Clinical Pharmacology

"Adverse Drug Event of the month"

Carbamazepine and Open Neural Tube Defect- a case of anti-epileptic drug induced teratogenecity

Case report:
A 25 year old female patient G3 P2 A1 L1with a history of epilepsy of 3 years duration presented to Therapeutic Drug Monitoring OPD of KEM hospital for estimation of serum carbamazepine (CBZ) levels. Patient was diagnosed as a case of neurocysticercosis in December 2001 and was taking CBZ in the dose of 200 mg thrice daily since then. While on therapy the patient conceived in the month of November 2003. During pregnancy, CBZ was advised in the same dose after weighing the risk and benefits of antiepileptic therapy along with 5mg of folic acid per day and patient was informed about the risks.

The patient did not follow up subsequently and directly presented at the 8 months of gestation. Ultrasonography done at that time showed the fetus to have Arnold Chiari malformation. The patient delivered a male child on 23/09/04 by lower segment cesarean section (LSCS). The newborn weighed 2.45 kg with Total Length (TL) of 49cm and Head Circumference (HC) of 32 cm. On examination, child was noted to have a 4cm x 4 cm open neural tube defect in lumbar region with cerebrospinal fluid (CSF) leak and bowel bladder incontinence. There was no associated craniofacial or finger nail malformation.

In the mother, prenatal serum CBZ (9.24 mg/ml) and CBZ epoxide (2.53) levels were within therapeutic range. (The therapeutic range of CBZ being 4 mg/ml to 12 mg/ml.) After 15 days of delivery serum CBZ levels for mother were 15.24 mg/ml and CBZ epoxide levels were 2.62 mg/ml while for the child CBZ levels were 1.93 mg/ml and CBZ epoxide was not measurable. Parents refused neurosurgical intervention in view of guarded prognosis and patient was discharged home on 17/09/04.

Eight years prior the patient had delivered a female child, when she was not on CBZ therapy and the child was born without any congenital anomalies.

Discussion
Carbamazepine (CBZ) is an iminostilbene derivative chemically related to tricyclic antidepressants. CBZ is used as an antiepileptic in treatment of generalized tonic clonic seizures as well as simple and complex partial seizures. It is also used for patients with manic-depressive illness, postherpetic and trigeminal neuralgia and phantom limb pain (1).
Infants of epileptic mothers are at two-fold greater risk of major congenital malformations than offsprings of nonepileptic mothers that is 4% to 8% compared to 2% to 4%. These malformations include congenital heart defects, open neural tube defects, craniofacial abnormalities and others.

Common teratogenic effects of CBZ include small head circumference, finger and toe nail hypoplasia, craniofacial defects, mild mental retardation and developmental delay (2). Incidence of Neural tube defect in general population is 0.1% where as exposure to CBZ in utero without concurrent exposure to valproic acid carries 1% risk of neural tube defect (10 times that of general population) (3).

Causal role for anticonvulsants in congenital malformations is suggested by association of congenital defects with higher concentration of the drug or polytherapy as compared to monotherapy (1) One possible factor is decreased activity of the enzyme epoxide hydrolase with resulting increased concentration of CBZ epoxide, which may be teratogenic (4). Also in pregnancy, metabolism of carbamazepine is increased so that increased epoxide metabolites are generated and these epoxide radicals are known to be teratogenic. Lymphocyte toxicity test is done to evaluate the epoxide hydrolase status of the patient. However this test could not be performed in the patient.

During pregnancy, risks and benefits of antiepileptic therapy should be weighed carefully as discontinuation of treatment itself may pose risk to mother as well as fetus. Current guidelines suggest use of a single antiepileptic drug with the lowest effective dose and frequent monitoring of serum levels. The incidence of teratogenicity with Primidone is highest (14.3 %) followed by valproate (11.1%), phenytoin (9.1%), carbamazepine (5.7%) and phenobarbital (5.1%) (5).

Adequate prepregnancy councelling is essential for women who have epilepsy. Women who become pregnant should be advised of the availability of noninvasive screening tests and invasive diagnostic tests for congenital birth defects (including NTDs). Procedures for prenatal diagnosis include: (i) assessment of serum markers such as maternal serum alpha-foetoprotein and acetylcholinesterase activity at 15 to 20 weeks; (ii) prenatal Ultrasonography at 16 to 20 weeks; and (iii) amniocentesis after 15 weeks of pregnancy if a positive screening test is present. The levels of these two serum markers are increased in neural tube defects and a value of more than two multiples of the median is considered significant. Detailed counseling of the couple needs to be an integral part of the prenatal screening programme (6, 7)

Women in intermediate- to high-risk categories for NTDs (NTD-affected previous pregnancy, family history, insulin-dependent diabetes, epilepsy treatment with valproic acid or carbamazepine) should be advised high-dose folic acid (4.0 mg-5.0 mg daily) supplementation. This should be taken as folic acid alone, not in a multivitamin format, due to risk of excessive intake of other vitamins such as vitamin A (8)

References
1. Mcnamara J D. Drugs effective in treatment of epilepsies. In: Hardman JG, Limbird LE, Gilman AG, editors. Goodman & Gilman’s The pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill, Medical Publishing Division; 2001. p. 461-487.

2. Dollery C,Boobis A,Rawlins M,Thomas S,Wilkins M, editors. In:Therapeutic Drugs. 2nd ed. UK:Churchill Livingston Company,1986. p. C44-7.

3. Rosa FW. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med. 1991;324:674-7.

4. Ornoy A, Cohen E. Outcome of children born to epileptic mothers treated with carbamazepine during pregnancy. Archives of Diseases in Childhood 1996; 75 517-520

5. Kaneko S, Battino D, Anderman E, Wada K, Kan R, Takeda A, et al. Congenital Malformation due to antiepileptic drugs. Epilepsy Res 1989:33;145-58.

6. Wilson RD, Davies G, Desilets V, Reid GJ, Summers A, Wyatt P et al. The use of folic acid for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can 2003;25:959-73.

7. Rajesh R, Thomas SV. Prenatal screening for neural tube defects. Natl Med J India 2001;14:343-6.

8. Nulman I, Laslo D, Koren G. Treatment of epilepsy in pregnancy. Drugs 1999;57:535-44.


Department of Clinical Pharmacology,
Department of Obstetrics and Gynecology
Department Of Medicine
Seth G S Medical College and KEM Hospital,
Mumbai.