Reproductive Toxicology 39 (2013) 50–57
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Pregnancy outcome in women exposed to antiepileptic drugs: Teratogenic role of maternal epilepsy and its pharmacologic treatment Matteo Cassina a,∗,1 , Arianna Dilaghi b,1 , Elena Di Gianantonio a , Elena Cesari c , Marco De Santis c , Guido Mannaioni d , Alessandra Pistelli b,2 , Maurizio Clementi a,2 a
Teratology Information Service, Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy Centro di Riferimento Regionale di Tossicologia Perinatale – Clinical Toxicology Unit, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy c Telefono Rosso – Teratology Information Service, Department of Obstetrics and Gynecology, Catholic University of Sacred Heart, Roma, Italy d Department of Pharmacology, University of Firenze, Firenze, Italy b
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Article history: Received 8 August 2012 Received in revised form 3 April 2013 Accepted 4 April 2013 Available online xxx Keywords: Epilepsy Antiepileptic drugs Pregnancy Teratogenicity Birth defects
a b s t r a c t Infants born to epileptic women treated with antiepileptic drugs (AEDs) have an increased risk of major congenital malformations (MCMs). In order to determine the role of maternal epilepsy we conducted a prospective cohort study on three cohorts of pregnant women: (i) 385 epileptic women treated with AEDs, (ii) 310 non-epileptic women treated with AEDs, (iii) 867 healthy women not exposed to AEDs (control group). The rate of MCMs in the epileptic group (7.7%) was not statistically higher than in the non-epileptic one (3.9%) (p = 0.068). The rate in the first group was higher compared to the control group (p = 0.001), while the rate in the second one was not (p = 0.534). Our data confirm that AEDs therapy is the main cause of the increased risk of malformations in the offspring of epileptic women; however a teratogenic role of the maternal epilepsy itself cannot be excluded. © 2013 Published by Elsevier Inc.
1. Introduction Antiepileptic drugs (AEDs) during pregnancy have been considered the cause of potential side effects in the fetus since the 1970s. Indeed, antiepileptic drugs as a class have been shown to cause major congenital malformations (MCMs) [1–3], and also adverse effects on cognitive development after prenatal exposure [4]. Although some studies have hypothesized that mothers’ epilepsy itself plays an important role in causing fetal abnormalities [5–7], recent findings have suggested that AEDs therapy is the main cause of malformations [8–10] and a large number of studies have assessed the rate of major congenital malformations and long-term effects associated with in utero AEDs exposure. The teratogenic potential of AEDs is an important issue since these drugs are regularly used not only to treat epilepsy but also psychiatric disorders (schizophrenia, bipolar and anxiety disorders) and other neurological diseases (trauma, headache and
∗ Corresponding author at: Genetica Clinica ed Epidemiologica, Dipartimento di Salute della Donna e del Bambino, Via Giustiniani 3, 35128 Padova, Italy. Tel.: +39 0498211424; fax: +39 0498211425. E-mail address:
[email protected] (M. Cassina). 1 These authors contributed equally to this work. 2 These authors contributed equally to this work. 0890-6238/$ – see front matter © 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.reprotox.2013.04.002
neuropathic pain) which are conditions affecting women in childbearing age and requiring a daily long-term therapy [11]. In particular, the number of drugs associated and the therapy management during gestation may influence pregnancy outcome [12]. Most studies in the literature have evaluated the incidence of MCMs in the offspring of epileptic women exposed or not exposed to AEDs during pregnancy. It has become apparent from these studies that the rate of congenital malformations significantly increases in newborns exposed to AEDs during the first trimester of pregnancy and it is higher if more than one AED is taken [3], it is dose dependent and affected by other variables such as parental history of MCMs [12]. The highest risk has been observed with high dose of valproic acid exposure as compared to other AEDs such as carbamazepine, phenytoin and lamotrigine [13]. Few studies have investigated the role of epilepsy in the pathogenesis of MCMs, evaluating the outcome of pregnancies of healthy women and epileptic women not exposed to AEDs or other teratogens. According to these studies the risk associated to the disease is unclear, yet it appears to be minimal [10,14]. To better clarify the role of AEDs and epilepsy itself in the outcome of MCMs, we conducted a prospective observational study on three groups of pregnant women: (i) epileptic women treated with AEDs during pregnancy, (ii) women treated with AEDs in order to control non-epileptic disorders, and (iii) healthy women not
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Table 1 Maternal characteristics and risk factors.
Exposed pregnancies Maternal age (years) Mean ± SD Min–Max Gestational week at 1st TIS contact Mean ± SD Min–Max Alcohol exposure during pregnancy Tobacco exposure during pregnancy
Epileptic women [E]
Non epileptic women [NE]
Controls [C]
385
310
867
31.5 ± 5.2 17–49
33.3 ± 5.6 17–46
32.9 ± 4.8 16–46
10 ± 6 4–40 30/280 (10.7%) 46/312 (14.7%)
9±5 4–38 44/258 (17.1%) 107/282 (37.9%)
12 ± 7 3–40 88/532 (16.5%) 129/653 (19.8%)
[E] vs [NE] p-value
[E] vs [C] p-value
[NE] vs [C] p-value
