Journal of Postgraduate Medicine
 Open access journal indexed with Index Medicus & ISI's SCI  
Users online: 177  
Home | Subscribe | Feedback | Login 
About Latest Articles Back-Issues Article Submission Resources Sections Etcetera Contact
 
  NAVIGATE Here 
  Search
 
 :: Next article
 :: Previous article 
 :: Table of Contents
  
 RESOURCE Links
 ::  Similar in PUBMED
 ::  Search Pubmed for
 ::  Search in Google Scholar for
 ::Related articles
 ::  [PDF Not available] *
 ::  Citation Manager
 ::  Access Statistics
 ::  Reader Comments
 ::  Email Alert *
 ::  Add to My List *
* Registration required (free) 


  IN THIS Article
 ::  Introduction
 ::  Acknowledgement
 ::  References

 Article Access Statistics
    Viewed12029    
    Printed155    
    Emailed9    
    PDF Downloaded0    
    Comments [Add]    

Recommend this journal


   
Year : 1987  |  Volume : 33  |  Issue : 4  |  Page : 163-77

Pregnancy, epilepsy and pharmacotherapy.







How to cite this article:
Sharma R R. Pregnancy, epilepsy and pharmacotherapy. J Postgrad Med 1987;33:163


How to cite this URL:
Sharma R R. Pregnancy, epilepsy and pharmacotherapy. J Postgrad Med [serial online] 1987 [cited 2019 Nov 14];33:163. Available from: http://www.jpgmonline.com/text.asp?1987/33/4/163/5268




  ::   Introduction Top

We now possess a variety of specific anticonvulsant drugs which may produce adverse effects in pregnancy. The effects of epilepsy on pregnancy and that of pregnancy on epilepsy are subtle and complex. The interactions between anticonvulsant drug therapy, pregnancy and the growing fetus and their implications on the control of epilepsy need evaluation for accurate clinical diagnosis and management. Whilst managing epilepsy in pregnancy, the obstetrician feels insecure due to an incomplete understanding of epilepsy. In turn, the neurosurgeon and the neurologist feel handicapped by their limited appreciation of the finer aspects of pregnancy.
Dowling's (1977)[10] statement: "it is difficult to interest doctors and medical students in epilepsy" must be understood in the context of that by Lance (1977)[39] "a doctor's negative attitude may deleteriously affect the perspective of the epileptic patients." If expert medical management is to be made available for the control of seizures in pregnant women and for the safety of the fetus, neuroscientists and obstetricians need to work together so that epilepsy no longer possess a great problem in the majority of the patients. We can thus help women with epilepsy to lead normal life including marriage, child bearing and employment.[18]"Evils do not disappear because people disapprove of them unless conditions at their roots are changed" (Friedenberg, 1965).[17]
The aim of this presentation is to help bring about such changes by providing basic information regarding interactions between epilepsy, pregnancy, fetus and antiepileptic drugs.
EPILEPTIC DISORDERS DURING PREGNANCY
I. Definition
Epilepsy is a symptom characterized by a paroxysmal and transitory disturbance of cerebral functions, which develop suddenly, cease spontaneously and exhibit a conspicuous tendency to recurrence.[72] Commonly the attacks of epilepsy are known as seizures or fits. Between 0.3 and 0.6% of pregnant women have epilepsy.[5]
II. Classification
The various seizure disorders may be classified as follows:[8]
1. Generalized seizures
(a) Convulsive.
(i) Tonic-clonic major motor without focal onset (grand mal).
(ii) Clonic (myoclonic) generalized.
(b) Non-convulsive.
(i) Brief typical absence (Petit mal).
(ii) Brief atypical absence.
2. Focal seizures
(a) Simple.
(i) Motor (Brief focal only).
(ii) Sensory (Focal with Jacksonian march),
(iii) Autonomic (Multifocal).
(iv) Focal continuous-epilepsia partialis continua.
(b) Complex.
(i) Psychomotor predominating.
(ii) Psychosensory predominating.
3. Pseudoseizures (Hysterical seizures)
4. Conditions with some features of epilepsy
Narcolepsy, fainting, nightmares, rage attacks (dyscontrol), transient ischaemic attack, migraine and Stokes-Adam syndrome.
EFFECTS OF PREGNANCY ON THE SEIZURES
It is not uncommon for some epileptic women to be free from attacks during pregnancy. Others may worsen when pregnant. The truth probably is that epilepsy may be influenced for better or worse by many different factors.[72]
I. Maternal factors
Hormonal and metabolic factors, respiratory changes, psychological problems, non-compliance and the altered disposition of antiepileptic drugs may modify the seizure frequency. The onset of epilepsy during pregnancy may be due to coincidence.[63] Several other factors may be related to the exacerbation of epilepsy during pregnancy e.g. maternal age at delivery, number of previous deliveries, duration of epilepsy prior to pregnancy and its therapy.[30]
II. Epileptogenecity of pregnancy
There are some women whose first seizure occurs in pregnancy but there is no study which provides statistical evidence that pregnancy is likely to start the common varieties of epilepsy.[27] Non eclamptic, non-febrile, 'gestational epilepsy' occurs for the first time in pregnancy, remits in the puerperium and then returns only in subsequent pregnancies.[27] Knight and Rhind[37] found only two such patients amongst their 59, epileptic mothers studied through 153 pregnancies. Furthermore, it is rare in a case of preexisting epilepsy for seizures to recur during pregnancy after a prolonged seizure-free period. The apparent rarity of these phenomena suggests that pregnancy per se is not a potent epileptogenic agent.[27]
III. Type of epilepsy
Women with partial complex (temporal lobe) seizures or generalized epilepsy with focal characteristics are worse off during pregnancy whereas those with the classic Petit mal epilepsy are better off. Bardy5 noted the highest incidence of grand mal seizures during last trimester of pregnancy while most psychomotor seizures were noted during puerperium. Status epilepticus,[20] which is not more frequent during pregnancy, presents as a life threatening emergency for both mother and child.[63]
Amongst major catagories, constitutional (idiopathic), generalized, tonic-clonic seizures are the most common presentation of chronic seizure disorders, noted during pregnancy while the non-convulsive, generalized seizures (Petitmal) are rarely seen in this age group. Consistently repeated, acute, focal or generalized tonic-clonic seizures with focal onset, may be an expression of an underlying focal or generalized cerebral pathological lesions.
II. Course of epilepsy
There is no reliable data which allows prediction of an individual's course of epilepsy during pregnancy[63] except the pregestational fit frequency.[9],[37] A history of catamenial seizures seems not to be a risk factor.[9] Women, seizure-free for the previous 2 years usually remain seizure-free during pregnancy. Women, who remain seizure-free for 9 months preceding pregnancy are at 20-40% risk of exacerbation of seizures during pregnancy. And those who convulse at least once monthly before hand usually worsen during pregnancy. Women, who had very frequent seizures (more frequently in a month) were four times more likely to have an increased frequency of seizures during pregnancy than those with occasional seizures (less than one in three months). In Knight and Rhind's study[37] of 153 pregnancies in 59 epileptics, the seizure frequency was increased in 45%, unchanged in 50% and decreased in 5%. Similar results were also obtained by others[17],[60] while a few[4],[54] have reported unchanged frequency during pregnancy and puerperium. Mothers carrying male fetus were twice as likely to deteriorate than those carrying a female fetus.[37]
ASSESSMENT AND THERAPEUTIC CONSIDERATIONS
When the patient is a known epileptic (idiopathic) and is on antiepileptic drug therapy, the problem, primarily, revolves around the maintenance of serum concentration of drug in the therapeutic range. The range during the non-pregnant state might be inappropriate during pregnancy because of changes in the relation between the drug concentration and its effect. There is altered antiepileptic drug disposition during pregnancy when the daily dose is kept constant.
If the seizures occur for the first time during the later half of pregnancy the first suspicion should be of eclampsia particularly if there is associated hypertension, proteinuria and edema.[69] In the absence of these features, if acute, generalized or focal seizures suddenly develop in a non-epileptic pregnant woman, then non-obstetric diagnostic possibilities must be considered and such patients should be investigated and treated in the same manner as those developing epilepsy unassociated with pregnancy.
A particularly likely cause during pregnancy is expansion of an arterio-venous malformation or a brain tumor. During puerperium, a siezure may be the first evidence of cortical venous thrombosis.[27] Non-obstetric causes of epilepsy, in this age group include brain tumours (pituitary adenoma, meningioma, glioma, neurofibroma etc.); cerebrovascular lesions i.e. occlusive (cortical venous thrombosis, dural sinus thrombosis) and haemorrhagic (aneurysms, arterio-venous malformations); head injuries; drug intoxication or withdrawal (sedative, alcohol); infections (meningitis, infective granulomas, encephalitis); metabolic (uremia, hepatic failure, hypo- and hypernatremia, alkalosis, hyperventilation, acute porphyriaetec) and endoernola disorders (hypo- or hyperglycemia, hypo- and hyperglycemia, diabetic ketoacidosis, pituitary apoplexy). These should be excluded before labelling non-febrile seizures as idiopathic.
In a patient in whom seizures develop for the first time during pregnancy, a detailed neurological history and examination is mandatory. A history of preexisting medical illness, drug intake, head injury, infection or a tumor may provide a working clue to the correct diagnosis. Complete hematological (including metabolic) studies, skull X-rays and electroencephalography should be done. Lumbar puncture is contraindicated only in the presence of signs of increased intracranial pressure (headache, vomiting and papilloedema).
CT scan of brain is strongly recommended, the amount of radiation produced by this procedure being approximately that of the usual series of plain skull X-rays.[8] The constrast material employed in CT scans and in cerebral angiography is physiologically inert with respect to iodine and does not produce fetal thyroid abnormalities.[8] Therefore, pregnancy is not a contraindication for neuroradiological diagnostic studies. However, concern for safety of the mother and her fetus compels us to consider carefully any investigation that requires radiation exposure.
Treatment of the patient with a seizure disorder is directed at eliminating the cause of the seizures and suppressing the expression of the seizures to overcome their deleterious effects on mother and fetus, and in cases of uncontrolled seizures therapeutic abortion is sometimes indicated.[35]
PHARMACOTHERAPY OF SEIZURES IN PREGNANCY
I. Aim
During pregnancy and in the puerperium a fine balance should be maintained. No harm should occur to the baby because of the drug. At the same time no harm must come to the mother or baby because mother is being inadequately treated.[63] It has been suggested that a regimen should be established to provide optimal seizure control with the fewest side effects using the least possible number of drugs.[47]
II. Objective
In case of a single seizure some experts prefer to with old treatment.8 In case of repetative seizures, there is no such doubt-the fits must be controlled by drugs. Whenever possible, it is preferable to treat patients adequately with one anticonvulsant drug, making sure that its blood levels are in the therapeutic range. This is important as in the pregnant epileptic plasma drug concentration declines if oral dose is kept constant.[8] Monotherapy is preferred to polytherapy as the latter increases the incidence of congenital malformations in the fetus.
III. Therapy
There is no unanimity regarding the drug of choice. Various workers, according to their experiences, choose one of the following three drugs for major chronic convulsive seizures during pregnancy(i) diphenylhydantoin[8] (ii) phenobarbitone[44] (iii) carbamazepine.
Diphenylhydantoin is given in the oral dose of 300-600 mg per day to achieve therapeutic range of 10-25 ug/ml of serum which is attained in approximately 2 weeks.[9] If seizures are not controlled despite high doses of this drug then another antiepileptic drug is either added to it or substituted for it. Phenobarbitone is given in the oral dose of 90-120 mg daily in divided doses. The therapeutic level of phenobarbitone for seizure control is in range of 15-30 ug/ml of serum. Both these drugs are effective against variety of seizure disorders except Petit mal fits. When good control of seizure is not yet achieved with diphenylhydantoin and phenobarbitone, alone or in combination, then carbamazepine may be substituted in the divided doses of 600 mg daily and periodic monitoring of bone marrow function is done to look for the bone marrow depression which is a rare consequence.
Petit mal seizure is rarely seen during pregnancy. Ethosuximide 250-500 mg three to four times daily, is the drug of choice. Caution has to be exercised as this drug is nephrotoxic and is toxic to the bone marrow. Diazepam may also be helpful in the dose of 5 to 10 mg three to four times daily. Troxidone is specifically contraindicated in pregnancy due to fetal trimethadione syndrome.[16]
Valproic acid is a broad spectrum anticonvulsant drug but has significant teratogenic effect on fetus and is also hepatotoxic for mothers and thus should be avoided during pregnancy. After appropriate counselling, those women who do inadvertently take valproate in the first few months of pregnancy, should be subjected to amniocentesis for alpha-fetoprotein estimation[27] in order to detect dysraphic states.
In the management of status epilepticus during pregnancy, oxygenation must be assured and blood must be examined for baseline levels of antiepileptic drugs, blood gases, electrolytes and glucose. Diazepam 10 mg is given intravenously over a period of two minutes and is repeated at 20 minute intervals for 2-3 times if necessary. In pregnant women, close to delivery diazepam crosses the placenta in significant amount and can cause generalized hypotonia and respiratory depression in neonates. Facilities for managing neonatal respiratory depression must be readily available. The maternal circulation must be maintained and cardiac rhythm should be monitored. Glucose is administered and dexamethasone (8 mg) is given intravenously to lower intracranial pressure. Diphenylhydantoin in the dose of 200-500 mg is given intravenously at a rate not faster than 50 mg per minute. Total dose should not exceed 1 gm.
It is useful to monitor such patient electro-encephalographically since EEG seizure patterns may recur before appearance of subsequent seizures. If seizure pattern still continues, amobarbitol sodium in a dose of 120 to 250 mg (maximum upto 500 mg) can be given intravenously at a rate not to exceed 30 mg per minute. Should seizure still persist then the use of paraldehyde or general anaesthesia is made.
There is no evidence that intravenous use of antiepileptic drugs which might be employed in the treatment of status epilepticus affect the fetus adversely. The injurious effects of continuous convulsions on the fetus are, on the other hand, only too well known.
Status epilepticus in the pregnant woman is often related to subtherapeutic plasma levels of antiepileptic drugs because of non-compliance by the patient or inadequate maintenance of dose levels. If blood levels of the anti-epileptic drugs are maintained at levels found to be therapeutic before pregnancy, only 10-15% of epileptic women will convulse more frequently during pregnancy.[9] The control of seizures is better guided by the frequent estimates of serum antiepileptic drug levels during pregnancy. Improvement in seizure frequency follows attainment of adequate antiepileptic drug levels in serum or replacement of one drug by another that is more effective. The risk of recurrent seizures especially of status epilepticus-which result in maternal and fetal anoxia necessitates intensive antiepileptic therapy despite the theoretical risk of drug induced congenital anomalies.
CONSEQUENCES OF PSYCHO-PHYSIOLOGICAL CHANGES
I. On Antiepileptic Drug Pharmacokinetics
The natural history of epilepsy,[8] in pregnant epileptic women interdigitates with antiepileptic drug metabolism and psycho-physiological changes occurring during pregnancy i.e. compliance, sleep deprivation, metabolic and hormonal changes, weight gain, mild chronic respiratory alkalosis and psychological changes.
(a) Compliance
Good compliance and adequate levels of antiepileptic drugs are not easily attained.[30] First of all, the pregnant epileptic woman is now increasingly aware of teratogenic effects of antiepileptic drugs. Either she or another physician may reduce or stop antiepileptic drug in an attempt at reducing the possibility of bearing an abnormal baby or that of harmful effects of these drugs on newborns and on breast feeding. Carelessness in drug taking is also an important factor. Poor compliance is not uncommon amongst epileptic mothers.[65]
(b) Altered disposition of the drugs
The physiological changes of pregnancy can lead to clinically important reductions in the blood concentrations of antiepileptic drugs in many ways.[29],[40],[45],[48],[54],[61]
(i) Blood volume and weight gain:
The total body water increases by as much as 8 litres during pregnancy.[57] Added to this, the volume of fetus and placenta increases the volume of distribution of the antiepileptic drugs given orally and therefore tend to lower the serum levels of these drugs if oral dose is kept unchanged.
(ii) Serum proteins:
Serum proteins relevent to drug binding undergo considerable changes in concentration.[66] Albumin (which binds acidic drugs such as diphenylhydantoin) decreases in concentration by up to 10 gm/litre.[59] In the presence of such reduced binding, any previous relation between serum diphenylhydantoin concentration and therapeutic effect will no longer hold since a greater proportion of the total drug concentration will be pharmacologically active. In such circumstances the clinical value of measuring diphenylhydantoin levels in serum is greatly reduced unless serum binding capacity is measured or is correlated with the fall in serum albumin.[62]
(iii) Intestinal absorption:[58]
The absorption of the oral antiepileptic drugs from the bowel may be significantly reduced.
(iv) Liver metabolism:[48]
Liver metabolism increases during pregnancy. Therefore, the maternal liver with an increased capacity for hydroxylation for some antiepileptic drugs e.g. diphenylhydantoin, results in lower plasma level of these drugs during pregnancy if the dose of such drugs is kept constant. Diphenylhydantoin is cleared at twice the rate found in the non-pregnant women.[41]
(v) Renal clearance:
Renal plasma flow has almost doubled by the last trimester of pregnancy.[11] Drugs which are eliminated unchanged by the kidneys are usually eliminated more rapidly but so far this has been shown to be clinically important in only a few cases.[61] The renal clearance may increase for diphenylhydantoin and phenobarbitone during the pregnancy, however the plasma protein binding of phenobarbitone remains unchanged.
(vi) Interaction with other drugs ingested during pregnancy, e.g. benzodiazepines, lowers the concentration of diphenylhydantoin.
(vii) Vitamin changes:
The pregnant epileptic woman on antiepileptic therapy shows significantly lower serum folic acid levels than the normal pregnant woman. Folic acid, often given during pregnancy, is known to cause a reduction in the serum concentration of diphenylhydantoin and may itself have an epileptogenic effect.[65] In one study there was an inverse correlation between serum folate and diphenylhydantoin or phenobarbitone levels. The number of epileptic seizures during pregnancy showed no relation to serum folate levels.[24] According to this report, a low dose of 100 or 1000 ug of folate is a sufficient supplement for pregnant women on these drugs.
(viii) Therapeutic range:
It is not clear whether pregnancy alters the effects of drugs. It is possible that established therapeutic ranges might be inappropriate during pregnancy because of changes in the relationship between concentration and effect of these drugs but this factor is difficult to study.[61]
(c) Precaution
To avoid consequences of altered disposition of antiepileptic drugs during pregnancy, blood levels of these drugs should be measured each month and more frequently if seizures recur. The daily dose of diphenylhydantoin may triple especially in the second half of pregnancy.
II. On The Seizure Susceptibility
(a) Metabolic changes
Mild compensatory alkalosis due to hyperventilation and lower concentrations of sodium, potassium, calcium and magnesium during pregnancy may precipitate seizures.
(b) Hormonal changes
In pregnancy, chorionic gonadotrophin reaches its peak in the first trimester and decreases towards the end of the pregnancy, while progesterone and oestradiol levels in blood and urine increase to reach maximum values during last trimester of pregnancy.
Since the cerebral cortex is more sensitive to stimuli in pregnancy due to hormone-mediated intracellular electrolyte changes, the alteration in concentrations of these hormones should play some role in increasing susceptibility to seizures.[30] Activation of focal spikes and precipitation of epileptic seizures were reported in epileptic patients following intravenous injection of estrogen.[43] Canger et al[6] have found that patients with increased seizure frequency tended to have slightly higher estrogen levels than other pregnant epileptics. On the other hand, progesterone and testosterone have produced mild reduction of seizure susceptibility in rats, cats and dogs.[42],[49] Backstrom,[2],[3] has reported a positive correlation between the number of secondary generalized seizures and the mean estrogen/progesterone ratios, as well as a negative correlation to plasma progesterone levels in non-pregnant women with partial epilepsy. Therefore, the estrogen/progesterone ratio seems to be more relevant to susceptibility to seizures than the level of estrogen alone.[30]
In the second and third trimesters, the cortisone level was higher in patients who had seizures during pregnancy than those without seizures.[56]; It has been suggested that glucocorticoid has epileptogenic effect not only in experimental animals but also in humans.[14],[64],[71] There was no significant correlation between the changes in concentrations of human growth hormone, TSH, T3, T4 and frequency of seizures.[36]
(c) Psychological mechanisms
Anxiety, sleep deprivation and poor compliance contribute to precipitation of seizures.
CONSEQUENCES OF SEIZURES AND THEIR THERAPY
Today, the majority of epileptic women can safely conceive and give birth in the same way as non-epileptic women. However, since risks and difficulties during pregnancy, delivery and child care remain greater for epileptics than for non-epileptics, some special considerations are necessary.[30]
I. On Pregnancy, Labour and Puerperium
Present data indicates that there is a slightly increased risk of bleeding throughout pregnancy[70] and a higher incidence of ablato placentae in epileptic women.[46],[70] The incidence of spontaneous abortion is higher in epileptic mothers using anti-epileptic drugs than in normal pregnant women, while there was no significant difference in the incidence of artificial abortion.[52] The increase in the incidence of spontaneous abortion is at least partly explained by a decrease in thyroid hormonal concentrations as a result of antiepileptic medications during pregnancy,[33] since thyroid hormones play a significant role in maintaining pregnancy.[39] However, Koch et al[38] have reported that incidence of threatened abortion does not seem higher in epileptic women than in the general population.
Induction of labour and intervention during delivery are significantly more frequent in epileptic women[52] than in controls.[13] In the gravid epileptic patients, the duration of labour is slightly shorter and status epilepticus, pre-eclampsia, abruptio placentae, polyhydramnios, assisted delivery, caesarean section, prematurity and intrauterine growth retardation have all been reported to be higher.[25] Bleeding appears to be the only significantly increased complication during pregnancy, labour and delivery in epileptic women,[45] due to hypotonic uterine activity, antiepileptic drugs and placental complications.
In puerperium, plasma clearance of antiepileptic drugs decreases to pregestational rates within 6 weeks with most of the changes taking place in the first few weeks. The plasma levels of diphenylhydantoin and phenobarbitone increase approaching the levels before pregnancy[9] Therefore, blood levels of these drugs should be monitored each week post partum.[51] If the daily dose of an antiepileptic drug has been increased during pregnancy then appropriate adjustments should be made after delivery in order to avoid intoxication.
II. On Fetus and Newborn
(a) Passage of drugs to fetus
Placenta is essentially a lipid barrier between the maternal and fetal circulations. Drugs cross the placenta by passive diffusion. A lipid soluble un-ionised drug of low molecular weight will cross the placenta more rapidly than a more polar drug.[61]
For most antiepileptic drugs, the ratio of concentration in the umbilical cord blood and that in the maternal venous blood is one,[53] while with valproic acid and diazepam it is significantly higher.[68]
(b) Deleterious effects of the drugs and seizures
(i) On fetus: Malformations, morbidity, mortality.
No drug is totally safe for the fetus but polytherapy carries more risk than monotherapy. Higher rates of retardation in utero,[5],[30] (due to lower thyroxine and thyrotropine levels); fetal distress[50] (due to hypoxia in mother in the subpartum period); neonatal mortality[23] (1.2 to 2.5 fold); congenital malformations,[1],[15] (2 to 2.5 fold); hemorrhagic tendencies in fetus and neonates (due to decrease in vitamine-K dependent clotting factors),[9] and physical and mental subnormality in infants[22] are all well documented as a result of seizures and their therapy in pregnant women. While the majority of epileptic pregnant mothers taking antiepileptic drugs give birth to healthy babies, 14% of live births from these women have congenital defects compared to 5.6% of control.[15],[67] The incidence of major malformations is 5-10%,[28] and for minor malformations the rate is more than double.[31] Commonest malformations are congenital heart diseases, cleft lip and cleft palate. Renal, genital, skeletal and C.N.S. malformations are less common.
Fetal hydantoin syndromm[21] and fetal trimehtadione syndrome[16],[19] are well known entities. The fetal hydantoin syndrome is characterized by craniofacial anomalies (variation in size and shape of head with widening of fontanelle and prominent ridges of cranial sutures, hyperteleorism, saddled, broad nasal bridge and short upturned nose, epicanthal folds, ptosis and strabismus, prominent low-set malformed ears; and wide mouth with prominent lips), psycosomatic retardation (mental dullness and short stature) and limb defects (hypoplasia of the distal phalanges and nails, finger-like thumbs, and variations in palmer creases hand markings). In trimethadione syndrome, affected infants show developmental delay, speech disturbances, low set ears, V-shaped eyebrows, palatal anomalies and irregular teeth. Carbamazepine is known to cause significant bone marrow depression. In causing these congenital anomalies, antiepileptic drugs may interact with genetic factors and may interfere with cellular proliferation at palatal shelves. Valproate has been incriminated in the causation of hydrocephalus and spina bifida and therefore it has been suggested that women exposed to valproic acid in the first trimester should be offered amniocentesis.[12],[67]
(ii) On infants: Barbiturate withdrawl
They may show transient symptoms of antiepileptic withdrawal,[26],[30] i.e. hyperirritability, tremors, convulsions, vomiting, poor suckling, excessive crying, and rarely hyperactivity and sleep disturbances. If seizures occur, small doses of phenobarbitone (3-5 mg/kg/day) may be necessary.
(iii) On child: Risk of seizures
The risk of an epileptic adult having child with epilepsy is only about one in 30.[27] Janz et al[29] reported on a retrospective study of 768 children of 414 families in which one parent had epilepsy and the other neither epilepsy nor febrile convulsions. Epilepsy occurred in 3.4% of all children-a risk about five times that of the general population. The risks were higher when the parent had epilepsy of unknown origin, when it was the mother rather than the father who was epileptic, and when the children themselves had already shown febrile convulsions. If a child of an epileptic parent does have febrile convulsions then the child's chances of having epilepsy are increased.[27]
III On Breast Feeding
The supply of mother's milk is important to the infant as it provides immunological protection[30] Virtually all drugs pass into the breast milk. Previous dilution of drug in the mother's body, however, when coupled with the small amount of milk consumed by the infant usually mean that the amount of drug pass to the baby is clinically unimportant.6l There are two main categories of antiepileptic drugs so far as breast feeding is concerned.
(i) Drugs which reach the baby in an insignificant dose are diphenylhydrantoin and sodium valproate. Therefore breast feeding should not be stopped when epileptic mother is receiving these drugs.
(ii) Drugs which reach the baby in sufficient dose to be harmful are barbiturates, benzodiazepine, primidone etc. Mothers taking these drugs should reduce or discontinue breast feeding for the first 7 days postpartum.[32] Slow phenobarbitone and diazepam metabolism may present some hazards to the infant besides respiratory depression. If the mother desires to breast feed the anticonvulsant regimen should be modified before or during pregnancy.
CONCLUSION: MEDICAL PRACTICE: ADVICE
The epileptic mother should be kept informed on the nature of her illness and its outlook, the therapeutic requirement and attendant risks of treatment. The doctors have to balance two conflicting interests in treating the epileptic pregnant woman. Keeping the risks of seizures in mind especially that of status epilepticus, the patient should be advised to continue antiepileptic drug therapy in effective therapeutic dosages, as judged by periodic estimation of their serum levels and clinical effects, but with the patient's acceptance of the risks of congenital malformations in baby. It should be emphasised that the teratogenic hazards of antiepileptic drug therapy is slight (14% as compared to 5.6% in controls) and that the risk to the child from the maternal seizures with attendant hypoxia and acidosis is much greater.[67] Therefore more harm than good may result if a woman has an increased number of major seizures due to reduction of arrest of the anticonvulsant drug therapy.[27]

  ::   Acknowledgement Top

I gratefully thank Prof. S. K. Pandya, Head, Department of Neurosurgery, K.E.M. Hospital, Bombay for his persistent encouragement, guidance and invaluable suggestions during preparation of this article. I am truly thankful to Mr. V. B. Ambetkar for his secretarial assistance.

  ::   References Top

1.Annegers, J. F., Elvebeck, L. R., Hauser, W. A., Kurland, L. T. and Anderson, V. E.: Congenital malformations and seizure disorders in the off-spring of parents with epilepsy. Int. J. Epidemiol., 7: 241-247, 1978.  Back to cited text no. 1    
2.Backstrom, T.: Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle. Acta. Neurol. Scand., 54: 321-347, 1976.  Back to cited text no. 2    
3.Backstrom, T.: Premenstrual tension syndrome, catamenial epilepsy and their relation to plasma estrogen and progesterone. Senologia, 3: 15-26, 1978. Quoted by Kaneko, S.[30]  Back to cited text no. 3    
4.Bardy, A. H.: Seizure frequency in epileptic women during pregnancy and puerperium: A prospective study. In "Epilepsy, Pregnancy and The Child." Editors: D. Janz, L. Bossi, M. Dam, H. Helge, A. Richen, and D. Schmidt. Raven Press. New York, 1982, pp. 27-31.  Back to cited text no. 4    
5.Bjerkedal, T. and Balma, S. L,.: The course and outcome of pregnancy in women with epilepsy. Acta. Obstet. Gynecol. Scand., 52: 245-248, 1973.  Back to cited text no. 5    
6.Canger, R., Avanzini, G., Battino, D.., Bossi, L., Franceschetti, S. and Spina, S.: Modification of seizure frequency in pregnancy. Prospective data in 48 patients with epilepsy. In: "Epilepsy, Pregnancy and the Child." Editors: D. Janz, L. Bossi, M. Dam, H. Helge, A. Richens and D. Schmidt. Raven Press, New York, 1982, pp. 32-38.  Back to cited text no. 6    
7.Dalessio, D. J.: Seizure disorders and pregnancy. N. Engl. J. Med., 312: 559-563, 1985.  Back to cited text no. 7    
8.Dalessio, D. J.: Neurologic diseases. In: "Medical Complications during Pregnancy". Editors: G. N. Burrow and T. F. Ferris. Second Edition, W. B. Saunders Company, Philadelphia, 1982, pp. 435-473.  Back to cited text no. 8    
9.Donaldson, J. O.: Neurologic complications of pregnancy. Diseases of the nervous system. In: Clinical Neurobiology. Vol. 2, Editors: A. K. Asbury, G. M. Mckhann and W. I. McDonald, William Heinemann, London, 1986, pp. 1578-1584.   Back to cited text no. 9    
10.Dowling, St. J.: Epilepsy in general practice-A general practitioner's view. Proc. R. Soc. Med., 70; 266-269, 1977.  Back to cited text no. 10    
11.Dunlop, W.: Investigations into the influence of posture on renal plasma fl, and glomerular filtration rate during late pregnancy. Brit. J. Obstet. & Gynecol., 83: 17-23, 1976.  Back to cited text no. 11    
12.Editorial: Valproate and malformations. Lancet, 2: 1313-1314, 1982.  Back to cited text no. 12    
13.Egenaes, J.: Outcome of pregnancy in women with epilepsy in Norway 1967-1978: Complications during pregnancy and delivery: In: Proceedings of Workshop on Epilepsy, Pregnancy and the Child, Berlin, Federal Republic of Germany, September 14-16, 1980, Raven Press, New York, Epilepsia, 22: 366, 1981.  Back to cited text no. 13    
14.Ehlers, C. L. and Killam, E. K.: The influence of cortisone on EEG and seizure activity in the baboon, papiopapio. Electroenccph. Clin. Neurophysiol., 47: 404-410, 1979.  Back to cited text no. 14    
15.Fedrick, J.: Epilepsy and pregnancy. A report from the oxford record linkage study. Brit. Med. J., 2: 442-448, 1973.  Back to cited text no. 15    
16.Feldman, G. L., Weaver, D. W. and Lovrien, E. W.: The fetal trimethadione syndrome. Report of an additional family and further delineation of this syndrome. Amer. J. Dis. Child, 31: 1389-1392, 1977.   Back to cited text no. 16    
17.Friedenberg, E.: Coming of age in America, Random House, New York, 1965.  Back to cited text no. 17    
18.Fukushima, Y., Mikawa, H., Kudo, N. and Yamahana, Y.: Socio-medical study on epilepsy. Epilepsy and Marriage. Jpn. J. Clin. Psychiatr., 5: 101-107, 1976.   Back to cited text no. 18    
19.Goidman, A. S. and Yaffe, S. J.: Fetal trimethadione syndrome. Teratology, 17: 103, 1978 as quoted by Dalessio, D. J.[9]   Back to cited text no. 19    
20.Goodwin, J. F. and Lawson, C. W.: Status epilepticus complicating pregnancy. Brit. Med. J., 2: 332-333, 1947.  Back to cited text no. 20    
21.Hanson, J. W. and Smith, D. W.: The fetal hydantoin syndrome. J. Pediatric, 87: 285-290, 1975.  Back to cited text no. 21    
22.Helge, H.: Physical, mental and social development including diseases. In: Epilepsy, Pregnancy and The Child. Editors: D. Janz, L. Bossi, M. Dam, H. Helge, A. Richens and D. Schmidt. Raven Press, New York, 1982, pp. 391-395.   Back to cited text no. 22    
23.Hiilesmaa, V. K., Teramo, K., Granstrom, M. L. and Bardy, A. H.: Fetal growth and antiepileptic drugs: Preliminary results of the prospective Helsinki study. In: Epilepsy, Pregnancy and The Child. Editors: D. Janz, L. Bossi, M. Dam, H. Helgc, A. Richens and D. Schmidt, Raven Press, New York, 1982, pp. 203-205.  Back to cited text no. 23    
24.Hiilesmaa, V. K., Teramo, K., Granstrom, M. L. and Bardy, A. H.: Serum folate concentrations in women with epilepsy: relation to antiepileptic drug concentrations, number of seizures and fetal outcome. Brit. Med. J., 287: 577-579, 1983.  Back to cited text no. 24    
25.Hill, R. M. and Tennyson, L.: Premature delivery, gestational age, complications of delivery and vital data at birth on newborn infants of epileptic mothers: Review of literature. In: Proceedings of Workshop on Epilepsy, Pregnancy and the Child, Berlin, Federal Republic of Germany, September 14-16, 1980. Raven Press, New York, Epilepsia, 22: 372, 1981.  Back to cited text no. 25    
26.Hill, R. M., Verniaud, W. H., Horning, M. D., McCulley, L. B. and Morgan, N. F.: Infants exposed in utero to antiepileptic drugs. Amer. J. Dis. Child, 127: 645-653, 1979.  Back to cited text no. 26    
27.Hopkins, A.: Neurological disorders. In: "Medical Disorders in Obstetric Pract.,_ Editor: M. deSwiet, P. G. Publishing Pvt. Ltd., Singapore, Hong Kong. New Delhi, 1984, Ch. 14, pp. 456-482.  Back to cited text no. 27    
28.Janz, D.: The teratogenic risk of antiepileptic drugs. Epilepsia, 16: 159-169, 1975.  Back to cited text no. 28    
29.Janz, D., Beck-Mannagetta, G., Scheffner, D. and Scholz, G.: Epilepsy in children of epileptic parents: Retrospective study. In: Proceeding of Workshop on Epilepsy, Pregnancy and the Child, Berlin, Federal Republic of Germany, September 1416, 1980. Raven Press, New York. Epilepsia, 22: 371, 1981.  Back to cited text no. 29    
30.Kaneko, S.: Epilepsy and pregnancy. Progress in Clin. Neurosci, 2: 203-219, 1985.  Back to cited text no. 30    
31.Kaneko, S., Fukushima, Y., Sato, T., et al.: Hazards of fetal exposure to antiepileptic drugs; A preliminary report. In: "Antiepileptic Drugs and Pregnancy." Editors: T. Sato, S. Shinagawa. Excerpta Medica Amsterdam, 1984, pp. 132-138.  Back to cited text no. 31    
32.Kaneko, S., Fukushima, Y., Sato, T., Suzuki, K., Ogawa, Y. and Nomura, Y.: Perinatal antiepileptic drug disposition and breast feeding in epileptic mothers and their newborn. Canad. J. Neurol. Sci., 1985. Quoted by Kaneko, S.30  Back to cited text no. 32    
33.Kaneko, S., Otani, K., Fukushima, Y. et al.: Effects of antiepileptic drugs on hGH, TSH and thyroid hormone concentration during pregnancy. Biol. Res. Pregnancy, 3: 148-151, 1982. Quoted by Kaneko, S.30  Back to cited text no. 33    
34.Kaneko, S., Sato, T. and Suzuki, K.: The levels of anticonvulsants in breast milk. Brit. J. Clin. Pharmacol., 7: 624-626, 1979.   Back to cited text no. 34    
35.Kempers, R. D. and Miller, R. H.: Management of pregnancy associated with brain tumors. Amer. J. Obstet. & Gynecol., 87: 858-864, 1963.  Back to cited text no. 35    
36.Klingman, W. O.: The effect of ion exchange resins in the paroxysmal disorders of the nervous system. Amer. J. Psychiarty, 111: 184-195, 1954.  Back to cited text no. 36    
37.Knight, A. H. and Rhind, E. G.: Epilepsy and pregnancy: a study of 153 pregnancies in 59 patients. Epilepsia, 16: 99170, 1975.  Back to cited text no. 37    
38.Koch, S., Gopfert-Geyer, I., Juger-Roman, E. and Rating, D.: Obstetric complications in pregnancies of epileptic mothers and their obstetric histories. In: Epilepsy, Pregnancy and The Child. Editors: D. Janz, L. Bossi, M. Dam, H. Helge, A. Richens and D. Schimdt. Raven Press, New York, 1982, pp. 91-97.  Back to cited text no. 38    
39.Lance, J. W.: Empathy with epilepsy. Med. J. Aust., 25: 907-908, 1977.  Back to cited text no. 39    
40.Lander, C. M., Edward, V. E., Eadie, b1. J. and Tyrer, J. H.: Plasma anticonvulsant concentrations during pregnancy. Neurology, 27: 128-131, 1977.  Back to cited text no. 40    
41.Lander, C. M., Smith, M. T., Chalk, J. B., et al.: Bio availability in pharmacokinetics of phenytoin during pregnancy. Eur. J. Clin. Pharmacol., 27: 105-110, 1984. Quoted by Rubin P.C.[6]  Back to cited text no. 41    
42.Landgren, S., Backstrom, T. and Kalistrato, V. G.: The effect of progesterone on the spontaneous inter-ictal spike evoked by topical application of penicillin to the cat's cerebral cortex. Acta. Physiol. Scand., 102: 81-83, 1978.  Back to cited text no. 42    
43.Logothetis, J., Harner, R., Morrell, F. and Torres, F.: The role of estrogens in catamenial exacerbation of epilepsy. Neurology, 9: 352-360, 1959.  Back to cited text no. 43    
44.Mehta, P. J., Shah, S. J. and Shah, S. N.: Pregnancy Medicine. In: A.P.I. Textbook of Medicine. Editors: S. J. Shah, M. P. Anand, G. S. Sainani, A. B. Mehta and M. Vishawanathan. 4th edition. National Book Depot., Bombay, 1986, pp. 1261-1263.  Back to cited text no. 44    
45.Mirkin, B. L.: Drug distribution in pregnancy. In: "Fetal Pharmacology." Editor: L. Borcus. Raven Press, New York, 1973.  Back to cited text no. 45    
46.Monson, R. R., Rosenberg, M. S., Hertz, S. C., Shapiro, S., Heinonen, O. P. and Slone, D.: Diphenylhydantoin and selected congenital malformations. N. Engl. J. Med., 289: 1049-1052, 1973.   Back to cited text no. 46    
47.Montouris, G. D., Fenichel, G. M. and McLain, W.: The pregnant epileptic. A review and recommendations. Arch. Neurol., 36: 601-603, 1979.  Back to cited text no. 47    
48.Mygind, K. I., Dam, M.. and Christiansen, J.: Phenytoin and phenobarbitone plasma clearance during pregnancy. Acta. Neurol. Scand., 54: 160-166, 1976.  Back to cited text no. 48    
49.Newmark, M. E. and Penry, J. K.: Catamenial epilepsy. In, Advances in Epileptology: The XIIth Epilepsy International Symposium." Editors: M. Dam, L. Gram and J. K. Penry. Raven Press, New York, 1981, pp. 433-439.  Back to cited text no. 49    
50.Nomura, Y., Ogawa, Y., Shinagawa, S., Kaneko, S., Fukushima, Y. and Sato, T.: Fetal monitoring in pregnant women treated with antiepiieptic drugs. In: Antiepileptic Drugs and Pregnancy. Editors: T. Sato and S. Shinagawa. Excepta Medica, Amsterdam, 1984, pp. 98-105.  Back to cited text no. 50    
51.Novak, E. R., Jones, G. S. and Jones, H. W.: Physiology of menstruation and pregnancy. In: Novak's Text-book of Gynecology, Williams and Wilkins, Baltimore, 1975, pp. 17-57.  Back to cited text no. 51    
52.Ogawa, Y., Fukushi, A., Nomura, Y. et al. Complications of pregnancy labour and delivery in women with epilepsy. In: "Anti-epileptic Drugs and Pregnancy." Editors: T. Sato and S. Shinagawa. Excepta. Medica, Amsterdam, 1984, pp. 87-97. Quoted in Kaneko, S.30  Back to cited text no. 52    
53.Ogawa, Y., Nomura, Y., Kaneko, S., Suzuki, K. and Sato, T.: Insidious effect of antiepileptic drugs in the perinatal period. In: Epilepsy, Pregnancy and the Child. Editors: D. Janz, L. Bossi, M. Dam, H. Helge, A. Richens and D. Schmidt. Raven Press, New York, 1982, pp. 197-202.  Back to cited text no. 53    
54.Otani, K.: Risk factors of the increased seizure frequency during pregnancy and puerperium. Folia Psychiat. Neurol. Jpn., 39: 33-42, 1985.  Back to cited text no. 54    
55.Otani, K., Kaneko, S., Fukushima, Y., Sato, T., Nomura, Y. and Shinagawa, S.: Possible risk factors on the course of epilepsy during pregnancy. In: The XVth epilepsy international symposium (Washington D.C.), Abstract, 1983, pp. 270.  Back to cited text no. 55    
56.Otani, K., Kaneko, S., Shimamuda, S., et al.: Changes in serum levels of cortisol, estradiol, progesterone, HCG and folic acid in pregnant epileptic women. Canad. J. Neurol. Sci., 1985. Quoted by Kaneko, S.[30]  Back to cited text no. 56    
57.Pirani, B. B. K., Campbell, D. M. and McGillivray, I.: Plasma volume in normal first pregnancy. J. Obstet. Gynaec. Brit. Commonwealth, 80: 884-887, 1973.   Back to cited text no. 57    
58.Ramsay, R. E., Strauss, R. G., Wilder, J. and Willmore, L. J.: Status epilepticus in pregnancy: effect of phenytoin malabsorption on seizure control. Neurology, 28: 85-89, 1978.  Back to cited text no. 58    
59.Reboud, P., Groulade, J., Groslambert, P. and Colomb, M.: The influence of normal pregnancy and the postpartum state on plasma proteins in lipids. Amer. J. Obstet. Gynecol., 86: 820-828, 1963.   Back to cited text no. 59    
60.Remillard, G., Dansky, L., Andermann, E. and Andermann, F.: Seizure frequency during pregnancy and the puerperium. In: Epilepsy, Pregnancy and The: Child. Editors: D. Janz, L. Bossi, M Dam, H. Helge, A. Richens, and D Schmidt. Raven Press, New York, 1982, pp. 15-26.  Back to cited text no. 60    
61.Rubin, P. C.: Prescribing in pregnancy. General principles. Brit. Med. J., 293: 1415-1417, 1986.  Back to cited text no. 61    
62.Ruprah, M., Perucca, E. and Richens, A.: Decreased serum protein binding of phenytoin in late pregnancy. Lancet, 2: 316-317, 1980.  Back to cited text no. 62    
63.Schmidt, D.: The effects of pregnancy on the natural history of epilepsy. Review of the literature. Proceedings of Workshop on Epilepsy, Pregnancy and the Child. Berlin, Federal Republic of Germany, September 14-16, 1980. Epilepsia, 22: 365, 1981.  Back to cited text no. 63    
64.Starr, A. M.: Personality changes in Cushing's syndrome. J. Clin. Endocrinol., 12: 502-505, 1952.  Back to cited text no. 64    
65.Strauss, R. G. and Bernstein, R.: Folic acid and dilantin antagonism in pregnancy. Obstet. & Gynaecol., 44: 345-348, 1974.  Back to cited text no. 65    
66.Studd, J.: The plasma proteins in pregnancy. Clin. Obstet. Gynaecol., 2: 285-300, 1975.  Back to cited text no. 66    
67.Sutherland, J. M.: Some difficulties in the management of epileptic patients. Progress in Clin Neurosci, 2: 31-39, 1985.   Back to cited text no. 67    
68.Suzuki, K., Kaneko, S., Saito, F. et al.: Serum levels of anti-epileptic drugs in neonates and in their mothers with epilepsy during puerperium. In: "Antiepileptic Drugs and Pregnancy." Editors: T. Sato and S. Shinagawa. Excerpta Medica, Amsterdam, 1984, pp. 20-31.  Back to cited text no. 68    
69.Taber, B.: Convulsive seizures in pregnancy. In: "Manual of Gynaecology and Obstetric Emergency." IInd Edition. W. B. Saunders Company, Philadelphia, 1984, Ch: 32, pp. 154-157.  Back to cited text no. 69    
70.Teramo, K. and Hiilesma, W.: Pregnancy and fetal complications in epileptic pregnancies. Review of the literature. In: Proceedings of Workshop on Epilepsy, Pregnancy and the Child, Berlin, Federal Republic of Germany, September 14-16, 1980. Epilepsia, 22: 365, 1981.  Back to cited text no. 70    
71.Timilas, P. S., Woodbury, D. H. and Goodman, L. S.: Effect of adrenalectomy, hydrocortisone acetate and desoxycorticosterone acetate on brain excitability and electrolyte distribution in mice. J. Pharmacol. Exp. Ther., 112: 80-93, 1959.   Back to cited text no. 71    
72.Walton, J. N.: Paroxysmal and convulsive disorders of epilepsy. In: Brain's Diseases of the Nervous System. Editor: J. N. Walton. 8th edition. Oxford University Press, New York, 1977, Ch. 22, pp. 1093-1142.  Back to cited text no. 72    

Top
Print this article  Email this article
Previous article Next article
Online since 12th February '04
2004 - Journal of Postgraduate Medicine
Official Publication of the Staff Society of the Seth GS Medical College and KEM Hospital, Mumbai, India
Published by Wolters Kluwer - Medknow