Table E-1: Folate in the Reduction of Birth Defects in WWE

Table e-1: Folate in the Reduction of Birth Defects in WWE

Author / Class / Type of Study / FA Dose (mg/day) / Findings / Statistics
Comparing Malformation Rate Without and With FA:
Odds Ratio (95% confidence intervals)
Betts 1999 / III / Prospective Cohort Observational / 2.5 to 5 / 11/59 MCMs no FA vs. 0/97 MCMs with FA / by cmt (“Peto method” (Yusuf 1985))
OR 16.88 (4.79-59.52)
Kaaja 2003 / III / Prospective Observational Cohort (Epilepsy Groups all received FA, with and without AEDs) / Not stated 0.1 to 0.8 advised / 2/11 of subjects with low serum FA concentration had MCMs / Association of lower serum FA concentration and MCMs
(Logistic Regression significant for serum FA concentrations < 4.4 nmol/L; adjusted OR 5.8 (1.3-27))
p=0.02)
Vajda 2003 / III / Prospective Observational Cohort (Epilepsy Groups VPA and no AEDs) / Not stated / For VPA only:
9/10 MCMs VPA no FA vs. 35/100 MCMs
VPA with FA / By cmt
OR 1.67 (0.62-4.50)
Vajda 2004 / III / Prospective Observational Cohort / Not stated / 178/269 MCMs no FA vs. 16/23 MCMs with FA / By cmt
OR 0.86 (0.34-2.15)
Wyszynski 2005 / III / Retrospective Observational Cohort (Groups compared those receiving VPA, and other AED monotherapy, second control general population / Not stated / 72% of VPA treated WWE took FA vs 64% of WWE treated with other AEDs / VPA 16/149 (11%) developed birth defects
All 16 received FA or MVI

FA=Folic Acid

MVI=Multiple Vitamins

VPA=Valproate

MCMs=major congenital malformations

By cmt=by writing committee

OR=Odds Ratio

Table e-2: Hemorrhagic Complications with AED Exposure

Author / Class / Type of Study: Comparator Groups / Vitamin K Dose / Findings / Statistics
Comparing Bleeding Rate: Odds Ratio or Relative Risk (95% confidence intervals)
Choulika 2004 / III / Prospective Cohort:
Enzyme-inducing AED plus Vit K vs. Control plus Vit K / Newborn 1 mg IM at birth / Overall bleeding rate: AED exposed
12/169 (4.7%)
Controls
10/77 (11.6%)
Note: bleeds were bruises or petechiae, cephalohematoma or scleral hemorrhage / RR 0.51 (0.21-1.24), p=0.14
Kaaja 2002 / II / Prospective
cohort: Enzyme-inducing AED plus Vit K vs. Non-epileptic plus Vit K) / Newborn 1 mg IM at birth / Overall bleeding rate: enzyme-inducing AED exposed
5/662 (0.7%)
Controls
5/1342 (0.4%)
Logistic Regression showed no association with bleeding and exposure to enzyme-inducing AED (adjusted OR 1.1 (0.3 to 4.6) p = 0.8). / adjusted OR 1.1 (0.3 to 4.6) p = 0.8
No increased risk from AED exposure when controlling for premature delivery (<34 weeks) or other complications

Vit K=Vitamin K

IM=intramuscular

Table e-3: Placental and Breast Milk Transfer and evidence for symptomatic effects

Author / Class / Type of Study / AEDs / Placenta Transfer (cord: maternal conc.) / Breast Milk Transfer (milk: maternal conc.) / Accumulation/
Symptomatic Effects
Froesher (1984) / II / Prospective Cohort
N=19 / CBZ / CBZ =0.36
10,11-CBZ epoxide=
0.53 / 1/19 (5%) poor suckling.
CBZ no significant difference in plasma concentration with this infant.
No side effects suggesting accumulation in those with repeat assessments.
Gomita (1995) / II / Prospective Cohort
PB
Mothers n=26 Neonates n=-24 / PB / Ratio= 0.7 to 1 / Not clearly evaluable. / No signs of accumulation even with breast feeding with follow up of up to 3 to 5 months.
Ishizaki (1981) / II / Prospective Cohort / PB=6
PHT=3
VPA=4 / PB=0.95,
PHT= 0.97, VPA=1.71 / Cord VPA samples were significantly greater than maternal
t-test, p<0.001.
Poor suckling, tube feeding, jitteriness noted in 3 /6 PB-exposed infants.
No clear accumulation, however redistribution resulting in increases in PB and VPA at 2-6 days of life.
Johannessen (2005) / II / Prospective Cohort / LVT=8 / 4/8 had placental studies
ratio=1.14 (0.97-1.45) / 7/8 had lactation studies
Milk: maternal conc.= 1 (0.76-1.33) / Neonates asymptomatic and healthy during the study (up to 10 months).
No accumulation noted. Neonatal concentrations even with lactation <55.8 in most neonates.
Kuhunz (1983) / II / Prospective Cohort / CBZ=12 / CBZ=0.78 and 10,11-CBZ epoxide=0.75 / CBZ=0.39 and 10,11-CBZ epoxide=0.49 / 8/11 had sedation and/or withdrawal, 2 hospitalized. Not clearly linked to CBZ concentrations.
Kuhunz (1984) / III / Prospective Cohort / ETX=13 / 7/13 had placental transfer studies
ETX ratio=0.97 / 5/13 had milk studies.
Milk: maternal conc.=0.86 / Neonatal ETX concentrations were roughly 50% of mothers (neonate 15-40 mg/L; mother serum 28 to 84 mg/L).
Side effects were noted in 7/13 (54%) (hyper-excitability, early sedation, feeding difficulty). Two were considered severe.
Confounded- many were on PolyTx with PB, primidone.
Kuhunz (1988) / I / Prospective Cohort / PB=15, PRM=25 / Ratio PRM=0.88
PEMA=1.05
PB=0.84 / Ratio
PRM=0.72
PEMA=0.64
PB=0.36 / Neonatal and nursing concentrations done in a subset
Nursing resulted in low concentrations of PRM and PEMA in neonates.
Concentrations of PB ranged from 2 to 13 mg/L in 6 neonates studied. Free PB values increased to values that higher than mother (neonate 70-93% vs. mother 63%)
Sedation was noted in 2 neonates linked to higher free PB concentrations 90% (5.8-10 mg/L), however other neonates had similar values without side effects.
Withdrawal was noted in PRM exposed neonates.
Mirkin (1971) / II / Prospective Cohort / PHT=7 / Ratio=0.94 / 2/7 had lactation studies
Milk: maternal conc.= 0.18 to 0.45 / No neonates breast fed. PHT declined over the next 3-4 days of life. No mention of acute side effects.
Myllyen (2001) / II / Prospective Cohort
Mothersn=12 Neonates
n=15 / OXC,
10-hydroxy-10,11 di-hydroxy-CBZ (10-OH-CBZ)
10,11 trans-dihydroxy-10,11-dihydro-CBZ (10,11-D) / OXC=1.1
10-OH-CBZ =0.92
10,11-D =0.97 / No statistical difference noted in cord and maternal concentrations for OXC, 10-OH-CBZ or 10, 11-D.
No symptomatic effects mentioned or systematically examined.
Nau (1980) / II / Prospective Cohort / PRM=14 / Ratio PRM=0.99
PEMA=0.97
PB=1.0 / Ratio
PRM=0.72
PEMA=0.76
PB=0.41 / Side effects noted. Withdrawal, sedation, poor feeding happened in placental exposed 6/14 within first 5 days of birth. Two of these upon follow developed marked withdrawal (jitteriness, tremor, unmotivated crying, sleep disturbances). However, no clear difference in plasma concentration of PRM/PB/PEMA could be determined in those with and without side effects.
Nau (1981) / I / VPA
N=11 mothers, 12 neonates / VPA / 6/11 had placental studies
Ratio=1.7 / Ratio=0.03 / Showed that total VPA concentrations are higher in neonates at birth.
At birth 5/12 showed hypotonicity or sleepiness, 2/12 showed slight excitability that may have possibly been attributed to VPA.
Low milk penetration 15% and no accumulation.
Nau (1984) / II / VPA
N=17 / VPA=17 / Total VPA=1.7
Free VPA=0.82 / Ratio=0.025 / VPA crosses placenta with total VPA concentrations greater than maternal, however free concentrations comparable. Low milk concentrations. No acute accumulation up to 2 weeks. No link to side effects.
Ohman (2000) / II / Prospective Cohort
Mothersn=9
Neonates
N=10 / LTG / ratio 0.9 (0.6 to 1.3). / 4/9 had milk studies
ratio= 0.61 (0.55-0.77) / Assessed up to 72 hrs, however sampling points missing in 5/9.
Concentrations fraction in neonate: maternal 0.3 to 0.5. No evidence of accumulation. No side effects noted.
Ohman (2002) / II / Prospective Cohort / TPM=5 / Ratio=0.95 (0.85 to 1.06) / 3/5
Ratio=0.86 (0.67 to 1.1) / No signs of TPM accumulation with concentrations decreasing over first 72 hrs in all neonates.
Although milk: maternal ratios were 0.86, data for lactation at 2-3 weeks does not support accumulation. Two of three infants had TPM low concentrations (10-20% maternal plasma) with the other had undetectable concentrations.
Ohman (2005) / II / Prospective Cohort
N=6 / GBP / 5/6 had placental transfer studies
ratio=1.74 (1.3 to 2.11). / Milk: maternal conc.= 0.7-1.3. / Neonatal: maternal done in 3 patients 0.04-0.12.
No evidence of accumulation or definitive side effects. 1/6 hypotonia, but resolved quickly.
Steen (1982) / II / Prospective Cohort
PHT
N=6 / PHT / Ratio=0.13 / Studies done at 1-3 months of age. No association of infant accumulation or significant milk: maternal concentrations
Takeda (1992) / II / Pro-spective Cohort / CBZ=7, PB=13, PHT=7, VPA=8 / Total CBZ=0.73, PB=0.86, PHT= 0.91, VPA= 1.59
Free ratios CBZ=1.42, PB= 1.13,
PHT=1.1, VPA=0.5 / Total VPA concentrations higher in mother than neonate t-test (p<0.05)
Free PB (p<0.01), CBZ (p<0.05), VPA (p<0.01) significantly lower in mother.
No follow-up or mention of accumulation or neonatal outcome. Data showed neonatal--maternal free concentrations inversely correlated total neonatal-maternal concentration ratios. -0.9, p<0.005
Thomson (2007) / II / Prospective Cohort
Mothers n=14
Neonate n=15 / LVT / LVT ratios= 1.09. / From 4 to 23 days ratio:1.05 (0.78-1.55) / High-transfer across placenta and into milk but little accumulation.
Neonatal: maternal plasma ratio was low after nursing 0.13 (0.07 to 0.22). Neonatal concentrations declined 20% of cord concentrations by 36 hrs. Breast feeding did not affect the decline.
No adverse effects in neonates noted, but not systematically assessed
Yerby (1990) / III / Pro-spective Cohort / CBZ=18, PB=10, PHT=17 / CBZ=0.69, PB 0.78, PHT= 1
Free ratios CBZ= 1, PB=0.98, PHT= 1.25. / For placental transfer:
Total CBZ concentrations significantly lower in neonate than mother, t test p<0.05
All free concentrations not significantly different between mother and neonate.
Placental transfer for PB<PHT<CBZproportions based on free levels
No follow-up, no evidence of accumulation provided.

CBZ=Carbamazepine

ETX=Ethosuximide

GBP=Gabapentin

LVT=Levetiracetam

LTG=Lamotrigine

PB=Phenobarbital

PEMA=Phenylethyl-malonamide

PHT=Phenytoin

PRM=Primidone

OXC=Oxcarbazepine

TPM=Topiramate

VPA=Valproate

By cmt=by writing committee

OR=Odds Ratio

Table e-4: Pharmacokinetics of Lamotrigine during Pregnancy

Authors / Title of Article / AEDs Studied / Class / Design / Population Treated / Findings
Pennell P,Peng L, Newport DJ, et al. / Lamotrigine in pregnancy: Clearance, therapeutic drug monitoring, and seizure frequency / LTG / I / Prospective observational / n=53 / LTG free and total clearance increased throughout pregnancy with peak of 94% (total) and 89% (free) in 3rd trimester
Seizure frequency significantly increased when level was 65% of preconceptional individualized target concentration
Pennell P, Newport DJ, Stow, ZN, et al. / The Impact of Pregnancy and Childbirth on the Metabolism of Lamotrigine / LTG / II / Prospective observational, trough sampling only / n=14 / LTG Clearance increased until 32 weeks gestational age, with a peak of 230% above nongravid baseline;
Substantial inter-individual variability
Tran TA, Leppik, IE Blesi, K, et al. / Lamotrigine Clearance During Pregnancy / LTG / II / Retrospective review of prospective database / n=12; 9 had full data / >65% increase in clearance between nongravid baseline and 2nd and 3rd trimesters. Substantial inter-individual variability

LTG=Lamotrigine

Table e-5: Pharmacokinetics of Carbamazepine during Pregnancy

Authors / Title of Article / AEDs Studied / Class / Design / Population Treated / Findings
Battino D, Binelli S, Bossi L, Canger R, Croci D, Cusi C, De Giambattista M, Avanzini G. / Plasma concentrations of Carbamazepine and Carbamazepine 10,11-epoxide during Pregnancy and after Delivery / CBZ / III / Prospective / 9 on CBZ monotherapy / CBZ clearance was <10% higher during pregnancy than nongravid baseline. Plasma epoxide and epoxide/CBZ ratios were higher at 4-24 weeks GA. Plasma CBZ concentrations did not change during pregnancy.
Bernus I, Hooper WD, Dickinson RG, et al. / Metabolism of Carbamazepine and Co-Administered Anticonvulsants during Pregnancy / CBZ / III / Prospective / 10 (4 on polytherapy; 6 on monotherapy) / Mean CBZ clearance was 27% higher in pregnancy than nonpregnant baseline, but only in women on polytherapy with EIAEDs.
Tomson, Torbjorn, Lindbom, Ulla, Ekqvist, Britta, et al. / Disposition of Carbamazepine and Phenytoin in Pregnancy / CBZ, PHT / I / Prospective / 35 CBZ MonoTx, unchanged dose / Total CBZ concentration decreased in TM2 by 9% and TM3 by 12%; free CBZ concentrations were unchanged. CBZ-Epoxide concentrations, total and free, did not change.

CBZ=Carbamazepine

EIAEDS=Enzyme-inducing AEDs

GA=Gestational Age

MonoTx=Monotherapy

PHT=Phenytoin

TM2=2nd Trimester

TM3=3rd Trimester

Table e-6: Pharmacokinetics of Phenytoin during Pregnancy

Authors / Title of Article / AEDs Studied / Class / Design / Population Treated / Findings
Bardy AH, Hiilesmaa VK, Teramo KAW et al. / Serum Phenytoin during Pregnancy, Labor, and Puerperium / PHT / II / Prospective observational, monthly or biweekly; dosages increased for seizures / 111 (62 MonoTx) / PHT concentrations during pregnancy and at delivery were lower than nongravid baseline (by 68%).
Dickinson RG, Hooper WD, Wood B, et al. / The Effect of Pregnancy in Humans on the Pharmacokinetics of Stable Isotope Labeled Phenytoin / PHT / II / Single dose PK studies with labeled-PHT during pregnancy and PP / 5 Women, 14 PK studies / Mean plasma PHT Clearance was greater during pregnancy compared to non-pregnant baseline (0.025 vs. 0.021)(19%). Mean Vmax for PHT elimination was significantly greater in pregnancy compared to nongravid baseline (1170 vs. 780). Mean half-life was significantly shorter in pregnancy than nongravid baseline (31 vs. 39)
Lander CM, Livingstone I, Tyrer JH, Eadie MJ. / The Clearance of Anticonvulsant Drugs in Pregnancy / PHT 30, CBZ 9, PB 7, ETX 3, PRM 1 / II / Prospective; levels monthly; calculate CL, Vmax, KM / 34 pregnancies in 30 women on PHT / PHT Clearance in the pregnant patients was approximately double the published values in non-pregnant persons.
Tomson, Torbjorn, Lindbom, Ulla, Ekqvist, Britta, et al. / Disposition of Carbamazepine and Phenytoin in Pregnancy / CBZ, PHT / I / Prospective / 22 PHT MonoTx, unchanged dose / Total PHT concentration decreased in all 3 trimesters from baseline (max of 61%). Free PHT concentrations were decreased in the 3rd trimester by 16%. PHT free fraction increased by 2nd and 3rd trimesters (max 40%). Plasma PHT Clearance was significantly increased (by up to 117%) in all 3 trimesters compared to baseline. .Free PHT Clearance was increased in 3rd trimester by 25%.

CBZ=Carbamazepine

CL=Clearance

ETX=Ethosuximide

MonoTx=Monotherapy

PB=Phenobarbital

PHT=Phenytoin

PK=Pharmacokinetics

PP=Post partum

PRM=Primidone

Table e-7: Pharmacokinetics of Oxcarbazepine during Pregnancy

Authors / Title of Article / AEDs Studied / Class / Design / Population Treated / Findings
Christensen J, Sabers A, Sidenius P / Oxcarbazepine Concentrations during Pregnancy: a Retrospective Study in Patients with Epilepsy. / OXC / III / Retrospective / 9 pregnancies in 7 women / Compared to before pregnancy, the mean dose-corrected concentration of MHD was decreased by 28% in the 1st trimester, 26% in the 2nd trimester, and 36% in the 3rd trimester.
Mazzucchelli I, Onat FY, Ozkara C, Atakli D, Specchio LM, Neve AL, Gatti G, Perrucca E / Changes in the Disposition of Oxcarbazepine and its Metabolites during Pregnancy and the Puerperium / OXC / III / OXC and stereo-selective MHD metabolites were measured and active moiety calculated. / 5 / The concentration of the active moiety decreases during pregnancy and increases rapidly after delivery (up to 1.5-13-fold), but findings were significant only if the 1st trimester was excluded. Mean decrease in active moiety concentration was 61.5%, max in the 2nd trimester.

MHD=monohydroxy derivative

OXC=Oxcarbazepine

Table e-8: Pharmacokinetics of Valproic Acid, Primidone, Ethosuximide, and Levetiracetam during Pregnancy

Authors / Title of Article / AEDs Studied / Class / Design / Population Treated / Findings
Koerner M, Yerby M, Friel P, et al. / Valproic Acid Disposition and Protein Binding in Pregnancy / VPA / III / Prospective, monthly visits from 1st trimester to 8 weeks postpartum. Included polytherapies. / 9 / Total VPA Clearance increased in 2nd and 3rd trimesters compared to nongravid baseline, but no change in free VPA Clearance. VPA free fraction was increased in pregnancy.
Kuhnz W, Koch S, Jakob S, Hartmann A, Helge H, Nau H. / Ethosuximide in Epileptic Women during Pregnancy and Lactation Period. Placental transfer, Serum Concentrations in Nursed Infants and Clinical Status. / ETX / III / Prospective, 4 patients only, 3 on multiple polytherapies. / 4 / 2 patients demonstrated decreased Clearance; 1 increased Clearance and 1 no change.
Rating D, Nau H, Jager-Roman E, / Teratogenic and Pharmacokinetic Studies of Primidone during Pregnancy and in the Offspring of Epileptic Women / PRM / III / Prospective, no group means throughout course of pregnancy. / 14 / PRM, PB, PEMA levels all low compared to postpartum baseline. Metabolites/PRM ratios were lower in pregnancy.
Tomson T, Palm R, Kallen K, Ben-Menachem E, Soderfeldt B, Danielsson B, Johansson R, Luef G, Ohman I. / Pharmacokinetics of Levetiracetam during Pregnancy, Delivery, in the Neonatal Period, and Lactation. / LVT / II / Prospective, trough samples q Trimester and PP / 7 pregnancies in 6 women w/o dose change; 5 additional samples in 3rd TM and PP baseline / Maternal plasma concentrations during third trimester were decreased by 60% compared to nongravid baseline concentrations (p < 0.001, n = 7).

ETX=Ethosuximide

LVT=Levetiracetam

PB=Phenobarbital

PEMA= Phenylethyl-malonamide

PP=Post Partum

PRM=Primidone

VPA=Valproate