3.Leach J, Smith P, Craig J, Bagary M, Cavanagh D, Duncan S et al (2017) Epilepsy and pregnancy: for healthy pregnancies and happy outcomes. Suggestions for service improvements from the Multispecialty UK Epilepsy Mortality Group. Seizure 50:67–72. https://doi.org/10.1016/j.seizure.2017.05.004CrossRefPubMedGoogle Scholar
16.Yerby MS (2000) Quality of life, epilepsy advances, and the evolving role of anticonvulsants in women with epilepsy. Neurology 55(5 Suppl 1):21–31 discussion S 54-8Google Scholar
17.Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Perucca E, Sabers A, Thomas SV, Vajda F, EURAP Study Group (2015) Antiepileptic drugs and intrauterine death: a prospective observational study from EURAP. Neurology 85(7):580–588. https://doi.org/10.1212/WNL.0000000000001840CrossRefPubMedGoogle Scholar
18.Kasradze S, Gogatishvili N, Lomidze G, Ediberidze T, Lazariashvili M, Khomeriki K, Mamukadze S, Metreveli M, Gagoshidze T, Tatishvili N, Tomson T (2017) Cognitive functions in children exposed to antiepileptic drugs in utero – study in Georgia. Epilepsy Behav 66:105–112. https://doi.org/10.1016/j.yebeh.2016.10.014CrossRefPubMedGoogle Scholar
26.Viale L, Allotey J, Cheong-See F, Arroyo-Manzano D, Mccorry D, Bagary M, EBM CONNECT Collaboration et al (2015) Epilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis. Lancet 386(10006):1845–1852. https://doi.org/10.1016/S0140-6736(15)00045-8CrossRefPubMedGoogle Scholar
38.Rauchenzauner M, Ehrensberger M, Prieschl M, Kapelari K, Bergmann M, Walser G, Neururer S, Unterberger I, Luef G (2013) Generalized tonic-clonic seizures and antiepileptic drugs during pregnancy – a matter of importance for the baby? J Neurol 260:484–488. https://doi.org/10.1007/s00415-012-6662-8CrossRefPubMedGoogle Scholar
43.Galappatthy P, Liyanage CK, Lucas MN et al (2018) Obstetric outcomes and effects on babies born to women treated for epilepsy during pregnancy in a resource limited setting: a comparative cohort study. BMC Pregnancy Childbirth 18(1):230. https://doi.org/10.1186/s12884-018-1857-3CrossRefPubMedPubMedCentralGoogle Scholar
45.Mawhinney E, Craig J, Morrow J, Russell A, Smithson W, Parsons L, Morrison PJ, Liggan B, Irwin B, Delanty N, Hunt SJ (2013) Levetiracetam in pregnancy: results from the UK and Ireland epilepsy and pregnancy registers. Neurology 80(4):400–405. https://doi.org/10.1212/WNL.0b013e31827f0874CrossRefPubMedGoogle Scholar
Posts Tagged pregnancy
[Abstract + References] Therapeutic Drug Monitoring of Antiepileptic Drugs in Women with Epilepsy Before, During, and After Pregnancy – Review
During pregnancy, the pharmacokinetics of an antiepileptic drug is altered because of changes in the clearance capacity and volume of distribution. These changes may have consequences for the frequency of seizures during pregnancy and fetal exposure to antiepileptic drugs. In 2009, a review was published providing guidance for the dosing and therapeutic drug monitoring of antiepileptic drugs during pregnancy. Since that review, new drugs have been licensed and new information about existing drugs has been published. With this review, we aim to provide an updated narrative overview of changes in the pharmacokinetics of antiepileptic drugs in women during pregnancy. In addition, we aim to formulate advice for dose modification and therapeutic drug monitoring of antiepileptic drugs. We searched PubMed and the available literature on the pharmacokinetic changes of antiepileptic drugs and seizure frequency during pregnancy published between January 2007 and September 2018. During pregnancy, an increase in clearance and a decrease in the concentrations of lamotrigine, levetiracetam, oxcarbazepine’s active metabolite licarbazepine, topiramate, and zonisamide were observed. Carbamazepine clearance remains unchanged during pregnancy. There is inadequate or no evidence for changes in the clearance or concentrations of clobazam and its active metabolite N-desmethylclobazam, gabapentin, lacosamide, perampanel, and valproate. Postpartum elimination rates of lamotrigine, levetiracetam, and licarbazepine resumed to pre-pregnancy values within the first few weeks after pregnancy. We advise monitoring of antiepileptic drug trough concentrations twice before pregnancy. This is the reference concentration. We also advise to consider dose adjustments guided by therapeutic drug monitoring during pregnancy if the antiepileptic drug concentration decreases 15–25% from the pre-pregnancy reference concentration, in the presence of risk factors for convulsions. If the antiepileptic drug concentration changes more than 25% compared with the reference concentration, dose adjustment is advised. Monitoring of levetiracetam, licarbazepine, lamotrigine, and topiramate is recommended during and after pregnancy. Monitoring of clobazam, N-desmethylclobazam, gabapentin, lacosamide, perampanel, and zonisamide during and after pregnancy should be considered. Because of the risk of teratogenic effects, valproate should be avoided during pregnancy. If that is impossible, monitoring of both total and unbound valproate is recommended. More research is needed on the large number of unclear pregnancy-related effects on the pharmacokinetics of antiepileptic drugs.
Meador KJ, Baker GA, Browning N, et al. Effects of fetal antiepileptic drug exposure: outcomes at age 4.5 years. Neurology. 2012;78:1207–14.
Teramo K, Hiilesmaa V. Pregnancy and fetal complications in epileptic pregnancies. In: Janz D, Dam M, Bossi L, Helge H, Richens A, Schmidt D, editors. Epilepsy, pregnancy, child. New York: Raven Press; 1982. p. 53–9.
Harden CL, Pennell PB, Koppel BS, et al. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding. Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73:142–9.
Voinescu PE, Park S, Chen LQ, et al. Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy. Neurology. 2018;91(13):e1228–36. https://doi.org/10.1212/WNL.0000000000006240.
Tomson T, Landmark CJ, Battino D. Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications. Epilepsia. 2013;54:405–14.
Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs: best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49:1239–76.
Tomson T, Battino D, Bonizzoni E, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011;10:609–17.
Tomson T, Battino D, Bonizzoni E, et al. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol. 2018;17:530–8.
Briggs GG, Freeman RK, Towers CV. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. Philadelphia: Lippincott Williams and Wilkins; 2017.
Campbell E, Kennedy F, Russell A. Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers. J Neurol Neurosurg Psychiatry. 2014;85:1029–34.
Holmes L, Harvey E, Coull B. The teratogenicity of anticonvulsant drugs. N Engl J Med. 2001;344:1132–8.
Güveli BT, Rosti RO, Güzeltas A, et al. Teratogenicity of antiepileptic drugs. Clin Psychopharmacol Neurosci. 2017;15:19–27.
Meador KJ, Baker GA, Browning N, et al. Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age. Brain. 2011;134:396–404.
uptodate.com. Available from: https://www.uptodate.com/contents/search. Accessed 21 June 2018.
Johnson EL, Stowe ZN, Ritchie JC, et al. Carbamazepine clearance and seizure stability during pregnancy. Epilepsy Behav. 2014;33:49–53.
Reisinger TL, Newman M, Loring DW, et al. Antiepileptic drug clearance and seizure frequency during pregnancy in women with epilepsy. Epilepsy Behav. 2013;29:13–8.
Battino D, Tomson T, Bonizzoni E, et al. Seizure control and treatment changes in pregnancy: observations from the EURAP epilepsy pregnancy registry. Epilepsia. 2013;54:1621–7.
Thomas S, Syan U, Devi J. Predictors of seizures during pregnancy in women with epilepsy. Epilepsia. 2012;53:2010–3.
Öhman I, Sabers A, de Flon P, et al. Pharmacokinetics of topiramate during pregnancy. Epilepsy Res. 2009;87:124–9.
Patsalos PN, Gougoulaki M, Sander JW. Perampanel serum concentrations in adults with epilepsy: effect of dose, age, sex and concomitant anti-epileptic drugs. Ther Drug Monit. 2016;38:358–64.
López-Fraile IP, Cid AO, Juste AO, et al. Levetiracetam plasma level monitoring during pregnancy, delivery, and postpartum: clinical and outcome implications. Epilepsy Behav. 2009;15:372–5.
Sabers A, Buchholt J, Uldall P, et al. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res. 2001;47:151–4.
Sabers A, Ohman I, Christensen J, et al. Oral contraceptives reduce lamotrigine plasma levels. Neurology. 2003;61:570–1.
Vajda F, O’Brien T, Lander C, et al. The efficacy of the newer antiepileptic drugs in controlling seizures in pregnancy. Epilepsia. 2014;55:1229–34.
Öhman I, Beck O, Vitols S. Plasma concentrations of lamotrigine and its 2-N-glucuronide metabolite during pregnancy in women with epilepsy. Epilepsia. 2008;49:1075–80.
Pennell PB, Peng L, Newport DJ, et al. Lamotrigine in pregnancy: clearance, therapeutic drug monitoring, and seizure frequency. Neurology. 2008;70:2130–6.
Wegner I, Edelbroek P, De Haan GJ, et al. Drug monitoring of lamotrigine and oxcarbazepine combination during pregnancy. Epilepsia. 2010;51:2500–2.
Sabers A, Petrenaite V. Seizure frequency in pregnant women treated with lamotrigine monotherapy. Epilepsia. 2009;50:2163–6.
Reimers A, Brodtkorb E. Second-generation antiepileptic drugs and pregnancy: a guide for clinicians. Expert Rev Neurother. 2012;12:707–17.
Polepally AR, Pennell PB, Brundage RC, et al. Model-based lamotrigine clearance changes during pregnancy: clinical implication. Ann Clin Transl Neurol. 2014;1:99–106.
Fotopoulou C, Kretz R, Bauer S, et al. Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period. Epilepsy Res. 2009;85:60–4.
Tomson T, Battino D. Pharmacokinetics and therapeutic drug monitoring of newer antiepileptic drugs during pregnancy and the puerperium. Clin Pharmacokinet. 2007;46:209–19.
Novy J, Hubschmid M, Michel P, et al. Impending status epilepticus and anxiety in a pregnant woman treated with levetiracetam. Epilepsy Behav. 2008;13:564–6.
Westin A, Reimers A, Helde G, et al. Serum concentration/dose ratio of levetiracetam before, during and after pregnancy. Seizure. 2008;17:192–8.
Garrity LC, Turner M, Standridge SM. Increased levetiracetam clearance associated with a breakthrough seizure in a pregnant patient receiving once/day extended-release levetiracetam. Pharmacotherapy. 2014;34:e128–32.
Cappellari AM, Cattaneo D, Clementi E, et al. Increased levetiracetam clearance and breakthrough seizure in a pregnant patient successfully handled by intensive therapeutic drug monitoring. Ther Drug Monit. 2015;37:285–7.
Tomson T, Palm R, Källén K, et al. Pharmacokinetics of levetiracetam during pregnancy, delivery, in the neonatal period, and lactation. Epilepsia. 2007;48:1111–6.
Petrenaite V, Sabers A, Hansen-Schwartz J. Seizure deterioration in women treated with oxcarbazepine during pregnancy. Epilepsy Res. 2009;84:245–9.
Westin AA, Nakken KO, Johannessen SI, et al. Serum concentration/dose ratio of topiramate during pregnancy. Epilepsia. 2009;50:480–5.
Ornoy A, Zvi N, Arnon J, et al. The outcome of pregnancy following topiramate treatment: a study on 52 pregnancies. Reprod Toxicol. 2008;25:388–9.
Johannessen Landmark C, Huuse Farmen A, Larsen Burns M, et al. Pharmacokinetic variability of valproate during pregnany: implications for the use of therapeutic drug monitoring. Epilepsy Res. 2018;141:31–7.
Reimers A, Helde G, Becser Andersen N, et al. Zonisamide serum concentrations during pregnancy. Epilepsy Res. 2018;144:25–9.
Oles KS, Bell WL. Zonisamide concentrations during pregnancy. Ann Pharmacother. 2008;42:1139–41.
Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44:989–1008.
Wegner I, Edelbroek P, Bulk S, et al. Lamotrigine kinetics within the menstrual cycle, after menopause, and with oral contraceptives. Neurology. 2009;73:1388–93.
Herzog AG, Blum AS, Farina EL, et al. Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use. Neurology. 2009;72:911–4.
Thangaratinam S, Marlin N, Newton S, et al. AntiEpileptic drug Monitoring in PREgnancy (EMPiRE): a double-blind randomised trial on effectiveness and acceptability of monitoring strategies. Health Technol Assess. 2018;22:1–152.
FDA, CDER, CVM. Bioanalytical method validation guidance for industry. Silver Spring: Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER) and Center for Veterinary Medicine (CVM); 2018.
EMA. Guideline on bioanalytical method validation. Eur Med Agency Comm Med Prod Hum Use. 2015;44:1–23.
Art. 3 van het Besluit Geneesmiddelenwet. 2018. Available from: http://wetten.overheid.nl/BWBR0021672/2018-01-01#Paragraaf2. Accessed 22 Nov 2019.
Sabers A. Algorithm for lamotrigine dose adjustment before, during, and after pregnancy. Acta Neurol Scand. 2012;126:e1–4.
European Medicines Agency. New measures to avoid valproate exposure in pregnancy endorsed. London: European Medicines Agency (EMA); 2018. p. 1–4.
International League Against Epilepsy (ILAE) and European Academy of Neurology (EAN). Valproate in the treatment of epilepsy in women and girls. Pre-publication summary of recommendations from a joint Task Force of ILAE-Commission on European Affairs and European Academy of Neurology (EAN). 2018. Available from: https://www.ilae.org/files/ilaeGuideline/ValproateCommentILAE-0315.pdf. Accessed 22 Nov 2019.
Hernandez-Diaz S, Smith C, Shen A. Comparative safety of antiepileptic drugs during pregnancy. Neurology. 2012;78:1692–9.
Patsalos PN, Zugman M, Lake C, et al. Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: a comparison of free non-protein-bound concentrations. Epilepsia. 2017;58:1234–43.
Kacirova I, Grundmann M, Brozmanova H. Concentrations of carbamazepine and carbamazepine-10,11-epoxide in maternal and umbilical cord blood at birth: influence of co-administration of valproic acid or enzyme-inducing antiepileptic drugs. Epilepsy Res. 2016;122:84–90.
de Leon J, Spina E, Diaz FJ. Clobazam therapeutic drug monitoring: a comprehensive review of the literature with proposals to improve future studies. Ther Drug Monit. 2013;35:30–47.
Burns M, Baftiu A, Opdal M, et al. Therapeutic drug monitoring of clobazam and its metabolite: impact of age and comedication on pharmacokinetic variability. Ther Drug Monit. 2016;38:350–7.
Shorvon S, Perucca E, Engel J Jr. The treatment of epilepsy. 4th ed. Chichester: Wiley; 2016.
Kacirova I, Grundmann M, Brozmanova H. Serum levels of lamotrigine during delivery in mothers and their infants. Epilepsy Res. 2010;91:161–5.
Lyseng-Williamson K, Yang L. Spotlight on topiramate in epilepsy. CNS Drugs. 2008;22:171–4.
Sills G, Brodie M. Pharmacokinetics and drug interactions with zonisamide. Epilepsia. 2007;48:435–41.
Kawada K, Itoh S, Kusaka T, et al. Pharmacokinetics of zonisamide in perinatal period. Brain Dev. 2002;24:95–7.
To determine how pre-conception care (PCC) influenced the outcome of epilepsy, pregnancy and malformation risk in women with epilepsy (WWE)
All primigravida in the Kerala registry of epilepsy and pregnancy (KREP) with the final outcome of pregnancy known who were enrolled prospectively in pre-conception stage (PCC group) or first trimester of pregnancy (PRG group) were included. The two groups were compared for fetal and maternal outcomes including seizure control and complications of pregnancy.
There were 320 (30.4%) in PCC group and 732 in PRG group. Both groups were comparable for epilepsy classification, maternal birth defects and family history of epilepsy but the PCC group had significantly higher education (48.9%, p = .027) and employment (22.1%, p < .001). They had higher usage of folate in pre-pregnancy month (87.5%, p < .001) and first trimester (96.3%, p < .001) than PRG group. Fewer women in the PCC group were off AEDs in first trimester (5% vs 9.3%, p = .018). Within monotherapy group, use of levetiracetam (10.8%, p = .017), valproate ( 34%, p = .002) in PCC group and carbamazepine (39.1%, p = .04), phenobarbitone (13.3%, p = .001) in PRG group was significantly high. More women in this group were seizure free during pregnancy (62.8%, p = .005) than PRG group. Early fetal loss was better captured in PCC (90.6%,p = .025) than in the PRG. There was no difference in malformation rate between PCC (7.2%) and PRG groups (6.1%, p = .3).
PCC reduced the risk of seizures during pregnancy and improved the periconceptional use of folate but did not influence the fetal malformation risk.
Epilepsy is a common neurological disorder that may complicate reproductive health. Our aim in this study was to provide prospective ascertainment of obstetric and neonatal outcomes in women with epilepsy and investigate whether the risk of pregnancy, delivery, and neonatal complications differed between women with epilepsy and women without epilepsy.
Pregnant women with epilepsy and women without epilepsy (control group) were prospectively evaluated during the years 2013–2018. They were regularly followed by a neurologist and obstetrician until the end of pregnancy.
Delivery and perinatal outcomes were compared between 112 women diagnosed with epilepsy and 277 women without epilepsy. Epilepsy was a significant risk factor for preterm delivery, cesarean section, fetal hypoxia, and Apgar score ≤ 7 at 5 min in offspring (odds ratio (OR) = 2.83, 95% confidence interval (CI) 1.03–7.76; OR = 5.61, 95% CI 3.44–9.14; OR = 1.81, 95% CI 1.08–3.04; OR = 8.12, 95% CI 4.04–16.35, respectively). Seizures during pregnancy had influence on the preference of cesarean section as a mode of delivery (ОR = 3.39; 95% CI 1.40–8.17). The rate of perinatal hypoxia was significantly higher in children born by cesarean section (ОR = 2.84; 95% CI 1.04–7.76). There was no significant difference between women with epilepsy and controls in malformation rate.
Women with epilepsy had an increased risk of pregnancy and delivery complications. Cesarean section was associated with an increased risk of complications in offspring.
[ARTICLE] Maternal complications in pregnancy and childbirth for women with epilepsy: Time trends in a nationwide cohort – Full Text
Obstetric trends show changes in complication rates and maternal characteristics such as caesarean section, induced labour, and maternal age. To what degree such general time trends and changing patterns of antiepileptic drug use influence pregnancies of women with epilepsy (WWE) is unknown. Our aim was to describe changes in maternal characteristics and obstetric complications in WWE over time, and to assess changes in complication risks in WWE relative to women without epilepsy.
This was a nationwide cohort study of all first births in the Medical Birth Registry of Norway, 1999–2016. We estimated maternal characteristics, complication rates, and risks for WWE compared to women without epilepsy. Main maternal outcome measures were hypertensive disorders, bleeding in pregnancy, induction of labour, caesarean section, postpartum hemorrhage, preterm birth, small for gestational age, and epidural analgesia. Time trends were analyzed by logistic regression and comparisons made with interaction analyses.
426 347 first births were analyzed, and 3077 (0.7%) women had epilepsy. In WWE there was an increase in proportions of induced labour (p<0.005) and use of epidural analgesia (p<0.005), and a reduction in mild preeclampsia (p = 0.006). However, the risk of these outcomes did not change over time. Only the risk of severe preeclampsia increased significantly over time relative to women without epilepsy (p = 0.006). In WWE, folic acid supplementation increased significantly over time (p<0.005), and there was a decrease in smoking during pregnancy (p<0.005), but these changes were less pronounced than for women without epilepsy (p<0.005).
During 1999–2016 there were important changes in maternal characteristics and complication rates among WWE. However, outcome risks for WWE relative to women without epilepsy did not change despite changes in antiepileptic drug use patterns. The relative risk of severe preeclampsia increased in women with epilepsy.
Epilepsy is one of the most common chronic diseases during pregnancy.[1–4] Women with epilepsy (WWE) have been considered as high risk parturients with increased risk for maternal complications.[2–8] Almost half of women with ongoing or previous epilepsy use antiepileptic drugs (AEDs) in pregnancy to control seizures despite their potential adverse effects on the fetus and maternal complications.[2, 9–11] The pattern of antiepileptic drug use in pregnant WWE has changed markedly during the last two decades owing to newer antiepileptic drugs, primarily lamotrigine and levetiracetam, replacing older antiepileptic drugs, such as carbamazepine, phenytoin, and valproate. [12–14] The newer antiepileptic drugs are better tolerated and believed to have less fetal and maternal adverse effects, but are associated with increased seizure risk during pregnancy.[10, 11, 15–19] Increasing maternal age, increasing maternal body mass index (BMI), and decrease in smoking during pregnancy over the last two decades should also affect WWE.[20–23] These factors could be proportional or have a more complex interaction. Global trends show an increase in caesarean section rates and increased induction of labour.[24–26] Such interventions are common in WWE.[2, 4, 5, 7, 8] During the last decade, there has been an increasing focus on management of WWE during pregnancy and delivery and recent guidelines encourage close monitoring of pregnancies in WWE and strict indications for interventions.[25, 27–30] However, there is little data on how focused management and guidelines have affected maternal outcomes of WWE. A recent meta-analysis indicates a trend towards increasing rates of caesarean section and induction of labour in WWE. However, different geographical populations with great variation in obstetric practice were compared to describe differences over time, and no reference populations were included. Therefore, it is not known how changes in population characteristics, obstetric practice and general complication rates have affected WWE. We expect that changes during the recent years in folate use, indications for operative interventions, and AEDs used have all influenced maternal complications in WWE during pregnancy and when giving birth.
By analyzing a stable nationwide cohort over 18 years, our aim was to describe changes in maternal characteristics and maternal complication rates in WWE over time, and to assess changes in complication risks relative to women without epilepsy. For changes in outcome risks in WWE over time, the influence of AED use and other specific factors were assessed.
VD Kapadia – Medical Disorders in Pregnancy
Epilepsy is the most common neurological disorder, with 50 million people affected by it worldwide. Nearly 50% of these affected individuals are women. The burden of epilepsy in women in India is to the tune of 2.73 million, with 52% of them being in …
Continue —> Pregnancy and Epilepsy [PDF]
[NEWS] New guidance on use of valproate in women, girls of child bearing age with epilepsy published
Apr 2 2019
New guidance to support regulations around the use of valproate in women and girls of child bearing age with epilepsy has been published by specialists from 13 UK healthcare bodies including seven Royal Colleges.
And NICE has published a summary of updated guidance for healthcare professionals bringing together all its recommendations and other safety advice on the drug valproate.
The use of sodium valproate during pregnancy is associated with up to a 40 per cent risk of neuordevelopmental disorders and a 10 per cent risk of physical disabilities for an unborn child.
In March 2018, the Medicines and Healthcare products Regulatory Agency published guidelines which meant that valproate could no longer be prescribed for girls and women of childbearing age unless no other effective treatment was available.
Any girl or woman prescribed valproate should also be fully informed of the risks associated with the medication and the need for effective contraception.
But a year on, implementation of the guidelines have thrown up specific challenges with complex issues and individual situations where the best interests of the patient did not always appear to be met.
Claire Glazebrook, Director of Fundraising, Marketing and External Affairs at Epilepsy Society, said:
Over the last year our Helpline has received multiple calls from women, parents and healthcare professionals, all struggling to interpret the guidelines and what they mean for them as individuals. And we know that this experience is replicated across other patient organizations and clinics.
I hope this guidance will help to answer some of their questions and provide clarity in what can be a very emotional and challenging decision.
For some girls and women, they have no option but to take sodium valproate as it may be the only drug that will control their seizures. But that of course means there are some very important and potentially heartbreaking issues to consider around planning a family.
All these women and girls deserve consistency in the advice and information that they receive.”
The new pan-college guidance has been drawn up by Judy Shakespeare of the Royal College of General Practitioners and Sanjay Sisodiya of the Association of British Neurologists and Royal College of Physicians. Sanjay Sisodiya is also Director of Genomics at Epilepsy Society and Professor of Neurology at UCL.
He said: This work has come together through much valued contributions from specialists across all the national bodies involved.
“In some cases the new regulations have lead to situations where the best interests of the patients may not appear to be best served. Some of the points raised by the regulations are also complex ethical issues. We do not attempt to address all these issues in this document but hope that it will bring greater clarity for clinicians leading to better care for women and girls with epilepsy. All women and girls have individual needs and where possible should be involved in the choices they make about their own health and plans to start a family.”
Writing in the guidance, Professor Dame Sally Davies, Chief Medical Officer for England said:
I am very pleased that the Medical Royal Colleges have come together to produce this important and helpful guidance, so that doctors and other healthcare professionals across primary and secondary care are on the same page regarding the use of sodium valproate – including around instances where its use is still appropriate.”
Epilepsy is a common neurological condition in women worldwide. Hormonal changes occurring throughout a woman’s life can influence and be influenced by seizure mechanisms and antiepileptic drugs, presenting unique management challenges. Effective contraception is particularly important for women with epilepsy of childbearing potential because of antiepileptic drug-related teratogenicity and hormonal interactions; although studies reveal many women do not receive contraceptive and preconceptual counselling. Management challenges in this population include the higher risk of pregnancy complications and peripartum psychiatric problems than in women without epilepsy. Research is needed to clarify the precise role of folic acid supplementation in prevention of congenital malformations in children born to women with epilepsy. To optimise treatment of low bone density in women with epilepsy, studies investigating bone densitometryfrequency and calcium and vitamin D supplements are required. Understanding of the mechanisms linking seizures and the menopause will help to develop effective therapeutic strategies, and advances in managing epilepsy could improve quality of life for women with this condition.
Maternal use of antiepileptic agents during pregnancy and major congenital malformations in children
Bromley RL, Weston J, Marson AG.
JAMA 2017; 318:1700-1701.
Is maternal use of antiepileptic drugs during pregnancy associated with major congenital malformations in children?
Certain antiepileptic drugs were associated with increased rates of congenital malformations (eg, spina bifida, cardiac anomalies). Lamotrigine (2.31% in 4195 pregnancies) and levetiracetam (1.77% in 817 pregnancies) were associated with the lowest risk and valproate was associated with the highest risk (10.93% in 2565 pregnancies) compared with the offspring of women without epilepsy (2.51% in 2154 pregnancies).
Weston J, Bromley R, Jackson CF, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev 2016; 11:CD010224.
Both references are cited in the neurochecklist:
[Abstract] Antiepileptic drug treatment during pregnancy and delivery in women with epilepsy – A retrospective single center study
Pregnancies in women with epilepsy (WWE) increased significantly during our 11-year study period (41% increase).
Twelve different AEDs were prescribed to WWE during pregnancies in the 11-year period investigated (2005-2015) with Lamotrigine (36.1%), Carbamazepine (25.0%), and Valproic Acid (13.5%) most commonly used.
Valproic acid use was markedly reduced comparing the years 2005-2010 (18.4%) and 2011-2015 (9.4%), a reduction of 48%.
Unfortunately, a trend towards an increase in treating WWE with more than one AED was observed.
[Abstract] Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy
Objective To characterize the magnitude and time course of pregnancy-related clearance changes for different antiepileptic drugs (AEDs): levetiracetam, oxcarbazepine, topiramate, phenytoin, and valproate. A secondary aim was to determine if a decreased AED serum concentration was associated with increased seizure frequency.
Methods Women with epilepsy were enrolled preconception or early in pregnancy and prospectively followed throughout pregnancy and the first postpartum year with daily diaries of AED doses, adherence, and seizures. Study visits with AED concentration measurements occurred every 1–3 months. AED clearances in each trimester were compared to nonpregnant baseline using a mixed linear regression model, with adjustments for age, race, and hours postdose. In women on monotherapy, 2-sample t test was used to compare the ratio to target concentrations (RTC) between women with seizure worsening each trimester and those without.
Results AED clearances were calculated for levetiracetam (n = 18 pregnancies), oxcarbazepine (n = 4), topiramate (n = 10), valproate (n = 5), and phenytoin (n = 7). Mean maximal clearances were reached for (1) levetiracetam in first trimester (1.71-fold baseline clearance) (p = 0.0001), (2) oxcarbazepine in second trimester (1.63-fold) (p = 0.0001), and (3) topiramate in second trimester (1.39-fold) (p = 0.025). In 15 women on AED monotherapy, increased seizure frequency in the first, second, and all trimesters was associated with a lower RTC (p < 0.05).
Conclusion AED clearance significantly changes by the first trimester for levetiracetam and by the second trimester for oxcarbazepine and topiramate. Lower RTC was associated with seizure worsening. Early therapeutic drug monitoring and dose adjustment may be helpful to avoid increased seizure frequency.