Epilepsy in Pregnancy

Epilepsy in pregnancy – Medical Conditions in Pregnancy

Abbreviations used-

AED– Anti Epileptic Drug

WWE – Women with epilepsy

SUDEP– Sudden Unexpected Death in Epilepsy

Epilepsy in pregnancy has received much attention in the 2020 MBRRACE (Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries in UK) report. According to the report the number of maternal deaths of women with epilepsy has (almost) doubled in three years- during 2016 to 2018 twice as many women with epilepsy died during or up to a year after the end of pregnancy in 2016-18 from causes related to epilepsy, compared to 2013-15 ( 22 Vs 13)

Among the women who died

– SUDEP was the main cause of death.

– Very few women had documented pre-pregnancy counselling

– The majority had uncontrolled epilepsy pre-pregnancy, less than half had specialist review during pregnancy.

Below is a summary of points which should be included in the care of Pregnant Women With Epilepsy( Main Source- Green top Guideline 68. For GTG purists, I have clearly mentioned the points which have not been sourced from the GTG)

Epilepsies are a heterogeneous group of brain diseases with the common feature of seizure. A medical practitioner with specialist training in epilepsy, usually a neurologist makes the diagnosis of epilepsy and its categorization. With a prevalence of 0.5 to 1%, epilepsy is the most common neurological condition in pregnancy.

Pre- conception Counseling– The patient should be informed that most mothers have normal healthy babies and the risk of congenital malformations is low if they are not exposed to AEDs in the periconception period. ( The risk of congenital malformations in WWE not on AEDs is similar to hat in the general population) .

Inheritance- A small percentage of seizure disorders are inherited. Genetic counseling should be offered to women who have risk factors for inheritance of epilepsy, or there is any fear /doubt about inheritance.

The risk of congenital abnormalities in the fetus is dependent on the type, number and dose of AEDs. Parents should be informed that evidence on long-term outcomes is based on small numbers of children. The risk of recurrence of major congenital malformations is higher if there is a child with major congenital malformations ( about 16.8%) .

Carbamazepine and Lamotrigine – In utero exposure to these two drugs does not appear to adversely affect neurodevelopment of the offspring. Especially at lower doses, these two drugs have been associated with the least risk of major congenital malformation.

The congenital anomalies with which AEDs have been associated are–

Sodium valproate- neural tube defects, facial cleft and hypospadias.

Phenobarbital – cardiac malformations.

Phenytoin -Cardiac malformations and cleft palate.

Carbamazepine – Cleft palate.

Levetiracetam and phenytoin- There is very little evidence , but in the UK and Ireland registers, the risk of congenital malformations was very low ( 0.7 per 100) .

For the other AEDs ( eslicarbazepine, gabapentin, lacosamide, oxcarbazepine, perampanel, pregabalin, topiramate or zonisamide) – there is insufficient evidence.

Effect of AEDs on Neurodevelopment– In utero exposure to Sodium valproate, and potentially other AEDs, is associated with a possible adverse impact on long-term neurodevelopment of the newborn.

According to a Cochrane review in 2014, Children exposed to sodium valproate in utero had a significantly lower developmental quotient and IQ when compared with those born to WWE

who were not taking AEDs, and to those born to women without epilepsy.

High doses of sodium valproate were negatively associated with verbal ability, IQ, nonverbal

ability, memory and executive function and this was not observed with other AEDs

The information that should be noted on pre-conception or booking visit is –

– Whether she has received any pre-conceptional counseling earlier

– Folic acid intake

– Seizure type and frequency

– Last seizure

– Last Neurology follow up , Upcoming neurology follow up

Preconception care– 5 mg/day of folic acid prior to conception and to continue the intake until at least the end of the first trimester- Folate may reduce cognitive defects with AED exposure.

Minimum effective dose of AED should be given.

Minimize exposure to Valproate and polytherapy PRIOR to conception after careful evaluation of risks and benefits by epilepsy specialist.

Change in medication may affect her ability to drive.

It is prudent to continue contraception till cleared by neurologist and she has taken folic acid for 3 months.

EFFECT OF PREGNANCY ON EPILEPSY– two-thirds will not have seizure deterioration in pregnancy. Pregnant women who have experienced seizures in the year prior to conception require close monitoring for their epilepsy.

No need to routinely test AED Levels( But may be done in individual cases)

Effect of Epilepsy on pregnancy– Small but significant increase in obstetric risk. ( Increased risk of – spontaneous miscarriage, antepartum haemorrhage , hypertensive disorder, induction of labour , caesarean section, any preterm delivery less than 37 weeks, fetal growth restriction and postpartum haemorrhage) . ( No increase in odds of gestational diabetes or perinatal death)

In postpartum period– although the overall chance of seizures during and immediately after delivery is low, it is relatively higher than during pregnancy.

Antenatal care– It is important to acknowledge that the woman may have concerns regarding the effect of AED s on the pregnancy , and this may affect her compliance

Discussion of risk

– Provide verbal and written information to the women.

– Inform her that- Introduction of a few safety precautions may significantly reduce the risk of accidents and minimise anxiety.

– Seizures can be more harmful that the AED

If unplanned pregnancy while taking AEDs- Do not abruptly stop or change the drug without informed discussion. Urgent referral to epilepsy specialist.

In UK- All pregnant WWE should be provided with information about the UK Epilepsy and Pregnancy Register and invited to register.

WWE will need Routine antenatal care + extra care for their condition.

Management to be done by a multi disciplinary team

In every visit- Assess for risk factors for seizures- Sleep deprivation, stress

Seizure type and frequency

Adherence to AEDs.

Document whether the AED dose was increased during pregnancy ( Then the dose will need to be reviewed within 10 days of delivery).

Assess for cognitive disturbance and mood disturbance( AEDs affect cognition. Fear of seizure, psychosocial factors and low self esteem may lead to depression).

Advice on safety- e.g taking shower ( not dip bath in tub) , taking adequate rest.

Dating scan and anomaly scan.

Serial growth scans from 28 weeks ( Because there is risk of growth restriction) .

Consider antenatal assessment by anesthetist- to plan for intrapartum analgesia and to manage any possible issues with anesthesia. ( Not written in the GTG- but something that could improve patient safety)

If admitted to hospital, and there is a reasonable risk of seizures- admit in a room which allows for continuous observation by a carer, partner or nursing staff – The environment should be quiet to avoid sleep deprivation.

Monitoring of drug levels – The levels of most AEDs fall in pregnancy( Lamotrigine levels may fall by upto 70%) . However, routine therapeutic drug monitoring in pregnancy is not indicated. It may be indicated in case of suspicion of non-adherence, toxicity and intractable seizures .

.

If the WWE is getting admitted + reasonable risk of seizure- admit where continuous observation is possible- by carer / nursing staff

Serial growth scan from 28 weeks

Intrapartum care :

Place of birth– birth in a consultant-led maternity unit.

DURING LABOR- being tired, dehydrated and in pain can increase the risk of seizure.

Epilepsy is not an indication for continuous CTG.

Pain relief should be prioritized. Options should include- TENS, nitrous oxide and oxygen (Entonox), and regional analgesia.

WATER BIRTH- Not for women on AED( small potential risk of drowning) – Only women who are seizure free for significant period and who are not on AED are eligible for water birth.

Inform neonatologist- there is risk of neonatal withdrawal syndrome.

– Vitamin K to be given to the baby.

No need to give Vit K to the mom ( AED s affect liver enzymes- Oral Vitamin K could theoretically reduce the risk of Postpartum Haemorrhage) . But there are no studies which have evaluated this.

Seizure prevention- Continue AED during labor- if vomiting, start i.v alternatives.

Pethidine to be avoided( It gets metabolized to norpethidine which is epileptogenic.

Morphine and diamorphine can be used).

If very high risk of seizure( e.g recent seizure, h/o seizure in last labor, h/o recent seizure precipitated by lack of sleep) give long acting benzodiazepines like CLOBAZAM.

MANAGEMENT OF EPILEPTIC SEIZURE IN LABOR– Left lateral tilt, airway, oxygenation.

Any seizure lasting 5 min or more is associated with risk of progress to status epilepticus.

If I.V ACCESS is present– Lorazepam – usually 4 mg bolus – 0.1 mg /kgà can be repeated once in 10-20 min. or Diazepam 5 to 10 mg i.v slow.

If no i.v access– Diazepam 5 to 10 mg rectal. – if continued risk- repeat 10 to 15 min later.

Or midazolam 10 mg buccal.

Uncontrolled seizure- Phenytoin( 1000 mg i.v infusion) / fosphenytoin.

After stabilization of mother- start continuous CTG.

If there is persistent uterine hypertonus, consider administration of tocolytic agents.

If FHR Not beginning to recover in 5 min or if there is continuous seizure- expedite delivery ( i.e if vaginal delivery is not imminent- consider LSCS)

If General Anesthesia is necessary- Avoid pethidine and ketamine ( Both lower seizure threshold) and sevoflurane ( has epileptogenic potential) .

POSTPARTUM– Continue AED.

If dose was increased in pregnancy- review within 10 day to avoid toxicity. The risk of adverse cognitive outcomes is not increased in children exposed to AEDs through breast milk.

Tiredness, stress and lack of sleep can increased risk of seizure.

Avoid sleep deprivation- arrange help. Breast milk expression for night feeds( to avoid sleep deprivation) .

In the postpartum area- Patient should be in a single room where she can be observed continuously ( by carer/partner/nurse).

Screening for depressive symptoms ( Post partum depression 1 in 3 in WWE( 29% in WWE, 11% in controls) .

SAFETY- Nursing the baby on floor.

Keep the baby down if any aura.

Taking shower ( Not bath)

Not bathing the baby alone

Avoid alcohol and sleep deprivation.

Inform about symptoms of postpartum depression, and contact details for any assistance.

Ensure that family and friends have knowledge of first aid and emergency contact procedures.

Wearing identification tags.

AED Exposure through lactation-

WWE who are taking AEDs in pregnancy should be encouraged to breastfeed.

Based on current evidence, mothers should be informed that the risk of adverse cognitive outcomes is not increased in children exposed to AEDs through breast milk.

However the GTG states that the newborns should be monitored for adverse effects associated with AED exposure in utero. ( Not through breast milk) .

Babies born to WWE on AEDs may have

– adverse effects such as lethargy, difficulty in feeding, excessive sedation and

– withdrawal symptoms with inconsolable crying.

Remember , these are from in-utero exposure.

An individual assessment should be made for the level of monitoring the baby will need.

Contraception for WWE.

WWE Should be offered effective contraception to prevent unplanned pregnancy.

Some AEDs can induce microsomal enzymes, which may lead to reduced levels of ethinylestradiol and levonorgestrel.

NON ENZYME INDUCING AEDs- sodium valproate, levetiracetam, gabapentin, vigabatrin, tiagabine and pregabalin.

ENZYME INDUCING AEDs- carbamazepine, phenytoin, phenobarbital, primidone, oxcarbazepine, topiramate and eslicarbazepine.

Reliable methods of contraception which are not affected by Enzyme inducing AEDs- Copper intrauterine devices (IUDs), the levonorgestrel-releasing intrauterine system (LNG-IUS) and

medroxyprogesterone acetate injections.

WWE on Enzyme inducing AEDs- Counsel about risk of failure with some hormonal contraceptives.

Methods affected by Enzyme inducing AEDs-

– – oral contraceptives (combined hormonal contraception, progestogen-only pills)

( REMEMBER- It’s not only Combined OCs, but ALL Oral Contraceptives which are affected). The expected failure rate of oral contraception is three times higher (3.1 per 100 woman-years) in WWE taking enzyme-inducing AEDs compared with the normal population.

– – transdermal patches

– – vaginal ring

– – progestogen-only implants

So if a WWE on Enzyme inducing AED chooses to use any of the above methods- additional barrier contraception is recommended.

The interaction of Topiramate with COCs is dose dependent- dose below 200 mg / day has no effect, but higher doses ( 200 to 800 mg) increase the clearance of ethinyl estradiol.

If WWE on Enzyme inducing AEDs choose to use oral contraceptives ( despite the information provided) – The efficacy of the contraceptive can be increased by the following measures( though there is no data on how successful these measures are) –

– – increasing the oestrogen component to 50 micrograms (maximum 70 micrograms

– – reducing the pill-free interval from 7 days to 4 days , and

– – tricycling (taking three packs back to back).

– – AND using additional barrier contraception

Lamotrigine levels fall in women taking estrogen containing pills- This may lead to deterioration of seizures. ( The mechanism involved is – increasing the metabolism of glucuronidated drugs through induction of uridine diphosphate-glucuronosyl transferase (UGT1A4)) .

Lamotrigine concentrations are not known to fall in women on progestogen-only- pills, progestogen implants and injections and the LNG-IUS.

EMERGENCY CONTRACEPTION–

WWE on Enzyme inducing AEDs- Only the Copper IUD is recommended.

Ulipristal acetate should not be used.

Double dose of levonorgestrel can be given- But no data on effectiveness.

When inserting a Cu IUD in an epileptic woman, all emergency drugs should be available.

UKMEC Categories of contraception for WWE- ( The GTG guideline has tabulated the information)

Methods compared- Combined hormonal pill, Progestogen only pill, Progestogen only implant, Progesterone only Injectable( DMPA and NET-EN) , LNG -IUS and Cu -IUD.

For WWE not on any enzyme inducing AED– All the above methods are UKMEC category 1.

For WWE on enzyme inducing AEDs

– DMPA, LNG IUS and Cu IUD are UKMEC 1.

– Progesterone only implant and NET-EN are UKMEC 2.

– Combined oral contraceptive and POP are UKMEC 3.

WWE on Lamotrigine( which is not an enzyme inducer) – COC is UKMEC 3. All other methods are UKMEC 1.

UKMEC Criteria-

UK MEC Category 1: A condition for which there is no restriction for the use of the contraceptive method with the condition or in that circumstance.

UKMEC Category 2: A condition where the advantages of using the method generally outweigh the theoretical or

proven risks.

UKMEC Category 3: A condition where the theoretical or proven risks generally outweigh the advantages of using

the method. The provision of a method requires expert clinical judgement and/or referral to

a specialist provider, since use of the method is not usually recommended unless other

methods are not available or not acceptable.

UKMEC Category 4: A condition that represents unacceptable health risk if the method is used.

There is a TOG article on Epilepsy in pregnancy-

Bhatia M, Adcock JE, Mackillop L. The management of pregnant women with epilepsy: a multidisciplinary collaborative approach to care.

The Obstetrician & Gynaecologist 2017;19:279–88. DOI: 10.1111/tog.12413.

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