Consultant Neurologist, Director of the Special Centre for Epilepsy, York; Neurological Studies, Leeds Metropolitan University, Leeds, UK

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1 Seizure 2001; 10: doi: /seiz , available online at on CPD Education and self-assessment Epilepsy and pregnancy PAMELA CRAWFORD Consultant Neurologist, Director of the Special Centre for Epilepsy, York; Neurological Studies, Leeds Metropolitan University, Leeds, UK Visiting Professor in Clinical Correspondence to: Pamela Crawford, MD FRCP, York District Hospital, York, YO31 8HE, UK Pregnancies in women with epilepsy are high risk and need careful management by both the medical and obstetric teams due to the increased incidence of complications and adverse outcomes of pregnancy. By the time a pregnant woman with epilepsy presents, the foetus is virtually fully formed and the opportunity for altering drug treatment has passed. Women need to be counselled and told to seek advice about their anticonvulsant therapy should they wish to become pregnant. All major anticonvulsant drugs are teratogenic but the main risk to the developing foetus appears to be when the mother is on polytherapy especially if sodium valproate forms part of the combination. Folate supplements (5 mg) before conception are advisable. There appears to be a minor but significant increased risk of maternal complications in women with epilepsy such as hyperemesis gravidarum, pre-eclampsia and eclampsia, vaginal bleeding and premature labour. In the majority of women seizure control will not alter during pregnancy. Oral vitamin K should be given to the mother receiving enzyme-inducing antiepileptic drugs. Post-natal infant development: there is an increased risk of prematurity (9 11%), stillbirth, neonatal and perinatal death, haemorrhagic disease of the newborn, low Apgar scores and low birth weight (7 10%). Breast feeding: virtually all the anticonvulsant drugs are excreted in breast milk in low concentrations. Feeding difficulties, irritability and lethargy can occur. However, the benefits of breast feeding usually far outweigh any minor risks to the baby. c 2001 BEA Trading Ltd INTRODUCTION The management of pregnant women with epilepsy is becoming of increasing importance as the risk factors for adverse outcome of pregnancy are becoming more clearly delineated. The majority of women with epilepsy will have a normal pregnancy and delivery, an unchanged seizure frequency and over a 90% chance of a normal baby. However, many women still present in early pregnancy on anticonvulsant drug combinations which significantly increase their risk of a malformed infant. Pregnancies in women with epilepsy are high risk and need careful management by both the medical and obstetric teams due to the increased incidence of complications and adverse outcomes of pregnancy. PRE-CONCEPTION By the time a pregnant woman with epilepsy presents to an obstetrician or physician, the foetus is virtually fully formed and the opportunity for altering drug treatment has passed. Women of child-bearing age need to be counselled and told to seek advice about their anticonvulsant therapy should they wish to become pregnant. Not only does the necessity for anticonvulsant therapy need to be reconsidered, but the woman ought to be on the lowest possible dose of a single anticonvulsant agent which will adequately control seizures. All major first line anticonvulsant drugs (carbamazepine, sodium valproate, phenytoin, phenobarbitone and mysoline) are teratogenic but the main risk to the developing foetus appears to be when /01/ $35.00/0 c 2001 BEA Trading Ltd

2 Epilepsy and pregnancy 213 the mother is on polytherapy especially if sodium valproate forms part of the combination. Folate supplements before conception are advisable 1. The Department of Health has suggested that women with epilepsy should receive high dose folate supplements (5 mg) 2. A study from Birmingham demonstrated the benefits of pre-conception counselling and folic acid supplements. None of the women (85) who received counselling had a foetal abnormality detected during pregnancy or after delivery, compared to 11 out of 59 women who presented themselves to the clinic in a pregnant state. No patient in either group who took folic acid pre-conception had a foetal abnormality compared to 23% of women not taking folic acid 2a. PREGNANCY Pharmacokinetics of antiepileptic drugs in pregnant women In the majority of women seizure control will not alter during pregnancy. A third will have an increase in seizure frequency, but in many, this due to deliberate non-compliance because of worries over the adverse effects of anticonvulsants on the developing foetus. An increase in seizures seems to be unrelated to the type or duration of epilepsy or seizure frequency in previous pregnancies but tends to occur in women who have low anticonvulsant levels at the beginning of pregnancy 3. The reason for this increased risk are not fully understood but include deliberate non-compliance, sleep deprivation, alterations in antiepileptic drug kinetics, weight gain, metabolic changes and decreased albumin levels. At constant drug dosage, the serum levels of most antiepileptic drugs tend to decrease during pregnancy, but return to pre-pregnancy levels within a month of delivery 4. The changes in antiepileptic drug concentrations usually began within 10 weeks of pregnancy and returned to baseline values within a month of delivery in two thirds of the women receiving phenytoin. The return to pre-pregnancy levels appear to be slower for carbamazapine and phenobarbitone 5. Recent studies suggest that measuring total antiepileptic drug levels during pregnancy may be misleading, and monitoring of unbound levels should be taken instead if drug level monitoring is undertaken 2, 6. Practically it is sensible to increase the antiepileptic drug dosage if seizure frequency increases. It also has to be appreciated that many of the women may be deliberately non-compliant with therapy during pregnancy. There is also the problem of women who are seizure-free and driving, who would lose her driving license after a single seizure. In the majority of women the increase in seizure frequency is in the first trimester 7. However, this does not correlate with changes in anticonvulsant concentrations which differ for each drug 6. Effects of maternal seizures on the foetus Profound alterations in the acid base equilibrium occur immediately after a generalized tonic clonic seizure. These metabolic changes are probably transferred to the foetus, as there are alterations in the foetal heart rate compatible with foetal acidosis 8, 9. Prospective studies do not suggest that there is an association between maternal tonic clonic seizures during pregnancy and malformations 10, 11. However, organogenesis is a very short period of time and only a few patients experience seizures during this time. There are a few isolated reports indicating severe hypoxia in a mother can be teratogenic 12. It appears therefore that a healthy foetus is remarkably resistant to problems secondary to maternal seizures. There are anecdotal reports of intrauterine deaths in after a seizure 13, however, than these do appear to be rare. In a study of a 152 tonic clonic seizures during pregnancy in 154 women, there were no immediate foetal deaths or obstetric complications 14. Seizures during labour A tonic clonic seizure occurs during labour in 1 2% of women with epilepsy and within 24 hours of delivery in another 1 2%, which represents a risk of greater than nine times the average probability of a seizure during the rest of pregnancy 14. A generalized tonic clonic seizure during labour can cause a transient foetal bradycardia, reduced beat-tobeat variability, and decelerations for about 30 minutes after a seizure 15, 16. However, a case report suggests that foetal bradycardia during maternal seizures does not develop unless the mother develops acidosis 17. Vitamin K supplements It has been suggested that oral vitamin K should be given to the mother receiving enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine, oxcarbazepine, topiramate or phenobarbitone) in the last month of pregnancy to protect the foetus against haemorrhagic disease of the newborn 1. In these babies it tends to occur within 24 hours of birth and the protection given by only giving vitamin K to the baby after delivery may not be adequate.

3 214 P. Crawford Pre-term delivery Women taking enzyme-inducing antiepileptic drugs who require antenatal steroid therapy because of a perceived risk of pre-term delivery should receive a steroid regime providing a total of 48 mg beclomethasone (rather than 24 mg advocated for other women). This is because steroid metabolism is induced by enzyme-inducing antiepileptic drugs. Oral vitamin K therapy (20 mg daily) should also be started. Infants born to women receiving anticonvulsant drugs have at least double the risk of being born with an anomaly or a malformation 1. If the mother with epilepsy is on no treatment, there is a small increase in the risk of abnormalities such as a cleft palate or spina bifida. Paternal epilepsy does not influence this. After allowing for this the most likely aetiological factor to account for the increase in malformations appears to be anticonvulsant therapy 19. The four major anticonvulsant drugs (barbiturates, phenytoin, carbamazepine and sodium valproate) are all teratogenic in animal studies. The abnormalities reported are similar to those seen in humans. The majority of the malformations are minor and form part of what appears to be a foetal anticonvulsant syndrome 1, the incidence of which varies between 1.25% and 11.5% in exposed infants compared to 2.3% in the general population 1, Features described include hypertelorism, an abnormal midface, epicanthic folds, microcephaly, transverse palmar creases and minor skeletal abnormalities. More serious malformations include spina bifida and congenital heart disease which can be screened for in utero by ultrasound 1. Studies from Japan have clearly demonstrated that the risk of an abnormal foetus is related to the number and dosage of the anticonvulsant drugs 19. A prospective study showed that the risk of a malformed infant could be decreased from 13.5 to 6.2% by ensuring that more women received monotherapy in the lowest possible dose 19. The organs in the body are sensitive to exogenous agents that cause or are suspected of causing teratogenic effects at different dates. For example, a cleft palate cannot be caused by drugs administered 60 days after conception, since by this date the palate is closed 23. Days 21 to 56 represent the period when the foetus is considered to be most sensitive to the induction of malformations by exogenous agents, either in single organs or syndromes of malformations. This is also the period of extensive cell migration, morphogenetic movements, cell-to-cell and cell-tomatrix interactions etc. Known human teratogens which are active during this period, include sodium valproate and ethanol. After the eighth week, exposure to teratogens is not considered to result in any major morphological malformations. However, development is a continuum, in the foetal as well as the embryonic period. Moreover, any particular drug may affect processes in the embryonic as well as the foetal period 23. FOETAL DEVELOPMENT Major malformation patterns associated with antiepileptic drugs Phenytoin Hydantoins in monotherapy have been associated with a pattern of malformations called the foetal hydantoin syndrome 24. This consists of pre-natal and post-natal growth deficiency, microcephaly and developmental delay, in combination with dysmorphic craniofacial abnormalities and nail and distal pharyngeal hypoplasia. Unexpected major congenital malformations more often associated with phenytoin are facial clefts and congenital heart defects There appears to be no consistent dose response relationship for phenytoin and major or minor malformations, neither is there a relationship with maternal antiepileptic drug plasma levels 28, 29. Barbiturates Barbiturates in monotherapy have also been associated with congenital heart defects and facial clefts There also appears to be a specific pattern of minor anomalies and dysmorphic features such as growth deficiency and craniofacial and/or limb abnormalities 30, 31. Again no clear dose response relationship or relationship to plasma levels has been found. Carbamazapine Recent studies have suggested there is an association between carbamazapine and congenital malformations in about the same frequency as for barbiturates and phenytoin but the patterns of malformation are different. Initial studies suggested that carbamazapine therapy was associated with abnormal growth parameters such as reduced head circumference, weight and length at birth 32, 33. Later studies have reported associations with hip dislocation, inguinal hernia, hypospadias, congenital heart defects and neural tube defects (0.5 to 1%) 29, 34, 35.

4 Epilepsy and pregnancy 215 Sodium valproate Sodium valproate appears to be the only antiepileptic drug for which a dose response relationship has been observed. A high daily dose above 1000 mg/day or a high peak dose appears to increase the risk of major congenital malformations 29. Malformations associated with sodium valproate include neural tube defects (2.5%), craniofacial, skeletal, cardiovascular, urogenital and cerebral defects A relationship between valproate and radial ray aplasia, rib and vertebral anomalies has also been reported 40, 41. Data from the UK pregnancy register has shown that sodium valproate is significantly more teratogenic than carbamazepine and therefore sodium valproate should be avoided in pregnancy 41a. Ethosuximide Major congenital malformations, such as facial clefts, have been associated with ethosuximide, but mainly in combination therapies such as barbiturates 42. Benzodiazepines Initial reports suggested an association between orofacial clefts and benzodiazepines but later studies have not been able to confirm these findings 42. However, it has been suggested that the combination of sodium valproate and benzodiazepines may lead to more pronounced dysmorphism compared to children prenatally exposed to sodium valproate monotherapy 43. This may be due to an amplifying action on benzodiazepines on valproate teratogenicity 42, 44. Secondary prevention of major foetal malformations Ultrasound screening for major malformation can be performed in between 18 and 20 weeks of pregnancy. It may provide the mother the option of terminating the pregnancy. However, not all malformations can be detected pre-natally, and even when detected, it may not be possible to give the prognosis. Other methods include serum alpha foetoprotein and amniocentesis in order to measure the alpha 1 foetoprotein. Minor congenital malformations Genetic traits associated with epilepsy may contribute to malformations, development defects or dysfunction independent of drug exposure 45, 46. Eight prospective studies have looked at minor physical anomalies in children born to mothers with epilepsy. All studies show an increase in minor anomalies in children whose mothers have epilepsy compared to control children. An excess of dysmorphic features, especially epicanthus, was noted not only in the children but also in the mothers with epilepsy 47, 48. There does appear to be a slight increase in the risk of cognitive impairment among children born to mothers with epilepsy compared to those with non-epileptic parents 48. A recent retrospective study has shown that children born to mothers receiving sodium valproate during pregnancy are more likely to need additional help at school 48a. Which antiepileptic drug during pregnancy? An important question is which anticonvulsant drug carries the lowest risk during pregnancy. A recent overview suggests that of the older first-line therapies, carbamazepine therapy carries slightly less risk compared to valproate, phenytoin, phenobarbitone or mysoline 22. However, it is probably best if seizure control is good, to leave the treatment unchanged provided a single anticonvulsant is used in the lowest possible dose. Worries have been expressed about the incidence (1 2%) of spina bifida associated with sodium valproate 29, particularly as sodium valproate is treatment of choice for primary generalized epilepsies. However, spina bifida is an abnormality which can be screened for in early pregnancy and a more recent study has suggested there is a 0.5 1% risk of spina bifida associated with carbamazepine 49. The risk of sodium valproate teratogenicity may be decreased by keeping the total dose below 1000 mg and using Epilim chrono as the peak dose of sodium valproate is important with regards to teratogenicity 2, 29. However, as data from the UK pregnancy register has shown that sodium valproate is significantly more teratogenic than carbamazepine 41a and another study has highlighted educational problems in children exposed to sodium valproate during pregnancy 48a, sodium valproate should be avoided during pregnancy. A literature review suggests that drug combinations especially those including sodium valproate, should also be avoided. There seems to be an increased risk of foetal malformation, possibly related to the inhibition of metabolism of anticonvulsants, leading in particular to intermediary metabolites, which may play a role in teratogenicity 1. The two newer second-line anticonvulsant therapies (gabapentin and lamotrigine) do not appear to be teratogenic in animal studies. Pregnancies in women taking these drugs are few, but it is likely in the future that these will be the drugs of choice for women of childbearing age. Topiramate, one of the most recent anticonvulsants to be licensed, is

5 216 P. Crawford teratogenic in animal studies it causes limb and digit reduction. Tiagabine and levatiracetam, the most recently licensed antiepileptic drugs do not appear to be teratogenic in animal studies but human pregnancies are few 2. Maternal complications of epilepsy and pregnancy There appears to be a minor but significantly increased risk of maternal complications in women with epilepsy such as hyperemesis gravidarum, pre-eclampsia and eclampsia, vaginal bleeding and premature labour. The majority of reports suggest that spontaneous abortions are no more common in women with epilepsy compared to the general population 50, 51. Some studies have suggested pre-eclampsia is more frequent in women with epilepsy compared with controls and tends to be more severe Induction of labour is used more frequently in women with epilepsy, and was over four times more common in women with epilepsy compared with controls in one study 53. Another study showed that there was an increased incidence of instrumental delivery in women with epilepsy, with caesarean sections and forceps or vacuum extraction being more than twice as frequent as in controls 55. Some studies have suggested that the amount of blood lost during delivery is higher amongst women with epilepsy. Ablatio placentae, vitamin K deficiency and hypotonic uterine activity have been suggested as important causes of vaginal bleeding 52, 54. Other more recent studies have failed to confirm these findings and it may be that maternal coagulation deficiencies have been prevented by the use of prophylactic vitamin K supplements 15, 50, 56. Neither pre-term nor prolonged labour seemed to occur more frequently in women with epilepsy compared with controls 15, 50, 56. POST-NATAL INFANT DEVELOPMENT When a woman with epilepsy is pregnant the greater the risk of an adverse outcome of pregnancy extends to the child too. There is an increased risk of prematurity (9 11%), stillbirth, neonatal and perinatal death, haemorrhagic disease of the newborn, low Apgar scores and low birth weight (7 10%) 1. Low birth weight for gestational age is more frequent in infants of women with epilepsy than in controls 52, 57. There also appears to be an increased incidence of intrauterine growth retardation amongst infants of women with untreated epilepsy 56, 58, 59. A slight, but significantly smaller head circumference has been reported amongst infants born to mothers with epilepsy but neonatal birth length appears to be unaffected 11, 58, 60. Placenta weight, placental morphology and growth factor receptors are unaffected by antiepileptic drug exposure 61, 62. Low Apgar scores and the development of asphyxia has been found in a larger proportion of infants of women with epilepsy than in controls 57. In a study of sodium valproate monotherapy, almost half the babies developed foetal distress during labour compared to 9% of controls, and 28% had low Apgar scores compared with 5.5% amongst controls 40. Transient foetal distress can be caused by a maternal tonic clonic seizure during labour 63. Perinatal mortality in infants of women with epilepsy has been found to the two to three times higher than in the general population in several retrospective and prospective studies 15, 50, 52, 64. A fall in the perinatal mortality rate was found when the outcomes of pregnancy were compared from two periods, 1977 to 1981 and from 1987 to 1991, with a decrease from 4.7% to 2.1 %, respectively. However, the mortality rate was alsom consistently two to three times that of the control group, reflecting improved perinatal care in more recent years rather than an effect of changing antiepileptic drug prescriptions 64. Breast feeding and antiepileptic drugs The drug concentration profile in breast milk follows the plasma concentration curve, but a delay can often be seen. The drug concentrations in milk can substantially differ between the first and last portion of the feed, and between the left and right breast depending on the fat and protein content 65, 66. The total amounts of drug transferred to the infant via breast milk are usually much smaller than the amounts transferred via the placenta during pregnancy. However, as drug elimination mechanisms are not fully developed in early infancy, repeated administration of a drug via breast milk may lead to accumulation in the infant and pharmacological effects can occur 67. Relatively small amounts of phenytoin are transferred via breast milk and the serum levels of phenytoin in breast feeding infants are generally considerably below therapeutic levels. Phenobarbitone and primidone can accumulate in plasma in the breastfed baby due to slow elimination. It is therefore recommended that the infant is closely monitored and serum levels may be indicated. Carbamazapine concentrations in breast-fed babies are usually low and below the level where pharmacological effects might be anticipated. However, very rarely adverse reactions have occurred. Ethosuximide can be transferred via breast milk in relatively high daily doses and plasma concentrations in breast-fed babies can be close to

6 Epilepsy and pregnancy 217 therapeutic levels. Sodium valproate levels in breastfed babies are low. Vigabatrin and gabapentin are excreted mainly unchanged in the urine and therefore in infants with fully developed renal function, accumulation of these drugs is unlikely 66. Lamotrigine is, to a large extent, glucaronidated and in the newborn this capacity is not fully developed. A recent study suggested that lamotrigine can possibly accumulate in breast-fed infants particularly if a mother is also taking sodium valproate 68. There is no data relating to topiramate, levatiracetam or tiagabine. A recent study of child safety in the first year of life from Birmingham looked at untoward incidents. All apart from one women who had her first seizure whilst carrying her child, were potentially preventable. Mothers with juvenile myoclonic epilepsy seem particularly at risk as lack of sleep may precipitate myoclonic jerks and seizures 69. CONCLUSIONS Therefore, at present the advice to obstetric and medical teams looking after pregnant women with epilepsy is to use the lowest possible dose of a suitable single anticonvulsant which controls seizures, avoiding sodium valproate if possible 41a, 48a. The foetus should be screened by ultrasound for spina bifida, congenital heart disease and other malformations. In those women who did not receive advice before their pregnancy, the opportunity should be taken to refer them for re-evaluation of their diagnosis and treatment before further pregnancies occur. Guidelines for the management of women with epilepsy have been recently published and should be incorporated into obstetric unit protocols 18, 70. FURTHER READING 1. Crawford P., Appleton R., Betts T. et al. Best practice guidelines for the management of women with epilepsy. Seizure 1999; 8: Scottish Obstetric Guideline and Audit Project. The management of pregnancy in women with epilepsy, No. 5, SPCERH Publications, Betts T. and Crawford P. Women and Epilepsy. Martin Dunitz, London, Tomson T., Gram L., Sillanpaa M. and Johannessen S.I. (eds). Epilepsy and Pregnancy. Wrightson Biomedical Publishing Ltd., CONFLICTS OF INTEREST The Epilepsy Research Unit has received sponsorship and undertaken research work for all the major companies producing antiepileptic drugs. REFERENCES 1. Yerby, M. S. Pregnancy and teratogenesis. In: Women and Epilepsy (Ed. M. R. Trimble). Chichester, John Wiley & Sons, Betts, T. and Crawford, P. Women and Epilepsy. London, Martin Dunitz, a. Betts, T. and Fox, C. Proactive pre-conception counselling for women with epilepsy is it effective? Seizure 1999; 8: Otani, K. Risk factors for the increased seizure frequency during pregnancy and puerperium. Folia Psychiatrica et Neurologica Japonica 1985; 33: Johannessen, S. I. Pharmacokinetics of antiepileptic drugs in pregnant women. In: Epilepsy and Pregnancy (Eds T. Tomson, L. Gram, M. Sillanpaa and S. I. Johannessen). Wrightson Biomedical Publishing Ltd, 1997: pp Lander, C. M. and Eadie, M. J. Plasma antiepileptic drug concentrations during pregnancy. Epilepsia 1991; 32: Yerby, M. S., Friel, P. N., McCormack, K. et al. Antiepileptic drug disposition during pregnancy. Neurology 1992; 42 (Suppl. 5): Knight, R. H. and Rhind, E. G. Epilepsy and pregnancy: a study of 153 pregnancies in 59 patients. Epilepsia 1975; 16: Yerby, M., Koepsall, T. and Daling, J. Pregnancy complications and outcomes in a cohort of women with epilepsy. Epilepsia 1985; 26: Hiilesmaa, V. Effect of maternal seizures on the fetus. In: Epilepsy and Pregnancy (Eds T. Tomson, L. Gram, M. Sillanpaa and S. I. Johannessen). Wrightson Biomedical Publishing Ltd, 1997: pp Gaily, E., Granstrom, M. L., Hiilesmaa, V. and Bardy, A. Minor anomalies in offspring of epileptic mothers. Journal of Paediatrics 1988; 112: Steegers-Theunissen, R. P. M., Renier, W. O., Borm, G. F. et al. Factors influencing the risk of abnormal pregnancy outcome in epileptic women: a multicentre prospective study. Epilepsy Research 1994; 18: Goodlin, R. C., Heidrick, W. P., Papenfuss, H. L. and Kubitz, R. L. Fetal malformations associated with maternal hypoxia. American Journal of Obstetrics and Gynecology 1984; 149: Higgins, T. A. and Comerford, J. B. Epilepsy in pregnancy. Journal of Irish Medical Association 1974; 67: Bardy, A. Epilepsy and pregnancy. A prospective study of 154 pregnancies in epileptic women. Finland, University of Helsinki, Hiilesmaa, V. K., Bardy, A. and Terramo, K. Obstetric outcome in women with epilepsy. American Journal of Obstetrics and Gynecology 1985; 152: Yerby, M. S. Problems and management of the pregnant women with epilepsy. Epilepsia 1987; 28 (Suppl. 3): Goetting, M. G. and Davidson, B. N. Status epilepticus during labour. A case report. Journal of Reproductive Medicine 1987; 32: Scottish Obstetric Guideline and Audit Project. The management of pregnancy in women with epilepsy, No. 5, SPCERH Publications, Nakane, Y., Oltuma, T., Takahashi, R. et al. Multi-institutional

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