High dose folic acid supplementation in women with epilepsy: Are we sure it is safe?

Open ArchivePublished:March 07, 2015DOI:https://doi.org/10.1016/j.seizure.2015.02.030

      Highlights

      • All women with epilepsy and of childbearing potential should be supplemented with folic acid.
      • There are potentially significant drug interactions between high doses of folic acid and some AEDs.
      • High levels of folic acid throughout gestation may produce neural network hyperexcitability in the offspring.
      • It is not suggested to advocate high dose folic acid supplementation in women with epilepsy.

      Abstract

      Most experts agree that folic acid supplementation is a key preconception intervention, particularly in women with epilepsy who take anti-epileptic drugs (AEDs). Primary prevention of neural tube defect through folic acid supplementation results in reduction of risk in an otherwise healthy population. The current folic acid supplementation recommendation is that all women of childbearing potential be supplemented with at least 0.4 mg of folic acid daily prior to conception and during pregnancy. It is recommended that all women with epilepsy and of childbearing potential be supplemented with folic acid daily prior to conception and during pregnancy. However, considering the potential significant drug–drug interactions between high doses of folic acid and some AEDs in patients with epilepsy and also with the emerging evidence from animal studies that high levels of folic acid throughout gestation may have adverse effects on fetal brain development, it is not suggested to advocate high dose folic acid supplementation in women with epilepsy until more information is available about its appropriate, safe and optimal dosing.

      Keywords

      1. Introduction

      Primary prevention of neural tube defect through folic acid supplementation results in 62% (95% CI: 49–71%) reduction of risk in an otherwise healthy population [
      • Blencowe H.
      • Cousens S.
      • Modell B.
      • Lawn J.
      Folic acid to reduce neonatal mortality from neural tube disorders.
      ]. The current folic acid supplementation recommendation is that all women of childbearing potential be supplemented with at least 0.4 mg of folic acid daily prior to conception and during pregnancy [
      • Harden C.L.
      • Pennell P.B.
      • Koppel B.S.
      • Hovinga C.A.
      • Gidal B.
      • Meador K.J.
      • et al.
      Management issues for women with epilepsy – focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
      ]. Most experts agree that folic acid supplementation is a key preconception intervention, particularly in women with epilepsy who take anti-epileptic drugs (AEDs) [
      • Shannon G.D.
      • Alberg C.
      • Nacul L.
      • Pashayan N.
      Preconception healthcare and congenital disorders: systematic review of the effectiveness of preconception care programs in the prevention of congenital disorders.
      ]. In this review, I will try to emphasize that there is insufficient information to address the optimal dosing of folic acid supplementation in women with epilepsy, who take AEDs.

      2. Folic acid supplementation in women with epilepsy

      In 2009, a committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy during pregnancy, including preconceptional folic acid supplementation. They concluded that the risk of major congenital malformations in the offspring of women with epilepsy is possibly decreased by folic acid supplementation (two adequately sensitive Class III studies) and they recommended that preconceptional folic acid supplementation in women with epilepsy may be considered to reduce the risk of major congenital malformations (Level C) [
      • Shannon G.D.
      • Alberg C.
      • Nacul L.
      • Pashayan N.
      Preconception healthcare and congenital disorders: systematic review of the effectiveness of preconception care programs in the prevention of congenital disorders.
      ]. They also stated that “there was insufficient published information to address the dosing of folic acid and whether higher doses offer greater protective benefit to women with epilepsy taking AEDs” [
      • Shannon G.D.
      • Alberg C.
      • Nacul L.
      • Pashayan N.
      Preconception healthcare and congenital disorders: systematic review of the effectiveness of preconception care programs in the prevention of congenital disorders.
      ]. However, women with epilepsy are often recognized as a high risk group and guidelines consistently recommend prescription of high doses (up to 5 mg/day) of folic acid supplementation in this population [
      • Morrow J.I.
      • Hunt S.J.
      • Russell A.J.
      • Smithson W.H.
      • Parsons L.
      • Robertson I.
      • et al.
      Folic acid use and major congenital malformations in offspring of women with epilepsy: a prospective study from the UK Epilepsy and Pregnancy Register.
      ,
      • Kjaer D.
      • Horvath-Puhó E.
      • Christensen J.
      • Vestergaard M.
      • Czeizel A.E.
      • Sørensen H.T.
      • et al.
      Antiepileptic drug use, folic acid supplementation, and congenital abnormalities: a population-based case–control study.
      ]. One of the putative reasons for recommending high doses of folic acid in women with epilepsy is probably the fact that, women taking AEDs are at greater risk for low folate serum levels compared to the general population [
      • Dansky L.V.
      • Rosenblatt D.S.
      • Andermann E.
      Mechanisms of teratogenesis: folic acid and antiepileptic therapy.
      ,
      • Spiegelstein O.
      • Merriweather M.Y.
      • Wicker N.J.
      • Finnell R.H.
      Valproate-induced neural tube defects in folate-binding protein-2 (Folbp2) knockout mice.
      ]. Treatment with cytochrome P-450 enzyme-inducing AEDs (e.g., carbamazepine, phenytoin) is known to interfere with folate metabolism [
      • Dansky L.V.
      • Rosenblatt D.S.
      • Andermann E.
      Mechanisms of teratogenesis: folic acid and antiepileptic therapy.
      ]. Valproic acid may also interfere with folate metabolism [
      • Spiegelstein O.
      • Merriweather M.Y.
      • Wicker N.J.
      • Finnell R.H.
      Valproate-induced neural tube defects in folate-binding protein-2 (Folbp2) knockout mice.
      ]. Gestational folate deficiency has been associated with abnormal growth and development in both experimental animal and human studies and has been postulated as a putative mechanism for the teratogenic effects of AEDs. In one study, blood folate levels decreased with increasing plasma AED levels and with the number of AEDs. Low blood folate levels before and/or early in pregnancy were significantly associated with spontaneous abortion and the occurrence of developmental anomalies in the offspring [
      • Dansky L.V.
      • Rosenblatt D.S.
      • Andermann E.
      Mechanisms of teratogenesis: folic acid and antiepileptic therapy.
      ]. Therefore, it is reasonable to recommend that “preconceptional folic acid supplementation in women with epilepsy may be considered to reduce the risk of major congenital malformations” [
      • Shannon G.D.
      • Alberg C.
      • Nacul L.
      • Pashayan N.
      Preconception healthcare and congenital disorders: systematic review of the effectiveness of preconception care programs in the prevention of congenital disorders.
      ].

      3. Other benefits of folic acid supplementation

      In one study of 388 pregnancies in 244 patients, pregnancies with folic acid supplementation showed significant reduction of spontaneous abortion. The occurrence of a spontaneous abortion was much lower in women taking folic acid during pregnancy. Of women with folic acid supplementation, 9 out of 160 pregnancies (5.7%) experienced spontaneous abortion. In women without supplementation, 30 (13.2%) spontaneous abortions out of 228 pregnancies occurred. Odds ratio for spontaneous abortion was 2.6 (95% CI: 1.2–5.6, P = 0.01) for women with no folic acid supplementation. With regard to the dosage of folic acid supplement, the group of pregnancies with low dosage (0.4 mg/day; n = 33) showed no spontaneous abortion. All spontaneous abortions with concomitant folic acid supplementation occurred in the group with high folic acid supplementation dosage (5 mg/day; n = 127) [
      • Pittschieler S.
      • Brezinka C.
      • Jahn B.
      • Trinka E.
      • Unterberger I.
      • Dobesberger J.
      • et al.
      Spontaneous abortion and the prophylactic effect of folic acid supplementation in epileptic women undergoing antiepileptic therapy.
      ]. In another study, the effects of fetal AED exposure on verbal versus non-verbal abilities at 3 years of age were investigated. The authors concluded that, verbal abilities were lower than non-verbal in children exposed in utero to AEDs. Preconceptional folate use was associated with higher verbal outcomes. Mean for verbal index score adjusted for factors in the primary analysis model was 94 for children exposed to preconceptional folate, which differed from children not exposed (P = 0.01), who had mean of 89. Adjusted means for non-verbal index were 102 for children exposed to preconception folate versus 100 for those who were not exposed, which did not differ statistically [
      • Meador K.J.
      • Baker G.A.
      • Browning N.
      • Cohen M.J.
      • Clayton-Smith J.
      • Kalayjian L.A.
      • et al.
      Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age.
      ]. In another study, it was observed that low dose of folate supplementation may prevent carbamazepine-induced leukopenia or anemia in patients with epilepsy. As other AEDs may also reduce folate levels, these drugs may also be responsible for the development of anemia in patients with epilepsy. This may be avoided by prophylactic administration of folic acid to patients with epilepsy, who will be on long-term AED treatment [
      • Asadi-Pooya A.A.
      • Ghetmiri E.
      Folic acid supplementation reduces the development of some blood cell abnormalities in children receiving carbamazepine.
      ].

      4. Potential adverse effects of folic acid supplementation

      There are multiple case studies about drug–drug interactions between folic acid and some of the AEDs. In one study, the effect of folic acid (1 mg/day orally) on phenytoin steady-state pharmacokinetics was studied in four male folate-deficient patients with epilepsy. Blood and urine samples were collected just before and after 180 or 300 days of folic acid administration. After the addition of folic acid, total phenytoin plasma concentration decreased 7.5–47.6% in three of the four patients. Ratios of urinary metabolites to parent drug increased in those patients showing a decrease in plasma phenytoin caused by folic acid supplementation. This indicated that a folic acid-associated increase in phenytoin oxidative metabolism had occurred [
      • Berg M.J.
      • Fisher L.J.
      • Rivey M.P.
      • Vern B.A.
      • Lantz R.K.
      • Schottelius D.D.
      Phenytoin and folic acid interaction: a preliminary report.
      ]. In another study, seven adult male folate-deficient patients with epilepsy on phenytoin alone were supplemented with 1 mg daily oral folic acid. The total serum phenytoin concentration decreased significantly by an average of 22.6 ± 13.0% [
      • Berg M.J.
      • Ebert B.E.
      • Rivey M.P.
      • Schottelius D.D.
      Utilization of Km for phenytoin dosage after folate addition to patient regimen.
      ]. In one case report, serum phenytoin level of a patient who was seizure free for 3 years on 300 mg/day phenytoin, decreased from12.4 mg/L to 4.5 mg/L, 1 day after the addition of 5 mg/day folic acid to treat his macrocytic anemia. He experienced two generalized tonic-clonic seizures [
      • Steinweg D.L.
      • Bentley M.L.
      Seizures following reduction in phenytoin level after orally administered folic acid.
      ]. Pharmacokinetic studies of this interaction strongly suggest that folic acid is a cofactor in the metabolism of phenytoin. Higher levels of folate appear to increase the affinity of metabolizing enzymes, thus greatly increasing the efficiency of phenytoin degradation [
      • Steinweg D.L.
      • Bentley M.L.
      Seizures following reduction in phenytoin level after orally administered folic acid.
      ]. Another case report, described a patient with megaloblastic anemia who developed an increase in seizure frequency with a reduction in carbamazepine and phenobarbital serum levels following treatment with folic acid [
      • O’Hare J.
      • O’Driscoll D.
      • Duggan B.
      • Callaghan N.
      Increase in seizure frequency following folic acid.
      ]. Information about potential drug–drug interactions between folic acid supplementation and new AEDs is lacking.
      In addition to the above-mentioned potential drug–drug interactions between folic acid supplementation and AEDs in mother, folate might directly affect the developing brain of the fetus. Normally, the placenta concentrates folic acid into the fetal circulation; as a result the fetal levels are 2–4 times higher than the maternal levels; fetus requires this nutrient for its rapid growth and cell proliferation [
      • Hutson J.R.
      • Stade B.
      • Lehotay D.C.
      • Collier C.P.
      • Kapur B.M.
      Folic acid transport to the human fetus is decreased in pregnancies with chronic alcohol exposure.
      ]. In a recent animal study, the authors administered large doses of folic acid to rats before and during gestation and found that their offspring had a 42% decrease in their seizure threshold [
      • Girotto F.
      • Scott L.
      • Avchalumov Y.
      • Harris J.
      • Iannattone S.
      • Drummond-Main C.
      • et al.
      High dose folic acid supplementation of rats alters synaptic transmission and seizure susceptibility in offspring.
      ]. The authors used both in vivo and in vitro rodent paradigms. In an in vivo latency-to-seizure assay they found that intake of folic acid by pregnant rats resulted in offspring which had seizures twice as fast as controls when challenged by a condition which destabilized their neural activity. To further investigate this phenomenon, they established an in vitro neuronal culture assay system and showed that cultures grown in the presence of functional metabolite of folic acid (4Hfolate) have a reduced capacity to re-regulate network activity patterns following a perturbation, a result similar in principle to their in vivo study. Their experiments demonstrated that folic acid and its derivatives can alter connectivity and dynamics in a way that produces a lack of network stability or the hyperexcitability of individual neurons [
      • Girotto F.
      • Scott L.
      • Avchalumov Y.
      • Harris J.
      • Iannattone S.
      • Drummond-Main C.
      • et al.
      High dose folic acid supplementation of rats alters synaptic transmission and seizure susceptibility in offspring.
      ]. They speculated that, “by virtue of its relationship to the excitatory neurotransmitter l-glutamate, folic acid present at continued high levels during neuronal development causes an increase in neuronal activity. This in turn accelerates the developmental of neuronal connectivity, which then leads to a hyperexcitable network” [
      • Girotto F.
      • Scott L.
      • Avchalumov Y.
      • Harris J.
      • Iannattone S.
      • Drummond-Main C.
      • et al.
      High dose folic acid supplementation of rats alters synaptic transmission and seizure susceptibility in offspring.
      ]. However, these results should be interpreted with caution. The doses used in this animal study were substantially higher than that taken by humans (even at 5 mg/day). Therefore, it is difficult to extrapolate these data to humans. In another animal study, the authors investigated the impact of high folate intake on embryonic development in mice. Pregnant mice on a control diet (CD; recommended intake of folic acid for rodents) or folic acid-supplemented diet (FASD; 20-fold higher than the recommended intake) were examined for post-coitum embryonic loss and delay. Total plasma folate was 10-fold higher in FASD compared to CD mice. The authors observed that, the FASD was associated with embryonic delay and growth retardation. They concluded that high folate intake may have adverse effects on fetal mouse development [
      • Pickell L.
      • Brown K.
      • Li D.
      • Wang X.L.
      • Deng L.
      • Wu Q.
      • et al.
      High intake of folic acid disrupts embryonic development in mice.
      ].

      5. Conclusion

      Preconceptional folic acid supplementation in women with epilepsy may be considered to reduce the risk of congenital malformations. Therefore, it is recommended that all women with epilepsy and of childbearing potential be supplemented with folic acid daily prior to conception and during pregnancy. However, considering the potential significant drug–drug interactions between high doses of folic acid and some AEDs in patients with epilepsy and also with the emerging evidence from animal studies that high levels of folic acid throughout gestation may have adverse effects on fetal brain development, it is not suggested to advocate high dose folic acid supplementation in women with epilepsy until more information is available about its appropriate, safe and optimal dosing.

      Conflict of interest statement

      None.

      Acknowledgment

      No funding was received for this work.

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