Seizure 1993; 2:277-280

Pregnancy, epilepsy, management and outcome: a lO-year perspective

P.J. MARTIN & P.A.H. MILLAC

Department of Neurology, Leicester Royal Infirmary, Leicester LE1 5WW, UK

Correspondence to P.J. Martin at above address

We analysed the management and outcome of 348 pregnancies in 207 women with epilepsy from 1977 to 1981 and 1987 to 1991. Outcome was successful in 88%. There was a marked change in anticonvulsant prescribing away from phenobarbitone and phenytoin towards carbamazepine and sodium valproate but a large number of patients (24%) were treated with two or more anticonvulsants in the second cohort despite a move towards monotherapy. A significant reduction in congenital malformation (4.8%), spontaneous abortion (6.9%) or low birth weight babies (9.4%) was not seen. Until experience is gained with the newer agents, monotherapy remains of major importance in the management of the pregnant woman with epilepsy.

Key words: pregnancy; epilepsy; teratogenesis; congenital malformation.

INTRODUCTION

The prevalence of epilepsy in the general popu- lation is 0.6-1% and approximately 40% of this group are women of child-bearing potential 1. Because the fertil i ty of both men and women with epilepsy is reduced, about 0.5% of all pregnancies occur in women with epilepsy 2. Despite this common scenario, there is a rela- tive paucity of current l i terature on pregnancy outcome in women with epilepsy, most recent interest having focused on anticonvulsant teratogenici ty and its possible mechanisms 3.

Pregnancy in women with epilepsy is still considered to present a high risk and maternal mortal i ty from epilepsy (approximately one fatal i ty per year in England and Wales) al though low, has remained constant over the last 50 years whilst mortal i ty from other causes has declined 4. Epilepsy p e r se predis- poses to fetal malformation and the likelihood is fur ther increased by antiepileptic drug (AED) prescribing. On the other hand, adequate seizure control must be at tained during pregnancy and this may be made all the more difficult by enhanced AED metabolism, an increased volume of distribution and increased protein binding. In view of the trend towards monotherapy in epilepsy, the greater

awareness of potential AED teratogenicity and the move away from barbi turate therapy, we decided it would be helpful to review our ex- perience of pregnancy and epilepsy over the last decade.

PATIENTS AND METHODS

We studied two five-year cohorts of preg- nancies in women with epilepsy a decade apart. The case-notes of all pat ients booked to the Leicester Royal Infirmary Materni ty Hospital from 1977 to 1981 and from 1987 to 1991 were analysed. The results from the former group have been published previously 5. Data from the lat ter cohort were sorted using the Epicare database (Sanofi-Winthrop) in con- junction with standard commercial software. Both cohorts were compared with data from all registered pregnancies in the Leicester district for the same periods. Data are expressed as actual values or percentages where indicated. Birthweights were normally distributed and are therefore expressed as the mean with 95% confidence intervals. Birthweights between t rea tment groups were compared using non- paired t-tests.

1059-1311/93/040277+04 $08-00/0 (~ 1993 Bailliere Tindall

278 P.J. Martin & P.A.H. Millac

Table 1: Pregnancy details and outcomeintwo cohorts of women with epilepsy and theirrespective controlgroupsfrom 1977- 1981 and 1987-1991

1977-1981 1987-1991

Study group Control group Study group Control group

Number of patients 92 115 Number of pregnancies 188 160 AED treatment: None 36 (19%) 27 (17%)

One 88 (47%) 94 (59%) Two 64 (34%) 39 (24%)

Number of births 180 146 Mean birth weight (g) 3178 (3029-3263) 3174 (3058-3290) Low birth weight 20 (10.6%) 8.5% 15 (9.4%) Spontaneous abortions 8 (4.2%) N.A. 11 (6.9%) Induced abortions 0 (0%) N.A. 3 (2.1%) Perinatal deaths 8 (4.7%) 1.4% 3 (2.1%) Congenital malformations 5 (2.9%)* 2.7% 7 (4.8%)f

6.7% 7.5% N.A. 0.9% 4.1%

*Spina bifida (two cases), patent ductus arteriosus, hare lip, digital hypoplasia. ICerebral palsy, ventricular septa] defect, tetralogy of Fallot, dextrocardia, hypospadias, digital hypoplasia, undescended testis. N.A. Not available.

R E S U L T S

Detai ls of the pat ients , the i r t r e a t m e n t and the outcome of the i r p regnancies are shown in Table 1. Fewer pregnancies were achieved in the second cohort over a period of t ime when the b i r th ra te r ema ined constant both na t iona l ly (13.0 to 13.8 per 1000 populat ion) ~ and wi th in Leices tersh i re (13.6 to 13.7 per 1000 population).

A profound change in the pa t t e rn of AED prescr ib ing was seen due to a concerted effort to manage pa t ien ts wi th mono the rapy and to replace the older agents wi th the be t t e r toler- a ted AEDs. Thus the re was a move away from phenobarb i tone and pheny to in which were pre- scribed dur ing 84 (45%) and 63 (34%) preg- nancies respect ively, 1977-1981, but in only 10 (6%) and 25 (16%) pregnancies , respect- ively, 1987-1991. Conversely, sodium val- proate and ca rbamazep ine were used more fre- quen t ly in the la te r cohort t h a n the ear l ie r group (36 [19%] and 23 [12%] pregnancies respect ive ly 1977-1981; 46 [29%] and 80 [50%] pregnancies respect ive ly 1987-1991). Dose changes were made in response to a clinical de te r iora t ion in 16 mothers (10%) in the second group, no ad jus tments were made as a resul t of a fall in p lasma drug levels alone.

Mean b i r th weight r ema ined cons tant over the decade despite the t r end in AED prescrib- ing towards ca rbamazep ine and sodium val- proate. There was no signif icant var ia t ion in b i r th weight r e l a t ing to the type of AED pre- scribed a l though those mothers t r ea ted with pheny to in had s l ight ly heav ie r babies (mean wi th 95% confidence intervals): ca rbamazepine

3187 g (3027-3348 g, va lproa te 3233g (3016- 3450 g), pheny to in 3365 g (3149-3581 g). Bi r th weight did not va ry s ignif icant ly wi th the n u m b e r of AEDs prescr ibed a l though babies born to mothe r s receiving t r e a t m e n t were s l ight ly heav ie r t h an those whose mothers were not; no AED, 2874g (2481-3267g) ; one AED, 3190 g (3036-3343 g); two AEDs, 3287 g (3103-3471g) . Six out of seven babies in the second group wi th an Apgar score of less t h a n 5 at one minu te had mothers t ak ing carbamaze- pine bu t all scores were g rea te r t h a n 7 by 5 minutes .

The re were more abort ions in the second cohort, both induced and spontaneous , however the n u m b e r of pe r ina ta l dea ths was smaller . No re la t ionship of such events to type or n u m b e r of AEDs prescr ibed was detected. More ma ldeve lopments were observed in the second group and the i r charac te r is shown in Table 1. Six of the seven mothers in the la te r group whose babies had mal format ions were t ak ing two AEDs, the seven th m o th e r was not on AED t r ea tmen t . One mothe r gave bi r th to a hea l thy baby hav ing been t r ea t ed wi th v igaba t r in t h roughou t gestat ion. Overal l , 88% of the preg- nancies were uncompl ica ted and a hea l thy baby was del ivered; 89% of pregnancies were successful in the first group, 87% in the second group.

D I S C U S S I O N

The outcome of over 300 pregnancies in women wi th epilepsy has been compared a decade

Pregnancy and epilepsy

apart. The second group comprised more women with epilepsy, however they had fewer pregnancies despite a constant birth rate in the control groups. This finding may reflect an increase in the referral rate of primigravida with epilepsy or a move by women with epi- lepsy towards smaller families. Certainly, greater awareness of AED teratogenicity by women of child-bearing potential does not appear to have discouraged them from starting a family.

In the second cohort, seizure frequency de- teriorated sufficiently to require a change in AED dosage during 16 pregnancies (10%). This proportion corresponds favourably with other reports (17-33%) 1'~. Unfortunately we are unable to comment on the proportion of our patients whose plasma AED levels showed a significant fall during pregnancy without a clinical deterioration. No patient in either series developed status epilepticus during pregnancy.

A similar number of patients in each cohort were managed without AEDs during preg- nancy; this merely reflects that the proportion of women with mild epilepsy in the two groups were similar. However, fewer patients were prescribed two or more AEDs in the later group (24%) than the earlier group (34%), although the proportion requiring polytherapy remained disappointingly high. The move away from phenytoin and phenobarbitone was paralleled by a rise in t reatment with sodium valproate and carbamazepine. The latter became the favoured drug, probably due to reports of neural tube defects with the former although recently carbamazepine has also been impli- cated s.

As expected, the number of low birth-weight babies in both groups was greater than in the respective control groups but the fact tha t babies born to mothers treated with AEDs in the second cohort were heavier than those babies born to mothers not taking AEDs leads us to suggest that the factor responsible lies with the epilepsy itself rather than with AED treatment. Other studies have shown tha t intra-uterine growth retardation and a smaller head circumference are observed amongst babies born to women with epilepsy irrespec- tive of whether AEDs were prescribed during pregnancy 9. One factor may be tha t epileptic women themselves tend to be smaller than the general population 1°.

In both our first and second cohorts, the peri- natal mortali ty rate was approximately two to

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three times that of the respective control groups, although there was a fall from 4.7% to 2.1% in the study groups. The reasons for this decrease are probably many, including better perinatal care in general (there was also a fall in perinatal mortality in the two control groups) as well as a move away from the more toxic AEDs during pregnancy. The perinatal mortali ty rate in our first cohort was similar to other studies of that era 11 but reports of peri- natal mortality over the time span of our sec- ond group are scanty.

The number of spontaneous abortions was seen to rise over the decade, but in the later group the proportion of such events was still similar to the control group. However, the numbers were small and we would not wish to over-interpret these findings other than to con- firm tha t spontaneous abortion is at least as common a problem as congenital malfor- mation 12. There was a similar rise in the number of induced abortions and here we suggest social factors to be the prime reason. We are unable to comment on the number of induced abortions in the control groups.

In comparison with other studies the number of malformations observed in the first group was unusually low but that observed in the second group was quite typical. Overall there appears to be a risk of malformation in an indi- vidual pregnancy of 4 - 6 % 12. No specific fetal syndromes were identified in either series and despite greater use of valproate in the second group, there were no neural tube defects (but again the numbers are small). To our knowl- edge, only one other study (of almost identical numbers to ours) has analysed pregnancy out- come in two groups of women separated tem- porally 13. From 1972 to 1979 and from 1980- 1985 Lindhout et al. described a change in the nature of malformation presumed due to the trend in AED prescribing, with spinal defects becoming more prevalent and heart defects, facial clefts, dysmorphism and developmental retardation becoming less frequent. It is of di- rect relevance in our analysis that six out of seven mothers whose offspring had malfor- mations were treated with two AEDs through- out pregnancy. There is now good evidence to suggest tha t AED polypharmacy has at least as much, if not greater, teratogenic potential than the type of AED prescribed 14. The rise in congenital malformations seen in the control groups was due to a change in the reporting system which was instituted between the two studies in the mid 1980s.

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The presence of a low Apgar score at 1 minute did not appear to be a poor prognostic factor in our second group. In all seven babies the score had risen appropriately by 5 minutes. However, 60% of infants with low 1 minute Apgar scores have previously been reported to develop asphyxia as have 40% of infants with low Apgar scores at 5 minutes 15. It has there- fore been suggested that the newborn may be vulnerable to the effects of AEDs, particularly as fetal serum anticonvulsant levels parallel maternal levels at birth. Despite our findings, awareness of prolonged asphyxia in babies born to mothers treated with AEDs during pregnancy must be encouraged.

The clinician continues to be faced with a dilemma. On the one hand there must be adequate seizure control during pregnancy whilst on the other, the adverse effects of anti- convulsant preparations need to be avoided. Anticonvulsant withdrawal prior to starting a family may be feasible in some patients with mild epilepsy but this is unlikely to be a re- alistic approach in many. A compromise must therefore be sought and to this end we would make the following recommendations: to aim for monotherapy during pregnancy wherever possible using predominantly carbamazepine and sodium valproate until experience with the newer agents (vigabatrin, lamotrigine and gabapentin) is gained, to take a combined approach along with the obstetrician and general practitioner and to encourage the prospective mother that despite the potential hazards she has a 90% chance of giving birth to a healthy child.

ACKNOWLEDGEMENTS

The help of Mrs A. Jones in assisting with data collection and of Mrs D. Jackson for providing control data is gratefully acknowledged. Sanofi-Winthrop kindly provided the Epicare database and the funding of the Leicester Dis-

P.J. Martin & P.A.H. Millac

trict Health Authority Audit Committee is also appreciated.

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