The Cornwall Anti-psychotic Pregnancy Register The background work: The UK Epilepsy & Pregnancy Register Pregnancy, Epilepsy & Safety Dr Rohit Shankar MBBS, DPM, MRCPsych, CCT, PGC Cl. Research, PGC Aspergers Consultant in Adult Developmental Neuropsychiatry –Cornwall Partnership NHS Foundation Trust Hon. Associate Professor – Exeter Medical School

Investigators Chief Investigator – Dr Rohit Shankar Researcher – Mrs Zoe Doran Co- Investigators – Dr Richard Laugharne Mrs Clare Dale Dr John Craig Professor Ian Jones Dr Darren Mackintosh Dr Adrian Flynn Dr Mike Metcalfe

Presentation Focus A case study to highlight how good evidence influences practice A model for generating good evidence base

Case Scenario 30 year old female recent history of Bipolar Disorder well managed on Sodium Valproate 1500 mgs/day suffered side effects from Lithium in the past seeks to get pregnant and wants advice on medication

management is about balance Case & Risk Management Safety of child – 1. Acute Harm – delivery and breast feeding 2. Long term effects - congenital Safety of mum – Relapse 2. Adverse effects 3. Harm Evidenced Based Medicine management is about balance

Evidence Based Medicine - Discussion Was it right for her to be on Valproate? What is the risk of Valproate – for mum and foetus? What other non –antipsychotic ‘mood stabilizers’ would you consider? What is the evidence and how strong is it?

The Evidence The risk of birth defects with valproate is 2-5 times higher than other frequently used antiepileptic drugs absolute rates of birth defects 6-11% doses over 1000 mg/day associated with almost 2 times higher risk than doses less than 1000mg/day Children born to mothers using valproate have significantly lower IQ scores (9 points) rates of autism exposed before birth in the cohort studied were 8.9% Does prescribing controlled release valproate versus multiple daily administrations in pregnancy reduce the risk for malformations? Higher malformation rates observed with in utero exposure to valproate are more likely related to total daily dose, rather than peak serum levels.

How Strong is the Evidence? Outcome data available from 1109 pregnancies exposed to valproate in monotherapy FDA Category D for Mania Category D for Epilepsy Category X – for Migraine How did we get this Evidence? A pregnancy Category D medicine may still be given to a pregnant woman if the healthcare provider believes that the benefits to the woman outweigh the possible risks to the unborn child Pregnancy Category X means that the risks of taking the medication during pregnancy clearly outweigh the benefits.

The UK Epilepsy and Pregnancy Register 1996 The UK Epilepsy and Pregnancy Register is a prospective, observational and follow up study set up to determine the risks of major congenital malformations for infants exposed to antiepileptic drugs in utero Captures roughly 1 of 3 deliveries on AEDs Devised and led by Professor Morrow and Dr Craig (co-investigator in our study)

Morrow, Russell, Guthrie et al (2006) Malformation risks of anti-epileptic drugs in pregnancy: A prospective study from the UK Epilepsy and pregnancy register. JNNP January 2006 Hunt, Craig, Russell et al (2006) Levetiracetam in pregnancy: Preliminary results from the UK Epilepsy and pregnancy register. Neurology 67 Topiramate in pregnancy: Preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 2008 Folic acid use and major congenital malformations in offspring of women with epilepsy. A prospective study from the UK Epilepsy and Pregnancy Register. JNNP 2008 (80)5:506-511 (179574 0) Cummings, Stewart, et al (2011) Neurodevelopment of children exposed in utero to Lamotrigine, sodium valproate and Carbamazepine. Arch Dis Chid. March 17th 2011 Shallcross, Bromley, Irwin et al (2011) Childevelopment following in utero Exposure: Levetiracetam Vs Sodium Valproate. Neurology: 76: 383 Hoeritzauer, Mawhinney, (2012) Increased Levetiracetam clearance in pregnancy: Is seizure frequency affected?. Seizure 21(7);559-60. Mawhinney et al (2012) Valproate and the risk for congenital malformations: Is formulation and dosage regime important. Seizure 21 215-218 Ellen Mawhinney, John Craig, Jim Morrow, et al. (2013) Levetiracetam in Pregnancy Results from the UK and Ireland epilepsy and pregnancy registers. Neurology 80(4):400-5 Campbell, E., Devenney, E., Morrow, J. et al (2013) Recurrence risk of congenital malformations in infants exposed to antiepileptic drugs in utero. Epilepsia. 54 (1) 165-171 Campbell, E., Hunt, S., Kinney, M. Et al (2013) The effect of socioeconomic status on treatment and pregnancy outcomes in women with epilepsy in Scotland. Epilepsy & Behaviour. 28 354-357 Campbell, E., Kennedy. Russell, A. et al (2014) Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers. JNNP January 2014

Notable Points A prospective Register allows longitudinal collection of data Simple, not time consuming and focused on recruitment Not dependent on ‘power’ Answer important questions on potential for harm Cost effective Can be started in different countries though it is important that the Registers can ‘speak’ to each other – i.e. the data collection tools are similar

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