During pregnancy, women experience a series of physiological changes that have consequences for the pharmacokinetics and pharmacodynamics of the drugs and medications they take. Monitoring epilepsy in pregnancy is very challenging despite the narrowly focused goal of establishing an optimal seizure control regimen with the lowest possible dose of antiepileptic drug(s). To accomplish this, it is of particular importance to understand the physiological changes that the human body undergoes during pregnancy.
During the course of pregnancy, the plasma volume progressively increases and affects the drug disposition within the body. The volume of the drug distribution, its elimination, and its half-life; all will change considerably over time. The total drug plasma concentration declines, and in some cases, this can adversely affect seizure control. Additionally, the storage of fat increases and fat-soluble drug elimination slows down. Conversely, cardiac output and renal blood flow increase, influencing the renal elimination of the medications [Pennel, 2003
]. The activities of the cytochrome P450 superfamilies that are essential for drug metabolism in the liver are induced during pregnancy [Sabers et al., 2009]. Plasma protein concentration is lower, in particular, albumin and α1-acid glycoproteins, which are essential antiepileptic drugs (AEDs) transporters in the blood stream. This will be manifested as lower total drug level, but in most cases, the unbound concentration of the drug will not change so that their efficacy may remain unaffected. As a reminder, the therapeutic and toxic effects of AEDs are caused by the fraction of the drug in plasma that is not bound to the transport proteins, in other words, the unbound form of the drug. This unbound fraction also directly determines the transplacental crossing of the active compound and thus the exposure of the embryo and/or foetus.
Epilepsy is a brain disorder involving repeated, spontaneous seizures of any type. Seizures (convulsions) are episodes of disturbed brain function that cause changes in attention or behavior. They are caused by abnormally excited electrical signals in the brain [Vorvick et al., 2010
]. Epilepsy can be caused by variety of etiologic factors known or idiopathic, directly or indirectly affecting central nervous system e.g. stroke, ischemia, traumatic brain injury, infectious encephalitis, congenital brain defects, phenylketonuria, brain tumors, liver and kidney failure, to name just a few. The most characteristic symptoms of epilepsy are seizures, which vary greatly in severity from petit mal, absence seizures, to grand mal, generalized violent tonic-clonic convulsions. Treatment of this condition is difficult and in most cases, one seeks control, but no cure. Symptoms (seizures), however, can be successfully reduced or eliminated with the proper anticonvulsant medication treatment regimen. Based on severity and etiology, mono- or polytherapy is recommended for this lifelong disease.
The vast majority of patients suffering from seizures require daily AED therapy, and in most instances, this is a lifelong treatment. This is also true for epileptic women during their reproductive years. Approximately 25,000 children are born to mothers with epilepsy each year in USA alone [Meador et al., 2008
]. Although the majority of these children are normal, the risks associated with in utero
AED exposure are of considerable importance. These infants have significantly higher risks of having one of the features of the embryopathy (i.e., major malformations, microcephaly, growth retardation, and hypoplasia of the midface and fingers) associated with in utero
exposure to AEDs, than do control infants. While figures are quite variable based on the study design and their inherent limitations, Holmes and co-workers found that approximately 20.6% of children exposed to one AED, and 28% of those exposed to two or more drugs, had at least one feature characteristic of the fetal antiepileptic drug embryopathy [Holmes et al., 2001
]. Major malformations affected 4.5% and 8.6% of these infants, respectively. Other authors observed major birth defects in 3.2 – 7.8% of pregnancies complicated by AED monotherapy, and 6.0 – 9.3% in AED polytherapy [Artama et al., Canger et al., 1999; Cunnington et al., 2005; Kaaja et al., 2003
; Kaneko et al., 1999
; Mawer et al., 2010
; Morrow et al., 2006
; Samren et al. 1999
; Wide et al., 2004
; Wyszynski et al., 2004; 2005
]. The meta analysis of 26 studies compiled by Tomson and Battino revealed a major congenital malformation (MCM) rate of 6.1% in offspring of women with epilepsy who were treated with AEDs, 2.8% among children of women with untreated epilepsy, and 2.2% in the healthy control group [Tomson and Battino, 2009
]. Available data strongly suggest that this increased risk for adverse outcomes observed in women with epilepsy
(WWE) is not a consequence of epilepsy or seizures per se
, but is instead directly due to the teratogenic effects of AEDs. Studies showed that offspring born to epileptic women who did not take anticonvulsant drugs had the same risk of birth defects as the infants born to control, seizure free women [Holmes et al., 2001
In the past 20 years 15 new AEDs has been approved by the US Food and Drug Administration and/or European Medicines Agency and introduced to the market [Bialer, 2011
]. Individuals with seizures comprise the largest group of patients treated with AEDs; however, these agents are also widely used for treatment of other neurological disorders. From over 30 medications used primarily to control seizures, several such as clonazepam, lamotrigine, divalproex are frequently used by psychiatrist to treat bipolar disorder and anxiety. Neurologists often use topiramate, gabapentin, and levetiracetam in patients suffering migraine headaches and other pain. Other seizure medication like clonazepam are used for controlling panic disorder and social phobia, pregabalin is used in the treatment of fibromyalgia, lamotrigine for severe unremitting depression and maniac symptoms [Cascade et al., 2008
]. This expansion of the clinical application of these compounds has significantly increased the exposure of potentially pregnant women to AEDs. Although one must not lose sight of the fact that while the risk of some AEDs has been clearly established, there are unknown risks associated with exposure to the newer drugs, due to small sample sizes and polytherapy exposures. Still, most WWE will require AED therapy throughout their entire pregnancy to control seizures. Of particular concern is the potential for the mother to develop tonic-clonic seizures, which can result in significant adverse health outcomes for the fetus, including, but not limited to, intracranial hemorrhage, transient bradycardia and heartbeat abnormalities [Meador et al., 2008
]. The European and International Registry of Antiepileptic Drugs in Pregnancy (EURAP) has recently reported more favourable outcomes with regards to status epilepticus than the 30% maternal mortality and 50% pregnancy mortality reported in older studies [Pennell, 2006
; Tomson et al., 2011]; nevertheless, discontinuing AED therapy during pregnancy is still discouraged by most practitioners.
The most common malformations observed secondary to in utero
AED exposure are cardiac malformations, followed by hypospadias and facial clefts, which follows the pattern of the most common malformations seen in the general population. Treatment with certain AEDs is associated with a greater risk of specific malformations. The strongest data indicate that valproate exposure is associated with a 1-2% risk of neural tube defects (NTDs), a 10- to 20-fold increase over the general population (EURAP), an increased risk of neurodevelopmental deficits, reduced verbal abilities, and poorer attentional tasks [Bromley et al. 2009
; Kantola-Sorza et al., 2007
; McVearry et al., 2009
; Meador et al., 2008
; Nadebaum, 2011; Thomas et al., 2008
]. The astute clinician has always been credited with being the primary means of identifying potential human teratogens [Crombie, 1984
; Carey et al., 2009
], and this has been the case for AEDs as well.
Now that the teratogenicity of these compounds has been established for over 40 years, refining risk assessments depends on the quality of the epidemiological data that can be acquired. One of the greatest difficulties in evaluating the early literature concerning birth defects is the divergent methodologies used; in particular, the inclusion of cases into various groupings, which makes comparisons between studies difficult if not impossible, and clouds the etiology of the observed malformations. After the definition of the term MCM by Holmes et al. in 2001
, inclusion criteria of subjects into epidemiological studies were more homogenous. Unfortunately, prior to this date and even for some years after, the categories of major and minor malformations as reported in the literature were often variable and were poorly described, if they were described at all. Owing to the limited number of reports, the data published are valuable, even if compromised by less than desirable methodology [Morrow et al., 2006
]. Unfortunately, most studies on the teratogenic effects of AEDs are too small and underpowered to draw significant conclusions. This is not unexpected, given the relatively few pregnancies complicated each year by AEDs. As a result, multicenter design studies are the only feasible approach to gather unbiased data on a significant number of pregnancy outcomes. Data that are collected by highly specialized epilepsy centers are more likely to reflect that from the more intractable patients, which involves a more aggressive treatment regimen and potentially skews the data towards more abnormal outcomes. Registry data are one way to circumvent the relative scarcity of AED-exposed pregnancies, but it is most often data that are voluntarily reported that are subject to significant bias. Conclusions drawn largely from registry data must be carefully considered in the context of what we know about other AEDs, and what is understood about the pharmacology and physiology of the compound in question. Tomson and Battino 
provide an excellent overview of the difficulties inherent to the study design for the teratogenicity of AEDs.
This review is a new, updated and extended version of our previous paper published in the “Expert Review of Neurotherapeutics” [Hill et al., 2010
]. The field is moving rapidly in order to provide new data on the potential teratogenicity of the latest generation of AEDs. In this latest revision of this timely review of the teratogenicity of AEDs, we added two new sections to the Introduction, briefly describing the neurological disorder-epilepsy and providing brief but fundamental information on metabolism and pharmacodynamics of drugs during pregnancy. The core part of the manuscript, discussing each consecutive AEDs was extended by supplying information concerning the drug’s chemical structure, mechanism of action and pharmacokinetics. The subparagraph on AEDs and folate supplementation was substantially expanded and new information on VPA impairing children cognitive development was included.