COLLECTIVE REVIEW pregnancy, seizures; seizure, pregnancy

Emergency Department Approach to Managing Seizures in Pregnancy [Jagoda A, Riggio S: Emergency department approach to managing seizures in pregnancy. Ann Emerg Med January 1991;20:80-85.] INTRODUCTION The clinical management of seizures is particularly difficult when the patient is pregnant. Pregnancy introduces concerns of teratogenicity, confusion regarding pharmacokinetics, and controversy involving management strategies. Pregnant women with seizures either had epilepsy before conception, have new-onset seizures during gestation, or have eclamptic convulsions. To understand the management options available, it is necessary to review the epidemiologic factors, physiologic changes, and potential complications of both the seizures and the anticonvulsants used in treatment.

Andy Jagoda, MD* Bethesda, Maryland Silvana Riggio, MDt Philadelphia, Pennsylvania From the Division of Emergency Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland;* and the Mid-Atlantic Epilepsy Center, Medical College of Pennsylvania, Philadelphia.t Received for publication November 27, 1989. Revision received March 5, 1990. Accepted for publication April 6, 1990.

EPIDEMIOLOGY A N D SEIZURE CONTROL Approximately 0.5% of women of child-bearing age have epilepsy. 1 Improved therapeutics and elimination of social stigma have resulted in a larger percentage of women with epilepsy becoming pregnant, which in turn has increased the likelihood of an emergency department encounter. In addition, both phenytoin and phenobarbital induce hepatic hydroxylating enzymes, which can decrease the effectiveness of some birth control pills and contribute to the possibility of an unplanned pregnancy. 2 In a review of 2,165 women with known epilepsy, Schmidt ~ found that during gestation, 24% of women had an increase in seizure frequency, 22% had a decrease, and 53% had no change. This was a composite review spanning 96 years and reflecting diverse patient pools and therapeutic modalities. In women on anticonvulsants, noncompliance with medications and sleep deprivation have been identified as the two major factors resulting in an increase in seizure frequency.4, s When compliance is encouraged with close monitoring, the incidence of increased seizure frequency becomes as low as 4% to 16%.6, 7 Epilepsy can be classified into primary generalized, partial, complex partial, and secondary generalized. 8 Primary generalized epilepsy refers to an event that involves both cerebral hemispheres from the onset with no focal component (ie, no aura). It is associated with impaired consciousness; when motor signs are present, they are bilateral. Partial seizures are focal events and can be motor, sensory, or autonomic; when associated with impaired consciousness, they are referred to as complex partial seizures. Secondary generalized epilepsy results from simple partial seizures that spread diffusely, causing tonic-clonic activity. Remillard et al 9 found that women with primary generalized epilepsy were less likely to have increased seizures during pregnancy than women with secondary generalized epilepsy or complex partial seizures. Women with primary generalized epilepsy who have good seizure control before pregnancy, regardless of whether they are on medication, have the best chance of a seizure-free pregnancy. First seizures during pregnancy are categorized into gestational and newonset epilepsy. Gestational epilepsy refers to seizures that occur only during pregnancy. Less than 25% of women who have a first seizure during pregnancy have gestational seizures, lo These seizures frequently occur as

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Annals of Emergency Medicine

The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government. Address for reprints: LCDR Andy Jagoda, MD, Department of Military Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814.

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isolated events and do not portend future episodes in the same or subseq u e n t p r e g n a n c i e s . K n i g h t and Rhind 11 reported that 11 of 16 patients with gestational epilepsy had only one seizure. Gestational epilepsy cannot be distinguished from idiopathic epilepsy w i t h onset during pregnancy. Of women with epilepsy, 12.8% report onset during pregnancy, w h i c h is probably a coincidence in predisposed individuals.gA 2 However, there is the possibility that activation of a seizure focus results from physiologic changes of pregnancy such as water retention, hormonal changes, c h a n g e s in r e s p i r a t o r y p a t t e r n s , stress, or sleep deprivation. 11 Eclamptic seizures are a third type of convulsion that can be seen in pregnancy. They have a maternal mortality rate of 13% to 20% and an i n c i d e n c e of o c c u r r e n c e in the United States of 0.01% to 1%. 13 The cause of eclampsia has not been elucidated, and there is no predisposit i o n to d e v e l o p i n g e c l a m p s i a in women with epilepsy. 14

METABOLISM AND PHARMACOKINETICS Serum anticonvulsant blood levels decrease throughout pregnancy and do not return to prepregnancy levels u n t i l eight to 12 weeks postpartum.15A 6 Once noncompliance has been eliminated as a factor, explanations for low levels include impaired drug absorption, 17 increased plasma volume with increased volume of distribution, 18 decreased serum albumin, 19 induction of maternal liver enzymes by hormonal changes, 2° and increased renal clearance.~°, 21 Decreased protein binding and increased renal clearance appear to be the most significant factors affecting the serum levels. The anticonvulsant effect of a drug is dependent on the unbound fraction. 22 Decreased protein binding results in more free drug. 23 Thus, whole serum levels, which are usually measured, do not accurately reflect true drug availability. Phenytoin salivary levels have been found to closely correlate with the free fraction of serum phenytoin, and some clinicians recommend basing management on these levelsA 6 The clinical relevance is that what appears to be a subtherapeutic phenytoin level might not be as low as it appears because the free level might 112/81

actually still be therapeutic; consequently, clinicians should not treat only a blood level. The m o s t c o m m o n l y used antiepileptics are phenytoin, phenobarbital, and carbamazepine. The serum drug levels decrease throughout pregnancy. The most significant decrease occurs with phenytoin; the least significant decrease occurs with carbamazepine.18,;4 P h e n y t o i n clearance reaches twice the preconception level by 32 weeks; combined with the increased free fraction due to the decreased serum proteins, there is a 30% to 70% decrease in serum pheny t o i n levels.S, 25 This possibly explains why some investigators report the highest incidence of seizures in the last trimester. 26 All patients on phenobarbital have been observed to have a decrease in the serum free fraction. 5 In s u m m a r y , t h r o u g h o u t pregnancy, the free fraction of anticonvulsants will increase but so will drug clearance, resulting in a gradual decrease in free concentration. Blood levels should be monitored and dosing increased appropriately if necessary, particularly in the third trimester when risks of seizures are the greatest and the risks of teratogenicity are the least. TERATOGENICITY Teratogenicity of the anticonvulsants is a confusing issue that has experienced a significant change in thinking during the past ten years. It appears that the actual teratogenic potential is relatively small for phenytoin, phenobarbital, and carbamazepine. Trimethadione is strongly associated with fetal malformations and mental retardation and is contraindicated in pregnancy.27, 2s Valproic acid is relatively contraindicated in pregnancy. 29 It has been associated with a 1% to 2% incidence rate of neural tube defects, which is 20-fold the rate seen in control populations. In 1975, Hanson and Smith 3° described a fetal hydantoin syndrome characterized by craniofacial abnorm a l i t i e s , limb defects, d e f i c i e n t growth, and mental retardation. Recent studies do not support a specific hydantoin syndrome because similar groups of anomalies have been reported with the same incidence in patients on other a n t i c o n v u l s a n t s and on no medications at all. 31,32 The most often reported major malAnnals of Emergency Medicine

formations in children of epileptic mothers are cardiovascular anomalies and orofacial clefts. 31 There is a debate whether the congenital defects are due to drugs, genetics, or a combination of these. There is increasing evidence for a genetic contribution because malformations are seen in 14% of families of children with malformations compared with 3% of control families, and clefts are found with a higher incidence in children of fathers with epilepsy. 32 Infants born to mothers with epilepsy have a twofold to threefold greater risk for congenital heart disease and a fivefold to tenfold greater risk of orofacial clefts. 3z A drug effect is suggested by the observation that anomalies are found to be higher when the mother was treated with a n t i c o n v u l s a n t s and lower if the mothers were not on drugs. 33 Dansky et a134 found a higher rate of anomalies related to higher serum levels of phenytoin and phenobarbital and in children whose m o t h e r s were on multiple drugs. It is probably safe to say that congenital malformations in children of epileptic mothers are an expression of both genetics and drugs. The goal of therapy should be to keep drug exposure to a minimum. There is no evidence that IV administration of anticonvulsants has an increased risk of inducing teratogenicity, and any risk would certainly be less than that of untreated seizures. Carbamazepine is the only anticonvulsant that so far has not been identified with major malformations and is considered the prophylactic a g e n t of c h o i c e by s o m e c l i n i cians.lO,35 Recently, carbamazepine has been associated with minor malformations, including craniofacial defects and fingernail hypoplasia, and with developmental delay. 36 COMPLICATIONS Uncontrolled seizures pose the biggest threat to a successful pregnancy in a woman with epilepsy. As mentioned, complications from seizures far outweigh any concerns of drug teratogenicity. Seizures can result in hypoxia and t r a u m a to the fetus, making prevention imperative. Seizures cause fetal bradycardia and deceleration patterns consistent with asphyxia, even if they last less than one minute.18,37, 3s Similar slowing of fetal heart rate has been docu20:1 January 1991

SEIZURES IN PREGNANCY Jagoda & Riggio

FIGURE. Approach to managing seizures in pregnancy.

SEIZURE IN PREGNANCY

1

WEEKS GESTATION

I

1 1 1+

1 ;

LESS THAN 20 WEEKS

MORE THAN 20 WEEKS

_

il

HYPERTENSION, PROTEINURIA, EDEMA

HISTORY OF SEIZURES

+

1

ECLAMPSIA

1) DELIVER BABY WHEN IT BECOMES A VIABLE OPTION 2) TREAT AS NEEDED WITH DIAZEPAM 2 rng/mln to 20 mg followed by PHENYTOIN18 mg/Kg and/or PHENOBARB 100 mg/mln up to 2O mg/kg or MAGNESIUMSULFATE 4 gnVfollowed by 3 gm/hr HYDRALAZ]NE 10 mg IV as needed to control BP

I

-

I

1) FrO sleep deprivation medication noncompliance

1) Check electrolytes CBC, CBC, Mg, POd,Ca

2) Check serum drUg levels electrolytes, Mg, PC4,Ca

2) H ~ d CT

3) Consider Toxicology Screen

3) LP if fever or meningeal signs

4) Consider LP/CT g seizure vades from past events

4) Consider Toxicology Screen

ETIOLOGY IDENTIFIED

ETIOLOGY IDENTIFIED

,1Co nsider starting or increasing anticonvulsants

.lTreat appropriately (see text)

1) ConsiderGestational Epilepsy 2) No treatment indicated 3) Provide patient education and close follow-up

mented after eclamptic seizures. 39 Fetal death has been reported as the result of maternal seizures. 4° While there is c o n f l i c t i n g evidence, it does not appear that women with epilepsy have an increased rate of pre-eclampsia, eclampsia, abruptio placenta, perinatal mortality, prematurity, or abortion. 41-43 Hiilesmaa et al g7 followed 150 pregnancies and found no difference in the complication rates during pregnancy or delivery. In the same study, there were 170 grand mal convulsions in 48 pregnancies, none of which were associated with an obstetric complication. SEIZURE M A N A G E M E N T M a n a g e m e n t of t h e p r e g n a n t woman who has had or is having a seizure is similar to that of other seizure patients, with some added considerations (Figure). Treatment of status epilepticus and eclampsia will be specifically addressed in the next two sections. Evaluation begins by establishing the patient's stage of pregnancy. Patients more than 20 weeks must be evaluated for eclampsia. To make a diagnosis of eclampsia, the woman must have seizures plus two of the following: hypertension, proteinuria, and edema. Patients with eclampsia 20:1 January1991

require aggressive stabilization to maximize a safe delivery with minimal complications. Patients with noneclamptic convulsions should be queried regarding a history of seizures. If there is no history, then the seizure represents either new-onset epilepsy or gestational epilepsy; the two may be indistinguishable. In either case, the patient must be worked up as any new seizure patient would be, particularly if the seizure had a focal component. A metabolic profile and head c o m p u t e d t o m o g r a p h y (CT) w i t h proper abdominal shielding should be included. Drug toxicities and infections must be considered and investigated if indicated. If no source for the first seizure can be identified, gestational epilepsy is a possibility and no treatment is indicated. This is especially true in the first trimester when there is a greater teratogenic potential for use of the a n t i c d n v u l sants.11,12 P a t i e n t e d u c a t i o n and close follow-up must be provided. In patients with a history of seizures, precipitating factors must be s o u g h t . The two m o s t c o m m o n causes identified in the literature for increased seizures in a p r e g n a n t w o m a n are n o n c o m p l i a n c e w i t h m e d i c a t i o n s and sleep d e p r i v a tion. 3,5,1° Studies of sleep deprivation Annals of Emergency Medicine

are poorly described and define it as a delay of more than two hours from the usual working day's onset of sleep in patients who are already disposed to seizures through sleep deprivation before pregnancy.g,s, 44 The clinician must be careful in ascribing a seizure to sleep deprivation only w i t h o u t looking for other causes. However, if noncompliance or significant sleep deprivation is identified, it would be reasonable to correct it before considering an increase in the antiepileptic drugs, regardless of the serum level. If the seizure was different from past seizures, involving, for example, a new focal component or a new neurologic deficit, an extensive workup is indicated, including CT and possibly lumbar puncture. In patients with a history of epilepsy who have a seizure without an identified precipitating cause, anticonvulsants should be started or increased, d e p e n d i n g on the case. Monotherapy is always preferred to polytherapy. Neurologic and obstetric consultation should always be obtained, and close follow-up should be ensured. STATUS E P I L E P T I C U S IN PREGNANCY Status epilepticus is a rare complication occurring in less than 1% of known epileptics during their pregnancy compared with a 1.6% incidence seen in the general epilepsy population.3,11,26 When status epilepticus does occur during pregnancy, the mortality can be high unless control is obtained quickly. In the general epilepsy population, mortality is reported to range between 6% and 28%.45 Teramo and Hiilesmaa 4o reported 29 cases of status epilepticus in pregnancy; nine mothers and 14 infants died. It is well d o c u m e n t e d that the longer status epilepticus persists, the more difficult it becomes to stop and the higher become the morbidity and mortality rates. 46 Status epilepticus predisposes to neuronal damage, hypoxia, acidosis, rhabdomyolysis, cardiopulmonary compromise, and disseminated intravascular coagulation. Therefore, aggressive management is mandatory. The goals of management include maintaining cardiopul82/113

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m o n a r y function, t e r m i n a t i n g the seizure, preventing the seizure from recurring, identifying and correcting participating factors, and preventing systemic complications. M a n a g e m e n t of status epilepticus in the pregnant w o m a n is the same as for the n o n p r e g n a n t patient, m,47-49 Treatment begins by securing the airway, breathing, and circulation. When IV access is obtained, blood should be sent for anticonvulsant levels, electrolytes, glucose, calcium, phosphate, magnesium, toxicology screen, and blood count. Electrolyte abnormalities have been shown to precipitate seizures in nonpregnant patients,S0, 51 and it is presumed that they could cause seizures in the pregnant patient, 11 although the authors could not find any clear examples in the literature. It should be mentioned that measured sodium, potassium, and magnesium levels remain unchanged despite the significant fluid shifts during pregnancy. 52 Calcium levels tend to decrease throughout pregnancy, but t h e y correct once the hypoalbuminemia is accounted for. 53 As a result of the increased blood volume, h e m a t o c r i t decreases through the first two trimesters and then stabilizes or increases in the last trimester. 52 The WBC count can be greatly elevated as a result of pregnancy or seizures, but there should not be a bandemia, which would suggest infection.S2,S4 An arterial blood gas should be perf o r m e d i n i t i a l l y , and i n t u b a t i o n should be performed at the earliest signs of hypoxia or airway compromise. The patient should be placed on 100% oxygen, on an ECG monitor, and on a fetal monitor. A nasogastric tube and a Foley catheter should be considered. At the same time, the patient should receive 100 mg IM thiamine and 50 mL of 50% dextrose solution (unless rapid bedside blood glucose testing can be performed and is found to be within normal limits). Initial seizure control should be attempted with 2 m g / m i n diazepam until the seizure stops or a total of 20 mg is given. Diazepam is successful in terminating seizures within five m i n u t e s in 76% to 88% of cases.49,55, 56 Lorazepam (1 to 2 mg/ min to a total of 10 mg) is an alternative. Lorazepam has a much smaller v o l u m e of d i s t r i b u t i o n t h a n di114/83

azepam and, therefore, a longer duration of action. 57 There have been no major fetal complications reported with IV diazepam, although fetal heart rate variability and hypotension have been observed.S8, 59 Benzodiazepines are rapidly redistributed in the body; therefore, a longer acting anticonvulsant such as phenytoin or phenobarbital must be started concurrently. Phenytoin 18 mg/kg is given at a rate of 20 to 40 mg/min to minimize inducing hypotension. An alternative to phenytoin is phenobarbital given at 100 mg/min • until the seizure stops or a total of 20 mg/kg is given. Phenobarbital loading in mothers has been reported to prevent intraventricular hemorrhage in low b i r t h - w e i g h t i n f a n t s and therefore might be the anticonvulsant of choice. 6° In cases where phenytoin loading does not terminate the convulsion, the next option is either phenobarbital loading as described or a diazepam IV drip at 8 to 16 mg/hr. Phenobarbital and diazepam IV drips should not be used in the same patient due to the combined respiratory depressant effects. If the seizures are not controlled with these measures, there are three options to consider, although there are no good studies to support one over the other - paraldehyde, which is no longer available in a sterile injectable preparation, can be given rectally (5 to 10 mL of 2:1 dilution in mineral oil), 61-63 lidocaine (1 mg/kg IV followed by an IV drip at 2 to 4 mg/kg), 64 or general anesthesia. 65 Throughout management, the fetus m u s t be monitored, and delivery must be considered when it becomes a viable option.

MANAGEMENT OF ECLAMPTIC SEIZURES Eclampsia is the convulsive stage after pre-eclampsia and almost always occurs after the 20th week of pregnancy. The etiology of eclfimpsia is poorly understood, and postulates range from genetic to immunologic causes. 66 However, there is no controversy over m a n a g e m e n t goals: stop the seizures, control blood pressure, protect the mother, and deliver the baby as soon as possible. There is surprising controversy concerning t h e b e s t m e a n s of c o n t r o l l i n g eclamptic seizures.67, 68 Annals of Emergency Medicine

US obstetricians usually use magnesium sulfate to treat eclamptic seizures, whereas their British and European counterparts prefer to use benz o d i a z e p i n e s and phenytoin.13, 38, 59,69,70 Magnesium is purported to have anticonvulsant, antihypertensive, and sedative properties. It is also considered to be relatively safe for both the mother and fetus. The antihypertensive effects are minimal at therapeutic doses, and other antihypertensives, such as hydralazine, must be used for blood pressure control. Controlling blood pressure alone will not prevent eclamptic seizures. Magnesium is a smooth muscle relaxant with a narrow therapeutic range. It can induce respiratory depression and suppress muscular activity, thereby potentially masking seizure activity and delaying uterine contraction. Despite years of use, there are no controlled studies showing that magnesium decreases seizure duration or frequency. In fact, there is minimal evidence that it has any significant anticonvulsant activity. 71-73 EEG studies do not support any ability to suppress epileptiform activity. 72 There are many reports of refractory convulsions despite therapeutic magnesium levels.38,72,74,75 It seems illogical that magnesium should be preferred for treatment of eclamptic seizures when well-tested, time-proven anticonvulsants exist and are used for other types of seizures in both pregnant and nonpregnant patients. Diazepam has been used successfully in the management of eclampsia with good neonatal outcome.76, 77 P h e n y t o i n m a i n t e n a n c e has been used effectively in preeclampsia and eclampsia for seizure prophylaxis with no resulting maternal or neonatal side effects. 78 Magnesium might prove to be an effective agent, but until it is properly studied, Hachinski concludes after r e v i e w i n g a r g u m e n t s for and against its use, "magnesium should be relegated to the labs, clinical trials, or history. ''76 It is reasonable at this time to suggest that the same approach be used for eclamptic seizures as is used in treating status epilepticus. However, because of the existing controversy, it is recommended that emergency physicians discuss the therapeutic issues with the obstetricians and neurologists in their hospitals to arrive at agreeable management strategies. 20:1 January 1991

SEIZURES IN PREGNANCY Jagoda & Riggio

SUMMARY Seizures in pregnancy pose risks for both the mother and the fetus and must be managed aggressively. Antie p i l e p t i c drugs h a v e s o m e teratogenic potential, but the risks are not as profound as reported in earlier literature. There is definitely less risk to the fetus from anticonvulsant exposure than from uncontrolled seizures. The e v a l u a t i o n of a pregnant woman with new-onset seizures is the same as for the nonpregnant patient, including head computed tomography with appropriate abdominal shielding. Status epilepticus management is based on IV benz o d i a z e p i n e s , p h e n y t o i n , or phenobarbital. Good fetal outcome is dependent on rapid seizure control. Management of eclampsia is controversial. There is little evidence that magnesium sulfate has anticonvulsant properties, and its use as such will probably decline steadily in the future. At present, it is reasonable to manage eclamptic seizures in the same way that status epilepticus is managed. REFERENCES 1. So E, Penry J: Epilepsy in adults. A n n Neural 1981;9:3-16. 2. Mattson T, Cromer J, Darney P, et al: Use of contraceptives by w o m e n w i t h epilepsy. JAMA 1986;256: 238-240. 3. Schmidt D: The effect of pregnancy on the natural history of epilepsy, in Janz D, Dam M, Richens A, et al (eds): Epilepsy, Pregnancy and the Child. New York, Raven Press, 1982, p 3-14. 4. Schmidt D, Canger R, Avanzani G, et al: Change of seizure frequency in pregnant epileptic women. J Neural Neurosurg Psychiatry 1983;46:751-755.

14. Andermann E, Dansky L, Kinch R: Complications of pregnancy, laboi: and delivery in epileptic women: A prospective study, in Janz D, Dam M, Richens A, et al (eds): Epilepsy, Pregnancy, and the Child. N e w York, Raven Press, 1982, p 61-74. 15. Hopkins A: Epilepsy and anticonvulsant drugs. Br Med J 1987;294:497-501. 16. Knott C, Williams C, Reynold F: Phenytoin kinetics during pregnancy and the puerperium. Br J Obstet Gynaecol 1986;93:1030-1037. 17. Ramsey R, Strauss R, Willmoare L: Status epilepticus in pregnancy: Effect of phenytoin malabsorption on seizure control. Neurology 1978;28:85-89. 18. Yerby M: Problems and management of the pregnant woman with epilepsy. Epilepsia 1987;28S:$29-$36.

41. Phiibert A, Dam M: The epileptic mother and her child. Epilepsia i982;23:85-99.

19. Perucca E, Crema A: Plasma protein binding of drugs in pregnancy. CIin P h a r m a c o k i n e t 1982;7: 336-352.

42. Yerby M, Koepsell T, Daling D: Pregnancy complications and outcome in a cohort of women with epilepsy. Epilepsia 1985;26:631-635.

20. Mygind K, Dam M, Christiansen J: Phenytoin and phenobarbitone plasma clearance during pregnancy. Acta Neural Scand 1976;54:160-166.

43. Anneger J, Bamngartner K, Hauser W, et ah Epilepsy, antiepileptic drugs and the risk of spontaneous . abortion. Epilepsia 1988~29:451-458.

21. Bardy A, Teramo K, Hiilesmaa V: Apparent plasma clearances of phenytoin, phenobarbitone, primidone and carbamazepine during pregnancy, in Janz D, D a m M, Richens A, et al {eds): Epilepsy, Pregnancy and the Child. New York, Raven Press, 1982, p 141-145.

44. Schmidt D, Conger R, Cornaggia C: Seizure frequency during pregnancy and puerperium: The role of noncompliance and sleep deprivation, in Porter R, Mattson R, Ward A Jr, et al (eds): Advances in Epileptology, New York, Raven Press, 1984, p 221-225.

22. Leonard R: Phenytoin binding in pregnancy. Lancet 1980;2:1312-1313.

45. CeIesia G: Modern concepts of status epilepticus. JAMA 1976;235:1571-1574.

23. Ruprah M, Perucca E, Richens A: Serum protein binding of phenytoin in women: Effect of pregnancy and oral contraceptives, in Janz D, Dam M, Richens A, et al (eds): Epilepsy, Pregnancy and the Child. New York, Raven Press, 1982, p 115-116.

46. Hauser W: Status epilepticus: Frequency, etiology, and neurological sequelae, in Delgado-Escueta A, Wasterlain C, Treiman D, et al {eds): Advances in Neurology: Status Epilepticus. N e w York, Raven Press, 1983, p 537-541.

24. Batino D, Avanzini G, Bassi L, et al: Monitoring of antiepileptic drugs plasma levels during pregnancy and puerperium, in Janz D, Dam M, Richens A, et al (eds): Epilepsy, Pregnancy and the Child. New York, Raven Press, 1982, p 147-154.

47. Fougner A, Wilson S, Seltzer V: Status epilepticus in pregnancy: A case report, f Reprod Med 1985;30: 948-950.

25. Levy R, Yerby M: Effects of pregnancy on antiepileptic drug utilization. Epilepsia 1985;26S:$52-$57. 26. Bardy A: Incidence of seizures during pregnancy, labor and puerperium in epileptic women. Acta Neural Scand 1987;75:356-860. 27. l:eldman G, Weaver D, Lourien E: The fetal trimethadione syndrome, A m J Dis Child 1977;131:1389. 28. Zackai E, Mellman W, Neiderer B, et ah The fetal trimethadione syndrome. Pediatrics 1975;87:280-284. 29. Lindhout D, Schmidt D: In utero exposure to valproate and neural tube defects. Lancet 1986;h1392-1393. 30. Hanson J, Smith D: The fetal hydantoin syndrome. J Pediatr 1975;87:285-290. 31. Nakane Y, Oduma T, Takabashi R, et ah Multi-institutional study on the teratogcnicity and fetal toxicity of antiepileptic drugs: A report of a collaborative study group in Japan. Epilepsia 1980;21:663-680.

6. Robertson I: Epilepsy in pregnancy. Clin Obstet Gynecoi 1986;13:365-384.

32. Janz D: On major malformations and minor anomalies in the offspring of parents with epilepsy: Review of the literature, in Janz D, D a m M, Richens A, et al (edsl: Epilepsy, Pregnancy and the Child. New York, Raven Press, 1982, p 2Ii-222.

8. Delgado-Escueta A, Treiman D, Walsh G: The treatable epilepsies: Part I. N Engl J Med 1983;308:1508-1514. 9. Remillard G, Dansky L, Andermann E, et al: Seizure frequency during pregnancy and puerperium, in Janz D, Dam M, Richens A, et al (eds): Epilepsy, Pregnancy and the Child. New York, Raven Press, 1982, p 15-25.

33. Shapiro S, Hartz S, Siskind V, et al: Anticonvulsants and parental epilepsy in the development of birth defects. Lancet I976;1:272-275.

10. Dalessio D: Seizure disorders and pregnancy. N EngI J Med 1984;312:559-563.

34. Dansky L, Andermann E, Andermann F, et ah Maternal epilepsy and congenital malformations: Correlation with maternal plasma anticonvulsant levels during pregnancy, in Janz D, Dam M, Richens A, et al (eds): Epilepsy, Pregnancy and the Child. New York, Raven Press, 1982, p 251-258.

I1. Knight A, Rhind E: Epilepsy and pregnancy: A study of 153 pregnancies in 59 patients. Epilepsia 1975;16: 99-110.

35. Montouris G, Fenichel G, McLain W: The pregnant epileptic: A review and recommendations. Arch Neural 1979;36:601-603.

12. Morris H: Epilepsy and pregnancy. Cleveland Clin J Med 1989;56S:SI95-$201.

36. Jones K, Lacro R, Johnson K, et ah Pattern of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med 1989; 320: I661-1666.

13. Anderson G, Sibai B: Hypertension in pregnancy, in Gabbe S, Biebyl J, Simpsom J {eds): Obstetrics: Normal and Problem Pregnancies. N e w York, Churchill-Livingstone, 1986, p 819-863.

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39. Paul R, Koh K, Bernstein S: Changes in fetal heart rate: U t e r i n e contraction patterns associated w i t h eclampsia. A m J Obstet GynecoI 1978;130:165-169. 40. Teramo K, Hiilesmaa V: Pregnancy- and fetal complications in epileptic pregnancies: Review of the literature, in Janz D, Dam M, Richens A, et al (eds): Epilepsy, Pregnancy and the Child. New York, Raven Press, 1982, p 53-58.

5. Schmidt D, Beck-Mannagetta G, Janz D, et ah The effects of pregnancy on the course of epilepsy, in Janz D, Dam M, Richens A, et al (eds): Epilepsy, Pregnancy and the Child. New York, Raven Press, 1982, p 29-49.

7. Otani K: Risk factors for the increased seizure frequency during pregnancy and the puerperium. Folia Psychiatr Neural Jpn 1985;39:33-41.

1985;152:499-504. 38. Pritchard J, Cunningham G, Pritchard S: The Parkland Memorial Hospital protocol for t r e a t m e n t of eclampsia: Evaluation of 245 cases. A m J Obstet Gynecol 1984;148:951-960.

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Annals of Emergency Medicine

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