The Quality Standards subcommittee (QSS) seeks to develop scientifically sound and clinically relevant practice parameters for the practice of neurology. Practice parameters are strategies for patient management that assist physicians in clinical decision making. They may include:

STANDARD:
Generally accepted principles for patient management that reflect a high degree of clinical certainty.

GUIDELINE:
Recommendations for patient management that may identify a particular strategy or range of management strategies and that reflect moderate clinical certainty.

PRACTICE OPTION/ADVISORY:
Other strategies for patient management for which there is unclear clinical certainty (i.e., based on inconclusive or conflicting evidence or opinion).

Pregnancy may affect a patient's epilepsy, the patient's epilepsy may affect the developing fetus, and antiepileptic drugs (AEDs) may affect the developing fetus. Although there are many aspects of importance regarding pregnancy and epilepsy, such as fertility, the biological and social consequences of epilepsy, the impact of the underlying etiology of the epilepsy, genetic factors, etc. this practice parameter is intended to address the question: How should a woman with epilepsy and her AEDs be managed during pregnancy?

II. JUSTIFICATION:

A. Frequency: Epilepsy affects approximately 1 % of the population, and an estimated 1.1 million women in the United States with epilepsy are in the childbearing age range (1). Women with epilepsy (WWE) may experience an increase in seizures during pregnancy, and their children are at risk of a variety of adverse pregnancy outcomes (2).

B. Controversy: Controversy remains regarding the causes of the increased risk of adverse outcomes of pregnancy. AED are suspected of contributing to an increase in the risk of congenital malformations and dysmorphic features. Yet increased generalized convulsive seizures are associated with premature labor and fetal death. Clinicians are faced with significant difficulties when attempting to determine how tightly they should control maternal epilepsy and which AED is safest to use.

C. Potential for improving health outcomes: Better knowledge of the factors influencing the adverse outcomes of pregnancy could lead to the choice of more effective and safer therapies thus reducing the number of adverse outcomes, human suffering, and health care costs.

D. Potential to reduce variation in practice patterns: At present general practitioners, obstetricians, and neurologists may all individually manage a WWE. In fact the American College of Ob-Gyn. has developed a position statement asserting that phenobarbital is the only safe AED to use during pregnancy, a choice most neurologists would find unwise.

E. Economic impact: Protection of one child from potential adverse outcomes of pregnancy is enough justification for a parameter, but overall reduction in fetal death and malformations could offer enormous social and economic benefits.

F. Membership needs: Neurologists are the medical practitioners most likely to be involved in the management of poorly controlled persons with epilepsy. Such patients are the most likely to receive multiple AEDs. In addition neurologists are expected, perhaps more than is true for other disciplines and illnesses, to be expert in the management of the WWE during pregnancy.

G. Urgency: New medications have been and are being released, and although specific recommendations can be expected to change, general principles may be expected to survive. Urgency is less since multiple groups have offered suggestions, but a summary of opinions could be useful for all.

H. Government Constraints: With managed care and capitation WWE may have less access to neurologists. In no area of medicine does there exist a greater social and governmental interest than in pregnancy and fetal development, therefore neurologists have despite changing structures for delivering care, an even greater responsibility to offer guidelines for WWE.

I. Resources required: The staff of the QSS will need time to coordinate and assimilate input from national interest groups.

J. Adequacy of Scientific evidence: Scientific evidence is less available regarding the effects of AEDs in humans than in animals, but is sufficient to offer consensus opinion. It is not feasible, nor ethical, to use a matched series of patients with epilepsy to receive either AEDs or no AEDs during pregnancy. At this point in time retrospective comparisons are all that are available.

A. Literature review

1. How the search was conducted, articles selected, etc.: A Medline literature search for epilepsy and pregnancy was conducted for 1938-1995. Over one hundred and eighty articles and abstracts were reviewed in detail. Recently published consensus guidelines and book chapters were also reviewed. Of the 180 articles reviewed 15 constituted case control studies. The other 165 were either case series, case reports, or reviews. Of the 15 case control studies: 5 of 15 were prospective; 1 of 15 was a combination of prospective and retrospectively collected data; and 9 of 15 were retrospective. In the group of prospective studies 3 of 5 used matched controls, 2 of 5 used population based controls.

B. Rationale for selection of expert testimony:

It is proposed that these draft parameters be circulated to: established experts in the field of epilepsy; women's health; the leadership of the Epilepsy Foundation of America, and the American Epilepsy Society; and to selected experts in teratology and obstetrics.

C. Consensus process:

Following incorporation of the suggestions of those listed above, the QSS will again review the document, recirculate as considered desirable, and continue the process as outlined in prior QSS documents.

A. Background

Women with epilepsy who become pregnant are at increased risk for: worsening of their seizure frequency; alterations in the metabolism of their AED; and adverse pregnancy outcomes including fetal death, congenital malformations, congenital anomalies, and developmental delay. This unique constellation of issues and problems are superimposed upon the social stigma of epilepsy, which while thankfully diminished over time continues to be an additional obstacle for women patients.

B. Scope of the problem:

Some of these adverse outcomes are associated with early first trimester phenomena (congenital malformations), others such as developmental delay are more likely to be associated with an exposure of greater duration, or during the third trimester. While risks have not been established for all of the various outcomes there is data for many. The risk of congenital malformations ranges from 4 to 6 %, congenital anomalies somewhat less than 10 %, stillbirth rates 1.3 - 14 %, perinatal mortality 1.4 - 7.8 %. In the United States there are approximately 1.1 million WWE of childbearing age with a potential therefore of many affected children. The major difficulty is that clinicians are uncertain how much of the adverse outcome difficulty is secondary to AED, maternal seizures, or simply the genetics of having epilepsy.

C. Clinical considerations:

1. Historical findings:
The first report of a malformation associated with AED described a child exposed to mephenytoin in utero who developed microcephaly, cleft palate, malrotation of the intestine, a speech defect and an IQ of 60 (Muller–Kuppers 1963). The pregnancy was also complicated by vaginal bleeding.

In 1964 Janz & Fuchs performed a retrospective survey to evaluate the problem of AED–associated malformations at the University of Heidelberg. Four hundred and twenty–six pregnancies in 246 mothers with epilepsy were studied. The rates of miscarriages and stillbirths were increased for these patients, but the malformation rate was only 2.2% not significantly different from that of the general population of West Germany. The authors concluded that AED were not associated with an increased risk of malformations.

Pantarotto (1965) described a neonate with aplasia of the bone marrow after phenytoin exposure in utero. Centra and Rasore– Quartino (1965) reported the first case of congenital heart disease with in utero exposure to phenytoin and phenobarbital. Melchior et al (1967) described orofacial clefts with exposure to primidone or phenobarbital.

In a letter in Lancet in 1968 S.R. Meadow reported 6 cases of children with orofacial clefts, 4 of whom had additional abnormalities of the heart and dysmorphic facial features. All of these children had been exposed to AED in utero. He noted that similar abnormalities had been reported following the unsuccessful use of abortifactant folic acid antagonists. Since some AED act as folic acid antagonists he postulated that this might account for AED teratogenicity, and asked for other clinicians to inform him of similar cases.

The first report of malformations associated with a specific AED was published in 1970 (German et al). Trimethadione was implicated as a teratogen in 8 of 14 pregnancies in which it was taken in the first trimester.

Dr. Meadow's 1968 inquiry concerning AED associated malformations resulted in the collection of 30 additional cases. This prompted a retrospective survey in which 427 pregnancies in 186 women with epilepsy were identified. For the first time a clear increase in the malformation rates of IME was demonstrated. Speidel and Meadow concluded that: 1) congenital malformations are twice as common in IME exposed to AED; 2) no single abnormality was specific for AED exposure; 3) a group of these children would have a characteristic pattern of anomalies which at its fullest expression consisted of trigonocephaly, microcephaly, hypertelorism, low set ears, short neck, transverse palmar creases, and minor skeletal abnormalities.

2. Physical findings:

A variety of dysmorphic syndromes consisting of patterns of congenital anomalies associated with in utero AED exposure have been reported. Minor anomalies are considered structural deviations from the norm that do not constitute a threat to health and by definition, occur in less than 4 % of the population (Marden et al. 1964). To date, six clinical AED syndromes have been reported in the medical literature. A Fetal Trimethadione Syndrome was first described by Zachai and colleagues (1975). Children exposed to this drug in utero were more likely to be short in stature, microcephalic, have V-shaped eyebrows, epicanthal folds, low set ears, anteriorally folded helices, and irregular teeth. Inguinal hernias, hypospadias, and simian creases were also frequently observed. A retrospective study of trimethadiaone exposures in 53 pregnancies revealed fetal loss or major malformations in 87 % of the pregnancies (Feldman et al. 1977). Follow-up studies have reported significant rates of mental retardation among the exposed infants (Goldman et al. 1986). Trimethadione, introduced in the 1940's for the treatment of absence epilepsy, has been largely supplanted by less toxic-more effective compounds and is seldom used in the treatment of epilepsy.

The Fetal Hydantoin Syndrome (FHS) was initially described, in part, by Loughnan et al. (1973), and expanded upon including formally naming the syndrome by Hanson and Smith (1975). Among the many dysmorphic findings associated with this syndrome, hypoplasia and irregular ossification of the distal phalanges was originally believed to be the single most characteristic feature. Of the five children described by Hanson and Smith, only one was exposed to phenytoin monotherapy. The infants displayed facial dysmorphism including: epicanthal folds, hypertelorism, broad flat nasal bridges, an upturned nasal tip, wide prominent lips, and in addition distal digital hypoplasia (DDH), intrauterine growth retardation and mental retardation. Subsequently, Hanson et al. (1976), reported a prevalence of FHS of 11%, with an additional 30% of the in utero exposed children expressing some of the syndrome's features. He also suggested that these children are at greater risk for the development of neural crest tumors, although subsequent prospective studies have failed to verify this initial observation. A prospective study from the University of Helsinki, examined 121 infants of mothers with epilepsy, 82 exposed to phenytoin, found no cases of FHS. Hypertelorism and distal digital hypoplasia were the only dysmorphic features associated with phenytoin exposure in this study (Gaily et al 1988). As with the Fetal Alcohol Syndrome, it is now common nomenclature to consider children presenting with a more limited pattern of anomalies secondary to in utero hydantoin exposure to be expressing Fetal Hydantoin Effects (FHE; Hanson, 1986).

A Primidone Embryopathy has also been described. Affected children present with hirsute foreheads, thick nasal roots, anteverted nostrils, long philtrums, straight thin upper lips, and DDH. These children tend to be small for dates, have an increased risk for psychomotor retardation and heart defects (Rudd and Freedom 1979, Gustavson and Chen 1985). A case report of a family in whom all 4 siblings had clinical features of the FHE demonstrates the complexity involved in evaluating affected children. The first 2 children in this family were exposed to both phenytoin and primidone in utero. In an attempt to prevent dysmorphism in subsequent pregnancies, the phenytoin was discontinued. Unfortunately, the third and fourth children had the same dysmorphic features as their elder siblings having been exposed to primidone monotherapy (Krauss et al 1984).

A syndrome of facial dysmorphism, pre- and post-natal growth deficiency, developmental delay, and minor anomalies has been described in children exposed to phenobarbital. The clinical features were similar to those seen with in utero exposure to both phenytoin and alcohol, hence the author felt that it should not be classified as a separate syndrome (Seip 1976). He also noted that all three of these compounds can result in folate deficiency and hypothesized that such a deficiency could be the common mechanism for the dysmorphism seen with such in utero teratogen exposures.

Dysmorphic features in children exposed to valproic acid in utero were defined as a syndrome by Di Liberti et al (1984). These children have inferior epicanthal folds, flat nasal bridges, upturned nasal tips, thin vermilion borders, a shallow philtrum, and downturned mouths. Long thin overlapping fingers and toes, and hyper-convex nails have also been described. Recently, several cases of fetal valproate exposure and radial ray aplasia have been reported, but the prevalence of these abnormalities cannot be determined from case reports (Bron et al. 1990). Children exposed to valproate in utero also appear to be at greater risk for perinatal distress (43 %) and low Apgar scores (28 %), postnatal growth deficiency and microcephaly (Jager-Roman et al. 1986, Ardinger et al. 1988).

A Fetal Carbamazepine Syndrome has been described by a single group of investigators (Jones et al. 1989). Dysmorphic features include: up slanting palpebral fissures, epicanthal folds, short nose, long philtrum, DDH and microcephaly. Developmental delay was also found in 20 % of exposed children, although the authors used one standard deviation from the mean as the cut-off for abnormality, rather than the customary two standard deviations. Applying the conventional definitions to their data, eliminates any increased risk for developmental delay in the carbamazepine exposed children. Reduction in fetal head circumference has been reported in carbamazepine exposed children (Hiilesmaa et al. 1981). Although smaller than controls, the head sizes were still within the normal range and the differences between the IME and controls disappeared as the children matured.

The application of drug-specific syndromes remain controversial in diagnostic terms. Facial dysmorphism can be difficult to quantify and is certainly not specific to any one anticonvulsant drug. Infants of epileptic mothers with similar dysmorphic features have been described in the pre-anticonvulsant era (Baptisti 1938, Philbert and Dam 1982). The long-term outcome and hence, significance of these anomalies remain unclear. The hypothesized association of dysmorphism with mental retardation (Hanson et al. 1976) has not always been confirmed (Granstrom 1982, Hutch et al 1982). In those few cases which have been followed into early childhood, the dysmorphic features tend to disappear as the child grows older in some, but not all instances (Janz 1982). In all of these syndromes, the primary abnormalities involve the mid face. A retrospective study spanning 10 years of deliveries in Israel found hypertelorism to be the only anomaly seen more often in infants of epileptic mothers than controls; this was associated with all anticonvulsant drugs except primidone (Neri et al. 1983). In reviewing this literature, it appears as if the pediatric and neurological communities might be better served if all of these collections of anomalies were remained under the umbrella term of the Fetal Anti-epileptic Drug Syndrome (FADS), with minor manifestations being the Fetal Anti-epileptic Drug Effects (FADE), as opposed to a half-dozen overlapping drug specific syndromes.

3. Differential diagnosis:

There are two issues: the differential diagnosis of epilepsy; and the differential diagnosis of adverse pregnancy outcomes. In most instances maternal epilepsy will have been confirmed prior to pregnancy. Occasionally a woman will have her first or only seizures during gestation. The question of whether such women need AED is unresolved. Diagnostic techniques may be directed at prenatal diagnosis of adverse outcomes of pregnancy.

4. Confirmatory studies:

a. Indications: Folate determinations prior to conception may indicate the need for additional folate supplementation. AED levels may be necessary at regular intervals to monitor the direction and speed of change during pregnancy. Levels may be needed as often as once a month. If AED levels are to be utilized, unbound drug levels should be determined due to the dynamic changes in plasma protein binding which occur during pregnancy. Drug levels will however fall in all women. One must use clinical judgment and additional variables in determining whether and when to adjust AED dosage. EEG with or without CCTV monitoring may be useful if the nature of episodic seizure like phenomena are unclear. Level II ultrasound at 16 - 18 weeks permit a greater than 95 % accuracy in determining structural defects in the fetus.

b. Contraindications: AED levels should be obtained judiciously. Ultrasonography for prenatal diagnosis before 16 weeks is unlikely to be an accurate method of detecting fetal malformations. EEG should only be done to clarify or make a diagnosis of epilepsy. Serum alpha fetoprotein has little utility due to its high 20 %, false negative rate.

c. Evolving diagnostic studies: Improved fetal imaging techniques may permit earlier prenatal diagnosis. The measurements of trace elements, specific enzyme activities i.e. epoxide hydrolase and free radical scavenging enzymes, while not yet of proven value may become useful in identifying patients at risk for adverse outcomes of pregnancy.

D. Therapeutic considerations

1. Indications: Since there is incomplete data regarding selective benefit of one AED over another, if a patient is well controlled with an AED that medication should usually be continued during pregnancy. Trimethadione appears to be the only exception. The majority of pregnancies in which this drug has been used have had adverse outcomes. There is an association of an increased risk of neural tube defects with valproic acid exposure. Level II ultrasounds are effective in diagnosing this problem.

Unbound blood levels should be monitored, since plasma levels fall and binding changes unpredictably during pregnancy. Monthly determinations are not unreasonable.

For acute seizures during delivery, intravenous use of benzodiazepines should be considered for their rapid effectiveness.

2. Contraindications: Multiple AED use particularly if monotherapy will suffice. The use of trimethadione. The rapid withdrawal of AED particularly if the patient suffers from generalized tonic clonic convulsions.

3. Technique: There is no single technique that will help in deciding which and how much drug to use. Laboratories should offer a range of optimal serum drug levels, and employ accurate techniques. Ideally seizure control with monotherapy and a well educated patent have been established before pregnancy.

4. Documentation: Physicians should document the discussion of risks and alternative treatments that they have had with their WWE Patients should be encouraged to document their seizures. Cooperation between neurologists and obstetricians should be established for the optimal management of pregnant WWE.

5. Complications and treatment: Complications include the potential side effects of AED; the potential effects of maternal seizures. Risks of pregnancy for the mother include: worsening of seizure frequency; anemia, hemorrhage, premature labor, prolonged labor, and cesarean section. Complications for the fetus include: death, prematurity, small for gestational age, neonatal hemorrhage, congenital malformations, congenital anomalies, and developmental delay.

Despite every effort to avoid harm, and unrelated to any activity of doctor or parents, children may be born with handicaps. Treatment requires a cooperative effort between specialists and their availability and willingness to become involved with their patient's care.

6. Duration of care: Ideally care of a WWE begins prior to conception and continues through the first 8 - 12 weeks post partum. AED levels will continue to fluctuate in the post partum period.

7. Anticipated outcome: Ninety percent of pregnancies of WWE will result in a healthy child.

8. Information on patient preferences: Patient preferences are undetermined. Some patients may wish to withdraw from all medications prior to conception.

9. Recommended setting: The outpatient setting is appropriate for patient education, management and specialist coordination.

10. Qualifications for performance: Any neurologist should be expected to assist with the management of the WWE during pregnancy.

In view of the risks of epilepsy and pregnancy for mother and fetus, the fact that with the exception of Trimethadiaone there is no single AED which is safer than any other for use in pregnancy, and the fact that both seizures and AED have the potential for harm the following guidelines are recommended:

Pre-conception guideline:

Women of child-bearing age should be counseled early and educated about the risks of pregnancy and adverse pregnancy outcomes. Included in the educational counseling of the patient should be information regarding the increased risk of seizures during pregnancy as well as the increased risk of adverse pregnancy outcomes.

2. The importance of monotherapy should be emphasized with the patient and attempts to switch to monotherapy made if withdrawal from AED is not recommended.

3. Preconceptual supplementation has been recommended by the Centers for Disease Control for all women of childbearing age. The recommended dose is 0.4 mg/dy. We encourage this for WWE.

Post-conception guideline:

1. The patient, her family and the obstetrician should be educated about the risks of pregnancy.

2. The patient should be monitored regularly ideally monthly with AED concentrations. Unbound levels may be necessary to adequately monitor the patient.

3. The patient should continue folate supplementation during pregnancy. Vitamin K 10 mg/dy should be supplemented during the last 2 weeks of pregnancy. The patient and fetus should be monitored for evidence of malformation and growth retardation ideally with ultrasound.

4. AED should be changed only if necessary to improve seizure control.

Post-delivery guidelines:

1. AED concentrations should be monitored through the eighth post partum week.

2. The patient should be counseled on how to deal with seizures while managing child-care. Breast feeding can generally be performed safely in term infants.

-End-

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Mark S. Yerby M.D., M.P.H.
North Pacific Epilepsy Research
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