water and sodium retention, other electrolyte disturbances, emotional
stress, hormonal alterations, and changes in respiratory patterns.' """
The
Pregnant Epileptic
A Review and Recommendations Georgia
D.
Montouris, MD; Gerald M. Fenichel, MD; L. William McLain, Jr, MD
major concerns in the pregnant epileptic patient are loss of seizure control and the teratogenic effects of antiepileptic drugs on the fetus. Loss of seizure control is usually caused by a progressive decline of antiepileptic plasma levels throughout pregnancy. This decline can be prevented by monthly dose adjustments based on plasma level determinations. Although infant malformations are a more prevalent outcome of the pregnancies of epileptics than of nonepileptics, the role of antiepileptic drugs in teratogenicity is not fully established. Only trimethadione has been convincingly \s=b\ The
linked to fetal malformation. Recommendations for the management of epilepsy in pregnancy are made. (Arch Neural 36:601-603, 1979)
HPhe
efficacy of antiepileptic drugs, coupled with improved social atti¬ tudes toward epilepsy, allows epileptic patients to lead normal or nearly normal lives. Consequently, increas¬ ing numbers of female patients must consider the special problems of their
disease in pregnancy. In the Collabo¬ rative Perinatal Study sponsored by the National Institutes of Health, 0.44% of the pregnant women were
epileptic.1 Pregnancy in the epileptic provides a therapeutic challenge in maintain¬ ing a seizure-free state while minimiz¬ ing the adverse effects of antiepilep¬ tic drugs on the fetus. Although the issues are related, it is convenient to analyze separately the effects of preg¬ nancy on the mother's epilepsy and the effect of the mother's epilepsy and drug regimen on the fetus. REVIEW OF LITERATURE Effect of Pregnancy on Epilepsy
analyze the effect of pregnancy epilepsy, it is useful to divide patients into two categories: women who have been identified as epileptic prior to conception and in whom a To
on
Accepted
publication Dec 31, 1978. Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tenn. Dr McLain is currently with the Department of Neurology, University of Minnesota, Minneapolis. Reprint requests to Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN 37232 (Dr Fenichel). From the
for
level of seizure control has been estab¬ lished,1' and women who experience a seizure disorder, not related to toxe¬ mia, for the first time during preg¬ nancy. Less than 25% of women in the latter group will have seizures only during that and subsequent pregnan¬ cies. The term "gestational epilepsy" has been applied to this phenome¬ ""
non.'·"^
Most studies concerning the effects of pregnancy on seizure frequency have been retrospective. The earliest report was published in 1867- and, although lacking in statistics, claimed that pregnancy had a favorable effect on the frequency of convulsions. This was refuted by a 1910 report- that indicated that pregnancy had no predictable influence on epilepsy. Re¬ cent information suggests that in patients with established epilepsy before pregnancy, seizure frequency is increased in 45%, decreased in 5%, and unaltered in 50%." The likelihood of an increase in seizure frequency during pregnancy can be predicted from the history of seizure control during the two years prior to concep¬ tion." Of women with no more than one seizure during the nine months preceding pregnancy, only 25% expe¬ rience an increase in seizure frequen¬ cy during pregnancy. In comparison, when the seizure frequency before pregnancy is greater than one seizure per month, more than 60% will have a deterioration in seizure control. This deterioration is most likely to begin in the first trimester.4 Following preg¬ nancy, the previous seizure frequency is usually reestablished." The seizure frequency in different pregnancies is unpredictable both in women with preexisting epilepsy and in those who first have seizures during
pregnancy.'"
Among women who first manifest seizures during pregnancy, the sei¬ zures and EEG abnormalities tend to be focal." Many women in this cate¬ gory have preexisting cerebral disor¬ ders, such as vascular abnormalities or tumor, rather than primary general¬ ized epilepsy. A potential seizure focus could be activated by any of several changes that occur in pregnancy: "
Downloaded From: http://archneur.jamanetwork.com/ by a University of Manitoba User on 06/14/2015
In some women reporting decreased seizure frequency during pregnancy, the explanation may be better drug compliance. In one series, five of seven women whose seizure control had improved during pregnancy ad¬ mitted that they used antiepileptic
drugs
more
regularly.
'
Effect of Pregnancy on Antiepileptic Drug Metabolism A critical factor underlying the loss of seizure control during pregnancy is a decline in plasma antiepileptic drug levels when the oral dose is con¬ stant." There is little doubt that the "'
pharmacokinetics of most antiepilep¬ tic drugs is altered by pregnancy. Several investigators have reported increased plasma clearance for phenytoin and phénobarbital,""' although the plasma protein binding of pheny-
toin remains unaltered." Plasma lev¬ els of phenytoin and phénobarbital fall progressively throughout preg¬ nancy and increase after birth, ap¬ proaching pregravid levels. The in¬ creased need for antiepileptic drugs could be explained on the basis of fluid retention, a general increase in hepat¬ ic metabolic rate," intestinal malab¬ sorption, the effects of supplementa¬ ry vitamin intake, and the volume of fetal tissues and placenta." Placental transfer and fetal elimi¬ nation rates for antiepileptic drugs are known for phenytoin, phénobarbi¬ tal, primidone, and carbamaze¬ '-'
pine."
'" "" phenytoin concentrations identical in cord and maternal serum at term."·" Plasma phenytoin half-life in the newborn varies from 55 to 69 hours, and this is not affected by the presence of phénobarbital.1'" The fetal elimination rate of pheny¬ toin is slow during the first two days postpartum and then increases on the third day, with elimination completed by the fifth day. The greatest concen¬ tration of phenytoin is in the liver, adrenal glands, and kidneys, whereas the amniotic fluid and CSF are virtually devoid of the drug." In newborns loaded with phenytoin postnatally, the highest tissue concentra¬ tion is in the liver.1" Phénobarbital concentrations in hu¬ man umbilical cord plasma are 95% of those in the mother's plasma." Al¬ though the half-life of phénobarbital in newborns who have their first expe¬ rience with the drug postnatally is 59 to 182 hours,1""1" the ability to elimi¬ nate the drug improves with the length of time the infant is exposed.
are
Intrauterine exposure, therefore, re¬ sults in a shorter half-life in the newborn.-1 Following the postnatal administration of phénobarbital to the newborn, the highest tissue levels are in fat, heart, and liver.18 The concentration of phénobarbital in the brain compared with plasma phéno¬ barbital concentration is lower in the newborn than in adults. Phénobar¬ bital dependence states are more common in infants born to epileptic mothers but are not associated with intrauterine growth retardation.-Withdrawal symptoms may be seen when the mother has taken doses of 60 to 120 mg per day during the last trimester. The syndrome is character¬ ized by hyperexcitability, tremor, restlessness, and difficulty in sleep¬ ing. Seizures do not occur.2' In our experience, the oral dosages of carbamazepine required to main¬ tain plasma levels within the thera¬ peutic range are increased during pregnancy. Umbilical cord and mater¬ nal plasma levels are identical. The plasma half-life of carbamazepine in the newborn ranges from eight to 28 hours.17 This is not significantly different from the half-life observed in adults on chronic therapy. Effect of
Epilepsy on Pregnancy Several authors have indicated that epileptics have more difficulty with
pregnancy than nonepileptics.1 The data are inconclusive but suggest a twofold increase in the incidence of maternal complications during preg¬ nancy (hyperemesis, vaginal bleeding, toxemia) and of complications of delivery (induction of labor, applica¬ tion of forceps).-"' These studies were retrospective and lacked information on drug regi¬ men, plasma drug levels, and seizure frequency. Therefore, it is not possible to determine the relative contribu¬ tions of the epileptic state, the occur¬ rence of seizures, and the use of drugs in causing this increased risk. As might be anticipated from the increased complication rates, there is also an increase in the rates of prema¬ turity, small-for-dates babies, and neonatal mortality and morbidi¬ -'--*
ty.1—
Teratogenicity of Antiepileptic Drugs The risk of congenital malforma¬ tions among infants exposed in utero
to
antiepileptic drugs
is not
fully
established, but it is estimated to be two or three times greater than that
in the general population.7-''' Be¬ cause the incidence of most malforma¬ tions in non-drug exposed infants is less than 1%, increased rates can be
detected only if the study population is large or if the increased rate of malformation is considerable. The anomalies most frequently encoun¬ tered in the offspring of treated epileptics are cleft palate, cleft lip, and cardiac defects, especially defects of the cardiac septum.--""1" Some of the risk factors for teratogenicity that must be considered include the occur¬ rence of convulsions during pregnan¬ cy, the increased incidence of preg¬ nancy complications, socioeconomic factors, and the teratogenicity of
antiepileptic drugs. The fetal hydantoin syndrome is the most commonly reported defect asso¬ ciated with a specific antiepileptic drug."'"-""' It is characterized by craniofacial anomalies, limb defects, defi¬ cient growth, and mental retardation.
The craniofacial anomalies include a low and broad nasal bridge, epicanthal folds, a short upturned nose, hypertel-
orism, ptosis, strabismus, prominent ears that are low-set and malformed, a wide mouth with prominent lips, and
variations in the size and shape of the head, with sutural ridging or widen¬ ing of the fontanels. The limb defects include hypoplasia of the distal pha¬ langes and nails which tend to assume a more normal appearance with time, finger-like thumbs, and variations in palmar creases and dermatoglyphics. There is intrauterine growth failure that results in small stature despite normal growth postnatally. The de¬ gree of mental retardation is mild to moderate. Although it has been sug¬ gested that the incidence of this syndrome is high, no prospective epidemiological study has been per¬ formed to document the rate of occur¬ rence."'"
A second fetal disorder associated with maternal antiepileptic drugs is the trimethadione syndrome."'""' The causal relationship between fetal exposure and malformation is more firmly established for trimethadione than for any other antiepileptic drug. These infants have developmental
delay, speech disturbances, V-shaped eyebrows, epicanthal folds, low-set ears with an anteriorly folded helix, palatal anomalies, and irregular teeth.
Additional features in some infants intrauterine growth retardation, short stature, cardiac anomalies, ocu¬ lar defects, simian creases, microceph¬ aly, and hypospadius. It is clear that the trimethadione and hydantoin syn¬ dromes are similar. Furthermore, sim¬ ilar defects have also been described in infants exposed to phénobarbital or primidone in utero.4"44 "'7 To date, no reports incriminate carbamazepine as are
"'"
a
teratogenic agent.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Manitoba User on 06/14/2015
Hemorrhagic
Disease of the Newborn
to phenytoin, bar¬ trimethadione may de¬ velop bleeding tendencies during the first 24 hours after delivery owing to decreased levels of vitamin Indepen¬ dent clotting factors despite normal levels in the mother."'" ;T Drug-induced vitamin deficiency must be distin¬ guished from the physiological defi¬ ciency that occurs on the second to fifth day. The drug-induced bleeding occurs earlier and is life-threatening. The hemorrhagic disorder can be prevented by injections of phytonadione (vitamin K) into the new¬ born."'" '"' In this center, 1 mg is routinely given to all newborns after delivery. In infants exposed in utero to antiepileptic drugs, clotting studies are obtained two to four hours after the phytonadione is administered. If clotting factors remain abnormal, an additional dose is administered and the procedure is repeated until the factors are normal. If hemorrhage has occurred, fresh frozen plasma is
Fetuses
biturates,
exposed
or
given.'""7
RECOMMENDATIONS 1. In an epileptic woman contem¬ plating pregnancy, an antiepileptic drug regimen should be established that provides optimal seizure control with the fewest side effects using the
least number of drugs. Drug choice should be based on these considera¬ tions rather than on risk of teratoge¬ nicity, for this risk is small. The one exception is trimethadione, which probably should be avoided.""-7" Sin¬ gle-drug therapy is ideal whenever possible. Further, maintenance of therapeutic plasma levels is so diffi¬ cult during pregnancy that it is unwise to compound the difficulty with multiple drugs unless it is neces¬ sary for satisfactory seizure control. 2. Once an epileptic is pregnant, plasma drug levels should be brought to the therapeutic range, but major changes in the antiepileptic regimen should not be undertaken unless seizure control is poor. The challenge during pregnancy is to compensate for the decline in drug plasma levels by increasing the dosage. The patient should be seen at least monthly and plasma levels of all antiepileptic drugs should be determined, whether or not seizures have occurred. As the preg¬ nancy proceeds, the doses needed for maintenance will often reach levels that would be toxic in the nongravid state.
3. Status
epilepticus
is
epileptic
an
unfortu¬
uncommon occurrence in women pregnancy.
nate but not
during
is almost always subtherapeutic plasma levels of antiepileptic drugs due to either inadequate main¬ tenance or noncompliance. There is no established answer to the question of how to treat status epilepticus during pregnancy, considering the possible adverse effects on the fetus of rapid intravenous loading of medication as opposed to the danger of continuous convulsions. At present, no evidence contraindicates the intravenous use of standard drugs for status epilepticus in pregnancy. 4. After delivery, the infant should be inspected for congenital malforma¬ tions and given 1 mg of phytonadione. The infant's clotting factors are then studied after two to four hours, and repeated injections of phytonadione are administered if there is any abnormality. Infants exposed in utero to phénobarbital should be observed for withdrawal symptoms. 5. The antiepileptic drug dose re¬ quired to maintain the mother at a therapeutic level during pregnancy does not decline immediately postpartum. The high doses must be main¬ tained for variable periods, tapering being dictated by repeated plasma level determinations. The
cause
Name and Trademark of Drug
Nonproprietary
Carbamazepine- Tegretol. References 1. Niswander KR, Gordon M: The women and their pregnancies. US Department of Health, Education and Welfare, publication No. (NIH) 73-379, 1972, pp 257-259. 2. Baptisti A: Epilepsy and pregnancy: A review of the literature and a study of 37 cases. Am J Obstet Gynecol 35:818-824, 1938. 3. Burnett CWF: A survey of the relation between epilepsy and pregnancy. J Obstet Gynecol Br Commonw 53:535-553, 1946. 4. Sabin M, Oxorn H: Epilepsy and pregnancy. Obstet Gynecol 7:175-179, 1956. 5. Suter C, Klingman KO: Seizure states and pregnancy. Neurology 7:105-118, 1957. 6. Dimsdale H: The epileptic in relation to pregnancy. Br Med J 2:1147-1150, 1959. 7. Fedrich J: Epilepsy and pregnancy: A report from the Oxford Record Linkage Study. Br Med J 2:442-448, 1973. 8. Knight AH, Rhind EG: Epilepsy and pregnancy: A study of 153 pregnancies in 59 patients. Epilepsia 16:99-110, 1975. 9. Lander CM, Edwards VE, Eadie MJ, et al: Plasma anticonvulsant concentrations during pregnancy. Neurology 27:128-131, 1977. 10. Mygind KI, Dam M, Christiansen J: Phenytoin and phenobarbital plasma clearance during pregnancy. Acta Neurol Scand 54:160-166, 1976. 11. Hooper WD, Bochner F, Eadie MJ, et al: Plasma protein binding of diphenylhydantoin: Effects of sex hormones, renal and hepatic disease. Clin Pharmacol Ther 15:276-282, 1974. 12. Ramsay RE, Strauss RG, Wilder BJ, et al: Status epilepticus in pregnancy: Effect of phenytoin malabsorption on seizure control. Neurology 28:85-89, 1978. 13. Mirkin BL: Placental transfer and neonatal elimination of diphenylhydantoin. Am J Obstet Gynecol 109:930-933, 1971.
14. Mirkin BL:
Diphenylhydantoin:
Placental
transport, fetal localization, neonatal metabolism, and possible teratogenic effects. J Pediatr 78:329-337, 1971. 15. Melchior JC, Svensmark O, Trolle D:
Placental transfer of phenobarbital in epileptic and elimination in newborns. Lancet 2:860-861, 1967. 16. Martinez G, Snyder RD: Transplacental passage of primidone. Neurology 23:381-383, 1973. 17. Rane A, Bertilsson L, Palmer L: Disposition of placentally transferred carbamazepine (Tegretol) in the newborn. Eur J Clin Pharmacol 8:283-284, 1975. 18. Painter MJ, Pippinger C, Abern SB, et al: Tissue/plasma ratios of phenytoin and phenobarbital in the newborn. Ann Neurol 4:197, 1978. 19. Jalling B: Plasma concentrations of phenobarbital in treatment of seizures in newborns. Acta Paediatr Scand 64:514-524, 1975. 20. Painter MJ, Pippinger C, Carter G, et al: Metabolism of phenobarbital and phenytoin by neonates with seizures. Neurology 27:370, 1977. 21. Painter MJ, Pippinger C, MacDonald H, et al: Phenobarbital and diphenylhydantoin levels in neonates with seizures. J Pediatr 92:315-319, 1978. 22. Bleyer WA, Marshall RE: Barbiturate withdrawal syndrome in a passively addicted infant. JAMA 221:185-186, 1972. 23. Desmond M, Schwaniche R, Wilson G, et al: Maternal barbiturate utilization and neonatal withdrawal symptomology. J Pediatr 80:190-197, 1972. 24. Seip M: Effects of antiepileptic drugs in pregnancy on the fetus and newborn infant. Ann Clin Res 5:205-207, 1973. 25. Bjerkedal T, Bahna SL: The course and outcome of pregnancy in women with epilepsy. Acta Obstet Gynecol Scand 52:245-248, 1973. 26. Spiedel BD, Meadow SR: Maternal epilepsy and abnormalities of the fetus and newborn. Lancet 2:839-843, 1972. 27. Higgins TA, Comerford JB: Epilepsy in pregnancy. J Irish Med Assoc 67:317-320, 1974. 28. Janz D, Fuchs V: Are anti-epileptic drugs harmful when given during pregnancy? German Medical Monographs 9:20-23, 1964b. 29. Millar JH, Nevin NC: Congenital malformations and anticonvulsant drugs. Lancet 1:328, 1973. 30. Niswander JD, Wertelechi W: Congenital malformation among offspring of epileptic women. Lancet 1:1062, 1973. 31. Meadow R: The teratogenicity of epilepsy. Dev Med Child Neurol 16:375-376, 1974. 32. Shapiro S, Hartz SC, Sishind V, et al: Anticonvulsants and parental epilepsy in the development of birth defects. Lancet 1:272-275, 1976. 33. Lowe CR: Congenital malformations among infants born to epileptic women. Lancet 1:9-10, 1973. 34. Monson RR, Rosenberg L, Hartz SC, et al: Diphenylhydantoin and selected congenital malformations. N Engl J Med 289:1049-1052, 1973. 35. Janz D: The teratogenic risk of antiepileptic drugs. Epilepsia 16:159-169, 1975. 36. Beale Y, Lewenthal H, Aderet NB: Congenital malformation due to anticonvulsant drugs. Obstet Gynecol 45:439-442, 1975. 37. Annegers JF, Elvebach LR, Hauser WA, et al: Epilepsy, anticonvulsants and malformation. Birth Defects 11:157-160, 1975. 38. Meadow SR: Congenital abnormalities and anticonvulsive drugs. Proc R Soc Med 63:48-49, women
1970. 39. sant. 40. Kolk
Sauth J: Lancet
Teratogenic
effect of anticonvul-
2:1154, 1972.
Starreveld-Zimmerman AAE,
van
Der
WJ, Meinaidi H: Are anticonvulsants
tera-
togenic? Lancet 2:48-49,
1973.
41. Hill RM: Fetal malformations and
antiepi-
leptic drugs. Am J Dis Child 130:923-925, 1976. 42. Zellweger H: Anticonvulsants during preg-
Downloaded From: http://archneur.jamanetwork.com/ by a University of Manitoba User on 06/14/2015
nancy: A damage to the developing fetus? Clin Pediatr 13:338-345, 1974. 43. Annegers JF, Elvebach LR, Hauser WA, et al: Do anticonvulsants have a teratogenic effect? Arch Neurol 31:364-373, 1974. 44. Anderson RC: Cardiac defects in children of mothers receiving anticonvulsant therapy during pregnancy. J Pediatr 89:318-319, 1976. 45. Dansky L, Andermann E, Sherwin A, et al: The outcome of pregnancy in epileptic women.
Epilepsia 16:199, 1975. 46. Beasley SA, Landstrom DL: anticonvulsant medication during
The use of pregnancy. J Okla State Med Assoc 70:136-138, 1977. Paull LL: Mater47. Livingston S, Berman W, nal epilepsy and abnormalities of the fetus and newborn. Lancet 2:1265, 1973. 48. Davis RE: Congenital malformations and anticonvulsant drugs. Lancet 1:492-493, 1973. 49. Nelson MM, Forfar JO: Associations between drugs administered during pregnancy and congenital abnormalities of the fetus. Br Med J 1:523-527, 1971. 50. Hanson JW, Smith DW: The fetal hydantoin syndrome. J Pediatr 87:285-290, 1975. 51. Hanson JW, Myrianthopoulos NC, Harvey MAS, et al: Risks to offspring of women treated with hydantoin anticonvulsants with emphasis on fetal hydantoin syndrome. J Pediatr 89:662\x=req-\ 668, 1976. 52. Watson JD, Spellacy WN: Neonatal effects of maternal treatment with the anticonvulsants during diphenylhydantoin. Obstet Gynecol 37:881\x=req-\ 885, 1971. 53. Laughan PM, Gold H, Vance JC: Phenytoin teratogenicity in man. Lancet 1:70-72, 1973. 54. German J, Kowal A, Ehlers KH: Trimethadione and human teratogenesis. Teratology 3:349\x=req-\ 362, 1970. 55. German J, Ehlers KH, Kawal A, et al: Possible teratogenicity of the methadione and paramethadione. Lancet 2:261-262, 1970. 56. Zachai EH, Mellman WJ, Neiderer B: The fetal trimethadione syndrome. J Pediatr 87:280\x=req-\ 284, 1975. 57. Goodman RM, Katznelson MB-M, Hertz M, et al: Congenital malformations in four siblings of a mother taking anticonvulsant drugs. Am J Dis Child 130:684-687, 1976. 58. Mountain KR, Herst J, Gallies AS: Neonatal coagulation defect due to anticonvulsant drug treatment in pregnancy. Lancet 2:265-268, 1970. 59. Kohler HG: Hemorrhage in the newborn of epileptic mothers. Lancet 1:267, 1966. 60. Evans AR, Forrester RM, Discombe C: Neonatal hemorrhage following maternal anticonvulsant therapy. Lancet 1:517-518, 1970. 61. Davies PP: Coagulation defect due to anticonvulsant drug treatment in pregnancy. Lancet 1:413, 1970. 62. Stevenson MM, Gilbert EF: Anticonvulsants and hemorrhagic diseases of newborn infant. J Pediatr 77:516, 1970. 63. Bleyer WA, Skinner AL: Fatal neonatal hemorrhage after maternal anticonvulsant therapy. JAMA 235:626-627, 1978. 64. Solomon GE, Hilgartner MW, Lutt H: Coagulation defects caused by diphenylhydantoin. Neurology 22:1165-1171, 1972. 65. Margolin FG, Kanton NM: Hemorrhagic disease of newborn: An unusual case related to maternal ingestion of an antiepileptic drug. Clin Pediatr 11:59-60, 1972. 66. Douglas H: Hemorrhage in the newborn. Lancet 1:816-817, 1966. 67. Lawrence A: Antiepileptic drugs and the foetus. Br Med J 2:1267, 1963. 68. Stumpf DA, Frost M: Seizures, anticonvulsants, and pregnancy. Am J Dis Child 132:746\x=req-\ 748, 1978. 69. Feldman GL, Weaver DD, Lovrien EW: The fetal trimethadione syndrome. Am J Dis Child 131:1389-1392, 1977. 70. Smith DW: Teratogenicity of anticonvulsive medications. Am J Dis Child 131:1337-1339, 1977.
stress, hormonal alterations, and changes in respiratory patterns.' """
The
Pregnant Epileptic
A Review and Recommendations Georgia
D.
Montouris, MD; Gerald M. Fenichel, MD; L. William McLain, Jr, MD
major concerns in the pregnant epileptic patient are loss of seizure control and the teratogenic effects of antiepileptic drugs on the fetus. Loss of seizure control is usually caused by a progressive decline of antiepileptic plasma levels throughout pregnancy. This decline can be prevented by monthly dose adjustments based on plasma level determinations. Although infant malformations are a more prevalent outcome of the pregnancies of epileptics than of nonepileptics, the role of antiepileptic drugs in teratogenicity is not fully established. Only trimethadione has been convincingly \s=b\ The
linked to fetal malformation. Recommendations for the management of epilepsy in pregnancy are made. (Arch Neural 36:601-603, 1979)
HPhe
efficacy of antiepileptic drugs, coupled with improved social atti¬ tudes toward epilepsy, allows epileptic patients to lead normal or nearly normal lives. Consequently, increas¬ ing numbers of female patients must consider the special problems of their
disease in pregnancy. In the Collabo¬ rative Perinatal Study sponsored by the National Institutes of Health, 0.44% of the pregnant women were
epileptic.1 Pregnancy in the epileptic provides a therapeutic challenge in maintain¬ ing a seizure-free state while minimiz¬ ing the adverse effects of antiepilep¬ tic drugs on the fetus. Although the issues are related, it is convenient to analyze separately the effects of preg¬ nancy on the mother's epilepsy and the effect of the mother's epilepsy and drug regimen on the fetus. REVIEW OF LITERATURE Effect of Pregnancy on Epilepsy
analyze the effect of pregnancy epilepsy, it is useful to divide patients into two categories: women who have been identified as epileptic prior to conception and in whom a To
on
Accepted
publication Dec 31, 1978. Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tenn. Dr McLain is currently with the Department of Neurology, University of Minnesota, Minneapolis. Reprint requests to Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN 37232 (Dr Fenichel). From the
for
level of seizure control has been estab¬ lished,1' and women who experience a seizure disorder, not related to toxe¬ mia, for the first time during preg¬ nancy. Less than 25% of women in the latter group will have seizures only during that and subsequent pregnan¬ cies. The term "gestational epilepsy" has been applied to this phenome¬ ""
non.'·"^
Most studies concerning the effects of pregnancy on seizure frequency have been retrospective. The earliest report was published in 1867- and, although lacking in statistics, claimed that pregnancy had a favorable effect on the frequency of convulsions. This was refuted by a 1910 report- that indicated that pregnancy had no predictable influence on epilepsy. Re¬ cent information suggests that in patients with established epilepsy before pregnancy, seizure frequency is increased in 45%, decreased in 5%, and unaltered in 50%." The likelihood of an increase in seizure frequency during pregnancy can be predicted from the history of seizure control during the two years prior to concep¬ tion." Of women with no more than one seizure during the nine months preceding pregnancy, only 25% expe¬ rience an increase in seizure frequen¬ cy during pregnancy. In comparison, when the seizure frequency before pregnancy is greater than one seizure per month, more than 60% will have a deterioration in seizure control. This deterioration is most likely to begin in the first trimester.4 Following preg¬ nancy, the previous seizure frequency is usually reestablished." The seizure frequency in different pregnancies is unpredictable both in women with preexisting epilepsy and in those who first have seizures during
pregnancy.'"
Among women who first manifest seizures during pregnancy, the sei¬ zures and EEG abnormalities tend to be focal." Many women in this cate¬ gory have preexisting cerebral disor¬ ders, such as vascular abnormalities or tumor, rather than primary general¬ ized epilepsy. A potential seizure focus could be activated by any of several changes that occur in pregnancy: "
Downloaded From: http://archneur.jamanetwork.com/ by a University of Manitoba User on 06/14/2015
In some women reporting decreased seizure frequency during pregnancy, the explanation may be better drug compliance. In one series, five of seven women whose seizure control had improved during pregnancy ad¬ mitted that they used antiepileptic
drugs
more
regularly.
'
Effect of Pregnancy on Antiepileptic Drug Metabolism A critical factor underlying the loss of seizure control during pregnancy is a decline in plasma antiepileptic drug levels when the oral dose is con¬ stant." There is little doubt that the "'
pharmacokinetics of most antiepilep¬ tic drugs is altered by pregnancy. Several investigators have reported increased plasma clearance for phenytoin and phénobarbital,""' although the plasma protein binding of pheny-
toin remains unaltered." Plasma lev¬ els of phenytoin and phénobarbital fall progressively throughout preg¬ nancy and increase after birth, ap¬ proaching pregravid levels. The in¬ creased need for antiepileptic drugs could be explained on the basis of fluid retention, a general increase in hepat¬ ic metabolic rate," intestinal malab¬ sorption, the effects of supplementa¬ ry vitamin intake, and the volume of fetal tissues and placenta." Placental transfer and fetal elimi¬ nation rates for antiepileptic drugs are known for phenytoin, phénobarbi¬ tal, primidone, and carbamaze¬ '-'
pine."
'" "" phenytoin concentrations identical in cord and maternal serum at term."·" Plasma phenytoin half-life in the newborn varies from 55 to 69 hours, and this is not affected by the presence of phénobarbital.1'" The fetal elimination rate of pheny¬ toin is slow during the first two days postpartum and then increases on the third day, with elimination completed by the fifth day. The greatest concen¬ tration of phenytoin is in the liver, adrenal glands, and kidneys, whereas the amniotic fluid and CSF are virtually devoid of the drug." In newborns loaded with phenytoin postnatally, the highest tissue concentra¬ tion is in the liver.1" Phénobarbital concentrations in hu¬ man umbilical cord plasma are 95% of those in the mother's plasma." Al¬ though the half-life of phénobarbital in newborns who have their first expe¬ rience with the drug postnatally is 59 to 182 hours,1""1" the ability to elimi¬ nate the drug improves with the length of time the infant is exposed.
are
Intrauterine exposure, therefore, re¬ sults in a shorter half-life in the newborn.-1 Following the postnatal administration of phénobarbital to the newborn, the highest tissue levels are in fat, heart, and liver.18 The concentration of phénobarbital in the brain compared with plasma phéno¬ barbital concentration is lower in the newborn than in adults. Phénobar¬ bital dependence states are more common in infants born to epileptic mothers but are not associated with intrauterine growth retardation.-Withdrawal symptoms may be seen when the mother has taken doses of 60 to 120 mg per day during the last trimester. The syndrome is character¬ ized by hyperexcitability, tremor, restlessness, and difficulty in sleep¬ ing. Seizures do not occur.2' In our experience, the oral dosages of carbamazepine required to main¬ tain plasma levels within the thera¬ peutic range are increased during pregnancy. Umbilical cord and mater¬ nal plasma levels are identical. The plasma half-life of carbamazepine in the newborn ranges from eight to 28 hours.17 This is not significantly different from the half-life observed in adults on chronic therapy. Effect of
Epilepsy on Pregnancy Several authors have indicated that epileptics have more difficulty with
pregnancy than nonepileptics.1 The data are inconclusive but suggest a twofold increase in the incidence of maternal complications during preg¬ nancy (hyperemesis, vaginal bleeding, toxemia) and of complications of delivery (induction of labor, applica¬ tion of forceps).-"' These studies were retrospective and lacked information on drug regi¬ men, plasma drug levels, and seizure frequency. Therefore, it is not possible to determine the relative contribu¬ tions of the epileptic state, the occur¬ rence of seizures, and the use of drugs in causing this increased risk. As might be anticipated from the increased complication rates, there is also an increase in the rates of prema¬ turity, small-for-dates babies, and neonatal mortality and morbidi¬ -'--*
ty.1—
Teratogenicity of Antiepileptic Drugs The risk of congenital malforma¬ tions among infants exposed in utero
to
antiepileptic drugs
is not
fully
established, but it is estimated to be two or three times greater than that
in the general population.7-''' Be¬ cause the incidence of most malforma¬ tions in non-drug exposed infants is less than 1%, increased rates can be
detected only if the study population is large or if the increased rate of malformation is considerable. The anomalies most frequently encoun¬ tered in the offspring of treated epileptics are cleft palate, cleft lip, and cardiac defects, especially defects of the cardiac septum.--""1" Some of the risk factors for teratogenicity that must be considered include the occur¬ rence of convulsions during pregnan¬ cy, the increased incidence of preg¬ nancy complications, socioeconomic factors, and the teratogenicity of
antiepileptic drugs. The fetal hydantoin syndrome is the most commonly reported defect asso¬ ciated with a specific antiepileptic drug."'"-""' It is characterized by craniofacial anomalies, limb defects, defi¬ cient growth, and mental retardation.
The craniofacial anomalies include a low and broad nasal bridge, epicanthal folds, a short upturned nose, hypertel-
orism, ptosis, strabismus, prominent ears that are low-set and malformed, a wide mouth with prominent lips, and
variations in the size and shape of the head, with sutural ridging or widen¬ ing of the fontanels. The limb defects include hypoplasia of the distal pha¬ langes and nails which tend to assume a more normal appearance with time, finger-like thumbs, and variations in palmar creases and dermatoglyphics. There is intrauterine growth failure that results in small stature despite normal growth postnatally. The de¬ gree of mental retardation is mild to moderate. Although it has been sug¬ gested that the incidence of this syndrome is high, no prospective epidemiological study has been per¬ formed to document the rate of occur¬ rence."'"
A second fetal disorder associated with maternal antiepileptic drugs is the trimethadione syndrome."'""' The causal relationship between fetal exposure and malformation is more firmly established for trimethadione than for any other antiepileptic drug. These infants have developmental
delay, speech disturbances, V-shaped eyebrows, epicanthal folds, low-set ears with an anteriorly folded helix, palatal anomalies, and irregular teeth.
Additional features in some infants intrauterine growth retardation, short stature, cardiac anomalies, ocu¬ lar defects, simian creases, microceph¬ aly, and hypospadius. It is clear that the trimethadione and hydantoin syn¬ dromes are similar. Furthermore, sim¬ ilar defects have also been described in infants exposed to phénobarbital or primidone in utero.4"44 "'7 To date, no reports incriminate carbamazepine as are
"'"
a
teratogenic agent.
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Hemorrhagic
Disease of the Newborn
to phenytoin, bar¬ trimethadione may de¬ velop bleeding tendencies during the first 24 hours after delivery owing to decreased levels of vitamin Indepen¬ dent clotting factors despite normal levels in the mother."'" ;T Drug-induced vitamin deficiency must be distin¬ guished from the physiological defi¬ ciency that occurs on the second to fifth day. The drug-induced bleeding occurs earlier and is life-threatening. The hemorrhagic disorder can be prevented by injections of phytonadione (vitamin K) into the new¬ born."'" '"' In this center, 1 mg is routinely given to all newborns after delivery. In infants exposed in utero to antiepileptic drugs, clotting studies are obtained two to four hours after the phytonadione is administered. If clotting factors remain abnormal, an additional dose is administered and the procedure is repeated until the factors are normal. If hemorrhage has occurred, fresh frozen plasma is
Fetuses
biturates,
exposed
or
given.'""7
RECOMMENDATIONS 1. In an epileptic woman contem¬ plating pregnancy, an antiepileptic drug regimen should be established that provides optimal seizure control with the fewest side effects using the
least number of drugs. Drug choice should be based on these considera¬ tions rather than on risk of teratoge¬ nicity, for this risk is small. The one exception is trimethadione, which probably should be avoided.""-7" Sin¬ gle-drug therapy is ideal whenever possible. Further, maintenance of therapeutic plasma levels is so diffi¬ cult during pregnancy that it is unwise to compound the difficulty with multiple drugs unless it is neces¬ sary for satisfactory seizure control. 2. Once an epileptic is pregnant, plasma drug levels should be brought to the therapeutic range, but major changes in the antiepileptic regimen should not be undertaken unless seizure control is poor. The challenge during pregnancy is to compensate for the decline in drug plasma levels by increasing the dosage. The patient should be seen at least monthly and plasma levels of all antiepileptic drugs should be determined, whether or not seizures have occurred. As the preg¬ nancy proceeds, the doses needed for maintenance will often reach levels that would be toxic in the nongravid state.
3. Status
epilepticus
is
epileptic
an
unfortu¬
uncommon occurrence in women pregnancy.
nate but not
during
is almost always subtherapeutic plasma levels of antiepileptic drugs due to either inadequate main¬ tenance or noncompliance. There is no established answer to the question of how to treat status epilepticus during pregnancy, considering the possible adverse effects on the fetus of rapid intravenous loading of medication as opposed to the danger of continuous convulsions. At present, no evidence contraindicates the intravenous use of standard drugs for status epilepticus in pregnancy. 4. After delivery, the infant should be inspected for congenital malforma¬ tions and given 1 mg of phytonadione. The infant's clotting factors are then studied after two to four hours, and repeated injections of phytonadione are administered if there is any abnormality. Infants exposed in utero to phénobarbital should be observed for withdrawal symptoms. 5. The antiepileptic drug dose re¬ quired to maintain the mother at a therapeutic level during pregnancy does not decline immediately postpartum. The high doses must be main¬ tained for variable periods, tapering being dictated by repeated plasma level determinations. The
cause
Name and Trademark of Drug
Nonproprietary
Carbamazepine- Tegretol. References 1. Niswander KR, Gordon M: The women and their pregnancies. US Department of Health, Education and Welfare, publication No. (NIH) 73-379, 1972, pp 257-259. 2. Baptisti A: Epilepsy and pregnancy: A review of the literature and a study of 37 cases. Am J Obstet Gynecol 35:818-824, 1938. 3. Burnett CWF: A survey of the relation between epilepsy and pregnancy. J Obstet Gynecol Br Commonw 53:535-553, 1946. 4. Sabin M, Oxorn H: Epilepsy and pregnancy. Obstet Gynecol 7:175-179, 1956. 5. Suter C, Klingman KO: Seizure states and pregnancy. Neurology 7:105-118, 1957. 6. Dimsdale H: The epileptic in relation to pregnancy. Br Med J 2:1147-1150, 1959. 7. Fedrich J: Epilepsy and pregnancy: A report from the Oxford Record Linkage Study. Br Med J 2:442-448, 1973. 8. Knight AH, Rhind EG: Epilepsy and pregnancy: A study of 153 pregnancies in 59 patients. Epilepsia 16:99-110, 1975. 9. Lander CM, Edwards VE, Eadie MJ, et al: Plasma anticonvulsant concentrations during pregnancy. Neurology 27:128-131, 1977. 10. Mygind KI, Dam M, Christiansen J: Phenytoin and phenobarbital plasma clearance during pregnancy. Acta Neurol Scand 54:160-166, 1976. 11. Hooper WD, Bochner F, Eadie MJ, et al: Plasma protein binding of diphenylhydantoin: Effects of sex hormones, renal and hepatic disease. Clin Pharmacol Ther 15:276-282, 1974. 12. Ramsay RE, Strauss RG, Wilder BJ, et al: Status epilepticus in pregnancy: Effect of phenytoin malabsorption on seizure control. Neurology 28:85-89, 1978. 13. Mirkin BL: Placental transfer and neonatal elimination of diphenylhydantoin. Am J Obstet Gynecol 109:930-933, 1971.
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