Dose dependence of fetal malformations associated with valproate

Objective: To study the relationships between maternal valproate dose in pregnancy and the pattern of various fetal malformations. Methods: Analysis of data in the Australian Register of Antiepileptic Drugs in Pregnancy collected from 1999 to 2012. The specific type of fetal malformation in offspring exposed to valproate in utero was correlated with the dose of valproate taken by the mother in the first trimester. Results: Compared with other malformations, the mean dose of valproate taken during the first trimester was higher in mothers whose offspring had spina bifida (2,000 ± 707 vs 1,257 ± 918 mg/d) and hypospadias (2,417 ± 1,320 vs 1,235 ± 715 mg/d) (both p < 0.05). The overall mean maternal valproate dosage taken by women in the Register decreased over the last 5 years of the study period. This was paralleled by a statistically significant decrease in the rate of occurrence of spina bifida and hypospadias, but not other malformations. Conclusions: Human fetal malformations associated with valproate exposure during pregnancy do not all seem to bear the same quantitative relationship to drug dose, and reduction in valproate dose in earlier pregnancy is likely to offer greater dividends in protecting against spina bifida and hypospadias than against other types of fetal malformations

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

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\ua0=\ua02.332; P\ua

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

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]\ua00.412, 95% confidence interval [CI] 0.190-0.892), and were only 2.7% where VPA intake was ceased before pregnancy (HR\ua00.262, 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\ua01.500, 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

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\ua0=\ua01.185, 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

Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss

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