Hyperhomocysteinaemia in children receiving phenytoin and carbamazepine monotherapy: a cross-sectional observational study

Arch Dis Child. 2017 Apr;102(4):346-351. doi: 10.1136/archdischild-2016-311436. Epub 2016 Nov 7.


Objective: Long-term therapy with phenytoin and carbamazepine is known to cause hyperhomocysteinaemia. We evaluated the prevalence of hyperhomocysteinaemia in North Indian children receiving phenytoin or carbamazepine monotherapy for >6 months duration and the effect of folic acid supplementation on plasma homocysteine.

Methods: In this cross-sectional observational study we enrolled consecutive children aged 2-12 years with epilepsy who had received phenytoin or carbamazepine monotherapy for >6 months. Plasma total homocysteine, folic acid, vitamin B12 and antiepileptic drug concentrations were measured. Healthy age- and sex-matched controls were recruited. Children with homocysteine >10.4 µmol/L received folic acid supplementation for 1 month and homocysteine and folic acid concentrations were measured after 1 month follow-up.

Results: A total of 112 children receiving antiepileptic monotherapy for >6 months were enrolled. Hyperhomocysteinaemia was present in 54 children (90%) receiving phenytoin, 45 children (90%) receiving carbamazepine therapy and 17 (34%) controls (p<0.05). Mean plasma homocysteine concentrations were significantly higher (18.9±10.2 vs 9.1±3 µmol/L) and serum folic acid concentrations (10.04±8.5 ng/ml vs 12.6±4.8 p<0.001) and vitamin B12 concentrations (365±155 pg/mL vs 474±332 pg/mL, p=0.02) were significantly lower in the study group compared with the control group. Duration of antiepileptic drug therapy correlated significantly with elevated homocysteine and reduced folic acid concentrations (p<0.05). Supplementation with folic acid for 1 month led to a reduction in plasma homocysteine concentrations in the study group (from 20.9±10.3 µmol/L to 14.2±8.2 µmol/L, p<0.05).

Conclusions: Phenytoin or carbamazepine monotherapy for >6 months duration is associated with hyperhomocysteinaemia in 90% of North Indian children. Elevated homocysteine concentrations were normalised in these children with folic acid supplementation.

Keywords: Carbamazepine; Epilepsy; Folic Acid; Hyperhomocysteinemia; Phenytoin.

Publication types

  • Observational Study

MeSH terms

  • Anticonvulsants / adverse effects*
  • Carbamazepine / adverse effects*
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Cross-Sectional Studies
  • Epilepsy / drug therapy
  • Female
  • Folic Acid / therapeutic use
  • Humans
  • Hyperhomocysteinemia / chemically induced*
  • Long-Term Care
  • Male
  • Phenytoin / adverse effects*
  • Vitamin B Complex / therapeutic use


  • Anticonvulsants
  • Vitamin B Complex
  • Carbamazepine
  • Phenytoin
  • Folic Acid