Pregnancy, antiseizure medications and unexplained intrauterine foetal death.

OBJECTIVE: To assess the role of antiseizure medication (ASM) regimens and other factors in relation to the occurrence of intrauterine foetal death (IUFD) in pregnant women with epilepsy (WWE) enrolled in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs (APR). RESULTS: IUFDs occurred in 70 (3.01 %) of 2,323 prospective pregnancies from WWE with known outcomes in the APR. Factors associated with IUFD occurrence included older maternal age, enrolment in the APR at an earlier stage of pregnancy, history of pregnancies which did not result in livebirths, parental history of foetal malformations, and maternal use of carbamazepine, lamotrigine or ethosuximide. Individual ASM dosages were not associated with IUFD occurrence. Relative to no exposure, the risk of IUFD increased with the increasing number of ASMs used in combination (2 ASMs: relative risk, RR = 5.45 [95 % CI: 0.73-41.80]; 3 ASMs: RR = 10.70 [95 % CI: 1.27-90.17]), >3 ASMs: RR = 10.70 [95 % CI: 1.27-90.17]), but this finding was attenuated after adjusting for other factors implicated in IUFD occurrence. Several ASM pairs were associated with an increased risk of IUFD relative to no exposure, but these associations were lost after accounting for confounders. CONCLUSIONS: Although it is possible that prenatal ASM exposure may increase the risk of IUFD, other non-pharmacological factors are more relevant to the occurrence to IUFD in pregnant WWE.

Seizure control in successive pregnancies in Australian women with epilepsy.

OBJECTIVES: To investigate control of epileptic seizures during pairs of successive pregnancies in antiseizure medication (ASM)-treated women with epilepsy. MATERIALS AND METHODS: Analysis of seizure freedom rates during 436 pairs of successive pregnancies in Australian women with epilepsy, in nearly all instances long-standing epilepsy. RESULT: There was a higher rate of seizure-free second pregnancies compared with first paired pregnancies (63.1% vs. 51.4%; Relative Risk (R.R.) = 1.2277; 95% CI 1.0930, 1.3789) and of seizure-free pre-pregnancy years before second as compared with first paired pregnancies in the same women (63.6% vs. 52.4%; R.R. = 1.2616; 95% CI 1.1337, 1.4040). In 108 women whose ASM therapy was unaltered throughout both of their pregnancies, the seizure-freedom rate was higher in the second of the paired pregnancies (82.4% vs. 69.4%; R.R. = 1.1867, 95% CI 1.0189, 1.3821). CONCLUSIONS: Altered ASM therapy after the first of a pair of successive pregnancies did not fully account for the better overall seizure control in the corresponding second pregnancies. Some additional factor may have been in operation, possibly a greater preparedness to undertake a further pregnancy if seizures were already fully controlled.

Epileptic seizure control during and after pregnancy in Australian women.

OBJECTIVES: To study factors that affected previous epileptic seizure control throughout pregnancy, during labour, and in the post-natal weeks. MATERIALS & METHODS: Analysis of data concerning seizure freedom that was available at various stages of 2337 pregnancies in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs, mainly employing multiple variable logistic regression techniques. RESULTS: Based on data available at the outset of pregnancy, the risk of seizure-affected that is, not seizure-free pregnancy was statistically significantly (p < .05) higher in pregnancies where there was previously uncontrolled epilepsy (78.1% vs. 20.8%) and focal epilepsy (51.3% vs. 39.7%), and decreased with later onset-age epilepsy (41.8% vs. 52.2% with onset before age 13 years), The risk did not differ between initially antiseizure medication (ASM)-treated or untreated pregnancies. For epilepsy receiving ASM therapy, 90.6% of 160 pregnancies of women with uncontrolled focal epilepsy that began before the age of 13 were seizure-affected. None of the above factors influenced the risk of seizures during labour, though having seizures during pregnancy increased the hazard (3.93 vs. 0.6%). Either ASM-treated pregnancy or labour being seizure-affected increased the risk of post-partum period seizures (33.0% vs. 6.67% for both stages being seizure-free). Use of particular ASMs had no statistically significant effect on the seizure control situation at any of the pregnancy stages studied. CONCLUSIONS: Obtaining full seizure control before pregnancy appeared to be the main factor in maintaining seizure freedom during pregnancy, labour and the post-natal weeks.

Achieving neurologically desirable outcomes to pregnancy in women with epilepsy.

OBJECTIVES: To investigate possible factors that influenced whether pregnancy in women with epilepsy resulted in the desirable outcome of a live-born non-malformed infant and a mother whose pregnancy had been seizure free. RESULTS: The desirable outcome, as defined, occurred in 46.3% of unselected pregnancies in the database of the Australian Register of Antiepileptic Drugs in Pregnancy (APR). The only factor investigated that had a statistically significant (P < 0.05) effect, increasing the chance of such a desirable outcome, was freedom from seizures in the pre-pregnancy year. However, anti-seizure medication (ASM) doses, particularly valproate doses, had been reduced prior to 15.6% of the pregnancies, and this may have concealed factors that otherwise may have adversely affected the desirable outcome rate. Analysis of data for monotherapy with the more commonly used ASMs appears to suggest that employing levetiracetam at the outset of antiseizure therapy may offer a better chance of a desirable outcome to future pregnancies than monotherapy with other ASMs, but this finding is not confirmed statistically. CONCLUSIONS: In pregnancies where valproate use has already been minimized, seizure control throughout the pre-pregnancy year was associated with the best chance of a desirable outcome, as defined above. In most Australian women starting therapy for epilepsy initiating treatment with levetiracetam monotherapy may offer the best chance of such a desirable outcome to a future pregnancy, yet to be confirmed.

Pregnancy outcomes in women with surgically treated epilepsy.

OBJECTIVE: To ascertain whether epileptic seizure control during pregnancy differed between Australian women with previously surgically treated epilepsy, and those with only medically treated epilepsy. MATERIALS/METHODS: Analysis of data for 74 pregnancies of women with surgically treated focal epilepsy, compared with that from 1013 pregnancies in women with medically treated focal epilepsy, both groups drawn from the Australian Register of Antiepileptic Drugs in Pregnancy between 1999 and 2020. RESULTS: Seizures of all types, and also convulsive seizures, were less well controlled during pregnancy in the previously surgically treated cases, the difference for seizures of all types (68.9% versus 50.1%) being statistically significant (p < .05). This result was contrary to the outcome of a previously published study of the same question carried out in India. CONCLUSIONS: At present, it may be premature to conclude that previous epilepsy surgery will be associated with a better chance of seizure-free, or seizure-controlled, pregnancy.

The control of treated generalized and focal epilepsies during pregnancy.

OBJECTIVES: To examine factors contributing to failure to achieve full seizure control during pregnancy in women with anti-seizure medication (ASM) treated generalized epilepsy compared with focal epilepsy. RESULTS: Full seizure control was not attained in 51.4% of 1223 pregnancies of women with focal epilepsies in the Australian Pregnancy Register, and in 38.7% of 1026 pregnancies in women with generalized epilepsy (P < 0.05). For convulsive seizures only, the corresponding figures of 20.8% and 22.9% were reasonably similar. Where seizures had occurred in the pre-pregnancy year, 82.5% of the focal epilepsy pregnancies were seizure affected, and 70.1% of the generalized epilepsy ones (P < 0.05). Where the pre-pregnancy year was seizure free, the corresponding figures were 22.6% and 16.4% (P < 0.05), a roughly four-fold lower rate. Maternal age, epilepsy onset age, and epilepsy duration also differed between the focal and generalized epilepsy pregnancies. Multivariate regression analysis showed that generalized epilepsy and younger maternal age were associated with statistically significant decreased risks of seizure-affected pregnancy, and having seizure-affected pre-pregnancy years with an increased risk. However, for convulsive seizures only, the risk of seizure-affected pregnancy appeared increased in generalized epilepsy. CONCLUSIONS: The risk of seizure-affected pregnancy appears lower in women with generalized epilepsy, independently of pre-pregnancy seizure control, itself a major determinant of the risk. The risk of having only convulsive seizures in pregnancy was not lower in generalized epilepsy than in focal epilepsy. ASM therapy seemed less effective in controlling focal than generalized epileptic seizures during pregnancy.

The contribution of non-drug factors to fetal malformation in anti-seizure-medication-treated pregnancy.

PURPOSE: To assess the possible contribution of factors in additional to intrauterine anti-seizure medication (ASM) exposure in the occurrence of fetal malformation in women with ASM-treated epilepsy. RESULTS: Logistic regression analysis showed that maternal age over 31 years, family histories of fetal malformation, and conception after assisted fertility treatment, and also dosage of valproate, carbamazepine, and topiramate, made statistically significant (P<0.05) contributions to the fetal malformation rate in 2223 pregnancies in Australian women with epilepsy. The malformation rates were lower in pregnancies where the non-ASM-associated contributory factors were not present: statistically significantly so for all ASM-exposed pregnancies, and those pregnancies exposed to the more potent teratogenic drugs. CONCLUSION: It is important to consider the possible roles of identified, and also possible non-identified, non-ASM factors in relation to the occurrence of fetal malformations in the pregnancies of women with ASM-treated epilepsy.

Folic acid dose, valproate, and fetal malformations.

OBJECTIVE: To determine whether there is a relationship between folic acid dose and the degree of protection against valproate-associated and other antiepileptic drug (AED)-associated fetal structural malformations in women with AED-treated epilepsy. METHODS: Statistical analysis of data from the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy involving 2104 folic acid-treated pregnancies in women with epilepsy. RESULTS: Multiple variable logistic regression failed to demonstrate any statistically significant effect of folic acid dosage in reducing overall fetal malformation rates in women taking folic acid either before and during pregnancy (P = 0.640) or during early pregnancy only (P = 0.801), and in reducing spina bifida occurrence rates (P = 0.409). CONCLUSIONS: In the present state of knowledge, it would seem misguided to hope that a folic acid dose of 5 mg/day taken before and during pregnancy would protect against the occurrence of valproate-associated and other AED-associated fetal structural malformations. Future studies are required to determine whether high-dose periconceptional folate use may decrease the risk of other valproate-associated adverse fetal outcomes, including impaired post-natal neurobehavioral development.

Twin pregnancy in women with epilepsy.

OBJECTIVE: We report data from the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy (APR) to see if there are significant differences in relation to the courses and outcomes of the twin pregnancies contained in the register, as compared with the singleton ones. METHODS: The APR has been under the oversight of Melbourne institutional Human Ethics Research Committees; all women enrolled in the APR have provided written informed consent. Data from the APR were transferred to a spreadsheet and then analyzed using simple statistical techniques including logistic regression. RESULTS: The population studied comprised 44 twin and 2261 singleton pregnancies; thus, twin pregnancies accounted for 1.91% of all pregnancies studied. The women carrying twins tended to be older than the women with singleton pregnancies to a statistically significant extent, their pregnancies more often originated from assisted fertilization techniques, and their babies were more often delivered by cesarean section. There were no statistically significant differences in relation to antiepileptic drug (AED) therapy. Individual twins had statistically significantly lower mean birthweights than singleton babies and they were statistically significantly more often involved structurally malformed foetuses. In the first year of life, the twin pregnancies statistically significantly more often produced offspring that were affected by seizures in infancy. SIGNIFICANCE: The data suggest that there may be an increased hazard of fetal malformation in the offspring of twin pregnancy in women with epilepsy, but that with contemporary standards of management of epilepsy and pregnancy, there is unlikely to be an increased hazard of seizure-affected pregnancy.

Pregnancy after valproate withdrawal-Fetal malformations and seizure control.

OBJECTIVE: To assess the outcomes in women with epilepsy in relation to fetal malformation and epileptic seizure control during pregnancy when valproate (VPA) intake was ceased, or the drug's dose was reduced before pregnancy. METHODS: Statistical analysis of data collected in the Australian Pregnancy Register between 1999 and 2018 concerning 580 pregnancies previously treated with VPA, with the VPA dose reduced or the drug withdrawn prior to pregnancy in 158 cases. RESULTS: Although the available data have limitations, fetal malformation rates in the pregnancies studied were lower in the VPA changed pregnancies (4.5%) than in the VPA unchanged comparator pregnancies (10.9%, hazard ratio [HR] 0.412, 95% confidence interval [CI] 0.190-0.892), and were only 2.7% where VPA intake was ceased before pregnancy (HR 0.262, 95% CI 0.083-0.826). Seizure-affected pregnancies were more frequent in the VPA changed pregnancies than in the VPA unchanged ones (46.2% vs 30.8%, HR 1.500, 95% CI 1.203-1.870). Convulsive seizure-affected pregnancies also were increased, but the difference was not statistically significant. SIGNIFICANCE: Prepregnancy reduction in VPA dosage reduced the hazard of fetal malformations, whereas ceasing intake of the drug decreased the hazard to one similar to that which applies in the general population, but at a cost of decreased control of epileptic seizures during the pregnancies studied. Further investigations are needed to see whether such findings apply more widely in women with epilepsy.

Seizures in infancy in the offspring of women with epilepsy.

OBJECTIVES: To assess (a) the incidence of seizures in the first year of life in infants born to mothers with epilepsy and (b) factors that might contribute to the seizure incidence. MATERIALS & METHODS: Analysis of data collected in the Australian Register of Antiepileptic Drugs in Pregnancy during and at the end of the year after pregnancy. RESULTS: By the end of a year following pregnancy, seizures had occurred in the progeny of 47 pregnancies (2.40%), including febrile seizures in 18 (0.92%), the latter rate being higher than the 0.40% and 0.59% rates for the same situation in the general population reported in the recent literature. Seizures in infancy were more likely in the offspring of mothers with generalized as compared with focal epilepsies (3.65% vs 1.56%; RR = 2.332; P < .05) and within the generalized epilepsy mothers in those who were not seizure free during pregnancy (4.83% vs 2.89%). Seizures were also more likely in infants with foetal malformations, especially ones not discovered until after the first post-natal month. CONCLUSIONS: These findings may help in advising mothers with epilepsy regarding the chance of their offspring experiencing seizures in the first year of life; they also suggest the desirability of achieving maternal seizure control throughout pregnancy.

Antiepileptic drugs and depression during pregnancy in women with epilepsy.

OBJECTIVES: To assess the possibility that the occurrence of seizures or the use of antiepileptic drug (AED) therapy might have influenced the rate of occurrence of volunteered histories of patient-recognized depression during pregnancy in women with epilepsy. MATERIALS AND METHODS: Analysis of data from 2039 pregnancies in the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy (APR) followed during pregnancy and to the end of the year after its end. RESULTS: Patient-recognized depression occurrence rates during pregnancy were a little lower rather than higher in seizure-affected than in seizure-free pregnancies (5.67% vs 6.41%), though higher in AED-treated than AED-untreated pregnancies (6.24% vs 5.26%; RR = 1.185, 95% CI 0.612, 2.295). Logistic regression analysis showed that carbamazepine dosage had a statistically significant relationship with a decreasing rate of patient-recognized depression occurring during pregnancy and topiramate dosage with an increasing rate. CONCLUSIONS: Carbamazepine and topiramate both have established potentials for causing teratogenesis, and it is possible that replacement of carbamazepine with a less teratogenic AED, for example levetiracetam, might result in any subsequent depression that occurs in pregnancy being inappropriately attributed to the newly introduced agent.

The outcome of altering antiepileptic drug therapy before pregnancy.

We investigated the outcome of altering antiepileptic drug (AED) therapy in the year before pregnancy on 2233 occasions in Australian women in the 20-year period of functioning of the Raoul Wallenberg Australian Pregnancy Register (APR). Therapy had been altered in 358 instances (16%) in the months prior to the pregnancy (median interval: 18 weeks). Antiepileptic drug doses had been changed in 141 pregnancies (39.4%), being decreased in 94; drugs changed in 151 (42.2%); drugs withdrawn without replacement in 66 (18.4%) but resumed in 40 before pregnancy ended. The main drugs involved were valproate (34%), phenytoin (16.5%), topiramate (12.6%), and carbamazepine (11.4%). Antiepileptic drug doses were increased significantly more often (16.9% vs. 6.4%) when epilepsy before pregnancy was not controlled, and AED treatment ceased significantly less often (13.6% vs. 24.0%). The alterations were more often made in women with generalized epilepsies and in those whose seizure disorders were not fully controlled in the prepregnancy year, suggesting that avoidance of teratogenicity and achieving improved seizure control often motivated the changes. Overall, the alterations did not result in improved rates of seizure freedom during pregnancy, as compared with pregnancies where therapy was unchanged; however, fetal malformation rates were lower 3.6% vs. 5.4%, but this difference did not attain statistical significance. The same trends regarding seizure control and malformations persisted after pregnancies involving valproate exposure were excluded. In conclusion, this analysis of the APR cohort did not demonstrate that altering AEDs before pregnancy produced a significant improvement in seizure control and the reduction in fetal malformation rate that occurred was not statistically significant.

Valproate-associated foetal malformations-Rates of occurrence, risks in attempted avoidance.

OBJECTIVES: To gain insight into the main advantages and disadvantages that might result from valproate being unavailable for women who intend to become pregnant. MATERIALS AND METHODS: Analysis of data from the Australian Pregnancy Register concerning pregnancies exposed to valproate (N = 501) and pregnancies where previous valproate intake had been ceased before pregnancy (N = 101). RESULTS: The risk of foetal malformation associated with valproate exposure during pregnancy was dose-related, and there was a tendency for the more major malformations, including those often managed by therapeutic abortion, for example spina bifida, to occur at higher valproate doses. Had there been no exposure to valproate during pregnancy, some 80% of the foetal malformations that occurred might have been avoided. Cessation of previous valproate therapy before pregnancy was associated with an increased hazard of seizure-affected pregnancy. This was particularly the case for women with generalized epilepsies, in whom the incidence of seizure-affected pregnancy was increased by 50% to nearly 100%. CONCLUSIONS: Avoiding valproate intake during pregnancy is likely to reduce the incidence of foetal malformation, but at a cost of worsened maternal epilepsy control. Individualization of treatment is particularly important in considering withdrawal of valproate in the light of the fact that it is much more widely used in generalized epilepsy, there being fewer alternative drugs than for focal epilepsy and withdrawal is not without risk for both mother and baby. This study may provide a quantitative basis for assessing the balance between benefit and disadvantage for individual women with valproate-treated epilepsy who are considering pregnancy.

Antiepileptic drug combinations not involving valproate and the risk of fetal malformations.

OBJECTIVE: To investigate the relationship between antiepileptic drug (AED) polytherapy in pregnant women and the risk of fetal malformations as prescribing practice changed, with valproate being used less often and at lower doses. Specifically, the risks associated with two of the most common AEDs included in polytherapy over recent years, levetiracetam and topiramate, were examined. METHODS: An observational cohort study in which malformation rates were analyzed in 1,461 pregnancies exposed to AED monotherapy, and in 484 exposed to antiepileptic drug combinations, from the Australian Register of Antiepileptic Drugs in Pregnancy over a 15-year period (1999-2014). RESULTS: Fetal malformation rates had fallen over time in monotherapy pregnancies, but increased in polytherapy pregnancies, despite decreasing use and lower dosages of valproate. The rise in polytherapy malformation rates began around 2005 when levetiracetam and topiramate use began to increase. Excluding pregnancies involving valproate exposure, malformation rates were higher in the remaining polytherapy pregnancies as compared with the monotherapy ones (6.90% vs. 3.64%; odds ratio [OR] 1.96, 95% confidence interval [CI] 1.14-3.39). Malformation rates were similar in polytherapy pregnancies whether or not levetiracetam was included (7.14% vs. 8.38%), but were higher in polytherapy pregnancies involving topiramate (14.94% vs. 6.55%: OR 2.507, 95% CI 1.23-5.10). Logistic regression showed that topiramate in polytherapy had a positive dose relationship with teratogenicity risk (p = 0.025). SIGNIFICANCE: The malformation risk associated with AED polytherapy depends on the specific drugs involved. Topiramate, when used as part of AED polytherapy that did not include valproate, was associated with a dose-related increased risk of fetal malformations.

The clinical pharmacology of traditional antiepileptic drugs.

Despite the availability of newer agents, a number of antiepileptic drugs have continued to be employed reasonably widely, many years after their introduction to human therapeutics. These drugs comprise phenobarbitone and some of its congeners, phenytoin, ethosuximide, carbamazepine, valproate, and certain benzodiazepines. Details of their pharmacological profiles are outlined in the following account.

W. J. Adie and his "pyknolepsy," a century ago.

On November 8, 1923, William John Adie described an unusual disorder to the Section of Neurology of the Royal Society of Medicine. The condition comprised frequent momentary stereotyped impairments of consciousness that occurred in children, did not respond to antiseizure medications, and did not develop into epilepsy, as that term was then commonly understood, since no convulsive seizures occurred. After some time, the episodes terminated spontaneously, leaving the sufferer unhandicapped and neurologically intact. Almost certainly, Adie had described the present-day entity of childhood absence epilepsy. He termed it "pyknolepsy," knowing that the name "pyknolepsie" had been used for a similar disorder in Germany from 1916 onwards, though not reported elsewhere. Following Adie's account, published in 1924, reports of the disorder appeared in the English and French-language literature and continued to be published in German. It became increasingly accepted that pyknolepsy was a form of epilepsy that was part of Lennox's petit mal triad. The word pyknolepsy itself never became widely used and is now largely forgotten. Adie never took up the topic in print again. However, he had awakened English-language readers to one component in a broadening of the concept of what constituted epilepsy.

Teratogenicity of zonisamide and other little-used antiseizure medications.

PURPOSE: To investigate the risk of teratogenesis occurring in relation to intrauterine exposure to infrequently used antiseizure medications in Australia. METHODS: Analysis of data contained in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs. RESULTS: There was statistically significant evidence that zonisamide, but not any other of nine infrequently used antiseizure medications in Australia, was associated with a risk of teratogenesis related to the maternal dose of the drug taken in at least the earlier half of pregnancy. CONCLUSIONS: The teratogenesis associated with zonisamide, like that associated with topiramate and possibly acetazolamide, may be an expression of a class effect shared among sulphonamide-derived carbonic anhydrase inhibitors that possess anti-seizure activity.

The teratogenesis risk associated with antiseizure medication duotherapy in women with epilepsy.

PURPOSE: To investigate rates of occurrence of pregnancies associated with a foetal malformation (FM pregnancy rates) following simultaneous intrauterine exposure to two antiseizure medications in 524 pregnancies in women with epilepsy from the Australian Pregnancy Register who were treated simultaneously with various combinations and dosages of two antiseizure medications (duotherapy). RESULTS: FM pregnancy rates tended to be higher in those exposed simultaneously to two antiseizure medications, each of which was a statistically significant teratogen (valproate, topiramate, or carbamazepine), than when there was exposure to only one such teratogen. When there was exposure to only one such teratogen together with clonazepam or levetiracetam, for neither of which there was statistically significant evidence of heightened teratogenicity, the FM pregnancy rates also tended to be higher, but less so. When lamotrigine was the other component of the duotherapy with an established teratogen, FM pregnancy rates tended to be lower than that for the teratogen used as monotherapy. CONCLUSION: Leaving aside issues in relation to seizure control, our data suggest that it would be best to avoid using established teratogenic antiseizure medications (carbamazepine, valproate and topiramate) in combination with each other due to the increased FM risks. When combining an established teratogenic medication with a less teratogenic one, i.e. lamotrigine, levetiracetam or clonazepam, lamotrigine appears to be the safer option.

Teratogenesis in repeated pregnancies in antiepileptic drug-treated women.

PURPOSE: Considerable information is now available concerning the risk of teratogenesis in the individual pregnancy exposed to antiepileptic drugs (AEDs). However, there is comparatively little information available concerning the risk in the subsequent pregnancies of women who continue to take the AED associated with a fetal malformation in a previous pregnancy. This article addresses this matter. METHODS: Analysis of data concerning fetal abnormalities in 1,243 women who had 2,637 pregnancies between mid-1999 and 2010 recorded in the Australian Register of Antiepileptic Drugs in Pregnancy. Of the 2,637 pregnancies, 1,114 had been completed before initial enrolment in the Register. KEY FINDINGS: Women taking any AED who had given birth to a malformed baby in their first enrolled pregnancy and who continue taking the same drug were at increased risk of having a malformed offspring in their next pregnancy (35.7% vs. 3.1%; odds ratio [OR] 17.6; 95% confidence interval [95% CI] 4.5-68.7). Among these women, those taking valproate (VPA) were more likely to have malformed fetuses in their next pregnancies than those who had taken VPA without fetal abnormalities (57.2% vs. 7.0%, OR 17.8; 95% CI 2.7, 119.1). There were similar although not statistically significant trends in those who had taken AEDs other than VPA. Similar, although again not statistically significant, trends were found, when considering the pairings of the most recent preenrollment pregnancy and the following one. If a woman had two or more pregnancies that resulted in AED-associated fetal malformation, the types of malformation were often different. SIGNIFICANCE: Women whose last pregnancy resulted in a fetal malformation have a substantially increased risk of having further malformed fetuses if they become pregnant again while taking the same AED, particularly VPA. This suggests that maternal factors, perhaps genomic, predispose to at least VPA-associated malformations. This knowledge, together with information about the outcome of any previous pregnancy, should help in advising women with AED-treated epilepsy who plan further pregnancies.