May 15, 2006 • www.internalmedicinenews.com Women’s Health Clinical Rounds 47

D RUGS, PREGNANCY, A ND L ACTATION Lamotrigine + Valproate Valproic Acid Linked to Birth Defects or more than 20 years, the risk of with a significantly increased risk for neural tube defects (NTDs) asso- major malformations, especially NTDs; BY MICHELE G. SULLIVAN polytherapy with valproate was 11.8%— Fciated with first-trimester expo- and in the third, mothers who had a Mid-Atlantic Bureau significantly higher than the background sure to valproic acid has been well child with spina bifida were on a mean population rate of 2%-3%. known: The estimated risk is 2%, about dose of 1,640 mg/day vs. a mean of WASHINGTON — There is no evidence There was no significant relationship be- 10- to 20-fold higher than the baseline 941 mg/day among those whose chil- that lamotrigine monotherapy increases tween lamotrigine dosage and the inci- risk. With more widespread use of val- dren had no malformations. The same the risk of major congenital malformations dence of malformation, Dr. Messen- proic acid, partly due to increasing use studies indicated that at less than 600 in infants exposed prenatally to the drug, heimer said. The rate of malformations in of the drug for psychiatric conditions, mg/day, there was no increased risk. according to updated data from the Inter- women taking more than 400 mg/day more data and larger controlled studies These relatively new findings of ma- national Lamotrigine Pregnancy Registry. was slightly elevated at 4%. But only 100 on its teratogenic effects have accumu- jor malformations other than NTDs and However, when the drug was used as ad- women were taking such a high dose, lated over the past 3-4 years, revealing an the potentially increased risk of cognitive junctive therapy along with valproate, the and the confidence intervals were wide association with major malformations effects of valproic acid are important for rate of major congenital malformations Published reports have identified a sig- that previously had been women and physicians to was significantly higher than the rate for nificantly increased risk of major congen- reported anecdotally. The consider when women the background population, reported Dr. ital malformations among women taking main anomalies that have are planning a pregnancy. John A. Messenheimer of Glaxo- valproate as monotherapy (10.7%). These been identified are cardiac Sometimes, women who SmithKline, Research Triangle Park, N.C. studies prompted the American Epilepsy and limb malformations. have been on a drug for Since its inception in 1992, the lamot- Society’s pregnancy outcomes forum pan- The results of these epilepsy for many years rigine registry has recorded 2,000 preg- el to recommend last year that valproate studies reflect what we may no longer need it. If nancies exposed to the drug in the first be avoided as a first-line therapy for any in- found in a metaanalysis a switch to another drug is trimester. The interim report on data up dication in women of childbearing age. of data from 13 cohort not possible, patients need to September 2005 was presented as a The lamotrigine registry could not de- studies in the medical lit- to be monitored closely poster at the joint annual meeting of the termine whether valproate exposure alone erature, published be- for malformations, as has American Epilepsy Society and the Amer- could explain the higher rate of defects in tween 1982 and 2005. The been the practice for ican Clinical Neurophysiology Society. the lamotrigine/valproate group. The studies in the metaanaly- BY GIDEON NTDs, although there is Most of the women (707) were taking numbers of antiepileptic drugs used may be sis, published in April in a KOREN, M.D. no way to monitor for po- lamotrigine as monotherapy, 256 were on inextricably tied to the frequency and sever- Canadian journal, com- tential cognitive effects. polytherapy with lamotrigine but without ity of seizures, making it difficult to assess pared rates of major malformations Another approach for women who valproate, and 119 were on polytherapy the contribution of each factor, he said. among women who reported taking are dependent on valproic acid is to with lamotrigine and valproate. In adults, lamotrigine is approved as ad- valproic acid during the first trimester make every effort to keep the daily dose Of the 20 major congenital malforma- junctive therapy for the generalized with rates among pregnant women at 600 mg or below or, if that is not fea- tions reported, two were club feet, two seizures of Lennox-Gastaut syndrome and who were taking other antiepileptic sible, under 1,000 mg/day. Patients were cases of anencephaly, and three were for conversion to monotherapy in adults drugs (AEDs) and among women who should be monitored with ultrasound, ventricular septal defects. The remaining with partial seizures who are receiving were not taking any such drugs. fetal echocardiography, and maternal malformations included midline defects, treatment. It is also approved for mainte- Nearly 1,000 pregnant women were and amniotic α-fetoprotein testing. urogenital defects, cortical dysplasia, hy- nance treatment of bipolar disorder, and exposed to valproic acid in the 13 stud- Evidence that reducing the dose can poplastic left heart syndrome, hypoplasia it is a pregnancy category C drug. ies. The risk of major malformations, effectively reduce malformations came of the left ventricle, and diaphragmatic her- Physicians are asked to report exposed including NTDs, associated with expo- in a report last year from the Australian nia with abdominal organ displacement. pregnancies to the international registry sure to valproic acid was twofold pregnancy registry for women on The malformation rate in women on by calling 800-336-2176 as soon as the greater than the risk with exposure to AEDs, which found the risk of fetal mal- lamotrigine monotherapy was 2.8%; the pregnancy is identified. The complete in- other AEDs. The risk was 4.4-fold formations was 13 times higher among rate in those on polytherapy without val- terim report of the registry is available by greater than in the healthy controls, women taking more than 1,100 mg of proate was 2.7%. The rate in women on calling the same number. ■ representing a highly significant in- valproic acid per day as monotherapy, crease in risk among valproic acid–ex- compared with women not taking an posed pregnancies. antiepileptic drug. Although the fetal We could not include three studies malformation rate among those on low- Two Deaths After Mifepristone Medical comparing the neurobehavioral risks er doses was greater than the 2%-3% of in utero exposure to valproic acid risk in the general population, the dif- Abortion Prompt FDA to Issue Advisory and other AEDs in the metaanalysis, be- ference was not significant. cause of their different designs and the If possible, a different medication for wo additional deaths after medical Ǡ Weakness with or without abdominal variety of cognitive tests used. Still, all controlling seizures should be consid- Tabortion with mifepristone (Mifeprex) pain. three reported an association between ered. Carbamazepine (Tegretol) is con- have prompted the Food and Drug Ad- Ǡ No fever or other signs of infection valproic acid and developmental delays sidered by many neurologists and ob- ministration to issue a public health advi- more than 24 hours after taking miso- and cognitive deficits. The most promi- stetricians to be the AED of choice in sory alerting health care providers and ad- prostol. nent effect was on verbal IQ. More pregnancy, because the cumulative data vising review of prescribing information. Strong consideration should be given to studies on the neurodevelopmental ef- to date do not reveal any risks of ma- The drug’s manufacturer, Danco Labo- obtaining a complete blood count to iden- fects of in utero exposure that control jor malformations, except for spina bi- ratories, notified the agency of the deaths, tify those patients with hidden infection. for maternal education and other con- fida at about 1%, which is half the rate which took place in the United States. The FDA recommends that if physi- founding factors need to be conducted associated with valproic acid. One of the deaths has since been de- cians suspect infection in patients with this to further examine these associations. However, there are far fewer data on termined to not be related to either an presentation, they should consider imme- On the positive side, in 3 of the 13 the reproductive risks of newer anti- abortion or to the use of mifepristone and diately initiating treatment with antibi- studies that also looked at the dose-de- epileptics such as lamotrigine and misoprostol. The FDA is investigating the otics that include coverage of anaerobic pendent effects of valproic acid, the gabapentin. Of the newer drugs, lam- other death, which involved symptoms of bacteria, such as Clostridium sordellii. How- threshold dose to cause malformations otrigine seems to be the most promis- infection. ever, the agency does not recommend the was about 1,000 mg/day, which has ing in terms of adverse fetal outcomes, The agency advises physicians to discuss use of prophylactic antibiotics at this time. been reported over the past few years. but the number of pregnancies with with their patients the risk of sepsis as well Four previous deaths from sepsis have This is true for all malformations asso- data is much smaller than is available as early signs and symptoms that may been confirmed in U.S. women following ciated with valproic acid, including with valproic acid and carbamazepine. warrant immediate medical evaluation. medical abortion with mifepristone and NTDs. In one study, first-trimester val- In addition, the FDA advises physicians misoprostol from September 2003 to June proic acid plasma levels in women were DR. KOREN is professor of pediatrics, and emergency department personnel to 2005. All four cases of fatal infection test- higher among those who had a child pharmacology, pharmacy, medicine, and investigate the possibility of sepsis in pa- ed positive for C. sordellii. with a malformation; in another, a dai- medical genetics at the University of tients who are undergoing medical abor- For more information, go to: www.fda. ly dose of 1,000 mg was associated Toronto. tion and present with all of the following: gov/cder/drug/infopage/mifepristone. Ǡ Nausea, vomiting, or diarrhea. —Kerri Wachter