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Epilepsy and Case Report

S.S., an 18-year-old woman, was

Pregnancy: Maternal and brought by ambulance to the emer-

gency department in status epilepticus.
The nurse in the emergency depart-
Fetal Effects of Phenytoin ment learned that S.S. was 4 months
pregnant, had received no prenatal
Joyce M. Brewer, RN, MSN,CS,CNM,CFNP care, and had stopped taking her anti-
Patricia A. Waltman, RN, EdD, CNNP convulsant medication (phenytoin)
when she discovered that she was preg-

I n the United States, approxi-

mately 1 million women of child-
bearing age have had epilepsy
disorder infrequently leads to
admission to a critical care unit, a
pregnancy complicated by epilepsy
nant. S.S.s condition was stabilized
by administering intravenous pheny-
toin in a glucose-free solution at a
loading dose of 18 to 20 mg/kg at a
rate not to exceed 50 mg/min. Because
diagnosed. However, less than 1% of can become a critical care emergency. of the likelihood of fetal hypoxia, she
all pregnancies are complicated by The frequency and duration of was admitted to a high-risk obstetric
seizure disorders.1 The diagnosis of seizures may change during preg- unit to monitor her and her fetus.
epilepsy can be a devastating event nancy in women with epilepsy.2,3 Why did she stop taking her med-
in a womans life. She not only is told Epilepsy improves during pregnancy ication? What are the risks and bene-
that she will probably have to take in some women, worsens in others, fits of taking anticonvulsants during
medication for the rest of her life, and appears to be unaffected in pregnancy? Knowledge of the pharma-
she also is told that this medication most.4 A generalized tonic-clonic codynamics, effects, and implications
can have serious adverse effects. seizure occurs in approximately 1% of antiepileptic drugs used during
During her childbearing years she to 2% of women with epilepsy dur- pregnancy is important for critical
must make difficult decisions, such ing labor and in another 1% to 2% care nurses.
as whether to become pregnant or during the first 24 hours after deliv-
terminate a pregnancy, based on her ery.4 Status epilepticus, a rare com-
understanding of the possibility of plication of pregnancy, may occur tion of antiepileptic drugs by the
fetal anomalies associated with her without any preceding increase in mother. Status epilepticus is an
medical condition and medication. the frequency of seizures and may immediate threat to both mother
Although the diagnosis of seizure result from the unwise discontinua- and fetus and significantly increases
Authors the risk of maternal and fetal death.5
The changes in frequency and
Joyce M. Brewer is an assistant professor of nursing at the University of Mississippi
Medical Center School of Nursing in Jackson, Miss, where she teaches and has a clinical duration of seizure activity during
practice. She is certified as a nurse-midwife and as a family nurse practitioner and has an pregnancy appear to be due to
extensive background in the care of pregnant women.
increased hormonal production and
Patricia A. Waltman is an associate professor in the school of nursing and a neonatal physiological changes in pregnancy
nurse practitioner at the University of Mississippi Medical Center in Jackson, Miss. She
coordinates and teaches in the neonatal nurse practitioner track in the graduate nursing that alter or affect absorption of
program. phenytoin. Increases in levels of
899- estrogen and progesterone during
reprints@aacn.org. pregnancy alter the seizure thresh-


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old, estrogens by activating seizure eralized tonic-clonic seizures in with relatively few adverse effects.10,11
foci and progesterone by dampening 1938. Rapidly it became one of the If more drug is given than is needed,
activity.6 Seizure activity or suscepti- most commonly used drugs for the the maximal capacity for phenytoin
bility can also be affected by water control of epileptic seizures because metabolism can be approached,
and sodium retention, alterations in it had no sedative effects.7 Normally causing plasma levels to increase
sleep, and mild respiratory alkalosis started at a dosage of 300 mg daily, dramatically, resulting in toxic
associated with pregnancy. These the usual effective maintenance dose effects such as ataxia, nausea, vom-
physiological changes of pregnancy of phenytoin is 300 to 400 mg daily.8 iting, hypotension, motor restless-
often necessitate increasing the Therapeutic plasma levels of pheny- ness, dizziness, and fatigue. Deep
dosage of anticonvulsant medication toin for most patients are between coma may also result.10
to levels greater than those used 10 and 20 g/mL.8 A loading dose The time necessary to attain a
before pregnancy.6 can be given either orally or intra- steady-state level of phenytoin can
Women with epilepsy also have venously. During convulsion or sta- vary from several days to several
a slightly increased risk for certain tus epilepticus, the preferred route weeks, because the half-life of
obstetric complications. According is intravenous, with the infusion phenytoin varies substantially
to Pennell,4 the risk of vaginal bleed- given slowly at a dosage of 10 to 15 among patients (8 to 64 hours),
ing, abruptio placenta, eclampsia, mg/kg, not to exceed 50 mg/min to depending on the rate at which the
and premature labor is approxi- reduce the risk of hypotension and patient metabolizes the drug.7,12 The
mately doubled in pregnant women cardiac arrhythmias. Intramuscular time to peak absorption in most
with epilepsy compared with preg- administration should be avoided patients is 4 to 8 hours after an oral
nant women without epilepsy. because of erratic absorption and dose with bioavailability of 85% to
Women who have epilepsy and because of discomfort at the injec- 95%.7 Therapeutic drug monitoring
become pregnant often do not take tion site.3,7 is necessary every 1 to 2 months
their medication as prescribed Because phenytoin is poorly sol- during pregnancy and more fre-
because of their fear of fetal malfor- uble in water at an acidic pH, very quently if breakthrough seizures
mation or their misconception of little drug absorption occurs in the occur. After delivery, as the physio-
the importance of taking the medi- stomach. Absorption takes place logical alterations of pregnancy are
cation during pregnancy. According primarily in the proximal part of reversed, drug levels may fluctuate
to Yerby and Devinsky,1 the inci- the small intestine, where phenytoin rapidly, leading to toxic effects.6
dence of fetal malformations is is principally bound to albumin. Careful monitoring of the pheny-
increased in women with epilepsy Both the absorption and metabo- toin blood levels during the imme-
even when antiepilepsy drugs are lism of this drug vary greatly among diate postpartum period is
not used. In this article, we focus on patients because metabolic rate necessary so that the dosage can be
the pharmacokinetics and pharma- varies from patient to patient. adjusted as needed.
codynamics of phenytoin, one of the Careful monitoring of the phenytoin
most widely prescribed antiepilepsy level of patients with renal failure General Adverse
drugs. Both the maternal and fetal and altered albumin concentrations Effects of Phenytoin
effects are reviewed, with an empha- is necessary because these condi- Phenytoin has a number of gen-
sis on information needed by critical tions affect the drugs concentration. eral adverse effects, including dys-
care nurses to educate patients and Phenytoin is eliminated primarily morphic changes such as acne and
to administer and monitor these by hepatic metabolism and is excreted hirsutism. These changes can occur
medications. in urine.9 Doses of phenytoin must in the lips, nose, brow, and other
be carefully adjusted. The ability of facial structures. Peripheral neu-
Pharmacokinetics the liver to metabolize the drug ropathy may occur with long-term
of Phenytoin tends to reach maximum capacity therapy. These adverse effects are
Phenytoin was first introduced close to the therapeutic level. At most commonly associated with
for the treatment of partial and gen- therapeutic levels, phenytoin is safe, polytherapy when phenytoin is


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combined with other antiepilepsy develops between 18 and 30 days control of breakthrough seizure
drugs such as phenobarbital. after conception, many women do activity is of utmost importance to
Another common adverse effect is not know yet that they are pregnant minimize the effects of oxygen dep-
gingival hyperplasia, an overgrowth when these defects are occurring. rivation on the fetus.
of the gums, which is a dose-related Folic acid supplements can Maternal epilepsy and treatment
effect that often begins within the increase the activity of hepatic with antiepilepsy drugs during preg-
first 3 months of therapy and pro- microsomal enzymes and thus has- nancy presents increased risk to the
gresses during the first year. This ten the clearance of antiepilepsy fetus and the newborn infant (Table
condition develops in more than drugs, leading to a reduced concen- 2). The neonates have an increased
45% of adults who take this drug. tration of phenytoin.14 This situation risk for stillbirths, congenital mal-
Part of the educational process related necessitates the careful monitoring formations, hemorrhagic disease,
to the administration of phenytoin of both folate and phenytoin levels and hypocalcemia. The long-term
includes emphasizing the need for after therapy is initiated. The nor- cognitive function of offspring of
frequent oral care and regular dental mal range for folate is 5 to 25 pregnant women taking antiepilepsy
checkups because gingival hyperpla- ng/mL.15 Additionally, phenytoin drugs is also a concern.
sia may progress to the point that therapy may increase the metabo-
gum resection is required. In addi- lism of vitamin D, leading to a Congenital Malformations
tion to these general adverse effects, decrease in vitamin D levels that can The frequency of congenital mal-
some adverse effects specifically in turn cause alterations in calcium formations increases in pregnancies
affect pregnant women. homeostasis that lead to osteo- complicated by maternal epilepsy.
malacia and osteoporosis. Pregnant This increase occurs in pregnancies
Effects of Phenytoin women taking phenytoin should in which uncontrolled seizures
During Pregnancy receive the recommended 400 occur frequently during the first and
Known adverse effects of pheny- IU/day of cholecalciferol through- part of the second trimester of preg-
toin in pregnant women are listed in out pregnancy to prevent problems nancy. The fetus is most vulnerable
Table 1. Antiepileptic drugs inter- in vitamin D levels and calcium to malformations from medication
fere with metabolism of folate, and absorption. during this time. In the third tri-
patients taking phenytoin may During labor and delivery, mester, seizure activity puts the
therefore become deficient in folate, women taking antiepilepsy drugs fetus at risk for hypoxic episodes,
leading to the development of are at increased risk for obstetric which leads to other complications
macrocytic anemia and possible complications. Weak uterine con- with the pregnancy. Fetal malforma-
complications during pregnancy. tractions may result in increased tions occur in about 10% of pregnant
During the past decade, it has interventions during labor and women with epilepsy (1000/year), of
become widely accepted that mater- delivery, including induction, artifi- which 2% are severe (200/year).16
nal deficiency in folate is associated cial rupture of membranes, use of However, when the frequency of
with neural tube defects in the forceps, vacuum assistance, and epilepsy and the prevalence of major
fetus.13 Because the neural tube cesarean delivery.4 malformations in the general popu-

Effects of Epilepsy and

Table 1 Known maternal adverse Antiepilepsy Drugs on the Table 2 Known fetal and neonatal
effects of phenytoin Fetus and Newborn Infant adverse effects of phenytoin
Nystagmus The pathophysiological conse- Fetal hydantoin syndrome
Ataxia quences of maternal seizures are a Facial clefting
Hirsutism Heart malformations
Gingival hyperplasia major risk for the fetus. Maternal Limb deformities
Peripheral neuropathy grand mal seizures associated with Vitamin K deficiency
Vitamin D and folate deficiency Vitamin D deficiency
Megaloblastic anemia
apnea can cause transient hypoxia Possible cognitive deficit
and acidosis in the fetus.6 Prompt


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lation is considered, less than 1% of Congenital heart disease and time, the partial thromboplastin
all malformations are associated with cleft lip or cleft palate are the major time, or both.24 Women should
maternal epilepsy.17 According to malformations most consistently receive injections of phytonadione
Samuels,14 attributed to maternal use of anti- early in labor, or phytonadione sup-
epilepsy drugs. Several large-scale plements during the last month of
There is little doubt that anticon- studies of infants born to women pregnancy to reduce bleeding ten-
vulsant medications are associat- with epilepsy who were taking anti- dencies in the newborn and during
ed with an increase in congenital epilepsy drugs indicated that approx- the immediate neonatal period.
malformations, but the magni- imately 2% experienced congenital Additionally, the newborn should
tude of this risk and the associa- heart disease and a similar percent- receive an injection of phytona-
tion of certain anomalies with age had cleft lip or cleft palate. These dione immediately after birth.
specific drugs remain debatable. rates are 4-fold greater than the Without this additional phytona-
rates in the general population for dione, the newborn is at risk for
Whether the malformations are congenital heart disease and 10-fold vitamin K deficiency and hemor-
caused primarily by the maternal greater than the rates for cleft lip or rhage, usually within the first 24
epilepsy itself or by exposure to cleft palate. Phenytoin was the most hours after birth. Sites of hemor-
antiepilepsy drugs is controversial. A commonly implicated antiepilepsy rhage are the skin, liver, gastroin-
recent study,18 however, suggests that drug in both of these studies.19,22 testinal tract, intracranial sites, and
antiepilepsy drugs rather than the The risk for neural tube defects thorax. Intracranial hemorrhage
epilepsy itself are the major contribu- is also increased in offspring of has been reported in approximately
tor to the development of malforma- women taking anticonvulsant med- 25% of these cases. The course may
tions. The dosage and timing of ications.23 Research indicates that be fulminating, and approximately
exposure to antiepilepsy drugs dur- phenytoin causes a decreased plasma 40% of infants reported to have
ing pregnancy are considered major concentration of folate in epileptic intracranial hemorrhage have
contributing factors.18 patients, probably through deple- died.19 Infants should be monitored
Fetal hydantoin syndrome is a tion of total hepatic folate.13 Serum carefully for signs of bleeding,
rare disorder that is caused by expo- level of folate decreases when including petechiae and large
sure of a fetus to phenytoin. Major phenytoin therapy is initiated alone cephalohematomas that indicate col-
signs of this disorder include abnor- with no folic acid supplementation. lection of blood between the perio-
malities of the skull and facial fea- This situation creates an extraordi- steum and the skull.
tures, growth deficiencies, and narily high degree of risk for women Cephalohematomas generally are
underdeveloped nails on the fingers of childbearing age who use pheny- due to birth trauma, and if a large
and toes. The full-blown syndrome is toin. Therapy recommendations cephalohematoma occurs, computed
estimated to occur in approximately suggest that women begin taking tomography of the head should be
5% to 10% of newborns exposed to folic acid supplements before ordered to rule out an underlying
phenytoin in utero.19 An additional becoming pregnant and continue skull fracture.
30% have subtle changes compatible taking the supplements throughout
with the prenatal effects of hydan- the first trimester to reduce the risk Neonatal Hypocalcemia
toin.20 The teratogenic mechanism of of neural tube defects. As discussed previously, pheny-
phenytoin may be related to an accu- toin alters metabolism of vitamin D
mulation of epoxides, which are Hemorrhagic Disease and inhibits the intestinal absorp-
highly reactive oxidative metabolites of the Newborn tion of calcium in pregnant women,
of phenytoin.21 Fetal hydantoin syn- Phenytoin interferes with vita- resulting in osteomalacia with
drome does occur with fetal exposure min K in the formation of precursor hypocalcemia. Decreased levels of
to phenytoin alone, but in most protein for coagulation factors II, vitamin D in the maternal system
cases, it occurs in offspring of women VII, IX, and X, resulting in prolon- can lead to low levels of vitamin D
given several antiepilepsy drugs.19 gation of either the prothrombin and calcium in the fetus, thus


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increasing the risk for neonatal epilepsy should not be concerned ease and use of antiepilepsy drugs
hypocalcemia.25,26 In order to reduce that taking phenytoin will result in during pregnancy. Women with
the risk related to neonatal hypocal- lower IQ for the baby, but they must epilepsy should be taught that even
cemia, the pregnant woman should be aware that learning problems without medication for their epilepsy,
be given cholecalciferol supple- may occur. they have a higher risk of delivering
ments throughout pregnancy. Most an infant with congenital malfor-
infants with hypocalcemia are Management Guidelines: mation and cognitive impairment.
asymptomatic, and early, mild Phenytoin During Pregnancy Although the exact mechanism is
hypocalcemia often resolves without Guidelines for the management unknown, it is theorized that genetic
treatment. If the mother has not of women taking phenytoin during factors contribute to the increased
received supplemental cholecalci- pregnancy and for initial monitor- prevalence of malformations in
ferol during pregnancy or the infant ing of newborns exposed to pheny- infants born to mothers with epilepsy
begins to have clinical signs such as toin are summarized in Table 3. It is independent of maternal medica-
jitteriness, the infants serum calcium important to manage the seizure tions.23 With anticonvulsant medica-
level should be measured. Because activity of pregnant women while tion, that risk may be even higher. It
neonatal jitteriness can also occur minimizing effects on the fetus and is equally important, however, and
with hypoglycemia, a blood glucose neonate. The major emphasis is pre- should be stressed to these women,
level should also be determined at vention and counseling young that more than 90% of babies born to
the same time to help differentiate women with epilepsy about the dis- women with epilepsy are born with-
possible causes.

Cognitive Function Table 3 Management guidelines for phenytoin during pregnancy4-6,19,24

The effect of maternal epilepsy
on IQ in the offspring has been stud- Maternal and fetal management
ied. Small head size can occur in Provide counseling before pregnancy about risk of treatment of epilepsy on the
developing fetus and neonate and the importance of taking medication
neonates prenatally exposed to Attempt to withdraw antiepilepsy drugs from women who wish to become pregnant
antiepilepsy drugs.19 Infants with and have been free of seizures for at least 2 years
Attempt to use only a single antiepilepsy drug for seizure control
fetal hydantoin syndrome may have Use lowest dose and plasma level that prevent tonic-clonic seizures
cognitive impairments, but whether Have pregnant women take a folic acid supplement of at least 0.4 mg/day to mini-
these impairments are permanent mize risk of neural tube defects
Have pregnant women take a cholecalciferol (vitamin D) supplement of at least 400
or disappear over time is unclear.27 IU/day to minimize risk of neonatal hypocalcemia
Research does point to significantly Stress the importance of taking prenatal vitamins, which contain folic acid and
smaller head size in infants who are Advise frequent oral care and regular dental checkups
prenatally exposed to several anti- Administer oral phytonadione (vitamin K) 10 mg/day to the mother during the last
epilepsy drugs as compared with month of pregnancy; if this supplement has not been given, administer parenteral
phytonadione to the pregnant woman at the onset of labor to minimize risk of fetal
only a single antiepilepsy drug. hemorrhage
Most infants exposed to only a sin- Monitor plasma phenytoin levels regularly
Schedule regular fetal ultrasound examinations during pregnancy to monitor fetal
gle drug have normal intellectual growth and detect malformations
capacity, and the smaller head size Determine maternal serum levels of -fetoprotein to detect fetal neural tube defects
does not seem to be related to cogni- Management of phenytoin-exposed newborns
Carefully observe and monitor for malformations, bleeding, and clinical signs of
tive functioning in adulthood. In hypocalcemia
one study,28 persistent learning Do not discharge early, before 72 hours after birth, because problems may develop
during this time
problems were found in approxi- Administer phytonadione at birth as recommended for all newborns
mately 12% of phenytoin-exposed Measure serum calcium level if jitteriness is observed
infants as compared with 1% of the Measure serum glucose level at same time as serum calcium level to rule out
general population. On the basis of Allow mother to breast feed if desired
these results, pregnant women with


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Pediatrics suggests that women who vention of neural tube defects. Pediatrics.
Conclusion of Case Report have been free of seizures for at least 14.
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Epilepsy and Pregnancy: Maternal and Fetal Effects of Phenytoin
Joyce M. Brewer and Patricia A. Waltman
Crit Care Nurse 2003;23 93-98
Copyright 2003 by the American Association of Critical-Care Nurses
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