Is carbamazepine a human teratogen?

doi:10.1016/j.jocn.2015.07.011

Journal of Clinical Neuroscience

Volume 23, January 2016, Pages 34-37

https://doi.org/10.1016/j.jocn.2015.07.011 Get rights and content

Highlights

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Carbamazepine in monotherapy is associated with a two-fold increase of foetal malformations.
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Carbamazepine is not an adequate comparator for the malformation risk in pregnancy.
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Levetiracetam related risks are comparable to those of untreated women in pregnancy.

Abstract

The foetal outcomes of 2,635 pregnancies recorded in the Australian Pregnancy Register were studied. In at least the initial 4 months of 515 pregnancies, there had been no intrauterine exposure to antiepileptic drugs, though the women involved in 264 of these pregnancies took antiepileptic drugs in later pregnancies. Compared with these 515 drug-unexposed pregnancies, foetal malformations risks were increased more than five-fold in association with valproate monotherapy, and more than doubled in association with carbamazepine monotherapy (p < 0.05). There were no statistically significant increases in malformation rates associated with other more commonly used antiepileptic drugs, while the malformation risk in relation to levetiracetam exposure was lower than that in the drug-unexposed pregnancies. The published literature has rather consistently shown raised malformation rates associated with carbamazepine monotherapy, though only once was it statistically significant. There now appears to be enough evidence to make it likely that carbamazepine possesses some teratogenic capacity. This makes it unwise to employ the malformation rate associated with carbamazepine monotherapy as a comparator when assessing the foetal hazards from exposure to newer antiepileptic drugs. Levetiracetam may prove a better comparator if adequate untreated control material is unobtainable.

Introduction

The hazard of potential foetal malformation associated with intrauterine antiepileptic drug (AED) exposure continues to concern women both when they are considering becoming pregnant and while pregnant, and also troubles those responsible for their medical care. A significant amount of relevant information is already available and it has become generally accepted that valproate is a dose related teratogen. There are also published data suggesting that exposure to other AED, for instance phenobarbitone, topiramate and carbamazepine, could be responsible for foetal malformations but the evidence is not yet persuasive [1]. However any teratogenic hazard for which these drugs are responsible appears to be less than that associated with valproate exposure. The situation in relation to carbamazepine is especially important as it remains more widely used than its fellows in managing epilepsy in pregnant women. Also, carbamazepine is usually employed as the standard against which the antiepileptic efficacy of newer AED in focal epilepsies is assessed. It therefore is of some importance to determine whether or not enough evidence is available to settle the issue of carbamazepine’s teratogenic hazard. This matter has been examined in the data collected in the Australian Pregnancy Register, as described below.

Section snippets

Materials and methods

The nature of the data source, the Australian Pregnancy Register, and its method of information collection and storage have been described in previous publications [2], [3]. The Register, which began collecting data in 1999, is estimated to capture some 8% to 9% of all Australian pregnancies in women with epilepsy [4]. In essence, the Register depends on pregnant women, the great majority of whom have epilepsy and take AED, making contact with it after becoming aware of its existence. All

Results

The study involved 2,638 pregnancies in 1,521 women, 1,895 of the pregnancies being prospective and 743 retrospective (the latter in 374 women). As mentioned above, AED dosage data were available only for the prospective pregnancies. Some 264 of the 515 pregnancies that were not associated with AED exposure in at least the initial 4 months of pregnancy had occurred in 158 women who took AED during their subsequent pregnancies.

Table 1 shows the rates of occurrence of foetal malformations of any

Discussion

The present analysis has produced evidence, some of it statistically significant, that carbamazepine when employed in AED monotherapy has some teratogenetic capacity. To our knowledge only one of a number of previously published individual studies of the use of the drug in monotherapy during pregnancy, that of Samren et al. [6], has produced similar statistically significant evidence, though all but one of these studies, that of Morrow et al. [7], found increased relative risk or odds ratio

Conflicts of Interest/Disclosures

The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

Acknowledgements

We gratefully acknowledge the help provided by professional and lay colleagues in referring patients to the Australian Pregnancy Register, and also thank the Scientific Advisory Board and the Ethical Research Committees of St. Vincent’s Hospital, Monash Medical Centre, the Royal Melbourne Hospital and other institutions for their continuing ethics oversight of its activities. The Epilepsy Society of Australia, The Royal Melbourne Hospital Neuroscience Foundation, Epilepsy Australia and NHMRC

References (27)

F.J. Vajda et al.
The Australian antiepileptic drug in pregnancy register: aspects of data collection and analysis
J Clin Neurosci
(2007)
F.J. Vajda et al.
The Australian register of antiepileptic drugs in pregnancy – changes with time in its epileptic population
J Clin Neurosci
(2014)
E. Perucca
Birth defects after prenatal exposure to antiepileptic drugs
Lancet Neurol
(2005)
T. Tomson et al.
Dose-dependent risk of malformation with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry
Lancet Neurol
(2011)
S.A. Chaudhry et al.
The fetal safety of levetiracetam
Reprod Toxicol
(2014)
S. Kaneko et al.
Congenital malformations due to antiepileptic drugs
Epilepsy Res
(1999)
G. Mawer et al.
Pregnancy with epilepsy: obstetric and neonatal outcome of a controlled study
Seizure
(2010)
S. Matalon et al.
The teratogenic effect of carbamazepine: a meta-analysis of 1255 exposures
Reprod Toxicol
(2002)
K. Meador et al.
Pregnancy outcomes in women with epilepsy: a systematic review and analysis of published pregnancy registers and cohorts
Epilepsy Res
(2008)
B.J. Wlodarczyk et al.
Antiepileptic drugs and pregnancy outcomes
Am J Med Genet A
(2011)

F.J. Vajda et al.

Changing patterns of antiepileptic drug use in pregnant Australian women

Acta Neurol Scandinav

(2010)

M. Riley et al.

Birth Defects in Victoria 1983–1998, Perinatal Data Collection Unit, 2008

(2000)

E.B. Samrén et al.

Antiepileptic drug regimens and major congenital abnormalities in the offspring

Ann Neurol

(1999)

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Trends in the choice of antiseizure medications in juvenile myoclonic epilepsy: A retrospective multi-center study from Turkey between 2010 and 2020
2022, Seizure
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The rate of congenital malformations through the use of VPA during pregnancy has been reported at a rate of 10.9% [19]. Furthermore, the use of VPA during pregnancy has been demonstrated to increase the rates of autism, psychomotor retardation, and attention-deficit/hyperactivity disorder [20]. The common view of clinical guidelines from the International Association for Combating Epilepsy (ILAE), the European Academy of Neurology (EAN), and the European Medicines Agency (EMA), is to avoid using VPA in females unless other treatments are unsuccessful [18].
Purpose:Valproic acid (VPA) is frequently used and effective in juvenile myoclonic epilepsy (JME). Recently, levetiracetam (LEV) has been suggested as a monotherapy in JME. This study aimed to evaluate antiseizure medication (ASM) use in patients with JME.
Methods: Treatment choices in a total of 257 patients (age range 8–18 years, 152 girls, 105 boys) with JME diagnosed and treated between 2010 and 2020 were evaluated retrospectively. Seizure remission was defined as complete seizure control for at least 12 months.
Results: Across the study period and entire patient group, VPA was most commonly chosen as the initial ASM (50.9%), followed by LEV (44.4%), and lamotrigine (4.7%). VPA was also the most frequent first choice in the subgroup of boys (73.3%), while LEV was the commonest first choice in girls (57.9%). The sex difference regarding the ASM of the first choice was statistically significant (p<0.001). While VPA was the most frequent initial ASM in the first 5 years of the study period (2010–2015,n = 66, 64%), LEV had taken over as the most popular first ASM in the last 5 years (n = 83, 53.9%, p = 0.005). The most frequent reasons for discontinuation were inefficacy for LEV and adverse effects for VPA (p = 0.001). During follow-up, 237 patients (92.2%) were seizure-free for at least 12 months, and 159 (61.9%) were also in electrographic remission. Seizure remission occurred earlier than electroencephalographic remission (p<0.001).
Conclusion: This study revealed that LEV has become the most frequently chosen initial ASM in the treatment of JME. Although LEV appears to have a better adverse effect profile, VPA seems more likely to be effective in achieving seizure control.
Construction of a room-temperature phosphorescent quantum dot probe and quantitative detection of thyroxine and carbamazepine
2021, Journal of Molecular Structure
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However, CBZ has some side effects. According to some literature, CBZ may improve bacterial resistance [20], which influences fetal teratogenesis [21] and the survival of aquatic organisms [22]. Therefore, it is quite important to detect CBZ.
In this paper, a new quantitative detection system for thyroxine (T₄) and carbamazepine (CBZ) was constructed. A mixture of MPA-capped Mn and ZnS quantum dots (MPA-Mn:ZnS QDs) exhibiting room-temperature phosphorescence (RTP) was prepared, which serves as the detection signal. The hexadecyltrimethylammonium bromide/ MPA-Mn:ZnS QDs (CTAB/QD) compound binds T₄ to produce a CTAB/QDs&T₄ complex, which results in phosphorescent quenching of the quantum dots. By adding CBZ to CTAB/QDs&T₄, the phosphorescent quenching remains, allowing the quantitative detection of T₄ and CBZ. Under the best experimental conditions, the linear relationship of QDs/CTAB-T₄ is T₄△RTP=0.4137C_T4+0.1034, the correlation coefficient is R²=0.999, the detection limit is 1.95 nmol/L, and the detection range is 4.85 nmol/L to 1.59 μmol/L; the linear relationship of CTAB/QDs&T₄CBZ is CBZ△RTP=0.4178x+0.112, the correlation coefficient is R²=0.995, the detection limit is 3.43 nmol/L and the detection range is 7.9 nmol/L to 1.555 μmol/L. This method has many advantages, such as anti-interference (which can overcome the autofluorescence interference of biological samples), nontoxicity, sensitivity, simple operation and low cost, and can be applied to the quantitative detection of T₄ and CBZ in human serum samples.
A proof of concept study demonstrating that environmental levels of carbamazepine impair early stages of chick embryonic development
2019, Environment International
Citation Excerpt :
Growth retardation and various cognitive deficits were also described (Afshar et al., 2010; Diav-citrin et al., 2011; Matalon et al., 2002; Ornoy and Cohen, 1996; Pearse et al., 1992). Yet, available data is somewhat conflicting since type, severity and frequency of defects vary between studies (Matlow and Koren, 2012; Vajda et al., 2016; Vorhees et al., 1990). Similar to humans, rodents that were exposed to clinical doses of CBZ during gestation developed birth-defects (Afshar et al., 2010; Finnell et al., 1986; Piersma et al., 1998).
Carbamazepine (CBZ) is an anticonvulsant drug used for epilepsy and other disorders. Prescription of CBZ during pregnancy increases the risk for congenital malformations. CBZ is ubiquitous in effluents and persistent during wastewater treatment. Thus, it is re-introduced into agricultural ecosystems upon irrigation with reclaimed wastewater. People consuming produce irrigated with reclaimed wastewater were found to be exposed to CBZ. However, environmental concentrations of CBZ (μg L⁻¹) are magnitudes lower than its therapeutic levels (μg ml⁻¹), raising the question of whether and how environmental levels of CBZ affect embryonic development.
The chick embryo is a powerful and highly sensitive amniotic model system that enables to assess environmental contaminants in the living organism. Since the chick embryonic development is highly similar to mammalians, yet, it develops in an egg, toxic effects can be directly analyzed in a well-controlled system without maternal influences. This research utilized the chick embryo to test whether CBZ is embryo-toxic by using morphological, cellular, molecular and imaging strategies. Three key embryonic stages were monitored: after blastulation (st.1HH), gastrulation/neurulation (st.8HH) and organogenesis (st.15HH).
Here we demonstrate that environmental relevant concentrations of CBZ impair morphogenesis in a dose- and stage- dependent manner. Effects on gastrulation, neural tube closure, differentiation and proliferation were exhibited in early stages by exposing embryos to CBZ dose as low as 0.1 μg L⁻¹. Quantification of developmental progression revealed a significant difference in the total score obtained by CBZ-treated embryos compared to controls (up to 5-fold difference, p < 0.05). Yet, defects were unnoticed as embryos passed gastrulation/neurulation.
This study provides the first evidence for teratogenic effect of environmental-relevant concentrations of CBZ in amniotic embryos that impair early but not late stages of development. These findings call for in-depth risk analysis to ensure that the environmental presence of CBZ and other drugs is not causing irreversible ecological and public-health damages.
Antiepileptic drugs and foetal malformation: analysis of 20 years of data in a pregnancy register
2019, Seizure
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Throughout, Australian neurologists were the major source of referral to the APR, but with a progressively increasing contribution from women referring themselves back to the APR in subsequent pregnancies (Fig. 2). Assuming similar fertility rates to other Australian women, only 8–9% the expected pregnancies of women with epilepsy in the country probably were captured by the APR [1]. Pregnancies were enrolled at various stages of intrauterine foetal development.
This paper reports additional data supplementing earlier publications based on Australian Pregnancy Register (APR) data.
Over 20 years, the APR has collected Information on pregnancies in Australian women with epilepsy (WWE), untreated WWE and those taking AEDs for other indications. Contact is by telephone, at set intervals. Treatment is not interfered with. Data are analysed using conventional statistical techniques, confidence interval methods, and logistic regression.
By 2018, the APR contained details of 2148 pregnancies. AEDs were taken throughout 1972 of the pregnancies (91.8%). The remaining 176 (8.2%) did not receive AEDs, at least early in pregnancy.
There were (i) dose-related increased incidences of pregnancies carrying foetal malformations associated with maternal intake of valproate and topiramate when topiramate was a component of AED polytherapy (P < .05), (ii) a similar dose-related trend in relation to carbamazepine intake, (iii) no evidence that levetiracetam and lamotrigine were unsafe from the foetal standpoint, (iv) insufficient data to permit conclusions regarding teratogenicity in relation to other AEDs, and (v) no evidence that pre-conception folate supplementation reduced the hazard of AED-associated foetal malformation. AED polytherapy did not increase foetal hazard unless valproate or topiramate was involved in the AED combination. Genetic factors probably contributed to the malformation hazard. Seizures occurring in earlier pregnancy probably did not contribute to the malformation hazard.
If it were not for the importance of maintaining seizure control, the above findings suggest that it would be better to avoid using certain AEDs, particularly valproate and topiramate, during pregnancy.
Use of Antidiabetic, Antihypertensive, and Psychotropic Drugs in Pregnancy
2018, Side Effects of Drugs Annual
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Major anomalies were identified 6.7% of mothers prescribed carbamazepine vs 2.5% of controls or untreated epilepsy [65M]. This is approximately twice the general population rate and was confirmed in a 2016 cohort study [66C]. Spina bifida (OR 3.6, 95% CI 1.1–4.5) and cleft palate (OR 2.4, CI 1.1–4.5) are also reported risks with carbamazepine [67M].
The Side Effects of Drugs Annuals are yearly reviews of literature that has been published on the adverse effects of drugs. The Side Effects of Drugs Annuals contributes to the contents of Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions. This literature review includes studies, meta-analyses, and case reports on the use of antidiabetic, antihypertensive, and psychotropic drugs in pregnancy. The review includes insulin, metformin, and glyburide, beta blockers, centrally-acting adrenergic agents, renin–angiotensin system blockers, diuretics, calcium channel blockers, antidepressants, antiepileptics, mood stabilizers, and antipsychotics. For this first chapter on the use of medications in pregnancy we focused on literature from July 1, 2016 to December 31, 2017. If this search led us to relevant material published prior those dates, it was also included in the review.
Developmental toxicity of antiepileptic drugs-An update
2018, Comprehensive Toxicology: Third Edition
Antiepileptic drugs (AEDs) are a diverse class of pharmaceutical that is used to control epilepsy. More recently, AEDs have been prescribed for other indications besides epilepsy, including psychiatric indications and pain management. Thus, AED usage has dramatically increased. Although AEDs can be helpful, a concern is that they will exhibit teratogenicity when used during pregnancy. Here, we review data and studies that have been performed over the last 5–7 years to provide a recent compilation of AED teratogenic studies. This covers structural malformations, such as neural tube defects, but also spans the effects of AEDs on neurobehavioral deficits as well. Data show that not all AEDs are equally teratogenic and in some cases some have shown to exhibit very low teratogenicity, if at all. Still, further study is required to best understand how AEDs may be used to ensure proper healthcare for the expecting mother and eliminate the risk to the developing fetus.

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ReviewIs carbamazepine a human teratogen?

Highlights

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Conflicts of Interest/Disclosures

Acknowledgements

J Clin Neurosci

J Clin Neurosci

Lancet Neurol

Lancet Neurol

Reprod Toxicol

Epilepsy Res

Seizure