Risk of fetal death and malformation related to seizure medications
C. Akos Szabo, MD
There is increasing interest regarding the efficacy and safetyof seizure medications in special populations, such as in children,the elderly, and pregnant women. The information regarding thesafety of newer medications to the embryo and fetus in pregnantwomen with epilepsy is still sparse, but there is a renewedeffort to evaluate the risks in order to better advise womenof child-bearing age. Several pregnancy registries in the UnitedStates, Europe, and Australia are collecting data on the riskof major malformations caused by seizure medications. More informationabout epilepsy can be found on the next page.
In this issue of Neurology, a study by Meador et al.,1 titled"In Utero Antiepileptic Drug Exposure: Fetal Death and Malformations,"compares the risk of fetal death and congenital malformationsfor four commonly used seizure medications, including lamotrigine,carbamazepine, phenytoin, and valproic acid. These data arepart of an ongoing study looking at short- and long-term developmentaleffects of seizure medications in children of mothers with epilepsy.
What are the risks of epileptic seizures and seizure medications during pregnancy?
Fetal exposure to seizure medications may lead to fetal deathor congenital malformations, affecting the brain and spinalcord, orofacial cavities, heart, kidneys and urinary tracts,genitals, and skeleton. They are reported to occur in about6% of pregnancies in women with epilepsy, constituting twicethe risk compared to the general population. To what extentthese abnormalities are related to seizures, the underlyingepilepsy or psychosocial factors, or seizure medications isunclear. Nonetheless, most women with epilepsy need to be treatedduring pregnancy. Epileptic seizures are potentially dangerousto the pregnant woman and the fetus. Isolated seizures can leadto falls or other forms of physical injury, while frequent orprolonged seizures can lead to physical stress endangering thehealth of the woman and fetus.
Are seizure medications necessary during pregnancy?
As treatment is necessary, which are the medications that areboth effective and safe? Most studies have reported on the riskassociated with the older seizure medications. These studiesincluded women with uncontrollable seizures who were treatedwith a combination of seizure medications. In these studies,it was difficult to test the effect of uncontrolled seizuresand seizure medications, and which medications posed the greatestrisk. Prospective studies are needed, collecting data on womenwhose seizures are controlled on monotherapy, in order to understandthe risks associated with each seizure medication.
The study of Meador et al. looked at the outcomes of 333 pregnanciesin women who, in large part, were well-controlled on only oneseizure medication. This study compared the effects of carbamazepine,phenytoin, lamotrigine, and valproic acid. Women were includedif they were otherwise healthy, with a normal intelligence,without a previous history of infection with syphilis or HIV,or recent alcohol or drug abuse. The rate of all serious adverseevents was 30 (9%) of 333 pregnancies, with congenital malformationsoccurring in 22 (7%). The rate of fetal death and congenitalmalformations was significantly greater with valproic acid (20%)when compared to the other agents, including lamotrigine (1%),carbamazepine (8%), and phenytoin (11%). Although lamotriginehad the fewest complications, the difference was not statisticallysignificant compared to carbamazepine and phenytoin. The mainlimitations of the comparison between the medications less likelyto cause fetal malformations are the small number of subjectsin each group. Nonetheless, the rate of malformations attributedto valproic acid appears to be dependent on the dose of medicationused. If low doses of valproic acid (500 to 1,000 mg/day) canbe used to adequately treat seizures, the risk is comparableto other antiepileptic medications.
What does this mean for women with epilepsy who want to become pregnant?
In summary, there is mounting evidence that the risk for fetaldeath and congenital malformations in mothers with epilepsymay be affected by the medication they are prescribed. Valproicacid appears to be associated with significantly increased riskfor fetal death and congenital malformations, though the riskappears to be dependent on the dose used. Physicians and womenof childbearing age both need to be aware of these risks whenchoosing the appropriate seizure medication during pregnancy.Because women often do not know they are pregnant during thefirst 4 to 8 weeks of the pregnancy, it is very important toplan the timing of pregnancy very carefully. Women with epilepsyneed to have their seizure medications optimized prior to conception,using a single agent which is most effective for their seizuretype and at the lowest dose possible. Finally, all women ofchildbearing age need to be on folate, which has been shownto reduce the risk of malformations in women taking seizuremedications.
A seizure is a disruption in the normal electrical activityof the brain. Normally the brain is very active, passing electricalmessages back and forth between nerve cells. When a person hasa seizure, there is abnormal firing of nerve cells and the messagesbecome jumbled in part or all of the brain.
A seizure may cause a variety of different symptoms, such astwitching or shaking in an arm, leg, one side of the face, orthe whole body; repetitive movements or gestures; confusion;feelings of fear or other emotions; hallucinations (odd smells,tastes, sounds, or seeing things that are not there); loss ofconsciousness; and convulsions.
Anyone may have a seizure in certain conditions. Common causesare fever (in young children) (see febrile seizures, below);head trauma (during birth or any time later); infection of thebrain or nervous system (e.g., meningitis); brain tumors; verylow blood sugar; stroke (a brain attack); lack of oxygen tothe brain; and poisoning (e.g., alcohol and various drugs).
Febrile seizures are generally benign and occur in childrenfrom ages 3 months to 5 years, with average age at onset of18 to 22 months. They occur in the setting of a febrile illness,usually as the fever is rising fast. They are associated withcommon childhood infections such as ear infections, tonsillitis,upper airway infections, and gastrointestinal infections. Mostare associated with viral illnesses.
Febrile seizures are more common in boys. They also tend torun in families. About one third of children who have a firstfebrile seizure will have a second one, almost always within2 years. The earlier the onset of febrile seizures, the greaterchance that they will recur. However, fewer than 5% of childrenwith febrile seizures go on to develop epilepsy.
Although febrile seizures are usually benign, it is criticalthat the child be evaluated immediately to identify the causeof the fever and treat conditions such as meningitis or intoxication.
Epilepsy is an episodic recurrence of seizures that are notdue to fever, active infection, drug effects, or other triggeringcauses. It may be caused by a variety of conditions that injurea part or all of the brain, such as problems in developmentof the brain that occurs before birth, inherited disorders ofthe brain or nervous system, brain trauma, brain tumors, stroke,infections, and poisoning. About 70% of cases have no knowncause.
Each year there are 125,000 new cases of epilepsy. About 2.5million people in the United States have some form of epilepsy.
The doctor will need to know as much as possible about whathappened during, immediately before, and after the seizure.How often seizures occur, whether there are any warning signs,and whether the patient remembers anything about the seizureare all important. Someone who has witnessed the seizures canprovide valuable information that the patient may not know.
Electroencephalography (EEG) is a simple and painless studythat records the brain’s electrical activity picked upby tiny wires taped to the head. Specific brain wave patternsmay be noted during or between seizures in patients with epilepsyand may help with diagnosis.
Imaging studies to look at the brain may be helpful in locatingtumors, scars, or other abnormalities that may be causing seizures.Magnetic resonance imaging (MRI) and computed tomography (CT)scans create pictures of the inside of the brain.
Drugs called anticonvulsants are used most commonly to treatseizures. There are a number of different medications that canbe used, alone or in combination. These drugs are effectivein 60 to 80% of cases. Close supervision by a doctor is essentialto watch for side effects and obtain the best seizure control.
People with epilepsy can help control seizures by avoiding alcoholand caffeine, avoiding unusual stress, getting enough sleep,taking their medications as prescribed, and working closelywith their doctor. A special diet may be helpful in controllingcertain types of seizures in children but requires very closemedical supervision. Surgery may be very helpful when medicationfails and the area of the brain where the seizure occurs isknown.
Meador KJ, Baker GA, Finnell RH, et al. In utero antiepileptic drug exposure: fetal death and malformations. Neurology 2006;67:407–412.[Abstract/Free Full Text]
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