Fetal valproate spectrum disorder explained

Fetal valproate spectrum disorder
Field:Medical genetics, pediatrics
Synonyms:Fetal valproate syndrome (FVS), fetal valproic acid syndrome, valproic acid embryopathy
Symptoms:Neural tube defects, distinctive facial features, congenital heart defects, limb abnormalities, developmental delays, autism spectrum disorder
Complications:Intellectual disability, cognitive impairments, physical disabilities
Onset:Prenatal
Duration:Lifelong
Causes:Prenatal exposure to valproic acid (VPA)
Diagnosis:Based on clinical features, history of VPA exposure, diagnostic imaging, genetic counseling
Differential:Other antiepileptic drug-related fetopathies, fetal alcohol spectrum disorder
Prevention:Avoiding valproic acid during pregnancy, using alternative medications, folic acid supplementation
Treatment:Multidisciplinary management including regular monitoring, early intervention therapies, surgical correction of anomalies, supportive therapies
Prognosis:Variable; depends on severity and type of anomalies
Frequency:Rare; exact prevalence unknown, fewer than 50,000 cases in the U.S.

Fetal valproate spectrum disorder (FVSD), previously known as fetal valproate syndrome (FVS), is a rare disease caused by prenatal exposure to valproic acid (VPA), a medication commonly used to treat epilepsy, bipolar disorder, and migraines. This exposure can lead to a range of neurodevelopmental and physical symptoms, including cognitive impairments, developmental delays, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and congenital malformations.[1] [2] [3]

Overview

Valproate causes birth defects;[4] exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida with the risks being related to the strength of medication used and use of more than one drug.[5] [6] "Fetal Valproate Syndrome" (FVS) has been used to refer to the effects of valproate exposure in utero.[7] However, similar to the discussion about the adverse effect of exposure to alcohol in utero ("fetal alcohol spectrum disorder"), a 2019 study proposed the term "Fetal valproate spectrum disorder" (FVSD) because valproate exposure can lead to a wide range of possible presentations, which can be influenced by various factors (including dosage and timing of exposure). The dysmorphic features associated with VPA exposure can be subtle and age-dependent, making it challenging to designate individuals as having the characteristic dysmorphism or not, especially for those with limited expertise in the area. While the presence of typical facial dysmorphism is suggestive of the condition, it is not required for diagnosis. This change in terminology to FVSD would benefit individuals affected by the neurodevelopmental effects of VPA exposure without significant malformations, since they can experience impairments in their everyday functioning similar to those with classical FVS.[8] Characteristics of valproate syndrome may include facial features that tend to evolve with age, including a triangle-shaped forehead, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth.[9] While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.[10]

Children of mothers taking valproate during pregnancy are at risk for lower IQs.[11] [12] [13] Maternal valproate use during pregnancy increased the probability of autism in the offspring compared to mothers not taking valproate from 1.5% to 4.4%.[14] A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.[15] The normal incidence for autism in the general population in 2018 was estimated at 1 in 44 (2.3%).[16] An updated March 2023 report estimates the number increased to 1 in 36 in 2020 (approximately 4% of boys and 1% of girls).[17] A 2009 study found that the 3-year-old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.[18] [19] [20]

Sodium valproate has been associated with paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy.[21] [22]

Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate.[23] Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although valproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have worse outcomes for the fetus than exposure to valproate). Studies have shown that taking folic acid supplements can reduce the risk of congenital neural tube defects.[24] The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the European Union, Australia[25], New Zealand[26], the UK[27] and the United States, and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.[28]

Paternal exposure

A 2023 retrospective study of Norway, Denmark, and Sweden found a significantly increased risk of neurodevelopmental disabilities in the children of fathers exposed to valproate up to 3 months prior to conception, compared to offspring paternally exposed to lamotrigine/levetiracetam.[29] This led the EMA to recommend "the need to consider effective contraception, while using valproate and for at least 3 months after treatment discontinuation. Male patients should not donate sperm during treatment and for at least 3 months after treatment discontinuation."

See also

Notes and References

  1. Web site: Fetal valproate spectrum disorder. . 2024-05-31 . https://web.archive.org/web/20240530234625/https://rarediseases.info.nih.gov/diseases/5447/fetal-valproate-spectrum-disorder . 2024-05-30 . live . 2024 .
  2. Web site: Fetal valproate spectrum disorder . 2024-05-31 . . https://web.archive.org/web/20240531004121/https://www.orpha.net/en/disease/detail/1906 . 2024-05-31 . live . 2020 .
  3. Clayton-Smith . Jill . Bromley . Rebecca . Dean . John . Journel . Hubert . Odent . Sylvie . Wood . Amanda . Williams . Janet . Cuthbert . Verna . Hackett . Latha . Aslam . Neelo . Malm . Heli . James . Gregory . Westbom . Lena . Day . Ruth . Ladusans . Edmund . Jackson . Adam . Bruce . Iain . Walker . Robert . Sidhu . Sangeet . Dyer . Catrina . Ashworth . Jane . Hindley . Daniel . Diaz . Gemma Arca . Rawson . Myfanwy . Turnpenny . Peter . Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability . . December 2019 . 14 . 1 . 180 . 10.1186/s13023-019-1064-y. free . 31324220 . 6642533.
  4. https://www.bbc.com/news/world-europe-39657139 New evidence in France of harm from epilepsy drug valproate
  5. Koch S, Göpfert-Geyer I, Jäger-Roman E, Jakob S, Huth H, Hartmann A, Rating D, Helge H . [Anti-epileptic agents during pregnancy. A prospective study on the course of pregnancy, malformations and child development] . de . Deutsche Medizinische Wochenschrift . 108 . 7 . 250–257 . February 1983 . 6402356 . 10.1055/s-2008-1069536 .
  6. Moore SJ, Turnpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T, Dean JC . A clinical study of 57 children with fetal anticonvulsant syndromes . Journal of Medical Genetics . 37 . 7 . 489–497 . July 2000 . 10882750 . 1734633 . 10.1136/jmg.37.7.489 .
  7. Ornoy A . Valproic acid in pregnancy: how much are we endangering the embryo and fetus? . Reproductive Toxicology . 28 . 1 . 1–10 . July 2009 . 19490988 . 10.1016/j.reprotox.2009.02.014 . 2009RepTx..28....1O .
  8. Clayton-Smith J, Bromley R, Dean J, Journel H, Odent S, Wood A, Williams J, Cuthbert V, Hackett L, Aslam N, Malm H, James G, Westbom L, Day R, Ladusans E, Jackson A, Bruce I, Walker R, Sidhu S, Dyer C, Ashworth J, Hindley D, Diaz GA, Rawson M, Turnpenny P . Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability . Orphanet Journal of Rare Diseases . 14 . 1 . 180 . July 2019 . 31324220 . 6642533 . 10.1186/s13023-019-1064-y . free .
  9. Kulkarni ML, Zaheeruddin M, Shenoy N, Vani HN . Fetal valproate syndrome . Indian Journal of Pediatrics . 73 . 10 . 937–939 . October 2006 . 17090909 . 10.1007/bf02859291 . 38371596 .
  10. Adab N, Kini U, Vinten J, Ayres J, Baker G, Clayton-Smith J, Coyle H, Fryer A, Gorry J, Gregg J, Mawer G, Nicolaides P, Pickering L, Tunnicliffe L, Chadwick DW . The longer term outcome of children born to mothers with epilepsy . Journal of Neurology, Neurosurgery, and Psychiatry . 75 . 11 . 1575–1583 . November 2004 . 15491979 . 1738809 . 10.1136/jnnp.2003.029132 . This argues that the fetal valproate syndrome constitutes a real clinical entity that includes developmental delay and cognitive impairments, but that some children might exhibit some developmental delay without marked dysmorphism. .
  11. 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 . Child's Nervous System . 28 . 5 . 729–737 . May 2012 . 22246336 . 10.1007/s00381-011-1673-9 . 20344828 .
  12. Web site: NEAD: In Utero Exposure To Valproate Linked to Poor Cognitive Outcomes in Kids . Cassels C . 8 December 2006 . Medscape . 23 May 2007 . live . https://web.archive.org/web/20110731160315/http://www.medscape.com/viewarticle/549073 . 31 July 2011 .
  13. Meador KJ, Baker GA, Finnell RH, Kalayjian LA, Liporace JD, Loring DW, Mawer G, Pennell PB, Smith JC, Wolff MC . In utero antiepileptic drug exposure: fetal death and malformations . Neurology . 67 . 3 . 407–412 . August 2006 . 16894099 . 1986655 . 10.1212/01.wnl.0000227919.81208.b2 .
  14. Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M . Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism . JAMA . 309 . 16 . 1696–1703 . April 2013 . 23613074 . 4511955 . 10.1001/jama.2013.2270 .
  15. Rasalam AD, Hailey H, Williams JH, Moore SJ, Turnpenny PD, Lloyd DJ, Dean JC . Characteristics of fetal anticonvulsant syndrome associated autistic disorder . Developmental Medicine and Child Neurology . 47 . 8 . 551–555 . August 2005 . 16108456 . 10.1017/S0012162205001076 . 1 November 2024 .
  16. Maenner MJ, Shaw KA, Bakian AV, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2018. MMWR Surveill Summ 2021;70(No. SS-11):1–16. DOI: http://dx.doi.org/10.15585/mmwr.ss7011a1
  17. Maenner MJ, Warren Z, Williams AR, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2020. MMWR Surveill Summ 2023;72(No. SS-2):1–14. DOI: http://dx.doi.org/10.15585/mmwr.ss7202a1
  18. https://www.nytimes.com/2009/04/16/health/research/16child.html I.Q. Harmed by Epilepsy Drug in Utero
  19. Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT, Cohen M, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW . Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs . The New England Journal of Medicine . 360 . 16 . 1597–1605 . April 2009 . 19369666 . 2737185 . 10.1056/NEJMoa0803531 .
  20. https://www.drugs.com/fda/valproate-products-safety-communication-risk-impaired-cognitive-development-children-exposed-utero-12994.html Valproate Products: Drug Safety Communication - Risk of Impaired Cognitive Development in Children Exposed In Utero (During Pregnancy)
  21. Luat AF, Asano E, Chugani HT . Paroxysmal tonic upgaze of childhood with co-existent absence epilepsy . Epileptic Disorders . 9 . 3 . 332–336 . September 2007 . 17884759 . 10.1684/epd.2007.0119 .
  22. Ouvrier RA, Billson F . Benign paroxysmal tonic upgaze of childhood . Journal of Child Neurology . 3 . 3 . 177–180 . July 1988 . 3209843 . 10.1177/088307388800300305 . 38127378 .
  23. http://www.lawyersandsettlements.com/lawsuit/valproate-not-to-be-used-migraine-during-pregnancy.html Valproate Not To Be Used for Migraine During Pregnancy, FDA Warns
  24. Web site: Depakote- divalproex sodium tablet, delayed release. 10 November 2015. live. https://web.archive.org/web/20160305202922/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08a65cf4-7749-4ceb-6895-8f4805e2b01f. 5 March 2016.
  25. Web site: Therapeutic Goods Administration . 11 July 2017 . VALPRO EC500 sodium valproate 500 mg enteric coated tablet blister pack (286316) . 24 November 2024 . Australian Register of Theraputic Goods.
  26. Web site: Information for Prescribers/Consumers Search . 2024-11-23 . www.medsafe.govt.nz.
  27. Web site: Valproate medicines (Epilim▼, Depakote▼): contraindicated in women and girls of childbearing potential unless conditions of Pregnancy Prevention Programme are met . 2024-11-23 . GOV.UK . en.
  28. Web site: New measures to avoid valproate exposure in pregnancy endorsed. 31 May 2018. European Medicines Agency. 16 October 2019. 16 October 2019. https://web.archive.org/web/20191016133949/https://www.ema.europa.eu/en/medicines/human/referrals/valproate-related-substances-0. live.
  29. Web site: PRAC non-interventional imposed PASS final study report assessment report . EMA . 34.

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