Second-generation antiepileptic drugs and pregnancy: a guide for clinicians

Figures & data

Table 1. The three generations of antiepileptic drugs and the year of their introduction in Europe.

Generation of AED	AED	Year of introduction
First generation	Bromide	1857
	PB	1912
	PHT	1939
	PRM	1960
	STM^†	1960
	CBZ	1965
	VPA	1970
Second generation	VGB^†	1989
	OXC	1990
	LTG	1991
	GBP	1994
	FBM^†	1994
	TPM	1995
	TGB^†	1996
	LEV	2000
	PGB	2005
	ZNS	2007
	STP^†	2007
	RUF^†	2007
Third generation	ESL	2010
	LCM	2010
	RTG (ezogabine)	2011

^† Marketed at a low scale or for restricted use.

AED: Antiepileptic drug; CBZ: Carbamazepine; ESL: Eslicarbazepine; FBM: Felbamate; GBP: Gabapentin; LCM: Lacosamide; LEV: Levetiracetam; LTG: Lamotrigine; OXC: Oxcarbazepine; PB: Phenobarbital; PGB: Pregabaline; PHT: Phenytoin; PRM: Primidone; RTG: Retigabine; RUF: Rufinamide; STP: Stiripentol; STM: Sulthiame; TGB: Tiagabine; TPM: Topiramate; VPA: Valproate; VGB: Vigabatrin; ZNS: Zonisamide.

Data taken from [8,9].

Table 2. Data from the the European and international Registry of Antiepileptic drugs in Pregnancy on major congenital malformations after monotherapy exposure to commonly used second-generation antiepileptic drugs.

AED	Exposures (n)	Frequency of malformations (%)
LTG	1280	2.9
OXC	184	3.3
LEV	126	1.6
TPM	73	6.8

AED: Antiepileptic drug; LEV: Levetiracetam; LTG: Lamotrigine; OXC: Oxcarbazepine; TPM: Topiramate.

Modified with permission from [12].

Table 3. Overview of elimination pathways, pharmacokinetic changes during pregnancy and teratogenic potentials of common second-generation antiepileptic drugs.

LTG	Mainly glucuronidation via UGT, 10% unchanged in urine	Decrease by 40–60%	Low
LEV	Mainly unchanged in urine, a third metabolized by peripheral hydrolysis	Decrease by approximately 40%	Promising
OXC	Glucuronidation via UGT	Decrease by 30–40%^†	Promising
TPM	Mainly unchanged in urine, 20–30% hepatic biotransformation	Decrease by 30–40%	Concerning
GBP	Unchanged in urine	Not studied	Insufficiently studied
PGB	Unchanged in urine	Not studied	Not studied
ZNS	Mainly hepatic biotransformation, 15–30% unchanged in urine	Not studied	Not studied

^† Monohydroxy metabolite.

AED: Antiepileptic drug; GBP: Gabapentin; LEV: Levetiracetam; LTG: Lamotrigine; OXC: Oxcarbazepine; PGB: Pregabalin; TPM: Topiramate; UGT: Uridine-diphosphate glucuronosyl transferase; ZNS: Zonisamide.

Data taken from [12,18,19,34,35,52,57,65,71,72,74,77].

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Tomson T, Battino D, Bonizzoni E et al..; EURAP study group. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 10(7), 7–617 (2011).

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