|Relevant tools: A.4, A.11, A.12, A.13|
The diagnosis of epilepsy and the use of anti-epileptic drugs (AEDs) in women of childbearing age present particular challenges. Advice on contraception for young women with epilepsy should ideally be given before they become sexually active, in order to avoid unplanned pregnancies and the associated risks to the health of the mother and the unborn baby.
Specific AEDs can reduce the effectiveness of hormonal contraceptives. The NICE guideline therefore emphasises that the possibility of interaction with oral contraceptives should be discussed, and an assessment made as to the risks and benefits of treatment with individual drugs.
Twenty three percent of the population of people with epilepsy are women of childbearing age.1
The updated Quality and Outcomes Framework (QOF) indicator EP003 calls on GPs to report on “the percentage of women aged 18 or over and who have not attained the age of 55 who are taking antiepileptic drugs who have a record of information and counselling about contraception, conception and pregnancy in the preceding 12 months".2
The important gender-specific considerations for women include:
- potential interaction between AEDs and hormonal contraceptives
- impact of seizures and AEDs on conception and fertility
- risks to mother and baby in pregnancy, labour and post-pregnancy
- impact of seizures and AEDs on menstrual cycles
- impact of menopause and hormone replacement therapy (HRT) on seizure control.3
Most women with epilepsy have problem-free pregnancies and healthy babies. However, the diagnosis of epilepsy and the use of AEDs in women can present particular problems:4
- major (eg neural tube defects such as spina bifida) and minor (eg underdevelopment of the mid-face resulting in features such as a flat nasal bridge) congenital malformations occur more commonly in infants exposed to AEDs during pregnancy4
- women taking enzyme-inducing AEDs and the combined oral contraceptive (COC) pill are at increased risk of pill failure due to accelerated oestrogen metabolism. This may result in breakthrough bleeding and/or unplanned pregnancy.4,5
In some areas, extra screening may be offered as obstetrics and gynaecology departments have required guidelines around women and epilepsy and will operate high-risk group antenatal clinics.
Advice on contraception for young women with epilepsy should ideally be given before they become sexually active. Providing young women with information enables them to understand why it is advisable to try and avoid an unplanned pregnancy and to plan their choice of contraception. This is because an unplanned pregnancy might be associated with an increased risk to the health of the mother and her unborn baby.5-6
Which contraception is most suitable for the individual will depend on several factors. This includes the risk of interaction with their AEDs, and the risk of malformation in an unborn child should they become pregnant while taking their current AED treatment.
Hepatic enzyme-inducing AEDs (see Table 1) can reduce the effectiveness of oral contraceptives (combined oral contraceptive pill, progestogen pill and emergency contraceptive pills).5-6 Enzyme-inducing AEDs speed up how quickly the liver breaks down these contraceptives. This potentially reduces contraceptive efficacy, increasing the risk of an unplanned pregnancy.2,4,5
It is thought that the enzyme-inducing AEDs also reduce the effectiveness of contraceptive patches, the vaginal ring, Noristerat contraceptive injections and contraceptive implants through the same mechanisms. However, women can be advised that there is no evidence of enzyme inducing AEDs reducing the effectiveness of depot injections of progestogen, intrauterine devices (coils) or intrauterine systems.4-6
Women using enzyme-inducing AEDs who choose to use the combined oral contraceptive pill should be started on a combined oral contraceptive pill to provide a dose of at least 50 μg of oestrogen. In the case of changes to the menstrual cycle, the dose should be increased to up to 70 μg and ‘tricycling’ is recommended.7
Women taking enzyme-inducing AEDs who need to use the emergency contraceptive pill would need to take a single dose of 3 mg of levonorgestrel to ensure its efficacy.8
The 2012 NICE guideline therefore emphasises that the possibility of interaction with oral contraceptives should be discussed and an assessment made as to the risks and benefits of treatment with individual drugs.6
|AEDs that induce hepatic enzymes||AEDs that do NOT induce hepatic enzymes|
|Primidone||Lamotrigine (see below)|
|Topiramate (doses >200 mg)||Pregabalin|
Contraceptive interactions with lamotrigine
Studies suggest that an interaction between any oestrogen-based cont raceptive and lamotrigine may occur, reducing lamotrigine levels. If doses of the combined oral contraceptive pill are increased to prevent breakthrough bleeding, seizures and toxicity may occur during the ‘pill-free week’, or if the pill is withdrawn.8 Therefore women taking lamotrigine who wish to use the combined oral contraceptive may require specialist input.
A hormonal contraceptive should only be used as the sole method of contraception if there is no other alternative (see Table 2). If the oral contraceptive pill is chosen as the sole method of contraception, women should be advised to promptly notify their physician if they experience changes in menstrual pattern (eg breakthrough bleeding) while taking lamotrigine, as this may be an indication of decreased contraceptive efficacy. Women taking lamotrigine should notify their physician if they plan to start or stop the use of oral contraceptives or other female hormonal preparations.9
Table 2: Recommendations on type of contraception for women with epilepsy6
|Combined oral contraceptive (COC)|
If a patient is using a COC, an AED that does not induce hepatic enzymes is preferred.
When COC is given with an enzyme-inducing AED, one containing a minimum of oestrogen 50 μg should be used if maximal contraceptive effect is required.
If breakthrough bleeding occurs with 50 μg of oestrogen the dose should be increased up to 70 μg a day, and tricycling should be considered.7
|Progestogen-only pill||The progestogen-only pill is not recommended for women taking hepatic enzyme-inducing AEDs.5|
|Depot progestogen injections||Depot injections of progestogen may be used with enzyme-inducing AEDs.5|
|Progestogen implants||Progestogen implants are not suitable for women taking enzyme-inducing AEDs.|
The dose of levonorgestrel should be increased to 3 mg (2x1.5 mg) taken as a single dose in women taking enzyme-inducing AEDs.
The new emergency contraceptive pill EllaOne should not be used in women taking enzyme-inducing AEDs as its efficacy might be reduced.11
|Intrauterine devices (IUDs)||As well as a regular method of contraception, an IUD may be used as a method of emergency contraception for all women with epilepsy.5|
A major concern of many pregnant women with epilepsy is the effect that taking AEDs may have on their baby.5 However, it should be noted that most women with epilepsy will have a normal pregnancy and delivery.5 Women with epilepsy who are pregnant should be encouraged to register with the UK Epilepsy and Pregnancy Register, available at www.epilepsyandpregnancy.co.uk5 The aim of the register is to obtain and publish information on the frequency of major malformations, such as heart defects, spina bifida and cleft lip, among infants whose mothers take one or more AEDs to prevent seizures.
Providing information and counselling about conception will enable GPs to identify which women need referring to their specialist for pre-conception counselling. It will also ensure that women with epilepsy or taking AEDs are aware of any associated risks, and how to potentially reduce those risks.3,12
Conception counselling should cover:
- a discussion of any possible issues with fertility (for example, if the patient has reported menstrual irregularity, you might want to discuss this further)
- the stage of pregnancy at which the baby’s organs develop and the neural tube closes, and the risk of malformations and neurodevelopmental impairment in children exposed to AEDs
- the risks associated with seizures in pregnancy
- the importance of folic acid 5 mg once daily (greater than the standard recommended dose)13
- the importance of effective contraception, and the reason why it is best to plan her pregnancies where possible.3
Women who wish to discuss making changes to their treatment should be referred to their specialist. Women who want to actively start planning a baby should be referred to a specialist for pre-conception counselling.
During pre-conception counselling a specialist will review a woman’s epilepsy diagnosis, seizure frequency and type, her need for treatment, AED type and dose. A decision might be agreed for the patient to continue to take her current medication [the risk of seizures might outweigh the teratogenic risks associated with her AED(s)]. Alternatively the specialist might begin to make gradual changes to the woman’s AED treatment, including possibly withdrawing therapy altogether, or changing her treatment from one drug to another.5
The risk of MCMs varies according to AED type and dose. In addition, polytherapy (using two or more AEDs) further increases the risk of MCM in the unborn child.5
Where possible, therefore, women who wish to become pregnant should be treated on the lowest possible effective dose of their AED. If the woman has been seizure-free for some time, the risk of recurrent seizures is low, and if she is aware of the risks of recurrent seizures, it may be appropriate to withdraw or reduce medication prior to conception.4,5
Expert assessment is required in order to make a judgement of the relative risks of seizures versus the risks associated with the use of AEDs in pregnancy.
Neurodevelopment and sodium valproate
Several studies have suggested that in utero exposure to maternal sodium valproate increases the risk of neurodevelopmental impairments in the child. Although there are methodological issues with these studies, women and mothers should be told of this risk.10
2012 NICE guidance suggests that GPs should discuss, with women and their families, the risk of AEDs causing malformations and possible neurodevelopment delay to an unborn child.6
Specifically, there should be a discussion around the risks of continued use of sodium valproate to the unborn child. Patients should be made aware that higher doses of sodium valproate (more than 800 mg/day) and polytherapy, particularly with sodium valproate, are associated with a greater risk.6
Additionally, the development of skills in children exposed to maternal sodium valproate should be closely followed by GPs and health visitors to ensure that early interventions can be put in place if necessary.
Risk associated with seizures in pregnancy
According to the NICE guidance CG137, seizure frequency does not generally change in pregnant women with epilepsy.6
There is no evidence to suggest that focal (partial), absence and myoclonic seizures adversely affect the unborn baby. Frequent tonic-clonic seizures increase the risk to the baby but the absolute risk is low.6 There is also an increase in the risk of maternal status epilepticus and SUDEP.6
While it is not clear whether pregnancy is an independent risk factor for SUDEP, or whether women are simply abandoning their AEDs for fear of causing harm to their babies, there are several important recommendations to try and reduce the risk of SUDEP.16,18
|Unless the epilepsy specialist is already aware|
|GPs are advised to urgently refer women for specialist epilepsy opinion as soon as they present as pregnant.|
|GPs should urgently refer women who report worsening or increased seizures in pregnancy to their epilepsy specialist for review.|
|Before and during pregnancy, GPs should inform women about the risk of not taking their AEDs as prescribed during pregnancy.|
|A discussion about the way organ development is patterned early in pregnancy might also help women to make an informed decision about continuing their AED treatment.|
These recommendations fall in line with the updated Quality and Outcomes Framework for 2013/14.2
Withdrawing medication after conception may not reduce the risk of MCMs and could increase the risk of uncontrolled seizures.
General management of pregnancy, labour and post-natal care
- Women are advised to give birth in hospital.
- Breastfeeding is generally recommended.
- Child safety advice is available from Epilepsy Action.
- 'Epilepsy and having a baby', an Epilepsy Action booklet, is written especially for women and is available at www.epilepsy.org.uk
- GPs should remain vigilant in identifying possible malformations and neurodevelopmental impairment in infants exposed to maternal AEDs. This is to ensure early and appropriate investigation of suspected problems in neurodevelopment.
- The rate of withdrawal of AEDs should be slow, usually over a few months,5 and any changes to AED therapy should be made before contraception is stopped.5
An initiative has been developed to register every pregnancy in women with epilepsy onto a nationwide database. It is hoped that the relative risks of all available AEDs will then become
clearer. To register with the UK Epilepsy and Pregnancy Register, the patient should phone 0800 389 1248 or forms can be obtained online at www.epilepsyandpregnancy.co.uk
Advice on breastfeeding depends on the AED the mother is receiving. For further information, the relevant prescribing information should be consulted.6 Blood levels of AEDs are probably lower in the breastfed infant than exposure in utero, and breastfeeding and subsequent weaning usually allow for a gradual withdrawal.5
A Continuing Medical Education (CME) module on pregnancy and epilepsy is available at www.medscape.org/viewarticle/752226
Irregular periods and menstrual disorders might be more common in women with epilepsy, especially women who have frequent seizures. Irregular periods may be caused by epilepsy itself, seizure patterns or AEDs.4
Polycystic ovary syndrome (PCOS)
Women with temporal lobe epilepsy, or taking the AED sodium valproate, are at an increased risk of PCOS compared to other women.19
Women with catamenial epilepsy will have a cluster or increase in seizure frequency at key points of their menstrual cycle, either:20
- mid-cycle (at ovulation)
- throughout second half of menstrual cycle.
Menopause and HRT
Evidence suggests that menopause starts earlier in women with epilepsy (but within the expected range). Other studies have suggested that seizure frequency and severity increases
the risk of premature menopause.4
Women with epilepsy might notice a change in their seizure pattern during or after menopause. Some women have more seizures and some women may have fewer seizures.21
Research suggests that women with catamenial epilepsy are at risk of having more seizures than usual in the time leading up to the menopause and in peri-menopause. After the menopause some women have improvement in their seizure control.21
Hormone replacement therapy (HRT)
One small study suggested that women with a history of catamenial epilepsy are at a higher risk of seizure increase with HRT use.22
In one study, HRT was shown to increase the clearance of lamotrigine, which may increase the risk of seizures. The form of HRT studied was conjugated equine oestrogen plus medroxyprogesterone acetate (CEE/MPA).22
1 Joint Epilepsy Council, 2005. Epilepsy prevalence, incidence and other statistics. [online] (Accessed 12/04/2012).
2 British Medical Association, 2013. QOF guidance, 2013-2014. [online] (Accessed 01/05/2013).
3 Baker G et al. 2011. Primary Care Guidance for the Management of Women with Epilepsy. London: The Royal Society of Medicine Press.
4 Crawford P, 2005. Best practice guidelines for the management of women with epilepsy. Epilepsia. 46(Suppl. 9): 117–124.
5 Scottish Intercollegiate Guidelines Network (SIGN), 2003. Diagnosis and management of epilepsy in adults. A national clinical guideline. Edinburgh: SIGN.
6 National Institute for Health and Clinical Excellence (NICE), 2012. The epilepsies: The diagnosis and management of the epilepsies in adults and children in primary and secondary care. [CG137]. London: NICE.
8 Faculty of Sexual and Reproductive Healthcare, Clinical Effectiveness Unit, 2010. Anti-epileptic drugs and contraception. [online] (Accessed 12/04/12).
9 Lamictal SPC, 2011 GlaxoSmithKline UK.
10 Bromley RL et al. 2009. Cognitive abilities and behaviour of children exposed to anti-epileptic drugs in utero. Current Opinion in Neurology. 22: 162-166.
11 Ella SPC, 2011. HRA Pharma.
12 National Institute for Health and Clinical Excellence (NICE), 2012. Epilepsy: Appendix C – Outline care algorithms Adults. [CG137]. London: NICE.
13 Joint Formulary Committee. British National Formulary. 7.3.1 Combined hormonal contraceptives. (online) London: BMJ Group and Pharmaceutical Press. (Accessed on 31/01/12).
14 Holmes LB et al. 2001. The teratogenicity of anticonvulsant drugs. The New England Journal of Medicine. 344: 1132-1138.
15 Olafsson E et al. 1998. Pregnancies of women with epilepsy: A population-based study in Iceland. Epilepsia. 39: 887-892.
16 Cantwell et al. 2011. Saving mothers' lives: Reviewing maternal deaths to make motherhood safer: 2006-2008. The eighth report of the confidential enquiries into maternal deaths in the United Kingdom. British Journal Obstetrics and Gynaecology.118 (1): 1-203.
17 Lewis G. 2007. The Confidential Enquiry into Maternal and Child Health (CEMACH). Saving Mother's Lives: Reviewing Maternal Deaths to Make Motherhood Safer'-2003-2005. The Seventh Report on Confidential Enquiry into Maternal Deaths in the United Kingdom. London. CEMACH.
19 Schachter SC, Herzog AG, 2001. Valproate and the polycystic ovarian syndrome: Final thoughts. Epilepsia. 42: 311-315.
20 Herzog AG, 2008. Catamenial epilepsy: Definition, prevalence, pathophysiology and treatment. Seizure. 17: 151-159.
21 Harden CL et al. 1999. The effect of menopause and perimenopause on the course of epilepsy. Epilepsia. 40: 1402-1407.
22 Harden CL, 2008. Hormone replacement therapy: Will it affect seizure control and AED Levels? Seizure. 17: 176-80.