The subject of pregnancy is the single most worrying concern for women with epilepsy. They may choose to avoid pregnancy altogether or to terminate anticonvulsant medication (AEDs) during pregnancy. Much research bears out these concerns: higher risks of some complications during pregnancy, including congenital malformation, are indicated among women with epilepsy. Although the decision to bear a child should be made by the parents themselves according to their particular life plan, their access to adequate medical information is a necessity. In our meetings with patients, we consistently attempt to provide information based on the latest published data, but the individual content of presentation to patients has been left to the style of each doctor independently; thus, we know little about how these practices differ among the doctors as an independent group within our hospital. Therefore, for this research project, we examined existing medical records of women with epilepsy retrospectively to evaluate statistics regarding their pregnancies.
Summary: Purpose: To survey and summarize the treatment of pregnant women with epilepsy and to obtain data for the improvement of daily treatment regimens.
Methods: We reviewed medical records of 36 deliveries of 25 mothers with epilepsy at Yokohama City University Hospital from September 1991 to December 2000 and statistically compared the differences in drug-taking profiles, complications during pregnancy, types of delivery, and complications at delivery between the epilepsy group and a control group (656 total deliveries after 22 weeks except for epilepsy cases in 1991 and 1992 at Yokohama City University Hospital).
Results: Of the 25 mothers with epilepsy, three with idiopathic generalized epilepsy, 12 were symptomatic for partial epilepsy. Their mean age at delivery was 29.0 years. The mean age at onset of epilepsy was 13.9 years. Of the 36 pregnancies, 30 (83.3%) cases continued antiepileptic drug (AED) taking throughout the pregnancies; 23 (63.9%) cases received monotherapy. Phenobarbital was the most frequently used drug in monotherapies. Seven (19.4%) cases received polytherapy. Seven (19.4%) patients experienced epileptic seizures during pregnancy. One case showed a low serum AED level. No statistically significant difference was found in complications during pregnancy, types of delivery, or complications at delivery, excluding abnormal rotation in the birth canal. Congenital malformation (cleft lip with palate) was observed in one (2.9%) case. The mother was 39 years old at delivery and had myoma uteri. Onset of epilepsy was at 14 years. She had been taking three kinds of AEDs: 1,400 mg/day of sodium valproate (VPA), 1.5 mg/day of clonazepam (CZP), and 200 mg/day of zonisamide (ZNS). Serum concentrations at pregnancy week 10 were 85.3 μg/ml VPA, 18.1 μg/L CZP, and 10.5 μg/ml ZNS. She also had been taking folic acid, 5 mg/day, but the serum concentration was not measured.
Conclusions: The method of treatment and the management of pregnancy were left to the discretion of each doctor. However, in most cases, monotherapy was selected; and the frequency of complications was not significantly different from that of the control group, excluding the frequency of abnormal rotation in the birth canal. However, we could have been more proactive in calculating the risks of pregnancy for women with epilepsy and adjusted treatment in anticipation of a planned pregnancy, before the patient actually became pregnant. Additionally, a closer working relationship between the obstetrician and the physician who treats the epilepsy would seem to be a further requirement for the patient's well-being, as well as her child's, during pregnancy.
SUBJECTS AND METHODS
The medical records of 36 newborns of 25 mothers with epilepsy at Yokohama City University Hospital from September 1991 to December 2000 (8 years 4 months) were reviewed. Total deliveries excluding epilepsy cases of 1991 and 1992 at Yokohama City University Hospital (656 cases) were used as controls for the χ2 test on the frequency of complications during pregnancy.
|1(1)||34||Unclear||1||CBZ, PRM, PB||Near miscarriage||+||Drug-induced, forceps||Mild pain, coiling of the cord||39W6D||Female||3,530||51||9|
|2(2)||26||Unclear||16||PB, VPA||Anemia||+||Drug-induced||Mild pain, prolonged||41W6D||Male||3,660||50.5||9|
|3(3)||24||Unclear||12||PHT, PBa||Drug-induced||Mild pain, prolonged||42W1D||Male||2,950||49||8|
|4(4)||25||Unclear||Unclear||PB||Near miscarriage||Drug-induced||Mild pain||40W1D||Male||3,476||50.5||9|
|5(5)||24||SPE||20||PB||Premature rupture of the membrane||+||Cesarean||40W0D||Male||2,902||50||9|
|6(6)||24||SPE||3||VPA||Toxemia of pregnancy||+||Spontaneous||38W5D||Female||3,050||50.5||8|
|7(7)||33||SPE||12||PHT, PB||Anemia, near miscarriage||Spontaneous|| |
|9(8)||22||SPE||11||PB||Anemia, premature rupture of the membrane||Spontaneous|
|10(1)||36||Unclear||1||CBZ, PRM, ZNS, PB||Near miscarriage||Spontaneous||Coiling of the cord||38W0D||Male||2,872||49||10|
|11(9)||37||Unclear||Unclear||Unclear||Premature rupture of the membrane||Drug-induced||Mild pain||40W0D||Male||3,186||50||9|
|12(10)||33||SPE||26||PB||Anemia, premature rupture of the membrane||Spontaneous||Coiling of the cord||40W4D||Female||3,060||50||9|
|18(14)||26||Unclear||3||VPAa||Drug-induced, forceps||Mild pain, abnormal rotation, prolonged||40W3D||Female||3,006||49||9|
|19(15)||16||Unclear||5||CBZ||Near miscarriage, IUGR||Cesarean||Coiling of the cord||Female||2,914||50||5|
|20(16)||32||IGE||5||VPA||Premature rupture of the membrane||Spontaneous||Coiling of the cord||34W0D||Male||2,550||48||9|
|21(17)b||33||Unclear||11||CBZ||Toxemia of pregnancy, near miscarriage, premature rupture of the membrane||Cesarean||36W1D||Female||1,458||43||8|
|22(17)b||33||Unclear||11||CBZ||Toxemia of pregnancy, near miscarriage, premature rupture of the membrane||Cesarean||36W1D||Male||1,176||37||8|
|24(19)||28||SPE||12||VPA, CBZ, DZP||Near miscarriage, premature rupture of the membrane||Drug-induced||37W1D||Male||2,662||51||8|
|25(20)||29||SPE||16||CBZ, PB||Near miscarriage||Cesarean||36W2D||Female||2,220||47||7|
|26(11)||25||SPE||14||CBZ||Hydramnion||+||Drug-induced||Mild pain, abnormal rotation, prolonged||38W0D||Male||2,914||50.5||9|
|28(21)||29||IGE||19||PB||Spontaneous||Coiling of the cord||40W6D||Female||2,670||47||9|
|32(23)||34||SPE||19||PB||Toxemia of pregnancy, premature rupture of the membrane||Breech extraction||39W4D||Female||2,976||49||9|
|33(24)||26||SPE||22||CBZ, ZNS||Anemia, near miscarriage||+||Spontaneous||41W3D||Male||3,308||52||9|
|34(10)||38||SPE||26||PB||Anemia, premature rupture of the membrane||Drug-induced||36W2D||Male||2,444||45||9|
|35(21)||30||SPE||19||PB||Toxemia of pregnancy, premature rupture of the membrane||Spontaneous||37W1D||Male||2,788||48.5||10|
|36(25)c||39||SPE||14||VPA, CZP, ZNS||IUGR, premature rupture of the membrane||Spontaneous||37W1D||Female||1,712||44||2|
(n = 36)
(n = 656)
|Anemia||11 (30.6)||183 (27.9)|
|Near miscarriage||6 (16.7)||54 (8.2)|
|Toxemia of pregnancy||6 (16.7)||56 (8.5)|
|Premature rupture of the membranes||12 (33.3)||156 (23.8)|
|IUGR||2 (5.6)||34 (5.1)|
|Hydramnion||1 (2.8)||8 (1.2)|
|Mild pain||9 (25.0)||131 (20.0)|
|Prolonged delivery||6 (16.7)||63 (9.6)|
|Coiling of the cord||6 (16.7)||167 (25.5)|
|Abnormal rotation in the birth canal||3 (8.3)||16 (2.4) |
p < 0.05
|Drug-induced delivery||11 (30.6)||197 (30.0)|
|Cesarean section||7 (19.4)||74 (11.3)|
|Forceps delivery||2 (5.6)||53 (8.1)|
|Low birth weight||2 (5.6)||18 (2.7)|
|Congenital malformation||1 (2.8)||27 (4.1)|
|Preterm delivery||5 (13.9)||104 (15.9)|
|Postterm delivery||2 (5.6)||18 (2.7)|
|Apgar score||<8 3 (8.3)||47 (16.8)a|
The total number of deliveries over the 22-week period were 3,486. Deliveries of 25 mothers with epilepsy were 36 cases (1.0% of total deliveries). In this period, deliveries of schizophrenic mothers were 24 (0.7%); mothers with mood disorder, nine (0.3%); mothers with neurosis, 15 (0.4%); and others, 10 (0.3%).
Profiles of the mothers
Age at delivery was 16–39 years; mean, 29.0 years (SD, 4.9). Types of epilepsy included idiopathic generalized epilepsy, three; symptomatic partial epilepsy, 12; and unclear, 10. Age at onset was 1–27 years; mean, 13.9 years (7.3). Duration of illness at the time of delivery was 3–35 years; mean, 15.4 (8.1) years. Fifteen (41.7%) of 25 mothers received treatment for epilepsy at the Department of Psychiatry; three (12.0%) at the Department of Neurology; three (12.0%) at the Department of Neurosurgery; one (4%) at the Department of Pediatrics; and one (4%) at the Department of Internal Medicine. The patient treated in Pediatrics was 16 years old at her delivery. The patient treated by Internal Medicine had from systemic lupus erythematosus (SLE).
Conditions of taking drugs included 30 (83.3%) cases of 36 pregnancies continued taking drugs throughout pregnancy. Three (8.3%) patients discontinued drug taking during pregnancy. One patient had not taken any AEDs. The condition was unclear in one case. In each of three cases in which patients discontinued AEDs during pregnancy, the drug prescriptions were stopped after week 13 of pregnancy. Patients receiving monotherapy were Twenty-three (63.9%) patients received monotherapy; polytherapy was received by seven (19.4%) patients.
The drugs used in monotherapy were phenobarbital (PB), 10 (27.8%) of all 36 cases, 43.5% of monotherapy; carbamazepine (CBZ), eight cases (22.2%, 34.8%), valproate (VPA), four cases (11.1%, 17.4%), and clonazepam (CZP), one case (2.8%, 4.3%).
Drug profiles of polytherapy cases all differed from each other. They include combinations of two drugs; four (11.1%) of 36 cases: PB + VPA, PB + CBZ, PB + CBZ, and CBZ + zonisamide (ZNS); and three drugs; three (8.3%) cases: PB + CBZ + primidone (PRM), VPA + CZP + ZNS, and CBZ + VPA + diazepam (DZP); four drugs: one (2.8%) case: PB + CBZ + PRM + ZNS.
EEGs were given 0 to 2 times (mean, 0.71). Serum AED levels were measured 0 to 7 times (mean, 1.8). Serum folic acid level was measured only once in one case. Serum AED levels tended to be measured more frequently in patients who experienced seizures during pregnancy.
Epileptic seizures during pregnancy
Seizures were observed in seven patients. Four showed a therapeutic range of serum AED levels. One showed a low serum level; the patient had been taking 800 mg/day of VPA, 13.6 μg/ml.
Complications during pregnancy: 12 (33.3%) of 36 cases of premature rupture of the membranes, 11 (30.6%) cases of anemia, six (16.7%) cases of near miscarriage, six (16.7%) cases of toxemia of pregnancy, two (5.6%) cases of intrauterine growth retardation, and one (2.8%) case of hydramnion were observed in the epilepsy group. In the control group, 156 (23.8%) of 656 cases of premature rupture of the membranes, 183 (27.9%) cases of anemia, 54 (8.2%) cases of near miscarriage, 56 (8.5%) cases of toxemia of pregnancy, 34 (5.1%) cases of intrauterine growth retardation, and eight (1.2%) cases of hydramnion were observed. Although near miscarriage, toxemia of pregnancy, and hydramnion were more frequent in the epilepsy group, significant statistical differences were not found.
Types of delivery: 18 (50%) spontaneous deliveries, 11 (30.6%) drug-induced deliveries, seven (19.4%) cesarean sections, and two (5.6%) forceps deliveries were observed in the epilepsy group. In the control group, 197 (30%) drug-induced deliveries, 74 (11.3%) cesarean sections, and 53 (8.1%) forceps deliveries were observed. Significant statistical differences were not found.
Complications at delivery: nine (25%) cases of mild pain, six (16.7%) cases of prolonged delivery, six (16.7%) cases of coiling of the cord, and three (8.3%) cases of abnormal rotation in the birth canal were observed in the epilepsy group. In the control group, 131 (20%) cases of mild pain, 63 (9.6%) cases of prolonged delivery 167 (25.5%) cases of coiling of the cord, and 16 (2.4%) cases of abnormal rotation in birth canal were observed. Abnormal rotation in the birth canal was significantly more frequent in the epilepsy group (p < 0.05).
Regarding the sex of newborns, 16 (44.4%) were male, and 20 (55.6%) were female. Durations of pregnancy ranged from 238 (34 weeks 0 days) to 303 days (43 weeks 2 days). The mean was 274.9 days (SD,14.2). Five (13.9%) babies were born before week 37, and two (5.6%) were born after week 42. Birth weights ranged from 1,176 to 3,660 g; the mean was 2,786.1 g (533.0). Seven (19.4%) were <2,500 g. Body heights ranged from 37 to 52 cm; the mean was 48.7 cm (2.8). In the control group, 51.6% were male, and 48.4% were female; 104 (15.8%) were born before week 37, and 18 (2.7%) were born after week 42. One hundred five (16.0%) weighed <2,500 g. Postterm deliveries were more frequent in the epilepsy group, but significant statistical differences were not evident.
Congenital malformations: In one (2.8%) of 36, cleft lip and palate were observed. In this case, the mother was 39 years old at the time of delivery and had myoma uteri. Her age at onset of epilepsy was 14 years. Seizure type was generalized tonic–clonic convulsion and loss of consciousness. She had been continuously taking 1,400 mg VPA, 1.5 mg CZP, and 200 mg ZNS per day. Serum concentrations on week 10 were 85.3 μg/ml (VPA), 18.1 μg/L (CZP), and 10.5 μg/ml (ZNS). Serum concentration of folic acid was not measured. The patient had been seizure free for ≥5 years at the time of delivery. In the EEG on week 20, 2- to 3-Hz high-voltage slow waves bursting dominant on the frontal area were observed, but a spike was not found. Duration of pregnancy was 37 weeks 1 day. Birth weight was 1,712 g. Apgar score was 2. In the control group, 27 (4.1%) congenital malformations were observed. Differences in frequency of congenital malformations were statistically not significant.
The mothers were treated in five different hospital departments. Although recently the number of epilepsy patients who receive treatment from neurologists or neurosurgeons has been increasing, 15 (41.7%) of 25 mothers received treatment by psychiatrists. Compared with other pregnancies of women with other psychiatric disorders, pregnancies of women with epilepsy were more frequent. Pregnancy involving epilepsy patients remains a serious area of concern among psychiatrists who treat epilepsy.
Mean age at onset of epilepsy was 13.9 years. Some researchers indicate that a younger age at onset may result in less likelihood of the patient's marrying (1,2). Among our cases, the number of the patients whose onset was before 10 years old (five cases) were equal to the number of the cases whose onset was after 20 years old, and such a tendency was not found.
Most of the cases (30 cases; 83.3%) continued AEDs throughout the pregnancies. From the descriptions in the medical records, we could not clarify how the doctors estimated the risks and the benefits of taking AEDs and decided to continue the prescriptions of AEDs. In three (8.3%) patients, AEDs were discontinued after week 13, as less danger of effects of drugs on congenital malformation is thought to occur, and relapse of seizures was not observed. To reduce the risks of other complications, it seemed better to discontinue AEDs even after the first trimester. Practically, it was likely that drug discontinuance was discussed after the diagnosis of pregnancy. But to reduce the risks of congenital malformations, earlier discontinuance should have been suggested to patients in prepregnant counseling.
Twenty-three (63.9%) patients were treated with monotherapy. PB was most frequently used in this type of treatment, followed by CBZ, VPA, and then CZP. In polytherapies as well, PB and CBZ were preferred. The incidence of congenital malformation were reported to be reduced in monotherapy, as well as by avoiding the combination of VPA and CBZ (3). From that viewpoint, prescriptions seemed to have been reasonable. Few patients were treated with phenytoin (PHT), perhaps because of difficulties in adjustment of serum concentration, or for cosmetic reason. In this study, it was unclear whether the effects of prescriptions were the results of an effort to adjust drugs for pregnancy.
Regarding complications during pregnancy, in some studies, higher risks of miscarriage (4,5), toxemia of pregnancy (4,6), vaginal bleeding (7,8), premature separation of the placenta (7,8), preterm delivery (6), and surgical procedures (9) were reported. Several negative reports considered each type of complication (4,11,12). At this time, it seems unclear that the risks of complications are definitively higher in women with epilepsy. In our study, statistically significant differences between the epilepsy group and the control group did not exist, with the exception of abnormal rotation in the birth canal. Epileptic seizures were observed in seven patients. The types and frequency of seizures were difficult to determine based only on the information from the medical records. Serum AED levels were measured in five of seven cases. Four cases showed a so-called ‘therapeutic range.’ One case showed a low serum level (23.1 μg/ml), although the mother was prescribed 800 mg/day VPA, perhaps because of noncompliance.
AEDs also were suggested to influence the body dimensions of infants (10,13–15). A recent study in Sweden reported low birth weights and smaller head circumferences in infants of mothers with epilepsy under treatment (16). In our cases, no differences in the birth weight were found between the epilepsy group and the control group.
Many reports suggested that the incidence of malformation increased in the offspring of mothers with epilepsy under treatment (17–19). The risks of congenital malformations in pregnancy involving women with epilepsy were estimated to be about twice that of controls (16). In this research, one case showed a malformation of a cleft lip and palate. The frequency was lower than that in the controls. The mother had several risk factors, including delivery at 39 years old and myoma uteri; therefore, AEDs alone were not blamed for the malformations.
Although VPA was used at 1,400 mg/day and showed relatively high concentrations, the serum AEDs levels were all within therapeutic range. She had not experienced a seizure for >5 years at the time of pregnancy; and in the EEG at week 20, a spike was not found (a slow-wave burst was detected).VPA was reported to increase the risk of malformation. Kaneko et al. (18) recommended, in their guidelines for the pregnancy of women with epilepsy, that the daily dose of VPA should be <1,000 mg. ZNS-related malformation in monotherapy has not been reported. However, as in this case, research reports malformations in polytherapy including ZNS (20). Taking these findings into account, it seemed that more effort should be made to adjust prescriptions.
In this research, we reviewed our practices regarding treatment of pregnancies in women with epilepsy. Statistically, the frequency of complications of pregnancy, including congenital malformations, was not shown to be significantly different from that in a control group. Obtaining data regarding how each doctor provided information to patients and adjusted treatment individually was difficult, as physicians from various hospital departments worked independently, with no centralized treatment method. A more systematic ‘team’ approach, involving the cooperation of obstetricians and other specialists who treat epilepsy, is strongly indicated.