Pregnancy, folic acid, and antiseizure medication

Folate, also known as vitamin B₉, is a naturally occurring essential nutrient found in a variety of foods, including vegetables, fruits, seafood, eggs, dairy products, meat, and grains. Folic acid on the other hand, represents the synthetic and biochemically more stable form of folate, used in supplements and fortified foods. It is converted to folate upon absorption. The nutrient enters the folate cycle and is converted to the metabolically active 5‑methyltetrahydrofolate (MTHF). In conjunction with cobalamin (vitamin B₁₂), MTHF is necessary for the remethylation of homocysteine to produce methionine, an important methyl donor. Without MTHF, cobalamin, riboflavin (vitamin B₂), and pyridoxine (vitamin B₆), homocysteine concentrations increase. Serum folate (MTHF) is the primary marker of folate status. Food intake before blood sampling may affect folate concentrations. Red blood cell folate is considered a better indicator of body stores and nutritional status, but the reliability of the analytical methods is questioned, and many laboratories no longer offer this analysis. Homocysteine is the metabolic marker of folate status. Homocysteine concentrations start to rise when serum folate falls below 25–27 nmol/L, indicating an insufficient intracellular folate status [12]. Folate concentrations depend on the intake of folate through the diet, on the intake of folic acid in fortified food and in supplements, as well as on individual factors such as body mass index, socioeconomic factors, country, and race/ethnicity [11]. When folic acid intake is excessive, unmetabolized folic acid (UMFA) can accumulate in plasma. Genetic risk factors also determine folate status. These are common and include single-nucleotide polymorphisms (SNPs) in genes regulating the one-carbon metabolism. Such SNPs may disturb vitamin B uptake, transport, and enzymatic activity, causing an increased demand for folate intake [13]. The most important SNP is the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T genotype, which reduces enzyme activity by 50% in homozygous persons and causes low folate concentrations and homocysteinemia [13].

Folate demand increases during pregnancy due to the rapid growth of the fetus, the placenta, and the maternal tissue. Folate deficiency during pregnancy is associated with maternal anemia as well as poor implantation and vascularization of the placenta and subsequently with spontaneous abortions, preterm birth, preeclampsia, fetal growth restriction, and other placenta-related pregnancy complications [3]. Folate deficiency is also associated with congenital malformations such as neural tube and cardiac defects as well as neurodevelopmental disorders such as autism spectrum disorder [14]. The exact mechanisms involved are largely unknown, but suggested mechanisms are alterations in DNA and RNA synthesis, accumulation of toxic concentrations of homocysteine, and altered gene methylation [3].

In the general population, periconceptional folic acid supplementation prevents neural tube defects [3]. Therefore, the World Health Organization (WHO) recommends all persons planning pregnancy to take 0.4 mg folic acid supplements daily preconceptionally and throughout pregnancy. Recent studies reported that periconceptional folic acid supplementation was associated with a decreased risk of adverse neurodevelopment in the children, such as autism spectrum disorders and language impairment, and with improved cognitive performance [15]. As unplanned pregnancies are common and adherence to the supplement guidelines low, in many countries—including the United States (US) and since 2021 the United Kingdom—it is mandatory to fortify certain foods with folic acid [16]. After initiating this program, the frequency of neural tube defects decreased in the US [11]. Most other Western and Nordic European countries do not fortify foods with folic acid. However, since the individual folate need depends on many factors, supplementation according to the serum folate concentration is emphasized by guidelines for persons with childbearing potential in the general population and is recommended by the WHO [11]. The recommendations are based on high-quality data regarding the association between folate concentrations and neural tube defects. Serum folate concentrations of > 28–30 nmol/L or red blood cell folate concentrations > 906 nmol/L have been extensively evaluated in pregnant populations, and there is clear evidence that maternal red blood cell folate concentrations > 906 nmol/L protect against folic acid-related neural tube defects in the fetus [15]. Persons from the general population may reach a preventive red blood cell folate concentration of more than 906 nmol/L within 4 weeks of supplementation with a daily intake of 800 µg folic acid [17]. The prevalence of having a red blood cell folate concentration of < 906 nmol/L was 35% after 40 weeks with a daily folic acid supplement of 140 µg and 18% with 400 µg [18].

Some ASMs interact with the uptake and metabolism of folate, especially those that induce cytochrome P450 enzymes [19]. Carbamazepine, phenobarbital, phenytoin, and primidone increase folate catabolism, which in turn may impede the remethylation of homocysteine to methionine, thereby increasing homocysteine concentrations. Low folate or high homocysteine concentrations have been reported after chronic use of valproate, topiramate, gabapentin, oxcarbazepine, and levetiracetam while there are fewer data for lamotrigine [19].

The few studies on folate among pregnant persons with epilepsy have uncovered that individuals using lamotrigine had lower folate metabolite concentrations compared to untreated persons with epilepsy [20]. High ASM concentrations have been associated with high concentrations of UMFA and inactive folate metabolites, and with a low ratio between MTHF and its inactive metabolites, indicating increased folate catabolism [4].

Valproate in particular has been associated with impaired folate absorption and metabolism, accumulation of homocysteine, impaired DNA methylation, inhibition of folate receptors and carriers, and with low brain and placental folate concentrations [21]. In zebrafish embryos, folic acid supplementation reduced valproate-induced structural brain defects and neurotoxicity [22]. Regarding other ASMs, folic acid supplementation protected against lamotrigine-induced offspring malformations in mice [23]. In human placentas, lacosamide downregulated folate carriers potentially affecting folate supply to the fetus [24]. In human embryonic stem cells exposed to carbamazepine, gabapentin, lamotrigine, levetiracetam, or topiramate, all ASMs were associated with DNA damage, particularly levetiracetam and topiramate, whereas folic acid decreased this DNA damage [25].

Folic acid supplements could thus potentially reduce the risk of ASM toxicity in pregnancy [21, 26]. As many of the adverse outcomes in children seen after maternal folate deficiency in the general population overlap with those seen after prenatal ASM exposure, authors have suggested that some of the adverse effects of ASM in the fetus could be mediated through folate deficiency. Children in the prospective Norwegian Mother, Father and Child (MoBa) cohort study prenatally exposed to ASM had a threefold higher risk of preterm birth if the mother did not use periconceptional folic acid compared with children of mothers who did [27]. If persons with epilepsy were untreated during pregnancy, the risk of preterm birth was not modified by folic acid (Fig. 1; [27]). On the other hand, periconceptional folic acid supplementation has not convincingly been shown to reduce the risk of ASM-associated congenital malformations, in contrast to findings in the general population [28‐32]. Data from the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) have even indicated an increased risk of congenital malformations after folic acid supplementation [29]. There are conflicting results as to whether supplementation with folic acid is associated with a reduced risk of spontaneous abortions [33, 34]. However, in people using ASM, plasma folate and red blood cell folate concentrations were significantly lower prior to pregnancy in those who had a spontaneous abortion or a child with congenital anomalies compared to persons with a healthy pregnancy outcome [35]. Also, children born to mothers carrying the MTHFR 677TT mutation had a higher risk of congenital anomalies compared to those carrying the MTHFR 677CC wildtype alleles [36].

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study found that periconceptional folic acid supplement use was associated with improved child IQ scores in ASM-exposed children of persons with epilepsy [37, 38]. At the age of 6 years, the mean IQ for children exposed to periconceptional folate supplementation was 108 (95% confidence interval [CI]: 106–111) compared with 101 (95% CI: 98–104) for children not exposed to folic acid (Fig. 2; [37]). This association was also present in sub-analyses of children exposed to lamotrigine. However, maternal dietary folate intake did not affect the child outcome [39]. In some studies [40‐43], but not all [44‐46], it was found that children prenatally exposed to ASM also had a higher risk for autistic traits or language impairment if the mother reported no use of periconceptional folic acid compared to children of supplement users. Similar associations were not seen for women with epilepsy not using ASM [40‐42].

Many clinical guidelines recommend high doses of folic acid (1–5 mg) during pregnancy for persons who are using ASM, as well as for those who previously had children with congenital malformations, who smoke, and who have diabetes, obesity, or inflammatory bowel disease, in order to prevent congenital malformations [2]. However, there are concerns that high-dose folic acid and UMFA can be harmful for the mother [47]. Some studies have indicated that the use of high-dose folic acid promotes cancer growth and increases DNA de novo point mutations [48, 49], although other studies have shown a protective or null effect on cancer development [50]. Studies of pregnant people have not shown an increased risk of cancer among those taking regular doses (0.4–0.8 mg) of folic acid supplementation [51]. However, there are still conflicting results regarding the effect of folic acid in higher doses and as to whether there is a threshold for the dose, duration, or timing of folate supplementation that could potentially increase the risk of cancer [47, 52].

Folic acid intake can mask vitamin B₁₂ deficiency, and vitamin B₁₂ concentrations should therefore be routinely checked before starting folic acid supplementation [52]. Vitamin B₁₂ deficiency should be treated in conjunction with folic acid supplementation.

It has been suggested that high maternal prenatal folate concentrations could harm the child. A recent observational cohort study including all children in Scandinavia found an increased risk of cancer in children of mothers with epilepsy filling prescriptions for high-dose folic acid supplements (1 mg or more) during pregnancy. Children of high-dose folic acid users without epilepsy and children of mothers using ASM, but not high-dose folic acid, had no increased risk of cancer (Fig. 3; [53]). In pregnant persons without epilepsy and in mice, excess folic acid intake and high folate concentrations have also been associated with increased risk of adverse neurodevelopment in the offspring [54, 55]. In humans, high doses of folic acid during pregnancy and high UMFA concentrations in the umbilical cord blood were associated with increased risk of child autism spectrum disorder [56‐58], and with impaired psychomotor development in children at 1 year of age [59]. However, in children of persons treated with ASM and folic acid in pregnancy, UMFA was detected but not related to adverse neurodevelopment in the children [60].

For individuals using ASM, the optimal folic acid supplement dose before, during, and after pregnancy is not known. There is no consensus on the timing and dose of folic acid, with clinical guidelines varying internationally (Table 1).

In an effort to assess how many clinicians adhere to clinical guidelines, the ILAE conducted a global survey showing that 52 of the 57 responding ILAE chapters had guidelines that included folate recommendations [10]. Most respondents stated that their guidelines recommended ≥ 4 mg folic acid daily, but ranging from 0.4 mg to ≥ 4 mg [10]. Besides supplementing folic acid in relation to pregnancy, some guidelines, including the ILAE as well as Norwegian guidelines, recommend 0.4 mg folic acid daily to all individuals treated with ASM of childbearing age, regardless of their pregnancy plans, due to the high prevalence of unplanned pregnancies in persons with epilepsy [61, 67, 68].

There are no current prospective studies designed to investigate different folic acid doses in people using ASM. The high-dose folic acid recommendations are largely based on a study that randomized pregnant persons who previously had given birth to a child with a congenital malformation to receive either 4 mg folic acid, no supplement, or a multivitamin supplement without folic acid. The results favored folic acid, but the study was not designed to investigate high-dose vs. low-dose supplementation [69] Another multicenter, double-blind randomized controlled trial of 1060 women planning a pregnancy reported that supplementation with 4.0 mg vs. 0.4 mg of folic acid was not associated with reduced occurrence of congenital malformations, but was associated with a lower risk of other adverse pregnancy outcomes such as spontaneous abortion, small for gestational age, and preterm delivery [15]. However, these studies did not specifically examine persons with epilepsy. In the NEAD study that showed an association between folic acid and improved IQ scores in children prenatally exposed to ASM, most of the women used more than 1 mg folic acid, and a dose-dependent effect was found [37]. In the Norwegian MoBa study, the plasma folate concentration in pregnant individuals with epilepsy in gestational week 18 was inversely associated with autistic traits (Fig. 4), but not with language impairment [40, 41] in children prenatally exposed to ASM. The patient-reported folic acid doses were also associated with the degree of autistic symptoms (Fig. 4; [40]).

In the absence of clear evidence on which folic acid dose is optimal to maximize potential benefits but also to avoid harm, we previously suggested a supplement of at least 0.4 mg daily for people of childbearing potential using ASM, but keeping the folic acid doses at ≤ 4 mg daily [70].