Malformation in index pregnancy in womenwith epilepsy is

not followed by recurrence in subsequent pregnancyShehanaaz Begum, Sankara P. Sarma, and Sanjeev V. Thomas

Epilepsia, 54(12):e163–e167, 2013doi: 10.1111/epi.12411

S. Begum is a SeniorResearch Fellow inKerala Registry ofEpilepsy andPregnancy,Department ofNeurology.

SUMMARY

Use of antiepileptic drugs (AEDs) in pregnant women with epilepsy (WWE) is associ-

ated with an increased risk of major congenital malformations (MCM). Previous stud-

ies have suggested that WWE who had a malformation in their index pregnancy were

at an increased risk of recurrence in future pregnancies.We aimed to assess the risk of

recurrence of MCM in 1,616 WWE from Kerala Registry of Epilepsy and Pregnancy.

The pregnancy outcome of women (n = 246) with two prospective pregnancies in the

registry were analyzed. They had partial seizures with or without generalization

(57.3%) or generalized seizures (42.7%). Polytherapy was used in 26.4% (index preg-

nancy) and 23.6% (follow-up pregnancy). The mean dosage of AED for valproate was

498 mg/day and carbamazepine was 555 mg/day. The malformation rate in the index

pregnancy was 8.5% (21/246) and in the follow-up pregnancy was 8.9% (22/246) with

only one recurrence. There was no increased risk of MCM in follow-up pregnancy for

those who had MCM in the index pregnancy (p = 0.70; OR 0.49; 95% CI 0.06–3.80). Theuse of any specific drug, continuation of the same drug or a change in drug therapy

between two pregnancies did not alter the recurrence risk.

KEYWORDS: Womenwith epilepsy, Antiepileptic drugs, Teratogenesis, Recurrence,

Major congenital malformations.

The use of antiepileptic drugs (AEDs) is associated withrisk of major congenital malformation (MCM) of about 5–9% in comparison to a background risk of 1–3% (Meadoret al., 2008; Tomson et al., 2011). There is inadequate dataon risk of recurrence of malformations to provide evidencebased counseling to women with epilepsy (WWE) who areconsidering a second pregnancy. Data from the UnitedKingdom Epilepsy and Pregnancy Register (UKEPR) andthe Australian Pregnancy Register (APR) indicate that therisk of malformation recurrence in subsequent pregnancy isincreased if the index pregnancy had a malformation(Campbell et al., 2013; Vajda et al., 2013). There is little

prospective data on the recurrence risk from other parts ofthe world. We aimed to estimate the risk of recurrence ofMCM in follow-up pregnancy for the index pregnancies thathad MCM from the data from the registry in Kerala, India.

Materials and MethodsKerala Registry of Epilepsy and Pregnancy (KREP) is

prospectively following up WWE from preconception per-iod, through pregnancy and delivery until their children are12 years of age. The main objective is to estimate the MCMrisk in this cohort. We ascertain malformation status antenatally (detailed anomaly scan and serum alpha feto proteinestimation) and postnatally (clinical examination at birth,echocardiography and abdomen ultrasonography at3 months of age followed by further verifications up to1 year of age) (Beghi & Annegers, 2001; Thomas et al.,2001; Tomson et al., 2011) We had 2,140 registrationsbetween April 1998 andMarch 2013.

In this study, we considered all WWE who had two ormore pregnancies registered in KREP. For each woman wedefined index pregnancy as the first pregnancy in the

Accepted September 10, 2013; Early View publication October 18,2013.

Kerala Registry of Epilepsy and Pregnancy, Sree Chitra Tirunal Institutefor Medical Sciences and Technology, Trivandrum, Kerala State, India

Address correspondence to Sanjeev V. Thomas, Professor of Neurology,Department of Neurology, Sree Chitra Tirunal Institute for Medical Sci-ences and Technology, Trivandrum 695011, India. E-mail: sanjeev.v.thomas@gmail.com

Wiley Periodicals, Inc.© 2013 International League Against Epilepsy

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BRIEFCOMMUNICATION

registry and follow-up pregnancy as the next pregnancy forwhich she was registered again. Pre index pregnancies, ifany were not included. All live births and terminations afteranomaly scans (irrespective of malformation status) wereincluded. Pregnancy loss (abortions, intrauterine deathsor stillbirths) without anomaly scans were excluded. Allcases where major malformations were detected on antena-tal ultrasonography (in the case of abortions or medicalterminations), neonatal physical examination, and echocar-diography or abdomen ultrasonography at 3 months of agewere included as positive cases. Malformation rate is thenumber of positive cases expressed as a percentage of thetotal number of pregnancies where malformation status wasascertained.

The prescribed daily dose was recorded from the clinicalrecords and compliance was ascertained through the dailymedication- seizure – pregnancy calendar maintained by thepatient. No drug levels were monitored. The highest dailydose any time in a month is taken as the representative dailydose for that month. The mean of the daily dose for themonths of pregnancy is recorded as the mean daily dose forthat pregnancy.

A MCM is defined as an abnormality that can interferewith the quality of life and warrants definite management.Asymptomatic cardiac malformations detected by echocar-diography were rigorously defined as: atrial septal defect: adefect >5 mm size in the interatrial septum confirmed byDoppler echo at 3 months of age, patent ductus arteriosus:Persistent flow across the ductus at 3 months of age. Anydefects in the ventricular septum or other complex malfor-mations such as tetralogy of Fallot were included as MCMs.We excluded fromMCM all patent foramen ovale (defect ininteratrial septum <5 mm) and trivial valvular regurgitationor stenosis (detected only on Doppler echo and not demand-ing medical attention). Minor asymptomatic and unex-plained dilatations of the pelvi-ureteric system of thekidneys detected only on ultrasonography were alsoexcluded. Congenital malformation rates were further ana-lyzed with respect to individual AED exposure and monoand polytherapy. Statistical significance of differences wereascertained by Fisher’s exact t-test, McNemar test orchi-square test and odds ratios (ORs) with 95% confidenceintervals (CIs).

ResultsOf the 1,616 WWE who had pregnancies under KREP,

there were 634 repeat pregnancies. We excluded 142 preg-nancies without malformation screening: spontaneous abor-tions prior to malformation screening (61), incompletescreening for malformation (13), medical termination ofpregnancy prior to malformation screening (27), intrauter-ine deaths (9), stillbirths (4), lost to follow-up (4) or thirdpregnancy (24). Remaining 492 pregnancies in 246 womenwere included in this analysis. Their mean age (SD) at time

of index pregnancy was 24.1 (3.7) years. The mean intervalbetween two pregnancies was 1,233 � 693 days. The sei-zures were classified as generalized seizures in 105 (42.7%)and partial with or without generalization in 141 (57.3%).Four WWE had inter district change of residence betweentwo consecutive pregnancies. The AED usage and seizurecontrol in index and follow-up pregnancies of WWE aregiven in Table 1.

The overall control of convulsive seizures during preg-nancy was good (22% in index pregnancy and 15.4% in fol-low-up pregnancy); the proportion of women who weretotally seizure free was 45.9% in index pregnancy and63.8% in follow-up pregnancy (See Table 1). AED treat-ment was unchanged between pregnancies for 166 WWE(67.5%) while it was changed for 73 (29.7%) (See Table 2).The malformation rate in the index pregnancy was 21/246(8.5%; 95% CI 5.7–12.7) and in the follow-up pregnancywas 22/246 (8.9%; 95% CI 6.0–13.2). These rates werecomparable to that for the group who had only one preg-nancy in the registry (7.2%; 95% CI 5.9–8.8). MCM hadoccurred for 42 of the 246 women in index or follow-uppregnancy of which only one had MCM in both pregnan-cies. There was no increased risk of MCM in follow-uppregnancy for those who had MCM in the index pregnancy(See Table 2).

There were 166 women (67.5%) who had same treatmentin the index and follow-up pregnancy. AED treatment waschanged for 73 patients (29.7%). Seven women were offAEDs in both pregnancies. The risk of recurrence of MCMwas not different for those who had a change versus thosewho did not have a change in the AED therapy betweenindex and follow-up pregnancy. There was no difference inthe recurrence risk, for any given AED exposure.

There was no difference in the risk of malformationrecurrence between those exposed to valproate (VPA) andthose exposed to AEDs other than VPA in the index preg-nancy (See Table 2). Out of the 64 WWE on VPA in indexpregnancy, 16 stopped it before follow-up pregnancy.Among the 48 who were on VPA in index and follow-uppregnancy, MCM occurred in four index and six follow-uppregnancies but none of them were recurrence for the sameperson (See Table 2).

DiscussionThe background of a pregnancy registry had given us an

opportunity to prospectively estimate the risk of recurrenceof malformations in consecutive pregnancies for WWE. Wedid not observe any excess risk of MCM in follow-up preg-nancy if the index pregnancy had a MCM. In this study of492 pregnancies in 246 women, 43 pregnancies had MCM(42 women). Only one woman had recurrence of MCM inthe follow-up pregnancy. The MCM rates (8.5% in indexpregnancy and 8.9% in follow-up pregnancy) were compa-rable to the rate of MCM in other pregnancy registries

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S. Begum et al.

Table 2. Malformation (MCM) rate for the follow-up pregnancy according to themalformation status in the index

pregnancy andAED usage

Index pregnancy malformation status

Follow-up pregnancy

OR CI pMCM-Yes (%) MCM-No

All index pregnancies (246)

MCM-Yes (21) 1 20 0.49 0.06–3.80 0.703

MCM-No (225) 21 204

VPA used (64)

MCM – Yes (7) 0 7 0.90 0.819–0.978 1.000

MCM –No (57) 6 51

Other AEDs (182)

MCM – Yes (14) 1 13 0.79 0.10–6.42 1.000

MCM –No (168) 15 153

AED changed (73)

MCM – Yes (9) 0 9 0.89 0.82–0.97 0.300

MCM–No (64) 7 (10.9) 54

AED unchanged (166)

MCM-Yes (12) 1 11 0.91 0.11–7.57 0.930

MCM-No (154) 14 (9.1) 140

Valproate used in both pregnancies (48)

MCM-Yes (4) 0 4 0.86 0.77–0.97 1.000

MCM-No (44) 6 (13.6) 38

Table 1. Antiepileptic drug usage andmalformations in index and follow-up pregnancy

AED

Index pregnancy Follow-up pregnancy

N (%) Mean dosage (SD) mg/day

Proportion (%) with

seizures

N (%)

Mean dosage

(SD) mg/day

Proportion (%) with

seizures

Any seizure type GTCS Any seizure type GTCS

All cases 246 54.1 22 246 36.2 15.4

1 171 47.9 20.5 163 34.4 15.9

2 or more 65 78.4 29.2 58 56.9 20.7

No AED 10 0 0 25a 0 0

Phenobarbitone 54 83 (44) 59.3 27.7 47 81 (37) 51.1 19.1

Lamotrigine 6 185 (105) 66.7 50 9 170 (113) 44.4 22.2

Primidone 3 425 (153) 100 33.3 3 333 (288) 33.3 0

Clonazepam 7 1.2 (0.7) 71.4 28.5 5 1.3 (0.7) 60 40

Phenytoin 46 193 (98) 69.5 23.9 33 251 (84) 57.6 24.2

Clobazam 20 7.1 (6) 95 35 18 12 (6.7) 66.6 11.1

Carbamazepine 108 555 (280) 61 16.6 94 552 (308) 41.5 13.8

Valproate 64 498 (311) 42.1 31.3 66 472 (277) 25.8 15.2

Topiramate 0 2 75 (35) 100 0

Leviteracetam 1 1,500 100 100 4 1,208 25 0

Oxcarbazepine 5 897 (258) 80 40 5 1,023 (377) 80 80

Cardiacb 7 (33.3) 8 (36.4)

Nervous systemc 2 (9.5) 4 (18)d

Skeletale 5 (23.8) 0

Genito urinary 4 (19) 5 (22.7)

Gastro intestinal 1 (4.8) 4 (18)

Multiple system 2 (9.5) 1 (4.5)

aIncludes 7 who were off AEDs in the index pregnancy also.bCardiac: ASD, PDA, TOF.cNervous system: neural tube defect, hydrocephalus.eSkeletal: Polydactyly, Congenital Talipes Equino Varus.dOne case with NTD also had CTEV in follow-up pregnancy.

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(Campbell et al., 2013; Vajda et al., 2013). The use of anyspecific drug, continuation of the same drug or a change indrug therapy between two pregnancies did not alter therecurrence risk.

Our results differ from that from the registries in UnitedKingdom and Australia, where researchers had demon-strated an increased risk of recurrence of MCM in follow-uppregnancy, if the index pregnancy had MCM (Campbellet al., 2013; Vajda et al., 2013). All three studies had simi-lar proportion of repeat registrations (20–23%) within theregistry and the spectrum of malformations is comparable.The maternal age, seizure types and AED usage are compa-rable between these registries. There are differencesbetween these studies in terms of population (Caucasian vs.Asian), methodology (United Kingdom registry hadexcluded women with family history of malformations andpregnancy loss without malformations), selection criteria(Australian study had included retrospective cases also) andAED exposure (higher dosage and more of newer AEDs inUnited Kingdom and Australia).

The malformation risk for valproate was higher thanthat of other AEDs in this study, as observed elsewhere.Nevertheless, we did not observe any excess risk ofrecurrence of MCM associated with any AED exposureparticularly valproate. It is possible that the low recurrencerisk in our study is related to the low dosage of AEDexposure in contrast to the dosage in the other registries.The mean dosage of VPA monotherapy in the UnitedKingdom registry was 948.1 mg/day for the normal groupand 1,065 mg/day for the MCM group. The comparablevalues for carbamazepine were 632 and 682 mg/day in theUnited Kingdom registry. In the Australian registry, themean daily dose of VPA was 882 mg/day (first pregnancy)and 803 mg/day (second pregnancy) for the normal groupand 1,148 or 1,057 mg/day for the MCM group. The meandose in KREP for valproate was 474 mg/day (indexpregnancy), 452 mg/day (follow-up pregnancy) for normaloutcome and 693 mg/day (index pregnancy) 665 mg/day(follow-up pregnancy) for the MCM group. These expo-sures are in the range of 50% (for normal outcome) to 65%(for the MCM group) that of United Kingdom registry. Therisk of recurrence appears to be low in the setting of lowdose of AEDs. The teratogenic impact of AEDs had beenshown to be dose dependent (Tomson et al., 2011).Although the dosage of AEDs were on lower side in thisstudy, there was good control of convulsive seizures (15–22%). The control of seizures with valproate was superior toother AEDs although the dosage is rather low (Table 1)(Thomas et al., 2012). The overall seizure control duringpregnancy in this study is comparable to that reportedfrom EURAP Study Group (2006) and Australia (Vajdaet al., 2008). One should not directly extrapolate seizurecontrol during pregnancy to seizure control in non-preg-nant state as the treatment objectives and strategies inthese situations are not identical. It appears that the

recurrence risk for malformation is low when the AEDexposure is at low dosage. Another reason could be theethnic difference between populations as this study isexclusively on Asian Indians while the other two studiesare mostly on Caucasian population.

Birth defects in a population have a polygenic etiology.About 10% of MCM is attributed to environmental factorsand only <1% are related to chemicals, prescription drugsand high ionizing radiations (Brent, 2004). Population basedstudies from different geographical areas have pointedtowards a genetic basis for malformation recurrence (Stol-tenberg et al., 1999). Studies from Norway and Denmarkhave shown that malformation recurrence risk remainedlow, when women had moved to new geographical location(Lie et al., 1994) or when partners had changed (Christen-sen et al., 1995). Caution should be exercised while extrap-olating from large epidemiological studies to higher riskgroups such as WWE who constitute only 0.1–0.2% of thepopulation. There was little geographical movementbetween pregnancies in this study. The absence of increasedrisk in this study is unlikely to be due to geographicmovement or changes in partners. Drugs probably add to thepolygenic mechanism and induce malformations if the fetusis exposed to a suprathreshold dosage at a critical point inorganogenesis (Brent, 2004).

In this study, normal outcome in index pregnancy wasnot associated with reduced risk of MCM in follow-uppregnancy, even when the AEDs are same in bothpregnancies. In our series, 14 of the 154 (9.1%) who hadnormal index pregnancy outcome had MCM in follow-uppregnancy, even while the AEDs were unchanged. Simi-lar trends were observed with and without valproate (seeTable 2).

Our data suggests that the malformation recurrence riskmay be dose dependent and at low dose there may not beincreased risk of recurrence. We believe that there is anopportunity to try low dose of AEDs in well controlledwomen planning pregnancy. An occasional myoclonus ormild partial seizure may be more acceptable to some womenwho are considering pregnancy than the potential risk ofmajor malformation associated with standard doses of an-tiepileptic drugs. A limitation of this study is the rathersmall number of cases (n = 246) available to analyse theimpact of various antiepileptic drugs on malformationrecurrence. The comparable numbers for the United King-dom registry and Australian registries were 646 and 228respectively. The outcome of 1,006 follow-up pregnancies(503 with malformation in index pregnancy and 503 withoutmalformation in index pregnancy) need to be ascertained inorder to achieve a power (1 – beta) of 80%. Hence great cau-tion should be applied while interpreting these data particu-larly with AED specific risk of recurrence of MCM. Thepopulation genetic contribution and socioeconomic andenvironmental factors also need to be addressed in futurestudies.

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DisclosureNone of the authors have any conflicts of interest to disclose. We

confirm that we have read the Journal’s position on issues involved inethical publication and affirm that this report is consistent with thoseguidelines.

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