למיקטל והריון

האם ישנה בעיה להרות עם למיקטל? גם מבחינת כניסה להריון וגם מהבחינה של נזק לעובר

שלום ראומה, קיימת אי בהירות לגבי מידת בטיחותה של התרופה LAMICTAL = LAMOTRIGINE - לשימוש בהריון. את ההחלטה הסופית יש לקבל בעצה אחת עם הנוירולוג המטפל ועם רופא הנשים. ניתן להרחיב על הנושא במאמר סקירה המצורף בקישור הבא : http://jnnp.bmjjournals.com/cgi/rapidpdf/jnnp.2005.074203v1 ובתקציר הבא : http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16239185&query_hl=1 וכן ע"י עיון בתקציר הבא : Lamotrigine and the risk of malformations in pregnancy Marianne Cunnington, PhD, Patricia Tennis, PhD and the International Lamotrigine Pregnancy Registry Scientific Advisory Committee* From GlaxoSmithKline, Worldwide Epidemiology, Harlow, UK. Address correspondence and reprint requests to Dr. M. Cunnington, GlaxoSmithKline, Worldwide Epidemiology, Harlow, UK; e-mail: [email protected] Objective: To report the frequency of major malformations in lamotrigine-exposed pregnancies from September 1, 1992, through March 31, 2004, in the International Lamotrigine Pregnancy Registry. Methods: Health care professionals throughout the world can voluntarily enroll lamotrigine-exposed pregnancies in this observational study. Only pregnancies with unknown outcomes at the time of enrollment were included in the analysis. The percentage of outcomes with major birth defects was calculated as the total number of outcomes with major birth defects divided by the sum of the number of outcomes with major birth defects + the number of live births without defects. Results: Among 414 first-trimester exposures to lamotrigine monotherapy, 12 outcomes with major birth defects were reported (2.9%, 95% CI 1.6% to 5.1%). Among the 88 first-trimester exposures to lamotrigine polytherapy including valproate, 11 outcomes with major birth defects were reported (12.5%; 95% CI 6.7% to 21.7%). Among 182 first-trimester exposures to lamotrigine polytherapy excluding valproate, 5 outcomes with major birth defects were reported (2.7%, 95% CI 1.0% to 6.6%). No distinctive pattern of major birth defects was apparent among the offspring exposed to lamotrigine monotherapy or polytherapy. Conclusions: The risk of all major birth defects after first-trimester exposure to lamotrigine monotherapy (2.9%) was similar to that in the general population and in other registries enrolling women exposed to antiepileptic monotherapy (3.3% to 4.5%). However, the sample size was too small to detect any but very large increases in specific birth defects. -------------------------------------------------------------------------------- The frequency of poor pregnancy outcomes in women with epilepsy compared with that in the general population is higher.1–5 One recognized contributor to poor pregnancy outcomes in women with epilepsy is the teratogenicity of older antiepileptic drugs such as phenytoin, phenobarbital, and valproate.1,2 The risk of birth defects increases with increasing daily dose of older antiepileptic drugs and with polytherapy relative to monotherapy.1,6 While the teratogenicity of older antiepileptic drugs is well documented, that of newer-generation antiepileptic drugs introduced after 1990 has been studied only to a limited degree. Many of the newer antiepileptic drugs differ chemically from the older drugs and therefore may differ in their reproductive-toxicology profiles. The newer antiepileptic drug lamotrigine was not teratogenic in a battery of animal preclinical studies when administered during the period of organogenesis to pregnant mice, rats, or rabbits at oral doses 3 to 10 times higher than the upper human dose (500 mg/day) although mice and rats but not rabbits showed maternal toxicity and secondary fetal toxicity at these doses.8 Lamotrigine was not associated with an increased risk of birth defects in clinic-based4 and registry-based7–9 studies prospectively monitoring pregnancy outcomes, case reports,10,11 or pharmacokinetic studies12,13 involving monotherapy exposure. The International Lamotrigine Pregnancy Registry was established to expand the evidence base of the risks and benefits of taking lamotrigine during pregnancy.7,14 This ongoing, primarily prospective observational study monitors lamotrigine exposure in pregnancy to detect major structural malformations that may be drug related. This article, which updates a previously published preliminary report7 involving fewer pregnancy exposures, discusses outcomes of pregnancies reported to the International Lamotrigine Pregnancy Registry from September 1, 1992, through March 31, 2004. וקריאת מאמר המערכת הזה : Editorial: What can we say to women of reproductive age with epilepsy? Patricia Penovich, MD and Eija Gaily, MD From the Minnesota Epilepsy Group PA, Department of Neurology (Dr. Penovich), University of Minnesota, St. Paul, MN; and Epilepsy Unit (Dr. Gaily), Hospital for Children and Adolescents, Helsinki University, Finland. Address correspondence and reprint requests to Dr. Patricia Penovich, Minnesota Epilepsy Group PA, Department of Neurology, University of Minnesota, 310 North Smith, Suite 300, St. Paul, MN 55102; e-mail: [email protected] It is not yet established which antiepileptic drugs (AEDs) are most likely to allow an uncomplicated pregnancy and delivery of a baby who develops normally. Two recent studies of the risk of major malformations, a national birth registry1 and a prospective single experience,2 consisted mainly of carbamazepine (CBZ) or valproate (VPA) exposed pregnancies. Both suggested that first semester exposure to VPA monotherapy carried a higher risk of fetal malformation than exposure to CBZ monotherapy. There is an increased risk3 for abnormalities in infants exposed in utero to phenobarbital, a drug that not long ago was the recommended drug for pregnant women with epilepsy (WWE). In this and a future issue of Neurology, three birth registries are reported. Cunnington et al.4 report results from the lamotrigine (LTG) registry and Wyszynski et al.5 report results from VPA-exposed pregnancies. Both reports track major birth defects evident by ultrasound or inspection within the first few days of life. Artama et al.6 report on the rate of malformations in offspring of WWE after exposure to several AEDs in monotherapy and polytherapy compared to offspring of untreated WWE. Cunnington et al.4 report a 2.9% incidence of major defects in the infants of 414 WWE treated with LTG monotherapy. When LTG was used in polytherapy, there was a 12.5% incidence if it was used with VPA (88 exposures) and a 2.5% incidence with other AEDs (182 exposures). This multinational registry (12 years of observations) enrolled patients voluntarily by physician report, with postpartum physician information. Wyszynski et al.5 report results from the North American AED Pregnancy Registry for VPA monotherapy, finding a 10.7% incidence of major malformations compared with a 2.9% incidence with other AED monotherapy use and a 2.6% incidence in a group of women without epilepsy. The study benefits from voluntary enrollment of WWE, by the use of two predelivery and one postpartum interview; and from evaluation of medical records. Dysmorphologists made two independent evaluations of the abnormalities. The investigators controlled for maternal seizures and other confounding data. The relative risk of having an affected infant with VPA use was 7.3 compared with the general population rate. There was a trend for higher malformation occurrence with lower maternal education, smoking, and greater alcohol use. Artama et al.6 describe a 9-year study comparing the rate of malformations in children of 1,411 WWE who took predominantly CBZ, oxcarbazepine (OXC), phenytoin, or VPA to the rate in children of WWE who did not take AEDs in the first trimester. The untreated population-based data are derived from registration for payment of AEDs in Finland (100% reimbursement). Malformations at birth were analyzed. Of 2,350 infants (939 exposed to AED; 1,411 not exposed), 3.4% had malformations (4.6% in the exposed cohort; 2.8% in the nonexposed cohort). Risk was greater in polytherapy (7.2%), with more than half of the malformations seen in children exposed to VPA polytherapy and a 10-fold risk at doses >1,500 mg/day. Whether in mono- or polytherapy, VPA use led to a fourfold risk for malformation. They also report the largest series thus far of OXC-exposed infants (99), noting only one malformation. All three studies prospectively enrolled many WWE, but the numbers of pregnancies are too small to answer some important questions. Only Artama et al. report risks of specific malformations. There were no patterns of malformations with LTG or VPA, although neural tube defects may be more common in VPA-exposed fetuses than in the "other AED" group. The effect of the AED itself was not clarified by any of the studies. Pregnancy registries for women taking LTG or VPA monotherapy for indications other than epilepsy are not available. None of the studies clarified nutritional contributions, including folate supplementation. Does folate decrease the risk of malformations in WWE? Wyszynski et al.5 report 4 infants with spina bifida in the 106 VPA-exposed women who took folate, accounting for an incidence of 3.8%. Would this rate be higher without folate? Is folate needed throughout pregnancy or only preconception and through organogenesis? In addition to structural defects, there are possible long-term cognitive effects of prenatal exposure to AEDs. Previous population-based prospective studies did not find that prenatal exposure to phenytoin (PHT) monotherapy7,8 or to CBZ monotherapy9 impaired intelligence. No sufficient prospective data on VPA monotherapy are available, but fetal VPA exposure may be harmful for verbal intelligence.9 Vinten et al.10 report the results of neuropsychological testing at ages 6 to 16 years in 249 children of WWE. Two-thirds of mothers had focal epilepsy, and one-third had idiopathic generalized epilepsy. One hundred twenty children were exposed to monotherapy: 52, CBZ; 41, VPA; 21, PHT; and 6, other. Forty-nine children were exposed to polytherapy, and 80 had no AED exposure. The mean verbal (but not performance or full-scale) IQ of those exposed to VPA monotherapy was lower than that of those exposed to other monotherapy regimens or those who had no exposure to AEDs. The number of VPA monotherapy-exposed children in the study of Vinten et al.10 comprises the largest cognitive study to date. The most important potential confounding factor was controlled for elegantly and simply by measuring maternal intelligence. However, the results must be interpreted with caution. The retrospective design reduced the reliability of exposure data, and inclusion, based on the parents’ willingness to participate, may create a bias in IQ results. It remains unexplained why only verbal intelligence was affected. The Artama et al. study suggests that there may be a dose-response effect of valproate. None of the studies provides an explanation for the disturbance in fetal development. Without good animal models for human teratogenicity, the mechanism for the abnormalities remains unknown. Does VPA metabolism, P450 oxidation with a free radical intermediary,11 contribute to the teratogenicity? Or, might VPA’s inhibition of metabolism of other drugs also contribute? Can we make a leap of faith and utilize drugs without such metabolic intermediates more confidently in pregnancy? LTG undergoes glucuronidation and not oxidation, yet some of the same malformations are seen. Future studies will be needed to address these important questions. Although these studies do not provide absolute answers, they are important and needed to counsel WWE who contemplate pregnancy. The results from LTG monotherapy-exposed pregnancies are not alarming and may be somewhat reassuring; however, as the authors note, the sample size is too small for definite conclusions. There are now data demonstrating structural and functional teratogenicity of VPA from several independent studies. However, because the choice of drug depends on the epilepsy syndrome, we cannot yet exclude the possibility that the results from prenatal VPA exposure may be in part associated with some maternal epilepsy characteristic that may predispose the child to malformations or developmental problems. The emerging data, however, should make the clinician consider an alternative to VPA therapy in WWE prior to conception. Maintaining effective AED therapy during pregnancy is crucial. Maternal tonic-clonic status epilepticus may cause catastrophic damage to the fetal brain,12 and even partial seizures may produce infant distress.13 Although new generation AEDs offer alternative treatment choices for many patients, many women with idiopathic generalized epilepsy continue to need VPA for seizure control.14 Data on the risk of malformations after prenatal exposure to newer AEDs are unfortunately almost completely lacking, other than for the present study on LTG.4 With this present knowledge, the risks for mother and child can be most effectively minimized by careful planning of AED therapy before pregnancy, by supplementing with folate, and by using monotherapy with the lowest effective dose of the AED that is most effective against seizures in that patient. -------------------------------------------------------------------------------- P.P. has received speaker's fees from GlaxoSmithKline, RW Johnson, Shire, Novartis, and UCB and served on an advisory committee for Abbott NUCB. E.G. has received speaker's fees from UCB and GlaxoSmithKline. References Kaaja E, Kaaja R, Hiilesmaa V. Major malformations in offspring of women with epilepsy. Neurology 2003;60:575–579.[Abstract/Free Full Text] Wide K, Winbladh B, Källen B. Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based study. Acta Paediatr 2004;93:174–176.[Medline] Holmes LB, Wyszynski DF, Lieberman E. The AED (antiepileptic drug) Pregnancy Registry: a 6-year experience. Arch Neurol 2004;61:673–678.[Abstract/Free Full Text] Cunnington M, Tennis P, and International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy. Neurology 2005;64:955–960.[Abstract/Free Full Text] Wyszynski DF, Nambisan M, Surve T, et al. Increased rate of major malformations in offspring exposed to valproate during pregnancy. 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Effects of maternal seizures on the fetus. In: Tomsonm T, Gram L, Sillanpää M, Johannesen S, eds. Epilepsy and pregnancy. Peterfield, UK and Bristol, PA: Wrightson Biomedical, 1996:135–141. Ramos RM, Cantrell DC, Cuningham DC, et al. Effects of partial seizures on the infants of women with epilepsy. Epilepsia 1997;38(suppl 8):230. Bourgeois B. Chronic management of seizures in the syndromes of idiopathic generalized epilepsy. Epilepsia 2003;44(suppl 2):27–32. בהצלחה.