Overdose of Vitamin A
Teratogenic Effects on the Fetus
I. Vitamin A
Vitamin A levels tend to fall during early pregnancy, and then start to rise at the 13th to 16th week exceeding the normal range by the 21st week and reaching a concentration of one-and-one half times normal at the 37th week (1-6).
There are three forms of vitamin A, which are biologically active: retinol (vitamin A1 alcohol ), which maintains mucous membrane structure and function and is the circulating form of the vitamin; retinal (vitamin A1 aldehyde ), which plays a role in retinal development; and retinoic acid (RA), which contributes to the regulation of pattern formation in the early embryo (2). Biologically active forms of retinoic acid that occur naturally and that can act as dysmorphogens include: all trans-RA; 9-cis-RA; 3,4-didehydro-RA; 14-hydroxy-4,14 retroretinol; and 4-oxo-RA (3).
A normal supply of vitamin A is critical for embryonic development and proves to be a requirement for brain development; particularly in its early stages. Retinoids play an important role during normal neural development and neural plate formation. The neural plate is the site where retinol binds and is converted effectively into retinoic acid (RA). Retinoic acid is the short-lived active form of vitamin A and is responsible for the regulation of gene expression. An excess of vitamin A and its metabolites, particularly retinoic acid on the CNS can be teratogenic (2-5).
Animal and human experiments have shown a correlation between retinoid exposure and central nervous system malformation. Effects of retinoids on CNS development were performed in the Xenopus embryo, which developed microcephaly and the absence of eyes, forebrain, and midbrain after 4-oxo-RA treatment from blastula to early neurula stage. Exposure to RA in mammalian embryos caused a loss of anterior hindbrain structures, and in cultured mouse embryos an inhibition of the migration of cranial neural crest cells. In rats, RA application exhibited defects in cortical cytoarchitecture and a range of behavioural abnormalities as adults (4).
Similarly, in mice, when exposing postnatal pups briefly to teratogenic RA doses, some of the exposed pups grew into mice that appeared more or less normal, however, others exhibited very abnormal behaviour.Other findings include neuroanatomic consequences similar to the main human symptoms of retinoid toxicity known as “all-trans RA syndrome”, when exposing RA to mouse brain sections (6). Short-term effects of the exposure resulted in impaired lung function and pseudotumour cerebri together with an increase in intracranial pressure resulting in swelling of the brains (3,4). These toxic symptoms were particularly pronounced at the youngest stages in development when the skulls were all membranous and respiratory reflexes still poor.
The evidence is clear that toxicities of vitamin A can be harmful and careful attention should be paid to the recommended daily allowances, particularly for women who are in their childbearing age. A balanced nutritional diet is vital and plays a role in the production of reproductive health and pregnancy outcomes.
Resources:
1. Sommer A, West KP. Effects of alternative maternal micronutrient Supplement On Low Birth Weight In rural Nepal: Double-Blind Randomised Trial. BMJ. 2003;26:571.
2. O’Donnell J. Polar Hysteria: An Expression of Hypervitaminosis A. Am J Ther. 2004;11:507-516.
3. West KP, Katz J, Khatry SK, LeCLrq SC, Pradhan EK, Shresth SR, Connor PB, Dali SM, Christian P, Pokhrei RP, Sommer A. Double-Blind, Cluster Randomised Trial of Low Dose Supplementation With Vitamin A or b- Carotene on Mortality Related to Pregnancy in Nepal. BMJ. 1999;318:570-575.
4. Ganguly J. Biochemistry of Vitamin A. Florida. CRC Press Inc, 1989.
5. Mulder GB, Manley N, Grant J, Schmidt K, Zeng W, Eckhoff C, Maggio-Price L. Effects of Excess Vitamin A on Development of Cranial Neural Crest-Derived Structures: A Neonatal and Embriological Study. NLM : Teratology. 2000;62:214-26.
6. Luo T, Wagner E, Crandall JE, Drager UC. A Retinoic Acid Critical Period in Early Postnatal Mouse Brain. Biological Psychiatry. 2004;56:971-980.
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