Ana M. Palacios

Teratogenic effects of antiepileptic drugs

Many antiepileptic drugs (AEDs) have therapeutic applications that extend beyond epilepsy to include neuropathic pain, migraine headaches and psychiatric disorders. The risk of some AEDs has been clearly established, but for newer drugs, small sample sizes and polytherapy exposures preclude a conclusive determination of their teratogenic potential. Most women with epilepsy will require AED therapy throughout their entire pregnancy to control seizures; the vast majority of pregnancies in women with epilepsy have positive outcomes. A conservative estimate suggests that AED monotherapy doubles, and polytherapy triples, the risk for major congenital malformations. Furthermore, while evidence is still accruing, recent investigations suggest that exposure to select AEDs results in altered cognitive function later in development. There is no evidence to suggest that additional folic acid supplementation ameliorates the increased risk of congenital malformations conferred by in utero AED exposure.

Antiepileptic drugs and pregnancy outcomes.

The treatment of epilepsy in women of reproductive age remains a clinical challenge. While most women with epilepsy (WWE) require anticonvulsant drugs for adequate control of their seizures, the teratogenicity associated with some antiepileptic drugs (AEDs) is a risk that needs to be carefully addressed. Antiepileptic medications are also used to treat an ever broadening range of medical conditions such as bipolar disorder, migraine prophylaxis, cancer, and neuropathic pain. Despite the fact that the majority of pregnancies of WWE who are receiving pharmacological treatment are normal, studies have demonstrated that the risk of having a pregnancy complicated by a major congenital malformation is doubled when comparing the risk of untreated pregnancies. Furthermore, when AEDs are used in polytherapy regimens, the risk is tripled, especially when valproic acid (VPA) is included. However, it should be noted that the risks are specific for each anticonvulsant drug. Some investigations have suggested that the risk of teratogenicity is increased in a dose‐dependent manner. More recent studies have reported that in utero exposure to AEDs can have detrimental effects on the cognitive functions and language skills in later stages of life. In fact, the FDA just issued a safety announcement on the impact of VPA on cognition (Safety Announcement 6‐30‐2011). The purpose of this document is to review the most commonly used compounds in the treatment of WWE, and to provide information on the latest experimental and human epidemiological studies of the effects of AEDs in the exposed embryos.

Genetic basis of susceptibility to teratogen induced birth defects

Birth defects remain the leading cause of infant death in US. The field of teratology has been focused on the causes and underlying mechanisms of birth defects for decades, yet our understanding of these critical issues remain unacceptably vague. Conclusions from years of animal and human studies made it clear that the vast majority of birth defects have multifactorial origins, with contributions from environmental and genetic factors. The environment comprises not only of the physical, biological, and chemical external environment surrounding the pregnant woman, but it also includes the internal environment of the womans body that interact with the developing embryo in a complex fashion. The importance of maternal and embryonic genetic factors consisting of countless genetic variants/mutations that exist within every individual contribute to birth defect susceptibility is only now being more fully appreciated. This great complexity of the genome and its diversity within individuals and populations seems to be the principal reason why the same teratogenic exposure can induce severe malformation in one embryo, while fail to do so to other exposed embryos. As the interaction between genetic and environmental factors has long been recognized as the first “Principle of Teratology” by Wilson and Warkany [1965. Teratology: Principles and techniques. Chicago: University of Chicago Press], it is only recently that the appropriate investigative tools have been developed with which to fully investigate this fundamental principle. The introduction of high throughput technologies like whole genome sequencing or genome‐wide association studies are promising to deliver an enormous amount of new data that will shed light on the genomic factors that contribute susceptibility to environmental teratogens. In this review, we attempt to summarize the epidemiological and experimental literature concerning birth defects whose phenotypic expression can be clearly related to the interactions between several select environmental factors and those genetic pathways in which they are most likely to have significant modifying effects.

Brief report novel mechanism for valproate-induced teratogenicity.

BACKGROUND Valproic acid (VPA) is a commonly prescribed drug for those affected by epilepsy and bipolar disorders. VPA has a well known teratogenic potential, causing a variety of birth defects including neural tube defects (NTDs) and other congenital malformations, when women are treated with this medication during pregnancy. Unfortunately, the mechanism by which VPA is teratogenic remains unknown, although a range of potential mechanisms including histone deacetylase inhibition and folate antagonism have been proposed. The latter is of considerable importance, as clinicians need to know if additional folate supplements can prevent VPA-induced defects. METHODS We herein approach this question experimentally, using enzyme-linked immunosorbent assay assays and cell culture modeling, to demonstrate that VPA serves as a noncompetitive inhibitor of the high affinity folate receptors. RESULTS Binding affinities experimentally determined through enzyme-linked immunosorbent assay assays indicate that VPA serves as a noncompetitive substrate that can lessen the ability of the three primary folate forms to bind to the high affinity folate receptors. Tests in HEK293T cells indicate that the membrane-bound folate receptors of VPA treated cells bind significantly lower amounts of folic acid than do untreated cells. CONCLUSION If these data translate to the overall transport and subsequent bioavailability of folates, noncompetitive inhibition of the folate receptors by VPA may serve to lower the bioavailable folates in VPA treated mothers. This represents a novel mechanism by which in utero VPA exposure could be disrupting developmental processes by noncompetitively binding to the folate receptors during embryogenesis, thus inducing the wide range of defects seen in babies born to VPA treated mothers.

Eggs early in complementary feeding increase choline pathway biomarkers and DHA: a randomized controlled trial in Ecuador

Background: Choline status has been associated with stunting among young children. Findings from this study showed that an egg intervention improved linear growth by a length-for-age z score of 0.63. Objective: We aimed to test the efficacy of eggs introduced early in complementary feeding on plasma concentrations of biomarkers in choline pathways, vitamins B-12 and A, and essential fatty acids. Design: A randomized controlled trial, the Lulun (“egg” in Kichwa) Project, was conducted in a rural indigenous population of Ecuador. Infants aged 6–9 mo were randomly assigned to treatment (1 egg/d for 6 mo; n = 80) and control (no intervention; n = 83) groups. Socioeconomic data, anthropometric measures, and blood samples were collected at baseline and endline. Household visits were made weekly for morbidity surveillance. We tested vitamin B-12 plasma concentrations by using chemiluminescent competitive immunoassay and plasma concentrations of choline, betaine, dimethylglycine, retinol, essential fatty acids, methionine, dimethylamine (DMA), trimethylamine, and trimethylamine-N-oxide (TMAO) with the use of liquid chromatography–tandem mass spectrometry. Results: Socioeconomic factors and biomarker concentrations were comparable at baseline. Of infants, 11.4% were vitamin B-12 deficient and 31.7% marginally deficient at baseline. In adjusted generalized linear regression modeling, the egg intervention increased plasma concentrations compared with control by the following effect sizes: choline, 0.35 (95% CI: 0.12, 0.57); betaine, 0.29 (95% CI: 0.01, 0.58); methionine, 0.31 (95% CI: 0.03, 0.60); docosahexaenoic acid, 0.43 (95% CI: 0.13, 0.73); DMA, 0.37 (95% CI: 0.37, 0.69); and TMAO, 0.33 (95% CI: 0.08, 0.58). No significant group differences were found for vitamin B-12, retinol, linoleic acid (LA), α-linolenic acid (ALA), or ratios of betaine to choline and LA to ALA. Conclusion: The findings supported our hypothesis that early introduction of eggs significantly improved choline and other markers in its methyl group metabolism pathway. This trial was registered at clinicaltrials.gov as NCT02446873.

Brief report novel mechanism for valproate-induced teratogenicity: Novel Mechanism for Valproate-Induced Teratogenicity

BACKGROUND Valproic acid (VPA) is a commonly prescribed drug for those affected by epilepsy and bipolar disorders. VPA has a well known teratogenic potential, causing a variety of birth defects including neural tube defects (NTDs) and other congenital malformations, when women are treated with this medication during pregnancy. Unfortunately, the mechanism by which VPA is teratogenic remains unknown, although a range of potential mechanisms including histone deacetylase inhibition and folate antagonism have been proposed. The latter is of considerable importance, as clinicians need to know if additional folate supplements can prevent VPA-induced defects. METHODS We herein approach this question experimentally, using enzyme-linked immunosorbent assay assays and cell culture modeling, to demonstrate that VPA serves as a noncompetitive inhibitor of the high affinity folate receptors. RESULTS Binding affinities experimentally determined through enzyme-linked immunosorbent assay assays indicate that VPA serves as a noncompetitive substrate that can lessen the ability of the three primary folate forms to bind to the high affinity folate receptors. Tests in HEK293T cells indicate that the membrane-bound folate receptors of VPA treated cells bind significantly lower amounts of folic acid than do untreated cells. CONCLUSION If these data translate to the overall transport and subsequent bioavailability of folates, noncompetitive inhibition of the folate receptors by VPA may serve to lower the bioavailable folates in VPA treated mothers. This represents a novel mechanism by which in utero VPA exposure could be disrupting developmental processes by noncompetitively binding to the folate receptors during embryogenesis, thus inducing the wide range of defects seen in babies born to VPA treated mothers.

Novel Mechanism for Valproate-Induced Teratogenicity

BACKGROUND Valproic acid (VPA) is a commonly prescribed drug for those affected by epilepsy and bipolar disorders. VPA has a well known teratogenic potential, causing a variety of birth defects including neural tube defects (NTDs) and other congenital malformations, when women are treated with this medication during pregnancy. Unfortunately, the mechanism by which VPA is teratogenic remains unknown, although a range of potential mechanisms including histone deacetylase inhibition and folate antagonism have been proposed. The latter is of considerable importance, as clinicians need to know if additional folate supplements can prevent VPA-induced defects. METHODS We herein approach this question experimentally, using enzyme-linked immunosorbent assay assays and cell culture modeling, to demonstrate that VPA serves as a noncompetitive inhibitor of the high affinity folate receptors. RESULTS Binding affinities experimentally determined through enzyme-linked immunosorbent assay assays indicate that VPA serves as a noncompetitive substrate that can lessen the ability of the three primary folate forms to bind to the high affinity folate receptors. Tests in HEK293T cells indicate that the membrane-bound folate receptors of VPA treated cells bind significantly lower amounts of folic acid than do untreated cells. CONCLUSION If these data translate to the overall transport and subsequent bioavailability of folates, noncompetitive inhibition of the folate receptors by VPA may serve to lower the bioavailable folates in VPA treated mothers. This represents a novel mechanism by which in utero VPA exposure could be disrupting developmental processes by noncompetitively binding to the folate receptors during embryogenesis, thus inducing the wide range of defects seen in babies born to VPA treated mothers.