Teratogenic effects of antiepileptic drugs
People with epilepsy are prescribed antiepileptic medications with the aim of Normal brain function involves "communication" between millions of nerve cells with drug levels, as there is not a good correlation between drug level and effect. . antiepileptic medication receive pre-pregnancy counselling and discuss their. The term “fetal anticonvulsant syndrome” is used to include various anatomic structure present at birth that interferes significantly with function and/or . Other studies have supported a dose-relationship for VPA, with an increased risk for. While most women with epilepsy require anticonvulsant drugs for adequate control of Seizures (convulsions) are episodes of disturbed brain function that cause . by supplying information concerning the drug's chemical structure, .. Menegola and colleagues showed a direct correlation between somite.
Neurology : Antiepileptic medications
The data set of the large population-based Hungarian Case-Control Surveillance of Congenital Abnormalities, —, was evaluated, and the authors reported an increased risk for posterior cleft palate with CBZ Puho et al.
When compared to the background rate for major malformations in this hospital-based pregnancy registry 1. The MCMs reported in this study included one cleft lip and palate and four heart defects. Two other studies have reported specifically increased cardiac malformations associated with PB exposure in utero Canger et al.
One study showed an increased risk for cleft palate with PHT Puho et al. The distribution of dose did not differ between the group of infants with MCMs mean The overall frequency of MCMs was 2.
Other AEDs The newer generation of AEDs consists of a large number of structurally diverse compounds, most of which have demonstrated teratogenic effects in preclinical animal experiments. With the possible exception of LTG, none has sufficient human pregnancy experience to assess their safety or teratogenicity. Preliminary reports of experience with these agents during pregnancy are reported in the following text, but prospective population-based studies in postmarketing evaluation with larger numbers of outcomes are essential to establish safety in human pregnancies.
A series of GBP exposures during pregnancy evaluated prospective and retrospective outcomes for 51 fetuses of women with epilepsy and other disorders, with 44 live births.
Anticonvulsant - Wikipedia
No malformations were seen in the 11 patients on GBP monotherapy. However, the number of outcomes is too small to make any definitive conclusions. Three had major congenital malformations 2.
Sixteen had an MCM 9. Of the 70 monotherapy cases, 4. Four MCMs were oral clefts 2. A case series from Argentina included 35 women on OXC monotherapy, and all infants were healthy; of the 20 infants exposed to polytherapy with OXC, one had a cardiac malformation Meischenguiser et al. The prospective study from Denmark Sabers et al. Another small series of nine infants exposed to OXC monotherapy reported one major malformation Kaaja et al.
One case series reported on 26 pregnancies with ZNS exposure Kondo et al. Two of the 26 fetuses 7. Information on specific benzodiazepines is limited to relatively small series. Neonatal outcomes were compared for all births. A modest increased risk for preterm birth and low birth weight occurred in the exposed group.
Pyloric stenosis and alimentary tract atresia were noted to occur with an unusual frequency, but earlier reports of orofacial clefts were not confirmed. Reports from the Hungarian Case-Control Surveillance of Congenital Abnormalities —utilizing a case-time-control study design, reported similar risks for valium. The group exposed to valium early in pregnancy had an OR of 1.
Other studies have specifically examined clonazepam. A report from a hospital-based malformation surveillance program of 43 infants exposed to clonazepam monotherapy Lin et al. Neurodevelopmental Outcomes Studies investigating cognitive outcome in children of women with epilepsy report an increased risk of mental deficiency, affecting 1.
Two studies reported that children of women with epilepsy on no AEDs during pregnancy have no behavioral deficits compare to matched controls Holmes et al. How antiepileptic medications work? Normal brain function involves "communication" between millions of nerve cells neurons. At any one time, there are nerve cells which are resting, exciting or inhibiting other nerve cells.
A nerve cell is made up of a cell body and branches called axons and dendrites which join other neurons at junctions called synapses. Electrical signals are sent from the cell body along the axon to the synapse, these electrical signals being the result of ion sodium, potassium, calcium currents across channels in the nerve cell membrane.
Chemical signals neurotransmitters pass across synapses between neurons. Neurotransmitters cross the synaptic gap between neurons and fix to receptor points of the adjoining neuron. Some neurotransmitters function to excite the joining neuron eg. Other neurotransmitters function to inhibit the joining neuron eg.
GABA and inhibit electrical signals passing down that neuron.
It is by these electrical and chemical pathways that the millions of neurons within the brain communicate and function normally. Seizures occur when there is an imbalance within these excitatory and inhibitory circuits in the brain, either throughout the brain generalised epilepsy or in a localised part of the brain focal epilepsysuch that neurons "fire off" in an abnormal fashion. Specifically, they act by either: Altering chemical transmission between neurons by affecting neurotransmitters GABA, glutamate in the synapes.
Close monitoring of serum levels in pregnancy may be advisable with some AEDs. In particular, the use of VPA as a monotherapy or polytherapy should be avoided in women of child-bearing years whenever possible.What is STRUCTURE-ACTIVITY RELATIONSHIP? What does STRUCTURE-ACTIVITY RELATIONSHIP mean?
Please refer to Box 1 for a summary of the literature concerning folate and birth defect risk associated with AED exposure. Box 1Prophylactic folic acid supplementation Based on significant evidence [ ], the US Public Health Service recommends that all women of childbearing potential consume 0. Additionally, it must be noted that folic acid must be present within the first 25 days post-conception to protect against NTDs. Since the most-studied antiepileptic drug AEDvalproic acid VPAis an established disruptor of folate metabolism, it was expected that folic acid supplementation would ameliorate its teratogenicity.
On the contrary, there is a growing literature of case reports concerning the lack of any benefit derived from folic acid supplementation in women receiving VPA therapy during pregnancy [ — ].
As recently reviewed by Ornoy, there is no evidence to demonstrate that the risk of NTDs can be reduced further by folic acid supplementation in women taking VPA [ ], a position previously articulated by Yerby [ ]. For example, it was found that folic acid intake of approximately 0. They observed that 6.
The investigators take care to note that the dosage of folic acid was not considered in these analyses, and it is possible that folic acid supplementation at higher dosages may be more preventive in women with epilepsy who are taking AEDs, although this has not been experimentally established [ ].
Therefore, it remains unclear whether a periconceptional dose of folic acid greater than 0.
Antiepileptic drug safety in pregnancy: possible dangers for the pregnant woman and her foetus
In summary, while low folate levels have been associated with an increased risk of major congenital malformations and NTDs in women taking AEDs [ ], the majority of studies examining folic acid supplementation have found no decrease in risk, particularly for VPA [ 59, ]. Mechanisms of AED teratogenicity Given the limitations inherent in human epidemiological and clinical studies of AED-complicated pregnancies, there is a great deal to be learned from fundamental reproductive and molecular studies using model organisms.
The following section is devoted to a comprehensive review of the literature of just a few of the frontline AEDs, as teratogenic studies of the newer AEDs are not well reported in public scientific literature.
Small increases in the rate of cleft palate, dilated cerebral ventricles and growth retardation were observed in mouse fetuses that were similarly treated during the period of organogenesis [ 72 — 75 ]. In mice chronically exposed to CBZ in their diet prior to and throughout gestation, a significant number of fetuses were observed with congenital defects of the CNS or urogenital system [ 76 ].
In experiments comparing teratogenicity of CBZ with other anticonvulsant drugs, it was consistently less teratogenic than PHT or primidone [ 727477 ]. In rats, CBZ had a limited teratogenic and embryotoxic effect [ 78 ]. Of the few abnormalities that were induced by gastric intubation throughout the period of organogenesis, edema was the most commonly observed, although fetuses with gastroschisis, omphaloceles, hydronephrosis, ventricular septal defects, hydrocephaly and skeletal defects were also reported.
The mechanism by which CBZ exerts its teratogenicity is largely unknown. The primary pathway of metabolism for CBZ involves the oxidative formation of carbamazepine,epoxide, which is thought to be responsible for the teratogenicity of the parent drug [ 80 ].
This was confirmed in a study on pregnant mice where carbamazepine,epoxide treatment significantly increased the incidence of malformations in fetuses [ 8182 ]. Gabapetin Experimental studies in rodents show that GBP exposure during pregnancy causes delayed ossification of bones in the skull, vertebrae, forelimbs and hindlimbs.
In addition, the length and weight of mouse fetuses decreased significantly with the administration of GBP during mid- and late-gestation E13— Malformations most commonly observed in the exposed fetuses were craniofacial defects, including brachygnathia, pointed snouts, open eyes, cataracts and thickened short necks, as well as limb defects, including rudimentary and malrotated limbs.
Lamotrigine When pregnant rats were treated with LMT from E14 to E19 the neuronal migration stagepathological studies of the pups reported dose-dependent alterations in the neocortex and hippocampus.
Prenatal exposure to LMT induced hippocampal and cortical malformations in a dose-dependent manner. Moreover, these effects were found at plasma LMT concentrations that are within the human therapeutic range for the drug [ 84 ]. The LMT exposure resulted in a significant increase of resorptions and craniofacial malformations exencephaly, cleft palate, arched palate and midfacial hypoplasiaurogenital abnormalities and varying degrees of caudal regression and skeletal defects were also noted.
These observed effects were most likely secondary to the severe maternal toxicity observed in the treated dams [ 8586 ].