In an article that appeared in Focus Pharmacovigilance in 2014 the main adverse effects of antiepileptic drugs were discussed.1 In this article it was emphasised that the use of these drugs during pregnancy may lead to an increased risk of foetal malformations and how the extent of this risk varies depending on the type and dose of the drug administered.
The purpose of this new article is to provide an update of the knowledge in this regard and to inform about recent measures taken by the European Medicines Agency (EMA) and, consequently, AIFA (Italian Medicines Agency) to limit the use of valproate, the drug associated with the highest level of risk for foetus.1
The regulatory provisions
The current regulatory provisions state that “valproate should not be used in girls and women of childbearing age unless other treatments have proved ineffective or not tolerated”. Special contraindications have also been established for women of childbearing age and for pregnancy. For women of childbearing age, valproate is contraindicated unless the conditions set out in the pregnancy prevention programme are guaranteed, the nature of which is specified in detail by the legislation.2 In the case of pregnant women, the type of contraindication varies depending on the type of disease. In bipolar disorder, valproate is always contraindicated during pregnancy, while in epilepsy “valproate is contraindicated during pregnancy, unless appropriate alternative treatment is not possible”. The AIFA provisions also state that for women of childbearing age on valproate therapy, a clinical reassessment of treatment may be necessary to determine if the requirements of the pregnancy prevention programme are met. This article by Focus Farmacovigilanza intends to investigate in particular the risks associated with the use of valproate, in comparison to the risk associated with other antiepileptic drugs, in patients with epilepsy in drug therapy during pregnancy.
Although an association between taking antiepileptic drugs in pregnancy and foetal malformations was identified in the late 1960s, knowledge about the risk associated with specific drugs has progressed considerably over the last decade thanks to data generated by different prospective registers.3-6 The overall assessment of these data indicates that the risk level can be considered low for lamotrigine, oxcarbazepine and levetiracetam, moderately higher for carbamazepine, phenytoin and topiramate, even higher for phenobarbital and maximum for valproate. The most recent results of the international EURAP register, which includes a follow-up the infants born for up to 12 months, are particularly significant in this regard. This is an important detail because some major malformations are often identified only a few months after birth. The data published in the journal Lancet Neurology in April 20186 refer to 7,355 pregnancies in women treated with 8 major antiepileptic drugs as monotherapy: lamotrigine (n=2,514), carbamazepine (n=1,957), valproate (n=1,381), levetiracetam (n=599), oxcarbazepine (n=333), phenobarbital (n=294), topiramate (n=152) and phenytoin (n=125). A dose-dependence risk for teratogenic effects has been shown only for lamotrigine, carbamazepine, phenobarbital and valproate. For this reason, the results for the latter drugs are reported in Table 1 separately by dose group.
Table 1. Frequency of major malformations following in-utero exposure to 8 antiepileptic drugs in monotherapy6
|Drug||% of cases with major malformations (95% CI)|
80 - ≤130 mg/day
≤ 650 mg/day
>650 - ≤1.450 mg/day
Although the EURAP registry does not include women not treated with antiepileptics, the risk associated with lamotrigine exposure (doses ≤325 mg/day), levetiracetam and oxcarbazepine does not differ much from that expected in the general population. For valproate, in addition to the teratogenic risk (among the various reported abnormalities, the increase in risk of spina bifida and other neural-tube defects is of particular importance), an increase in the risk of developing cognitive impairment during the first years of life (particularly after prenatal exposure at doses ≤1,000 mg/day), autism, autism spectrum disorders and attention deficit and hyperactivity disorder (ADHD) has also been described.7-10 It is also relevant to point out that the increased risk of teratogenic effects associated with polytherapy with antiepileptic drugs (compared to the use of the same drugs as monotherapy) is largely attributable to the presence of valproate in cases exposed to polytherapy.11,12
What to do in pregnancy
In the vast majority of cases, the need to maintain drug therapy during pregnancy is not under discussion, but evidence of differences in the level of risk between one drug and another must be taken into account in the choice of therapy in patients of childbearing age. Based on the data summarised above, the EMA has put a series of restrictions and recommendations in place, made by the Italian Medicines Agency (AIFA), aimed at minimising the exposure to valproate during pregnancy. These measures were tightened in 2018 following the emergence of inadequate risk awareness among both prescribers and patients.13,14
The current Summary of Product Characteristics establishes that “valproate ... should not be used in children, adolescents, or women of childbearing age and pregnant women, unless alternative treatments are ineffective or not tolerated, due to its high teratogenic potential and the risk of developmental disorders in newborns exposed to valproate in utero ... Preferably, valproate should be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged-release formulation to avoid high plasma concentration peaks. The daily dose should be divided into at least two single doses... The risks and benefits must be carefully reconsidered during regular treatment reassessments, in puberty and urgently when a woman of childbearing age treated with valproate becomes or plans to become pregnant. Women of childbearing should use effective contraception during treatment and be informed of the risks associated with the use of valproate during pregnancy... The prescribing physician must ensure that the patient is fully informed of the risks as well as provided with relevant materials, such as a patient information leaflet, in order to help her understanding of the risks”.
The Dear Doctor letter from AIFA
According to the ‘Dear Doctor letter’ sent by AIFA to Italian doctors on 6 August 20181 the prescribing physician must ensure that:
- the personal situation was assessed for each case, that the patient was involved in the discussion, that the patient was accountable, that the different treatment options were presented and that the patient understood the risks and measures necessary to minimise these risks
- all patients have been evaluated for the potential for pregnancy
- the patient has understood and accepted the risks of congenital malformations and neurodevelopmental disorders, including the severity of these risks, for children exposed to valproate in utero
- the patient has understood the need to undergo a pregnancy test before the start of therapy and during treatment, if necessary
- the patient has received advice on contraception and is in a position to respect the need to use an effective contraceptive method for the whole duration of treatment with valproate
- the patient has understood the need for a regular (at least yearly) clinical re-evaluation of therapy by a specialist experienced in the treatment of epilepsy or bipolar disorder
- the patient has understood the need to consult her doctor as soon as she decides to plan a pregnancy to ensure a timely evaluation and transition to an alternative treatment before conception and before stopping contraceptive use.
- the patient has understood the need to urgently consult a physician in case of pregnancy
- the patient has received the “Patient Guide”
- the patient has confirmed that she understands the risks and the consequent necessary precautions associated with the use of valproate (signing the “Annual Risk Acceptance Form”).
- these provisions also apply in the case of non-sexually active women, unless the prescribing physician has obvious reasons to indicate that there is no risk of pregnancy.
The AIFA letter also includes an attachment with more detailed instructions on:
- use of valproate in girls
- need to exclude pregnancy before starting valproate
- use of an effective contraceptive method
- annual re-evaluation of treatment by a specialist
- use of the “Annual Risk Acceptance Form” (at the beginning of treatment, at the time of treatment revaluation and at least annually
- what to do with valproate treatment at the time of pregnancy planning and during pregnancy
- specific tasks of the pharmacist, for example the delivery of the letter for the patient.
Doctors are alerted that the printouts of valproate-containing medicines will be updated accordingly. It is also recommended that women who become pregnant while taking valproate are enrolled in the European Registry of pregnancies exposed to anti-epileptic drugs (EURAP). Finally, a specific warning is to be included on the external packaging of valproate-based medicinal products.
The methods of using valproate during pregnancy
Documents produced by scientific societies provide recommendations on how to best use valproate in the context of regulatory restrictions.16 In some patients, valproate may be the only drug capable of adequately controlling epileptic seizures and the importance of seizure control should not be underestimated as some types of seizures are associated with risk of mortality and morbidity. In this regard, there is consensus on the need to rationalise the therapy, with possible replacement of valproate with alternative drugs where indicated, well in advance of conception.16 The risk/benefit ratio of a change in therapy during pregnancy may not be favourable for mother and foetus, and there is evidence in particular of loss or deterioration of seizure control in women who had suspended valproate use during pregnancy.17 As also recognised by the Regulatory Agency, it is known that for some women with epilepsy it may not be possible to stop the valproate and it is necessary to continue treatment during pregnancy, with appropriate specialist evaluation. It is therefore appropriate to emphasise the importance of encouraging collaboration between specialists in patient management. The EMA also recommends that “girls and women who have been prescribed valproate should not stop treatment with this drug without consulting their doctor, because this interruption could have adverse effects not only on themselves, but also on the foetus”.18
Pharmacology Unit, Department of Internal Medicine and Medical Therapy, University
- J Neurol Neurosurg Psychiatry 2014;85:1029-34. CDI
- Neurology 2012;78:1692-9. CDI
- Neurology 2013;81:999-1003. CDI
- Lancet Neurol 2018;17:530-8. CDI
- Epilepsia 2010;51:2058-65. CDI
- Arch Dis Child 2011;96:643-7. CDI
- Epilepsy Behav 2011;22:240-6. CDI NS
- Lancet Neurol 2013;12:244-52. CDI
- Arch Neurol 2011;68:1275-81. CDI
- Neurology 2015;85:866-72. CDI
- Epilepsia 2015;56:1006-19. CDI
- Epilepsia 2016;57:e173-7. CDI
- http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Valproate_and_related_substances/ human_referral_prac_000066.jsp&mid=WC0b01ac05805c516f