MANORI WIJAYATH STAFF SPECIALIST- NEUROLOGY WOMEN WITH EPILEPSY MANORI WIJAYATH STAFF SPECIALIST- NEUROLOGY

PREVALENCE OF EPILEPSY IN WOMEN Commonest medical condition in pregnant female USA- Year 2000, 3-5 /1000 births are for WWE Australia - 1500–2000 women on AEDs become pregnant each year

WOMEN WITH EPILEPSY (WWE) Pregnancy Pregnancy complications PIH, LSCS, premature labour, miscarriages, bleeding Seizure frequency and seizure freedom Management Medications medication related foetal complications Lactation Contraception

Sz free: 66.6% continuing:33.4% Seizure control and treatment changes in pregnancy: Observations from the EURAP epilepsy pregnancy registry Epilepsia, 54(9):1621–1627, 2013 Prospective 3,806 pregnancies of 3,451 WWE on AEDs (monotherapy with CBZ,LTG,PB,VPA) Enrolment : 8.9/40 (SD 3.3) IGE: 39.3%, Focal: 47.01%, undetermined: 13.6% Sz Frequency Sz free: 66.6% continuing:33.4% Sz freedom for at least 9 months prior to pregnancy - 84–92% chance of remaining sz free 1st vs 2/3 T Unchanged 70.5% Reduction 12% Increase 15.8%

DO WWE HAVE AN INCREASED RISK OF PREGNANCY-RELATED COMPLICATIONS? Class I study (Viinikainen et al., 2006)-n=179 Cesarean instrumental delivery Preeclampsia/ PIH No significantly increased risk of above BUT lack statistical precision to comment of an increased risk Premature contractions and premature labour and delivery Non smoking – no increase Smoking- substantial increase Spontaneous abortion- inadequate data

Perinatal foetal outcome with intrauterine AED exposure

Worsening of sz in 2nd than 1st T LTG- (19.9%) than in those exposed to CBZ (14.6%, p < 0.001), PB (11.7%, p < 0.01), or during delivery in 2.6% of pregnancies exposed to CBZ and to LTG, in 1.9% of those exposed to PB, and in 1.4% of those exposed to VPAVPA (13.2%, p < 0.0001). The mean dose increase from the first to the third trimester was 5% for CBZ, 26% for LTG, 11% for PB, and 6% for VPA. Adding a second AED was more common among LTG pregnancies (58/1,251 4.6%, p < 0.0001)

*Adverse effects of AEDs on the foetus are dose-dependent Facts to remember in Rx *Altered pharmacokinetics- eg- pronounced decline in serum concentrations for AEDs eliminated by glucuronidation (UGT) *Adverse effects of AEDs on the foetus are dose-dependent (Meador et al., 2009a; Tomson et al.,2011; Hernandez-Diaz et al., 2012;) *Aim at reducing GTCS- maternal and foetal morbidity and mortality *Review and possibly revise treatment well before conception *Titrate to the lowest effective dose before pregnancy (Harden et al., 2009, Tomson & Battino, 2012)

Recurrent GTCS>4/SE Foetal loss malformations Epilepsy Seizures AEDs Recurrent GTCS>4/SE Foetal loss malformations Poor cognitive development neurocognitive (Adab et al., 2004; Meador et al., 2009b) effects

free concentrations may be preferable in such situations- PHT, VPA (Johannessen & Tomson, 2006; Patsalos et al., 2008) pH, gastric emptying, intestinal motility No Rx failures LTG, OXC, Variable, cannot predict (Tomson & Battino, 2007; Patsalos et al., 2008

TREND Utilization of antiepileptic drugs during pregnancy: the EURAP registry -1999-2005

LAMOTRIGINE LTG clearance markedly increases in late pregnancy (Ohman et al., 2008; Pennell et al., 2008; Tomson et al., 2013)   55% protein bound met by UGT decline markedly (50-60%) Starts in T1 marked in mid T3trimester less pronounced when combined with VPA Rapid return to pre pregnant level post delivery starts D1 and completed in 2 to 3/52 postpartum

AED Metabolism Protein binding Change to [serum] monitoring Carbamazepine   Phenytoin  Phenobarbital Valproate Topiramate Levetiracetam Oxcarbazepine  MHD- mono-hydroxycarbazepine Hepatic, CYP  Hepatic, CYP Hepatic, glucuronidation Kidney 75% 90% 50% >90% 15% - 40% Total-9–12% Unbound- minimal change Total-55% Unbound- 25%    55% T3 Total-40% 30% to 40% T3 Variable 40%-60% - T3(VARIABLE) 30-40% Corrected 7-8days PP Advisable  Advisable   Needed Insufficient evidence NA If available

AEDs whose pharmacokinetic properties are affected, the extent variable between individuals. Polytherapy makes it even more difficult to predict

What should we monitor? AAN/AES guidelines

MAJOR CONGENITAL MALFORMATIONS heart malformations, (VSD) orofacial defects, (cleft lip/cleft palate) urologic defects, (hypospadias) skeletal abnormalities, (radial ray defects, phalangeal hypoplasia, ) neural tube defects. (spina bifida) (Meador et al. 2008a)

Mechanism? Uncertain folate deficiency, ischemia, neuronal suppression, reactive intermediates (e.g. free radicals or epoxides) AED-induced neuronal apoptosis  T1exposure- highest risk of anatomical defects T3exposure- highest risk of behavioural

Anatomical terratogenesis MCMs- 4.5% as opposed to 2.1% in controls Increased risk for MCMs only with VPA(5.6%, p = 0.005) AED polytherapy (8.6%,p = 0.02) (Meador et al. 2008a) VPA as mono or in poly has the highest risk dose-dependent esp VPA and LTG

Behavioural terratogenesis WWE on RX neuronal apoptosis in neonatal rat brain -Clon, Diaz, PB, PHT, synergistic effect of two AEDs, given at below threshold dosages AEDs inherently not producing apoptosis in monotherapy, (CBZ, LTG and TPM) can enhance apoptosis induced by another WWE no RX No difference to normal controls

Doses during pregnancy ? Sz freq in unRx WWE? Exposure to antiepileptic drugs in utero and child development: A prospective population-based study *†Gyri Veiby, ‡§Anne K. Daltveit, ¶Synnve Schjølberg, ‡¶Camilla Stoltenberg, ¶#Anne-Siri Øyen, ‡¶Stein E. Vollset, *†Bernt A. Engelsen, and *†Nils E. Gilhus Doses during pregnancy ? Sz freq in unRx WWE?

FOLIC ACID Insufficient data but 2x class II studies proved benefit Recommend- 0.4mg, preceonception (AAN) Vit K Inadequate evidence Practise- If enzyme-inducing AEDs used, routinely receive vitamin K at delivery (AAN)

AEDs and lactation Safe short t ½ >80% protein bound Contraindications Long t ½- cumulative effect- sedation with BDZ High milk to plasma ratio- ETX, ZNS Most 1st G AEDs can be considered safe VPA, CBZ, PB, PHT, Primidone 2nd G AEDs- not much known clinically significant amounts in BM – LEV, LTG, OXC, TPM but therotical infant dose < therapeutic dose for neonates considered moderately safe ***remember to drop the LTG dose, PP

AED and contraception COCP, levenogestral implants- avoid with CBZ, PHT, PB, TPM, OXC Start with oestradiol >50mcg/day Preferred – intrauterine device/Depo- 10wkly COCP can reduce the LTG level – 25-70%

Australian Pregnancy Registry THANK YOU Australian Pregnancy Registry