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Keywords:

  • Epilepsy;
  • Pregnancy;
  • Antiepileptic drugs;
  • Recurrence risk

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References

Purpose:  Use of antiepileptic drugs in pregnancy is associated with congenital malformations and developmental delay. Previous studies have suggested that women who have had one child with a congenital malformation are at increased risk of having other children with malformations. We sought to confirm the magnitude of risk in a large cohort drawn from the United Kingdom Epilepsy and Pregnancy Register.

Methods:  The United Kingdom Epilepsy and Pregnancy Register is a prospective, observational registration and follow-up study set up to determine the relative safety of antiepileptic drugs in pregnancy. We have extracted data for those women who prospectively registered more than one pregnancy and calculated the recurrence risks for fetal malformations.

Key Findings:  Outcome data were available for 1,534 pregnancies born to 719 mothers. For women whose first child had a congenital malformation there was a 16.8% risk of having another child with a congenital malformation, compared with 9.8% for women whose first child did not have a malformation (relative risk 1.73, 95% confidence interval [CI] 1.01–2.96). The risk for recurrence was 50% for women who had had two previous children with a congenital malformation. There was a trend toward a higher risk for recurrent malformations in pregnancies exposed to valproate (21.9%, relative risk 1.47, 95% CI 0.68–3.20) and topiramate (50%, relative risk 4.50, 95% CI 0.97–20.82), but not for other drugs such as carbamazepine and lamotrigine. Recurrence risks were also higher for pregnancies exposed to polytherapy regimens and for those where the dose of antiepileptic drug treatment had been increased after the first pregnancy.

Significance:  Women who have had a child with a malformation are at increased risk of having other children with malformations. This is in keeping with previous reports that have suggested that genetic influences may be one of the factors determining the teratogenic risk of antiepileptic drugs.

Exposure to antiepileptic drugs (AEDs) in pregnancy increases the risk of major congenital malformations (MCMs) from the background risk of 1–2% to 4–9% (Olafsson et al., 1998; Kaneko et al., 1999; Holmes et al., 2001; Morrow et al., 2006). Studies from several epilepsy pregnancy registers, including the United Kingdom Epilepsy and Pregnancy Register (UKEPR), have confirmed that this risk is highest for valproate (Morrow et al., 2006; Tomson et al. 2011; Hernández-Díaz et al. 2012). Preliminary results from the North American AED Pregnancy Registry (Hernández-Díaz et al., 2012) and the UKEPR (Hunt et al., 2008) have also raised concerns regarding the teratogenic potential of topiramate.

Previous studies have suggested that if a woman has had a child with a congenital malformation (CM) that her risk of having further children with malformations or developmental delay is significantly greater, at between 39% and 55% (Moore et al., 2000; Dean et al., 2002). It has been hypothesized that genetic influences are likely to be involved in contributing to the increased risk. The importance of specific genetic targets has also been investigated (Dean et al., 1999; Kini et al. 2007, Azzato et al., 2010). Prior studies have generally included small numbers of cases and need to be replicated in much larger cohorts.

Clarification of the risks for recurrence is important as this would enable women to be counseled more accurately. This is particularly relevant for women with genetic epilepsy syndromes, for whom valproate offers the highest chance of seizure freedom (Marson et al., 2007). Confirmation of an increased recurrence risk would support the hypothesis that underlying genetic mechanisms are likely to be involved in determining whether AED exposure in an individual pregnancy results in a CM.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References

The UKEPR is an observational, registration and follow-up study that was set up to determine the relative safety of all AEDs taken in pregnancy. In this report we focus on outcomes of women who had two or more pregnancies registered from December 1996 through to August 2011. Full methodological details have been published previously (Morrow et al., 2006).

Clinical data for all women with two or more registered pregnancies were reviewed. Only pregnancies for which the outcome was unknown at the time of registration and which resulted in a live birth or a pregnancy loss that had a CM were included for analysis. Women with a family history of MCMs were excluded from analysis. Abnormalities that were felt to be due to prematurity were not included.

The main outcome measure was the risk of CMs (MCM or minor congenital malformation [mCM]). The CM rate, rather than just the MCM rate, was reported so that our results could be compared with previous studies (Moore et al., 2000; Dean et al., 2002). The CM rate in pregnancies occurring after a first pregnancy that had resulted in a CM was compared for those where the first registered pregnancy had not had a CM.

The UKEPR does not routinely assess rates of neurodevelopmental delay; however, if developmental delay was reported by the mother or reporting physician, this has been included in analysis as a mCM. Although ascertainment of neurodevelopmental delay will be low in this study, it was also included so that our outcome measures might be compared with previous reports (Moore et al., 2000; Dean et al., 2002).

An MCM was defined as an abnormality of an essential embryonic structure requiring significant treatment and present at birth or discovered in the first 6 weeks of life. Disorders not conforming to this definition were assigned as mCMs based on the definitions and lists of disorders in the European Concerted Action on Congenital Anomalies and Twins (EUROCAT) registry (de Wals et al., 1984).

Congenital malformation rates were further analyzed by AED exposure into monotherapy and polytherapy groups and by individual AED. Twin concordance rates were also calculated.

Statistical analysis

Malformation rates were calculated as the [total number of live births with a malformation] + [total number of pregnancy losses with a malformation]/[total number of live births] + [total number of pregnancy losses with a malformation]. Analysis of variance (ANOVA), Kruskal-Wallis, and chi-square tests were used to compare characteristics between groups. Significance was determined at p < 0.05. Relative risks with 95% confidence intervals (95% CIs) were used to compare groups. CIs were calculated using the traditional method (Wilson, 1927). Twin concordance was calculated as [Number of both twins affected/(Number of one twin affected + Number of both twins affected)] × 100.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References

Through August 2011, from 6,955 prospectively registered pregnancies with complete outcome data we identified 719 women who had registered two or more live births, and who accounted for 1,534 pregnancies. Of these 1,371 involved singleton pregnancies and 163 twin or multiple pregnancies. Included in the analysis were 12 induced abortions that had been performed due to prenatally discovered CMs and two stillbirths with CMs in women who had reported more than one pregnancy. (See Fig. 1 for diagrammatic representation of CM and MCM recurrence risk figures). Characteristics for women with multiple registered pregnancies and those with single registrations are compared in Table 1.

image

Figure 1.   Diagrammatic representation of MCM and CM recurrence risk according to outcome of first pregnancy.

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Table 1.   Characteristics for women with multiple registered pregnancies compared to those with one registered pregnancy
 Multiple registered pregnancies (Total 1,534)Single registered pregnancy (Total 5,421)p-Value
  1. Bold indicates statistically significant values.

MCM rate (first registered pregnancy) (%)39/646 (6.0)178/5,421 (3.3) 0.0006
Monotherapy (%)1,126 (73.4)3,983 (73.5)0.98
Polytherapy (%)334 (21.8)994 (18.3) 0.003
No AEDs (%)74 (4.8)444 (8.2) <0.0001
Monotherapy AED exposures (%)    
 Valproate243 (21.6)864 (21.7)0.97
 Topiramate30 (2.7)68 (1.7)0.05
 Carbamazepine343 (30.5)1,220 (30.6)0.94
 Lamotrigine422 (37.5)1,383 (34.7)0.09
Parity (at first registered pregnancy) (%)   
 Primigravida72.545.6 <0.0001
 Para 116.827.0 <0.0001
 Para 26.513.1 <0.0001
 Para 3–5 3.710.3 <0.0001
 Para 6–100.01.4 0.0045
 Para >100.00.10.85
 Unknown0.52.5 0.0017
Preconceptual folic acid (%)729 (47.5)2,682 (49.5)0.19

The same AEDs in all pregnancies were being taken by 76.8%, 7.6% had one or more AEDs added to their drug regimens, 6.2% had a reduction in number of AEDs between pregnancies, and 9.4% changed AED between pregnancies; of these the most frequent changes were from valproate monotherapy (25%) or polytherapy (19.1%), from other AED polytherapy (22.1%), and from carbamazepine or lamotrigine monotherapy (22.1%). Group characteristics for singleton pregnancies by outcome are shown in Table 2.

Table 2.   Characteristics for singleton pregnancies
  Total (n = 1,371)Normal outcomes (n = 1,211)Abnormal outcomes (n = 160)p-Value
  1. GTCS, generalized tonic–clonic seizure; SD, standard deviation. Bold indicates statistically significant values.

Mean (SD) gestational age (weeks)39.0 (4.3)39.3 (4.0)38.7 (6.4) 0.02
M:F ratio of offspring1:11:11.4:1 0.05
Preconceptual folic acid consumption (%)53.753.158.20.26
GTCS in pregnancy (%)25.125.225.50.99
Monotherapy, % (total number)73.5 (1,007)74.2 (898)68.1 (109)0.11
Valproate, % (no. of exposures) [Mean dose]20.5 (206) [977.5 mg]18.6 (167) [948.1 mg]35.8 (39) [1065.0 mg] <0.0001
Topiramate, % (no. of exposures) [Mean dose]2.6 (26) [262.5 mg]2.1 (19) [271.1 mg]6.4 (7) [308.3 mg] 0.004
Carbamazepine, % (no. of exposures) [Mean dose]32.0 (322) [632.0 mg]32.1 (288) [632.0 mg]31.2 (34) [682.4 mg]0.83
Lamotrigine, % (no. of exposures) [Mean dose]36.5 (368) [269.8 mg]38.5 (346) [271.2 mg]20.2 (22) [260.2 mg] <0.0001
Polytherapy, % (total number)21.8 (299)21.0 (254)28.1 (45) 0.04
Valproate: Number of exposures (mean dose)105 (1138.5 mg)84 (1149.4 mg)21 (1095.0 mg)0.11
Topiramate: Number of exposures (mean dose)38 (355.4 mg)30 (346.6 mg)8 (384.4 mg)0.30
Carbamazepine: Number of exposures (mean dose)121 (844.4 mg)109 (853.8 mg)12 (763.3 mg) 0.0006
Lamotrigine: Number of exposures (mean dose)171 (352.8 mg)140 (359.7 mg)31 (321.7 mg)0.31

Of the 646 women for whom we had prospectively collected data on their first registered pregnancy, 83 of these pregnancies resulted in a child with a CM (12.8%). Fourteen of these women went on to have at least one more child with a CM (total recurrence rate of 16.9%). Of the remaining 563 women whose first pregnancy had not resulted in a child with a CM, 55 went on to have a child with a CM (9.8%). The relative risk for a woman having another child with a CM, if her first child had had a CM, compared with if her first child had not, was 1.73 (95% CI 1.01–2.96, p = 0.04). The risk for recurrence was 50% for women who had had two previous children with a CM (Fig. 2). In contrast, the risk of having a child with a CM reduced with each consecutive child without a CM (Fig. 3).

image

Figure 2.   Risk of recurrence of CMs according to number of previous consecutive pregnancies resulting in a child with a CM.

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image

Figure 3.   Risk of CMs according to number of previous consecutive pregnancies resulting in a healthy child.

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The risk of CMs after abnormal and normal outcomes in the first pregnancy varied according to AED regimen and AED dose changes in pregnancy (Tables 3 and 4). For pregnancies exposed to valproate, the total recurrence risk following an initial child with a CM was 21.9%. This was higher for women who took valproate as part of a polytherapy regimen and for women whose AED dose remained unchanged or was increased before the next pregnancy (25%, 30.8%, and 33.3% respectively). In comparison the risk of having a child with a CM following a pregnancy exposed to valproate that had not resulted in a CM was 14.8% (relative risk 1.47, 95% CI 0.68–3.20, p = 0.327). The relative risk was increased to 2.50 (95% CI 0.65–9.65, p = 0.18) if only polytherapy exposures were included.

Table 3.   Risk of abnormalities by AED regimen in pregnancies after one abnormal outcome
 Risk of CM in first pregnancy (monotherapy exposures) (%)Total (n = 83) (%)Monotherapy (%)Polytherapy (%)Dose reduced (%)Dose unchanged (%)Dose increased (%)Drug changed (%)
Valproate17.27/32 (21.9)3/20 (15.0)3/12 (25.0)1/5 (20.0)4/13 (30.8)1/3 (33.3)1/11 (9.0)
Topiramate27.33/6 (50.0)1/3 (33.3)2/3 (66.6)0/0 (0.0)2/4 (50.0)1/1 (100)0/1 (0.0)
Others9.04/45 (8.9)3/32 (9.4)1/13 (7.7)0/9 (0.0)3/18 (16.7)1/15 (6.7)0/3 (0.0)
Table 4.   Risk of abnormalities by AED regimen for pregnancies after one normal outcome
 Risk of CM in first pregnancy (Monotherapy exposures) (%)Total (%)Monotherapy (%)Polytherapy (%)
Valproate17.219/128 (14.8)15/88 (17.0)4/40 (10.0)
Topiramate27.32/18 (11.1)2/8 (25.0)0/10 (0.0)
Others9.034/417 (8.2)29/356 (8.1)5/61 (8.2)

The numbers for topiramate were small. However, the total recurrence risk following a child with a CM in first pregnancy was 50%. This was higher for those exposed to topiramate as part of a polytherapy regimen and if AED dose was increased before the second pregnancy (66.6% and 100%, respectively). In contrast, the risk of CMs following a pregnancy exposed to topiramate that had not resulted in a CM was 11.1% (relative risk of recurrent CMs after one abnormal outcome; 4.50, 95% CI 0.97–20.82, p = 0.054). This increased to 13.75 (95% CI 0.83–228.96, p = 0.06) if only polytherapy exposures were included.

Other medication regimens were composed mainly of carbamazepine and lamotrigine. For these exposures, the overall recurrence risk after one child with a CM was 8.9%. This was not that different from relative risk after pregnancies that had not resulted in a CM (8.2%) (relative risk for recurrent CMs after one abnormal outcome; 1.09, 95% CI 0.41–2.93, p = 0.86).

In six women who had consecutive children with MCMs, the same MCM occurred in both children in only one case (16.7%). In this case the woman had two consecutive children with spina bifida following exposure to valproate polytherapy during pregnancy. If all CMs were considered, another eight women had children with consecutive minor or major malformations; of these three (37.5%) had the same CM. These were two cases of siblings diagnosed with neurodevelopmental or speech and language delay (one set exposed to topiramate monotherapy, one to topiramate polytherapy) and one pair of siblings with craniosynostosis (both receiving valproate polytherapy). This woman subsequently had a child with cleft lip and palate, following a switch to topiramate polytherapy.

There were 17 abnormalities in the multiple birth group, with a concordance rate of 30.8% four women with both children affected, nine women only one child affected). Fourteen children with CMs were exposed to monotherapy in utero and three to polytherapy. All cases where both twins were affected were monotherapy exposures (two mothers to valproate, one carbamazepine, and one lamotrigine).

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References

Although the total recurrence risk for CMs in this study at 16.9% was lower than that reported by other groups (39% (Dean et al., 2002) and 55% (Moore et al., 2000)), we found that a woman was significantly more likely to have a child with a CM if her first a child had also had a CM. The risk was even greater when she had had two or more infants with a CM. In contrast, we found that the risk for CMs fell if women had borne previously healthy children. Concordance rates for multiple pregnancies were also elevated compared with the overall rate of CMs.

There appeared to be differences between AED regimens, with exposure to valproate and topiramate, but not for other AEDs such as lamotrigine and carbamazepine, being associated with increased recurrence risks. Even with a sample size of >1,500, we were, however, unable to confirm whether for individual AED regimens these differences were statistically significant. This clearly demonstrates the need for very large sample sizes.

For valproate- and topiramate-exposed pregnancies, whether the AEDs were taken as part of a monotherapy or polytherapy regimen was important. Dose changes were also important for these two AEDs, with recurrence risks for both being higher for pregnancies if the original dose of AED was not changed or increased. For topiramate, recurrence rates for CMs were extremely high, with risks of 33.3% and 66.6% for monotherapy and polytherapy regimens, respectively. This nearly reached statistical significance despite the small numbers involved. This raises further concerns with regard to the teratogenic potential of this drug and suggests that more research into the safety of topiramate in pregnancy is warranted.

Data for monotherapy exposures to valproate were less concerning, with malformation rates being similar in women with and without previous children with CMs (15% and 17%, respectively). This needs to be confirmed in a larger cohort but suggests that factors other than genetic influences may be important in determining susceptibility to teratogenicity with valproate.

Data for other drugs, including lamotrigine, were encouraging; there was no increase in recurrence risk above baseline, irrespective of type of regimen or change in dose. Taken along with data published from the International Lamotrigine Pregnancy Registry (Cunnington et al., 2011) and the North American AED Pregnancy Register (Holmes et al., 2011) these results are reassuring for those women who need to take lamotrigine in pregnancy.

There are clearly fundamental differences in group characteristics in our study. Women with two or more abnormal outcomes were more likely to be taking polytherapy regimens and women with any abnormality were more likely to be on regimens including topiramate or valproate and to be on higher doses of these drugs. This in itself would increase risk of subsequent fetal malformations. By dividing the groups according to AED and regimen we have attempted to delineate the extent to which the changes we have observed are due to drug regimen or to inherent genetic susceptibility to teratogenicity with these drugs.

The women with multiple registered pregnancies who were included in this study had a significantly higher MCM rate than the remainder of the women included in the UKEPR, who have only one registered pregnancy (6.0% compared to 3.3%). The reason for this may be partly explained by the higher number of polytherapy regimens (21.8% compared to 18.3%) and lower number of women on no AED treatment during pregnancy (4.8% compared to 8.2%) in this group. It might also reflect more referrals from secondary and tertiary level epilepsy clinics, which tend to treat more women with uncontrolled epilepsy and who require more intensive AED treatment.

Women who registered multiple pregnancies were more often primigravida at the time of being recruited to the UKEPR. Of the 182 women who had previously had children before they registered their first pregnancy, five reported MCMs (2.7%), four minor CMs (2.2%), and two other unspecified abnormalities in previous children (total CM rate 6.0%). This is similar to the CM rate in primiparous women and suggests that there was not a significant referral bias in this group. Therefore, although we are unable to fully explain the different CM rates between those women who registered multiple pregnancies and those who registered a single pregnancy, we feel our results are likely to be clinically relevant.

There are several methodologic differences between our study and the previous studies published by Moore et al. (2000) and Dean et al. (2002) that might explain the differences in results. The UKEPR relies on patients and health care workers to provide information on congenital malformations and the presence of dysmorphic features and fetal anticonvulsant syndromes at 3 months after birth. In the studies performed by Dean et al. and Moore et al., participants were assessed individually by the authors at a mean of 9 years (range 2 days to 39 years) and 6.48 years (range 0.33–16.42 years) of age, respectively, for features of anticonvulsant syndromes and developmental delay. In addition, patients in these studies were enrolled not only from local obstetric services, but also from medical genetics services and the Foetal Anticonvulsant Syndrome Association, which may have introduced a degree of ascertainment bias.

As a result, it is possible that our ascertainment of dysmorphic features and particularly neurodevelopmental delay will be lower than in the previous studies. Indeed, given that our follow-up is at 3 months, in this cohort developmental delay was often not reported to us until the mother was registering her subsequent pregnancy.

Of the minor malformations included, 19.6% were fetal valproate syndrome or dysmorphic features, 7.9% developmental delay, 12.6% cardiac, 15.7% skeletal malformations, 10.2% gastrointestinal or genitourinary, 6.3% renal, and 26.8% other malformations such as hearing/ear and ocular malformations, cutaneous lesions, tongue tie, and probable spina bifida occulta. It is possible that ascertainment of these types of CM is increased in women who have had previous children with CMs due to increased physician awareness and screening for CMs. Minor malformations were reported in 11.4% of pregnancies, which followed a child with a known mCM, compared to only 4.4% of normal children. Although this may be due to reporting, it is also possible that genetic factors and differences in AED exposure between these groups may also be important.

Although inclusion of mCMs may be deemed to be problematic, our findings were upheld when only MCMs are included in the analysis (recurrence risk 15.8% following the birth of a child with a MCM compared with 5.4% following a normal child or a child with mCM). Therefore, it is likely that our results reflect true differences between the groups.

Finally, there may be a degree of negative selection in our data, as many women who have had children with significant abnormalities might elect not to attempt further pregnancies. It is obviously difficult to estimate the effect of this.

In summary our data would suggest that there is an increased risk of CMs if a woman has already had a child with a CM. In addition to underlying genetic factors, AED choice, dose, and type of regimen may all play a part in determining the magnitude of this risk. Studies in large cohorts such as ours will hopefully provide more accurate data on the risk of abnormalities in pregnancies following an initially normal or abnormal outcome. Such information might permit us to provide more accurate information for women attending genetic or preconceptual counseling. This could aid women and physicians when making difficult treatment decisions. Similar analyses by the other pregnancy registers would clearly be of value.

Disclosure

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References

EM, ED, IR, LP, and PJM report no conflicts of interest. JM has received unrestricted educational grants from Eisai, GlaxoSmithKline, Novartis, Sanofi-Aventis, Pfizer, and UCB for the running of the United Kingdom Epilepsy and Pregnancy Register. AR has received a grant from UCB for funding of a nurse 2006–2009, and received small contributions from UCB, GlaxoSmithKline, Eisai, Forth Medical, Cyberonics, and Optima Medical to cover the costs of the United Kingdom Epilepsy Surgery Meeting in Glasgow in 2011. WHS has been invited to attend advisory board meetings for NAPP and Sanofi-Aventis within the last year. BI has received sponsorship to attend meetings and honoraria for presentations from Eisai, UCB, and Sanofi-Aventis. SH has received sponsorship to attend meetings from Eisai, UCB, and GlaxoSmithKline. He has also received honoraria for presentations from Pfizer and UCB. JC has received grants to undertake research and honoraria for giving lectures from UCB-Pharma, Sanofi-Synthelabo, GlaxoSmithKline, Janssen-Cilag, Pfizer, and Eisai.

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References
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