Greater seizure frequency is often associated with decreased and thus subtherapeutic anticonvulsant serum levels, a lower seizure threshold, or both. An impressive number of pregnancyassociated alterations can result in sub therapeutic serum levels. These include nausea and vomiting, slower gastrointestinal motility, antacid use that diminishes drug absorption, pregnancy hypervolemia ofset by protein binding, induction of hepatic enzymes such as cytochrome oxidases, placental enzymes that metabolize drugs, and increased glomerular iltration that hastens drug clearance. Importantly, some women discontinue medication because of teratogenicity concerns. Finally, the seizure threshold can be afected by pregnancyrelated sleep deprivation and by hyperventilation and pain during labor.
Women with epilepsy have a small increased risk of pregnancy complications that include spontaneous abortion, hemorrhage, hypertensive disorders, preterm birth, fetal-growth restriction, and cesarean delivery (Harden, 2009b; Viale, 2015). Importantly, MacDonald (2015) also reports a tenfold higher maternal death rate, and, as mentioned earlier, epilepsy accounted for 5 percent of maternal deaths in the United Kingdom.
Postpartum depression rates are also reportedly higher in epileptic women (Turner, 2009). Finally, children of epileptic mothers have a 10-percent risk of developing a seizure disorder.
For years, it was diicult to separate efects of epilepsy from those of its therapy as the primary cause of fetal malforma tions. As discussed in Chapter 8 (p. 148), it is now believed that untreated epilepsy is not associated with an elevated fetal malformation rate (Thomas, 2008). That said, the fetus of an has an indisputably greater risk for congenital malformations.
Moreover, mono therapy is associated with a lower birth defect rate compared with multiagent therapy. hus, if necessary, increasing monotherapy dosage is at least initially preferable to adding another agent (Buhimschi, 2009).
Specific drugs, when given alone, increase the malformation rate (Chap. 12, p. 240). Some of these are listed in Table 60-2.
Phenytoin and phenobarbital increase the major malformation rate two-to threefold above baseline (Perucca, 2005; Thomas, 2008). Valproate is a particularly potent teratogen, which has a dose-dependent efect and raises the malformation risk four-to eightfold (Eadie, 2008; lein, 2014; Wyszynski, 2005). Val proate is also associated with lower cognitive performance (Kas radze, 2017). In general, with poly therapy, the risk rises with each drug added. A metaanalysis of 31 studies found lamotrig ine and levetiracetam to carry the lowest risk of malformations (Weston, 2016).
The American Academy of Neurology and the American Epilepsy Society have guidelines regarding treatment in pregnant women (Harden, 2009a-c). The major goal is seizure prevention. To accomplish this, treatment for nausea and vomiting is provided, seizure-provoking stimuli are avoided, and medication compliance is emphasized. The fewest necessary anticonvulsants are given at the lowest dosage efective for seizure control. Although some providers routinely monitor serum drug levels, these concentrations may be unreliable because of altered protein binding. Free or unbound drug levels, although perhaps more accurate, are not widely available. Importantly, there is no evidence that such monitoring improves seizure control (Adab, 2006). For these reasons, drug levels may be most informative if measured following seizures or if noncompliance is suspected.