DOI: 10.1111/j.1471-0528.2009.02354.x www.bjog.

org

General obstetrics

Complications during pregnancy in women with epilepsy: population-based cohort study

I Borthen,a,b MG Eide,b G Veiby,a,e AK Daltveit,c,d NE Gilhusa,e
a Department of Clinical Medicine, University of Bergen, Bergen, Norway b Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway c Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway d Medical Birth Registry of Norway, Norwegian Institute of Public Health, Bergen, Norway e Department of Neurology, Haukeland University Hospital, Bergen, Norway Correspondence: Dr I Borthen, Department of Gynecology and Obstetrics, Haukeland University Hospital, N-5021 Bergen, Norway. Email ingrid.borthen@med.uib.no

Accepted 22 July 2009. Published Online 23 September 2009.

Objective To investigate whether women with epilepsy have an

increased risk of complications during pregnancy and to explore the impact of antiepileptic drug (AED) use.
Design Population-based cohort study. Setting Data from Medical Birth Registry of Norway based on all

births in Norway 19992005.

Population All births (n = 372 128) delivered in Norway, ensured

through linkage with the National Population Registry run by Statistics Norway. All singleton births and the rst child in multiple pregnancies were included, leaving 365 107 pregnancies for analyses.
Main outcome measures Pre-eclampsia (mild and severe),

an increased risk of mild pre-eclampsia, [odds ratio 1.3: 95% condence interval (1.11.5)] and delivery before week 34 [1.2: (1.01.5)]. Antiepileptic drugs were used in 33.6% (n = 942) of the pregnant women with epilepsy. Compared to women without epilepsy, women with epilepsy and AED use had an increased risk of mild pre-eclampsia [1.8: (1.32.4)], gestational hypertension [1.5: (1.02.2)], vaginal bleeding late in pregnancy [1.9: (1.13.2)], and delivery before 34 weeks of gestation [1.5: (1.12.0)]. No signicant increase in the risk of these complications was observed in women with epilepsy not using AED. These results remained unchanged after exclusion of multiple pregnancies.
Conclusion Women with epilepsy have a low complication rate,

gestational hypertension, eclampsia, vaginal bleeding (early and late) and preterm birth.
Results We compared 2805 pregnancies in women with a current or past history of epilepsy (0.8%) and 362 302 pregnancies in women without a history of epilepsy. Women with epilepsy had

but special attention should be paid to those using AED during pregnancy.
Keywords Antiepileptic drugs, complications, epilepsy,

pre-eclampsia, pregnancy.

Please cite this paper as: Borthen I, Eide M, Veiby G, Daltveit A, Gilhus N. Complications during pregnancy in women with epilepsy: population-based cohort study. BJOG 2009;116:17361742.

Introduction
Epilepsy is a common neurological disorder in obstetrical practice.1 In pregnant women, the prevalence is reported to be 0.30.7%.24 Women with epilepsy are often considered at high risk in pregnancy,5 although over 90% of pregnancies in such women proceed without any apparent problems.4,6 The risk of pre-eclampsia, placental bleeding and preterm birth has been reported to be two to three times increased in women with epilepsy,711 but this has not been reported in other studies.1,4,1214 It is unclear whether the

risk of complications is because of epilepsy per se or the use of antiepileptic drugs (AED),13,15,16 or the combination of these factors. If the effect of AEDs is important, the change to newer AEDs may lead to a change in these risks. Understanding the inuence of AEDs on pregnancy outcome is important for developing initiatives aimed at preventing adverse outcomes. This area remains understudied, with practitioners lacking important information useful for optimal clinical practice.15 Our aim of the present study was to investigate whether women with epilepsy have an increased risk of complications in pregnancy, and to explore the impact of AED use.

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Complications during pregnancy in women with epilepsy

Methods
Our data included all births (n = 372 128) from December 1st 1998 to October 6th 2005 in the population-based Medical Birth Registry of Norway (MBRN). We included all singleton births and the rst child in multiple pregnancies leaving 365 107 pregnancies for analyses. The study population was divided into pregnancies in women who gave a past or present history of epilepsy (henceforth designated as women with epilepsy), n = 2805 (0.8%) and those who did not, n = 362 302 (reference group). The MBRN is based on the compulsory notication of all births in Norway after 12 weeks of gestation, including abortions induced on medical indications.17 Complete ascertainment of the births is ensured through linkage with the National Population Registry run by Statistics Norway. Miscarriages and stillbirths before week 21 were included in our study. In Norway, more than 99% of pregnant women receive antenatal care, mainly provided by general practitioners.18 A standardised antenatal form is lled in for each pregnancy, starting at the rst antenatal visit, and brought to the obstetrical unit at delivery. These data are transferred to the MBRN notication form by the midwives attending the delivery.17 Furthermore, all data related to the delivery are recorded by the midwife and follow-up data are added until discharge.17 An unchanged MBRN notication form was used in the study period. The maternal epilepsy diagnosis is notied in a checkbox in the notication form, or by a code according to the International Classication of Diseases, 10th revision (ICD-10). Data on maternal education were obtained from Statistics Norway. Data on all other variables were obtained from the MBRN. The outcomes of interest in this study were mild or severe pre-eclampsia, gestational hypertension, eclampsia, preterm birth, premature rupture of membranes, placenta previa and early or late bleeding in pregnancy. The term all pre-eclampsia includes mild, severe or unspecied preeclampsia. Pre-eclampsia is reported to the MBRN as a specic diagnosis abstracted from the medical chart. Diagnostic criteria are: an increase in blood pressure to a value higher than 140/90 mmHg (one or both values exceeded) on two measurements taken at least 6 hours apart and after 20th week of gestation. Alternatively, either the diastolic blood pressure has to be at least 15 mmHg higher or the systolic blood pressure has to be at least 30 mmHg higher, compared with measures before the 20th week. Proteinuria (protein excretion at least 0.3 g per 24 hours, usually equivalent to 1+ on two different urine reagent strips), also had to be present.19 Mild pre-eclampsia is dened as systolic blood pressure in the range 140159 mmHg and diastolic blood pressure 90109 mmHg on two measurements taken 6 hours apart after 20th week of gestation, combined with proteinuria. Severe pre-eclampsia was

dened as blood pressure 160/110 and proteinuria of 0.5 g per 24 hours (or 2+ on two different strips).20 Preeclampsia diagnosed before 34th week of gestation is always included in the severe group, as are also pregnancies with a diagnosis of HELLP syndrome. A small proportion of preeclampsia cases were classied as unspecied (n = 601, 0.16% of the total population). Pregnancy-induced hypertension (dened as blood pressure 140/90 with no proteinuria on two measurements taken at least 6 hours apart after 20th week of gestation.); eclampsia (before, during and until 7 days after delivery); placenta previa; premature rupture of membranes (>24 hours before delivery) were notied either by checkboxes in the MBRN notication form or by an ICD-10 diagnosis. Any vaginal bleeding notied by the doctors during pregnancy (rst trimester, early i.e. 12 weeks; and third trimester, late, i.e. 28 weeks), and pregestational and gestational diabetes were notied by checkboxes in the MBRN notication form. Medication is notied according to the Anatomical Therapeutic Chemical (ATC)-Classication System, consisting of a ve-digit ATC-number. Pregnancies exposed to AED were identied by including all AEDs, as registered by a relevant ACT-number (yes/no). The most commonly used AEDs were carbamazepine (46%), lamotrigine (25%) and valproate (22%). AED was mainly used as monotherapy (86%).21 Socio-demographic data included maternal age (<24, 25 29, 3034, 35+ years); smoking during pregnancy (yes/no); parity (0, 1+) and highest attained maternal educational level (10 years, 1014 years, 15 years). Gestational age was calculated from the ultrasonographic measurements performed at 1819 weeks of gestation. In Norway, 97.8% of pregnant women are routinely examined with ultrasound before week 20.18 When ultrasound data were unavailable, gestational age was estimated on basis of the rst day of the last menstrual period. Gestational age was categorised as <34 weeks, 3436 weeks and 37 weeks. Supplement of folic acid and multivitamins (4 times/week) prior to pregnancy and during pregnancy was recorded by a checkbox in the MBRN form (yes/no).

Statistical analysis
Crude and adjusted odds ratios (OR) with 95% condence limits (CI) were calculated by multiple logistic regression in SPSS 15.0 for Windows (SPSS Inc., Chicago, IL, USA). Potential confounding variables analysed as categorical variables included in the multivariable regression models were maternal age at delivery, smoking during pregnancy, maternal educational level at delivery and diabetes. Diabetes was either gestational diabetes or diabetes type 1 or 2. Diabetes as a confounding variable was not included in the analysis of bleeding. Women with pre-pregnancy hypertension were excluded in the analysis of pre-eclampsia and

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gestational hypertension. Folic acid was evaluated as a potential confounder during analysis. Cross tabulated measures for small samples with expected cell-count <5, were analysed by Fishers Exact test and presented as unadjusted P-values with corresponding OR. Two-sided P-values <0.05 were considered statistically signicant. Interactions were evaluated in stratied analysis and with interaction terms in the logistic models.

Results
In our study population, 2805 pregnancies (0.8%) occurred in women with a current or past history of epilepsy. They were younger, had shorter pregnancies (Table 1) and lower education. Among women with past or present epilepsy, 24.7% with AED use and 28.1% without AED use had more than 14 years of education compared with 34.6% in the reference group (P < 0.001). Smoking was reported in pregnancy by 25.5% (n = 240) of women with epilepsy using AED and by 23.9% (n = 445) of those not using AED compared to 19.0% (n = 68 728) in the reference group (P < 0.001). Among pregnant women with epilepsy, 5.7% developed pre-eclampsia compared to 4.3% in the reference group, OR 1.3 (CI 1.11.6) (Table 2). For mild pre-eclampsia the frequencies were 3.6% versus 2.5%, respectively, OR 1.4 (1.21.7). There was no increased risk of placenta previa,

OR 0.7 (0.31.7), premature rupture of membranes, OR 1.1 (1.01.3) or eclampsia for pregnant women with epilepsy. About 33.6% (n = 942) of the women with epilepsy were exposed to AED. We repeated the analyses for pregnant women with epilepsy and AED use and women with epilepsy and no AED use, separately. The risks of both all preeclampsia and mild pre-eclampsia were signicantly increased in pregnant women with epilepsy using AED compared to the reference group, OR 1.5 (1.21.2.0) and 1.7 (1.22.3) respectively (Table 3). Pregnant women with epilepsy using AED also had increased risks of gestational hypertension, OR 1.5 (1.02.2), vaginal bleeding late in pregnancy 1.9 (1.13.2) and delivery before week 34, OR 1.6 (1.22.1), when compared to the reference group. Pregnant women with epilepsy with AED use and pre-eclampsia or late vaginal bleeding did not deliver before week 34 more often than women in the reference group, OR 1.0 (0.52.2) and OR 1.2 (0.35.6) respectively. Among pregnant women with epilepsy not using AED, no increased risks were observed for any of the investigated complications. A borderline difference in pre-eclampsia rate was observed when comparing epilepsy women with and without AED, OR 1.4 (1.01.9). We investigated whether the effects varied by parity or gestational age. No statistically signicant interactions between these factors and occurrence of pre-eclampsia,

Table 1. Characteristics of the study population, Medical Birth Registry of Norway 19992005 Maternal characteristic Epilepsy all n = 2805 28.8 (5.2) P < 0.001* 42.2 (1185) ns 275 (19.4) P < 0.001* 3464 (723) P < 0.001* 4.0 (114) ns 4.0 (111) P < 0.001 (32) P < 0.001 18.8 (526) P < 0.001 43.6 (1223) P < 0.001 Epilepsy with AED n = 942 28.9 (5.2) P < 0.05* 43.4 (409) ns 274 (20.6) P < 0.001* 3435 (770) P < 0.001* 4.3 (41) ns 0.5 (5) ns 0.7 (7) ns 31.6 (298) P < 0.001 66 (622) P < 0.001 Epilepsy without AED n = 1863 28.8(5.2) P < 0.001* 41.7 (776) ns 276 (18.7) P < 0.05* 3479 (698) P < 0.01* 3.8 (73) ns 5.7 (106) P < 0.001 1.3 (25) P < 0.001 12.2 (228) P < 0.001 32.3 (601) P < 0.001 No epilepsy (reference) n = 362 302 29.3 (5.0) 40.7 (147 310) 277 (17.2) 3520 (668) 3.9 (14 270) 0.5 (1825) 0.6 (2197) 9.6 (34 794) 28.5 (103 380)

Age in years, mean (SD) Nulliparous % (n) Length of pregnancy in days Weight of baby in grams Multiple pregnancies % (n) Chronic hypertension % (n) Diabetes type 1 and 2% (n) Periconsep. folat use % (n) Folat use in preg. % (n)

Mean and standard deviation given for age, length of pregnancy and weight of baby. *Independent samples t tests. ns, non signicant.

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Complications during pregnancy in women with epilepsy

Table 2. Pregnancy outcomes in epileptic women compared with women with no epilepsy. Crude and adjusted measurements. Medical Birth Registry of Norway 19992005 Outcomes No epilepsy % (n ) Pre-eclampsia All Mild Severe Gestational hypertension Vaginal bleeding Early 12 weeks Late 28 weeks Gestational age <34 weeks 3436 weeks Epilepsy % (n ) OR (95% CI) P OR* (95% CI) P*

4.3 2.5 1.6 1.9

(15 568) (9152) (5823) (6795)

5.7 3.6 2.0 2.2

(153) (96) (53) (58)

1.3 1.4 1.2 1.2

(1.11.6) (1.21.7) (0.91.6) (0.91.5)

0.001 0.001 0.149 0.309 0.314 0.171 0.025 0.069

1.3 1.4 1.2 1.2

(1.11.5) (1.11.7) (0.91.6) (0.91.5)

0.001 0.002 0.175 0.262 0.281 0.206 0.039 0.165

2.1 (7439) 0.8 (2794) 3.2 (11 733) 4.8 (17 229)

1.8 (50) 1.0 (28) 4.0 (112) 5.5 (154)

0.9 (0.71.2) 1.3 (0.91.9) 1.2 (1.01.5) 1.2 (1.01.4)

0.9 (0.71.1) 1.3 (0.91.9) 1.2 (1.01.5) 1.1 (1.01.3)

*Adjusted for maternal age, smoking, maternal education and diabetes except for vaginal bleeding where diabetes is excluded. OR, odds ratio; CI, condence interval.

Table 3. Pregnancy outcomes in epileptic women without and with AED, compared with women with no epilepsy Outcomes Epilepsy, no AED % ( n) Pre-eclampsia All Mild Severe Gestational hypertension Vaginal bleeding Early 12 weeks Late 28 weeks Gestational age <34 weeks 3436 weeks OR* (95% CI) Epilepsy AED % (n) OR* (95% CI) No epilepsy % (n)

5.2 3.2 2.0 1.8

(92) (56) (35) (32)

1.2 1.2 1.2 1.0

(1.01.5) (0.91.6) (0.91.7) (0.71.4)

6.5 4.3 1.9 2.8

(61) (40) (18) (26)

1.5 1.7 1.2 1.5

(1.22.0) (1.22.3) (0.81.9) (1.02.2)

4.3 2.5 1.6 1.9

(15 559) (9147) (5819) (6792)

1.5 (28) 0.8 (14) 3.5 (66) 5.3 (99)

0.7 (0.51.1) 1.0 (0.61.6) 1.1 (0.91.4) 1.1 (0.91.3)

2.3 (22) 1.5 (14) 4.9 (46) 5.8 (55)

1.1 (0.71.7) 1.9 (1.13.2) 1.6 (1.22.1) 1.2 (0.91.6)

2.1 (7432) 0.8 (2791) 3.2 (11 726) 4.8 (17 214)

*Adjusted for maternal age, smoking, maternal education and diabetes except for vaginal bleeding where diabetes is excluded. OR, odds ratio; CI, condence interval.

eclampsia or vaginal bleeding were found in the group with epilepsy. A statistically signicant interaction occurred between parity and gestational hypertension, OR 1.8 (1.0 3.0) for nulliparous and OR 0.6 (0.31.0) for parous, P for interaction 0.034. An interaction also occurred between AED use and parity (nonusers as reference) with respect to gestational hypertension; OR 2.4 (1.05.4) for nulliparous and OR 0.4 (0.21.0) for parous women, P for interaction 0.043. As crude and adjusted measures were nearly similar, only the adjusted values are reported. Excluding multiple pregnancies (4.0% in women with epilepsy and 3.9% in the reference group), or miscarriages and abortions below 21 weeks of gestation (0.5% in women with epilepsy and 0.3% in the reference group), did not inuence the results

(data not shown). Only one (0.04%) of the pregnancies among women with epilepsy was induced due to congenital malformations below 21 weeks of gestation, compared with 110 (0.03%) in the reference group. Folic acid use was evaluated as a potential confounder and had no impact on any of the results above.

Discussion
Principal ndings and interpretation
This study showed that in general, pregnant women with a past or present history of epilepsy had a satisfactory antenatal course with few complications compared with the general obstetric population. Pregnant women with epilepsy

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using AED had a 1.5-fold increased risk of mild preeclampsia, a nearly two-fold increased risk of late vaginal bleeding, a 1.5-fold increased risk of gestational hypertension and delivery before week 34. Pregnant women with epilepsy without use of AED had no increased risk of any of the complications studied. Our cohort data were based on the mandatory reporting to a population-based registry over a 6-year period. The cohort design, comprising the whole population, excludes the possibility of selection bias. The large study size provides high precision and the standardised collection of data provides high validity in the estimates of effect. Reported maternal epilepsy in 0.8% of pregnancies indicates high diagnostic sensitivity, the prevalence in other epidemiologic studies being 0.50.7.1,2 Earlier reports on MBRN data have demonstrated high diagnostic validity regarding maternal disease and outcome.22,23 As a large proportion of the epilepsy group was untreated, potential under-reporting of AED-treatment is a concern and any misclassication may lead to underestimating of the risks. However, information on both epilepsy and use of drugs is compulsory in the MBRN and the drug registration is made at the rst visit in pregnancy. Recall bias is therefore avoided. A new study from Norway also conrms our ndings of AED use in 0.3% of women during pregnancy.24 The large proportion with untreated epilepsy may reect that pregnancy is often planned in a phase where AED is not regarded as necessary, and also that some women with more severe epilepsy may avoid pregnancy. Patients on AED may differ from untreated patients according to the type or aetiology of the epilepsy or in terms of seizure characteristics. In the MBRN, neither the type of epilepsy nor occurrence of epileptic seizures during pregnancy is notied. Our study had the opportunity to subdivide hypertensive disorders into gestational hypertension, mild and severe preeclampsia. We found that women with epilepsy had an increased risk of mild pre-eclampsia but not so for severe pre-eclampsia. In previous studies where women with epilepsy with and without AED were combined, no pre-eclampsia increase in women with epilepsy was observed.1,4,14 However, one of these studies observed an increased risk for gestational hypertension.1 These studies report risks in hospital-based populations and have methodological limitations due to recruitment bias and small sample sizes. In our study, we cannot totally exclude potential confounding by other risk factors for pre-eclampsia, such as obesity.25 In a registerbased study from Sweden,16 only AED-using women were included, and an increased risk of pre-eclampsia in such women was observed. This indicates that exposure to AED during pregnancy increases the risk for mild pre-eclampsia. A recent study shows that carbamazepine in particular was associated with a higher risk for pre-eclampsia.21 Our data

give no clues to the underlying biological mechanisms, but we might speculate that AED have a primary effect on placenta. The incidence of pre-eclampsia is higher in nulliparous than in parous women.25 In our epilepsy cohort, we observed a two-fold increased risk of pre-eclampsia in nulliparous compared to parous women, the same as in the reference group. With respect to gestational hypertension, we found a stronger effect of epilepsy and of AED use in nulliparous than in parous women. Nulliparous with gestational hypertension have higher maternal and fetal morbidity when compared to normotensive nulliparas.26 Women with severe hypertension are at highest risk for adverse maternal or perinatal outcomes such as placental abruption, acute renal failure, induction of labour, low birth weight, preterm birth and admission to a neonatal unit.26 However, we found no increased risk of preterm birth in pre-eclamptic or hypertensive pregnancies among women with epilepsy. In the present study, a two-fold risk of late vaginal bleeding among women with epilepsy using AED was found. This is in contrast to recent studies where no increased risk was found, 1,4 but in accordance with a previous study from Norway.7 AED-induced folate deciency and alteration in the metabolism of vitamin K-dependent blood clotting factors have been suggested as possible causes of vaginal bleeding in late pregnancy.27 Neonatal bleeding disorders due to a deciency of vitamin K-dependent clotting factors have been reported with use of enzyme-inducing AED, and may be prevented by the use of prophylactic vitamin K supplements,28 recommended in Norway during the last 4 weeks of pregnancy,29 and received by 80% of the pregnant women with epilepsy treated with enzyme-inducing drugs.30 A lower use in the general population of pregnant women with epilepsy has been reported,31 and vitamin K use in our population with epilepsy was probably well below 80%, however, there is no information regarding vitamin K prescription in the MBRN. A recent study debates the use of vitamin K in late pregnancy for women taking enzyme-inducing AEDs,32 and the UK NICE guidelines now recommend 1 mg of vitamin K to the neonates at delivery, and does not recommend giving vitamin K to the women in pregnancy.33

Conclusions and implications for clinicians

Our large cohort study has demonstrated that women with epilepsy have few complications during pregnancy. This may reect the satisfactory antenatal care in Norway, including 99% of the obstetric population.18 We have found that women with epilepsy not using AED have no increased risk of pre-eclampsia, hypertension or preterm labour. In contrast, women with epilepsy using AED have an increased risk of mild pre-eclampsia, gestational hypertension and delivery

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Complications during pregnancy in women with epilepsy

before week 34 as well as late vaginal bleeding. Special attention should be paid to nulliparous with epilepsy and AED use during pregnancy, as their risk for gestational hypertension is increased more than two-fold. Future studies that evaluate perinatal outcome in women with epilepsy with hypertensive disorders of pregnancy should focus on those with hypertension with and without proteinuria and their use of specic medication. Careful documentation of seizures, type of epilepsy and environmental factors will contribute to an even better knowledge on the course of pregnancy in women with epilepsy.

Disclosure of interest
I hereby declare on behalf of all authors that there are no conicts of interest as mentioned in the author guidelines.

Contribution to authorship
IB conceived and designed the study, analysed and interpreted the data and drafted the article. She is the guarantor. MGE designed the study, interpreted the data and revised the article. AKD and NEG conceived and designed the study, interpreted the data and revised the article. GV interpreted the data and revised the article. All authors approved the nal version.

Details of ethics approval

Research on anonymous registry data are routinely exempted from ethical review and informed consent requirements by the ethics research committees in Norway. This study was considered exempt by The Norwegian Institute of Public Health institutional review board.

Funding
This study was supported by the Norwegian Research Council through the NevroNor research programme.

Acknowledgements
None. j

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