Maternal carbamazepine and infant spina bifida

doi:10.1016/0890-6238(94)90003-5

Reproductive Toxicology

Volume 8, Issue 3, May–June 1994, Pages 203-205

https://doi.org/10.1016/0890-6238(94)90003-5 Get rights and content

Abstract

Women with epilepsy giving birth during 1973 to 1991 were identified by record linkage of Swedish health registries. Among 3,625 identified infants, 9 had spina bifida. A nested case-control study was performed, comparing drugs used in early pregnancy in the 9 cases and 18 controls, matched for year of delivery, maternal age, and parity. Six of the spina bifida mothers had used carbamazepine and two had used valproic acid. Among the controls, 5 women used carbamazepine and one valproic acid. There is an apparent excess risk for spina bifida after use of either of these two drugs, but it is notstatistically significant when the analysis is restricted to drug-using women. The findings support earlier reports in the literature of an association between carbamazepine and spina bifida.

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Cited by (54)

Genotoxicity assessment of antiepileptic drugs (AEDs) in human embryonic stem cells
2019, Epilepsy Research
Several antiepileptic drugs (AEDs) are administrated during pregnancy according to recent therapeutic protocols. Ten percent of pregnant women with epilepsy give birth to offspring with malformations and teratogenic defects. Since the mechanism of action of AEDs is not yet completely understood, therefore, it could be hypothesized that they may cause cyto- or genotoxicity in embryonic fetus cells.
To investigate this hypothesis, the genotoxicity and cell survival of AEDs treated human embryonic stem cells (hESCs) were investigated by single-cell gel electrophoresis (Comet assay) and MTS assay, respectively. HESCs (Royan H6 cell line) were treated in-vitro with high therapeutic doses of Carbamazepine, Gabapentin, Lamotrigine, Levetiracetam or Topiramate as monotherapy or combination therapy of each drug with Folic acid.
After hESCs pluripotency confirmation, the effect of AEDs on cellular DNA damage of hESCs was investigated. levetiracetam and topiramate were found to damage the DNA significantly compared to untreated cells. The amount of DNA damage produced by carbamazepine and lamotrigine was similar while for gabapentin, the amount of DNA migration was very low and produced less DNA damage than the others. A considerable reduction in DNA damages occurred in genotoxicity in the presence of Folic acid in comparison to AEDs monotherapies.
According to our results, all mentioned AEDs caused DNA damage, while Levetiracetam and topiramate caused more extensive DNA damages than the others. Noticeably, the addition of Folic acid to the treated cells decreased the DNA damages considerably.
Approach to the Agitated Emergency Department Patient
2018, Journal of Emergency Medicine
Citation Excerpt :
Additionally, the risk rate was a difference of 5 cases per 10,000 births, leading some experts to suggest this as a reasonable second-line agent (103,110). If longer-term agents are required, valproic acid, lithium, and carbamazepine should be avoided due to an increased risk of teratogenicity, especially in the first trimester (111–119). Restraints should be avoided whenever possible, as patients in the second or third trimester are at risk of inferior vena cava compression (103).
Acute agitation is a common occurrence in the emergency department (ED) that requires rapid assessment and management.
This review provides an evidence-based summary of the current ED evaluation and management of acute agitation.
Acute agitation is an increasingly common presentation to the ED and has a broad differential diagnosis including metabolic, neurologic, infectious, toxicologic, and psychiatric etiologies. Missed diagnosis of a dangerous etiology of the patient's agitation may result in severe morbidity and mortality. Assessment and management of the agitated patient should occur concurrently. Focused history and physical examination are recommended, though control of the patient's agitation may be required. All patients should receive a point-of-care glucose test, with additional testing depending upon the specific patient presentation. Initial management should involve verbal de-escalation techniques, followed by pharmacologic interventions, with physical restraints reserved as a last resort. Pharmacologic options include first-generation antipsychotics, second-generation antipsychotics, benzodiazepines, and ketamine. Finally, the management of pediatric, pregnant, and elderly patients warrants special consideration.
Acute agitation is an important presentation that requires prompt recognition and treatment. A focused and thorough examination coupled with appropriate management strategies can assist emergency clinicians to safely and effectively manage these patients.
Alteration of bioelectrically-controlled processes in the embryo: A teratogenic mechanism for anticonvulsants
2014, Reproductive Toxicology
Citation Excerpt :
Although less common, oral clefts, cardiovascular defects and urogenital defects have also been reported after phenytoin therapy [14,15]. In utero exposure to carbamazepine has been associated with cleft palate [16], neural tube defects [14,16,17] hypospadias and cardiovascular defects [16]. The use of newer AEDs such as lamotrigine, topiramate and levetiracetam has increased in recent years.
Maternal use of anticonvulsants during the first trimester of pregnancy has been associated with an elevated risk of major congenital malformations in the offspring. Whether the increased risk is caused by the specific pharmacological mechanisms of certain anticonvulsants, the underlying epilepsy, or common genetic or environmental risk factors shared by epilepsy and malformations has been controversial. We hypothesize that anticonvulsant therapies during pregnancy that attain more successful inhibition of neurotransmission might lead to both better seizure control in the mother and stronger alteration of bioelectrically-controlled processes in the embryo that result in structural malformations. We propose that development of pharmaceuticals that do not alter cell resting transmembrane voltage levels could result in safer drugs.
Teratogenic effects of antiepileptic drugs
2012, The Lancet Neurology
Citation Excerpt :
Comparing overall malformation rates might therefore be misleading with regard to the consequences of exposure to different drugs, in particular if some AEDs are associated with more severe malformations than others. Findings from studies in the 1980s and 1990s suggested a specific increase in the risk of neural tube defects associated with maternal use of valproate55,56 and possibly also of carbamazepine.57 Findings from the NAAPR suggested that infants exposed to lamotrigine in early pregnancy had a ten times increased rate of cleft palate or cleft lip58 and infants exposed to topiramate a ten times increased risk of cleft lip than unexposed infants.59
Most women with active epilepsy need treatment with antiepileptic drugs during pregnancy. Antiepileptic drugs are also frequently used for other indications, such as migraine, pain syndromes, and psychiatric disorders, which are prevalent among women of childbearing age. Possible teratogenic effects of antiepileptic drugs are therefore of wide concern and the risks imposed by the drugs must be weighed against the risks associated with the disorder being treated. Adverse drug effects on the fetus can present as fetal loss, intrauterine growth retardation, congenital malformations, impaired postnatal development, and behavioural problems. For optimum use of antiepileptic drugs in women of childbearing age and rational management of epilepsy during pregnancy, a thorough understanding of the teratogenic effects of antiepileptic drugs and knowledge of the differences in risks between various treatment options are needed.
Use of Antiepileptic Medications in Pregnancy in Relation to Risks of Birth Defects
2011, Annals of Epidemiology
Citation Excerpt :
Many of the previous studies have included small numbers, limiting analyses to risks of all birth defects as a single outcome (20–26) or to all AEDs in relation to specific birth defect groups (27). The studies that have examined specific birth defect cases exposed to specific AEDs (4, 8, 9, 23, 28–33) have also been limited by small numbers, but their findings have suggested increased risks similar to those observed in the present study. Three studies had numbers of exposed cases similar to or greater than those in our analyses (14, 33–35) and showed strikingly similar patterns of increased risks, including positive associations between valproic acid and NTDs, OCs, HDs, and hypospadias as well as suggestions for a positive association between carbamazepine and NTDs.
To evaluate use of specific antiepileptic drugs (AEDs) in pregnancy in relation to specific birth defects.
Using data from the National Birth Defects Prevention Study, we assessed use of AEDs and the risk of neural tube defects (NTDs), oral clefts (OCs), heart defects (HDs), hypospadias, and other major birth defects, taking specific agent, timing, and indication into consideration.
Drug-specific increased risks were observed for valproic acid in relation to NTDs [adjusted odds ratio (aOR), 9.7;, 95% confidence interval (CI), 3.4–27.5], OCs (aOR, 4.4; 95% CI, 1.6–12.2), HDs (aOR, 2.0; 95% CI, 0.78–5.3), and hypospadias (aOR. 2.4; 95% CI, 0.62–9.0), and for carbamazapine in relation to NTDs (aOR, 5.0; 95% CI, 1.9–12.7). Epilepsy history without AED use did not seem to increase risk.
Valproic acid, which current guidelines suggest should be avoided in pregnancy, was most notable in terms of strength and breadth of its associations. Carbamazapine was associated with NTDs, even after controlling for folic acid use. Sample sizes were still too small to adequately assess risks of less commonly used AEDs, but our findings support further study to identify lower risk options for pregnant women.
Teratogenic Effects of Antiepileptic Medications
2009, Neurologic Clinics

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Original contributionsMaternal carbamazepine and infant spina bifida

Abstract

Reprod Toxicol

Lancet

Lancet

Spina bifida in infants of women treated with carbamazepine during pregnancy

New Engl J Med

Original contributions
Maternal carbamazepine and infant spina bifida