Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability

Jill Clayton-smith, Rebecca Bromley, John Dean, Hubert Journel, Sylvie Odent, Amanda Wood, Janet Williams, Verna Cuthbert, Latha Hackett, Neelo Aslam, Heli Malm, Gregory James, Lena Westbom, Ruth Day, Edmund Ladusans, Adam Jackson, Iain Bruce, Robert Walker, Sangeet Sidhu, Catrina DyerJane Ashworth, Daniel Hindley, Gemma Arca Diaz, Myfanwy Rawson, Peter Turnpenny

Research output: Contribution to journalArticle

Abstract

Background
A pattern of major and minor congenital anomalies, facial dysmorphic features, and neurodevelopmental difficulties, including cognitive and social impairments has been reported in some children exposed to sodium valproate (VPA) during pregnancy. Recognition of the increased risks of in utero exposure to VPA for congenital malformations, and for the neurodevelopmental effects in particular, has taken many years but these are now acknowledged following the publication of the outcomes of several prospective studies and registries. As with other teratogens, exposure to VPA can have variable effects, ranging from a characteristic pattern of major malformations and significant intellectual disability to the other end of the continuum, characterised by facial dysmorphism which is often difficult to discern and a more moderate effect on neurodevelopment and general health. It has become clear that some individuals with FVSD have complex needs requiring multidisciplinary care but information regarding management is currently lacking in the medical literature.

Methods
An expert group was convened by ERN-ITHACA, the European Reference Network for Congenital Malformations and Intellectual Disability comprised of professionals involved in the care of individuals with FVSD and with patient representation. Review of published and unpublished literature concerning management of FVSD was undertaken and the level of evidence from these sources graded. Management recommendations were made based on strength of evidence and consensus expert opinion, in the setting of an expert consensus meeting. These were then refined using an iterative process and wider consultation.

Results
Whilst there was strong evidence regarding the increase in risk for major congenital malformations and neurodevelopmental difficulties there was a lack of high level evidence in other areas and in particular in terms of optimal clinical management.. The expert consensus approach facilitated the formulation of management recommendations, based on literature evidence and best practice. The outcome of the review and group discussions leads us to propose the term Fetal Valproate Spectrum Disorder (FVSD) as we feel this better encompasses the broad range of effects seen following VPA exposure in utero.

Conclusion
The expert consensus approach can be used to define the best available clinical guidance for the diagnosis and management of rare disorders such as FVSD. FVSD can have medical, developmental and neuropsychological impacts with life-long consequences and affected individuals benefit from the input of a number of different health professionals.
Original languageEnglish
Article number180
JournalOrphanet Journal of Rare Diseases
Volume14
Issue number1
DOIs
Publication statusPublished - 19 Jul 2019

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Valproic Acid
Intellectual Disability
Consensus
Teratogens
Information Management
Health
Expert Testimony
Practice Guidelines
Registries
Publications
Referral and Consultation
Prospective Studies
Pregnancy

Bibliographical note

© The Author(s). 2019 Open Access This article is 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, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Keywords

  • Antiepileptic drug
  • Expert consensus
  • Fetal valproate syndrome
  • Guideline
  • Management
  • Teratogen

Cite this

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. In: Orphanet Journal of Rare Diseases. 2019 ; Vol. 14, No. 1.
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abstract = "BackgroundA pattern of major and minor congenital anomalies, facial dysmorphic features, and neurodevelopmental difficulties, including cognitive and social impairments has been reported in some children exposed to sodium valproate (VPA) during pregnancy. Recognition of the increased risks of in utero exposure to VPA for congenital malformations, and for the neurodevelopmental effects in particular, has taken many years but these are now acknowledged following the publication of the outcomes of several prospective studies and registries. As with other teratogens, exposure to VPA can have variable effects, ranging from a characteristic pattern of major malformations and significant intellectual disability to the other end of the continuum, characterised by facial dysmorphism which is often difficult to discern and a more moderate effect on neurodevelopment and general health. It has become clear that some individuals with FVSD have complex needs requiring multidisciplinary care but information regarding management is currently lacking in the medical literature.MethodsAn expert group was convened by ERN-ITHACA, the European Reference Network for Congenital Malformations and Intellectual Disability comprised of professionals involved in the care of individuals with FVSD and with patient representation. Review of published and unpublished literature concerning management of FVSD was undertaken and the level of evidence from these sources graded. Management recommendations were made based on strength of evidence and consensus expert opinion, in the setting of an expert consensus meeting. These were then refined using an iterative process and wider consultation.ResultsWhilst there was strong evidence regarding the increase in risk for major congenital malformations and neurodevelopmental difficulties there was a lack of high level evidence in other areas and in particular in terms of optimal clinical management.. The expert consensus approach facilitated the formulation of management recommendations, based on literature evidence and best practice. The outcome of the review and group discussions leads us to propose the term Fetal Valproate Spectrum Disorder (FVSD) as we feel this better encompasses the broad range of effects seen following VPA exposure in utero.ConclusionThe expert consensus approach can be used to define the best available clinical guidance for the diagnosis and management of rare disorders such as FVSD. FVSD can have medical, developmental and neuropsychological impacts with life-long consequences and affected individuals benefit from the input of a number of different health professionals.",
keywords = "Antiepileptic drug, Expert consensus, Fetal valproate syndrome, Guideline, Management, Teratogen",
author = "Jill Clayton-smith and Rebecca Bromley and John Dean and Hubert Journel and Sylvie Odent and Amanda Wood and Janet Williams and Verna Cuthbert and Latha Hackett and Neelo Aslam and Heli Malm and Gregory James and Lena Westbom and Ruth Day and Edmund Ladusans and Adam Jackson and Iain Bruce and Robert Walker and Sangeet Sidhu and Catrina Dyer and Jane Ashworth and Daniel Hindley and Diaz, {Gemma Arca} and Myfanwy Rawson and Peter Turnpenny",
note = "{\circledC} The Author(s). 2019 Open Access This article is 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, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.",
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month = "7",
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doi = "10.1186/s13023-019-1064-y",
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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 2019, '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, vol. 14, no. 1, 180. https://doi.org/10.1186/s13023-019-1064-y

Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability. / 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.

In: Orphanet Journal of Rare Diseases, Vol. 14, No. 1, 180, 19.07.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability

AU - Clayton-smith, Jill

AU - Bromley, Rebecca

AU - Dean, John

AU - Journel, Hubert

AU - Odent, Sylvie

AU - Wood, Amanda

AU - Williams, Janet

AU - Cuthbert, Verna

AU - Hackett, Latha

AU - Aslam, Neelo

AU - Malm, Heli

AU - James, Gregory

AU - Westbom, Lena

AU - Day, Ruth

AU - Ladusans, Edmund

AU - Jackson, Adam

AU - Bruce, Iain

AU - Walker, Robert

AU - Sidhu, Sangeet

AU - Dyer, Catrina

AU - Ashworth, Jane

AU - Hindley, Daniel

AU - Diaz, Gemma Arca

AU - Rawson, Myfanwy

AU - Turnpenny, Peter

N1 - © The Author(s). 2019 Open Access This article is 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, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

PY - 2019/7/19

Y1 - 2019/7/19

N2 - BackgroundA pattern of major and minor congenital anomalies, facial dysmorphic features, and neurodevelopmental difficulties, including cognitive and social impairments has been reported in some children exposed to sodium valproate (VPA) during pregnancy. Recognition of the increased risks of in utero exposure to VPA for congenital malformations, and for the neurodevelopmental effects in particular, has taken many years but these are now acknowledged following the publication of the outcomes of several prospective studies and registries. As with other teratogens, exposure to VPA can have variable effects, ranging from a characteristic pattern of major malformations and significant intellectual disability to the other end of the continuum, characterised by facial dysmorphism which is often difficult to discern and a more moderate effect on neurodevelopment and general health. It has become clear that some individuals with FVSD have complex needs requiring multidisciplinary care but information regarding management is currently lacking in the medical literature.MethodsAn expert group was convened by ERN-ITHACA, the European Reference Network for Congenital Malformations and Intellectual Disability comprised of professionals involved in the care of individuals with FVSD and with patient representation. Review of published and unpublished literature concerning management of FVSD was undertaken and the level of evidence from these sources graded. Management recommendations were made based on strength of evidence and consensus expert opinion, in the setting of an expert consensus meeting. These were then refined using an iterative process and wider consultation.ResultsWhilst there was strong evidence regarding the increase in risk for major congenital malformations and neurodevelopmental difficulties there was a lack of high level evidence in other areas and in particular in terms of optimal clinical management.. The expert consensus approach facilitated the formulation of management recommendations, based on literature evidence and best practice. The outcome of the review and group discussions leads us to propose the term Fetal Valproate Spectrum Disorder (FVSD) as we feel this better encompasses the broad range of effects seen following VPA exposure in utero.ConclusionThe expert consensus approach can be used to define the best available clinical guidance for the diagnosis and management of rare disorders such as FVSD. FVSD can have medical, developmental and neuropsychological impacts with life-long consequences and affected individuals benefit from the input of a number of different health professionals.

AB - BackgroundA pattern of major and minor congenital anomalies, facial dysmorphic features, and neurodevelopmental difficulties, including cognitive and social impairments has been reported in some children exposed to sodium valproate (VPA) during pregnancy. Recognition of the increased risks of in utero exposure to VPA for congenital malformations, and for the neurodevelopmental effects in particular, has taken many years but these are now acknowledged following the publication of the outcomes of several prospective studies and registries. As with other teratogens, exposure to VPA can have variable effects, ranging from a characteristic pattern of major malformations and significant intellectual disability to the other end of the continuum, characterised by facial dysmorphism which is often difficult to discern and a more moderate effect on neurodevelopment and general health. It has become clear that some individuals with FVSD have complex needs requiring multidisciplinary care but information regarding management is currently lacking in the medical literature.MethodsAn expert group was convened by ERN-ITHACA, the European Reference Network for Congenital Malformations and Intellectual Disability comprised of professionals involved in the care of individuals with FVSD and with patient representation. Review of published and unpublished literature concerning management of FVSD was undertaken and the level of evidence from these sources graded. Management recommendations were made based on strength of evidence and consensus expert opinion, in the setting of an expert consensus meeting. These were then refined using an iterative process and wider consultation.ResultsWhilst there was strong evidence regarding the increase in risk for major congenital malformations and neurodevelopmental difficulties there was a lack of high level evidence in other areas and in particular in terms of optimal clinical management.. The expert consensus approach facilitated the formulation of management recommendations, based on literature evidence and best practice. The outcome of the review and group discussions leads us to propose the term Fetal Valproate Spectrum Disorder (FVSD) as we feel this better encompasses the broad range of effects seen following VPA exposure in utero.ConclusionThe expert consensus approach can be used to define the best available clinical guidance for the diagnosis and management of rare disorders such as FVSD. FVSD can have medical, developmental and neuropsychological impacts with life-long consequences and affected individuals benefit from the input of a number of different health professionals.

KW - Antiepileptic drug

KW - Expert consensus

KW - Fetal valproate syndrome

KW - Guideline

KW - Management

KW - Teratogen

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