oxford textbook of epilepsy and epileptic seizures 152 remained unchanged throughout pregnancy in 63.6 % , of whom 92.7 % were seizure free during the entire pregnancy ( 33 ). Loss of seizure control was associated with a history of loca lization-related epilepsy, being on more than one AED, and taking oxcarbazepine in pregnanc y. For lamotrigine, however, some are of the opinion that close mon- itoring is mandatory and that drug levels should be increased if serum levels fall, to prevent deterioration in seiz ure control ( 120 ). That close monitoring may be effective at minimizing seizure deteriora tion was shown in 42 women receiving lamotrigine where monthly monitoring and dose adjustme nt was associated with only 19 % having an increased seizure frequency ( 121 ). Whether suc h practices expose the fetus to additional risks has not been established. Reasons for loss of seizure control are varied. Poor compliance with AED treatment because of nausea or the fear of harm from AEDs to the fetus can result in loss of control. Measuri ng compli- ance is problematic and monitoring serum levels or self-reporting may not be rel iable. The ability to study longer-term compliance is therefore of interest. In one study t hat measured AED levels in hair samples it was shown that 15 % of pregnant women had little or no AED in their proximal compared with distal hair measure- ments of AEDs ( 110 ). Most women with epilepsy will have a normal uncomplicated vaginal delivery. However, in app roximately 2 \200\2234 % the stress of labor may result in an increased risk of seizures du ring labor or in the following 24 hours ( 33 ). Tonic \200\223clonic seizures may result in fetal hypoxia and it is therefore generally recommended that deliv- ery takes place in a u nit equipped with facilities for maternal and neonatal resuscitation. Factors that increase the risk of seizures such as sleep deprivation, pain, overbreathing, and emotional dis- tr ess should be reduced as much as possible and early considera- tion given for epidural anes thesia. The analgesic pethidine may have a proconvulsant effect and is best avoided if poss ible. During pregnancy total serum AED levels may fall with less marked reductions in non-protein bound (free) drug concentra- tions ( 111 , 112 ) ( Table 13.5 ). Many factors may contribu te to this fall including increased metabolism/excretion, increased plasma volume, and redu ced protein binding. Total AED concentrations do not predict response during pregnancy and therefore if serum assessments are to be made, measurement of the unbound fraction is the m ethod of choice ( 113 ). This is especially relevant for those AEDs, such as valproate and phenytoin, that are moderately or highly protein bound. AEDs should be continued throughout labor. If necessary, all AEDs can be given by nasogastr ic tube; phenytoin, sodium val- proate, phenobarbitone, levetiracetam, diazepam, and clonaz epam can be given parenterally and carbamazepine rectally. Several studies have demonstrated pronounced alterations in the pharmacokinetics of lamotri gine during pregnancy ( 114 \200\223118 ). Apparent clearance increases steadily throughout pregnancy, peak- ing at about the 32nd week of gestation, when a 330 % increase from basel ine has been observed. The observed fall in lamotrigine levels during pregnancy has been re ported as being associated with a decline in seizure control. Seizures in labor should be terminated as soon as possible using intravenous lorazepam or d iazepam. For persisting seizures treat- ment should be for status epilepticus and delivery expedited. Where there is doubt about whether seizures are due to eclampsia or epilepsy a s low bolus of 4 mg of magnesium sulfate over 3 \200\2235 minutes, followed by 1 mg/hour for 24 hours is recommended in addition to intravenous lorazepam or diazepam ( http://www.sign. ac.uk/guidelines/fulltext/70/index.html ). There is currently no consensus on how best to monitor AED levels during pregnancy. It has previously been advocated that a baseline, preconception, unbound (free) AED level, repeate d at the beginning of each trimester and in the last 4 weeks of preg- nancy should be the m inimum level of monitoring ( 119 ). More frequent measurements will be necessary if seizure control deteri- orates, side effects ensue, or compliance is an issue. For most AEDs routi ne monitoring of serum levels is probably not necessary. AED levels revert to prepregnancy levels after birth at a variable rate ( 115 ). Hence, if the dose of an AED has been increased during pregnancy because of falling AED levels it may be useful to meas- ure serum levels repeatedly during the \201 rst 6 \200\2238 weeks aft er delivery to anticipate and manage the potential development of drug toxic- ity. However, the decision to reduce the AED dosage following delivery back to the preconception dosage, and the rate of dose reduction, should be made on an individual basis and with great care. In particular, if the increase in dose has resulted in a sustained improvement in seizure control with no evidence of toxicity the dose should not be changed. If the dose of AED has been increased during pregnancy and a decision is subsequently taken to reduce the dose ba ck to preconceptual levels postpartum, then substantial care should be taken as too rapid a dose reduction may result in uncontrolled seizures and maternal harm. Table 13.3 MCM rates for AEDs \200\224 comparing monotherapy and polytherapy exposures Reference % MCM Monotherapy Polytherapy Samren et al. 1997 8.0 9.8 The effects of epilepsy and antiepileptic drugs on pregnancy The over-representation of epi lepsy as one of the leading indirect causes of maternal mortality in pregnancy raises signi \201 cant con- cerns. The con \201 dential enquiries into maternal deaths in the UK, cov ering the period from 1985 \200\2231999 identi \201 ed that maternal mor- tality was over- represented among women with epilepsy, with over a 10-fold increased risk compared with wha t might be expected con- sidering the prevalence of epilepsy. While the reasons for the inc reased risk are not fully understood follow up reports have con- sistently reported that SU DEP accounts for most of the excess deaths. Olafsson et al. 1998 3.4 8.7 Canger et al. 1999 5.7 5.3 Kaneko et al. 1999 7.8 9.6 (2 AEDs), 11.5 (3 AEDs), 13.5 (4 AEDs), 15.4 (5 AEDs) Samren et al. 1999 3.3 4.7 (2 AEDs), 4.4 (3 AEDs), 8 (4 + AEDs) Holmes et al. 2001 4.5 8.6 Kaaja et al. 2003 3.2 5.8 (2 AEDs), 8.3 (3 + AEDs) Morrow et al. 2006 3.7 6.0 CHAPTER 13 reproductive aspects of epilepsy 153 Table 13.4 Features of fetal valproate syndrome For the period 2000 \200\2232002, of the 10 out of the 13 epilepsy-related deaths (of 256 d eaths) that had a postmortem examination, nine cases were felt either to have died, or prob ably to have died from SUDEP. In two out of the seven cases where blood levels of AEDs were measured there was no measurable trace of AEDs. In the most recent report spanning 2006 \200\2232008, 14 of the 261 maternal deaths were recorded as being due to epilepsy ( 122 ). Of the 14, nine were taking lamotrigine, none of whom had their AED level measured in preg nancy and 11 were felt to have died as a result of SUDEP. Of the \201 ve that had AED lev els measured at autopsy, three had a subthera- peutic level and two a low level. Of note, t he proportion of deaths felt to be due to epilepsy has not increased over the years studied . \227\206 Tall forehead \227\206 Medial eyebrow de \201 ciency \227\206 Flat nasal bridge \227\206 Broad nasal root \227\206 Shallow philtrum \227\206 Long upper lip \227\206 Thin vermillion border Data on whether women with epilepsy are at increased risk of obstetric complications are co n \202 icting. Complications reported include an increased rate of vaginal bleeding, spont aneous abor- tion, pre-eclampsia, and premature or prolonged labor. Higher frequencies of l abor induction and arti \201 cial labor have also been reported, but whether this is due t o a greater frequency of medical indications or is due to increased concern on the part of obstetri- cians or mothers-to-be is uncertain. The adverse outcomes most consistently repor ted are increased stillbirths and neonatal deaths, although there is some evidence that the latter has been improving. That women with epilepsy who have seizures during pregnancy may also be more likely to have preterm, small or low birth weight babies compared with women without epilepsy has been shown in a study from Taiwan ( 123 ). Management of the postpartum period Breastfeeding should be encouraged and may even have th e addi- tional advantage that it ensures the baby is withdrawn gradually from being exposed to AED therapy. AEDs are excreted in breast milk at a level inversely proportional to the degree of maternal serum protein binding ( 131 \200\223137 ). Hence the amount transferred to the infant in breast milk varies substantially between AEDs ( Table 13.6 ). Concentratio ns of AEDs can differ substantially between the start and end of a meal, and between the ri ght and left breast depending on the fat and protein contents of the milk. For some AEDs, s uch as phenobarbital and primidone, reduced neona- tal serum protein binding and immature e limination mechanisms can result in drug accumulation. This can result in sedation of the i nfant and necessitate the discontinuation of breastfeeding. For most AEDs including phenyto in, carbamazepine, and valproate, breastfeeding is usually without problems as these drugs are highly protein bound and therefore are poorly excreted into breast milk. Information on the concentration in breast milk of the newer AEDs is rather limited, however preliminary data indicate that lamotrig- ine passes into breast milk in signi \201 cant levels. When c ombined with the effects of immature hepatic uridine diphosphate glucuro- nyltransferase en zyme systems neonatal exposure to lamotrigine might result in high blood concentrations in some infants, a prob- lem that could be compounded if valproate is also taken ( 138 ). For levetiracetam, plasma concentrations in breastfed infants are low despite extensive transfe r of levetiracetam into breast milk ( 139 ). There have been some concerns that breastfeedi ng during AED therapy might have a detrimental effect on cognitive development. Data from t he Neurodevelopmental Effects of Antiepileptic Drugs Study is reassuring, albeit the number s studied were small. Intelligent quotients for breastfed children did not differ from Vitamin K Since 1958 over 40 cases of neonatal bleeding associated with maternal AED treatm ent have been reported ( 124 ). It is felt that this is due to reduced clotting factors, co nsequent to increased vitamin K clearance by hepatic enzyme-inducing AEDs such as phenytoin , phenobarbital, and carbamazepine. Newborn infants that have been exposed to enzyme-induci ng AEDs in utero may show increased levels of PIVKA II (protein induced by vitamin K absenc e of factor II), an indirect marker of vitamin K de \201 ciency ( 125 , 126 ). While there is no evidence directly linking this bio- chemical marker to a clinically increased risk o f bleeding in the neonate, its suppression with vitamin K 1 supplementation given as 10 mg orally each day from the 36th week of gestation ( 127 ) has resulted in early guidelines fo r best practice advocating maternal supplementation with vitamin K 1 , with all infants als o being given 1 mg vitamin K 1 intramuscularly at birth ( 119 , 128 ). However, the results of the only case \200\223control study performed did not show that there was an increased risk for bleeding in infants exposed in utero to enzyme-inducing AEDs (mainly carbamazepine and phenytoin) ( 129 ) although it was felt that supplementation might be necessary in sel ected cases, such as when prematurity was anticipated or there was a history of maternal al cohol abuse. Based on this report and a further review of all available literature the Amer ican Academy of Neurology updated its recommendations in 2009, stating that there was curre ntly inadequate evidence to determine if newborns of women with epilepsy taking AEDs had a substantially increased risk of haemorrhagic complications ( 130 ). At present giving oral supplementation with vitamin K is not possible in the UK as there is currently no orally av ailable preparation that can be prescribed for this indication. At birth it is recommended that infants receive vitamin K, with 1 mg of vitamin K given intramuscularly (as is the cas e for all newborns). Table 13.5 Pharmacokinetics of antiepileptic drugs in pregnancy Antiepileptic drug Decrease in total plasma concentration ( % ) Decrease in free concentration ( % ) Phenobarbital Phenytoin Carbamazepine Valproate Lamotrigine Oxcarbazepine MHD Levetiracetam 55 61 10 \200\22340 39 40 \200\22360 36 \200\22350 50 \200\22360 50 18 4 25 MHD = monohydroxy metabolite. oxford textbook of epilepsy and epileptic seizures 154 Table 13.6 Antiepileptic drugs studied in breast milk as a proportion of blood levels 11 . Reddy DS , Rogawski MA . Neurosteriod replacement therapy for catamenial epilepsy . Neurotherapeutics 2009 ; 6 : 392 \200\223 401 . 12 . Mattson RH , Cramer JA , Caldwell BV , Siconol \201 BC . Treatment of Antiepileptic drug (reference) Proportion appearing in breast milk ( % ) seizures with medroxyprogesterone acetate: preliminary report . Neurology 1984 ; 34 : 1255 \200\223 8 . 13 . Herzog AG , Drislane FW , Schomer DL , Pennell PB , Brom \201 eld EB , 3 18 \200\22345 36 36 61 70 \200\223130 72 86 86 105 Valproate ( 131 ) Phenytoin ( 132 ) Carbamazepine ( 133 ) Phenobarbitone ( 134 ) Lamotrigin e ( 115 ) Gabapentin ( 137 ) Primidone ( 134 ) Ethosuximide ( 135 ) Topiramate ( 136 ) Leve tiracetam ( 139 ) Dworetzky BA , et al . Differential effects of antiepileptic drugs on neuroactive steroids in men with epilepsy . Epilepsia 2006 ; 47 : 1945 \200\223 8 . 14 . Herzog AG , Coleman AE , Jacobs AR , Klein P , Friedman MN , Drislane FW , Schomer DL . Relationship of sexual dysfunction to epilepsy laterality and reproductive hormone levels in women . Epilepsy Behav 2003 ; 4 : 407 \200\223 13 . 15 . Morrell MJ , Flynn KL , Done S , Flaster E , Kalayjian L , Pack AM . Sexual dysfunctio n, sex steroid hormone abnormalities, and depression in women with epilepsy treated with an tiepilepsy drugs . 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