Abstract
For infants exposed to antiepileptic drugs (AEDs) in utero, the risk for congenital malformations is approximately 4 to 6%, twice the rate reported in the general population. A variety of malformations have been reported in association with prenatal exposure to AEDs. However, a particular association of valproate and carbamazepine with neural tube defects (NTDs)—specifically, with spina bifida aperta (SB)—has been identified. The prevalence of SB is approximately 1 to 2% with valproate exposure and 0.5% with carbamazepine. Reported risk factors for NTDs include previous pregnancy with an NTD, maternal insulin-dependent diabetes mellitus, various nutritional deficiencies and occupational exposures, and high prepregnancy weight. Deficiencies of folate have been implicated in the development of birth defects, including NTDs. The value of periconceptional folic acid supplementation for women in the general population is accepted. However, it is unclear whether folic acid supplementation protects against the embryotoxic and teratogenic effects of AEDs because animal and human studies and case reports have shown variable results. Nevertheless, folic acid supplementation is recommended for women with epilepsy as it is for other women of childbearing age. Even with supplementary folic acid, women taking valproate or carbamazepine should undergo perinatal diagnostic ultrasound to rule out NTDs.
The majority of women with epilepsy bear normal, healthy children. However, women with epilepsy have an increased risk for adverse pregnancy outcomes, of which congenital malformations are the most widely reported. In 1963, the first report of a malformation associated with antiepileptic drugs (AEDs) described a child exposed to mephenytoin in utero who developed microcephaly, cleft palate, a speech defect, and an IQ of 60.1 Speidel and Meadow2 initiated a retrospective survey of 427 pregnancies in 186 women with epilepsy and found increased rates of malformations for infants of mothers with epilepsy (IME). They concluded that (a) congenital malformations were twice as common in infants exposed to AEDs in utero; (b) no single abnormality was specific for AED exposure; and (c) a group of these children had a characteristic pattern of anomalies that, at its fullest expression, consisted of trigonocephaly, microcephaly, hypertelorism, low-set ears, short neck, transverse palmar creases, and minor skeletal abnormalities.
Infants exposed to AEDs in utero are twice as likely to develop birth defects as infants not exposed to these drugs. Malformation rates in the general population range from 2 to 3%. Reported malformation rates in various populations of exposed infants range from 1.25 to 11.5%.3-10⇓⇓⇓⇓⇓⇓⇓ These combined estimates yield a 4 to 6% risk for malformations in a pregnancy of a woman with epilepsy.
Specific AEDs and neural tube defects.
A variety of congenital malformations have been reported, with a particular preponderance of orofacial clefts. Almost every AED has been associated with the increased risk, yet most of these drugs do not produce any specific pattern of major malformations.
Sodium valproate and carbamazepine may be exceptions. They have been independently associated with the development of neural tube defects (NTDs). Robert and Guibaud11 were the first to make this association. Working in a birth defects registry in the Rhône Alps region of France, they reported NTDs in IME exposed to valproic acid in utero. More recent studies have revealed an association between carbamazepine exposure in utero and NTDs.12-14⇓⇓ Subsequent evaluations of these exposures identified spina bifida aperta (SB) as the specific NTD associated with valproic acid or carbamazepine exposure.15 Methodologic problems make frequency estimates imprecise because most published data are case reports, case series, or very small cohorts from registries that were not designed to evaluate pregnancy outcomes. The prevalence of SB with valproate exposure is approximately 1 to 2%16 and with carbamazepine 0.5%.12,17⇓ However, a prospective study in the Netherlands found that IME exposed to valproate had a 5.4% prevalence rate of SB.18 Average daily maternal valproate doses were higher for the IME with SB (1,640 ± 136 mg/day) than for the unaffected IME (941 ± 48 mg/day). Another group of investigators has found that valproate doses of 1,000 mg/day or less or plasma concentrations of 70 μg/mL or less are unlikely to cause malformations.10
Pathophysiology of neural tube defects.
NTDs are uncommon malformations, occurring in 6/10,000 pregnancies. Spina bifida and anencephaly are the most commonly reported NTDs and affect approximately 4,000 pregnancies, resulting in 2,500 to 3,000 births in the United States each year.19,20⇓ The types of NTD associated with AED exposure are primarily myelomeningocele and anencephaly, which are the result of abnormal neural tube closure between the third and fourth weeks of gestation.
Previous thinking about NTDs visualized the fusion of the neural tube as a process in which the lateral edges met in the middle and fused both rostrally and caudally, similar to a bidirectional zipper. Recent studies have suggested that there are multiple sites for neural tube closure21,22⇓ and that different etiologies may lead to different types of abnormality.
There are four separate sites along the neural tube at which neurulation develops. The first is midcervical. The second is at the cranial junction of the prosencephalon and mesencephalon. The third is at the site of the future mouth, or stomodeum. This region fuses in a caudal direction only. The fourth is the region over the rhombencephalon, between the second and third regions.21
There are differences in the specific sites and timing of each individual closure region. The majority of human NTDs can be explained by failure at one or more closure sites. Anencephaly with frontal and parietal defects is due to failure at closure site two. Holocrania, which also involves defects of the posterior cranium extending to the foramen magnum, is due to failure of closure of areas two and four. Lumbar SB results from failure at closure site one. The development of closure sites appears to be under genetic control and also to be affected by environmental factors. In twins, concordance rates are only 56% for anencephaly and 71% for SB. In Great Britain there is a male preponderance of lumbar SB and a female preponderance of holocrania and anencephaly. Valproic acid even appears to have species-differential effects, being associated with SB in humans and exencephaly in mice.23
A number of risk factors are associated with NTDs. A previous pregnancy with an NTD has the strongest association, with a relative risk (RR) of 10. There are strong ethnic and geographic associations with NTDs. Rates per 1,000 are 0.22 for whites, 0.58 for persons of Hispanic descent, and 0.08 for persons of African descent. The incidence of NTDs in Mexico is 3.26/1,000, whereas for Mexican-born persons living in California it is 1.6/1,000 and for United States-born persons of Mexican descent it is 0.68/1,000.24 Mothers with insulin-dependent diabetes mellitus have a 7.9-fold increased rate of NTDs in their offspring.25 Deficiencies of glutathione, folate, vitamin C, riboflavin, zinc, cyanocobalamin, and selenium and excessive exposure to vitamin A have been associated with NTDs. Higher rates are seen in children of farmers, cleaning women, and nurses.26,27⇓ Prepregnancy weight has also been demonstrated to be a factor. Werler et al.28 compared RR for NTDs in control women weighing 50–59 kg and found that the RR increased to 1.9 for women weighing 80–89 kg and to 4.0 for those weighing more than 110 kg. AEDs may be a necessary but not sufficient risk factor for the development of NTDs.
Folate deficiency as a potential mechanism of AED teratogenicity.
Folate is a coenzyme necessary for the development of white and red blood cells and proper function of the CNS. Normal concentrations are typically measured in the serum (SF = 6–20 ng/mL) and erythrocytes (RBCF = 160–640 ng/mL). Low levels of folate are associated with hyperhomocysteinemia, and concentrations required to prevent this are 6.6 ng/mL for SF and 140 ng/mL for RBCF.
Deficiencies of folate have been implicated in the development of birth defects. Dansky et al.29 found significantly lower blood folate concentrations in women with epilepsy with abnormal pregnancy outcomes. Co-treatment of mice with folic acid, with or without vitamins and amino acids, reduced malformation rates and increased fetal weight and length in mouse pups exposed to phenytoin in utero.30 Biale and Lewenthal31 reported a 15% malformation rate in newborns of mothers who took AEDs with no folic acid supplementation (10 of 66 children), whereas none of the 33 children of mothers who received folic acid supplementation in addition to their AED regimens had congenital abnormalities. Eight trials have demonstrated that periconceptional folic acid reduces the risk for recurrence of NTDs in women with a previous affected pregnancy (table). 28,32-39⇓⇓⇓⇓⇓⇓⇓⇓
Studies of periconceptional folic acid supplementation and risk for recurrent NTDs
Unfortunately, periconceptional folic acid supplementation may not be protective for women with epilepsy. Craig et al.40 reported the case of a young woman whose seizures were controlled for 4 years by 2,000 mg/day of valproic acid. Although she took 4 mg/day of folic acid for 18 months before her pregnancy, she delivered a child with a lumbosacral NTD, a ventricular and atrial septal defect, cleft palate, and bilateral talipes. Two Canadian women delivered children with NTDs despite folic acid supplementation.41 One woman, taking 3.5 mg/day of folic acid for 3 months before conception and 1,250 mg/day of valproic acid, aborted a child with lumbosacral SB, Arnold-Chiari malformation, and hydrocephalus. A second woman who took 5 mg/day of folic acid had one spontaneous abortion of a fetus with an encephalocele and two therapeutic abortions of fetuses with lumbosacral SB. These cases might have been predicted, given the demonstrated failure of folate to reduce NTD frequency and embryotoxicity in vitro and in vivo in rodent models.42,43⇓ In fact, not all research supports the association of folate deficiency with malformations. Mills et al.44 found no difference between serum folate levels in mothers of children with NTDs and controls. A number of other studies failed to demonstrate a protective effect of periconceptional folic acid supplementation.45-50⇓⇓⇓⇓⇓ These studies are problematic, however, because of small sample sizes, failure to document folic acid supplementation, and recall bias in the retrospective investigations.
There is evidence suggesting that women with similar folate intakes may have different serum concentrations because of differences in folate metabolism. Absorption does not account for the difference in plasma concentration between cases and controls.51
Conclusion.
The utility of folic acid supplementation for the general population is clearly established. Whether or not it reduces risk for women with epilepsy taking AEDs is unclear. The recommended daily allowances of folic acid have been increased to 400 μg/day for nonpregnant women, 600 μg/day for pregnant women, and 500 μg/day for lactating women. The increased folate catabolism during pregnancy, coupled with the variation in requirements among individual women, has led some to call for higher folic acid supplementation on the order of 500–600 μg/day.52 Women with epilepsy, as well as all women of childbearing age, should receive folic acid supplementation. The dosage recommended by the Centers for Disease Control and Prevention,53 400 μg/day, may not be high enough for many women who do not metabolize folate effectively. Even with folic acid supplementation, women taking valproate or carbamazepine should avail themselves of prenatal diagnostic ultrasound to rule out NTDs.
Footnotes
-
Publication of this supplement was supported by an unrestricted educational grant from GlaxoSmithKline. The sponsor has provided M.S.Y. with personal honoraria during his career.
References
Disputes & Debates: Rapid online correspondence
- Management issues for women with epilepsy: Neural tube defects and folic acid supplementation
REQUIREMENTS
If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.