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Orphanet J Rare Dis. 2019 Jul 19;14(1):180. doi: 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.

Author information

1
Division of Evolution and Genomic Sciences School of Biological Sciences, University of Manchester, Manchester, UK. Jill.Clayton-Smith@mft.nhs.uk.
2
Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK. Jill.Clayton-Smith@mft.nhs.uk.
3
Division of Evolution and Genomic Sciences School of Biological Sciences, University of Manchester, Manchester, UK.
4
Paediatric Psychosocial Department, Royal Manchester Children's Hospital, Manchester Academic Health Sciences Centre, Manchester, UK.
5
Clinical Genetics, Clinical Genetics Service, Ashgrove House, Foresterhill, Aberdeen, UK.
6
Génétique Médicale - Consultation, CHBA Centre Hospitalier Bretagne Atlantique - CH Chubert, 20 boulevard du Général Maurice Guillaudot, BP 70555, 56017, Vannes Cedex, France.
7
Service de Génétique Clinique, CNRS UMR 6290, Université de Rennes, CHU de Rennes - Hôpital Sud, 16 Boulevard de Bulgarie, 35203, Rennes Cedex 2, France.
8
Aston Brain Centre, School of Life and Health Sciences, Aston Triangle, Birmingham, UK.
9
Brain and Mind, Clinical Sciences, Murdoch Children's Research Institute, Parkville, Melbourne, Australia.
10
INFACT/FACSA, Independent Fetal Anti-Convulsant Trust & FACS Syndrome Association, Preston, UK.
11
Department of Paediatric Rheumatology, Royal Manchester Children's Hospital, Oxford Road, Manchester, M13 9WL, UK.
12
Child and Adolescent Mental Health Services (CAMHS), Royal Manchester Children's Hospital, Oxford Road, Manchester, M13 9WL, UK.
13
Teratology Information Service, University of Helsinki and Department of Emergency Medicine and Services, Helsinki University Hospital, Tukholmankatu 17, 00029 HUS, Helsinki, Finland.
14
Department of Neurosurgery, Great Ormond Street Hospital, Great Ormond Street, London, UK.
15
Craniofacial Unit, Great Ormond Street Hospital, Great Ormond Street, London, WC1N 3JH, UK.
16
Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
17
Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
18
Lund University, Barnmed klin, SUS, Lund, Sweden.
19
Guardian Medical Centre, Guardian Street, Warrington, UK.
20
Department of Paediatric Cardiology, Royal Manchester Children's Hospital, Oxford Road, Manchester, UK.
21
Department of Neurology, Salford Royal Hospital NHS Trust, Stott Lane, Salford, UK.
22
Paediatric ENT Department, Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
23
Department of Paediatric Anaesthesia, Royal Manchester Children's Hospital, Oxford Road, Manchester, M13 9WL, UK.
24
Department of Paediatric Nephrology, Royal Manchester Children's Hospital, Oxford Road, Manchester, UK.
25
Cleft Lip and Palate Team, Royal Manchester Children's Hospital, Oxford Road, Manchester, UK.
26
Manchester Royal Eye Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
27
Community Paediatrics, Bolton NHS Foundation Trust, Breightmet Health Centre, Bolton, UK.
28
Department of Neonatology, Hospital Clinic (Maternitat), Sabino Arana 1, 08028, Barcelona, Spain.
29
Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
30
Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Gladstone Rd, Exeter, UK.

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.

KEYWORDS:

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

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