SUMMARY.

a.n.a.lgesics are not a high-risk drug cla.s.s for use during pregnancy (Table 8.2). The high-level summary is that none are a.s.sociated with an increased risk of congenital anomalies, if the risk is known (Table 8.2). The appropriate caveats are that dosage and frequency of dosage must be managed carefully during pregnancy, especially in the third trimester.

For example, meperidine probably requires no adjustment in dose or frequency because its pharmac.o.kinetics do not change appreciably from the nonpregnant to pregnant states. In contrast, morphine has a decreased half-life and increased clearance, perhaps indicating a need for upward dose adjustment and or greater frequency (Table 8.3).

Important neonatal complications to monitor for are: (1) bleeding disorders (salicylates); (2) neonatal dependence (narcotics and barbiturates); and (3) withdrawal (narcotics and barbiturates). In large doses, maternal respiratory depression may occur with narcotic a.n.a.lgesia. Large a.n.a.lgesic doses are sometimes an attempt to compensate for more rapid metabolism of opiates during pregnancy (Table 8.2).

Key references Al-Alaiyan S, Seshia M, Casiro O. Neurodevelopmental outcome of infants exposed to indometracin antenatally. J Perinat Med 1996; 24 24: 405.

CLASP (Collaborative Low-Dose Aspirin Study in Pregnancy) Collaborative Group. Low-dose aspirin in pregnancy and early childhood development. Follow-up of the collaborative low-dose aspirin study in pregnancy. Br J Obstet Gynaecol 1995; 102 102: 861.

Hulse G, O'Neil G. Using naltrexone implants in the management of the pregnant heroin user. Aust NZ J Obstet Gynaecol 2002; 42 42: 569.

Hulse GK, O'Neil G, Arnold-Reed DE. Methadone maintenance vs. implantable naltrexone treatment in the pregnant heroin user. Int J Gynaecol Obstet 2004; 85 85: 170.

Kallen B. Drug treatment of rheumatic disease during pregnancy. Scand J Rheumatol 1998; 27 27 (Suppl. 107): 119. (Suppl. 107): 119.

Kallen B, Lygner PE. Delivery outcome in women who used drugs for migraine during pregnancy with special reference to sumatriptan. Headache 2001; 41 41: 351.

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

Obstet Gynecol 1999; 93 93: 858.

Rasenen J, Jouppila P. Fetal cardiac function and ductus arteriosus during indomethacin and sulindac therapy for threatened preterm labor. A randomized study. Am J Obstet Gynecol 1995; 173 173: 20.

164.

a.n.a.lgesics during pregnancy Regan J, Chambers F, Gorman W, MacSullivan R. Neonatal abstinence syndrome due to prolonged administration of fentanyl in pregnancy. Br J Obstet Gynaecol 2000; 107 107: 570.

Schenker S, Yang Y, Perez A, Henderson GI, Lee MP. Sumatriptan (Imitrex) transport by the human placenta. Proc Soc Exper Biol Med 1995; 210 210: 213.

Further references are available on the book's website at http://www.drugsandpregnancy.com 9.Anticonvulsant drugs during pregnancy Pregnancy complications 165.

Anticonvulsant polytherapy 170.

Effect of pregnancy on Birth defects, epilepsy, and anticonvulsant levels 166.

anticonvulsants 170.

Congenital anomalies and maternal Anticonvulsant agents 170.

anticonvulsant therapy 166.

Special considerations 177.

Etiology of malformations 168.

Key references 180.

Syndromes and isolated congenital anomalies a.s.sociated with anticonvulsants 168.

Seizure disorders are among the most common serious medical conditions encountered during pregnancy (Cantrell et al et al., 1994) and are estimated to occur among 0.51 percent of all pregnancies (Janz, 1975). It is thought that one million women of childbearing age have a seizure disorder (Yerby, 1991), and an estimated three or four of 1000 gravidas are epileptic (Morrow et al et al., 2006).

PREGNANCY COMPLICATIONS.

Epilepsy has been reported to be a.s.sociated with an increase in pregnancy complications in both the mother and the fetus (Cantrell et al et al., 1994). Some of the maternal complications include an increased risk of pregnancy-induced hypertension, preterm delivery, and low birth weight (Bjerkedal and Bahna, 1973; Wilhelm et al et al., 1990). The major risk to the fetus is an increase in congenital malformations, about two- to three-fold higher than the general population (Yerby, 1994). Specifically, cl.u.s.ters of anomalies seem present with some drugs. For example, neural tubes defects (i.e., spina bifida) are a.s.sociated with valproic acid and carbemazepine (Yerby, 2000, 2003). Several maternal and fetal complications are a.s.sociated with epilepsy during pregnancy (Table 9.1).

Antiseizure medications during pregnancy and the occurrence of syndromes (fetal hydantoin syndrome, fetal valproate syndrome) is an area where the emerging field of pharmacogenetics has made progress. The genetic enzyme complement of the gravida and her fetus mediate the effects of these antiseizure medications. Pharmac.o.kinetics are important in the management of pregnancy complicated by epilepsy. Piecemeal information is 166 166 Anticonvulsant drugs during pregnancy Table 9.1 Reported complications of epilepsy and pregnancy Maternal Reported complications of epilepsy and pregnancy Maternal Fetal or neonatal Abruptio placentae Congenital anomalies Caesarean delivery Drug withdrawal Eclampsia Feeding difficulties Hyperemesis gravidarum Hypoxemia Hypotonic labor Low birth weight Increased seizure activity Malnutrition Preeclampsia Neonatal hemorrhage Pregnancy-induced hypertension Perinatal deaths Preterm delivery Prematurity v.a.g.i.n.al bleeding Stillbirths Seizures Cantrell et al., 1994.

available regarding pharmac.o.kinetics of antiseizure medications during pregnancy (Table 9.2).

EFFECT OF PREGNANCY ON ANTICONVULSANT LEVELS.

Physiologic changes a.s.sociated with pregnancy may affect the metabolism, plasma protein binding, maternal serum level, and clearance of anticonvulsants and other drugs. In one review, pharmac.o.kinetics of several anticonvulsants during pregnancy showed that the levels of phenytoin and phen.o.barbital decreased during pregnancy and that the clearance of phenytoin, phen.o.barbital, carbamazepine, and valproate increased during pregnancy (Levy and Yerby, 1985). The level of anticonvulsants during pregnancy for a given dose varies among women and cannot be predicted given the limited data available. Therefore, it is recommended that anticonvulsant levels be monitored throughout pregnancy because seizure activity may increase in some pregnant women (Levy and Yerby, 1985). A survey of the published literature on anticonvulsant pharmac.o.kinetics indicates that dose and frequency of anticonvulsants given during pregnancy to control seizures probably require adjustment (Table 9.2).

Dose and frequency management of anticonvulsant therapy during pregnancy can opti-mize therapy given the limited information available. Generalizing the findings from studies published on pharmac.o.kinetics of anticonvulsant during pregnancy, it is observed that (1) clearance is increased; (2) steady state concentration is decreased; and (3) plasma protein binding is decreased. These changes indicate that dose adjustment and monitoring levels should be considered because of the expanded volume of distribution a.s.sociated with pregnancy, the decreased steady state concentrations, and the increased clearance of the drug.

CONGENITAL ANOMALIES AND MATERNAL ANTICONVULSANT.

THERAPY.

Women with epilepsy requiring anticonvulsant therapy are known to have a two- to three-fold increased risk of having an infant with a congenital anomaly (Hill, 1973; Table 9.2 Table 9.2 Pharmac.o.kinetics of antiseizure medications during pregnancy Agent Pharmac.o.kinetics of antiseizure medications during pregnancy Agent n EGA.

Route AUC V.

C.

CS.

t Cl PPB Control groupa Authors d max S.

1/2.

(weeks) Carbamazepine 14.1640 PO.

Dam et al. (1979) Carbamazepine 46.1240 PO.

Yes (2) Bardy et al. (1982) Carbamazepine 8.3037 PO.

Yes (2) Bologa et al. (1991) Carbamazepine 12.1240

Yes (2) Froescher et al. (1981) Carbamazepine 6.840 PO.

Yes (2) Battino et al. (1982) Carbamazepine 9.832 PO, IV.

Yes (2) Battino et al. (1985) Carbamazepine 100.620 PO.

No Omtzigt et al. (1993) Carbamazepine 5.840 PO.

Yes (2) Yerby et al. (1985) Phen.o.barbital 5.1240 PO.

Yes (2) Lander et al. (1984) Phen.o.barbital 12.840 PO.

Yes (2) Battino et al. (1985) Congenital anomalies and maternal anticonvulsant therapy Phen.o.barbitone Phen.o.barbitone 23.1240 PO.

Yes (2) Bardy et al. (1982) Phen.o.barbitone 8.1640 PO.

Yes (2) Dam et al. (1979) Phenytoin 111.

840 PO.

Yes (2) Bardy et al. (1982) Phenytoin 7.1640 PO.

Yes (2) Dam et al. (1979) Phenytoin 48.142 PO.

Yes (2) Dansky et al. (1982) Phenytoin 3.840 PO.

Yes (2) Battino et al. (1985) Phenytoin 15.840 PO.

Yes (2) Chen et al. (1982) Phenytoin 5.1636 PO, IV.

Yes (2) Lander et al. (1984) Phenytoin 16.840 PO.

Yes (1) Ruprah et al. (1982) Phenytoin and 75.840 PO.

Yes (2) Chen et al. (1982) phen.o.barbitone Primidone 10.1240 PO.

Yes (2) Bardy et al. (1982) Primidone 5.840 PO.

Yes (2) Battino et al. (1985) Primidone and 9.840 PO.

Yes (2) Battino et al. (1984) phen.o.barbitone Primidone 5.3338 PO.