# Handbook of Genetic Counseling/Seizure Medications

Seizure Medications

## Contracting

* Introductions and small talk
* Confirm referring physician
* Assess understanding of the reason for the referral to genetics
* How much information has your physician given you about the possible effects of taking seizure medications while pregnant?
* Despite the increased risk of problems, there is a greater than 90% chance that the baby will be just fine
* Control of seizures is important because they may cause injury to you or the fetus
* Stillbirths or miscarriages are more common for women who have epilepsy, occurring in 1.7 percent of pregnancies (about three times the amount in the general population)
* There is a small increase in mortality rates during the first year of life for children of mothers with epilepsy. That risk is only about 0.6 percent, but is higher if seizures are not well controlled. (increased risks probably related to periods where the fetus does not get enough oxygen due to changes in the circulation of blood in the uterus and placenta during seizures)
* What concerns or questions do you have that you would like to discuss today?
* Outline session agenda
** Medical and family history questions
** Some of the possible effects that anticonvulsants can have on the pregnancy
** Options available to you
** Discussion of concerns and questions

## Elicit Medical History

* Confirm LMP: __________
* EDC: __________
* Today's gestational age: __________
* Have you had an ultrasound?
* Date of ultrasound: __________
* Results of ultrasound: __________
* How has the pregnancy been going so far?
* Have you had any seizures during your pregnancy
* What medications are you taking?
** Amount and frequency of each.
** When did you start taking each?
* At what age did you begin having seizures?
* What type of seizures do you typically have?
* Any complications other than the seizures? Infections, colds, exposures etc.

## Elicit Family History

(3 generations)
* Anyone else with seizures?
* Anyone had: multiple SAB, SB, early deaths or babies that required surgery as infants?
* Anyone born with birth defects such as cleft lip or palate, spina bifida, or heart problems
* MR/LD
* Has anyone in family had cancer (dx. <50) or chronic illnesses (heart disease, diabetes)

## Discuss possible side effects of taking anticonvulsants during pregnancy

* Stress importance of taking medicines- to keep you healthy and therefore the baby healthy
* Although it's very important for you to take these medications, sometimes seizure medications can have some effects on a developing baby
* There appears to be an increased risk of Stillbirth correlated with carbamazepine or valproic acid intake during first 6 weeks (2-5% risk of causing stillbirth)
* All pregnancies are at a 3-5% risk of birth defects or mental retardation
* Women who take anticonvulsants are at a 2-3 times increased risk for some specific problems (consensus seems to be about 7-10%)
* This doesn't mean that the baby will be born with a problem, it just means that we know that based on your special circumstances, your pregnancy is at an increased risk
* Some of the things that we sometimes see in children who have been exposed to seizure medications during pregnancy include:
** Subtle changes in the facial features of the baby
*** such as the shape of the eyes and nose
*** usually so subtle features that you might not even recognize them
** Sometimes we see changes in the length of the fingers (slightly shortened) and the fingernails may be small
** But sometimes children can be born with more apparent changes such as a cleft lip/palate or spina bifida
** Occasionally we see kids who have some delays in development (usually ranging from borderline normal intelligence to mild mental retardation)
** Heart defects have been reported in infants of a group of women who were treated with a number of different anticonvulsants (RR of 2.2, 1.4-3.5)
** RR of other birth defects when the group of meds was considered together was 2.5 (1.5-2.4) for oral clefts and 2.5 (1.2-5.0) for urinary tract anomalies
*** But this was for the group of meds considered together and not for individual meds
* Some children who have been exposed to anticonvulsants during pregnancy have several of these features and some have none
* Just based on your history I can't tell you whether or not your baby will have some or none of these features
* However, we can offer you a level II ultrasound that can often determine if the there is a major birth defect

## Options

* Level II ultrasound -- performed at 18 -20 weeks
** Done by an experienced technician
** Can detect many of the birth defects for which your fetus is at increased risk
** Developing organs will be looked at in detail
** Can often detect abnormalities in the formation of the limbs, spine, heart, and brain
** U/S is good to make us suspicious of some birth defects but it can't tell us everything
** We won't know if there is mental deficiency by u/s
** Also, u/s is dependent upon cooperation of the baby. Sometimes we just can't get a great view and may not be able to see everything we are looking for
** But it can usually provide some reassurance to see that organs and body parts have formed properly
* MSAFP at about 16-18 weeks is optimal
** Screening performed on a sample of your blood
** Can provide an indication that a fetus may be at a higher or lower risk than the general population to have an ONTD, but it will not tell us for certain if there is a neural tube defect
** Detects about 80-90% of ONTD's (so it can miss some)
** Blood test can also look at other markers in the blood and determine if there may be an increased risk for two chromosomal abnormalities (for which you are not at an increased risk for based on your history of seizures and medications)
* Amniocentesis at about 15-18 weeks
** Can detect about 95-98% of open neural tube defects (when test both AFP and AchE)
** Procedural risk for miscarriage of 1 in 200
** Although you are not at an increased risk for other specific types of birth defects caused by changes in the chromosomes or hereditary material, amnio can also look at the chromosomes and determine if there is a chromosome abnormality with high accuracy

## Other medications

* Studies of women have shown that neither other medication you are taking (Zoloft and Zantac) cause an increase in birth defects when compared to what would be expected in the general population. However, high levels of Zantac are found in breastmilk and it is recommended that a woman who is taking Zantac not breast-feed

## Psychosocial Considerations

* Guilt over doing something that may cause birth defects
* Catch 22 (don't want to hurt the fetus, but need to make sure that mom is healthy because if mom were having seizures that too would put the fetus at risk)
* Are there other health concerns or circumstances that would make this a difficult pregnancy
* Assess support system and coping strategies

## Follow-up

* Questions?
* Registry for patients taking anticonvulsants…
* Do you plan to breast feed the baby?
* Provide information about Epilepsy foundation at 1-800-EFA-1000 or www.efa.org

## Carbitrol, Epitol, Tegretol (Carbamazepine) Facts

* Anticonvulsant and mood stabilizer
* Clearance increases during pregnancy so doses may need adjustment
* Series of 125 infants exposed, 17 (12%) had congenital anomalies
* Several other reports show a 2-3 times as great of risk for birth defects as in the general population (this is similar to reports of children born to women treated with other anticonvulsants)
* Study with controls who had trivial exposure to ethanol
** Found malformations in 18% of babies exposed to Carbitrol during pregnancy
** Hypoplastic fingernails, short nose, long philtrum, upslanting palpebral fissures, distal digital hypoplasia and microcephaly
** But major birth defects not increased
** 20% of exposed were found to have developmental delay (5 of 25 offspring)
*** problems with the design though
* may be confounded by SES status or parental IQ
* used only one standard deviation as the cut off rather than two
* Other studies fail to show any significant effects of prenatal exposure on head size, IQ, or neurologic function
* Incidence of spina bifida
** When data from 22 published studies was pooled, a relative risk of 14 was calculated
** Questions about adequacy of data because many of 21 published studies that were used reported 0-1 cases
** Nested case control study showed odds ration of 6.0 for NTD's but not statistically significant, but is suggestive of a relationship
** May therefore be a risk and the risk is generally quoted at 1 in 200 to 1 in 100 (up to 10 times the risk for general population which is about 1 in 1,000)
** Folate supplements often recommended because carbamazepine is folic acid antagonist
* When in combination with other anticonvulsant drugs especially valproic acid, higher frequencies of birth defects have been observed
* Considered "probably safe" to consume while breastfeeding

## Topamax (Topiramate) Facts

* Mechanism of action unknown --Appears to block the spread of seizures rather than raise the seizure threshold
* Not well studied in humans
* Most studies have been done on mice, rats, and rabbits
** developmental toxicity shown at all doses tested (lowest 20% of human dose)
** Show craniofacial malformations most commonly such as cleft lip and palate
** Caused limb reduction anomalies in rats at 10 times human dose
** Delays in physical development seen when used during late pregnancy and lactation in rats
** Skeletal abnormalities at 6 times the human dose in rabbits (maternal toxic dose)
** Intrauterine death in 2 times the human dose (maternal toxic dose)
* 8 exposed pregnancies
** 5 chose to terminate
** 3 infants were normal
* Case report (abstract) one woman only on topamax throughout gestation (700mg) had infant with prenatal onset growth deficiency and multiple minor anomalies (5th nail hypoplasia, generalized hirsutism, third fontanelle, short nose and anteverted nares)

## Zoloft (Setraline) Facts

* SSRI antidepressant
* Studies in rats and rabbits
** 20 times the dose in pregnant rats and rabbits produced NO INCREASE in birth defects
** Neonatal survival was decreased at maternal doses of 5 times higher than recommended in humans
* Report of 147 women followed prospectively
** Comparable incidence of malformations to that found in unexposed controls
* Offspring of 112 women in another study
** Babies DID NOT have an increase in birth defects compared to control population
** Admission to a special care nursery were associated with late pregnancy exposure
* Case report of infant with withdrawal symptoms
** Agitation, poor feeding, constant crying, insomnia
** Intense for 48 hours then subsided
* Nystagmus reported in another infant and resolved after 72 hours
* Zoloft is excreted in breast milk, along with active metabolite
* Studies suggest that there is minimal transfer of active drug to the infant though

## Zantac (Ranitidine) facts

* Histamine H2 antagonist used for peptic ulcer disease
* No increase in birth defects or fetal toxicity in rats or rabbits
* Frequency of major malformations NOT increased among children of 142 women taking various H2 receptor antagonists
* No increase in incidence of birth defects in 330 infants exposed to Zantac during first trimester
* Cohort study with 176 infants showed rate of birth defects NO greater than expected
* Not recommended during breast feeding because may accumulate in breast milk up to 6-12% of maternal daily dose

## References

* Jones KL, Lacro RV, Johnson KA, Adams J. Pattern of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med 1989;320:1661-6.
* Reprotox database - www.reprotox.org
* Teratology talk by Dr. Hopkin -- Winter quarter 2002 "Teratogenicity of Antiepileptics"
* Website by Dr. Mark Yerby, North Pacific Epilepsy Research (1998)
* http://www.seizures.net/articles.html
* Creasy, RK and Resni, R. ed. Maternal Fetal Medicine. 1994. Chapter 60 Neurologic Disorders. Michael J. aminoff, MD.
* Milunsky, A. ed. Genetic Disorders and the Fetus (4th edition). 1998. Johns Hopkins University Press.

## Notes

The information in this outline was last updated in 2002.