Introduction
A North American Registry of Epilepsy and Pregnancy has been established as a surveillance mechanism to identify adverse pregnancy outcomes which may be associated with fetal exposure to antiepileptic drugs (AED). As public attitudes become more receptive, and medical management more effective, women with epilepsy (WWE), are choosing parenthood in increasingly larger numbers. In the United States alone there are an estimated 800,000 to 1.1 million women with epilepsy of child bearing age. Previous research has demonstrated that the offspring of these patients have rates of congenital malformations ranging from 1.25 to 11.5%.

There are several factors which could contribute to this risk:
· AED
· Seizures During Gestation
· Maternal Epilepsy

AED are the variable over which we have some control. Unfortunately, there does not exist data which permits physicians to determine the relative safety of specific AED. With the introduction of several new AED none of which has been tested in pregnancy, further uncertainty exists about the potential safety of AED in pregnant patients.

We have developed a prospective registry for pregnant women with epilepsy, which by monitoring systematically their pregnancy can serve as an early warning system for adverse outcomes associated with the specific AED alone or in combination. This has required a cooperative effort between the scientific and pharmaceutical communities. The genesis of this effort is described.

Background
The prevalence of epilepsy has been reported variably between 0.6 to 1.0 % (Hauser et al. 1991). There are an estimated 800,000 to 1.1 million women with epilepsy (WWE) who are of childbearing age in the United States alone. These women are at risks for a variety of adverse outcomes of pregnancy: worsening of their seizure frequency, alterations in the metabolism of their AED, 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 addition obstacle for our women patients.

WWE are unique in that their underlying seizure disorder necessitates the use of antiepileptic drugs (AED). Without them these patients are at increased risk for seizures, personal injury, loss of employment or driving privileges, and the rare sudden unexplained death in epilepsy. Convulsions are undesirable during pregnancy. First trimester seizures have been found to result in an increased risk of congenital malformations in the offspring 12.3 % vs. 4 % for children exposed to maternal seizure at other times (Lindhout et al 1992). Generalized, tonic-clonic seizures place both mother and fetus at risk for hypoxia and acidosis (Stumpf and Frost 1978). Although rare, stillbirths have occurred following a single generalized convulsion (Burnett 1946, Higgins and Comerford 1974) or series of seizures (Suter and Klingman 1957). Status epilepticus carries a high mortality rate for mother and fetus.In Teramo and Hiilesmaa's review, status epilepticus was an uncommon complication of epileptic pregnancies. Yet of the 29 reported cases, nine of the mothers and 14 of the infants died during or shortly after an episode of status (Teramo and Hiilesmaa 1982). The child of a woman who had three generalized tonic clonic seizures during her pregnancy, (at 19, 28, and 32 weeks gestation), developed an intracerebral hemorrhage (Minkoff et al. 1985).

Generalized (though not partial) convulsions occurring during labor can have a profound effect on fetal heart rate (Teramo et al. 1979). The increased rate of neonatal hypoxia and low Apgar scores may be related to such events (Yerby, Koepsell, and Daling 1985).

The potential problems with seizures in WWE who are pregnant means that the majority of such patients will continue to take their medications. AED are however associated with an increased risk of: congenital malformations, congenital anomalies, neonatal hemorrhage, feeding difficulties, and developmental delay.

There are a number of potential factors which could account for the increased rates of malformations seen in children of mothers with epilepsy (CME). Maternal seizures during pregnancy, the genetics of having epilepsy, falls and injuries from seizures, lower socioeconomic status and its attendant limited access to prenatal care.

There are however a series of observations which strongly implicate AED as the cause of the teratogenicity seen.

1) Comparisons of the malformation rates in the offspring of mothers with epilepsy treated with AED as opposed to those with no AED treatment reveal consistently higher rates in the children of the treated group as illustrated in table 2 (Nakane et al 1980, Speidel & Meadow 1972, Monson et al 1973, Annegers et al 1978, Lowe 1973, South 1972).

2) Mean plasma AED concentrations are higher in mothers with malformed infants than mothers with healthy children (Dansky et al 1980).

3) Infants of mothers on polytherapy have higher malformation rates than those exposed to monotherapy (Nakane 1979, Lindhout et al 1984). 4) Maternal seizures during pregnancy do not appear to increase the risk of congenital malformations (Fedrick 1983).

Though it seems logical to assume that polytherapy carries more inherent risks than monotherapy, high drug levels and multiple drugs may be associated with the severity of epilepsy. Seizure frequency or severity may, therefore, be a confounding factor, and anticonvulsants may be only associated with but not causally responsible for malformations. Majewski and co–workers (1980) described increased malformation rates and central nervous system injury in IME exposed to maternal seizures. More recently Lindhout and co-workers (1992) described a marked increase in malformations in infants exposed to seizures in the first trimester, 12.3% vs. 4.0% in those not exposed. Malformations were actually seen more often in infants exposed to partial seizures than generalized tonic clonic ones.

A primary question in evaluating the relationship between maternal epilepsy and Congenital malformations is whether or not the association is further confounded by the genetics of epilepsy itself. There are few studies comparing malformation rates in groups of treated as opposed to untreated mothers with epilepsy. Except for the two most recent studies they reveal a consistent increase in malformation rates in infants exposed to AED in utero, (Table 2)

Data to differentiate which AED are safest to use are not available. This fact coupled with the introduction of 3 new AED in North America (gabapentin, felbamate, and lamotrigine), and several more on the horizon further complicates therapeutic choices. Little is known about the possible teratogenic effects of these new AEDs whether used in monotherapy of in combination with other agents. Most previous reports are of limited utility due to their small sample sizes and various methodologic limitations. An editorial in Lancet (1991) states "...it is easy to be influenced by the flow of negative case-reports. Despite mounting evidence, the case remains to be proven...by large prospective, multicenter and ideally international investigations based on pregnancy registers."

Objective
The objective of this registry is to signal possible associations between AED fetal exposure and adverse pregnancy outcomes. It should allow epidemic monitoring of the new AEDs. It should serve as an "early warning system" to advise patients and clinicians of potential problems with particular AED alone or in combination.

Organization
A senior scientist to administer the project was recruited through open solicitation for proposals based on guidelines established by a Scientific Advisory Board. A separate Steering Committee was organized to refine the protocol, manage the registry, and suggest analysis.

Initial discussions of the problems of epilepsy and pregnancy took place on December 3rd, 1993. An informal group of academic medical researchers and epidemiologists from several pharmaceutical companies which manufactured AED constituted the foundation of the committee. The problem of the safety of AED in pregnancy was identified. Methods for rectifying these problems were discussed. Previous surveillance methods developed by the epidemiologists of Burroughs-Wellcome for their products Acyclovir and lamotrigine provided useful models. Funding of the registry was to be done by creating a consortium of the pharmaceutical corporations which manufacture AED.

In meetings over the next 18 months a surveillance mechanism was proposed and variables of interest were identified. The structure of the registry was formulated. The populations to be approached and mechanisms for so doing were determined. Methods for maintaining patient confidentiality were discussed. Rules for using the data and maintaining the scientific integrity of the registry were established.

Requests for proposals based on our work were then issued by announcing the grant in a variety of publications. Seven groups expressed interest, and 6 of these submitted proposals. The Scientific Advisory Board reviewed the proposals and selected the most competitive. An award made to Dr. Lewis Holmes and his colleagues of the Massachusetts General Hospital in Boston Massachusetts. A contract was then developed for completion of the project. The general structure is described below.

Scientific Advisory Committee
The registry is to be monitored and assisted by a Scientific Advisory Committee. This committee is comprised of academic medical researchers with no financial interest in any pharmaceutical corporation.

The committee is to advise and assist the PI in the establishment and operation of the registry. This committee has final approval over the announcement and publication of registry data and conclusions.

The Steering Committee
The Steering Committee consists of all of the members of the Scientific Advisory Board plus representatives of the corporations financing the registry. The representatives are trained in epidemiology and/or neurology. The Steering Committee provides a link between each corporation and the registry. It also serves as an advisor to the registry on organizational and analytical issues relative to the project. Neither the Steering Committee nor the sponsoring corporations have the ability to actually analyze data or report outcomes. It has input but only the Scientific Advisory Committee has control over publication of findings or reports from the registry.

Source Populations
The geographic regions to be included initially are Canada and the United States.

Target populations are:
1- Women with epilepsy with exposure to AED during pregnancy;
2- Women with epilepsy without exposure to any AED during pregnancy.
3-Women without epilepsy but with exposure to AED during pregnancy will be included but not targeted.

The AED exposure interval of interest will be any time between the last menstrual period and delivery, abortion, intrauterine or fetal death.

Data Collection
Potential subjects will be actively recruited directly and through their physicians. Neurologists and OB/Gyn physicians are considered the most likely to care for such patients. These physicians will be encouraged to enroll their pregnant patients with epilepsy, through advertisements in professional journals and lectures and information booths at national and regional meetings of their professional societies.

Potential subjects will be recruited directly through announcements and articles in the newsletters of voluntary health organizations such as the Epilepsy Foundation's Spokesman, the information hotline, and Internet.

Reporting by Patients
It is anticipated that most pregnancies will be reported to the registry by patients, An 888 number 888-233-2334, can be utilized to telephone the registry. At the time of the call, the patient will be sent an informed consent form, a registration form, and a card to inform the patient's treating physicians (those who prescribed the AED, as well as those supervising the pregnancy). The following data will be collected by the registry.

· age
· race
· physician supervising epilepsy
· physician supervising pregnancy
· AED taken since LMP, dose and schedule
· LMP
· expected date of birth
· family h/o birth defects
· Seizure types & frequency
· use of vitamin supplements prior to pregnancy
· other exposures: alcohol, cigarettes etc.

Confirmation will be obtained from the treating physicians, who will also be told that a follow up interview will be performed 2 months after the anticipated date of delivery. This follow up will occur with both the patient and her physicians.

Reporting by Physicians
Physicians can report potential subjects directly by calling 888-233-2334. After obtaining permission to contact the patient, the registry will call the woman and obtain consent and the same information as collected above.

Follow up reporting
Two months after the expected date of delivery, a follow up reporting form will be sent to the treating physicians and a telephone interview will be conducted with the patient. The following data will be collected.

· Pregnancy outcome
· AED type, dose and schedule
· Other exposures during pregnancy
· Infections during pregnancy
· Seizure frequency during pregnancy

Outcomes of Interest
The outcomes of pregnancy will be obtained from the physician and patient and where adverse outcomes are determined permission to obtain the hospital and medical records for review and confirmation will be requested from the patient. The outcomes of interest are listed below.

· live birth without abnormality
· spontaneous abortion
· induced abortion because of prenatal diagnosis
· induced abortion without prenatal diagnosis
· live birth with congenital malformations
· maternal death
· lost to follow up

Data Analysis and Reporting
Descriptive data will be presented for the outcomes of interest. Drug specific and seizure specific (by seizure type), incidence of birth defects will be calculated. Human teratogens tend to cause specific defects rather than increases in all types of malformations. The registry will therefore look for clusters of specific defects or groups of defects. The distribution of specific defects or groups of defects will be compared between the cohorts of women by AED exposure, seizure type and frequency.

Discussion
We believe this registry represents a novel approach to utilizing academic expertise and private/corporate resources for a public health project. Women with epilepsy are faced with a dilemma when they consider pregnancy. Generally medications are to be avoided by pregnant women but WWE are at risk for seizures without medication. Seizures themselves are associated with potential injury, miscarriage, and fetal death. At present we lack knowledge about the relative safety of specific AED, or the relative risks of these AED vs. fetal exposure to maternal seizures. With the advent of new AED which have not been used in pregnant women prior to marketing, these issues become more acute.

Current surveillance mechanisms are voluntary and because they are not population based, anecdotal. They do not permit one to develop risk estimates and thus lack utility. Our goal is to improve upon this situation by designing a prospective, proactive population based registry.

There are three potential problems with such a registry. First it must enroll a substantial proportion of the population of women with epilepsy for its prevalence figures to have any meaning. For a study to have the statistical power necessary to distinguish the effects of specific medications approximately 2000 women are needed. There are an estimated 800,000 to 1.1 million women with epilepsy in the child bearing years in the United States and approximately 80,000 - 110,000 in Canada. If we register 1% we can feel fairly comfortable with the ability to extrapolate our data. This will still require a substantial effort.

The potential for conflict of interest and suppression of negative information about an AED exist. The registry is supported financially by pharmaceutical corporations. Although it is in the best interest of each company to understand the safety profile of their products, they also have a vested interest in promoting and selling their individual medications. Adverse outcomes associated with a specific drug could result in a commercial advantage for its competitors. In addition associations are not necessarily causal. Reporting must be accurate and balanced so that people with epilepsy are informed and protected, but not mislead or unnecessarily alarmed. The use of a Scientific Advisory Board as a buffer between the corporations (represented on the Steering Committee), and the PI will help to reduce the potential for inadvertent or inappropriate influence by any particular company. Reports will also be submitted to peer reviewed scientific journals, where the editorial and review process provides yet another layer of review.

There was some understandable hesitancy from corporate sponsors who feared a false signal of an adverse outcome. Our response was that WWE were all ready using these drugs. Some would become pregnant and some would have adverse outcomes regardless. In a "worse case" scenario a drug could be found to be associated with a higher than expected rate of adverse outcomes. It could then be more appropriately labeled, the public warned and corporate liability reduced. If a drug is found not to be associated with adverse outcomes. The public can be informed and the product utilized safely. It is a win win situation for the public, WWE, their offspring and AED manufacturers.

Conclusion
A prospective registry of pregnancy and epilepsy has been designed for North America. It will attempt to enroll pregnant WWE. It will describe the pregnancy outcomes of these groups and determine whether the risk of these outcomes is associated with specific AED after controlling for other factors such as maternal seizures and other medications. It is hoped that at least 1% of the population of interest will be enrolled, and that this registry may become a surveillance mechanism serving the public's health.

Mark S. Yerby M.D., M.P.H.
North Pacific Epilepsy Research
Mother Joseph Plaza
9427 SW Barnes Road - Suite 595
Phone: 503-291-5300
Fax: 503-291-5303

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