Neurological factors and Cesarean section in Australian women with epilepsy.

OBJECTIVES: To analyze the records of the pregnancies of 2283 Australian women with epilepsy in the Australian Register of Antiepileptic Drugs in Pregnancy database to identify neurological factors relevant to the Cesarean sections carried out in these pregnancies. RESULTS: The Cesarean section rate in Australian women overall increased by an average of 0.59% annually over 20 years, from 26.0% to its calculated 2020 value of 37.3%. For the operations in women with epilepsy, the corresponding figures were 0.71% annually, and 34.4% and 48.7%. The average annual rate of increase for pre-labor operations was 0.89% to a 2020 value of 39.1%, the annual rate for operations during labor showing no statistically significant change. Multivariate regression analysis identified a number of characteristics of women with epilepsy that were statistically significantly associated with an increased likelihood of Cesarean section, but of these only seizures continuing to occur in the third trimester and having chronic illness, in particular migraine, were neurological ones. In 70 migraine-affected women, the Cesarean section rate was 51.4%, compared with 39% in the remaining pregnancies (P < 0.05). CONCLUSIONS: Having seizures in the final trimester of pregnancy and having chronic neurological illness, especially migraine, favored Cesarean section being carried out in Australian women with epilepsy, but did not adequately account for the increasing rates of occurrence of the operation over the past 20 years.

Antiepileptic drugs and foetal malformation: analysis of 20 years of data in a pregnancy register.

PURPOSE: This paper reports additional data supplementing earlier publications based on Australian Pregnancy Register (APR) data. METHOD: Over 20 years, the APR has collected Information on pregnancies in Australian women with epilepsy (WWE), untreated WWE and those taking AEDs for other indications. Contact is by telephone, at set intervals. Treatment is not interfered with. Data are analysed using conventional statistical techniques, confidence interval methods, and logistic regression. RESULTS: By 2018, the APR contained details of 2148 pregnancies. AEDs were taken throughout 1972 of the pregnancies (91.8%). The remaining 176 (8.2%) did not receive AEDs, at least early in pregnancy. There were (i) dose-related increased incidences of pregnancies carrying foetal malformations associated with maternal intake of valproate and topiramate when topiramate was a component of AED polytherapy (P < .05), (ii) a similar dose-related trend in relation to carbamazepine intake, (iii) no evidence that levetiracetam and lamotrigine were unsafe from the foetal standpoint, (iv) insufficient data to permit conclusions regarding teratogenicity in relation to other AEDs, and (v) no evidence that pre-conception folate supplementation reduced the hazard of AED-associated foetal malformation. AED polytherapy did not increase foetal hazard unless valproate or topiramate was involved in the AED combination. Genetic factors probably contributed to the malformation hazard. Seizures occurring in earlier pregnancy probably did not contribute to the malformation hazard. CONCLUSIONS: If it were not for the importance of maintaining seizure control, the above findings suggest that it would be better to avoid using certain AEDs, particularly valproate and topiramate, during pregnancy.

Antiepileptic drug polytherapy in pregnant women with epilepsy.

OBJECTIVE: To study seizure control and rates of foetal malformation in pregnancies of women with epilepsy treated with antiepileptic drug polytherapy. METHODS: The use of conventional statistical methods to analyse the Australian Pregnancy Register records of 1810 pregnancies in women with epilepsy, 508 treated with antiepileptic drug polytherapy. RESULTS: Polytherapy-treated pregnancies were less often seizure free than monotherapy-treated ones, for both focal (36.0% vs 51.9%: P < .05) and primary generalized epilepsies (41.1% vs 69.3%; P < .05). Drug combinations with dissimilar and similar mechanisms of action achieved similar rates of seizure freedom during pregnancy (36.3% vs 38.3%). The increased rate of malformed foetuses in polytherapy pregnancies depended on valproate or topiramate being in the drug combinations. The combinations of lamotrigine and levetiracetam offered the chance of seizure control and foetal safety. CONCLUSIONS: In pregnancy, the use of antiepileptic drug combinations is not necessarily disadvantageous to mother and foetus if valproate and topiramate are avoided.

Anti-epileptic drug exposure and risk of foetal death in utero.

OBJECTIVE: To clarify whether anti-epileptic drug exposure during pregnancy is associated with an increased risk of intrauterine foetal death. METHODS: Analysis of data from 2064 pregnancies with known outcomes included in the Australian Register of Antiepileptic Drugs in Pregnancy, 170 of the pregnancies being unexposed to the drugs in at least the first half of pregnancy. RESULTS: The relative risk (6.46; 95% C.I. 0.90, 46.22) of intrauterine death appeared higher, though not statistically significantly higher, in drug-exposed pregnancies compared with unexposed ones (3.44% vs 0.59%). There was no statistically significantly increased hazard associated with AED polytherapy as compared with monotherapy. Logistic regression analysis showed a statistically significantly increased and dose-related hazard of intrauterine death in relation to carbamazepine exposure. CONCLUSIONS: Intrauterine exposure to anti-epileptic drugs, particularly carbamazepine, may be associated with an increased risk of foetal death during pregnancy.

Antiepileptic drugs, foetal malformations and spontaneous abortions.

BACKGROUND: Some recent studies have found an association between foetal malformations in earlier antiepileptic drug (AED)-exposed pregnancies and an increased hazard of such malformations in subsequent pregnancies. We investigated this matter further, and also considered the possible role of spontaneous abortions in previous pregnancies, in this situation. METHODS: Analysis of foetal malformation data for current and previous pregnancies in women taking AEDs and women with untreated epilepsy in the Australian Register of Antiepileptic Drugs in Pregnancy (APR) from 1999 to late 2014. RESULTS: Antiepileptic drug-treated women with either a malformed foetus or a spontaneous abortion in their previous pregnancy had a statistically significant twofold to threefold increased risk of foetal malformation in their next pregnancy, compared with similarly treated women with normal offspring in their previous pregnancy. This was not seen in the same circumstances in women with untreated epilepsy. On AED treatment, the women were more likely to have spontaneous abortions than in their previous untreated pregnancies. Possibly some of the increased abortion rate resulted from drug-related malformations that were incompatible with continuing intrauterine survival. CONCLUSIONS: In assessing the hazard of an AED-treated woman having a malformed foetus, it is important to know both the AEDs being taken and, if there had been a previous pregnancy, whether a foetal malformation or a spontaneous abortion occurred in it.

Is carbamazepine a human teratogen?

The foetal outcomes of 2,635 pregnancies recorded in the Australian Pregnancy Register were studied. In at least the initial 4months of 515 pregnancies, there had been no intrauterine exposure to antiepileptic drugs, though the women involved in 264 of these pregnancies took antiepileptic drugs in later pregnancies. Compared with these 515 drug-unexposed pregnancies, foetal malformations risks were increased more than five-fold in association with valproate monotherapy, and more than doubled in association with carbamazepine monotherapy (p<0.05). There were no statistically significant increases in malformation rates associated with other more commonly used antiepileptic drugs, while the malformation risk in relation to levetiracetam exposure was lower than that in the drug-unexposed pregnancies. The published literature has rather consistently shown raised malformation rates associated with carbamazepine monotherapy, though only once was it statistically significant. There now appears to be enough evidence to make it likely that carbamazepine possesses some teratogenic capacity. This makes it unwise to employ the malformation rate associated with carbamazepine monotherapy as a comparator when assessing the foetal hazards from exposure to newer antiepileptic drugs. Levetiracetam may prove a better comparator if adequate untreated control material is unobtainable.

Does pregnancy per se make epilepsy worse?

OBJECTIVE: To determine whether being pregnant in its own right alters epileptic seizure control. MATERIALS/METHODS: Study of 148 pregnancies in women who took no antiepileptic drugs before pregnancy and in at least the earlier half of pregnancy, 69 taking none throughout pregnancy. RESULTS: More women (P < 0.01) had seizures of any type during pregnancy (45.9%) than in the prepregnancy year (34.5%), and also convulsive seizures (30.4% vs 12.3%). After excluding potential confounding factors, viz. late prepregnancy drug withdrawal, treatment resumption in pregnancy possibly preventing seizure recurrence, the figures became seizures of any type 56.6% during and 35.5% before pregnancy and convulsive seizures 39.4% during and 18.2% before pregnancy (both P < 0.01). There was a non-statistically significant greater tendency for seizure control to be lost during pregnancy in genetic generalized than in focal epilepsies (54.2% vs 35.5%). CONCLUSIONS: Irrespective of its effects on antiepileptic drug disposition, being pregnant per se seems to impair epileptic seizure control.

Names of infamy: tainted eponyms.

The use of eponyms is controversial. A distinction must be made between those doctors and scientists after whom disorders and syndromes are named in honour of their discoveries, and those whose discoveries were made as a result of maltreatment of defenceless prisoners, utilizing specimens from victims of Nazi extermination policies, and euthanasia victims of racial policies. The second group of scientists should have their names expunged from the historical record, and their deeds brought to the attention of their colleagues. We are not however advocating the abolition of eponyms in general, only tainted ones.

The outcomes of pregnancy in women with untreated epilepsy.

PURPOSE: To determine the outcomes in regards to seizure control and foetal malformation in pregnant women with epilepsy not treated with antiepileptic drugs (AEDs). METHOD: Analysis of data from the Australian Register of AEDs in Pregnancy on 148 women with epilepsy who were not receiving AEDs before and during at least the first trimester of pregnancy. RESULTS: Seizure control was less likely to be maintained in AED-untreated pregnancies. Whether AED therapy had been ceased in preparation for pregnancy, or had not been employed for long periods before pregnancy, made no statistically significant difference to seizure control outcomes, but those who ceased therapy in preparation for pregnancy were more likely to again be taking AED therapy by term. Foetal malformation rates were reasonably similar in untreated pregnancies, and in treated pregnancies if pregnancies exposed to known AED teratogens (valproate and probably topiramate) were excluded from consideration. CONCLUSION: Leaving epilepsy untreated during pregnancy appears disadvantageous from the standpoint of seizure control: it also does not reduce the hazard of foetal malformation unless it avoids valproate or topiramate intake during pregnancy.

Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve.

Nogo-A is a well-known myelin-enriched inhibitory protein for axonal growth and regeneration in the central nervous system (CNS). Besides oligodendrocytes, our previous data revealed that Nogo-A is also expressed in subpopulations of neurons including retinal ganglion cells, in which it can have a positive role in the neuronal growth response after injury, through an unclear mechanism. In the present study, we analyzed the opposite roles of glial versus neuronal Nogo-A in the injured visual system. To this aim, we created oligodendrocyte (Cnp-Cre(+/-)xRtn4/Nogo-A(flox/flox)) and neuron-specific (Thy1-Cre(tg+)xRtn4(flox/flox)) conditional Nogo-A knock-out (KO) mouse lines. Following complete intraorbital optic nerve crush, both spontaneous and inflammation-mediated axonal outgrowth was increased in the optic nerves of the glia-specific Nogo-A KO mice. In contrast, neuron-specific deletion of Nogo-A in a KO mouse line or after acute gene recombination in retinal ganglion cells mediated by adeno-associated virus serotype 2.Cre virus injection in Rtn4(flox/flox) animals decreased axon sprouting in the injured optic nerve. These results therefore show that selective ablation of Nogo-A in oligodendrocytes and myelin in the optic nerve is more effective at enhancing regrowth of injured axons than what has previously been observed in conventional, complete Nogo-A KO mice. Our data also suggest that neuronal Nogo-A in retinal ganglion cells could participate in enhancing axonal sprouting, possibly by cis-interaction with Nogo receptors at the cell membrane that may counteract trans-Nogo-A signaling. We propose that inactivating Nogo-A in glia while preserving neuronal Nogo-A expression may be a successful strategy to promote axonal regeneration in the CNS.

The teratogenicity of the newer antiepileptic drugs - an update.

OBJECTIVE: To assess the risk of teratogenicity from maternal intake of the more widely used newer antiepileptic drugs, especially lamotrigine, levetiracetam and topiramate. MATERIALS AND METHODS: Use of confidence interval and regression methods to compare risks of foetal malformation in pregnancies in women exposed (n = 1572) and in women with epilepsy not exposed (n = 153) to antiepileptic drugs in the first trimester. RESULTS: Compared with the foetal malformation rate in women with epilepsy who were untreated in the first trimester (3.3%), the malformation rates for lamotrigine (4.6%), levetiracetam (2.4%) and topiramate (2.4%), all in monotherapy, were not statistically significantly different. However, the malformation rates for topiramate as part of polytherapy (14.1%) and for valproate in both monotherapy (13.8%) and polytherapy (10.2%) were statistically significantly higher. Regression analysis of combined monotherapy and polytherapy data showed no statistically significant increased risk of teratogenesis associated with lamotrigine or levetiracetam, but a statistically significant and dose-related risk for first trimester topiramate (P = 0.01) and valproate (P < 0.0001) exposure. CONCLUSIONS: Evidence from this and other studies suggests that lamotrigine and levetiracetam have low risk for teratogenesis, but that topiramate exposure early in pregnancy may be associated with dose-related anatomical teratogenesis, as valproate is already known to be.

The Australian Register of antiepileptic drugs in pregnancy: changes over time in the epileptic population.

The demographic characteristics, details of pregnancies, epilepsies, and treatment of 855 pregnant women with epilepsy enrolled in the Australian Antiepileptic Drugs in Pregnancy Register during 1999-2005 were compared with the corresponding data for the 801 women enrolled from 2006-2012. We estimate that the Register captures approximately 1 in 12 of all pregnancies in Australian women with epilepsy. A number of statistically significant changes were found, with nearly all explained by factors such as re-enrolment of women who had enrolled earlier pregnancies, changes in general population behaviour, altered attitudes to prescribing valproate and using it in lower doses, and the advent of newer antiepileptic drugs which have displaced the use of older agents. It appears that the Register has continued to capture a reasonably representative sample of pregnant Australian women with epilepsy as time has passed.

Prediction of the hazard of foetal malformation in pregnant women with epilepsy.

The data collected in the Australian Register of antiepileptic drugs in pregnancy have been studied in the hope of defining simple items of information that could be recorded at initial interview of pregnant women with epilepsy, and which might allow estimation of the risk of the pregnancy resulting in a malformed foetus. Analysis of the data showed that dose of valproate, but not intake of other commonly used antiepileptic drugs, in the current pregnancy, and a past history of a pregnancy involving a malformed foetus, statistically significantly increased the malformation hazard in the current pregnancy, and that continuing alcohol intake might decrease it. Plotting the hazard against valproate dose in monotherapy, with or without histories of (i) previous pregnancies with foetal malformations (FMs), and (ii) continuing alcohol intake, provided quantitative information concerning the degree of increased risk. It is hoped that this information may help in advising about the risk of foetal malformation (FM) in individual pregnancies.

Associations between particular types of fetal malformation and antiepileptic drug exposure in utero.

OBJECTIVE: To study associations between patterns of fetal malformation and individual antiepileptic drugs taken during pregnancy. METHODS: Multiple variable logistic regression and other statistical analyses of data relating to 1733 fetuses from 1703 pregnancies (147 of which were not exposed to antiepileptic drugs during pregnancy). RESULTS: There were statistically significant (P < 0.05) associations between (i) valproate exposure and spina bifida, malformations of the heart and great vessels, digits, skull bones, and brain, but not hypospadias, cleft palate/lip and mouth abnormalities, (ii) topiramate exposure and hypospadias and brain maldevelopments, and (iii) carbamazepine (CBZ) exposure and renal tract abnormalities. CONCLUSIONS: The valproate findings are mostly in keeping with the published literature, but the topiramate finding regarding hypospadias and the association between CBZ exposure and various renal tract abnormalities raise questions of organ specific teratogenesis. More extensive data are desirable, particularly in relation to topiramate, which is being used increasingly as a migraine prophylactic in women of childbearing potential.

Dose issues in antiepileptic therapy.

Antiepileptic drug (AED) therapy is complex, with numerous traditional drugs and more than 10 second-generation drugs being approved since the mid-1990s. The burden of epilepsy is compounded by the adverse effects of these drugs, which comprise a variety of manifestations, the most devastating of which is their association with physical and cognitive foetal malformations in babies exposed to these agents in utero. Many effects are dose-related - a clear understanding of these adverse effects is desirable to be able to adjust medications and medication regimens to suit individual patient needs and to try to prevent them, by a careful introduction, slow escalation, well-considered combination and possible pre-exposure testing of patients for their tolerance, to each proposed AED. The overall problem and the profiles of the main agents are outlined from the perspective of dose-related issues.

Teratogenicity of the newer antiepileptic drugs--the Australian experience.

Data on the use in pregnancy of the new antiepileptic drugs (AED) are limited. We analysed data collected by the Australian Pregnancy Register to provide information on their relative teratogenicity. The database containing pregnancy outcomes from 1317 women with epilepsy (WWE) was examined for three widely used new AED in monotherapy in the first trimester--lamotrigine, levetiracetam and topiramate. This was compared with outcomes of pregnant WWE on monotherapy with three traditional AED, and with untreated women. The incidence of malformations associated with lamotrigine monotherapy was 12/231 (5.2%), with topiramate 1/31 (3.2%) and with levetiracetam 0/22 (0%). This compares with rates of 1/35 (2.9%) for phenytoin, 35/215 (16.3%) for valproate (VPA), 19/301 (6.3%) for carbamazepine and 6/116 (5.2%) for untreated women. There was no evidence of dose-dependent risks of foetal malformation, except with VPA monotherapy. We conclude that the new AED appear no more teratogenic than traditional drugs in monotherapy.

Language skills of school-aged children prenatally exposed to antiepileptic drugs.

OBJECTIVES: Fetal exposure to some antiepileptic drugs (AEDs) carries increased risk of major birth defects, and may be associated with reduced intellectual abilities. The impact on language remains unclear. This study aimed to investigate the impact of fetal AED exposure on language skills. METHODS: Women with epilepsy and their children were recruited to this observational study through the Australian Pregnancy Register for Women with Epilepsy and Allied Disorders. Language skills of 102 AED-exposed children were assessed using the Clinical Evaluation of Language Fundamentals, fourth edition (CELF-4). Assessments were conducted blind to drug. Maternal epilepsy, pregnancy, and medical histories were obtained from prospectively collected records. RESULTS: Mean CELF-4 Core Language scores of children exposed to sodium valproate in monotherapy (mean 91.5, SD 17.5) or polytherapy (mean 73.4, SD = 22.3) were significantly below the standardized test mean of 100 (p < 0.05). Mean language scores of children exposed to carbamazepine or lamotrigine monotherapy, or polytherapy without sodium valproate, were not significantly different from normal. First-trimester sodium valproate dose was negatively correlated with language scores, and significantly predicted language scores after controlling for other group differences. CONCLUSIONS: Fetal exposure to sodium valproate increases the risk of language impairment. This should be taken into account when making treatment decisions for women with epilepsy of childbearing age.

Foetal malformations after exposure to antiepileptic drugs in utero assessed at birth and 12 months later: observations from the Australian pregnancy register.

BACKGROUND: In studies investigating foetal malformations associated with antiepileptic drug exposure during pregnancy, the common practice has been to assess the incidence and nature of the malformations at, or soon after, birth. The adequacy of this approach to determine the true incidence of the malformations has received little attention. AIMS OF THE STUDY: To compare the incidence and natures of the foetal malformations recognized by, or soon after, birth with similar data for malformations recognized in the first post-natal year. METHODS: Analysis of data from the Australian Register of Antiepileptic Drugs in Pregnancy. RESULTS: Up to 25% of the malformations recognized by the end of the first post-natal year had not been detected by, or soon after, birth. There was a tendency for the late-recognized malformations to differ from the early-recognized ones in relation to the body parts involved. CONCLUSIONS: Early assessment and delayed assessment of infants for the presence of foetal malformations are complementary, with the latter resulting in finding a higher incidence of malformations. However, omission of an early post-natal assessment may result in biases because of loss of subjects to follow-up.

The Australian Pregnancy Register of Anti-epileptic Drugs: 10 years of progress.

The need for collecting a nationwide database for antiepileptic drug (AED) use in pregnancy is described as well as the rationale, methods, funding and logistics of the Australian Pregnancy Register of Anti-epileptic Drugs (APR). Various aspects of treatment with AED have been reported, not only in relation to teratogenicity but also in terms of efficacy of AED, their use in mono and polytherapy, dose-effect relationships and foetal outcomes. The overall effect of the APR in terms of scientific education is also discussed.

Is lamotrigine a significant human teratogen? Observations from the Australian Pregnancy Register.

Lamotrigine (LTG) is increasingly being prescribed in pregnancy for women with epilepsy in place of valproate (VPA), because of the teratogenic risks associated with the latter. It is therefore important to know the teratogenic hazard associated with LTG, relative to VPA and to other commonly used antiepileptic drugs (AEDs). Data from the Australian Register of Antiepileptic Drugs in Pregnancy was examined to determine the incidence of teratogenicity determined 1 year from completion of pregnancy in women who took AEDs in monotherapy during pregnancy. Compared with a 3.4% malformation incidence in women who took no AEDs (N = 118), the incidences for LTG (N = 243), carbamazepine (CBZ) (N = 302) and VPA (N = 224) were, respectively, 4.9%, 5.3% and 15.2%, the latter statistically significantly greater than the risk for no AED therapy in pregnant women with epilepsy. Logistic regression analysis showed no tendency for foetal hazard to increase with increasing LTG dose in pregnancy, unlike the situation for VPA. However, seizure control in pregnancy tended to be not as good in the women taking LTG compared with those taking VPA, though the data examined were not adequate to permit definite conclusions regarding this matter. We conclude that LTG monotherapy in pregnancy is safer than valproate monotherapy from the point of view of foetal malformations, and no more hazardous in this regard than therapy with other commonly used AEDs.