Using current evidence in selecting antiepileptic drugs for use during pregnancy (original) (raw)
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Antiepileptic drug use during pregnancy: Perinatal outcomes
Seizure, 2011
Purpose: This study was undertaken to (1) measure the frequency of AED monotherapy or polytherapy during pregnancy and AED discontinuation prior to pregnancy in a cohort of women with treated epilepsy; and (2) describe the frequency of major congenital malformations according to maternal use of AED during pregnancy. Methods: A cohort of epileptic pregnant women was identified within the Quebec Pregnancy Registry and was divided into three groups based on maternal AED use during pregnancy: AED monotherapy, AED polytherapy and no AED use. Results: Of the 349 pregnancies meeting eligibility criteria, 79.6% were exposed to AED monotherapy and 5.8% to polytherapy during pregnancy; 14.6% discontinued AED prior to pregnancy. The most commonly used AEDs were carbamazepine (29.9%) and valproic acid (19.7%); the most common AED polytherapy combination was carbamazepine combined with clobazam (2.5%). Of 111 deliveries in the group of women on monotherapy during pregnancy, 9.9% (n = 11) were born with major congenital malformations; in the group of women treated with polytherapy, 19.0% (n = 8 over 42) of babies had major congenital malformations compared to 20.0% in women who discontinued AEDs prior to pregnancy. Conclusion: This study demonstrates that the majority of women suffering from epilepsy were treated with monotherapy rather than polytherapy during pregnancy. While most used other agents, an important number of women continued to use valproate in pregnancy despite the long standing evidence of its teratogenicity and increasing evidence of its neuro-toxicity to the fetus. ß
Antiepileptics in Pregnancy: A Review
2021
Exposure to Anticonvulsant drugs by pregnant women to prevent seizures are among the most common causes of potential harm to the foetus. Even though prenatal exposure to antiepileptic drugs (AEDs) is known to cause relatively higher risks of major congenital malformations, prospective studies have provided refined data that allow us to differentiate the risks of different types and doses of AEDs. Women with epilepsy (WWE) are recommended to continue antiepileptic drugs (AEDs) during pregnancy to reduce maternal and foetal trauma associated with seizures. Substantial pharmacokinetic changes occur with most of the medications during pregnancy and postpartum, and inter individual variability supports the use of therapeutic drug monitoring for most AEDs. During pregnancy, vigilance and close monitoring should also include intrauterine foetal growth, obstetric complications, and neonatal complications.
Epilepsy and Anticonvulsant Therapy During Pregnancy
Novel Treatment of Epilepsy, 2011
Hanson and Smith. Similar inborn defects were described for all older anticonvulsant drugs (primidone, valproate, phenobarbital, phenytoin, carbamazepine, trimethadion). The frequency and severity of defects associated with use trimethadion were so high to warrant consideration of early elective termination of pregnancy. The teratogenic mechanism of AEDs is only partially understood. 2.1 Fetal anticonvulsant syndrome Fetal anticonvulsant syndrome is associated with exposure to dilantin, diphenylhydantoin, phenytoin, hydantoin, and valproic acid during 1st trimester of pregnancy, in lower degree also with other (carbamazepine). The abnormalities include (Jones, 1997; Žižka, 1997; Ornoy, 2009): a. An increase of major congenital anomalies: congenital heart defects (septal defects, tetratology of Fallot, aortic coarctation etc.), cleft lip and palate, limb defects with hypoplasia of nails and distal phalanges, finger-like thumbs, abnormal palmar creases, dislocation of hip, malformation of brain, especially neural tube defects. b. Specific syndrome including facial dysmorphy with wide anterior fontanel, ocular hypertelorism, broad, depressed nasal bridge, short nose with bowed upper lip, midface hypoplasia, epicantus, often also malformation of external genitalia and neural tube. c. Intrauterine growth retardation. d. Developmental disorders mainly affecting cognitive functions and behaviour. Small variations were noted according to the drug used. A significant association was seen between maternal use of valproic acid and spina bifida, and a weaker, non-significant one between carbamazepine and spina bifida. Facial clefts were associated with both diphenylhydantoin and phenobarbitone use and also with polytherapy (Källén et al., 1989). As AEDs have effect also on cognitive development, children exposed to valproate have increased risk of delayed early development in comparison to the control group (Bromley et al., 2010). It seems, that a distinctive pattern of abnormalities in infants is associated with the use of anticonvulsant drugs during pregnancy rather than with epilepsy itself (Holmes et al., 2001). 3. Embryotoxicity and its evaluation 3.1 Animal studies How embryotoxic potential of drug may be detected? The first opportunity is an animal study. Every drug has to be tested in animal studies with a respect to protect the unborn child from adverse effects. Animal studies can, but do not always, predict whether a drug will be teratogenic in humans. Unfortunately, animal studies have shown as poor predictors in the case of thalidomide that did not produce malformations in rats and mice. On the other hand, some drugs have been found teratogenic in animals and not in humans. Therefore, minimally two different animal models are required for routine testing. Animals are often given far higher doses of drugs than humans would ever receive. Interspecies differences regarding the teratogenicity of drugs, that can increase doubts about results, result from differing pharmacokinetic processes, different metabolites, concentration-time relationships in an embryo, placental transfer and elimination rate. The only way to ascertain the ultimate risk or safety of drugs during pregnancy is to verify them in human studies (Einarson & Koren, 1999). www.intechopen.com Epilepsy and Anticonvulsant Therapy During Pregnancy 185 3.2 Epidemiological studies As pregnant women cannot be enrolled in randomized, controlled studies from obvious ethical reasons, the teratogenicity have to be established in prospective or retrospective epidemiological studies. Data have been collected in a registry of birth defects (CDC-The International Clearinghouse for Birth Defects Monitoring Systems, EUROCAT-A European Network of Population-based Registries for the Epidemiological Surveillance of Congenital Anomalies), by specific registry collecting data about AEDs exposure (EURAP-European and International Registry of Antiepileptic Drugs in Pregnancy, NAAPR-North American AED Pregnancy Registry) or by services offering consultation about drug safety (OTIS
Antiepileptics and Pregnancy: A Review
2013
Epilepsy in a pregnant woman is a serious and potentially life-threatening condition for both mother and child. Most pregnant women with epilepsy will need to take at least one antiepileptic drug. The goal for all concerned is a healthy, seizure-free mother and an undamaged child. However, epilepsy as well as antiepileptic drugs cause some serious effect on the fetus. So, for epileptic women it is important to obtain appropriate information about possibility to have children and about risks connected with their pregnancy. Every physician should be informed about risk to the fetus that is associated with seizures and drugs used for treatment during pregnancy. Drugs used in girls and young women should be chosen with the respect to the future reproduction, because the use of antiepileptic drugs (AED) in women with epilepsy is in fact a balance between seizure control and adverse effects of drugs. The purpose of this review is to provide an update on management of Women with Epilepsy (WWE) prior to and during epilepsy.
The Australian Register of Antiepileptic Drugs in Pregnancy: The first 1002 pregnancies
Australian & New Zealand Journal of Obstetrics & Gynaecology, 2007
Background: Prospective studies are needed to assess the maternal and fetal hazards of antiepileptic drug (AED) therapy in pregnancy.Aims: To make the Australian Register of AEDs in Pregnancy better known to the Australian obstetric community by presenting results derived from it.Methods: Analysis of data collected by the Register between 1999 and December 2006.Results: The Register contained data on 1002 epileptic or AED-treated pregnancies, 992 with known outcomes, 83 not exposed to AEDs in at least their first trimester, and 30 prescribed AEDs for indications other than epilepsy. Statistically significant findings included more frequent folate supplementation and decreased alcohol intake during pregnancy in women with epilepsy; a dose-related increased risk of fetal malformation associated with valproate therapy; a tendency towards lower birthweights in live-born malformed offspring; and a substantially reduced decreased risk of seizures in pregnancy with one year seizure freedom before pregnancy. The small numbers of patients may have prevented other differences from reaching a P < 0.05 value.Conclusions: The Register has already produced important information for the management of pregnant women with epilepsy in Australia, but greater rates of recruitment into the Register are desirable to allow it to achieve its full potential.
Reproductive Toxicology, 2013
Infants born to epileptic women treated with antiepileptic drugs (AEDs) have an increased risk of major congenital malformations (MCMs). In order to determine the role of maternal epilepsy we conducted a prospective cohort study on three cohorts of pregnant women: (i) 385 epileptic women treated with AEDs, (ii) 310 non-epileptic women treated with AEDs, (iii) 867 healthy women not exposed to AEDs (control group). The rate of MCMs in the epileptic group (7.7%) was not statistically higher than in the non-epileptic one (3.9%) (p = 0.068). The rate in the first group was higher compared to the control group (p = 0.001), while the rate in the second one was not (p = 0.534). Our data confirm that AEDs therapy is the main cause of the increased risk of malformations in the offspring of epileptic women; however a teratogenic role of the maternal epilepsy itself cannot be excluded.
Epilepsia, 1994
Exposure to antiepileptic drug (AED) treatment in utero occurs in 1 of every 250 newborns. The absolute risk of major malformations in these infants is about 7-lo%, -3-5% higher than in the general population. Specific risk factors include high maternal daily dosage or serum concentrations of AED, low folate levels, polytherapy , and generalized seizures during pregnancy. Adverse pregnancy outcomes, including congenital heart malformations, facial clefts, spina bifida aperta, hypospadias, growth retardation, and psychomotor and mental retardation, are associated with, although not necessarily caused by, AED exposure. Specific cognitive defects, hypertelorism, and nail hypoplasia can be causally related to specific AED exposures. To prevent teratogenic side effects, the prospective mother should be treated with AEDs only when absolutely necessary. Monotherapy with the AED that is most effective in the lowest possible daily dose (divided into at least two or three administrations) should be prescribed. High-dose folate supplementation (4.5 mg/day) reduces the risk of a neural tube defect in a child whose sibling had such a defect, but its impact on the specific teratogenic risks of AEDs is unknown. A substantial proportion of fetal malformations may be secondarily prevented by prenatal diagnosis, consisting of a fetal structural ultrasound examination at weeks 18 and 20 of gestation and, with VPA or CBZ administration, an a ,-fetoprotein analysis of amniotic fluid at week 16. Determination of a specific defect prevention strategy depends largely on parental attitudes toward prenatal diagnosis and termination of pregnancy, which should be discussed before conception. The availability of many new AEDs, many of which will be used in polytherapy, will make prospective evaluation of large numbers of pregnancy outcome on a population basis even more important in the future.
Second-generation antiepileptic drugs and pregnancy: a guide for clinicians
Expert Review of Neurotherapeutics, 2012
When treating pregnant women with antiepileptic drugs (AEDs), clinicians have to balance potential fetal adverse effects against the risks of uncontrolled maternal disease. Only recently have emerging scientic data provided a rational basis for treatment decisions considering both aspects. The focus of research is currently moving from the first to the second AED generation. Lamotrigine is relatively well studied, and data on other novel AEDs, such as levetiracetam, oxcarbazepine, topiramate, zonisamide, gabapentin and pregabalin, are in progress. Safety issues appear to be favorable for lamotrigine, and preliminary results are also promising for levetiracetam and oxcarbazepine. Drugs metabolized by uridine-diphospate glucuronosyl transferase or excreted unchanged by the kidneys are particularly susceptible to increased body clearance during pregnancy. Lamotrigine is subject to both mechanisms, and therapeutic serum levels may sometimes be difficult to maintain. The authors review the recommendations and clinical research on modern AED treatment during pregnancy, highlighting current experience with second-generation drugs.