Antiepileptic drug (AED) consideration in Women at child-bear age.

適孕年齡婦女癲癇用藥的考量

Medical Scientific Liaison, MSL Willy Wen,文偉立 GSK Neuroscience (2012~) Taipei Medical University Pharmacy (2006-2009)

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983 305 pregnancies February 1997 to 31 December 2008

Background

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Bodil Hammer Bech BMJ 2014; 349 3

Definition Maternal Outcome

Epilepsia, Vol. 29, No. 4, 1988

Pre-Pregnancy and Preganacy

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http://disable.yam.org.tw/life/131 6

MYTH DURING PREGNANCY

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AED are extremely toxicities?

表一 孕期用藥安全五等級

Ａ 依據有對照組的試驗顯示，在人類沒有致畸胎之慮，所以並無危險性。

Ｂ 動物實驗無胎兒危害，但沒有人類的研究報告；或動物實驗看到不良作用，但人類實驗沒有不良作用，一般孕期仍可使用。

Ｃ 在人或動物沒有適當的研究；或動物實驗有不良作用，但缺乏人類研究報告，無法排除危險性，在使用上要注意。

Ｄ 證據顯示具有危險性，對胎兒有不良影響，除非母體疾病必需、使用的好處大於壞處時才可以使用。

Ｘ 胎兒的致畸胎作用明顯大於任何好處，孕婦禁止使用。

藥學雜誌 97期 新光醫院藥劑部藥師 江文心 8

Communication: major Malformation (MCM)

• General Population:

2-3%

T. Tomson et al. / Seizure 28 (2015) 46–50 9

• *The dose level of 500-600 mg/day

• Female patients already established on valproate treatment considering future pregnancy

• Treatment should be reassessed and changes carefully considered for every woman on valproate treatment that is considering pregnancy.

• In women with focal epilepsies withdrawal of valproate or a switch to an alternative treatment should always be considered.

• A switch from valproate to alternative treatments should be considered for every woman who is not suitable for, or who has failed, treatment withdrawal.

• Woman already on valproate treatment while pregnant, unplanned pregnancy

• The general rule is to continue treatment with valproate in a woman who discovers that she is pregnant.

• A reduction in valproate dose can be considered in women when the risks of doing so are acceptable to the woman.

1. Hernandez-Diaz S, Smith CR, Shen A, et al. Comparative safety of antiepileptic drugs during pregnancy. Neurology 2012;78:1692-1699. 2. Campbell E, Kennedy F, Russell A, et al. Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers. J Neurol Neurosurg Psychiatry 2014;85:1029-1034. 3. Tomson T, Battino D, Bonizzoni E, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol 2011;10:609-617.

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Expert Rev. Neurother. 15(10), 1171–1187 (2015)

Low MCM rate and no negative impact on neonatal or neurodevelopmental outcomes

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Dosage is key factor.

Association between dose of specific antiepileptic and spontaneous abortion, stratified on ever epilepsy diagnosis in mother. Estimates shown are risk ratios (95% confidence intervals). Owing to sparse data it was not possible to analyse valproate for women without an epilepsy diagnosis. High daily dose for different drugs was defined as: •carbamazepine >500 mg/day, •clonazepam >4 mg/day, •lamotrigine >150 mg/day, •xcarbazepine >500 mg/day, •valproate >750 mg/day

Bodil Hammer Bech BMJ 2014;349:g5159 12

MYTH OF REPRODUCTIVE OUTCOME

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Method: •Minnesota Comprehensive Epilepsy Program (Hauser and Kurland, 1975) •1,491 pregnancies, 471 parents with epilepsy (M 788/ F 703) •Pregnancy outcomes

• Live birth • Stillbirths (fetal deaths > 20 weeks gestation or 22 wks from last menstrual period) • Spontaneous abortions (fetal loss < 20 week gestation)

•Ageadjusted rate ratio for spontaneous abortion of 0.80 (95% confidence interval 0.45-1.40) •The cumulative risk of spontaneous abortion of 18% for AED, similar to risks reported in nonepilepsy.

Annegers, Epilepsin, 29(4):451458. 1988 14

Tomson Neurology® 2015;85:580–588

1. Method and Results

1. EURAP registry at first to determine the risk of major congenital malformations (MCMs).

2. Of 7,055 pregnancies,AED included: LTG, CBZ, VPA, LEV, OXC, PB

3. Intrauterine death: 592 SA / 40 stillbiths

4. Higher with polytherapy. But no relationship with AED dose in montherapy.

2. Polytherapy vs monotherapy, RR 1.38 [1.14-1.66]

3. Parental history of MCMs, RR 1.92 [1.20-3.07]

4. Maternal age, RR 1.06 [1.04-1.07]

5. Number of previous intrauterine deaths, RR 1.09 [1.00-1.19]

6. Later enrollment vs Early enrollment, RR 0.84 [0.82-0.86] 2. Limitation (the exclusion criteria)

1. women without epilepsy

2. follow-up had not been completed

3. if AEDs were changed or withdrawn during the first trimester

4. if pregnancies were exposed to other potentially teratogenic drugs

MYTH OF OFFSPRING IQ

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World IQ Map

18 http://www.washsummit.com/world-iq-map/

Impact on Offspring IQ. VPA high and low dose: 800mg

Neurology 84 January 27, 2015 19

LACTATION AND DEVELOPMENT

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Background

1. The infant’s theoretical dose (Less than 10% of recommendation):

Therapeutic pediatric dose

Relative infant dose, adjusted by mothers weight dose

2. Safety data are limitation.

3. Breastfeeding may be key issue or questions, after delivery.

4. Monitoring Neonate with AED exposure:

Weight change

Drowsiness

Rash

Hepatic dysfunction

Fig. 1. Exclusive or mixed breastfeeding at ages 0–6 months. Frequency of breastfeeding in epilepsy groups and the reference group at 0 to 6 months after delivery. AED indicates antiepileptic drug. Copyright (2013) the American Medical Association (AMA). All rights reserved. Reprinted, with permission from the JAMA Network [36]. Personal use of this material is permitted. However, permission to reuse this material for any other purpose must be obtained from AMA.

Seizure 28 (2015) 57–65 22

Safe AEDs

1. Phenytoin

• M/P ratio from 0.1 to 0.6 (Tomsen 2005)

• Case reports of adverse effects mainly include infants whose mothers were using phenytoin in combination with other AEDs . (Drugs and lactation database. National Library of Medicine, US; 2014)

2. Valporate

• M/P ratio from 0.01 to 0.3. (Bar-Oz 2000)

• No definite adverse reactions have been reported with maternal monotherapy. (Drugs and lactation database. National Library of Medicine, US; 2014)

3. Carbamazepine

• M/P ratio from 0.2 to 0.7. (Bar-Oz 2000)

• A few case reports of liver dysfunction with jaundice and elevated liver enzymes, as well as reports of poor suckling and reduced weight gain. (Frey 1990, Kuhnz 1983, Merlob 1992)

Seizure 28 (2015) 57–65 23

Moderately safe AEDs

1. Lamotrigine

• M/P ratio of 0.4 (range 0.1–1.4) (Newport DJ 2008)

• Infants have a limited capacity to metabolize lamotrigine via hepatic UDP glucuronidation.

• Serum levels in breastfed infants are variable,18% [10~27%]

• Adverse effects in infants are rarely reported. (Drugs and lactation database. National Library of Medicine, US; 2014, Available )

• Maternal lamotrigine dose is often increased during pregnancy to account for increased drugclearance.

• rash, poor suckling, and drowsiness

2. Levetiracetam

• M/P ratio of 1.0 (range 0.8–1.6).

• Serum concentrations in infant are low (Johannessen SI 2005; Tomson T 2007)

• There are no reports of adverse effects in nursed infants.

Seizure 28 (2015) 57–65 24

Moderately safe AEDs cont’d

1. Oxcarbazepine

• M/P ratio around 0.5 (Bulau P, 1998)

• serum concentrations of oxcarbazepine and its active monohydroxy derivative (eslicarbazepine) appear to be low in breastfed infants. (Bulau 1998, Lutz 2007)

• there are no case reports on side effects (Drugs and lactation database. National Library of Medicine, US; 2014, Available )

2. Topiramate

• M/P ratio of 0.9 [0.7-1.1] (Ohman 2002)

• serum levels in breastfed infants are low with maternal doses at 200 mg daily or less. (Ohman 2002)

• diarrhoea and reduced weight gain. (Westegran T 2014)

3. Pregabalin (Ohman I, De 2011)

• M/P ratio of 1.0

• infant serum levels of only 8% of the mother’s level.

Seizure 28 (2015) 57–65 25

Possibly hazardous AEDs

1. Phenobarbital

• M/P ratio around 0.3-0.5

• potential to accumulate during breastfeeding

• drowsiness or poor weight gain (Drugs and lactation database. National Library of Medicine, US; 2014, Available )

2. Beznodiazepines

• M/P ratio of 0.5 [0.2-2.8]

• due to a long half-life and slowed elimination in neonates.

• Sedative effects such as drowsiness and reduced weight gain.

3. Zonisamide

• M/P ratio of 0.8

• neonates have a low capacity to eliminate zonisamide half-life of 100 h.

Seizure 28 (2015) 57–65 26

Results of AED breastfeeding review. Lactation studies of anticonvulsants

Br J Clin Pharmacol / 79:4 / 55 Lactation studies of anticonvulsants 9 27

G. Veiby et al. / Seizure 28 (2015) 57–65

Epilepsy groups with no maternal antiepileptic drug use Maternal antiepileptic drug use

Maternal antiepileptic drug polytherapy Maternal lamotrigine monotherapy

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Recommendations for breastfeeding in mothers taking antiepileptic drugs

Breastfeeding should be encouraged

Most AEDs are compatible with breastfeeding with a safe or moderately safe risk of side effects in the infant. Online information: http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm

Observe the infant Monitor for drowsiness, reduced suckling activity, and poor weight gain; especially infants that are premature or in poor health. If side effects are suspected, consider analysis of drug serum-levels in the infant. Evaluate if developmental milestones are reached as expected

Consider mixed nutrition For AEDs with undetermined breastfeeding safety, or if side effects are suspected in the infant, consider mixed nutrition with partial breastfeeding and formula milk supplement.

Breastfeed at the lowest drug level

Take AED immediately after breastfeeding, or immediately before the infant’s longest sleep period.

Consider postpartum dose adjustment

If maternal AED drug dose has been increased during the pregnancy, ensure postpartum dose tapering until the mother’s optimal serum-level is reached

Discuss safety issues Discuss measures that may prevent maternal depression, sleep deprivation, and missed medications postpartum. Suggest safe breastfeeding techniques in case of seizures.

S. Shovon Seizure 28 (2015) 57–65 29

CONCLUSION

Management of epilepsy during pregnancy: evidence-based strategies

1. In Women with or without epilepsy history

1. Keep lowest dose of AED as possible.

2. Avoid Polytherapy.

3. Folic acid supplement. (High dose? 0.4-0.8 enough?)

4. Use Lactation strategy while breastfeeding

2. Don’t forget consult your pharmacist.

31 L.M.V.R. Moura et al. / Epilepsy & Behavior 44 (2015) 151–154 T. Lavi-Blau et al. / Epilepsy & Behavior 55 (2016) 113–119