The Effects of Valproic Acid on the Skeletal Development and the Ameliorative Effects of Combined Use of Folic Acid and Vitamin E in Pregnant Albino Rats

Gamal Abdel Salam; Omar ABd Alaziz Allam

doi:doi:10.11648/j.ijcda.20150103.13

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The Effects of Valproic Acid on the Skeletal Development and the Ameliorative Effects of Combined Use of Folic Acid and Vitamin E in Pregnant Albino Rats

Gamal Abdel Salam, Omar ABd Alaziz Allam

Published in International Journal of Clinical and Developmental Anatomy (Volume 1, Issue 3)

Received: 6 August 2015 Accepted: 13 August 2015 Published: 19 August 2015

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Abstract

Objectives: To evaluate skeletal developmental defects secondary to chronic valproic acid (VPA) use during pregnancy and the extent of ameliorative effect of combined use of vitamin E and folic acid (FA) during VPA therapy. Materials and Methods: Thirty virgin female albino rats were allowed to get pregnant and were divided into three equal groups: Control group received no medications; VPA group received oral VPA 400 mg/kg body weight (BW) starting on gestational day (GD) 1 till GD20 and Prophylaxis group received oral VPA (400 mg/kg BW) and vitamin E 250 mg/kg BW and folic acid 100 µg/kg BW using gastric tube starting on GD1 till GD20. At GD20, uterine horns were examined for resorption sites, alive or dead fetuses. Extracted living fetuses were examined for BW, crown-rump length (CRL), and antero-posterior (AP) and biparietal diameters and for congenital malformations. Results: VPA significantly reduced all body measurements of living dams compared to control dams. Prophylaxis therapy significantly increased BW, CRL and AP skull diameter compared to VPA dams. The GD20 fetus of VPA group showed delayed ossification of skull bones with wide anterior fontanel (AF) and widely separated parietal bones, very small ossification center (OC) for hyoid bone. Caudal vertebrae were unossified or showed very small OC with no evident OC for calcaneous, metatarsal bones or distal phalanges. Fetuses of prophylaxis group showed slightly wide AF than that of control animals and parietal bones are separated to lesser extent than VPA group. Mandible is developed, with an OC for hyoid bone and sternebrae are seen. Six caudal vertebrae and few OC in phalanges are seen, but no OC in calcaneous. Conclusion: VPA chronic administration during pregnancy showed deleterious effects on fetal body measurements and skeletal system development. Concomitant administration of vitamin E and FA significantly ameliorated these changes.

Published in	International Journal of Clinical and Developmental Anatomy (Volume 1, Issue 3)
DOI	10.11648/j.ijcda.20150103.13
Page(s)	70-78
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2015. Published by Science Publishing Group

Keywords

Valproic Acid, Folic Acid, Vitamin E, Pregnancy, Skeletal Defects

References

[1]	Chiba S: Comprehensive management for women with epilepsy. Brain Nerve. 2011; 63(4):301-8.
[2]	Velíšková J, Desantis KA: Sex and hormonal influences on seizures and epilepsy. Horm Behav. 2013; 63(2):267-77.
[3]	Nanau RM, Neuman MG: Adverse drug reactions induced by valproic acid. Clin Biochem. 2013; 46(15):1323-38.
[4]	Fricke-Galindo I, Jung-Cook H, LLerena A, López-López M: Pharmacogenetics of adverse reactions to antiepileptic drugs. Neurologia. 2015. pii: S0213-4853(15)00056-0.
[5]	Star K, Edwards IR, Choonara I: Valproic acid and fatalities in children: a review of individual case safety reports in VigiBase. PLoS One. 2014; 9(10):e108970.
[6]	Vella T, Mifsud J: Interactions between valproic acid and quetiapine/olanzapine in the treatment of bipolar disorder and the role of therapeutic drug monitoring. J Pharm Pharmacol. 2014; 66(6):747-59.
[7]	Perucca E: Optimizing antiepileptic drug treatment in tumoral epilepsy. Epilepsia. 2013; 54 Suppl 9:97-104.
[8]	Kjaer I, Kjaer TW, Graem N: Ossification sequence of occipital bone and vertebrae in human fetuses. J Craniofac Genet Dev Biol. 1993; 13(2):83-8.
[9]	Sliwonik I: Development of parietal bone based on ossification in the fetus. Ann Acad Med Stetin. 2002; 48:145-62.
[10]	Cardoso HF, Ríos L: Age estimation from stages of epiphyseal union in the presacral vertebrae. Am J Phys Anthropol. 2011; 144(2):238-47.
[11]	Olsen ØE, Lie RT, Lachman RS, Maartmann-Moe H, Rosendahl K: Ossification sequence in infants who die during the perinatal period: population-based references. Radiology. 2002; 225(1):240-4.
[12]	Zhang Q, Wang H, Udagawa J, Otani H: Morphological and morphometric study on sphenoid and basioccipital ossification in normal human fetuses. Congenit Anom (Kyoto). 2011; 51(3):138-48.
[13]	Garzón-Alvarado DA, González A, Gutiérrez ML: Growth of the flat bones of the membranous neurocranium: a computational model. Comput Methods Programs Biomed. 2013; 112(3):655-64.
[14]	Burdan F, Szumiło J, Dudka J, Klepacz R, Błaszczak M, Solecki M, Korobowicz A, Chałas A, Klepacki J, Palczak M, Zuchnik-Wrona A, Hadała-Kiś A, Urbanowicz Z, Wójtowicz Z: Morphological studies in modern teratological investigations. Folia Morphol (Warsz). 2005; 64(1):1-8.
[15]	Baran O, Nergiz Y, Tuncer MC: The effects of valproic acid, vitamin E and folic acid on ribs of rat fetuses in the prenatal period. Ann Anat. 2006;188(2):117-25.
[16]	Ornoy A: Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Reprod Toxicol. 2009; 28(1):1-10.
[17]	Soysal H, Unur E, Düzler A, Karaca O, Ekinci N: Effects of intraperitoneal administration of the phenytoin on the skeletal system of rat fetus. Seizure. 2011; 20(3):187-93.
[18]	Fadel RA, Sequeira RP, Abu-Hijleh MF, Obeidat M, Salem AH: Effect of prenatal administration of therapeutic doses of topiramate on ossification of ribs and vertebrae in rat fetuses. Rom J Morphol Embryol. 2012; 53(2):321-7.
[19]	Koo J, Zavras A: Antiepileptic drugs (AEDs) during pregnancy and risk of congenital jaw and oral malformation. Oral Dis. 2013; 19(7):712-20.
[20]	Tanoshima M, Kobayashi T, Tanoshima R, Beyene J, Koren G, Ito S: Risks of congenital malformations in offspring exposed to valproic acid in utero: A systematic review and cumulative meta-analysis. Clin Pharmacol Ther. 2015; Epub ahead of print.
[21]	Al Deeb S, Al Moutaery K, Arshaduddin M, Tariq M: Vitamin E decreases valproic acid induced neural tube defects in mice. Neurosci Lett. 2000; 292(3):179-82.
[22]	Padmanabhan R, Shafiullah MM: Amelioration of sodium valproate-induced neural tube defects in mouse fetuses by maternal folic acid supplementation during gestation. Congenit Anom (Kyoto). 2003; 43(1):29-40.
[23]	Dawson JE, Raymond AM, Winn LM: Folic acid and pantothenic acid protection against valproic acid-induced neural tube defects in CD-1 mice. Toxicol Appl Pharmacol. 2006; 11(2):124-32.
[24]	Hsieh CL, Wang HE, Tsai WJ, Peng CC, Peng RY: Multiple point action mechanism of valproic acid-teratogenicity alleviated by folic acid, vitamin C, and N-acetylcysteine in chicken embryo model. Toxicology. 2012;291(1-3):32-42.
[25]	Tunali S, Kahraman S, Yanardag R. Vitamin U, a novel free radical scavenger, prevents lens injury in rats administered with valproic acid. Hum Exp Toxicol. 2014. pii: 0960327114561665.
[26]	Gezginci-Oktayoglu S, Turkyilmaz IB, Ercin M, Yanardag R, Bolkent S. Vitamin U has a protective effect on valproic acid-induced renal damage due to its anti-oxidant, anti-inflammatory, and anti-fibrotic properties. Protoplasma. 2015. [Epub ahead of print]
[27]	Tung EW, Winn LM: Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: a role for oxidative stress in valproic acid-induced neural tube defects. Mol Pharmacol. 2011; 80(6):979-87.
[28]	Mallela M, Hrubec T: Reduction in valproic acid-induced neural tube defects by maternal immune stimulation: role of apoptosis. Birth Defects Res B Dev Reprod Toxicol. 2012; 95(4):296-303.
[29]	Umur AS, Selcuki M, Bursali A, Umur N, Kara B, Vatansever HS, Duransoy YK: Simultaneous folate intake may prevent adverse effect of valproic acid on neurulating nervous system. Childs Nerv Syst. 2012; 28(5):729-37.
[30]	Tiboni GM, Chiarelli F, Verrotti A: Inhibition of nitric oxide synthesis enhances teratogenic effects induced by valproic Acid. In Vivo. 2013; 27(4):513-8.
[31]	Tiboni GM, Ponzano A: Prevention of valproic acid-induced neural tube defects by sildenafil citrate. Reprod Toxicol. 2015; pii: S0890-6238(15)00038-6.
[32]	Rubinchik-Stern M, Shmuel M, Eyal S: Antiepileptic drugs alter the expression of placental carriers: An in vitro study in a human placental cell line. Epilepsia. 2015; 56(7):1023-32.
[33]	Tomson T, Marson A, Boon P, Canevini MP, Covanis A, Gaily E, Kälviäinen R, Trinka E: Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia. 2015;56(7):1006-19.

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Gamal Abdel Salam, Omar ABd Alaziz Allam. (2015). The Effects of Valproic Acid on the Skeletal Development and the Ameliorative Effects of Combined Use of Folic Acid and Vitamin E in Pregnant Albino Rats. International Journal of Clinical and Developmental Anatomy, 1(3), 70-78. https://doi.org/10.11648/j.ijcda.20150103.13

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ACS Style

Gamal Abdel Salam; Omar ABd Alaziz Allam. The Effects of Valproic Acid on the Skeletal Development and the Ameliorative Effects of Combined Use of Folic Acid and Vitamin E in Pregnant Albino Rats. Int. J. Clin. Dev. Anat. 2015, 1(3), 70-78. doi: 10.11648/j.ijcda.20150103.13

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AMA Style

Gamal Abdel Salam, Omar ABd Alaziz Allam. The Effects of Valproic Acid on the Skeletal Development and the Ameliorative Effects of Combined Use of Folic Acid and Vitamin E in Pregnant Albino Rats. Int J Clin Dev Anat. 2015;1(3):70-78. doi: 10.11648/j.ijcda.20150103.13

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@article{10.11648/j.ijcda.20150103.13,
  author = {Gamal Abdel Salam and Omar ABd Alaziz Allam},
  title = {The Effects of Valproic Acid on the Skeletal Development and the Ameliorative Effects of Combined Use of Folic Acid and Vitamin E in Pregnant Albino Rats},
  journal = {International Journal of Clinical and Developmental Anatomy},
  volume = {1},
  number = {3},
  pages = {70-78},
  doi = {10.11648/j.ijcda.20150103.13},
  url = {https://doi.org/10.11648/j.ijcda.20150103.13},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijcda.20150103.13},
  abstract = {Objectives: To evaluate skeletal developmental defects secondary to chronic valproic acid (VPA) use during pregnancy and the extent of ameliorative effect of combined use of vitamin E and folic acid (FA) during VPA therapy. Materials and Methods: Thirty virgin female albino rats were allowed to get pregnant and were divided into three equal groups: Control group received no medications; VPA group received oral VPA 400 mg/kg body weight (BW) starting on gestational day (GD) 1 till GD20 and Prophylaxis group received oral VPA (400 mg/kg BW) and vitamin E 250 mg/kg BW and folic acid 100 µg/kg BW using gastric tube starting on GD1 till GD20. At GD20, uterine horns were examined for resorption sites, alive or dead fetuses. Extracted living fetuses were examined for BW, crown-rump length (CRL), and antero-posterior (AP) and biparietal diameters and for congenital malformations. Results: VPA significantly reduced all body measurements of living dams compared to control dams. Prophylaxis therapy significantly increased BW, CRL and AP skull diameter compared to VPA dams. The GD20 fetus of VPA group showed delayed ossification of skull bones with wide anterior fontanel (AF) and widely separated parietal bones, very small ossification center (OC) for hyoid bone. Caudal vertebrae were unossified or showed very small OC with no evident OC for calcaneous, metatarsal bones or distal phalanges. Fetuses of prophylaxis group showed slightly wide AF than that of control animals and parietal bones are separated to lesser extent than VPA group. Mandible is developed, with an OC for hyoid bone and sternebrae are seen. Six caudal vertebrae and few OC in phalanges are seen, but no OC in calcaneous. Conclusion: VPA chronic administration during pregnancy showed deleterious effects on fetal body measurements and skeletal system development. Concomitant administration of vitamin E and FA significantly ameliorated these changes.},
 year = {2015}
}

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TY  - JOUR
T1  - The Effects of Valproic Acid on the Skeletal Development and the Ameliorative Effects of Combined Use of Folic Acid and Vitamin E in Pregnant Albino Rats
AU  - Gamal Abdel Salam
AU  - Omar ABd Alaziz Allam
Y1  - 2015/08/19
PY  - 2015
N1  - https://doi.org/10.11648/j.ijcda.20150103.13
DO  - 10.11648/j.ijcda.20150103.13
T2  - International Journal of Clinical and Developmental Anatomy
JF  - International Journal of Clinical and Developmental Anatomy
JO  - International Journal of Clinical and Developmental Anatomy
SP  - 70
EP  - 78
PB  - Science Publishing Group
SN  - 2469-8008
UR  - https://doi.org/10.11648/j.ijcda.20150103.13
AB  - Objectives: To evaluate skeletal developmental defects secondary to chronic valproic acid (VPA) use during pregnancy and the extent of ameliorative effect of combined use of vitamin E and folic acid (FA) during VPA therapy. Materials and Methods: Thirty virgin female albino rats were allowed to get pregnant and were divided into three equal groups: Control group received no medications; VPA group received oral VPA 400 mg/kg body weight (BW) starting on gestational day (GD) 1 till GD20 and Prophylaxis group received oral VPA (400 mg/kg BW) and vitamin E 250 mg/kg BW and folic acid 100 µg/kg BW using gastric tube starting on GD1 till GD20. At GD20, uterine horns were examined for resorption sites, alive or dead fetuses. Extracted living fetuses were examined for BW, crown-rump length (CRL), and antero-posterior (AP) and biparietal diameters and for congenital malformations. Results: VPA significantly reduced all body measurements of living dams compared to control dams. Prophylaxis therapy significantly increased BW, CRL and AP skull diameter compared to VPA dams. The GD20 fetus of VPA group showed delayed ossification of skull bones with wide anterior fontanel (AF) and widely separated parietal bones, very small ossification center (OC) for hyoid bone. Caudal vertebrae were unossified or showed very small OC with no evident OC for calcaneous, metatarsal bones or distal phalanges. Fetuses of prophylaxis group showed slightly wide AF than that of control animals and parietal bones are separated to lesser extent than VPA group. Mandible is developed, with an OC for hyoid bone and sternebrae are seen. Six caudal vertebrae and few OC in phalanges are seen, but no OC in calcaneous. Conclusion: VPA chronic administration during pregnancy showed deleterious effects on fetal body measurements and skeletal system development. Concomitant administration of vitamin E and FA significantly ameliorated these changes.
VL  - 1
IS  - 3
ER  -

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Author Information

Gamal Abdel Salam

Anatomy Department, Faculty of Medicine, Benha University, Benha City, Egypt
Omar ABd Alaziz Allam

Anatomy Department, Faculty of Medicine, Benha University, Benha City, Egypt

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Gamal Abdel Salam, Omar ABd Alaziz Allam. (2015). The Effects of Valproic Acid on the Skeletal Development and the Ameliorative Effects of Combined Use of Folic Acid and Vitamin E in Pregnant Albino Rats. International Journal of Clinical and Developmental Anatomy, 1(3), 70-78. https://doi.org/10.11648/j.ijcda.20150103.13

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ACS Style

Gamal Abdel Salam; Omar ABd Alaziz Allam. The Effects of Valproic Acid on the Skeletal Development and the Ameliorative Effects of Combined Use of Folic Acid and Vitamin E in Pregnant Albino Rats. Int. J. Clin. Dev. Anat. 2015, 1(3), 70-78. doi: 10.11648/j.ijcda.20150103.13

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AMA Style

Gamal Abdel Salam, Omar ABd Alaziz Allam. The Effects of Valproic Acid on the Skeletal Development and the Ameliorative Effects of Combined Use of Folic Acid and Vitamin E in Pregnant Albino Rats. Int J Clin Dev Anat. 2015;1(3):70-78. doi: 10.11648/j.ijcda.20150103.13

Copy | Download

@article{10.11648/j.ijcda.20150103.13,
  author = {Gamal Abdel Salam and Omar ABd Alaziz Allam},
  title = {The Effects of Valproic Acid on the Skeletal Development and the Ameliorative Effects of Combined Use of Folic Acid and Vitamin E in Pregnant Albino Rats},
  journal = {International Journal of Clinical and Developmental Anatomy},
  volume = {1},
  number = {3},
  pages = {70-78},
  doi = {10.11648/j.ijcda.20150103.13},
  url = {https://doi.org/10.11648/j.ijcda.20150103.13},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijcda.20150103.13},
  abstract = {Objectives: To evaluate skeletal developmental defects secondary to chronic valproic acid (VPA) use during pregnancy and the extent of ameliorative effect of combined use of vitamin E and folic acid (FA) during VPA therapy. Materials and Methods: Thirty virgin female albino rats were allowed to get pregnant and were divided into three equal groups: Control group received no medications; VPA group received oral VPA 400 mg/kg body weight (BW) starting on gestational day (GD) 1 till GD20 and Prophylaxis group received oral VPA (400 mg/kg BW) and vitamin E 250 mg/kg BW and folic acid 100 µg/kg BW using gastric tube starting on GD1 till GD20. At GD20, uterine horns were examined for resorption sites, alive or dead fetuses. Extracted living fetuses were examined for BW, crown-rump length (CRL), and antero-posterior (AP) and biparietal diameters and for congenital malformations. Results: VPA significantly reduced all body measurements of living dams compared to control dams. Prophylaxis therapy significantly increased BW, CRL and AP skull diameter compared to VPA dams. The GD20 fetus of VPA group showed delayed ossification of skull bones with wide anterior fontanel (AF) and widely separated parietal bones, very small ossification center (OC) for hyoid bone. Caudal vertebrae were unossified or showed very small OC with no evident OC for calcaneous, metatarsal bones or distal phalanges. Fetuses of prophylaxis group showed slightly wide AF than that of control animals and parietal bones are separated to lesser extent than VPA group. Mandible is developed, with an OC for hyoid bone and sternebrae are seen. Six caudal vertebrae and few OC in phalanges are seen, but no OC in calcaneous. Conclusion: VPA chronic administration during pregnancy showed deleterious effects on fetal body measurements and skeletal system development. Concomitant administration of vitamin E and FA significantly ameliorated these changes.},
 year = {2015}
}

Copy | Download

TY  - JOUR
T1  - The Effects of Valproic Acid on the Skeletal Development and the Ameliorative Effects of Combined Use of Folic Acid and Vitamin E in Pregnant Albino Rats
AU  - Gamal Abdel Salam
AU  - Omar ABd Alaziz Allam
Y1  - 2015/08/19
PY  - 2015
N1  - https://doi.org/10.11648/j.ijcda.20150103.13
DO  - 10.11648/j.ijcda.20150103.13
T2  - International Journal of Clinical and Developmental Anatomy
JF  - International Journal of Clinical and Developmental Anatomy
JO  - International Journal of Clinical and Developmental Anatomy
SP  - 70
EP  - 78
PB  - Science Publishing Group
SN  - 2469-8008
UR  - https://doi.org/10.11648/j.ijcda.20150103.13
AB  - Objectives: To evaluate skeletal developmental defects secondary to chronic valproic acid (VPA) use during pregnancy and the extent of ameliorative effect of combined use of vitamin E and folic acid (FA) during VPA therapy. Materials and Methods: Thirty virgin female albino rats were allowed to get pregnant and were divided into three equal groups: Control group received no medications; VPA group received oral VPA 400 mg/kg body weight (BW) starting on gestational day (GD) 1 till GD20 and Prophylaxis group received oral VPA (400 mg/kg BW) and vitamin E 250 mg/kg BW and folic acid 100 µg/kg BW using gastric tube starting on GD1 till GD20. At GD20, uterine horns were examined for resorption sites, alive or dead fetuses. Extracted living fetuses were examined for BW, crown-rump length (CRL), and antero-posterior (AP) and biparietal diameters and for congenital malformations. Results: VPA significantly reduced all body measurements of living dams compared to control dams. Prophylaxis therapy significantly increased BW, CRL and AP skull diameter compared to VPA dams. The GD20 fetus of VPA group showed delayed ossification of skull bones with wide anterior fontanel (AF) and widely separated parietal bones, very small ossification center (OC) for hyoid bone. Caudal vertebrae were unossified or showed very small OC with no evident OC for calcaneous, metatarsal bones or distal phalanges. Fetuses of prophylaxis group showed slightly wide AF than that of control animals and parietal bones are separated to lesser extent than VPA group. Mandible is developed, with an OC for hyoid bone and sternebrae are seen. Six caudal vertebrae and few OC in phalanges are seen, but no OC in calcaneous. Conclusion: VPA chronic administration during pregnancy showed deleterious effects on fetal body measurements and skeletal system development. Concomitant administration of vitamin E and FA significantly ameliorated these changes.
VL  - 1
IS  - 3
ER  -

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