Preconception and pregnancy management in women with epilepsy
In women with epilepsy (WWE), the balance between seizure control and minimization of teratogenic risk during pregnancy is a challenge. At a Sanofi-sponsored webinar, epilepsy experts Professor Mar Carreno of the Hospital Clinic Barcelona in Spain, Professor Joanna Jedrzejczak of the Centre of Postgraduate Medical Education in Warsaw, Poland, and Professor Candan Gürses of the Koç University School of Medicine in Istanbul, Turkey, discussed preconception and pregnancy management in WWE, including the importance of avoiding valproate in women of childbearing potential (WOCBP).
Pregnancy planning essential for WWE
“Preconception consultation, counselling and planning are key in managing epilepsy and seizures in pregnancy,” said Carreno.
A retrospective cohort study found that WWE with planned pregnancies had more favorable outcomes than those with unplanned pregnancies, with a signifi-cantly lower frequency of seizures (15.7 percent vs 34.6 percent; p=0.018), lower likelihood of altering their antiepileptic drug (AED) regimen (0 percent vs 25.9 percent; p<0.001), and greater treatment compliance (medication discontinued by patients, 7.7 percent vs 21.3 percent; p=0.07) during pregnancy. (Figure 1) [Seizure 2014;23:112-116]
Before puberty and sexual activity, girls and WWE should receive tailored information about contraception, conception and pregnancy. [UK National Institute for Health and Care Excellence (NICE) 2020, https://pathways.nice.org. uk/pathways/epilepsy; Epileptic Disord 2019;21:497-517]
The rate of hormonal contraception is low in WWE compared with those without epilepsy (19 percent vs 26 percent). [Lancet Neurol 2019;18:481-491] “The use of progesterone-only pill, combined contraceptive pill and vaginal ring is not recommended in WWE due to their reduced efficacy. In WWE, nonhormonal intrauterine device [IUD] would be the contraceptive method of choice,” explained Carereno.
Due to the high risk of foetal developmental disorders, valproate should be avoided in WOCBP, unless without suitable alternatives. In WWE taking valproate, effective contraception must be used with-out interruption throughout treatment, preferably with an effective user-independent contraceptive, such as an IUD or implant, or two complementary forms of contraception (including a barrier method). [UK Epilim SmPC 2020, https://www.medi-cines.org.uk/emc/medicine/6781#CLINICAL_PRECAUTIONS; Sodium Valproate Hong Kong Prescribing Information]
Prepregnancy counselling on AED and other risks in pregnancy
“WWE should be advised on the best possible seizure control with AED regimens, along with adequate folic acid supplementation as well as medical and social support. However, a significant proportion of pregnancies in WWE are unplanned, as the maternal and foetal risks and potential drug interactions between AEDs and contraceptives are not fully explained,” said Carreno. [International League Against Epilepsy 2019, https://www.ilae.org/journals/epigraph/epigraphy-vol-21-issue-4-fall-2019/six-ways-to-maximise-reproductive-health-in-women-with-epilepsy]
Some AEDs (eg, topiramate) are associated with intrauterine growth retardation. [Epileptic Disord 2019;21:497-517; Ann Neurol 2017;82:457-465] Valproate is associated with the highest risk (6.7–12.4 percent) of major congenital malformations (MCMs). [Epileptic Disord 2019;21:497-517; J Neurol Neurosurgery Psychiatry 2014;85:1029-1034] The MCM risk is dose-dependent for valproate, and probably also dose-dependent for other AEDs such as carbamazepine, pheno-barbital and lamotrigine. [Epileptic Disord 2019;21:497-517] Foetal exposure to valproate also carries a significant dose- dependent risk of paediatric cognitive and neurodevelopmental disorders, including autism spectrum disorders. [Epileptic Disord 2019;21:497-517]
With careful planning, most pregnancy risks for WWE can be avoided or reduced. Management of WOCBP should consider the risk of seizure as well as the teratogenic risks associated with AED exposure, including effects on intrauterine growth, MCMs, and developmental and behavioural outcomes, with a treatment change if appropriate. Valproate should be avoided whenever possible, and discontinued or switched to other treatments. Treatment modifications should begin as early as 1 year before planned pregnancy. Folic acid supplementation should also be started in WWE planning pregnancy before conception, at a dose of 0.4 mg/day, to reduce the risk of neural tube defects. Nevertheless, effects of higher intake are not well known, and care should be taken to keep folate consumption at <1 mg/day. The US Centers for Disease Control and Prevention (CDC) recommends women at high risk of having subsequent neural tube defect–affected pregnancy to seek advice from physicians. [Epileptic Disorder 2019;21:497-517; US CDC 1992, https://www.cdc.gov/mmwr/preview/mmwrhtml/00019479.htm] “A collaborative, multidisciplinary approach is needed for WWE – before, during and after pregnancy,” said Carreno.
Epilepsy treatment before and during pregnancy
“In WWE planning pregnancy, epilepsy treatment should be optimized before conception,” said Jedrzejzak. “The ideal AED regimen in pregnancy should prioritize monotherapy over polytherapy, avoid valproate if possible, and consider dose- dependent effects and AED level fluctuations. It is important that patients are involved in all treatment decisions and understand the associated risks.” [NICE 2020, http://pathways.nice.org.uk/pathways/epilepsy]
Valproate is not recommended as a first therapeutic option in girls and WOCBP. If initiated, valproate should be used under specialist supervision and at the lowest effective dose. A Pregnancy Prevention Programme (PPP) is mandatory for WOCBP taking valproate. (Figure 2) [UK sodium valproate SmPC 2020, https://www.medicines.org.uk/emc/product/1209/smpc; J Neurol 2020, doi: 10.1007/s00415-020-09809-0; Sodium Valproate Hong Kong Prescribing Information]
A European expert panel recently recommended that valproate should not be used as a first-line AED in girls ≥10 years of age. If a WOCBP is taking valproate, it should be stopped if pregnancy is planned, if there is a significant risk of unplanned pregnancy, or if the epilepsy syndrome is not self-limiting. Switching or discontinuing valproate treatment should be tailored to the patient and under expert supervision. [J Neurol 2020, doi: 10.1007/s00415-020-09809-0]
According to the European expert panel, valproate should be one of the last therapeutic options in focal epilepsy. In highly drug-resistant focal epilepsy that is responsive to valproate, the lowest effective drug dose should be prescribed, and a PPP followed. “In idiopathic generalized epilepsy controlled on valproate, treatment should be switched or discontinued before puberty, or when planning pregnancy. The least teratogenic alternatives should be considered for switching, and patients should be informed about the risks of seizure during treatment changes. The new AED treatment should be gradually titrated to the appropriate dose, and then valproate should be tapered off. Switching and withdrawal from valproate should occur at least 1 year before a planned pregnancy, as this requires 4–8 weeks of downtitration and at least 1 month of full body clearance,” said Jedrzejzak. [J Neurol 2020, doi: 10.1007/s00415-020-09809-0]
In case of unplanned pregnancy in a WWE taking valproate, the patient must be referred for urgent expert review. Valproate should be reduced to the minimum effective dose to prevent seizures, particularly during the first trimester. Where possible, treatment should be switched, preferably to levetiracetam as this can be introduced more quickly than other AED alternatives.
Newborns exposed to valproate in utero should be assessed for possible MCMs up to 1 year of age, and longer for possible neurodevelopmental delays. [J Neurol 2020, doi: 10.1007/s00415-020-09809-0]
Measures to minimize valproate risk
“Women and girls diagnosed with epilepsy, even in adolescence, must be informed about pregnancy and pre-conception care, regardless of which drug they use,” said Gürses. (Figure 1) [International League Against Epilepsy 2019, https://www.ilae.org/journals/epigraph/epigraphy-vol-21-issue-4-fall-2019/six-ways-to-maximise-reproductive-health-in-women-with-epilepsy]
In terms of risk minimization measures for valproate, the Pharmacovigilance and Risk Assessment Committee (PRAC) at the European Medicines Agency (EMA) introduced new measures in May 2018 to strengthen the earlier restrictions on valproate use in WOCBP and pregnancy, which were insufficiently effective. The strengthened measures include contraindications to valproate for epilepsy treatment in pregnancy unless there is no suitable alternative, and in WOCBP unless PPP conditions are fulfilled. There are similar contraindications to valproate use in bipolar disorder in pregnancy and WOCBP. [EMA 2018, https://www.ems.europa.eu/en/doc-uments/referral/valproate-article-31-refer-ral-prac-assessment-report_en.pdf]
“The purpose of the revised PRAC measures is to avoid unnecessary exposure to valproate during pregnancy and to increase the effectiveness of communication, understanding and awareness of both healthcare professionals [HCPs] and patients. New revisions to drug labelling in Europe clarify valproate contraindications, increase warnings, and provide a QR code linked to further information,” highlighted Gürses.
The new recommendations also included implementation of a PPP. “The PPP includes measures to ensure HCPs are aware of and inform patients about the risks and recommendations regarding valproate in pregnancy. A web-based platform is used to provide educational materials, including guides for HCPs and patients, a patient alert card, and an annual risk acknowledgement form. The annual risk acknowledgement form must be completed by both the patient and specialist to ensure discussion and understanding of the risks of valproate during pregnancy. The form addresses valproate risks, conditions of the PPP, and the need for regular treatment reviews and use of effective contraceptive methods. It also stresses the importance of prepregnancy planning consultation and need for urgent consultation if a patient becomes pregnant while taking valproate,” said Gürses. “Continuous HCP-patient conversations are required.