and whose mother took gabapentin and valproic acid during pregnancy (Moore et al et al., 2000).

Experimental animal studies with mice, rats, and rabbits have not found an increased frequency of congenital anomalies among offspring exposed to gabapentin during embryogenesis.

Oxcarbazepine Important note: oxcarbazepine is an anticonvulsant drug closely related to a known human teratogen, carbamazepine. This drug has been part of a polytherapy regimen in most published reports of its use during pregnancy, confounding its possible causal role.

Among 248 pregnancies exposed to oxcarbazepine monotherapy during pregnancy, there were six congenital anomalies (2.4 percent), which is similar to that expected in the general population. Among 61 infants whose mothers were given polytherapy that included oxcarbazepine, four birth defects (6.6 percent) occurred (Montouris, 2005), which is greater than that in the general population.

Among 35 infants born to epileptic women treated with oxcarbazepine monotherapy in one series, no congenital anomalies were found (Meischenguiser et al et al., 2004). Among 20 infants born to women who took polytherapy anticonvulsant regimen that included 176 176 Anticonvulsant drugs during pregnancy oxcarbazepine, one baby was born with a major cardiac congenital anomaly. One of nine infants born to epileptic women treated in the first trimester with oxcarbazepine monotherapy had multiple major birth defects involving the genitourinary tract (Kaaja et al et al., 2003). Isolated case reports involving polytherapy (including oxcarbazepine) of single infants with spina bifida, short spine, hypospadias, or limb reduction defects have been published (Lindhout et al et al., 1992; Lindhout and Omtzigt, 1994). The causal meaning of case reports is not possible to ascertain. Animal teratology studies (one published, Bennett et al. et al. , 1996, one unpublished) of oxcarbazepine were negative. , 1996, one unpublished) of oxcarbazepine were negative.

Tiagabine Among nine infants whose mothers took tiagabine during pregnancy, one infant had a congenital anomaly, but this was not similar to any of the anomalies in the 'fetal anticonvulsant syndrome' (Morrell, 1996).

In unpublished experimental animal studies (rats, rabbits) employing doses much higher than the human dose, and at doses toxic to the mother, there were increased frequencies of congenital anomalies in rats but not rabbits. None of this information is relevant to the a.s.sessment of human risk of birth defects following exposure to tiagabine during embryogenesis.

Topiramate In a case series three normal infants were reported whose mothers were treated with topiramate sometime during gestation (Morrell, 1996). In another case report, a pattern of minor anomalies similar to the 'fetal anticonvulsant syndrome' were observed in an infant whose mother took topiramate monotherapy throughout pregnancy (Hoyme et et al al., 1998). The relevance of these anecdotal reports, if any, to human risks following exposure to topiramate during embryogenesis is unknown.

The results of studies of rats, mice, and rabbits exposed to topiramate during embryogenesis are conflicting. Rats had limb defects at the highest doses, mice had craniofacial defects, and rabbits had vertebral anomalies. The inconsistent findings and the lack of peer review of these unpublished studies confound any possible interpretation of these data.

Vigabatrin Among 47 infants born to women who took vigabatrin during the first trimester two (4.3 percent) had congenital anomalies (Wilton et al et al., 1998).

In several studies, major anomalies were increased among mice exposed to vigabatrin during embryogenesis, and cleft palate occurred among rabbits exposed to maternally and fetotoxic doses. No increased frequency of congenital anomalies was found among rats exposed to vigabatrin during embryogenesis.

Zonisamide Zonisamide is an anticonvulsant used either in monotherapy or polytherapy to treat a broad spectrum of epileptic conditions (Oguni et al et al., 1988; Schmidt et al et al., 1993). In one Special considerations Special considerations 177.

small prospective case series of 26 infants born to women treated throughout pregnancy with zonisamide as part of a polytherapy anticonvulsant regimen, two infants (7.7 percent) were reported with major congenital anomalies (anencephaly, atrial septal defect) (Kondo et al et al., 1996). A child whose mother took zonisamide, carbamazepine, phenytoin, sodium valproate, and a barbiturate during pregnancy was reported with features of anticonvulsant embryopathy (Noda et al et al., 1996).

Increased frequencies of congenital anomalies were found in animal studies of teratogenicity of zonisamide in rats (cardiac), mice (visceral, skeletal), dogs (cardiac), and monkeys (pregnancy wastage) (Terada et al et al., 1987a,b,c).

SPECIAL CONSIDERATIONS.

In general, women with epilepsy should be given preconceptual counseling, and a management plan developed (Box 9.5). If a pregnant woman presents on anticonvulsant therapy, she should be given counseling regarding the two- to three-fold increased risk of malformations.

She should also be offered high-resolution ultrasound and alpha-fetoprotein screening at appropriate gestational intervals. It should be emphasized that these techniques, although helpful, may not rule out anticonvulsant embryopathy. Anticonvulsant therapy should be continued if necessary. It may be possible to discontinue medications in certain patients who have been seizure-free for protracted periods of time, especially in patients who have had pet.i.t mal seizures. Trimethadione and paramethadione are generally contraindicated during pregnancy, and valproic acid should be avoided if possible. One of the succinimides, ethosuximide, would appear to be a better choice for pet.i.t mal seizures in the rare pregnant patient where it is indicated. Monitoring of serum levels of anticonvulsants may be indicated in some pregnant women, especially those with increased seizure activity. A suggested management protocol for pregnant patients with epilepsy is summarized in Box 9.5.

Patients should be counseled that anticonvulsant therapy during pregnancy is a.s.sociated with risks of serious birth defects. For example, with valproic acid and carbamazepine, the risk for neural tube defects, spina bifida in particular, is increased with exposure during the first trimester (Table 9.4). Risks for other congenital anomalies are increased when a.s.sociated with exposure to other anticonvulsants during embryogenesis (Table 9.3). Risk for valproic acid-a.s.sociated neural tube defects is increased at (1) high doses (> 800 mg/day) and (2) polytherapy. Interestingly, recent a.n.a.lyses indicate that the risk for neural tube defects with exposure to oxcarbazepine or to lamotrigene is not different from the risk with carbamazepine (Perucca, 2005).

Table 9.4 Frequency of spina bifida in a.s.sociation with anticonvulsants Valproic acid n/N Frequency of spina bifida in a.s.sociation with anticonvulsants Valproic acid n/N Carbamazepine n/N Other n/N Total 10/740.

10/1132.

6/4489.

Unconfounded total 9/612.

9/984.

6/4489.

Proportion 1/68.

1/109.

1/748.

Number expected (background risk) 1/1500.

n, number affected; N, number exposed.

Adapted from Rosa, 1991.

178.

Anticonvulsant drugs during pregnancy Box 9.5 Suggested protocol for counseling management of pregnant women with epilepsy pregnant women with epilepsy Counsel regarding a possible epilepsy-a.s.sociated two- to three-fold increased risk of malformations above background (3.55%) Indicate that risk for neural tube defects (NTDs) is increased (see Table 9.4), as indicated Continue anticonvulsants if necessary to control seizures Seizures may cause congenital anomalies and threaten maternal health; therefore, controlling seizures is a high priority During embryogenesis [210 weeks estimated gestation age (EGA) by menstrual dates, or first 8 weeks of gestation by conception dates] avoid certain anticonvulsants if possible: *

Avoid trimethadione and paramethadione if possible *

Avoid valproic acid if possible *

Avoid carbamazepine if possible *

Avoid polytherapy if possible *

Avoid large anticonvulsant doses, use minimal necessary to control seizures Discontinue anticonvulsants in only select patients and with neurological medical consultation Serial high-resolution ultrasound examinations at appropriate intervals Maternal alpha-fetoprotein screening at appropriate intervals Serum anticonvulsant level monitoring Dose t.i.tration to achieve therapeutic levels Bear in mind that pregnancy changes the pharmac.o.kinetics of anticonvulsants, which may indicate the need to adjust dose and/or frequency to prevent maternal seizures *

Clearance is uniformly increased during pregnancy *

C (steady state concentration) is lowered ss *

Plasma protein binding (PPB) is decreased during pregnancy for anticonvulsants that have been studied Ratings by the FDA Pregnancy Risk Categories and Teratogen Information System (TERIS) Risk for Congenital Anomalies (Table 9.5) provide informative support for clinical decisions.

Pharmacogenetics The metabolism of folic acid is inhibited by many anticonvulsant drugs. This alteration in folate metabolism is presumed to be provoked by hepatic enzyme induction and folate malabsorption (Janz, 1982; Maxwell et al et al., 1972). Phen.o.barbitone, phenytoin, carbamazepine, valproic acid, and primidone have been implicated in these metabolic alterations (Donaldson, 1991). Human and animal studies support the finding that folic acid supplementation decreases the rate of congenital malformations in infants of epileptic mothers who are receiving anticonvulsants during pregnancy (Biale and Lewenthal, 1984; Dansky et al et al., 1987; Zhu and Zhou, 1989). Therefore, it is recommended that all Special considerations Special considerations 179.

Table 9.5 Comparison of Teratogen Information System (TERIS) risk for congenital anomalies and the Food and Drug Administration (FDA) pregnancy risk categories Drug Comparison of Teratogen Information System (TERIS) risk for congenital anomalies and the Food and Drug Administration (FDA) pregnancy risk categories Drug TERIS risk FDA pregnancy risk rating Phenytoin/Fosphenytoin Small to moderate D.

Carbamazepine Small to moderate Dm Valproic acid Fetal valproate syndrome: moderate Dm Neural tube defects: small to moderate Other malformations: small Neurobehavioral abnormalities: small Primidone Small to moderate D.

Trimethadione/ Paramethadione High D.

Ethosuximide Undetermined C.

Methsuximide Undetermined C.

Phensuximide Undetermined D.

Phen.o.barbital Chronic anticonvulsive treatment: small D.

occasional, short-term therapy for other reasons: minimal to small Zonisamide Undetermined NA.

Compiled from: Friedman et al., Obstet Gynecol 1990; 75 75: 594; Briggs et al., 2005; Friedman and Polifka, 2006.

women of childbearing age receive 0.40.5 mg per day of folic acid preconceptually and at least through the first trimester of pregnancy. Epileptic mothers with a positive history of neural tube defects or orofacial clefts in previous children, or paternal or maternal family history should be supplemented preconceptually and through the first trimester with 45 mg per day of folic acid, especially women taking valproic acid or carbamazepine (Perucca, 2005).

In addition, mothers receiving the above anticonvulsants should be given 20 mg of vitamin K in the final month of pregnancy (Delblay et al et al., 1982). The newborn should 1 receive 1 mg of vitamin K at birth and again in 12 h. Umbilical cord prothrombin, par-1 tial thromboplastin values, and vitamin-K-dependent clotting factors should be evaluated shortly after delivery (Bleyer and Skinner, 1976, Srinivasan et al et al., 1982). Folic acid and vitamin D supplements should be considered for pregnant women on phenytoin and other similar anticonvulsants, in addition to vitamin K supplementation in the third trimester (Yerby, 2003).

Unfortunately, no anticonvulsant is known to be free from risk. Further, it is not possible to unravel the relationship of the disease being treated, the treatment for the disease, and the genetic complement of the mother and fetus in a.s.sessing the risk for birth defects in epileptic pregnancies.

The management of pregnancy in women with epilepsy requires the coordinated efforts of the patient's primary treating physician and her neurologist. With proper management, 90 percent of women with epilepsy can antic.i.p.ate uneventful pregnancies and normal children.

180.

Anticonvulsant drugs during pregnancy Key references Dessens AB, Cohen-Kettenis PT, Mellenbergh GJ, Koppe JG, van de Poll NE, Boer K.

a.s.sociation of prenatal phen.o.barbital and phenytoin exposure with small head size at birth and with learning problems. Acta Paediatr 2000; 89 89: 533.

Holmes LB, Harvey EA, Coull BA et al. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001; 344 344: 1132.

Kaaja E, Kaaja R, Hiilesmaa V. Major malformations in offspring of women with epilepsy.

Neurology 2003; 60 60: 575.

Little BB. Pharmac.o.kinetics during pregnancy. Evidence-based maternal dose formulation.

Obstet Gynecol 1999; 93 93: 858.

Montouris G. Gabapentin exposure in human pregnancy. results from the Gabapentin Pregnancy Registry. Epilepsy Behav 2003; 4 4: 310.

Montouris G. Safety of the newer antiepileptic drug oxcarbazepine during pregnancy. Curr Med Res Opin 2005; 21 21: 693.

Morrow J, Russell A, Guthrie E et al. Malformation risks of antiepileptic drugs in pregnancy: A prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006; 77 77: 1938.

Perucca E. Birth defects after prenatal exposure to antiepileptic drugs. Lancet Neurol 2005; 4 4: 781.

Sabers A, Dam M, a-Rogvi-Hansen B et al. Epilepsy and pregnancy. Lamotrigine as main drug used. Acta Neurol Scand 2004; 109 109: 9.

Van d.y.k.e DC, Ellingrod VL, Berg MJ, Niebyl JR, Sherbondy AL, Trembath DG.

Pharmacogenetic screening for susceptibility to fetal malformations in women. Ann Pharmacother 2000; 34 34: 63945.

Further references are available on the book's website at http://www.drugsandpregnancy.com 10.Psychotropic use during pregnancy Pharmac.o.kinetics 182.

Miscellaneous 200.

Antidepressants 182.

Specific conditions 204.

Antipsychotics 189.

Key references 205.

Sedatives, hypnotics, and tranquilizers 194.

Major psychiatric disorders such as bipolar disorders (0.51.5 percent) or schizophrenia (11.5 percent) are relatively uncommon during pregnancy (Yonkers et al et al., 2004). Many women consume some type of psychoactive agent during pregnancy, ranging from 5 to 10 percent. More than one-quarter of women reported symptoms of depression in one large survey (Little and Yonkers, 2001). Thus, physicians treating pregnant women are likely to regularly encounter psychotropic use during pregnancy. Management of psychiatric illness during pregnancy is similar to the nonpregnant state, with notable exceptions. Exceptions are that pharmac.o.kinetics of drugs, including psychotropics, change with the physiological alterations of pregnancy. Additionally, psychotropics include mood stabilizers (valproic acid, carbamazepine, lithium) that are generally agreed to cause major birth defects (i.e., teratogenic), and should be avoided during embryogenesis. Newer antidepressants, serotonin selective reuptake inhibitors (SSRIs) are not a.s.sociated with significant birth defect risks (Einarson and Einarson, 2005), but may be a.s.sociated with complications in neonatal adaptation (Kallen, 2004; Oberlander et al et al., 2004). Mental illness usually does not worsen during pregnancy, and has a prognosis similar to the nongravid state. Importantly, newer antidepressants (e.g., SSRIs) seem to be more effective in women than the older agents (e.g., tricyclics) (Yonkers, 2003).

Depression is an affective disorder that can be unipolar or bipolar. Anhedonia (lack of pleasure) and a depressed mood are major diagnostic criteria. Patients with depression also have physical symptoms (too much or too little sleep, altered appet.i.te, altered activity decreased motion or agitated pacing, low energy) and cognitive symptoms (rumina-tive guilty thoughts, suicidal ideation, poor concentration, indecision). Patients with bipolar disorders have periods of mania and depression (American Psychiatric a.s.sociation, 1993; Yonkers and Cunningham, 1993). The hypothesis at the root of medical treatment of depression is that at least some cases of depression may be caused by an insufficient amount of serotonin and/or norepinephrine in certain areas of the brain. Psychosis is thought to be secondary to elevated amounts of dopamine in certain regions of the brain.

182.

Psychotropic use during pregnancy A number of psychotropic agents are available to which pregnant women and their fetuses may be exposed, including antidepressants, antipsychotics, sedatives, hypnotics, and tranquilizers. Pregnancy-a.s.sociated physiological changes affect pharmac.o.kinetics of most drugs, and psychotropics are not an exception.

PHARMAc.o.kINETICS.

The limited data on pharmac.o.kinetics of psychotropics during pregnancy are not consistent. While diazepam has no change in the clearance and increased half-life in gravidas compared to nonpregnant women, oxazepam has a decreased half-life and increased clearance (Table 10.1). Notably, nortriptyline levels are lower in the pregnant state compared to nonpregnant, suggesting that an increase in dose or frequency may be needed to maintain therapeutic levels.

ANTIDEPRESSANTS.

Antidepressants can generally be cla.s.sified into three major groups: (1) tricyclics, (2) selective serotonin re-uptake inhibitors (SSRIs), and (3) monoamine oxidase inhibitors (MOAs) (Box 10.1).

Box 10.1 Commonly used antidepressant agents Tricyclics Selective serotonin re-uptake inhibitors Imipramine (Janimine, Tofranil, Tipramine) (SSRIs) Amitriptyline (Amitril, Elavil, Endep, Emitrip, Citalopram (Celexa) Enovil) Escitalopram (Lexapro) Desipramine (Norpramin, Pertofrane) Fluoxetine (Prozac) Nortriptyline (Aventyl, Pamelor) Fluvoxamine (Luvox) Doxepin (Adapin, Sinequan) Paroxetine (Paxil) Protriptyline (Vivactil) Setraline (Zoloft) Amoxapine (Asendin) Serotonin norepinephrine reuptake inhibitors Clomipramine (Anafranil) (SNRIs) Tetracyclics Duloxetine (Cymbalta) Maprotiline (Ludiomil) Venlafaxine (Effexor) Monoamine oxidase inhibitors (MAOs) Other Isocarboxazid (Marplan) Bupropion (Wellbutrin) Phenelzine (Nardil) Mirtazepine (Avanza, Norset, Remergil, Selegeline (MAO A and MAO B activity) Remeron, Zispin) Tranylcypromine (Parnate) Nefazdone Trazodone (Desyrel) Tricyclics Women of reproductive age are frequently prescribed tricyclic antidepressants, and there has been no apparent decline in prescriptions in recent years (Wen and Walker, 2004).

Table 10.1 Pharmac.o.kinetics during pregnancy of some psychotropic drugs Agent Pharmac.o.kinetics during pregnancy of some psychotropic drugs Agent n EGA.

Route AUC.

V.

C.

C.

t Cl PPB.

Control groupa Authors d max SS.

1/2.

(weeks) Clorazepate 7.3742 IM.

Yes (1) Rey et al. (1979) Diazepam 14.3739 IV.