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The Australian Pregnancy Registry, affiliated European Register of Antiepileptic drugs in Pregnancy (EURAP), recruits informed consenting women with epilepsy on treatment with antiepileptic drugs (AEDs), those untreated, and women on AEDs for other indications. Enrolment is considered prospective if it has occurred before presence or absence of major foetal malformations (FMs) are known, or retrospective, if they had occurred after the birth of infant or detection of major FM. Telephone Interviews are conducted to ascertain pregnancy outcome and collect data about seizures. To date 630 women have been enrolled, with 565 known pregnancy outcomes. Valproate (VPA) above 1100 mg/day was associated with a significantly higher incidence of FMs than other AEDs ( P < 0.05). This was independent of other AED use or potentially confounding factors on multivariate analysis (OR = 7.3, P < 0.0001). Lamotrigine (LTG) monotherapy ( n = 65), has so far been free of malformations. Although seizure control was not a primary outcome, we noted that more patients on LTG than on VPA required dose adjustments to control seizures. Data indicate an increased risk of FM in women taking VPA in doses >1100 mg/day compared with other AEDs. The choice of AED for pregnant women with epilepsy requires assessment of balance of risks between teratogenicity and seizure control. [ABSTRACT FROM AUTHOR]

Pyruvate kinase (PK) deficiency, a rare, congenital haemolytic anaemia caused by mutations in the PKLR gene, is associated with many clinical manifestations, but the full disease burden has yet to be characterised. The Peak Registry (NCT03481738) is an observational, longitudinal registry of adult and paediatric patients with PK deficiency. Here, we described comorbidities and complications in these patients by age at most recent visit and PKLR genotype. As of 13 May 2022, 241 patients were included in the analysis. In total, 48.3% had undergone splenectomy and 50.5% had received chelation therapy. History of iron overload (before enrolment/during follow-up) was common (52.5%), even in never-transfused patients (20.7%). Neonatal complications and symptoms included jaundice, splenomegaly and hepatomegaly, with treatment interventions required in 41.5%. Among adults, osteopenia/osteoporosis occurred in 19.0% and pulmonary hypertension in 6.7%, with median onset ages of 37, 33 and 22 years, respectively. Biliary events and bone health problems were common across PKLR genotypes. Among 11 patients who had thromboembolic events, eight had undergone prior splenectomy. Patients with PK deficiency may have many complications, which can occur early in and throughout life. Awareness of their high disease burden may help clinicians better provide appropriate monitoring and management of these patients., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Cardiac stress can trigger production of a 40-kDa peptide fragment derived from the amino terminus of the cardiac myosin-binding protein C. Cardiac stress, as well as cMyBP-C mutations, can trigger production of 1 such truncated protein fragment, a 40-kDa peptide fragment derived from the amino terminus of cMyBP-C. Genetic expression of this 40-kDa fragment in mouse cardiomyocytes (cMyBP-C 40k ) leads to cardiac disease, fibrosis, and death within the first year. Fibrosis can occur in many cardiovascular diseases, and mitogen-activated protein kinase--activated protein kinase-2 signaling has been implicated in a variety of fibrotic processes. Recent studies demonstrated that mitogen-activated protein kinase--activated protein kinase-2 inhibition using the cell-permeant peptide inhibitor MMI-0100 is protective in the setting of acute myocardial infarction. We hypothesized that MMI-0100 might also be protective in a chronic model of fibrosis, produced as a result of cMyBP-C 40k cardiomyocyte expression., Methods and Results: Nontransgenic and cMyBP-C 40k inducible transgenic mice were given MMI-0100 or PBS daily for 30 weeks. In control groups, long-term MMI-0100 was benign, with no measurable effects on cardiac anatomy, function, cell viability, hypertrophy, or probability of survival. In the inducible transgenic group, MMI-0100 treatment reduced cardiac fibrosis, decreased cardiac hypertrophy, and prolonged survival., Conclusions: Pharmaceutical inhibition of mitogen-activated protein kinase--activated protein kinase-2 signaling via MMI-0100 treatment is beneficial in the context of fibrotic cMyBPC 40k disease., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

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., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2013 John Wiley & Sons A/S.)

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., (© 2010 John Wiley & Sons A/S.)

Objective: To trace the pattern of antiepileptic drug (AED) use in pregnant Australian women annually from 1999 to 2007, and correlate it with the pattern of AED use in the wider community., Methods: Analysis of data from the Australian Register of AEDs in Pregnancy, related to Australian population data for AED prescriptions., Results: Over the study period, prescribing of carbamazepine, phenytoin and valproate for pregnant women decreased, and prescribing of lamotrigine, topiramate and levetiracetam increased. These changes tended to parallel prescribing trends in the wider community, except for valproate, whose prescribing in the overall community increased as its prescribing, and its dosage prescribed, decreased in pregnancy. Concomitant with this, there was a trend towards fewer births of foetuses with abnormalities., Conclusions: While otherwise following national AED prescribing trends, Australian prescribers are reducing the use and dose of valproate in pregnant women, likely in recognition of the teratogenic hazards of this drug.

Background: Prospective studies are needed to assess the maternal and fetal hazards of antiepileptic drug (AED) therapy in pregnancy., Aims: To make the Australian Register of AEDs in Pregnancy better known to the Australian obstetric community by presenting results derived from it., Methods: Analysis of data collected by the Register between 1999 and December 2006., Results: The Register contained data on 1002 epileptic or AED-treated pregnancies, 992 with known outcomes, 83 not exposed to AEDs in at least their first trimester, and 30 prescribed AEDs for indications other than epilepsy. Statistically significant findings included more frequent folate supplementation and decreased alcohol intake during pregnancy in women with epilepsy; a dose-related increased risk of fetal malformation associated with valproate therapy; a tendency towards lower birthweights in live-born malformed offspring; and a substantially reduced decreased risk of seizures in pregnancy with one year seizure freedom before pregnancy. The small numbers of patients may have prevented other differences from reaching a P<0.05 value., Conclusions: The Register has already produced important information for the management of pregnant women with epilepsy in Australia, but greater rates of recruitment into the Register are desirable to allow it to achieve its full potential.

1. To investigate the mechanism of the fall in steady-state plasma phenytoin concentration relative to drug dose that occurs during pregnancy, single dose pharmacokinetic studies with stable isotope labelled phenytoin were carried out at different stages of pregnancy, and 2 to 4 months post-natally, in five epileptic women receiving regular oral therapy with the drug. 2. Steady-state apparent plasma clearances of phenytoin (dose/steady-state concentration) correlated closely with simultaneous plasma clearances of the intravenous stable-isotope drug (measured as dose/AUC) suggesting that the patients were complaint with therapy when their phenytoin dosage requirement increased during the pregnancy, and that the oral drug was fully bioavailable. 3. In retrospect, two of the five subjects were probably studied too early post-natally for phenytoin elimination kinetics to have returned to non-pregnant values. Despite this, (i) the mean +/- s.d. t 1/2 for phenytoin was statistically significantly shorter in pregnancy than post-natally (31 +/- 14 vs 39 +/- 28 h), (ii) the mean +/- s.d. whole plasma clearance was also statistically significant greater (0.025 +/- 0.012 vs 0.021 +/- 0.013 kg-1 h-1) and (iii) the mean +/- s.d. Vmax for phenytoin elimination was statistically significantly greater in pregnancy (1170 +/- 600 mg day-1) than post-natally (780 +/- 470 mg day-1). Although the mean +/- s.d. apparent Km was higher in pregnancy (18.2 +/- 8.4 mg l-1, expressed in terms of whole plasma drug concentrations, compared with 10.2 +/- 7.4 mg l-1 post-natally), the difference was not statistically significant. However, if the apparent Km value was expressed in terms of plasma water phenytoin concentrations the difference (pregnant 2.50 +/- 0.85 mg l-1: post-natally 1.16 +/- 0.65 mg l-1) was statistically significant. 4. Human pregnancy appears to result in an increased capacity to eliminate phenytoin.

1 Various statistical techniques were used to study the effects of age, sex and concurrent therapy with other anticonvulsants on the relation between plasma phenobarbitone levels and doses of (i) phenobarbtione, (ii) methylphenobarbitone or (iii) primidone, in epileptic patients. 2 Methylphenobarbitone and primidone are converted to phenobarbitone in the body. The mean doses of phenobarbitone, methylphenobarbitone and primidone which produced the same plasma phenobarbitone level (15 microgram/ml) were, respectively, 1.75,2.75 and 7.75 mg kg-1 day-1. 3 For both phenobarbitone and methylphenobarbitone dose requirement to achieve a given plasma phenobarbitone level fell progressively with age. Sex influenced the relation between plasma phenobarbitone level and phenobarbitone or methylphenobarbitone dose. Interactions were detected between primidone and both phenytoin and carbamazepine. 4 In individual patients, within the limits of dosage studied, the relation between plasma phenobarbitone level and drug dose was not rectilinear if phenobarbitone itself was taken, but was rectilinear if methylphenobarbitone was taken.