Valproic acid in pregnancy: how much are we endangering the embryo and fetus?
Abstract
Valproic acid (VPA) is a known human teratogen. Exposure in pregnancy is associated with approximately three-fold increase in the rate of major anomalies, mainly spina bifida and only rarely anencephaly (NTD), cardiac, craniofacial, skeletal and limb defects and a possible set of dysmorphic features, the "valproate syndrome" with decreased intrauterine growth. This was demonstrated by prospective and retrospective studies. There is also, mainly in the children with the "valproate syndrome", a significant increase in the rate of developmental problems, manifested by decreased verbal intelligence often with communication problems of the autistic spectrum disorder (ASD). VPA is teratogenic in most animal species tested, but the human embryo seems to be the most susceptible. A daily dose of 1000 mg or more and/or polytherapy are associated with a higher teratogenic risk. It seems that several other AEDs potentiate the teratogenic effects of VPA. Thus, when valproate cannot be avoided in pregnancy, the lowest possible effective dose should be prescribed in 2-3 divided doses, preferably as monotherapy. Women exposed to valproate in pregnancy should be given periconceptional folic acid and followed up in a high risk pregnancy clinic. Appropriate ultrasonographic and other examinations, focusing on the possible different anomalies described with this agent, should be carried out. The specific inhibition by VPA of histone deacetylase and changes in gene expression may explain the teratogenicity of this drug. Other possible explanations are: increased fetal oxidative stress induced by VPA, with the brain being more susceptible to oxidative stress in comparison to other fetal organs, or the folic acid inhibitory action of this drug.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Maternal exposure to VPA is associated with increased risk of ASD incidence in offspring.
“More specifically, clinical studies have shown that maternal exposure to VPA, a branched short-chain fatty acid used as an antiepileptic drug, is associated with increased risk of ASD incidence in offspring (Christensen et al., 2013; Ornoy, 2009).”
From Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder (2019) · cites this paper as Ornoy, 2009
Cites
Phiel, C. J., Zhang, F., Huang, E. Y., Guenther, M. G., Lazar, M. A., & Klein, P. S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101287200 · Cited by 1,758 · see citing works
Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Animal Model of Autism
Schneider, T., & Przewłocki, R. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300518 · Cited by 959 · see citing works
Morrow, J. (2005) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2005.074203 · Cited by 879 · see citing works
The longer term outcome of children born to mothers with epilepsy
Adab, N. (2004) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2003.029132 · Cited by 579 · see citing works
A clinical study of 57 children with fetal anticonvulsant syndromes
Moore, S. J., Turnpenny, P., Quinn, A., Glover, S., Lloyd, D. J., Montgomery, T., & Dean, J. C. S. (2000) · Journal of Medical Genetics · doi:10.1136/jmg.37.7.489 · Cited by 562 · see citing works
Characteristics of fetal anticonvulsant syndrome associated autistic disorder
Rasalam, A., Hailey, H., Williams, J., Moore, S., Turnpenny, P., Lloyd, D., & Dean, J. (2005) · Developmental Medicine & Child Neurology · doi:10.1017/s0012162205001076 · Cited by 456 · see citing works
Fetal valproate syndrome and autism: additional evidence of an association
Williams, G., King, J. O., Cunningham, M. L., Stephan, M., Kerr, B. A., & Hersh, J. H. (2001) · Developmental Medicine & Child Neurology · doi:10.1017/s001216220100038x · Cited by 422 · see citing works
MATERNAL EPILEPSY AND ABNORMALITIES OF THE FETUS AND NEWBORN
Speidel, B. D., & Meadow, S. R. (1972) · The Lancet · doi:10.1016/s0140-6736(72)92209-x · Cited by 419 · see citing works
Samrén, E. B., van Duijn, C. M., Koch, S., Hiilesmaa, V. K., Klepel, H., Bardy, A. H., Mannagetta, G. B., Deichl, A. W., Gaily, E., Granström, I. L., et al. (1997) · Epilepsia · doi:10.1111/j.1528-1157.1997.tb01480.x · Cited by 406 · see citing works
DiLiberti, J. H., Farndon, P. A., Dennis, N. R., & Curry, C. J. (1984) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320190308 · Cited by 397 · see citing works
Increased rate of major malformations in offspring exposed to valproate during pregnancy
Wyszynski, D. F., Nambisan, M., Surve, T. Y., Alsdorf, R., Smith, C. R., & Holmes, L. B. (2005) · Neurology · doi:10.1212/01.wnl.0000154516.43630.c5 · Cited by 389 · see citing works
Ingram, J. L., Peckham, S. M., Tisdale, B., & Rodier, P. M. (2000) · Neurotoxicology and Teratology · doi:10.1016/s0892-0362(99)00083-5 · Cited by 381 · see citing works
Congenital malformations due to antiepileptic drugs
Kaneko, S., Battino, D., Andermann, E., Wada, K., Kan, R., Takeda, A., Nakane, Y., Ogawa, Y., AVANZINI, G., Fumarola, C., et al. (1999) · Epilepsy Research · doi:10.1016/s0920-1211(98)00084-9 · Cited by 374 · see citing works
Arndt, T. L., Stodgell, C., & Rodier, P. M. (2005) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2004.11.001 · Cited by 369 · see citing works
Valproate Induces Replication-independent Active DNA Demethylation
Detich, N., Bovenzi, V., & Szyf, M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303740200 · Cited by 345 · see citing works
Fetal Valproate Syndrome: Clinical and Neuro‐developmental Features in Two Sibling Pairs
Christianson, A. L., Chester, N., & Kromberg, J. G. R. (1994) · Developmental Medicine & Child Neurology · doi:10.1111/j.1469-8749.1994.tb11858.x · Cited by 340 · see citing works
Antiepileptic drug use of women with epilepsy and congenital malformations in offspring
Artama, M., Auvinen, A. P., Raudaskoski, T., Isojärvi, I., & Isojärvi, J. I. T. (2005) · Neurology · doi:10.1212/01.wnl.0000163771.96962.1f · Cited by 305 · see citing works
Verification of the fetal valproate syndrome phenotype
Ardinger, H. H., Atkin, J., Blackston, R. D., Elsas, L. J., Clarren, S. K., Livingstone, S., Flannery, D. B., Pellock, J. M., Harrod, M. J., Lammer, E. J., et al. (1988) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320290123 · Cited by 301 · see citing works
Normal intelligence in children with prenatal exposure to carbamazepine
Gaily, E. K., Kantola‐Sorsa, E., Hiilesmaa, V., ISOAHO, M., Matila, R., Kotila, M., Nylund, T., Bardy, A. H., Kaaja, E., & Granström, M.-L. (2004) · Neurology · doi:10.1212/wnl.62.1.28 · Cited by 295 · see citing works
Fetal valproate syndrome and autism: additional evidence of an association
Williams, G. M., King, J. O., Cunningham, M. L., et al. (2001) · Developmental Medicine & Child Neurology · doi:10.1111/j.1469-8749.2001.tb00188.x · Cited by 290 · see citing works
Additional educational needs in children born to mothers with epilepsy
Adab, N. (2001) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.70.1.15 · Cited by 283 · see citing works
Ornoy, A. (2007) · Reproductive Toxicology · doi:10.1016/j.reprotox.2007.04.004 · Cited by 281 · see citing works
Self-citationA New Neurobehavioral Model of Autism in Mice: Pre- and Postnatal Exposure to Sodium Valproate
Wagner, G. C., Reuhl, K. R., Cheh, M. A., McRae, P. A., & Halladay, A. K. (2006) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-006-0117-y · Cited by 278 · see citing works
In utero antiepileptic drug exposure
Meador, K. J., Baker, G. A., Finnell, R. H., Kalayjian, L. A., Liporace, J. D., Loring, D. W., Mawer, G. E., Pennell, P. B., Clayton‐Smith, J., & Wolff, M. (2006) · Neurology · doi:10.1212/01.wnl.0000227919.81208.b2 · Cited by 277 · see citing works
ANTICONVULSANTS AND PARENTAL EPILEPSY IN THE DEVELOPMENT OF BIRTH DEFECTS
Shapiro, S., Hartz, S. C., Siskind, V., Mitchell, A. A., Slone, D., Rosenberg, L. A., Monson, R. R., Heinonen, O. P., Idänpään-Heikkilä, J. J., Häró, S., et al. (1976) · The Lancet · doi:10.1016/s0140-6736(76)91403-3 · Cited by 270 · see citing works
VALPROIC ACID AND SPINA BIFIDA
Bjérkedal, T., Czeizel, A. E., Goujard, J., Källén, B. A. J., Mastroiacova, P., Nevin, N. C., Oakley, G. P., & Robert, E. (1982) · The Lancet · doi:10.1016/s0140-6736(82)90018-6 · Cited by 267 · see citing works
Wide, K., Winbladh, B., & Källén, B. A. J. (2004) · Acta Paediatrica · doi:10.1111/j.1651-2227.2004.tb00701.x · Cited by 263 · see citing works
Chen, P. S., Wang, C.-C., Bortner, C. D., Peng, G.-S., Wu, X., Pang, H., Lu, R.-B., Gean, P.-W., Chuang, D.-M., & Hong, J.-S. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.06.053 · Cited by 262 · see citing works
Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth
Dean, J., Hailey, H., Moore, S. J., Lloyd, D. J., Turnpenny, P. D., & Little, J. (2002) · Journal of Medical Genetics · doi:10.1136/jmg.39.4.251 · Cited by 253 · see citing works
The risk of spina bifida aperta after first-trimester exposure to valproate in a prenatal cohort.
Omtzigt, J. G. C., Los, F. J., Grobbee, D. E., Pijpers, L., Jahoda, M. G. J., Brandenburg, H., Stewart, P. A., Gaillard, H. L., Sachs, E. S., & Wladimiroff, J. W. (1992) · PubMed · Cited by 252 · see citing works
ANTICONVULSANTS AND PARENTAL EPILEPSY IN THE DEVELOPMENT OF BIRTH DEFECTS
Shapiro, S., Slone, D., Hartz, S. C., Rosenberg, L. A., Siskind, V., Monson, R. R., Mitchell, A. A., & Heinonen, O. P. (1976) · Obstetrical & Gynecological Survey · doi:10.1097/00006254-197608000-00012 · Cited by 245 · see citing works
Teratogenicity of sodium valproate
Alsdorf, R., & Wyszynski, D. F. (2005) · Expert Opinion on Drug Safety · doi:10.1517/14740338.4.2.345 · Cited by 237 · see citing works
The teratogenic effect of carbamazepine: a meta-analysis of 1255 exposures
Matalon, S., Schechtman, S., Goldzweig, G., & Ornoy, A. (2002) · Reproductive Toxicology · doi:10.1016/s0890-6238(01)00199-x · Cited by 235 · see citing works
Self-citationMajor malformations in offspring of women with epilepsy
Kaaja, E., Kaaja, R., & Hiilesmaa, V. K. (2003) · Neurology · doi:10.1212/01.wnl.0000044157.28073.dc · Cited by 217 · see citing works
Malformations in Offspring of Women with Epilepsy: A Prospective Study
Canger, R., Battino, D., Canevini, M. P., Fumarola, C., Guidolin, L., Vignoli, A., Mamoli, D., Palmieri, C., Molteni, F., Granata, T., et al. (1999) · Epilepsia · doi:10.1111/j.1528-1157.1999.tb00851.x · Cited by 196 · see citing works
Association of valproate‐induced teratogenesis with histone deacetylase inhibition in vivo
Gurvich, N., Berman, M. G., Wittner, B. S., Gentleman, R. C., Klein, P. S., & Green, J. B. A. (2005) · The FASEB Journal · doi:10.1096/fj.04-3425fje · Cited by 191 · see citing works
A male with fetal valproate syndrome and autism
Williams, P. G., & Hersh, J. H. (1997) · Developmental Medicine & Child Neurology · doi:10.1111/j.1469-8749.1997.tb07500.x · Cited by 182 · see citing works
Birth defects after prenatal exposure to antiepileptic drugs
Perucca, E. (2005) · The Lancet Neurology · doi:10.1016/s1474-4422(05)70224-6 · Cited by 180 · see citing works
Malformation Rates in Children of Women with Untreated Epilepsy
Fried, S., Kozer, E., Nulman, I., Einarson, T. R., & Koren, G. (2004) · Drug Safety · doi:10.2165/00002018-200427030-00004 · Cited by 159 · see citing works
Wegner, C., & Nau, H. (1992) · PubMed · Cited by 158 · see citing works
Teratogenicity of valproic acid
Dalens, B. J., Raynaud, E., & Gaulme, J. (1980) · The Journal of Pediatrics · doi:10.1016/s0022-3476(80)80517-8 · Cited by 155 · see citing works
Spectrum of neural-tube defects in 34 infants prenatally exposed to antiepileptic drugs.
Lindhout, D., Omtzigt, J. G. C., & Cornel, M. C. (1992) · PubMed · Cited by 155 · see citing works
Valproic acid‐induced spina bifida: A mouse model
Ehlers, K., Stürje, H., Merker, H., & Nau, H. (1992) · Teratology · doi:10.1002/tera.1420450208 · Cited by 150 · see citing works
Lindhout, D., & Omtzigt, J. G. C. (1994) · Epilepsia · doi:10.1111/j.1528-1157.1994.tb05952.x · Cited by 140 · see citing works
Evaluation of valproic acid (VPA) developmental toxicity and pharmacokinetics in Sprague-Dawley rats
Binkerd, P. E. (1988) · Fundamental and Applied Toxicology · doi:10.1016/0272-0590(88)90112-1 · Cited by 140 · see citing works
Epilepsy, pregnancy, and the child
Janz, D. (1982) · Raven Press eBooks · Cited by 139 · see citing works
Eriksson, K. J., Viinikainen, K., Mönkkönen, A., Äikiä, M., Nieminen, P., Heinonen, S. T., & Kälviäinen, R. K. (2005) · Epilepsy Research · doi:10.1016/j.eplepsyres.2005.06.001 · Cited by 139 · see citing works
Bennett, P. N. (2011) · Cited by 136 · see citing works
The Role of Pharmacogenetics in the Metabolism of Antiepileptic Drugs
Klotz, U. E. (2007) · Clinical Pharmacokinetics · doi:10.2165/00003088-200746040-00001 · Cited by 132 · see citing works
The Course and Outcome of Pregnancy in Women with Epilepsy
Bjerkedal, T., & Bahna, S. L. (1973) · Acta Obstetricia Et Gynecologica Scandinavica · doi:10.3109/00016347309158321 · Cited by 131 · see citing works
Ornoy, A. (2006) · Reproductive Toxicology · doi:10.1016/j.reprotox.2006.03.014 · Cited by 130 · see citing works
Self-citationOrnoy, A. (2003) · Toxicology Letters · doi:10.1016/s0378-4274(02)00505-2 · Cited by 126 · see citing works
Self-citationKini, U., Adab, N., Vinten, J., Fryer, A., & Clayton‐Smith, J. (2005) · Archives of Disease in Childhood Fetal & Neonatal · doi:10.1136/adc.2004.067421 · Cited by 110 · see citing works
The Australian Register of Antiepileptic Drugs in Pregnancy: The first 1002 pregnancies
Vajda, F. J. E., Hitchcock, A. A., Graham, J. E., et al. (2007) · Australian and New Zealand Journal of Obstetrics and Gynaecology · doi:10.1111/j.1479-828x.2007.00781.x · Cited by 109 · see citing works
Dravet, C., Julian, C., Legras, C., et al. (1992) · PubMed · Cited by 108 · see citing works
Increased oxidative stress in epileptic children treated with valproic acid
Verrotti, A., Scardapane, A., Franzonı, E., et al. (2008) · Epilepsy Research · doi:10.1016/j.eplepsyres.2007.11.005 · Cited by 107 · see citing works
Mawer, G. E., Clayton‐Smith, J., Coyle, H., & Kini, U. (2002) · Seizure · doi:10.1016/s1059-1311(02)00135-8 · Cited by 104 · see citing works
Antiepileptic drug treatment in pregnancy: drug side effects in the neonate and neurological outcome
Koch, S., Jäger‐Roman, E., Lösche, G., Nau, H., Rating, D., & Helge, H. (1996) · Acta Paediatrica · doi:10.1111/j.1651-2227.1996.tb14137.x · Cited by 103 · see citing works
Wiltse, J. A. (2005) · Critical Reviews in Toxicology · doi:10.1080/10408440591007403 · Cited by 102 · see citing works
Narotsky, M. G. (1994) · Fundamental and Applied Toxicology · doi:10.1006/faat.1994.1029 · Cited by 101 · see citing works
Is benzodiazepine use during pregnancy really teratogenic?
Ornoy, A., Arnon, J., Shechtman, S., Moerman, L., & Lukashova, I. (1998) · Reproductive Toxicology · doi:10.1016/s0890-6238(98)00035-5 · Cited by 100 · see citing works
Self-citationPossible teratogenicity of valproic acid
Gómez, M. R. (1981) · The Journal of Pediatrics · doi:10.1016/s0022-3476(81)80743-3 · Cited by 100 · see citing works
Major malformations with valproic acid.
Koren, G., Nava‐Ocampo, A. A., Moretti, M. E., Sussman, R., & Nulman, I. (2006) · Europe PMC (PubMed Central) · Cited by 98 · see citing works
Fetal valproate syndrome: is there a recognisable phenotype?
Winter, R. M., Donnai, D., Burn, J., & Tucker, S. M. (1987) · Journal of Medical Genetics · doi:10.1136/jmg.24.11.692 · Cited by 95 · see citing works
Management issues for women with epilepsy
Yerby, M. S. (2003) · Neurology · doi:10.1212/wnl.61.6_suppl_2.s23 · Cited by 94 · see citing works
Pregnancy Outcome after In Utero Exposure to Valproate
Diav‐Citrin, O., Shechtman, S., Bar‐Oz, B., Cantrell, D., Arnon, J., & Ornoy, A. (2008) · CNS Drugs · doi:10.2165/00023210-200822040-00004 · Cited by 91 · see citing works
Self-citationDawson, J., Raymond, A. F., & Winn, L. M. (2005) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2005.07.008 · Cited by 87 · see citing works
Valproic Acid Teratogenicity: A Toxicogenomics Approach
Kultima, K., Nyström, A., Scholz, B., Gustafson, A.-L., Dencker, L., & Stigson, M. (2004) · Environmental Health Perspectives · doi:10.1289/txg.7034 · Cited by 87 · see citing works
Hendrickx, A. G., Nau, H., Binkerd, P. E., Rowland, J. M., Rowland, J. R., Cukierski, M. J., & Cukierski, M. A. (1988) · Teratology · doi:10.1002/tera.1420380405 · Cited by 83 · see citing works
von Unruh, G., Froescher, W., Hoffmann, F., & Niesen, M. (1984) · Therapeutic Drug Monitoring · doi:10.1097/00007691-198409000-00003 · Cited by 80 · see citing works
Inhibition of histone deacetylase as a new mechanism of teratogenesis
Menegola, E., Renzo, F. D., Broccia, M. L., & Giavini, E. (2006) · Birth Defects Research Part C Embryo Today Reviews · doi:10.1002/bdrc.20082 · Cited by 77 · see citing works
Pregnancy, Teratogenesis, and Epilepsy
Yerby, M. S. (1994) · Neurologic Clinics · doi:10.1016/s0733-8619(18)30075-6 · Cited by 76 · see citing works
Pittschieler, S., Brezinka, C., Jahn, B., Trinka, E., Unterberger, I., Dobesberger, J., Walser, G., Auckenthaler, A., Embacher, N., Bauer, G., et al. (2008) · Journal of Neurology · doi:10.1007/s00415-008-0029-1 · Cited by 74 · see citing works
Genton, P., Semah, F., & Trinka, E. (2006) · Drug Safety · doi:10.2165/00002018-200629010-00001 · Cited by 72 · see citing works
Elmazar, M. M. (1992) · Fundamental and Applied Toxicology · doi:10.1016/0272-0590(92)90137-7 · Cited by 71 · see citing works
Vitamin E decreases valproic acid induced neural tube defects in mice
Deeb, S. A., Moutaery, K. A., Arshaduddin, M., & Tariq, M. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(00)01457-9 · Cited by 67 · see citing works
Viinikainen, K., Eriksson, K. J., Mönkkönen, A., et al. (2006) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2006.08.007 · Cited by 64 · see citing works
Valproate embryopathy in three sets of siblings: Further proof of hereditary susceptibility
Malm, H. T., Kajantie, E., Kivirikko, S., et al. (2002) · Neurology · doi:10.1212/wnl.59.4.630 · Cited by 63 · see citing works
Craig, J. J., Morrison, P. J., Morrow, J. I., et al. (1999) · Seizure · doi:10.1053/seiz.1999.0283 · Cited by 62 · see citing works
Wegner, C., & Nau, H. (1991) · Reproductive Toxicology · doi:10.1016/0890-6238(91)90017-a · Cited by 61 · see citing works
Ehlers, K., Elmazar, M. M., & Nau, H. (1996) · Journal of Nutrition · doi:10.1093/jn/126.1.67 · Cited by 60 · see citing works
Danielsson, B. R. G., Danielsson, C., & Nilsson, M. F. (2007) · Reproductive Toxicology · doi:10.1016/j.reprotox.2007.04.005 · Cited by 60 · see citing works
Valproate teratogenicity and epilepsy syndrome
Bromfield, E. B., Dworetzky, B. A., Wyszynski, D. F., et al. (2008) · Epilepsia · doi:10.1111/j.1528-1167.2008.01696.x · Cited by 56 · see citing works
Nicolai, J., Vles, J. S. H., & Aldenkamp, A. P. (2008) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2008.03.004 · Cited by 53 · see citing works
Laegreid, L. M., Kyllerman, M., Hedner, T., Hagberg, B. A., & Viggedahl, G. (1993) · Neuropediatrics · doi:10.1055/s-2008-1071520 · Cited by 53 · see citing works
Biochemical and Molecular Teratology of Fetal Hydantoin Syndrome
Buehler, B. A., Rao, V., & Finnell, R. H. (1994) · Neurologic Clinics · doi:10.1016/s0733-8619(18)30074-4 · Cited by 53 · see citing works
Male Infertility: Possible Association with Valproate Exposure
Yerby, M. S., & McCoy, G. B. (1999) · Epilepsia · doi:10.1111/j.1528-1157.1999.tb00752.x · Cited by 50 · see citing works
Holmes, L. B., Coull, B. A., Dorfman, J. D., & Rosenberger, P. B. (2005) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2004.08.048 · Cited by 48 · see citing works
Induction of the homeotic gene Hoxa1 through valproic acid's teratogenic mechanism of action
Stodgell, C., Ingram, J. L., O’Bara, M. A., Tisdale, B., Nau, H., & Rodier, P. M. (2006) · Neurotoxicology and Teratology · doi:10.1016/j.ntt.2006.08.004 · Cited by 47 · see citing works
Rodríguez‐Pinilla, E., Mejías, C., Prieto‐Merino, D., et al. (2008) · Drug Safety · doi:10.2165/00002018-200831060-00008 · Cited by 46 · see citing works
Proximal phocomelia and radial ray aplasia in fetal valproic syndrome
Verloès, A., Frikiche, A., Gremillet, C., et al. (1990) · European Journal of Pediatrics · doi:10.1007/bf02106290 · Cited by 42 · see citing works
Ring chromosome 22 and autism: Report and review
MacLean, J. E., Teshima, I. E., Szatmári, P., & Nowaczyk, M. G. J. M. (2000) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(20000228)90:5 · Cited by 35 · see citing works
Kini, U., Lee, R., Jones, A., et al. (2007) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2007.08.002 · Cited by 34 · see citing works
Developing diagnostic criteria for the fetal anticonvulsant syndromes
Dean, J., Moore, S., & Turnpenny, P. D. (2000) · Seizure · doi:10.1053/seiz.2000.0392 · Cited by 31 · see citing works
Excretion of Valproic Acid into Semen of Rabbits and Man
Swanson, B. N., Harland, R. C., DICKINSON, R. G., et al. (1978) · Epilepsia · doi:10.1111/j.1528-1157.1978.tb05034.x · Cited by 31 · see citing works
Should valproate be taken during pregnancy?
Eadie, M. J., & Vajda, F. J. E. (2005) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.1.1.21.53605 · Cited by 26 · see citing works
Janz, D. (1994) · Journal of Perinatal Medicine · doi:10.1515/jpme.1994.22.5.367 · Cited by 24 · see citing works
Effect of valproic acid on fetal and maternal organs in the mouse: A morphological study
Emmanouil-Nikoloussi, E.-N., Foroglou, N., Kerameos-Foroglou, C., et al. (2004) · Morphologie · doi:10.1016/s1286-0115(04)97999-4 · Cited by 20 · see citing works
Isolated Fetal Bilateral Radial Ray Reduction Associated with Valproic Acid Usage
Langer, B., Haddad, J., Gasser, B., et al. (2009) · Fetal Diagnosis and Therapy · doi:10.1159/000263924 · Cited by 19 · see citing works
Prenatal exposure to antiepileptic drugs
Perucca, E., & Tomson, T. (2006) · The Lancet · doi:10.1016/s0140-6736(06)68627-3 · Cited by 18 · see citing works
[Is valproic acid teratogenic?].
Robert, E., Robert, J., & Lapras, C. (1983) · PubMed · Cited by 16 · see citing works
Differential transplacental binding of valproic acid: influence of free fatty acids.
Albani, F., Riva, R., Contin, M., et al. (1984) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.1984.tb02414.x · Cited by 15 · see citing works
Omphalocele in a newborn baby exposed to sodium valproate in utero
Boussemart, T., Bonneau, D., Berthier, M., et al. (1995) · European Journal of Pediatrics · doi:10.1007/bf01954275 · Cited by 13 · see citing works
Lung hypoplasia – a possible teratogenic effect of valproate
Janas, M. S., Arrøe, M., HANSEN, S. H., et al. (1998) · Apmis · doi:10.1111/j.1699-0463.1998.tb01350.x · Cited by 12 · see citing works
Microsatellites proximal to leptin and leptin receptor as risk factors for spina bifida
Shaw, G. M., Barber, R. C., Todoroff, K., Lammer, E. J., & Finnell, R. H. (2000) · Teratology · doi:10.1002/(sici)1096-9926(200003)61:3 · Cited by 12 · see citing works
Fetal valproate syndrome with reduction deformity of limb
Okada, T., Tomoda, T., Hisakawa, H., et al. (1995) · Pediatrics International · doi:10.1111/j.1442-200x.1995.tb03686.x · Cited by 9 · see citing works
Irwin (2001) · doi:10.1002/1096-8628(20010115)98:2
Rodier (1996) · doi:10.1002/(sici)1096-9861(19960624)370:2
Flagged first, then by citations
Cited by
Sorted by citations
Sgritta, M., Dooling, S. W., Buffington, S. A., Momin, E. N., Francis, M. B., Britton, R. A., & Costa-Mattioli, M. (2019) · Neuron · doi:10.1016/j.neuron.2018.11.018 · Cited by 865 · see citing works
Experience and the developing prefrontal cortex
Kolb, B., Mychasiuk, R., Muhammad, A., Li, Y., Frost, D. O., & Gibb, R. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1121251109 · Cited by 564 · see citing works
Adams, J. B., Audhya, T., McDonough-Means, S., Rubin, R. A., Quig, D., Geis, E., Gehn, E., Loresto, M., Mitchell, J., Atwood, S., et al. (2011) · Nutrition & Metabolism · doi:10.1186/1743-7075-8-34 · Cited by 442 · see citing works
Altered gut microbiota and activity in a murine model of autism spectrum disorders
de Theije, C. G. M., Wopereis, H., Ramadan, M., van Eijndthoven, T., Lambert, J., Knol, J., Garssen, J., Kraneveld, A. D., & Oozeer, R. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2013.12.005 · Cited by 433 · see citing works
Therapeutic potential of mood stabilizers lithium and valproic acid:Beyond bipolar disorder
Chiu, C.-T., Wang, Z., Hunsberger, J. G., & Chuang, D.-M. (2013) · Pharmacological Reviews · doi:10.1124/pr.111.005512 · Cited by 404 · see citing works
Kataoka, S., Takuma, K., Hara, Y., Maeda, Y., Ago, Y., & Matsuda, T. (2013) · International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711001714 · Cited by 341 · see citing works
Prenatal factors associated with autism spectrum disorder (ASD)
Ornoy, A., Weinstein-Fudim, L., & Ergaz, Z. (2015) · Reproductive Toxicology · doi:10.1016/j.reprotox.2015.05.007 · Cited by 238 · see citing works
Self-citationAutism Spectrum Disorders and Epigenetics
Grafodatskaya, D., Chung, B., Szatmari, P., & Weksberg, R. (2010) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2010.05.005 · Cited by 235 · see citing works
An epigenetic framework for neurodevelopmental disorders: From pathogenesis to potential therapy
Millan, M. J. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.11.015 · Cited by 229 · see citing works
Antiepileptic drugs and pregnancy outcomes
Wlodarczyk, B. J., Palacios, A. M., George, T. M., & Finnell, R. H. (2012) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.35438 · Cited by 138 · see citing works
Prenatal environmental risk factors for autism spectrum disorder and their potential mechanisms
Love, C., Sominsky, L., O’Hely, M., Berk, M., Vuillermin, P., & Dawson, S. L. (2024) · BMC Medicine · doi:10.1186/s12916-024-03617-3 · Cited by 110 · see citing works
Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism
Kim, J.-W., Seung, H., Kim, K. C., Gonzales, E. L. T., Oh, H. A., Yang, S. M., Ko, M. J., Han, S.-H., Banerjee, S., & Shin, C. Y. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.09.014 · Cited by 102 · see citing works
Effects of Rat Prenatal Exposure to Valproic Acid on Behaviour and Neuro-Anatomy
Mychasiuk, R., Richards, S., Nakahashi, A., Kolb, B., & Gibb, R. (2012) · Developmental Neuroscience · doi:10.1159/000341786 · Cited by 82 · see citing works
Beversdorf, D. Q., & MISSOURI AUTISM SUMMIT CONSORTIUM* (2016) · Journal of Developmental & Behavioral Pediatrics · doi:10.1097/dbp.0000000000000351 · Cited by 74 · see citing works
Hara, Y., Ago, Y., Higuchi, M., Hasebe, S., Nakazawa, T., Hashimoto, H., Matsuda, T., & Takuma, K. (2017) · Hormones and Behavior · doi:10.1016/j.yhbeh.2017.09.013 · Cited by 61 · see citing works
Schieve, L. A., Tian, L. H., Baio, J., Rankin, K., Rosenberg, D., Wiggins, L., Maenner, M. J., Yeargin-Allsopp, M., Durkin, M., Rice, C., et al. (2014) · Annals of Epidemiology · doi:10.1016/j.annepidem.2013.12.014 · Cited by 50 · see citing works
Sabers, A., Bertelsen, F. C. B., Scheel-Krüger, J., Nyengaard, J. R., & Møller, A. (2014) · Neuroscience Letters · doi:10.1016/j.neulet.2014.07.036 · Cited by 43 · see citing works
Raza, S., Harker, A., Richards, S., Kolb, B., & Gibb, R. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.12.055 · Cited by 37 · see citing works
Lee, H. J., Dreyfus, C., & DiCicco‐Bloom, E. (2016) · Developmental Neurobiology · doi:10.1002/dneu.22359 · Cited by 34 · see citing works
On the complex relationship between genes and environment in the etiology of autism
Engel, S. M., & Daniels, J. L. (2011) · Epidemiology · doi:10.1097/ede.0b013e31821daf1c · Cited by 28 · see citing works
Mood-Stabilizing Anticonvulsants, Spina Bifida, and Folate Supplementation: Commentary
Patel, N., Viguera, A. C., & Baldessarini, R. J. (2018) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000000813 · Cited by 23 · see citing works
- Authors
- Ornoy, A.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Ornoy, Asher
- ORCID
- Ornoy, Asher
- Venue
- Reproductive Toxicology
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 28
- Issue
- 1
- Pages
- 1-10
- ISSN
- 0890-6238 (ISSN-L)
- OpenAlex
- W2082629538
- Cited by
- 526
- References
- 108
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 23 · 2023: 40 · 2022: 35 · 2021: 32 · 2020: 39 · 2019: 24 · 2018: 39 · 2017: 37 · 2016: 39 · 2015: 38 · 2014: 26 · 2013: 34 · 2012: 26
- FWCI
- 3.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Reproductive Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy and Medication Impact
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Keywords
- valproic acid, teratogenicity, pregnancy, spina bifida, neural tube defects, autism spectrum disorder, developmental disorders, antiepileptic drugs, drug interactions, dose reduction, folic acid supplementation, histone deacetylase inhibition, oxidative stress, fetal growth restriction
- MeSH terms
- Abnormalities, Drug-Induced, Adolescent, Animals, Anticonvulsants, Autistic Disorder, Child, Child Development, Child, Preschool, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Interactions, Embryo, Mammalian, Female, Fetus, Folic Acid, Humans, Infant, Maternal-Fetal Exchange, Milk, Human, Nervous System Diseases, Neural Tube Defects, Placenta, Pregnancy, Prenatal Exposure Delayed Effects, Semen, Syndrome, Teratogens, Valproic Acid, Risk Assessment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
