DR KIM CHRISTIAN DANIELSSON (Orcid ID : 0000-0003-1090-0590)

Accepted Article
Article type : Original Research Article

The effect of parity on risk of complications in women with epilepsy: a

population based cohort study

Running headline : The effect of parity in women with epilepsy

Kim C. Danielsson 1 ,2 , Ingrid Borthen 2 , Nils Erik Gilhus 2 , 3 & Nils-Halvdan Morken 1 ,4

1
Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, 2Department of
Clinical Medicine, University of Bergen, Bergen, 3Department of Neurology, Haukeland University
Hospital, 4Department of Clinical Science, University of Bergen, Bergen, Norway.

Corresponding author:

Kim Christian Danielsson

Department of Obstetrics and Gynecology, Haukeland University Hospital, 5021 Bergen, Norway

E-mail: kim.christian.danielsson@helse-bergen.no

Disclosure of interests:

None of the authors have any conflict of interest to disclose.

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/aogs.13360

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 Abstract

Introduction: Women with epilepsy have increased risk of complications in pregnancy with
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consequences for the mother and child. There are no studies on the influence of parity on
complications in women with epilepsy.

Material and methods: This was a population-based cohort study of all first and second births in the
Medical Birth Registry of Norway 1999-2013. Risks were estimated, and complication rates
compared in distinct women with epilepsy treatment categories. Outcomes were any hypertensive
disorder, bleeding in pregnancy, induction of labour, cesarean section, postpartum hemorrhage and
preterm birth.

Results: We examined 361 588 women, of whom 211 248 had a second birth and 1074 (0.5 %) of
these had a diagnosis of epilepsy in both births. Of these, 406 used antiepileptic drugs in both
pregnancies with, lamotrigine (N=118), carbamazepine (N=83), valproate (N=44), and levetiracetam
(N=27) being the four most common monotherapies. In the second birth, only risk of elective
cesarean section (adjusted OR = 1.7, 95% CI: 1.4 -2.0) and induction of labour (adjusted OR = 1.5,
95% CI: 1.2 -1.7) were increased in women with epilepsy compared to women without epilepsy.
There was a significant reduction in any hypertensive disorder, mild preeclampsia, emergency
cesarean section, postpartum hemorrhage (>500ml), and preterm birth from first to second birth in
women with epilepsy, and also a significant increase in elective cesarean section.

Conclusions: Second births in women with epilepsy do not represent an increased risk of non-
iatrogenic complications, independent of antiepileptic drug use. There is a significant reduction in
complications from first to second births in women with epilepsy.

Keywords

Pregnancy; Epilepsy; Antiepileptic drugs; Complications; Recurrence; Subsequent pregnancy.

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 Abbreviations:

WWE: women with epilepsy

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AED: antiepileptic drugs

MBRN: Medical Birth Registry of Norway

NorPD: The Norwegian Prescription Database

BMI: body mass index

Key message

Parity has a significant effect on risks of pregnancy and obstetric complications in women with
epilepsy. Only the iatrogenic interventions elective cesarean section and induction of labour was
increased in second births in a non-selected national cohort of women with epilepsy. Women with
epilepsy follow a similar pattern as women without epilepsy with a reduced risk of pregnancy and
obstetric complications from first to second birth.

Introduction

Epilepsy is the most common neurologic disorder requiring continuous drug treatment during
pregnancy, and 30 - 70% of pregnant women with epilepsy (WWE) use antiepileptic drugs (AEDs).(1-4)
WWE, and WWE with AEDs in particular, have previously been described as high risk parturients
with an increased rate of obstetric complications such as; bleeding in pregnancy, hypertensive
pregnancy disorders, induction of labour, cesarean section, postpartum hemorrhage and preterm
delivery.(5-9) Guidelines and review articles have highlighted focused management and individual
assessment for WWE in pregnancy to improve maternal morbidity and mortality.(7, 10-12)
Complications in WWE imply possible consequences for the mother and her child and may affect
reproductive intentions for some women.(13, 14) Pregnancy and obstetric complications increase risks
for recurrence next time, and also affect risks for new complications in later pregnancies.(13-18) Thus,
subsequent pregnancies in the same woman are not independent events, and results from previous
cross-sectional studies not taking this into account should be interpreted with caution.

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 Only two previous studies have examined first pregnancies separately for hypertensive
complications in WWE.(2, 19) None have examined outcomes in second pregnancies, compared
subsequent pregnancies, or assessed recurrence risks. Both the epilepsy and the use of AEDs are
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often persistent risk factors possibly influencing complications in later pregnancies and recurrence
rates. Any difference in risk change from the first to the second pregnancy in WWE compared to
women without epilepsy could elucidate mechanisms for complications in WWE, as recurrence risks
can be used to explore etiological factors.(20)

Studies have focused on consequences of epilepsy and maternal AED use during pregnancy for fetal
malformations and child development.(21-24) In contrast, potential effects of epilepsy and specific
AEDs on pregnancy have been much less studied. Optimal therapy in epilepsy represents a balance
between seizure suppression and AED side-effects. For women in fertile age, potential AED effects
for the fetus as well as on the pregnancy should be of the highest relevance. It is necessary to
estimate the specific effect of parity on complications in WWE with and without AEDs in order to
give WWE optimal treatment and advice in preconceptional counselling.

Our aim was to estimate risks in first and second pregnancy and birth, and to estimate the effect of
parity on changes in risks and recurrence rates for hypertensive pregnancy disorders, bleeding in
pregnancy, induction of labour, cesarean section, postpartum hemorrhage and preterm delivery in
WWE. The effect of AEDs in monotherapy was defined, and WWE were compared to women
without epilepsy.

Material and methods

We used population-based data from the Medical Birth Registry of Norway (MBRN) during 1999-
2013. A unique social security number given to all citizens in Norway enables linkage of data from
various national data sources and all births to the same mother (sibship data). Linked data from the
National Population Database ensures notification of all births and deaths in the country. Reporting
to the MBRN is compulsory and data are prospectively registered throughout pregnancy, delivery
and postpartum period on an unchanged form since 1999. All data are forwarded to the MBRN by
the attending midwife or obstetrician. Data includes maternal and paternal social factors, maternal

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 health prior to and during pregnancy, complications and interventions during pregnancy and birth,
perinatal outcome, and complications in children.
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First and second births were analyzed. Women with their first birth before the study period were
excluded, as were birth orders higher than second. Women with missing social security number (0.9
%) were excluded. All births ≥22 weeks of gestation (singleton and multiple) were included.

The Norwegian Prescription Database (NorPD, commenced in 2004) provided detailed data on all
medications dispensed from pharmacies by prescription. Mandatory registration in NorPD of every
dispensed medical prescription is made by a pharmacist. Statistics Norway provided data on
maternal level of education.

Exposure variables were a diagnosis of epilepsy at both births and the use of AEDs in both
pregnancies. Maternal epilepsy was registered in a specific checkbox or by adding written text in a
blank space available at the MBRN form. Information on type of epilepsy or seizure activity was not
available. The epilepsy diagnosis in MBRN has previously been found to be valid in 92.3 % of cases.(3)
Information on AED use in pregnancy (identified by ATC classification) was recorded as written text
with no information on dose or therapeutic changes over time. We analyzed total AED use and the
four most common AEDs in monotherapy, this to obtain both homogenous and large enough groups.
Monotherapy was defined as using the same single AED in the first and second pregnancy. Linkage
to NorPD enabled validation of the AED registration in the MBRN, (data available 2004 - 2012).

Main outcomes in the first and second births were; a compound variable of any hypertensive
disorder in pregnancy, mild- and severe preeclampsia, bleeding in pregnancy, induction of labour at
term, emergency and elective cesarean section, postpartum hemorrhage (>500ml and >1500ml),
and spontaneous preterm birth. Spontaneous preterm birth, < 37 weeks, (induction of labour and
preterm elective cesarean sections were excluded from analyses) was calculated from ultrasound
assessment of due date or last menstrual period (ultrasound dates were missing in 4251 women, 2.0
% of births). The compound variable of any hypertensive disorder included occurrence of gestational
hypertension, mild preeclampsia (blood pressure ≥140/90 mmHg combined with proteinuria ≥ 0,3g
per 24 hours) or severe preeclampsia (blood pressure ≥160/110mmHg, protein excretion ≥3 g per 24

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 hours or oliguria, clinical symptoms of preeclampsia, early onset preeclampsia, eclampsia, or HELLP
syndrome [hemolysis, elevated liver enzymes, low platelets]). Complications were registered in
checkboxes in the MBRN. Bleeding in pregnancy included any vaginal bleeding throughout
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pregnancy reported by health workers in the primary care or in hospital. Induction of labour
included induction at term (37-41 weeks), regardless of method. Cesarean section was reported as
an elective or emergency procedure. Bleeding during delivery and within the next 24 hours after
delivery (postpartum hemorrhage) was reported as > 500ml and >1500ml. Other epilepsy core
outcomes suggested by The CROWN initiative were either not properly addressed in the MBRN or
severely underpowered for inclusion in our study.(9)

Other variables were: maternal age (≤19 years, 20-24 years, 25-29 years, 30-34 years, 35-39 years
and ≥40 years), maternal education (≤10 years, 11-13 years, ≥14 years), chronic disease (kidney
disease, hypertension, diabetes mellitus), multifetal pregnancies, high body mass index (BMI
≥30kg/m²), smoking during pregnancy, use of folic acid supplementation in standard dose
(0,4mg/day), inter-delivery interval (inter-delivery interval: > 6 years), augmented contractions in
labour, vaginal operative delivery (vacuum or forceps), and placenta previa. BMI was available from
2006 onwards. Data on ethnicity and marital status were not available due to ethical restrictions.

Statistical analyses

All WWE were compared to all women without epilepsy. Risk of the various outcomes in first and
second births were estimated by treatment category i.e. WWE with and without AED, and by the
four most common monotherapies. Changes in risks from first to second birth and recurrence rates
were estimated in treatment categories. The recurrence rates in WWE and women without epilepsy
were compared.

We estimated proportions and crude odds ratios (ORs) using contingency tables. P-values were
calculated by Fisher’s exact test and independent sample t-tests, where appropriate. We used
logistic regression to adjust for possible confounding by maternal age, educational level, multifetal
pregnancy, and chronic diseases (pre-existing hypertension, kidney disease, and diabetes mellitus)
for all outcomes. Furthermore adjustment by interdelivery-interval, induction of labour, placenta
previa, caesarean section, augmented contractions, operative vaginal delivery, and vaginal bleeding

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 in pregnancy was made where appropriate. In addition, the effect of parity was evaluated with
logistic regression interaction analyses. The covariates BMI (only registered since 2006) and smoking
were restrained by missing cases and therefore studied with stratification-based sensitivity analyses
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applied on all results and not included in the final logistic regression model. The impact of folic acid
supplementation was similarly analyzed further with stratification-based sensitivity analyses. All
analyses were performed with IBM SPSS (Statistical Package for Social Sciences) version 23.0 or later.

Ethical approval

The study was approved by the Regional Ethics Committee (REK 2013/186) and the Norwegian Data
Protection Authority.

Results

During the study period 361 588 women gave birth, of whom 211 248 had a second birth. There
were 1074 (0.5 %) women with registered epilepsy at both births. Maternal characteristics are
presented in Table 1. WWE had significantly longer inter-delivery interval, and significantly fewer
had the same partner in the second birth compared to women without epilepsy. A second
pregnancy was registered in 38.0 % of WWE compared to 58.6 % of women without epilepsy (p-
value < 0.005). 326 WWE used the same specified AED in monotherapy in both pregnancies, and the
four most common drugs were: lamotrigine (118 women), carbamazepine (83 women), valproate
(44 women), and levetiracetam (27 women). The use of AED, AED polytherapy and treatment
changes between the two births are reported in Table 2.

All first births were analyzed separately (see Supporting Information Table S1). We found increased
risks of any hypertensive disorder, mild preeclampsia, induction of labour, all and elective cesarean
section, bleeding in pregnancy, and preterm birth in WWE compared to women without epilepsy.
First births of WWE who had a subsequent birth were compared to those with only one birth in the
study period. WWE with only one birth had a significantly higher risk for preterm birth, but
otherwise there were no significant differences.

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 In the second birth there was no increased risk for WWE when compared to women without
epilepsy for the compound variable any hypertensive disorder, mild- or severe preeclampsia,
bleeding in pregnancy, emergency cesarean section, any postpartum hemorrhage, or preterm birth.
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The results were the same for all analyzed treatment categories of WWE; with and without AED, and
for the four AED monotherapies (Table 3 and Supporting Information Table S2). In the second birth
there was an increased risk of elective cesarean section (aOR = 1.7, 95% CI: 1.4-2.0) and induction of
labour (aOR = 1.5, 95% CI: 1.2-1.7) in WWE compared to women without epilepsy. The risk of
elective cesarean section was similarly increased in WWE with AED (aOR = 1.7, 95% CI: 1.3-2.3),
without AED (aOR = 1.6, 95% CI: 1.2-2.2), and in WWE with valproate (aOR = 2.8, 95% CI: 1.3-6.1).
WWE with lamotrigine or levetiracetam did not have any increased risks for cesarean section. Risk of
induction of labour was increased in WWE with AEDs (aOR = 1.8, 95% CI: 1.4-2.3), WWE with
lamotrigine (aOR = 1.9, 95% CI: 1.2-3.2), and WWE with levetiracetam (aOR = 4.8, 95% CI: 2.1-11.0).

Prevalence of outcomes in WWE changed from the first to the second birth similar to the changes
seen in women without epilepsy (Figure 1). When the first and second births of WWE were
compared within treatment categories, the reduction in risk was significant for any hypertensive
disorder, mild preeclampsia, emergency cesarean section, and postpartum hemorrhage (>500ml) in
total WWE, WWE with and WWE without AEDs (Table 4). For preterm birth and severe preeclampsia
the reduction was significant in WWE and WWE without AED. The risk of elective cesarean section
increased significantly from the first to the second birth in WWE, WWE with and without AED. All
changes in outcome risks from the first to the second birth were significant also in women without
epilepsy.

In WWE the recurrence rate of any hypertensive disorder was 21.4 %, whereas the prevalence of any
hypertensive disorder in the second birth without preceding occurrence was only 2.7 %. Thus the
risk of recurrence was highly significant (aOR = 10.3, 95% CI: 5.5-19.6) (Supporting Information Table
S3). Similarly, the recurrence rate of all complications, except postpartum hemorrhage and severe
preeclampsia, was significantly increased in WWE, WWE with and without AEDs. In women without
epilepsy, the risk of recurrence was also significantly increased for all outcomes. When the risk of
recurrent complications in WWE was compared with women without epilepsy, only induction of
labour and elective cesarean section was increased for WWE (Supporting Information Table S4).

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 All estimates for second births were robust in sensitivity analyses including smoking, BMI > 30kg/m2,
and folic acid supplementation. Interaction analyses of epilepsy and parity did not show any
significant interaction (results not shown). The analyses showed that parity had a higher impact than
Accepted Article
epilepsy as a predictor for all complications except preterm birth.

AED use as recorded in MBRN, was validated by a corresponding prescription in NorPD during the
pregnancy. The positive predictive values were: 91.7 % for all AEDs, 86.3 % for lamotrigine, 86.7 for
carbamazepine, 88.2 % for valproate and, 94.4 % for levetiracetam.

Discussion

WWE have in their second pregnancy and birth no increased risk of any hypertensive disorder, mild
or severe preeclampsia, vaginal bleeding in pregnancy, preterm birth, emergency cesarean section,
or postpartum hemorrhage compared to women without epilepsy. This was true for WWE in general
as well as for WWE on the most common AED monotherapies. This finding contrasts previous
studies, where increased pregnancy risks have been found for WWE.(5-8) Our study shows that the
increased risk occurs for the first, but not for the subsequent birth. This was confirmed by our
observation of a significant risk reduction from the first to the second birth in WWE. This risk
reduction in WWE showed a similar pattern as for women without epilepsy.

We found significant impact of parity on complications in WWE in two dimensions; when compared
to women without epilepsy and when comparing first to the second birth in WWE. The present study
shows increased risks of complications in the first birth in WWE in line with previous results.(5-8) In
the second birth, complications occurred with the same frequency as in WWE without AED and in
women without epilepsy. As WWE had a similar risk change as women without epilepsy from first to
second birth, non-epilepsy factors are important for risk development in WWE.

The risk of elective cesarean section and induction of labour in WWE both with and without AEDs
remained increased for the second birth, and the risk of recurrence was increased compared to
women without epilepsy. Elective cesarean section and induction of labour are both interventions
decided by physicians, with consent from the patient, with the aim to end the pregnancy before or

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 without natural labour. Epilepsy or AED use in itself should not be regarded as indications for neither
elective cesarean section nor induction of labour.(11, 25) Previously, the background for increased
cesarean section and induction of labour in WWE has been thought to be multifactorial and
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mediated by fetal conditions, maternal conditions, and the diagnosis of epilepsy.(4, 5) As there were
no increased complications in second pregnancies; and no change in use of AED, this was probably
not the reason for the increased elective cesarean section or induction of labour. Although most
WWE remain seizure free in pregnancy, the progressing pregnancy can result in increased physical or
mental stress.(26) Lowered seizure threshold or adverse outcomes are feared consequences in WWE.
The increased rates of elective cesarean section and induction of labour in the second birth most
likely represent preventive measures directly linked to the diagnosis of epilepsy, as convenience is
rarely an indication for elective cesarean section in Norway and trial of labour after previous
cesarean section is readily recommended and practiced accordingly.(11, 16) Events and indications for
delivery in first pregnancy have impact on mode of delivery in subsequent births.(13) This could
explain some of the increased risk of elective cesarean section seen in subsequent pregnancies both
in WWE and women without epilepsy.

This study represents a selected epilepsy population since the included women have given birth at
least two times, thereby possibly excluding those with severe complications and severe cases of
epilepsy in women who would choose not to repeat a pregnancy. Seizure frequency, lifestyle, or
socioeconomic status that encourages subsequent pregnancies in WWE is expected to affect risks
also in the second pregnancy. However, background data for WWE with subsequent births in this
study did not differ from the same nullipara population, with the exception of less obesity in women
who had a second birth. Major complications among WWE with only one birth did not differ from
WWE with subsequent pregnancies. Thus it is not likely that obstetric complications have been a
reason for ending reproduction in WWE. Seizure activity and adverse fetal outcomes can possibly
influence a choice of further reproduction in WWE. Our study was not able to examine such
associations.

Our large and unselected nationwide cohort enabled assessment of complications in first and second
birth separately, and risks associated with the most common AEDs in monotherapy. The sib-ship
structure of our data enabled us to account for the obvious dependence between two births from
the same woman. The standardized data collection provided information of high validity.(3) The study

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 population had a diagnosis of epilepsy with proven high validity in both the first and second birth.
The separate recordings confirm more definitely the epilepsy diagnosis, particularly relevant in WWE
without AEDs, and to a greater extent exclude women with non-epileptic seizures. Linkage to NorPD
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confirmed the high validity of AED registration in the MBRN.

The MBRN does not register seizure activity or type of epilepsy, this being a limitation of our study.
However, a previous study did not find any association between seizure activity and complications in
pregnancy.(3) WWE with specified AED monotherapy had low frequencies of most complications,
and therefore our study lacks strength for several variables despite our large cohort of pregnant
women. We lacked information on ethnicity and marital status which were not released due to
ethical considerations.

We found a significant reduction in risk of pregnancy and obstetric complications from first to
second pregnancy in WWE. Second pregnancies in WWE did not have any increased risk of
complications. Only the iatrogenic interventions, induction of labour and elective cesarean section
were increased in second births. These interventions also had an increased risk of recurrence in
WWE compared to women without epilepsy. This suggests that the epilepsy alone is not the reason
for the increase in complications seen in first pregnancies in WWE, as the epilepsy and AED
treatment remained unchanged from first to second pregnancy. The reduction of complications was
also seen in women without epilepsy. However, the reduction of complications in WWE was so
pronounced that there was no longer any difference between WWE and women without epilepsy at
the second pregnancy and birth. The reduction in obstetric complications, to the level seen in
women without epilepsy, is important and should be considered in all individual risk assessments,
and counselling, of WWE.

Acknowledgements

We are grateful for data provision and linkage that was performed by Medical Birth Registry of
Norway, Norwegian Prescription Database and Statistics Norway.

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 Funding

This research was kindly supported by the Fund of Torbjørg Hauge’s Legacy.
Accepted Article
References

1. Artama M, Gissler M, Malm H, Ritvanen A, Drug and Pregnancy Group. Effects of maternal
epilepsy and antiepileptic drug use during pregnancy on perinatal health in offspring: nationwide,
retrospective cohort study in Finland. Drug safety. 2013;36(5):359-69.

2. Borthen I, Eide MG, Veiby G, Daltveit AK, Gilhus NE. Complications during pregnancy in
women with epilepsy: population-based cohort study. BJOG. 2009;116(13):1736-42.

3. Borthen I, Eide MG, Daltveit AK, Gilhus NE. Obstetric outcome in women with epilepsy: a
hospital-based, retrospective study. BJOG. 2011;118(8):956-65.

4. Richmond JR, Krishnamoorthy P, Andermann E, Benjamin A. Epilepsy and pregnancy: an

obstetric perspective. Am J Obstet Gynecol. 2004;190(2):371-9.

5. Borthen I, Gilhus NE. Pregnancy complications in patients with epilepsy. Curr Opin Obstet
Gynecol. 2012;24(2):78-83.

6. Viale L, Allotey J, Cheong-See F, Arroyo-Manzano D, McCorry D, Bagary M, et al. Epilepsy in

pregnancy and reproductive outcomes: a systematic review and meta-analysis. Lancet. 2015.

7. MacDonald SC, Bateman BT, McElrath TF, Hernandez-Diaz S. Mortality and Morbidity During
Delivery Hospitalization Among Pregnant Women With Epilepsy in the United States. JAMA
neurology. 2015;72(9):981-8.

8. Kilic D, Pedersen H, Kjaersgaard MI, Parner ET, Vestergaard M, Sorensen MJ, et al. Birth
outcomes after prenatal exposure to antiepileptic drugs--a population-based study. Epilepsia.
2014;55(11):1714-21.

9. Al Wattar BH, Tamilselvan K, Khan R, Kelso A, Sinha A, Pirie AM, et al. Development of a core
outcome set for epilepsy in pregnancy (E-CORE): a national multi-stakeholder modified Delphi
consensus study. BJOG. 2017;124(4):661-7.

This article is protected by copyright. All rights reserved.

 10. Knight M, Nair M, Tuffnell D, Shakespeare J, Kenyon S, Kurinczuk J, J., et al. Saving Lives,
Improving Mothers’ Care - Lessons learned to inform maternity care from the UK and
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Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2013–15.: Oxford: National
Perinatal Epidemiology Unit, University of Oxford 2017.; 2017 [cited 2018 10.02.2018]. Available
from: https://www.npeu.ox.ac.uk/downloads/files/mbrrace-uk/reports/MBRRACE-
UK%20Maternal%20Report%202017%20-%20Web.pdf.

11. Forening NG. Veileder i fødselshjelp 2014. Available from:

http://legeforeningen.no/Fagmed/Norsk-gynekologisk-forening/Veiledere/Veileder-i-fodselshjelp-
2014/.

12. Harden C, Thomas SV, Tomson T (Editors). Epilepsy in Women. Somerset, NJ, USA: John
Wiley & Sons; 2013.

13. Hemminki E, Shelley J, Gissler M. Mode of delivery and problems in subsequent births: a
register-based study from Finland. Am J Obstet Gynecol. 2005;193(1):169-77.

14. Hernandez-Diaz S, Toh S, Cnattingius S. Risk of pre-eclampsia in first and subsequent

pregnancies: prospective cohort study. BMJ. 2009;338:b2255.

15. Ebbing C, Rasmussen S, Skjaerven R, Irgens LM. Risk factors for recurrence of hypertensive
disorders of pregnancy, a population-based cohort study. Acta Obstet Gynecol Scand.
2017;96(2):243-50.

16. Al-Zirqi I, Vangen S, Forsen L, Stray-Pedersen B. Effects of onset of labor and mode of
delivery on severe postpartum hemorrhage. Am J Obstet Gynecol. 2009;201(3):273 e1-9.

17. Laughon SK, Albert PS, Leishear K, Mendola P. The NICHD Consecutive Pregnancies Study:
recurrent preterm delivery by subtype. Am J Obstet Gynecol. 2014;210(2):131 e1-8.

18. Lykke JA, Paidas MJ, Langhoff-Roos J. Recurring complications in second pregnancy. Obstet
Gynecol. 2009;113(6):1217-24.

19. Danielsson K, Borthen I, Morken NH, Gilhus NE. Hypertensive pregnancy complications in
women with epilepsy and antiepileptic drugs: a population-based cohort study of first pregnancies in
Norway. BMJ Open. 2018;In press.

20. Wilcox AJ. The analysis of recurrence risk as an epidemiological tool. Paediatr Perinat
Epidemiol. 2007;21 Suppl 1:4-7.

This article is protected by copyright. All rights reserved.

 21. Weston J, Bromley R, Jackson CF, Adab N, Clayton-Smith J, Greenhalgh J, et al. Monotherapy
treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane
Database Syst Rev. 2016;11:CD010224.
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22. Bromley R, Weston J, Adab N, Greenhalgh J, Sanniti A, McKay AJ, et al. Treatment for
epilepsy in pregnancy: neurodevelopmental outcomes in the child. Cochrane Database Syst Rev.
2014(10):CD010236.

23. Gerard EE, Meador KJ. Managing Epilepsy in Women. Continuum. 2016;22(1 Epilepsy):204-
26.

24. Tomson T, Xue H, Battino D. Major congenital malformations in children of women with
epilepsy. Seizure. 2015;28:46-50.

25. RCOG. Epilepsy in Pregnancy (Green-top Guidlines No. 68) 2016 [cited 2017]. Available from:
https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg68/.

26. Battino D, Tomson T, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al. Seizure control and
treatment changes in pregnancy: observations from the EURAP epilepsy pregnancy registry.
Epilepsia. 2013;54(9):1621-7.

Supporting Information legends

Table S1. Complications in first birth of women with epilepsy women with epilepsy with and without
antiepileptic drugs (1999-2013).

Table S2. Complications in second births of women with epilepsy with specified antiepileptic drug
monotherapies compared to women without epilepsy.

Table S3. Recurrence in second births conditioned on the same complication in the first birth,
comparison of women with epilepsy with women without epilepsy.

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 Figure and table legends

Figure 1. Prevalence of complications in first and second birth for women with and without epilepsy.
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The figure shows prevalence (in percent) of complications in 361 588 first births and in 211 248
consecutive second births from the same women. Complications are defined in women with epilepsy
(WWE), WWE with and without antiepileptic drugs (AEDs), and women without epilepsy. Statistics
and comparisons in the first births, the second births, and changes from the first to the second births
are also shown in Supporting Information Table S1, Table 3, and Table 4 respectively.

Table 1. Characteristics for women with second births in Norway 1999-2013.

Table 2. Antiepileptic drug use in first and second birth of 1074 women with epilepsy, Medical Birth
Registry of Norway 1999-2013.

Table 3. Complications in second births of women with epilepsy (WWE) with and without
antiepileptic drugs (AEDs) compared to women without epilepsy.

Table 4. Change in prevalence from first to second birth in women with epilepsy (WWE) with and
without antiepileptic drugs (AEDs).

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 Table 1. Characteristics for women with second births in Norway 1999-2013

Women without Epilepsy Women with Epilepsy p-value

N= 212222 N=211148 N=1074 <0.005
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MATERNAL AGE
≤19 years 721 (0.3) 4 (0.4) 0.862
20-24 years 23959 (11.3) 146 (13.6) 0.021
25-29 years 71418 (33.8) 365 (34.0) 0.911
30-34 years 81613 (38.7) 370 (34.5) 0.005
35-39 years 29598 (14.0) 168 (15.6) 0.126
≥40 years 3839 (1.8) 21 (2.0) 0.737

INTERDELIVERY INTERVAL
Months 37.3 39.2 <0.005
>6 years 13485 (6.4) 79 (7.4) 0.195

EDUCATION
≤10 years 27474 (13.0) 202 (18.8) <0.005
11-13 years 144801 (68.6) 760 (70.8) 0.124
≥ 14 years 26015 (12.3) 69 (6.4) <0.005
Other or missing 12858 (6.1) 43 (4.0) <0.005

PLURALITY
Multifetal 3486 (1.7) 10 (0.9) 0.064

GESTATIONAL AGE
Weeks + days 39+5 39+4 0.025

BIRTH WEIGHT
Mean (gram) 3606 3577 0.085

2
BMI >30 kg/m
(from year 2006, N =148748) 7090 (12.9) 46 (13.2) 0.869
Missing data 92953 (62.8) 420 (54.6) <0.005

SMOKING
Yes 19586 (9.3) 148 (13.8) <0.005
Missing data 36758 (17.4) 165 (15.4) 0.078

CHRONIC DISEASE
(Kidney disease, DM, HT) 3280 (1.6) 30 (2.8) 0.001

FOLIC ACID
Before Pregnancy 54732 (25.9) 419 (39.0) <0.005
During Pregnancy 126236 (59.8) 793 (73.8) <0.005

SAME PARTNER
(First and second pregnancy) 192778 (91.3) 946 (88.1) <0.005

DM: Diabetes Mellitus HT: Hypertension

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 Table 2. Antiepileptic drug use in first and second birth of 1074 women with epilepsy, Medical Birth
Registry of Norway 1999-2013.

N % of WWE
Accepted Article
Without AEDs in both birthsa 470 43.8
Any AED in both birthsa 406 37.8
Discontinuing AEDs from first to second birtha 107 10.0
Any AED only in second birtha 91 8.4
Same AED monotherapy in both births 326 30.4
Lamotrigine monotherapy in both births 118 11.0
Carbamazepine monotherapy in both births 83 7.7
Valproate monotherapy in both births 44 4.1
Levetiracetam monotherapy in both births 27 2.5
Other AED monotherapies in both birthsb 54 5.0
Any AED polytherapy in both births 44 4.1
Change of AED treatment between births 36 3.4

WWE: Women with epilepsy

AED: Antiepileptic drugs

a
These four categories add up to the total epilepsy population
b
Other AED than lamotrigine, carbamazepine, valproate, or levetiracetam

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ccepted Articl
Table 3. Complications in second births of women with epilepsy (WWE) with and without antiepileptic drugs (AEDs) compared to women without epilepsy.

Women without
WWE WWE without AED WWE with AED
Epilepsy
N= 211 248 N=210 174 N=1074 N=470 N=406

N (% ± 2SE) N (% ± 2SE) aOR 95% CI N (% ± 2SE) aOR 95% CI N (% ± 2SE) aOR 95% CI

a
Any Hypertensive Disorder 7754 (3.7 ± 0.08) 47 (4.4 ± 1.24) 1.19 0.89-1.59 13 (2.8 ± 1.52) 0.74 0.43-1.29 19 (4.7 ± 2.10) 1.26 0.79-2.00

a
Mild Preeclampsia 3037 (1.4 ± 0.06) 22 (2.0 ± 0.86) 1.41 0.92-2.15 8 (1.7 ± 1.20) 1.17 0.58-2.34 9 (2.2 ± 1.46) 1.52 0.78-2.94

a
Severe Preeclampsia 1599 (0.8 ± 0.04) 9 (0.8 ± 0.56) 1.10 0.57-2.12 3 (0.6 ± 0.74) 0.83 0.27-2.60 5 (1.2 ± 1.10) 1.63 0.67-3.95

Induction of Labour 21378 (11.2 ± 0.14) 152 (15.8 ± 2.36) 1.46 1.22-1.73 49 (11.5 ± 3.08) 0.99 0.73-1.34 67 (18.6 ± 4.10) 1.79 1.37-2.33

b
Emergency Cesarean Section 13818 (6.6 ± 0.10) 77 (7.2 ± 1.48) 1.04 0.82-1.31 30 (6.4 ± 2.26) 0.93 0.64-1.35 37 (9.1 ± 2.86) 1.31 0.93-1.84

Elective Cesarean Section 14429 (6.9 ± 0.12) 120 (11.2 ± 1.92) 1.65 1.36-2.01 50 (10.6 ± 2.84) 1.60 1.19-2.15 49 (12.1 ± 3.24) 1.72 1.27-2.33

c
Bleeding in Pregnancy 9577 (4.6 ± 0.10) 50 (4.7 ± 1.28) 1.01 0.76-1.34 24 (5.1 ± 2.04) 1.12 0.74-1.69 20 (4.9 ± 2.16) 1.10 0.70-1.72

d
PPH > 500ml 27489 (13.1 ± 0.14) 155 (14.4 ± 2.14) 1.00 0.84-1.20 52 (11.1 ± 2.90) 0.76 0.57-1.03 66 (16.3 ± 2.66) 1.09 0.83-1.43

d
PPH > 1500ml 3268 (1.6 ± 0.06) 18 (1.7 ± 0.78) 0.98 0.62-1.57 7 (1.5 ± 1.12) 0.92 0.43-1.94 7 (1.7 ± 1.30) 0.95 0.45-2.02

e
Preterm Birth 7047 (4.2 ± 0.10) 34 (4.5 ± 1.50) 1.06 0.75-1.52 13 (3.6 ± 1.98) 0.87 0.50-1.53 14 (5.2 ± 2.70) 1.27 0.73-2.21

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ccepted Articl
aOR: Adjusted Odds Ratio

± 2SE: 2 x Standard Error, representing upper and lower limit of 95% confidence interval (CI)

PPH: Postpartum Hemorrhage.

All outcomes are adjusted for: Maternal age, Educational level, Multifetal pregnancy, and other relevant chronic disease
a
Also adjusted for: Long interdelivery interval.
b
Also adjusted for: Induction of Labour.
c
Also adjusted for: Placenta previa.
d
Also adjusted for: Induction of Labor, Cesarean Section, Augmented Contractions, and Operative Vaginal Delivery.
e
Also adjusted for: Vaginal Bleeding in Pregnancy.

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ccepted Articl
Table 4. Change in prevalence from first to second birth in women with epilepsy (WWE) with and without antiepileptic drugs (AEDs).

Women without epilepsy WWE WWE without AED WWE with AED
N = 358761/ N = 210174 N = 2827/ N = 1074 N = 1774/ N = 470 N = 1053/ N = 406

Prevalence aOR 95 % CI Prevalence aOR 95 % CI Prevalence aOR 95 % CI Prevalence aOR 95 % CI

Any Hypertensive 10.2% /

a 7.6% / 3.7% 0.47 0.45-0.58 9.4% / 4.4% 0.44 0.32-0.60 9.0% / 2.8% 0.29 0.16-0.51 0.43 0.26-0.72
Disorder 4.7%

a
Mild Preeclampsia 3.2% / 1.4% 0.45 0.43-0.46 4.6% / 2.0% 0.43 0.28-0.69 4.3% / 1.7% 0.38 0.18-0.80 5.0% / 2.2% 0.43 0.21-0.88

a
Severe Preeclampsia 2.1% / 0.8% 0.36 0.35-0.38 2.4% / 0.8% 0.34 0.17-0.69 2.6% / 0.6% 0.24 0.08-0.78 2.1% / 1.2% 0.58 0.22-1.55

14.0% / 17.2% / 14.6% / 21.5% /

Induction of labour 0.78 0.76-0.79 0.90 0.73-1.10 0.76 0.54-1.05 0.83 0.61-1.13
11.2% 15.8% 11.5% 18.6%

Emergency Cesarean 13.5% / 15.2% / 14.8% / 16.0% /

b 0.45 0.45-0.46 0.43 0.33-0.53 0.39 0.26-0.58 0.53 0.36-0.77
Section 6.6% 7.2% 6.4% 9.1%

7.4% / 7.0% / 8.1% /

Elective Cesarean Section 4.0% / 6.9% 1.79 1.75-1.83 1.57 1.24-1.99 1.57 1.11-2.22 1.56 1.08-2.27
11.2% 10.6% 12.1%

c
Bleeding in Pregnancy 4.7% / 4.6% 0.97 0.95-1.00 5.6% / 4.7% 0.82 0.59-1.13 5.9% / 5.1% 0.86 0.54-1.35 5.1% / 4.9% 0.96 0.57-1.62

d 17.0% / 17.5% / 16.4% / 19.4% /

PPH > 500ml 0.74 0.73-0.75 0.80 0.65-0.97 0.63 0.46-0.87 0.81 0.60-1.10
13.1% 14.4% 11.1% 16.3%

d
PPH > 1500ml 2.1% / 1.6% 0.74 0.71-0.77 2.4% / 1.7% 0.70 0.42-1.19 2.2% / 1.5% 0.67 0.30-1.51 2.7% / 1.7% 0.64 0.28-1.48

e
Preterm Birth 6.8% / 4.2% 0.61 0.59-0.62 8.7% / 4.5% 0.49 0.34-0.72 8.8% / 3.6% 0.39 0.22-0.70 8.4% / 5.2% 0.60 0.33-1.09

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ccepted Articl
All numbers and prevalences are given for the first/ second birth.

aOR: Adjusted Odds Ratio

PPH: Postpartum Hemorrhage

All outcomes are adjusted for: Maternal age, Educational level, Multifetal pregnancy, and other relevant chronic disease
a
Also adjusted for: Long interdelivery interval.
b
Also adjusted for: Induction of Labour.
c
Also adjusted for: Placenta previa.
d
Also adjusted for: Induction of Labor, Cesarean Section, Augmented Contractions, and Operative Vaginal Delivery.
e
Also adjusted for: Vaginal Bleeding in Pregnancy.

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 Any Hypertensive Disorder Mild Preeclampsia Severe Preeclampsia
12 6 3
10 5 2.5
8 4 2
6 3 1.5
Accepted Article
4 2 1
2 1 0.5
0 0 0
First Second First Second First Second

Elective Cesarean Section Emergency Cesarean Section Bleeding In Pregnancy

20 7
14
6
12 15 5
10
4
8 10
6 3
4 5 2
2 1
0 0 0
First Second First Second First Second

Postpartum Hemorrhage Induction of Labour Preterm Birth

25 25 10

20 20 8

15 15 6

10 10 4

5 5 2

0 0 0
First Second First Second First Second

Women without Epilepsy: WWE: WWE without AED: WWE with AED:

Figure 1. Prevalence of complications in first and second birth for women with and without epilepsy.
The figure shows prevalence (in percent) of complications in 361 588 first births and in 211 248 consecutive second births from the same women. Complications are
defined in women with epilepsy (WWE), WWE with and without antiepileptic drugs (AEDs), and women without epilepsy. Statistics and comparisons in the first births, the
second births, and changes from the first to the second births are also shown in Table S1, Table 3, and Table 4 respectively.

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