.
2.
3.
4.
5.
United States Department of Health and Human Services, Centers for Disease
Control and Prevention, National Center for Health Statistics, Bridged-Race
Population Estimates, United States. July 1st resident population by state, county,
age, sex, bridged-race, and Hispanic origin on CDC WONDER On-line Database.
http://wonder.cdc.gov.
Hirtz D, Thurman DJ, Gwinn-Hardy K, et al., How common are the “common”
neurologic disorders? Neurology 2007;68:326-337.
Yerby MS. Quality of life, epilepsy advances, and the evolving role of
anticonvulsants in women with epilepsy. Neurology 2000;55:S21-31.
Chadwick D. Starting and stopping treatment for seizures and epilepsy. Epilepsia
2006;47(Suppl 1):58-61.
Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of
valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an
unblinded randomised controlled trial. Lancet 2007;369(9566):970-971.
© 2009 American Academy of Neurology
References
6.
Czeizel AE, Dobó M, Vargha P. Hungarian cohort-controlled trial of periconceptional
multivitamin supplementation shows a reduction in certain congenital abnormalities.
Birth Defects Res A Clin Mol Teratol. 2004;70(11):853-861.
7. Recommendations for the use of folic acid to reduce the number of cases of spina
bifida and other neural tube defects. Morbidity and Mortality Weekly Report 1992;
September 11/41(RR-14):001.
8. American Academy of Pediatrics Vitamin K Ad Hoc Task Force: Controversies
concerning vitamin K and the newborn. Pediatrics. 1993 May;91(5):1001-1003.
9. Pennell PB, Peng L, Newport DJ, et al. Lamotrigine in pregnancy: clearance,
therapeutic drug monitoring, and seizure frequency. Neurology 2008;70:2130-2136.
10. Sankar R. Teratogenicity of antiepileptic drugs: role of drug metabolism and
pharmacogenomics. Acta Neurol Scand 2007;117:65-71.
For a complete list of references, please access the full guidelines at
www.aan.com/guidelines
© 2009 American Academy of Neurology
Questions/Comments
© 2009 American Academy of Neurology
Thank you for your
participation!
© 2009 American Academy of Neurology