Epilepsy affects 1 in 200 women of childbearing age and is the commonest neurological disorder to complicate pregnancy. There is exposure to antiepileptic drugs in 0.3-0.6% of pregnancies.

 

Aim

 

To control seizures and minimise risk to mother and fetus.

 

Pre-conception

 

1)      Before pregnancy the ongoing management and treatment regimen should be reviewed to ascertain whether the woman continues to need medication and whether she is taking the most appropriate anti-epileptic drug (AED) to balance control of seizures with teratogenic risks. Patients with epilepsy should therefore be referred to a Consultant Neurologist for detailed assessment and counselling. Complex cases (e.g. unstable epilepsy, patients taking more than one anti-epileptic drug etc.) should be referred to a Consultant Neurologist with an interest in epilepsy.

 

2)      Counsel and advise women:

• In the majority of cases the pregnancy course is uncomplicated and the neonatal outcome good for women with epilepsy. Leaflet available on “Starting a Family” from British Epilepsy Association: http://www.epilepsy.org.uk/info/family.html

·         Slight increased risk of fetal abnormalities even if on no medication (3.5%) compared to general population (2%)

·         Teratogenicity of medication (major malformation rate: monotherapy: 6-7%, two or more drugs:15%, some combinations of multiple therapy e.g. carbamazepine and phenytoin carry a risk as high as 50%).

·         Neural tube defects are associated with sodium valproate and carbamazepine; congenital heart defects and orofacial defects with phenobarbitone and phenytoin. Other major malformations i.e. urogenital defects and skeletal abnormalities have also been reported.

·         Sodium valproate appears in recent studies to have a higher teratogenic risk compared to other AEDs (Valproate 6.2%, Carbamazepine 2.2%, Lamotrigine 2.9%) and therefore consideration should be given to changing from sodium valproate to another AED. The effect of teratogenicity appears to be dose dependent and therefore if the patient needs to be on sodium valproate (or conceives on valproate) the lowest dose to afford seizure control should be used.

·         Slight increased risk of developmental delay, cognitive impairment and dysmorphic features with sodium valproate and carbamazepine, which is dose related. May not be obvious at birth.

·         Risk of child developing epilepsy (5-20% if one first degree relative affected and over 25% if two first degree relatives are affected).

·         Polytherapy may be associated with low birth weight.

·         Refer to geneticist if family history of predisposing genetic factors.

 

3)      For most women with epilepsy the risk of uncontrolled seizures outweighs the teratogenic risk of medication and therefore the withdrawal of AEDs before pregnancy not a reasonable option. However consideration should be given to withdrawal from anti-epileptic medication (in collaboration with a Consultant Neurologist) if the patient has been fit free for 3 years in order to reduce teratogenic risk. Tapering off medication should ideally be at least 6 months before the planned conception to provide reassurance that seizures are not going to recur. Women should be counselled that the UK DVLA recommend that driving should be suspended from the first reduction in medication up to the first 6 months after completion of withdrawal even if there are no seizures. Many women choose not to undergo withdrawal in view of this.

 

4)      Newer anti-epileptic drugs (e.g. lamotrigine, levetiracetam, vigabatrin, gabapentin, tiagabine, topirimate): The risks of these anti-epileptics are as yet unquantified due to lack of data although studies on Lamotrigine suggest it may be no more teratogenic than the older AEDs. None of the drugs are licensed for use in pregnancy. The advantages and disadvantages of changing medication pre-conception should be discussed with a Consultant Neurologist on an individual basis. If a patient conceives on any of these drugs and their epilepsy is well controlled it is probably better to continue with the medication.

 

5)      Monitor seizures whilst planning pregnancy

 

6)      Establish optimum drug regime.

 

a)      Minimum dose.

b)      Monotherapy.

c)      Consider more frequently lower doses to avoid high peak concentrations.

 

7)      Commence daily folic acid 5mgs at least 12 weeks prior to conception if possible.

 

8)      If fit free, baseline levels of anti epileptic drugs are unnecessary. Baseline measurements of plasma drug concentrations are only necessary for unstable patients taking phenytoin. In other patients baseline levels only indicate compliance.

 

 

Pregnancy

 

All patients with epilepsy should be referred for booking as early as possible.

 

Women with epilepsy are not at increased risk of obstetric complications provided that the appropriate care is available during pre-conception, pregnancy, labour, delivery and postnatally.

 

Booking referrals for unstable epilepsy should be faxed and an appointment made for the patient to be seen within a week.  Consultant Neurologist to have input into immediate management.  

 

1) Management at booking appointment and during pregnancy

 

·         Establish whether epilepsy stable or not and refer appropriately as above. Seizure frequency increases by 25-30% in pregnancy, particularly in patients with poorly controlled epilepsy or on Lamotrigine.

 

·         If fit free, baseline levels of anti epileptic drugs are unnecessary. Baseline measurements of plasma drug concentrations are only necessary for unstable patients taking Phenytoin. In other patients baseline levels only indicate compliance.

 

·         Advise continuation of folic acid (5mg) until the end of the first trimester gestation to reduce the risk of neural tube defects.

 

·         Arrange ultrasound scan at 12 –14 weeks for dating and to check for anencephaly.

 

·         Arrange a detailed anomaly scan with a Consultant Obstetrician /Radiologist:

-   Phenytoin/phenobarbitone: Cardiac anomalies, Craniofacial anomalies.

-   Sodium valproate: Neural tube defects, cardiac anomalies

-   Carbamazepine: Neural tube defects

 

·         Regular antenatal clinic visits should be arranged (to be decided by local clinician - 36 week visit important to ensure vitamin K prescribed if necessary –see below)

 

·         Consider growth scans if on polytherapy

 

·         Morning sickness - alter drug times if hyperemesis gravidarum. Consider giving alternative route if vomiting is severe or prolonged.

 

·         Babies of epileptic mothers are theoretically at increased risk of intracranial haemorrhage of the newborn (Grade C evidence). It is recommended that vitamin K 20mgs orally daily is prescribed from 36 weeks until delivery to mothers taking hepatic enzyme-inducing drugs (phenytoin, phenobarbitone, primidone, carbamazepine and topiramate). (Not necessary with sodium valproate – contact local hospital pharmacy if any doubt as to whether an anti-epileptic drug is hepatic enzyme inducing or not. Most of the newer AEDs are not enzyme inducers).

 

·         Report to UK Epilepsy and Pregnancy Register regardless which anti-epileptic drugs are taken (www.epilepsyandpregnancy.co.uk)

 

2) Labour

 

Women should continue their medication during labour. 1-2% of epileptic women experience seizures in labour and a further 1-2% in the following 24 hours. Stress, pain, sleep deprivation, over breathing and dehydration increase the risk of seizures during labour.

 

If a seizure occurs maternal airway and oxygenation should be maintained. Seizures occurring during labour should be treated with I/V diazepam 10mgs. If there is doubt whether a seizure in labour is due to eclampsia or epilepsy, then, in addition to intravenous diazepam, the protocol for eclampsia (magnesium sulphate) should also be administered.

 

Diamorphine should be used in preference to pethidine for analgesia during labour. Pethidine is metabolised to norpethidine, which is epileptogenic and therefore must be used with caution.

 

Epilepsy per se is not an indication for induction of labour or Caesarean section. Recurrent seizures near term consider elective LSCS – decision to be taken by Consultant Obstetrician.

 

Inform Paediatricians (see below)

 

Postnatal

 

Babies                         Babies should have vitamin K 0.1mg / kg IM at birth to reduce risks of haemorrhagic disease.          

 

Babies of women on phenobarbitone often experience withdrawal, they are jittery and irritable – monitor for fits.

 

Breast-feeding            Encourage as anti-epileptic drugs excreted in low concentrations in breast milk and therefore considered safe. Some of the newer AEDs (e.g. Lamotrigine) are excreted in higher concentrations in breast milk. If a women intends to breast feed her medications should be discussed with a neurologist prior to delivery so that a management plan can be formulated. Breast-feeding should still be encouraged but the levels of AED in the baby may need to be monitored.

 

Drugs                          Any increase in drugs during pregnancy will need to be decreased slowly to pre-pregnancy doses over 3-4 weeks to avoid toxicity.

 

Any lady having a seizure during labour must be observed closely for the next

72 hours.

 

Women should be given safety advice with respect to caring for her baby after delivery: Leaflets on “Pregnancy and caring for young children” available from British Epilepsy Association. http://www.epilepsy.org.uk/info/young.html

 

 

Contraception

 

In general the OCP, POP and progestagen implants are not good contraception for women with epilepsy and alternative, better forms of contraception should be encouraged e.g. the Mirena IUS.

 

Combined Oral Contraception

Enzyme inducing anti-epileptic drugs (phenytoin, carbamazepine, barbiturates, and topiramate and lamotrigine) make the contraceptive pill less effective. Women on these drugs who wish to rely on the combined oral contraceptive pill should be prescribed a preparation containing at least 50΅g oestradiol. If women have breakthrough bleeding the dose of oestrogen should be increased to 75΅g or 100΅g per day and tricycling 3 packets (taking 3 packets without a break) should be considered. Women should be advised about the increased risk of contraceptive failure (rising from a general population rate of 0.1 to 3 pregnancies per 100 women years) even at higher doses.

 

For women taking Lamotrigine the dose often need to markedly increased if the OCP is commenced and seizure control may be difficult. For this reason the OCP is not recommended for Lamotrigine users.

 

Progestagen only pill and Implants

Generally the progesterone only pill (POP) and progesterone implant (Implanon) are not recommended as reliable contraception in women taking AEDs. If women choose to take the POP higher doses of the progesterone only pill will be required and women should be informed that of the reduced contraceptive efficacy of the POP. Women are advised to take two rather than one daily pill of Micronor (norethisterone 350΅g or Microval (Levonorgestrel 30΅g).

 

Depo-Provera is a useful alternative to oral contraception but a shorter repeat injection interval is recommended (10 week interval between injections instead of 12).

 

The morning after pill can be used in women with epilepsy after unprotected sexual intercourse. A higher dose is recommended in patients taking hepatic enzyme inducing drugs

-   1^st dose – Levenorgestrol 1.5mgs (2 tablets)

-   2^nd dose 12 hours later – Levenorgestrol 0.75mgs (1 tablet)

 

 

UK Epilepsy and Pregnancy Register:

 

All pregnant women with epilepsy should be provided with information about the UK Epilepsy and Pregnancy Register, and invited to register (or allow their clinician to notify the pregnancy). Registration can be done online at: http://www.epilepsyandpregnancy.co.uk/

 

 

References

 

National Institute for Clinical Excellence, 2004. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care.

 

Scottish Intercollegiate Guideline Network, 2003: Diagnosis and Management of Epilepsy in Adults

 

Adab N and Chadwick D. Management of women with epilepsy during pregnancy. The Obstetrician and Gynaecologist 2006; 8:20-25

 

Morrow J et al. Malformation risks of anti-epileptic drugs in pregnancy: a prospective study from the UK Epilepsy and pregnancy Register. J Neurol Neurosurg Psychiatry. 2006 Feb; 77 (2): 193-8.

 

Craig JJ et al. the UK Epilepsy and Pregnancy Register; update of results 1996-2003. Epilepsia 2004; 45:229

 

Sabers A et al. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res. 2001 Nov; 47(1-2): 151-4.

 

Vadja FJ et al. Critical relationship between sodium valproate dose and human teratogenicity: results of the Australian register of anti-epileptic drugs in pregnancy. J Clin neuroscience 2004 Nov; 11(8): 854-8

 

Adab et al. The longer-term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psych 2004 Nov; 75 (11): 1575-8

 

Pennell PB. Pregnancy in women who have epilepsy. Neurol Clin 2004; 22(4): 799-820

 

Tomson T et al. Navigating toward fetal and maternal health; the challenge of treating epilepsy in pregnancy. Epilepsia 2004 Oct; 45(10): 1171-5

 

Crawford P et al Best Practice guidelines for the Management of women with Epilepsy: Seizure 1999 8:201-217.

 

Wiebe. S. Managing women With Epilepsy: BMJ 2000; 320:3-4

 

Fairgrieve S et al.  Population Based, prospective Study of the care of women with Epilepsy in pregnancy BMJ 2000;321:674-5

 

Crawford P. et al. The interaction of phenytoin and carbamazepine with combined oral contraceptive steroids. Br J Pharmacol 1990:30;892-896

 

Benfield T. FPA Contraceptive Handbook. London: Family Planning Association, 1996

 

Howe AM et al. Prothrombin and PIVKA-II levels in cord blood from newborn exposed to anticonvulsants during pregnancy. Epilepsia 1999;40(7):980-984

 

Cornelissen M et al. Increased incidence of neonatal vitamin K deficiency resulting from maternal anticonvulsant therapy. Am J Obstet Gynaecol 1993;168(3 Pt1):923-8

 

Cornelissen M et al. Supplementation of vitamin K in pregnant women receiving anticonvulsant therapy prevents neonatal vitamin K deficiency. Am J Obstet Gynaecol 1993; 168 (3 Pt1):884-8

 

 

Regional Epilepsy Guidelines (Final Version)

Special Interest Group

PJ Marsden April 2006 (Revision date –April 2009)

 

 

 

Proforma for  Management of  Pregnant Women with Epilepsy

 

 

Pre-Conception

 

Folic Acid prescribed 5mg daily                                         YES / NO – Gestation…………

 

Change to Single Drug therapy                                           YES / NO / N/A

 

Perform baseline plasma drug concentrations

if epilepsy unstable                                                               YES /  NO   

 

 

Pregnancy

 

Booking Visit

   

Gestation at booking                                                            …………

 

Assess epilepsy seizure diary                                 YES / NO 

 

Referred to Neurologist                                                        YES/ NO

 

Leaflet given to mother                                                         YES/ NO       

 

Anti-epileptic medication at booking (& dose)……………………………………………

 

Changes to medication during pregnancy………………………………………………..

 

Regional Audit and UK register informed                          YES / NO

 

Ultrasound

 

12 –14 week scan for anecephaly                                      YES / NO     

 

19-20 Anomaly Scan                                                            YES / NO    

 

36 weeks review

 

Oral Vitamin K 20mg  prescribed                                       YES/ NO

If on hepatic enzyme inducing drug

 

Delivery

 

Baby IM Vitamin K 0.1mg/kg                                                YES / NO

 

 

Contraception …………………………………………………………….

….